WO2008157330A1 - Chemical compounds - Google Patents

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Publication number
WO2008157330A1
WO2008157330A1 PCT/US2008/066885 US2008066885W WO2008157330A1 WO 2008157330 A1 WO2008157330 A1 WO 2008157330A1 US 2008066885 W US2008066885 W US 2008066885W WO 2008157330 A1 WO2008157330 A1 WO 2008157330A1
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Prior art keywords
chloro
oxy
methyl
oxadiazol
phenyl
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PCT/US2008/066885
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French (fr)
Inventor
Christopher Joseph Aquino
Hamilton Dickson
Andrew James Peat
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Smithkline Beecham Corporation
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Publication of WO2008157330A1 publication Critical patent/WO2008157330A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to compounds that are non-nucleoside reverse transcriptase inhibitors, and the use in the treatment of viral infections, for example, human immunodeficiency virus infections.
  • HIV human immunodeficiency virus
  • AIDS acquired immunodeficiency syndrome
  • ARC Al DS-related complex
  • HIV is a retrovirus; the conversion of its RNA to DNA is accomplished through the action of the enzyme reverse transcriptase.
  • Compounds that inhibit the function of reverse transcriptase inhibit replication of HIV in infected cells. Such compounds are useful in the prevention or treatment of HIV infection in humans.
  • NNRTIs Non-nucleoside reverse transcriptase inhibitors
  • NRTIs nucleoside reverse transcriptase inhibitors
  • NNRTIs interact with a specific site of HIV- 1 reverse transcriptase that is closely associated with, but distinct from, the NRTI binding site.
  • NNRTIs are notorious for rapidly eliciting resistance due to mutations of the amino acids surrounding the NNRTI-binding site (E. De Clercq, Il Famaco 54, 26-45, 1999). Failure of long-term efficacy of NNRTIs is often associated with the emergence of drug-resistant virus strains (J.
  • WO 02/070470, WO 01/17982, and US 2006/0025480A1 disclosed certain benzophenones as non-nucleoside reverse transcriptase inhibitors.
  • each R 1 independently is halogen, -CN, CrC 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, hydroxyl, C r C 8 alkoxy, -C(O)OR 4 , -C(O)N(R 4 ) 2 , -OR 4 , -R 5 CN, or -N(R 4 ) 2 ; each R 2 independently is halogen, -CN, CrC 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, hydroxyl, C 1 -C 8 alkoxy, -C(O)OR 4 , -C(O)N(R 4 ) 2 , -OR 4 , -R 5 CN or -N(
  • A is C 5 -C 12 aryl or C 5 -C 12 heterocycle;
  • R 3 is -R 5 Ar or C 4 -C 12 aryl, each optionally substituted with at least one C 1 -C 8 alkyl, halogen, hydroxyl, oxo, C 1 -C 8 alkoxy, -C(O)OR 4 , -C(O)N(R 4 ) 2 , -OR 4 , -N(R 4 ) 2 , -N(O) 2 ,
  • each R 4 is independently hydrogen, C 1 -C 8 alkyl optionally substituted with at least one hydroxyl or halogen; or C 3 -C 7 cycloalkyl; each R 5 is independently C 1 -C 8 alkylene, C 1 -C 8 alkenylene, C 1 -C 8 alkynylene, each optionally substituted with at least one hydroxyl or hydrogen;
  • Het is C 3 -C 10 heterocycle and is optionally substituted with at least one C 1 -C 6 alkyl, oxo, hydroxyl, R 5 S(O) 2 R 4 , or halogen; and Ar is C 4 -C 12 aryl and is optionally substituted with at least one C 1 -C 6 alkyl or halogen; or pharmaceutically acceptable derivatives thereof.
  • the present invention features a compound of formula (I) wherein m is 2.
  • the present invention features a compound of formula I wherein n is 2.
  • the present invention features a compound of formula (I) wherein R 3 is C 4 -C 12 aryl optionally substituted with at least one C 1 -C 8 alkyl, halogen, hydroxyl, oxo, C 1 -C 8 alkoxy,
  • the present invention features a compound of formula (I) wherein R 3 is R 5 Ar and wherein Ar is optionally substituted with at least one C 1 -C 8 alkyl, halogen, hydroxyl, oxo,
  • each R 3 is phenyl, optionally substituted with at least one d-C 8 alkyl, halogen, hydroxyl, oxo, d-C 8 alkoxy, -C(O)OR 4 , -C(O)N(R 4 ) 2 , -OR 4 , -N(R 4 ) 2 , -N(O) 2 , -CN, -OR 5 Het, -OR 5 N(R 4 ) 2 , - C(O)N(R 4 )Het, -C(O)Het, -C(O)N(R 4 )R 5 S(O) 2 R 4 , -S(O) 2 N(R 4 ) 2 , -S(O) 2 N(R 4 ) 2 , -S(O) 2 N(R 4 ) 2 , -S(O) 2 N(R 4 ) 2 , -S(O) 2 N(R 4 ) 2 , -S(
  • the present invention features a compound of formula (I) wherein n is 2 and each R 2 is halogen.
  • the present invention features a compound of formula I wherein m is 2 and the first R 1 is halogen and the second R 1 is -CN.
  • the present invention features a compound of formula (I) wherein m is 2, n is 2, and R 3 is C 4 -C 12 aryl optionally substituted with at least one C 1 -C 8 alkyl, halogen, hydroxyl, oxo, C 1 -C 8 alkoxy, -C(O)OR 4 , -C(O)N(R 4 ) 2 , -OR 4 , -N(R 4 ) 2 , -N(O) 2 , -CN, - OR 5 Het, -OR 5 N(R 4 ) 2 , -C(O)N(R 4 )Het, -C(O)Het, -C(O)N(R 4 )R 5 S(O) 2 R 4 , -S(O) 2 N(R 4 ) 2 , - S(O) 2 R 4 , -C(O)R 4 ; -N(R 4 )C(O)R 5 SR 4 ,
  • the present invention features a compound of formula I wherein R 3 is C 4 -C 12 aryl optionally substituted with at least one halogen, OR 4 , -OR 5 Het, or -OR 5 N(R 4 ) 2 .
  • the present invention also features a compound of formula (II)
  • each R 1 independently is halogen, -CN, C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, hydroxyl, C 1 -C 8 alkoxy, -C(O)OR 4 , -C(O)N(R 4 ) 2 , -OR 4 , -R 5 CN, or -N(R 4 ) 2 ; each R 2 independently is halogen, -CN, C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, hydroxyl, C 1 -C 8 alkoxy, -C(O)OR 4 , -C(O)N(R 4 ) 2 , -OR 4 , -R 5
  • R 3 is -R 5 Ar or C 4 -C 12 aryl, each optionally substituted with at least one C 1 -C 8 alkyl, halogen, hydroxyl, oxo, C 1 -C 8 alkoxy, -C(O)OR 4 , -C(O)N(R 4 ) 2 , -OR 4 , -N(R 4 ) 2 , -N(O) 2 ,
  • each R 4 is independently hydrogen, C 1 -C 8 alkyl optionally substituted with at least one hydroxyl or halogen; or C 3 -C 7 cycloalkyl; each R 5 is independently C 1 -C 8 alkylene, C 1 -C 8 alkenylene, C 1 -C 8 alkynylene, each optionally substituted with at least one hydroxyl or hydrogen;
  • Het is C 3 -C 10 heterocycle and is optionally substituted with at least one C 1 -C 6 alkyl, oxo, hydroxyl, R 5 S(O) 2 R 4 , or halogen; and Ar is C 4 -C 12 aryl and is optionally substituted with at least one C 1 -C 6 alkyl or halogen; or pharmaceutically acceptable derivatives thereof.
  • the present invention also features a compound of formula (II)'
  • each R 1 independently is halogen, -CN, C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, hydroxyl, C 1 -C 8 alkoxy, -C(O)OR 4 , -C(O)N(R 4 ) 2 , -OR 4 , -R 5 CN, or -N(R 4 ) 2 ; each R 2 independently is halogen, -CN, C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, hydroxyl, C 1 -C 8 alkoxy, -C(O)OR 4 , -C(O)N(R 4 ) 2 , -OR 4 , -R 5
  • R 3 is -R 5 Ar or C 4 -C 12 aryl, each optionally substituted with at least one halogen, hydroxyl, oxo, C 1 -C 8 alkoxy, -C(O)OR 4 , -C(O)N(R 4 ) 2 , -OR 4 , -N(R 4 ) 2 , -N(O) 2 , -CN, -OR 5 Het, -
  • Het is C 3 -C 10 heterocycle and is optionally substituted with at least one C 1 -C 6 alkyl, oxo, hydroxyl, R 5 S(O) 2 R 4 , or halogen; and
  • Ar is C 4 -C 12 aryl and is optionally substituted with at least one C 1 -C 6 alkyl or halogen; or a pharmaceutically acceptable salt thereof.
  • the present invention also features a compound of formula (II)' wherein m is 2; n is 2; each R 1 independently is halogen or -CN; each R 2 independently is halogen;
  • R 3 is C 4 -C 12 aryl, optionally substituted with at least one -OR 4 , -N(R 4 ) 2 , -OR 5 Het, - OR 5 N(R 4 ) 2 or C 1 -C 8 alkyl optionally substituted with hydroxyl; each R 4 is independently hydrogen or C 1 -C 8 alkyl optionally substituted with at least one hydroxyl; each R 5 is independently C 1 -C 8 alkylene optionally substituted with at least one hydroxyl;
  • Het is C 3 -C 10 heterocycle and is optionally substituted with at least one C 1 -C 6 alkyl; or a pharmaceutically acceptable salt thereof.
  • Compounds of the present invention include:
  • the present invention features a compound selected from the group consisting of:
  • One aspect of the present invention includes the compounds substantially as hereinbefore defined with reference to any one of the Examples.
  • One aspect of the present invention includes a pharmaceutical composition comprising one or more compounds of the present invention and a pharmaceutically acceptable carrier.
  • One aspect of the present invention includes one or more compounds of the present invention for use as an active therapeutic substance.
  • the present invention features compounds of the present invention for use in medical therapy for example, in the treatment of HIV infections and associated conditions.
  • the present invention also features the use of compounds of the present invention in the manufacture of a medicament for use in the treatment of viral infections and associated conditions, for example in the treatment of HIV infections and associated conditions.
  • the present invention features a method for the treatment of viral infections and associated conditions, for example, HIV infections and associated conditions, comprising the administration of compounds of the present invention.
  • alkyl alone or in combination with any other term, refers to a straight or branched chain hydrocarbon, containing from one to twelve carbon atoms, unless specified otherwise.
  • alkyl as used herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, tert-butyl, sec-butyl, isopentyl, n-pentyl, n-hexyl, and the like.
  • C x- C y alkyl refers to an alkyl group, as herein defined, containing the specified number of carbon atoms. Similar terminology will apply for other preferred terms and ranges as well.
  • alkenyl refers to a straight or branched chain aliphatic hydrocarbon containing one or more carbon-to-carbon double bonds. Examples include, but are not limited to, vinyl, allyl, and the like.
  • alkynyl refers to a straight or branched chain aliphatic hydrocarbon containing one or more carbon-to-carbon triple bonds, which may occur at any stable point along the chain. Examples include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like.
  • alkylene refers to an optionally substituted straight or branched chain divalent hydrocarbon radical, preferably having from one to ten carbon atoms, unless specified otherwise.
  • alkylene as used herein include, but are not limited to, methylene, ethylene, n-propylene, n-butylene, and the like.
  • Preferred substituent groups include C 1 -C 8 alkyl, hydroxyl or oxo.
  • alkenylene refers to a straight or branched chain divalent hydrocarbon radical, preferably having from two to ten carbon atoms, unless specified otherwise, containing one or more carbon-to-carbon double bonds. Examples include, but are not limited to, vinylene, allylene or 2-propenylene, and the like.
  • alkynylene refers to a straight or branched chain divalent hydrocarbon radical, preferably having from two to ten carbon atoms, unless otherwise specified, containing one or more carbon-to-carbon triple bonds. Examples include, but are not limited to, ethynylene and the like.
  • cycloalkyl refers to an optionally substituted non- aromatic cyclic hydrocarbon ring. Unless otherwise indicated, cycloalkyl is composed of three to eight carbon atoms. Exemplary "cycloalkyl” groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • cycloalkyl includes an optionally substituted fused polycyclic hydrocarbon saturated ring and aromatic ring system, namely polycyclic hydrocarbons with less than maximum number of non-cumulative double bonds, for example where a saturated hydrocarbon ring (such as a cyclopentyl ring) is fused with an aromatic ring (herein “aryl,” such as a benzene ring) to form, for example, groups such as indane.
  • Preferred substituent groups include C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 8 alkoxy, hydroxyl, halogen, C 1 -C 8 haloalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, cyano, amide, amino, and C 1 -C 8 alkylamino.
  • cycloalkenyl refers to an optionally substituted non- aromatic cyclic hydrocarbon ring containing one or more carbon-to-carbon double bonds which optionally includes an alkylene linker through which the cycloalkenyl may be attached.
  • exemplary "cycloalkenyl” groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl.
  • Preferred substituent groups include CrC 8 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, d-C 8 alkoxy, hydroxyl, halogen, d-C 8 haloalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, cyano, amide, amino, and CrC 8 alkylamino.
  • cycloalkylene refers to a divalent, optionally substituted non-aromatic cyclic hydrocarbon ring.
  • cycloalkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, and cycloheptylene.
  • Preferred substituent groups include d-C 8 alkyl, C 2 - C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 8 alkoxy, hydroxyl, halogen, C 1 -C 8 haloalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, cyano, amide, amino, and C 1 -C 8 alkylamino.
  • cycloalkenylene refers to a divalent optionally substituted non-aromatic cyclic hydrocarbon ring containing one or more carbon-to- carbon double bonds.
  • exemplary "cycloalkenylene” groups include, but are not limited to, cyclopropenylene, cyclobutenylene, cyclopentenylene, cyclohexenylene, and cycloheptenylene.
  • Preferred substituent groups include C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 8 alkoxy, hydroxyl, halogen, C 1 -C 8 haloalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, cyano, amide, amino, and C 1 -C 8 alkylamino.
  • heterocycle refers to an optionally substituted mono- or polycyclic ring system optionally containing one or more degrees of unsaturation and also containing one or more heteroatoms.
  • Preferred heteroatoms include N, O, and/or S, including N-oxides, sulfur oxides, and sulfur dioxides. More preferably, the heteroatom is N.
  • heterocyclyl ring is three to twelve-membered, unless otherwise indicated, and is either fully saturated or has one or more degrees of unsaturation. Such rings may be optionally fused to one or more of another "heterocyclic” ring(s), cycloalkyl ring(s) or aryl ring(s).
  • heterocycle “heterocyclic” or “heterocyclyl” includes heteroaryl.
  • heterocyclic groups include, but are not limited to, tetrahydrofuran, pyran, 1 ,4-dioxane, 1 ,3-dioxane, piperidine, piperazine, pyrrolidine, morpholine, tetrahydrothiopyran, aziridine, azetidine and tetrahydrothiophene.
  • substituents it is understood that the substituents may be attached to any atom in the ring, whether a heteroatom or a carbon atom, provided that a stable chemical structure results.
  • Preferred substituent groups include C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 8 alkoxy, hydroxyl, halogen, C 1 -C 8 haloalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, cyano, amide, amino, and C 1 -C 8 alkylamino.
  • aryl refers to an optionally substituted carbocyclic aromatic moiety (such as phenyl or naphthyl) containing the specified number of carbon atoms, preferably 6-14 carbon atoms or 6-10 carbon atoms.
  • aryl also refers to optionally substituted ring systems, for example anthracene, phenanthrene, or naphthalene ring systems.
  • aryl groups include, but are not limited to, phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, indanyl, phenathridinyl, and the like.
  • aryl also includes each possible positional isomer of an aromatic hydrocarbon radical, such as 1 -naphthyl, 2-naphthyl, 5-tetrahydronaphthyl, 6-tetrahydronaphthyl, 1 phenanthridinyl, 2-phenanthridinyl, 3-phenanthridinyl, 4-phenanthridinyl, and the like.
  • Preferred substituent groups include C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 8 alkoxy, hydroxyl, halogen, C 1 -C 8 haloalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, cyano, amide, amino, and C 1 -C 8 alkylamino.
  • heteroaryl refers to an optionally substituted monocyclic five to seven membered aromatic ring unless otherwise specified, or to an optionally substituted fused bicyclic aromatic ring system comprising two of such aromatic rings.
  • These heteroaryl rings contain one or more nitrogen, sulfur, and/or oxygen atoms, where N-oxides, sulfur oxides, and sulfur dioxides are permissible heteroatom substitutions.
  • the heteroatom is N.
  • heteroaryl groups used herein include, but should not be limited to, furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, benzothiophene, indole, indazole, benzimidizolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl.
  • Preferred substituent groups include C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 8 alkoxy, hydroxyl, halogen, C 1 -C 8 haloalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkoxy, cyano, amide, amino, and alkylamino.
  • halogen refers to fluorine, chlorine, bromine, or iodine.
  • haloalkyl refers to an alkyl group, as defined herein, which is substituted with at least one halogen.
  • branched or straight chained “haloalkyl” groups useful in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, and t-butyl substituted independently with one or more halogens, e.g., fluoro, chloro, bromo, and iodo.
  • haloalkyl should be interpreted to include such substituents as perfluoroalkyl groups and the like.
  • alkoxy refers to a group -OR', where R' is alkyl as defined.
  • suitable alkoxy radicals include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like.
  • cycloalkoxy refers to a group -OR', where R' is cycloalkyl as defined.
  • alkoxycarbonyl refers to groups such as: where the R' represents an alkyl group as herein defined.
  • aryloxycarbonyl refers to groups such as: where the Ay represents an aryl group as herein defined.
  • nitro refers to a group -NO 2 .
  • cyano refers to a group -CN.
  • azido refers to a group -N 3 .
  • amino refers to a group -NR'R", where R' and R" independently represent H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
  • alkylamino includes an alkylene linker through which the amino group is attached.
  • amide refers to a group -C(O)NR 1 R", where R' and R" independently represent H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
  • the compounds of the present invention may crystallize in more than one form, a characteristic known as polymorphism, and such polymorphic forms (“polymorphs") are within the scope of the present invention.
  • Polymorphism generally can occur as a response to changes in temperature, pressure, or both. Polymorphism can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics known in the art such as x-ray diffraction patterns, solubility, and melting point. Though a crystalline form of compounds of the present invention are generally preferred, the invention also contemplates amorphous forms of the compounds produced by methods known in the art (e.g. spray drying, milling, freeze drying, and so forth).
  • Certain of the compounds described herein contain one or more chiral centers, or may otherwise be capable of existing as multiple stereoisomers.
  • the scope of the present invention includes mixtures of stereoisomers as well as purified enantiomers or enantiomerically and/or diastereomerically enriched mixtures. Also included within the scope of the invention are the individual isomers of the compounds of the present invention, as well as any wholly or partially equilibrated mixtures thereof.
  • the present invention also includes the individual isomers of the compounds represented by the formulas above as mixtures with isomers thereof in which one or more chiral centers are inverted.
  • solvate refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of the present invention, or a salt or other pharmaceutically acceptable derivative thereof) and a solvent.
  • solvents for the purpose of the invention, should not interfere with the biological activity of the solute.
  • suitable solvents include, but are not limited to water, methanol, ethanol, ethyl acetate, acetone, acetonitrile, trifluoroacetic acid and acetic acid.
  • the solvent used is a pharmaceutically acceptable solvent.
  • suitable pharmaceutically acceptable solvents include water, ethanol, and acetic acid. Most preferably the solvent used is water.
  • the term "pharmaceutically acceptable derivative” means any pharmaceutically acceptable salt, ester, salt of an ester, ether, amides, or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing directly or indirectly a compound of this invention or an inhibitorily active metabolite or residue thereof.
  • Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal, for example, by allowing an orally administered compound to be more readily absorbed into the blood, or which enhance delivery of the parent compound to a biological compartment, for example, the brain or lymphatic system, relative to the parent species.
  • the present invention features a compound of formula (I)
  • each R 1 independently is halogen, -CN, CrC 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, hydroxyl, C r C 8 alkoxy, -C(O)OR 4 , -C(O)N(R 4 ) 2 , -OR 4 , -R 5 CN, or -N(R 4 ) 2 ; each R 2 independently is halogen, -CN, CrC 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, hydroxyl, C r C 8 alkoxy, -C(O)OR 4 , -C(O)N(R 4 ) 2 , -OR 4 , -R 5 CN or -N(R 4 ) 2 ; each R 2 independently is halogen, -CN, CrC 5 al
  • A is C 5 -Ci 2 aryl or C 5 -Ci 2 heterocycle
  • R 3 is -R 5 Ar or C 4 -Ci 2 aryl, each optionally substituted with at least one CrCe alkyl, halogen, hydroxyl, oxo, C r C 8 alkoxy, -C(O)OR 4 , -C(O)N(R 4 ) 2 , -OR 4 , -N(R 4 ) 2 , -N(O) 2 ,
  • each R 4 is independently hydrogen, Ci-C 8 alkyl optionally substituted with at least one hydroxyl or halogen; or C 3 -C 7 cycloalkyl; each R 5 is independently d-C 8 alkylene, CrC 8 alkenylene, CrC 8 alkynylene, each optionally substituted with at least one hydroxyl or hydrogen; He
  • Ar is C 4 -Ci 2 aryl and is optionally substituted with at least one CrC 6 alkyl or halogen; or pharmaceutically acceptable derivatives thereof.
  • the present invention features a compound of formula (I) wherein R 3 is C 4 -Ci 2 aryl optionally substituted with at least one CrC 8 alkyl, halogen, hydroxyl, oxo, CrC 8 alkoxy, -C(O)OR 4 , -C(O)N(R 4 ) 2 , -OR 4 , -N(R 4 ) 2 , -N(O) 2 , -CN, -OR 5 Het, -OR 5 N(R 4 ) 2 ,
  • the present invention features a compound of formula (I) wherein R 3 is R 5 Ar and wherein Ar is optionally substituted with at least one CrC 8 alkyl, halogen, hydroxyl, oxo, CrC 8 alkoxy, -C(O)OR 4 , -
  • each R 3 is phenyl, optionally substituted with at least one CrC 8 alkyl, halogen, hydroxyl, oxo, CrC 8 alkoxy, -C(O)OR 4 , -C(O)N(R 4 ) 2 , -OR 4 , -N(R 4 ) 2 , -N(O) 2 , -CN, -OR 5 Het, -OR 5 N(R 4 ) 2 ,
  • the present invention features a compound of formula (I) wherein n is 2 and each R 2 is halogen.
  • the present invention features a compound of formula (I) wherein m is 2 and each R 1 is halogen.
  • the present invention features a compound of formula (I) wherein m is 2 and the first R 1 is halogen and the second R 1 is -CN.
  • the present invention features a compound of formula (I) wherein m is 2 and each R 1 is in the meta position.
  • the present invention features a compound of formula (I) wherein n is 2 and each R 2 is in the ortho position relative to the ether linkage.
  • the present invention features a compound of formula (I) wherein m is 2, n is 2, and R 3 is C 4 -Ci 2 aryl optionally substituted with at least one d-C 8 alkyl, halogen, hydroxyl, oxo, C r C 8 alkoxy, -C(O)OR 4 , -C(O)N(R 4 ) 2 , -OR 4 , -N(R 4 ) 2 , -N(O) 2 , -CN, -OR 5 Het, -OR 5 N(R 4 ) 2 , -C(O)N(R 4 )Het, -C(O)Het, -C(O)N(R 4 )R 5 S(O) 2 R 4 , -S(O) 2 N(R 4 ) 2 , -S(O) 2 R 4 , -C(O)R 4 ; -N(R 4 )C(O)R 5 SR 4 ,
  • the present invention features a compound of formula (I) wherein R 3 is C 4 -C 12 aryl substituted in the ortho position with at least one of C 1 -C 8 alkyl or halogen.
  • the present invention also features a compound of formula (II)
  • each R 1 independently is halogen, -CN, C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, hydroxyl, C 1 -C 8 alkoxy, -C(O)OR 4 , -C(O)N(R 4 ) 2 , -OR 4 , -R 5 CN, or -N(R 4 ) 2 ; each R 2 independently is halogen, -CN, C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, hydroxyl, C 1 -C 8 alkoxy, -C(O)OR 5 , -C(O)N(R 4 ) 2 , -OR 4 , -R 5
  • R 3 is -R 5 Ar or C 4 -C 12 aryl, each optionally substituted with at least one C 1 -C 8 alkyl, halogen, hydroxyl, oxo, C 1 -C 8 alkoxy, -C(O)OR 4 , -C(O)N(R 4 ) 2 , -OR 4 , -N(R 4 ) 2 , -N(O) 2 ,
  • each R 4 is independently hydrogen, C 1 -C 8 alkyl optionally substituted with at least one hydroxyl or halogen; or C 3 -C 7 cycloalkyl; each R 5 is independently C 1 -C 8 alkylene, C 1 -C 8 alkenylene, C 1 -C 8 alkynylene, each optionally substituted with at
  • Ar is C 4 -C 12 aryl and is optionally substituted with at least one C 1 -C 6 alkyl or halogen; or pharmaceutically acceptable derivatives thereof.
  • the present invention features a compound of formula (II) wherein R 3 is C 4 -C 12 aryl optionally substituted with at least one CrC 8 alkyl, halogen, hydroxyl, oxo, CrC 8 alkoxy, -C(O)OR 4 , -C(O)N(R 4 ) 2 , -OR 4 , -N(R 4 ) 2 , -N(O) 2 , -CN, -OR 5 Het, -OR 5 N(R 4 ) 2 , -C(O)N(R 4 )Het, -C(O)Het, -C(O)N(R 4 )R 5 S(O) 2 R 4 , -S(O) 2 N(R 4 ) 2 , -S(O) 2 R 4
  • the present invention features a compound of formula (II) wherein R 3 is R 5 Ar and wherein Ar is optionally substituted with at least one CrCe alkyl, halogen, hydroxyl, oxo, CrC 8 alkoxy, -C(O)OR 4 , -C(O)N(R 4 ) 2 , -OR 4 , -N(R 4 ) 2 , -N(O) 2 , -CN, -OR 5 Het, -OR 5 N(R 4 ) 2 , -C(O)N(R 4 )Het, -C(O)Het, -C(O)N(R 4 )R 5 S(O) 2 R 4 , -S(O) 2 N(R 4 ),, -S(O) 2 R 4 , -C(O)R 4 ; - N(R 4 )C(O)R 5 SR 4 , -N(R 4 )R 5 S(O) 2 R 4
  • each R 3 is phenyl, optionally substituted with at least one C 1 -C 8 alkyl, halogen, hydroxyl, oxo, C 1 -C 8 alkoxy, -C(O)OR 4 , -C(O)N(R 4 ) 2 , -OR 4 , -N(R 4 ) 2 , -N(O) 2 , -CN, -OR 5 Het, -OR 5 N(R 4 ) 2 , -C(O)N(R 4 )Het, -C(O)Het, -C(O)N(R 4 )R 5 S(O) 2 R 4 , -S(O) 2 N(R 4 ),, -S(O) 2 R 4 , -C(O)R 4 ; -N(R 4 )C(O)R 5 SR 4 , -N(R 4 )R 5 S(O)
  • the present invention features a compound of formula (II) wherein R 3 is C 4 -C 12 aryl substituted in the ortho position with at least one of C 1 -C 8 alkyl or halogen.
  • the present invention features a compound of formula (II) wherein n is 2 and each R 2 is halogen.
  • the present invention features a compound of formula (II) wherein m is 2 and each R 1 is halogen.
  • the present invention features a compound of formula (II) wherein m is 2 and the first R 1 is halogen and the second R 1 is -CN.
  • the present invention features a compound of formula (II) wherein m is 2 and each R 1 is in the meta position.
  • the present invention features a compound of formula (I) wherein n is 2 and each R 2 is in the ortho position relative to the ether linkage.
  • the present invention features a compound of formula (II) wherein m is 2, n is 2, and R 3 is C 4 -C 12 aryl optionally substituted with at least one C 1 -C 8 alkyl, halogen, hydroxyl, oxo, C 1 -C 8 alkoxy, -C(O)OR 4 , -C(O)N(R 4 ) 2 , -OR 4 , -N(R 4 ) 2 , -N(O) 2 , -CN, -OR 5 Het, -OR 5 N(R 4 ) 2 , -C(O)N(R 4 )Het, -C(O)Het, -C(O)N(R 4 )R 5 S(O) 2 R 4 , -S(O) 2 N(R 4 ),, -S(O) 2 R 4 , -C(O)R 4 ; -N(R 4 )C(O)R 5 SR 4 ,
  • the present invention features a compound of formula (II) wherein R 3 is C 4 -C 12 aryl optionally substituted with at least one halogen, OR 4 , -OR 5 Het, or -OR 5 N(R 4 ) 2 .
  • the present invention also features a compound of formula (II)'
  • each R 1 independently is halogen, -CN, CrC 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, hydroxyl, C r C 8 alkoxy, -C(O)OR 4 , -C(O)N(R 4 ) 2 , -OR 4 , -R 5 CN, or -N(R 4 ) 2 ; each R 2 independently is halogen, -CN, CrC 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, hydroxyl, C r C 8 alkoxy, -C(O)OR 4 , -C(O)N(R 4 ) 2 , -OR 4 , -R 5 CN or -N(R 4 ) 2 ; each R 2 independently is halogen, -CN, CrC 5 al
  • R 3 is -R 5 Ar or C 4 -Ci 2 aryl, each optionally substituted with at least one halogen, hydroxyl, oxo, CrC 8 alkoxy, -C(O)OR 4 , -C(O)N(R 4 ) 2 , -OR 4 , -N(R 4 ) 2 , -N(O) 2 , -CN, -OR 5 Het, -
  • each R 4 is independently hydrogen, C 1 -C 8 alkyl optionally substituted with at least one hydroxyl or halogen; or C 3 -C 7 cycloalkyl; each R 5 is independently d-C 8 alkylene, CrC 8 alkenylene, CrC 8 alkynylene, each optionally substituted with at least one hydroxyl or hydrogen; Het is C 3 -Ci 0 heterocycle and is optionally substituted with at least one CrC 6 alkyl, oxo, hydroxyl, R 5 S(O) 2 R 4 , or halogen; and
  • Ar is C 4 -Ci 2 aryl and is optionally substituted with at least one CrC 6 alkyl or halogen; or a pharmaceutically acceptable salt thereof.
  • the present invention also features a compound of formula (II)' wherein m is 2; n is 2; each R 1 independently is halogen or -CN; each R 2 independently is halogen;
  • R 3 is C 4 -Ci 2 aryl, optionally substituted with at least one -OR 4 , -N(R 4 ) 2 , -OR 5 Het, -
  • each R 4 is independently hydrogen or CrC 8 alkyl optionally substituted with at least one hydroxyl
  • each R 5 is independently CrC 8 alkylene optionally substituted with at least one hydroxyl
  • Het is C 3 -Ci 0 heterocycle and is optionally substituted with at least one CrC 6 alkyl; or a pharmaceutically acceptable salt thereof.
  • the present invention features a compound selected from the group consisting of:
  • Compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. Solvated forms and unsolvated forms are encompassed within the scope of the present invention. Compounds of the present invention may exist in a mixture of forms and/or solvates or as a mixture of amorphous material and one or more forms and/or solvates. In general, all physical forms are intended to be within the scope of the present invention. Forms may be distinguished by various physical characteristics known in the art such as x-ray diffraction patterns, solubility, and melting point.
  • Salts of the compounds of the present invention may be made by methods known to a person skilled in the art. For example, treatment of a compound of the present invention with an appropriate base or acid in an appropriate solvent will yield the corresponding salt.
  • salts of the present invention are pharmaceutically acceptable salts.
  • Salts encompassed within the term “pharmaceutically acceptable salts” refer to non-toxic salts of the compounds of this invention. Salts of the compounds of the present invention may comprise acid addition salts.
  • Representative salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, calcium edetate, camsylate, carbonate, clavulanate, citrate, dihydrochloride, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate
  • Pharmaceutically acceptable salts of the compounds according to the invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
  • suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicyclic, succinic, toluene-p- sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids.
  • Other acids, such as oxalic while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
  • Esters of the compounds of the present invention are independently selected from the following groups: (1 ) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n- propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted by, for example, halogen, or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono
  • any alkyl moiety present advantageously contains from 1 to 18 carbon atoms, particularly from 1 to 6 carbon atoms, more particularly from 1 to 4 carbon atoms.
  • Any cycloalkyl moiety present in such esters advantageously contains from 3 to 6 carbon atoms.
  • Any aryl moiety present in such esters advantageously comprises a phenyl group.
  • Ethers of the compounds of the present invention include, but are not limited to methyl, ethyl, butyl and the like.
  • the term "effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician.
  • the term "therapeutically effective amount” means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder.
  • the term also includes within its scope amounts effective to enhance normal physiological function.
  • module as used herein is intended to encompass antagonist, agonist, inverse agonist, partial agonist or partial antagonist, inhibitors and activators.
  • treatment refers to alleviating the specified condition, eliminating or reducing the symptoms of the condition, slowing or eliminating the progression of the condition and preventing or delaying the initial occurrence of the condition in a subject, or reoccurrence of the condition in a previously afflicted subject.
  • the present invention features compounds according to the invention for use in medical therapy, for example for the treatment (including prophylaxis) of a viral infection, for example an HIV infection and associated conditions.
  • the compounds according to the invention are especially useful for the treatment of AIDS and related clinical conditions such as AIDS related complex (ARC), progressive generalized lymphadenopathy (PGL), Kaposi's sarcoma, thromobocytopenic purpura, AIDS-related neurological conditions such as AIDS dementia complex, multiple sclerosis or tropical paraperesis, anti-HIV antibody-positive and HIV-positive conditions, including such conditions in asymptomatic patients.
  • AIDS related complex ARC
  • PDL progressive generalized lymphadenopathy
  • Kaposi's sarcoma Kaposi's sarcoma
  • thromobocytopenic purpura AIDS-related neurological conditions
  • AIDS dementia complex such as AIDS dementia complex, multiple sclerosis or tropical paraperesis
  • anti-HIV antibody-positive and HIV-positive conditions including such conditions in asymptomatic patients.
  • the present invention further provides a method for the treatment of a clinical condition in a patient, for example, a mammal including a human which clinical condition includes those which have been discussed hereinbefore, which comprises treating said patient with a pharmaceutically effective amount of a compound according to the invention.
  • the present invention also includes a method for the treatment (including prophylaxis) of any of the aforementioned diseases or conditions.
  • the present invention provides a method for the treatment or prevention of the symptoms or effects of a viral infection in an infected patient, for example, a mammal including a human, which comprises administering to said patient a pharmaceutically effective amount of a compound according to the invention.
  • the viral infection is a retroviral infection, in particular an HIV infection.
  • the present invention further includes the use of a compound according to the invention in the manufacture of a medicament for administration to a subject for the treatment of a viral infection, in particular and HIV infection.
  • the compounds according to the invention may also be used in adjuvant therapy in the treatment of HIV infections or HIV-associated symptoms or effects, for example Kaposi's sarcoma.
  • Reference herein to treatment extends to prophylaxis as well as the treatment of established conditions, disorders and infections, symptoms thereof, and associated clinical conditions.
  • the above compounds according to the invention and their pharmaceutically acceptable derivatives may be employed in combination with other therapeutic agents for the treatment of the above infections or conditions.
  • Combination therapies according to the present invention comprise the administration of a compound of the present invention or a pharmaceutically acceptable derivative thereof and another pharmaceutically active agent.
  • the active ingredient(s) and pharmaceutically active agents may be administered simultaneously (i.e., concurrently) in either the same or different pharmaceutical compositions or sequentially in any order.
  • the amounts of the active ingredient(s) and pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • therapeutically effective amounts of a compound of the present invention, as well as salts, solvates, or other pharmaceutically acceptable derivatives thereof, may be administered as the raw chemical. Additionally, the active ingredient may be presented as a pharmaceutical composition.
  • the invention further provides pharmaceutical compositions that include effective amounts of compounds of the the present invention and salts, solvates, or other pharmaceutically acceptable derivatives thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • the compounds of the present invention and salts, solvates, or other pharmaceutically acceptable derivatives thereof, are as herein described.
  • the carrier(s), diluent(s) or excipient(s) must be acceptable, in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient of the pharmaceutical composition.
  • a process for the preparation of a pharmaceutical formulation including admixing a compound of the present invention or salts, solvates, or other pharmaceutically acceptable derivatives thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients.
  • a therapeutically effective amount of a compound of the present invention will depend upon a number of factors. For example, the species, age, and weight of the recipient, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration are all factors to be considered. The therapeutically effective amount ultimately should be at the discretion of the attendant physician or veterinarian. Regardless, an effective amount of a compound of the present invention for the treatment of humans suffering from frailty, generally, should be in the range of 0.1 to 100 mg/kg body weight of recipient (mammal) per day. More usually the effective amount should be in the range of 0.1 to 10 mg/kg body weight per day. Thus, for a 70 kg adult mammal one example of an actual amount per day would usually be from 7 to 700 mg.
  • This amount may be given in a single dose per day or in a number (such as two, three, four, five, or more) of sub-doses per day such that the total daily dose is the same.
  • An effective amount of a salt, solvate, or other pharmaceutically acceptable derivative thereof, may be determined as a proportion of the effective amount of a compound of the present invention per se. Similar dosages should be appropriate for treatment of the other conditions referred to herein.
  • compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose.
  • a unit may contain, as a non-limiting example, 0.5 mg to 1 g of a compound of the formula (I), depending on the condition being treated, the route of administration, and the age, weight, and condition of the patient.
  • Preferred unit dosage formulations are those containing a daily dose or sub- dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient.
  • Such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art.
  • compositions may be adapted for administration by any appropriate route, for example by an oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route.
  • Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s).
  • the carrier(s) or excipient(s) By way of example, and not meant to limit the invention, with regard to certain conditions and disorders for which the compounds of the present invention are believed useful certain routes will be preferable to others.
  • compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions, each with aqueous or non-aqueous liquids; edible foams or whips; or oil-in- water liquid emulsions or water-in-oil liquid emulsions.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • powders are prepared by comminuting a compound to a suitable fine size and mixing with an appropriate pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol.
  • Flavorings, preservatives, dispersing agents, and coloring agents can also be present.
  • Capsules are made by preparing a powder, liquid, or suspension mixture and encapsulating with gelatin or some other appropriate shell material.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol can be added to the mixture before the encapsulation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture.
  • binders examples include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants useful in these dosage forms include, for example, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets.
  • a powder mixture may be prepared by mixing a compound, suitably comminuted, with a diluent or base as described above.
  • Optional ingredients include binders such as carboxymethylcellulose, aliginates, gelatins, or polyvinyl pyrrolidone, solution retardants such as paraffin, resorption accelerators such as a quaternary salt, and/or absorption agents such as bentonite, kaolin, or dicalcium phosphate.
  • the powder mixture can be wet-granulated with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials, and forcing through a screen.
  • a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet-forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil.
  • the lubricated mixture is then compressed into tablets.
  • the compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material, and
  • Oral fluids such as solutions, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of a compound.
  • Syrups can be prepared, for example, by dissolving a compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle.
  • Suspensions can be formulated generally by dispersing a compound in a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives; flavor additives such as peppermint oil, or natural sweeteners, saccharin, or other artificial sweeteners; and the like can also be added.
  • dosage unit formulations for oral administration can be microencapsulated.
  • the formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
  • the compounds of the present invention and salts, solvates, or other pharmaceutically acceptable derivatives thereof can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
  • the compounds of the present invention and salts, solvates, or other pharmaceutically acceptable derivatives thereof may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
  • the compounds may also be coupled with soluble polymers as targetable drug carriers.
  • soluble polymers can include polyvinylpyrrolidone (PVP), pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethyl-aspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues.
  • PVP polyvinylpyrrolidone
  • pyran copolymer polyhydroxypropylmethacrylamide-phenol
  • polyhydroxyethyl-aspartamidephenol polyhydroxyethyl-aspartamidephenol
  • polyethyleneoxidepolylysine substituted with palmitoyl residues e.g., palmitoyl residues.
  • the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug; for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polyd
  • compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986), incorporated herein by reference as related to such delivery systems.
  • compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils.
  • the formulations may be applied as a topical ointment or cream.
  • the active ingredient When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water- miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
  • compositions adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
  • compositions adapted for topical administration in the mouth include lozenges, pastilles, and mouthwashes.
  • compositions adapted for nasal administration where the carrier is a solid, include a coarse powder having a particle size for example in the range 20 to 500 microns. The powder is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops include aqueous or oil solutions of the active ingredient.
  • Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered dose pressurized aerosols, nebulizers, or insufflators.
  • compositions adapted for rectal administration may be presented as suppositories or as enemas.
  • Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations.
  • Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • sterile liquid carrier for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
  • formulations may include other agents conventional in the art having regard to the type of formulation in question.
  • formulations suitable for oral administration may include flavoring or coloring agents.
  • the present invention features compounds for use in medical therapy particularly for the treatment of viral infections such as an HIV infection. Compounds according to the invention have been shown to be active against HIV infections, although these compounds may be active against HBV infections as well.
  • the compounds according to the invention are particularly suited to the treatment of HIV infections and associated conditions.
  • Compounds of the present invention are useful as inhibitors of both wild type and mutant variants of HIV reverse transcriptase.
  • Reference herein to treatment extends to treatment of established infections, symptoms, and associated clinical conditions such as AIDS related complex (ARC), Kaposi's sarcoma, and AIDS dementia.
  • the present invention further provides a method of treatment of HIV mutant viruses that exhibit NNRTI drug resistance by administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable derivative thereof to a mammal, in particular a human.
  • the compounds of the present invention may be used to treat wild-type HIV-1 as well as several resistant mutants, for example, K103N, V106A, or Y181 C.
  • the present invention provides a method for the treatment of the symptoms or effects of a viral infection in an infected animal, for example, a mammal including a human, which comprises treating said animal with a therapeutically effective amount of a compound according to the invention.
  • the viral infection is a retroviral infection, in particular an HIV infection.
  • a further aspect of the invention includes a method for the treatment of the symptoms or effects of an HBV infection.
  • the compounds of the present invention may also be used in adjuvant therapy in the treatment of HIV infections or HIV-associated symptoms or effects, for example Kaposi's sarcoma.
  • the compounds of the present invention and their salts, solvates, or other pharmaceutically acceptable derivatives thereof may be employed alone or in combination with other therapeutic agents.
  • the compound(s) of the present invention and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order.
  • the amounts of the compound(s) of the present invention and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
  • the administration in combination of a compound of the present invention and salts, solvates, or other pharmaceutically acceptable derivatives thereof with other treatment agents may be in combination by administration concomitantly in: (1 ) a unitary pharmaceutical composition including both compounds; or (2) separate pharmaceutical compositions each including one of the compounds.
  • the combination may be administered separately in a sequential manner wherein one treatment agent is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time.
  • the present invention may be used in combination with one or more agents useful in the prevention or treatment of HIV.
  • agents useful in the prevention or treatment of HIV include:
  • Nucleotide reverse transcriptase inhibitors such as zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavidine, adefovir, adefovir dipivoxil, fozivudine, todoxil, emtricitabine, alovudine, amdoxovir, elvucitabine, and similar agents;
  • Non-nucleotide reverse transcriptase inhibitors include an agent having anti- oxidation activity such as immunocal, oltipraz, etc.
  • an agent having anti- oxidation activity such as immunocal, oltipraz, etc.
  • Protease inhibitors such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, atazanavir, tipranavir, palinavir, lasinavir, and similar agents;
  • Entry inhibitors such as enfuvirtide (T-20), T-1249, PRO-542, PRO-140, TNX- 355, BMS-806, 5-Helix and similar agents; lntegrase inhibitors such as L-870,810 and similar agents;
  • Budding inhibitors such as PA-344 and PA-457, and similar agents; and CXCR4 and/or CCR5 inhibitors such as vicriviroc (Sch-C), Sch-D, TAK779, maraviroc (UK 427,857), TAK449, as well as those disclosed in WO 02/74769, PCT/US03/39644, PCT/US03/39975, PCT/US03/39619, PCT/US03/39618, PCT/US03/39740, and PCT/US03/39732, and similar agents.
  • the scope of combinations of compounds of this invention with HIV agents is not limited to those mentioned above, but includes in principle any combination with any pharmaceutical composition useful for the treatment of HIV. As noted, in such combinations the compounds of the present invention and other HIV agents may be administered separately or in conjunction. In addition, one agent may be prior to, concurrent to, or subsequent to the administration of other agent(s).
  • the compounds of the present invention may be used in the treatment of a variety of disorders and conditions and, as such, the compounds of the present invention may be used in combination with a variety of other suitable therapeutic agents useful in the treatment (including prophylaxis) of those disorders or conditions.
  • the compounds may be used in combination with any other pharmaceutical composition where such combined therapy may be useful to modulate chemokine receptor activity and thereby prevent and treat inflammatory and/or immunoregulatory diseases.
  • compositions of this invention may include other agents conventional in the art having regard to the type of pharmaceutical composition in question, for example, those suitable for oral administration may include such further agents as sweeteners, thickeners, and flavoring agents.
  • the compounds of the present invention may be prepared according to the following reaction schemes and examples, or modifications thereof using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are known to those of ordinary skill in the art.
  • protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of synthetic chemistry.
  • Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts (1991 ) Protecting Groups in Organic Synthesis, John Wiley & Sons, incorporated by reference with regard to protecting groups). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of the present invention. Those skilled in the art will recognize if a stereocenter exists in compounds of the present invention.
  • the scope of the present invention includes all possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well.
  • a compound is desired as a single enantiomer, such may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as are known in the art. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. ENeI, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994), incorporated by reference with regard to stereochemistry.
  • L (liters); ml. (milliliters); ⁇ l_ (microliters); psi (pounds per square inch);
  • RT room temperature
  • h hours
  • min minutes
  • TLC thin layer chromatography
  • mp melting point
  • RP reverse phase
  • T r retention time
  • TFA trifluoroacetic acid
  • TEA triethylamine
  • THF tetrahydrofuran
  • TFAA trifluoroacetic anhydride
  • CD 3 OD deuterated methanol
  • CDCI 3 deuterated chloroform
  • DMSO dimethylsulfoxide
  • SiO 2 (silica); atm (atmosphere);
  • MP-TsOH polystyrene resin bound equivalent of p-TsOH from Argonaut Technologies.
  • HATU 1-[Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyidinium 3-oxide, hexafluorophosphate
  • DIPEA N,N-diisopropylethylamine
  • PS-triphenylphosphine polystyrene resin bound equivalent of triphenylphosphine
  • Mass spectra were obtained on Waters Corporation ZQ, ZMD, Quattro Micro or SQD mass spectrometers from Waters Corporation, Milford, MA using either Atmospheric Chemical Ionization (APCI) or Electrospray Ionization (ESI). Analytical thin layer chromatography was used to verify the purity of intermediate(s) which could not be isolated or which were too unstable for full characterization as well as to follow the progress of reaction(s).
  • APCI Atmospheric Chemical Ionization
  • ESI Electrospray Ionization
  • the absolute configuration of compounds was assigned by Ab lnitio Vibrational Circular Dichroism (VCD) Spectroscopy.
  • VCD Circular Dichroism
  • the experimental VCD spectra were acquired in CDCI 3 using a Bomem Chiral RTM VCD spectrometer operating between 2000 and 800 cm "1 .
  • the Gaussian 98 Suite of computational programs was used to calculate model VCD spectrums.
  • the stereochemical assignments were made by comparing this experimental spectrum to the VCD spectrum calculated for a model structure with (R)- or (S ⁇ configuration. Incorporated by reference with regard to such spectroscopy are: J. R. Chesseman, MJ. Frisch, FJ. Devlin and PJ. Stephens, Chem. Phys. Lett. 252 (1996) 21 1 ; PJ. Stephens and FJ. Devlin, Chirality 12 (2000) 172; and Gaussian 98, Revision A.1 1.4, MJ. Frisch et al., Gaus
  • Compounds of formula (I) can be prepared according to routes depicted in Scheme 1.
  • an appropriately substituted acyl hydrazide (A) is coupled as in Route A with an appropriately substituted carboxylic acid (or acid chloride) employing a coupling reagent (for example, HATU) in solution (for example, THF) to yield intermediate (C).
  • Intermediate (C) may be formed in an analogous manner (Route B) from an appropriately substituted carboxylic acid (B) and an appropriately substituted acyl hydrazide again employing a coupling reagent (for example, HATU) and appropriate solvent (for example, THF).
  • Step 1 the choice of coupling reagent and solvent is not restricted to those describe herein and a variety of others may be selected by those skilled in the art.
  • Intermediate (C) may be purified and isolated by standard means to those skilled in the art (such as silica gel chromatography) but this is not necessary.
  • Intermediate (C) may then be dehydrated with a standard dehydrating agent (for example, Burgess Reagent) to afford the cyclized oxadiazole compound of formula (I).
  • a standard dehydrating agent for example, Burgess Reagent
  • the dehydrating agent is not restricted to Burgess Reagent and other reagents may be chosen by one skilled in the art.
  • Step C 2-[(3-bromo-5-chlorophenyl)oxy]-3,4-difluoro-1 -nitrobenzene
  • Step D 1 ,1-dimethylethyl ethyl ⁇ 3-[(3-bromo-5-chlorophenyl)oxy]-2-fluoro-4- nitrophenyl ⁇ propanedioate
  • Step E ethyl ⁇ 3-[(3-bromo-5-chlorophenyl)oxy]-2-fluoro-4-nitrophenyl ⁇ acetate
  • Step F ethyl ⁇ 4-amino-3-[(3-bromo-5-chlorophenyl)oxy]-2-fluorophenyl ⁇ acetate
  • Step G ethyl ⁇ 3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl ⁇ acetate
  • Step D 1 ,1-dimethylethyl ethyl ⁇ 3-[(3-chloro-5-cyanophenyl)oxy]-2-fluoro-4-nitrophenyl ⁇ propanedioate
  • Step E ethyl ⁇ 3-[(3-chloro-5-cyanophenyl)oxy]-2-fluoro-4-nitrophenyl ⁇ acetate
  • Step F ethyl ⁇ 4-amino-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl ⁇ acetate
  • Step A 2-[(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]-2-propanol
  • Step B (2S)-3-methyl-1 ,2,3-butanetriol
  • (2S)-3-methyl-1 ,2,3-butanetriol (85.3 mmol, 1 eq) was treated with 4- methylbenzenesulfonyl chloride (16.3 g, 85.3 mmol, 1 eq) in dry pyridine (66 ml.) at ice bath temperature until complete solution was obtained.
  • the reaction mixture was then sealed under nitrogen and aged in a freezer (-20 0 C) for 3 days.
  • the reaction mixture was warmed to ambient temperature and treated with 1 N HCI (500 ml.) with stirring.
  • Step D [(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl 4-methylbenzenesulfonate
  • Step A / ⁇ - ⁇ -[(S-bromo- ⁇ -chlorophenyOoxyl ⁇ -chloro ⁇ -fluorophenylJacetyO-S- (methyloxy)benzohydrazide
  • Step B 2-( ⁇ 3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl ⁇ methyl)-5-[3- (methyloxy)phenyl]-1 ,3,4-oxadiazole
  • Example 1 1 S-chloro- ⁇ -ir ⁇ -chloro ⁇ -fluoro-S- ⁇ - ⁇ -fmethyloxylphenyll-I .S ⁇ -oxadiazol- 2-yl ⁇ methyl)phenylloxy ⁇ benzonitrile
  • Example 12 3-chloro-5-r(6-chloro-2-fluoro-3- ⁇ r5-(3-hvdroxyphenyl)-1 ,3,4-oxadiazol-2- yllmethyltohenvDoxylbenzonitrile
  • Step A / ⁇ - ⁇ -[(S-bromo- ⁇ -chlorophenyOoxyl ⁇ -chloro ⁇ -fluorophenylJacetyl)- ⁇ (methyloxy)benzohydrazide
  • Step B 2-( ⁇ 3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl ⁇ methyl)-5-[4- (methyloxy)phenyl]-1 ,3,4-oxadiazole
  • Step A / ⁇ - ⁇ -[(S-bromo- ⁇ -chlorophenyOoxyl ⁇ -chloro ⁇ -fluorophenylJacetyO-S- cyanobenzohydrazide.
  • Step B 3-[5-( ⁇ 3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl ⁇ methyl)-1 ,3,4- oxadiazol-2-yl]benzonitrile
  • Step C 3-chloro-5-[(6-chloro-3- ⁇ [5-(3-cyanophenyl)-1 ,3,4-oxadiazol-2-yl]methyl ⁇ -2- fluorophenyl)oxy]benzonitrile
  • Example 17 4-[5-( ⁇ 4-chloro-3-[(3-chloro-5-cvanophenyl)oxy1-2-fluorophenyl ⁇ methyl)- 1 ,3,4-oxadiazol-2-yl1- ⁇ /, ⁇ /-diethylbenzenesulfonamide
  • Step A 4- ⁇ [2-( ⁇ 3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2 -fluorophenyl ⁇ acetyl)hydrazino]carbonyl ⁇ - ⁇ /, ⁇ /-diethylbenzenesulfonamide
  • Step B 4-[5-( ⁇ 3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl ⁇ methyl)-1 ,3,4- oxadiazol-2-yl]- ⁇ /, ⁇ /-diethylbenzenesulfonamide
  • Step C 4-[5-( ⁇ 4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl ⁇ methyl)-1 ,3,4- oxadiazol-2-yl]- ⁇ /, ⁇ /-diethylbenzenesulfonamide
  • Step A 4-[5-( ⁇ 3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl ⁇ methyl)-1 ,3,4- oxadiazol-2-yl]benzonitrile
  • Step B 3-chloro-5-[(6-chloro-3- ⁇ [5-(4-cyanophenyl)-1 ,3,4-oxadiazol-2-yl]methyl ⁇ -2- fluorophenyl)oxy]benzonitrile
  • Step A 2-( ⁇ 3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl ⁇ methyl)-5-[2-fluoro- 3-(methyloxy)phenyl]-1 ,3,4-oxadiazole
  • Step B 3-chloro-5- ⁇ [6-chloro-2-fluoro-3-( ⁇ 5-[2-fluoro-3-(methyloxy)phenyl]-1 ,3,4- oxadiazol-2-yl ⁇ methyl)phenyl]oxy ⁇ benzonitrile
  • Step A 3-[5-( ⁇ 3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl ⁇ methyl)-1 ,3,4- oxadiazol-2-yl]- ⁇ /, ⁇ /-dimethylaniline
  • Step B 3-chloro-5- ⁇ [6-chloro-3-( ⁇ 5-[3-(dimethylamino)phenyl]-1 ,3,4-oxadiazol-2- yl ⁇ methyl)-2-fluorophenyl]oxy ⁇ benzonitrile
  • Step A 2-( ⁇ 3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl ⁇ methyl)-5- ⁇ 3- [(difluoromethyl)oxy]phenyl ⁇ -1 ,3,4-oxadiazole
  • Step B 3-chloro-5-( ⁇ 6-chloro-3-[(5- ⁇ 3-[(difluoromethyl)oxy]phenyl ⁇ -1 ,3,4-oxadiazol-2- yl)methyl]-2-fluorophenyl ⁇ oxy)benzonitrile
  • Example 24 4-chloro-5-[5-( ⁇ 4-chloro-3-[(3-chloro-5-cvanophenyl)oxy1-2- fluorophenyl ⁇ methyl)-1 ,3,4-oxadiazol-2-yl1-2-fluorobenzenesulfonamide
  • Example 25 methyl S-r ⁇ -W-chloro-S-rO-chloro- ⁇ -cvanophenvDoxyl ⁇ - fluorophenyl ⁇ methyl)-1 ,3,4-oxadiazol-2-yllbenzoate
  • Example 27 S-r ⁇ -W-chloro-S-rO-chloro- ⁇ -cvanophenvDoxyl ⁇ -fluorophenyllmethyl)- 1 ,3,4-oxadiazol-2-yllbenzoic acid
  • Example 29 S-r ⁇ -W-chloro-S-rO-chloro- ⁇ -cvanophenvDoxyl ⁇ -fluorophenyllmethyl)- 1 ,3,4-oxadiazol-2-yll- ⁇ /-(2,3-dihvdroxypropyl)benzamide
  • Step A 3-[5-( ⁇ 4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl ⁇ methyl)-1 ,3,4- oxadiazol-2-yl]- ⁇ /-[(2,2-dimethyl-1 ,3-dioxolan-4-yl)methyl]benzamide
  • Step B 3-[5-( ⁇ 4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl ⁇ methyl)-1 ,3,4- oxadiazol-2-yl]- ⁇ /-(2,3-dihydroxypropyl)benzamide
  • Example 31 S-r ⁇ -W-chloro-S-rO-chloro- ⁇ -cvanophenvDoxyl ⁇ -fluorophenyllmethyl)- 1 ,3,4-oxadiazol-2-yll- ⁇ /-r2-(4-morpholinyl)ethyllbenzamide
  • Example 33 S-f ⁇ -W-chloro-S-fO-chloro- ⁇ -cvanophenvDoxyi ⁇ -fluorophenyllmethyl)- 1 ,3,4-oxadiazol-2-yll- ⁇ /-(3-hvdroxypropyl)benzamide
  • Example 34 ⁇ -r ⁇ -( ⁇ 4-chloro-3-r(3-chloro- ⁇ -cvanophenyl)oxyl-2-fluorophenyl ⁇ methyl)- 1 ,3,4-oxadiazol-2-yll-2-methylbenzenesulfonamide
  • Example 35 4-chloro-5-[5-( ⁇ 4-chloro-3-[(3-chloro-5-cvanophenyl)oxy1-2- fluorophenyl ⁇ methyl)-1 ,3,4-oxadiazol-2-yl1-2-fluoro- ⁇ /-methylbenzenesulfonamide
  • Example 36 4-chloro-3-[5-( ⁇ 4-chloro-3-[(3-chloro-5-cvanophenyl)oxy1-2- fluorophenyl ⁇ methyl)-1 ,3,4-oxadiazol-2-yl1- ⁇ /-cvclopropylbenzenesulfonamide
  • Example 37 3-chloro-5- ⁇ r6-chloro-2-fluoro-3-( ⁇ 5-r4-( ⁇ r(4S)-2,2,5,5-tetramethyl-1.3- dioxolan-4-yl1methyl ⁇ oxy)phenyl1-1 ,3,4-oxadiazol-2-yl ⁇ methyl)phenyl1oxy ⁇ benzonitrile
  • Step A methyl 4-( ⁇ [(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl ⁇ oxy)benzoate
  • Step B 4-( ⁇ [(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl ⁇ oxy)benzohydrazide
  • Step C 3-chloro-5- ⁇ [6-chloro-2-fluoro-3-( ⁇ 5-[4-( ⁇ [(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4- yl]methyl ⁇ oxy)phenyl]-1 ,3,4-oxadiazol-2-yl ⁇ methyl)phenyl]oxy ⁇ benzonitrile
  • Example 38 3-chloro-5-r(6-chloro-3-fr5-(4-fr(2SV2.3-dihvdroxy-3-methyl butylloxy ⁇ phenyl)-1 ,3,4-oxadiazol-2-yllmethyl ⁇ -2-fluorophenyl)oxylbenzonitrile
  • Example 39 3-chloro-5-r(6-chloro-2-fluoro-3-fr5-(4-fr3-hvdroxy-2-(hvdroxymethvn propylloxy ⁇ phenyl)-1 ,3,4-oxadiazol-2-yllmethyl ⁇ phenyl)oxylbenzonitrile
  • Step A (2,2-dimethyl-1 ,3-dioxan-5-yl)methanol
  • Step C methyl 4- ⁇ [(2,2-dimethyl-1 ,3-dioxan-5-yl)methyl]oxy ⁇ benzoate
  • Step D 4- ⁇ [(2,2-dimethyl-1 ,3-dioxan-5-yl)methyl]oxy ⁇ benzohydrazide
  • Step E 3-chloro-5-[(6-chloro-3- ⁇ [5-(4- ⁇ [(2,2-dimethyl-1 ,3-dioxan-5-yl)methyl]oxy ⁇ phenyl)-1 ,3,4-oxadiazol-2-yl]methyl ⁇ -2-fluorophenyl)oxy]benzonitrile
  • Step F 3-chloro-5-[(6-chloro-2-fluoro-3- ⁇ [5-(4- ⁇ [3-hydroxy-2-(hydroxymethyl) propyl]oxy ⁇ phenyl)-1 ,3,4-oxadiazol-2-yl]methyl ⁇ phenyl)oxy]benzonitrile
  • Step A 1 ,1-dimethylethyl (2R)-2-( ⁇ [(4-methylphenyl)sulfonyl]oxy ⁇ methyl)-4- morpholinecarboxylate
  • Step B 1 ,1-dimethylethyl (2R)-2-[( ⁇ 4-[(methyloxy)carbonyl]phenyl ⁇ oxy)methyl]-4- morpholinecarboxylate
  • Step C 1 ,1-dimethylethyl (2/?)-2-( ⁇ [4-(hydrazinocarbonyl)phenyl]oxy ⁇ methyl)-4- morpholinecarboxylate
  • Step D 1 ,1-dimethylethyl (2/?)-2-[( ⁇ 4-[5-( ⁇ 4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl ⁇ methyl)-1 ,3,4-oxadiazol-2-yl]phenyl ⁇ oxy)methyl]-4-morpholinecarboxylate
  • Step E 3-chloro-5-[(6-chloro-2-fluoro-3- ⁇ [5-(4- ⁇ [(2R)-2-morpholinylmethyl] oxy ⁇ phenyl)-1 ,3,4-oxadiazol-2-yl]methyl ⁇ phenyl)oxy]benzonitrile
  • Example 41 3-chloro-5- ⁇ 6-chloro-2-fluoro-3-r(5-f4-r ⁇ (2ffl-4-r2-(methylsulfonvnethyll-2- morpholinyl ⁇ methyl)oxylphenyl ⁇ -1 ,3,4-oxadiazol-2-yl)methyllphenyl ⁇ oxy)benzonitrile
  • Example 43 methyl 4-r5-( ⁇ 4-chloro-3-r(3-chloro-5-cvanophenyl)oxyl-2- fluorophenyl ⁇ methyl)-1 ,3,4-oxadiazol-2-yllbenzoate
  • Example 44 4-r5-( ⁇ 4-chloro-3-r(3-chloro-5-cvanophenyl)oxyl-2-fluorophenyl ⁇ methvO- 1 ,3,4-oxadiazol-2-yllbenzoic acid
  • Example 45 3-chloro-5-( ⁇ 6-chloro-3-r(5- ⁇ 4-r(1 ,1-dioxido-4-thiomorpholinyl) carbonyllphenyl ⁇ -1 ,3,4-oxadiazol-2-yl)methyll-2-fluorophenyl ⁇ oxy)benzonitrile
  • Example 46 4-r5-( ⁇ 4-chloro-3-r(3-chloro-5-cvanophenyl)oxyl-2-fluorophenyl ⁇ methyl)- 1 ,3,4-oxadiazol-2-yll- ⁇ /-r2-(methylsulfonyl)ethyllbenzamide
  • Example 47 4-r5-( ⁇ 4-chloro-3-r(3-chloro-5-cvanophenyl)oxyl-2-fluorophenyl ⁇ methyl)- 1 ,3,4-oxadiazol-2-yl1- ⁇ /-[2-(4-morpholinyl)ethyl1benzamide
  • Example 48 4-r5-( ⁇ 4-chloro-3-r(3-chloro-5-cvanophenyl)oxyl-2-fluorophenyl ⁇ methyl)- 1 ,3,4-oxadiazol-2-yll- ⁇ /-(2,3-dihvdroxypropyl)benzamide
  • Step A 4-[5-( ⁇ 4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl ⁇ methyl)-1 ,3,4- oxadiazol-2-yl]- ⁇ /-[(2,2-dimethyl-1 ,3-dioxolan-4-yl)methyl]benzamide
  • Step B 4-[5-( ⁇ 4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl ⁇ methyl)-1 ,3,4- oxadiazol-2-yl]- ⁇ /-(2,3-dihydroxypropyl)benzamide.
  • Example 54 3-r(3- ⁇ r5-(2-bromophenyl)-1 ,3,4-oxadiazol-2-yllmethyl ⁇ -6-chloro-2- fluorophenyl)oxy1-5-chlorobenzonitrile
  • Example 59 / ⁇ /- ⁇ 3-r5-( ⁇ 4-chloro-3-r(3-chloro-5-cvanophenyl)oxyl-2-fluorophenyl ⁇ methyl)- 1 ,3,4-oxadiazol-2-yllphenyl ⁇ -3-(methylthio)propanamide
  • Example 60 / ⁇ /- ⁇ 3-r5-( ⁇ 4-chloro-3-r(3-chloro-5-cvanophenyl)oxyl-2-fluorophenyl ⁇ methyl)- 1 ,3,4-oxadiazol-2-yllphenyl ⁇ -3-(methylsulfonyl)propanamide
  • Example 62 2-[(3-chloro-5-cvanophenyl)oxy1-3-fluoro-4-[(5-phenyl-1 ,3,4-oxadiazol-2- vDmethylibenzonitrile
  • Example 63 3-chloro-5-fr6-chloro-2-fluoro-3- ⁇ 5-r2-methyl-4-( ⁇ r(4SV2.2.5.5-tetramethyl- 1 ,3-dioxolan-4-yllmethyl ⁇ oxy)phenyll-1 ,3,4-oxadiazol-2-yl ⁇ methyl) phenyl! oxylbenzonitrile
  • Step A methyl 4-hydroxy-2-methylbenzoate
  • Step B Methyl 2-methyl-4-( ⁇ [(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4- yl]methyl ⁇ oxy)benzoate
  • Step D 3-chloro-5- ⁇ [6-chloro-2-fluoro-3-( ⁇ 5-[2-methyl-4-( ⁇ [(4S)-2,2,5,5-tetramethyl-1 ,3- dioxolan-4-yl]methyl ⁇ oxy)phenyl]-1 ,3,4-oxadiazol-2-yl ⁇ methyl)phenyl]oxy ⁇ benzonitrile
  • Example 64 3-chloro-5-r(6-chloro-3-fr5-(4-fr(2SV2.3-dihvdroxy-3-methylbutylloxy>-2- methylphenyl)-1 ,3,4-oxadiazol-2-yllmethyl ⁇ -2-fluorophenyl)oxylbenzonitrile
  • Example 65 S-chloro- ⁇ -Re-chloro ⁇ -fluoro-S-fr ⁇ -O-fluoro ⁇ -methylDhenylVI .3.4- oxadiazol-2-yllmethyl ⁇ phenyl)oxylbenzonitrile
  • Example 68 3-chloro-5-fr6-chloro-3- ⁇ 5-r2-chloro-4- ⁇ r(4SV2.2.5.5-tetramethyl-1.3- dioxolan-4-vHmethyl ⁇ oxy)phenyl1-1 ,3,4-oxadiazol-2-yl ⁇ methyl)-2- fluorophenylioxylbenzonitrile
  • Step B methyl 2-chloro-4-( ⁇ [(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4- yl]methyl ⁇ oxy)benzoate
  • Step C 2-chloro-4-( ⁇ [(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4- yl]methyl ⁇ oxy)benzohydrazide
  • Step D 3-chloro-5- ⁇ [6-chloro-3-( ⁇ 5-[2-chloro-4-( ⁇ [(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4- yl]methyl ⁇ oxy)phenyl]-1 ,3,4-oxadiazol-2-yl ⁇ methyl)-2-fluorophenyl]oxy ⁇ benzonitrile
  • Example 70 3-chloro-5-r(6-chloro-3-fr5-(4-fr(1.1 dimethylethylVdimethvnsilyll oxy ⁇ -2-methylphenyl)-1 ,3,4-oxadiazol-2-yllmethyl ⁇ -2-fluorophenyl)oxyl benzonitrile (Intermediate)
  • Step A 4- ⁇ [(1 ,1-dimethylethyl)(dimethyl)silyl]oxy ⁇ -2-methylbenzoic acid.
  • Step B 3-chloro-5-[(6-chloro-3- ⁇ [5-(4- ⁇ [(1 , 1 -dimethylethyl)(dimethyl)silyl]oxy ⁇ -2- methylphenyl)-1 ,3,4-oxadiazol-2-yl]methyl ⁇ -2-fluorophenyl)oxy]benzonitrile
  • Step A 3-chloro-5- ⁇ [6-chloro-2-fluoro-3-( ⁇ 5-[2-methyl-4-(methyloxy)phenyl]-1 ,3,4- oxadiazol-2-yl ⁇ methyl)phenyl]oxy ⁇ benzonitrile
  • Step B 3-chloro-5-[(6-chloro-2-fluoro-3- ⁇ [5-(4-hydroxy-2-methylphenyl)-1 ,3,4-oxadiazol- 2-yl]methyl ⁇ phenyl)oxy]benzonitrile
  • Step A 1 ,1-Dimethylethyl (3R)-3-( ⁇ [(4-methylphenyl)sulfonyl]oxy ⁇ methyl)-1- piperidinecarboxylate
  • Step B 1 ,1-dimethylethyl (3R)-3-[( ⁇ 4-[5-( ⁇ 4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl ⁇ methyl)-1 ,3,4-oxadiazol-2-yl]-3-methylphenyl ⁇ oxy)methyl]-1- piperidinecarboxylate
  • Step C 3-chloro-5-[(6-chloro-2-fluoro-3- ⁇ [5-(2-methyl-4- ⁇ [(3R)-3-piperidinylmethyl] oxy ⁇ phenyl)-1 ,3,4-oxadiazol-2-yl]methyl ⁇ phenyl)oxy]benzonitrile
  • Example 75 3-chloro-5-( ⁇ 6-chloro-2-fluoro-3-r(5- ⁇ 4-r(2-hvdroxy-2-methylpropyl)oxyl-2- methylphenyl ⁇ -1 ,3,4-oxadiazol-2-yl)methyl1phenyl ⁇ oxy)benzonitrile
  • Example 76 3-chloro-5-r(6-chloro-2-fluoro-3-fr5-(4-fr(2SV2-hvdroxy-3-(4-morDholinvn propylloxy ⁇ -2-methylphenyl)-1 ,3,4-oxadiazol-2-yllmethyl ⁇ phenyl)oxylbenzonitrile
  • Example 77 3-chloro-5-r(6-chloro-3-fr5-(4-fr(2SV3-(dimethylamino)-2-hvdroxypropyll oxy ⁇ -2-methylphenyl)-1 ,3,4-oxadiazol-2-yllmethyl ⁇ -2-fluorophenyl)oxylbenzonitrile
  • Example 78 3-chloro-5-r(6-chloro-2-fluoro-3-fr5-(4-fr(2SV2-hvdroxy-3-(1-Dyrrolidinvn propylloxy ⁇ -2-methylphenyl)-1 ,3,4-oxadiazol-2-yllmethyl ⁇ phenyl)oxylbenzonitrile
  • Example 80 3-chloro-5-r(6-chloro-2-fluoro-3-fr5-(4-fr(2SV2-hvdroxy-3-(1- piperazinyl)propylloxy ⁇ -2-methylphenyl)-1 ,3,4-oxadiazol-2- yllmethyltohenvDoxylbenzonitrile
  • Step A 1 ,1-dimethylethyl 4-[(2S)-3-( ⁇ 4-[5-( ⁇ 4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl ⁇ methyl)-1 ,3,4-oxadiazol-2-yl]-3-methylphenyl ⁇ oxy)-2-hydroxypropyl]-1- piperazinecarboxylate
  • Step B 3-chloro-5-[(6-chloro-2-fluoro-3- ⁇ [5-(4- ⁇ [(2S)-2-hydroxy-3-(1 -piperazinyl) propyl]oxy ⁇ -2-methylphenyl)-1 ,3,4-oxadiazol-2-yl]methyl ⁇ phenyl)oxy]benzonitrile
  • Step A (2R)-1 -[(2-hydroxyethyl)amino]-3-[(phenylmethyl)oxy]-2-propanol
  • Step B ⁇ /-(2-hydroxyethyl)- ⁇ /- ⁇ (2R)-2-hydroxy-3-[(phenylmethyl)oxy]propyl ⁇ -4- methylbenzenesulfonamide
  • the flask previously containing the diol was rinsed with additional THF (15 ml_), and that solution was added to the reaction via syringe.
  • the reaction was warmed to rt and stirred for 1 h.
  • the reaction was cooled to 0 0 C, and 1-(p-toluenesulfonyl)imidazole (2.85 g, 12.8 mmol) was added in a single portion.
  • the reaction was warmed to rt and stirred overnight.
  • the reaction was cooled to 0 0 C and quenched by the addition of half-saturated aqueous ammonium chloride solution.
  • the mixture was poured into a separatory funnel with ethyl acetate.
  • Step D ⁇ (2R)-4-[(4-Methylphenyl)sulfonyl]-2-morpholinyl ⁇ methanol
  • Step E 1 ,1-dimethylethyl (2R)-2-(hydroxymethyl)-4-morpholinecarboxylate
  • Step F 1 ,1-dimethylethyl (2R)-2-[( ⁇ 4-[5-( ⁇ 4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl ⁇ methyl)-1 ,3,4-oxadiazol-2-yl]-3-methylphenyl ⁇ oxy)methyl]-4- morpholinecarboxylate
  • Step G 3-chloro-5-[(6-chloro-2-fluoro-3- ⁇ [5-(2-methyl-4- ⁇ [(2R)-2- morpholinylmethyl]oxy ⁇ phenyl)-1 ,3,4-oxadiazol-2-yl]methyl ⁇ phenyl)oxy]benzonitrile
  • Example 82 3-chloro-5-r(6-chloro-2-fluoro-3- ⁇ r5-(2-methyl-4- ⁇ r2-(4- morpholinyl)ethyl1oxy ⁇ phenyl)-1 ,3,4-oxadiazol-2-yl1methyl ⁇ phenyl)oxy1benzonitrile
  • Example 84 3-chloro-5-[(6-chloro-3- ⁇ [5-(4- ⁇ [3-(dimethylamino)propyl1oxy ⁇ -2- methylphenyl)-1 ,3,4-oxadiazol-2-yl1methyl ⁇ -2-fluorophenyl)oxy1benzonitrile
  • Method A A solution of 2- ⁇ 4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl ⁇ acetohydrazide (35.4 mg, 100 ⁇ mol, 1 eq) and DIPEA (52 ⁇ l_, 300 ⁇ mol, 3 eq) in dry THF (1 ml.) was added in combinatorial fashion to vials containing solid carboxylic acid (see table for stoichiometry) and HATU (38 mg, 100 ⁇ mol, 1 eq) and stirred for 16 h at 55 0 C to form the intermediate diacyl hydrazides.
  • reaction mixtures were allowed to cool to ambient temperature and then treated with a solution of methoxycarbonylsulfamoyl-triethylammonium hydroxide, inner salt (Burgess Reagent, 120 mg, 500 ⁇ mol, 5 eq) in dry THF (1 ml.) for 8 h at 55 0 C.
  • the reaction mixtures were evaporated to dryness, dissolved in DCM (1.5 ml_), washed with water, the organic phases isolated and concentrated to dryness.
  • the crude products were purified by RP- HPLC on a GeminiTM C-18, 3 x 7.5 cm, 5 micron column eluted with 10 to 100% CH 3 CN in water with 0.07% NH 4 OH buffer at 50ml_/min.
  • Method B A solution of 2- ⁇ 4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl ⁇ acetohydrazide (17.7 mg, 50 ⁇ mol, 1 eq) and DIPEA (26 ⁇ l_, 150 ⁇ mol, 3 eq) in dry THF (0.5 ml.) was added in combinatorial fashion to vials containing solid carboxylic acid (see table for stoichiometry) and HATU (19 mg, 50 ⁇ mol, 1 eq) and stirred for 16 h at 55 0 C to form the intermediate diacyl hydrazides.
  • reaction mixtures were allowed to cool to ambient temperature and then treated with a solution of methoxycarbonylsulfamoyl-triethylammonium hydroxide, inner salt (Burgess Reagent, 60 mg, 250 ⁇ mol, 5 eq) in dry THF (0.5 ml.) for 8 h at 55 0 C.
  • the reaction mixtures were evaporated to dryness, dissolved in DCM (1.5 ml_), washed with water, the organic phases isolated and concentrated to dryness.
  • the crude products were purified by RP- HPLC on a GeminiTM C-18, 3 x 7.5 cm, 5 micron column eluted with 10 to 100% CH 3 CN in water with 0.07% NH 4 OH buffer at 50mL/min.
  • Example 92 3-chloro-5-ir6-chloro-2-fluoro-3- ⁇ 5-r2-fluoro-6-(trifluoromethvnphenyll-1.3.4- oxadiazol-2-yl ⁇ methyl)phenylloxy ⁇ benzonitrile
  • Example 96 3-chloro-5-fr6-chloro-2-fluoro-3-( ⁇ 5-r2-methyl-4- ⁇ r2-(methylsulfonvn ethyllamino ⁇ methyl)phenyll-1 ,3,4-oxadiazol-2-yl ⁇ methyl)phenylloxy ⁇ benzonitrile
  • Step A 3-chloro-5- ⁇ [6-chloro-3-( ⁇ 5-[4-( ⁇ [(2,2-dimethyl-1 ,3-dioxolan-4- yl)methyl]amino ⁇ methyl)-2-methylphenyl]-1 ,3,4-oxadiazol-2-yl ⁇ methyl)-2- fluorophenyl]oxy ⁇ benzonitrile
  • Step B 3-chloro-5-[(6-chloro-3- ⁇ [5-(4- ⁇ [(2,3-dihydroxypropyl)amino]methyl ⁇ -2- methylphenyl)-1 ,3,4-oxadiazol-2-yl]methyl ⁇ -2-fluorophenyl)oxy]benzonitrile
  • Step B 3-chloro-5- ⁇ [6-chloro-2-fluoro-3-( ⁇ 5-[3-fluoro-2-methyl-4-(methyloxy)phenyl]- 1 ,3,4-oxadiazol-2-yl ⁇ methyl)phenyl]oxy ⁇ benzonitrile
  • Example 100 S-chloro- ⁇ -rfe-chloro ⁇ -fluoro-S-fr ⁇ -O-fluoro ⁇ -hvdroxy ⁇ -methylDhenvIV 1 ,3,4-oxadiazol-2-yllmethyl ⁇ phenyl)oxylbenzonitrile
  • the HeLa cell assay described herein is a modified version of Kimpton J. and Emerman M., Detection of replication-competent and pseudotyped human immunodeficiency virus with a sensitive cell line on the basis of activation of an integrated ⁇ -galactosidase gene, J. Virol. 66:2232-2239 (1992), in which HIV- 1 infection is detected by the activation of an HIV-LTR driven ⁇ -galactosidase reporter that is integrated into the genome of a CD4 + HeLa cell line. Quantitation of ⁇ -galactosidase is achieved by measuring the activation of a chemiluminescent substrate (Applied Biosystems). The concentration of each compound required to inhibit 50% (IC 50 ) of the HIV-1 induced ⁇ -galactosidase signal, relative to untreated controls, is determined for each isogenic, recombinant virus.
  • HeLa-CD4-LTR- ⁇ -gal cell line (AIDS Research and Reference Reagent Program, Division of AIDS, NIAID)
  • Hygromycin B (GibcoBRL #1687-010)
  • PBS Phosphate Buffered Saline
  • DMSO Dimethyl Sulfoxide
  • HeLa-CD4-LTR- ⁇ -gal cells are propagated in DMEM containing 10% fetal bovine serum + 0.2 mg/ml geneticin + 0.1 mg/ml hygromycin B. Cells are split by standard trypsinization when confluency reaches 80% (roughly every 2 to 3 days).
  • DNA encoding the HIV-1 reverse transcriptase is subcloned from a M13 phage into a general shuttle vector, pBCSK+, as a -1.65 kbp EcoRI/Hindlll ended DNA fragment.
  • the HIV DNA insert of the resulting plasmid is completely sequenced on both strands prior to use in site directed mutagenesis experiments. Specific amino acid replacements are made using Stratagene Quick Change reagents and mutagenic oligonucleotides. The mutations that are made include K103N, V106A, Y181 C, and Y188L. Following mutagenesis, the entire mutant RT coding sequence is verified by sequencing both DNA strands.
  • Ten million MT4 T-cells (maintained in RPMI containing 10% fetal bovine serum, split 1 :5 every 5 to 6 days) are co-transfected with EcoRI/Hindlll digested mutant RT plasmid and .Bst Ell-digested HIV-1 HXB2 ⁇ RT DNA in the presence of DMRIE-C transfection reagent (Gibco) according to supplier's recommended protocol. Each mutant RT coding sequence is crossed into the RT-deleted HIV-1 viral DNA backbone by in vivo homologous recombination. Transfected cell cultures are expanded and monitored until syncitia formation and CPE are extensive.
  • Virus is harvested by clear spin of the culture supernatants, filtration of the supernatants through a 0.45 micron membrane and frozen at - 80 0 C as primary stocks. Recombinant progeny virus is sequenced in the RT region to confirm the mutant genotype. Some virus stocks require further expansion by infection of MT4 cells, harvested as above and stored as frozen aliquots. All stocks are titered in HeLa MAGI cells for assay.
  • HIV-1 virus stocks are titered in the HeLa-CD4-LTR- ⁇ -gal assay system to establish the appropriate infecting dose.
  • the endpoint for this assay is relative light units (RLUs), and titer is recorded as RLUs/ml.
  • Virus stocks are diluted (serial 1 :2) into DMEM containing 10% FBS plus 25ug/ml DEAE-dextran and assayed as described in the "Experimental Protocol" section below without test compound.
  • a "multiplicity of infection” defined as infectious units per cell is usually not calculated but is typically «1.0. Relationship of RLUs/ml to other measures of infectivity such as HeLa PFU/ml or MT4 TCID50/ml may not be consistent from lot to lot or strain to strain and should be determined for each lot.
  • Day 2 1 . Thaw virus stock in a water bath (room temperature) and dilute into DMEM +10% FBS + 25ug/ml DEAE-dextran to an infectious dose of approximately 10 million RLU/ml. The dilution of virus will vary depending on the titer of the stock (see “Titering of virus stocks" above). 2. Remove all of the media from every well with an 8 or 12-channel manifold aspirator. Work with one plate at a time to prevent drying of the Hel_a-CD4-LTR- ⁇ -gal monolayer. Add 35ul (approximately 350,000 total RLUs) of diluted virus to each well. Incubate @ 37 0 C, 5% CO 2 for 2 hours.
  • test compounds are titrated robotically on a
  • Test compounds are titrated into DMEM + 10% FBS + 0.135% DMSO (0.1% final). The final volume of titrated compound in each well should be at least 15OuI and DMSO should be at 0.135% (0.1% final) including the no compound controls.
  • Table 1 provides data regarding activity of certain compounds of the present invention against HIV wild type (WT) and several resistant mutants, including K103N, V106A, and Y181 C. TABLE 1
  • B indicates an activity level of between 10 nM and 1 ⁇ M.
  • C indicates an activity level of greater than 1 ⁇ M.
  • Compounds of the present invention demonstrate anti-HIV activity in the range of IC 50 of about 1 nM to about 50 ⁇ M. In one aspect of the invention, compounds of the present invention have anti-HIV activity in the range of up to about 1OnM. In another aspect of the invention, compounds of the present invention have anti-HIV activity in the range of from about 1OnM to about 1 ⁇ M. In another aspect of the invention, compounds of the present invention have anti-HIV activity in the range of greater than 1 ⁇ M.
  • Test compounds were employed in free, salt or solvated form.

Abstract

The present invention relates to compounds that are a non-nucleoside reverse transcriptase inhibitors, and to processes for the preparation and use of the same. Specifically, the present invention includes methods of using such compounds in the treatment of human immunodeficiency virus infection.

Description

CHEMICAL COMPOUNDS Field of the Invention
The present invention relates to compounds that are non-nucleoside reverse transcriptase inhibitors, and the use in the treatment of viral infections, for example, human immunodeficiency virus infections.
Background of the Invention
The human immunodeficiency virus ("HIV") is the causative agent for acquired immunodeficiency syndrome ("AIDS"), a disease characterized by the destruction of the immune system, particularly of CD4+ T-cells, with attendant susceptibility to opportunistic infections, and its precursor Al DS-related complex ("ARC"), a syndrome characterized by symptoms such as persistent generalized lymphadenopathy, fever and weight loss. HIV is a retrovirus; the conversion of its RNA to DNA is accomplished through the action of the enzyme reverse transcriptase. Compounds that inhibit the function of reverse transcriptase inhibit replication of HIV in infected cells. Such compounds are useful in the prevention or treatment of HIV infection in humans.
Non-nucleoside reverse transcriptase inhibitors (NNRTIs), in addition to the nucleoside reverse transcriptase inhibitors (NRTIs), have gained a definitive place in the treatment of HIV- 1 infections. NNRTIs interact with a specific site of HIV- 1 reverse transcriptase that is closely associated with, but distinct from, the NRTI binding site. NNRTIs, however, are notorious for rapidly eliciting resistance due to mutations of the amino acids surrounding the NNRTI-binding site (E. De Clercq, Il Famaco 54, 26-45, 1999). Failure of long-term efficacy of NNRTIs is often associated with the emergence of drug-resistant virus strains (J. Balzarini, Biochemical Pharmacology, VoI 58, 1-27, 1999). Moreover, the mutations that appear in the reverse transcriptase enzyme frequently result in a decreased sensitivity to other reverse transcriptase inhibitors, which results in cross-resistance.
WO 02/070470, WO 01/17982, and US 2006/0025480A1 disclosed certain benzophenones as non-nucleoside reverse transcriptase inhibitors. As antiviral use in therapy and prevention of HIV infection continues, the emergence of new resistant strains is expected to increase. There is therefore an ongoing need for new inhibitors of reverse transcriptase, which have different patterns of effectiveness against the various mutants.
Summary of the Invention The present invention features compounds of formula (I):
Figure imgf000003_0001
wherein m is 1 , 2, 3 or 4; n is 1 , 2, 3, or 4; each R1 independently is halogen, -CN, CrC5 alkyl, C2-C5 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, hydroxyl, CrC8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -R5CN, or -N(R4)2; each R2 independently is halogen, -CN, CrC5 alkyl, C2-C5 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, hydroxyl, C1-C8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -R5CN or -N(R4)2;
A is C5-C12 aryl or C5-C12 heterocycle; R3 is -R5Ar or C4-C12 aryl, each optionally substituted with at least one C1-C8 alkyl, halogen, hydroxyl, oxo, C1-C8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -N(R4)2, -N(O)2,
-CN, -OR5Het, -OR5N(R4)2, -C(O)N(R4)Het, -C(O)Het, -C(O)N(R4)R5S(O)2R4, -
S(O)2N(R4),, -S(O)2R4, -C(O)R4; -N(R4)C(O)R5SR4, -N(R4)R5S(O)2R4, or -N(R4)S(O)2R4; each R4 is independently hydrogen, C1-C8 alkyl optionally substituted with at least one hydroxyl or halogen; or C3-C7 cycloalkyl; each R5 is independently C1-C8 alkylene, C1-C8 alkenylene, C1-C8 alkynylene, each optionally substituted with at least one hydroxyl or hydrogen;
Het is C3-C10 heterocycle and is optionally substituted with at least one C1-C6 alkyl, oxo, hydroxyl, R5S(O)2R4, or halogen; and Ar is C4-C12 aryl and is optionally substituted with at least one C1-C6 alkyl or halogen; or pharmaceutically acceptable derivatives thereof.
The present invention features a compound of formula (I) wherein m is 2. The present invention features a compound of formula I wherein n is 2.
The present invention features a compound of formula (I) wherein R3 is C4-C12 aryl optionally substituted with at least one C1-C8 alkyl, halogen, hydroxyl, oxo, C1-C8 alkoxy,
-C(O)OR4, -C(O)N(R4)2, -OR4, -N(R4)2, -N(O)2, -CN, -OR5Het, -OR5N(R4)2, -
C(O)N(R4)Het, -C(O)Het, -C(O)N(R4)R5S(O)2R4, -S(O)2N(R4),, -S(O)2R4, -C(O)R4; -
N(R4)C(O)R5SR4, -N(R4)R5S(O)2R4, or -N(R4)S(O)2R4..
The present invention features a compound of formula (I) wherein R3 is R5Ar and wherein Ar is optionally substituted with at least one C1-C8 alkyl, halogen, hydroxyl, oxo,
C1-C8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -N(R4)2, -N(O)2, -CN, -OR5Het, -OR5N(R4)2, -
C(O)N(R4)Het, -C(O)Het, -C(O)N(R4)R5S(O)2R4, -S(O)2N(R4),, -S(O)2R4, -C(O)R4; -
N(R4)C(O)R5SR4, -N(R4)R5S(O)2R4, or -N(R4)S(O)2R4. The present invention features a compound of formula (I) each R3 is phenyl, optionally substituted with at least one d-C8 alkyl, halogen, hydroxyl, oxo, d-C8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -N(R4)2, -N(O)2, -CN, -OR5Het, -OR5N(R4)2, - C(O)N(R4)Het, -C(O)Het, -C(O)N(R4)R5S(O)2R4, -S(O)2N(R4)2, -S(O)2R4, -C(O)R4; - N(R4)C(O)R5SR4, -N(R4)R5S(O)2R4, or -N(R4)S(O)2R4.
The present invention features a compound of formula (I) wherein n is 2 and each R2 is halogen. The present invention features a compound of formula I wherein m is 2 and the first R1 is halogen and the second R1 is -CN.
The present invention features a compound of formula (I) wherein m is 2, n is 2, and R3 is C4-C12 aryl optionally substituted with at least one C1-C8 alkyl, halogen, hydroxyl, oxo, C1-C8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -N(R4)2, -N(O)2, -CN, - OR5Het, -OR5N(R4)2, -C(O)N(R4)Het, -C(O)Het, -C(O)N(R4)R5S(O)2R4, -S(O)2N(R4)2, - S(O)2R4, -C(O)R4; -N(R4)C(O)R5SR4, -N(R4)R5S(O)2R4, or -N(R4)S(O)2R4.
The present invention features a compound of formula I wherein R3 is C4-C12 aryl optionally substituted with at least one halogen, OR4, -OR5Het, or -OR5N(R4)2.
The present invention also features a compound of formula (II)
Figure imgf000004_0001
wherein m is 1 , 2, 3 or 4; n is 1 , 2, 3 or 4; each R1 independently is halogen, -CN, C1-C5 alkyl, C2-C5 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, hydroxyl, C1-C8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -R5CN, or -N(R4)2; each R2 independently is halogen, -CN, C1-C5 alkyl, C2-C5 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, hydroxyl, C1-C8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -R5CN or -N(R4)2;
R3 is -R5Ar or C4-C12 aryl, each optionally substituted with at least one C1-C8 alkyl, halogen, hydroxyl, oxo, C1-C8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -N(R4)2, -N(O)2,
-CN, -OR5Het, -OR5N(R4)2, -C(O)N(R4)Het, -C(O)Het, -C(O)N(R4)R5S(O)2R4, -
S(O)2N(R4)2, -S(O)2R4, -C(O)R4; -N(R4)C(O)R5SR4, -N(R4)R5S(O)2R4, or -N(R4)S(O)2R4; each R4 is independently hydrogen, C1-C8 alkyl optionally substituted with at least one hydroxyl or halogen; or C3-C7 cycloalkyl; each R5 is independently C1-C8 alkylene, C1-C8 alkenylene, C1-C8 alkynylene, each optionally substituted with at least one hydroxyl or hydrogen;
Het is C3-C10 heterocycle and is optionally substituted with at least one C1-C6 alkyl, oxo, hydroxyl, R5S(O)2R4, or halogen; and Ar is C4-C12 aryl and is optionally substituted with at least one C1-C6 alkyl or halogen; or pharmaceutically acceptable derivatives thereof.
The present invention also features a compound of formula (II)'
Figure imgf000005_0001
wherein m is 1 , 2, 3, or 4; n is 1 , 2, 3, or 4; each R1 independently is halogen, -CN, C1-C5 alkyl, C2-C5 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, hydroxyl, C1-C8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -R5CN, or -N(R4)2; each R2 independently is halogen, -CN, C1-C5 alkyl, C2-C5 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, hydroxyl, C1-C8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -R5CN or -N(R4)2;
R3 is -R5Ar or C4-C12 aryl, each optionally substituted with at least one halogen, hydroxyl, oxo, C1-C8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -N(R4)2, -N(O)2, -CN, -OR5Het, -
OR5N(R4)2, -C(O)N(R4)Het, -C(O)Het, -C(O)N(R4)R5S(O)2R4, -S(O)2N(R4),, -S(O)2R4, - C(O)R4; -N(R4)C(O)R5SR4, -N(R4)R5S(O)2R4,-N(R4)S(O)2R4 or CrC8alkyl optionally substituted with hydroxyl; each R4 is independently hydrogen, C1-C8 alkyl optionally substituted with at least one hydroxyl or halogen; or C3-C7 cycloalkyl; each R5 is independently C1-C8 alkylene, C1-C8 alkenylene, C1-C8 alkynylene, each optionally substituted with at least one hydroxyl or hydrogen;
Het is C3-C10 heterocycle and is optionally substituted with at least one C1-C6 alkyl, oxo, hydroxyl, R5S(O)2R4, or halogen; and
Ar is C4-C12 aryl and is optionally substituted with at least one C1-C6 alkyl or halogen; or a pharmaceutically acceptable salt thereof. The present invention also features a compound of formula (II)' wherein m is 2; n is 2; each R1 independently is halogen or -CN; each R2 independently is halogen;
R3 is C4-C12 aryl, optionally substituted with at least one -OR4, -N(R4)2, -OR5Het, - OR5N(R4)2 or C1-C8 alkyl optionally substituted with hydroxyl; each R4 is independently hydrogen or C1-C8 alkyl optionally substituted with at least one hydroxyl; each R5 is independently C1-C8 alkylene optionally substituted with at least one hydroxyl;
Het is C3-C10 heterocycle and is optionally substituted with at least one C1-C6 alkyl; or a pharmaceutically acceptable salt thereof.
Compounds of the present invention include:
2-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-5-[3- (methyloxy)phenyl]-1 ,3,4-oxadiazole;
3-chloro-5-{[6-chloro-2-fluoro-3-({5-[3-(methyloxy)phenyl]-1 ,3,4-oxadiazol-2- yl}methyl)phenyl]oxy}benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(3-hydroxyphenyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile; 2-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-5-[4-
(methyloxy)phenyl]-1 ,3,4-oxadiazole;
3-chloro-5-{[6-chloro-2-fluoro-3-({5-[4-(methyloxy)phenyl]-1 ,3,4-oxadiazol-2- yl}methyl)phenyl]oxy}benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-hydroxyphenyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(3-cyanophenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2- fluorophenyl)oxy]benzonitrile;
4-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]-Λ/,Λ/-diethylbenzenesulfonamide; 3-chloro-5-[(6-chloro-3-{[5-(4-cyanophenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2- fluorophenyl)oxy]benzonitrile;
3-chloro-5-{[6-chloro-2-fluoro-3-({5-[2-fluoro-3-(methyloxy)phenyl]-1 ,3,4- oxadiazol-2-yl}methyl)phenyl]oxy}benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-fluoro-3-hydroxyphenyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-{[6-chloro-3-({5-[3-(dimethylamino)phenyl]-1 ,3,4-oxadiazol-2- yl}methyl)-2-fluorophenyl]oxy}benzonitrile;
3-chloro-5-({6-chloro-3-[(5-{3-[(difluoromethyl)oxy]phenyl}-1 ,3,4-oxadiazol-2- yl)methyl]-2-fluorophenyl}oxy)benzonitrile; 2-chloro-5-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-
1 ,3,4-oxadiazol-2-yl]benzenesulfonamide;
4-chloro-5-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)- 1 ,3,4-oxadiazol-2-yl]-2-fluorobenzenesulfonamide; methyl 3-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)- 1 ,3,4-oxadiazol-2-yl]benzoate; 3-chloro-5-[(6-chloro-3-{[5-(2,6-dimethylphenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2- fluorophenyl)oxy]benzonitrile;
3-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]benzoic acid; 3-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]benzamide;
3-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]-Λ/-(2,3-dihydroxypropyl)benzamide;
3-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]-Λ/-[2-(methylsulfonyl)ethyl]benzamide;
3-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]-Λ/-[2-(4-morpholinyl)ethyl]benzamide;
3-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]-Λ/-cyclopropylbenzamide; 3-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]-Λ/-(3-hydroxypropyl)benzamide;
5-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]-2-methylbenzenesulfonamide;
4-chloro-5-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)- 1 ,3,4-oxadiazol-2-yl]-2-fluoro-Λ/-methylbenzenesulfonamide;
4-chloro-3-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)- 1 ,3,4-oxadiazol-2-yl]-Λ/-cyclopropylbenzenesulfonamide;
3-chloro-5-{[6-chloro-2-fluoro-3-({5-[4-({[(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4- yl]methyl}oxy)phenyl]-1 ,3,4-oxadiazol-2-yl}methyl)phenyl]oxy}benzonitrile; 3-chloro-5-[(6-chloro-3-{[5-(4-{[(2S)-2,3-dihydroxy-3-methyl butyl]oxy}phenyl)-
1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-{[3-hydroxy-2-(hydroxymethyl) propyl]oxy}phenyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-{[(2R)-2-morpholinylmethyl] oxy}phenyl)- 1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-({6-chloro-2-fluoro-3-[(5-{4-[({(2R)-4-[2-(methylsulfonyl)ethyl]-2- morpholinyl}methyl)oxy]phenyl}-1 ,3,4-oxadiazol-2-yl)methyl]phenyl}oxy)benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(3-nitrophenyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile; Methyl 4-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-
1 ,3,4-oxadiazol-2-yl]benzoate; 4-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]benzoic acid;
3-chloro-5-({6-chloro-3-[(5-{4-[(1 ,1-dioxido-4-thiomorpholinyl) carbonyl]phenyl}- 1 ,3,4-oxadiazol-2-yl)methyl]-2-fluorophenyl}oxy)benzonitrile; 4-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]-Λ/-[2-(methylsulfonyl)ethyl]benzamide;
4-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]-Λ/-[2-(4-morpholinyl)ethyl]benzamide;
4-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]-Λ/-(2,3-dihydroxypropyl)benzamide;
4-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]benzamide;
3-[(3-{[5-(3-aminophenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-6-chloro-2- fluorophenyl)oxy]-5-chlorobenzonitrile; 3-chloro-5-{[6-chloro-2-fluoro-3-({5-[2-(methyloxy)phenyl]-1 ,3,4-oxadiazol-2- yl}methyl)phenyl]oxy}benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methylphenyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(2-chlorophenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2- fluorophenyl)oxy]benzonitrile;
3-[(3-{[5-(2-bromophenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-6-chloro-2- fluorophenyl)oxy]-5-chlorobenzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-fluorophenyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile; 3-chloro-5-{[6-chloro-3-({5-[2-chloro-3-(methyloxy)phenyl]-1 ,3,4-oxadiazol-2- yl}methyl)-2-fluorophenyl]oxy}benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(3-chlorophenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2- fluorophenyl)oxy]benzonitrile;
3-chloro-5-({6-chloro-2-fluoro-3-[(5-phenyl-1 ,3,4-oxadiazol-2- yl)methyl]phenyl}oxy)benzonitrile;
/\/-{3-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]phenyl}-3-(methylthio)propanamide;
/\/-{3-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]phenyl}-3-(methylsulfonyl)propanamide; 3-({6-bromo-2-fluoro-3-[(5-phenyl-1 ,3,4-oxadiazol-2-yl)methyl]phenyl}oxy)-5- chlorobenzonitrile; 2-[(3-chloro-5-cyanophenyl)oxy]-3-fluoro-4-[(5-phenyl-1 ,3,4-oxadiazol-2- yl)methyl]benzonitrile;
3-chloro-5-{[6-chloro-2-fluoro-3-({5-[2-methyl-4-({[(4S)-2,2,5,5-tetramethyl-1 ,3- dioxolan-4-yl]methyl}oxy)phenyl]-1 ,3,4-oxadiazol-2-yl}methyl) phenyl] oxy}benzonitrile; 3-chloro-5-[(6-chloro-3-{[5-(4-{[(2S)-2,3-dihydroxy-3-methylbutyl]oxy}-2- methylphenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(3-fluoro-2-methylphenyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(2-chloro-3-fluorophenyl)-1 ,3,4-oxadiazol-2-yl]methyl}- 2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-{[6-chloro-3-({5-[2-chloro-4-(methylsulfonyl)phenyl]-1 ,3,4-oxadiazol-2- yl}methyl)-2-fluorophenyl]oxy}benzonitrile;
3-chloro-5-{[6-chloro-3-({5-[2-chloro-4-({[(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4- yl]methyl}oxy)phenyl]-1 ,3,4-oxadiazol-2-yl}methyl)-2-fluorophenyl]oxy}benzonitrile; 3-chloro-5-[(6-chloro-3-{[5-(2-chloro-4-{[(2S)-2,3-dihydroxy-3- methylbutyl]oxy}phenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(4-{[(1 , 1 dimethylethyl)(dimethyl)silyl]oxy}-2- methylphenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-hydroxy-2-methylphenyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-[(3-{[5-(4-bromo-2-methylphenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-6-chloro-2- fluorophenyl)oxy]-5-chlorobenzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-4-{[(3R)-3- piperidinylmethyl]oxy}phenyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile; 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-4-{[(2S)-2- oxiranylmethyl]oxy}phenyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-({6-chloro-2-fluoro-3-[(5-{4-[(2-hydroxy-2-methylpropyl)oxy]-2- methylphenyl}-1 ,3,4-oxadiazol-2-yl)methyl]phenyl}oxy)benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-{[(2S)-2-hydroxy-3-(4-morpholinyl) propyl]oxy}-2-methylphenyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(4-{[(2S)-3-(dimethylamino)-2-hydroxypropyl]oxy}-2- methylphenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-{[(2S)-2-hydroxy-3-(1- pyrrolidinyl)propyl]oxy}-2-methylphenyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile; 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-{[(2S)-2-hydroxy-3-(4-methyl-1- piperazinyl)propyl]oxy}-2-methylphenyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-{[(2S)-2-hydroxy-3-(1- piperazinyl)propyl]oxy}-2-methylphenyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-4-{[(2R)-2- morpholinylmethyl]oxy}phenyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-4-{[2-(4- morpholinyl)ethyl]oxy}phenyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-4-{[3-(4- morpholinyl)propyl]oxy}phenyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(4-{[3-(dimethylamino)propyl]oxy}-2-methylphenyl)- 1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile; and pharmaceutically acceptable derivatives thereof.
The present invention features a compound selected from the group consisting of:
3-chloro-5-[(6-chloro-3-{[5-(4-{[(2S)-2,3-dihydroxy-3-methylbutyl]oxy}-2-methylphenyl)- 1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-4-{[(2S)-2-oxiranylmethyl]oxy}phenyl)-1 ,3,4- oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-{[(2S)-2-hydroxy-3-(4-morpholinyl) propyl]oxy}-2- methylphenyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile; 3-chloro-5-[(6-chloro-3-{[5-(4-{[(2S)-3-(dimethylamino)-2-hydroxypropyl] oxy}-2-methylphenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-{[(2S)-2-hydroxy-3-(4-methyl-1- piperazinyl)propyl]oxy}-2-methylphenyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile; 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-{[(2S)-2-hydroxy-3-(1-piperazinyl)propyl]oxy}-2- methylphenyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-4-{[(2R)-2-morpholinylmethyl]oxy}phenyl)-
1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile;
3-[(3-{[5-(5-amino-2-methylphenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-6-chloro-2- fluorophenyl)oxy]-5-chlorobenzonitrile; 3-chloro-5-{[6-chloro-3-({5-[4-(1 ,2-dihydroxyethyl)-2-methylphenyl]-1 ,3,4-oxadiazol-2- yl}methyl)-2-fluorophenyl]oxy}benzonitrile; and pharmaceutically acceptable salts thereof.
One aspect of the present invention includes the compounds substantially as hereinbefore defined with reference to any one of the Examples.
One aspect of the present invention includes a pharmaceutical composition comprising one or more compounds of the present invention and a pharmaceutically acceptable carrier.
One aspect of the present invention includes one or more compounds of the present invention for use as an active therapeutic substance.
The present invention features compounds of the present invention for use in medical therapy for example, in the treatment of HIV infections and associated conditions.
The present invention also features the use of compounds of the present invention in the manufacture of a medicament for use in the treatment of viral infections and associated conditions, for example in the treatment of HIV infections and associated conditions.
The present invention features a method for the treatment of viral infections and associated conditions, for example, HIV infections and associated conditions, comprising the administration of compounds of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
Terms are used within their accepted meanings. The following definitions are meant to clarify, but not limit, the terms defined.
As used herein the term "alkyl" alone or in combination with any other term, refers to a straight or branched chain hydrocarbon, containing from one to twelve carbon atoms, unless specified otherwise. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl, tert-butyl, sec-butyl, isopentyl, n-pentyl, n-hexyl, and the like.
As used throughout this specification, the preferred number of atoms, such as carbon atoms, will be represented by, for example, the phrase "Cx-Cy alkyl," which refers to an alkyl group, as herein defined, containing the specified number of carbon atoms. Similar terminology will apply for other preferred terms and ranges as well. As used herein the term "alkenyl" refers to a straight or branched chain aliphatic hydrocarbon containing one or more carbon-to-carbon double bonds. Examples include, but are not limited to, vinyl, allyl, and the like.
As used herein the term "alkynyl" refers to a straight or branched chain aliphatic hydrocarbon containing one or more carbon-to-carbon triple bonds, which may occur at any stable point along the chain. Examples include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like.
As used herein, the term "alkylene" refers to an optionally substituted straight or branched chain divalent hydrocarbon radical, preferably having from one to ten carbon atoms, unless specified otherwise. Examples of "alkylene" as used herein include, but are not limited to, methylene, ethylene, n-propylene, n-butylene, and the like. Preferred substituent groups include C1-C8 alkyl, hydroxyl or oxo.
As used herein, the term "alkenylene" refers to a straight or branched chain divalent hydrocarbon radical, preferably having from two to ten carbon atoms, unless specified otherwise, containing one or more carbon-to-carbon double bonds. Examples include, but are not limited to, vinylene, allylene or 2-propenylene, and the like.
As used herein, the term "alkynylene" refers to a straight or branched chain divalent hydrocarbon radical, preferably having from two to ten carbon atoms, unless otherwise specified, containing one or more carbon-to-carbon triple bonds. Examples include, but are not limited to, ethynylene and the like.
As used herein, the term "cycloalkyl" refers to an optionally substituted non- aromatic cyclic hydrocarbon ring. Unless otherwise indicated, cycloalkyl is composed of three to eight carbon atoms. Exemplary "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. As used herein, the term "cycloalkyl" includes an optionally substituted fused polycyclic hydrocarbon saturated ring and aromatic ring system, namely polycyclic hydrocarbons with less than maximum number of non-cumulative double bonds, for example where a saturated hydrocarbon ring (such as a cyclopentyl ring) is fused with an aromatic ring (herein "aryl," such as a benzene ring) to form, for example, groups such as indane. Preferred substituent groups include C1-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C8 alkoxy, hydroxyl, halogen, C1-C8 haloalkyl, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, cyano, amide, amino, and C1-C8 alkylamino.
As used herein, the term "cycloalkenyl" refers to an optionally substituted non- aromatic cyclic hydrocarbon ring containing one or more carbon-to-carbon double bonds which optionally includes an alkylene linker through which the cycloalkenyl may be attached. Exemplary "cycloalkenyl" groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl. Preferred substituent groups include CrC8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, d-C8 alkoxy, hydroxyl, halogen, d-C8 haloalkyl, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, cyano, amide, amino, and CrC8 alkylamino.. As used herein, the term "cycloalkylene" refers to a divalent, optionally substituted non-aromatic cyclic hydrocarbon ring. Exemplary "cycloalkylene" groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, and cycloheptylene. Preferred substituent groups include d-C8 alkyl, C2- C6 alkenyl, C2-C6 alkynyl, C1-C8 alkoxy, hydroxyl, halogen, C1-C8 haloalkyl, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, cyano, amide, amino, and C1-C8 alkylamino.
As used herein, the term "cycloalkenylene" refers to a divalent optionally substituted non-aromatic cyclic hydrocarbon ring containing one or more carbon-to- carbon double bonds. Exemplary "cycloalkenylene" groups include, but are not limited to, cyclopropenylene, cyclobutenylene, cyclopentenylene, cyclohexenylene, and cycloheptenylene. Preferred substituent groups include C1-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C8 alkoxy, hydroxyl, halogen, C1-C8 haloalkyl, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, cyano, amide, amino, and C1-C8 alkylamino.
As used herein, the term "heterocycle", "heterocyclic" or "heterocyclyl" refers to an optionally substituted mono- or polycyclic ring system optionally containing one or more degrees of unsaturation and also containing one or more heteroatoms. Preferred heteroatoms include N, O, and/or S, including N-oxides, sulfur oxides, and sulfur dioxides. More preferably, the heteroatom is N.
Preferably the heterocyclyl ring is three to twelve-membered, unless otherwise indicated, and is either fully saturated or has one or more degrees of unsaturation. Such rings may be optionally fused to one or more of another "heterocyclic" ring(s), cycloalkyl ring(s) or aryl ring(s). The term "heterocycle", "heterocyclic" or "heterocyclyl" includes heteroaryl. Examples of "heterocyclic" groups include, but are not limited to, tetrahydrofuran, pyran, 1 ,4-dioxane, 1 ,3-dioxane, piperidine, piperazine, pyrrolidine, morpholine, tetrahydrothiopyran, aziridine, azetidine and tetrahydrothiophene. When the heterocyclic ring has substituents, it is understood that the substituents may be attached to any atom in the ring, whether a heteroatom or a carbon atom, provided that a stable chemical structure results. Preferred substituent groups include C1-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C8 alkoxy, hydroxyl, halogen, C1-C8 haloalkyl, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, cyano, amide, amino, and C1-C8 alkylamino. As used herein, the term "aryl" refers to an optionally substituted carbocyclic aromatic moiety (such as phenyl or naphthyl) containing the specified number of carbon atoms, preferably 6-14 carbon atoms or 6-10 carbon atoms. The term aryl also refers to optionally substituted ring systems, for example anthracene, phenanthrene, or naphthalene ring systems. Examples of "aryl" groups include, but are not limited to, phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, indanyl, phenathridinyl, and the like. Unless otherwise indicated, the term aryl also includes each possible positional isomer of an aromatic hydrocarbon radical, such as 1 -naphthyl, 2-naphthyl, 5-tetrahydronaphthyl, 6-tetrahydronaphthyl, 1 phenanthridinyl, 2-phenanthridinyl, 3-phenanthridinyl, 4-phenanthridinyl, and the like. Preferred substituent groups include C1-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C8 alkoxy, hydroxyl, halogen, C1-C8 haloalkyl, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, cyano, amide, amino, and C1-C8 alkylamino.
As used herein, the term "heteroaryl" refers to an optionally substituted monocyclic five to seven membered aromatic ring unless otherwise specified, or to an optionally substituted fused bicyclic aromatic ring system comprising two of such aromatic rings. These heteroaryl rings contain one or more nitrogen, sulfur, and/or oxygen atoms, where N-oxides, sulfur oxides, and sulfur dioxides are permissible heteroatom substitutions. Preferably, the heteroatom is N.
Examples of "heteroaryl" groups used herein include, but should not be limited to, furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, benzothiophene, indole, indazole, benzimidizolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. Preferred substituent groups include C1-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C8 alkoxy, hydroxyl, halogen, C1-C8 haloalkyl, C3-C8 cycloalkyl, C3-C8 cycloalkoxy, cyano, amide, amino, and alkylamino.
As used herein the term "halogen" refers to fluorine, chlorine, bromine, or iodine. As used herein the term "haloalkyl" refers to an alkyl group, as defined herein, which is substituted with at least one halogen. Examples of branched or straight chained "haloalkyl" groups useful in the present invention include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, and t-butyl substituted independently with one or more halogens, e.g., fluoro, chloro, bromo, and iodo. The term "haloalkyl" should be interpreted to include such substituents as perfluoroalkyl groups and the like.
As used herein the term "alkoxy" refers to a group -OR', where R' is alkyl as defined. Examples of suitable alkoxy radicals include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and the like. As used herein the term "cycloalkoxy" refers to a group -OR', where R' is cycloalkyl as defined.
As used herein the term "alkoxycarbonyl" refers to groups such as:
Figure imgf000015_0001
where the R' represents an alkyl group as herein defined.
As used herein the term "aryloxycarbonyl" refers to groups such as:
Figure imgf000015_0002
where the Ay represents an aryl group as herein defined.
As used herein the term "nitro" refers to a group -NO2. As used herein the term "cyano" refers to a group -CN.
As used herein the term "azido" refers to a group -N3.
As used herein the term amino refers to a group -NR'R", where R' and R" independently represent H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl. Similarly, the term "alkylamino" includes an alkylene linker through which the amino group is attached.
As used herein the term "amide" refers to a group -C(O)NR1R", where R' and R" independently represent H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
As used herein throughout the present specification, the phrase "optionally substituted" or variations thereof denote an optional substitution, including multiple degrees of substitution, with one or more substituent group. The phrase should not be interpreted so as to be imprecise or duplicative of substitution patterns herein described or depicted specifically. Rather, those of ordinary skill in the art will appreciate that the phrase is included to provide for modifications, which are encompassed within the scope of the appended claims.
The compounds of the present invention may crystallize in more than one form, a characteristic known as polymorphism, and such polymorphic forms ("polymorphs") are within the scope of the present invention. Polymorphism generally can occur as a response to changes in temperature, pressure, or both. Polymorphism can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics known in the art such as x-ray diffraction patterns, solubility, and melting point. Though a crystalline form of compounds of the present invention are generally preferred, the invention also contemplates amorphous forms of the compounds produced by methods known in the art (e.g. spray drying, milling, freeze drying, and so forth).
Certain of the compounds described herein contain one or more chiral centers, or may otherwise be capable of existing as multiple stereoisomers. The scope of the present invention includes mixtures of stereoisomers as well as purified enantiomers or enantiomerically and/or diastereomerically enriched mixtures. Also included within the scope of the invention are the individual isomers of the compounds of the present invention, as well as any wholly or partially equilibrated mixtures thereof. The present invention also includes the individual isomers of the compounds represented by the formulas above as mixtures with isomers thereof in which one or more chiral centers are inverted.
As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of the present invention, or a salt or other pharmaceutically acceptable derivative thereof) and a solvent. Such solvents, for the purpose of the invention, should not interfere with the biological activity of the solute. Non-limiting examples of suitable solvents include, but are not limited to water, methanol, ethanol, ethyl acetate, acetone, acetonitrile, trifluoroacetic acid and acetic acid. Preferably the solvent used is a pharmaceutically acceptable solvent. Non-limiting examples of suitable pharmaceutically acceptable solvents include water, ethanol, and acetic acid. Most preferably the solvent used is water.
As used herein, the term "pharmaceutically acceptable derivative" means any pharmaceutically acceptable salt, ester, salt of an ester, ether, amides, or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing directly or indirectly a compound of this invention or an inhibitorily active metabolite or residue thereof. Particularly favored derivatives and prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a mammal, for example, by allowing an orally administered compound to be more readily absorbed into the blood, or which enhance delivery of the parent compound to a biological compartment, for example, the brain or lymphatic system, relative to the parent species.
The present invention features a compound of formula (I)
Figure imgf000016_0001
wherein m is 1 , 2, 3 or 4; n is 1 , 2 or 3, 4; each R1 independently is halogen, -CN, CrC5 alkyl, C2-C5 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, hydroxyl, CrC8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -R5CN, or -N(R4)2; each R2 independently is halogen, -CN, CrC5 alkyl, C2-C5 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, hydroxyl, CrC8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -R5CN or -N(R4)2;
A is C5-Ci2 aryl or C5-Ci2 heterocycle;
R3 is -R5Ar or C4-Ci2 aryl, each optionally substituted with at least one CrCe alkyl, halogen, hydroxyl, oxo, CrC8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -N(R4)2, -N(O)2,
-CN, -OR5Het, -OR5N(R4)2, -C(O)N(R4)Het, -C(O)Het, -C(O)N(R4)R5S(O)2R4, - S(O)2N(R4)2, -S(O)2R4, -C(O)R4; -N(R4)C(O)R5SR4, -N(R4)R5S(O)2R4, or -N(R4)S(O)2R4; each R4 is independently hydrogen, Ci-C8 alkyl optionally substituted with at least one hydroxyl or halogen; or C3-C7 cycloalkyl; each R5 is independently d-C8 alkylene, CrC8 alkenylene, CrC8 alkynylene, each optionally substituted with at least one hydroxyl or hydrogen; Het is C3-Ci0 heterocycle and is optionally substituted with at least one CrC6 alkyl, oxo, hydroxyl, R5S(O)2R4, or halogen; and
Ar is C4-Ci2 aryl and is optionally substituted with at least one CrC6 alkyl or halogen; or pharmaceutically acceptable derivatives thereof.
The present invention features a compound of formula (I) wherein R3 is C4-Ci2 aryl optionally substituted with at least one CrC8 alkyl, halogen, hydroxyl, oxo, CrC8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -N(R4)2, -N(O)2, -CN, -OR5Het, -OR5N(R4)2,
-C(O)N(R4)Het, -C(O)Het, -C(O)N(R4)R5S(O)2R4, -S(O)2N(R4),, -S(O)2R4, -C(O)R4;
-N(R4)C(O)R5SR4, -N(R4)R5S(O)2R4, or -N(R4)S(O)2R4. The present invention features a compound of formula (I) wherein R3 is R5Ar and wherein Ar is optionally substituted with at least one CrC8 alkyl, halogen, hydroxyl, oxo, CrC8 alkoxy, -C(O)OR4, -
C(O)N(R4)2, -OR4, -N(R4)2, -N(O)2, -CN, -OR5Het, -OR5N(R4)2, -C(O)N(R5)Het, -C(O)Het,
-C(O)N(R4)S(O)2R4, -S(O)2N(R4)2, -S(O)2R4, -C(O)R4; -N(R4)R5C(O)R5SR4, -
N(R4)R5S(O)2R4, or -N(R4)S(O)2R4.
The present invention features a compound of formula (I) wherein each R3 is phenyl, optionally substituted with at least one CrC8 alkyl, halogen, hydroxyl, oxo, CrC8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -N(R4)2, -N(O)2, -CN, -OR5Het, -OR5N(R4)2,
-C(O)N(R5)Het, -C(O)Het, -C(O)N(R4)R5S(O)2R4, -S(O)2N(R4)2, -S(O)2R4, -C(O)R4;
-N(R4)C(O)R5SR4, -N(R4)R5S(O)2R4, or -N(R4)S(O)2R4.
The present invention features a compound of formula (I) wherein n is 2 and each R2 is halogen. The present invention features a compound of formula (I) wherein m is 2 and each R1 is halogen. The present invention features a compound of formula (I) wherein m is 2 and the first R1 is halogen and the second R1 is -CN. The present invention features a compound of formula (I) wherein m is 2 and each R1 is in the meta position. The present invention features a compound of formula (I) wherein n is 2 and each R2 is in the ortho position relative to the ether linkage. The present invention features a compound of formula (I) wherein m is 2, n is 2, and R3 is C4-Ci2 aryl optionally substituted with at least one d-C8 alkyl, halogen, hydroxyl, oxo, CrC8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -N(R4)2, -N(O)2, -CN, -OR5Het, -OR5N(R4)2, -C(O)N(R4)Het, -C(O)Het, -C(O)N(R4)R5S(O)2R4, -S(O)2N(R4)2, -S(O)2R4, -C(O)R4; -N(R4)C(O)R5SR4, -N(R4)R5S(O)2R4, or -N(R4)S(O)2R4. The present invention features a compound of formula (I) wherein R3 is C4-C12 aryl optionally substituted with at least one halogen, OR4, -OR5Het, or -OR5N(R4)2.
The present invention features a compound of formula (I) wherein R3 is C4-C12 aryl substituted in the ortho position with at least one of C1-C8 alkyl or halogen.
The present invention also features a compound of formula (II)
Figure imgf000018_0001
wherein m is 1 , 2, 3 or 4; n is 1 , 2, 3 or 4; each R1 independently is halogen, -CN, C1-C5 alkyl, C2-C5 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, hydroxyl, C1-C8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -R5CN, or -N(R4)2; each R2 independently is halogen, -CN, C1-C5 alkyl, C2-C5 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, hydroxyl, C1-C8 alkoxy, -C(O)OR5, -C(O)N(R4)2, -OR4, -R5CN or -N(R4)2;
R3 is -R5Ar or C4-C12 aryl, each optionally substituted with at least one C1-C8 alkyl, halogen, hydroxyl, oxo, C1-C8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -N(R4)2, -N(O)2,
-CN, -OR5Het, -OR5N(R4)2, -C(O)N(R4)Het, -C(O)Het, -C(O)N(R4)R5S(O)2R4, - S(O)2N(R4)2, -S(O)2R4, -C(O)R4; -N(R4)C(O)R5SR4, -N(R4)R5S(O)2R4, or -N(R4)S(O)2R4; each R4 is independently hydrogen, C1-C8 alkyl optionally substituted with at least one hydroxyl or halogen; or C3-C7 cycloalkyl; each R5 is independently C1-C8 alkylene, C1-C8 alkenylene, C1-C8 alkynylene, each optionally substituted with at least one hydroxyl or hydrogen; Het is C3-C10 heterocycle and is optionally substituted with at least one C1-C6 alkyl, oxo, hydroxyl, R5S(O)2R4, or halogen; and
Ar is C4-C12 aryl and is optionally substituted with at least one C1-C6 alkyl or halogen; or pharmaceutically acceptable derivatives thereof. The present invention features a compound of formula (II) wherein R3 is C4-C12 aryl optionally substituted with at least one CrC8 alkyl, halogen, hydroxyl, oxo, CrC8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -N(R4)2, -N(O)2, -CN, -OR5Het, -OR5N(R4)2, -C(O)N(R4)Het, -C(O)Het, -C(O)N(R4)R5S(O)2R4, -S(O)2N(R4)2, -S(O)2R4, -C(O)R4; -N(R4)C(O)R5SR4, -N(R4)R5S(O)2R4, or -N(R4)S(O)2R4.
The present invention features a compound of formula (II) wherein R3 is R5Ar and wherein Ar is optionally substituted with at least one CrCe alkyl, halogen, hydroxyl, oxo, CrC8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -N(R4)2, -N(O)2, -CN, -OR5Het, -OR5N(R4)2, -C(O)N(R4)Het, -C(O)Het, -C(O)N(R4)R5S(O)2R4, -S(O)2N(R4),, -S(O)2R4, -C(O)R4; - N(R4)C(O)R5SR4, -N(R4)R5S(O)2R4, or -N(R4)S(O)2R4.
The present invention features a compound of formula (II) wherein each R3 is phenyl, optionally substituted with at least one C1-C8 alkyl, halogen, hydroxyl, oxo, C1-C8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -N(R4)2, -N(O)2, -CN, -OR5Het, -OR5N(R4)2, -C(O)N(R4)Het, -C(O)Het, -C(O)N(R4)R5S(O)2R4, -S(O)2N(R4),, -S(O)2R4, -C(O)R4; -N(R4)C(O)R5SR4, -N(R4)R5S(O)2R4, or -N(R4)S(O)2R4.
The present invention features a compound of formula (II) wherein R3 is C4-C12 aryl substituted in the ortho position with at least one of C1-C8 alkyl or halogen.
The present invention features a compound of formula (II) wherein n is 2 and each R2 is halogen. The present invention features a compound of formula (II) wherein m is 2 and each R1 is halogen. The present invention features a compound of formula (II) wherein m is 2 and the first R1 is halogen and the second R1 is -CN. The present invention features a compound of formula (II) wherein m is 2 and each R1 is in the meta position. The present invention features a compound of formula (I) wherein n is 2 and each R2 is in the ortho position relative to the ether linkage. The present invention features a compound of formula (II) wherein m is 2, n is 2, and R3 is C4-C12 aryl optionally substituted with at least one C1-C8 alkyl, halogen, hydroxyl, oxo, C1-C8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -N(R4)2, -N(O)2, -CN, -OR5Het, -OR5N(R4)2, -C(O)N(R4)Het, -C(O)Het, -C(O)N(R4)R5S(O)2R4, -S(O)2N(R4),, -S(O)2R4, -C(O)R4; -N(R4)C(O)R5SR4, -N(R4)R5S(O)2R4, or -N(R4)S(O)2R4. The present invention features a compound of formula (II) wherein R3 is C4-C12 aryl optionally substituted with at least one halogen, OR4, -OR5Het, or -OR5N(R4)2. The present invention also features a compound of formula (II)'
Figure imgf000019_0001
wherein m is 1 , 2, 3, or 4; n is 1 , 2, 3, or 4; each R1 independently is halogen, -CN, CrC5 alkyl, C2-C5 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, hydroxyl, CrC8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -R5CN, or -N(R4)2; each R2 independently is halogen, -CN, CrC5 alkyl, C2-C5 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, hydroxyl, CrC8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -R5CN or -N(R4)2;
R3 is -R5Ar or C4-Ci2 aryl, each optionally substituted with at least one halogen, hydroxyl, oxo, CrC8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -N(R4)2, -N(O)2, -CN, -OR5Het, -
OR5N(R4)2, -C(O)N(R4)Het, -C(O)Het, -C(O)N(R4)R5S(O)2R4, -S(O)2N(R4)2, -S(O)2R4, -
C(O)R4; -N(R4)C(O)R5SR4, -N(R4)R5S(O)2R4,-N(R4)S(O)2R4 or CrC8alkyl optionally substituted with hydroxyl; each R4 is independently hydrogen, C1-C8 alkyl optionally substituted with at least one hydroxyl or halogen; or C3-C7 cycloalkyl; each R5 is independently d-C8 alkylene, CrC8 alkenylene, CrC8 alkynylene, each optionally substituted with at least one hydroxyl or hydrogen; Het is C3-Ci0 heterocycle and is optionally substituted with at least one CrC6 alkyl, oxo, hydroxyl, R5S(O)2R4, or halogen; and
Ar is C4-Ci2 aryl and is optionally substituted with at least one CrC6 alkyl or halogen; or a pharmaceutically acceptable salt thereof.
The present invention also features a compound of formula (II)' wherein m is 2; n is 2; each R1 independently is halogen or -CN; each R2 independently is halogen;
R3 is C4-Ci2 aryl, optionally substituted with at least one -OR4, -N(R4)2, -OR5Het, -
OR5N(R4)2 orCi-C8 alkyl optionally substituted with hydroxyl; each R4 is independently hydrogen or CrC8 alkyl optionally substituted with at least one hydroxyl; each R5 is independently CrC8 alkylene optionally substituted with at least one hydroxyl;
Het is C3-Ci0 heterocycle and is optionally substituted with at least one CrC6 alkyl; or a pharmaceutically acceptable salt thereof. The present invention features a compound selected from the group consisting of:
3-chloro-5-[(6-chloro-3-{[5-(4-{[(2S)-2,3-dihydroxy-3-methylbutyl]oxy}-2-methylphenyl)-
1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-4-{[(2S)-2-oxiranylmethyl]oxy}phenyl)-1 ,3,4- oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile; 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-{[(2S)-2-hydroxy-3-(4-morpholinyl) propyl]oxy}-2- methylphenyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(4-{[(2S)-3-(dimethylamino)-2-hydroxypropyl] oxy}-2-methylphenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile; 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-{[(2S)-2-hydroxy-3-(4-methyl-1- piperazinyl)propyl]oxy}-2-methylphenyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-{[(2S)-2-hydroxy-3-(1-piperazinyl)propyl]oxy}-2- methylphenyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile; 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-4-{[(2R)-2-morpholinylmethyl]oxy}phenyl)-
1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile;
3-[(3-{[5-(5-amino-2-methylphenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-6-chloro-2- fluorophenyl)oxy]-5-chlorobenzonitrile;
3-chloro-5-{[6-chloro-3-({5-[4-(1 ,2-dihydroxyethyl)-2-methylphenyl]-1 ,3,4-oxadiazol-2- yl}methyl)-2-fluorophenyl]oxy}benzonitrile; and pharmaceutically acceptable salts thereof.
Compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. Solvated forms and unsolvated forms are encompassed within the scope of the present invention. Compounds of the present invention may exist in a mixture of forms and/or solvates or as a mixture of amorphous material and one or more forms and/or solvates. In general, all physical forms are intended to be within the scope of the present invention. Forms may be distinguished by various physical characteristics known in the art such as x-ray diffraction patterns, solubility, and melting point.
Other compounds of this invention may be prepared by one skilled in the art following the teachings of the specification coupled with knowledge in the art using reagents that are readily synthesized or commercially available.
Salts of the compounds of the present invention may be made by methods known to a person skilled in the art. For example, treatment of a compound of the present invention with an appropriate base or acid in an appropriate solvent will yield the corresponding salt.
Typically, but not absolutely, the salts of the present invention are pharmaceutically acceptable salts. Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention. Salts of the compounds of the present invention may comprise acid addition salts. Representative salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, calcium edetate, camsylate, carbonate, clavulanate, citrate, dihydrochloride, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylsulfate, monopotassium maleate, mucate, napsylate, nitrate, N-methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, potassium, salicylate, sodium, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, tosylate, triethiodide, trimethylammonium, and valerate salts. Other salts, which are not pharmaceutically acceptable, may be useful in the preparation of compounds of this invention and these should be considered to form a further aspect of the invention.
Pharmaceutically acceptable salts of the compounds according to the invention include those derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycollic, lactic, salicyclic, succinic, toluene-p- sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
Other compounds of this invention may be prepared by one skilled in the art following the teachings of the specification coupled with knowledge in the art using reagents that are readily synthesized or commercially available. Any reference to any of the above compounds also includes a reference to a pharmaceutically acceptable salt thereof.
Esters of the compounds of the present invention are independently selected from the following groups: (1 ) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n- propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted by, for example, halogen,
Figure imgf000022_0001
or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a Ci-2o alcohol or reactive derivative thereof, or by a 2,3-di (C6-24)acyl glycerol.
In such esters, unless otherwise specified, any alkyl moiety present advantageously contains from 1 to 18 carbon atoms, particularly from 1 to 6 carbon atoms, more particularly from 1 to 4 carbon atoms. Any cycloalkyl moiety present in such esters advantageously contains from 3 to 6 carbon atoms. Any aryl moiety present in such esters advantageously comprises a phenyl group.
Ethers of the compounds of the present invention include, but are not limited to methyl, ethyl, butyl and the like. As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician. The term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function.
The term "modulators" as used herein is intended to encompass antagonist, agonist, inverse agonist, partial agonist or partial antagonist, inhibitors and activators. As used herein, the term "treatment" refers to alleviating the specified condition, eliminating or reducing the symptoms of the condition, slowing or eliminating the progression of the condition and preventing or delaying the initial occurrence of the condition in a subject, or reoccurrence of the condition in a previously afflicted subject. The present invention features compounds according to the invention for use in medical therapy, for example for the treatment (including prophylaxis) of a viral infection, for example an HIV infection and associated conditions. The compounds according to the invention are especially useful for the treatment of AIDS and related clinical conditions such as AIDS related complex (ARC), progressive generalized lymphadenopathy (PGL), Kaposi's sarcoma, thromobocytopenic purpura, AIDS-related neurological conditions such as AIDS dementia complex, multiple sclerosis or tropical paraperesis, anti-HIV antibody-positive and HIV-positive conditions, including such conditions in asymptomatic patients.
The present invention further provides a method for the treatment of a clinical condition in a patient, for example, a mammal including a human which clinical condition includes those which have been discussed hereinbefore, which comprises treating said patient with a pharmaceutically effective amount of a compound according to the invention. The present invention also includes a method for the treatment (including prophylaxis) of any of the aforementioned diseases or conditions.
According to another aspect, the present invention provides a method for the treatment or prevention of the symptoms or effects of a viral infection in an infected patient, for example, a mammal including a human, which comprises administering to said patient a pharmaceutically effective amount of a compound according to the invention. According to one aspect of the invention, the viral infection is a retroviral infection, in particular an HIV infection.
The present invention further includes the use of a compound according to the invention in the manufacture of a medicament for administration to a subject for the treatment of a viral infection, in particular and HIV infection.
The compounds according to the invention may also be used in adjuvant therapy in the treatment of HIV infections or HIV-associated symptoms or effects, for example Kaposi's sarcoma. Reference herein to treatment extends to prophylaxis as well as the treatment of established conditions, disorders and infections, symptoms thereof, and associated clinical conditions. The above compounds according to the invention and their pharmaceutically acceptable derivatives may be employed in combination with other therapeutic agents for the treatment of the above infections or conditions. Combination therapies according to the present invention comprise the administration of a compound of the present invention or a pharmaceutically acceptable derivative thereof and another pharmaceutically active agent. The active ingredient(s) and pharmaceutically active agents may be administered simultaneously (i.e., concurrently) in either the same or different pharmaceutical compositions or sequentially in any order. The amounts of the active ingredient(s) and pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect.
For use in therapy, therapeutically effective amounts of a compound of the present invention, as well as salts, solvates, or other pharmaceutically acceptable derivatives thereof, may be administered as the raw chemical. Additionally, the active ingredient may be presented as a pharmaceutical composition.
Accordingly, the invention further provides pharmaceutical compositions that include effective amounts of compounds of the the present invention and salts, solvates, or other pharmaceutically acceptable derivatives thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The compounds of the present invention and salts, solvates, or other pharmaceutically acceptable derivatives thereof, are as herein described. The carrier(s), diluent(s) or excipient(s) must be acceptable, in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient of the pharmaceutical composition.
In accordance with another aspect of the invention there is also provided a process for the preparation of a pharmaceutical formulation including admixing a compound of the present invention or salts, solvates, or other pharmaceutically acceptable derivatives thereof, with one or more pharmaceutically acceptable carriers, diluents or excipients.
A therapeutically effective amount of a compound of the present invention will depend upon a number of factors. For example, the species, age, and weight of the recipient, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration are all factors to be considered. The therapeutically effective amount ultimately should be at the discretion of the attendant physician or veterinarian. Regardless, an effective amount of a compound of the present invention for the treatment of humans suffering from frailty, generally, should be in the range of 0.1 to 100 mg/kg body weight of recipient (mammal) per day. More usually the effective amount should be in the range of 0.1 to 10 mg/kg body weight per day. Thus, for a 70 kg adult mammal one example of an actual amount per day would usually be from 7 to 700 mg. This amount may be given in a single dose per day or in a number (such as two, three, four, five, or more) of sub-doses per day such that the total daily dose is the same. An effective amount of a salt, solvate, or other pharmaceutically acceptable derivative thereof, may be determined as a proportion of the effective amount of a compound of the present invention per se. Similar dosages should be appropriate for treatment of the other conditions referred to herein.
Pharmaceutical formulations may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Such a unit may contain, as a non-limiting example, 0.5 mg to 1 g of a compound of the formula (I), depending on the condition being treated, the route of administration, and the age, weight, and condition of the patient. Preferred unit dosage formulations are those containing a daily dose or sub- dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. Such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art.
Pharmaceutical formulations may be adapted for administration by any appropriate route, for example by an oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal, or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s). By way of example, and not meant to limit the invention, with regard to certain conditions and disorders for which the compounds of the present invention are believed useful certain routes will be preferable to others. Pharmaceutical formulations adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions, each with aqueous or non-aqueous liquids; edible foams or whips; or oil-in- water liquid emulsions or water-in-oil liquid emulsions. For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Generally, powders are prepared by comminuting a compound to a suitable fine size and mixing with an appropriate pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavorings, preservatives, dispersing agents, and coloring agents can also be present. Capsules are made by preparing a powder, liquid, or suspension mixture and encapsulating with gelatin or some other appropriate shell material. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol can be added to the mixture before the encapsulation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Examples of suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants useful in these dosage forms include, for example, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets. A powder mixture may be prepared by mixing a compound, suitably comminuted, with a diluent or base as described above. Optional ingredients include binders such as carboxymethylcellulose, aliginates, gelatins, or polyvinyl pyrrolidone, solution retardants such as paraffin, resorption accelerators such as a quaternary salt, and/or absorption agents such as bentonite, kaolin, or dicalcium phosphate. The powder mixture can be wet-granulated with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials, and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet-forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material, and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.
Oral fluids such as solutions, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of a compound. Syrups can be prepared, for example, by dissolving a compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated generally by dispersing a compound in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives; flavor additives such as peppermint oil, or natural sweeteners, saccharin, or other artificial sweeteners; and the like can also be added. Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.
The compounds of the present invention and salts, solvates, or other pharmaceutically acceptable derivatives thereof, can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
The compounds of the present invention and salts, solvates, or other pharmaceutically acceptable derivatives thereof may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
The compounds may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone (PVP), pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethyl-aspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug; for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels. Pharmaceutical formulations adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986), incorporated herein by reference as related to such delivery systems.
Pharmaceutical formulations adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils.
For treatments of the eye or other external tissues, for example mouth and skin, the formulations may be applied as a topical ointment or cream. When formulated in an ointment, the active ingredient may be employed with either a paraffinic or a water- miscible ointment base. Alternatively, the active ingredient may be formulated in a cream with an oil-in-water cream base or a water-in-oil base.
Pharmaceutical formulations adapted for topical administrations to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent.
Pharmaceutical formulations adapted for topical administration in the mouth include lozenges, pastilles, and mouthwashes.
Pharmaceutical formulations adapted for nasal administration, where the carrier is a solid, include a coarse powder having a particle size for example in the range 20 to 500 microns. The powder is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose. Suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or as nasal drops, include aqueous or oil solutions of the active ingredient. Pharmaceutical formulations adapted for administration by inhalation include fine particle dusts or mists, which may be generated by means of various types of metered dose pressurized aerosols, nebulizers, or insufflators.
Pharmaceutical formulations adapted for rectal administration may be presented as suppositories or as enemas. Pharmaceutical formulations adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations. Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
In addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question. For example, formulations suitable for oral administration may include flavoring or coloring agents. The present invention features compounds for use in medical therapy particularly for the treatment of viral infections such as an HIV infection. Compounds according to the invention have been shown to be active against HIV infections, although these compounds may be active against HBV infections as well.
The compounds according to the invention are particularly suited to the treatment of HIV infections and associated conditions. Compounds of the present invention are useful as inhibitors of both wild type and mutant variants of HIV reverse transcriptase. Reference herein to treatment extends to treatment of established infections, symptoms, and associated clinical conditions such as AIDS related complex (ARC), Kaposi's sarcoma, and AIDS dementia. The present invention further provides a method of treatment of HIV mutant viruses that exhibit NNRTI drug resistance by administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable derivative thereof to a mammal, in particular a human. In particular, the compounds of the present invention may be used to treat wild-type HIV-1 as well as several resistant mutants, for example, K103N, V106A, or Y181 C.
The present invention provides a method for the treatment of the symptoms or effects of a viral infection in an infected animal, for example, a mammal including a human, which comprises treating said animal with a therapeutically effective amount of a compound according to the invention. According to a particular embodiment of this aspect of the invention, the viral infection is a retroviral infection, in particular an HIV infection. A further aspect of the invention includes a method for the treatment of the symptoms or effects of an HBV infection.
The compounds of the present invention may also be used in adjuvant therapy in the treatment of HIV infections or HIV-associated symptoms or effects, for example Kaposi's sarcoma.
The compounds of the present invention and their salts, solvates, or other pharmaceutically acceptable derivatives thereof, may be employed alone or in combination with other therapeutic agents. The compound(s) of the present invention and the other pharmaceutically active agent(s) may be administered together or separately and, when administered separately, administration may occur simultaneously or sequentially, in any order. The amounts of the compound(s) of the present invention and the other pharmaceutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect. The administration in combination of a compound of the present invention and salts, solvates, or other pharmaceutically acceptable derivatives thereof with other treatment agents may be in combination by administration concomitantly in: (1 ) a unitary pharmaceutical composition including both compounds; or (2) separate pharmaceutical compositions each including one of the compounds. Alternatively, the combination may be administered separately in a sequential manner wherein one treatment agent is administered first and the other second or vice versa. Such sequential administration may be close in time or remote in time.
The present invention may be used in combination with one or more agents useful in the prevention or treatment of HIV. Examples of such agents include:
Nucleotide reverse transcriptase inhibitors such as zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavidine, adefovir, adefovir dipivoxil, fozivudine, todoxil, emtricitabine, alovudine, amdoxovir, elvucitabine, and similar agents;
Non-nucleotide reverse transcriptase inhibitors (including an agent having anti- oxidation activity such as immunocal, oltipraz, etc.) such as nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, capravirine, TMC-278, TMC-125, etravirine, and similar agents;
Protease inhibitors such as saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, atazanavir, tipranavir, palinavir, lasinavir, and similar agents;
Entry inhibitors such as enfuvirtide (T-20), T-1249, PRO-542, PRO-140, TNX- 355, BMS-806, 5-Helix and similar agents; lntegrase inhibitors such as L-870,810 and similar agents;
Budding inhibitors such as PA-344 and PA-457, and similar agents; and CXCR4 and/or CCR5 inhibitors such as vicriviroc (Sch-C), Sch-D, TAK779, maraviroc (UK 427,857), TAK449, as well as those disclosed in WO 02/74769, PCT/US03/39644, PCT/US03/39975, PCT/US03/39619, PCT/US03/39618, PCT/US03/39740, and PCT/US03/39732, and similar agents. The scope of combinations of compounds of this invention with HIV agents is not limited to those mentioned above, but includes in principle any combination with any pharmaceutical composition useful for the treatment of HIV. As noted, in such combinations the compounds of the present invention and other HIV agents may be administered separately or in conjunction. In addition, one agent may be prior to, concurrent to, or subsequent to the administration of other agent(s).
The compounds of the present invention may be used in the treatment of a variety of disorders and conditions and, as such, the compounds of the present invention may be used in combination with a variety of other suitable therapeutic agents useful in the treatment (including prophylaxis) of those disorders or conditions. The compounds may be used in combination with any other pharmaceutical composition where such combined therapy may be useful to modulate chemokine receptor activity and thereby prevent and treat inflammatory and/or immunoregulatory diseases.
It should be understood that in addition to the ingredients particularly mentioned above, the pharmaceutical compositions of this invention may include other agents conventional in the art having regard to the type of pharmaceutical composition in question, for example, those suitable for oral administration may include such further agents as sweeteners, thickeners, and flavoring agents.
The compounds of the present invention may be prepared according to the following reaction schemes and examples, or modifications thereof using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are known to those of ordinary skill in the art.
In all of the examples described below, protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of synthetic chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts (1991 ) Protecting Groups in Organic Synthesis, John Wiley & Sons, incorporated by reference with regard to protecting groups). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes as well as the reaction conditions and order of their execution shall be consistent with the preparation of compounds of the present invention. Those skilled in the art will recognize if a stereocenter exists in compounds of the present invention. Accordingly, the scope of the present invention includes all possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well. When a compound is desired as a single enantiomer, such may be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods as are known in the art. Resolution of the final product, an intermediate, or a starting material may be affected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. ENeI, S. H. Wilen, and L. N. Mander (Wiley-lnterscience, 1994), incorporated by reference with regard to stereochemistry.
EXPERIMENTAL SECTION Abbreviations:
As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Specifically, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams);
L (liters); ml. (milliliters); μl_ (microliters); psi (pounds per square inch);
M (molar); mM (millimolar);
Hz (Hertz); MHz (megahertz); mol (moles); mmol (millimoles);
RT (room temperature); h (hours); min (minutes); TLC (thin layer chromatography); mp (melting point); RP (reverse phase);
Tr (retention time); TFA (trifluoroacetic acid);
TEA (triethylamine); THF (tetrahydrofuran);
TFAA (trifluoroacetic anhydride); CD3OD (deuterated methanol);
CDCI3 (deuterated chloroform); DMSO (dimethylsulfoxide);
SiO2 (silica); atm (atmosphere);
EtOAc (ethyl acetate); CHCI3 (chloroform);
HCI (hydrochloric acid); Ac (acetyl);
DMF (N,N-dimethylformamide); Me (methyl);
Cs2CO3 (cesium carbonate); EtOH (ethanol); Et (ethyl); tBu (tert-butyl);
MeOH (methanol) p-TsOH (p-toluenesulfonic acid);
MP-TsOH (polystyrene resin bound equivalent of p-TsOH from Argonaut Technologies). HATU (1-[Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyidinium 3-oxide, hexafluorophosphate)
DIPEA (N,N-diisopropylethylamine)
Burgess Reagent (Methoxycarbonylsulfamoyl-triethylammonium hydroxide, inner salt)
PS-triphenylphosphine (polystyrene resin bound equivalent of triphenylphosphine)
Unless otherwise indicated, all temperatures are expressed in 0C (degrees
Centigrade). All reactions conducted at room temperature unless otherwise noted.
1H-NMR spectra were recorded on a Varian UnitylNOVA 400 MHz spectrometer, a Varian Mercury VX 400 MHz spectrometer, or a Varian UnitylNOVA 500 MHz spectrometer. Chemical shifts are expressed in parts per million (ppm, δ units). Coupling constants are in units of hertz (Hz). Splitting patterns describe apparent multiplicities and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), or br (broad). Mass spectra were obtained on Waters Corporation ZQ, ZMD, Quattro Micro or SQD mass spectrometers from Waters Corporation, Milford, MA using either Atmospheric Chemical Ionization (APCI) or Electrospray Ionization (ESI). Analytical thin layer chromatography was used to verify the purity of intermediate(s) which could not be isolated or which were too unstable for full characterization as well as to follow the progress of reaction(s).
The absolute configuration of compounds was assigned by Ab lnitio Vibrational Circular Dichroism (VCD) Spectroscopy. The experimental VCD spectra were acquired in CDCI3 using a Bomem Chiral RTM VCD spectrometer operating between 2000 and 800 cm"1. The Gaussian 98 Suite of computational programs was used to calculate model VCD spectrums. The stereochemical assignments were made by comparing this experimental spectrum to the VCD spectrum calculated for a model structure with (R)- or (S ^configuration. Incorporated by reference with regard to such spectroscopy are: J. R. Chesseman, MJ. Frisch, FJ. Devlin and PJ. Stephens, Chem. Phys. Lett. 252 (1996) 21 1 ; PJ. Stephens and FJ. Devlin, Chirality 12 (2000) 172; and Gaussian 98, Revision A.1 1.4, MJ. Frisch et al., Gaussian, Inc., Pittsburgh PA, 2002.
Compounds of formula (I) can be prepared according to routes depicted in Scheme 1. For example, an appropriately substituted acyl hydrazide (A) is coupled as in Route A with an appropriately substituted carboxylic acid (or acid chloride) employing a coupling reagent (for example, HATU) in solution (for example, THF) to yield intermediate (C). Intermediate (C) may be formed in an analogous manner (Route B) from an appropriately substituted carboxylic acid (B) and an appropriately substituted acyl hydrazide again employing a coupling reagent (for example, HATU) and appropriate solvent (for example, THF). In either case, the choice of coupling reagent and solvent is not restricted to those describe herein and a variety of others may be selected by those skilled in the art. Intermediate (C) may be purified and isolated by standard means to those skilled in the art (such as silica gel chromatography) but this is not necessary. Intermediate (C) may then be dehydrated with a standard dehydrating agent (for example, Burgess Reagent) to afford the cyclized oxadiazole compound of formula (I). The dehydrating agent is not restricted to Burgess Reagent and other reagents may be chosen by one skilled in the art. Scheme 1 :
Route A
Figure imgf000034_0001
Example 1 : ethyl {S-rP-bromo-δ-chlorophenvDoxyM-chloro^-fluorophenyllacetate (Intermediate)
Figure imgf000034_0002
Step A: 1-bromo-3-chloro-5-methoxybenzene
Figure imgf000035_0001
A solution of 1-bromo-3-chloro-5-fluorobenzene (50.0 g, 239 mmol) in DMF (300 ml.) was treated with sodium methoxide (15.5 g, 286 mmol) and the reaction was stirred overnight at rt. The mixture was diluted with ethyl acetate (500 ml.) and washed with water (700 ml_). The organic layer was isolated, washed with brine, dried over magnesium sulfate, filtered, and concentrated to give 51.0 g of the title compound which was used without purification. 1H NMR (DMSOd6) § 7.23 (t, 1 H), 7.13 - 7.15 (m, 1 H), 7.05 (t, 1 H), 3.77 (s, 3 H).
Step B: 3-bromo-5-chlorophenol
Figure imgf000035_0002
A solution of 1-bromo-3-chloro-5-methoxybenzene (50.0 g, 226 mmol) in dichloromethane (200 ml.) was treated with boron tribromide (226 ml_, 226 mmol, 1.0 M solution in dichloromethane) and the mixture stirred for 4 h at rt. Additional boron tribromide (678 ml_, 678 mmol, 1.0 M solution in dichloromethane) was added and the reaction stirred overnight. The mixture was quenched with water, and the organic phase separated and concentrated to dryness. The residue was dissolved in hexanes and extracted with 1.0 N sodium hydroxide. The aqueous layer was isolated, acidified with 1.0 N hydrochloric acid and extracted with ethyl acetate. The organic layer was isolated, washed with brine, dried over magnesium sulfate, filtered and concentrated to give 43 g of the title compound. 1H NMR (DMSOd6) δ 10.36 (s, 1 H), 7.01 - 7.10 (m, 1 H), 6.86 - 6.94 (m, 1 H), 6.75 - 6.84 (m, 1 H).
Step C: 2-[(3-bromo-5-chlorophenyl)oxy]-3,4-difluoro-1 -nitrobenzene
Figure imgf000035_0003
To a suspension of sodium f-butoxide in THF (600 ml.) was added 3-bromo-5- chlorophenol (34.4 g, 166 mmol) at 0 0C, and the mixture stirred at rt for 15 min. The mixture was cooled to 0 0C and 1 ,2,3-trifluoro-4-nitrobenzene (28.0 g, 158 mmol) was added dropwise. The mixture was stirred for 3 h at rt and concentrated to dryness. The residue was dissolved in ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and concentrated to give 51.4 g of the title compound. 1H NMR (DMSOd6) δ 8.07 - 8.19 (m, 1 H), 7.64 - 7.75 (m, 1 H), 7.45 - 7.51 (m, 1 H), 7.35 - 7.41 (m, 1 H), 7.30 (s, 1 H).
Step D: 1 ,1-dimethylethyl ethyl {3-[(3-bromo-5-chlorophenyl)oxy]-2-fluoro-4- nitrophenyl}propanedioate
Figure imgf000036_0001
To a suspension of sodium hydride (60% dispersion in mineral oil, 13.7 g, 343 mmol) in
THF (600 ml.) was added f-butylethylmalonate (29.9 ml_, 151 mmol) and the mixture stirred at 0 0C for 30 min. A solution of 2-[(3-bromo-5-chlorophenyl)oxy]-3,4-difluoro-1- nitrobenzene (50.0 g, 137 mmol) in THF was added at 0 0C and the mixture stirred overnight at rt. The reaction was quenched with water and most of the solvent removed. The residue was dissolved in ethyl acetate and washed consecutively with water and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 73.1 g of the title compound. 1H NMR (DMSOd6) δ 8.06 (d, 1 H), 7.59 - 7.70 (m, 1 H), 7.45 - 7.55 (m, 1 H), 7.21 (s, 1 H), 7.14 (s, 1 H), 5.24 (s, 1 H), 4.15 (q, 2 H), 1.30 - 1.38 (m, 9 H), 1.16 (t, 3 H).
Step E: ethyl {3-[(3-bromo-5-chlorophenyl)oxy]-2-fluoro-4-nitrophenyl}acetate
Figure imgf000036_0002
To a solution of 1 ,1-dimethylethyl ethyl {3-[(3-bromo-5-chlorophenyl)oxy]-2-fluoro-4- nitrophenyl}propanedioate (73.1 g, 137 mmol) in dichloromethane (500 ml.) at 0 0C was added trifluoroacetic acid (350 ml.) and the mixture stirred at 60 0C for 45 min. The reaction was cooled to 0 0C and the reaction neutralized with saturated sodium bicarbonate. The mixture was diluted with ethyl acetate, the organic phase separated and concentrated to dryness. The residue was recrystallized from hexanes to give 53 g of the title compound. 1H NMR (DMSOd6) δ 8.03 (dd, 1 H), 7.56 - 7.72 (m, 1 H), 7.50 (t,
1 H), 7.22 (t, 1 H), 7.15 (t, 1 H), 4.09 (q, 2 H), 3.93 (s, 2 H), 1.15 (t, 3 H).
Step F: ethyl {4-amino-3-[(3-bromo-5-chlorophenyl)oxy]-2-fluorophenyl}acetate
Figure imgf000037_0001
To a solution of ethyl {3-[(3-bromo-5-chlorophenyl)oxy]-2-fluoro-4-nitrophenyl}acetate (41.8 g, 96.8 mmol) in THF (600 ml.) was added a solution of sodium hydrosulfite (101 g, 581 mmol) in water (1.2 L) and the reaction stirred at rt for 1 h. The mixture was diluted with ethyl acetate and water. The organic layer was isolated, washed with brine, dried over magnesium sulfate, filtered and concentrated to dryness to give the title compound (39.0 g). 1H NMR (DMSOd6) δ 7.27 - 7.45 (m, 1 H), 6.97 - 7.02 (m, 1 H), 6.85 - 6.97 (m,
2 H), 6.60 (d, 1 H), 5.67 - 6.23 (m, 2 H), 4.02 (q, 2 H), 3.54 (s, 2 H), 1.13 (t, 3 H).
Step G: ethyl {3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}acetate
Figure imgf000037_0002
To a solution of f-butylnitrite (3.40 ml_, 28.5 mmol), and copper(ll)chloride (3.10 g, 22.8 mmol) in acetonitrile (100 ml.) at 50 0C was added ethyl {4-amino-3-[(3-bromo-5- chlorophenyl)oxy]-2-fluorophenyl}acetate (4.57 g, 1 1.7 mmol) and the reaction stirred for 15 min at 50 0C. The mixture was cooled to 0 0C, diluted with ethyl acetate, washed with 5% HCI and brine, and concentrated to dryness. The crude material was adsorbed onto silica gel and purified via silica gel chromatography to give 2.54 g of the title compound. 1H NMR (DMSOd6) δ 7.45 - 7.50 (m, 2 H), 7.38 (t, 1 H), 7.08 (t, 1 H), 7.01 (t, 1 H), 4.08 (q, 2 H), 3.81 (s, 2 H), 1.15 (t, 3 H).
Example 2: 2-{3-r(3-bromo-5-chlorophenyl)oxyl-4-chloro-2-fluorophenyl}acetohvdrazide (Intermediate)
Figure imgf000038_0001
Ethanol (10 ml_), ethyl {3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}acetate (1.10 g, 2.61 mmol) and hydrazine (0.33 ml_, 10.4 mmol) were combined and stirred at reflux for 8 h. The reaction was cooled to rt and the precipitate was filtered off to give 1.01 g of the title compound. 1H NMR (DMSOd6) δ 9.14 - 9.30 (m, 1 H), 7.48 (t, 1 H), 7.45 (dd, 1 H), 7.33 (t, 1 H), 7.1 1 (t, 1 H), 7.04 (t, 1 H), 4.10 - 4.36 (m, 2 H), 3.48 (s, 2 H).
Example 3: ethyl {4-amino-3-[(3-chloro-5-cvanophenyl)oxy1-2-fluorophenyl}acetate (Intermediate)
Figure imgf000038_0002
Step A: 3-chloro-5-(methyloxy)benzonitrile
Figure imgf000038_0003
3,5-Dichlorobenzonitrile (52.93 g, 307.7 mmol) was dissolved in anhydrous DMF (300 ml.) and cooled to 0 0C in an ice bath. Sodium methoxide (18.28 g, 338.5 mmol) was added as a solid and the mixture stirred from 0 0C to RT overnight. The reaction mixture was poured onto a slurry of 10% HCI and ice. The resultant solid was filtered off, washed with water, and dried overnight. This material was dissolved in a mixture of EtOAc and DCM, filtered to remove insoluble material, washed with water, dried over magnesium sulfate, filtered and concentrated to afford the title compound (46.48 g, 90%). 1H NMR (400 MHz, CDCI3) δ ppm 7.20 (t, 1 H), 7.10 (t, 1 H), 7.03 (dd, 1 H), 3.82 (s, 3 H).
Step B: 3-chloro-5-hydroxybenzonitrile
Figure imgf000039_0001
3-Chloro-5-methoxybenzonitrile (46.48 g, 277.4 mmol) and anhydrous lithium iodide (60.77 g, 454.4 mmol) were suspended in anhydrous 2,4,6-collidine (200 ml.) and heated at 185 0C for 8 h under dry nitrogen. Upon cooling to rt, the reaction mixture solidified. The solid was broken up and poured onto a slurry of 10% HCI and ice with additional concentrated HCI added to acidify the mixture. This mixture was extracted with EtOAc (3 x 200 ml_), the organic phases combined, dried over magnesium sulfate, filtered and concentrated to dryness. The resultant solid was triturated in a mixture of hexanes and EtOAc and filtered to afford an off-white solid. A second crop of product was obtained from the filtrate. The two portions were combined and dried under vacuum to afford the title compound (32.40 g, 76%). 1H NMR (400 MHz, DMSO-c/6) δ ppm 10.69 (s, 1 H), 7.37 (t, 1 H), 7.09 - 7.13 (m, 2 H). LCMS m/z = 152.1 (M+H).
Step B (alternate procedure): 3-chloro-5-hydroxybenzonitrile
Figure imgf000039_0002
To a stirred solution of lithium chloride (84 g) in DMF (500 ml.) was added 3-chloro-5- methoxybenzonitrile (167 g) and the resultant mixture heated at 180 0C for 12 h. The reaction was poured onto 300 g of ice and the residue partitioned between EtOAc and water. The organic layer was dried over magnesium sulfate, filtered, and evaporated to dryness. The residue was recrystallized from EtOAc and petroleum ether (1 :5) to afford the title compound (130 g, 67%).
Step C: 3-chloro-5-[(2,3-difluoro-6-nitrophenyl)oxy]benzonitrile
Figure imgf000039_0003
3-Chloro-5-hydroxybenzonitrile (20.00 g, 130.2 mmol) was dissolved in anhydrous THF (500 ml.) and cooled to 0 0C. Sodium hydride (60% dispersion in mineral oil, 4.81 g, 143.2 mmol) was added and stirred for 30 min. 2,3,4-trifluoronitobenzene (23.06 g, 130.2 mmol) was added and the reaction was allowed to come to rt. Stirring was continued until TLC showed completion. The reaction mixture was poured onto a slurry of 10% HCI and ice, extracted with EtOAc, dried over magnesium sulfate, filtered and concentrated to dryness. The resultant oil was triturated with hexanes and diethyl ether to afford a solid which was filtered off. The filtrate was evaporated and triturated in hexanes to give a second crop of solid. The two crops were combined to give the title compound (30 g). 1H NMR (400 MHz, CDCI3) δ ppm 7.98 (ddd, 1 H), 7.43 (t, 1 H), 7.34 (ddd, 1 H), 7.21 (t, 1 H), 7.08 (dd, 1 H).
Step D: 1 ,1-dimethylethyl ethyl {3-[(3-chloro-5-cyanophenyl)oxy]-2-fluoro-4-nitrophenyl} propanedioate
Figure imgf000040_0001
To a suspension of sodium hydride (60% dispersion in mineral oil, 3.87 g, 96.7 mmol) in THF (300 ml.) was added f-butylethylmalonate (12.7 g, 67.7 mmol) and the mixture was stirred at 0 0C for 30 min. A solution of 3-chloro-5-[(2,3-difluoro-6- nitrophenyl)oxy]benzonitrile (20.0 g, 64.5 mmol) was added at 0 0C and the mixture was allowed to warm to rt. After 3 h, additional sodium hydride (60% dispersion in mineral oil, 2.58 g, 64.5 mmol) was added and the reaction was stirred for 1 h. The reaction mixture was quenched with water and concentrated to small volume. The residue was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and concentrated to dryness to give the title compound (31.4 g). 1H NMR (DMSO- d6) δ 8.1 1 (d, 1 H), 7.83 (s, 1 H), 7.65 (m, 1 H), 7.58 (s, 1 H), 7.56 (m, 1 H), 5.25 (s, 1 H), 4.16 (q, 2 H), 1.36 (s, 9 H), 1.17 (t, 3 H).
Step E: ethyl {3-[(3-chloro-5-cyanophenyl)oxy]-2-fluoro-4-nitrophenyl}acetate
Figure imgf000040_0002
To a solution of 1 ,1-dimethylethyl ethyl {3-[(3-chloro-5-cyanophenyl)oxy]-2-fluoro-4- nitrophenyl}propanedioate (31.2 g, 65.3 mmol) in dichloromethane (300 ml.) at 0 0C was added trifluoroacetic acid (150 ml.) and the mixture stirred at 60 0C for 45 min. The reaction was cooled to 0 0C and neutralized with saturated sodium bicarbonate. The mixture was diluted with ethyl acetate and the organics separated. The solvent was removed to give 26.2 g of the title compound. 1H NMR (DMSO-c/6) δ 8.03 (dd, 1 H), 7.79 (t, 1 H), 7.46 - 7.65 (m, 3 H), 4.06 (q, 2 H), 3.91 (s, 2 H), 1.12 (t, 3 H).
Step F: ethyl {4-amino-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetate
Figure imgf000041_0001
To a solution of ethyl {S-^S-chloro-δ-cyanopheny^oxyl^-fluoro^-nitrophenylJacetate
(26.2 g, 69.3 mmol) in THF (200 ml.) was added a solution of sodium hydrosulfite (72.3 g, 415 mmol) in water (400 ml.) and the reaction was stirred at rt for 1 h. The mixture was diluted with ethyl acetate and water. The organic layer was isolated, washed with brine, dried over magnesium sulfate, filtered and concentrated to dryness to give the title compound (14.4 g). 1H NMR (DMSOd6) δ 7.72 (t, 1 H), 7.26 - 7.32 (m, 1 H), 7.19 (t, 1 H), 6.94 (t, 1 H), 6.57 (dd, 1 H), 5.42 (s, 2 H), 4.04 (q, 2 H), 3.55 (s, 2 H), 1.13 (t, 3 H).
Example 4: ethyl {4-chloro-3-r(3-chloro-5-cvanophenyl)oxyl-2-fluorophenyl}acetate (Intermediate)
Figure imgf000041_0002
To a solution of f-butylnitrite (12.3 ml_, 103 mmol), and copper(ll)chloride (11.2 g, 82.6 mmol) in acetonitrile (100 ml.) at 50 0C was added ethyl {4-amino-3-[(3-chloro-5- cyanophenyl)oxy]-2-fluorophenyl}acetate (14.4 g, 41.3 mmol) and the reaction was stirred for 15 min at 50 0C. The mixture was cooled to 0 0C, diluted with ethyl acetate, and washed consecutively with 5% hydrochloric acid and brine. The crude material was adsorbed onto silica gel and purified via silica gel chromatography to give 9.38 g of the title compound. 1H NMR (DMSOd6) § 7.80 (t, 1 H), 7.49 (dd, 1 H), 7.44 - 7.46 (m, 1 H), 7.38 - 7.42 (m, 2 H), 4.08 (q, 2 H), 3.81 (s, 2 H), 1.15 (t, 3 H). Example 4 (alternate procedure): ethyl M-chloro-S-rO-chloro-δ-cvanophenvDoxyl^- fluorophenyl}acetate
Figure imgf000042_0001
DMF (10 ml_), ethyl {3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}acetate (1.77 g, 4.19 mmol), zinc cyanide (245 mg, 2.10 mmol) and tetrakis(triphenylphosphine) palladium(O) (1.21 g, 1.05 mmol) were combined and stirred in an Emry Personal Chemistry microwave reactor at 135 0C for 10 min. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 1.05 g of the title compound.
Example 5: 2-{4-chloro-3-[(3-chloro-5-cvanophenyl)oxy1-2-fluorophenyl}acetohydrazide (Intermediate)
Figure imgf000042_0002
Ethanol (20 ml_), ethyl {4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetate (3.00 g, 8.15 mmol) and hydrazine (1.02 ml_, 32.6 mmol) were combined and stirred at reflux for two h. The reaction was concentrated to dryness and the crude material purified via silica gel chromatography (Solvent A: 50% THF in dichloromethane; Solvent B: 5% methanol in dichloromethane; 5 to 40% gradient) to give 2.5 g of the title compound. 1H NMR (DMSOd6) § 9.17 (s, 1 H), 7.65 - 7.86 (m, 1 H), 7.37 - 7.49 (m, 3 H), 7.31 (t, 1 H), 4.20 (s, 2 H), 3.45 (s, 2 H).
Example 6: {4-chloro-3-r(3-chloro-5-cvanophenyl)oxyl-2-fluorophenyl}acetic acid (Intermediate)
Figure imgf000042_0003
THF (5 ml_), ethyl {4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl} acetate (450 mg, 1.22 mmol) and lithium hydroxide (3.67 ml_, 3.67 mmol, 1.0 M solution in water) were combined and stirred overnight at rt. The reaction was quenched with citric acid buffer to achieve pH 4. The mixture was extracted with ethyl acetate and the solvent removed to give 410 mg of the title compound. 1H NMR (DMSO-c/6) δ 7.79 (t, 1 H), 7.43 - 7.49 (m, 2 H), 7.33 - 7.42 (m, 2 H), 3.70 (s, 2 H).
Example 7: ethyl {4-bromo-3-[(3-chloro-5-cvanophenyl)oxy1-2-fluorophenyl}acetate (Intermediate)
Figure imgf000043_0001
To a solution of f-butylnitrite (2.55 ml_, 21.5 mmol) and copper(l)bromide (2.46 g, 17.2 mmol) in acetonitrile (100 ml.) at 50 0C was added ethyl {4-amino-3-[(3-chloro-5-cyano phenyl)oxy]-2-fluorophenyl}acetate (3.00 g, 8.62 mmol) and the reaction was stirred for 15 min at 50 0C. The mixture was cooled to 0 0C, diluted with ethyl acetate, and washed with 5% HCI and then brine. The organic layer was adsorbed onto silica gel and the crude material was purified via silica gel chromatography to give 1.73 g of the title compound. 1H NMR (DMSOd6) § 7.80 (t, 1 H), 7.61 (dd, 1 H), 7.42 - 7.47 (m, 1 H), 7.37 (t, 1 H), 7.33 (t, 1 H), 4.08 (q, 2 H), 3.80 (s, 2 H), 1.15 (t, 3 H).
Example 8: 2-{4-bromo-3-r(3-chloro-5-cvanophenyl)oxyl-2-fluorophenyl}acetohvdrazide (Intermediate)
Figure imgf000043_0002
Ethanol (20 ml_), ethyl {4-bromo-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetate (1.57 g, 3.81 mmol) and hydrazine (0.480 ml_, 15.2 mmol) were combined and the mixture was stirred at reflux for two h. The reaction was cooled and the solvent was removed to give 1.51 g of the title compound. 1H NMR (DMSO-c/6) δ 9.17 (s, 1 H), 7.72 - 7.97 (m, 1 H), 7.51 - 7.59 (m, 1 H), 7.41 - 7.48 (m, 1 H), 7.36 - 7.42 (m, 1 H), 7.25 (t, 1 H), 4.20 (s, 2 H), 3.39 - 3.62 (m, 2 H). Example 9: r(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yllmethyl 4-methylbenzenesulfonate (Intermediate)
Figure imgf000044_0001
Step A: 2-[(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]-2-propanol
Figure imgf000044_0002
To a solution of methyl (4S)-2,2-dimethyl-1 ,3-dioxolane-4-carboxylate (65.52 g, 409 mmol, 1 eq) in diethyl ether (2 L) was added methylmagnesium bromide (300 ml_, 900 mmol, 2.2 eq, 3 M in diethyl ether) dropwise with stirring and cooling in an ice bath. The reaction mixture was stirred for 2 h at ice bath temperature at which time TLC indicated complete consumption of the starting material. The reaction mixture was quenched by dropwise addition of a minimal amount of water, stirred vigorously for 10 min, and filtered through Celite™. The filter cake was washed with diethyl ether and the combined filtrates were dried over magnesium sulfate, filtered and concentrated to dryness. The product was purified by vacuum distillation (63 - 72 0C, 1 - 3 mm Hg) to give the title compound as a clear oil (49.9 g, 311 mmol, 76%). 1 H NMR (300 MHz, DMSO- cfe) δ ppm 4.37 (s, 1 H), 3.80 - 3.89 (m, 2 H), 3.72 - 3.76 (m, 1 H), 1.31 (s, 3 H), 1.24 (s, 3 H), 1.04 (s, 3 H), 1.02 (s, 3 H).
Step B: (2S)-3-methyl-1 ,2,3-butanetriol
OH HO^ J^ ^OH
2-[(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]-2-propanol (13.67 g, 85.3 mmol, 1 eq) was treated with pyridinium p-toluenesulfonate (2.14 g, 8.5 mmol, 0.1 eq) in water (113 mL) and methanol (28 mL) and refluxed for 5 h. The reaction mixture was cooled to ambient temperature and stirred overnight. The reaction mixture was concentrated to dryness and chased with ethanol (3x) and toluene (3x) to azeotrope off residual water. The residue was purified by flash chromatography on a 80 g silica gel cartridge eluted with EtOAc to give the title compound (10.50 g, 85.3 mmol, quantitative). 1 H NMR (300 MHz, DMSOd6) δ ppm 4.47 (d, 1 H), 4.33 (dd, 1 H), 4.17 (s, 1 H), 3.52 - 3.62 (m, 1 H), 3.16 - 3.33 (m, 2 H), 1.05 (s, 3 H), 1.00 (s, 3 H).
Step C: (2S)-2,3-dihydroxy-3-methylbutyl 4-methylbenzenesulfonate
Figure imgf000045_0001
(2S)-3-methyl-1 ,2,3-butanetriol (85.3 mmol, 1 eq) was treated with 4- methylbenzenesulfonyl chloride (16.3 g, 85.3 mmol, 1 eq) in dry pyridine (66 ml.) at ice bath temperature until complete solution was obtained. The reaction mixture was then sealed under nitrogen and aged in a freezer (-20 0C) for 3 days. The reaction mixture was warmed to ambient temperature and treated with 1 N HCI (500 ml.) with stirring. The reaction mixture was cooled in an ice bath and the precipitate filtered off, washed with cold 1 N HCI (500 ml.) and air dried to give the title compound (17.04 g, 62.1 mmol, 73%) as a white solid. The filtrate was extracted with EtOAc, washed with 1 N HCI (3x) and saturated sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated to dryness. The residue was recrystallized from toluene to give a second batch of the title compound (2.23 g, 8.1 mmol, 10%) as a light purple solid. 1 H NMR (300 MHz, DMSOd6) δ ppm 7.78 (d, 2 H), 7.48 (d, 2 H), 5.25 (m, 1 H), 4.45 (br s, 1 H), 4.24 (dd, 1 H), 3.77 (dd, 1 H), 3.36 (d, 1 H), 2.42 (s, 3 H), 1.04 (s, 3 H), 0.92 (s, 3 H).
Step D: [(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl 4-methylbenzenesulfonate
Figure imgf000045_0002
To a solution of (2S)-2,3-Dihydroxy-3-methylbutyl 4-methylbenzenesulfonate (2.0 g, 7.3 mmol) in THF, were added 2,2-bis(methyloxy)propane (1.1 ml_, 8.7 mmol) and toluenesulfonic acid (42 mg, 0.22 mmol). After stirring overnight at rt, more 2,2- bis(methyloxy)propane (1.1 ml_, 8.7 mmol) was added and the reaction was stirred overnight. The reaction was neutralized with triethylamine (1 ml_), the solvent was removed and the crude material was purified via silica gel chromatography to give 1.78 g of the title compound. 1H NMR (DMSOd6) δ 7.78 (d, 2 H), 7.45 (d, 2 H), 4.13 - 4.29 (m, 1 H), 3.90 - 4.06 (m, 1 H), 3.75 - 3.88 (m, 1 H), 2.37 (s, 3 H), 1.22 (s, 3 H), 1.15 (s, 3 H), 1.13 (s, 3 H), 0.91 (s, 3 H). Example 10: 2-({3-r(3-bromo-5-chlorophenyl)oxyl-4-chloro-2-fluorophenyl}methyl)-5-r3- (methyloxy)phenyll-1 ,3,4-oxadiazole
Figure imgf000046_0001
Step A: /^-^-[(S-bromo-δ-chlorophenyOoxyl^-chloro^-fluorophenylJacetyO-S- (methyloxy)benzohydrazide
Figure imgf000046_0002
DMF (5 ml_), 2-{3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}acetohydrazide (311 mg, 0.762 mmol), m-anisic acid (126 mg, 0.838 mmol), HATU (347 mg, 0.914 mmol) and DIPEA (0.300 ml_, 1.52 mmol) were combined and the mixture was stirred at rt. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed to give 250 mg of the title compound. 1H NMR (DMSO-c/6) δ 10.36 (s, 1 H), 10.17 (s, 1 H), 7.26 - 7.55 (m, 6 H), 7.04 - 7.17 (m, 2 H), 7.01 (d, 1 H), 3.75 (s, 3 H), 3.66 (s, 2 H).
Step B: 2-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-5-[3- (methyloxy)phenyl]-1 ,3,4-oxadiazole
Figure imgf000046_0003
THF (5 ml_), /^-^-[(S-bromo-δ-chlorophenyOoxyl^-chloro^-fluorophenylJacetyO-S- (methyloxy)benzohydrazide (250 mg, 0.461 mmol) and Burgess Reagent (439 mg, 1.85 mmol) were combined and the reaction mixture was stirred overnight at rt. The mixture was adsorbed onto silica gel and the crude material was purified via silica gel chromatography to give 220 mg of the title compound. 1H NMR (DMSO-c/6) δ 7.45-7.54 (m, 5 H), 7.41 (m, 1 H), 7.15-7.18 (m, 1 H), 7.14 (m, 1 H), 7.06 (m, 1 H), 4.46 (s, 2 H), 3.80 (s, 3 H). Example 1 1 : S-chloro-δ-irδ-chloro^-fluoro-S-^δ-β-fmethyloxylphenyll-I .S^-oxadiazol- 2-yl}methyl)phenylloxy}benzonitrile
Figure imgf000047_0001
DMF (3.0 mL), 2-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl} methyl)-5- [3-(methyloxy)phenyl]-1 ,3,4-oxadiazole (200 mg, 0.382 mmol), zinc cyanide (35.7 mg, 0.302 mmol) and tetrakis(triphenylphosphine) palladium(O) (66.2 mg, 0.0573 mmol) were combined and the reaction mixture was stirred in an Emry Personal Chemistry microwave reactor at 130 0C for 10 min. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 54 mg of the title compound. 1H NMR (DMSOd6) δ 7.81 (m, 1 H), 7.47-7.56 (m, 6 H), 7.43 (m, 1 H), 7.17-7.20 (m, 1 H), 4.47 (s, 2 H), 3.82 (s, 3 H).
Example 12: 3-chloro-5-r(6-chloro-2-fluoro-3-{r5-(3-hvdroxyphenyl)-1 ,3,4-oxadiazol-2- yllmethyltohenvDoxylbenzonitrile
Figure imgf000047_0002
Dichloromethane (5 mL), 3-chloro-5-{[6-chloro-2-fluoro-3-({5-[3-(methyloxy) phenyl]- 1 ,3,4-oxadiazol-2-yl}methyl)phenyl]oxy}benzonitrile (154 mg, 0.328 mmol) and boron tribromide (1.6 mL, 1.63 mmol, 1 M solution in dichloromethane) were combined and the reaction mixture was stirred overnight at rt. The reaction was quenched with cold water followed by saturated sodium bicarbonate. The organic layer was separated and adsorbed onto silica gel. The crude material was purified via silica gel chromatography to give 130 mg of the title compound. 1H NMR (DMSOd6) δ 9.91 (s, 1 H), 7.77 (s, 1 H), 7.44-7.52 (m, 4 H), 7.29-7.34 (m, 3 H), 6.95 (m, 1 H), 4.43 (s, 2 H).
Example 13 : 2-({3-r(3-bromo-5-chlorophenyl)oxyl-4-chloro-2-fluorophenyl}methyl)-5-r4- (methyloxy)phenyll-1 ,3,4-oxadiazole
Figure imgf000048_0001
Step A : /^-^-[(S-bromo-δ-chlorophenyOoxyl^-chloro^-fluorophenylJacetyl)-^ (methyloxy)benzohydrazide
Figure imgf000048_0002
DMF (5 ml_), 2-{3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}acetohydrazide (210 mg, 0.515 mmol), p-anisic acid (86.0 mg, 0.566 mmol), HATU (234 mg, 0.618 mmol) and DIPEA (0.180 ml_, 1.03 mmol) were combined and the reaction mixture was stirred at rt. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed to give 254 mg of the title compound. 1H NMR (DMSO- d6) δ 10.25 (s, 1 H), 10.13 (s, 1 H), 7.83 (d, 2 H), 7.36 - 7.58 (m, 3 H), 7.08 - 7.14 (m, 1 H), 6.90 - 7.07 (m, 3 H), 3.78 (s, 3 H), 3.66 (s, 2 H).
Step B: 2-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-5-[4- (methyloxy)phenyl]-1 ,3,4-oxadiazole
Figure imgf000048_0003
THF (5 ml_), /^-^-[(S-bromo-δ-chlorophenyOoxyl^-chloro^-fluorophenylJacetyl)^- (methyloxy)benzohydrazide (254 mg, 0.468 mmol) and Burgess Reagent (446 mg, 1.87 mmol) were combined and the reaction mixture was stirred overnight at rt. The mixture was adsorbed onto silica gel and the crude material was purified via silica gel chromatography to give 182 mg of the title compound. 1H NMR (DMSO-c/6) δ 7.84-7.86 (m, 2 H), 7.47-7.53 (m, 3 H), 7.06-7.13 (m, 4 H), 4.43 (s, 2 H), 3.81 (s, 3 H).
Example 14: 3-chloro-5-{r6-chloro-2-fluoro-3-({5-r4-(methyloxy)phenyll-1 ,3,4-oxadiazol- 2-yl}methyl)phenylloxy}benzonitrile
Figure imgf000049_0001
DMF (3.0 ml_), 2-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-5-[4- (methyloxy)phenyl]-1 ,3,4-oxadiazole (182 mg, 0.347 mmol), zinc cyanide (37.0 mg, 0.313 mmol) and tetrakis(triphenylphosphine) palladium(O) (66.0 mg, 0.0520 mmol) were combined and the reaction mixture was stirred in an Emry Personal Chemistry microwave reactor at 135 0C for 10 min. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 132 mg of the title compound. 1H NMR (DMSOd6) δ 7.78-7.85 (m, 3 H), 7.45-7.52 (m, 4 H), 7.06-7.09 (m, 2 H), 4.41 (s, 2 H), 3.80 (s, 3 H).
Example 15: 3-chloro-5-r(6-chloro-2-fluoro-3-{r5-(4-hvdroxyphenyl)-1 ,3,4-oxadiazol-2- yllmethyltohenvDoxylbenzonitrile
Figure imgf000049_0002
Dichloromethane (5 ml_), 3-chloro-5-{[6-chloro-2-fluoro-3-({5-[4-(methyloxy)phenyl]-1 ,3,4- oxadiazol-2-yl}methyl)phenyl]oxy}benzonitrile (132 mg, 0.281 mmol) and boron tribromide (1.40 ml_, 1.40 mmol, 1 M solution in dichloromethane) were combined and the reaction mixture was stirred overnight at rt. The reaction was quenched with cold water, followed by saturated sodium bicarbonate. The organic layer was separated and adsorbed onto silica gel. The crude material was purified via silica gel chromatography to give 94 mg of the title compound. 1H NMR (DMSOd6) δ 10.23 (s, 1 H), 7.71-7.77 (m, 3 H), 7.44-7.51 (m, 4 H), 6.88 (d, 2 H), 4.39 (s, 2 H).
Example 16: 3-chloro-5-[(6-chloro-3-{[5-(3-cvanophenyl)-1 ,3,4-oxadiazol-2-yl1methyl}-2- fluorophenyl )oxy1benzonitrile
Figure imgf000050_0001
Step A: /^-^-[(S-bromo-δ-chlorophenyOoxyl^-chloro^-fluorophenylJacetyO-S- cyanobenzohydrazide.
Figure imgf000050_0002
DMF (5 ml_), 2-{3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}acetohydrazide (134 mg, 0.328 mmol), 3-cyanobenzoic acid (53.1 mg, 0.361 mmol), HATU (149 mg, 0.394 mmol) and DIPEA (0.110 ml_, 0.656 mmol) were combined and the reaction mixture was stirred at rt. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed to give 108 mg of the title compound. LCMS (ESI+) m/z 535 [M+H].
Step B: 3-[5-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]benzonitrile
Figure imgf000050_0003
THF (5 ml_), /\^({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl} acetyl)-3-cyanobenzohydrazide (108 mg, 0.201 mmol) and Burgess Reagent (191 mg, 0.804 mmol) were combined and the reaction mixture was stirred overnight at rt. The mixture was adsorbed onto silica gel and the crude material was purified via silica gel chromatography to give 70 mg (70% pure) of the title compound. 1H NMR (DMSO- d6) δ 8.32 (d, 1 H), 8.17 - 8.25 (m, 1 H), 8.00 - 8.12 (m, 1 H), 7.69 - 7.82 (m, 1 H), 7.41 ■ 7.56 (m, 3 H), 7.09 - 7.19 (m, 1 H), 6.93 - 7.11 (m, 1 H), 4.46 (s, 2 H).
Step C: 3-chloro-5-[(6-chloro-3-{[5-(3-cyanophenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2- fluorophenyl)oxy]benzonitrile
Figure imgf000051_0001
DMF (3.0 ml_), 3-[5-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)- 1 ,3,4-oxadiazol-2-yl]benzonitrile (67.0 mg, 0.129 mmol), zinc cyanide (6.04 mg, 0.0516 mmol) and tetrakis(triphenylphosphine) palladium(O) (37.2 mg, 0.0323 mmol) were combined and the reaction mixture was stirred in an Emry Personal Chemistry microwave reactor at 135 0C for 10 min. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 18 mg of the title compound. 1H NMR (DMSOd6) δ 8.31 (m, 1 H), 8.20-8.23 (m, 1 H), 8.03-8.07 (m, 1 H), 7.73-7.78 (m, 2 H), 7.48-7.51 (m, 3 H), 7.44-7.46 (m, 1 H), 4.45 (s, 2 H).
Example 17: 4-[5-({4-chloro-3-[(3-chloro-5-cvanophenyl)oxy1-2-fluorophenyl}methyl)- 1 ,3,4-oxadiazol-2-yl1-Λ/,Λ/-diethylbenzenesulfonamide
Figure imgf000051_0002
Step A: 4-{[2-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2 -fluorophenyl} acetyl)hydrazino]carbonyl}-Λ/,Λ/-diethylbenzenesulfonamide
Figure imgf000051_0003
DMF (5 ml_), 2-{3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}acetohydrazide (150 mg, 0.368 mmol), Λ/,Λ/-diethyl-4-sulfomoylbenzoic acid (94.5 mg, 0.368 mmol), HATU (140 mg, 0.368 mmol) and DIPEA (0.13 ml_, 0.736 mmol) were combined and the reaction mixture was stirred at rt. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed to give 183 mg of the title compound. LCMS (ESI+) m/z 648 [M+H].
Step B: 4-[5-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]-Λ/,Λ/-diethylbenzenesulfonamide
Figure imgf000052_0001
THF (3 ml_), 4-{[2-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl} acetyl)hydrazino]carbonyl}-Λ/,Λ/-diethylbenzenesulfonamide (183 mg, 0.283 mmol) and Burgess Reagent (269 mg, 1.13 mmol) were combined and the reaction mixture was stirred overnight at rt. The mixture was adsorbed onto silica gel and the crude material was purified via silica gel chromatography to give 153 mg of the title compound. 1H NMR (DMSOd6) δ 8.08 - 8.17 (m, 2 H), 7.90 - 8.00 (m, 2 H), 7.41 - 7.57 (m, 3 H), 7.13 - 7.20 (m, 1 H), 7.06 (t, 1 H), 4.49 (s, 2 H), 3.18 (q, 4 H), 1.02 (t, 6 H).
Step C: 4-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]-Λ/,Λ/-diethylbenzenesulfonamide
Figure imgf000052_0002
DMF (3.0 ml_), 4-[5-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)- 1 ,3,4-oxadiazol-2-yl]-Λ/,Λ/-diethylbenzenesulfonamide (151 mg, 0.240 mmol), zinc cyanide (14.1 mg, 0.120 mmol) and tetrakis(triphenylphosphine) palladium(O) (69.3 mg, 0.0600 mmol) were combined and the reaction mixture was stirred in an Emry Personal Chemistry microwave reactor at 135 0C for 10 min. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 74 mg of the title compound. 1H NMR (DMSOd6) δ 8.1 1-8.14 (m, 2 H), 7.96-7.99 (m, 2 H), 7.81 (m, 1 H), 7.52-7.56 (m, 3 H), 7.50 (m, 1 H), 4.50 (s, 2 H), 3.19 (q, 4 H), 1.03 (t, 6 H). Example 18: 3-chloro-5-r(6-chloro-3-{r5-(4-cvanophenyl)-1 ,3,4-oxadiazol-2-yllmethyl}-2- fluorophenvDoxylbenzonitrile
Figure imgf000053_0001
Step A: 4-[5-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]benzonitrile
Figure imgf000053_0002
THF (5 mL), 2-{3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}acetohydrazide (150 mg, 0.368 mmol), 4-cyanobenzoic acid (54.1 mg, 0.368 mmol), HATU (140 mg, 0.368 mmol) and DIPEA (0.13 mL, 0.736 mmol) were combined and the reaction mixture was stirred at rt for 45 min. Burgess Reagent (438 mg, 1.84 mmol) was added and the reaction was stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 117 mg of the title compound. LCMS (APCI+) m/z 519 [M+H].
Step B: 3-chloro-5-[(6-chloro-3-{[5-(4-cyanophenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2- fluorophenyl)oxy]benzonitrile
Figure imgf000053_0003
DMF (3.0 mL), 4-[5-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)- 1 ,3,4-oxadiazol-2-yl]benzonitrile (109 mg, 0.209 mmol), zinc cyanide (12.3 mg, 0.105 mmol) and tetrakis(triphenylphosphine) palladium(O) (60.3 mg, 0.0523 mmol) were combined and the reaction mixture was stirred in an Emry Personal Chemistry microwave reactor at 135 0C for 10 min. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 75 mg of the title compound. 1H NMR (DMSOd6) δ 8.06-8.08 (m, 2 H), 8.00-8.02 (m, 2 H), 7.78 (m, 1 H), 7.46-7.53 (m, 4 H), 4.46 (s, 2 H).
Example 19: 3-chloro-5-{r6-chloro-2-fluoro-3-({5-r2-fluoro-3-(methyloxy)phenyll-1 ,3,4- oxadiazol-2-yl}methyl)phenyl1oxy}benzonitrile
Figure imgf000054_0001
Step A: 2-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-5-[2-fluoro- 3-(methyloxy)phenyl]-1 ,3,4-oxadiazole
Figure imgf000054_0002
THF (5 ml_), 2-{3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}acetohydrazide (150 mg, 0.368 mmol), 3-methoxy-2-fluorobenzoic acid (62.6 mg, 0.368 mmol), HATU (140 mg, 0.368 mmol) and DIPEA (0.13 ml_, 0.736 mmol) were combined and the reaction mixture was stirred at rt for 45 min. Burgess Reagent (438 mg, 1.84 mmol) was added and the reaction was stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 160 mg of the title compound. 1H NMR (DMSOd6) δ 7.34 - 7.56 (m, 4 H), 7.21 - 7.31 (m, 2 H), 7.07 - 7.14 (m, 1 H), 6.97 - 7.05 (m, 1 H), 4.46 (s, 2 H), 3.86 (s, 3 H).
Step B: 3-chloro-5-{[6-chloro-2-fluoro-3-({5-[2-fluoro-3-(methyloxy)phenyl]-1 ,3,4- oxadiazol-2-yl}methyl)phenyl]oxy}benzonitrile
Figure imgf000054_0003
DMF (3.0 ml_), 2-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-5-[2- fluoro-3-(methyloxy)phenyl]-1 ,3,4-oxadiazole (156 mg, 0.288 mmol), zinc cyanide (16.8 mg, 0.144 mmol) and tetrakis(triphenylphosphine) palladium(O) (83.2 mg, 0.0720 mmol) were combined and the reaction mixture was stirred in an Emry Personal Chemistry microwave reactor at 135 0C for 10 min. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 87 mg of the title compound. 1H NMR (DMSOd6) δ 7.80 (m, 1 H), 7.40-7.55 (m, 5 H), 7.27-7.33 (m, 2 H), 4.49 (s, 2 H), 3.89 (s, 3 H).
Example 20: 3-chloro-5-r(6-chloro-2-fluoro-3-{r5-(2-fluoro-3-hvdroxyphenvn-1.3.4- oxadiazol-2-yllmethyl}phenyl)oxylbenzonitrile
Figure imgf000055_0001
Dichloromethane (5 ml_), 3-chloro-5-{[6-chloro-2-fluoro-3-({5-[2-fluoro-3- (methyloxy)phenyl]-1 ,3,4-oxadiazol-2-yl}methyl)phenyl]oxy}benzonitrile (53.0 mg, 0.109 mmol) and boron tribromide (0.54 ml_, 0.543 mmol, 1 M solution in dichloromethane) were combined and the reaction mixture was stirred overnight at rt. The reaction was quenched with cold water, followed by saturated sodium bicarbonate. The organic layer was separated and adsorbed onto silica gel. The crude material was purified via silica gel chromatography to give 43 mg of the title compound. 1H NMR (DMSO-c/6) δ 10.33 (s, 1 H), 7.76 (s, 1 H), 7.42-7.52 (m, 4 H), 7.24-7.30 (m, 1 H), 7.10-7.16 (m, 2 H), 4.45 (s, 2 H).
Example 21 : 3-chloro-5-{r6-chloro-3-({5-r3-(dimethylamino)phenyll-1 ,3,4-oxadiazol-2- yl}methyl)-2-fluorophenylloxy}benzonitrile
Figure imgf000055_0002
Step A: 3-[5-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]-Λ/,Λ/-dimethylaniline
Figure imgf000056_0001
THF (5 ml_), 2-{3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}acetohydrazide (150 mg, 0.368 mmol), 3-N',N'-dimethylaminobenzoic acid (60.8 mg, 0.368 mmol), HATU (140 mg, 0.368 mmol) and DIPEA (0.13 ml_, 0.736 mmol) were combined and the reaction mixture was stirred at rt for 45 min. Burgess Reagent (438 mg, 1.84 mmol) was added and the reaction was stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 145 mg of the title compound. 1H NMR (DMSOd6) δ 7.46 - 7.58 (m, 3 H), 7.30 - 7.42 (m, 1 H), 7.17 (dd, 3 H), 7.05 - 7.09 (m, 1 H), 6.94 (d, 1 H), 4.31 - 4.57 (m, 2 H), 2.94 (s, 6 H).
Step B: 3-chloro-5-{[6-chloro-3-({5-[3-(dimethylamino)phenyl]-1 ,3,4-oxadiazol-2- yl}methyl)-2-fluorophenyl]oxy}benzonitrile
Figure imgf000056_0002
DMF (3.0 ml_), 3-[5-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)- 1 ,3,4-oxadiazol-2-yl]-Λ/,Λ/-dimethylaniline (140 mg, 0.261 mmol), zinc cyanide (15.3 mg, 0.130 mmol) and tetrakis(triphenylphosphine) palladium(O) (75.4 mg, 0.0652 mmol) were combined and the reaction mixture was stirred in an Emry Personal Chemistry microwave reactor at 135 0C for 10 min. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 70 mg of the title compound. 1H NMR (DMSOd6) δ 7.77 (d, 1 H), 7.40 - 7.60 (m, 4 H), 7.29 - 7.38 (m, 1 H), 7.15 (d, 2 H), 6.82 - 6.97 (m, 1 H), 4.43 (s, 2 H), 2.91 (s, 6 H).
Example 22: 3-chloro-5-({6-chloro-3-r(5-{3-r(difluoromethvnoxylphenyl}-1.3.4-oxadiazol- 2-yl)methyll-2-fluorophenyl}oxy)benzonitrile
Figure imgf000057_0001
Step A: 2-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-5-{3- [(difluoromethyl)oxy]phenyl}-1 ,3,4-oxadiazole
Figure imgf000057_0002
THF (5 ml_), 2-{3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}acetohydrazide (150 mg, 0.368 mmol), 3-(difluoromethoxy)benzoic acid (69.2 mg, 0.368 mmol), HATU (140 mg, 0.368 mmol) and DIPEA (0.13 ml_, 0.736 mmol) were combined and the reaction mixture was stirred at rt for 45 min. Burgess Reagent (438 mg, 1.84 mmol) was added and the reaction was stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 152 mg of the title compound. 1H NMR (DMSOd6) δ 7.79 (d, 1 H), 7.66 - 7.70 (m, 1 H), 7.63 (t, 1 H), 7.55 (s, 3 H), 7.42 (dd, 1 H), 7.35 (s, 1 H), 7.13 - 7.16 (m, 1 H), 7.02 - 7.1 1 (m, 1 H), 4.48 (s, 2 H).
Step B: 3-chloro-5-({6-chloro-3-[(5-{3-[(difluoromethyl)oxy]phenyl}-1 ,3,4-oxadiazol-2- yl)methyl]-2-fluorophenyl}oxy)benzonitrile
Figure imgf000057_0003
DMF (3.0 ml_), 2-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-5-{3- [(difluoromethyl)oxy]phenyl}-1 ,3,4-oxadiazole (148 mg, 0.292 mmol), zinc cyanide (17.1 mg, 0.146 mmol) and tetrakis(triphenylphosphine) palladium(O) (84.3 mg, 0.0730 mmol) were combined and the reaction mixture was stirred in an Emry Personal Chemistry microwave reactor at 135 0C for 10 min. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 85 mg of the title compound. 1H NMR (DMSOd6) δ 7.77 - 7.82 (m, 2 H), 7.67 - 7.70 (m, 1 H), 7.64 (t, 1 H), 7.50 - 7.56 (m, 3 H), 7.48 (t, 1 H), 7.43 (dd, 1 H), 7.36 (s, 1 H), 4.48 (s, 2 H).
Figure imgf000058_0001
Scheme 2. General Procedure A for the Synthesis of Oxadiazoles of Formula (I).
General Procedure A
THF (0.066 - 0.226 M), 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl }acetohydrazide (1.0 eq), carboxylic acid (1.0 eq), HATU (1.0 eq) and DIPEA (2.0 eq) were combined and the mixture was stirred at rt for 45 min. Burgess Reagent (5 eq) was added and the reaction was stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give the title compound.
Figure imgf000058_0002
Scheme 3. General Procedure B for the Synthesis of Oxadiazoles of Formula (I).
General Procedure B
THF (0.054 - 0.059 M), {4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetic acid (1.0 eq), aryl hydrazide (1.0 eq), HATU (1.0 eq) and DIPEA (2.0 eq) were combined and the mixture was stirred at rt for 45 min. Burgess Reagent (5 eq) was added and the reaction was stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give the title compound.
Example 23: 2-chloro-5-r5-({4-chloro-3-r(3-chloro-5-cvanophenyl)oxyl-2- fluorophenyl}methyl)-1 ,3,4-oxadiazol-2-yllbenzenesulfonamide
Figure imgf000059_0001
THF (3 ml_), 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetohydrazide (70 mg, 0.198 mmol), 3-(aminosulfonyl)-4-chlorobenzoic acid (46.7 mg, 0.198 mmol), HATU (75.2 mg, 0.198 mmol) and DIPEA (0.069 ml_, 0.395 mmol) were combined and the reaction mixture was stirred at rt for 45 min. Burgess Reagent (236 mg, 0.990 mmol) was added and the reaction was stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 32 mg of the title compound. 1H NMR (DMSOd6) δ 8.46 (d, 1 H), 8.08 (dd, 1 H), 7.80 - 7.86 (m, 3 H), 7.74 - 7.80 (m, 1 H), 7.48 - 7.55 (m, 3 H), 7.43 - 7.47 (m, 1 H), 4.47 (s, 2 H).
Example 24: 4-chloro-5-[5-({4-chloro-3-[(3-chloro-5-cvanophenyl)oxy1-2- fluorophenyl}methyl)-1 ,3,4-oxadiazol-2-yl1-2-fluorobenzenesulfonamide
Figure imgf000059_0002
THF (3 ml_), 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetohydrazide (70 mg, 0.198 mmol), 5-(aminosulfonyl)-2-chloro-4-fluorobenzoic acid (50.1 mg, 0.198 mmol), HATU (75.2 mg, 0.198 mmol) and DIPEA (0.069 ml_, 0.395 mmol) were combined and the reaction mixture was stirred at rt for 45 min. Burgess Reagent (236 mg, 0.990 mmol) was added and the reaction was stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 67 mg of the title compound. 1H NMR (CDCI3) δ 8.46 (d, 1 H), 7.47 (d, 1 H), 7.31-7.36 (m, 2 H), 7.23 (m, 1 H), 7.00-7.05 (m, 1 H), 6.94 (m, 1 H), 5.37 (s, 2 H), 4.39 (s, 2 H).
Example 25: methyl S-rδ-W-chloro-S-rO-chloro-δ-cvanophenvDoxyl^- fluorophenyl}methyl)-1 ,3,4-oxadiazol-2-yllbenzoate
Figure imgf000060_0001
THF (25 ml_), 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetohydrazide (378 mg, 1.07 mmol), 3[(methyloxy)carbonyl]benzoic acid (192 mg, 1.07 mmol), HATU (406 mg, 1.07 mmol) and DIPEA (0.37 ml_, 2.14 mmol) were combined and the reaction mixture was stirred at rt for 45 min. Burgess Reagent (1.27 g, 5.35 mmol) was added and the reaction was stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 275 mg of the title compound. 1H NMR (DMSOd6) δ 8.39 - 8.43 (m, 1 H), 8.18 (d, 1 H), 8.14 (d, 1 H), 7.75 - 7.79 (m, 1 H), 7.72 (t, 1 H), 7.48 - 7.52 (m, 3 H), 7.46 (t, 1 H), 4.47 (s, 2 H), 3.86 (s, 3 H).
Example 26: 3-chloro-5-r(6-chloro-3-{r5-(2,6-dimethylphenyl)-1 ,3,4-oxadiazol-2- yl1methyl}-2-fluorophenyl)oxy1benzonitrile
Figure imgf000060_0002
THF (5 ml_), 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetohydrazide (80.0 mg, 0.226 mmol), 2,6-dimethylbenzoic acid (34.0 mg, 0.226 mmol), HATU (85.9 mg, 0.226 mmol) and DIPEA (0.080 ml_, 0.452 mmol) were combined and the reaction mixture stirred overnight at rt. Complete conversion to the diacylhydrazide was only achieved after additional heating overnight at 80 0C. Burgess Reagent (215 mg, 0.904 mmol) was added and the mixture was stirred for 4 h. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 31 mg of the title compound. 1H NMR (400 MHz, CDCI3) δ 7.22 - 7.34 (m, 4 H), 7.07 - 7.12 (m, 3 H), 6.96 - 7.01 (m, 1 H), 4.33 (s, 2 H), 2.19 (s, 6 H).
Example 27: S-rδ-W-chloro-S-rO-chloro-δ-cvanophenvDoxyl^-fluorophenyllmethyl)- 1 ,3,4-oxadiazol-2-yllbenzoic acid
Figure imgf000061_0001
THF (3 ml_), methyl 3-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}methyl)-1 ,3,4-oxadiazol-2-yl]benzoate (457 mg, 0.918 mmol) and LiOH (2.75 ml_, 2.75 mmol, 1.0 M solution in water) were combined and the reaction mixture was stirred for 3 h at rt. The reaction was quenched with citric acid buffer, diluted with ethyl acetate and was washed consecutively with water and brine. The organic layer was dried over magnesium sulfate and the solvent was removed to give the title compound (416 mg). 1H NMR (DMSOd6) δ 13.36 (s, 1 H), 8.36 - 8.45 (m, 1 H), 8.07 - 8.18 (m, 2 H), 7.74 - 7.80 (m, 1 H), 7.69 (t, 1 H), 7.48 - 7.54 (m, 3 H), 7.45 (t, 1 H), 4.46 (s, 2 H).
Example 28: 3-r5-({4-chloro-3-r(3-chloro-5-cvanophenyl)oxyl-2-fluorophenyl}methyl)- 1 ,3,4-oxadiazol-2-yl1benzamide
Figure imgf000061_0002
THF (5 ml_), 3-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)- 1 ,3,4-oxadiazol-2-yl]benzoic acid (50.0 mg, 0.103 mmol), DIPEA (0.04 ml_, 0.206 mmol), HATU (58.9 mg, 0.155 mmol) and ammonia (0.52 ml_, 0.515 mmol, 1.0 M in dioxane) were combined and the reaction mixture was stirred at rt for 4 h. The solvent was removed and the crude material was purified via silica gel chromatography to give 27 mg of the title compound. 1H NMR (DMSOd6) δ 8.35 - 8.47 (m, 1 H), 8.18 (d, 1 H), 7.96 - 8.12 (m, 2 H), 7.73 - 7.82 (m, 1 H), 7.63 (t, 1 H), 7.47 - 7.58 (m, 4 H), 7.45 (t, 1 H), 4.46 (s, 2 H).
Example 29: S-rδ-W-chloro-S-rO-chloro-δ-cvanophenvDoxyl^-fluorophenyllmethyl)- 1 ,3,4-oxadiazol-2-yll-Λ/-(2,3-dihvdroxypropyl)benzamide
Figure imgf000062_0001
Step A: 3-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]-Λ/-[(2,2-dimethyl-1 ,3-dioxolan-4-yl)methyl]benzamide
Figure imgf000062_0002
THF (5 ml_), 3-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)- 1 ,3,4-oxadiazol-2-yl]benzoic acid (70.0 mg, 0.145 mmol), 1-(2,2-dimethyl-1 ,3-dioxolan-4- yl)methanamine (22.8 mg, 0.173 mmol), HATU (55.1 mg, 0.145 mmol) and DIPEA (0.05 ml_, 0.290 mmol) were combined and the reaction mixture was stirred at rt for 4 h. The solvent was removed and the crude material was purified via silica gel chromatography to give 68 mg of the title compound. 1H NMR (CDCI3) δ 8.37 - 8.42 (m, 1 H), 8.13 (d, 1 H), 7.94 (d, 1 H), 7.58 (t, 1 H), 7.32 - 7.36 (m, 1 H), 7.25 - 7.32 (m, 2 H), 7.14 (t, 1 H), 7.01 (s, 1 H), 6.48 - 6.61 (m, 1 H), 4.30 - 4.38 (m, 3 H), 4.09 (dd, 1 H), 3.73 - 3.82 (m, 1 H), 3.70 (dd, 1 H), 3.44 - 3.55 (m, 1 H), 1.44 (s, 3 H), 1.34 (s, 3 H).
Step B: 3-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]-Λ/-(2,3-dihydroxypropyl)benzamide
Figure imgf000062_0003
THF (5 ml_), 3-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)- 1 ,3,4-oxadiazol-2-yl]-Λ/-[(2,2-dimethyl-1 ,3-dioxolan-4-yl)methyl]benzamide (68.0 mg, 0.1 14 mmol), HCI (0.1 ml_, 1.0 M solution in water), were combined and the reaction mixture was stirred overnight at rt. The reaction was neutralized with saturated sodium bicarbonate and the organic layer was separated. The crude material was purified via silica gel chromatography to give 29 mg of the title compound. 1H NMR (CDCI3) δ 8.41 (s, 1 H), 8.16 (d, 1 H), 7.99 (d, 1 H), 7.61 (t, 1 H), 7.28-7.37 (m, 3 H), 7.20 (m, 1 H), 7.02 (s, 1 H), 6.75-6.79 (m, 1 H), 4.37 (s, 2 H), 3.93-3.95 (m, 1 H), 3.60-3.75 (m, 4 H), 3.49 (d, 2 H).
Example 30: 3-r5-({4-chloro-3-r(3-chloro-5-cvanophenyl)oxyl-2-fluorophenyl}methyl)- 1 ,3,4-oxadiazol-2-yll-Λ/-r2-(methylsulfonyl)ethyllbenzamide
Figure imgf000063_0001
THF (5 ml_), 3-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)- 1 ,3,4-oxadiazol-2-yl]benzoic acid (70.0 mg, 0.145 mmol), 2-(methylsulfonyl)ethanamine (17.8 mg, 0.145 mmol), HATU (55.1 mg, 0.145 mmol) and DIPEA (0.05 ml_, 0.290 mmol) were combined and the reaction mixture was stirred at rt for 4 h. The solvent was removed and the crude material was purified via silica gel chromatography to give 37 mg of the title compound. 1H NMR (CDCI3) δ 8.37 (s, 1 H), 8.16 (d, 1 H), 7.91 (d, 1 H), 7.57 (t, 1 H), 7.23 - 7.40 (m, 3 H), 7.15 (t, 1 H), 7.09 (t, 1 H), 7.00 (d, 1 H), 4.34 (s, 2 H), 4.02 (q, 2 H), 3.25 - 3.44 (m, 2 H), 2.99 (s, 3 H).
Example 31 : S-rδ-W-chloro-S-rO-chloro-δ-cvanophenvDoxyl^-fluorophenyllmethyl)- 1 ,3,4-oxadiazol-2-yll-Λ/-r2-(4-morpholinyl)ethyllbenzamide
Figure imgf000063_0002
THF (5 ml_), 3-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)- 1 ,3,4-oxadiazol-2-yl]benzoic acid (100 mg, 0.207 mmol), 2-(4-morpholinyl)ethanamine (26.9 mg, 0.207 mmol), HATU (78.7 mg, 0.207 mmol) and DIPEA (0.070 ml_, 0.414 mmol) were combined and the reaction mixture was stirred at rt for 4 h. The solvent was removed and the crude material was purified via silica gel chromatography to give 81 mg of the title compound. 1H NMR (CDCI3) δ 8.44 (s, 1 H), 8.15 (d, 1 H), 7.95-7.98 (m, 1 H), 7.61 (t, 1 H), 7.29-7.37 (m, 3 H), 7.18 (m, 1 H), 7.04 (s, 1 H), 4.37 (s, 2 H), 3.72-3.77 (m, 4 H), 3.57-3.62 (m, 2 H), 2.51-2.68 (m, 6 H). Example 32: S-rδ-W-chloro-S-rO-chloro-δ-cvanophenvπoxyl^-fluorophenyllmethyl)- 1 ,3,4-oxadiazol-2-yll-Λ/-cvclopropylbenzamide
Figure imgf000064_0001
THF (5 ml_), 3-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)- 1 ,3,4-oxadiazol-2-yl]benzoic acid (75.0 mg, 0.155 mmol), cyclopropyl amine (8.83 mg, 0.155 mmol), HATU (58.9 mg, 0.155 mmol) and DIPEA (0.050 ml_, 0.310 mmol) were combined and the mixture was stirred at rt for 4 h. The solvent was removed and the crude material was purified via silica gel chromatography to give 49 mg of the title compound. 1H NMR (CDCI3) δ 8.35 (s, 1 H), 8.11 (d, 1 H), 7.95 (d, 1 H), 7.58 (t, 1 H), 7.27 - 7.45 (m, 3 H), 7.09 - 7.22 (m, 1 H), 7.03 (s, 1 H), 6.35 (s, 1 H), 4.36 (s, 2 H), 2.93 (dd, 1 H), 0.85 - 1.01 (m, 2 H), 0.56 - 0.76 (m, 2 H).
Example 33: S-fδ-W-chloro-S-fO-chloro-δ-cvanophenvDoxyi^-fluorophenyllmethyl)- 1 ,3,4-oxadiazol-2-yll-Λ/-(3-hvdroxypropyl)benzamide
Figure imgf000064_0002
THF (5 ml_), 3-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)- 1 ,3,4-oxadiazol-2-yl]benzoic acid (75.0 mg, 0.155 mmol), 3-amino-1-propanol (1 1.6 mg, 0.155 mmol), HATU (58.9 mg, 0.155 mmol) and DIPEA (0.050 ml_, 0.310 mmol) were combined and the mixture was stirred at rt for 4 h. The solvent was removed and the crude material was purified via silica gel chromatography to give 63 mg of the title compound. 1H NMR (CDCI3) δ 8.41 (m, 1 H), 8.13-8.15 (m, 1 H), 7.96-7.99 (m, 1 H), 7.60 (t, 1 H), 7.31-7.37 (m, 3 H), 7.18 (t, 1 H), 7.03 (m, 1 H), 6.78-6.83 (m, 1 H), 4.37 (s, 2 H), 3.77 (t, 2 H), 3.65-3.69 (m, 2 H), 1.82-1.88 (m, 2 H).
Example 34: δ-rδ-({4-chloro-3-r(3-chloro-δ-cvanophenyl)oxyl-2-fluorophenyl}methyl)- 1 ,3,4-oxadiazol-2-yll-2-methylbenzenesulfonamide
Figure imgf000065_0001
THF (3 ml_), 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetohydrazide (80 mg, 0.226 mmol), 3-(aminosulfonyl)-4-methylbenzoic acid (48.3 mg, 0.226 mmol), HATU (85.6 mg, 0.226 mmol), and DIPEA (0.079 ml_, 0.452 mmol) were combined and the mixture was stirred at rt for 45 min. Burgess Reagent (268 mg, 1.13 mmol) was added and the reaction was stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 54 mg of the title compound. 1H NMR (CDCI3) δ 8.50 (s, 1 H), 7.98 (d, 1 H), 7.26-7.39 (m, 4 H), 7.16 (s, 1 H), 6.95 (s, 1 H), 5.52 (s, 2 H), 4.31 (s, 2 H), 2.68 (s, 3 H).
Example 35: 4-chloro-5-[5-({4-chloro-3-[(3-chloro-5-cvanophenyl)oxy1-2- fluorophenyl}methyl)-1 ,3,4-oxadiazol-2-yl1-2-fluoro-Λ/-methylbenzenesulfonamide
Figure imgf000065_0002
THF (3 ml_), 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetohydrazide (80 mg, 0.226 mmol), 2-chloro-4-fluoro-5-[(methylamino)sulfonyl]benzoic acid (60.3 mg, 0.226 mmol), HATU (85.6 mg, 0.226 mmol) and DIPEA (0.079 ml_, 0.452 mmol) were combined and the mixture was stirred at rt for 45 min. Burgess Reagent (268 mg, 1.13 mmol) was added and the reaction was stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 85 mg of the title compound. 1H NMR (DMSOd6) δ 8.25 (d, 1 H), 8.02-8.06 (m, 2 H), 7.78 (t, 1 H), 7.48- 7.55 (m, 3 H), 7.45 (t, 1 H), 4.50 (s, 2 H), 2.51 (d, 3 H).
Example 36: 4-chloro-3-[5-({4-chloro-3-[(3-chloro-5-cvanophenyl)oxy1-2- fluorophenyl}methyl)-1 ,3,4-oxadiazol-2-yl1-Λ/-cvclopropylbenzenesulfonamide
Figure imgf000066_0001
The title compound (77 mg) was prepared using a procedure analogous to General Procedure A from 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}acetohydrazide (80 mg, 0.226 mmol) and 2-chloro-5- [(cyclopropylamino)sulfonyl]benzoic acid (62.2 mg, 0.226 mmol). 1H NMR (DMSO- cfe) δ 8.31 (d, 1 H), 8.19 (d, 1 H), 7.86 - 8.02 (m, 2 H), 7.74 - 7.86 (m, 1 H), 7.48 - 7.61 (m, 3 H), 7.40 - 7.50 (m, 1 H), 4.51 (s, 2 H), 2.08 - 2.22 (m, 1 H), 0.40 - 0.57 (m, 2 H), 0.26 - 0.42 (m, 2 H).
Example 37: 3-chloro-5-{r6-chloro-2-fluoro-3-({5-r4-({r(4S)-2,2,5,5-tetramethyl-1.3- dioxolan-4-yl1methyl}oxy)phenyl1-1 ,3,4-oxadiazol-2-yl}methyl)phenyl1oxy}benzonitrile
Figure imgf000066_0002
Step A: methyl 4-({[(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl}oxy)benzoate
Figure imgf000066_0003
DMF (3 ml_), [(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl 4- methylbenzenesulfonate (413 mg, 1.31 mmol), methyl 4-hydroxybenzoate (200 mg, 1.31 mmol) and potassium carbonate (723 mg, 5.24 mmol) were combined and the mixture was stirred in an Emry Personal Chemistry microwave reactor at 120 0C for 25 min. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 365 mg of the title compound. 1H NMR (CDCI3) δ 8.00 (d, 2 H), 6.94 (d, 2 H), 4.1 1 - 4.30 (m, 2 H), 4.02 (dd, 1 H), 3.89 (s, 3 H), 1.47 (s, 3 H), 1.42 (s, 3 H), 1.41 (s, 3 H), 1.21 (s, 3 H).
Step B: 4-({[(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl}oxy)benzohydrazide
Figure imgf000067_0001
Ethanol (10 ml_), methyl 4-({[(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4- yl]methyl}oxy)benzoate (164 mg, 0.557 mmol) and hydrazine (2.0 mL) were combined and the mixture was heated at reflux for 3 h. The solvent was removed to give the title compound in quantitative yield. 1H NMR (CDCI3) δ 7.69 (d, 2 H), 7.21 (s, 1 H), 6.94 (d, 2 H), 4.15 - 4.26 (m, 2 H), 4.06 (s, 2 H), 3.98 (dd, 1 H), 1.45 (s, 3 H), 1.39 (s, 3 H), 1.38 (s, 3 H), 1.18 (s, 3 H).
Step C: 3-chloro-5-{[6-chloro-2-fluoro-3-({5-[4-({[(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4- yl]methyl}oxy)phenyl]-1 ,3,4-oxadiazol-2-yl}methyl)phenyl]oxy}benzonitrile
Figure imgf000067_0002
THF (5 mL), {4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetic acid (92.5 mg, 0.272 mmol), 4-({[(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-
4yl]methyl}oxy)benzohydrazide (80.0 mg, 0.272 mmol), HATU (103 mg, 0.272 mmol,) and DIPEA (0.09 mL, 0.544 mmol) were combined and the mixture was stirred at rt for 45 min. Burgess Reagent (312 mg, 1.36 mmol) was added and the reaction was stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 131 mg of the title compound. 1H NMR (CDCI3) δ 7.90-7.93 (m, 2H), 7.35 (m, 1 H), 7.26-7.31 (m, 2H), 7.16 (m, 1 H), 6.99-7.01 (m, 3H), 4.30 (s, 2H), 4.14- 4.22 (m, 2H), 3.98-4.01 (m, 1 H), 1.45 (s, 3H), 1.39 (s, 3H), 1.38 (s, 3H), 1.18 (s, 3H).
Example 38: 3-chloro-5-r(6-chloro-3-fr5-(4-fr(2SV2.3-dihvdroxy-3-methyl butylloxy}phenyl)-1 ,3,4-oxadiazol-2-yllmethyl}-2-fluorophenyl)oxylbenzonitrile
Figure imgf000068_0001
Dichloromethane (5 ml_), 3-chloro-5-{[6-chloro-2-fluoro-3-({5-[4-({[(4S)-2,2,5,5- tetramethyl-1 ,3-dioxolan-4-yl]methyl}oxy)phenyl]-1 ,3,4-oxadiazol-2- yl}methyl)phenyl]oxy}benzonitrile (129 mg, 0.216 mmol), and HCI (0.2 ml_, 1 N solution in water) were combined and the mixture was stirred at rt overnight. LCMS indicated only slight formation of desired product. The mixture was heated at 50 0C for 40 min then the reaction was neutralized with aqueous saturated sodium bicarbonate and the organics were separated. The solvent was removed and the crude material was purified via silica gel chromatography to give 31 mg of the title compound. 1H NMR (DMSOc/6)P7.83-7.78 (m, 3 H), 7.52-7.45 (m, 4 H), 7.09 (d, 2 H), 5.03 (d, 1 H), 4.41 (s, 2 H), 4.40 ( m, 1 H), 4.26 (d, 1 H), 3.84 (t, 1 H), 3.51 (t, 1 H), 1.1 1 (s, 3 H), 1.04 (s, 3 H).
Example 39: 3-chloro-5-r(6-chloro-2-fluoro-3-fr5-(4-fr3-hvdroxy-2-(hvdroxymethvn propylloxy}phenyl)-1 ,3,4-oxadiazol-2-yllmethyl}phenyl)oxylbenzonitrile
Figure imgf000068_0002
Step A: (2,2-dimethyl-1 ,3-dioxan-5-yl)methanol
Figure imgf000068_0003
To a solution of 2-(hydroxymethyl)-1 ,3-propanediol (2.0 g, 18.8 mmol) in THF (40 ml.) were added 2,2-bis(methyloxy)propane (2.70 ml_, 21.7 mmol) and toluenesulfonic acid monohydrate (107 mg, 0.56 mmol). After stirring overnight at rt, additional 2,2- bis(methyloxy)propane (2.70 ml_, 21.7 mmol) was added and the reaction was stirred overnight. The reaction was neutralized with triethylamine (2 ml_), the solvent was removed and the crude material was purified via silica gel chromatography to give 2.51 g of the title compound. 1H NMR (DMSOd6) δ 4.49 (t, 1 H), 3.77 (dd, 2 H), 3.46 - 3.62 (m, 2 H), 3.33 (t, 2 H), 1.57 - 1.73 (m, 1 H), 1.25 (d, 6 H) Step B: (2,2-dimethyl-1 ,3-dioxan-5-yl)methyl 4-methylbenzenesulfonate
Figure imgf000069_0001
A solution of (2,2-dimethyl-1 ,3-dioxan-5-yl)methanol (2.51 g, 17.1 mmol) and N, N- dimethylaminopyiridine (208 mg, 1.7 mmol) in dichloromethane (100 ml.) was cooled to 0 0C and p-toluenesulfonyl chloride (3.59 g, 18.8 mmol) and triethylamine (4.8 ml. 34.2 mmol) were added. The mixture was stirred overnight at rt, diluted with water, and the organic layer was separated. The solvent was removed and the crude material was purified via silica gel chromatography to give 4.16 g of the title compound. 1H NMR (DMSOd6) δ 7.78 (d, 2 H), 7.47 (d, 2 H), 4.09 (d, 2 H), 3.84 (dd, 2 H), 3.52 (dd, 2 H), 2.41 (s, 3 H), 1.79 - 1.94 (m, 1 H), 1.28 (s, 3 H), 1.18 (s, 3 H).
Step C: methyl 4-{[(2,2-dimethyl-1 ,3-dioxan-5-yl)methyl]oxy}benzoate
Figure imgf000069_0002
DMF (3 ml_), (2,2-dimethyl-1 ,3-dioxan-5-yl)methyl 4-methylbenzenesulfonate (394 mg, 1.31 mmol), methyl 4-hydroxybenzoate (200 mg, 1.31 mmol) and potassium carbonate (361 mg, 2.62 mmol) were combined and the mixture was stirred in an Emry Personal Chemistry microwave reactor at 120 0C for 25 min. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 321 mg of the title compound. 1H NMR (CDCI3) δ 7.96 (d, 2 H), 6.90 (d, 2 H), 4.12 (d, 2 H), 4.10 (d, 1 H), 4.07 (d, 1 H), 3.86 (s, 3 H), 3.82 - 3.89 (m, 3 H), 1.45 (s, 3 H), 1.39 (s, 3 H).
Step D: 4-{[(2,2-dimethyl-1 ,3-dioxan-5-yl)methyl]oxy}benzohydrazide
Figure imgf000069_0003
Ethanol (10 ml_), methyl 4-{[(2,2-dimethyl-1 ,3-dioxan-5-yl)methyl]oxy}benzoate (204 mg, 0.729 mmol) and hydrazine (2.0 mL) were combined and the mixture was heated at reflux for 3 h. The solvent was removed to give 203 mg of the title compound. 1H NMR (CDCI3) δ 7.67 (d, 2 H), 7.18 (s, 1 H), 6.92 (d, 2 H), 4.06 - 4.14 (m, 5 H), 4.03 (s, 2 H), 3.85 (dd, 2 H), 1.45 (s, 3 H), 1.39 (s, 3 H).
Step E: 3-chloro-5-[(6-chloro-3-{[5-(4-{[(2,2-dimethyl-1 ,3-dioxan-5-yl)methyl]oxy} phenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile
Figure imgf000070_0001
The title compound (126 mg) was prepared using a procedure analogous to General Procedure B from {4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetic acid (92.5 mg, 0.272 mmol) and 4-{[(2,2-dimethyl-1 ,3-dioxan-5-yl)methyl]oxy}benzohydrazide (76.1 mg, 0.272 mmol). 1H NMR (DMSOd6) δ 7.86 (d, 2 H), 7.77 - 7.85 (m, 1 H), 7.45 - 7.59 (m, 4 H), 7.13 (d, 2 H), 4.44 (s, 2 H), 4.11 (d, 2 H), 3.99 (dd, 2 H), 3.74 (dd, 2 H), 2.00 - 2.12 (m, 1 H), 1.35 (s, 3 H), 1.31 (s, 3 H).
Step F: 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-{[3-hydroxy-2-(hydroxymethyl) propyl]oxy}phenyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile
Figure imgf000070_0002
Dichloromethane (5 mL), 3-chloro-5-[(6-chloro-3-{[5-(4-{[(2,2-dimethyl-1 ,3-dioxan-5- yl)methyl]oxy} phenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile (1 14 mg, 0.195 mmol), and HCI (0.5 mL, 1 N solution in water) were combined and the mixture was stirred at rt for 15 min. The reaction was neutralized with aqueous saturated sodium bicarbonate and the organics were separated. The solvent was removed and the crude material was purified via silica gel chromatography to give 73 mg of the title compound. 1H NMR (DMSOd6) δ 7.85 (d, 2 H), 7.80 (s, 1 H), 7.43 - 7.58 (m, 4 H), 7.11 (d, 2 H), 4.47 - 4.60 (m, 2 H), 4.44 (s, 2 H), 4.04 (d, 2 H), 3.43 - 3.63 (m, 4 H), 1.91 - 2.03 (m, 1 H). Example 40: 3-chloro-5-r(6-chloro-2-fluoro-3-ir5-(4-{r(2f?V2-morpholinylmethyll oxy}phenyl)-1 ,3,4-oxadiazol-2-yllmethyl}phenyl)oxylbenzonitrile
Figure imgf000071_0001
Step A: 1 ,1-dimethylethyl (2R)-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)-4- morpholinecarboxylate
Figure imgf000071_0002
A solution of 1 ,1-Dimethylethyl (2R)-2-(hydroxymethyl)-4-morpholinecarboxylate (1.78 g, 8.2 mmol) and Λ/,Λ/-dimethylaminopyridine (100 mg, 0.82 mmol) in dichloromethane (40 ml.) was cooled to 0 0C. p-Toluenesulfonylchloride (1.72 g, 9.0 mmol) and triethylamine (2.29 ml_, 16.4 mmol) were added, and the mixture was stirred overnight at rt. The reaction mixture was washed twice with 50 ml. water and the organic layer was dried over magnesium sulfate. The solvent was removed, and the crude material was purified via silica gel chromatography to give 2.45 g of the title compound. 1H NMR (CDCI3) δ 7.76 (d, 2 H), 7.32 (d, 2 H), 3.92 - 4.06 (m, 2 H), 3.65 - 3.90 (m, 3 H), 3.51 - 3.63 (m, 1 H), 3.31 - 3.49 (m, 1 H), 2.77 - 2.99 (m, 1 H), 2.52 - 2.74 (m, 1 H), 2.42 (s, 3 H), 1.42 (s, 9 H).
Step B: 1 ,1-dimethylethyl (2R)-2-[({4-[(methyloxy)carbonyl]phenyl}oxy)methyl]-4- morpholinecarboxylate
Figure imgf000071_0003
DMF (3 ml_), 1 ,1-dimethylethyl (2R)-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)-4- morpholinecarboxylate (486 mg, 1.31 mmol), methyl 4-hydroxybenzoate (200 mg, 1.31 mmol) and potassium carbonate (361 mg, 2.62 mmol) were combined and the mixture was stirred in an Emry Personal Chemistry microwave reactor at 120 0C for 25 min. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 243 mg of the title compound. 1H NMR (CDCI3) δ 7.97 (d, 2 H), 6.92 (d, 2 H), 4.04 - 4.11 (m, 2 H), 3.97 - 4.03 (m, 1 H), 3.90 - 3.98 (m, 2 H), 3.87 (s, 3 H), 3.75 - 3.84 (m, 1 H), 3.59 (t, 1 H), 2.74 - 3.06 (m, 2 H), 1.46 (s, 9 H).
Step C: 1 ,1-dimethylethyl (2/?)-2-({[4-(hydrazinocarbonyl)phenyl]oxy}methyl)-4- morpholinecarboxylate
Figure imgf000072_0001
Ethanol (10 ml_), 1 ,1-dimethylethyl (2R)-2-[({4-[(methyloxy)carbonyl]phenyl}oxy)methyl]-
4-morpholinecarboxylate (173 mg, 0.492 mmol) and hydrazine (2.0 ml.) were combined and the mixture was heated at reflux for 4 h. The solvent was removed to give 173 mg of the title compound. 1H NMR (DMSOd6) § 9.57 (s, 1 H), 7.74 (d, 2 H), 6.95 (d, 2 H), 4.27 - 4.52 (m, 2 H), 3.96 - 4.05 (m, 2 H), 3.76 - 3.92 (m, 2 H), 3.59 - 3.72 (m, 2 H), 3.32 - 3.45 (m, 1 H), 2.56 - 2.97 (m, 2 H), 1.36 (s, 9 H).
Step D: 1 ,1-dimethylethyl (2/?)-2-[({4-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}methyl)-1 ,3,4-oxadiazol-2-yl]phenyl}oxy)methyl]-4-morpholinecarboxylate
Figure imgf000072_0002
The title compound (146 mg) was prepared using a procedure analogous to General Procedure B from {4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetic acid (92.5 mg, 0.272 mmol) and 1 ,1-dimethylethyl (2R)-2-({[4-
(hydrazinocarbonyl)phenyl]oxy}methyl)-4-morpholinecarboxylate (95.5 mg, 0.272 mmol). 1H NMR (DMSOd6) § 7.83 (d, 2 H), 7.76 - 7.80 (m, 1 H), 7.42 - 7.54 (m, 4 H), 7.10 (d, 2 H), 4.41 (s, 2 H), 4.06 (t, 2 H), 3.76 - 3.94 (m, 2 H), 3.61 - 3.73 (m, 2 H), 3.37 - 3.46 (m, 1 H), 3.01 - 3.12 (m, 1 H), 2.81 - 2.95 (m, 1 H), 1.36 (s, 9 H).
Step E: 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-{[(2R)-2-morpholinylmethyl] oxy}phenyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile
Figure imgf000073_0001
Dichloromethane (5 ml_), 1 ,1-dimethylethyl (2R)-2-[({4-[5-({4-chloro-3-[(3-chloro-5- cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4-oxadiazol-2-yl]phenyl}oxy)methyl]-4- morpholinecarboxylate (141 mg, 0.215 mmol) and trifluoroacetic acid (0.5 ml.) were combined and the mixture was stirred at rt for 15 min. The mixture was neutralized with a saturated sodium bicarbonate solution, the organics were separated and the solvent was removed. The crude material was purified via silica gel chromatography to give 75 mg of the title compound. 1H NMR (DMSOd6) δ 7.84 (d, 2 H), 7.81 (m, 1 H), 7.48-7.54 (m, 4 H), 7.1 1 (d, 2 H), 4.44 (s, 2 H), 3.99 (d, 2 H), 3.65-3.74 (m, 3 H), 3.42-3.48 (m, 1 H), 2.84-2.87 (m, 1 H), 2.59-2.68 (m, 2 H).
Example 41 : 3-chloro-5-α6-chloro-2-fluoro-3-r(5-f4-rα(2ffl-4-r2-(methylsulfonvnethyll-2- morpholinyl}methyl)oxylphenyl}-1 ,3,4-oxadiazol-2-yl)methyllphenyl}oxy)benzonitrile
Figure imgf000073_0002
Dioxane (3.0 ml_), 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-{[(2R)-2-morpholinylmethyl] oxy}phenyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile (34.0 mg, 0.0612 mmol) and (methylsulfonyl)ethene (7.80 mg, 0.0735 mmol) were combined and the mixture was stirred at rt for 4 days. The solvent was removed and the crude material was purified via silica gel chromatography to give 35 mg of the title compound. 1H NMR (DMSO-c/ε) δ 7.82 (d, 2 H), 7.78 (s, 1 H), 7.45-7.52 (m, 4 H), 7.09 (d, 2 H), 4.41 (s, 2 H), 3.99-4.03 (m, 2 H), 3.73-3.81 (m, 2 H), 3.46-3.52 (m, 1 H), 3.24-3.30 (m, 3 H), 2.99 (s, 3 H), 2.87-2.90 (m, 2 H), 2.68-2.74 (m, 3 H).
Example 42: 3-chloro-5-r(6-chloro-2-fluoro-3-{r5-(3-nitrophenyl)-1 ,3,4-oxadiazol-2- yllmethyl}phenyl)oxylbenzonitrile
Figure imgf000074_0001
The title compound (146 mg) was prepared using a procedure analogous to General Procedure A from 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}acetohydrazide (520 mg, 1.47 mmol) and 3-nitrobenzoic acid (245 mg, 1.47 mmol). 1H NMR (DMSOd6) δ 8.60 (m, 1 H), 8.43-8.46 (m, 1 H), 8.35-8.38 (m, 1 H), 7.86- 7.90 (m, 1 H), 7.79 (m, 1 H), 7.54 (m, 3 H), 7.50 (m, 1 H), 4.51 (s, 2 H).
Example 43: methyl 4-r5-({4-chloro-3-r(3-chloro-5-cvanophenyl)oxyl-2- fluorophenyl}methyl)-1 ,3,4-oxadiazol-2-yllbenzoate
Figure imgf000074_0002
The title compound (454 mg) was prepared using a procedure analogous to General Procedure A from 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}acetohydrazide (600 mg, 1.69 mmol) and 4-[(methyloxy)carbonyl]benzoic acid (305 mg, 1.69 mmol). 1H NMR (DMSOd6) δ 8.07-8.14 (m, 4 H), 7.81 (m, 1 H), 7.48- 7.56 (m, 4 H), 4.49 (s, 2 H), 3.88 (s, 3 H).
Example 44: 4-r5-({4-chloro-3-r(3-chloro-5-cvanophenyl)oxyl-2-fluorophenyl}methvO- 1 ,3,4-oxadiazol-2-yllbenzoic acid
Figure imgf000075_0001
THF (15 ml_), methyl 4-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}methyl)-1 ,3,4-oxadiazol-2-yl]benzoate (454 mg, 0.912 mmol) and lithium hydroxide (2.74 ml_, 2.74 mmol, 1.0 M solution in water) were combined and the mixture was stirred for 3 h at rt. The reaction was quenched with citric acid buffer to achieve pH 4. The mixture was diluted with ethyl acetate and washed consecutively with water and brine. The organic layer was dried over magnesium sulfate and the solvent was removed to give 435 mg of the title compound. 1H NMR (DMSO-c/6) δ 8.04-8.13 (m, 4 H), 7.80 (s, 1 H), 7.48-7.58 (m, 4 H), 4.49 (s, 2 H).
Example 45: 3-chloro-5-({6-chloro-3-r(5-{4-r(1 ,1-dioxido-4-thiomorpholinyl) carbonyllphenyl}-1 ,3,4-oxadiazol-2-yl)methyll-2-fluorophenyl}oxy)benzonitrile
Figure imgf000075_0002
THF (3 ml_), 4-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)- 1 ,3,4-oxadiazol-2-yl]benzoic acid (70.0 mg, 0.145 mmol), thiomorpholine 1 ,1-dioxide (19.6 mg, 0.145 mmol), HATU (55.1 mg, 0.145 mmol) and DIPEA (0.050 ml_, 0.289 mmol) were combined and the mixture was stirred at rt for 4 h. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 65 mg of the title compound. 1H NMR (DMSOd6) δ 7.97 (d, 2 H), 7.78 (s, 1 H), 7.66 (d, 2 H), 7.45-7.53 (m, 4 H), 4.46 (s, 2 H), 3.92-4.04 (m, 2 H), 3.57-3.67 (m, 2 H), 3.17-3.25 (m, 4 H).
Example 46: 4-r5-({4-chloro-3-r(3-chloro-5-cvanophenyl)oxyl-2-fluorophenyl}methyl)- 1 ,3,4-oxadiazol-2-yll-Λ/-r2-(methylsulfonyl)ethyllbenzamide
Figure imgf000076_0001
THF (3 ml_), 4-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)- 1 ,3,4-oxadiazol-2-yl]benzoic acid (70.0 mg, 0.145 mmol) 2-(methylsulfonyl)ethanamine (17.9 mg, 0.145 mmol), HATU (55.1 mg, 0.145 mmol) and DIPEA (0.050 ml_, 0.289 mmol) were combined and the mixture was stirred at rt for 4 h. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 27 mg of the title compound. 1H NMR (DMSOd6) δ 8.91 (t, 1 H), 7.98-8.04 (m, 4 H), 7.79 (s, 1 H), 7.47- 7.53 (m, 4 H), 4.47 (s, 2 H), 3.66-3.69 (m, 2 H), 3.38 (m, 2 H), 3.02 (s, 3 H).
Example 47: 4-r5-({4-chloro-3-r(3-chloro-5-cvanophenyl)oxyl-2-fluorophenyl}methyl)- 1 ,3,4-oxadiazol-2-yl1-Λ/-[2-(4-morpholinyl)ethyl1benzamide
Figure imgf000076_0002
THF (3 ml_), 4-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)- 1 ,3,4-oxadiazol-2-yl]benzoic acid (70.0 mg, 0.145 mmol), 2-(4-morpholinyl)ethanamine (18.9 mg, 0.145 mmol), HATU (55.1 mg, 0.145 mmol) and DIPEA (0.050 ml_, 0.289 mmol) were combined and the mixture was stirred at rt for 4 h. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 49 mg of the title compound. 1H NMR (DMSOd6) δ 8.60 (m, 1 H), 7.97-8.03 (m, 4 H), 7.79 (s, 1 H), 7.47- 7.55 (m, 4 H), 4.47 (s, 2 H), 3.53-3.58 (m, 4 H), 3.35-3.41 (m, 2 H), 2.36-2.43 (m, 4 H), 1.19-1.25 (m, 2 H).
Example 48: 4-r5-({4-chloro-3-r(3-chloro-5-cvanophenyl)oxyl-2-fluorophenyl}methyl)- 1 ,3,4-oxadiazol-2-yll-Λ/-(2,3-dihvdroxypropyl)benzamide
Figure imgf000077_0001
Step A: 4-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]-Λ/-[(2,2-dimethyl-1 ,3-dioxolan-4-yl)methyl]benzamide
Figure imgf000077_0002
THF (3 ml_), 4-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)- 1 ,3,4-oxadiazol-2-yl]benzoic acid (70.0 mg, 0.145 mmol), 1-(2,2-dimethyl-1 ,3-dioxolan-4- yl)methanamine (19.0 mg, 0.145 mmol), HATU (55.1 mg, 0.145 mmol) and DIPEA (0.050 ml_, 0.289 mmol) were combined and the mixture was stirred at rt for 4 h. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 43 mg of the title compound. LCMS (ESI+) m/z 597 [M+H].
Step B: 4-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]-Λ/-(2,3-dihydroxypropyl)benzamide.
Figure imgf000077_0003
Methanol (5 ml_), 4-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)- 1 ,3,4-oxadiazol-2-yl]-Λ/-[(2,2-dimethyl-1 ,3-dioxolan-4-yl)methyl]benzamide (46.0 mg, 0.0771 mmol) and Dowex™ acidic resin (400 mg) were combined and the mixture was stirred overnight at rt. The reaction mixture was filtered, the solvent was removed and the crude material was purified via silica gel chromatography to give 32 mg of the title compound. 1H NMR (DMSOd6) δ 8.56 (t, 1 H), 7.99 (m, 4 H), 7.78 (s, 1 H), 7.45-7.53 (m, 4 H), 4.78 (d, 1 H), 4.53 (t, 1 H), 4.46 (s, 2 H), 3.59-3.63 (m, 1 H), 3.30-3.40 (m, 3 H), 3.13-3.19 (m, 1 H).
Example 49: 4-r5-({4-chloro-3-r(3-chloro-5-cvanophenyl)oxyl-2-fluorophenyl}methyl)- 1 ,3,4-oxadiazol-2-yllbenzamide
Figure imgf000078_0001
THF (3 ml_), 4-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)- 1 ,3,4-oxadiazol-2-yl]benzoic acid (70.0 mg, 0.145 mmol), ammonia (0.29ml_, 0.145 mmol, 0.5 M solution in dioxane), HATU (55.1 mg, 0.145 mmol) and DIPEA (0.0500 ml_, 0.289 mmol) were combined and the mixture was stirred at rt for 4 h. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 39 mg of the title compound. 1H NMR (DMSOd6) δ 8.13 (s, 2 H), 7.98-8.03 (m, 4 H), 7.80 (m, 1 H), 7.49-7.55 (m, 4 H), 4.47 (s, 2 H).
Example 50: 3-r(3-fr5-(3-aminophenylV1.3.4-oxadiazol-2-yllmethyl}-6-chloro-2- fluorophenyl)oxyl-5-chlorobenzonitrile
Figure imgf000078_0002
Water (2 ml_), THF (4 ml_), 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(3-nitrophenyl)-1 ,3,4- oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile (50.0 mg, 0.103 mmol), and sodium hydrosulfite (108 mg, 0.619 mmol) were combined and the mixture was stirred for one h at rt. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was further washed with brine and dried over magnesium sulfate. The solvent was removed and the crude material was purified via silica gel chromatography to give 28 mg of the title compound. 1H NMR (DMSO-c/6) δ 7.80 (s, 1 H), 7.47-7.55 (m, 4 H), 7.15-7.19 (m, 2 H), 7.03 (d, 1 H), 6.72-6.75 (m, 1 H), 5.47 (s, 2 H), 4.44 (s, 2 H). Example 51 : 3-chloro-5-{r6-chloro-2-fluoro-3-({5-r2-(methyloxy)phenyll-1 ,3,4-oxadiazol- 2-yl}methyl)phenylloxy}benzonitrile
Figure imgf000079_0001
The title compound (67 mg) was prepared using a procedure analogous to General Procedure A from 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}acetohydrazide (70.0 mg, 0.198 mmol) and 2-(methyloxy)benzoic acid (30.1 mg, 0.198 mmol). 1H NMR (DMSOd6) δ 7.77 (s, 1 H), 7.72 (d, 1 H), 7.43-7.57 (m, 5 H), 7.20 (d, 1 H), 7.06 (t, 1 H), 4.42 (s, 2 H), 3.79 (s, 3 H).
Example 52: 3-chloro-5-r(6-chloro-2-fluoro-3-ir5-(2-methylphenylV1 ,3.4-oxadiazol-2- yllmethyltohenvDoxylbenzonitrile
Figure imgf000079_0002
The title compound (45 mg) was prepared using a procedure analogous to General Procedure A from 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}acetohydrazide (70.0 mg, 0.198 mmol) and 2-methylbenzoic acid (26.9 mg, 0.198 mmol). 1H NMR (DMSOd6) δ 7.77 (m, 2 H), 7.43-7.53 (m, 5 H), 7.32-7.39 (m, 2 H), 4.44 (s, 2 H), 2.51 (s, 3 H).
Example 53: 3-chloro-5-r(6-chloro-3-fr5-(2-chlorophenylV1 ,3.4-oxadiazol-2-yllmethyl>-2- fluorophenvDoxylbenzonitrile
Figure imgf000079_0003
The title compound (69 mg) was prepared using a procedure analogous to General Procedure A from 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}acetohydrazide (70.0 mg, 0.198 mmol) and 2-chlorobenzoic acid (31.0 mg, 0.198 mmol). 1H NMR (DMSOd6) δ 7.89-7.92 (m, 1 H), 7.81 (m, 1 H), 7.67-7.70 (m, 1 H), 7.60-7.64 (m, 1 H), 7.51-7.56 (m, 4 H), 7.47 (m, 1 H), 4.50 (s, 2 H).
Example 54: 3-r(3-{r5-(2-bromophenyl)-1 ,3,4-oxadiazol-2-yllmethyl}-6-chloro-2- fluorophenyl)oxy1-5-chlorobenzonitrile
Figure imgf000080_0001
The title compound (77 mg) was prepared using a procedure analogous to General Procedure A from 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}acetohydrazide (70.0 mg, 0.198 mmol) and 2-bromobenzoic acid (39.8 mg, 0.198 mmol). 1H NMR (DMSOd6) δ 7.80-7.83 (m, 2 H), 7.77 (t, 1 H), 7.47-7.57 (m, 5 H), 7.43 (t, 1 H), 4.46 (s, 2 H).
Example 55: 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-fluorophenyl)-1 ,3,4-oxadiazol-2- yllmethyl}phenyl)oxylbenzonitrile
Figure imgf000080_0002
The title compound (72 mg) was prepared using a procedure analogous to General Procedure A from 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}acetohydrazide (70.0 mg, 0.198 mmol) and 2-fluorobenzoic acid (27.7 mg, 0.198 mmol). 1H NMR (DMSOd6) δ 7.93 (t, 1 H), 7.78 (m, 1 H), 7.61-7.67 (m, 1 H), 7.35- 7.53 (m, 6 H), 4.46 (s, 2 H).
Example 56: 3-chloro-5-{r6-chloro-3-({5-r2-chloro-3-(methyloxy)phenyll-1 ,3,4-oxadiazol- 2-yl}methyl)-2-fluorophenylloxy}benzonitrile
Figure imgf000081_0001
The title compound (29 mg) was prepared using a procedure analogous to General Procedure A from 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}acetohydrazide (70.0 mg, 0.198 mmol) and 2-chloro-3-(methyloxy)benzoic acid (36.9 mg, 0.198 mmol). 1H NMR (DMSOd6) δ 7.77 (s, 1 H), 7.36-7.53 (m, 7 H), 4.46 (s, 2 H), 3.88 (s, 3 H).
Example 57: S-chloro-δ-rfe-chloro-S-frδ-O-chlorophenylVI ,3.4-oxadiazol-2-yllmethyl>-2- fluorophenvDoxylbenzonitrile
Figure imgf000081_0002
The title compound (61 mg) was prepared using a procedure analogous to General Procedure A from 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}acetohydrazide (70.0 mg, 0.198 mmol) and 3-chlorobenzoic acid (31.0 mg, 0.198 mmol). 1H NMR (DMSOd6) δ 7.86-7.89 (m, 2 H), 7.77 (m, 1 H), 7.65-7.68 (m, 1 H), 7.56-7.60 (m, 1 H), 7.47-7.52 (m, 3 H), 7.45 (m, 1 H), 4.44 (s, 2 H).
Example 58: 3-chloro-δ-({6-chloro-2-fluoro-3-r(δ-phenyl-1 ,3,4-oxadiazol-2- yl)methyllphenyl}oxy)benzonitrile
Figure imgf000081_0003
The title compound (74 mg) was prepared using a procedure analogous to General Procedure A from 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}acetohydrazide (70.0 mg, 0.198 mmol) and benzoic acid (24.2 mg, 0.198 mmol). 1H NMR (DMSOd6) δ 7.90 (m, 2 H), 7.78 (m, 1 H), 7.48-7.58 (m, 6 H), 7.46 (m, 1 H), 4.44 (s, 2 H).
Example 59: /\/-{3-r5-({4-chloro-3-r(3-chloro-5-cvanophenyl)oxyl-2-fluorophenyl}methyl)- 1 ,3,4-oxadiazol-2-yllphenyl}-3-(methylthio)propanamide
Figure imgf000082_0001
THF (5 ml_), 3-[(3-{[5-(3-aminophenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-6-chloro-2- fluorophenyl)oxy]-5-chlorobenzonitrile (100 mg, 0.219 mmol), 3-(methylthio)propanoyl chloride (30.3 mg, 0.219 mmol) and DIPEA (0.08 ml_, 0.438 mmol) were combined and the mixture was stirred at rt. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude used without purification in the next step. 1H NMR (400 MHz, DMSOd6) δ 10.24 (s, 1 H), 8.30 (t, 1 H), 7.80 (t, 1 H), 7.73 - 7.78 (m, 1 H), 7.60 (d, 1 H), 7.52 - 7.56 (m, 2 H), 7.48 - 7.52 (m, 2 H), 7.45 - 7.49 (m, 1 H), 4.47 (s, 2 H), 2.73 (t, 2 H), 2.63 (t, 2 H), 2.07 (s, 3 H).
Example 60: /\/-{3-r5-({4-chloro-3-r(3-chloro-5-cvanophenyl)oxyl-2-fluorophenyl}methyl)- 1 ,3,4-oxadiazol-2-yllphenyl}-3-(methylsulfonyl)propanamide
Figure imgf000082_0002
Dichloromethane (5 ml_), /V-{3-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}methyl)-1 ,3,4-oxadiazol-2-yl]phenyl}-3-(methylthio)propanamide (52.0 mg, 0.093 mmol) and m-chloroperoxybenzoic acid (46.0 mg, 0.205 mmol, 77% max.) were combined and the mixture was stirred for 30 min at rt. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate and water. The solvent was removed and the crude material was purified via silica gel chromatography to give 34 mg of the title compound. 1H NMR (DMSOd6) δ 10.37 (s, 1 H), 8.27 (s, 1 H), 7.74 - 7.79 (m, 1 H), 7.67 - 7.73 (m, 1 H), 7.56 - 7.61 (m, 1 H), 7.47 - 7.54 (m, 4 H), 7.42 - 7.46 (m, 1 H), 4.45 (s, 2 H), 3.39 (t, 2 H), 2.99 (s, 3 H), 2.80 (d, 2 H). Example 61 : 3-({6-bromo-2-fluoro-3-r(5-phenyl-1 ,3,4-oxadiazol-2-yl)methyllphenyl}oxy)- 5-chlorobenzonitrile
Figure imgf000083_0001
THF (15 ml_), 2-{4-bromo-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}acetohydrazide (300 mg, 0.754 mmol), benzoic acid (91.9 mg, 0.754 mmol), HATU (286 mg, 0.754 mmol) and DIPEA (0.26 ml_, 1.51 mmol) were combined and the mixture was stirred at rt for 45 min. Burgess Reagent (897 mg, 3.77 mmol) was added and the reaction was stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 235 mg of the title compound. 1H NMR
(DMSOd6) δ 7.91-7.89 (m, 2 H), 7.78-7.77 (m, 1 H), 7.64-7.48 (m, 5 H), 7.44-7.40 (m, 2 H), 4.43 (s, 2 H).
Example 62: 2-[(3-chloro-5-cvanophenyl)oxy1-3-fluoro-4-[(5-phenyl-1 ,3,4-oxadiazol-2- vDmethylibenzonitrile
Figure imgf000083_0002
DMF (3.0 ml_), 3-({6-bromo-2-fluoro-3-[(5-phenyl-1 ,3,4-oxadiazol-2- yl)methyl]phenyl}oxy)-5-chlorobenzonitrile (50.0 mg, 0.103 mmol), zinc cyanide (6.04 mg, 0.0517 mmol) and tetrakis(triphenylphosphine) palladium(O) (29.7 mg, 0.0258 mmol) were combined and the mixture was stirred in an Emry Personal Chemistry microwave reactor at 135 0C for 10 min. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 154 mg of the title compound. 1H NMR (DMSO- d6) δ 7.90 (m, 2 H), 7.83 (m, 2 H), 7.52-7.67 (m, 6 H), 4.53 (s, 2 H).
Example 63: 3-chloro-5-fr6-chloro-2-fluoro-3-α5-r2-methyl-4-({r(4SV2.2.5.5-tetramethyl- 1 ,3-dioxolan-4-yllmethyl}oxy)phenyll-1 ,3,4-oxadiazol-2-yl}methyl) phenyl! oxylbenzonitrile
Figure imgf000084_0001
Step A: methyl 4-hydroxy-2-methylbenzoate
Figure imgf000084_0002
A flask was charged with DMF (50 ml_), 4-hydroxy-2-methylbenzoic acid (5.00 g, 32.0 mmol), potassium bicarbonate (3.95 g, 39.5 mmol) and the mixture was stirred at rt for a few min. Methyl iodide was added and the reaction was stirred at 40 0C for 3 h. The reaction was quenched with water, diluted with ethyl acetate and the organic layer was separated. The solvent was removed and the crude material was purified via silica gel chromatography to give 4.9 g of the title compound. 1H NMR (DMSO-c/6) δ 9.94 - 10.14 (m, 1 H), 7.70 (d, 1 H), 6.60 (m, 2 H), 3.70 (s, 3 H), 2.41 (s, 3 H).
Step B: Methyl 2-methyl-4-({[(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4- yl]methyl}oxy)benzoate
Figure imgf000084_0003
Methyl 4-hydroxy-2-methylbenzoate (2.38 g, 14.4 mmol) was combined with [(4S)- 2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl 4-methylbenzenesulfonate (4.51 g, 14.4 mmol), and K2CO3 (3.96 g, 28.7 mmol) in NMP (20 ml.) and heated with stirring at 150 0C for 8 h. The reaction mixture was diluted with EtOAc, washed successively with water, saturated NaHCO3, and brine, dried over MgSO4, filtered and concentrated to dryness. The crude product was purified on an 80 g silica gel cartridge eluted with 0 to 40% EtOAc/hexanes to give the title compound (2.85 g, 0.92 mmol, 64%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.83 (d, 1 H), 6.96 (d, 1 H), 6.91 (dd, 1 H), 4.14 - 4.22 (m, 1 H), 4.06 - 4.13 (m, 2 H), 3.78 (s, 3 H), 2.52 (s, 3 H), 1.36 (s, 3 H), 1.31 (s, 3 H), 1.31 (s, 3 H), 1.1 1 (s, 3 H). Step C: 2-methyl-4-({[(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4- yl]methyl}oxy)benzohydrazide
Figure imgf000085_0001
Ethanol (10 ml_), methyl 2-methyl-4-({[(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4- yl]methyl}oxy)benzoate (253 mg, 0.821 mmol) and hydrazine (2.0 mL) were combined and the mixture was heated at reflux for 2 days. The solvent was removed to give 256 mg of the title compound. 1H NMR (DMSOd6) § 9.27 (s, 1 H), 7.24 (d, 1 H), 6.85 (d, 1 H), 6.80 (dd, 1 H), 4.38 (s, 2 H), 3.96 - 4.16 (m, 3 H), 2.32 (s, 3 H), 1.34 (s, 3 H), 1.29 (s, 3 H), 1.29 (s, 3 H), 1.09 (s, 3 H).
Step D: 3-chloro-5-{[6-chloro-2-fluoro-3-({5-[2-methyl-4-({[(4S)-2,2,5,5-tetramethyl-1 ,3- dioxolan-4-yl]methyl}oxy)phenyl]-1 ,3,4-oxadiazol-2-yl}methyl)phenyl]oxy}benzonitrile
Figure imgf000085_0002
The title compound (152 mg) was prepared using a procedure analogous to General Procedure B from {4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetic acid (100 mg, 0.294 mmol) and 2-methyl-4-({[(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4- yl]methyl}oxy)benzohydrazide (90.6 mg, 0.294 mmol). 1H NMR (DMSO-c/6) δ 7.78 (m, 1 H), 7.71 (d, 1 H), 7.44-7.52 (m, 4 H), 7.03 (m, 1 H), 6.96 (m, 1 H), 4.41 (s, 2 H), 4.12- 4.18 (m, 1 H), 4.04-4.09 (m, 2 H), 2.50 (s, 3 H), 1.32 (s, 3 H), 1.27 (d, 6 H), 1.08 (s, 3 H).
Example 64: 3-chloro-5-r(6-chloro-3-fr5-(4-fr(2SV2.3-dihvdroxy-3-methylbutylloxy>-2- methylphenyl)-1 ,3,4-oxadiazol-2-yllmethyl}-2-fluorophenyl)oxylbenzonitrile
Figure imgf000086_0001
Methanol (5 ml_), 3-chloro-5-{[6-chloro-2-fluoro-3-({5-[2-methyl-4-({[(4S)-2,2,5,5- tetramethyl-1 ,3-dioxolan-4-yl]methyl}oxy)phenyl]-1 ,3,4-oxadiazol-2- yl}methyl)phenyl]oxy}benzonitrile (122 mg, 0.199 mmol), and a catalytic amount of pyridinium p-toluene sulfonate were combined. The mixture was stirred overnight at rt, upon which LCMS indicated no reaction. The reaction mixture was heated for 4 h at 60 0C and neutralized with saturated sodium bicarbonate. The reaction mixture was diluted with ethyl acetate and the organic layer was separated. The solvent was removed and the crude material was purified via silica gel chromatography to give 68 mg of the title compound. 1H NMR (DMSOd6) δ 7.77 (s, 1 H), 7.70 (d, 1 H), 7.44-7.52 (m, 4 H), 6.92- 6.95 (m, 2 H), 5.00 (d, 1 H), 4.41 (s, 2 H), 4.39 (s, 1 H), 4.24 (d, 1 H), 3.82 (t, 1 H), 3.50 (t, 1 H), 2.50 (s, 3 H), 1.10 (s, 3 H), 1.04 (s, 3 H).
Example 65: S-chloro-δ-Re-chloro^-fluoro-S-frδ-O-fluoro^-methylDhenylVI .3.4- oxadiazol-2-yllmethyl}phenyl)oxylbenzonitrile
Figure imgf000086_0002
The title compound (65 mg) was prepared using a procedure analogous to General Procedure A from 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}acetohydrazide (70 mg, 0.198 mmol) and 3-fluoro-2-methylbenzoic acid (30.5 mg, 0.198 mmol). 1H NMR (CDCI3) δ 7.64 (d, 1 H), 7.36 - 7.38 (m, 1 H), 7.32 - 7.34 (m, 1 H), 7.30 - 7.31 (m, 1 H), 7.25 - 7.27 (m, 1 H), 7.19 - 7.23 (m, 1 H), 7.16 (t, 1 H), 7.03 - 7.04 (m, 1 H), 4.36 (s, 2 H), 2.59 (d, 3 H).
Example 66: 3-chloro-5-r(6-chloro-3-{r5-(2-chloro-3-fluorophenyl)-1 ,3,4-oxadiazol-2- yllmethyl}-2-fluorophenyl)oxylbenzonitrile
Figure imgf000087_0001
The title compound (63 mg) was prepared using a procedure analogous to General Procedure A from 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}acetohydrazide (70 mg, 0.198 mmol) and 2-chloro-3-fluorobenzoic acid (34.7 mg, 0.198 mmol). 1H NMR (CDCI3) δ 7.78 (d, 1 H), 7.35 - 7.42 (m, 3 H), 7.31 - 7.35 (m, 2 H), 7.16 (t, 1 H), 7.02 - 7.05 (m, 1 H), 4.39 (s, 2 H).
Example 67: 3-chloro-5-ir6-chloro-3-α5-r2-chloro-4-(methylsulfonvnphenyll-1.3.4- oxadiazol-2-yl}methyl)-2-fluorophenyl1oxy}benzonitrile
Figure imgf000087_0002
The title compound (72 mg) was prepared using a procedure analogous to General Procedure A from 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}acetohydrazide (70 mg, 0.198 mmol) and 2-chloro-4- (methylsulfonyl)benzoic acid (42.4 mg, 0.198 mmol). 1H NMR (CDCI3) δ 8.19 (d, 1 H), 8.10 (d, 1 H), 7.93 (dd, 1 H), 7.33 - 7.37 (m, 1 H), 7.30 - 7.33 (m, 1 H), 7.26 - 7.30 (m, 1 H), 7.16 (t, 1 H), 6.95 - 6.97 (m, 1 H), 4.38 (s, 2 H), 3.09 (s, 3 H).
Example 68: 3-chloro-5-fr6-chloro-3-α5-r2-chloro-4-αr(4SV2.2.5.5-tetramethyl-1.3- dioxolan-4-vHmethyl}oxy)phenyl1-1 ,3,4-oxadiazol-2-yl}methyl)-2- fluorophenylioxylbenzonitrile
Figure imgf000087_0003
Step A: methyl 2-chloro-4-hydroxybenzoate
Figure imgf000088_0001
2-chloro-4-hydroxybenzoic acid (98.0 g, 46.4 mmol) was treated with concentrated H2SO4 (6.5 ml_, 122 mmol) in methanol (45 ml.) and stirred at reflux for 1.5 h. The reaction mixture was cooled in an ice bath. 1 N NaOH (122 ml.) was added dropwise with stirring and cooling and the resultant precipitate was filtered off, washed three times with water and air dried to give the title compound (7.05 g, 37.8 mmol, 81 %) as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.69 (s, 1 H), 7.77 (d, 1 H), 6.90 (d, 1 H), 6.81 (dd, 1 H), 3.79 (s, 3 H).
Step B: methyl 2-chloro-4-({[(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4- yl]methyl}oxy)benzoate
Figure imgf000088_0002
Methyl 2-chloro-4-hydroxybenzoate (2.37 g, 12.7 mmol) was combined with [(4S)- 2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl 4-methylbenzenesulfonate (4.00 g, 12.7 mmol, 1 eq), and K2CO3 (3.51 g, 25.4 mmol) in NMP (25 ml.) and heated with stirring at 150 0C for 14 h. The reaction mixture was diluted with EtOAc, washed once with water, and three times with brine, dried over MgSO4, filtered and concentrated to dryness. The crude product was purified on a 120 g silica gel cartridge eluted with 0 to 30% EtOAc/hexanes to give the title compound (0.91 g, 2.77 mmol, 22%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.84 (d, 1 H), 7.24 (d, 1 H), 7.08 (dd, 1 H), 4.25 (dd, 1 H), 4.05 - 4.17 (m, 2 H), 3.82 (s, 3 H), 1.36 (s, 3 H), 1.31 (s, 3 H), 1.30 (s, 3 H), 1.12 (s, 3 H).
Step C: 2-chloro-4-({[(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4- yl]methyl}oxy)benzohydrazide
Figure imgf000089_0001
Ethanol (10 ml_), methyl 2-chloro-4-({[(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4- yl]methyl}oxy)benzoate (120mg, 0.366 mmol) and hydrazine (2.0 mL) were combined and the mixture was heated at reflux for 2 days. The solvent was removed to give 123 mg of the title compound. 1H NMR (DMSOd6) § 9.41 (s, 1 H), 7.28 (d, 1 H), 7.11 (d, 1 H), 6.96 (dd, 1 H), 4.40 (s, 2 H), 4.10 - 4.21 (m, 1 H), 3.98 - 4.08 (m, 2 H), 1.32 (s, 3 H), 1.26 (d, 6 H), 1.07 (s, 3 H).
Step D: 3-chloro-5-{[6-chloro-3-({5-[2-chloro-4-({[(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4- yl]methyl}oxy)phenyl]-1 ,3,4-oxadiazol-2-yl}methyl)-2-fluorophenyl]oxy}benzonitrile
Figure imgf000089_0002
The title compound (122 mg) was prepared using a procedure analogous to General Procedure B from {4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetic acid (96.6 mg, 0.284 mmol) and 2-chloro-4-({[(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4- yl]methyl}oxy)benzohydrazide (93.2 mg, 0.284 mmol). 1H NMR (DMSOd6) § 7.79 - 7.86 (m, 2 H), 7.50 - 7.57 (m, 3 H), 7.47 (t, 1 H), 7.35 (d, 1 H), 7.16 (dd, 1 H), 4.47 (s, 2 H), 4.26 (dd, 1 H), 4.06 - 4.18 (m, 2 H), 1.35 (s, 3 H), 1.30 (s, 3 H), 1.29 (s, 3 H), 1.11 (s, 3 H).
Example 69: 3-chloro-5-r(6-chloro-3-{r5-(2-chloro-4-{r(2S)-2,3-dihvdroxy-3- methylbutyl1oxy}phenyl)-1 ,3,4-oxadiazol-2-yl1methyl}-2-fluorophenyl)oxy1benzonitrile
Figure imgf000089_0003
THF (3 ml_), water (2 ml_), and 3-chloro-5-{[6-chloro-3-({5-[2-chloro-4-({[(4S)-2,2,5,5- tetramethyl-1 ,3-dioxolan-4-yl]methyl}oxy)phenyl]-1 ,3,4-oxadiazol-2-yl}methyl)-2- fluorophenyl]oxy}benzonitrile (80.0 mg, 0.126 mmol) were combined and treated with 2 drops of sulfuric acid. The mixture was stirred at rt for 8 h, diluted with dichloromethane and washed with saturated sodium bicarbonate. The solvent was removed and the crude material was purified via silica gel chromatography to give 37 mg of the title compound. 1H NMR (DMSOd6) δ 7.83 (s, 1 H), 7.78 - 7.82 (m, 1 H), 7.48 - 7.57 (m, 3 H), 7.46 (t, 1 H), 7.25 (d, 1 H), 7.10 (dd, 1 H), 5.08 (d, 1 H), 4.46 (s, 2 H), 4.45 (s, 1 H), 4.31 (dd, 1 H), 3.87 - 3.94 (m, 1 H), 3.50 - 3.57 (m, 1 H), 1.13 (s, 3 H), 1.07 (s, 3 H).
Example 70: 3-chloro-5-r(6-chloro-3-fr5-(4-fr(1.1 dimethylethylVdimethvnsilyll oxy}-2-methylphenyl)-1 ,3,4-oxadiazol-2-yllmethyl}-2-fluorophenyl)oxyl benzonitrile (Intermediate)
Figure imgf000090_0001
Step A: 4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}-2-methylbenzoic acid.
Figure imgf000090_0002
To a solution of 4-hydroxy-2-methylbenzoic acid (4.20 g, 27.6 mmol) in Λ/,Λ/-dimethyl formamide (20.0 ml.) were added f-butyldimethylsilylchloride (10.2 g, 67.63 mmol) and diisopropylethylamine (14.4 ml_, 82.8 mmol), and the mixture was stirred overnight at rt. The reaction mixture was diluted with hexane and quenched with 1 M phosphoric acid until pH 4 was achieved. The organic layer was separated, washed with brine and the solvent was removed. The crude material was purified via silica gel chromatography to give 4.4 g of the title compound. 1H NMR (CDCI3) δ 7.98 (d, 1 H), 6.43 - 6.83 (m, 2 H), 2.58 (s, 3 H), 0.96 (s, 9 H), 0.21 (s, 6 H).
Step B: 3-chloro-5-[(6-chloro-3-{[5-(4-{[(1 , 1 -dimethylethyl)(dimethyl)silyl]oxy}-2- methylphenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile
Figure imgf000091_0001
The title compound (2.64 g) was prepared using a procedure analogous to General Procedure A from 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}acetohydrazide (2.61 g, 7.37 mmol) and 4-{[(1 ,1- dimethylethyl)(dimethyl)silyl]oxy}-2-methylbenzoic acid (1.96 g, 7.37 mmol). 1H NMR (DMSOd6) δ 7.77 (s, 1 H), 7.68 (d, 1 H), 7.42 - 7.54 (m, 4 H), 6.78 - 6.88 (m, 2 H), 4.41 (s, 2 H), 2.47 (s, 3 H), 0.92 (s, 9 H), 0.19 (s, 6 H).
Example 71 : 3-chloro-5-r(6-chloro-2-fluoro-3-{r5-(4-hvdroxy-2-methylphenylV1.3.4- oxadiazol-2-yllmethyl}phenyl)oxylbenzonitrile
Figure imgf000091_0002
THF (40 ml_), 3-chloro-5-[(6-chloro-3-{[5-(4-{[(1 ,1-dimethylethyl)(dimethyl)silyl]oxy}-2- methylphenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile (2.64 g, 4.51 mmol) and tetrabutylammoniumfluoride (4.51 ml_, 4.51 mmol, 1.0 M solution in THF) were combined and the mixture was stirred at rt for 30 min. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 1.63 g of the title compound. 1H NMR (DMSOd6) δ 10.11 (s, 1 H), 7.80 (t, 1 H), 7.63 (d, 1 H), 7.52 - 7.56 (m, 2 H), 7.50 (d, 1 H), 7.45 - 7.48 (m, 1 H), 6.69 - 6.80 (m, 2 H), 4.42 (s, 2 H), 2.46 (s, 3 H).
Example 71 (alternate procedure): 3-chloro-5-r(6-chloro-2-fluoro-3-fr5-(4-hvdroxy-2- methylphenyl)-1 ,3,4-oxadiazol-2-yllmethyl}phenyl)oxylbenzonitrile
Figure imgf000092_0001
Step A: 3-chloro-5-{[6-chloro-2-fluoro-3-({5-[2-methyl-4-(methyloxy)phenyl]-1 ,3,4- oxadiazol-2-yl}methyl)phenyl]oxy}benzonitrile
Figure imgf000092_0002
THF (50 ml_), 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetohydrazide (1.22 g, 3.45 mmol), 2-methyl-4-(methyloxy)benzoic acid (573 mg, 3.45 mmol), HATU (1.31 mg, 3.45 mmol) and DIPEA (1.20 ml_, 6.89 mmol) were combined and the reaction mixture was stirred at rt for 45 min. Burgess Reagent (4.1 1 g, 17.3 mmol) was added and the reaction was stirred for 4 h. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 2.3 g (approximately 70% pure by LCMS) of a sticky residue. LCMS (ESI+) m/z 484 [M+H].
Step B: 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-hydroxy-2-methylphenyl)-1 ,3,4-oxadiazol- 2-yl]methyl}phenyl)oxy]benzonitrile
Figure imgf000092_0003
Dichloromethane (10 mL), 3-chloro-5-{[6-chloro-2-fluoro-3-({5-[2-methyl-4- (methyloxy)phenyl]-1 ,3,4-oxadiazol-2-yl}methyl)phenyl]oxy}benzonitrile (2.30 g, 4.7 mmol) and boron tribromide (23.8 mL, 23.8 mmol, 1 M solution in dichloromethane) were combined and the reaction mixture was stirred overnight at rt. The reaction was quenched with saturated sodium bicarbonate and diluted with ethyl acetate. The organic layer was separated and the solvent was removed. The crude material was purified via silica gel chromatography to give 980 mg of the title compound. Example 72: 3-r(3-fr5-(4-bromo-2-methylphenylV1.S^-oxadiazol^-yllmethylVe-chloro^- fluorophenyl)oxyl-5-chlorobenzonitrile
Figure imgf000093_0001
The title compound (2.41 g) was prepared using a procedure analogous to General Procedure A from 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}acetohydrazide (2.02 g, 5.71 mmol) and 4-bromo-2-methylbenzoic acid (1.23 g, 5.71 mmol). 1H NMR (DMSOd6) § 7.79 - 7.81 (m, 1 H), 7.74 (d, 1 H), 7.67 - 7.70 (m, 1 H), 7.58 (dd, 1 H), 7.50 - 7.54 (m, 3 H), 7.48 (t, 1 H), 4.46 (s, 2 H), 2.54 (s, 3 H).
Example 73: 3-chloro-5-r(6-chloro-2-fluoro-3-fr5-(2-methyl-4-fr(3ffl-3- piperidinylmethylloxy}phenyl)-1 ,3,4-oxadiazol-2-yllmethyl}phenyl)oxylbenzonitrile
Figure imgf000093_0002
Step A : 1 ,1-Dimethylethyl (3R)-3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1- piperidinecarboxylate
Figure imgf000093_0003
To a solution of 1 ,1-Dimethylethyl (3R)-3-(hydroxymethyl)-1-piperidinecarboxylate (Wirz, B.; Walther, W. Tetrahedron: Asymmetry 1992, 3, 1049-1054.) (2.67 g, 12.5 mmol) in dichloromethane (100 ml.) were added triethylamine (2.60 ml_, 18.7 mmol), 4-N,N- dimethylaminopyridine (0.153 g, 1.25 mmol), followed by p-toluenesulfonyl chloride (3.57 g, 18.7 mmol). The reaction was stirred for 2.5 days and adsorbed onto silica gel. Purification by flash chromatography afforded 4.41 g (95%) of the title compound. 1H NMR (400 MHz, DMSOd6): δ 7.73-7.78 (m, 2 H), 7.43-7.49 (m, 2 H), 3.81-3.90 (m, 2 H), 3.54-3.72 (br s, 2 H), 2.69-2.81 (m, 2 H), 2.39 (s, 3 H), 1.64-1.74 (m, 2 H), 1.47 (m, 1 H), 1.33 (s, 9 H), 1.03-1.30 (m, 2 H). Step B: 1 ,1-dimethylethyl (3R)-3-[({4-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}methyl)-1 ,3,4-oxadiazol-2-yl]-3-methylphenyl}oxy)methyl]-1- piperidinecarboxylate
Figure imgf000094_0001
DMF (3 mL), 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-hydroxy-2-methylphenyl)-1 ,3,4- oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile (30.0 mg, 0.0638 mmol), 1 ,1-dimethylethyl (3R)-3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1-piperidine carboxylate (23.6 mg, 0.0638 mmol) and potassium carbonate (26.4 mg, 0.191 mmol) were combined and the mixture was stirred in an Emry Personal Chemistry microwave reactor at 120 0C for 10 min. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 43 mg of the title compound (-70 pure by LCMS). LCMS (ESI+) m/z 667 [M+H].
Step C: 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-4-{[(3R)-3-piperidinylmethyl] oxy}phenyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile
Figure imgf000094_0002
Dichloromethane (3 mL), 1 ,1-dimethylethyl (3R)-3-[({4-[5-({4-chloro-3-[(3-chloro-5- cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4-oxadiazol-2-yl]-3- methylphenyl}oxy)methyl]-1-piperidinecarboxylate (43 mg, 0.0645 mmol) and trifluoroacetic acid (0.5 mL) were combined and the mixture was stirred at rt for 15 min. The mixture was neutralized with a saturated sodium bicarbonate solution, the organic layer was separated and the solvent was removed. The crude material was purified via silica gel chromatography to give 19 mg of the title compound. 1H NMR (CDCI3) δ 7.78 (d, 1 H), 7.35 - 7.40 (m, 1 H), 7.23 - 7.34 (m, 2 H), 7.09 - 7.18 (m, 1 H), 7.00 - 7.07 (m, 1 H), 6.74 - 6.86 (m, 2 H), 4.32 (s, 2 H), 3.67 - 3.99 (m, 2 H), 3.24 (dd, 1 H), 3.05 (d, 1 H), 2.59 - 2.69 (m, 3 H), 2.49 (t, 1 H), 1.97 - 2.16 (m, 3 H), 1.85 - 1.97 (m, 1 H), 1.63 - 1.80 (m, 1 H), 1.45 - 1.65 (m, 1 H), 1.15 - 1.36 (m, 1 H).
Example 74: 3-chloro-5-r(6-chloro-2-fluoro-3-fr5-(2-methyl-4-fr(2SV2- oxiranylmethylloxy}phenyl)-1 ,3,4-oxadiazol-2-yllmethyl}phenyl)oxylbenzonitrile
Figure imgf000095_0001
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-hydroxy-2-methylphenyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile (700 mg, 1.49 mmol) was dissolved in DMF (10 ml_). Cesium fluoride (1.16 g, 4.47 mmol) was added and the mixture stirred at rt for one h. (2S)-2-Oxiranylmethyl 3-nitrobenzenesulfonate (1.16 g, 4.47 mmol) was added and the mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 690 mg of the title compound. 1H NMR (CDCI3) δ 7.77 (d, 1 H), 7.21 - 7.35 (m, 3 H), 7.13 (t, 1 H), 6.98 - 7.03 (m, 1 H), 6.78 - 6.86 (m, 2 H), 4.30 (s, 2 H), 4.27 (dd, 1 H), 3.96 (dd, 1 H), 3.29 - 3.41 (m, 1 H), 2.87 - 2.96 (m, 1 H), 2.75 (dd, 1 H), 2.62 (s, 3 H).
Example 75: 3-chloro-5-({6-chloro-2-fluoro-3-r(5-{4-r(2-hvdroxy-2-methylpropyl)oxyl-2- methylphenyl}-1 ,3,4-oxadiazol-2-yl)methyl1phenyl}oxy)benzonitrile
Figure imgf000095_0002
2,2-Dimethyloxirane (7 ml_), 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-hydroxy-2- methylphenyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile (84.0 g, 0.179 mmol) and potassium carbonate (74.1 mg, 0.537 mmol) were combined and the mixture was stirred overnight at 66 0C. The volatiles were evaporated, the resulting residue was adsorbed onto silica gel, and the crude material was purified via silica gel chromatography to give 50 mg of the title compound. 1H NMR (CDCI3) δ 7.81 (d, 1 H), 7.36 - 7.39 (m, 1 H), 7.29 - 7.33 (m, 2 H), 7.17 (t, 1 H), 7.01 - 7.05 (m, 1 H), 6.81 - 6.90 (m, 2 H), 4.34 (s, 2 H), 3.84 (s, 2 H), 2.65 (s, 3 H), 1.36 (s, 6 H).
Example 76: 3-chloro-5-r(6-chloro-2-fluoro-3-fr5-(4-fr(2SV2-hvdroxy-3-(4-morDholinvn propylloxy}-2-methylphenyl)-1 ,3,4-oxadiazol-2-yllmethyl}phenyl)oxylbenzonitrile
Figure imgf000096_0001
Dioxane (3 ml_), 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-4-{[(2S)-2- oxiranylmethyl]oxy}phenyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile (53.0 mg, 0.101 mmol) and morpholine (0.1 mL) were combined and the mixture was stirred at 70 0C overnight. The solvent was removed and the crude material was purified via silica gel chromatography to give 37 mg of the title compound. 1H NMR (CDCI3) δ 7.77 (d, 1 H), 7.34 (t, 1 H), 7.25 - 7.30 (m, 2 H), 7.14 (t, 1 H), 6.97 - 7.03 (m, 1 H), 6.79 - 6.86 (m, 2 H), 4.30 (s, 2 H), 4.11 (s, 1 H), 3.97 - 4.05 (m, 2 H), 3.65 - 3.80 (m, 4 H), 2.63 - 2.72 (m, 2 H), 2.61 (s, 3 H), 2.40 - 2.58 (m, 3 H), 1.44 - 1.63 (m, 2 H).
Example 77: 3-chloro-5-r(6-chloro-3-fr5-(4-fr(2SV3-(dimethylamino)-2-hvdroxypropyll oxy}-2-methylphenyl)-1 ,3,4-oxadiazol-2-yllmethyl}-2-fluorophenyl)oxylbenzonitrile
Figure imgf000096_0002
Dioxane (3 mL), 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-4-{[(2S)-2- oxiranylmethyl]oxy}phenyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile (80.0 mg, 0.152 mmol) and dimethylamine (3.0 mL, 0.5 M solution in THF) were combined and the mixture was stirred at 70 0C overnight. The solvent was removed and the crude material was purified via silica gel chromatography to give 41 mg of the title compound. 1H NMR (CDCI3) δ 7.79 (d, 1 H), 7.37 (t, 1 H), 7.29 - 7.34 (m, 2 H), 7.16 (t, 1 H), 7.02 - 7.05 (m, 1 H), 6.82 - 6.89 (m, 2 H), 4.33 (s, 2 H), 3.96 - 4.11 (m, 3 H), 2.64 (s, 3 H), 2.50 - 2.60 (m, 1 H), 2.39 (dd, 1 H), 2.33 (s, 6 H). Example 78: 3-chloro-5-r(6-chloro-2-fluoro-3-fr5-(4-fr(2SV2-hvdroxy-3-(1-Dyrrolidinvn propylloxy}-2-methylphenyl)-1 ,3,4-oxadiazol-2-yllmethyl}phenyl)oxylbenzonitrile
Figure imgf000097_0001
Dioxane (3 ml_), 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-4-{[(2S)-2- oxiranylmethyl]oxy}phenyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile (80.0 mg, 0.152 mmol) and pyrrolidine (0.1 ml.) were combined and the mixture was stirred at 70 0C overnight. The solvent was removed and the crude material was purified via silica gel chromatography to give 37 mg of the title compound. 1H NMR (CDCI3) δ 7.77 (d, 1 H), 7.34 (t, 1 H), 7.25 - 7.31 (m, 2 H), 7.12 - 7.14 (m, 1 H), 7.01 (s, 1 H), 6.79 - 6.87 (m, 2 H), 4.30 (s, 2 H), 3.92 - 4.13 (m, 3 H), 2.80 (dd, 1 H), 2.65 - 2.74 (m, 2 H), 2.61 (s, 3 H), 2.39 - 2.58 (m, 3 H), 1.67 - 1.94 (m, 4 H).
Example 79: 3-chloro-5-r(6-chloro-2-fluoro-3-fr5-(4-fr(2SV2-hvdroxy-3-(4-methyl-1- piperazinyl)propylloxy}-2-methylphenyl)-1 ,3,4-oxadiazol-2- yllmethyl}phenvDoxylbenzonitrile
Figure imgf000097_0002
Dioxane (3 ml_), 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-4-{[(2S)-2- oxiranylmethyl]oxy}phenyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile (80.0 mg, 0.152 mmol) and N-methyl piperazine (0.1 ml.) were combined and the mixture was stirred at 70 0C overnight. The solvent was removed and the crude material was purified via silica gel chromatography to give 44 mg of the title compound. 1H NMR (CDCI3) δ 7.79 (d, 1 H), 7.37 (t, 1 H), 7.29 - 7.34 (m, 2 H), 7.16 (t, 1 H), 7.02 - 7.06 (m, 1 H), 6.81 - 6.89 (m, 2 H), 4.33 (s, 2 H), 4.06 - 4.17 (m, 1 H), 3.93 - 4.06 (m, 2 H), 2.67 - 2.83 (m, 2 H), 2.64 (s, 3 H), 2.37 - 2.61 (m, 8 H), 2.30 (s, 3 H). Example 80: 3-chloro-5-r(6-chloro-2-fluoro-3-fr5-(4-fr(2SV2-hvdroxy-3-(1- piperazinyl)propylloxy}-2-methylphenyl)-1 ,3,4-oxadiazol-2- yllmethyltohenvDoxylbenzonitrile
Figure imgf000098_0001
Step A: 1 ,1-dimethylethyl 4-[(2S)-3-({4-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}methyl)-1 ,3,4-oxadiazol-2-yl]-3-methylphenyl}oxy)-2-hydroxypropyl]-1- piperazinecarboxylate
Figure imgf000098_0002
Dioxane (3 ml_), 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-4-{[(2S)-2- oxiranylmethyl]oxy}phenyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile (80.0 mg, 0.152 mmol) and 1 ,1-dimethylethyl 1-piperazinecarboxylate (250 mg) were combined and the mixture was stirred at 70 0C overnight. The solvent was removed and the crude material was purified via silica gel chromatography to give 84 mg of the title compound. LCMS (ESI+) m/z 712 [M+H]
Step B: 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-{[(2S)-2-hydroxy-3-(1 -piperazinyl) propyl]oxy }-2-methylphenyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile
Figure imgf000098_0003
Dichloromethane (3 ml_), 1 ,1-dimethylethyl 4-[(2S)-3-({4-[5-({4-chloro-3-[(3-chloro-5- cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4-oxadiazol-2-yl]-3-methylphenyl}oxy)-2- hydroxypropyl]-1-piperazinecarboxylate (84 mg, 0.1 18 mmol) and trifluoroacetic acid (0.5 ml.) were combined and the mixture was stirred at rt for 15 min. The mixture was neutralized with a saturated sodium bicarbonate solution, the organics were separated and the solvent was removed. The crude material was purified via silica gel chromatography to give 39 mg of the title compound. 1H NMR (CDCI3) δ 7.77 (d, 1 H), 7.34 (t, 1 H), 7.25 - 7.32 (m, 2 H), 7.14 (t, 1 H), 6.98 - 7.03 (m, 1 H), 6.79 - 6.87 (m, 2 H), 4.31 (s, 2 H), 4.04 - 4.15 (m, 1 H), 3.97 - 4.04 (m, 2 H), 2.86 - 3.00 (m, 4 H), 2.63 - 2.73 (m, 2 H), 2.62 (s, 3 H), 2.50 - 2.56 (m, 2 H), 2.39 - 2.51 (m, 2 H).
Example 81 : 3-chloro-5-r(6-chloro-2-fluoro-3-{r5-(2-methyl-4-{r(2/?)-2- morpholinylmethyl1oxy}phenyl)-1 ,3,4-oxadiazol-2-yl1methyl}phenyl)oxy1benzonitrile
Figure imgf000099_0001
Step A: (2R)-1 -[(2-hydroxyethyl)amino]-3-[(phenylmethyl)oxy]-2-propanol
Figure imgf000099_0002
Benzyl (R)-(-)-glycidyl ether (3.00 g, 18.3 mmol) was dissolved in n-propanol (30 ml.) with stirring. Ethanolamine (4.4 ml_, 73 mmol) was added via syringe, and the reaction was heated to reflux for 16 h. The reaction was cooled to rt and poured into ethyl acetate and half-saturated aqueous sodium bicarbonate. The layers were separated and the organic layer was washed with brine. The combined aqueous layers were extracted with dichloromethane (2x) and ethyl acetate (1x). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated. Purification by flash chromatography provided 4.14 g of the title compound. 1H NMR (400 MHz, DMSO- cfe) δ 7.21-7.34 (m, 5 H), 4.69 (br s, 1 H), 4.44 (s, 2 H), 4.42 (m, 1 H), 3.66 (m, 1 H), 3.27- 3.44 (m, 4 H), 2.40-2.59 (m, 5 H).
Step B: Λ/-(2-hydroxyethyl)-Λ/-{(2R)-2-hydroxy-3-[(phenylmethyl)oxy]propyl}-4- methylbenzenesulfonamide
Figure imgf000099_0003
(2R)-1-[(2-Hydroxyethyl)amino]-3-[(phenylmethyl)oxy]-2-propanol (4.12 g, 18.3 mmol) from Step A was dissolved in dichloromethane (120 ml.) and cooled to 0 0C with stirring. Triethylamine (5.10 ml_, 36.6 mmol) was added followed by p-toluenesulfonyl chloride (3.84 g, 20.1 mmol). The reaction was allowed to warm to rt and stirred for a total of 5 h. The reaction was concentrated onto silica gel and purified by flash chromatography to afford 4.85 g (70% over 2 steps) of the title compound. 1H NMR (400 MHz, DMSO- cfe) δ 7.62-7.69 (m, 2 H), 7.24-7.41 (m, 7 H), 5.11 (d, 1 H), 4.82 (t, 1 H), 4.46 (s, 2 H), 3.84 (m, 1 H), 3.46-3.55 (m, 2 H), 3.34 (d, 2 H), 3.20-3.29 (m, 2 H), 3.05 (m, 1 H), 2.93 (dd, 1 H), 2.37 (s, 3 H).
Step C: (2R)-4-[(4-Methylphenyl)sulfonyl]-2-{[(phenylmethyl)oxy]methyl}-morpholine
Figure imgf000100_0001
Sodium hydride (1.28 g, 60% dispersion in mineral oil, 32.0 mmol) was washed with hexanes (2x), and THF (80 ml.) was added. The mixture was cooled to 0 0C with stirring. Λ/-(2-Hydroxyethyl)-Λ/-{(2R)-2-hydroxy-3-[(phenylmethyl)oxy]propyl}-4- methylbenzenesulfonamide (4.85 g, 12.8 mmol) was dissolved in THF (15 ml.) and added to the reaction flask slowly via syringe. The flask previously containing the diol was rinsed with additional THF (15 ml_), and that solution was added to the reaction via syringe. The reaction was warmed to rt and stirred for 1 h. The reaction was cooled to 0 0C, and 1-(p-toluenesulfonyl)imidazole (2.85 g, 12.8 mmol) was added in a single portion. The reaction was warmed to rt and stirred overnight. The reaction was cooled to 0 0C and quenched by the addition of half-saturated aqueous ammonium chloride solution. The mixture was poured into a separatory funnel with ethyl acetate. The layers were separated, and the organic layer was washed with brine. The combined aqueous layers were extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by flash chromatography afforded 3.07 g (66%) of the title compound. 1H NMR (300 MHz,
DMSOd6) δ 7.61-7.69 (m, 2 H), 7.47-7.55 (m, 2 H), 7.26-7.43 (m, 5 H), 4.48 (s, 2 H), 3.88 (m, 1 H), 3.68 (m, 2 H), 3.38-3.61 (m, 4 H), 2.45 (s, 3 H), 2.26 (m, 1 H), 2.08 (dd, 1 H).
Step D: {(2R)-4-[(4-Methylphenyl)sulfonyl]-2-morpholinyl}methanol
Figure imgf000100_0002
(2R)-4-[(4-Methylphenyl)sulfonyl]-2-{[(phenylmethyl)oxy]methyl}-morpholine (3.07 g, 8.49 mmol) was dissolved in ethyl acetate (100 ml.) with stirring. Palladium (10 wt% on carbon, 0.452 g) was added and the reaction was placed under 1 atmosphere of hydrogen using a balloon apparatus. The reaction was stirred under these conditions for 6 days and filtered through a Celite pad washing with ethyl acetate. The filtrate was concentrated and purification by flash chromatography gave 1.64 g (71%) of the title compound. 1H NMR (400 MHz, DMSOd6) δ 7.59 (d, 2 H), 7.44 (d, 2 H), 4.74 (t, 1 H), 3.81 (m, 1 H), 3.32-3.53 (m, 5 H), 3.26 (m, 1 H), 2.39 (s, 3 H), 2.18 (m, 1 H), 1.95 (m, 1 H).
Step E: 1 ,1-dimethylethyl (2R)-2-(hydroxymethyl)-4-morpholinecarboxylate
Figure imgf000101_0001
Sodium metal (2.78 g, 121 mmol) was placed in a flask with naphthalene (17.0 g, 133 mmol) in THF (140 ml.) and sonicated for 2.5 h to give a dark green solution. In a separate flask {(2R)-4-[(4-methylphenyl)sulfonyl]-2-morpholinyl}methanol (1.64 g, 6.04 mmol) was dissolved in THF (40 ml.) and cooled to 0 0C. The sodium naphthalenide solution (20 ml.) was added slowly via syringe and the reaction was checked by TLC. An additional 5 ml. of the sodium naphthalenide solution was added slowly via syringe. The reaction was stirred for 5 min and quenched by the addition of 2 N aqueous hydrochloric acid solution (-150 ml_). The mixture was poured into a separatory funnel and extracted with diethyl ether (2x). The diethyl ether layers were discarded. The aqueous layer was basified with solid sodium hydroxide and extracted with dichloromethane, 4:1 dichloromethane:isopropanol, and 4:1 ethyl acetate:isopropanol. These combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Very little material was obtained and was thus discarded. To the aqueous layer was added 100 ml. of dioxane and di-f-butyl dicarbonate (1.32 g, 6.05 mmol). The addition of three large scoops of solid sodium bicarbonate and additional di- f-butyl dicarbonate (1.32 g, 6.05 mmol) was followed by one large scoop of solid sodium hydroxide. The mixture was stirred overnight, and the majority of the dioxane was removed in vacuo. The aqueous layer was extracted with dichloromethane (2x) and ethyl acetate (1x). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by flash chromatography provided 1.07 g (82%) of the title compound. 1H NMR (400 MHz, CDCI3): δ 3.75-3.96 (m, 3 H), 3.66 (dd, 1 H), 3.43-3.60 (m, 3 H), 2.92 (m, 1 H), 2.74 (m, 1 H), 1.45 (s, 9 H).
Step F: 1 ,1-dimethylethyl (2R)-2-[({4-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}methyl)-1 ,3,4-oxadiazol-2-yl]-3-methylphenyl}oxy)methyl]-4- morpholinecarboxylate
Figure imgf000102_0001
Dichloromethane (5 ml_), 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-hydroxy-2-methyl phenyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile (120 mg, 0.255 mmol), 1 ,1- dimethylethyl (2R)-2-(hydroxymethyl)-4-morpholinecarboxylate (165 mg, 0.765 mmol), triphenylphosphine (534 mg, 2.04 mmol), and diisopropyl azodicarboxylate (206 mg, 1.02 mmol) were combined at 0 0C, and the reaction mixture was stirred at rt for 6 h. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography. The title compound co-eluted with approximately 30% of unreacted starting material (132 mg combined weight). This was used without further purification in the next step. LCMS (ESI+) m/z 669 [M+H].
Step G: 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-4-{[(2R)-2- morpholinylmethyl]oxy}phenyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile
Figure imgf000102_0002
Dichloromethane (3 ml_), 1 ,1-dimethylethyl (2R)-2-[({4-[5-({4-chloro-3-[(3-chloro-5- cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4-oxadiazol-2-yl]-3- methylphenyl}oxy)methyl]-4-morpholinecarboxylate (132 mg, 0.197 mmol) and trifluoroacetic acid (0.5 ml.) were combined and the mixture was stirred at rt for 15 min. The mixture was neutralized with a saturated sodium bicarbonate solution, the organics were separated and the solvent was removed. The crude material was purified via silica gel chromatography to give 42 mg of the title compound. 1H NMR (CDCI3) δ 7.77 (d, 1 H), 7.34 (t, 1 H), 7.26 - 7.31 (m, 2 H), 7.14 (t, 1 H), 6.99 - 7.03 (m, 1 H), 6.78 - 6.86 (m, 2 H), 4.31 (s, 2 H), 3.98 - 4.06 (m, 1 H), 3.90 - 3.96 (m, 2 H), 3.82 - 3.89 (m, 1 H), 3.67 (t, 1 H), 3.02 (d, 1 H), 2.87 - 2.96 (m, 1 H), 2.81 - 2.87 (m, 1 H), 2.71 - 2.79 (m, 1 H), 2.61 (s, 3 H).
Example 82: 3-chloro-5-r(6-chloro-2-fluoro-3-{r5-(2-methyl-4-{r2-(4- morpholinyl)ethyl1oxy}phenyl)-1 ,3,4-oxadiazol-2-yl1methyl}phenyl)oxy1benzonitrile
Figure imgf000103_0001
Dichloromethane (5 ml_), 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-hydroxy-2-methylphenyl)- 1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile (120 mg, 0.255 mmol), 2-(4- morpholinyl)ethanol (86.5 mg, 0.765 mmol), PS-triphenylphosphine (680 mg, 2.04 mmol), and di-f-butyl azodicarboxylate (235 mg, 1.02 mmol) were combined at 0 0C and the reaction mixture was stirred at rt for 6 h. The reaction mixture was diluted with ethyl acetate, filtered and the filtrate washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 15 mg of the title compound. 1H NMR (CDCI3) δ 7.78 (d, 1 H), 7.34 (t, 1 H), 7.25 - 7.32 (m, 2 H), 7.16 (t, 1 H), 6.98 (d, 1 H), 6.75 - 6.83 (m, 2 H), 4.38 - 4.46 (m, 2 H), 4.33 (s, 2 H), 3.88 - 4.08 (m, 4 H), 3.67 - 3.77 (m, 2 H), 3.49 - 3.59 (m, 2 H), 3.06 (d, 2 H), 2.60 (s, 3 H).
Example 83: 3-chloro-5-r(6-chloro-2-fluoro-3-fr5-(2-methyl-4-fr3-(4-morpholinvn propylloxy}phenyl)-1 ,3,4-oxadiazol-2-yllmethyl}phenyl)oxylbenzonitrile
Figure imgf000103_0002
Dichloromethane (5 ml_), 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-hydroxy-2-methylphenyl)- 1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile (86.0 mg, 0.183 mmol) and 3-(4- morpholinyl)-1-propanol (79.6 mg, 0.549 mmol), PS-triphenylphosphine (488 mg, 1.46 mmol), and di-f-butyl azodicarboxylate (168 mg, 0.732 mmol) were combined at 0 0C and stirred at rt for 6 h. The reaction mixture was diluted with ethyl acetate, filtered and the filtrate washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 33 mg of the title compound. 1H NMR (CDCI3) δ 7.77 (d, 1 H), 7.33 - 7.37 (m, 1 H), 7.24 - 7.31 (m, 2 H), 7.15 (t, 1 H), 6.96 - 7.03 (m, 1 H), 6.73 - 6.83 (m, 2 H), 4.31 (s, 2 H), 4.09 (t, 2 H), 4.00 (s, 4 H), 3.56 (s, 2 H), 3.16 - 3.29 (m, 2 H), 2.82 - 2.96 (m, 2 H), 2.55 (s, 3 H), 2.23 - 2.34 (m, 2 H).
Example 84: 3-chloro-5-[(6-chloro-3-{[5-(4-{[3-(dimethylamino)propyl1oxy}-2- methylphenyl)-1 ,3,4-oxadiazol-2-yl1methyl}-2-fluorophenyl)oxy1benzonitrile
Figure imgf000104_0001
Dichloromethane (5 ml_), 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-hydroxy-2-methylphenyl)-
1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile (70.0 mg, 0.149 mmol), 3- (dimethylamino)-i-propanol (46.1 mg, 0.447 mmol), PS-triphenylphosphine (397 mg, 1.19 mmol), and di-f-butyl azodicarboxylate (135 mg, 0.588 mmol) were combined at 0 0C and the reaction mixture was stirred at rt for 6 h. The reaction mixture was diluted with ethyl acetate, filtered and the filtrate washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 27 mg of the title compound. 1H NMR (CDCI3) δ 7.77 (d, 1 H), 7.34 (t, 1 H), 7.27 - 7.32 (m, 2 H), 7.15 (t, 1 H), 6.96 - 7.01 (m, 1 H), 6.73 - 6.81 (m, 2 H), 4.31 (s, 2 H), 4.10 (s, 2 H), 3.18 - 3.32 (m, 2 H), 2.86 (s, 6 H), 2.61 (s, 3 H), 2.28 (s, 2 H).
General Procedures for Array Syntheses of Oxadiazoles (I)
Method A: A solution of 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}acetohydrazide (35.4 mg, 100 μmol, 1 eq) and DIPEA (52 μl_, 300 μmol, 3 eq) in dry THF (1 ml.) was added in combinatorial fashion to vials containing solid carboxylic acid (see table for stoichiometry) and HATU (38 mg, 100 μmol, 1 eq) and stirred for 16 h at 55 0C to form the intermediate diacyl hydrazides. The reaction mixtures were allowed to cool to ambient temperature and then treated with a solution of methoxycarbonylsulfamoyl-triethylammonium hydroxide, inner salt (Burgess Reagent, 120 mg, 500 μmol, 5 eq) in dry THF (1 ml.) for 8 h at 55 0C. The reaction mixtures were evaporated to dryness, dissolved in DCM (1.5 ml_), washed with water, the organic phases isolated and concentrated to dryness. The crude products were purified by RP- HPLC on a Gemini™ C-18, 3 x 7.5 cm, 5 micron column eluted with 10 to 100% CH3CN in water with 0.07% NH4OH buffer at 50ml_/min.
Method B: A solution of 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}acetohydrazide (17.7 mg, 50 μmol, 1 eq) and DIPEA (26 μl_, 150 μmol, 3 eq) in dry THF (0.5 ml.) was added in combinatorial fashion to vials containing solid carboxylic acid (see table for stoichiometry) and HATU (19 mg, 50 μmol, 1 eq) and stirred for 16 h at 55 0C to form the intermediate diacyl hydrazides. The reaction mixtures were allowed to cool to ambient temperature and then treated with a solution of methoxycarbonylsulfamoyl-triethylammonium hydroxide, inner salt (Burgess Reagent, 60 mg, 250 μmol, 5 eq) in dry THF (0.5 ml.) for 8 h at 55 0C. The reaction mixtures were evaporated to dryness, dissolved in DCM (1.5 ml_), washed with water, the organic phases isolated and concentrated to dryness. The crude products were purified by RP- HPLC on a Gemini™ C-18, 3 x 7.5 cm, 5 micron column eluted with 10 to 100% CH3CN in water with 0.07% NH4OH buffer at 50mL/min.
3-chloro-5-(6-chloro-2-fluoro-3-((5-(5-hydroxy-2-methylphenyl)-1 ,3,4-oxadiazol-2- yl)methyl)phenoxy)benzonitrile
3-(3-((5-(2-amino-6-methylphenyl)-1 ,3,4-oxadiazol-2-yl)methyl)-6-chloro-2- fluorophenoxy)-5-chlorobenzonitrile
3-(3-((5-(2-bromo-3-hydroxy-4,6-dimethylphenyl)-1 ,3,4-oxadiazol-2-yl)methyl)-6-chloro-2- fluorophenoxy)-5-chlorobenzonitrile 3-chloro-5-(6-chloro-2-fluoro-3-((5-(4-hydroxy-1 -methylnaphthalen-2-yl)-1 ,3,4-oxadiazol-
2-yl)methyl)phenoxy)benzonitrile
Final products obtained by either of the above methods were characterized by analytical LC-MS, the results of which are tabulated below.
Table 2. Synthetic Details for Oxadiazoles Prepared via Array Methods A and B ES+ m/z
Figure imgf000106_0001
Example 88: 3-chloro-5-r(6-chloro-2-fluoro-3-{r5-(2-methyl-5-nitrophenyl)-1 ,3,4- oxadiazol-2-vHmethyl}phenyl)oxy1benzonitrile
Figure imgf000106_0002
THF (3 ml_), 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetohydrazide (206 mg, 0.581 mmol), 2-methyl-5-nitrobenzoic acid (105 mg, 0.581 mmol), HATU (221 mg, 0.581 mmol) and DIPEA (0.20 ml_, 1.16 mmol) were combined and the mixture was stirred at RT. Burgess Reagent (268 mg, 1.13 mmol) was added and the reaction was stirred at RT for 4 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 120 mg of the title compound. 1 H NMR (400 MHz, CHLOROFORM-tf) δ ppm 8.74 (d, 1 H), 8.26 (dd, 1 H), 7.55 (d, 1 H), 7.31 - 7.40 (m, 3 H), 7.18 (t, 1 H), 7.03 (s, 1 H), 4.40 (s, 2 H), 2.83 (s, 3 H).
Example 89: 3-r(3-{r5-(5-amino-2-methylphenyl)-1 ,3,4-oxadiazol-2-yllmethyl}-6-chloro-2- fluorophenyl)oxy1-5-chlorobenzonitrile
Figure imgf000106_0003
A solution of 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-5-nitrophenyl)-1 ,3,4-oxadiazol- 2-yl]methyl}phenyl)oxy]benzonitrile (235 mg, 0.471 mmol) and sodium hydrosulfite (492 mg, 2.83 mmol) in water (3 ml.) and THF (6 ml.) was stirred for 3 hours at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water. The organic layer was further washed with brine and dried over magnesium sulfate. The solvent was removed and the crude material was purified via silica gel chromatography to give 88 mg of the title compound. 1 H NMR (400 MHz, DMSO-c/6) d ppm 7.77 (s, 1 H), 7.39 - 7.55 (m, 4 H), 7.02 (d, 1 H), 6.98 (d, 1 H), 6.64 (dd, 1 H), 5.17 (s, 2 H), 4.42 (s, 2 H), 2.31 (s, 3 H).
Example 90: 3-chloro-5-r(6-chloro-3-{r5-(2-ethylphenyl)-1 ,3,4-oxadiazol-2-yllmethyl}-2- fluorophenvDoxyibenzonitrile
Figure imgf000107_0001
THF (5 ml_), 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetohydrazide (50.0 mg, 0.141 mmol), 2-ethylbenzoic acid (21.2 mg, 0.141 mmol), HATU (53.6 mg, 0.141 mmol,) and DIPEA (0.049 ml_, 0.282 mmol) were combined and the reaction mixture was stirred at room temperature for 45 minutes. Methoxycarbonyl sulfamoyltriethylammonium hydroxide inner salt (130 mg, 0.565 mmol) was added and the reaction was stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 37 mg of the title compound. 1 H NMR (400 MHz, CHLOROFORM-tf) δ ppm 7.80 (d, 1 H), 7.38 - 7.48 (m, 1 H), 7.25 - 7.37 (m, 5 H), 7.13 (s, 1 H), 7.01 (s, 1 H), 4.33 (s, 2 H), 3.03 (q, 2 H), 1.19 (t, 3 H).
Example 91 : 3-chloro-5-fr6-chloro-2-fluoro-3-({5-r2-(trifluoromethvnphenyll-1.3.4- oxadiazol-2-yl}methyl)phenylloxy}benzonitrile
Figure imgf000107_0002
THF (5 ml_), 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetohydrazide (50.0 mg, 0.141 mmol), 2-(trifluoromethyl)benzoic acid (26.8 mg, 0.141 mmol), HATU (53.6 mg, 0.141 mmol,) and DIPEA (0.049 ml_, 0.282 mmol) were combined and the reaction mixture was stirred at room temperature for 45 minutes. Methoxycarbonyl sulfamoyltriethylammonium hydroxide inner salt (130 mg, 0.565 mmol) was added and the reaction was stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 59 mg of the title compound. 1 H NMR (400 MHz, CHLOROFORM-tf) δ ppm 7.95 - 8.07 (m, 1 H), 7.77 - 7.88 (m, 1 H), 7.62 - 7.74 (m, 2 H), 7.24 - 7.37 (m, 3 H), 7.13 (s, 1 H), 6.99 (s, 1 H), 4.34 (s, 2 H).
Example 92: 3-chloro-5-ir6-chloro-2-fluoro-3-α5-r2-fluoro-6-(trifluoromethvnphenyll-1.3.4- oxadiazol-2-yl}methyl)phenylloxy}benzonitrile
Figure imgf000108_0001
THF (5 ml_), 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetohydrazide (70 mg, 0.198 mmol), 2-fluoro-6-(trifluoromethyl)benzoic acid (41.1 mg, 0.198 mmol), HATU (75.2 mg, 0.198 mmol,) and DIPEA (0.069 ml_, 0.396 mmol) were combined and the reaction mixture was stirred at room temperature for 45 minutes. Methoxycarbonyl sulfamoyltriethylammonium hydroxide inner salt (236 mg, 0.990 mmol) was added and the reaction was stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 12 mg of the title compound. 1 H NMR (400 MHz, CHLOROFORM-tf) δ ppm 7.65 - 7.81 (m, 1 H), 7.57 - 7.65 (m, 1 H), 7.44 (t, 1 H), 7.31 (d, 2 H), 7.17 - 7.26 (m, 1 H), 7.13 (s, 1 H), 6.97 (s, 1 H), 4.35 (s, 2 H).
Example 93: 3-chloro-5-r(6-chloro-2-fluoro-3-fr5-(4-formyl-2-methylphenylV1.3.4- oxadiazol-2-yllmethyl}phenyl)oxylbenzonitrile
Figure imgf000109_0001
To a solution of 3-chloro-5-[(6-chloro-3-{[5-(4-ethenyl-2-methylphenyl)-1 ,3,4-oxadiazol-2- yl]methyl}-2-fluorophenyl)oxy]benzonitrile (136 mg, 0.283 mmol) in dioxane (8 ml.) and water (4 mL) was added sodium periodate (182 mg, 0.849 mmol), followed by osmium tetroxide (2.5 % solution in t-butanol) (0.070 mL, 5.67 uL) and the reaction mixture was stirred for 2 hours at RT. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 71 mg of the title compound. 1 H NMR (400 MHz, DMSO-c/6) d ppm 10.02 (s, 1 H), 8.01 (d, 1 H), 7.91 (s, 1 H), 7.86 (s, 1 H), 7.77 (s, 1 H), 7.48 - 7.53 (m, 3 H), 7.45 (s, 1 H), 4.47 (s, 2 H), 2.62 (s, 3 H).
Example 94: 3-chloro-5-r(6-chloro-3-{r5-(4-ethenyl-2-methylphenyl)-1 ,3,4-oxadiazol-2- yllmethyl}-2-fluorophenvDoxylbenzonitrile
Figure imgf000109_0002
To a solution of 3-[(3-{[5-(4-bromo-2-methylphenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-6- chloro-2-fluorophenyl)oxy]-5-chlorobenzonitrile (2.07 g, 3.88 mmol), potassium vinyltrifluoroborate (775mg, 5.83 mmol) and triethylamine (0.8. mL) in n-propanol (20 mL) was added PdCI2(dppf)DCM (127 mg, 0.155 mmol) and the reaction mixture was stirred at 100 0C for 5 hours. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 1.81 g of the title compound. 1 H NMR (400 MHz, DMSOd6) d ppm 7.76 - 7.82 (m, 2 H), 7.50 - 7.56 (m, 4 H), 7.45 - 7.50 (m, 2 H), 6.75 (dd, 1 H), 5.99 (d, 1 H), 5.39 (d, 1 H), 4.47 (s, 2 H), 2.56 (s, 3 H).
Example 95: 3-chloro-5-{r6-chloro-3-({5-r4-(1 ,2-dihydroxyethyl)-2-methylphenyll-1 ,3,4- oxadiazol-2-yl}methyl)-2-fluorophenyl1oxy}benzonitrile
Figure imgf000110_0001
To a solution of 3-chloro-5-[(6-chloro-3-{[5-(4-ethenyl-2-methylphenyl)-1 ,3,4-oxadiazol-2- yl]methyl}-2-fluorophenyl)oxy]benzonitrile (90.0 mg, 0.188 mmol) in dioxane (4 ml.) and water (2 mL) was added NMO (26.5 mg, 0.226 mmol), followed by osmium tetroxide (2.5 % solution in t-butanol) (0.050 mL, 3.75 umol) and the reaction mixture was stirred for 2 hours at RT. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 15 mg of the title compound. 1 H NMR (400 MHz, CHLOROFORM-d) d ppm 7.80 (d, 1 H), 7.30 - 7.36 (m, 2 H), 7.21 - 7.30 (m, 3 H), 7.12 - 7.18 (m, 1 H), 6.97 (s, 1 H), 4.75 - 4.93 (m, 1 H), 4.32 (s, 2 H), 3.72 - 3.84 (m, 1 H), 3.56 - 3.68 (m, 1 H), 2.78 - 2.92 (m, 1 H), 2.62 (s, 3 H), 2.13 - 2.34 (m, 1 H).
Example 96: 3-chloro-5-fr6-chloro-2-fluoro-3-({5-r2-methyl-4-αr2-(methylsulfonvn ethyllamino} methyl)phenyll-1 ,3,4-oxadiazol-2-yl}methyl)phenylloxy}benzonitrile
Figure imgf000110_0002
To a solution of 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-formyl-2-methylphenyl)-1 ,3,4- oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile and 2-(methylsulfonyl)ethanamine in DCE was added sodium triacetoxyborohydride and the reaction mixture was stirred at RT overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 44 mg yield (72%). 1 H NMR (400 MHz, CHLOROFORM-d) d ppm 7.82 (d, 1 H), 7.36 (t, 1 H), 7.29 - 7.35 (m, 2 H), 7.22 - 7.29 (m, 2 H), 7.17 (t, 1 H), 7.00 - 7.04 (m, 1 H), 4.35 (s, 2 H), 3.84 (s, 2 H), 3.10 - 3.33 (m, 4 H), 2.99 (s, 3 H), 2.65 (s, 3 H), 1.66 - 1.90 (m, 1 H). Example 97: 3-chloro-5-r(6-chloro-3-{r5-(4-{r(2,3-dihvdroxypropyl)aminolmethyl}-2- methylphenyl)-1 ,3,4-oxadiazol-2-yllmethyl}-2-fluorophenyl)oxylbenzonitrile
Figure imgf000111_0001
Step A: 3-chloro-5-{[6-chloro-3-({5-[4-({[(2,2-dimethyl-1 ,3-dioxolan-4- yl)methyl]amino}methyl)-2-methylphenyl]-1 ,3,4-oxadiazol-2-yl}methyl)-2- fluorophenyl]oxy}benzonitrile
To a solution of 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-formyl-2-methylphenyl)-1 ,3,4- oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile and 2-(methylsulfonyl)ethanamine in DCE was added sodium triacetoxyborohydride and the reaction mixture was stirred at RT overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 120 mg of the title compound. 1 H NMR (400 MHz, CHLOROFORM-tf) δ ppm 7.79 (d, 1 H), 7.34 (s, 1 H), 7.25 - 7.32 (m, 4 H), 7.14 (s, 1 H), 7.01 (s, 1 H), 4.32 (s, 2 H), 4.20 - 4.28 (m, 1 H), 3.98 - 4.08 (m, 1 H), 3.80 - 3.87 (m, 2 H), 3.67 (t, 1 H), 2.72 (d, 2 H), 2.63 (s, 3 H), 1.39 (s, 3 H), 1.33 (s, 3 H).
Step B: 3-chloro-5-[(6-chloro-3-{[5-(4-{[(2,3-dihydroxypropyl)amino]methyl}-2- methylphenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile
To a solution of 3-chloro-5-{[6-chloro-3-({5-[4-({[(2,2-dimethyl-1 ,3-dioxolan-4- yl)methyl]amino}methyl)-2-methylphenyl]-1 ,3,4-oxadiazol-2-yl}methyl)-2- fluorophenyl]oxy}benzonitrile (120 mg, 0.189 mmol) in methanol (5 ml.) was added HCI (1.0 M solution) (0.757 ml_, 0.757 mmol) and the mixture was stirred at RT for 2 hours. The reaction mixture was diluted with EtOAc and washed sequentially with saturated NaHCO3 and brine. The solvent was removed and the crude material was purified via silica gel chromatography to give 73 mg of the title compound. 1 H NMR (400 MHz, CHLOROFORM-tf) δ ppm 7.78 (d, 1 H), 7.33 (s, 1 H), 7.18 - 7.32 (m, 4 H), 7.14 (s, 1 H), 6.99 (s, 1 H), 4.32 (s, 3 H), 3.72 - 3.91 (m, 3 H), 3.64 - 3.72 (m, 1 H), 3.50 - 3.61 (m, 1 H), 3.44 (s, 1 H), 2.75 - 2.85 (m, 1 H), 2.69 (dd, 1 H), 2.62 (s, 3 H). Example 98: 3-chloro-5-fr6-chloro-2-fluoro-3-α5-r2-methyl-4-(4- morpholinylmethyl)phenyll-1 ,3,4-oxadiazol-2-yl}methyl)phenylloxy}benzonitrile
Figure imgf000112_0001
To a solution of 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-formyl-2-methylphenyl)-1 ,3,4- oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile (70 mg, 0.145 mmol) and morpholine (0.025 ml, 0.290 mmol) in DCE (5.00 ml) was added sodium triacetoxyborohydride (77 mg, 0.363 mmol) and the mixture was stirred overnight at RT. The mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified to give the title compound, 69 mg. 1 H NMR (400 MHz, CHLOROFORM-c/) δ ppm 7.81 (d, 1 H), 7.37 (s, 1 H), 7.28 - 7.33 (m, 4 H), 7.16 (t, 1 H), 7.03 (s, 1 H), 4.35 (s, 2 H), 3.64 - 3.83 (m, 4 H), 3.51 (s, 2 H), 2.66 (s, 3 H), 2.31 - 2.55 (m, 4 H).
Example 99: 3-chloro-5-{r6-chloro-2-fluoro-3-({5-r3-fluoro-2-methyl-4-(methyloxy)phenyll- 1 ,3,4-oxadiazol-2-yl}methyl)phenylloxy}benzonitrile
Figure imgf000112_0002
Step A: 3-fluoro-2-methyl-4-(methyloxy)benzoic acid
To a solution of 4-methoxy-3-fluorobenzoic acid (5.80 g, 34.1 mmol) in THF (40 ml) at - 78 0C was added BuLi (46.9 ml, 75.0 mmol) over 30 minutes, and the mixture was stirred for an additional 1.5 hr. Methyl iodide (17.05 ml, 273 mmol) was added and the reaction mixture was warmed to RT. The mixture was quenched with water, and acidified with 1 N HCI. The precipitate was collected was further purified via reverse phase HPLC to give (3.37 g, 53.7 % yield) of the title compound. 1 H NMR (DMSO-c/6) δ ppm 12.71 (s, 1 H) 7.48 - 7.87 (m, 1 H) 7.02 (t, 1 H) 3.83 (s, 3 H) 2.39 (d, 3 H). Step B: 3-chloro-5-{[6-chloro-2-fluoro-3-({5-[3-fluoro-2-methyl-4-(methyloxy)phenyl]- 1 ,3,4-oxadiazol-2-yl}methyl)phenyl]oxy}benzonitrile
THF (50 ml_), 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetohydrazide (1.22 g, 3.45 mmol), 3-fluoro-2-methyl-4-(methyloxy)benzoic acid (635 mg, 3.45 mmol), HATU (1.31 g, 3.45 mmol,) and DIPEA (1.20 ml_, 6.89 mmol) were combined and the reaction mixture was stirred at room temperature for 45 minutes. Methoxycarbonyl sulfamoyltriethylammonium hydroxide inner salt (4.1 1g, 17.3 mmol) was added and the reaction was stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 1.44 g of the title compound. 1 H NMR (400 MHz, CHLOROFORM-tf) δ ppm 7.60 (d, 1 H), 7.36 (s, 1 H), 7.27 - 7.35 (m, 2 H), 7.16 (s, 1 H), 7.02 (s, 1 H), 6.89 (t, 1 H), 4.33 (s, 2 H), 3.93 (s, 3 H), 2.58 (s, 3 H).
Example 100: S-chloro-δ-rfe-chloro^-fluoro-S-frδ-O-fluoro^-hvdroxy^-methylDhenvIV 1 ,3,4-oxadiazol-2-yllmethyl}phenyl)oxylbenzonitrile
Figure imgf000113_0001
To a solution of 3-chloro-5-{[6-chloro-2-fluoro-3-({5-[3-fluoro-2-methyl-4- (methyloxy)phenyl]-1 ,3,4-oxadiazol-2-yl}methyl)phenyl]oxy}benzonitrile (1.43 g 2.85 mmol) in DCM (10 ml.) was added boron tribromide (1.0 M solution in DCM, 14.2 ml_, 14.2 mmol) and the reaction mixture was stirred overnight at RT. The reaction mixture was quenched with saturated NaHCOs, diluted with EtOAc, and the organics were separated. The solvent was removed and the crude material was purified via silica gel chromatography to give 1.03 g of the title compound. 1 H NMR (400 MHz, DMSO-c/6) δ ppm 10.56 (s, 1 H), 7.77 (s, 1 H), 7.36 - 7.55 (m, 5 H), 6.90 (t, 1 H), 4.41 (s, 2 H), 2.41 (d, 3 H).
BIOLOGICAL SECTION Inhibition of Viral Replication I. HeLa Cell Assay
The HeLa cell assay described herein is a modified version of Kimpton J. and Emerman M., Detection of replication-competent and pseudotyped human immunodeficiency virus with a sensitive cell line on the basis of activation of an integrated β-galactosidase gene, J. Virol. 66:2232-2239 (1992), in which HIV- 1 infection is detected by the activation of an HIV-LTR driven β-galactosidase reporter that is integrated into the genome of a CD4+ HeLa cell line. Quantitation of β -galactosidase is achieved by measuring the activation of a chemiluminescent substrate (Applied Biosystems). The concentration of each compound required to inhibit 50% (IC50) of the HIV-1 induced β -galactosidase signal, relative to untreated controls, is determined for each isogenic, recombinant virus.
A. Materials
HeLa-CD4-LTR- β -gal cell line (AIDS Research and Reference Reagent Program, Division of AIDS, NIAID)
DMEM (GibcoBRL # 12430-047)
Trypsin-EDTA (GibcoBRL #25300-054)
Heat inactivated Fetal Bovine Serum (FBS) (Hyclone # SH30070.03)
Geneticin (GibcoBRL # 10131-035) Hygromycin B (GibcoBRL #1687-010)
96-well, black, clear-bottom, tissue culture-treated plates (Costar # 3904)
0.45 micron cellulose acetate filtration unit (Corning # 430768)
DEAE-dextran (Sigma # D-9885)
Phosphate Buffered Saline (PBS) (GibcoBRL #14190-144) Dimethyl Sulfoxide (DMSO) (ATCC # 741625)
Gal-Screen Reporter Gene Assay System (Applied Biosystems # T1031 )
B. Growth and Maintenance of the CD4-HIV LTR- β -gal HeLa cell line.
HeLa-CD4-LTR- β -gal cells are propagated in DMEM containing 10% fetal bovine serum + 0.2 mg/ml geneticin + 0.1 mg/ml hygromycin B. Cells are split by standard trypsinization when confluency reaches 80% (roughly every 2 to 3 days).
C. Construction of HIV-1 reverse transcriptase (RT) mutants
DNA encoding the HIV-1 reverse transcriptase is subcloned from a M13 phage into a general shuttle vector, pBCSK+, as a -1.65 kbp EcoRI/Hindlll ended DNA fragment. The HIV DNA insert of the resulting plasmid, is completely sequenced on both strands prior to use in site directed mutagenesis experiments. Specific amino acid replacements are made using Stratagene Quick Change reagents and mutagenic oligonucleotides. The mutations that are made include K103N, V106A, Y181 C, and Y188L. Following mutagenesis, the entire mutant RT coding sequence is verified by sequencing both DNA strands.
D. Construction of isogenic HIV-1 RT mutant virus K103N, V106A, Y181 C, and Y188L mutant HIV-1 strains and wild type strains are isolated by a modified Recombinant Virus Assay (Kellam P. and Larder B., Recombinant virus assay: a rapid, phenotypic assay for assessment of drug susceptibility of human immunodeficiency virus type 1 isolates, Antimicrobial Agents and Chemotherapy, 38:23- 30, 1994). Ten million MT4 T-cells (maintained in RPMI containing 10% fetal bovine serum, split 1 :5 every 5 to 6 days) are co-transfected with EcoRI/Hindlll digested mutant RT plasmid and .Bst Ell-digested HIV-1 HXB2ΔRT DNA in the presence of DMRIE-C transfection reagent (Gibco) according to supplier's recommended protocol. Each mutant RT coding sequence is crossed into the RT-deleted HIV-1 viral DNA backbone by in vivo homologous recombination. Transfected cell cultures are expanded and monitored until syncitia formation and CPE are extensive. Virus is harvested by clear spin of the culture supernatants, filtration of the supernatants through a 0.45 micron membrane and frozen at - 800C as primary stocks. Recombinant progeny virus is sequenced in the RT region to confirm the mutant genotype. Some virus stocks require further expansion by infection of MT4 cells, harvested as above and stored as frozen aliquots. All stocks are titered in HeLa MAGI cells for assay.
E. Titering of virus stocks.
HIV-1 virus stocks are titered in the HeLa-CD4-LTR- β-gal assay system to establish the appropriate infecting dose. The endpoint for this assay is relative light units (RLUs), and titer is recorded as RLUs/ml. Virus stocks are diluted (serial 1 :2) into DMEM containing 10% FBS plus 25ug/ml DEAE-dextran and assayed as described in the "Experimental Protocol" section below without test compound.
A "multiplicity of infection" (MOI) defined as infectious units per cell is usually not calculated but is typically «1.0. Relationship of RLUs/ml to other measures of infectivity such as HeLa PFU/ml or MT4 TCID50/ml may not be consistent from lot to lot or strain to strain and should be determined for each lot.
F. Experimental Protocol Day 1
1. Seed 96-well plate(s) (Costar #3904) with HeLa-CD4-LTR- β-gal @ 3 X 103 cells per well in 100ul DMEM containing 10% FBS. Incubate @ 370C, 5% CO2 overnight.
Day 2 1 . Thaw virus stock in a water bath (room temperature) and dilute into DMEM +10% FBS + 25ug/ml DEAE-dextran to an infectious dose of approximately 10 million RLU/ml. The dilution of virus will vary depending on the titer of the stock (see "Titering of virus stocks" above). 2. Remove all of the media from every well with an 8 or 12-channel manifold aspirator. Work with one plate at a time to prevent drying of the Hel_a-CD4-LTR- β-gal monolayer. Add 35ul (approximately 350,000 total RLUs) of diluted virus to each well. Incubate @ 370C, 5% CO2 for 2 hours.
3. During the virus adsorption period prepare compound titration plates at 1.35X final concentration. In general, test compounds are titrated robotically on a
Beckman 2000 laboratory automation workstation (Beckman Coulter) in a fourfold stepwise manner from 2.7uM (2uM final) down to 0.01 nM (O.OOδnM final). This scheme will allow for 8 test compounds per 96-well plate with 10 dilution points and 2 controls per compound (n=1 ). Test compounds are titrated into DMEM + 10% FBS + 0.135% DMSO (0.1% final). The final volume of titrated compound in each well should be at least 15OuI and DMSO should be at 0.135% (0.1% final) including the no compound controls.
4. With a RapidPlate 96/384 liquid handling system (Zymark) remove 100ul of titrated compound from every well of the titration plate prepared in step 3 above and add to the virus adsorption plate (step 2 above).
5. Incubate @ 370C, 5% CO2 for 72 hours. Day 5
1. With a RapidPlate 96/384 liquid handling system (Zymark) reduce supernatants to 5OuL and add 5OuL of reconstituted Gal-Screen according to manufacturer's recommended protocol.
2. Mix plate(s) vigorously on a platform shaker.
3. Read plate(s) in a Topcount luminometer (Packard) at 1 s/well. G. Data Analysis
Raw data are transformed into percent of control by the following formula: (raw signal in each well / average raw signal for the two no compound controls in the same row)*100. Percent of control is plotted vs. compound concentration using either Robsage or Robofit programs (GSK). The default model is Y=Vmax*1-(xΛn/(KΛn+xΛn)), however, any other model giving a reasonable estimation of the IC50 ("K" in formula) may be used. Table 1 provides data regarding activity of certain compounds of the present invention against HIV wild type (WT) and several resistant mutants, including K103N, V106A, and Y181 C. TABLE 1
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
*"A" indicates an activity level of less than 10 nM.
"B" indicates an activity level of between 10 nM and 1 μM.
"C" indicates an activity level of greater than 1 μM.
Compounds of Example numbers 64, 74, 76, 77, 79, 80, 81 , 89, and 95 demonstrated "A" level activity against K103N, V106A, WTRVA, and Y181 C and "B" level activity against Y188L.
Compounds of the present invention demonstrate anti-HIV activity in the range of IC50 of about 1 nM to about 50 μM. In one aspect of the invention, compounds of the present invention have anti-HIV activity in the range of up to about 1OnM. In another aspect of the invention, compounds of the present invention have anti-HIV activity in the range of from about 1OnM to about 1 μM. In another aspect of the invention, compounds of the present invention have anti-HIV activity in the range of greater than 1 μM.
Test compounds were employed in free, salt or solvated form.
Although specific embodiments of the present invention are herein illustrated and described in detail, the invention is not limited thereto. The above detailed descriptions are provided as exemplary of the present invention and should not be construed as constituting any limitation of the invention. Modifications will be obvious to those skilled in the art, and all modifications that do not depart from the spirit of the invention are intended to be included with the scope of the appended claims.

Claims

What is claimed is:
1. A compound of formula (I)
Figure imgf000129_0001
wherein m is 1 , 2, 3 or 4; n is 1 , 2, 3 or 4; each R1 independently is halogen, -CN, C1-C5 alkyl, C2-C5 alkenyl, C2-C6 alkynyl, C3-
C7 cycloalkyl, hydroxyl, C1-C8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -R5CN, or -
N(R4)2; each R2 independently is halogen, -CN, C1-C5 alkyl, C2-C5 alkenyl, C2-C6 alkynyl, C3-
C7 cycloalkyl, hydroxyl, C1-C8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -R5CN or -
N(R4)2;
A is C5-C12 aryl or C5-C12 heterocycle;
R3 is -R5Ar or C4-C12 aryl, each optionally substituted with at least one C1-C8 alkyl, halogen, hydroxyl, oxo, C1-C8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -N(R4)2, -N(O)2,
-CN, -OR5Het, -OR5N(R4)2, -C(O)N(R4)Het, -C(O)Het, -C(O)N(R4)R5S(O)2R4,
-S(O)2N(R4)2, -S(O)2R4, -C(O)R4; -N(R4)C(O)R5SR4, -N(R4)R5S(O)2R4, or -
N(R4)S(O)2R4; each R4 is independently hydrogen, C1-C8 alkyl optionally substituted with at least one hydroxyl or halogen; or C3-C7 cycloalkyl; each R5 is independently C1-C8 alkylene, C1-C8 alkenylene, C1-C8 alkynylene, each optionally substituted with at least one hydroxyl or hydrogen;
Het is C3-C10 heterocycle and is optionally substituted with at least one C1-C6 alkyl, oxo, hydroxyl, R5S(O)2R4, or halogen; and
Ar is C4-C12 aryl and is optionally substituted with at least one C1-C6 alkyl or halogen; or a pharmaceutically acceptable salt thereof
2. A compound according to claim 1 wherein m is 2.
3. A compound according to claim 1 wherein n is 2.
4. A compound according to claim 1 wherein R3 is C4-C12 aryl optionally substituted with at least one d-C8 alkyl, halogen, hydroxyl, oxo, d-C8 alkoxy, - C(O)OR4, -C(O)N(R4)2, -OR4, -N(R4)2, -N(O)2, -CN, -OR5Het, -OR5N(R4)2, - C(O)N(R4)Het, -C(O)Het, -C(O)N(R4)R5S(O)2R4, -S(O)2N(R4)2, -S(O)2R4, -C(O)R4; - N(R4)C(O)R5SR4, -N(R4)R5S(O)2R4, or -N(R4)S(O)2R4.
5. A compound according to claim 1 wherein R3 is R5Ar and wherein Ar is optionally substituted with at least one d-C8 alkyl, halogen, hydroxyl, oxo, d-C8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -N(R4)2, -N(O)2, -CN, -OR5Het, -OR5N(R4)2, -C(O)N(R4)Het, -C(O)Het, -C(O)N(R4)R5S(O)2R4, -S(O)2N(R4)2, -S(O)2R4, -C(O)R4; -N(R4)C(O)R5SR4, -N(R4)R5S(O)2R4, or -N(R4)S(O)2R4.
6. A compound according to claim 1 wherein each R3 is phenyl, optionally substituted with at least one d-C8 alkyl, halogen, hydroxyl, oxo, d-C8 alkoxy, - C(O)OR4, -C(O)N(R4)2, -OR4, -N(R4)2, -N(O)2, -CN, -OR5Het, -OR5N(R4)2, - C(O)N(R4)Het, -C(O)Het, -C(O)N(R4)R5S(O)2R4, -S(O)2N(R4),, -S(O)2R4, -C(O)R4; - N(R4)C(O)R5SR4, -N(R4)R5S(O)2R4, or -N(R4)S(O)2R4.
7. A compound according to claim 1 wherein n is 2 and each R2 is halogen.
8. A compound according to claim 1 wherein m is 2 and the first R1 is halogen and the second R1 is -CN.
9. A compound according to claim 1 wherein m is 2, n is 2, and R3 is C4-Ci2 aryl optionally substituted with at least one d-C8 alkyl, halogen, hydroxyl, oxo, d-C8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -N(R4)2, -N(O)2, -CN, -OR5Het, -OR5N(R4)2, -C(O)N(R4)Het, -C(O)Het, -C(O)N(R4)R5S(O)2R4, -S(O)2N(R4)2, -S(O)2R4, -C(O)R4; -N(R4)C(O)R5SR4, -N(R4)R5S(O)2R4, or -N(R4)S(O)2R4.
10. A compound according to claim 1 wherein R3 is C4-C12 aryl optionally substituted with at least one halogen, OR4, -OR5Het, or -OR5N(R4)2.
11. A compound of formula (II)
Figure imgf000130_0001
wherein m is 1 , 2, 3 or 4; n is 1 , 2, 3 or 4; each R1 independently is halogen, -CN, CrC5 alkyl, C2-C5 alkenyl, C2-C6 alkynyl, C3-
C7 cycloalkyl, hydroxyl, CrC8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -R5CN, or -
N(R4)2; each R2 independently is halogen, -CN, CrC5 alkyl, C2-C5 alkenyl, C2-C6 alkynyl, C3-
C7 cycloalkyl, hydroxyl, Ci-C8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -R5CN or -
N(R4)2;
R3 is -R5Ar or C4-C12 aryl, each optionally substituted with at least one C1-C8 alkyl, halogen, hydroxyl, oxo, C1-C8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -N(R4)2, -N(O)2,
-CN, -OR5Het, -OR5N(R4)2, -C(O)N(R4)Het, -C(O)Het, -C(O)N(R4)R5S(O)2R4, -
S(O)2N(R4)2, -S(O)2R4, -C(O)R4; -N(R4)C(O)R5SR4, -N(R4)R5S(O)2R4, or -
N(R4)S(O)2R4; each R4 is independently hydrogen, C1-C8 alkyl optionally substituted with at least one hydroxyl or halogen; or C3-C7 cycloalkyl; each R5 is independently C1-C8 alkylene, C1-C8 alkenylene, C1-C8 alkynylene, each optionally substituted with at least one hydroxyl or hydrogen;
Het is C3-C10 heterocycle and is optionally substituted with at least one C1-C6 alkyl, oxo, hydroxyl, R5S(O)2R4, or halogen; and
Ar is C4-C12 aryl and is optionally substituted with at least one C1-C6 alkyl or halogen; or a pharmaceutically acceptable salt thereof.
12. A compound of formula (II)'
Figure imgf000131_0001
wherein m is 1 , 2, 3, or 4; n is 1 , 2, 3, or 4; each R1 independently is halogen, -CN, C1-C5 alkyl, C2-C5 alkenyl, C2-C6 alkynyl, C3-
C7 cycloalkyl, hydroxyl, C1-C8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -R5CN, or -
N(R4)2; each R2 independently is halogen, -CN, C1-C5 alkyl, C2-C5 alkenyl, C2-C6 alkynyl, C3-
C7 cycloalkyl, hydroxyl, C1-C8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -R5CN or -
N(R4)2;
R3 is -R5Ar or C4-C12 aryl, each optionally substituted with at least one halogen, hydroxyl, oxo, C1-C8 alkoxy, -C(O)OR4, -C(O)N(R4)2, -OR4, -N(R4)2, -N(O)2, -CN, - OR5Het, -OR5N(R4)2, -C(O)N(R4)Het, -C(O)Het, -C(O)N(R4)R5S(O)2R4, -S(O)2N(R4)2,
-S(O)2R4, -C(O)R4; -N(R4)C(O)R5SR4, -N(R4)R5S(O)2R4 ,-N(R4)S(O)2R4 or CrC8alkyl optionally substituted with hydroxyl; each R4 is independently hydrogen, d-C8 alkyl optionally substituted with at least one hydroxyl or halogen; or C3-C7 cycloalkyl; each R5 is independently d-C8 alkylene, CrC8 alkenylene, CrC8 alkynylene, each optionally substituted with at least one hydroxyl or hydrogen;
Het is C3-C10 heterocycle and is optionally substituted with at least one CrC6 alkyl, oxo, hydroxyl, R5S(O)2R4, or halogen; and
Ar is C4-C12 aryl and is optionally substituted with at least one C1-C6 alkyl or halogen; or a pharmaceutically acceptable salt thereof.
13. A compound of formula (II)' according to claim 12 wherein m is 2; n is 2; each R1 independently is halogen or -CN; each R2 independently is halogen;
R3 is C4-C12 aryl, optionally substituted with at least one -OR4, -N(R4)2, -OR5Het, -
OR5N(R4)2 or C1-C8 alkyl optionally substituted with hydroxyl; each R4 is independently hydrogen or C1-C8 alkyl optionally substituted with at least one hydroxyl; each R5 is independently C1-C8 alkylene optionally substituted with at least one hydroxyl; Het is C3-C10 heterocycle and is optionally substituted with at least one C1-
C6 alkyl; or a pharmaceutically acceptable salt thereof.
14. A compound selected from the group consisting of
2-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)- 5-[3-(methyloxy)phenyl]-1 ,3,4-oxadiazole;
3-chloro-5-{[6-chloro-2-fluoro-3-({5-[3-(methyloxy)phenyl]-1 ,3,4-oxadiazol-2- yl}methyl)phenyl]oxy}benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(3-hydroxyphenyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
2-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-5-[4- (methyloxy)phenyl]-1 ,3,4-oxadiazole;
3-chloro-5-{[6-chloro-2-fluoro-3-({5-[4-(methyloxy)phenyl]-1 ,3,4-oxadiazol-2- yl}methyl)phenyl]oxy}benzonitrile; 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-hydroxyphenyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(3-cyanophenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2- fluorophenyl)oxy]benzonitrile;
4-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]-Λ/,Λ/-diethylbenzenesulfonamide;
3-chloro-5-[(6-chloro-3-{[5-(4-cyanophenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2- fluorophenyl)oxy]benzonitrile;
3-chloro-5-{[6-chloro-2-fluoro-3-({5-[2-fluoro-3-(methyloxy)phenyl]-1 ,3,4- oxadiazol-2-yl}methyl)phenyl]oxy}benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-fluoro-3-hydroxyphenyl)-1 ,3,4- oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-{[6-chloro-3-({5-[3-(dimethylamino)phenyl]-1 ,3,4-oxadiazol-2- yl}methyl)-2-fluorophenyl]oxy}benzonitrile;
3-chloro-5-({6-chloro-3-[(5-{3-[(difluoromethyl)oxy]phenyl}-1 ,3,4-oxadiazol-2- yl)methyl]-2-fluorophenyl}oxy)benzonitrile;
2-chloro-5-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}methyl)-1 ,3,4-oxadiazol-2-yl]benzenesulfonamide;
4-chloro-5-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}methyl)-1 ,3,4-oxadiazol-2-yl]-2-fluorobenzenesulfonamide; methyl 3-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}methyl)-1 ,3,4-oxadiazol-2-yl]benzoate;
3-chloro-5-[(6-chloro-3-{[5-(2,6-dimethylphenyl)-1 ,3,4-oxadiazol-2-yl]methyl}- 2-fluorophenyl)oxy]benzonitrile;
3-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]benzoic acid;
3-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]benzamide;
3-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]-Λ/-(2,3-dihydroxypropyl)benzamide;
3-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]-Λ/-[2-(methylsulfonyl)ethyl]benzamide;
3-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]-Λ/-[2-(4-morpholinyl)ethyl]benzamide;
3-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]-Λ/-cyclopropylbenzamide; 3-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]-Λ/-(3-hydroxypropyl)benzamide;
5-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]-2-methylbenzenesulfonamide;
4-chloro-5-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}methyl)-1 ,3,4-oxadiazol-2-yl]-2-fluoro-Λ/-methylbenzenesulfonamide;
4-chloro-3-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}methyl)-1 ,3,4-oxadiazol-2-yl]-Λ/-cyclopropylbenzenesulfonamide;
3-chloro-5-{[6-chloro-2-fluoro-3-({5-[4-({[(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan- 4-yl]methyl}oxy)phenyl]-1 ,3,4-oxadiazol-2-yl}methyl)phenyl]oxy}benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(4-{[(2S)-2,3-dihydroxy-3-methyl butyl]oxy}phenyl)- 1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-{[3-hydroxy-2-(hydroxymethyl) propyl]oxy}phenyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-{[(2R)-2-morpholinylmethyl] oxy}phenyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-({6-chloro-2-fluoro-3-[(5-{4-[({(2R)-4-[2-(methylsulfonyl)ethyl]-2- morpholinyl}methyl)oxy]phenyl}-1 ,3,4-oxadiazol-2-yl)methyl]phenyl}oxy)benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(3-nitrophenyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
Methyl 4-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}methyl)-1 ,3,4-oxadiazol-2-yl]benzoate;
4-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]benzoic acid;
3-chloro-5-({6-chloro-3-[(5-{4-[(1 ,1-dioxido-4-thiomorpholinyl) carbonyl]phenyl}-1 ,3,4-oxadiazol-2-yl)methyl]-2-fluorophenyl}oxy)benzonitrile;
4-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]-Λ/-[2-(methylsulfonyl)ethyl]benzamide;
4-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]-Λ/-[2-(4-morpholinyl)ethyl]benzamide;
4-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]-Λ/-(2,3-dihydroxypropyl)benzamide;
4-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]benzamide;
3-[(3-{[5-(3-aminophenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-6-chloro-2- fluorophenyl)oxy]-5-chlorobenzonitrile; 3-chloro-5-{[6-chloro-2-fluoro-3-({5-[2-(methyloxy)phenyl]-1 ,3,4-oxadiazol-2- yl}methyl)phenyl]oxy}benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methylphenyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(2-chlorophenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2- fluorophenyl)oxy]benzonitrile;
3-[(3-{[5-(2-bromophenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-6-chloro-2- fluorophenyl)oxy]-5-chlorobenzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-fluorophenyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-{[6-chloro-3-({5-[2-chloro-3-(methyloxy)phenyl]-1 ,3,4-oxadiazol-2- yl}methyl)-2-fluorophenyl]oxy}benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(3-chlorophenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2- fluorophenyl)oxy]benzonitrile;
3-chloro-5-({6-chloro-2-fluoro-3-[(5-phenyl-1 ,3,4-oxadiazol-2- yl)methyl]phenyl}oxy)benzonitrile;
/\/-{3-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)- 1 ,3,4-oxadiazol-2-yl]phenyl}-3-(methylthio)propanamide;
/\/-{3-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)- 1 ,3,4-oxadiazol-2-yl]phenyl}-3-(methylsulfonyl)propanamide;
3-({6-bromo-2-fluoro-3-[(5-phenyl-1 ,3,4-oxadiazol-2-yl)methyl]phenyl}oxy)-5- chlorobenzonitrile;
2-[(3-chloro-5-cyanophenyl)oxy]-3-fluoro-4-[(5-phenyl-1 ,3,4-oxadiazol-2- yl)methyl]benzonitrile;
3-chloro-5-{[6-chloro-2-fluoro-3-({5-[2-methyl-4-({[(4S)-2,2,5,5-tetramethyl-1 ,3- dioxolan-4-yl]methyl}oxy)phenyl]-1 ,3,4-oxadiazol-2-yl}methyl) phenyl] oxy}benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(4-{[(2S)-2,3-dihydroxy-3-methylbutyl]oxy}-2- methylphenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(3-fluoro-2-methylphenyl)-1 ,3,4-oxadiazol- 2-yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(2-chloro-3-fluorophenyl)-1 ,3,4-oxadiazol-2- yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-{[6-chloro-3-({5-[2-chloro-4-(methylsulfonyl)phenyl]-1 ,3,4- oxadiazol-2-yl}methyl)-2-fluorophenyl]oxy}benzonitrile; 3-chloro-5-{[6-chloro-3-({5-[2-chloro-4-({[(4S)-2,2,5,5-tetramethyl-1 ,3- dioxolan-4-yl]methyl}oxy)phenyl]-1 ,3,4-oxadiazol-2-yl}methyl)-2- fluorophenyl]oxy}benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(2-chloro-4-{[(2S)-2,3-dihydroxy-3- methylbutyl]oxy}phenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(4-{[(1 , 1 dimethylethyl)(dimethyl)silyl]oxy}-2- methylphenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-hydroxy-2-methylphenyl)-1 ,3,4- oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile;
3-[(3-{[5-(4-bromo-2-methylphenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-6-chloro-2- fluorophenyl)oxy]-5-chlorobenzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-4-{[(3R)-3- piperidinylmethyl]oxy}phenyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-4-{[(2S)-2- oxiranylmethyl]oxy}phenyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-({6-chloro-2-fluoro-3-[(5-{4-[(2-hydroxy-2-methylpropyl)oxy]-2- methylphenyl}-1 ,3,4-oxadiazol-2-yl)methyl]phenyl}oxy)benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-{[(2S)-2-hydroxy-3-(4-morpholinyl) propyl]oxy}-2-methylphenyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(4-{[(2S)-3-(dimethylamino)-2-hydroxypropyl]oxy}- 2-methylphenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-{[(2S)-2-hydroxy-3-(1- pyrrolidinyl)propyl]oxy}-2-methylphenyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-{[(2S)-2-hydroxy-3-(4-methyl-1- piperazinyl)propyl]oxy}-2-methylphenyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-{[(2S)-2-hydroxy-3-(1- piperazinyl)propyl]oxy}-2-methylphenyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-4-{[(2R)-2- morpholinylmethyl]oxy}phenyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-4-{[2-(4- morpholinyl)ethyl]oxy}phenyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-4-{[3-(4- morpholinyl)propyl]oxy}phenyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile; 3-chloro-5-[(6-chloro-3-{[5-(4-{[3-(dimethylamino)propyl]oxy}-2-methylphenyl)- 1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile; and pharmaceutically acceptable salts thereof.
15. A compound selected from the group consisting of: 3-chloro-5-[(6-chloro-3-{[5-(4-{[(2S)-2,3-dihydroxy-3-methylbutyl]oxy}-2- methylphenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile; 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-4-{[(2S)-2-oxiranylmethyl]oxy}phenyl)- 1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-{[(2S)-2-hydroxy-3-(4-morpholinyl) propyl]oxy}- 2-methylphenyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile; 3-chloro-5-[(6-chloro-3-{[5-(4-{[(2S)-3-(dimethylamino)-2-hydroxypropyl] oxy}-2-methylphenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile; 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-{[(2S)-2-hydroxy-3-(4-methyl-1- piperazinyl)propyl]oxy}-2-methylphenyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-{[(2S)-2-hydroxy-3-(1-piperazinyl)propyl]oxy}-2- methylphenyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile; 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-4-{[(2R)-2- morpholinylmethyl]oxy}phenyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile; 3-[(3-{[5-(5-amino-2-methylphenyl)-1 ,3,4-oxadiazol-2-yl]methyl}-6-chloro-2- fluorophenyl)oxy]-5-chlorobenzonitrile;
3-chloro-5-{[6-chloro-3-({5-[4-(1 ,2-dihydroxyethyl)-2-methylphenyl]-1 ,3,4-oxadiazol-2- yl}methyl)-2-fluorophenyl]oxy}benzonitrile; and pharmaceutically acceptable salts thereof.
16. A pharmaceutical composition comprising a compound according to any one of claims 1 to 15, and a pharmaceutically acceptable carrier.
17. A pharmaceutical composition according to claim 16 in the form of a tablet, capsule, liquid or suspension.
18. A composition according to claim 16, wherein said composition comprises at least one additional therapeutic agent selected from the group consisting of zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavidine, adefovir, adefovir dipivoxil, fozivudine, todoxil, emtricitabine, alovudine, amdoxovir, elvucitabine, nevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz, capravirine, TMC-278, TMC-125, etravirine, saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir, brecanavir, palinavir, lasinavir, atazanavir, tipranavir, enfuvirtide (T-20), T-1249, PRO-542, PRO-140, TNX-355, BMS-806, L-870,810 PA- 344 and PA-457, vicriviroc (Sch-C), Sch-D, TAK779, maraviroc (UK 427,857), and TAK449
19. A compound according to any of claims 1 to 15 for use in medical therapy.
20. A compound according to any of claims 1 to 15 for use in the treatment of viral infections and associated conditions.
21. The use according to claim 20 wherein the viral infection is HIV infection.
22. Use of a compound according to any one of claims 1 to 15 in the manufacture of a medicament for use in the treatment of viral infections and associated conditions.
23. The use according to claim 22 wherein the viral infection is HIV infection.
24. A method for the treatment of viral infections and associated conditions, comprising administering to a human an antivirally effective amount of a compound according to any of claims 1 to 15.
25. The method according to claim 24 wherein the viral infection is HIV infection.
PCT/US2008/066885 2007-06-14 2008-06-13 Chemical compounds WO2008157330A1 (en)

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WO2011128395A1 (en) 2010-04-14 2011-10-20 Prosidion Limited N- substituted 3-amino 4 - ( pyrrolidine - 1 - carbonyl) pyrrolidine and its derivatives for use in the treatment of metabolic disorders
WO2011128394A1 (en) 2010-04-14 2011-10-20 Prosidion Limited 3-substituted 5-(pyrrolidine-1-carbonyl) pyrrolidine and its derivatives for use in the treatment of metabolic disorders
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