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WO2008157273A1 - Chemical compounds - Google Patents

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Publication number
WO2008157273A1
WO2008157273A1 PCT/US2008/066805 US2008066805W WO2008157273A1 WO 2008157273 A1 WO2008157273 A1 WO 2008157273A1 US 2008066805 W US2008066805 W US 2008066805W WO 2008157273 A1 WO2008157273 A1 WO 2008157273A1
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WO
WIPO (PCT)
Prior art keywords
chloro
methyl
oxadiazol
oxy
benzonitrile
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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PCT/US2008/066805
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French (fr)
Inventor
Christopher Joseph Aquino
Hamilton Dickson
Andrew James Peat
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Publication of WO2008157273A1 publication Critical patent/WO2008157273A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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 AIDS-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, // 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.
  • n is 1 , 2, 3, or 4; each R 1 independently is halogen, -CN, C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 6 alkynyl, C 3 -
  • each R 2 independently is halogen, -CN, C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 6 alkynyl, C 3 -
  • A is C 5 -Ci 2 aryl or C 5 -Ci 2 heterocycle
  • R 3 is -R 5 Het or C 3 -Ci 2 heterocycle, 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 , -
  • 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 -Ci 2 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 -Ci 2 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 3 -Ci 2 heterocycle 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 ,
  • the present invention features a compound of formula (I) wherein R 3 is R 5 Het and wherein Het is optionally substituted with at least one C 1 -Ce 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
  • each R 3 is C 4 -C 6 heterocycle, 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 , -N(R 4 )R
  • 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 3 -C 12 heterocycle 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 3 -C 12 heterocycle optionally substituted with at least one C 1 -C 8 alkyl, halogen, OR 4 , or - N(R 4 )S(O) 2 R 4 .
  • the present invention also features a compound of formula (II)
  • n is 1 , 2, 3 or 4; each R 1 independently is halogen, -CN, C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 6 alkynyl, C 3 -
  • each R 2 independently is halogen, -CN, C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 6 alkynyl, C 3 -
  • R 3 is -R 5 Het or C 3 -Ci 2 heterocycle, 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 , -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 )
  • Ar is C 4 -Ci 2 aryl and is optionally substituted with at least one C 1 -C ⁇ alkyl or halogen; or pharmaceutically acceptable derivatives thereof.
  • the present invention features a compound of formula (II) wherein R 3 is C 3 - Ci 2 heterocycle optionally substituted with at least one of 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 , -N(R 4 )
  • the present invention features a compound of formula (II) wherein R 3 is R 5 Het and wherein Het is 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 , -N(R 4
  • each R 3 is C 4 -C 6 heterocycle, 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
  • the present invention features a compound of formula (II) wherein R 3 is C 3 - Ci 2 heterocycle 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 (II) 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 3 -Ci 2 heterocycle 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 is C 3 -
  • Ci 2 heterocycle optionally substituted with at least one C 1 -C 8 alkyl, halogen, OR 4 , or -N(R 4 )S(O) 2 R 4 .
  • Compounds of the present invention include: 3-chloro-5-[(6-chloro-2-fluoro-3- ⁇ [5-(4-pyridinyl)-1 ,3,4-oxadiazol-2- yl]methyl ⁇ phenyl)oxy]benzonitrile;
  • Compounds of the present invention include:
  • 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.
  • 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 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.
  • 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 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.
  • cycloalkenylene refers to a divalent optionally substituted non-aromatic cyclic hydrocarbon ring containing one or more carbon-to- carbon double bonds.
  • 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).
  • 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.
  • heterocycle includes heteroaryl.
  • 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.
  • zido 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.
  • R' and R independently represent H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
  • optional substitution 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.
  • 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, 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 -
  • each R 2 independently is halogen, -CN, C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 6 alkynyl, C 3 -
  • A is C 5 -C 12 aryl or C 5 -C 12 heterocycle
  • R 3 is -R 5 Het or C 3 -C 12 heterocycle, 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 , -
  • 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 12 heterocycle and is optionally substituted with at least one of 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 of C 1 -C 6 alkyl or halogen; or pharmaceutically acceptable derivatives thereof.
  • the present invention features a compound of formula (I) wherein R 3 is C 3 -C 12 heterocycle optionally substituted with at least one of 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, -
  • the present invention features a compound of formula (I) wherein R 3 is R 5 Het and wherein Het is optionally substituted with at least one of 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 , -N(R 4
  • each R 3 is C 4 -C 6 heterocycle, 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
  • 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 3 -Ci 2 heterocycle optionally substituted with at least one of 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 (I) wherein R is C 8 -C I2 heterocycle optionally substituted with at least one C 1 -C 8 alkyl, halogen, OR 4 , or - N(R 4 )S(O) 2 R 4 .
  • the present invention features a compound of formula (I) wherein R 3 is C 4 -C 6 heterocycle optionally substituted with methyl, halogen or at least one of each methyl and halogen.
  • the present invention features a compound of formula (I) wherein R 3 is C 3 -Ci 2 heterocycle 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) wherein m is 1 , 2, 3 or 4; n is 1 , 2, 3 or 4; 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 -
  • each R 2 independently is halogen, -CN, C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 6 alkynyl, C 3 -
  • R 3 is -R 5 Het or C 3 -Ci 2 heterocycle, each optionally substituted with at least one of C 1 -
  • each R 4 is independently hydrogen, C 1 -C 8 alkyl optionally substituted with at least one of 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 12 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 (II) wherein R 3 is C 3 -
  • C 12 heterocycle optionally substituted with at least one of 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, -
  • the present invention features a compound of formula (II) wherein R 3 is R 5 Het and wherein Het is optionally substituted with at least one of 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, -
  • each R 3 is C 4 -C 6 heterocycle, 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
  • 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 (II) wherein n is 2 and each R 2 is in the orth position 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 3 -C 12 heterocycle optionally substituted with at least one of 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 (II) wherein R 3 is C 3 - C 12 heterocycle optionally substituted with at least one C 1 -C 8 alkyl, halogen, OR 4 , or -N(R 4 )S(O) 2 R 4 .
  • the present invention features a compound of formula (II) wherein R 3 is C 4 -C 6 heterocycle optionally substituted with methyl, halogen or at least one of each methyl and halogen.
  • the present invention features a compound of formula (II) wherein R 3 is C 3 - C 12 heterocycle 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 -
  • R 3 is -R 5 Het or C 3 -C I2 heterocycle, each optionally substituted with at least one of 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(R 4 )S(O) 2 R 4 C 6- io aryl optionally substituted with halogen or C 1 -C 8 alkyl; or C 1 -C 8 alkyl optionally substituted with hydroxyl; each R 4 is independently hydrogen, C 1 -C 8 alkyl optionally substituted with at least one of 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 12 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 features a compound of formula (II)' wherein m is 2; n is 2; each R1 is independently halogen, -CN, or R 5 CN; each R 2 independently is halogen, or -CN;
  • R 3 is C 3 -C 12 heterocycle, optionally substituted with at least one of C 1 -C 8 alkyl, -OR 4 ,
  • 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. 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
  • 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.
  • 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, C 1-4 alkyl, or C 1-4 alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucy
  • the phosphate esters may be further esterified by, for example, a C 1-2 o alcohol or reactive derivative thereof, or by a 2,3-di (C 6-24 )acyl glycerol.
  • 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.
  • 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.
  • modulators 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.
  • 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 the 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 the 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 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.
  • 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.
  • 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.
  • 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 may be employed with either a paraffinic or a water-miscible ointment base.
  • 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.
  • compositions 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.
  • compositions 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.
  • compositions 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 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.
  • 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/US
  • 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.
  • the compounds of the present invention and other HIV agents may be administered separately or in conjunction.
  • 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.
  • 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.
  • 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- Interscience, 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 silicon
  • atm atmosphere
  • EtOAc ethyl acetate
  • CHCI 3 chloroform
  • Et ethyl
  • tBu tert-butyl
  • MeOH methanol
  • p-TsOH p-toluenesulfonic acid
  • MP-TsOH polystyrene resin bound equivalent of p-TsOH from Argonaut
  • 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).
  • 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) 211 ; PJ. Stephens and FJ. Devlin, Chirality 12 (2000) 172; and Gaussian 98, Revision A.11.4, MJ. Frisch et al., Gaussian,
  • 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
  • CDCI3 ⁇ 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
  • 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
  • Example 4 (alternate procedure): ethyl ⁇ 4-chloro-3-[(3-chloro-5-cvanophenyl)oxy1-2- 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
  • Step D [(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl benzoate
  • (2S)-2,3-dihydroxy-3-methylbutyl benzoate (16.45 g, 73.4 mmol) was treated with a catalytic amount of 4-methylbenzenesulfonic acid hydrate in acetone (300 ml.) with stirring at ambient temperature for 3 days.
  • the reaction mixture was concentrated to dryness and crystallized from DCM/hexanes to recover unreacted starting material (5.80 g, 25.9 mmol, 35%) as a white solid.
  • the filtrate was concentrated to dryness and purified on a 330 g silica cartridge eluted with 0 to 40% EtOAc/hexanes to give the title compound (5.99 g, 22.7 mmol, 31%).
  • Step E [(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methanol
  • reaction mixture was concentrated to dryness, the residue dissolved in fresh toluene (70 ml.) and treated with 3 N NaOH (70 ml.) and 40% tetrabutylammonium hydroxide in water (8.0 ml_, 12.3 mmol, 0.2 eq) at 90 °C for 2 h.
  • the phases were separated and the organic phase was split into two equal portions. One of these portions was recombined with the aqueous phase and was diverted to other use. The remaining portion was dried over magnesium sulfate, filtered and concentrated to dryness.
  • Step A 4-[5-( ⁇ 3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl ⁇ methyl)- 1 ,3,4-oxadiazol-2-yl]pyridine
  • Step B 3-chloro-5-[(6-chloro-2-fluoro-3- ⁇ [5-(4-pyridinyl)-1 ,3,4-oxadiazol-2- yl]methyl ⁇ phenyl)oxy]benzonitrile
  • Example 1 3-chloro-5-r(6-chloro-2-fluoro-3- ⁇ r5-(3-pyridinylV1 ,3.4-oxadiazol-2- yllmethyltohenvDoxylbenzonitrile
  • Step A 3-[5-( ⁇ 3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl ⁇ methyl)- 1 ,3,4-oxadiazol-2-yl]pyridine
  • Step B 3-chloro-5-[(6-chloro-2-fluoro-3- ⁇ [5-(3-pyridinyl)-1 ,3,4-oxadiazol-2- yl]methyl ⁇ phenyl)oxy]benzonitrile
  • Example 12 3-chloro-5-r(6-chloro-2-fluoro-3-fr5-(3-methyl-4-Dyridinvn-1.3.4- oxadiazol-2-yllmethyl ⁇ phenyl)oxylbenzonitrile
  • Example 14 3-chloro-5-r(6-chloro-2-fluoro-3- ⁇ r5-(1/-/-indol-5-yl)-1 ,3,4-oxadiazol-2- Vl1methyl ⁇ phenyl)oxy1benzonitrile
  • Example 25 S-chloro- ⁇ -fre-chloro-S- ⁇ -r ⁇ -chloro ⁇ -fmethylthioM-Dyridinyll-i .3.4- oxadiazol-2-yl ⁇ methyl)-2-fluorophenylloxy ⁇ benzonitrile
  • Example 28 3-chloro-5-r(3-ir5-(3-chloro-4-pyridinylV1 ,3.4-oxadiazol-2-yllmethyl>-6- ethenyl-2-fluorophenvDoxylbenzonitrile
  • Example 30 S-chloro- ⁇ -Re-chloro ⁇ -fluoro-S-fr ⁇ -O-methyl-1-oxido ⁇ -pyridinvn-I .S ⁇ - oxadiazol-2-yllmethyl ⁇ phenyl)oxylbenzonitrile
  • Example 31 3-chloro-5-fr6-chloro-2-fluoro-3- ⁇ 5-r4-methyl-6-( ⁇ r(4SV2.2.5.5- tetramethyl-1 ,3-dioxolan-4-yllmethyl ⁇ oxy)-3-pyridinyll-1 ,3,4-oxadiazol-2- yl ⁇ methyl)phenylloxy ⁇ benzonitrile
  • Step A ethyl ⁇ -amino ⁇ -methyl-S-pyridinecarboxylate
  • reaction mixture was diluted with EtOAc, washed three times with dilute brine, dried over magnesium sulfate, filtered through CeliteTM and concentrated to dryness to give an orange semi-solid. This material was triturated with boiling ethanol, cooled in an ice bath, and a yellow solid filtered off. The filtrate was concentrated to dryness and purified by column chromatography (EtOAc/hexanes) to give the title compound (1.18 g, 6.5 mmol, 30%) as a white solid.
  • Step B ethyl ⁇ -chloro ⁇ -methyl-S-pyridinecarboxylate
  • Step C ethyl 4-methyl-6-( ⁇ [(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl ⁇ oxy)-3- pyridinecarboxylate
  • Ethyl ⁇ -chloro ⁇ -methyl-S-pyridinecarboxylate (0.40 g, 2.00 mmol, 1 eq) and [(4S)- 2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methanol (0.33 g, 2.00 mmol, 1 eq) were combined with Pd(OAc) 2 (36 mg, 0.16 mmol, 0.08 eq), 1 ,1 '-binaphthalen-2-yl[bis(1 ,1- dimethylethyl)]phosphane (80 mg, 0.20 mmol, 0.1 eq) and cesium carbonate (1.96 g, 6.00 mmol, 3 eq) in toluene (20 ml_), purged with nitrogen and heated 2 h at reflux.
  • the reaction mixture was stirred 16 h at 85 °C and then returned to reflux for 6 h.
  • the reaction mixture was cooled to ambient temperature, diluted with EtOAc, washed with water, dried over magnesium sulfate, filtered and concentrated to dryness.
  • the crude product was purified by column chromatography (EtOAc/hexanes) to give the title compound (0.31 g, 1.00 mmol, 50%).
  • Step D 4-methyl-6-( ⁇ [(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl ⁇ oxy)-3- pyridinecarbohydrazide
  • Step E 3-chloro-5- ⁇ [6-chloro-2-fluoro-3-( ⁇ 5-[4-methyl-6-( ⁇ [(4S)-2,2,5,5-tetramethyl- 1 ,3-dioxolan-4-yl]methyl ⁇ oxy)-3-pyridinyl]-1 ,3,4-oxadiazol-2- yl ⁇ methyl)phenyl]oxy ⁇ benzonitrile
  • the reaction mixture was concentrated to dryness, partitioned between EtOAc and saturated NaHCO 3 , the phases separated, and the aqueous phase extracted twice with EtOAc. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated to dryness.
  • the crude product was purified on a 40 g silica gel cartridge eluted with 40 to 100% EtOAc/hexanes to give the title compound (1 10 mg, 0.19 mmol, 63%) as a white foam.
  • Step A 4-iodo-5-methyl-2-( ⁇ [(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4- yl]methyl ⁇ oxy)py ⁇ dine
  • Step B 2- ⁇ [(2S)-2,3-dihydroxy-3-methylbutyl]oxy ⁇ -5-methyl-4-pyridinecarboxylic acid
  • Step C N'-( ⁇ 4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl ⁇ acetyl)-2- ⁇ [(2S)-2,3-dihydroxy-3-methylbutyl]oxy ⁇ -5-methyl-4-pyridinecarbohydrazide
  • Step D yV-( ⁇ 4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl ⁇ acetyl)-5- methyl-2-( ⁇ [(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl ⁇ oxy)-4- pyridinecarbohydrazide
  • Step E 3-chloro-5- ⁇ [6-chloro-2-fluoro-3-( ⁇ 5-[5-methyl-2-( ⁇ [(4S)-2,2,5,5-tetramethyl- 1 ,3-dioxolan-4-yl]methyl ⁇ oxy)-4-pyridinyl]-1 ,3,4-oxadiazol-2- yl ⁇ methyl)phenyl]oxy ⁇ benzonitrile
  • Step F 3-chloro-5-[(6-chloro-3- ⁇ [5-(2- ⁇ [(2S)-2,3-dihydroxy-3-methylbutyl]oxy ⁇ -5- methyl-4-pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl ⁇ -2-fluorophenyl)oxy]benzonitrile
  • the reaction mixture was concentrated to dryness, partitioned between DCM and saturated NaHCO 3 , the phases separated, and the aqueous phase extracted twice with DCM. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated to dryness.
  • the crude product was purified on a 40 g silica gel cartridge eluted with 40 to 100% EtOAc/hexanes to give the title compound (21 mg, 37 ⁇ mol, 57%) as a white foam.
  • Step B 3-chloro-5-[(6-chloro-2-fluoro-3- ⁇ [5-(2-fluoro-5-methyl-4-pyridinyl)-1 ,3,4- oxadiazol-2-yl]methyl ⁇ phenyl)oxy]benzonitrile
  • 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 (35 ⁇ L, 200 ⁇ mol, 2 eq) in dry THF (1 mL) was added to vials containing solid carboxylic acid (see Table 1 for stoichiometry) and HATU (38 mg, 100 ⁇ mol, 1 eq) and stirred for 3 h at ambient temperature to form the intermediate diacyl hydrazides.
  • reaction mixtures were then treated with a solution of methoxycarbonylsulfamoyl- triethylammonium hydroxide, inner salt (Burgess Reagent, 36 mg, 150 ⁇ mol, 1.5 eq) in dry THF (1 ml.) for 16 h at ambient temperature followed by 16 h at 60 °C. Additional Burgess Reagent (72 mg, 300 ⁇ mol, 3 eq) dissolved in dry THF (1 ml.) was added to each reaction mixture and stirred 16 h at 60 °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 SunfireTM C-18, 19 x 150 mm, 5 micron column eluted with 10 to 100% CH 3 CN in water with 0.1 % TFA buffer at 20 mL/min.
  • Method B A solution of 2- ⁇ 4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl ⁇ acetohydrazide (35.4 mg, 100 ⁇ mol, 1 eq) and DIPEA (35 ⁇ l_, 200 ⁇ mol, 2 eq) in dry THF (1 ml.) was added 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 °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 °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 50 mL/min.
  • Example 37 3-chloro-5-[(6-chloro-2-fluoro-3- ⁇ [5-(1 ,3,5-trimethyl-1 H-pyrazol-4-yl)-
  • Example 40 3-chloro-5-[(6-chloro-3- ⁇ [5-(2,5-dimethyl-3-furanyl)-1 ,3,4-oxadiazol-2- yl]methyl ⁇ -2-fluorophenyl)oxy]benzonitrile
  • Example 41 3-chloro-5-[(6-chloro-2-fluoro-3- ⁇ [5-(1-methyl-1 H-imidazol-2-yl)-1 ,3,4- oxadiazol-2-yl]methyl ⁇ phenyl)oxy]benzonitrile
  • Example 42 3-chloro-5-[(6-chloro-2-fluoro-3- ⁇ [5-(3-methyl-2-pyridinyl)-1 ,3,4- oxadiazol-2-yl]methyl ⁇ phenyl)oxy]benzonitrile
  • Example 43 3-chloro-5-[(6-chloro-3- ⁇ [5-(2,4-dimethyl-3-pyridinyl)-1 ,3,4-oxadiazol-2- yl]methyl ⁇ -2-fluorophenyl)oxy]benzonitrile
  • Example 47 3-chloro-5-[(6-chloro-3- ⁇ [5-(2,4-dimethyl-1 ,3-thiazol-5-yl)-1 ,3,4- oxadiazol-2-yl]methyl ⁇ -2-fluorophenyl)oxy]benzonitrile
  • Example 48 3-chloro-5-[(6-chloro-2-fluoro-3- ⁇ [5-(1-methyl-1 H-imidazol-5-yl)-1 ,3,4- oxadiazol-2-yl]methyl ⁇ phenyl)oxy]benzonitrile
  • Example 52 3-chloro-5-[(6-chloro-2-fluoro-3- ⁇ [5-(4-methyl-1 ,3-thiazol-5-yl)-1 ,3,4- oxadiazol-2-yl]methyl ⁇ phenyl)oxy]benzonitrile
  • Example 53 3-chloro-5-[(6-chloro-2-fluoro-3- ⁇ [5-(2-methyl-1 ,8-naphthyridin-3-yl)-
  • Example 54 3-chloro-5-[(6-chloro-2-fluoro-3- ⁇ [5-(3-methyl-2-thienyl)-1 ,3,4-oxadiazol-
  • Example 56 3-chloro-5-[(6-chloro-2-fluoro-3- ⁇ [5-(1 -methyl-1 H-pyrazol-5-yl)-1 ,3,4- oxadiazol-2-yl]methyl ⁇ phenyl)oxy]benzonitrile
  • Example 36 3-chloro-5-r(6-chloro-2-fluoro-3-fr5-(2-methyl-3-Dyridinvn-1.3.4- oxadiazol-2-yllmethyl ⁇ phenyl)oxylbenzonitrile
  • Example 37 3-chloro-5-r(6-chloro-2-fluoro-3- ⁇ r5-(1 ,3,5-trimethyl-1 /-/-pyrazol-4-yl)- 1 ,3,4-oxadiazol-2-yl1methyl ⁇ phenyl)oxy1benzonitrile
  • Example 39 3-chloro-5-r(6-chloro-2-fluoro-3-fr5-(1 -methyl-1 /-/-pyrrol-2-vn-1.3.4- oxadiazol-2-yllmethyl ⁇ phenyl)oxylbenzonitrile
  • Example 57 3-chloro-5-fr6-chloro-2-fluoro-3- ⁇ 5-r2-methyl-6-( ⁇ r(4SV2.2.5.5- tetramethyl-1 ,3-dioxolan-4-yllmethyl ⁇ oxy)-3-pyridinyll-1 ,3,4-oxadiazol-2- yl ⁇ methyl)phenylloxy ⁇ benzonitrile
  • Step A ethyl ⁇ -amino ⁇ -methyl-S-pyridinecarboxylate
  • the reaction mixture was diluted with EtOAc, washed four times with dilute brine, dried over MgSO 4 , filtered through CeliteTM and concentrated to dryness. The residue was purified on a 330 g silica gel cartridge eluted with 40 to 100% EtOAc/hexanes to give the title compound (3.20 g, 17.8 mmol, 35%) as a yellow solid.
  • Step B ethyl ⁇ -chloro ⁇ -methyl-S-pyridinecarboxylate
  • a solution of ethyl ⁇ -amino ⁇ -methyl-S-pyridinecarboxylate (1.58 g, 8.76 mmol, 1 eq) in 37% HCI (25 mL) was added a solution of sodium nitrite (1.57 g, 22.8 mmol, 2.6 eq) in water (13 mL) dropwise with stirring and cooling in an ice-acetone bath over 30 min such that the temperature did not rise above -5 °C.
  • Step C ethyl 2-methyl-6-( ⁇ [(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl ⁇ oxy)-3- pyridinecarboxylate
  • the reaction mixture was cooled to ambient temperature, diluted with EtOAc and water, filtered through CeliteTM, and the organic phase isolated. The organics were washed with brine, dried over MgSO 4 , filtered and concentrated to dryness.
  • the crude product was purified on a 40 g silica gel cartridge eluted with 0 to 50% EtOAc/hexanes to give the title compound (0.53g, 1.64 mmol, 78%) as a clear oil.
  • Step E 3-chloro-5- ⁇ [6-chloro-2-fluoro-3-( ⁇ 5-[2-methyl-6-( ⁇ [(4S)-2,2,5,5-tetramethyl- 1 ,3-dioxolan-4-yl]methyl ⁇ oxy)-3-pyridinyl]-1 ,3,4-oxadiazol-2- yl ⁇ methyl)phenyl]oxy ⁇ benzonitrile
  • Example 58 3-chloro-5-r(6-chloro-3-fr5-(6-fr(2SV2.3-dihvdroxy-3-methylbutylloxy>-2- methyl-3-pyridinyl)-1 , 3, 4-oxadiazol-2-yllmethyl ⁇ -2 -fluorophenyl )oxylbenzonitrile
  • Example 59 3-chloro-5- ⁇ r6-chloro-2-fluoro-3-( ⁇ 5-r4-methyl-2-( ⁇ r(4S)-2,2,5,5- tetramethyl-1 ,3-dioxolan-4-yl1methyl ⁇ oxy)-1 ,3-thiazol-5-yl1-1 ,3,4-oxadiazol-2- yl ⁇ methyl)phenylloxy ⁇ benzonitrile
  • Step A ethyl 4-methyl-2-( ⁇ [(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl ⁇ oxy)- 1 ,3-thiazole-5-carboxylate
  • Step B 4-methyl-2-( ⁇ [(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl ⁇ oxy)-1 ,3- thiazole-5-carboxylic acid
  • Step C 3-chloro-5- ⁇ [6-chloro-2-fluoro-3-( ⁇ 5-[4-methyl-2-( ⁇ [(4S)-2,2,5,5-tetramethyl- 1 ,3-dioxolan-4-yl]methyl ⁇ oxy)-1 ,3-thiazol-5-yl]-1 ,3,4-oxadiazol-2- yl ⁇ methyl)phenyl]oxy ⁇ benzonitrile
  • Example 60 3-chloro-5-r(6-chloro-2-fluoro-3-fr5-(4-methyl-2-oxo-2.3-dihvdro-1.3- thiazol-5-yl)-1 ,3,4-oxadiazol-2-yl1methyl ⁇ phenyl)oxy1benzonitrile
  • Step A 3-chloro-5-[(6-chloro-3- ⁇ [5-(2-chloro-4-methyl-1 ,3-thiazol-5-yl)-1 ,3,4- oxadiazol-2-yl]methyl ⁇ -2-fluorophenyl)oxy]benzonitrile
  • Step B 3-chloro-5-[(6-chloro-2-fluoro-3- ⁇ [5-(4-methyl-2- ⁇ [2- (methylsulfonyl)ethyl]amino ⁇ -1 ,3-thiazol-5-yl)-1 ,3,4-oxadiazol-2- yl]methyl ⁇ phenyl)oxy]benzonitrile
  • Example 62 3-chloro-5-r(6-chloro-2-fluoro-3-fr5-(4-methyl-1 H-imidazol-5-ylV1.3.4- oxadiazol-2-yllmethyl ⁇ phenyl)oxylbenzonitrile
  • Step A N'-( ⁇ 4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl ⁇ acetyl)-4- methyl-1 H-imidazole-5-carbohydrazide
  • Step B 3-chloro-5-[(6-chloro-2-fluoro-3- ⁇ [5-(4-methyl-1 H-imidazol-5-yl)-1 ,3,4- oxadiazol-2-yl]methyl ⁇ phenyl)oxy]benzonitrile N'-( ⁇ 4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl ⁇ acetyl)-4-methyl-1 H- imidazole-5-carbohydrazide (120 mg, 0.26 mmol) was treated with POCI3 at reflux until complete solution was obtained at which point LC-MS indicated complete conversion.
  • Step A methyl 1 ,4-dimethyl-1 H-pyrazole-5-carboxylate
  • Methyl 4-methyl-1 H-pyrazole-5-carboxylate (700 mg, 5.55 mmol, 1 eq) was combined with iodomethane (0.70 mL, 11.1 mmol, 2 eq) and cesium carbonate (5.41 g, 16.6 mmol, 3 eq) in acetonitrile and stirred overnight at room temperature.
  • the reaction mixture was filtered and the filtrate concentrated to dryness.
  • the residue was triturated with DCM, filtered and the filtrate concentrated to dryness.
  • the residue was purified on a 40 g silica gel cartridge eluted with 10 to 90% EtOAc/hexanes to give the two regioisomeric products.
  • the first eluting isomer was identified as the desired title compound (300 mg, 1.95 mmol, 35%) by NOESY and HMBC NMR.
  • 1 H NMR 400 MHz, DMSO-d 6 ) ⁇ ppm 7.38 (s, 1 H), 4.02 (s, 3 H), 3.84 (s, 3 H), 2.18 (s, 3 H).
  • LC-MS ES + ) m/z 154.80 [M+H].
  • Step B 1 ,4-dimethyl-1 H-pyrazole-5-carbohydrazide Methyl 1 ,4-dimethyl-1 H-pyrazole-5-carboxylate (270 mg, 1.75 mmol, 1 eq) dissolved in ethanol (23 ml.) was treated with hydrazine hydrate (4.7 ml.) at reflux for 3 h with stirring. The reaction mixture was concentrated to small volume, diluted with water and extracted four times with EtOAc. The organic phases were combined, dried over MgSO 4 , filtered and concentrated to dryness.
  • Step C 3-chloro-5-[(6-chloro-3- ⁇ [5-(1 ,4-dimethyl-1 H-pyrazol-5-yl)-1 ,3,4-oxadiazol-2- yl]methyl ⁇ -2-fluorophenyl)oxy]benzonitrile
  • Example 64 3-chloro-5-r(6-chloro-2-fluoro-3- ⁇ r5-(4-methyl-1 H-pyrazol-5-yl)-1 ,3,4- oxadiazol-2-yl1methyl ⁇ phenyl)oxy1benzonitrile
  • Step A 4-methyl-1 H-pyrazole-5-carbohydrazide
  • Step B N'-( ⁇ 4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl ⁇ acetyl)-4- methyl-1 H-pyrazole-5-carbohydrazide
  • N'-( ⁇ 4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl ⁇ acetyl)-4-methyl-1 H- pyrazole-5-carbohydrazide (431 mg, 0.94 mmol) was treated with POCI3 (20 mL) at reflux for 4 h.
  • the reaction mixture was concentrated to dryness, dissolved in EtOAc and washed with saturated aqueous Na 2 CO 3 and the aqueous phase back extracted twice with EtOAc.
  • the organic phases were combined, dried over MgSO 4 , filtered and concentrated to dryness.
  • Example 65 3-chloro-5-r(6-chloro-3-fr5-(1.4-dimethyl-i H-imidazol-5-ylV1.3.4- oxadiazol-2-yllmethyl ⁇ -2-fluorophenyl)oxylbenzonitrile
  • Step A ethyl 1 ,4-dimethyl-1 H-imidazole-5-carboxylate
  • ethyl 1 ,4-dimethyl-1 H-imidazole-5-carboxylate 185 mg, 1.10 mmol, 1 eq
  • ethanol 25 ml.
  • hydrazine hydrate 5 ml.
  • Additional hydrazine hydrate (20 ml.) was added to the reaction mixture and heated at reflux for an additional 16 h with stirring.
  • the reaction mixture was concentrated to dryness, chased with twice with ethanol and twice with toluene, and pumped dry to give a white solid.
  • the crude product was triturated wit 5% CH3OH/DCM and filtered.
  • Step C 3-chloro-5-[(6-chloro-3- ⁇ [5-(1 ,4-dimethyl-1 H-imidazol-5-yl)-1 ,3,4-oxadiazol-2- yl]methyl ⁇ -2-fluorophenyl)oxy]benzonitrile
  • Example 66 3-chloro-5-ir6-chloro-2-fluoro-3- ⁇ 5-r4-methyl-2-(methylsulfonylV1 H- imidazol-5-yll-1 ,3,4-oxadiazol-2-yl ⁇ methyl)phenylloxy ⁇ benzonitrile
  • Step A ethyl 4-methyl-2-(methylthio)-1 H-imidazole-5-carboxylate
  • Step B ethyl 4-methyl-2-(methylsulfonyl)-1 H-imidazole-5-carboxylate
  • Step D N'-( ⁇ 4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl ⁇ acetyl)-4- methyl-2-(methylsulfonyl)-1 H-imidazole-5-carbohydrazide
  • Step E 3-chloro-5- ⁇ [6-chloro-2-fluoro-3-( ⁇ 5-[4-methyl-2-(methylsulfonyl)-1 H-imidazol- 5-yl]-1 ,3,4-oxadiazol-2-yl ⁇ methyl)phenyl]oxy ⁇ benzonitrile
  • Step A 3-chloro-5-[(6-chloro-3- ⁇ [5-(cyanomethyl)-1 ,3,4-oxadiazol-2-yl]methyl ⁇ -2- fluorophenyl)oxy]benzonitrile
  • Cyanoacetic acid (240 mg, 2.82 mmol, 1 eq) was combined with 2- ⁇ 4-chloro-3-[(3- chloro- ⁇ -cyanophenyOoxy ⁇ -fluorophenylJacetohydrazide (1.00 g, 2.82 mmol, 1 eq), DIPEA (1.00 ml_, 5.65 mmol, 2 eq), and HATU (1.07 g, 2.82 mmol, 1 eq) in dry THF (20 mL) and stirred at ambient temperature for 30 min at which time LC-MS indicated complete conversion to the intermediate diacyl hydrazide.
  • Step B 3-chloro-5- ⁇ [6-chloro-3-( ⁇ 5-[(1Z)-1-cyano-2-(ethyloxy)-1-propen-1-yl]-1 ,3,4- oxadiazol-2-yl ⁇ methyl)-2-fluorophenyl]oxy ⁇ benzonitrile and 3-chloro-5- ⁇ [6-chloro-3- ( ⁇ 5-[(1 E)-1-cyano-2-(ethyloxy)-1-propen-1-yl]-1 ,3,4-oxadiazol-2-yl ⁇ methyl)-2- fluorophenyl]oxy ⁇ benzonitrile
  • Second eluting isomer 81 mg, 0.17 mmol, 38%; LC-MS (ES-) m/z 471.02, 473.13 [M-1]; LC-MS (ES + ) m/z 473.14, 475.13 [M+H].
  • Step C 3-[(3- ⁇ [5-(3-amino-5-methyl-1 H-pyrazol-4-yl)-1 ,3,4-oxadiazol-2-yl]methyl ⁇ -6- chloro-2-fluorophenyl)oxy]-5-chlorobenzonitrile
  • Example 68 3-chloro-5-r(6-chloro-3-fr5-(3.5-dimethyl-1 H-pyrrol-2-ylVI .3.4- oxadiazol-2-yllmethyl ⁇ -2-fluorophenyl)oxylbenzonitrile
  • reaction mixture was cooled to room temperature, treated with methoxycarbonylsulfamoyl- triethylammonium hydroxide, inner salt (Burgess Reagent, 120 mg, 0.50 mmol, 5 eq) and additional dry THF (1 ml.) for 6 h at 55 °C.
  • the reaction mixture was evaporated to dryness, dissolved in DCM (1.5 ml_), washed with water, the organic phase isolated and concentrated to dryness.
  • Method C 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 °C 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
  • Method D 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 °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 °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 E 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 °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 4 h at 55 °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 F Reactions run according to Method E which did not appear to be complete by LC-MS prior to purification were resubjected to treatment with a solution of methoxycarbonylsulfamoyl-triethylammonium hydroxide, inner salt (Burgess Reagent, 120 mg, 500 ⁇ mol, 5 eq) in dry THF (1 mL) for 16 h at 55 °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 G An appropriate volume of a solution of 2- ⁇ 4-chloro-3-[(3-chloro-5- cyanophenyl)oxy]-2-fluorophenyl ⁇ acetohydrazide (0.11 M, 1 eq) and DIPEA (0.22 M, 2 eq) in dry THF was added in combinatorial fashion to vials containing solid carboxylic acid (see table for mass, 1 eq) and an appropriate mass of HATU (1 eq) and stirred for 16 h at 55 °C to form the intermediate diacyl hydrazides.
  • reaction mixtures were allowed to cool to ambient temperature and then treated with an appropriate volume of a solution of methoxycarbonylsulfamoyl-triethylammonium hydroxide, inner salt (Burgess Reagent, 0.55 M, 5 eq) in dry THF for 8 h at 55 °C.
  • the reaction mixtures were evaporated to dryness, dissolved in DCM, 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 H An appropriate volume of a solution of 2- ⁇ 4-chloro-3-[(3-chloro-5- cyanophenyl)oxy]-2-fluorophenyl ⁇ acetohydrazide (0.11 M, 1 eq) and DIPEA (0.22 M, 2 eq) in dry THF was added in combinatorial fashion to vials containing solid carboxylic acid (see table for mass, 1 eq) and an appropriate mass of HATU (1 eq) and stirred for 16 h at 55 °C. The reaction mixtures were evaporated to dryness, partitioned between EtOAc and water, and insoluble material filtered off to give the cyclized final product.
  • Example 233 (2£)-3-f3-chloro-5-r(6-chloro-3-fr5-(3.5-dimethyl-4-isoxazolvn-1.3.4- oxadiazol-2-yllmethyl ⁇ -2-fluorophenyl)oxylphenyl ⁇ -2-propenenitrile
  • Step A 2- ⁇ 3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl ⁇ acetohydrazide
  • Step B 2-( ⁇ 3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl ⁇ methyl)-5-(3,5- dimethyl-4-isoxazolyl)-1 ,3,4-oxadiazole
  • Step C 2-( ⁇ 4-chloro-3-[(3-chloro-5-ethenylphenyl)oxy]-2-fluorophenyl ⁇ methyl)-5-(3,5- dimethyl-4-isoxazolyl)-1 ,3,4-oxadiazole
  • Step D 3-chloro-5-[(6-chloro-3- ⁇ [5-(3,5-dimethyl-4-isoxazolyl)-1 ,3,4-oxadiazol-2- yl]methyl ⁇ -2-fluorophenyl)oxy]benzaldehyde
  • Step E (2£)-3- ⁇ 3-chloro-5-[(6-chloro-3- ⁇ [5-(3,5-dimethyl-4-isoxazolyl)-1 ,3,4- oxadiazol-2-yl]methyl ⁇ -2-fluorophenyl)oxy]phenyl ⁇ -2-propenenitrile
  • Example 234 3-chloro-5- ⁇ r6-chloro-3-( ⁇ 5-r3,5-dimethyl-1 -(methylsulfonyl)-i H-pyrazol- 4-vH-1 ,3,4-oxadiazol-2-yl ⁇ methyl)-2-fluorophenyl1oxy ⁇ benzonitrile
  • Example 235 3-chloro-5-fr6-chloro-2-fluoro-3-( ⁇ 5-ri-(2-hvdroxy-2-methylpropyn-3.5- dimethyl-1H-pyrazol-4-vH-1 ,3,4-oxadiazol-2-yl ⁇ methyl)phenylloxy ⁇ benzonitrile
  • Example 236 S-chloro- ⁇ -fre-chloro ⁇ -fluoro-S-fl ⁇ - ⁇ -O-hvdroxy-S-methylbutvn-S. ⁇ - dimethyl-1H-pyrazol-4-yll-1 ,3,4-oxadiazol-2-yl ⁇ methyl)phenylloxy ⁇ benzonitrile
  • Example 237 3-chloro-5-( ⁇ 6-chloro-3-r(5-f3.5-dimethyl-1-r2-(methylsulfonvnethyll-1 H- Pyrazol-4-yl ⁇ -1 ,3,4-oxadiazol-2-yl)methyll-2-fluorophenyl ⁇ oxy)benzonitrile
  • Step A ethyl 3,5-dimethyl-1-[2-(methylsulfonyl)ethyl]-1 /-/-pyrazole-4-carboxylate
  • ethyl 3,5-dimethyl-1 H-pyrazole-4-carboxylate (1.00 g, 5.95 mmol)
  • methyl vinyl sulfone 0.521 ml, 5.95 mmol
  • K 2 CO 3 2.465 g, 17.84 mmol
  • DMF 15 ml
  • Step B 3,5-dimethyl-1-[2-(methylsulfonyl)ethyl]-1/-/-pyrazole-4-carboxylic acid
  • Step C 3-chloro-5-( ⁇ 6-chloro-3-[(5- ⁇ 3,5-dimethyl-1 -[2-(methylsulfonyl)ethyl]-1 H- pyrazol-4-yl ⁇ -1 ,3,4-oxadiazol-2-yl)methyl]-2-fluorophenyl ⁇ oxy)benzonitrile
  • Example 238 2-f4-r5- ⁇ 4-chloro-3-r(3-chloro-5-cvanoDhenvnoxyl-2- fluorophenyl ⁇ methyl)-1 ,3,4-oxadiazol-2-yll-3,5-dimethyl-1 H-pyrazol-1 - ⁇ / ⁇ -N- ⁇ 2- (methylsulfonyl)ethyllacetamide
  • Example 239 3-chloro-5- ⁇ 6-chloro-3-r(5-f 1 -r(2SV2.3-dihvdroxy-3-methylbutyll-3.5- dimethyl-1 /-/-pyrazol-4-yl ⁇ -1 ,3,4-oxadiazol-2-yl)methyll-2- fluorophenyl ⁇ oxy)benzonitrile
  • Step A ethyl 3,5-dimethyl-1- ⁇ [(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl ⁇ -1 H- py razol e-4-carboxyl ate
  • a solution of ethyl 3,5-dimethyl-1 /-/-pyrazole-4-carboxylate (300 mg, 1.79 mmol), [(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl 4-methylbenzenesulfonate (561 mg, 1.79 mmol) and CS 2 CO3 (1.75 g, 5.37 mmol) in DMF was irradiated in a personal microwave reactor for 25 minutes at 130 °C.
  • Step B 3,5-dimethyl-1- ⁇ [(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl ⁇ -1 H- pyrazole-4-carbohydrazide
  • Step C 3-chloro-5-[(6-chloro-3- ⁇ [5-(3,5-dimethyl-1 - ⁇ [(4S)-2,2,5,5-tetramethyl-1 ,3- dioxolan-4-yl]methyl ⁇ -1H-pyrazol-4-yl)-1 ,3,4-oxadiazol-2-yl]methyl ⁇ -2- fluorophenyl)oxy]benzonitrile
  • Step D 3-chloro-5-( ⁇ 6-chloro-3-[(5- ⁇ 1 -[(2S)-2,3-dihydroxy-3-methylbutyl]-3,5- dimethyl-1 H-pyrazol-4-yl ⁇ -1 ,3,4-oxadiazol-2-yl)methyl]-2- fluorophenyl ⁇ oxy)benzonitrile
  • 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.
  • Hel_a-CD4-LTR- ⁇ -gal cell line (AIDS Research and Reference Reagent Program, Division of AIDS, NIAID) DMEM (GibcoBRL # 12430-047) Trypsin-EDTA (GibcoBRL #25300-054)
  • PBS Phosphate Buffered Saline
  • DMSO Dimethyl Sulfoxide
  • Gal-Screen Reporter Gene Assay System (Applied Biosystems # T1031 ) B. Growth and Maintenance of the CD4-HIV LTR- ⁇ -gal HeLa cell line.
  • 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).
  • 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,
  • mutant RT coding sequence is verified by sequencing both DNA strands.
  • 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 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°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 Hel_a-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.
  • test compounds are titrated robotically on a Beckman 2000 laboratory automation workstation (Beckman Coulter) in a four-fold stepwise manner from 2.7uM (2uM final) down to 0.01 nM (O.OO ⁇ nM final).
  • 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).
  • Table 2 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.
  • A indicates an activity level of less than 10 nM.
  • 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.

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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 AIDS-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, // 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, 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-Ci2 aryl or C5-Ci2 heterocycle;
R3 is -R5Het or C3-Ci2 heterocycle, 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-Ci2 heterocycle and is optionally substituted with at least one C1-C6 alkyl, oxo, hydroxyl, R5S(O)2R4, or halogen; and
Ar is C4-Ci2 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 C3-Ci2 heterocycle 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 R5Het and wherein Het is optionally substituted with at least one C1-Ce 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 each R3 is C4-C6 heterocycle, 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 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 C3-C12 heterocycle 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 C3-C12 heterocycle optionally substituted with at least one C1-C8 alkyl, halogen, OR4, or - N(R4)S(O)2R4.
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 -R5Het or C3-Ci2 heterocycle, 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-Ce 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-Ci2 heterocycle and is optionally substituted with at least one C1-C6 alkyl, oxo, hydroxyl, -R5S(O)2R4, or halogen; and
Ar is C4-Ci2 aryl and is optionally substituted with at least one C1-Cβ alkyl or halogen; or pharmaceutically acceptable derivatives thereof.
The present invention features a compound of formula (II) wherein R3 is C3- Ci2 heterocycle optionally substituted with at least one of 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 (II) wherein R3 is R5Het and wherein Het 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)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 each R3 is C4-C6 heterocycle, 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 C3- Ci2 heterocycle 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 (II) 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 C3-Ci2 heterocycle 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 R is C3-
Ci2 heterocycle optionally substituted with at least one C1-C8 alkyl, halogen, OR4, or -N(R4)S(O)2R4.
Compounds of the present invention include: 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-pyridinyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(3-pyridinyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(3-methyl-4-pyridinyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile; 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-methyl-3-pyridinyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(1/-/-indol-5-yl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(1/-/-indol-6-yl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-[(3-{[5-(1 H-benzimidazol-5-yl)-1 ,3,4-oxadiazol-2-yl]methyl}-6-chloro-2- fluorophenyl)oxy]-5-chlorobenzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(6-chloro-3-pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}- 2-fluorophenyl)oxy]benzonitrile; 3-chloro-5-[(6-chloro-3-{[5-(2-chloro-6-methyl-4-pyridinyl)-1 ,3,4-oxadiazol-2- yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(6-methyl-3-pyridinyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(2-chloro-4-pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}- 2-fluorophenyl)oxy]benzonitrile; 3-chloro-5-[(6-chloro-3-{[5-(3-chloro-4-pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}- 2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(4-chloro-3-pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}- 2-fluorophenyl)oxy]benzonitrile; 3-chloro-5-[(6-chloro-3-{[5-(2,5-dichloro-4-pyridinyl)-1 ,3,4-oxadiazol-2- yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(5-chloro-2-{[2-(methylsulfonyl)ethyl]amino}-4- pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile trifluoroacetate;
3-chloro-5-{[6-chloro-3-({5-[5-chloro-2-(methylthio)-4-pyridinyl]-1 ,3,4- oxadiazol-2-yl}methyl)-2-fluorophenyl]oxy}benzonitrile;
3-[(6-bromo-3-{[5-(3-chloro-4-pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2- fluorophenyl)oxy]-5-chlorobenzonitrile;
2-[(3-chloro-5-cyanophenyl)oxy]-4-{[5-(3-chloro-4-pyridinyl)-1 ,3,4-oxadiazol-2- yl]methyl}-3-fluorobenzonitrile; 3-chloro-5-[(3-{[5-(3-chloro-4-pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}-6-ethenyl-
2-fluorophenyl)oxy]benzonitrile;
3-[(6-bromo-3-{[5-(3-chloro-1-oxido-4-pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}- 2-fluorophenyl)oxy]-5-chlorobenzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(3-methyl-1-oxido-4-pyridinyl)-1 ,3,4- oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-{[6-chloro-2-fluoro-3-({5-[4-methyl-6-({[(4S)-2,2,5,5-tetramethyl-1 ,3- dioxolan-4-yl]methyl}oxy)-3-pyridinyl]-1 ,3,4-oxadiazol-2- yl}methyl)phenyl]oxy}benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(6-{[(2S)-2,3-dihydroxy-3-methylbutyl]oxy}-4- methyl-3-pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(2-{[(2S)-2,3-dihydroxy-3-methylbutyl]oxy}-5- methyl-4-pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-fluoro-5-methyl-4-pyridinyl)-1 ,3,4- oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile; 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(5-methyl-2-{[2-
(methylsulfonyl)ethyl]amino}-4-pyridinyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-3-pyridinyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile; 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(1 ,3,5-trimethyl-1 H-pyrazol-4-yl)-1 ,3,4- oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(3-methyl-2-furanyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile; 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(1-methyl-1 H-pyrrol-2-yl)-1 ,3,4-oxadiazol-
2-yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(2,5-dimethyl-3-furanyl)-1 ,3,4-oxadiazol-2- yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(1-methyl-1 H-imidazol-2-yl)-1 ,3,4- oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(3-methyl-2-pyridinyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(2,4-dimethyl-3-pyridinyl)-1 ,3,4-oxadiazol-2- yl]methyl}-2-fluorophenyl)oxy]benzonitrile; 3-chloro-5-[(6-chloro-3-{[5-(3-ethyl-1-methyl-1 H-pyrazol-5-yl)-1 ,3,4-oxadiazol-
2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-1 ,6-naphthyridin-3-yl)-1 ,3,4- oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-3-furanyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(2,4-dimethyl-1 ,3-thiazol-5-yl)-1 ,3,4-oxadiazol-2- yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(1-methyl-1 H-imidazol-5-yl)-1 ,3,4- oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile; 3-chloro-5-[(6-chloro-3-{[5-(3,5-dimethyl-4-isoxazolyl)-1 ,3,4-oxadiazol-2- yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(2,5-dimethyl-1 ,3-oxazol-4-yl)-1 ,3,4-oxadiazol-2- yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(3-methyl-4-isoxazolyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-methyl-1 ,3-thiazol-5-yl)-1 ,3,4-oxadiazol- 2-yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-1 ,8-naphthyridin-3-yl)-1 ,3,4- oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile; 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(3-methyl-2-thienyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(1-methyl-1 H-indol-2-yl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile; 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(1 -methyl-1 H-pyrazol-5-yl)-1 ,3,4- oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile; and pharmaceutically acceptable derivatives thereof.
Compounds of the present invention include:
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(3-methyl-4-pyridinyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(3-chloro-4-pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}- 2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(5-chloro-2-{[2-(methylsulfonyl)ethyl]amino}-4- pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile; 3-chloro-5-[(6-chloro-3-{[5-(6-{[(2S)-2,3-dihydroxy-3-methylbutyl]oxy}-4- methyl-3-pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(2-{[(2S)-2,3-dihydroxy-3-methylbutyl]oxy}-5- methyl-4-pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(5-methyl-2-{[2- (methylsulfonyl)ethyl]amino}-4-pyridinyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-3-furanyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(3,5-dimethyl-4-isoxazolyl)-1 ,3,4-oxadiazol-2- yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(3-methyl-4-isoxazolyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-methyl-1 ,3-thiazol-5-yl)-1 ,3,4-oxadiazol- 2-yl]methyl}phenyl)oxy]benzonitrile; 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(3-methyl-2-thienyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(1 -methyl-1 H-pyrazol-5-yl)-1 ,3,4- oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile; and pharmaceutically acceptable derivatives 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 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 "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 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 "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). 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. The term "heterocycle", "heterocyclic" or "heterocyclyl includes heteroaryl. 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 imgf000014_0001
where the R' represents an alkyl group as herein defined.
As used herein the term "aryloxycarbonyl" refers to groups such as:
Figure imgf000014_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, 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 -R5Het or C3-C12 heterocycle, 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-C12 heterocycle and is optionally substituted with at least one of C1-C6 alkyl, oxo, hydroxyl, R5S(O)2R4, or halogen; and
Ar is C4-C12 aryl and is optionally substituted with at least one of C1-C6 alkyl or halogen; or pharmaceutically acceptable derivatives thereof.
The present invention features a compound of formula (I) wherein R3 is C3-C12 heterocycle optionally substituted with at least one of 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 R5Het and wherein Het is optionally substituted with at least one of 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 each R3 is C4-C6 heterocycle, 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 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 C3-Ci2 heterocycle optionally substituted with at least one of 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 R is C8-CI2 heterocycle optionally substituted with at least one C1-C8 alkyl, halogen, OR4, or - N(R4)S(O)2R4. The present invention features a compound of formula (I) wherein R3 is C4-C6 heterocycle optionally substituted with methyl, halogen or at least one of each methyl and halogen. The present invention features a compound of formula (I) wherein R3 is C3-Ci2 heterocycle 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)OR4, -C(O)N(R4)2, -OR4, -R5CN or -
N(R4)2; R3 is -R5Het or C3-Ci2 heterocycle, each optionally substituted with at least one of 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 of 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-C12 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 C3-
C12 heterocycle optionally substituted with at least one of 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 R5Het and wherein Het is optionally substituted with at least one of 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 (II) wherein each R3 is C4-C6 heterocycle, 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 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 (II) wherein n is 2 and each R2 is in the orth position to the ether linkage.
The present invention features a compound of formula (II) wherein m is 2, n is 2, and R3 is C3-C12 heterocycle optionally substituted with at least one of 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 (II) wherein R3 is C3- C12 heterocycle optionally substituted with at least one C1-C8 alkyl, halogen, OR4, or -N(R4)S(O)2R4. The present invention features a compound of formula (II) wherein R3 is C4-C6 heterocycle optionally substituted with methyl, halogen or at least one of each methyl and halogen.
The present invention features a compound of formula (II) wherein R3 is C3- C12 heterocycle 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 imgf000019_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 -R5Het or C3-CI2 heterocycle, each optionally substituted with at least one of 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, -
N(R4)S(O)2R4; C 6- io aryl optionally substituted with halogen or C1-C8 alkyl; or C1-C8 alkyl optionally substituted with hydroxyl; each R4 is independently hydrogen, C1-C8 alkyl optionally substituted with at least one of 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-C12 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 features a compound of formula (II)' wherein m is 2; n is 2; each R1 is independently halogen, -CN, or R5CN; each R2 independently is halogen, or -CN;
R3 is C3 -C12 heterocycle, optionally substituted with at least one of C1-C8 alkyl, -OR4,
-N(R4)2, -C(O)N(R4)R5S(O)2R4, -N(R4)R5S(O)2R4, C 6- io aryl optionally substituted with halogen or C1-C8 alkyl; or C1-C8 alkyl optionally substituted with hydroxyl; each R4 is independently hydrogen or C1-C8 alkyl optionally substituted with at least one of hydroxyl or halogen; each R5 is independently C1-C8 alkylene or C1-C8 alkenylene, each optionally substituted with at least one hydroxyl or hydrogen; 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-(6-{[(2S)-2,3-dihydroxy-3-methylbutyl]oxy}-4-methyl-3- pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(5-methyl-2-{[2-(methylsulfonyl)ethyl]amino}-4- pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile; 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-methyl-2-{[2-(methylsulfonyl)ethyl]amino}-1 ,3- thiazol-5-yl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(1 ,4-dimethyl-1 H-pyrazol-5-yl)-1 ,3,4-oxadiazol-2- yl]methyl}-2-fluorophenyl)oxy]benzonitrile; 3-chloro-5-[(6-chloro-3-{[5-(1 ,4-dimethyl-1 H-imidazol-5-yl)-1 ,3,4-oxadiazol-2- yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-[(3-{[5-(3-amino-5-methyl-1 H-pyrazol-4-yl)-1 ,3,4-oxadiazol-2-yl]methyl}-6-chloro-2- fluorophenyl )oxy]-5-chlorobenzonitrile;
3-chloro-5-(6-chloro-3-((5-(3,5-dimethyl-1 H-pyrazol-4-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-2-fluorophenoxy)benzonitrile;
3-(3-((5-(5-amino-1-(2-fluorophenyl)-3-methyl-1 H-pyrazol-4-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-6-chloro-2-fluorophenoxy)-5-chlorobenzonitrile;
3-(3-((5-(5-amino-1-(3-chlorophenyl)-3-methyl-1 H-pyrazol-4-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-6-chloro-2-fluorophenoxy)-5-chlorobenzonitrile; 3-{[3-({5-[5-amino-3-methyl-1 -(3-methylphenyl)-1 H-pyrazol-4-yl]-1 ,3,4-oxadiazol-2- yl}methyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile;
3-[(3-{[5-(5-amino-3-methyl-4-isoxazolyl)-1 ,3,4-oxadiazol-2-yl]methyl}-6-chloro-2- fluorophenyl )oxy]-5-chlorobenzonitrile;
(2£)-3-{3-chloro-5-[(6-chloro-3-{[5-(3,5-dimethyl-4-isoxazolyl)-1 ,3,4-oxadiazol-2- yl]methyl}-2-fluorophenyl)oxy]phenyl}-2-propenenitrile;
3-chloro-5-{[6-chloro-2-fluoro-3-({5-[1-(2-hydroxy-2-methylpropyl)-3,5-dimethyl-1 /-/- pyrazol-4-yl]-1 ,3,4-oxadiazol-2-yl}methyl)phenyl]oxy}benzonitrile;
2-{4-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]-3,5-dimethyl-1/-/-pyrazol-1-yl}-N-[2-(methylsulfonyl)ethyl]acetamide; 3-chloro-5-({6-chloro-3-[(5-{1-[(2S)-2,3-dihydroxy-3-methylbutyl]-3,5-dimethyl-1 H- pyrazol-4-yl}-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, C1-4alkyl, or C1-4alkoxy 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 C1-2o 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 the 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 the 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- Interscience, 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 °C (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) 211 ; PJ. Stephens and FJ. Devlin, Chirality 12 (2000) 172; and Gaussian 98, Revision A.11.4, MJ. Frisch et al., Gaussian, Inc., Pittsburgh PA, 2002.
Experimental Section
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 imgf000036_0001
More specifically, 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 stirred at rt for 45 min. Burgess Reagent (5.0 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 1 : ethyl {S-rO-bromo-δ-chlorophenvDoxyl^-chloro^-fluorophenyllacetate (Intermediate)
Figure imgf000036_0002
Step A: 1-bromo-3-chloro-5-methoxybenzene
Figure imgf000036_0003
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 (DMSO-c/6) δ 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 imgf000037_0001
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 (DMSO-c/6) 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 imgf000037_0002
To a suspension of sodium f-butoxide in THF (600 mL) was added 3-bromo-5- chlorophenol (34.4 g, 166 mmol) at 0 °C, and the mixture stirred at rt for 15 min. The mixture was cooled to 0 °C 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 (DMSO-d6) § 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 imgf000038_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 O °C 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 °C 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 (DMSO-d6) 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 imgf000038_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 °C was added trifluoroacetic acid (350 ml.) and the mixture stirred at 60 °C for 45 min. The reaction was cooled to 0 °C 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 (DMSO-c/6) 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 imgf000039_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 (DMSO-c/6) 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 imgf000039_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 °C was added ethyl {4-amino-3-[(3-bromo- 5-chlorophenyl)oxy]-2-fluorophenyl}acetate (4.57 g, 11.7 mmol) and the reaction stirred for 15 min at 50 °C. The mixture was cooled to 0 °C, 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 (DMSO-d6) § 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-[(3-bromo-5-chlorophenyl)oxy1-4-chloro-2- fluorophenyl}acetohvdrazide (Intermediate)
Figure imgf000040_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 (DMSO- cfe) 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-r(3-chloro-5-cvanophenyl)oxyl-2-fluorophenyl}acetate (Intermediate)
Figure imgf000040_0002
Step A: 3-chloro-5-(methyloxy)benzonitrile
Figure imgf000040_0003
3,5-Dichlorobenzonitrile (52.93 g, 307.7 mmol) was dissolved in anhydrous DMF (300 ml.) and cooled to 0 °C in an ice bath. Sodium methoxide (18.28 g, 338.5 mmol) was added as a solid and the mixture stirred from 0 °C 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 imgf000041_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 °C 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-d6) 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 imgf000041_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 °C 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 imgf000041_0003
3-Chloro-5-hydroxybenzonitrile (20.00 g, 130.2 mmol) was dissolved in anhydrous THF (500 mL) and cooled to 0 °C. 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 imgf000042_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 °C 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 °C 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 imgf000043_0001
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 °C was added trifluoroacetic acid (150 ml.) and the mixture stirred at 60 °C for 45 min. The reaction was cooled to 0 °C 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 imgf000043_0002
To a solution of ethyl {3-[(3-chloro-δ-cyanophenyOoxy^-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 (DMSO-c/6) 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 imgf000043_0003
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 °C 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 °C. The mixture was cooled to 0 °C, 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 (DMSO-d6) § 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 {4-chloro-3-[(3-chloro-5-cvanophenyl)oxy1-2- fluorophenyl}acetate
Figure imgf000044_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 °C 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-r(3-chloro-5-cvanophenyl)oxyl-2- fluorophenyl}acetohvdrazide (Intermediate)
Figure imgf000044_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 (DMSO-c/6) δ 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 imgf000045_0001
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-r(3-chloro-5-cvanophenyl)oxyl-2-fluorophenyl}acetate (Intermediate)
Figure imgf000045_0002
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 °C 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 °C. The mixture was cooled to 0 °C, 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 (DMSeO-d6) δ 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-[(3-chloro-5-cvanophenyl)oxy1-2- fluorophenyl}acetohvdrazide (Intermediate)
Figure imgf000046_0001
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- cfe) 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).
Intermediate 9: [(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yllmethanol
Figure imgf000046_0002
Step A: 2-[(4S)-2,2-dimethyl-1 ,3-dioxolan-4-yl]-2-propanol
Figure imgf000046_0003
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 °C, 1-3 mm Hg) to give the title compound as a clear oil (49.9 g, 31 1 mmol, 76%). 1 H NMR (300 MHz, DMSO-d6) 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
Figure imgf000047_0001
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.) at reflux 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 an 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, DMSO-d6) 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 benzoate
Figure imgf000047_0002
(2S)-3-methyl-1 ,2,3-butanetriol (12.61 g, 86 mmol, 1 eq) was treated with benzoyl chloride (10.0 ml_, 86 mmol) in dry pyridine (100 m L) at -10 °C for 30 min. The reaction mixture was sealed under nitrogen and aged in a refrigerator (5 °C) for 16 h.
The reaction mixture was diluted with EtOAc, washed with water and 1 N HCI (3x), dried over magnesium sulfate, filtered and concentrated to an oil which solidified on standing to give the title compound (16.45 g, 73.4 mmol, 85%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.01 (m, 2 H), 7.60 - 7.71 (m, 1 H), 7.49 - 7.58
(m, 2 H), 5.09 (br. s., 1 H), 4.49 (dd, 1 H), 4.45 (m, 1 H), 4.14 (dd, 1 H), 3.55 (dd, 1
H), 1.15 (s, 3 H), 1.09 (s, 3 H).
Step D: [(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl benzoate
Figure imgf000047_0003
(2S)-2,3-dihydroxy-3-methylbutyl benzoate (16.45 g, 73.4 mmol) was treated with a catalytic amount of 4-methylbenzenesulfonic acid hydrate in acetone (300 ml.) with stirring at ambient temperature for 3 days. The reaction mixture was concentrated to dryness and crystallized from DCM/hexanes to recover unreacted starting material (5.80 g, 25.9 mmol, 35%) as a white solid. The filtrate was concentrated to dryness and purified on a 330 g silica cartridge eluted with 0 to 40% EtOAc/hexanes to give the title compound (5.99 g, 22.7 mmol, 31%). 1 H NMR (400 MHz, DMSO-c/6) δ ppm 7.98 (m, 2 H), 7.64 - 7.74 (m, 1 H), 7.53 - 7.59 (m, 2 H), 4.33 - 4.45 (m, 2 H), 4.09 (dd, 1 H), 1.36 (s, 3 H), 1.31 (s, 3 H), 1.30 (s, 3 H), 1.13 (s, 3 H).
Step E: [(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methanol
Figure imgf000048_0001
(2S)-2,3-dihydroxy-3-methylbutyl benzoate (13.6 g, 60.6 mmol, 1 eq) was combined with 2,2-bis(methyloxy)propane (11.2 ml_, 90.9 mmol, 1.5 eq) and 4- methylbenzenesulfonic acid (0.58 g, 3.0 mmol, 0.05 eq) in toluene (135 ml.) and heated at 50 °C for 1 h at which time TLC indicated complete conversion to the acetonide protected diol. The reaction mixture was concentrated to dryness, the residue dissolved in fresh toluene (70 ml.) and treated with 3 N NaOH (70 ml.) and 40% tetrabutylammonium hydroxide in water (8.0 ml_, 12.3 mmol, 0.2 eq) at 90 °C for 2 h. The phases were separated and the organic phase was split into two equal portions. One of these portions was recombined with the aqueous phase and was diverted to other use. The remaining portion was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product was purified on a 12O g silica gel cartridge eluted with 20 to 60% EtOAc/hexanes to give the title compound (3.15 g, 19.7 mmol, 65% (based on half-reaction stoichiometry)) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.80 (t, 1 H), 3.73 (dd, 1 H), 3.48 - 3.58 (m, 1 H), 3.39 - 3.48 (m, 1 H), 1.31 (s, 3 H), 1.25 (s, 3 H), 1.22 (s, 3 H), 1.02 (s, 3 H).
Example 10: 3-chloro-5-r(6-chloro-2-fluoro-3-{r5-(4-pyridinyl)-1 ,3,4-oxadiazol-2- yllmethyltohenvDoxylbenzonitrile
Figure imgf000049_0001
Step A: 4-[5-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)- 1 ,3,4-oxadiazol-2-yl]pyridine
Figure imgf000049_0002
THF (5ml_), 2-{3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}- acetohydrazide (150 mg, 0.368 mmol), pyridine-4-carboxylic acid (45.3 mg, 0.368 mmol), HATU (140 mg, 0.368 mmol,) and DIPEA (0.13 ml_, 0.736 mmol) were combined and stirred at rt for 45 min. Burgess Reagent (438 mg, 1.84 mmol) was added and the reaction 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 147 mg of the title compound. 1H NMR (DMSO-d6) § 8.74 - 8.85 (m, 2 H), 7.80 - 7.92 (m, 2 H), 7.50 - 7.58 (m, 2 H), 7.49 (t, 1 H), 7.14 - 7.19 (m, 1 H), 7.03 - 7.12 (m, 1 H), 4.51 (s, 2 H).
Step B: 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-pyridinyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile
Figure imgf000049_0003
DMF (3.0 ml_), 4-[5-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2- fluorophenyl}methyl)-1 ,3,4-oxadiazol-2-yl]pyridine (142 mg, 0.287 mmol), zinc cyanide (16.8 mg, 0.143 mmol) and tetrakis(triphenylphosphine) palladium(O) (82.9 mg, 0.0718 mmol) were combined and stirred in an Emry Personal Chemistry microwave reactor at 135 °C 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 35 mg of the title compound. 1H NMR (DMSO-d6) δ 8.77 (m, 2 H), 7.83-7.86 (m, 2 H), 7.77 (m, 1 H), 7.45-7.51 (m, 4 H), 4.48 (s, 2 H).
Example 1 1 : 3-chloro-5-r(6-chloro-2-fluoro-3-{r5-(3-pyridinylV1 ,3.4-oxadiazol-2- yllmethyltohenvDoxylbenzonitrile
Figure imgf000050_0001
Step A: 3-[5-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)- 1 ,3,4-oxadiazol-2-yl]pyridine
Figure imgf000050_0002
THF (5 ml_), 2-{3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2- fluorophenyl}acetohydrazide (150 mg, 0.368 mmol), pyridine-3-carboxylic acid (45.3 mg, 0.368 mmol), HATU (140 mg, 0.368 mmol,) and DIPEA (0.13 ml_, 0.736 mmol) were combined and stirred at rt for 45 min. Burgess Reagent (438 mg, 1.84 mmol) was added and the reaction 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 98 mg of the title compound. 1H NMR (DMSO-d6) § 9.01 - 9.20 (m, 1 H), 8.67 - 8.87 (m, 1 H), 8.16 - 8.42 (m, 1 H), 7.37 - 7.74 (m, 4 H), 7.11 - 7.24 (m, 1 H), 6.99 - 7.1 1 (m, 1 H), 4.49 (s, 2 H).
Step B: 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(3-pyridinyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)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]pyridine (98 mg, 0.198 mmol), zinc cyanide (1 1.6 mg, 0.0989 mmol) and tetrakis(triphenylphosphine) palladium(O) (57.2 mg, 0.0495 mmol) were combined and stirred in an Emry Personal Chemistry microwave reactor at 135 °C 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 9 mg of the title compound. 1H NMR (DMSO-c/ε) δ 9.08 (s, 1 H), 8.75 (m, 1 H), 8.27 (m, 1 H), 7.77 (m, 1 H), 7.58 (m, 1 H), 7.44-7.53 (m, 4 H), 4.46 (s, 2 H).
Example 12: 3-chloro-5-r(6-chloro-2-fluoro-3-fr5-(3-methyl-4-Dyridinvn-1.3.4- oxadiazol-2-yllmethyl}phenyl)oxylbenzonitrile
Figure imgf000051_0002
The title compound (195 mg) was prepared using a procedure analogous to General Procedure A from 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}acetohydrazide (400 mg, 1.13 mmol) and 3-methyl-4-pyridinecarboxylic acid (155 mg, 1.13 mmol). 1H NMR (DMSO-d6) δ 8.67 (s, 1 H), 8.59 (d, 1 H), 7.81 (t, 1 H), 7.75 (d, 1 H), 7.52 - 7.55 (m, 3 H), 7.49 (t, 1 H), 4.50 (s, 2 H), 2.55 (s, 3 H).
Example 13: 3-chloro-5-r(6-chloro-2-fluoro-3-fr5-(4-methyl-3-pyridinvn-1.3.4- oxadiazol-2-yllmethyl}phenyl)oxylbenzonitrile
Figure imgf000052_0001
The title compound (48 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 4-methyl-3-pyridinecarboxylic acid (27.1 mg, 0.198 mmol). 1H NMR (DMSO-d6) § 8.93 (s, 1 H), 8.59 (d, 1 H), 7.80 (t, 1 H), 7.51 - 7.55 (m, 3 H), 7.43 - 7.49 (m, 2 H), 4.49 (s, 2 H), 2.57 (s, 3 H).
Example 14: 3-chloro-5-r(6-chloro-2-fluoro-3-{r5-(1/-/-indol-5-yl)-1 ,3,4-oxadiazol-2- Vl1methyl}phenyl)oxy1benzonitrile
Figure imgf000052_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 (80 mg, 0.226 mmol) and 1 H-indole-5-carboxylic acid (36.4 mg, 0.226 mmol). 1H NMR (DMSO-d6) § 11.28 - 1 1.58 (m, 1 H), 8.12 (s, 1 H), 7.74 - 7.82 (m, 1 H), 7.64 (d, 1 H), 7.48 - 7.54 (m, 4 H), 7.42 - 7.47 (m, 2 H), 6.48 - 6.59 (m, 1 H), 4.43 (s, 2 H).
Example 15: 3-chloro-5-r(6-chloro-2-fluoro-3-{r5-(1/-/-indol-6-yl)-1 ,3,4-oxadiazol-2- Vl1methyl}phenyl)oxy1benzonitrile
Figure imgf000052_0003
The title compound (22 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 1 H-indole-6-carboxylic acid (36.4 mg, 0.226 mmol). 1H NMR (DMSO-d6) δ 11.46 (s, 1 H), 7.98 (s, 1 H), 7.80 (dd, 1 H), 7.70 (d, 1 H), 7.53 - 7.60 (m, 5 H), 7.48 (t, 1 H), 6.38 - 6.59 (m, 1 H), 4.47 (s, 2 H).
Example 16: 3-r(3-fr5-(1/-/-benzimidazol-5-vn-1.3.4-oxadiazol-2-yllmethyl>-6-chloro- 2-fluorophenyl)oxyl-5-chlorobenzonitrile
Figure imgf000053_0001
The title compound (9 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 1 H-benzimidazole-5- carboxylic acid (36.6 mg, 0.226 mmol). 1H NMR (CDCI3) δ 9.57 (s, 1 H), 8.28 (s, 1 H), 7.81 - 7.93 (m, 1 H), 7.68 - 7.81 (m, 1 H), 7.23 - 7.39 (m, 4 H), 7.13 (t, 1 H), 6.90 6.94 (m, 1 H), 4.31 (s, 2 H).
Example 17: 3-chloro-5-r(6-chloro-3-{r5-(6-chloro-3-pyridinyl)-1 ,3,4-oxadiazol-2- yllmethyl}-2-fluorophenyl)oxylbenzonitrile
Figure imgf000053_0002
The title compound (35 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 6-chloro-3- pyridinecarboxylic acid (31.2 mg, 0.198 mmol). 1H NMR (DMSO-c/6) δ 8.92 (m, 1 H), 8.31 (m, 1 H), 7.77 (m, 1 H), 7.71 (m, 1 H), 7.51 (m, 3 H), 7.46 (m, 1 H), 4.46 (s, 2 H).
Example 18: 3-chloro-5-r(6-chloro-3-fr5-(2-chloro-6-methyl-4-pyridinvn-1.3.4- oxadiazol-2-yllmethyl}-2-fluorophenyl)oxylbenzonitrile
Figure imgf000054_0001
The title compound (35 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-6-methyl-4- pyridinecarboxylic acid (34.0 mg, 0.198 mmol). 1H NMR (DMSO-c/6) δ 7.79 (m, 2 H), 7.72 (m, 1 H), 7.53 (m, 3 H), 7.48 (t, 1 H), 4.49 (s, 2 H), 2.54 (s, 3 H).
Example 19: 3-chloro-5-r(6-chloro-2-fluoro-3-fr5-(6-methyl-3-Dyridinvn-1.3.4- oxadiazol-2-yllmethyl}phenyl)oxylbenzonitrile
Figure imgf000054_0002
The title compound (47 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 6-methyl-3- pyridinecarboxylic acid (27.2 mg, 0.198 mmol). 1H NMR (CDCI3) δ 9.13 (m, 1 H), 8.23 (m, 1 H), 7.34 (m, 4 H), 7.17 (m, 1 H), 7.04 (m, 1 H), 4.37 (s, 2 H), 2.67 (s, 3 H).
Example 20: 3-chloro-5-r(6-chloro-3-fr5-(2-chloro-4-pyridinylV1 ,3.4-oxadiazol-2- yllmethyl}-2-fluorophenyl)oxylbenzonitrile
Figure imgf000054_0003
The title compound (34 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-4- pyridinecarboxylic acid (31.2 mg, 0.198 mmol). 1H NMR (DMSO-d6) δ 8.61 (d, 1 H), 7.90 (s, 1 H), 7.78 (m, 1 H), 7.77 (s, 1 H), 7.46-7.53 (m, 4 H), 4.48 (s, 2 H).
Example 21 : S-chloro-δ-Ke-chloro-S-irδ-O-chloro^-pyridinvD-i ,3,4-oxadiazol-2- yllmethyl}-2-fluorophenyl)oxylbenzonitrile
Figure imgf000055_0001
The title compound (44 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-chloro-4- pyridinecarboxylic acid (31.2 mg, 0.198 mmol). 1H NMR (DMSO-d6) δ 8.89 (s, 1 H), 8.72 (d, 1 H), 7.93 (d, 1 H), 7.81 (t, 1 H), 7.51-7.57 (m, 3 H), 7.48 (m, 1 H), 4.53 (s, 2 H).
Example 22: 3-chloro-5-r(6-chloro-3-{r5-(4-chloro-3-pyridinyl)-1 ,3,4-oxadiazol-2- yl1methyl}-2-fluorophenyl)oxy1benzonitrile
Figure imgf000055_0002
The title compound (9 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-chloro-4- pyridinecarboxylic acid (31.1 mg, 0.198 mmol). 1H NMR (DMSO-d6) δ 9.01 (s, 1 H), 8.69 (d, 1 H), 7.77 (m, 2 H), 7.48 - 7.51 (m, 3 H), 7.44 (m, 1 H), 4.49 (s, 2 H).
Example 23: 3-chloro-5-r(6-chloro-3-{r5-(2,5-dichloro-4-pyridinyl)-1 ,3,4-oxadiazol-2- yl1methyl}-2-fluorophenyl)oxy1benzonitrile
Figure imgf000056_0001
THF (25 ml_), 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}acetohydrazide (700 mg, 1.98 mmol), 2,5-dichloro-4-pyridinecarboxylic acid (380 mg, 1.98 mmol), HATU (380 mg, 1.98 mmol) and DIPEA (0.700 ml_, 3.96 mmol) were combined and stirred at rt for 45 min. Burgess Reagent (2.36 g, 9.90 mmol) was added and the reaction stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material purified via silica gel chromatography to give 340 mg of the title compound. 1H NMR (DMSO-d6) δ 8.74 (s, 1 H), 7.98 (s, 1 H), 7.77 (m, 1 H), 7.50 (m, 3 H), 7.46 (m, 1 H), 4.50 (s, 2 H).
Example 24: 3-chloro-5-r(6-chloro-3-fr5-(5-chloro-2-fr2-(methylsulfonvnethyllamino>-
4-pyridinyl)-1 ,3,4-oxadiazol-2-yllmethyl}-2-fluorophenyl)oxylbenzonitrile trifluoroacetate
Figure imgf000056_0002
n-Butanol (1 ml_), 3-chloro-5-[(6-chloro-3-{[5-(2,5-dichloro-4-pyridinyl)-1 ,3,4- oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile (70.0 mg, 0.137 mmol), 2- (methylsulfonyl)ethanamine (25.3 mg, 0.206 mmol), 4,5-Bis(diphenylphosphino)-9,9- dimethylxanthene (3.5 mg, 0.0060 mmol), potassium carbonate (75.6 mg, 0.548 mmol), and trisdibenzylideneacetone palladium (II) (2.51 mg, 0.00274 mmol) were combined and stirred in an Emry Personal Chemistry microwave reactor at 150 °C for 15 min. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material purified via reverse phase HPLC to give 3.5 mg of the title compound. 1H NMR (CDCI3) δ 8.15 (s, 1 H), 7.19 - 7.37 (m, 6 H), 6.99 (s, 1 H), 4.42 (s, 2 H), 3.94 - 3.98 (m, 2 H), 3.40 - 3.43 (m, 2 H), 3.00 (s, 3 H). Example 25: S-chloro-δ-fre-chloro-S-αδ-rδ-chloro^-fmethylthioM-Dyridinyll-i .3.4- oxadiazol-2-yl}methyl)-2-fluorophenylloxy}benzonitrile
Figure imgf000057_0001
THF (5 mL), 3-chloro-5-[(6-chloro-3-{[5-(2,5-dichloro-4-pyridinyl)-1 ,3,4-oxadiazol-2- yl]methyl}-2-fluorophenyl)oxy]benzonitrile (47.0 mg, 0.0921 mmol) and sodium thiomethoxide (12.9 mg, 0.184 mmol) were combined and stirred at rt for 4 h. The solvent was removed and the crude material was purified via silica gel chromatography to give 25 mg of the title compound. 1H NMR (CDCI3) δ 8.38 (s, 1 H), 7.78 (s, 1 H), 7.36 - 7.38 (m, 1 H), 7.34 (d, 1 H), 7.29 - 7.33 (m, 1 H), 7.16 (t, 1 H), 7.03 (dd, 1 H), 4.40 (s, 2 H), 2.61 (s, 3 H).
Example 26: 3-r(6-bromo-3-fr5-(3-chloro-4-pyridinvn-1.3.4-oxadiazol-2-yllmethyl>-2- fluorophenyl)oxyl-5-chlorobenzonitrile
Figure imgf000057_0002
THF (25 mL), 2-{4-bromo-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}acetohydrazide (700 mg, 1.76 mmol), 3-chloro-4-pyridinecarboxylic acid (276 mg, 1.76 mmol), HATU (669 mg, 1.76 mmol,) and DIPEA (0.610 mL, 3.52 mmol) were combined and stirred at rt for 45 min. Burgess Reagent (2.06 g, 8.80 mmol) was added and the reaction 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 430 mg of the title compound. 1H NMR (DMSO-d6) δ 8.85 (s, 1 H), 8.68 (d, 1 H), 7.89 (d, 1 H), 7.71 - 7.82 (m, 1 H), 7.64 (dd, 1 H), 7.27 - 7.54 (m, 3 H), 4.49 (s, 2 H). Example 27: 2-r(3-chloro-5-cvanophenyl)oxyl-4-{r5-(3-chloro-4-pyridinyl)-1 ,3,4- oxadiazol-2-yllmethyl}-3-fluorobenzonitrile
Figure imgf000058_0001
DMF (3.0 ml_), 3-[(6-bromo-3-{[5-(3-chloro-4-pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2- fluorophenyl)oxy]-5-chlorobenzonitrile (50.0 mg, 0.0961 mmol), zinc cyanide (5.63 mg, 0.0481 mmol) and tetrakis(triphenylphosphine) palladium(O) (27.7 mg, 0.0240 mmol) were combined and stirred in an Emry Personal Chemistry microwave reactor at 135 °C 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 (DMSO-d6) δ 8.88 (s, 1 H), 8.71 (d, 1 H), 7.91 (d, 1 H), 7.86-7.85 (m, 2 H), 7.67-7.50 (m, 3 H), 4.61 (s, 2 H).
Example 28: 3-chloro-5-r(3-ir5-(3-chloro-4-pyridinylV1 ,3.4-oxadiazol-2-yllmethyl>-6- ethenyl-2-fluorophenvDoxylbenzonitrile
Figure imgf000058_0002
n-Propanol (2ml_), 3-[(6-bromo-3-{[5-(3-chloro-4-pyridinyl)-1 ,3,4-oxadiazol-2- yl]methyl}-2-fluorophenyl)oxy]-5-chlorobenzonitrile ( 70.0 mg, 0.135 mmol), potassium vinyltrifluoroborate (22.4 mg, 0.168 mmol), dichloro[1 ,1 '- bis(diphenylphosphino) ferrocene] palladium(ll) (2.20 mg, 0.00270 mmol) and triethylamine (0.021 ml_, 0.149 mmol) were combined. The mixture was stirred overnight at 100 °C. LC-MS indicated only 20% conversion to product. Additional potassium vinyltrifluoroborate (22.4 mg, 0.168 mmol), dichloro[1 ,1 '- bis(diphenylphosphino)ferrocene] palladium(ll) (2.20 mg, 0.00270 mmol) and triethylamine (0.021 ml_, 0.149 mmol) were added and the mixture stirred for an additional 6 h at 100 °C. The reaction mixture was diluted with ethyl acetate and washed with water. The solvent was removed and the crude material purified via silica gel chromatography to give 40 mg of the title compound. 1H NMR (DMSO-c/ε) δ 8.85 (s, 1 H), 8.69 (d, 1 H), 7.90 (d, 1 H), 7.73 (s, 1 H), 7.60 (d, 1 H), 7.46-7.39 (m, 2 H), 7.33-7.31 (m, 1 H), 6.70-6.63 (m, 1 H), 5.94 (d, 1 H), 5.39 (d, 1 H), 4.48 (s, 2 H).
Example 29: 3-r(6-bromo-3-fr5-(3-chloro-1-oxido-4-pyridinyl)-1 ,3,4-oxadiazol-2- yllmethyl}-2-fluorophenyl)oxyl-5-chlorobenzonitrile
Figure imgf000059_0001
Dichloromethane (5 ml_), 3-[(6-bromo-3-{[5-(3-chloro-4-pyridinyl)-1 ,3,4-oxadiazol-2- yl]methyl}-2-fluorophenyl)oxy]-5-chlorobenzonitrile (190 mg, 0.365 mmol) and m- chloroperoxybenzoic acid (164 mg, 0.731 mmol, 77% max.) were combined and stirred overnight at rt. The solvent was removed and the crude material adsorbed onto silica gel. The crude material was purified via silica gel chromatography to give 167 mg of the title compound. 1H NMR (DMSO-d6) δ 8.73 (d, 1 H), 8.32 (dd, 1 H), 7.90 (d, 1 H), 7.80 (t, 1 H), 7.66 (dd, 1 H), 7.49 - 7.52 (m, 1 H), 7.44 - 7.48 (m, 2 H), 4.48 (s, 2 H).
Example 30: S-chloro-δ-Re-chloro^-fluoro-S-frδ-O-methyl-1-oxido^-pyridinvn-I .S^- oxadiazol-2-yllmethyl}phenyl)oxylbenzonitrile
Figure imgf000059_0002
Dichloromethane (5 ml_), 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(3-methyl-4-pyridinyl)- 1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile (190 mg, 0.418 mmol) and m- chloroperoxybenzoic acid (188 mg, 0.835 mmol, 77% max.) were combined and stirred overnight at rt. The solvent was removed and the crude material adsorbed onto silica gel. The crude material was purified via silica gel chromatography to give 154 mg of the title compound. 1H NMR (DMSO-d6) δ 8.37 (s, 1 H), 8.19 (d, 1 H), 7.80 (t, 1 H), 7.77 (d, 1 H), 7.51 - 7.55 (m, 3 H), 7.49 - 7.50 (m, 1 H), 4.47 (s, 2 H), 2.49 (s, 3 H).
Example 31 : 3-chloro-5-fr6-chloro-2-fluoro-3-α5-r4-methyl-6-({r(4SV2.2.5.5- tetramethyl-1 ,3-dioxolan-4-yllmethyl}oxy)-3-pyridinyll-1 ,3,4-oxadiazol-2- yl}methyl)phenylloxy}benzonitrile
Figure imgf000060_0001
Step A: ethyl β-amino^-methyl-S-pyridinecarboxylate
Figure imgf000060_0002
5-bromo-4-methyl-2-pyridinamine (4.00 g, 21.4 mmol, 1 eq) was combined with Pd(OAc)2 (480 mg, 2.1 mmol, 0.1 eq), 1 ,3-propanediylbis(diphenylphosphane) (882 mg, 2.1 mmol, 0.1 eq), DIPEA (1 1 ml_, 64 mmol, 3 eq), and ethanol (50 ml.) in DMSO (50 ml.) in a Porter-Fischer Vessel and purged with nitrogen. The reaction mixture was placed under an atmosphere of carbon monoxide (60 psi) and heated at 75 °C for 3 days with vigorous stirring. The reaction mixture was diluted with EtOAc, washed three times with dilute brine, dried over magnesium sulfate, filtered through Celite™ and concentrated to dryness to give an orange semi-solid. This material was triturated with boiling ethanol, cooled in an ice bath, and a yellow solid filtered off. The filtrate was concentrated to dryness and purified by column chromatography (EtOAc/hexanes) to give the title compound (1.18 g, 6.5 mmol, 30%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.46 (s, 1 H), 6.63 (s, 2 H), 6.25 (s, 1 H), 4.19 (q, 2 H), 2.37 (s, 3 H), 1.27 (t, 3 H). LC-MS (ES+) m/z 181.21 [M+H]
Step B: ethyl β-chloro^-methyl-S-pyridinecarboxylate
Figure imgf000061_0001
To a solution of ethyl β-amino^-methyl-S-pyridinecarboxylate (0.37 g, 2.05 mmol, 1 eq) in 37% HCI (5 ml.) was added a solution of sodium nitrite (0.37 g, 5.3 mmol) in water (3 ml.) dropwise with stirring and cooling such that the temperature did not rise above -5 °C. This was followed by portionwise addition of copper(l) chloride, again maintaining temperature below -5 °C. The resultant mixture was stirred 30 min at -7 °C, warmed to ambient temperature and stirred 16 h. A duplicate reaction was run on a second batch of ethyl 6-amino-4-methyl-3-pyridinecarboxylate (0.80 g, 4.4 mmol) under the same conditions and stoichiometry. These two reactions were combined and poured onto a mixture of ice and diethyl ether. The pH was adjusted to >12 with 6 N NaOH and the phases separated. The aqueous phase was extracted twice with diethyl ether, the organic phases combined, dried over magnesium sulfate, filtered and concentrated to dryness. The crude product was purified by column chromatography (EtOAc/hexanes) to give the title compound (0.40 g, 2.00 mmol, 31 %). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (s, 1 H), 7.60 (s, 1 H), 4.33 (q, 2 H), 2.55 (s, 3 H), 1.33 (t, 3 H). LC-MS (ES+) m/z 199.98, 201.90 [M+H]
Step C: ethyl 4-methyl-6-({[(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl}oxy)-3- pyridinecarboxylate
Figure imgf000061_0002
Ethyl β-chloro^-methyl-S-pyridinecarboxylate (0.40 g, 2.00 mmol, 1 eq) and [(4S)- 2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methanol (0.33 g, 2.00 mmol, 1 eq) were combined with Pd(OAc)2 (36 mg, 0.16 mmol, 0.08 eq), 1 ,1 '-binaphthalen-2-yl[bis(1 ,1- dimethylethyl)]phosphane (80 mg, 0.20 mmol, 0.1 eq) and cesium carbonate (1.96 g, 6.00 mmol, 3 eq) in toluene (20 ml_), purged with nitrogen and heated 2 h at reflux. The reaction mixture was stirred 16 h at 85 °C and then returned to reflux for 6 h. The reaction mixture was cooled to ambient temperature, diluted with EtOAc, washed with water, dried over magnesium sulfate, filtered and concentrated to dryness. The crude product was purified by column chromatography (EtOAc/hexanes) to give the title compound (0.31 g, 1.00 mmol, 50%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.64 (s, 1 H), 6.86 (s, 1 H), 4.44 (dd, 1 H), 4.36 (dd, 1 H), 4.28 (q, 2 H), 4.09 (dd, 1 H), 2.51 (s, 3 H), 1.36 (s, 3 H), 1.28 - 1.34 (m, 9 H), 1.1 1 (s, 3 H).
Step D: 4-methyl-6-({[(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl}oxy)-3- pyridinecarbohydrazide
Figure imgf000062_0001
Ethyl 4-methyl-6-({[(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl}oxy)-3- pyridinecarboxylate (0.31 g, 1.00 mmol, 1 eq) was treated with hydrazine hydrate (10 ml.) in ethanol (15 ml.) at reflux for 4 h. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with water, dried over magnesium sulfate, filtered and concentrated to dryness. The crude product was purified on a 40 g silica gel cartridge eluted with 10% CH3OH/DCM to give the title compound (0.26 g, 0.84 mmol, 84%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.51 (t, 1 H), 8.10 (s, 1 H), 6.77 (s, 1 H), 4.46 (d, 2 H), 4.29 - 4.41 (m, 2 H), 4.07 (dd, 1 H), 2.33 (s, 3 H), 1.35 (s, 3 H), 1.29 (s, 3 H), 1.29 (s, 3 H), 1.1 1 (s, 3 H). LC-MS (ES-) m/z 308.31 (M-1 ); LC-MS (ES+) m/z 310.09 [M+H]
Step E: 3-chloro-5-{[6-chloro-2-fluoro-3-({5-[4-methyl-6-({[(4S)-2,2,5,5-tetramethyl- 1 ,3-dioxolan-4-yl]methyl}oxy)-3-pyridinyl]-1 ,3,4-oxadiazol-2- yl}methyl)phenyl]oxy}benzonitrile
Figure imgf000062_0002
4-methyl-6-({[(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl}oxy)-3- pyridinecarbohydrazide (0.24 g, 0.76 mmol, 1 eq) was combined with {4-chloro-3-[(3- chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetic acid (0.26 g, 0.76 mmol, 1 eq), HATU (0.29 g, 0.76 mmol, 1 eq) and DIPEA (266 μl_, 1.53 mmol, 2 eq) in dry THF (9 ml.) and stirred at ambient temperature 2.5 h at which time LC-MS indicated complete conversion to the intermediate diacyl hydrazide. To this reaction mixture was added methoxycarbonylsulfamoyl-triethylammonium hydroxide, inner salt (Burgess Reagent, 0.91 g, 3.8 mmol, 5 eq) and the resultant mixture was stirred 1.5 h at ambient temperature. The reaction mixture was concentrated to dryness, partitioned between EtOAc and saturated NaHCOs and the phases separated. The organic phase was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product was purified on a 40 g silica gel cartridge eluted with 20 to 60% EtOAc/hexanes to give the title compound (0.35 g, 0.58 mmol, 76%) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.56 (s, 1 H), 7.78 (t, 1 H), 7.48 - 7.55 (m, 3 H), 7.47 (t, 1 H), 6.95 (s, 1 H), 4.45 (s, 2 H), 4.32 - 4.44 (m, 2 H), 4.07 (dd, 1 H), 2.50 (s, 3 H), 1.33 (s, 3 H), 1.27 (s, 3 H), 1.27 (s, 3 H), 1.09 (s, 3 H). LC-MS (ES-) m/z 61 1.36, 613.43 (M-1 ); LC-MS (ES+) m/z 613.19, 615.11 [M+H]
Example 32: 3-chloro-5-r(6-chloro-3-fr5-(6-fr(2SV2.3-dihvdroxy-3-methylbutylloxy>-4- methyl-3-pyridinyl)-1 ,3,4-oxadiazol-2-yllmethyl}-2-fluorophenyl)oxylbenzonitrile
Figure imgf000063_0001
3-chloro-5-{[6-chloro-2-fluoro-3-({5-[4-methyl-6-({[(4S)-2,2,5,5-tetramethyl-1 ,3- dioxolan-4-yl]methyl}oxy)-3-pyridinyl]-1 ,3,4-oxadiazol-2- yl}methyl)phenyl]oxy}benzonitrile (187 mg, 0.31 mmol, 1 eq) was treated with pyridinium p-toluenesulfonic acid (92 mg, 0.37 mmol, 1.2 eq) in dry CH3OH (10 mL) at 60 °C for 8 h. The reaction mixture was concentrated to dryness, partitioned between EtOAc and saturated NaHCO3, the phases separated, and the aqueous phase extracted twice with EtOAc. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated to dryness. The crude product was purified on a 40 g silica gel cartridge eluted with 40 to 100% EtOAc/hexanes to give the title compound (1 10 mg, 0.19 mmol, 63%) as a white foam. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.57 (t, 1 H), 7.81 (t, 1 H), 7.51 - 7.58 (m, 3 H), 7.50 (t, 1 H), 6.88 (s, 1 H), 4.98 (d, 1 H), 4.54 (dd, 1 H), 4.47 (s, 2 H), 4.41 (s, 1 H), 4.15 (dd, 1 H), 3.55 (ddd, 1 H), 2.53 (s, 3 H), 1.14 (s, 3 H), 1.08 (s, 3 H). LC-MS (ES-) m/z 571.25, 573.45 (M-1 ); LC-MS (ES+) m/z 573.10, 575.04 [M+H]
Example 33: 3-chloro-5-r(6-chloro-3-fr5-(2-fr(2SV2.3-dihvdroxy-3-methylbutylloxy>-5- methyl-4-pyridinyl)-1 ,3,4-oxadiazol-2-yllmethyl}-2-fluorophenyl)oxylbenzonitrile
Figure imgf000064_0001
Step A: 4-iodo-5-methyl-2-({[(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4- yl]methyl}oxy)pyιϊdine
Figure imgf000064_0002
2-fluoro-4-iodo-5-methylpyridine (0.41 g, 1.75 mmol, 1 eq; Asymchem, USA, CAS # 153034-94-7) and [(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methanol (0.28 g, 1.75 mmol, 1 eq) were combined with 40% tetrabutylammonium hydroxide in water in a mixture of toluene (6 mL) and 6 N NaOH (6 mL) and stirred vigorously at 90 °C for 8 h. The reaction mixture was diluted with EtOAc, the organic phase isolated, dried over magnesium sulfate, filtered and concentrated to dryness. The crude product was purified on a 40 g silica gel cartridge eluted with 0 to 20% EtOAc/hexanes to give the title compound (0.47 g, 1.22 mmol, 70%) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.02 (s, 1 H), 7.41 (s, 1 H), 4.32 (dd, 1 H), 4.26 (dd, 1 H), 4.05 (dd, 1 H), 2.26 (s, 3 H), 1.35 (s, 3 H), 1.28 (s, 3 H), 1.28 (s, 3 H), 1.09 (s, 3 H). LC-MS (ES+) m/z 378.02 [M+H]
Step B: 2-{[(2S)-2,3-dihydroxy-3-methylbutyl]oxy}-5-methyl-4-pyridinecarboxylic acid
Figure imgf000065_0001
2.5 M n-BuLi in hexanes (1.0 ml_, 2.5 mmol, 2 eq) was added to dry THF (1 mL) and cooled to -78 °C. To this solution was added 4-iodo-5-methyl-2-({[(4S)-2,2,5,5- tetramethyl-1 ,3-dioxolan-4-yl]methyl}oxy)pyridine (468 mg, 1.24 mmol, 1 eq) in dry THF (2 mL) dropwise with stirring and continued cooling. After 5 min at this same temperature, carbon dioxide was bubbled briefly (1 min) through the reaction mixture resulting in a rapid change in color from yellow to grey and then white. The reaction mixture was concentrated to dryness and the residue treated with 4 N HCI/Dioxane. The reaction mixture was again concentrated to dryness and the crude reaction mixture purified by RP-HPLC on a Sunfire™ C-18 column eluted with 5 to 70% CH3CN in water with 0.1% TFA buffer to give the title compound (80 mg, 0.31 mmol, 25%). LC-MS (ES-) m/z 254.10 (M-1 ); LC-MS (ES+) m/z 256.12 [M+H]
Step C: N'-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetyl)-2- {[(2S)-2,3-dihydroxy-3-methylbutyl]oxy}-5-methyl-4-pyridinecarbohydrazide
Figure imgf000065_0002
2-{[(2S)-2,3-dihydroxy-3-methylbutyl]oxy}-5-methyl-4-pyridinecarboxylic acid (74 mg, 0.29 mmol, 1 eq) was combined with 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}acetohydrazide (103 mg, 0.29 mmol, 1 eq), DIPEA (100 μL, 0.58 mmol, 2 eq), and HATU (11 1 mg, 0.29 mmol, 1 eq) in dry THF (3 mL) and stirred at ambient temperature for 2 h. The reaction mixture was concentrated to dryness, partitioned between EtOAc and saturated NaHCO3 and the phases separated. The organic phase was dried over magnesium sulfate, filtered and concentrated to dryness. The crude product was purified on a 12 g silica gel cartridge eluted with EtOAc to give the title compound (95 mg, 0.16 mmol, 55%) as a clear glass. LC-MS (ES-) m/z 589.43, 591.43 (M-1 ); LC-MS (ES+) m/z 591.14, 593.10 [M+H] Step D: yV-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetyl)-5- methyl-2-({[(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl}oxy)-4- pyridinecarbohydrazide
Figure imgf000066_0001
N'-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetyl)-2-{[(2S)-2,3- dihydroxy-3-methylbutyl]oxy}-5-methyl-4-pyridinecarbohydrazide (95 mg, 0.16 mmol, 1 eq) was combined with 2,2-bis(methyloxy)propane (30 μl_, 0.24 mmol, 1.5 eq) and 4-methylbenzenesulfonic acid (2 mg, 8 μmol, 0.05 eq) in toluene (3 ml.) and heated at 60 °C for 1 h. The reaction mixture was concentrated to dryness, then acetone (3 ml.) was added and the 2,2-bis(methyloxy)propane replaced. The reaction mixture was stirred 3 days at ambient temperature. The reaction mixture was concentrated to dryness, partitioned between EtOAc and saturated NaHCO3 and the phases separated. The organic phase was dried over magnesium sulfate, filtered, and concentrated to give the title compound (100 mg, 0.16 mmol, 99%) as a white foam. LC-MS (ES-) m/z 629.45, 631.51 (M-1 ); LC-MS (ES+) m/z 631.28, 633.24 [M+H]
Step E: 3-chloro-5-{[6-chloro-2-fluoro-3-({5-[5-methyl-2-({[(4S)-2,2,5,5-tetramethyl- 1 ,3-dioxolan-4-yl]methyl}oxy)-4-pyridinyl]-1 ,3,4-oxadiazol-2- yl}methyl)phenyl]oxy}benzonitrile
Figure imgf000066_0002
N'-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetyl)-5-methyl-2- ({[(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl}oxy)-4-pyridinecarbohydrazide (100 mg, 0.16 mmol, 1 eq) was combined with methoxycarbonylsulfamoyl- triethylammonium hydroxide, inner salt (Burgess reagent, 57 mg, 0.24 mmol, 1.5 eq) in dry THF (3 mL) and the resultant mixture stirred 16 h at ambient temperature. Additional Burgess reagent (114 mg, 0.48 mmol, 3 eq) dissolved in dry THF (2.5 mL) was added to the reaction mixture and stirred 2 days. The reaction mixture was concentrated to dryness, dissolved in EtOAc, washed with water, dried over magnesium sulfate, filtered and concentrated to dryness. The crude product was purified on a 12 g silica gel cartridge eluted with 0 to 60% EtOAc/hexanes to give the title compound (40 mg, 65 μmol, 41%) as a clear oil. LC-MS (ES-) m/z 61 1.20, 613.27 (M-1 ); LC-MS (ES+) m/z 613.22, 615.23 [M+H]
Step F: 3-chloro-5-[(6-chloro-3-{[5-(2-{[(2S)-2,3-dihydroxy-3-methylbutyl]oxy}-5- methyl-4-pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile
Figure imgf000067_0001
3-chloro-5-{[6-chloro-2-fluoro-3-({5-[5-methyl-2-({[(4S)-2,2,5,5-tetramethyl-1 ,3- dioxolan-4-yl]methyl}oxy)-4-pyridinyl]-1 ,3,4-oxadiazol-2- yl}methyl)phenyl]oxy}benzonitrile (40 mg, 65 μmol, 1 eq) was treated with pyridinium p-toluenesulfonic acid (50 mg, 0.20 mmol, 3 eq) in dry CH3OH (7 mL) at 70 °C for 8 h. The reaction mixture was concentrated to dryness, partitioned between DCM and saturated NaHCO3, the phases separated, and the aqueous phase extracted twice with DCM. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated to dryness. The crude product was purified on a 40 g silica gel cartridge eluted with 40 to 100% EtOAc/hexanes to give the title compound (21 mg, 37 μmol, 57%) as a white foam. 1H NMR (400 MHz, CDCI3) δ ppm 8.13 (d, 1 H), 7.38 (dd, 1 H), 7.28 - 7.37 (m, 2 H), 7.26 (s, 1 H), 7.19 (dd, 1 H), 7.02 (dd, 1 H), 4.55 (dd, 1 H), 4.34 - 4.41 (m, 3 H), 3.80 (dd, 1 H), 2.57 (s, 3 H), 1.32 (s, 3 H), 1.29 (s, 3 H). LC-MS (ES-) m/z 571.29, 573.27 (M-1 ); LC-MS (ES+) m/z 573.10, 575.06 [M+H]
Example 34: 3-chloro-5-r(6-chloro-2-fluoro-3-fr5-(2-fluoro-5-methyl-4-DyridinylV1.3.4- oxadiazol-2-yllmethyl}phenyl)oxylbenzonitrile
Figure imgf000067_0002
Step A: 2-fluoro-5-methyl-4-pyridinecarboxylic acid
Figure imgf000068_0001
Employing the method of Schlosser and Rausis {Eur. J. Org. Chem. 2004, 5, 1018), 2.5M n-BuLi/hexanes (4.5 ml_, 1 1.3 mmol, 0.67 eq) and 2.0M n-BuMgCI/THF (2.8 ml_, 5.6 mmol, 0.33 eq) were mixed together with stirring and cooling in an ice bath for 30 min. To the resultant slurry was added a solution of 2-fluoro-4-iodo-5- methylpyridine (4.00 g, 16.9 mmol, 1 eq; Asymchem, USA, CAS # 153034-94-7) in dry toluene (33 ml.) dropwise with stirring and cooling in an ice bath. The resultant mixture was stirred at the same temperature for 45 min. An excess of freshly crushed dry ice was added to the reaction mixture which was then acidified with 1 N HCI and extracted three times with diethyl ether. The organics were combined, dried over magnesium sulfate, filtered and concentrated to give the title compound (0.53 g, 3.4 mmol, 20%) as a yellow, oily solid. LC-MS (ES-) m/z 154.12 (M-1 ); LC-MS (ES+) m/z 156.08 [M+H]
Step B: 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-fluoro-5-methyl-4-pyridinyl)-1 ,3,4- oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile
Figure imgf000068_0002
2-fluoro-5-methyl-4-pyridinecarboxylic acid (175 mg, 1.13 mmol, 1 eq) was combined with 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetohydrazide (400 mg, 1.13 mmol, 1 eq), DIPEA (390 μL, 2.26 mmol, 2 eq) and HATU (430 mg, 1.13 mmol, 1 eq) in dry THF (6 mL) and stirred at ambient temperature for 30 min at which time LC-MS indicated complete conversion to the intermediate diacyl hydrazide. To this reaction mixture was added methoxycarbonylsulfamoyl-triethylammonium hydroxide, inner salt (Burgess Reagent, 1.35 g, 5.65 mmol, 5 eq) and the resultant mixture was stirred 16 h at ambient temperature. The reaction mixture was concentrated to dryness, partitioned between EtOAc and water, the phases separated, and the aqueous phase extracted twice with EtOAc. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated to dryness. The crude product was purified on a 40 g silica gel cartridge eluted with 20 to 40% EtOAc/hexanes to give the title compound (0.43 g, 0.91 mmol, 80%) as a clear oil. 1H NMR (400 MHz, DMSO-D6) δ ppm 8.35 (d, 1 H), 7.79 - 7.82 (m, 1 H), 7.53 - 7.56 (m, 4 H), 7.48 - 7.52 (m, 1 H), 4.51 (s, 2 H), 2.54 (s, 3 H). LC-MS (ES-) m/z 471.19, 473.25 (M-1 ); LC-MS (ES+) m/z 473.18, 475.01 [M+H]
Example 35: 3-chloro-5-r(6-chloro-2-fluoro-3-fr5-(5-methyl-2-fr2-
(methylsulfonyl)ethyllamino}-4-Pyridinyl)-1 ,3,4-oxadiazol-2-
Vl1methyl}phenyl)oxy1benzonitrile
Figure imgf000069_0001
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-fluoro-5-methyl-4-pyridinyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile (85 mg, 0.18 mmol, 1 eq) was combined with [2- (methylsulfonyl)ethyl]amine (222 mg, 1.8 mmol) which was prepared according to literature precedent {Bioorg. Med. Chem. Lett. 2006, 16, 4686) and DIPEA (47 μL, 0.27 mmol, 1.5 eq) in DMSO (0.5 mL) and heated in a microwave synthesizer at 150 °C for 2 h. The crude reaction mixture was purified by RP-HPLC on a Sunfire™ C-18 column eluted with 10 to 100% CH3CN in water with 0.1% TFA buffer to give the title compound (20 mg, 0.035 mmol, 19%). 1H NMR (400 MHz, CDCI3) δ ppm 9.49 (br. s., 1 H), 7.88 (s, 1 H), 7.54 (s, 1 H), 7.30 - 7.40 (m, 3 H), 7.20 (t, 1 H), 6.99 (s, 1 H), 4.43 (s, 2 H), 3.98 (t, 2 H), 3.45 (t, 2 H), 3.00 (s, 3 H), 2.58 (s, 3 H). LC-MS (ES-) m/z 574.18, 576.22 (M-1 ); LC-MS (ES+) m/z 576.15, 578.1 1 [M+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 (35 μL, 200 μmol, 2 eq) in dry THF (1 mL) was added to vials containing solid carboxylic acid (see Table 1 for stoichiometry) and HATU (38 mg, 100 μmol, 1 eq) and stirred for 3 h at ambient temperature to form the intermediate diacyl hydrazides. The reaction mixtures were then treated with a solution of methoxycarbonylsulfamoyl- triethylammonium hydroxide, inner salt (Burgess Reagent, 36 mg, 150 μmol, 1.5 eq) in dry THF (1 ml.) for 16 h at ambient temperature followed by 16 h at 60 °C. Additional Burgess Reagent (72 mg, 300 μmol, 3 eq) dissolved in dry THF (1 ml.) was added to each reaction mixture and stirred 16 h at 60 °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 Sunfire™ C-18, 19 x 150 mm, 5 micron column eluted with 10 to 100% CH3CN in water with 0.1 % TFA buffer at 20 mL/min.
Method B: A solution of 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}acetohydrazide (35.4 mg, 100 μmol, 1 eq) and DIPEA (35 μl_, 200 μmol, 2 eq) in dry THF (1 ml.) was added 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 °C 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 °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 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 50 mL/min.
Final products obtained by either of the above methods were characterized by analytical LC-MS and are listed below and in Table 1.
Example 36: 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-3-pyridinyl)-1 ,3,4- oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile
Example 37: 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(1 ,3,5-trimethyl-1 H-pyrazol-4-yl)-
1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile Example 38: 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(3-methyl-2-furanyl)-1 ,3,4- oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile
Example 39: 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(1-methyl-1 H-pyrrol-2-yl)-1 ,3,4- oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile
Example 40: 3-chloro-5-[(6-chloro-3-{[5-(2,5-dimethyl-3-furanyl)-1 ,3,4-oxadiazol-2- yl]methyl}-2-fluorophenyl)oxy]benzonitrile Example 41 : 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(1-methyl-1 H-imidazol-2-yl)-1 ,3,4- oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile
Example 42: 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(3-methyl-2-pyridinyl)-1 ,3,4- oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile Example 43: 3-chloro-5-[(6-chloro-3-{[5-(2,4-dimethyl-3-pyridinyl)-1 ,3,4-oxadiazol-2- yl]methyl}-2-fluorophenyl)oxy]benzonitrile
Example 44: 3-chloro-5-[(6-chloro-3-{[5-(3-ethyl-1-methyl-1 H-pyrazol-5-yl)-1 ,3,4- oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile
Example 45: 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-1 ,6-naphthyridin-3-yl)- 1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile
Example 46: 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-3-furanyl)-1 ,3,4- oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile
Example 47: 3-chloro-5-[(6-chloro-3-{[5-(2,4-dimethyl-1 ,3-thiazol-5-yl)-1 ,3,4- oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile Example 48: 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(1-methyl-1 H-imidazol-5-yl)-1 ,3,4- oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile
Example 49: 3-chloro-5-[(6-chloro-3-{[5-(3,5-dimethyl-4-isoxazolyl)-1 ,3,4-oxadiazol-
2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile
Example 50: 3-chloro-5-[(6-chloro-3-{[5-(2,5-dimethyl-1 ,3-oxazol-4-yl)-1 ,3,4- oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile
Example 51 : 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(3-methyl-4-isoxazolyl)-1 ,3,4- oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile
Example 52: 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-methyl-1 ,3-thiazol-5-yl)-1 ,3,4- oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile Example 53: 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-1 ,8-naphthyridin-3-yl)-
1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile
Example 54: 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(3-methyl-2-thienyl)-1 ,3,4-oxadiazol-
2-yl]methyl}phenyl)oxy]benzonitrile
Example 55: 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(1-methyl-1 H-indol-2-yl)-1 ,3,4- oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile
Example 56: 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(1 -methyl-1 H-pyrazol-5-yl)-1 ,3,4- oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile
Table 1. Synthetic Details for Oxadiazoles Prepared via Array Methods A or B
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0003
1H NMR data for select compounds included in the above table are as follows:
Example 36: 3-chloro-5-r(6-chloro-2-fluoro-3-fr5-(2-methyl-3-Dyridinvn-1.3.4- oxadiazol-2-yllmethyl}phenyl)oxylbenzonitrile
Figure imgf000074_0001
1H NMR (400 MHz, CDCI3) δ ppm 8.92 - 9.04 (m, 1 H), 8.69 (d, 1 H), 7.78 - 7.86 (m, 1 H), 7.29 - 7.41 (m, 3 H), 7.20 (s, 1 H), 7.01 (s, 1 H), 4.44 (s, 2 H), 3.17 (s, 3 H).
Example 37: 3-chloro-5-r(6-chloro-2-fluoro-3-{r5-(1 ,3,5-trimethyl-1 /-/-pyrazol-4-yl)- 1 ,3,4-oxadiazol-2-yl1methyl}phenyl)oxy1benzonitrile
Figure imgf000074_0002
1H NMR (400 MHz, CDCI3) δ ppm 7.28 - 7.40 (m, 3 H), 7.17 (s, 1 H), 7.02 (s, 1 H), 4.35 (s, 2 H), 3.84 (s, 3 H), 2.57 (s, 3 H), 2.44 (s, 3 H). Example 38: 3-chloro-5-r(6-chloro-2-fluoro-3-fr5-(3-methyl-2-furanylV1.3.4- oxadiazol-2-yllmethyl}phenyl)oxylbenzonitrile
Figure imgf000075_0001
1H NMR (400 MHz, CDCI3) δ ppm 7.52 (s, 1 H), 7.28 - 7.40 (m, 3 H), 7.18 (s, 1 H), 7.04 (s, 1 H), 6.45 (s, 1 H), 4.35 (s, 2 H), 2.40 (s, 3 H).
Example 39: 3-chloro-5-r(6-chloro-2-fluoro-3-fr5-(1 -methyl-1 /-/-pyrrol-2-vn-1.3.4- oxadiazol-2-yllmethyl}phenyl)oxylbenzonitrile
Figure imgf000075_0002
1H NMR (400 MHz, CDCI3) δ ppm 7.38 (s, 1 H), 7.28 - 7.35 (m, 2 H), 7.15 - 7.19 (m, 1 H), 7.05 (s, 1 H), 6.85 (s, 1 H), 6.78 - 6.83 (m, 1 H), 6.18 - 6.26 (m, 1 H), 4.31 (s, 2 H), 4.04 (s, 3 H).
Example 40: 3-chloro-5-r(6-chloro-3-fr5-(2.5-dimethyl-3-furanvn-1.3.4-oxadiazol-2- yllmethyl}-2-fluorophenyl)oxylbenzonitrile
Figure imgf000075_0003
1H NMR (400 MHz, CDCI3) δ ppm 7.37 - 7.40 (m, 1 H), 7.25 - 7.35 (m, 2 H), 7.17 (s, 1 H), 7.04 (s, 1 H), 6.31 (s, 1 H), 4.32 (s, 2 H), 2.56 (s, 3 H), 2.29 (s, 3 H).
Example 45: 3-chloro-5-r(6-chloro-2-fluoro-3-fr5-(2-methyl-1 ,6-naphthyridin-3-vn- 1 ,3,4-oxadiazol-2-yllmethyl}phenyl)oxylbenzonitrile
Figure imgf000076_0001
1H NMR (400 MHz, CDCI3) δ ppm 9.33 (s, 1 H), 8.84 (d, 1 H), 8.81 (s, 1 H), 7.90 (d, 1 H), 7.33 - 7.41 (m, 3 H), 7.17 - 7.20 (m, 1 H), 6.96 - 7.11 (m, 1 H), 4.44 (s, 2 H), 3.15 (s, 3 H).
Example 57: 3-chloro-5-fr6-chloro-2-fluoro-3-α5-r2-methyl-6-({r(4SV2.2.5.5- tetramethyl-1 ,3-dioxolan-4-yllmethyl}oxy)-3-pyridinyll-1 ,3,4-oxadiazol-2- yl}methyl)phenylloxy}benzonitrile
Figure imgf000076_0002
Step A: ethyl β-amino^-methyl-S-pyridinecarboxylate
5-bromo-6-methyl-2-pyridinamine (10.0 g, 50.8 mmol, 1 eq), Pd(OAc)2 (1.14 g, 5.1 mmol, 0.1 eq), 1 ,3-propanediylbis(diphenylphosphane) (2.09 g, 5.1 mmol, 0.1 eq), DIPEA (26.5 ml_, 152 mmol, 3 eq), ethanol (75 ml_), and DMSO (75 ml.) were combined in a Porter-Fischer Vessel and purged with carbon monoxide. The reaction mixture was placed under an atmosphere of carbon monoxide (60 psi) and heated at 80 °C for 7 days with vigorous stirring. The reaction mixture was diluted with EtOAc, washed four times with dilute brine, dried over MgSO4, filtered through Celite™ and concentrated to dryness. The residue was purified on a 330 g silica gel cartridge eluted with 40 to 100% EtOAc/hexanes to give the title compound (3.20 g, 17.8 mmol, 35%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.82 (d, J=8.61 Hz, 1 H), 6.65 (s, 2 H), 6.29 (d, J=8.71 Hz, 1 H), 4.18 (q, J=7.06 Hz, 2 H), 2.52 (s, 3 H), 1.27 (t, J=7.10 Hz, 3 H).
Step B: ethyl β-chloro^-methyl-S-pyridinecarboxylate To a solution of ethyl β-amino^-methyl-S-pyridinecarboxylate (1.58 g, 8.76 mmol, 1 eq) in 37% HCI (25 mL) was added a solution of sodium nitrite (1.57 g, 22.8 mmol, 2.6 eq) in water (13 mL) dropwise with stirring and cooling in an ice-acetone bath over 30 min such that the temperature did not rise above -5 °C. Stirring was continued for 30 min post-addition at -5 °C and followed by portionwise addition of copper(l) chloride (1.08 g, 1 1.0 mmol, 1.25 eq), again maintaining temperature below -5 °C. The resultant mixture was stirred 30 min at ice-acetone bath temperature, warmed to ambient temperature and stirred overnight. The reaction mixture was poured onto a mixture of ice and diethyl ether, the pH was adjusted to >12 with 6 N NaOH and the phases were separated. The aqueous phase was extracted twice with diethyl ether, the organic phases combined, dried over MgSO4, filtered and concentrated to dryness. The crude product was purified on a 120 g silica gel cartridge eluted with 0 to 100% EtOAc/hexanes to give the title compound (0.7Og, 3.51 mmol, 40%). LC-MS (ES+) m/z 200.18, 201.99 [M+H].
Step C: ethyl 2-methyl-6-({[(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl}oxy)-3- pyridinecarboxylate
Ethyl 6-chloro-2-methyl-3-pyridinecarboxylate (0.42 g, 2.09 mmol, 1 eq) and [(4S)- 2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methanol (0.36 g, 2.09 mmol, 1 eq) were combined with Pd(OAc)2 (38 mg, 0.17 mmol, 0.08 eq), 1 ,1 '-binaphthalen-2-yl[bis(1 ,1- dimethylethyl)]phosphane (83 mg, 0.21 mmol, 0.1 eq) and cesium carbonate (2.04 g, 6.30 mmol, 3 eq) in toluene (15 mL), purged with nitrogen, and heated for 16 h at 100 °C. The reaction mixture was cooled to ambient temperature, diluted with EtOAc and water, filtered through Celite™, and the organic phase isolated. The organics were washed with brine, dried over MgSO4, filtered and concentrated to dryness. The crude product was purified on a 40 g silica gel cartridge eluted with 0 to 50% EtOAc/hexanes to give the title compound (0.53g, 1.64 mmol, 78%) as a clear oil. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.13 (d, J=8.61 Hz, 1 H), 6.80 (d, J=8.70 Hz, 1 H), 4.43 - 4.52 (m, 1 H), 4.32 - 4.39 (m, 1 H), 4.27 (q, J=7.05 Hz, 2 H), 4.09 (dd, J=7.60, 3.66 Hz, 1 H), 2.67 (s, 3 H), 1.36 (s, 3 H), 1.27 - 1.34 (m, 9 H), 1.12 (s, 3 H). LC-MS (ES+) m/z 324.07 [M+H]. Step D: 2-methyl-6-({[(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl}oxy)-3- pyridinecarbohydrazide
Ethyl 2-methyl-6-({[(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl}oxy)-3- pyridinecarboxylate (0.37 g, 1.13 mmol, 1 eq) was treated with hydrazine hydrate (10 ml.) in ethanol (15 ml.) at reflux for 3.5 h. The reaction mixture was concentrated to dryness and chased with EtOH. The crude product was purified on a 40 g silica gel cartridge eluted with 0 to10% CH3OH/DCM to give the title compound (0.28 g, 0.90 mmol, 80%) as a clear oil. LC-MS (ES+) m/z 310.34 [M+H].
Step E: 3-chloro-5-{[6-chloro-2-fluoro-3-({5-[2-methyl-6-({[(4S)-2,2,5,5-tetramethyl- 1 ,3-dioxolan-4-yl]methyl}oxy)-3-pyridinyl]-1 ,3,4-oxadiazol-2- yl}methyl)phenyl]oxy}benzonitrile
2-methyl-6-({[(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl}oxy)-3- pyridinecarbohydrazide (0.136 g, 0.441 mmol, 1 eq) was combined with {4-chloro-3- [(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetic acid (0.150 g, 0.441 mmol, 1 eq), HATU (0.168 g, 0.441 mmol, 1 eq) and DIPEA (154 μl_, 0.882 mmol, 2 eq) in dry THF (9 ml.) and stirred at ambient temperature for 3 h at which time LC-MS indicated complete conversion to the intermediate diacyl hydrazide. To this reaction mixture was added methoxycarbonylsulfamoyl-triethylammonium hydroxide, inner salt (Burgess Reagent, 0.525 g, 2.20 mmol, 5 eq) and the resultant mixture was stirred for 16 h at ambient temperature. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with water, dried over MgSO4, filtered and concentrated to dryness. The crude product was purified on a 40 g silica gel cartridge eluted with 10 to 50% EtOAc/hexanes to give the title compound (0.24 g, 0.39 mmol, 89%) as a clear oil. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.09 (d, J=8.70 Hz, 1 H), 7.82 (s, 1 H), 7.52 - 7.59 (m, 3 H), 7.51 (s, 1 H), 6.90 (d, J=8.70 Hz, 1 H), 4.43 - 4.54 (m, 3 H), 4.32 - 4.41 (m, 1 H), 4.11 (dd, J=6.96, 3.20 Hz, 1 H), 2.70 (s, 3 H), 1.36 (s, 3 H), 1.32 (s, 3 H), 1.29 (s, 3 H), 1.12 (s, 3 H). LC-MS (ES+) m/z 613.31 , 615.25 [M+H].
Example 58: 3-chloro-5-r(6-chloro-3-fr5-(6-fr(2SV2.3-dihvdroxy-3-methylbutylloxy>-2- methyl-3-pyridinyl)-1 , 3, 4-oxadiazol-2-yllmethyl}-2 -fluorophenyl )oxylbenzonitrile
Figure imgf000079_0001
3-chloro-5-{[6-chloro-2-fluoro-3-({5-[2-methyl-6-({[(4S)-2,2,5,5-tetramethyl-1 ,3- dioxolan-4-yl]methyl}oxy)-3-pyridinyl]-1 ,3,4-oxadiazol-2- yl}methyl)phenyl]oxy}benzonitrile (235 mg,0.38 mmol, 1 eq) was treated with pyridinium p-toluenesulfonic acid (1 16 mg, 0.46 mmol, 1.2 eq) in dry CH3OH (10 ml.) at reflux for 5 h. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with saturated aqueous NaHCOs, dried over MgSO4, filtered and concentrated to dryness. The crude product was purified on a 40 g silica gel cartridge eluted with 40 to 100% EtOAc/hexanes to give the title compound (11 1 mg, 0.194 mmol, 51%) as a white foam. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.06 (d, J=8.61 Hz, 1 H), 7.81 (s, 1 H), 7.51 - 7.58 (m, 3 H), 7.49 (br. s., 1 H), 6.82 (d, J=8.70 Hz, 1 H), 4.99 (d, J=5.68 Hz, 1 H), 4.57 (d, J=10.99 Hz, 1 H), 4.47 (s, 2 H), 4.41 (s, 1 H), 4.1 1 - 4.20 (m, 1 H), 3.56 (t, J=6.68 Hz, 1 H), 2.69 (s, 3 H), 1.15 (s, 3 H), 1.10 (s, 3 H). LC-MS (ES-) m/z 571.11 [M-1]. LC-MS (ES+) m/z 573.04 [M+H].
Example 59: 3-chloro-5-{r6-chloro-2-fluoro-3-({5-r4-methyl-2-({r(4S)-2,2,5,5- tetramethyl-1 ,3-dioxolan-4-yl1methyl}oxy)-1 ,3-thiazol-5-yl1-1 ,3,4-oxadiazol-2- yl}methyl)phenylloxy}benzonitrile
Figure imgf000079_0002
Step A: ethyl 4-methyl-2-({[(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl}oxy)- 1 ,3-thiazole-5-carboxylate
Ethyl 2-chloro-4-methyl-1 ,3-thiazole-5-carboxylate (0.41 1 g, 2.00 mmol, 1 eq) and [(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methanol (0.320 g, 2.00 mmol, 1 eq) were combined with Pd(OAc)2 (36 mg, 0.16 mmol, 0.08 eq), 1 ,1 '-binaphthalen-2-yl[bis(1 ,1- dimethylethyl)]phosphane (80 mg, 0.20 mmol, 0.1 eq) and cesium carbonate (1.96 g, 6.00 mmol, 3 eq) in toluene (15 ml_), purged with nitrogen and heated for 6 h at 100°C. The reaction mixture was cooled to ambient temperature, filtered through Celite™, and partitioned between EtOAc and water. The organic phase was isolated, dried over MgSO4, filtered and concentrated to dryness. The crude product was purified on a 40 g silica gel cartridge eluted with 0 to 20% EtOAc/hexanes to give the title compound (0.483 g, 1.46 mmol, 73%) as a clear oil. LC-MS (ES+) m/z 330.13 [M+H].
Step B: 4-methyl-2-({[(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl}oxy)-1 ,3- thiazole-5-carboxylic acid
Ethyl 4-methyl-2-({[(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl}oxy)-1 ,3- thiazole-5-carboxylate (0.483 g, 1.46 mmol, 1 eq) dissolved in THF (4.4 ml.) was treated with 1 M LiOH (4.4 mL, 4.4 mmol, 3 eq) at room temperature for 2 h with stirring. Methanol was added to the reaction mixture until complete solution was obtained and stirring was continued for 2 h at room temperature. The reaction mixture was concentrated to small volume and partitioned between ether and 10% citric acid. The phases were separated and the aqueous phase was extracted thrice with ether. The organics were combined, dried over MgSO4, filtered and concentrated to dryness to give the crude title compound (quantitative) as a clear oil which was carried forward without further purification. 1 H NMR (400 MHz, DMSO-d6) δ ppm 4.58 (dd, J=1 1.03, 2.15 Hz, 1 H), 4.36 - 4.46 (m, 1 H), 4.1 1 (dd, J=7.97, 2.11 Hz, 1 H), 2.49 (s, 3 H), 1.36 (s, 3 H), 1.27 - 1.31 (m, 6 H), 1.09 (s, 3 H), (COOH not detected). LC-MS (ES+) m/z 302.09 [M+H].
Step C: 3-chloro-5-{[6-chloro-2-fluoro-3-({5-[4-methyl-2-({[(4S)-2,2,5,5-tetramethyl- 1 ,3-dioxolan-4-yl]methyl}oxy)-1 ,3-thiazol-5-yl]-1 ,3,4-oxadiazol-2- yl}methyl)phenyl]oxy}benzonitrile
4-methyl-2-({[(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl}oxy)-1 ,3-thiazole-5- carboxylic acid (0.250 mg, 0.83 mmol, 1 eq) was combined with 2-{4-chloro-3-[(3- chloro-δ-cyanophenyOoxy^-fluorophenylJacetohydrazide (0.293 g, 0.83 mmol, 1 eq), HATU (0.315 g, 0.83 mmol, 1 eq) and DIPEA (0.290 mL, 1.66 mmol, 2 eq) in dry THF (10 ml.) and stirred at ambient temperature for 3 h at which time LC-MS indicated complete conversion to the intermediate diacyl hydrazide. To this reaction mixture was added methoxycarbonylsulfamoyl-triethylammonium hydroxide, inner salt (Burgess Reagent, 0.525 g, 2.20 mmol, 5 eq) and the resultant mixture was stirred 3 days at ambient temperature. The reaction mixture was concentrated to dryness, dissolved in EtOAc, washed with water, dried over MgSO4, filtered and concentrated to dryness. The crude product was purified on a 40 g silica gel cartridge eluted with 20 to 60% EtOAc/hexanes to give the title compound (0.400 mg, 0.65 mmol, 78% (2 steps)) as a clear oil. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.82 (s, 1 H), 7.47 - 7.58 (m, 4 H), 4.64 (dd, J=11.17, 2.01 Hz, 1 H), 4.42 - 4.50 (m, 3 H), 4.14 (dd, J=8.06, 2.20 Hz, 1 H), 2.48 (br. s., 3 H), 1.36 (s, 3 H), 1.29 - 1.31 (m, 6 H), 1.10 (s, 3 H). LC-MS (ES-) m/z 617.07, 619.10 [M-I]. LC-MS (ES+) m/z 619.14, 621.08 [M+H].
Example 60: 3-chloro-5-r(6-chloro-2-fluoro-3-fr5-(4-methyl-2-oxo-2.3-dihvdro-1.3- thiazol-5-yl)-1 ,3,4-oxadiazol-2-yl1methyl}phenyl)oxy1benzonitrile
Figure imgf000081_0001
3-chloro-5-{[6-chloro-2-fluoro-3-({5-[4-methyl-2-({[(4S)-2,2,5,5-tetramethyl-1 ,3- dioxolan-4-yl]methyl}oxy)-1 ,3-thiazol-5-yl]-1 ,3,4-oxadiazol-2- yl}methyl)phenyl]oxy}benzonitrile (395 mg, 0.64 mmol, 1 eq) was treated with pyridinium p-toluenesulfonic acid (192 mg, 0.77 mmol, 1.2 eq) in dry CH3OH (15 mL) at reflux for 5 h followed by 16 h at 60 °C. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with water, dried over MgSO4, filtered and concentrated to dryness. The crude product was purified on a 40 g silica gel cartridge eluted with 40 to 100% EtOAc/hexanes to give the title compound (142 mg, 0.298 mmol, 47%) as a clear oil. 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.04 (s, 1 H), 7.82 (s, 1 H), 7.45 - 7.57 (m, 4 H), 4.41 (s, 2 H), 2.31 (s, 3 H). LC-MS (ES-) m/z 475.05, 477.01 [M-1]. LC-MS (ES+) m/z 476.99, 478.97 [M+H]. Example 61 : 3-chloro-5-r(6-chloro-2-fluoro-3-fr5-(4-methyl-2-fr2-
(methylsulfonyl)ethyllamino}-1 ,3-thiazol-5-yl)-1 ,3,4-oxadiazol-2- yllmethyltohenvDoxylbenzonitrile
Figure imgf000082_0001
Step A: 3-chloro-5-[(6-chloro-3-{[5-(2-chloro-4-methyl-1 ,3-thiazol-5-yl)-1 ,3,4- oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile
2-chloro-4-methyl-1 ,3-thiazole-5-carboxylic acid (351 mg, 1.98 mmol, 1 eq) was combined with 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}acetohydrazide (700 mg, 1.98 mmol, 1 eq), DIPEA (1.03 ml_, 5.93 mmol, 3 eq), and HATU (750 mg, 1.98 mmol, 1 eq) in dry THF (15 ml.) and stirred at ambient temperature for 30 min at which time LC-MS indicated complete conversion to the intermediate diacyl hydrazide. To this reaction mixture was added methoxycarbonylsulfamoyl-triethylammonium hydroxide, inner salt (Burgess Reagent, 2.36 g, 9.90 mmol, 5 eq) and the resultant mixture was stirred 3 days at ambient temperature. The reaction mixture was diluted with EtOAc, washed with water, dried over MgSO4, filtered and concentrated to dryness. The crude product was purified on a 80 g silica gel cartridge eluted with 10 to 40% EtOAc/hexanes to give the title compound (0.716 g, 1.44 mmol, 76%) as a white foam. 1 H NMR (400 MHz, DMSO-de) δ ppm 7.82 (s, 1 H), 7.48 - 7.59 (m, 4 H), 4.48 (s, 2 H), 2.59 (s, 3 H). LC-MS (ES+) m/z 494.88, 496.95 [M+H].
Step B: 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-methyl-2-{[2- (methylsulfonyl)ethyl]amino}-1 ,3-thiazol-5-yl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile
3-chloro-5-[(6-chloro-3-{[5-(2-chloro-4-methyl-1 ,3-thiazol-5-yl)-1 ,3,4-oxadiazol-2- yl]methyl}-2-fluorophenyl)oxy]benzonitrile (150 mg, 0.303 mmol, 1 eq) was combined with [2-(methylsulfonyl)ethyl]amine (373 mg, 3.03mmol, 10 eq) and potassium carbonate (84 mg, 0.606 mmol, 2 eq) in DMF (3 mL) and heated at 100°C for 3 h. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3 and the phases separated. The organic phase was washed twice with brine, dried over MgSO4, filtered and concentrated to dryness. The crude product was 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 to give the title compound (1.9 mg, 3.3 μmol, 1%) as a white solid. LC-MS (ES+) m/z 581.99 [M+H].
Example 62: 3-chloro-5-r(6-chloro-2-fluoro-3-fr5-(4-methyl-1 H-imidazol-5-ylV1.3.4- oxadiazol-2-yllmethyl}phenyl)oxylbenzonitrile
Figure imgf000083_0001
Step A: N'-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetyl)-4- methyl-1 H-imidazole-5-carbohydrazide
4-methyl-1 H-imidazole-5-carboxylic acid (200 mg, 1.59 mmol, 1 eq) was combined with 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetohydrazide (562 mg, 1.59 mmol, 1 eq), DIPEA (550 μl_, 3.2 mmol, 2 eq), and HATU (603 mg, 1.59 mmol, 1 eq) in dry THF (20 mL) and stirred at ambient temperature for 3 days. The reaction mixture was concentrated to dryness, partitioned between EtOAc and saturated aqueous NaHCO3 and the insoluble material filtered off to give the title compound (46 mg) as a white solid. The organic phase of the filtrate was isolated, dried over MgSO4, filtered and concentrated to dryness. The residue was triturated with methanol, cooled and filtered to give a second batch (96 mg) of the title compound as a white solid. The filtrate was concentrated to dryness and the residue purified on a 40 g silica gel cartridge eluted with 0 to 10% CH3OH/DCM to give a third batch of the title compound (120 mg) as a white solid. Total yield: 262 mg, 0.57 mmol, 36%. LC-MS (ES-) m/z 460.14, 462.09 [M-1]. LC-MS (ES+) m/z 462.16, 464.17 [M+H].
Step B: 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-methyl-1 H-imidazol-5-yl)-1 ,3,4- oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile N'-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetyl)-4-methyl-1 H- imidazole-5-carbohydrazide (120 mg, 0.26 mmol) was treated with POCI3 at reflux until complete solution was obtained at which point LC-MS indicated complete conversion. The reaction mixture was concentrated to dryness, dissolved in EtOAc and washed with saturated aqueous Na2CO3. The organic phase was isolated, dried over MgSO4, filtered and concentrated to dryness. The crude product was purified on a 40 g silica gel cartridge eluted with 0 to 10% CH3OH/DCM to give the title compound (64 mg, 0.14 mmol, 55%) as a purple oil. 1 H NMR (400 MHz, DMSO- d6) δ ppm 12.56 (br. s., 1 H), 7.82 (s, 1 H), 7.71 (s, 1 H), 7.42 - 7.60 (m, 4 H), 4.43 (s, 2 H), 2.46 (s, 3 H). LC-MS (ES-) m/z 441.98, 444.01 [M-1]. LC-MS (ES+) m/z 444.02, 445.98 [M+H].
Example 63: 3-chloro-5-r(6-chloro-3-{r5-(1 ,4-dimethyl-1 H-pyrazol-5-yl)-1 ,3,4- oxadiazol-2-yl1methyl}-2-fluorophenyl)oxy1benzonitrile
Figure imgf000084_0001
Step A: methyl 1 ,4-dimethyl-1 H-pyrazole-5-carboxylate
Methyl 4-methyl-1 H-pyrazole-5-carboxylate (700 mg, 5.55 mmol, 1 eq) was combined with iodomethane (0.70 mL, 11.1 mmol, 2 eq) and cesium carbonate (5.41 g, 16.6 mmol, 3 eq) in acetonitrile and stirred overnight at room temperature. The reaction mixture was filtered and the filtrate concentrated to dryness. The residue was triturated with DCM, filtered and the filtrate concentrated to dryness. The residue was purified on a 40 g silica gel cartridge eluted with 10 to 90% EtOAc/hexanes to give the two regioisomeric products. The first eluting isomer was identified as the desired title compound (300 mg, 1.95 mmol, 35%) by NOESY and HMBC NMR. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.38 (s, 1 H), 4.02 (s, 3 H), 3.84 (s, 3 H), 2.18 (s, 3 H). LC-MS (ES+) m/z 154.80 [M+H].
Step B: 1 ,4-dimethyl-1 H-pyrazole-5-carbohydrazide Methyl 1 ,4-dimethyl-1 H-pyrazole-5-carboxylate (270 mg, 1.75 mmol, 1 eq) dissolved in ethanol (23 ml.) was treated with hydrazine hydrate (4.7 ml.) at reflux for 3 h with stirring. The reaction mixture was concentrated to small volume, diluted with water and extracted four times with EtOAc. The organic phases were combined, dried over MgSO4, filtered and concentrated to dryness. The crude product was purified on a 40 g silica gel cartridge eluted with 100% EtOAc to 10% CH3OH/DCM to give the title compound (0.313 g, quantitative) as a white solid. LC-MS (ES-) m/z 153.12 [M-1]. LC-MS (ES+) m/z 155.20 [M+H].
Step C: 3-chloro-5-[(6-chloro-3-{[5-(1 ,4-dimethyl-1 H-pyrazol-5-yl)-1 ,3,4-oxadiazol-2- yl]methyl}-2-fluorophenyl)oxy]benzonitrile
1 ,4-dimethyl-1 H-pyrazole-5-carbohydrazide (150 mg, 0.97 mmol, 1 eq) was combined with {4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetic acid (331 mg, 0.97 mmol, 1 eq), DIPEA (0.34 ml_, 1.9 mmol, 2 eq), and HATU (370 mg, 0.97 mmol, 1 eq) in dry THF (10 mL) and stirred at ambient temperature for 3 h at which time LC-MS indicated complete conversion to the intermediate diacyl hydrazide. To this reaction mixture was added methoxycarbonylsulfamoyl- triethylammonium hydroxide, inner salt (Burgess Reagent, 2.36 g, 9.90 mmol, 5 eq) and the resultant mixture was stirred 3 days at ambient temperature. The reaction mixture was concentrated to dryness, partitioned between EtOAc and water, the organic phase isolated, dried over MgSO4, filtered and concentrated to dryness. The crude product was purified on a 40 g silica gel cartridge eluted with 20 to 70% EtOAc/hexanes. Appropriate fractions were combined, concentrated and chased with ethanol to give impure product as a white solid. This material was recrystallized from boiling ehanol to give the title compound (138 mg, 0.30 mmol, 31 %) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.82 (s, 1 H), 7.48 - 7.58 (m, 4 H), 7.46 (s, 1 H), 4.50 (s, 2 H), 4.06 (s, 3 H), 2.17 (s, 3 H). LC-MS (ES+) m/z 458.13 [M+H].
Example 64: 3-chloro-5-r(6-chloro-2-fluoro-3-{r5-(4-methyl-1 H-pyrazol-5-yl)-1 ,3,4- oxadiazol-2-yl1methyl}phenyl)oxy1benzonitrile
Figure imgf000086_0001
Step A: 4-methyl-1 H-pyrazole-5-carbohydrazide
methyl 4-methyl-1 H-pyrazole-5-carboxylate (367 mg, 2.91 mmol, 1 eq) dissolved in ethanol (25 ml.) was treated with hydrazine hydrate (5.0 ml.) at reflux for 2 h with stirring. The reaction mixture was concentrated to small volume, diluted with water and extracted two times with DCM and the aqueous portion was set aside. The organic phases were combined, dried over MgSO4, filtered and concentrated to dryness. The crude product was purified on a 40 g silica gel cartridge eluted with 0 to 20% CH3OH/DCM to give the title compound (0.145 g) as a white solid. The aqueous portion was concentrated to dryness, chased with methanol and toluene, and pumped dry to give a second batch of the title compound (0.210 g). Total yield: 0.355 g, 2.53 mmol, 87%. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.06 (br. s., 1 H), 7.57 (s, 1 H), 4.30 (s, 2 H), 2.18 (s, 3 H), (pyrazole NH not observed).
Step B: N'-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetyl)-4- methyl-1 H-pyrazole-5-carbohydrazide
4-methyl-1 H-pyrazole-5-carbohydrazide (230 mg, 1.64 mmol, 1 eq) was combined with {4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetic acid (560 mg, 1.64 mmol, 1 eq), DIPEA (0.570 ml_, 3.3 mmol, 2 eq), and HATU (630 mg, 1.64 mmol, 1 eq) in dry THF (15 ml.) and stirred overnight at ambient temperature. The reaction mixture was concentrated to dryness, partitioned between EtOAc and water and the insoluble material filtered off to give the title compound (87 mg) as a white solid. The organic phase of the filtrate was isolated, dried over MgSO4, filtered and concentrated to dryness. The residue was triturated with ethanol, cooled and filtered to give a second batch of the title compound (350 mg) as a white solid. Total yield: 437 mg, 0.95 mmol, 58%. 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.02 (s, 1 H), 9.80 (s, 1 H), 7.82 (s, 1 H), 7.63 (s, 1 H), 7.41 - 7.55 (m, 4 H), 3.65 (br. s., 2 H), 2.19 (s, 3 H), (pyrazole NH not observed). LC-MS (ES-) m/z 460.17, 462.07 [M-1]. LC-MS (ES+) m/z 462.05, 464.07 [M+H]. Step C: 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-methyl-1 H-pyrazol-5-yl)-1 ,3,4- oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile
N'-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetyl)-4-methyl-1 H- pyrazole-5-carbohydrazide (431 mg, 0.94 mmol) was treated with POCI3 (20 mL) at reflux for 4 h. The reaction mixture was concentrated to dryness, dissolved in EtOAc and washed with saturated aqueous Na2CO3 and the aqueous phase back extracted twice with EtOAc. The organic phases were combined, dried over MgSO4, filtered and concentrated to dryness. The crude product was purified on a 40 g silica gel cartridge eluted with 40 to 100 EtOAc/hexanes to give the title compound (104 mg, 0.234 mmol, 25%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.81 (s, 1 H), 7.75 (s, 1 H), 7.43 - 7.60 (m, 4 H), 4.47 (s, 2 H), 2.25 (s, 3 H) (pyrazole NH not observed). LC-MS (ES-) m/z 442.14, 444.13 [M-1]. LC-MS (ES+) m/z 444.03, 446.05 [M+H].
Example 65: 3-chloro-5-r(6-chloro-3-fr5-(1.4-dimethyl-i H-imidazol-5-ylV1.3.4- oxadiazol-2-yllmethyl}-2-fluorophenyl)oxylbenzonitrile
Figure imgf000087_0001
Step A: ethyl 1 ,4-dimethyl-1 H-imidazole-5-carboxylate
Ethyl 4-methyl-1 H-imidazole-5-carboxylate (463 mg, 3.00 mmol, 1 eq) was combined with iodomethane (0.19 mL, 3.00 mmol, 1 eq) and potassium carbonate (828 mg, 6.00 mmol, 2 eq) in acetonitrile and stirred overnight at reflux. The reaction mixture was cooled to ambient temperature, inorganics filtered off, and the filtrate concentrated to dryness. The residue was purified on an 80 g silica gel cartridge eluted with 100% EtOAc to 10% CH3OH/DCM to give the two regioisomeric products. The first eluting isomer was identified as the title compound (185 mg, 1.95 mmol, 35%) by comparative NOESY and HMBC NMR. 1 H NMR (400 MHz, DMSO- d6) δ ppm 7.74 (s, 1 H), 4.25 (q, J=7.14 Hz, 2 H), 3.76 (s, 3 H), 2.34 (s, 3 H), 1.30 (t, J=7.10 Hz, 3 H). LC-MS (ES+) m/z 169.08 [M+H]. Step B: 1 ,4-dimethyl-1 H-imidazole-5-carbohydrazide
ethyl 1 ,4-dimethyl-1 H-imidazole-5-carboxylate (185 mg, 1.10 mmol, 1 eq) dissolved in ethanol (25 ml.) was treated with hydrazine hydrate (5 ml.) at reflux for 16 h with stirring. Additional hydrazine hydrate (20 ml.) was added to the reaction mixture and heated at reflux for an additional 16 h with stirring. The reaction mixture was concentrated to dryness, chased with twice with ethanol and twice with toluene, and pumped dry to give a white solid. The crude product was triturated wit 5% CH3OH/DCM and filtered. The filtrate was concentrated to dryness and was purified on a 40 g silica gel cartridge eluted with 0 to 20% CH3OH/DCM to give the title compound (90 mg, 0.58 mmol, 52%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.12 (br. s., 1 H), 7.56 (s, 1 H), 4.45 (br. s., 2 H), 3.64 (s, 3 H), 2.21 (s, 3 H).
Step C: 3-chloro-5-[(6-chloro-3-{[5-(1 ,4-dimethyl-1 H-imidazol-5-yl)-1 ,3,4-oxadiazol-2- yl]methyl}-2-fluorophenyl)oxy]benzonitrile
1 ,4-dimethyl-1 H-imidazole-5-carbohydrazide (90 mg, 0.58 mmol, 1 eq) was combined with {4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetic acid (200 mg, 0.58 mmol, 1 eq), DIPEA (0.203 ml_, 1.17 mmol, 2 eq), and HATU (222 mg, 0.58 mmol, 1 eq) in dry THF (5.3 ml.) and stirred at ambient temperature for 16 h. To this reaction mixture was added methoxycarbonylsulfamoyl-triethylammonium hydroxide, inner salt (Burgess Reagent, 695 mg, 2.92 mmol, 5 eq) and the resultant mixture was stirred for 16 h at room temperature followed by 16 h at 55 °C. The reaction mixture was concentrated to dryness and partitioned between DCM and saturated aqueous NaHCO3. The organic phase was isolated, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on a 40 g silica gel cartridge eluted with 100% EtOAc to 15% CH3OH/DCM to give impure product. This material was repurified on a 40 g silica gel cartridge eluted with 100% EtOAc to give the title compound (56 mg, 0.122 mmol, 21 %) as a white solid. 1 H NMR (400 MHz, DMSO-de) δ ppm 7.80 - 7.83 (m, 2 H), 7.47 - 7.58 (m, 4 H), 4.46 (s, 2 H), 3.82 (s, 3 H), 2.30 (s, 3 H). LC-MS (ES-) m/z 456.30, 457.96 [M-1]. LC-MS (ES+) m/z 458.06, 460.04 [M+H]. Example 66: 3-chloro-5-ir6-chloro-2-fluoro-3-α5-r4-methyl-2-(methylsulfonylV1 H- imidazol-5-yll-1 ,3,4-oxadiazol-2-yl}methyl)phenylloxy}benzonitrile
Figure imgf000089_0001
Step A: ethyl 4-methyl-2-(methylthio)-1 H-imidazole-5-carboxylate
Ethyl 5-methyl-2-thioxo-2,3-dihydro-1 H-imidazole-4-carboxylate (1.040 g, 5.58 mmol) was combined with iodomethane (0.348 ml_, 5.58 mmol) and potassium carbonate (0.772 g, 5.58 mmol) in THF (10 ml.) and stirred for 2 h at ambient temperature. The reaction mixture was filtered, the solids washed three times with THF, and the filtrate set aside. The filtered solids were triturated with water and filtered to give the title compound as a pale yellow solid (110 mg). The aqueous filtrate was extracted three times with EtOAc, the organics combined, dried over MgSOφ filtered and concentrated to dryness to give a second batch of the title compound as a white solid (250 mg). The filtrate of the reaction mixture was concentrated to dryness and purified on 80 g silica eluted with 10 to 60% EtOAc/hexanes to give a third batch of the title compound as a yellow solid (220 mg, N3753-10-301 ). Overall yield: 580 mg, 2.90 mmol, 52%. LC-MS (ES+) m/z 201.18 [M+H]
Step B: ethyl 4-methyl-2-(methylsulfonyl)-1 H-imidazole-5-carboxylate
To a solution of ethyl 4-methyl-2-(methylthio)-1 H-imidazole-5-carboxylate (0.406 g, 2.027 mmol) in Dichloromethane (DCM) (25 ml.) was added mCPBA (1.000 g, 4.46 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 20 min and then at rt for 2 h at which time TLC indicated complete conversion. The reaction was quenched by addition of sodium sulfite (7.8 g, 61.9 mmol) dissolved in water (40 mL), and the phases separated. The pH of the aqueous phase was adjusted to 10 with satd. sodium carbonate and extracted three times with DCM. The organics were combined, dried over MgSOφ filtered and concentrated to dryness to give the title compound (0.38 g, 1.64 mmol, 81%) as a white solid. LC-MS (ES+) m/z 233.18 [M+H]. Step C: 4-methyl-2-(methylsulfonyl)-1 H-imidazole-5-carboxylic acid
Ethyl 4-methyl-2-(methylsulfonyl)-1 H-imidazole-5-carboxylate (0.37 g, 1.593 mmol) dissolved in THF (3.2 mL) was treated with 1 M LiOH (3.2 ml_, 3.20 mmol) at 70 °C for 24 h with stirring. The reaction mixture was concentrated to dryness and chased once with EtOH and thrice with toluene to remove residual water. The crude title compound (0.325 g, 1.59 mmol) was carried forward without further purification. LC- MS (ES+) m/z 205.00 [M+H]. LC-MS (ES-) m/z 203.06 [M-1].
Step D: N'-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetyl)-4- methyl-2-(methylsulfonyl)-1 H-imidazole-5-carbohydrazide
2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetohydrazide (0.563 g, 1.590 mmol) was combined with 4-methyl-2-(methylsulfonyl)-1 H-imidazole-5- carboxylic acid (0.325 g, 1.59 mmol) and DIPEA (0.555 mL, 3.18 mmol) in THF (25 mL) and treated with HATU (0.605 g, 1.590 mmol) at 25 °C for 2 days. The reaction mixture was concentrated to dryness, dissolved in EtOAc, washed with saturated aqueous NaHCOβ, dried over MgSOφ filtered and concentrated to dryness. The residue was triturated with cold EtOH and filtered. The filtrate was concentrated to dryness and purified on 40 g silica gel eluted with EtOAc to give N'-({4-chloro-3-[(3- chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetyl)-4-methyl-2-(methylsulfonyl)-1 H- imidazole-5-carbohydrazide (.200 g, 0.370 mmol, 23.28 % yield (2 steps)) as a white solid. LC-MS (ES-) m/z 538.04, 540.08 [M-1]. LC-MS (ES+) m/z 539.94, 541.92 [M+H].
Step E: 3-chloro-5-{[6-chloro-2-fluoro-3-({5-[4-methyl-2-(methylsulfonyl)-1 H-imidazol- 5-yl]-1 ,3,4-oxadiazol-2-yl}methyl)phenyl]oxy}benzonitrile
N'-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetyl)-4-methyl-2-
(methylsulfonyl)-1 H-imidazole-5-carbohydrazide (.200 g, 0.370 mmol) was placed in phosphorus oxychloride (20 mL, 215 mmol) and heated at reflux for 1.5 h. The temperature was decreased to 80 °C and the reaction mixture was stirred overnight. The reaction mixture was poured onto ice, stirred vigorously for 20 min, and was extracted twice with DCM. The organic phases were combined, washed with saturated aqueous NaHCOβ, dried over MgSOφ filtered and concentrated to dryness. The crude material was purified on 40 g silica gel eluted with 50 to 100% EtOAc/hexanes to give 3-chloro-5-{[6-chloro-2-fluoro-3-({5-[4-methyl-2- (methylsulfonyl)-i H-imidazol-5-yl]-1 ,3,4-oxadiazol-2-yl}methyl)phenyl]oxy}benzonitrile (.081 g, 0.155 mmol, 41.9 % yield) as a tan solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.82 (s, 1 H), 7.45 - 7.58 (m, 4 H), 4.47 (s, 2 H), 3.36 (s, 3 H), 2.52 (s, 3 H). LC-MS (ES-) m/z 520.03, 522.05 [M-1]. LC-MS (ES+) m/z 521.94, 523.91 [M+H].
Example 67: 3-r(3-fr5-(3-amino-5-methyl-1 H-pyrazol-4-ylV1 ,3.4-oxadiazol-2- yllmethyl}-6-chloro-2-fluorophenyl)oxyl-5-chlorobenzonitrile
Figure imgf000091_0001
Step A: 3-chloro-5-[(6-chloro-3-{[5-(cyanomethyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2- fluorophenyl)oxy]benzonitrile
Cyanoacetic acid (240 mg, 2.82 mmol, 1 eq) was combined with 2-{4-chloro-3-[(3- chloro-δ-cyanophenyOoxy^-fluorophenylJacetohydrazide (1.00 g, 2.82 mmol, 1 eq), DIPEA (1.00 ml_, 5.65 mmol, 2 eq), and HATU (1.07 g, 2.82 mmol, 1 eq) in dry THF (20 mL) and stirred at ambient temperature for 30 min at which time LC-MS indicated complete conversion to the intermediate diacyl hydrazide. To this reaction mixture was added methoxycarbonylsulfamoyl-triethylammonium hydroxide, inner salt (Burgess Reagent, 3.36 g, 14.1 mmol, 5 eq) and additional dry THF (20 mL) and the resultant mixture was stirred 3 days at ambient temperature. The reaction mixture was concentrated to dryness, dissolved in EtOAc, washed with water, dried over MgSO4, filtered, and concentrated to dryness. The crude product was purified on a 12O g silica gel cartridge eluted with 30 to 80% EtOAc/hexanes to give the title compound (0.18 g, 0.45 mmol, 16%) as an off-white solid. LC-MS (ES-) m/z 401.10, 403.10 [M-1]. LC-MS (ES+) m/z 403.05, 405.02 [M+H]. Step B: 3-chloro-5-{[6-chloro-3-({5-[(1Z)-1-cyano-2-(ethyloxy)-1-propen-1-yl]-1 ,3,4- oxadiazol-2-yl}methyl)-2-fluorophenyl]oxy}benzonitrile and 3-chloro-5-{[6-chloro-3- ({5-[(1 E)-1-cyano-2-(ethyloxy)-1-propen-1-yl]-1 ,3,4-oxadiazol-2-yl}methyl)-2- fluorophenyl]oxy}benzonitrile
3-chloro-5-[(6-chloro-3-{[5-(cyanomethyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2- fluorophenyl)oxy]benzonitrile (0.18 g, 0.45 mmol, 1eq) was combined with triethyl orthoacetate (0.082 ml_, 0.45 mmol, 1 eq) in acetic anhydride (3 ml.) and heated at 105 °C for 4 h. Additional triethyl orthoacetate (0.082 ml_, 0.45 mmol, 1 eq) was added to the reaction mixture and heating continued for 2 h. The reaction mixture was diluted with water, extracted with DCM, dried over MgSO4, filtered, and concentrated to dryness. The crude product was purified on a 40 g silica gel cartridge eluted with 30 to 100% EtOAc/hexanes to give the two title compounds. First eluting isomer: 101 mg, 0.21 mmol, 48%; LC-MS (ES-) m/z 471.15, 473.20 [M- 1]; LC-MS (ES+) m/z 473.15, 475.16 [M+H]. Second eluting isomer: 81 mg, 0.17 mmol, 38%; LC-MS (ES-) m/z 471.02, 473.13 [M-1]; LC-MS (ES+) m/z 473.14, 475.13 [M+H].
Step C: 3-[(3-{[5-(3-amino-5-methyl-1 H-pyrazol-4-yl)-1 ,3,4-oxadiazol-2-yl]methyl}-6- chloro-2-fluorophenyl)oxy]-5-chlorobenzonitrile
In separate reaction flasks, the two isomers, 3-chloro-5-{[6-chloro-3-({5-[(1Z)-1- cyano-2-(ethyloxy)-1-propen-1-yl]-1 ,3,4-oxadiazol-2-yl}methyl)-2- fluorophenyl]oxy}benzonitrile and 3-chloro-5-{[6-chloro-3-({5-[(1 E)-1-cyano-2- (ethyloxy)-1-propen-1-yl]-1 ,3,4-oxadiazol-2-yl}methyl)-2-fluorophenyl]oxy}benzonitrile (101 mg and 81 mg), were dissolved in ethanol (3 mL) and treated with hydrazine hydrate (3.0 mL) at reflux with stirring for 2 h at which time LC-MS indicated conversion to identical products. The reaction mixtures were combined and concentrated to small volume, diluted with water, and extracted three times with EtOAc. The organic phases were combined, dried over MgSO4, filtered and concentrated to dryness. The crude product was purified by RP-HPLC on an XTerra™ C-18 column eluted with 10 to 100% CH3CN/H2O (0.2% NH4OH) to give the title compound (4.2 mg, 0.009 mmol, 2%). LC-MS (ES-) m/z 456.96, 459.13 [M-1]; LC-MS (ES+) m/z 459.13, 461.13 [M+H]. Example 68: 3-chloro-5-r(6-chloro-3-fr5-(3.5-dimethyl-1 H-pyrrol-2-ylVI .3.4- oxadiazol-2-yllmethyl}-2-fluorophenyl)oxylbenzonitrile
Figure imgf000093_0001
3,5-dimethyl-1 H-pyrrole-2-carboxylic acid (30 mg, 0.22 mmol, 2.2 eq) was combined with 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}acetohydrazide (35.4 mg, 0.10 mmol, 1 eq), DIPEA (0.052 ml_, 0.30 mmol, 3 eq), and HATU (38 mg, 0.10 mmol, 1 eq) in dry THF (1 ml.) and stirred overnight at 55 °C. The reaction mixture was cooled to room temperature, treated with methoxycarbonylsulfamoyl- triethylammonium hydroxide, inner salt (Burgess Reagent, 120 mg, 0.50 mmol, 5 eq) and additional dry THF (1 ml.) for 6 h at 55 °C. The reaction mixture was evaporated to dryness, dissolved in DCM (1.5 ml_), washed with water, the organic phase isolated and concentrated to dryness. The crude product was 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 to give the title compound (13.1 mg). LC-MS (ES+) m/z 457.38, 459.22 [M+H].
General Procedures for Array Syntheses of Oxadiazoles (I)
Method C: 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 °C 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 °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 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 D: 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 °C 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 °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 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 E: 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 °C 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 4 h at 55 °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 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 F: Reactions run according to Method E which did not appear to be complete by LC-MS prior to purification were resubjected to treatment with a solution of methoxycarbonylsulfamoyl-triethylammonium hydroxide, inner salt (Burgess Reagent, 120 mg, 500 μmol, 5 eq) in dry THF (1 mL) for 16 h at 55 °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 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 G: An appropriate volume of a solution of 2-{4-chloro-3-[(3-chloro-5- cyanophenyl)oxy]-2-fluorophenyl}acetohydrazide (0.11 M, 1 eq) and DIPEA (0.22 M, 2 eq) in dry THF was added in combinatorial fashion to vials containing solid carboxylic acid (see table for mass, 1 eq) and an appropriate mass of HATU (1 eq) and stirred for 16 h at 55 °C to form the intermediate diacyl hydrazides. The reaction mixtures were allowed to cool to ambient temperature and then treated with an appropriate volume of a solution of methoxycarbonylsulfamoyl-triethylammonium hydroxide, inner salt (Burgess Reagent, 0.55 M, 5 eq) in dry THF for 8 h at 55 °C. The reaction mixtures were evaporated to dryness, dissolved in DCM, 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 H: An appropriate volume of a solution of 2-{4-chloro-3-[(3-chloro-5- cyanophenyl)oxy]-2-fluorophenyl}acetohydrazide (0.11 M, 1 eq) and DIPEA (0.22 M, 2 eq) in dry THF was added in combinatorial fashion to vials containing solid carboxylic acid (see table for mass, 1 eq) and an appropriate mass of HATU (1 eq) and stirred for 16 h at 55 °C. The reaction mixtures were evaporated to dryness, partitioned between EtOAc and water, and insoluble material filtered off to give the cyclized final product.
Final products obtained by either of the above methods were characterized by analytical LC-MS, the results of which are tabulated below.
3-chloro-5-(6-chloro-3-((5-(4-chloro-2-ethyl-1 H-imidazol-5-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-2-fluorophenoxy)benzonitrile 3-chloro-5-(6-chloro-3-((5-(2-(dimethylamino)-4-methylpyrimidin-5-yl)-1 ,3,4- oxadiazol-2-yl)methyl)-2-fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-2-fluoro-3-((5-(3-methyl-1 H-pyrazol-4-yl)-1 ,3,4-oxadiazol-2- yl)methyl)phenoxy)benzonitrile
3-chloro-5-(6-chloro-3-((5-(5-chloro-1 ,3-dimethyl-1 H-pyrazol-4-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-2-fluorophenoxy)benzonitrile 3-(3-((5-(2-amino-4-methylpyrimidin-5-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-6-chloro-2- fluorophenoxy)-5-chlorobenzonitrile
3-chloro-5-(6-chloro-3-((5-(2,4-dimethylpyrimidin-5-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-2- fluorophenoxy)benzonitrile 3-chloro-5-(6-chloro-3-((5-(4,5-dichloroisothiazol-3-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-2- fluorophenoxy)benzonitrile
3-(3-((5-(1 H-benzo[d]imidazol-2-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-6-chloro-2- fluorophenoxy)-5-chlorobenzonitrile
3-chloro-5-(6-chloro-3-((5-(2,5-dimethyl-1-(2,2,2-trifluoroethyl)-1 H-pyrrol-3-yl)-1 ,3,4- oxadiazol-2-yl)methyl)-2-fluorophenoxy)benzonitrile tert-butyl 4-(5-(4-chloro-3-(3-chloro-5-cyanophenoxy)-2-fluorobenzyl)-1 ,3,4- oxadiazol-2-yl)-3,5-dimethyl-1 H-pyrrole-2-carboxylate
3-chloro-5-(6-chloro-2-fluoro-3-((5-(4-methyl-1 ,2,3-thiadiazol-5-yl)-1 ,3,4-oxadiazol-2- yl)methyl)phenoxy)benzonitrile 3-chloro-5-(6-chloro-2-fluoro-3-((5-(2-methylthiophen-3-yl)-1 ,3,4-oxadiazol-2- yl)methyl)phenoxy)benzonitrile
3-chloro-5-(6-chloro-2-fluoro-3-((5-(2-mercapto-1 -methyl-1 H-imidazol-5-yl)-1 ,3,4- oxadiazol-2-yl)methyl)phenoxy)benzonitrile
3-chloro-5-(6-chloro-3-((5-(2-chloro-4-methylthiazol-5-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-2-fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-3-((5-(3,5-dimethyl-1 H-pyrazol-4-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-2-fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-2-fluoro-3-((5-(1-methyl-3-(trifluoromethyl)-1 H-pyrazol-5-yl)-
1 ,3,4-oxadiazol-2-yl)methyl)phenoxy)benzonitrile methyl 5-(5-(4-chloro-3-(3-chloro-5-cyanophenoxy)-2-fluorobenzyl)-1 ,3,4-oxadiazol-2- yl)-1 -methyl-1 H-pyrazole-3-carboxylate
3-chloro-5-(6-chloro-2-fluoro-3-((5-(1 ,2,5-trimethyl-1 H-pyrrol-3-yl)-1 ,3,4-oxadiazol-2- yl)methyl)phenoxy)benzonitrile
3-chloro-5-(6-chloro-2-fluoro-3-((5-(4-methylisoxazol-5-yl)-1 ,3,4-oxadiazol-2- yl)methyl)phenoxy)benzonitrile
3-(3-((5-(4-acetyl-1 -methyl-1 H-pyrrol-2-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-6-chloro-2- fluorophenoxy)-5-chlorobenzonitrile
3-chloro-5-(6-chloro-3-((5-(2-(ethoxymethyl)-4-methylthiazol-5-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-2-fluorophenoxy)benzonitrile 3-chloro-5-(6-chloro-3-((5-(2,4-dimethyloxazol-5-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-2- fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-3-((5-(1 ,3-dimethyl-1 H-pyrazol-5-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-2-fluorophenoxy)benzonitrile ethyl 4-(5-(4-chloro-3-(3-chloro-5-cyanophenoxy)-2-fluorobenzyl)-1 ,3,4-oxadiazol-2- yl)-3,5-dimethyl-1 H-pyrrole-2-carboxylate
3-chloro-5-(6-chloro-3-((5-(4-chloro-1 ,3-dimethyl-1 H-pyrazol-5-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-2-fluorophenoxy)benzonitrile
3-(3-((5-(4-acetyl-3,5-dimethyl-1 H-pyrrol-2-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-6-chloro- 2-fluorophenoxy)-5-chlorobenzonitrile
3-chloro-5-(6-chloro-3-((5-(2-chlorofuran-3-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-2- fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-2-fluoro-3-((5-(3,4,5-trichlorothiophen-2-yl)-1 ,3,4-oxadiazol-2- yl)methyl)phenoxy)benzonitrile 2-(5-(5-(4-chloro-3-(3-chloro-5-cyanophenoxy)-2-fluorobenzyl)-1 ,3,4-oxadiazol-2-yl)-
2,4-dimethyl-1 H-pyrrol-3-yl)ethyl acetate
3-chloro-5-(6-chloro-3-((5-(3-chlorothiophen-2-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-2- fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-3-((5-(3-chloro-5-methylisoxazol-4-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-2-fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-2-fluoro-3-((5-(pyrimidin-5-yl)-1 ,3,4-oxadiazol-2- yl)methyl)phenoxy)benzonitrile
3-chloro-5-(6-chloro-3-((5-(4-chloro-1-methyl-1 H-pyrazol-5-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-2-fluorophenoxy)benzonitrile 3-chloro-5-(6-chloro-2-fluoro-3-((5-(2-methyl-1 H-indol-7-yl)-1 ,3,4-oxadiazol-2- yl)methyl)phenoxy)benzonitrile
(E)-3-chloro-5-(6-chloro-3-((5-(5-(3-(2,3-dimethoxyphenyl)acryloyl)-3,4-dimethyl-1 H- pyrrol-2-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-2-fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-2-fluoro-3-((5-(3-methyl-5-phenyl-1 H-indol-2-yl)-1 ,3,4-oxadiazol- 2-yl)methyl)phenoxy)benzonitrile
3-(3-((5-(4-acetyl-5-(ethoxymethyl)-3-methyl-1 H-pyrrol-2-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-6-chloro-2-fluorophenoxy)-5-chlorobenzonitrile
3-(3-((5-(1 -benzyl-5-methyl-1 H-imidazol-4-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-6-chloro-2- fluorophenoxy)-5-chlorobenzonitrile (E)-3-chloro-5-(6-chloro-3-((5-(4-(3-(2,3-dimethoxyphenyl)acryloyl)-3,5-dimethyl-1 H- pyrrol-2-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-2-fluorophenoxy)benzonitrile
(E)-ethyl 5-(5-(4-chloro-3-(3-chloro-5-cyanophenoxy)-2-fluorobenzyl)-1 ,3,4-oxadiazol-
2-yl)-2-(3-ethoxy-3-oxoprop-1-enyl)-4-methyl-1 H-pyrrole-3-carboxylate 2-tert-butyl 3-ethyl 5-(5-(4-chloro-3-(3-chloro-5-cyanophenoxy)-2-fluorobenzyl)-1 ,3,4- oxadiazol-2-yl)-4-methyl-1 H-pyrrole-2,3-dicarboxylate methyl 3-(5-(5-(4-chloro-3-(3-chloro-5-cyanophenoxy)-2-fluorobenzyl)-1 ,3,4- oxadiazol-2-yl)-2-(dimethylcarbamoyl)-4-methyl-1 H-pyrrol-3-yl)propanoate
3-(3-((5-(5-amino-1-(2-fluorophenyl)-3-methyl-1 H-pyrazol-4-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-6-chloro-2-fluorophenoxy)-5-chlorobenzonitrile
3-(3-((5-(5-amino-1-(4-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-6- chloro-2-fluorophenoxy)-5-chlorobenzonitrile
3-chloro-5-(6-chloro-3-((5-(2-chloro-6-(trifluoromethyl)pyridin-3-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-2-fluorophenoxy)benzonitrile 3-(3-((5-(5-amino-1-(3-chlorophenyl)-3-methyl-1 H-pyrazol-4-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-6-chloro-2-fluorophenoxy)-5-chlorobenzonitrile
3-(3-((5-(4-bromo-1 ,3-dimethyl-1 H-pyrazol-5-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-6- chloro-2-fluorophenoxy)-5-chlorobenzonitrile
3-(3-((5-(4-bromo-1-methyl-1 H-pyrazol-5-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-6-chloro-2- fluorophenoxy)-5-chlorobenzonitrile
3-(3-((5-(5-amino-1-cyclohexyl-1 H-1 ,2,3-triazol-4-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-6- chloro-2-fluorophenoxy)-5-chlorobenzonitrile
3-chloro-5-(6-chloro-2-fluoro-3-((5-(5-oxo-4,5-dihydropyrazolo[1 ,5-a]quinazolin-3-yl)-
1 ,3,4-oxadiazol-2-yl)methyl)phenoxy)benzonitrile 3-chloro-5-(6-chloro-3-((5-(6-chloro-4-oxo-1 ,4-dihydroquinolin-8-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-2-fluorophenoxy)benzonitrile
3-(3-((5-(5-bromo-3-methyl-1 H-indol-2-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-6-chloro-2- fluorophenoxy)-5-chlorobenzonitrile
3-(3-((5-(3-amino-1-(4-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-6- chloro-2-fluorophenoxy)-5-chlorobenzonitrile
3-chloro-5-(6-chloro-3-((5-(2,3-dioxo-1 ,2,3,4-tetrahydroquinoxalin-5-yl)-1 ,3,4- oxadiazol-2-yl)methyl)-2-fluorophenoxy)benzonitrile
3-(3-((5-(5-amino-1-methyl-1 H-pyrazol-4-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-6-chloro-2- fluorophenoxy)-5-chlorobenzonitrile 3-chloro-5-(6-chloro-2-fluoro-3-((5-(3-methyl-1 H-indol-2-yl)-1 ,3,4-oxadiazol-2- yl)methyl)phenoxy)benzonitrile
3-chloro-5-(6-chloro-2-fluoro-3-((5-(1 ,2,3,4-tetrahydroquinolin-8-yl)-1 ,3,4-oxadiazol-2- yl)methyl)phenoxy)benzonitrile 3-chloro-5-(6-chloro-2-fluoro-3-((5-(2-methyl-1 H-benzo[d]imidazol-7-yl)-1 ,3,4- oxadiazol-2-yl)methyl)phenoxy)benzonitrile
3-(3-((5-(4-amino-1 ,2,5-oxadiazol-3-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-6-chloro-2- fluorophenoxy)-5-chlorobenzonitrile
3-(3-((5-(3-amino-1-(4-fluorophenyl)-1 H-pyrazol-4-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-6- chloro-2-fluorophenoxy)-5-chlorobenzonitrile
3-chloro-5-(6-chloro-3-((5-(4-chloro-1-methyl-1 H-pyrazolo[3,4-b]pyridin-5-yl)-1 ,3,4- oxadiazol-2-yl)methyl)-2-fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-2-fluoro-3-((5-(2-oxo-1 ,2-dihydroquinolin-8-yl)-1 ,3,4-oxadiazol-2- yl)methyl)phenoxy)benzonitrile 3-chloro-5-(6-chloro-3-((5-(3-chloro-4-methylthiophen-2-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-2-fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-3-((5-(5-chloro-2-(methylthio)pyrimidin-4-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-2-fluorophenoxy)benzonitrile
3-(3-((5-(5-amino-1-(pyridin-4-yl)-1 H-pyrazol-4-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-6- chloro-2-fluorophenoxy)-5-chlorobenzonitrile
3-chloro-5-(6-chloro-3-((5-(3-chloro-1 H-indol-2-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-2- fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-3-((5-(2-chloroquinolin-3-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-2- fluorophenoxy)benzonitrile 3-(3-((5-(1 -benzyl-5-chloro-1 H-1 ,2,3-triazol-4-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-6- chloro-2-fluorophenoxy)-5-chlorobenzonitrile
3-chloro-5-(6-chloro-3-((5-(3-chloro-5-methylisoxazol-4-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-2-fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-3-((5-(4-chloro-1-methyl-1 H-pyrazol-5-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-2-fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-3-((5-(3-chlorobenzo[b]thiophen-2-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-2-fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-3-((5-(3-chloroquinoxalin-2-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-2- fluorophenoxy)benzonitrile 3-chloro-5-(6-chloro-3-((5-(5-chloro-1-methyl-1 H-pyrazol-4-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-2-fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-3-((5-(2,5-dichlorothiophen-3-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-2- fluorophenoxy)benzonitrile 3-chloro-5-(6-chloro-3-((5-(3,5-dichloroisothiazol-4-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-2- fluorophenoxy)benzonitrile ethyl 3-chloro-4-(5-(4-chloro-3-(3-chloro-5-cyanophenoxy)-2-fluorobenzyl)-1 ,3,4- oxadiazol-2-yl)-1 H-pyrrole-2-carboxylate
3-chloro-5-(6-chloro-3-((5-(5-chloro-2-phenylpyrimidin-4-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-2-fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-3-((5-(5-chloro-1-methyl-3-(trifluoromethyl)-1 H-pyrazol-4-yl)-
1 ,3,4-oxadiazol-2-yl)methyl)-2-fluorophenoxy)benzonitrile
3-(3-((5-(4-amino-3,5,6-trichloropyridin-2-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-6-chloro-2- fluorophenoxy)-5-chlorobenzonitrile 3-chloro-5-(6-chloro-3-((5-(2-chloro-6-methylpyridin-3-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-2-fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-3-((5-(2-chlorothiophen-3-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-2- fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-3-((5-(4,6-dichloropyridin-3-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-2- fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-3-((5-(3,5-dichloropyridin-2-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-2- fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-3-((5-(2-chloropyridin-3-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-2- fluorophenoxy)benzonitrile 3-chloro-5-(6-chloro-3-((5-(5-chloro-2-(ethylthio)pyrimidin-4-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-2-fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-3-((5-(2,3-dichloropyridin-4-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-2- fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-3-((5-(3-chloro-6,7-dimethylquinoxalin-2-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-2-fluorophenoxy)benzonitrile
3-(3-((5-(5-amino-3-methyl-1-m-tolyl-1 H-pyrazol-4-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-6- chloro-2-fluorophenoxy)-5-chlorobenzonitrile
3-(3-((5-(3-amino-4-(propylsulfonyl)thiophen-2-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-6- chloro-2-fluorophenoxy)-5-chlorobenzonitrile benzyl 5-(5-(4-chloro-3-(3-chloro-5-cyanophenoxy)-2-fluorobenzyl)-1 ,3,4-oxadiazol-2- yl)-3,4-dimethyl-1 H-pyrrole-2-carboxylate
3-(3-((5-(3-amino-1-(2-chlorophenyl)-1 H-pyrazol-4-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-6- chloro-2-fluorophenoxy)-5-chlorobenzonitrile 3-(3-((5-(5-amino-1-(pyridin-2-yl)-1 H-pyrazol-4-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-6- chloro-2-fluorophenoxy)-5-chlorobenzonitrile
3-(3-((5-(3-amino-1-benzyl-1 H-pyrazol-4-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-6-chloro-2- fluorophenoxy)-5-chlorobenzonitrile
3-chloro-5-(6-chloro-3-((5-(1 ,3-dichloro-6,7-dihydro-5H-cyclopenta[c]pyridin-4-yl)- 1 ,3,4-oxadiazol-2-yl)methyl)-2-fluorophenoxy)benzonitrile
3,3-dimethylbutan-2-yl 5-(5-(4-chloro-3-(3-chloro-5-cyanophenoxy)-2-fluorobenzyl)-
1 ,3,4-oxadiazol-2-yl)-4-methyl-1 H-pyrrole-3-carboxylate
3-chloro-5-(6-chloro-3-((5-(5-(4-chlorophenyl)-2-(trifluoromethyl)furan-3-yl)-1 ,3,4- oxadiazol-2-yl)methyl)-2-fluorophenoxy)benzonitrile 3-chloro-5-(6-chloro-2-fluoro-3-((5-(5-phenyl-2-(trifluoromethyl)furan-3-yl)-1 ,3,4- oxadiazol-2-yl)methyl)phenoxy)benzonitrile
3-chloro-5-(6-chloro-2-fluoro-3-((5-(5-methyl-1 -(pyridin-2-yl)-1 H-pyrazol-4-yl)-1 ,3,4- oxadiazol-2-yl)methyl)phenoxy)benzonitrile
3-chloro-5-(6-chloro-3-((5-(5-(2-chlorophenyl)-2-(trifluoromethyl)furan-3-yl)-1 ,3,4- oxadiazol-2-yl)methyl)-2-fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-3-((5-(5-chloro-1-methyl-3-(trifluoromethyl)-1 H-pyrazol-4-yl)-
1 ,3,4-oxadiazol-2-yl)methyl)-2-fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-3-((5-(1-(4-chlorophenyl)-5-(trifluoromethyl)-1 H-pyrazol-4-yl)-
1 ,3,4-oxadiazol-2-yl)methyl)-2-fluorophenoxy)benzonitrile 3-chloro-5-(6-chloro-2-fluoro-3-((5-(1 -methyl-3-(trifluoromethyl)-1 H-pyrazol-4-yl)-
1 ,3,4-oxadiazol-2-yl)methyl)phenoxy)benzonitrile
3-chloro-5-(6-chloro-2-fluoro-3-((5-(5-(4-methoxyphenyl)-2-(trifluoromethyl)furan-3- yl)-1 ,3,4-oxadiazol-2-yl)methyl)phenoxy)benzonitrile
3-chloro-5-(6-chloro-2-fluoro-3-((5-(3-methyl-5-(trifluoromethyl)isoxazol-4-yl)-1 ,3,4- oxadiazol-2-yl)methyl)phenoxy)benzonitrile
3-chloro-5-(6-chloro-3-((5-(3,5-dimethyl-1 H-pyrazol-4-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-2-fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-2-fluoro-3-((5-(4-methyl-2-(pyridin-3-yl)-1 H-imidazol-5-yl)-1 ,3,4- oxadiazol-2-yl)methyl)phenoxy)benzonitrile 3-chloro-5-(6-chloro-3-((5-(1 ,5-dimethyl-1 H-pyrazol-4-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-2-fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-2-fluoro-3-((5-(2-methylpyrazolo[1 ,5-a]pyrimidin-3-yl)-1 ,3,4- oxadiazol-2-yl)methyl)phenoxy)benzonitrile 3-chloro-5-(6-chloro-3-((5-(1 ,3-dimethyl-1 H-pyrazol-4-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-2-fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-2-fluoro-3-((5-(5-formyl-2,4-dimethyl-1 H-pyrrol-3-yl)-1 ,3,4- oxadiazol-2-yl)methyl)phenoxy)benzonitrile
3-chloro-5-(6-chloro-3-((5-(3,5-dimethyl-1 -phenyl-1 H-pyrazol-4-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-2-fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-2-fluoro-3-((5-(4-methyl-2-phenylthiazol-5-yl)-1 ,3,4-oxadiazol-2- yl)methyl)phenoxy)benzonitrile
5-(5-(4-chloro-3-(3-chloro-5-cyanophenoxy)-2-fluorobenzyl)-1 ,3,4-oxadiazol-2-yl)-
N,N-diethyl-1-methyl-1 H-pyrazole-3-carboxamide 3-chloro-5-(6-chloro-2-fluoro-3-((5-(1 -methyl-3-propyl-1 H-pyrazol-5-yl)-1 ,3,4- oxadiazol-2-yl)methyl)phenoxy)benzonitrile
4-methoxybenzyl 4-(5-(4-chloro-3-(3-chloro-5-cyanophenoxy)-2-fluorobenzyl)-1 ,3,4- oxadiazol-2-yl)-3,5-dimethyl-1 H-pyrrole-2-carboxylate
3-chloro-5-(6-chloro-3-((5-(5-(4-chlorobenzoyl)-1 ,2,4-trimethyl-1 H-pyrrol-3-yl)-1 ,3,4- oxadiazol-2-yl)methyl)-2-fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-3-((5-(1 ,3-dimethyl-5-nitro-1 H-indol-2-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-2-fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-2-fluoro-3-((5-(4-methyl-2-(pyridin-2-yl)thiazol-5-yl)-1 ,3,4- oxadiazol-2-yl)methyl)phenoxy)benzonitrile 3-chloro-5-(6-chloro-2-fluoro-3-((5-(4-methyl-2-(thiophen-2-yl)thiazol-5-yl)-1 ,3,4- oxadiazol-2-yl)methyl)phenoxy)benzonitrile
3-chloro-5-(6-chloro-3-((5-(2-((4,6-dimethoxypyrimidin-2-yl)methylthio)-1-methyl-1 H- imidazol-5-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-2-fluorophenoxy)benzonitrile
3-(3-((5-(2-(2-(benzyloxy)-5-chlorobenzyl)-1 -methyl-1 H-imidazol-5-yl)-1 ,3,4- oxadiazol^-yOmethyO-θ-chloro^-fluorophenoxy^δ-chlorobenzonitrile
3-(3-((5-(3-tert-butyl-1 -methyl-1 H-pyrazol-5-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-6-chloro-
2-fluorophenoxy)-5-chlorobenzonitrile
3-methylbutan-2-yl 5-(5-(4-chloro-3-(3-chloro-5-cyanophenoxy)-2-fluorobenzyl)-1 ,3,4- oxadiazol-2-yl)-2,4-dimethyl-1 H-pyrrole-3-carboxylate 3-chloro-5-(6-chloro-2-fluoro-3-((5-(2-phenyl-5-(trifluoromethyl)oxazol-4-yl)-1 ,3,4- oxadiazol-2-yl)methyl)phenoxy)benzonitrile
3-chloro-5-(6-chloro-2-fluoro-3-((5-(2-methyl-5-(trifluoromethyl)oxazol-4-yl)-1 ,3,4- oxadiazol-2-yl)methyl)phenoxy)benzonitrile 3-chloro-5-(6-chloro-2-fluoro-3-((5-(2-phenyl-5-(trifluoromethyl)oxazol-4-yl)-1 ,3,4- oxadiazol-2-yl)methyl)phenoxy)benzonitrile
3-(3-((5-(5-amino-3-methylisoxazol-4-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-6-chloro-2- fluorophenoxy)-5-chlorobenzonitrile
3-chloro-5-(6-chloro-2-fluoro-3-((5-(2-methyl-6-(trifluoromethyl)pyridin-3-yl)-1 ,3,4- oxadiazol-2-yl)methyl)phenoxy)benzonitrile
3-chloro-5-(6-chloro-3-((5-(2-(diethylamino)-4,6-dimethylpyrimidin-5-yl)-1 ,3,4- oxadiazol-2-yl)methyl)-2-fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-3-((5-(3,5-dimethylpyridin-2-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-2- fluorophenoxy)benzonitrile 3-chloro-5-(6-chloro-2-fluoro-3-((5-(4-methyl-2-phenylpyrimidin-5-yl)-1 ,3,4-oxadiazol-
2-yl)methyl)phenoxy)benzonitrile
3-chloro-5-(6-chloro-2-fluoro-3-((5-(7-methoxy-2-methylquinolin-3-yl)-1 ,3,4-oxadiazol-
2-yl)methyl)phenoxy)benzonitrile
3-chloro-5-(6-chloro-2-fluoro-3-((5-(2-methylimidazo[1 ,2-a]pyridin-3-yl)-1 ,3,4- oxadiazol-2-yl)methyl)phenoxy)benzonitrile
3-chloro-5-(6-chloro-2-fluoro-3-((5-(4-methyl-2-(pyrazin-2-yl)thiazol-5-yl)-1 ,3,4- oxadiazol-2-yl)methyl)phenoxy)benzonitrile
3-chloro-5-(6-chloro-2-fluoro-3-((5-(3-methylbenzofuran-2-yl)-1 ,3,4-oxadiazol-2- yl)methyl)phenoxy)benzonitrile 3-chloro-5-(6-chloro-2-fluoro-3-((5-(4-methyl-2-(pyridin-3-yl)thiazol-5-yl)-1 ,3,4- oxadiazol-2-yl)methyl)phenoxy)benzonitrile
3-chloro-5-(6-chloro-2-fluoro-3-((5-(1 -methyl-4-nitro-1 H-pyrrol-2-yl)-1 ,3,4-oxadiazol-2- yl)methyl)phenoxy)benzonitrile
3-chloro-5-(6-chloro-2-fluoro-3-((5-(5-methyl-1 -(pyridin-4-yl)-1 H-pyrazol-4-yl)-1 ,3,4- oxadiazol-2-yl)methyl)phenoxy)benzonitrile
3-chloro-5-(6-chloro-2-fluoro-3-((5-(5-methyl-2-styryloxazol-4-yl)-1 ,3,4-oxadiazol-2- yl)methyl)phenoxy)benzonitrile
3-chloro-5-(6-chloro-2-fluoro-3-((5-(2-(4-fluorophenyl)-5-methyloxazol-4-yl)-1 ,3,4- oxadiazol-2-yl)methyl)phenoxy)benzonitrile 3-chloro-5-(6-chloro-3-((5-(1 -(4-chlorobenzyl)-5-methyl-1 H-imidazol-4-yl)-1 ,3,4- oxadiazol-2-yl)methyl)-2-fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-2-fluoro-3-((5-(5-methyl-2-phenyloxazol-4-yl)-1 ,3,4-oxadiazol-2- yl)methyl)phenoxy)benzonitrile 3-(3-((5-(4-acetyl-5-(methoxymethyl)-3-methyl-1 H-pyrrol-2-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-6-chloro-2-fluorophenoxy)-5-chlorobenzonitrile
3-(3-((5-(1 H-indol-7-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-6-chloro-2-fluorophenoxy)-5- chlorobenzonitrile
3-chloro-5-(6-chloro-3-((5-(5-chloro-1-(2-chlorobenzyl)-3-methyl-1 H-pyrazol-4-yl)- 1 ,3,4-oxadiazol-2-yl)methyl)-2-fluorophenoxy)benzonitrile
(1 S,4R)-bicyclo[2.2.1]heptan-2-yl 5-(5-(4-chloro-3-(3-chloro-5-cyanophenoxy)-2- fluorobenzyl)-1 ,3,4-oxadiazol-2-yl)-2,4-dimethyl-1 H-pyrrole-3-carboxylate
3-chloro-5-(6-chloro-3-((5-(2-(2,3-dihydrobenzo[b][1 ,4]dioxin-2-yl)-4-methylthiazol-5- yl)-1 ,3,4-oxadiazol-2-yl)methyl)-2-fluorophenoxy)benzonitrile 3-(3-((5-(2-((benzo[c][1 ,2,5]oxadiazol-5-yloxy)methyl)-4-methylthiazol-5-yl)-1 ,3,4- oxadiazol^-y^methy^-θ-chloro^-fluorophenoxy^δ-chlorobenzonitrile
3-(3-((5-(2-(benzylamino)-4-methylthiazol-5-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-6-chloro-
2-fluorophenoxy)-5-chlorobenzonitrile ethyl 5-(5-(4-chloro-3-(3-chloro-5-cyanophenoxy)-2-fluorobenzyl)-1 ,3,4-oxadiazol-2- yl)-2-formyl-4-methyl-1 H-pyrrole-3-carboxylate
3-chloro-5-(6-chloro-3-((5-(1-(4-cyanophenyl)-3-(trifluoromethyl)-1 H-pyrazol-4-yl)-
1 ,3,4-oxadiazol-2-yl)methyl)-2-fluorophenoxy)benzonitrile
N-(5-(5-(4-chloro-3-(3-chloro-5-cyanophenoxy)-2-fluorobenzyl)-1 ,3,4-oxadiazol-2-yl)-
4-methylthiazol-2-yl)-2-fluorobenzamide N-(5-(5-(4-chloro-3-(3-chloro-5-cyanophenoxy)-2-fluorobenzyl)-1 ,3,4-oxadiazol-2-yl)-
4-methylthiazol-2-yl)-4-methylbenzamide
N-(5-(5-(4-chloro-3-(3-chloro-5-cyanophenoxy)-2-fluorobenzyl)-1 ,3,4-oxadiazol-2-yl)-
4-methylthiazol-2-yl)benzamide
N-(5-(5-(4-chloro-3-(3-chloro-5-cyanophenoxy)-2-fluorobenzyl)-1 ,3,4-oxadiazol-2-yl)- 4-methylthiazol-2-yl)-3-fluorobenzamide
3-chloro-5-(6-chloro-3-((5-(5-chloro-1-isobutyl-3-methyl-1 H-pyrazol-4-yl)-1 ,3,4- oxadiazol-2-yl)methyl)-2-fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-3-((5-(1 -(2-chlorobenzyl)-3,5-dimethyl-1 H-pyrazol-4-yl)-1 ,3,4- oxadiazol-2-yl)methyl)-2-fluorophenoxy)benzonitrile 3-chloro-5-(6-chloro-3-((5-(2-(4-chlorophenylamino)-4-methylthiazol-5-yl)-1 ,3,4- oxadiazol-2-yl)methyl)-2-fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-3-((5-(3,4-dichlorofuran-2-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-2- fluorophenoxy)benzonitrile 3-chloro-5-(6-chloro-3-((5-(4-chloro-1-ethyl-1 H-pyrazol-5-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-2-fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-3-((5-(4,6-dimethylpyrimidin-5-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-2- fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-3-((5-(3-ethyl-4-methyl-1 H-pyrazol-5-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-2-fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-2-fluoro-3-((5-(4-methyl-3-(thiophen-2-yl)-1 H-pyrazol-5-yl)-1 ,3,4- oxadiazol-2-yl)methyl)phenoxy)benzonitrile
3-chloro-5-(6-chloro-2-fluoro-3-((5-(4-methyl-2-(pyridin-4-yl)-1 H-imidazol-5-yl)-1 ,3,4- oxadiazol-2-yl)methyl)phenoxy)benzonitrile 3-chloro-5-(6-chloro-2-fluoro-3-((5-(4-methyl-2-(pyridin-2-yl)-1 H-imidazol-5-yl)-1 ,3,4- oxadiazol-2-yl)methyl)phenoxy)benzonitrile
3-(3-((5-(1 H-pyrrol-2-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-6-chloro-2-fluorophenoxy)-5- chlorobenzonitrile
3-(3-((5-(5-amino-3-methylisoxazol-4-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-6-chloro-2- fluorophenoxy)-5-chlorobenzonitrile
3-chloro-5-(6-chloro-3-((5-(4-chloro-1 H-pyrazol-3-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-2- fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-2-fluoro-3-((5-(3-methyl-1 H-pyrrol-2-yl)-1 ,3,4-oxadiazol-2- yl)methyl)phenoxy)benzonitrile 3-chloro-5-(6-chloro-3-((5-(3-chloro-1 H-pyrrol-2-yl)-1 ,3,4-oxadiazol-2-yl)methyl)-2- fluorophenoxy)benzonitrile
3-chloro-5-(6-chloro-2-fluoro-3-((5-(4-methyloxazol-5-yl)-1 ,3,4-oxadiazol-2- yl)methyl)phenoxy)benzonitrile
3-chloro-5-(6-chloro-2-fluoro-3-((5-(5-methyl-1 H-1 ,2,3-triazol-4-yl)-1 ,3,4-oxadiazol-2- yl)methyl)phenoxy)benzonitrile
Table 2. Synthetic Details for Oxadiazoles Prepared via Array Methods C through H
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
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
Example 233: (2£)-3-f3-chloro-5-r(6-chloro-3-fr5-(3.5-dimethyl-4-isoxazolvn-1.3.4- oxadiazol-2-yllmethyl}-2-fluorophenyl)oxylphenyl}-2-propenenitrile
Figure imgf000126_0001
Step A: 2-{3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}acetohydrazide
A solution of ethyl {3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}acetate (2.0 g, 4.7 mmol) and hydrazine (594 μl_, 19.0 mmol) in ethanol (20 mL) was heated at reflux for 23 h. The reaction was cooled and the precipitate was collected via vacuum filtration to afford the title compound (1.22g). The filtrate was concentrated and the resulting solid was triturated with ethanol to provide an additional crop (0.18 g) of the title compound. The two crops were combined to provide 1.4Og (73%) of a tan solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 9.18 (br s, 1 H), 7.45-7.41 (m, 2H), 7.30 (t, 1 H), 7.09-7.08 (m, 1 H), 7.01-7.00 (m, 1 H), 4.20 (s, 2H), 3.45 (s, 2H).
Step B: 2-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-5-(3,5- dimethyl-4-isoxazolyl)-1 ,3,4-oxadiazole
A solution of 2-{3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2- fluorophenyl}acetohydrazide (400 mg, 0.98 mmol), 3,5-dimethyl-4- isoxazolecarboxylic acid (138 mg, 0.98 mmol), HATU (373 mg, 0.98 mmol) and DIPEA (0.34 mL, 1.96 mmol) in THF (5 mL) was heated at 45 °C overnight. The reaction was cooled to rt, Burgess Reagent (933 mg, 3.92 mmol) was added and the reaction was stirred overnight. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The organic extracts were combined, dried over Na2SO4, filtered, concentrated and the crude material was purified by column chromatography (5% to 100% EtOAc/hexanes gradient) to afford the title compound (350 mg, 70%) as a white solid. 1H NMR (400 MHz, DMSO-c/6): δ ppm 7.55-7.48 (m, 3H), 7.15 (t, 1 H), 7.08 (t, 1 H), 4.46 (s, 2H), 2.62 (s, 3H), 2.38 (s, 3H). Step C: 2-({4-chloro-3-[(3-chloro-5-ethenylphenyl)oxy]-2-fluorophenyl}methyl)-5-(3,5- dimethyl-4-isoxazolyl)-1 ,3,4-oxadiazole
A solution of 2-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-5- (3,5-dimethyl-4-isoxazolyl)-1 ,3,4-oxadiazole (1 10 mg, 0.21 mmol), potassium vinyltrifluoroborate (56 mg, 0.42 mmmol), PdCI2(dppf)-DCM (7 mg, 0.0084 mmol) and triethylamine (59 μl_, 0.42 mmol) in n-PrOH (2 mL) was heated at 100 °C overnight, cooled to rt and purified by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA) to afford the title compound as the trifluoroacetate salt. The salt was diluted with EtOAc (20 mL) and washed with saturated sodium bicarbonate solution (20 mL) dried over Na2SO4, filtered and concentrated to afford the title compound (85 mg, 88%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.53-7.45 (m, 2H), 7.34-7.33 (m, 1 H), 7.02-6.99 (m, 1 H), 6.83-6.82 (m, 1 H), 6.69-6.61 (m, 1 H), 5.90 (d, 1 H), 5.32 (d, 1 H), 4.44 (s, 2H), 2.60 (s, 3H), 2.36 (s, 3H). MS: m/z 459.98 (M+1 ).
Step D: 3-chloro-5-[(6-chloro-3-{[5-(3,5-dimethyl-4-isoxazolyl)-1 ,3,4-oxadiazol-2- yl]methyl}-2-fluorophenyl)oxy]benzaldehyde
A solution of 2-({4-chloro-3-[(3-chloro-5-ethenylphenyl)oxy]-2-fluorophenyl}methyl)-5- (3,5-dimethyl-4-isoxazolyl)-1 ,3,4-oxadiazole (75 mg, 0.16 mmol), osmium tetraoxide (2.5% in tBuOH, 38 μL, 0.003 mmol), sodium periodate (103 mg, 0.48 mmol) in dioxane (2 mL) and water (1 mL) was stirred at room temperature for 2 h. Water (10 mL) was added and the aqueous solution was extracted with EtOAc (2 x 2OmL). The organic phases were compbined, dried over Na2SO4, filtered, concentrated and purified by column chromatography (20% to 100% EtOAc/hexanes gradient) to afford the title compound (45 mg, 53%) as a white solid. 1H NMR (400 MHz, CDCI3): δ ppm 9.90 (s, 1 H), 7.59 (t, 1 H), 7.34-7.31 (m, 1 H), 7.28-7.24 (m, 1 H), 7.21-7.20 (m, 2H), 4.33 (s, 2H), 2.68 (s, 3H), 2.49 (s, 3H).
Step E: (2£)-3-{3-chloro-5-[(6-chloro-3-{[5-(3,5-dimethyl-4-isoxazolyl)-1 ,3,4- oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]phenyl}-2-propenenitrile
A solution of diethylphosphonoacetonitrile (18 μL, 0.1 1 mmol) in THF (0.5 mL) was cooled to 0 °C in an ice bath and potassium f-butoxide (1 M in THF, 0.1 1 mL, 0.11 mmol) was added dropwise. The reaction was stirred at O °C for 30 min and a solution of 3-chloro-5-[(6-chloro-3-{[5-(3,5-dimethyl-4-isoxazolyl)-1 ,3,4-oxadiazol-2- yl]methyl}-2-fluorophenyl)oxy]benzaldehyde (45 mg, 0.10 mmol) in THF (1 ml.) was added dropwise. The reaction was stirred at 0 °C for 30 min, warmed to room temperature and stirred for an additional 60 min. The reaction was quenched with water (1 ml.) and concentrated to an oil. The crude material was purified by purified by Reverse-Phase HPLC (water/acetonitrile with 0.1 % TFA) to afford the title compound (9 mg, 14%) as a white solid. 1H NMR (400 MHz, DMSO-c/6): δ ppm 7.33- 7.22 (m, 2H), 7.16-7.13 (m, 1 H), 6.90 (d, 1 H), 5.94 (d, 1 H), 4.31 (s, 2H), 2.68 (s, 3H), 2.49 (s, 3H). MS: m/z 484.98 (M+1 ).
Example 234: 3-chloro-5-{r6-chloro-3-({5-r3,5-dimethyl-1 -(methylsulfonyl)-i H-pyrazol- 4-vH-1 ,3,4-oxadiazol-2-yl}methyl)-2-fluorophenyl1oxy}benzonitrile
Figure imgf000128_0001
To a solution of 3-chloro-5-[(6-chloro-3-{[5-(3,5-dimethyl-1 /-/-pyrazol-4-yl)-1 ,3,4- oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile (50 mg, 0.109 mmol) in DCM (5.0 ml) was added mesyl chloride (8.50 μl, 0.109 mmol) at 0 °C. The mixture was warmed to RT and 30 minutes later the solvent was removed. The crude material was purified via silica gel chromatography to give (37 mg, 63.2 % yield) of the title compound. 1 H NMR (400 MHz, CHLOROFORM-tf) δ ppm 7.19 - 7.39 (m, 3 H), 7.14 (s, 1 H), 6.96 (s, 1 H), 4.31 (s, 2 H), 3.35 (s, 3 H), 2.80 (s, 3 H), 2.44 (s, 3 H).
Example 235: 3-chloro-5-fr6-chloro-2-fluoro-3-({5-ri-(2-hvdroxy-2-methylpropyn-3.5- dimethyl-1H-pyrazol-4-vH-1 ,3,4-oxadiazol-2-yl}methyl)phenylloxy}benzonitrile
Figure imgf000128_0002
To a solution of 3-chloro-5-[(6-chloro-3-{[5-(3,5-dimethyl-1 H-pyrazol-4-yl)-1 ,3,4- oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile (75 mg, 0.164 mmol) in 2,2- dimethyloxirane (10 ml, 0.164 mmol) was added potassium carbonate (67.9 mg, 0.491 mmol) and the mixture was stirred at 80 °C for 3 days. The reaction mixture was adsorbed onto silcia gel and purified via silica gel chromatography to give (56 mg, 64.5 % yield) of the title compound. 1 H NMR (400 MHz, CHLOROFORM-tf) δ ppm 7.18 - 7.39 (m, 3 H), 7.12 (s, 1 H), 6.98 (s, 1 H), 4.28 (s, 2 H), 3.93 (s, 2 H), 2.51 (s, 3 H), 2.39 (s, 3 H), 1.05 - 1.25 (m, 6 H).
Example 236: S-chloro-δ-fre-chloro^-fluoro-S-flδ-π-O-hvdroxy-S-methylbutvn-S.δ- dimethyl-1H-pyrazol-4-yll-1 ,3,4-oxadiazol-2-yl}methyl)phenylloxy}benzonitrile
Figure imgf000129_0001
A sealed tube containing 3-chloro-5-[(6-chloro-3-{[5-(3,5-dimethyl-1 H-pyrazol-4-yl)-
1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile (75 mg, 0.164 mmol), 3- hydroxy-3-methylbutyl 4-methylbenzenesulfonate (85 mg, 0.327 mmol), potassium carbonate (67.9 mg, 0.491 mmol) and DMF (4 ml) was heated at 80 °C for 2 days. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via silica gel chromatography to give 3-chloro-5-{[6-chloro-2-fluoro-3-({5-[1-(3-hydroxy-3-methylbutyl)-3,5-dimethyl- 1 H-pyrazol-4-yl]-1 ,3,4-oxadiazol-2-yl}methyl)phenyl]oxy}benzonitrile (23 mg, 0.042 mmol, 25.8 % yield). 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.37 - 7.41 (m, 1 H), 7.29 - 7.37 (m, 2 H), 7.19 (s, 1 H), 7.01 (s, 1 H), 4.35 (s, 2 H), 4.28 (t, 2 H), 2.59 (s, 3 H), 2.46 (s, 3 H), 2.00 (t, 2 H), 1.31 (s, 6 H).
Example 237: 3-chloro-5-({6-chloro-3-r(5-f3.5-dimethyl-1-r2-(methylsulfonvnethyll-1 H- Pyrazol-4-yl}-1 ,3,4-oxadiazol-2-yl)methyll-2-fluorophenyl}oxy)benzonitrile
Figure imgf000129_0002
Step A: ethyl 3,5-dimethyl-1-[2-(methylsulfonyl)ethyl]-1 /-/-pyrazole-4-carboxylate A microwave vial was charged with ethyl 3,5-dimethyl-1 H-pyrazole-4-carboxylate (1.00 g, 5.95 mmol), methyl vinyl sulfone (0.521 ml, 5.95 mmol), K2CO3 (2.465 g, 17.84 mmol) and DMF (15 ml), and the mixture was irradiated for 30 minutes at 135 °C in a personal microwave reactor. The reaction mixture was diluted with EtOAc, washed with brine and dried over magnesium sulfate. The solvent was removed to give ethyl 3,5-dimethyl-1-[2-(methylsulfonyl)ethyl]-1 H-pyrazole-4-carboxylate (1.61 g, 99 % yield). 1 H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.47 (t, J=6.2 Hz, 2 H), 4.30 (q, J=IA Hz, 2 H), 3.65 (t, J=6.2 Hz, 2 H), 2.61 (s, 3 H), 2.60 (s, 3 H), 2.42 (s, 3 H), 1.37 (t, J=IA Hz, 3 H).
Step B: 3,5-dimethyl-1-[2-(methylsulfonyl)ethyl]-1/-/-pyrazole-4-carboxylic acid
To a solution of ethyl 3,5-dimethyl-1-[2-(methylsulfonyl)ethyl]-1 H-pyrazole-4- carboxylate (788 mg, 2.87 mmol) in THF (3 ml.) was added NaOH (1.723 ml, 8.62 mmol) (5.0M solution) and the mixture was stirred at 60 °C overnight. The mixture was diluted with EtOAc and washed with 1.0 N HCI. The solvent was removed to give 3,5-dimethyl-1-[2-(methylsulfonyl)ethyl]-1 H-pyrazole-4-carboxylic acid (589 mg, 83 % yield) which was used in the next step without purification. 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.13 (s, 1 H), 4.35 (t, J=6.9 Hz, 2 H), 3.60 (t, J=6.9 Hz, 2 H), 2.89 (s, 3 H), 2.44 (s, 3 H), 2.23 (s, 3 H).
Step C: 3-chloro-5-({6-chloro-3-[(5-{3,5-dimethyl-1 -[2-(methylsulfonyl)ethyl]-1 H- pyrazol-4-yl}-1 ,3,4-oxadiazol-2-yl)methyl]-2-fluorophenyl}oxy)benzonitrile
To a solution of 2-{4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}acetohydrazide (80 mg, 0.226 mmol), 3,5-dimethyl-1-[2- (methylsulfonyl)ethyl]-1 H-pyrazole-4-carboxylic acid (55.6 mg, 0.226 mmol) and HATU (86 mg, 0.226 mmol) in THF (5 ml) was added DIPEA (0.079 ml, 0.452 mmol) and the mixture was stirred at 70 °C overnight. Burgessreagent (269 mg, 1.129 mmol) was added and the mixture was stirred at room temperature for 6 hours. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via reverse phase HPLC to give 3- chloro-5-({6-chloro-3-[(5-{3,5-dimethyl-1-[2-(methylsulfonyl)ethyl]-1 H-pyrazol-4-yl}- 1 ,3,4-oxadiazol-2-yl)methyl]-2-fluorophenyl}oxy)benzonitrile (6.6 mg, 0.012 mmol, 5.18 % yield). 1 H NMR (400 MHz, CHLOROFORM-tf) δ ppm 7.34 (s, 1 H), 7.25 - 7.32 (m, 2 H), 7.12 - 7.18 (m, 1 H), 6.97 (s, 1 H), 4.49 (t, J=6.3 Hz, 2 H), 4.30 (s, 2 H), 3.62 (t, J=6.3 Hz, 2 H), 2.64 (s, 3 H), 2.59 (s, 3 H), 2.39 (s, 3 H).
Example 238: 2-f4-r5-α4-chloro-3-r(3-chloro-5-cvanoDhenvnoxyl-2- fluorophenyl}methyl)-1 ,3,4-oxadiazol-2-yll-3,5-dimethyl-1 H-pyrazol-1 -\/\}-N-\2- (methylsulfonyl)ethyllacetamide
Figure imgf000131_0001
To a solution of {4-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2- fluorophenyl}methyl)-1 ,3,4-oxadiazol-2-yl]-3,5-dimethyl-1 H-pyrazol-1 -yl}acetic acid (45 mg, 0.087 mmol), 2-(methylsulfonyl)ethanamine (10.74 mg, 0.087 mmol) and HATU (33.1 mg, 0.087 mmol) in THF (6 ml) was added DIPEA (0.030 ml, 0.174 mmol) and the mixture was stirred at RT for 30 minutes. The reaction mixture was diluted with EtOAc and washed with water. The solvent was removed and the crude material was purified via reverse phase HPLC to give 2-{4-[5-({4-chloro-3-[(3-chloro- 5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4-oxadiazol-2-yl]-3,5-dimethyl-1 H- pyrazol-1-yl}-N-[2-(methylsulfonyl)ethyl]acetamide (27 mg, 50 % yield). 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.42 (t, J=5.5 Hz, 1 H), 7.81 (s, 1 H), 7.43 - 7.60 (m, 4 H), 4.78 (s, 2 H), 4.43 (s, 2 H), 3.49 (t, J=6.2 Hz, 2 H), 3.27 (t, J=6.7 Hz, 2 H), 3.01 (s, 3 H), 2.42 (s, 3 H), 2.28 (s, 3 H).
Example 239: 3-chloro-5-α6-chloro-3-r(5-f 1 -r(2SV2.3-dihvdroxy-3-methylbutyll-3.5- dimethyl-1 /-/-pyrazol-4-yl}-1 ,3,4-oxadiazol-2-yl)methyll-2- fluorophenyl}oxy)benzonitrile
Figure imgf000131_0002
Step A: ethyl 3,5-dimethyl-1-{[(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl}-1 H- py razol e-4-carboxyl ate A solution of ethyl 3,5-dimethyl-1 /-/-pyrazole-4-carboxylate (300 mg, 1.79 mmol), [(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl 4-methylbenzenesulfonate (561 mg, 1.79 mmol) and CS2CO3 (1.75 g, 5.37 mmol) in DMF was irradiated in a personal microwave reactor for 25 minutes at 130 °C. The reaction mixture was diluted with EtOAc and washed with brine. The solvent was removed and the crude material was purified via silica gel chromatography to give ethyl 3,5-dimethyl-1-{[(4S)-2,2,5,5- tetramethyl-1 ,3-dioxolan-4-yl]methyl}-1 /-/-pyrazole-4-carboxylate (301 mg). 1 H NMR (CHLOROFORM-d) δ ppm 4.29 (q, 2 H) 4.01 - 4.19 (m, 3 H) 2.57 (s, 3 H) 2.43 (s, 3 H) 1.43 (s, 3 H) 1.36 (t, 3 H) 1.31 (s, 3 H) 1.28 (s, 3 H) 1.24 (s, 3 H)
Step B : 3,5-dimethyl-1-{[(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl}-1 H- pyrazole-4-carbohydrazide
A solution of ethyl 3,5-dimethyl-1 -{[(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl}- 1 /-/-pyrazole-4-carboxylate (176 mg, 0,568 mmol) and hydrazine (5 ml.) in ethanol (10 ml.) was stirred at reflux for two days. The solvent was evaporated and the crude material (172 mg) was used without purification in the next step. 1 H NMR (DMSO-c/β) δ ppm 8.73 (s, 1 H) 4.40 (br. s., 2 H) 4.08 - 4.20 (m, 1 H) 4.03 - 4.08 (m, 1 H) 3.90 - 4.02 (m, 1 H) 2.31 (s, 3 H) 2.16 (s, 3 H) 1.30 (s, 3 H) 1.20 (s, 3 H) 1.14 (s, 3 H) 1.12 (s, 3 H).
Step C: 3-chloro-5-[(6-chloro-3-{[5-(3,5-dimethyl-1 -{[(4S)-2,2,5,5-tetramethyl-1 ,3- dioxolan-4-yl]methyl}-1H-pyrazol-4-yl)-1 ,3,4-oxadiazol-2-yl]methyl}-2- fluorophenyl)oxy]benzonitrile
A mixture of 3,5-dimethyl-1 -{[(4S)-2,2,5,5-tetramethyl-1 ,3-dioxolan-4-yl]methyl}-1 H- pyrazole-4-carbohydrazide (136 mg, 0.459 mmol), {4-chloro-3-[(3-chloro-5- cyanophenyl)oxy]-2-fluorophenyl}acetic acid (156 mg, 0.459 mmol), HATU (174 mg, 0.459 mmol) and DIPEA (0.16 ml_, 0.918 mmol) in THF was stirred at RT. for 90 minutes. Burgess reagent (437 mg, 1.84 mmol) was added and the reaction mixture was stirred for another 5 hours. The reaction mixture was diluted with EtOAc and washed with brine. The solvent was removed and the crude material was purified via silica gel chromatography to give the title compound (89 mg). LC-MS (ES+) m/z 600.25, [M+H].
Step D: 3-chloro-5-({6-chloro-3-[(5-{1 -[(2S)-2,3-dihydroxy-3-methylbutyl]-3,5- dimethyl-1 H-pyrazol-4-yl}-1 ,3,4-oxadiazol-2-yl)methyl]-2- fluorophenyl}oxy)benzonitrile
A solution of 3-chloro-5-[(6-chloro-3-{[5-(3,5-dimethyl-1-{[(4S)-2,2,5,5-tetramethyl- 1 ,3-dioxolan-4-yl]methyl}-1 H-pyrazol-4-yl)-1 ,3,4-oxadiazol-2-yl]methyl}-2- fluorophenyl)oxy]benzonitrile (82.0 mg 0.137 mmol) and pyridinium p- toluenesulfonate (10.3 mg, 0.041 mmol) in methanol (5 ml.) was stirred for 8 hours at 70 °C. The reaction mixture was neutralized with TEA (1 mL), the solvent was removed, and the crude material was purified via silica gel chromatography to give the title compound (36 mg). 1 H NMR (DMSO-c/6) δ ppm 7.78 (s, 1 H) 7.19 - 7.56 (m, 4 H) 6.14 (none, 0 H) 4.87 (d, 1 H) 4.45 (s, 1 H) 4.38 (s, 2 H) 4.15 (s, 1 H) 3.86 (dd, 1 H) 3.40 - 3.64 (m, 1 H) 2.43 (s, 3 H) 2.24 (s, 3 H) 1.08 (s, 3 H) 1.05 (s, 3 H) LC-MS (ES+) m/z 560.23, [M+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
Hel_a-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 - 80°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.
E. Titering of virus stocks.
HIV-1 virus stocks are titered in the Hel_a-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 @ 37°C, 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 HeLa-CD4- LTR-β-gal monolayer. Add 35ul (approximately 350,000 total RLUs) of diluted virus to each well. Incubate (S) 37°C, 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 four-fold 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 @ 37°C, 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 2 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 2
Ex. Structure K103N V106A WTRVA Y181C
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_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 examples 61 , 63, 65, 67, 83, 1 11 , 153, 189, 233, 238, and 239 demonstrated "A" activity level against K103N, V106A, WTRVA, Y181 C and Y188L.
Compounds of examples 1 14 and 235 demonstrated "A" activity levels against K103N, WTRVA, and Y181 C and "B" activity levels against V106A and 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 imgf000146_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 -R5Het or C3-C12 heterocycle, 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-C12 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 C3-C12 heterocycle 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.
5. A compound according to claim 1 wherein R3 is R5Het and wherein Het 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)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 n is 2 and each R2 is halogen.
7. A compound according to claim 1 wherein m is 2 and the first R1 is halogen and the second R is -CN.
8. A compound according to claim 1 wherein m is 2, n is 2, and R3 is C3-C12 heterocycle 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.
9. A compound according to claim 1 wherein R3 is C3-C12 heterocycle optionally substituted with at least one C1-C8 alkyl, halogen, OR , or -N(R4)S(O)2R
10. A compound of formula (II)
Figure imgf000147_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 -R5Het or C3-C12 heterocycle, 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-C12 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.
11. A compound of formula (II)'
Figure imgf000148_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 -R5Het or C3-C12 heterocycle, each optionally substituted with at least one of 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, -N(R4)S(O)2R4; C 6 - io aryl optionally substituted with halogen or C1-C8 alkyl; or C1-C8 alkyl optionally substituted with hydroxyl; each R4 is independently hydrogen, C1-C8 alkyl optionally substituted with at least one of 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-C12 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)' according to claim 11 wherein m is 2; n is 2; each R1 is independently halogen, -CN, or R5CN; each R2 independently is halogen, or -CN;
R3 is C3 -C12 heterocycle, optionally substituted with at least one of C1-C8 alkyl, -OR4, -
N(R4)2, -C(O)N(R4)R5S(O)2R4, -N(R4)R5S(O)2R4, C 6 - 10 aryl optionally substituted with halogen or C1-C8 alkyl; or C1-C8 alkyl optionally substituted with hydroxyl; each R4 is independently hydrogen or C1-C8 alkyl optionally substituted with at least one of hydroxyl or halogen; each R5 is independently C1-C8 alkylene or C1-C8 alkenylene, each optionally substituted with at least one hydroxyl or hydrogen; or a pharmaceutically acceptable salt thereof.
13. A compound selected from the group consisting of 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-pyridinyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(3-pyridinyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(3-methyl-4-pyridinyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-methyl-3-pyridinyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile; 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(1H-indol-5-yl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(1H-indol-6-yl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-[(3-{[5-(1/-/-benzimidazol-5-yl)-1 ,3,4-oxadiazol-2-yl]methyl}-6-chloro-2- fluorophenyl)oxy]-5-chlorobenzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(6-chloro-3-pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2- fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(2-chloro-6-methyl-4-pyridinyl)-1 ,3,4-oxadiazol-2- yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(6-methyl-3-pyridinyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(2-chloro-4-pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2- fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(3-chloro-4-pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2- fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(4-chloro-3-pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2- fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(2,5-dichloro-4-pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}- 2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(5-chloro-2-{[2-(methylsulfonyl)ethyl]amino}-4- pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile trifluoroacetate;
3-chloro-5-{[6-chloro-3-({5-[5-chloro-2-(methylthio)-4-pyridinyl]-1 ,3,4-oxadiazol-2- yl}methyl)-2-fluorophenyl]oxy}benzonitrile;
3-[(6-bromo-3-{[5-(3-chloro-4-pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2- fluorophenyl)oxy]-5-chlorobenzonitrile;
2-[(3-chloro-5-cyanophenyl)oxy]-4-{[5-(3-chloro-4-pyridinyl)-1 ,3,4-oxadiazol-2- yl]methyl}-3-fluorobenzonitrile;
3-chloro-5-[(3-{[5-(3-chloro-4-pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}-6-ethenyl-2- fluorophenyl)oxy]benzonitrile;
3-[(6-bromo-3-{[5-(3-chloro-1-oxido-4-pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2- fluorophenyl)oxy]-5-chlorobenzonitrile; 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(3-methyl-1-oxido-4-pyridinyl)-1 ,3,4-oxadiazol- 2-yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-{[6-chloro-2-fluoro-3-({5-[4-methyl-6-({[(4S)-2,2,5,5-tetramethyl-1 ,3- dioxolan-4-yl]methyl}oxy)-3-pyridinyl]-1 ,3,4-oxadiazol-2- yl}methyl)phenyl]oxy}benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(6-{[(2S)-2,3-dihydroxy-3-methylbutyl]oxy}-4-methyl-3- pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(2-{[(2S)-2,3-dihydroxy-3-methylbutyl]oxy}-5-methyl-4- pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-fluoro-5-methyl-4-pyridinyl)-1 ,3,4- oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(5-methyl-2-{[2-(methylsulfonyl)ethyl]amino}- 4-pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-3-pyridinyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(1 ,3,5-trimethyl-1 H-pyrazol-4-yl)-1 ,3,4- oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(3-methyl-2-furanyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(1-methyl-1 H-pyrrol-2-yl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(2,5-dimethyl-3-furanyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2- fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(1-methyl-1 H-imidazol-2-yl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(3-methyl-2-pyridinyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(2,4-dimethyl-3-pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}- 2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(3-ethyl-1-methyl-1 H-pyrazol-5-yl)-1 ,3,4-oxadiazol-2- yl]methyl}-2-fluorophenyl)oxy]benzonitrile; 3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-1 ,6-naphthyridin-3-yl)-1 ,3,4- oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-3-furanyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(2,4-dimethyl-1 ,3-thiazol-5-yl)-1 ,3,4-oxadiazol-2- yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(1-methyl-1 H-imidazol-5-yl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(3,5-dimethyl-4-isoxazolyl)-1 ,3,4-oxadiazol-2- yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(2,5-dimethyl-1 ,3-oxazol-4-yl)-1 ,3,4-oxadiazol-2- yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(3-methyl-4-isoxazolyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-methyl-1 ,3-thiazol-5-yl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-1 ,8-naphthyridin-3-yl)-1 ,3,4- oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(3-methyl-2-thienyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(1-methyl-1 H-indol-2-yl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(1-methyl-1 H-pyrazol-5-yl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile; and pharmaceutically acceptable derivatives thereof.
14. A compound selected from the group consisting of:
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(3-methyl-4-pyridinyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(3-chloro-4-pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2- fluorophenyl)oxy]benzonitrile; 3-chloro-5-[(6-chloro-3-{[5-(5-chloro-2-{[2-(methylsulfonyl)ethyl]amino}-4- pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(6-{[(2S)-2,3-dihydroxy-3-methylbutyl]oxy}-4-methyl-3- pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(2-{[(2S)-2,3-dihydroxy-3-methylbutyl]oxy}-5-methyl-4- pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(5-methyl-2-{[2-(methylsulfonyl)ethyl]amino}- 4-pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(2-methyl-3-furanyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(3,5-dimethyl-4-isoxazolyl)-1 ,3,4-oxadiazol-2- yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(3-methyl-4-isoxazolyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-methyl-1 ,3-thiazol-5-yl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(3-methyl-2-thienyl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(1-methyl-1 H-pyrazol-5-yl)-1 ,3,4-oxadiazol-2- yl]methyl}phenyl)oxy]benzonitrile; and pharmaceutically acceptable derivatives thereof.
15. A compound selected from the group consisting of:
3-chloro-5-[(6-chloro-3-{[5-(6-{[(2S)-2,3-dihydroxy-3-methylbutyl]oxy}-4-methyl-3- pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(5-methyl-2-{[2-(methylsulfonyl)ethyl]amino}- 4-pyridinyl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-2-fluoro-3-{[5-(4-methyl-2-{[2-(methylsulfonyl)ethyl]amino}- 1 ,3-thiazol-5-yl)-1 ,3,4-oxadiazol-2-yl]methyl}phenyl)oxy]benzonitrile;
3-chloro-5-[(6-chloro-3-{[5-(1 ,4-dimethyl-1 H-pyrazol-5-yl)-1 ,3,4-oxadiazol-2- yl]methyl}-2-fluorophenyl)oxy]benzonitrile; 3-chloro-5-[(6-chloro-3-{[5-(1 ,4-dimethyl-1 H-imidazol-5-yl)-1 ,3,4-oxadiazol-2- yl]methyl}-2-fluorophenyl)oxy]benzonitrile;
3-[(3-{[5-(3-amino-5-methyl-1 H-pyrazol-4-yl)-1 ,3,4-oxadiazol-2-yl]methyl}-6- chloro-2-fluorophenyl)oxy]-5-chlorobenzonitrile;
3-chloro-5-(6-chloro-3-((5-(3,5-dimethyl-1 H-pyrazol-4-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-2-fluorophenoxy)benzonitrile;
3-(3-((5-(5-amino-1-(2-fluorophenyl)-3-methyl-1 H-pyrazol-4-yl)-1 ,3,4-oxadiazol-2- yl)methyl)-6-chloro-2-fluorophenoxy)-5-chlorobenzonitrile;
3-(3-((5-(5-amino-1-(3-chlorophenyl)-3-methyl-1 H-pyrazol-4-yl)-1 ,3,4-oxadiazol- 2-yl)methyl)-6-chloro-2-fluorophenoxy)-5-chlorobenzonitrile;
3-{[3-({5-[5-amino-3-methyl-1-(3-methylphenyl)-1 H-pyrazol-4-yl]-1 ,3,4-oxadiazol- 2-yl}methyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile;
3-[(3-{[5-(5-amino-3-methyl-4-isoxazolyl)-1 ,3,4-oxadiazol-2-yl]methyl}-6-chloro-2- fluorophenyl)oxy]-5-chlorobenzonitrile;
(2E)-3-{3-chloro-5-[(6-chloro-3-{[5-(3,5-dimethyl-4-isoxazolyl)-1 ,3,4-oxadiazol-2- yl]methyl}-2-fluorophenyl)oxy]phenyl}-2-propenenitrile;
3-chloro-5-{[6-chloro-2-fluoro-3-({5-[1-(2-hydroxy-2-methylpropyl)-3,5-dimethyl- 1/-/-pyrazol-4-yl]-1 ,3,4-oxadiazol-2-yl}methyl)phenyl]oxy}benzonitrile;
2-{4-[5-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-1 ,3,4- oxadiazol-2-yl]-3,5-dimethyl-1/-/-pyrazol-1-yl}-N-[2-(nnethylsulfonyl)ethyl]acetannide;
3-chloro-5-({6-chloro-3-[(5-{1-[(2S)-2,3-dihydroxy-3-methylbutyl]-3,5-dimethyl-1H- pyrazol-4-yl}-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, and similar agents 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), or 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 and 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.
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