Title of Invention

NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS I FOR TREATING HIV MEDIATED DISEASES

Abstract

This invention relates to novel heterocyclic compounds of formula (I) wherein R< 1 >-< >R<4>, X< 1 > and X<2> are as defined in the summary and pharmaceutically acceptable salts and solvates thereof, methods to inhibit or modulate Human Immunodeficiency Virus (HIV) reverse transcriptase with compounds of formula (I), pharmaceutical compositions containing of formula (I) admixed with at least one solvent, carrier or excipient and processes to prepare compounds of formula (I). The compounds are useful for treating disorders in which HIV and genetically related viruses are to implicatedThis invention relates to novel heterocyclic compounds of formula (I) wherein R<l>-< >R<4>, X<1> and X<2> are as defined in the summary and pharmaceutically acceptable salts and solvates thereof, methods to inhibit or modulate Human Immunodeficiency Virus (HIV) reverse transcriptase with compounds of formula (I), pharmaceutical compositions containing of formula (I) admixed with at least one solvent, carrier or excipient and processes to prepare compounds of formula (I). The compounds are useful for treating disorders in which HIV and genetically related viruses are to implicated.

Full Text

NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS I FOR TREATING HIV MEDIATED DISEASES This application claims benefit under Title 35 U.S.C. 119(e) of U.S. Provisional Application No. 60/457,144, filed March 24, 2003, which is hereby incorporated by reference in its entirety. The related application filed herewith, Non-Nucleoside Reverse Transcriptase Inhibitors (J. P. Dunn et al), is hereby incorporated by reference in its entirety. The invention relates to the field of antiviral therapy and, in particular, to non-nucleoside reverse transcriptase inhibitors for treating Human Immunodeficiency Virus (HIV) mediated diseases. The invention provides novel heterocyclic compounds, pharmaceutical compositions comprising these compounds, methods for treatment or prophylaxis of HIV mediated diseases employing said compounds in monotherapy or in combination therapy, and a process for preparing novel heterocyclic compounds. The human immunodeficiency virus HIV is the causative agent of acquired immunodeficiency syndrome (AIDS), a disease characterized by the destruction of the immune system, particularly of the CD4+ T-cell, with attendant susceptibility to opportunistic infections. HIV infection is also associated with a precursor AIDS - related complex (ARC), a syndrome characterized by symptoms such as persistent generalized lymphadenopathy, fever and weight loss. In common with other retroviruses, the HIV genome encodes protein precursors known as gag and gag-pol which are processed by the viral protease to afford the protease, reverse transcriptase (RT), endonuclease/integrase and mature structural proteins of the virus core. Interruption of this processing prevents the production of normally infectious virus. Considerable efforts have been directed towards the control of HIV by inhibition of virally encoded enzymes. Currently available chemotherapy targets two crucial viral enzymes; HIV protease and HIV reverse transcriptase, (J. S. G. Montaner et al. Antiretroviral therapy: 'the state of the art", Biomed & Pharmacother. 1999 53:63-72; R. W. Shafer and D. A. Vuitton, Highly active retroviral therapy (HAART) for the treatment of infection with human immunodeficiency virus type 1, Biomed. & Pharmacother.1999 53:73-86; E. De Clercq, New Developments in Anti-HIV Cehmotherap. Curr, Med. Cliem. 2001 8:1543-1572). Two general classes of RTI inhibitors FS/23.01.2004 have been identified: nucleoside reverse transcriptase inhibitors (NRTI) and non-nucleoside reverse transcriptase inhibitors (NNRTI). NRTIs typically are 2',3'-dideoxynucleoside (ddN) analogs which must be phosphorylated prior to interacting with viral RT. The corresponding triphosphates function as competitive inhibitors or alternative substrates for viral RT. After incorporation into nucleic acids the nucleoside analogs terminate the chain elongation process. HIV reverse transcriptase has DNA editing capabilities which enable resistant strains to overcome the blockade by cleaving the nucleoside analog and continuing the elongation. Currently clinically used NRTIs include zidovudine (AZT), didanosme (ddl), zalcitabine (ddC), stavudine (d4T), lamivudine (3TC) and tenofovir (PMPA). NNRTIs were first discovered in 1989. NNRTI are allosteric inhibitors which bind reversibly at a nonsubstrate binding site on the HTV reverse transcriptase thereby altering the shape of the active site or blocking polymerase activity. (R. W. Buckheit, Jr,, Non-nucleoside reverse transcriptase inhibitors: perspectives for novel therapeutic compotatds and sti'ategies for treatment of HIV infection, Expert Opin. Investig. Drugs 2001 10(8)1423-1442; E. De Clercq The role ofnonO-nuceloside reverse transcriptase inhibitors (NNRTIs) in the therapy ofHTV-1 infection, Antiviral Res. 1998 38:153-179; G. Moyle, The Emerging Roles of Non-Nucleoside Reverse Traitscriptase Inhibitors in Antiviral Therapy, Drugs 2001 61(l):19-26) Although over thirty structural classes of NNRTIs have been identified in the laboratory only three compounds have been approved for HTV therapy: efavirenz, nevirapine and delavirdhie. Although initially viewed as a promising class of compounds, in vitro and in vivo studies quickly revealed the NNRTIs presented a low barrier to the emergence of drug resistant HTV strains and class-specific toxicity. Drug resistance frequently develops with only a single point mutation in the RT. While combination therapy with NRTTs, Pis and NNRTIs has, in many cases, dramatically lowered viral loads and slowed disease progression, significant therapeutic problems remain. The cocktails are not effective in all patients, potentially severe adverse reactions often occur and the rapidly-replicating HTV virus has proven adroit at creating mutant drug-resistant variants of wild type protease and reverse transcriptase. There remains a need for safer drugs with activity against wild type and commonly occurring resistant strains of HTV. Benzyl-pyridazinone compounds have been extensively investigated as thyroxin analogs which can decrease plasma cholesterol without stimulating cardiac activity (A. H. Underwood et al A thyromimetic- that decreases plasma cholesterol -without increasing cardiovascular' activity Nature 1986 324(6096):425-429; P. D. Leeson et al Selective thyromimetics. Cardiac-sparing thyroid hormone analogs containing 3'-ajylmethyl substituents 1 Med Chem 1989 32(2):320-326; P. D. Leeson et al EP 0188351). W09624343 (D. J. Dunnington) discloses oxo-pyridazinylmethyl substituted tyrosines are selective antagonists for the haematopoietic phosphatase' SH2 domain which may render them useful to increase erythropoiesis and haematopoiesis. WO 9702023 (D. J. Dunnington) and WO9702024 (D. J. Dunnington) further disclose these compounds are specific inhibitors of the human Stat 6 SH2 domain and may be useful for treating asthma, allergic rhinitis and anemia. WO2001085670 (H. Shiohara et al) discloses related malonamide derivatives useful for treating circulatory diseases. EP 810218 (D. A. Allen et al) discloses benzoyl substituted benzyl-pyridazinone compounds which are cyclooxygenase inhibitors and potential antiinflammatory or analgesic compounds. None of the references teaches therapy for HIV infections or inhibition of HIV reverse transcriptase. The present invention relates to a compounds according to formula I, methods for treating diseases mediated by human immunodeficieny virus by administration of a compound according to formula I, pharmaceutical compositions for treating diseases mediated by human immunodeficieny virus containing a compound according to formula I, and processes to prepare a compound according to formula I In another embodiment of the invention there is provided a compound according to formula I wherein X1 is OR5 or SR5; R3 is hydrogen or fluoro; R4 is selected from the group consisting of' hydrogen, chloro, fluoro and methyl; R is optionally substituted phenyl; and, R , R , R , X and n are as defined hereinabove. la another embodiment of the present invention there is provided a compound according to formula I wherein X1 is OR5 or SR5; R1 is methyl, ethyl, trifluoromethyl or halogen; R3 is hydrogen or fluoro; R4 is selected from the group consisting of hydrogen, chloro, fluoro and methyl; R5 is optionally substituted phenyl; and, R2, R7, X2 and n are as defined hereinabove: In another embodiment of the present invention there is provided a compound according to formula I wherein X1 is OR5 or SR5;' R1 is methyl, ethyl, trifluoromethyl or halogen; R3 is hydrogen or fluoro; R4 is. selected from the group consisting of hydrogen, chloro, fluoro and methyl; R5 is monosubstituted phenyl; and, R2, R7, X2 and n are as defined hereinabove. In another embodiment of the present invention there is provided a compound according to formula I wherein X1 is OR5 or SR5; R1 is methyl, ethyl, trifluoromethyl or halogen; R3 is hydrogen or fluoro; R4 is selected from the group consisting of hydrogen, chloro, fluoro and methyl; R is 2,5-disubstituted phenyl; and, R , R, X and n are as defined hereinabove. In another embodiment of the present invention there is provided a compound according to formula I wherein X1 is OR5 or SR5; R1 is methyl, ethyl, trifluoromethyl or halogen; R3 is hydrogen or fluoro; R4 is selected from the group consisting of hydrogen, chloro, fluoro and methyl; R is 3,5-disubstituted phenyl; and, R , R, X and n are as defined hereinabove. In another embodiment of the present invention there is provided a compound according to fonnula I wherein X1 is OR5 or SR5; R1 is methyl, ethyl, trifluoromethyl or halogen; R3 is hydrogen or fluoro; R4 is selected from the group consisting of hydrogen, chloro, fluoro and methyl, R5 is 2,4-disubstituted phenyl; and R2, R7, X2 and n are as defined hereinabove. In another embodiment of the present invention there is provided a compound according to formula I wherein X1 is OR5 or SR5; R1 is methyl, ethyl, trifluoromethyl or halogen; R3 is hydrogen or fluoro; R4 is selected from the group consisting of hydrogen, chloro, fluoro and methyl; R5 is 2,6-disubstituted phenyl; and, R2, R7, X2 and n are as defined hereinabove. In another embodiment of the present invention there is provided a compound according to formula I wherein X1 is OR5 or SR5; R1 and R2 are independently hydrogen, Ci.6 alkyl, C1-6 haloalkyl, C3.8 cycloalkyl, C1-6 alkoxy, C1-6 alkylthio, Ci-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 haloalkoxy, C1-6 haloalkylthio, halogen, amino, alkylamino, dialkylamino, aminoacyl, nitro and cyano; R is hydrogen or fluoro; and, R , R , R , X and n are as defined hereinabove. In anotlier embodiment of the present invention there is provided a compound according to fonnula I wherein X1 is OR5; R1 is methyl, ethyl, trifluoromethyl or halogen; R2 and R4 are independently hydrogen, fluoro, chloro, methyl or ethyl; R is hydrogen or fluoro; R is optionally substituted phenyl; n is 0 to 2; and R7 and X2 are as defined hereinabove. hi another embodiment of the present invention there is provided a compound according to formula I wherein X1 is OR5; R1 is methyl, ethyl, trifluoromethyl or halogen; R2 and R4 are independently hydrogen, fluoro, chloro, methyl or ethyl; R3 is hydrogen or fluoro; R5 is monosubstituted phenyl; n is 0 to 2; and R7 and X2 are as defined hereinabove. In another embodiment of the present invention there is provided a compound according to formula I wherein X1 is OR5; R1 is methyl, ethyl, trifluoromethyl or halogen; R2 and R4 are independently hydrogen, fluoro, chloro, methyl or ethyl; R3 is hydrogen or fluoro; R5 is monosubstituted phenyl and the substituent is selected from the group consisting of halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio and C1-6 haloalkoxy; and, R4, R7, X2 and n are as defined hereinabove. In another embodiment of the present invention there is provided a compound according to formula I wherein X1 is OR5; R1 is methyl, ethyl, trifluoromethyl or halogen; R2 and R4 are independently hydrogen, fluoro, chloro, methyl or ethyl; R3 is hydrogen or fluoro; R5 is 2,5-disubstituted phenyl; n is 0 to 2; and R7 and X2 are as defined hereinabove. In another embodiment of the present invention there is provided a compound according to formula I wherein X1 is OR5; R1 is methyl, ethyl, trifluoromethyl or halogen; R2 and R4 are independently hydrogen, fluoro, chloro, methyl or ethyl; R is hydrogen or fluoro; R is 2,5-disubstitnted phenyl and the substituents are independently selected-from the group consisting of halogen, cyano, Q_6 alkyl, C1-6 haloalkyl, C1-e alkoxy, C^ alkylthio and Cx.6 haloalkoxj'; and, R4, R;, X" and n are as defined hereinabove. In another embodiment of the present invention there is provided a compound according to formula I wherein X1 is OR5; R1 is methyl, ethyl, trifluorometliyl or halogen; R2 and R4 are independently hydrogen, fluoro, chloro, methyl or ethyl; R is hydrogen or fluoro; R is 3,5-disubstituted phenyl; n is 0 to 2; and R7 and X2 are as defined hereinabove. In another embodiment of the present invention there is provided a compound according to formula I wherein X1 is OR5; R1 is methyl, ethyl, trifluoromethyl or halogen; R2 and R4 are independently hydrogen, fluoro, chloro, methyl or ethyl;' R is hydrogen or fluoro; R is 3,5-iisubstituted phenyl and the substituents are independently selected from the group consisting of mlogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio and C1-6 haloalkoxy; and, R4, 3.', X' and n are as defined hereinabove, h another embodiment of the present invention there is provided a compound according to formula I wherein X1 is OR5; R1 is methyl, ethyl, trifluoromethyl or halogen; R2 and' R4 are ndependently hydrogen, fluoro, chloro, methyl or ethyl; R is hydrogen or fluoro; R is 2,4-lisubstituted phenyl; n is 0 to 2; and R and X are as defined hereinabove. In another embodiment of the present invention there is provided .a compound according to formula I wherein X1 is OR5; R1 is methyl, ethyl, trifluoromethyl or halogen; R2 and R4 are independently hydrogen, fluoro, chloro, methyl or ethyl; R3 is hydrogen or fluoro; R5 is 2,4-disubstituted phenyl and the substituents are independently selected from the group consisting of halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio and C1-6 haloalkoxy; and, R4, R\ X* and n are as defined hereinabove. IQ another embodiment of the present invention there is provided a compound according to formula I wherein X1 is OR5; R1 is methyl, ethyl, trifluoromethyl or halogen; R2 and R4 are independently hydrogen, fluoro, chloro, methyl or ethyl; R is hydrogen or fluoro; R is 2,6-disubstituted phenyl; n is 0 to 2; and R7 and X2 are as defined hereinabove. In another embodiment of the present invention there is provided a compound according to formula I wherein X1 is OR5; R3 is methyl, ethyl, trifluoromethyl or halogen; R2 and R4 are independently hydrogen, fluoro, chloro, methyl or ethyl; R is hydrogen or fluoro; R is 2,6-disubstituted phenyl and the substituents are independently selected from the group consisting of halogen, cyano, Ci.6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio and C1-6 haloalkoxy; and, R4, R', T and n are as defined hereinabove. In another embodiment of the present invention there is provided a compound according to formula I wherein X1 is OR5 or SR5; R3 and R4 are independently hydrogen, chloro, fluoro or methyl; R5 is optionally substituted pyridinyl, pyrimidinyl, pyrazinyl and pyrrolyl; and, X2, R1, Rz, RJ, R' and n are as defined hereinabove. hi another embodiment of the present invention there is provided a compound according to formula I wherein R1 and R2 along with the carbon atoms to which they are attached form a phenyl, dihydropyran, dihydrofuran or furan ring; and, X,X,R,R,R,R,R and n are as defined hereinabove. In another embodiment of the present invention there is provided a compound according to formula I wherein X1 is OR5 or SR5; R1 and R2 along with the carbon atoms to which they are attached form a phenyl, dihydrop3Tan, dihydrofuran or furan ring; R3 is hydrogen, R4 is hydrogen or fluoro; R is optionally substituted phenyl; and, X", R and n are as defined hereinabove. In another embodiment of the present invention there is provided a method for treating an EUV infection, or preventing an HIV infection, or treating AIDS or ARC, comprising administering to a host in need thereof a therapeutically effective amount of a compound of formula I. wherein, X1, X2, R1, R2. R3, R4, R5, R6, R7 and n are as defined hereinabove, and hydrates, solvates, clathrates and acid addition salts thereof. In another embodiment of the present invention there is provided a method for treating an HTV infection, or preventing an HIV infection, or treating AIDS or ARC, comprising administering to a host in need thereof a therapeutically effective amount of a compound of formula I wherein: X1 is OR ; R is methyl, ethyl, trifluoromethyl or halogen; R and R are independently hydrogen, fluoro, chloro, methyl or ethyl; R3 is hydrogen or fluoro; R5 is optionally substituted phenyl; and, X2, R' and n are as defined hereinabove. In another embodiment of the present invention there is provided a method for treating an HTV infection, or preventing an HIV infection, or treating AIDS or ARC, comprising coadministering to a host in need thereof a therapeutically effective amount of a compound of formula I wherein, X1, X2, R1, R2, R3, R4, R5, R6, R7 and n are as defined hereinabove, and hydrates, solvates, clathrates and acid addition salts thereof, and at least one compound selected from the group consisting of HIV protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, CCR5 inhibitors and viral fusion inhibitors. In another embodiment of the present invention there is provided a method for treating an HTV infection, or preventing an HTV infection, or treating AIDS or ARC, comprising coadministering to a host in need thereof a therapeutically effective amount of a compound of formula I wherein, X1, X2, R1, R2, R3, R4, R5, R6, R7 and n are as defined hereinabove, and hydrates, solvates, clathrates and acid addition salts thereof, and at least one compound selected . from the group consisting of zidovudine, lamivudine, didanosine, zalcitabine, stavudine, rescriptor, sustiva, viramune efavirenz, nevirapine and delavirdine and/or the group consisting of saquinavir, ritonavir, nelfinavir, indinavir, amprenavir and lopinavir. In another embodiment of the present invention there is provided a method for inhibiting a retrovirus reverse transcriptase comprising administering a compound of formula I wherein, X , X2, R1, R\ R3, R4, R5, R6, R7 and n are as defined hereinabove, and hj'drates, solvates, clathrates and acid addition salts thereof. In another embodiment of the present invention there is provided a method for inhibiting a retrovirus reverse transcriptase having at least one mutation with respect to wild type virus . comprising administering to a host in need thereof, a therapeutically effective amount of a compound of formula I wherein, X1, X2, R1, R2, R3, R4, R5, R6, R7 and n are as defined hereinabove; and, hydrates, solvates, clathrates; and, acid addition salts thereof. In another embodiment of the present invention there is provided a method treating an HIV infection, or preventing an HIV infection, or treating AIDS or ARC, wherein the host is infected with a strain of HTV which exhibits reduced susceptibility to efavirenz, nevirapine or delavirdine comprising administering to a host in need thereof a therapeutically effective amount of a compound of formula I wherein, X1, X2, R1, R2, R3, R45 R5, R6, R7 and n are as defined hereinabove; and, hydrates, solvates, clathrates and acid addition salts thereof. In another embodiment of the present invention there is provided a pharmaceutical composition comprising a therapeutically effective quantity of a compound of formula I wherein, wherein, X1, X2, R1, R2, R3, R\ R5, R6, R7 and n are as defined hereinabove, and hydrates, solvates, clathrates and acid addition salts thereof with the proviso that if X2 is ortfzo-phenylene, R5 can not unsubstituted phenyl, in admixture with at least one pharmaceutically acceptable carrier or diluent sufficient upon administration in a single or multiple dose regimen for treating diseases mediated by human immunodeficieny virus inhibit HTV. In another embodiment of the present invention there is provided a process for preparing a heterocycle of formula I, wherein X1 is OR5 or OCH2R5 and R5 is an optionally substituted aryl, or heteroaryl moiety; X is O, S, or NR and R -R and R are as defined hereinabove, which process comprises the steps of: (i)(a) coupling an aryl compound of formula Ila wherein X4 is hydrogen, alkoxycarbonyl or CN, with (A) an arylboronic acid or an aryl halide, or (B) an aralkyl halide to produce an ether of formula lib; and, if X4 is hydrogen; {b) (A) brominating the methyl"group withN-bromosuccinimide and (B) displacing the bromide (X4 = Br) with sodium cyanide to produce the corresponding nitrile (X4 = CN), and, optionally, (C) hydrolyzing the nitrile to an alkoxycarbonyl (X4 = C02alkyl) or an O-alkyl imidate hydrochloride (X4 = C(=NH2+)OR CI); {ii)(A) treating a compound of formula Hb (X4 = alkoxycarbonyl) sequentially with hydrazine hj'drate to form the acyl hydrazide (lib; X4 = CONHNH2) and, (a) phosgene, or a phosgene equivalent, to produce an oxadiazolone of formula I wherein X2 is O; or, (b) sequentially with an alkyl isocyanate (R7NCO) to produce a diacylhydrazone (Hb; X4 = C(=0)NHNHC(=0)NHR7) and with base to produce the triazolone I (X2 ~ NR7); or, (B) treating a nitrile of formula lib (X4 ~ CN) sequentially (a) with acid and alcohol to produce the O-alkyl imidate hydrochloride (X4 — C(=NH2+)OR CI), (b) with O-methylthiocarbazine (NH2NHC(=S)OMe)to produce lib wherein. X is a methoxythiadiazoline according to formula (III), and (c) with aqueous acid to hydrolyze said methoxythiadiazoline and produce a compound of formula I wherein X2 is S. In another embodiment of the present invention there is provided a process as described above for preparing a compound of formula I wherein X1 is OR5, R5 is optionally substituted aryl or heteroaiyl and the ether is prepared by coupling an arylboronic acid and a phenol IIa in the presence of a Cu(II) salt. In another embodiment of the present invention there is provided a process as described above for preparing a compound of formula I wherein X1 is OR5, R5 is optionalty substituted aryl or heteroaiyl and the ether is prepared by coupling an aryl halide and a phenol Da in the presence of a Cu(T) salt. In another embodiment of the present invention there is provided a process as described above for preparing a compound of formula I wherein X1 is OCH2R5 orOR5, R5 is an optionally ' substituted aryl or heteroaiyl moiety and the ether is prepared by coupling an aryl halide or heteroaiyl halide further substituted by elecctron withdrawing groups, or an optionally substituted aralkyl halide and a phenol Ha, in the presence of a base. In another embodiment of the present invention there is provided a process as described above for preparing a compound of formula I wherein X1 is -OCH2R5, R5 is optionally substituted aryl and the ether is formed by coupling an alcohol R5CH2OH and Ha said coupling catalyzed by an a dialkylazodicarboxylate and triaryl ortrialkylphosphine. In another embodiment of the present invention there is provided a process as described above for preparing an oxadiazolone compound of formula I by treating a compound of formula -l Ib wherein X1 is OR5 or -OCH2R5, R5 is optionally substituted aryl or heteroaryl, X4 is C(=0)NHNH2 with phosgene. la another embodiment of the present invention there is provided a process as described above for preparing an oxadiazolone compound of formula I by treating a compound of formula Hb wherein X1 is OR5 or -OCH2R5, R5 is optionally substituted aryl or heteroaryl, X4 is C(=O)NHNH2 with carbonyl diimidazole. la another embodiment of the present invention there is provided a process as described above for preparing a triazolone compound of formula I by treating a compound of formula lib wherein X1 is OR5 or -OCH2R5, R5 is optionally substituted aryl, X4 is C(=0)TSIHNH2 sequentially with methyl isocyanate or ethyl isocyanate and methanolic sodium hydroxide. In another embodiment of the present invention there is provided a process as described above for preparing a thiadiazolone compound of formula I by treating a compound of formula lib wherein X1 is OR5 or -OCH2R5> R5 is optionally substituted aryl, X4 is C(=NH24) Cf sequentially with hydrazinecarbothioic acid O-methyl ester and aqueous acid. The phrase "a" or "an" entity as used herein refers to one or more of that entity; for example, a compound refers to one or more compounds or at least one compound. As such, the terms "a" (or "an"), "one or more", and "at least one" can be used interchangeably herein. The phrase "as defined hereinabove" refers to the first definition provided in the Summary of the Invention. The term "C1-6 alkyl" as used herein denotes an unbranched or branched chain, saturated, monovalent hydrocarbon residue containing 1 to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, lower alkyl groups include methyl, ethyl, propyl, z-propyl, 72-butyl, /-butyl, z'-butyl or pentyl, isopentyl, neopentyl, hexyl. The term "haloalkyl" as used herein denotes an unbranched or branched chain alkyl group as defined above wherein 1,2,3 or more Irydrogen atoms are substituted by a halogen. Examples are 1-fluoromethyl, 1-chloromethyl, 1-bromomethyl, l-iodomethjd, trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl, 1-fluoroethyl, 1-chloroethyl, 1-bromoethyl, 1-iodoethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2-dichloroethyl, 3-bromopropyl or 2,2,2-trifIuoroethyl. The term "cycloalkyl" as used herein denotes a saturated carbocyclic ring containing 3 to 8 carbon atoms, i.e. c3'clopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyploheptyl or cyclooctyL The term "aryl" as used herein means a monocyclic or polycyclic-aromatic group comprising carbon and hydrogen atoms. Examples of suitable aryl groups include, but are not limited to, phenyl, tolyl, indenyl, and 1- or 2-naphthyI, as well as benzo-fosed carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl. An aryl group can be unsubstituted or substituted with one or more suitable substituents which substituents include C1-6alkyl, C1_6 haloalkyl, C3_8 cycloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1-6 haloalkoxy, C`-6 haloalkylthio, halogen, amino, alkylamino, dialkylamino, aminoacyl, acyl, alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl, N5N-dialkylcarbamoyl, nitro and cyano. A "heteroaryl group" or "heteroaromatic"as used herein means a monocyclic- or polycyclic aromatic ring comprising 15 carbon atoms, hydrogen atoms, and one or more heteroatoms, preferably, 1 to 3 heteroatoms, independently selected from nitrogen, oxygen, and sulfur. As well known to those skilled in the art, heteroaryl rings have less aromatic character than their all-carbon counter parts. Thus, for the purposes of the invention, a heteroaryl group need only have some degree of aromatic character. Illustrative examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3,)- and (l,2,4)-tria2;olyl, pyrazinyl, pyrimidinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazotyl, thienyl, isoxazolyl, indolyl, quinolinyl, and oxazolyL A heteroaryl group can be unsubstituted or substituted with one or more suitable substituents selected from hydroxy, oxb, cyano, alkyl, alkoxy, haloalkoxy, alkylthio, halo, haloalkyl, nitro, alkoxycarbonyl, amino, alkylamino, dialkylamino, aminoacyl, alkylsulfonyl, arylsulfinyl, alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, acyl unless otherwise indicated. A nitrogen atom in the heteroaryl ring can optionally be an N-oxide. The term "heterocyclyl" means the monovalent saturated cyclic radical, consisting of one or more rings, preferably one to two rings, of three to eight atoms per ring, incorporating one or more ring heteroatoms (chosen from N,0 or S(O)0-2)5 and which can optionally be substituted with one or more, preferably one to three substituents selected from hydroxy, oxo, cyano, alkyl, alkoxy, haloalkoxy, alkylthio, halo, haloalkyl, nitro. alkoxycarbon}4, amino, alkylamino, dialkylamino, aminoacyl. alkylsulfonyl, arylsulfinyl, alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, acyl unless otherwise indicated. Examples of heterocyclic radicals include, but are not limited to, furanyl, tetrahydropyranyl, -tetrahydrothiophenyl and the like.. The term "alkoxy group" as used herein means an -O-alkyl group, wherein alkyl is as defined above such as methoxy, ethoxy, n-propyloxy, z-propyloxy, w-butyloxy, /-butyloxy, f-butyloxy, pentyloxy, hexyloxy, heptyloxy including their isomers. The term "alkylthio group" as used herein means an -S-alkyl group, wherein alkyl is as defined above such as meththio, eththio, ?z-propylthio3 z-propylthio, w-butylthio, z-butylthio, £-butylthio, pentylthio including their isomers. The term "haloalkoxy group" as used herein means an -O-haloalkyl group, wherein haloalkyl is as defined above. Examples of haloalkoxy groups include, but are not limited to, 2,2,2-trifluoroethoxy, difluoromethoxy and 1,1,1,3,3,3-hexafluoro-iso-propoxy. The term "haloalkthio group" as used herein means an -S-haloalkyl group, wherein haloalkyl is as defined above. An example of haloalkthio groups includes, but are not limited to, 2,2,2-trifluoroeththanthiol. The term "aryloxy group" as used herein means an O-aryl group wherein aryl is as defined above. An aryloxy group can be unsubstituted or substituted with, one or more suitable substituents. Preferably, the aryl ring of an aryloxy group is a monocyclic ring, wherein the ring comprises 6 carbon atoms, referred to herein as n(C6) aiyloxy". The term "optionally substituted aryloxy" means the aryl or group may be substituted with one to three groups selected from the group consisting of C1-6 alkyl, Cue haloalkyl, C3_8 cycloalkyl, C^ alkoxy, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, Ci-6 haloalkoxy, Ci.6 haloalkylthio, halogen, amino, alkylamino, dialkylamino, aminoacyl, acjd, alkoxycarbonyl, carbamoyl, N-alkylcarbamoyI, N,N-dialkylcarbamoyl, nitro and cyano. The term "heteroaryloxy group" as used herein means an O-heteroaryl group, wherein heteroaryl is as defined above. The heteroaryl ring of a heteroaryloxy group can be unsubstituted or substituted with one or more suitable substituents. Examples of heteroaryl groups -include, but are not limited to3 2-pyridyloxy, 3-pyrrolyloxy, 3-pyrazolyloxy, 2-imidazolyloxy, 3-pyrazinydoxy, and 4-pyrimidyloxy. The term "acid" or "alkylcarbonyl" as used herein denotes a radical of formula C(=O)R wherein R is hydrogen, unbranched or branched alkyl containing 1 to 6 carbon atoms or a phenyl group. The term "alkoxycarbonyl" as used herein' denotes a radical of formula C(K))OR wherein R is,. unbranched or branched alkyl as described above. The term "acylamino" as used herein denotes a radical of formula -NH-(acyl) where acyl is as. defined herein. The term "arylboronic acid" as used herein denotes a radical of formula ArB(OH)2 wherein Ar is an optionally substituted aiyl group as described above. The term "alkylene" as used herein denotes a divalent linear or branched saturated hydrocarbon radical, having from one to six carbons inclusive, unless otherwise indicated. Examples of alkylene radicals include, but are not limited to, methylene, ethylene, propjdene, 2-methyl-propylene, butylene, 2-ethyIbutylene. The term "arylalkyl" or "aralkyl" as used herein denotes the radical R'R"-, wherein R' is an aryl radical as defined herein, and R" is an alkylene radical as defined herein and the arylalkyl group is attached through the alkylene radical. Examples of arylalkyl radicals include, but are not limited to, benzyl, phenylethyl, 3-phenylpropyl. The term "halogen" as used herein means fluorine, chlorine, bromine, or iodine. Correspondingly, the meaning of the term "halo" encompasses fluoro, chloro, bromo, and iodo. The term "hydrohalic acid" refers to an acid comprised of hydrogen and a halogen. The term "alkylsulfmyl" as used herein means the radical -S(0)R', wherein Rf is alkyl as defined herein. Examples of alkylaminosulfonyl include, but are not limited to methylsulfinyl and iso-propylsulfinyl. The term "alkylsulfonyl" as used herein means the radical -S(O)2R'3 wherein R' is alkyl as defined herein. Examples of alkylaminosulfonyl include, but are not limited to methylsulfonyl and zso-propylsulfonyl. The terms "amino", "alkylamino" and "dialkylamino" as used herein refer to -NH2s -NHR and -NR2 respectively and R is alkyl as defined above. The two alkyl groups attached to a nitrogen in a dialkyl moiety can be the same or different. The terms "aminoalkyl", "alkylaminoalkyl" and "dialkylaminoalkyl" as used herein refer to NH2(CH2)n-, RHN(CH2)n-, and R2N(CH2)n-respectively wherein n is 1 to 6 and R is alkyl as defined above The prefix "carbamoyl" as used herein means the radical -CONH2. The prefix 1TN-alkylcabamoyl" and "N,N-dialkylcarbamoyl" means a radical CONHR' or CONR'R" respectively wherein the RT and R" groups are independently alkyl as defined herein. The term "conjugate base" as used herein means the chemical species produced when an acid (including here a carbon acid) gives up its proton. Compounds of formula I exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertable species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium and attempts to isolate an individual tautomers usually produce a mixture whose chemical and physical properties are consistent with a mixture of compounds. The position of the equilibrium is dependent on chemical features within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates while; in phenols, the enol form predominates. Common prototropic tautomers include keto/enol (-C(=o)-CH- -C(-OH)=CH-), amide/imidic acid (-C(=O)-NH-1; -C(-OH)=N-) and amidine (-C(=NR)-NH- * -C(-NHR)=N-) tautomers. The latter two are particularly common'in heteroaryl and heterocyclic rings and the present invention encompasses all tautomeric forms of the compounds. Compounds of formula I which are basic can form pharmaceutically acceptable acid addition salts with inorganic acids such as hydrohalic acids (e.g. hydrochloric acid and hydrobromic acid), sulphuric acid, nitric acid and phosphoric acid, and the like, and with organic acids (e.g. with acetic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malic acid, salicylic acid, citric acid, methanesulphonic acid and p-toluenesulfonic acid, and the like). The term "solvate" as used herein means a compound of the invention or a salt, thereof, that further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents are volatile, non-toxic, and/or acceptable for administration to humans in trace amounts. The term "hydrate" as used herein means a compound of the invention or a salt thereof, that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces. The term "clathrate" as used herein means a compound of the invention or a salt thereof in the form of a crystal lattice that contains spaces (e. g., channels) that have a guest molecule (e. g.. a solvent or water) trapped within. The term "wild type" as used herein refers to the HIV virus strain which possesses the dominant genotype which naturally occurs in the normal population which has not been exposed to reverse transcriptase inhibitors. The term "wild type reverse transcriptase" used herein has refers to the reverse transcriptase expressed by the wild type strain which has been sequenced and deposited in the SwissProt database with an accession number P03366. The term "reduced susceptibility" as used herein refers to about a 10 fold, or greater, change in sensitivity of a particular viral isolate compared to the sensitivity exhibited by the wild type virus in the same experimental system ABBREVIATIONS The following abbreviations are used throughout this application and they have the meaning listed below: AIBN azo-bis-isobutytylnitrile atm atmospheres BBN or 9-BBN 9-borabicyclo[33.1]nonane Boc te7-£-butoxycarbonyl BOC2O Di-tert-butyl pyrocarbonate or boc anhydride Bn benzyl cbz or Z benzyloxycarbonyl DABCO diazabicyclooctane DAST diethylaminosulfur trifluoride DCE 1,2-dichloroethane DCM dichloromethane DEAD diethyl azodicarboxylate DIAD di-zso-propylazodicarboxylate DIBAL-H di-z^o-butylaluminumhydride DMA N,N-dimethyl acetamide DMAP 4~N?N-dimethylaminopyridine DMF N?N-dimethylformamide dppf l3r-Bis(diphenylphosphino)ferrocene EDCI l-(3 -dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride EtOAc ethyl acetate Et20 diethyl ether Et ethyl EtOH ethanol LAH lithium aluminum hydride LiHMDS _ lithium hexamethyl disilazane h hour(s) HO Ac . acetic acid r-Pr iso-propyl m minute(s) Me mzthyl MeCN acetonitrile MeOH methanol MTBE methyl Mwtyl ether NB S N-bromosuccinimide NMP N-methylpyrrolidone PCC pyridinium chlorochromate PDC pyridinium dichromate psi pounds per square inch pyr P3Tidine rt or RT room temperature TEA or Et3N triethylamine Tf trifiate CF3S02- TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography TMHD 2,256,6-tetramethylheptane-2,6-dione TsOH j?-toluenesulfonic acid EXAMPLES OF COMPOUNDS Examples of representative compounds within the scope of the invention are provided in the following tables. These examples and preparations are provided to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof. Table 1 exemplifies aryloxy derivatives. Table 2 exemplifies atylthio substituted compounds. Table 3 exemplifies benzyl substituted compounds. Table 4 exemplifies alkoxy and aralkoxy substituted compounds. Table 5 exemplifies compounds with aryloxy substituted heteroaryl compounds. Table 6 exemplifies benzoyl substituted compounds. In general, the nomenclature used in this Application is based on AUTONOM™ v.4.05 a Beilstein Institute computerized system for the generation of IUPAC systematic nomenclature. Table 1 contains representative examples of [3-phenoxyben2yl]pyrida2mones PREPARATION OF COMPOUNDS OF THE INVENTION Compounds of the present invention can be made by a variety of methods depicted in the illustrative synthetic reaction schemes shown and described below. The starting materials and reagents used in preparing these compounds generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser andFieser 's Reagents for Organic Sjmthesis; Wiley & Sons: New York, Volumes 1-21; R. C. LaRock, Comprehensive Organic Transformations, 2nd edition Wiley-VCH, New York 1999; Comprehensive Organic Synthesis, B. Trost and I. Fleming (Eds.) vol. 1-9 Pergamon, Oxford, 1991; Comprehensive Heterocyclic Chemistiyy A. R. Katritzky and C. W. Rees (Eds) Pergamon, Oxford 1984, vol. 1-9; Comprehensive Heterocyclic Chemistry II9 A. R. Katritzky and C. W. Rees (Eds) Pergamon, Oxford 1996, vol. 1-11; and Organic Reactions, Wiley & Sons: New York, 1991, Volumes 1-40. The following synthetic reaction schemes and examples axe merely illustrative of some methods by which the compounds of the present invention can be synthesized, and various modifications to these synthetic reaction schemes can be made and will be suggested to one skilled in the art having referred to the disclosure contained in this Application. The starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if desired using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized using conventional means, including physical constants and spectral data. Unless specified to the contrary, the reactions described herein preferably are conducted under an inert atmosphere at atmospheric pressure at a reaction temperature range of from about -78 °C to about 150 °C, more preferably from about 0°C to about 125 °C, and most preferably and conveniently at about room (or ambient) temperature, e.g., about 20 °C. Moreover, the reaction conditions are exemplary and alternative conditions are well known. The reaction sequences in the following examples are not meant to limit the scope of the invention as set forth in the claims. The heterocyclic compounds of the present invention are prepared by a two-stage process (Scheme 1) comprising construction of an appropriately substituted aryl ring 2 and subsequently introducing the heterocyclic ring 3. Although stages can be accomplished in any order, the heterocyclic ring is generally introduced after the modifications of the aryl ring are completed. Substituted alkyl m-hydroxyphenylacetate la or ?n-hydroxyphenylacetonitrile lb derivatives are convenient starting materials. They are often commercially available or readily prepared from commercially available precursors. Alternatively the aryl ring may be substituted with a methyl lc or carboxylic acid ester Id substituent which is subsequently converted to lb (for example, Preparation of Phenvlacetic Acid and Phenvlacetonitile Precursors f Scheme 1) Ethyl 3-hydroxy-4-methylphenylacetate (5a) was prepared from ethyl 3-methoxy-4-hydroxy-phenylacetate as shown in Scheme 2. The phenol was converted to the triflate ester 4b which was subjected to displacement with Me2Zn3 DH3AL-H and PdCl2(dppf) (E.-i. Negishi in Metal-catalyzed Cross-Coupling Reactions, F. Diederich and P. J. Stang (eds.), Wiley-VCH, Mannheim 1998, chap.l; E. Erdik, Tetrahedron 1992 48:9577-9648) to afford the 4c. Boron tribromide demethylation afforded 5a. Ethyl 3-hydroxy-4-ethylphenylacetate 5b was prepared by Friedel-Crafts acylation of 4d which afforded ethyl 4-acetyl-3-methoxyphenylacetate (4e). Reduction of the ketone with triethylsilane and TEA produced the corresponding 4-ethyl substituted derivative 4f which was demethylated with BBr3 to afford 5b. Ethyl 3-hydroxy~4-zso-propylphenylacetate (5c) was prepared by Wittig olefination of 4e and subsequent catalytic hydrogenation of the 2-propenyl substituent to yield 4h. Demethylation with boron tribromide produced 5c. Ethyl 3,4-dimethyl-54iydroxyphenylacetate (8) was prepared by formylation of 6a and esterificatioa of the resulting carboxylic acid 6b to produce ethyl 3-fonnyl-4-hydroxy-5~ methoxyphenyl acetate (7a). Reduction of the aldehyde and hydrogenolysis the resulting benzyl alcohol afforded 7b. The second methyl substituent was introduced by sequential treatment of 7b with triflic anhydride which yielded 7c and displacement with Me2Zn, PdCl2(dppf) and DIBAL-H [supra) to produce 7c. Boron tribromide mediated demethylation afforded 8. (Scheme 3) Ethyl 4-chloro-3-hydroxyphenyl acetate (10) was prepared from 4-chIoro-3-methox3^toluene by sequential free radical bromination (9b), nucleophilic displacement of the bromine atom with cyanide (9c) and a two-step hydrolysis of the nitrile to the amidine hydrochloride 9d and subsequently to the ethyl ester 9e. Boron tribromide mediated demethylation as described previously afforded 10. (Scheme 4) 6-Methyl derivatives were prepared from 3-hydroxy-2-metbylbenzoic acid (11) which was chlorinated (NaOCl/NaOH) and esterified to afford 13. Cupric acetate mediated coupling {infra) of benzeneboronic acid provided the diaiyl ether 14. The nitrile was introduced by sequential reduction, mesylation and cyanide displacement to afford 17. The mesylate underwent an in situ displacement by chloride during the mesylation reaction. * SCHEME 5 6- fluoro- and chloro- derivatives were available from 6-cliloro-2-fluoro-3-methylphenol (IS) and 3-bromo-2?4-dichlorotoluene (19), respectively (Scheme 6). The base-catafyzed reaction of 18 and j?-fluoro-nitrobenzene yielded daiiyl ether 20. Conversion of the nitro substiuent to the corresponding amine followed by "diazotization and reduction produced 4-chloro-2-fluoro-3-phenoxytoluene (22). One skilled in the art will appreciate that the availability of amino-■ substituted aryl groups affords the possibility to replace the amino substiuent with a variety of other substituents utilizing the Sandmeyer reaction. Cupric chloride-mediated coupling (see infra) of 19 afforded the corresponding 2?4-rdicliloro-3-phenoxytoluene (23). Elaboration of the acetonitrile sidechain in 24 and 25 was accomplished by benzylic brominatioaand displacement. Benzofran 31 and dihydrobenzofuran 29 derivatives (Scheme 7) were prepared from dihydrobenzofiiran (26). Acylation with ethyl chloro oxalate produced the a-ketoester 27 which, was reduced to the corresponding phenylacetic acid derivative 28a under Wolff-Kischner conditions. The preparation of 29 by a Wilgerodt reaction also has been reported (J. Dunn et ah J. Med Chem 1986 29:2326). Freidel-Crafts acylation with acetyl chloride afforded the acetyl derivative 28b which was converted to the acetate 28c under Baeyer-Villiger conditions and subsequently hydrolyzed to 29. The corresponding benzofuran analogs were prepared by benzylic bromination and concomitant dehydrohalogention to yield 31. The preparation of diaiyl ethers has been reviewed (J. S. Sawyer, Recent Advances in Diaiyl Ether Synthesis, Tetrahedron 2000 56:5045-5065). The diaiyl ethers required herein were prepared by three different methods (Scheme 8): (i) Cu(OAc)2 catalyzed condensation of substituted benzene boronic acids and phenols (D. A. Evans et aL, Synthesis of Diaiyl Ethers through the Copper-Promoted Aiylation of Phenols with Aiyl Boronic Acids, An Expedient Synthesis of Thyroxine, Tetrahedron Lett, 1998 39:2937-2940 and D. M. T. Chan et al, New N-and O-Atylations with Phenylboronic Acids and Cupric Acetate, Tetrahedron Lett. 1998 39:2933-2936; Scheme 1, conditions (a), (b), (e), (f), (i); (ii) by variations of the Ullmann diaiyl ether synthesis with Cu(I) salts (J.-F. Marcoux et aL, A General Copper-Catalyzed Synthesis of Diaryl Ethers, J. Am. Chem. Soc. 1997 119:10539-540; E. Buck et al, Ullmann Diaiyl Ether Synthesis: Rate Acceleratiortby 2f216,6-tetramethylhepta7ie-3,5-dione, Org. Lett, 2002 4(9): 1623-1626) ; conditions (c), (d) and (h); or by nucleophilic aromatic displacement reactions (Sawyer supra pp 5047-5059; conditions Scheme 1(g) and (j). An alternative process utilizing palladium-catalyzed coupling procedures also has been reported (G. Mann et al, Palladium-Catalyzed Coupling Involving Unactivated Aiyl Halides. Sterically Induced Reductive Elimination to Form the C-OBondin Diaiyl Ethers, J. Am. Chem. Soc, 1999 121:3224-3225). One skilled in the art will appreciate that optimal procedure will vary depending on the nature and position of substituents on the aryl rings. Substituted 7?z-cresol derivatives are also suitable substrates for coupling using these procedures. After introduction of the meta substituent the intermediate can be converted to the corresponding phenylacetonitrile derivative by bromination and cyanide displacement (Scheme 9). coupling of compounds with a fused aryl, heteroaryl or heterocyclic ring to produce diacyl ethers, alkylaryl ethers or arylaralkylethers can be carried out by the same procedures. The preparation of aralkyloxy benzofuranylacetate and aryloxydihydrobenzofuranylacetate derivatives is exemplified in Scheme 10. Aralkoxybenzofurans are prepared by Mitsunobu coupling of the alcohol and the hydroxybenzofuranacetic acid. Axalkyl aryl ethers were prepared using Mitsunobu conditions (Scheme 11; O. Mitsunobu, Synthesis 1981 1-28). Alternatively aralkyl ethers can be prepared via a classical Williamson ether synthesis (J. March, Advanced Organic Chemistry; 4th Edition; Wiley & Sons: New York, 1992;pp. 386-87) or utilizing palladium-catalyzed coupling (M. Palucki et al, Palladium-catalyzed Intermolecidar Carbon-Oxygen Bond Formation; A New Synthesis of Aryl Ethers, J. Am. Chem. Soc. 1997 119:3395-96). Preparation of Diphenvlamirie Intermediates (Scheme 1: X = NR6) Diphenylamine compounds with in the scope of the present invention can be prepared by ' palladium-catalyzed coupling reactions as described by Hartwig (Transition Metal Catalyzed Synthesis of Aryl Amines and Aiyl Ethers from Aryl Halides and Triflates: Scope and Mechanism, Angew. Chent Int Ed, Eng. 1998 37:2046-67) Preparation of Diphenvi Methane Intermediates (Scheme 1: 2: X = CH? or C=Q) Diphen3dmethane compounds of the present invention can be prepared by reduction of the corresponding benzoyl derivatives 42. While reductions are conveniently carried out with triethylsilylhydride and trifluoroacetic acid, a variety of other procedures to effect this transformation are well known within the art. The preparation of the requisite benzoyl derivatives has been described in U. S. Patent No. 5,886,178 (D. A. Allen et al). The synthesis of benzoyl substituted benzofuran derivatives have also been reported in U. S. Patent No. 4,780,480 (J. P. Dunn) and the scientific literature (J. P. Dunn et at Analgetic and Antiinflammatory 7-Aroylbenzofw-an-5>-ylacetic acids and 7-Aroylbenzothiophene-5-ylacetic Acids, J. Med. Chent 1986 29:2326) These references are hereby incorporated by reference in its entirety. Introduction of the Heterocyclic Ring (Scheme 1; 3) The oxadiazolone, thiadiazolone and triazolone compounds of the present invention can be prepared by cyclization of a diacyl hydrazone derivative according to formula V. Without wishing to be limited by a specific mechanism or sequence of reaction steps, the oxadiazolones can be prepared by treating an acylhydrazone IV with the appropriate, acyl derivative and cyclizing the resulting diacyl compound One skilled in the art will appreciate that IV is an ambident micleophile and initial reaction could be at either the carbonyl oxygen or the nitrogen and subsequent ring closure of either produces the same product 2-Oxo-2?3-dilrydro-l,3?4-oxadia2;Qles 49 can be prepared by cyclization of an acyl hydrazide 46b with phosgene (or equivalents such as carbonyl diimidazole, alkyl chloroformates and the like) to directly produce the desired oxadiazole. (A. Hetzheim, 1,3,4 Oaxadiazoles in Meihoden der Organischen Chemie (Houben-Weyl) E. Schaumann (ed), Hetarene IH/Teil 3, Band E8c; Thierne Verlag, Stuttgart; 1994, pp531-536) (Scheme 13) 2-Oxo-2,3-dihydro-1,3,4-thiadiazoles 53 are prepared by condensation of an O-alkyl imidate 51 and methoxythiocarbonyl hydrazide which produce a 2-methoxy-334-thidiazole derivative 52 which was hydrolyzed to the corresponding 2-oxo~2,3-dihydro-l.,3,4~thiadiazoie 53 under acidic conditions (H. Kristinsson et al, Synthesis of Heterocycles. V. l,3,4-Thiazo-2(3H)one, Helv. Chim. Acta 1982 65:2606). Alternatively, cyclization of N-acyl-N'-alkoxycarbonyl hydrazides with Lawesson's reagent can directly produce the thiadiazole (B. P. Rasmussen et ah Bull. Soc. Chim. Fr. 1985 62). Triazolones 48 were prepared by carbamoylation of an acyl hydrazide 46d with ethyl isocyanate to yield an N-acyl-N-carbamoylhydrazide 47 cyclized to the triazolone 48 upon treatment with methanolic potassium hydroxide. DOSAGE AND ADMINISTRATION The compounds of the present invention may be formulated in a wide variety of oral administration dosage forms and carriers. Oral administration can be in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions, sjiups, or suspensions. Compounds of the present invention are efficacious when administered by other routes of administration including continuous (intravenous drip) topical parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include a penetration enhancement agent), buccal, nasal, inhalation and suppository administration, among other routes of administration. The preferred manner of administration is generally oral using a convenient daily dosing regimen which can be adjusted according to the degree of affliction and the patient's response to the active ingredient. A compound or compounds of the present invention, as well as their pharmaceutically useable salts, together with one or more conventional excipients, carriers, or diluents, may be placed into the form of pharmaceutical compositions and unit dosages. The pharmaceutical compositions and unit dosage forms may be comprised of conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daity dosage range to be employed. The pharmaceutical compositions may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use. A typical preparation will contain from about 5% to about 95% active compound or compounds (w/w). The term "preparation" or "dosage form" is intended to include both solid and liquid formulations of the active compound and one skilled in the art will appreciate that an active ingredient can exist in different preparations depending on the target organ or tissue and on the-desired dose and pharmacokinetic parameters. The term "excipient" as used herein refers to a compound that is useful in preparing a pharmaceutical composition, generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipients that are acceptable for veterinary use as well as human pharmaceutical use. The term "excipient" as used herein includes both one and more than one such excipient Solid fonn preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier generally is a finely divided solid which is a mixture with the finely divided active component hi tablets, the active component generally is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. Suitable carriers include but are not limited to magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxyrnefhylcellulose, a low melting wax, cocoa butter, and the like. Solid form preparations may contain, in addition to the active component, colorants, flavors, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. Liquid formulations also are suitable for oral administration include liquid formulation including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions. These include solid -form preparations which are intended to be converted to liquid form preparations shortly before use. Emulsions may be prepared in solutions, for example, in aqueous propylene glycol solutions or may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or S3oithetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents. The compounds of the present invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water. The compounds of the present invention may be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also containing one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include lozenges comprising active agents in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient • in a suitable liquid carrier. The compounds of the present invention may be formulated for administration as suppositories. A low melting wax, such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and to solidify. The compounds of the present invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate. The compounds of the present invention may be formulated for-nasal administration. The solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, with a dropper, pipette or spray. The formulations may be provided in a single or multidose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spraj', this may be achieved for example by means of a metering atomizing spray pump. The compounds of the present invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration. The compound will generally have a small particle size for example of the order of five (5) microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. The active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC), for example, dichlorodifluoromethane, trichlorofliioromethane, or dichlorotetrafluoroethane, or carbon dioxide or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by a metered valve. Alternatively the active ingredients may be provided in a form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP). The powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of e.g., gelatin or blister packs from which the powder may be administered by means of an inhaler. When desired, formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient. For example, the compounds of the present invention can be formulated in transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous when sustained release of the compound is necessary and when patient compliance with a treatment regimen is crucial. Compounds in transdermal delivery systems are frequently attached to an skin-adhesive solid support. The compound of interest can also be combined with a penetration enhancer, e.g., Azone (1-dodecylaza-cycloheptan-2-one). Sustained release delivery systems are inserted subcutaneously into to the subdermal layer by surgery or injection. The subdermal implants encapsulate the compound in a lipid soluble membrane, e.g., silicone rubber, or a biodegradable polymer, e.g., polyactic acid. Suitable formulations along with pharmaceutical carriers, diluents and excipients are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pennsylvania. A skilled formulation scientist may modify the formulations within the teachings of the specification to provide numerous' formulations for a particular route of administration without rendering the compositions of the present invention unstable or compromising their therapeutic activity. The modification of the present compounds to render them more soluble in water or other vehicle, for example, may be easily accomplished by minor modifications (salt formulation, esterification, etc.), which are well within the ordinary skill in the art. It is also well within the ordinary skill of the art to modify the route of administration and dosage regimen of a particular compound in order to manage the pharmacokinetics of the present compounds for maximum beneficial effect in patients. The term "therapeutically effective amount" as used herein means an amount required to reduce symptoms of the disease in an individual. The dose will be adjusted to the individual requirements in each particular case. That dosage can vary within wide limits depending upon numerous factors such as the severity of the disease to be treated, the age and general health condition of the patient, other medicaments with which the patient is being treated, the route and form of administration and the preferences and experience of the medical practitioner involved. For oral administration, a daily dosage of between about 0.01 and about 100 mg/kg body weight per day should be appropriate in monotherapy and/or in combination therapy. A preferred daily dosage is between about 0.1 and about 500 mg/kg body weight, more preferred 0.1 and about 100 mg/kg body weight and most preferred 1.0 and about 10 mg/kg body weight per day. Thus, for administration to a 70 kg person, the dosage range would be about 7 mg to 0.7 g per day. The daily dosage can be administered as a single dosage or in divided dosages, typically between 1 and 5 dosages per day. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect for the individual patient is reached. One of ordinary skill in treating diseases described herein will be able, without undue experimentation and in reliance on personal knowledge, experience and the disclosures of this application, to ascertain a therapeutically effective amount of the compounds of the present invention for a given disease and patient hi embodiments of the invention, the active compound or a salt can be administered in combination with another antiviral agent, such as a nucleoside reverse transcriptase inhibitor, another nonnucleoside reverse transcriptase inhibitor or HIV protease inhibitor. When the active compound or its derivative or salt are administered in combination with another antiviral agent the activity may be increased over the parent compound. When the treatment is combination therapy, such administration may be concurrent or sequential with respect to that of the nucleoside derivatives. "Concurrent administration" as used herein thus includes administration of the agents at the same time or at different times. Administration of two or more' agents at the. same time can be achieved by a single formulation containing two or more active ingredients or by substantially simultaneous administration of two or more dosage forms with a single active agent. It will be understood that references herein to treatment extend to prophylaxis as well as to the treatment of existing conditions, and that the treatment of animals includes the treatment of humans as well as other animals. Furthermore, treatment of a HIV infection, as used herein, also includes treatment or prophylaxis of a disease or a condition associated with or mediated by HTV infection, or the clinical symptoms thereof. The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into "unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. The pharmaceutical compositions in Example 23 are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof. The compounds of formula I may be prepared by various methods known in the art of organic chemistry. The starting materials for the syntheses are either readily available from commercial sources or are known or may themselves be prepared by techniques known in the art. The following examples {infra) are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof. Stepl A solution of 4-Chloro-3-methoxytoluene (9a; 0.5 g; 3.2 mmol), NBS (0.57 g; 3.2 mmol) and benzoyl peroxide (0.031 g; 0.13 mmol) and 32 mL of DCE were heated at reflux for 3 h. The reaction mixture was cooled, diluted with CH2CI2 and washed with water and brine. The organic extract was dried filtered and evaporated to yield the bromomethyl compound 9b which was used without further purification. Step 2 The 28 g (0.166 mmol) of 9b from the previous step, NaCN (28 g; 0.58 mmol; 3.5 equiv.) and 500 mL of 90% aqueous EtOH were stirred at room temperature overnight. The crude residue was partitioned between EtOAc/H20 (359 mL of each), washed with brine, dried, filtered and evaporated. Silica gel chromatography and elution with a gradient (100% hexane 90:10 hexane:EtOAc) yielded 21 g of 9c. step 3 Gaseous HC1 was slowly bubbled into a cooled solution of 4-chloro-3-methoxyacetonitrile (9b) in toluene (lOmL), ether (10 mL) and EtOH (1 mL) for about 10 min. The reaction was stoppered and stored at -30 °C for one week. TLC failed to detect any remaining starting material. The solvent was evaporated and the yellow solid was stirred with Et20, filtered and washed with Et20 and dried in a vacuum oven to yield 0.57 g (90%) of ethyl 4-chloro-3- methoxyphenylmethylimidate (9d). step 4 A solution of 0.57 g of 9d and 10 mL of H2O was heated at 40 °C for 3 h. The reaction was cooled to rt and extracted with EtOAc. The reaction was dried (MgS04), filtered and evaporated and the resulting product 9e was used without further purification. EXAMPLE 2 4-chloro-3-(3-bromo-5-fluorophenoxy)phenyldacetonitrile step 1 A mixture of NBS (1.066 g; 5.99 mmol), benzoyl peroxide (0.069 g; 0.28 mmol) and 54 (1.80 g; 5.70 mmol) and 20 mL of CCl4 were heated to 90 °C for 2.5 h, cooled to it, poured into water (100 mL) and extracted with CH2C12 (2 x 80 mL) and the combined organic extracts dried (Na2SO4), filtered and evaporated to yield 2.25 g of bromomethyl derivative 55 as a colorless oil which was used directly in the subsequent step. step 2 A mixture 2.25 g of 55, NaCN (0.839 g; 17.12 mmol) and 20 mL of 90% aqueous ethanol were stirred at room temperature for 24 h. The volume was reduced to about 25% of the original volume in vacuo. The resulting mixture was diluted with EtOAc (80 mL) and poured into 40 mL saturated NaCl and 40 mL of H20. The organic phase was dried (Na2S04), filtered and evaporated and the crude product purified by silica gel chromatography and eluted with an hexane:EtOAc gradient (10:1 6:1) to yield 1.10 g (56.6%) of 56 as a colorless oil. step 1 To a cooled solution of ethyl 4-hydroxy-3-methoxyphenylacetate (4a; 13.7 g; 65.2 mmol) and 260 mL of CH2C12 under N2 atmosphere was added dropwise triflic anhydride (16 mL; 97.9 -mmol) followed by dropwise addition of pyridine (8.9 mL; 8.8 mmol). The reaction was stirred in an ice-water bath for 3 h. The solution was transferred to a separately funnel and washed with water and brine, dried (Na2SO4), filtered and evaporated, to yield 21 g (90%) of 4b. step 2 To a solution of ethyl 3-methoxy-4-trifluorosulfon3doxyplienylacetate (4b) in 4 mL of THF cooled in an ice-water bath was added slowly a solution of Pd(dppf)Cl2 (0.024 g; 0.029 mmol) and DIBAL-H (6 mL; 0.058 mmol; 1.0M in PhMe)and a small quantity of THF followed by dimethylzinc (0.29 mL; 0.58 mmol; 2.0 M in PhMe). After addition was completed the ice bath was removed and the reaction allowed to warm to it and then heated to reflux for 1 h. The reaction was carefully quenched with a small quantity of water, filtered through a pad of CELITE® and the solids washed thoroughly with EtOAc. The combined organic extracts were washed with water and brine, dried (MgSO44) and the solvent evaporated to afford 0.240 g (85%) of ethyl 3-methoxy-4-methylphenylacetate (4c). step 3 To a solution of 4c (2.2 g; 8.0 mmol) and 250 mL CH2C12 cooled to -78 °C was added dropwise via syringe BBr3 (9.8 mL; 0.104 mol). After 1 h at -78 °C the reaction was stirred for 4 h in an ice-water bath. The reaction mixture was recooled to -78 °C and the reaction quenched aqueous NaHCO3 then wanned to rt and the organic phase washed with water, saturated NaHCO33 and brine. The organic phase was dried (MgSO44) and the solvent evaporated to afford 1.4 g of ethyl 3-hydroxy-4-methylphenylacetate (5a). step 4 To a suspension of 5a (4.8 g; 25 mmol), 2-chlorobenzeneboronic acid (7.8 g; 50 mmol), Cu(OAc)2 (5 g; 27.5 mmol), powdered 4A molecular sieves (15 g) and 250 mL of CH2C12. After 4 days starting material was still evident by tic and an addition 5.0 g of the boronic acid was added. The reaction was stirred for an additional day and the suspension filtered through a pad of CELITE® and silica gel. The solids were washed well with CH2C12. The combined filtrates were washed sequentially with 2N HCl (2 x 25 mL), NaHCO33 (25mL), water and brine. The extracts were dried (MgSO4), filtered and evaporated. The crude product was purified by silica gel chromatogaphy and eluted with 25% EtOAc:hexane to yield 2.2 g (28%) of 33b step 6 A mixture of 0.72 g (2.6 mmol) of 57, HOAc (3.5 mL), HCl (7 mL) and H2O (3.5 mL) were heated at reflux for 6 h, cooled to rt, diluted with water and extracted with EtOAc. The combined extracts were washed sequentially with water, sat'd NaHCO33, and brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by chromatography on silica gel. The eluted product, which still contained the 3-chloropyridazine was dissolved in HOAc (20mL) and NaOAc (0.2 g) and reisolated to yield 0.4 g (50%) of 58 as a white solid; m.p. 116-118. step 1 To a stirred solution of ethyl 3-methoxyphenylacetate (16.0 g; 82.38 mmol) in CH2C12 (200 mL) at rt was added dropwise AcCl (9.88 mL; 138.9 mmol) followed by stannic chloride (16.9 mL; 169 mmol; 1.0 M solution in CH2C12) The reaction mixture was stirred at rt for 6 h and poured into an ice-water mixture. The aqueous phase was extracted with CH2C12 and the combined extracts were washed with, water, dried (Na2SO4) and the solvent removed in vacuo. The crude product 4e was purified by chromatography on silica gel and eluted with CH2CI2:BtOAc (20:1) to yield 13.96 g (69.5%) of a white solid. step 2 To a solution of 4e (19g; 80.42 mmol) and 200 mL of TFA cooled to 0°C was added an excess of Et3SiH and the reaction allowed to warm to rt for 3 L Excess TFA was removed in vacuo and the residue partitioned between water and CH2C12. The crude product was purified by chromatography on silica gel and eluted with CH2Cl2:hexane (3:1) to yield 3.0 g (16%) of 4f. step 3 A solution of ethyl 4-ethyl-3-methoxyphenylacetate (4f; 3.0 g; 13.50 mmol) and CH2C12 (80 mL) was cooled to -78 °C and a solution of (5.10 mL; 53.94 mmol; 1.0 M in CH2C12) over 30 min. After 1 h at -78 °C the reaction was allowed to warm to rt and stirred for 12 h. The reaction was cooled in an ice-water bath and the reaction quenched with 20 mL of water. The aqueous phase was extracted with CH2Cl2:EtOAc (4:1 v/v), dried (Na2S04), filtered and evaporated. The crude product was purified by silica gel chromatography and eluted with a CH?Cl2:EtOAc gradient (100:1 100:4) to yield 5b (2.0 g; 71%): m.s. 2092 (M+H)+. A solution of ethyl 4-ethyl-3-hydroxyphenylacetate (5b3 0.20 g; 0.96 mmol), 2-iodo-chlorobenzene (0.18 mL; 1.44 mmol), Cs2CO33 (0.469 g; 1.44 mmol), TMHD (0.020 inL; 0.096 mmol) and NMP (15 mL) was degassed with a stream of nitrogen for 15 m. Cuprous chloride (0.48 g; 4.8 mmol) was added and the solution was degassed. The reaction mixture was heated to 120 °C for 11 h then cooled to rt. The suspension was filtered through a pad of CELITE® and the solid washed thoroughly with EtOAc. The combined filtrate was washed with 2N HC1, dried (Na2SO4) and the solvent evaporated. The product was purified by chromatography on silica gel and eluted with EtOAc:hexane (1:10). to yield 0.31 g (39%) of 33d. step 1 To a suspension of PPh3CH3+ Br' (36.29 g; 101.6 mmol) in THF (150 mL) cooled to -40 °C was added dropwise n-BuLi (40.6 mL; 1.6M in hexanes) and the resulting solution was allowed to warm to -10 °C for 10 m and re-cooled to -40 °C. To the resulting solution was added in one portion ethyl 4-acetyl-3-methoxyphenylacetate (see Example 4; step 1) and the reaction mixture was stirred at 0 °C for 30 m and warmed to rt and stirred for an additional 2 h. The reaction mixture was diluted with hexane filtered through a pad of CELITE® and the solids wash with hexane:Et20 (5:1 v/v; 60 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), dried (Na2S04), filtered and evaporated to yield a yellow oil The product was purified by silica gel chromatography and eluted with CH2Cl2:hexane (1:1 2:1) to yield 9.1g of 4g. step 2 A suspension of 4g (9.0 g; 38.41 mmol), 5% Pd/C (380 mg) in 50 mL HOAc and 50 mL EtOH was shaken under a hydrogen atmosphere (50 psi) for 7 h. The mixture was filtered through a pad of CELITE® and the filtered catalyst was washed with EtOAc. The solvents' were evaporated under reduced pressure and the residue dissolved, in MTBE and carefully washed with sat'd HaHCO33, water and brine. The resulting solution was dried (Na2S04), filtered and evaporated to yield ethyl 4-iso-propyl-3-methoxyphenylacetate (4h; 9.0 g) as a yellow oil. step 3 A solution of 4h (3.38 g; 14.30 mmol) and CH2C12 (150 mL) were cooled to -78 °C and a solution of BBr3 (5.41 mL; 57.22 mmol) in 130 mL of CH2CI2 were added dropwise over a 30 m period. The reaction mixture was stirred at -78 °C for 1 h, allowed to warm to rt for 4 h and re-cooled to -78 °C and carefully quenched with sat'd. NaHCO33 (80 mL). The aqueous laj'er was extracted with CH2C12 (1 x 100 mL), EtOAc (50 mL) and the combined aqueous layers washed with water and brine, dried (Na2S04) and evaporated to yield a light brown oil. The phenol was purified by silica gel chromatography and eluted with CH2Cl2;hexane (3:1) CH2C12 CH2Cl2:EtOAc (100:4) to yield ethyl 4-^o-propyl-3-hydroxyphenylacetate (5c; 3.0 g; 94%) • step 4 To a solution of 5c (1.0 g; 4.5 mmol)„ 3-chlorobenzeneboronic acid (0.844 g; 5.4 mmol), cupric acetate (0.899 g; 4.95 mmol), 4A molecular sieves (5.0 g) and CH2C12 (50 mL) was added TEA (3.14 mL; 22.53 mmol) and the reaction was stirred for 3 days. The reaction mixture was filtered through a pad of CELITE®. The top layer containing the molecular sieves was removed and stirred with CH2C12 and refiltered. The combined organic filtrates were washed with 2N HC1, brine, dried (Na2S04)? filtered and evaporated. The crude product was chromatographed with silica gel and eluted with a gradient of hexane/EtOAc (90%hexane/EtOAc) to yield 33f (1.0 g; 66%). step 6 A mixture of 0.64 g (1.44 mmol) of 59, HOAc (12 mL), HC1 (24 mL) and H2Q (12 mL) were' heated at reflux for 16 h, cooled to rtand extracted with EtOAc. The combined extracts were, washed with H20, dried (Na2S04), filtered and concentrated in vacuo to afford a brown solid. The crude product was purified by chromatography on silica gel and eluted with a gradient of CH2Cl2:EtOAc (15:1 8:1) to yield 0.10 g (20%) of 60. To a stirred solution of 32b (0.8.0 g; 4.12 mmol) and 7 mL NMP under a N2 atmosphere was added l-bromo-3-fluorobenzene (0.69 mL; 6.18 mmol), TMHD (0.086 mL; 0.41 mmol), Cs2CO33 (2.68 g; 8.24 mmol) and Cu(T)Cl (0.204 g; 2.06 mmol). The reaction was heated to 120 °C for 3 h. The reaction mixture was cooled to ambient temperature, and quenched with a mixture of 2 N HC1 and EtOAc. The aqueous layer was thrice extracted with EtOAc and the combined organic layers were washed with water and brine, dried (Mg304), filtered and evaporated to dryness. The crude product was chromatographed on silica gel and eluted with hexane:Et20 (9:1) which yielded33c(0.60g;50%). step 1 A mixture of 4-bydroxy-3-methoxyphenylacetic acid (6a; 1.0 g; 5.49 rnmol) and hexamethylenetetramine (0.808 g; 5.76 mmol) and TFA (7 mL) were stirred and heated at 90 °C for 4 h. The reaction was cooled and excess TFA removed in vacuo and 35 mL of ice and water was added to the residue. The resulting dark brown solution was stirred at rt for 20 m. The aqueous solution was extracted with Bt20 (40 mL) and the extract was dried (Na2SO4), filtered and evaporated to afford 0.70 g of 6b (61%; m.s. (M+H)+ = 211.13; mw = 210). step 2 To a solution of 6b (4.0 g; 19.03 mmol) in EtOH (80 mL) was added con H2SO4 (1 mL). The reaction was heated at reflux for 6 h. Approximately 80% of Hie EtOH was removed in vacuo and the residue partitioned between EtOAc/EkO (1:1) the organic phase residue washed with 10% NaHCO333 water (100 mL), dried (Na2SO4), filtered and evaporated to afford a brown oil 7a (88%; m.s. (M+H)+= 239.19; mw = 238.3). step 3 A mixture of 7a (3.70 g; 15.53 rnmol), 5% Pd/C (0.350 g), HOAc (45 mL) were shaken under a H2 atmosphere (40 psi) for S h. TLC showed product and the corresponding benzyl alcohol. An additional 300 mg of Pd/C in 25 mL HOAc was added and hydrogenation continued for another 8 h. A second portion of 0.15 g of Pd/C in HOAc (15 mL) was added and reaction continued for another 12 h. The mixture was diluted with EtOAc and filtered through a pad of CELITE®. The catalyst was washed with EtOAc and the combined organic extracts dried (Na2SO4)- and evaporated. The product was purified by silica gel chromatography and eluted with CH2Cl2:hexane (4:1) to afford 2.64 g of 7b (75.8%). step 4 To a solution of 7b (5.87 g; 26.175 mmol) in CH2C12 cooled to 0 °C was added pyridine (3.60 mL; 44.51 mmol) followed by dropwise addition of triflic anhydride (6.605 mL; 39.26 mmol) over about 20 min. The reaction was stirred at 0 °C for 3.5 h. The reaction mixture was extracted with dilute HC1 and half-saturated NaHCO33, dried (Na2S04) and evaporated to yield 9.41 gof7casabrownoil(100%). step 5 To a suspension of PdCl2(dppf) (0.650 g; 0785 mmol) in THF (40 mL) cooled to 0 °C was added dropwise a solution of DIBAL-H (1.0 M in PhMe; 1.57 mL; 1.57 mmol). The resulting mixture was stirred at 0 °C for 5 minutes and a solution of 7c in 5 mL of THF was added followed by Me2Zn (23 mL;46.0 mmol; 1.0 M in PhMe). The mixture was stirred at 0 °C for 5 m and heated at reflux for 2.5 h then cooled to rt for 30 m. The reaction was poured into dilute HC1 and extracted with EtOAc (2 x 100 mL), dried (Na2SC>4), and evaporated. The crude product was purified by silica gel chromatography and eluted with CBtC^hexane (1:2 1:1 2:1 v/v) to yield 5.1 g (87.6%) of 8. step 6 A solution of ethyl 3?4-dimethyl-5-methoxyphenylacetate (8; 0.560 g; 2.519 mmol) and CH2C12 (40 mL) was cooled to -78 °C and a solution of BBr3 (10.1 mL; 10.1 mmol; 1.0 M in CH2C12) dropwise over 10 min. After 1 h at -78 °C the reaction was allowed to warm to rt and stirred for 12 h. The reaction was cooled in an ice-water bath and the reaction quenched with 15 mL of ice/water. The aqueous phase was extracted with CH2Cl2:EtOAc (3:1 v/v), dried (Na2SO4)3 filtered and evaporated to yield 8 (0.52 g; 99%; m.s. 209.21 (M+H)*). step 7 To a suspension of ethyl 3,4-dimethyl-5-hydroxyphenylacetate (8, 1.0 g; 4.8 mmol), 3-chIoro-benzeneboronic acid (0.901 g; 5.762 mmol), Cu(OAc)2 (0.959 g; 5.28 mmol), powdered 4A molecular sieves (5 g) and 40 mL of CH2C12. After 40 h starting material was still evident by tic and an addition 0.35 g of the boronic acid was added. The reaction was stirred for an additional 72 h. The reaction mixture was filtered through a pad of CELITE® and silica gel. The solids were washed well with CH2C12. The combined filtrates were washed sequentially with 2N HC1 (2 x 25 mL), NaHCO33 (25mL)3 water and brine. The extracts were dried (Na2S04)? filtered and evaporated. The crude product was purified by silica gel chromatogaphy and eluted with EtOAc:hexane(l:15 1:10) to yield 33e (1.0 g; 65%; m.s. (M+H)+ = 319.34,mw = 31S). step 8 To a solution of 1.0 g of 33e (3.14 mmol), 0.935 g (6.276 mmol) of 3,6-dichloropyrazine.in 10 mL dry DMF cooled in an ice-water bath was added portionwise 0.313 gNaH (7.825 mmol; 60% in oil). The reaction stirred at 0 °C for 5 m then was allowed to warm to ambient temperature and stirred for 14 hour. The reaction was poured onto a mixture of ice, water and sodium bisulfate. The mixture was extracted thoroughly with EtOAc and the combined extracts were washed with 5% LiCL, water and brine. The extract was dried (MgSO44), filtered and evaporated * and the residue chromatographed on silica gel and eluted with hexane:EtOAc (10:1 8:1) to yield 1.0 g (73.9%) of 61: m.s. (M+H)+ = 431.29) step 9 A mixture of 1.0 g (2.318 mmol) of 61, HOAc (12 mL), HC1 (24 mL) and H20 (12 mL) were heated at reflux for 16 h, cooled to it and extracted with EtOAc. The combined extracts were washed with H2O, dried (Na2SO4), filtered and concentrated in vacuo to afford a brown solid. The crude product was purified by chromatography on silica gel and eluted with a gradient of CH2Cl2:EtOAc (8:1) to yield 0.150 g (18%) of 62 as a brown solid; m.s. (M+H)+ = 341.27; mw = 340.8. step 1 To a suspension of 3~hydroxy-2-methylbenzoic acid (11; 22.8 g; 0.15 mol) and water (300 mL) cooled in an ice-water bath was added 3 M NaOH to adjust pH to about 10 (ca. 60 mL). NaOCl (208 mL; 5.35% aqueous solution; 0.15 mol) was added dropwise over about 30 m while maintaining the temperature between 2-6 °C. After the addition was completed, 90 mL of 3 M HC1 was added in one portion. The resulting precipitate was collected and dried on a sintered glass filter. The crude product was recrystallized from EtsO:hexane (ca, 3:1) to yield a yellow solid 12 (12.24 g; 44%). step 2 A solution of 12 (12.24 g; 65.6 mmol), MeOH (200 mL) and con H2S04 (3.85 mL) was stirred overnight at rt then heated to reflux for 6 h. The solution was cooled, concentrated to approximately 10% of the original volume and the residue redissolved in EtOAc. The organic phase was washed with sat'd. NaHCO33 and brine, dried^ filtered and evaporated. The crude product was purified by silica gel chromatography and eluted with a EtOAchexane gradient (1:9 4:6). The combined fractions were evaporated to yield 13 (8.32 g; 63.2%). step 3 To a solution of methyl 4-cliloro-3-hydroxy-2-methylbenzoate (13; 1,0 g; 4.98 mmol), . benzeneboronic acid (1.52 g; 12.5 mmol), cupric acetate (1.00 g; 5.48 mmol), 4A molecular sieves (1 g), and CH2C12 (25 mL) was added TEA (3.47 mL; 24.9 mmol) and the reaction was stirred overnight. Starting material was still detected by tic and an additional 0.62 g of benzeneboronic -acid was added and stirred for another 24 h. The reaction mixture was filtered through a pad of CELITE®. The top layer containing the molecular sieves was washed with CHC13. The combined organic filtrates were evaporated. The crude product' was chromatographed with silica gel and eluted with hexane/EtOAc gradient (100:0 85:15) to yield 14 (0.82 g; 60%). step 4 To a solution of methyl 4-chloro-2-methyl-3-phenoxybenzoate (14; 0.780g; 2.'81 mmol) dissolved in PhMe (20 mL) cooled in an ice-water bath was added dropwise DIBAL-H (7.41 mL; 7.41 mmol; 1.0 M in PhMe) The reaction was quenched by sequentially adding MeOH, H2O, and con HC1. The organic phase was extracted with Et2Q. The combined organic extracts were washed with sat'd, NaHCO33, water and brine, dried (Na23O4), filter and evaporated to yield 15 as , a white oil which was used in the next step without further purification. step 5 To a solution of 15 (0.736 g; 2.96 mmol) dissolved in pyridine (10 mL) was added dropwise methanesulfonyl chloride (0.252 pL; 5.92 mmol) over 5 min. After 30 min a small quantity of starting material was evident and an addition 25 jxL of methanesulfonyl chloride was added* The reaction was partitioned between Et20 and 5% HC1. The organic phase was twice washed with 5% HC1, water, sat'd. NaHCO33 and brine. The organic extract was dried (MgSO4), filtered and evaporated. The crude product was chromatographed on silica gel eluting with 10% EtOAcrhexane to yield the benzylic chloride 16 (0.220 g) as a colorless oil. step 6 The benzyl chloride 16 (0.220 g; 0.82 mmol) was dissolved hi EtOH (1 mL) and KCN (0.107 g; 1.64 mmol and 1 mL of water. The mixture was heated to reflux and CH3CN (0.3 mL) was added to produce a homogenous solution which was allow to reflux overnight. The reaction mixture was concentrated in vacuo and partitioned between water and CH2CI2. The organic phase was washed twice with brine, dried (MgSO44), filtered and evaporated to yield 17 (0.210 g) sufficiently pure for further processing. To a solution of ethyl 4-chloro-3-hiydroxyphenylacetate (34a; 1.4 g; 6.5 mmol) and NMP (13 mL) was added potassium carbonate (2.7g; 19.6 mmol) and 1.2 g of 3?5-difluoroben2:onitrile (1.2 g; 8.5 mmol). The reaction mixture was heated to 120 °C and monitored by TLC, After 3.5 h an additional 0.9 g of K2CO33 was added and at 5.5 h an additional 0.9 g of K2CO33 and 0.3 g of 3,5-difluorobenzonitrile was added. After 8 h of heating the reaction was cooled to rt and the reaction mixture was filtered through a pad of CELITE® and the solid cake was washed well ' with EtOAc. The filtrate was washed with 2 portions of 2N HC1, IN NaOH, water and brine. The organic extract was dried (MgSCU), filtered and evaporated to yield 1.3 g of the ether 35a. A solution of ethyl 4-chloro-3-hydroxyphenylacetate (34a; 2.0 g; 9.3 mmol), 2,5-dichloro-bromobenzene, Cs2CO33 (6.0 g; 18.6 mmol), TMHD (0.38 mL; 1.9 mmol) andNMP (15 mL) was degassed with a stream of nitrogen for 15 m. Cuprous chloride (0.5 g; 4.7 mmol) was added and the solution again was degassed. The reaction mixture was heated to 120 °C for 18 h then cooled to rt. The suspension was filtered through a pad of CELITE® and the solid washed thoroughly with EtOAc. The combined filtrate was washed with 2N HC1, dried (Na2SO4) and the solvent evaporated. The product was purified by chromatography on silica gel and eluted with EtOAcrhexane (1:10) to yield 35b (0.554 g; 16%). A solution of 2-chloro-4-methylphenol (36; 3.0 g; 21 mmol),, 4-bromobenzeneboronic acid (5.0 g; 24 mmol), cupric acetate (4.2 g; 23.1 mmol), 4A molecular sieves and CH2C12 (210 mL) was added TEA (9.8 mL; 70 mmol) and the reaction was stirred for 3 days. The reaction mixture was filtered through a pad of CELITE®. The top layer containing the molecular sieves was removed and stirred with CH2C12 and refiltered. The combined organic filtrates were washed with 2N HCI, brine, dried (Na2SO4), filtered and evaporated. The crude product was chromatographed with silica gel and eluted with a gradient of hexane/EtOAc (100:0 90:10) to yield 37a. To a solution of benzeneboronic acid (1.9 g; 15.8 mmol) dissolved in CH2CI2 (250 mL) was added 2-chloro-5-methylphenol (36; 2.5 g; 17.5 mmol), cupric acetate (3.5 g; 193 mmol)3 TEA ((12.3 mL; 87.7 mmol) and 12.5 g of 4A molecular sieves. The reaction was stirred for 24 h and an additional aliquot of benzeneboronic (2.4 g; 19.3 mmol) was added and stirring continued for an additional 48 hr. The reaction mixture was filtered through a bed of CELITE® and the filtered solids were washed thoroughly with CH2C12. The combined organic extracts were washed with 2N HCI, H20, sat'd NaHCO33? H2O and brine, dried (MgSO44) filtered and evaporated. The crude product was purified by silica gel chromatography and eluted with " hexane:EtOAc (9:1) to yield 37b (1,6 g; 47.1 %) as a clear oil. step 1 A solution of 4-chloro-2-fluoro~3-hydrox3'toluene (18; 0.161 g; 1.0 mmol)?jp-fluoromtro-benzene (0.141 g; 1.0 mmol), K2CO33 (0.276 g; 2 mmol) and DMF (4 mL) was heated to reflux for 4 h under a N2 atmosphere. The reaction was cooled to rt and poured into water and stirred for several minutes. The aqueous solution was extracted twice with CH2CI2 and the combined organic extracts washed with brine, dried (MgSQ*), filtered and evaporated to yield 20. step 2 A solution of 20 (1.58 g; 5.3 mmol), stannous chloride dihydrate (6.0 g; 26.6 mmol) and EtOH (5 mL) were heated to 70 °C stirred overnight. The reaction mixture was added to a small quantity of ice and made basic with 10% Na2CO33. The aqueous phase was extracted with EtOAC (5 mL) which resulted in an emulsion. About 7 mL of ethylenediamine was added to chelate tin which resulted in a blue aqueous solution. The EtOAc was washed with water and brine, dried (NaHCO33), filtered and evaporated to yield 1.35 g of 21 which was carried on to the next step. step 3 A solution of 21 (0.830 g; 3.3 mmol) was dissolved in HOAc (2.25 mL) and added to a solution of ice-water (7.5 mL) and HC1 (1.2 mL). A solution of NaN02 (0.254 g; 5.6 mmol) and H20 (1.5 mL) was added over a 10-15 m period. The resulting solution was stirred for several minutes then added dropwise over 15 m to a suspension of FeSO4'7 H2O (0.917 g; 3.3 mmol) and DMF (10.5 mL). The reaction was stirred for 0.5 h and a mixture of hexanes:EtOAc (1:1; 30 mL) was added. The organic phase was washed thrice with water, dried (MgSO44), filtered and concentrated in vacuo. The dark oil was purified by chromatography on silica gel and eluted with an EtOAc:hexane gradient (0:100 20:80) which yielded 22 as a clear oil (0.450 g; 58%). EXAMPLE 14 step 1 Cesium carbonate (11.4 g; 8.79 mmol) was added to a solution of 2-chloro-5-methylphenol (IS; 2.5 g; 17.53 mmol) and NMP (16 mL). The resulting slurry was degassed and the flask alternately purged and refilled with nitrogen. 1,3-Dibromo-fluorobenzene (3.54 g; 28.13 mmol), TMHD (0.92 mL; 0.81 g; 4.41 mmol) and CuQCl (0.87 g; 8.79 mmol) were added sequentially and the reaction mixture was heated to 110 °C for 6 h. The reaction mixture was cooled to ambient temperature, filtered through a bed of CBLITE® and the filter cake washed thoroughly with EtOAc. The filtrate was washed sequentially with dilute HC1, dilute NaOH, water and brine. The organic extract was dried (Na2SO4), filtered and evaporated. The residue was chromatographed on silica gel and eluted with hexane:Et20 which yielded 1.8 g (32%) of 37c as a colorless oil. step 2 A mixture of 37c (1.8 g; 5.704 mmol), NBS (1.066 g; 5.989 mmol), benzoyl peroxide (0.069 g; 0.28 mmol) and CC14 (20 mL) was heated to 90 °C for 2.5 h. The reaction mixture was cooled to room temperature and poured into 100 mL of H20. Tie mixture was extracted with CH2C12 (2 x 80 mL), dried (Na2SO4) and evaporated to yield 63a (2.25 g) as a colorless oil. step 3 A solution of 63a (2.25 g; 5.704 mmol), NaCN (0.839 g; 17.12 mmol) and 20 mL of 90% aqueous EtOH was stirred at room temperature for 24 h. The solvent was evaporated and the residue partitioned between EtOAc (100 mL) and H2O (100mL). The EtOAc phase was washed with H20 and saturated brine. The organic extracts were dried (Na2SO4) and evaporated. The crude product was purified by silica gel chromatography and eluted with a hexane/EtOAc gradient (10:1 6:1) to yield 1.10 g (56.6%) of 63b as a colorless oil. To a solution of ethyl 4-ethyl-3-hydroxyphenylacetate (4f; 1.0 g; 4.81 mmol), 3-chlorobenzeneboronic acid (1.56 g; 10.1 mmol), cupric acetate (0.96 g; 5.29 mmol), 4A molecular sieves (5 g), and CH2CI2 (48 mL) was added TEA (3.34 mL; 24.05 mmol) and the reaction was stirred for 4 days. The reaction mixture was filtered through a pad of CELITE®. The top layer containing the molecular sieves was removed and stirred with CH2C12 and refiltered. The combined organic filtrates were washed with 2N HC15 brine, dried (Na2SO4), filtered and evaporated. The crude product was chromatographed with silica gel and eluted with hexane/EtOAc (90%hexane/EtOAc) to yield 33e (0.38 g; 25%). To a flask was charged with 3-hydroxy-4-methylphen3dacetonitrile (32a; 0.92 g; 62 mmol), Cu(OAc)2 (1.3 g; 6.9 mmol), 3-bromobenzeneboronic acid (1.1 g; 5.5 mmol) and powdered 4A molecular sieves, was added CH2CI2 (62 mL) followed by pyridine (2.5 mL; 31 mmol). The reaction was stirred at rt for 3 days. The suspension was filtered through a bed of CELITE®/silica gel and the solid washed with CH2CI2. The combined filtrates were washed sequentially with' 2N HC1 (2 x 25 mL), NaHCO33 (25mL), water and brine. The extracts were dried (MgSO44), filtered and evaporated. The crude product 76 was sufficiently pure to use in the next step. step 1 To a solution of 2-fluoro-4-methylphenol (79; 3.0 g; 24 mmol), 3-bromobehzeneboronic acid (5.3 g; 24 mmol), cupric acetate (4.8 g; 23.1 mmol), 4A molecular sieves (15 g)and CH2C12 (240 mL) was added TEA (17 mL; 120 mmol) and the reaction was stirred for 4 days. The molecular sieves were filtered and washed well with CH2C12. The combined organic filtrates were washed with 2N HC1, brine, 2N NaOH, water and brine, dried (Na2SO4), filtered and evaporated. The crude product was chromatographed with silica gel and eluted with hexane:EtOAc (90%hexane:EtOAc) to yield 80 (5.7 g; estimated purity 72%). step 2 A solution of 80 (4.1 g; 14.6 mmol), NBS (2.6 g; 14.6 mmol), AEBN (0.25 g; 1.50 mmol) and 146 mL of CCl4 was heated at reflux for 5,0 h, cooled to rt and the precipitated succinimide filtered through a pad of CELITE®. The filtrate was evaporated and the crude product 81a was sufficiently pure to use in the next step. The crude bromomethyl compound 81a from the previous step was dissolved in 73 mL of 90% aq. EtOH and 2.5 g of NaCN (49.01 mmol) was added. The reaction mixture was stirred overnight at rt. The solid material was filtered through a pad of CELITE® and the filtrate was evaporated. The crude product purified by silica gel chromatography and eluted with 30% EtOAc:hexane to yield the nitrile 81b (2.4 g; 54%). step 1 To a solution of 28a (5.0g; 24.2 mmol) and anhydrous CH2C12 (75 mL) was added sequentially acetyl chloride ((2.42 mL; 33.9 mmol) and SnC14 (5.39 mL; 46.1 mmol; 1 M solution in CH2CI2). The reaction was stirred at room temperature for 50 minutes and poured into a mixture of ice and 2 N HC1 (200 mL). The organic phase was separated and diluted with about 50 mL of CH2CI2 and thrice washed with water (100 mL) and once with brine (100 mL). The-organic phase was dried (MgSO4), filtered and evaporated to yield 28b (6.0 g) which contained about 10% of 28a. The crude product was used without further purification. step 2 To an ice-cold solution of 28b (6.01 g; 24.2 mmol) and CH2C12 (100 mL) under a nitrogen atmosphere was added sequentially a solution of MCPBA (11.9 g; 48.4 mmol) and CH2C12 (12 mL) followed by TFA (2.14 mL; 27.8 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was cooled to 0°C and a 5% aqueous Na2SO3 solution (150 mL) was added slowly with stirring. The mixture was stirred for 5 minutes after addition was completed and precipitated zn-chlorobenzoic acid was filtered. The solid was with CH2C12 and the combined filtrates were washed with 10% NaOH (2 x 250 mL), 2 N HC1 (200 mL), water and brine. The resulting solution was dried (MgSO44), filtered through a pad of CELITE and concentrated in vacuo to yield 28c (4.1g). step 3 To a solution of dihydrofuran derivative 28c (14.6 g; 0.0553 mol) and CCI4 (500mL) was added NBS (10.3 g; 0.0580 mol) and AIBN (1.4 g). The reaction was heated to reflux for 30 minutes under a nitrogen atmosphere. The reaction was cooled, the solid succinimide filtered, and the organic phase was washed with 0.5 M NaHSCO4 (150 mL) and brine. The product was'dried (Na2SO4)9 filtered and evaporated to yield 15.2 g of a yellow syrup. The crude product was purified by silica gel chromatography and eluted with a EtOAc:hexane gradient (3:97 10:90) to yield 10.3.g (78.1%) of 30. step 4 A solution of 30 (10.3 g; 393 mmol), EtOH (250 mL) and saturated NaHCO33 (100 mL) were heated to reflux for 1 h. The reaction mixture was cooled to room temperature and theEtOH removed in vacuo. Ice was added to the residue aqueous solution and the reaction carefully acidified to about pH 2 with 2 N HCL The resulting mixture was extracted with EtOAc (2 x 300 mL) and the combined organic phase washed with brine, dried (NaSO4)5 filtered and evaporated to yield a brown oil (8.8 g). The crude product was run through a silica gel column with 15% EtOAcrhexane to yield 31 (5.44g; 62.9%) as a white solid. To a solution of ester 46a (517 mg, 2.03 mmol) dissolved in EtOH (10 mL) was added hydrazine hydrate (1.3 mL of an 85% solution) was and the mixture was heated to reflux overnight. The volatile materials were removed, and the residual material was dissolved in EtOAc (50 mL). The solution was washed with brine (20 mL) and dried (MgSC^), filtered, and the volatile materials were evaporated to provide the desired acyl hydrazine 46b (460 mg, 82%) as a white solid. An oven dried 100 mL flask was charged with the 46b (152 mg, 0.55 mmol) and flushed with nitrogen. CH2C12 (6 mL) and pyridine (45 pL, 0.55 mmol) were added, and the solution was stirred for 1 min. A solution of phosgene in methylene chloride (570 pL, 1.93 M, 1.098 mmol) was added dropwise via syringe, and the reaction was stirred for 10 m. Water (15 mL) and CH2C12 (10 mL) were added to the reaction mixture, the layers were separated, and the organic layer was washed with water (10 mL) and brine (10 mL). The solution was dried with anhydrous Na2SC>4, the solution was filtered, and the volatile materials were evaporated to provide 27 (168 mg, 100%; ms (EI): (M*) - 302). HC1 was bubbled through the ice cold solution of nitrite 50 (210 mg, 0.76 mmol) toluene (5 niL) and ethanol (49 pL, 0.87 mmol) for 10 min. The resulting mixture was stored in a sealed flask at 3 °C overnight Ethyl ether was added to the reaction mixture, and the imidate ester 51 (209 mg) was collected as a white solid by filtration. This material was added in 3 portions to a suspension of hydrazinecarbothioic acid O-methyl ester (55 mg,, 0.52 mmol) (Mattes, R. et al Cherm Ber. 19S0 113:1981-88) in anhydrous dioxane (3 mL). The heterogeneous reaction mixture was stirred at rt for 4 h, and then heated to reflux overnight The reaction was then cooled to it, and the solvent was removed by evaporation. Chilled water (20 mL) was added, and the mixture was thrice extracted CH2CI2 (20 mL). The organic layer was washed with water (20 mL), brine (20 mL), and dried over sodium sulfate. The solution was filtered, and the solvent was evaporated. Purification of the remaining material by flash chromatography (eluent: 25% to 50% ethyl acetate: hexanes) provided the desired methoxythiadiazole 52. A solution of 52, THF (3 mL) and con HC1 (1 mL) was stirred overnight. The solution was stirred overnight, ether (20 mL) was added, and the layers were separated. The organic layer was washed with water (10 mL), brine (10 mL), dried (MgSO44). The solvent d was evaporated, and the remaining material was purified by silica gel flash chromatography (10% 25% EtOAc:hexanes) to provide 76 mg of 53 (38% from imidate ester; ms (EI): (M+) = 353). To a solution of ester 46c (219 mg, 0.67 mmol) and EtOH (10 mL) was added hydrazine hydrate (1.2 mL; 85% aqueous solution) and the solution was heated to reflux for 4 h. The volatile materials were removed, and the remaining material was dissolved in EtOAc (50 mL). The solution was washed with water (20 mL), brine (20 mL), and dried (MgSC^). The solution was filtered, and the volatile materials were evaporated to provide acyl hydrazine 46d (200 mg, 96%) as a white solid. To a solution of 46d (96 mg, 0.31 mmol) and anhydrous THF (4 mL) under a N2 atmosphere was added ethyl isocyanate (40 fiL, 0.50 mmol) and the mixture was stirred overnight. The volatile materials were evaporated, and the resulting diacylhydrazone 47 dissolved in methanol (4 mL). Potassium hydroxide (173 mg, 3.1 mmol) was added, and the mixture was heated to reflux for 2 days. CH2C12 (20 mL) and water (10 mL) were added, and the aqueous layer was acidified with 10% HCL The layers were separated, and the aqueous layer was extracted twice with CH2C12 (20 mL). The combined organic layers were washed with water (10 mL), brine (10 mL), and dried (Na2SO4). The solution was filtered, the volatile materials evaporated, and the residue was purified by silica gel column chromatography and eluted with EtOAc to provide 48 (54 mg, 48% from acylhydrazine 47; ms: 364 (M+H)+). EXAMPLE 22 HIV Reverse Transcriptase Assay; Inhibitor IC50 determination HTV-1 RT assay was carried out in 96-well Millipore Multiscreen MADVNOB50 plates using purified recombinant enzyme and a poly(rA)/oligo(dT)i6 template-primer in a total volume of 50 JJL. The assay constituents were 50 mM Tris/HCl, 50 mM NaCl, 1 IDM EDTA, 6 mM MgCl2, 5 HM dTTP, 0.15 jxCi [3H] dTTP, 5 fig/ml poly (rA) pre annealed to 2.5 jig/ml oligo (dT)26 and a range of inhibitor concentrations in a final concentration of 10% DMSO. Reactions were initiated by adding 4 uM HIV-1 RT and after incubation at 37°C for 30 min, they were stopped by the addition of 50 )il ice cold 20%TCA and allowed to precipitate at 4°C for 30 min. The precipitates were collected by applying vacuum to the plate and sequentially washing with 3 x 200 jil of 10% TCA and 2 x 200 p,l 70% ethanol Finally, the plates were dried and radioactivity counted in The ingredients are combined and granulated using a solvent such as methanol. The formulation is then dried and formed into tablets (containing about 20 mg of active compound) with an appropriate tablet machine. The active ingredient is dissolved in a portion of the water for injection. A sufficient quantity of sodium chloride is then added with stirring to make the solution isotonic. The solution is made up to weight with the remainder of the water for injection, filtered through a 0.2 micron membrane filter and packaged under sterile conditions. All of the ingredients, except water, are combined and heated to about 60°C with stirring. A sufficient quantity of water at about 60° C is then added with vigorous stirring to emulsify the ingredients, and water then added q.s. about 100 g. Nasal Spray Formulations Several aqueous suspensions containing, from about 0.025-0.5 percent active compound are prepared as nasal spray formulations. The formulations optionalty contain inactive ingredients such as, for example, microcrystalline cellulose, sodium carboxymethylcellulose, dextrose, and the like. Hydrochloric acid may be added to adjust pH. The nasal spray formulations may be delivered via a nasal spray metered pump typically delivering about 50-100 microliters of formulation per actuation. A typical dosing schedule is 2-4 sprays every 4-12 hours. The features disclosed in the foregoing description, or the following claims, or the accompanying drawings, expressed in their specific forms or in terms of a means for performing the disclosed function, or a method or process for attaining the disclosed result, as appropriate, may, separately, or in any combination of such features, be utilized for realizing the invention in diverse forms thereof. The foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity and understanding. It will be obvious to one of skill in the art that changes and modifications may be practiced within the scope of the appended claims. Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the invention should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitled. AH patents, patent applications and publications cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual patent, patent application or publication were so individually denoted. Claims n is an integer from 0 to 2; and, hydratess solvates, clathrates and acid addition salts thereof, with, the proviso that if X is ortho-phenylene, R5 can not unsubstituted phenyl. 2. A compound according to claim 1 wherein: X1 is OR5 or SR5; R3 is hydrogen or fluoro; R4 is selected from the group consisting of hydrogen, chloro, fluoro and methyl; and R5 is optionally substituted phenyl. 3. A compound according to claim 2 wherein R1 is methyl, ethyl, trifluoromethyl or halogen. 4. A compound according to claim 3 wherein R5 is monosubstituted phenyl. 5. A compound according to claim 3 wherein R5 is 2,5-disubstituted phenyl. 6. A compound according to claim 3 wherein R5 is 3s5-disubstituted phenyl. 7. A compound according to claim 3 wherein R5 is 2,4-disubstituted phenyl. 8 A compound according to claim 3 wherein R5 is 2,6-disubstituted phenyl. 10. A compound according to claim 9 wherein; X1 is OR5; R1 is methyl, ethyl, trifluoromethyl or halogen; R2 and R4 are independently selected form the group consisting of hydrogen, fluoro, chloro, methyl and ethyl; R3 is hydrogen or fluoro; R5 is optionally substituted phenyl; and, n is an integer from 0 to 2. 11. A compound according to claim 10 wherein R5 is monosubstituted phenyl. 12. A compound according to claim 11 wherein R5 is a monosubstituted phenyl and the substituent is selected from the group consisting of halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, . Ci_6 alkoxy, C1-6 alkylthio and C1-6 haloalkoxy. 13. A compound according to claim 10 wherein R5 is 2,5-disubstituted phenyl. 14. A compound according to claim 13 wherein Rs is a 2,5-disubstituted phenyl and the substituents are independently selected from the group consisting of halogen, cyano, Ci_6 alkyl, C1-6 haloalkyl, Ci_6 alkoxy, C\s alkylthio and Ci_6 haloalkoxy. 15 A compound according to claim 10 wherein R5 is 3,5-disubstituted phenyl. 16. A compound according to claim 15 wherein R5 is a 3,5-disubstituted phenyl and the substituents are independently selected from the group consisting of halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-e alkylthio and C1-6 haloalkoxy. 17. A compound according to claim 10 wherein R5 is 2,4-disubstituted phenyl. 18. A compound according to claim 17 wherein R5 is a 2,4-disubstituted phenyl and the substituents are independently selected from the group consisting of halogen, cyano, C1-6 alkyl, C1.6 haloalkyl, C1_6 alkoxy, C1_6 alkylthio and C1_6 haloalkoxy. 19. A compound according to claim 10 wherein R5 is 2,6-disubstituted phenyl. 20. A compound according to claim 19 wherein R5 is a 2,6-disubstituted phenyl and the substituents are independently selected from the group consisting of halogen, cyano, C1_6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkylthio and C1-6 haloalkoxy. 21. A compound according to claim 1 wherein: X1 is OR5 or SR5; R3 and R4 are independently selected from the group consisting of hydrogen, chloro, fluoro, and methyl; and, R5 is optionally substituted pyrdinyl, pyrimidinyl, pyrazinyl or pyrrolyl. 22. A compound according to claim 1 wherein R1 and R2 along with the carbon atoms to which they are attached form a phenyl, dihydropyran, dihydrofuran or furan ring. 23. A compound according to claim 22 wherein: X1 is OR5 or SR5; R3 is hydrogen; R4 is hydrogen or fluoro; and, R5 is optionally substituted phenyl. wherein: X1 is selected from the group consisting of R5O, R5S(O)m R5CH2, R5CH2O, R5GH2S(O)n, R5OCH2, R5S(O)nCH2 and NR5R6; X2 is selected from, the group consisting of o-phenylene, 1,2-cyclohexenylene, O, S, and NR7; R1 and R2 are (i) each independently selected from the group consisting of hydrogen, C1-6 alkyl, C1-.6 haloalkyl, C3.8 cycloalkyl, C1-6 alkylthio, C1-6 alkylsulfinyl, C1-6 alkylsulfonyl, C1_6 haloalkoxy, C1-6 haloalkylthio, halogen, amino, alkylamino, dialkylamino, aminoacyl, nitro and cyano; or, alkylsnlfonyl, halogen, amino, alkylamino, dialkylamino, aminoalkyl, aliylaminoalkyl, and dialkylamino; n is an integer from 0 to 2; and, hydrates, solvates, clathrates and acid addition salts thereof. 25. Use according to claim 24 wherein: X1 is OR5; R1 is methyl, ethyl, trifluoromethyl or halogen; R2 and R are independently selected from the group consisting of hydrogen, fluoro, chloro, methyl and ethyl; R3 is hydrogen or fluoro; and, R5 is optionally substituted phenyl. 26. Use according to claim 24 further comprising co-administering at least one compound selected from the group consisting of HIV protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, CCR5 inhibitors and viral fusion inhibitors. 27. Use according to claim 26 wherein the reverse transcriptase inhibitor is selected from the group consisting of zidovudine, lamivudine, didanosine, zalcitabine, stavudine, rescriptor, sustiva, viramune, efavirenz, nevirapine and delavixdine and/or the protease inhibitor is selected from the group consisting of saquinavir, ritonavir, nelfinavir, indinavir, amprenavir and lopinavir. 28. Use according to claim 25 for inhibiting a retrovirus reverse transcriptase comprising administering a compound. 29. Use according to claim 28 wherein the host is infected with a strain of HIV expressing a reverse transcriptase with at least one mutation compared to wild type virus. 30. Use according to claim 24 wherein said strain of HTV exhibits reduced susceptibility to efavirenz, nevirapine or delavirdine. 31. A phaimaceutical composition comprising a therapeutically effective quantity of a compound of formula I wherein; X1 is selected from the group consisting of R5O, R5S(O)m R5CH2; R5CH2O, R5CH2S(O)n, R5OCH2, R5S(O)mCH2 and NR5R6; X2is selected from the group consisting of o-phe^'lene, 1,2-cyclohexenylene, O, S, and MR7; R1 and R2 are halogen, amino, alkylamino, dialkylatnino, aminoacyl, nitro and cyano; R5 is selected from the group consisting of phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl and pyrrolyl; wherein, said phenyl, said naphthyl, said pyridinyl, said pyrimidinyl, said pyrazinyl and said pyrrolyl groups are substituted with one to three substituents independently selected from the group consisting of hydrogen, C1-6 alkyl, C1-6 haloalkyl, C3_8 cycloalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylsulftnyl, Q.6 alkylsulfonyl, C1-6haloalkoxy, C1-6 haloalkylthio, halogen, amino, alkylamino, dialkylamino, aminoacyl, acyl? alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, nitro and cyano; R6 is hydrogen, C1-6 alkyl, or acyl; R is hydrogen or C1-6 alkyl optionally substituted with one or two substituents independently selected from the group consisting of hydroxy, alkoxy, thiol, alkylthio, C1-6 alkylsulfinyl, C^ alkylsulfonyl, halogen, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, and dialkylamino; n is an integer from 0 to 2; and, hydrates, solvates, clathrates and acid addition salts thereof, with the proviso that if X is ortho-phenylene, R5 can not unsubstituted phenyl, in admixture with at least one pharmaceutically acceptable carrier or diluent sufficient upon administration in a single or multiple dose regimen for treating diseases mediated by human immunodeficieny virus inhibit HTV. ■ 32. A process for preparing a heterocycle of formula I, wherein X1 is OR5 or OCH2R5 and R5 is an optionally substituted axyl or heteroaryl moiety, X2 is Oa S, or MR7 and R1-R4 and R7 are as defined hereinabove, comprising the steps of: (j)(a) coupling an aryl compound of formula Ha wherein X4 is ttydrogen, alkoxycarbonyl or CN with (A) an aiylboronic acid or an aryl halide, or (B) aralkyl halide to produce an ether of formula lib; and, if X4 is hydrogen, . (b) (A) brominating the methyl group with N-bromosuccinimide and (B) displacing the bromide (X4 = Br) with sodium cyanide to produce the corresponding nitrile (X4 = CN), and, optionally, (C) hydrolyzing the nitrile to an alkoxycarbonyl (X4 = CO2R) or an O-alkyl imidate hydrochloride (X4 = C(=NH2t)OR CO; (ii)(A) treating a compound of formula lib (X4 = alkoxycarbonyl) sequentially with hydrazine hydrate to form the acyl hydrazide (Ufa; X4 = CONHNH2) and, (a) phosgene, or a phosgene equivalent, to produce an oxadiazolone of formula I wherein X2 is O; or, (b) and sequentially with an alkyl isocyanate (R7NCO) to produce a diacylhydrazone (lib; X4 = C(=0)NHNHC(-0)NHR7) and with base to produce a triazolone I (X2 -NR7); or, (B) treating a nitrile of formula Hb (X4 = CN) sequentially (a) with acid and alcohol to , produce the O-alkyl imidate hydrochloride (X4 = C(=NH2")OR CI"), (b) with O- X4 is a methoxythiadiazoline according to formula (ID), and (c) with aqueous acid to produce a thiadiazolone compound of formula I wherein X2 is S. 33. A process according to claim 32 wherein said ether is formed by coupling an arylboronic acid and Ila in the presence of a copper (H) salt 34. A process according to claim 32 wherein said ether is formed by coupling an aiyl halide and Ila in the presence of a copper (I) salt. 35. A process according to claim 32 wherein said ether is formed by coupling an araliyl halide, aryl halide or heteroaryl halide said aryl halide being substituted with electronegative groups and said heteroaryl halide optionally substituted with electron withdrawing groups, and Ha, said coupling being base-catalyzed. 36. A process according to claim 32 wherein X1 is OCH2R5 and said ether is formed by coupling an alcohol and Ha said coupling is catalyzed an a dialiylazodicarboxylate and triaryl or trialkylphosphine. 38. A process according to claim 32 wherein said oxadiazolone is produced by cyclizing the acylhydrazide with phosgene, 39. A process according to claim 32 wherein said oxadiazolone is produced by cyclizing the acylhydrazide with carbonyldiimidazole. 40. A process according to claim 32 wherein said triazolone is formed by sequential treatment with methyl isocyanate or ethyl isocyanate and methanolic sodium hydroxide. 41. A process according to claim 32 wherein said thiadiazolone is formed by sequential treatment with hydrazinecarbothioic acid O-methyl ester and aqueous acid. 42. A compound according to anyone of claims 1-23 for use as medicament

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2361-CHENP-2005 CORRESPONDENCE OTHERS 05-06-2012.pdf

2361-CHENP-2005 CORRESPONDENCE OTHERS 01-10-2013.pdf

2361-CHENP-2005 CORRESPONDENCE OTHERS 18-11-2013.pdf

2361-CHENP-2005 EXMAINATION REPORT REPLY RECEIVED 02-05-2012.pdf

2361-CHENP-2005 FORM-3 18-11-2013.pdf

2361-CHENP-2005 POWER OF ATTORNEY 18-11-2013.pdf

2361-CHENP-2005 CORRESPONDENCE OTHERS 03-10-2013.pdf

2361-CHENP-2005 CORRESPONDENCE OTHERS 13-03-2014.pdf

2361-CHENP-2005 FORM-3 05-06-2012.pdf

2361-CHENP-2005 FORM-3 13-03-2014.pdf

2361-chenp-2005-abstract.pdf

2361-chenp-2005-assignement.pdf

2361-chenp-2005-claims.pdf

2361-chenp-2005-correspondnece-others.pdf

2361-chenp-2005-description(complete).pdf

2361-chenp-2005-form 1.pdf

2361-chenp-2005-form 26.pdf

2361-chenp-2005-form 3.pdf

2361-chenp-2005-form 5.pdf

2361-chenp-2005-form18.pdf

2361-chenp-2005-pct.pdf