Title of Invention

NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

Abstract

The present invention relates to novel pyrazole derivatives of formula (I) wherein Rl to R4 are as defined in the summary and pharmaceutically acceptable salts and solvates thereof, methods to inhibits or modulate Human Immunodeficiency Virus (HIV) reverse transcriptase with compounds of formula (I) and pharmaceutical compositions of formula (I) admixed with at least one solvent, carrier or excipient. The compounds are useful for treating disorders in which HIV and genetically related viruses are implicated (formula I).

Full Text

The invention relates to the field of antiviral therapy and, in paiticular, to non-nucleoside reveerse transcriptase inhibitors for treating Human Immunodeficiency Vims (HIV) mediated diseases. The invention provides novel pyiazole compounds, pharmaceutical compositions comprising these compounds, methods for treatment or prophylaxis of HCV mediated diseases employing said compounds in monotherapy or in combination therapy. The human immunodeficiency virus (HIV) is the causative agent of acquired immunodeficiency syndrome (AIDS), a disease cliaracrerized by the destruction of the immune system, particularly of the 004"^ 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/inlegrase 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 idrally encoded enzymes. Currentiy available chemotherapy targets two crucial viral enzymes: HTV protease and HIV reverse transcriptase. (J. S, G. Montaner et al. Aiiiiretroviral therapy: "Tlie State oftlie Art", Biomed. & Phannacother. 1999 53:63-72; R. W, Shafer and D. A. Vuitton, Highly active ojitiretroviral therapy (HAART)for the treatmeiU of infection with hiwmn immunodeficiency \'ints type 1, Biomed. & Pharmacother.1999 53:73-86; E. De Clercq, New Developments in Anti-HIV CJiemotlierap. Curr. Med. Chein. 2001 S-.i543-1572). Two general classes of reverse transcriptase inhibitors (RTIs) have been identified: nucleoside revise transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). NRTIs typically are 2',3'-dideoxy!iucleoEide (ddN) analogs that must be phosphorylated prior to interacting with viral RT. The corresponding triphosphates function as competitive inhibitors ox altemative substrates for viral RT, After incorpctration into nucleic acids the nucleoside analogs terminate the chain elongation process. HEV reverse transcriptase has DNA editing capabilities which enable resistant strains to overcome the blockade by clea^'mg the nucleoside analog and continuing the elongation. Currently clinically used NRTIs include zido\Tidine (A2T), didanosine (ddl), zalcitabine (ddC). stavudine (d4T), lamivudine (3TQ and tenofovir (PMPA). NNRTIs Were first discovCTed in 19S9.NNRTI are allosteric inhibitors wliich bindreversibly at a nonsubstrate binding site on the HIV reverse transcriptase thereby altering the shape of the active site or blocking polymerase activity. (R. W. Bucfcheit, Jr., Non~nucleoside re\'erse transcriptase ifihibitors: perspectives for novel therapeutic compounds and strategies for treatment of HIV infection. Expert Opin. Investig. Drugs 2001 10(8)1423-1442; E. De Qercq The role ofnon-nucleoside reverse trcaiscriptase inhibitors (NNRTIs) in the therapy ofHW-I infection, Antiviral Res. 1998 38:153-179; G. Moyle, Tlie Emerging Roles of Non-Nucleoside Reverse Transcriptase Inhibitors iji Antiviral Tlierapy, 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 HIV therapy: efavu-enz, nevirapine and delavirdjne. 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 HIV strains when used in monotherapy as well as having and class-specific toxicitjf. Drag resistance frequently develops with only a single point mutation in the RT. While combination therapy with NRTIs, Pis and NNRTIs has, in many case^, dramatically lowered viral loads and slowed disease progressdon, significant therapeutic problems remain. The cocktails are not effective in all patients, potentiaBy severe adverse reactions often occur and the rapidly reproducing HIV 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 HIV. WO 02/100852 (B. W. Dymock et at) discloses novel pj-razole derivatives, processes for preparmg the novel pjTazoles, pharmaceutical compositions containing the pyra2X>les and the use of pyrazoles as inhibitors of human immunodeficiency virus reverse transcriptase enzyme which is involved in viral replication. WO 02/30907 (B. W. Dymock et al.) also teaches novel pyrazoles useful for inhibiting HIV reverse transcriptase. These patents are hereby incorporated by reference in their entirety. US 6,005,109 (W. S. Faraci) EP 0 691 128 (G. M. Bright et at) and EP 0 959 074 (G. M. Bright et al.) disclose pyrazole derivatives which have corticotropin releasing factor antagonist activity. EP 1 072 597 (Banks, B. J. et al.) disclose pyrazole derivatives with endothelia antagonist activity. WO 97/04773 (J. I. Luengo et al.) discloses phenyl pyrazoles as endothelin receptor antagonists for treating cardiovascular or renal disease. WO 02/04424 (R. G; Corhau et al.) discloses the use of pyrazole derivatives in the manufacture of reverse transcriptase inhibitor or modulator, to novel pyrazole derivatives and to processes for the preparation pyrazole derivatives and for compositions containing novel pyrazole derivatives. WO02/0S5860 (L. H. Jones , et al) disclose pyrazole compounds, processes for the preparation of the pj'razole compounds and uses for the confounds to inhibit or modulate viral enzyuie reverse transcriptase. The use of the pyrazoles for the treatment diseases caused Human Immuno¬deficiency Vims CHTV) also is taught WO 00/66562 (V. B. Lohray et al.) disclose phenylsulfinyl-, phenylsulfcnyl- and phenylthio-substituted pyrazole compounds which inhibit r-hu COX-2 useful for inhibiting prostaglandin biosynthesis, and treating pain fever and inflammation. WO 01/16138 (T. Kolasta and M. V. Patel) and WO 01/64669 (H. Cheng et al.) also disclose sulfonylphenyl substituted pyrazole compounds which inhibit COX-2. Hydroxypyrazoles derivatives have been disclosed to have agrochemical pesticide activity. WO 99/33813 (P. Desbordes etal.) discloses fungicidal aryloxypyrazoles. The present mvention relates to a compounds according to fonnula I, methods for treating diseases mediated by human immimodeficieny virus by administration of a compound according to formula I and pharmaceutical corq)ositioiis for treatiag diseases mediated by human immunodeficieny virus containing a compound according to formula I, wherein R' is selected from the group consisting of Ci-ealiyl, Ci^shaloalkyl, Ca-ealkenyl, Cj, ealkynyl, C3.7 cycloalkyl, Ci.3alkoxy-Ci-3 alkyl, phenyl and benzyl, wherein, said phenyl and said benzyl optionally substituted with one to three substituents independently selected from the group consisting of Cj^fiaikyl, Ci^haloalkyl, C1.6 alkoxy, Ci.6haloalkoxy, Ci.6aIkyl1hio, nitro, halogen and cyan,o; R^ is phenyl or pyridyl optionally substituted with one to three groups independently selected from the group consisting of halogen, cyano, Ci,6alkyl, C].6aIk:oxy, Ci. ealkoxycarbonyl, and CONR^R'; ealkylamiiio, C].3 dialfcylamino, aiaino-C,,; aliyl, Ci_3 alkylatnino-Ci.s alkyl, and C1.3 dialIcylammo-Ci.3 alkyl; R"* is C1.6 alfeyl, Cs^ alkecyl, C;.^ alkynyl, C3_7 cycloalkyl, C1.3 altoxy-Ci.j alkyl, (CH2),R" or -(CH2)„-0-(CH2)pR"; whetein, said alkyl, said alkenyl, said alkynyl and said cycloalkyl are optionally substituted by-OH, -OR*, -NRV, -C(=Y)Z, -X(C=Y)Z, -S(0)q-Ci.6alkyl, -SOsKR^R^ or -SO2NHNH2; R" is a phenyl or a heteroaryl ring selected from the group consisting of pyridinyl, pyrimidinyl pyrazinyl, pyrrole, imidazole, pyrazol^ and tfaiophene, said heteroaryl ring and said phenyl optionally substituted with one to three groups independently selected from the group consisting of halogen, cyano, C1.3 alkyl, Ci.3 haloalkyl and C1.3 alkoxy; or R" is N[(CH2)2]2W wherein W is selected &om the group consisting of NR^ (CH2X, -N(C=0)Z, CHOR^ CHR^ CHNHC(=0)Z and CEJNR^'; n, 0 and p are as defined below and s is 0 or 1; R^, R^, R^ and R' (i) taken independently are selected from the group consisting of hydrogen, Cj. 6 alkyl, Ci^ hydroxyalkyl, C,.3 alkoxy-Ci.3 alkyl C,_3 altylamino-Ci.3 alkyl and C1.3 dialkylaniino-Ci.3 alkyl or (ii) when both R^ and R^ are attached to the same nitrogen atom they may be taken together, along with the nitrogen, to form a pyrrolidine, piperidine, piperazine ormorpholine; X, and Y are independently O or NR*; Z is hydrogen, hydroj:y-l, Ci-e alkojry, NR^'^ Ci-e alkyl, Ci.3alkosy-Ci.3alkyl wherein R^^ is R"^ or phenyl optionally substituted with one to three groups independendy selected from the group consisting of halogen, cyano. Ci.s alkyl, Ci-s haloalkyl and Cu alkoxy; n is 0 to 3; o and p are independently 0 to 4 and o + p k, rl and r2 are independently 0 to 4, and 5 > (rl + r2) > 2; and, acid addition salts, hydrates and solvates thereof; with the pro^aso diat when R' is (CHI)BR'\ n is 1 and R" is substituted phenyl, R^ is other than imsubstituted phenyl. wherein R\ R^, R^ and R* are as defined hereinabove; and, hydrates, solvates and acid addition salts thereof. In another eiobodunent of the present invention there is provided a conqjound according to formula I wherein R^ is selected from the group consisting of Ci.(iallcyl, Ci.6haloaltyl, Ca. 7cycloalkyl, Ci.jalkoxy-Ci.s alkyl and optionally substituted phenyl; R^ is optionally substituted phenyl; R" is C,^ alkyl, C3.7 cycloalkyl, -(CH2)„R^^ or -(CH2)o-0-CCH2)pR" wherein said aBcyl and said cycloalkyl are optionally substituted by -OH, -0R^ -NR^R^ -CC=Y)2, -X(C=Y)Z; R^^ is an optionally substituted phenyl; and, R' and other groups are as defined hereinabove. IQ another embodiment of the present invention there is provided a compound according to formula I wherein R' is selected from the group consisting of Ci^alkyl, Ci^haloalkyl, C^-Tcycloalkyl, C1.3alkoxy-C1.3aRy] and optionaUy substituted phenyl; R^ is optionally substituted phenyl; R^ is substituted Ci^ alkyl, -(CH2)DR^ wherein R^ is ma-IIDi, or Ila-c; R" is C1.6 alkyl, C3-7 cycloalkyl, (CH2)flR" or -(CH2)o-0-(CH2)pR" wherein said alkyl and said cycloalkyl are optionally substituted by-OH, -0R^ -MR^R^ -C(-Y)Z, -X(C=Y)Z; R'^ is an optionally substituted phenyl; and other groups are as defined hereinabove. In another embodiment of the present inventioD there is provided a compound according to formula I wherein R' is selected from ihe group consisting of Ci.6alkyl, Ci-^haloalkyl, C3. jcycloalkyl, Ci.jaltoxy-Ci.sallq'l and phenyl; 'S? is optionally substituted phenyl; R^ is -CCH.JnNR^', -(CH2)nC(=0)Z or (CH2)oXC(=0)Z; R^ is C,.^ alkyl. C3.7 cycloalkyl, (CH2)„R" or -(CH2) (CH2)pR" wherein said alkyl and said cycloallqd are optionally substituted by -OH, -OR , - ^fR^R^ -C(=Y)Z, -X(C=Y)Z; R" is an optionally substituted phenyl other groups are as defined heremabove. In another embodiment of the present invention there is provided a confound according to formula I wherein R^ is selected from the group consisting of Ci_6alkyl, Ci-elialoalkyl, C3. 7cycloalkyl, Ci-Balkoxy-Ci-jalkyl and optionally substituted phenyl; R^ is optionaEy substituted phenyl; R" is Ci^ealkyl, C^.^ cycloalkyl, -(CH2)Jl" or -(CH2)o-0-(CH2)pR" wherein said alkyl and said cycloalkyl are optionally substituted by -OH -0R^ -NRV, -C(=Y)Z, -X(C=^Y)Z; R'^ is an optionally substituted heteroaryl ring selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyrrole, imidazole, pyrazole and thiophene; and R^ and other groups are as defined herekiabove. In another embodiment of the present invention there is provided a compound according to formula I wherein R^sseJected from tfie group consisting of Ci-salkyl, Ci_fihaioallcyl, C3, 7cycloal]cyl, Ci.jalkoxy-Ci.jalkyi and optionally substituted phenyl; R^ is optionally substituted phenyl; R^ is substituted C1.6 alkyl, -(CH2)„R^ wherein R^ is Ula-IIIh or Ha-c; R" is Cj^alkyl, C3_7CycloaIkyl, -(CH2)„R" or -{CH2)o-0-(CH2)pR" wherein said alkyl and said cycloalkyl are optionally substituted by -OH, -OR*, -NR^R^ -C(=Y)Z, -X(C=Y)Z; R^' is an optionally substituted heteroaryl ring; and other groups are as defined hereinabove. In another embodiment of the present invention there is provided a compound according to formula I v/herein R' is selected from the group consisting of Ci-ealkyl, Ci^aloalkyl. C3. cycloalkyl, Ci,3alkoxy-C]_3alkyl and optionally substituted phenyl; R is optionally substimted 7' 3 phenyl; R is -(CH2)IlNR*R^ -(CH2)„C(=0)Z or -(CH2)„XC(=0)Z; and, R' is Ci.5alkyl, C3.7cycIoaIk7l, - (CHj)^' or -(CH2)o-0-(CH2)pR'^ wherein said alkyl and said cycloalkj-l are optionally substituted by -OH, - 0R^ -NR^R', -C(=Y)Z, -X(C=y)Z, R" is an optionally substituted heteroary! riag selected from the group consisting of pyridinyl, pyrimidinyl, pjTrazinyl, pyrrole, unidazole, pyrazole and thiophene: and other groups are as defined hereinabove. In another embodiment of the present invention there is provided a compound according to formula I wherein R' is selected from the group consisting of Ci^alkyl, Ci-ehaloalfcyl- C3_ 7cycloaIkyl, Ci.3alkoxy-Ci.3alkyl and optionally substituted phenyl; R~ is optionally substituted phenyl; R* is C,.6alkyl, C3.7 cycloalkyl, -(CH.)Ji" or -(CH2)o-0-(CH2)pR" wherem said alkyl and said cycloalkyl are optionaUy substituted by -OH, -OR*, -NR^', -C(=Y)Z, -X(C=Y)Z; R^^ is N[{CS2)2l2W wherein W is selected from the group consisting of NR^ (ai2)s, N(C=0)Z, CHOR^ CHR'^ CHNHC{=0)Z and CHNRV; and, R^ and other groups are as defined hereinabove. In another embodiment of the present iuvention there is prowded a compound according to formula I wherein R^ is selected from the group consisting of Ci-ealkyl, Ci-ghaloalkyl, €3. 7cyc]oalkyl, Ci.3alkoxy-Ci_3alkyl and optionally substituted phenyl; R^ is optionally substituted phenyl; R^ is substituted C1.6 alkyl, -{CH2)aR^ wherein R^ is IHa-imi; or Ila-c; R" is Ci-ealkyl, C3.7Cycloalkyl, -(CH2)„R" or -{CH2)o-0-(CHi)pR" wherein said alkyl and said cycloalkyl are optionally substituted by -OH, -0R^ -KR^R^ -C(=Y)Z, -X(C=Y)Z, R^' is N[(CH2)2]2W wherein W is selected from the group consisting of NR*, (CHa)^, N(C=0)Z, CHOR*, CHR* CHNHC{=0)Z and CHNR^R'; and, other groups are as defined heremabo^'e. In another embodiment of the present invention there is provided a compoimd according lo formula I wherein R^ is selected from the group consisting of Ci.6 alfcyl, d-e haloahcyl, C^-i cycloalkyl, C^ alkoxy-Ci.s allcyl and optionally substituted phenyl; R^ is optionally suhstimted phenyl; R^ is (CH2)„NR*R^ {CB2\C{=0)Z or (CH2)^C(=0)Z; R"* is Ci.6 allcyl, C3., cycloaikyl, (CH2)nR" or -(CH2)o-0-(CH2)pR" wherem said alfcyl and said cycloaikyl are optionally substituted by-OH, -OR^ -NR^R^ -C(=Y)Z, -X(C=Y}Z; R" is NtCCHjjJjW wherein W is selected from the group consisting of NR^ (CHa)^, -N(C=0)Z, CHOR^ CHR^ CHNHC(=0)Z and CHNR^' and other groups are as defined hereinabove. hi 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. conmrising admimstering to a host in need thereof a therapeutically effective amount of a confound of formula I wherein R\ R', R^ and R* are as defined hereinabove; and, hydrates, solvates and acid addition salts thereof. hi another embodiment of the present invention there is provided a method for treating an HIV infection, or preventing an HIV infection, or treating AIDS or ARC, comprising co¬administering to a host in need thereof a therapeutically effective amount of a compound of formula I wherein R', R^, R^ and R* are as defined hereinabove; and, hydrates, solvates and acid addition salts thereof, and at least one compound selected from the group consisting of HI\'^ protease inhibilOT's, nucleoside reverse tracscriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, CCR5 inhibitors and viral fusion inhibitors. In anotlier embodiment of the present invention there is pro'.dded a method for tieating an HTV infection, or preventing an HIV infection, or treating AIDS or ARC, comprising co¬administering to a host in need thereof a therapeutically effective amount of a conq)ound of formula I wherein R', R^, R^ and R* are as defined hereinabove; and, hydrates, solvates and acid addition salts thereof; and a reverse transcriptase inhibitor selected from the group consisliDg of zidovudine, lamivudine, didanosine, zalcitabine and stavudine, rescriptor, sustiva and viramune aud/or a protease inhibitor is selected from the group consisting of saquinavir, ritonavir, oelfinavir, indinavh, amprenavir, lopinavjrat and atazanavir. in another embodiment of the present invention there is provided a method for inhibiting a reuoviras reverse transcriptase comprising administering to a host in need thereof a therapeutically effective amount of a compound of formula I wherein R^, R^ R^ and R' are as defined hereinabove; and, hydrates, solvates and acid addition salts thereof- In another embodiment of the present invention there is provided a method for treating an HIV infection, or preventrng an HIV infection, or tieating AIDS or ARC, wherein the host is infected with a strain of HIV expressmg a reverse transcriptase with at least one mutation, comprising administering to a host in need thereof a therapeutically effective amount of a compound of formula I wherein R\ R^ R^ and R"" are as defined heieinabove; and, hydrates, solvates and acid addition salts. hi another embodiment of the present invention there is provided a method for treating an HIV infection, or preventing an HIV mfection, or treating AIDS or ARC, wherein said stram of HIV exhibits reduced susceptibiUty to efavirenz, delavirdine or nevirapine comprising administering to a host in need thereof a therapeutically effective amoimt of a compound of formula I wherein are as defined hereinabove; and, hydrates, solvates 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 compoimd of formula I wherein R\ R^, R^ and R* are as defined hereinabove; and, hydrates, solvates and acid addition salts thereof in admixture with al least one pharmaceutically acceptable carrier or diluent sufficient upon administration in a single or multiple dose regimen for treating diseases mediated by human iammnodeficisny virus or to inhibit HIV. 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 confounds or at least one confound. 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 defmition provided in the Smnmary of the lovention. The term "alkyl" as used herem denotes a unbranched or branched chain, saturated, monovalent hydrocarbon residue containing 1 to 6 carbon atoms. Examples of alkyl groups include, but are not lunited to, lower alkyl groups include methyl, ethyl, propyl, i-propyl, j7.-butyi, f-butyl, r-butyl or pentyl, isopentyl, neopentyl and hexyl. The term "alkylene" as used herein means a divalent unbranched or branched saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, having from 1 to 6 carbon atoms iaclusive, unless otherwise indicated. Examples of alkylene radicals include, but are not limited to, methylene, ethylene, propylene, 2-methylethyIene, 3-methylpropylene, 2-ethyletiiylene, pentylene, hexylene, and the like. The term "haloalkyl" as used herein denotes a mibranched or branched chain alkyl group as defined above wherein 1,2, 3 or more hydrogen atoms are substituted by a halogen. Examples aie 1-fluoromethyl, 1-chloromethyl, l-bromomethyl, l-iodomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, triiodomethyl, l-fluoroethyl, 1-chloroethyl, l-bromoethyl, 1-iodoediyl, 2-fluoroethyl, 2-chIoroethyl, 2-bromoethyl, 2-iodoethyl, 2,2-dichloroethyI, 3-bromopropyl or 2,2,2-trlfluoroethyl. The term "fluoroalkyl" refa:s to a "haloalkyl" wherem the halogen is fluorine ■'D^ The term "cycloaUcyl" as used herein denotes a saturated carbocyclic ring containing 3 to 7 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. The term "alkenyl" as used herein denotes an unsubstituted hydrocarbon chain radical having from 2 to 6 carbon atoms and having one or two olefinic double bonds. Examples are vinyl, 1-propenyl, 2-propenyl (allyl) or 2-butenyl (crotyl). The term "alkynyl" as used herein denotes an unsubstituted hydrocarbon chain radical having 6x>m 2 to 6 carbon atoms and ha^Tog one or where possible two triple bonds. Exarr^Ies are ethynyl, 1-propynyl, 2-propynyh l-butynyl, 2-butynyl or 3-butynyl. The term "alkoxy" as used herein denotes an unsubstituted unbranched or branched chain alkyloxy group wherein the "aUcyl" portion is as defined above such as methoxy, ethoxy, 71-propyloxy, j-propyloxy, n-butyloxy. i-butyloxy, f-butyloxy. pentyloxy and hexyloxy including their isomers. The term "haloalkoxy group" as used herein means an -O-haloalkyl group, wherem 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 "thioalkyl" or "alkylthio" as used herein refers to a group -SR where R is an alkyl group as defined herein such as methylthio, ethylthio. H-propylthio, f-propylthio and 7i-butylthio including their isomers. The term "alkoxyalkyl" as used herein refers to tbe radical R'R"-. wherein R' is an altoxy radical as defined herein, and R" is an alkylene radical as defined herein with the understanding that the attachment point of the alkoxyalkyl moiety will be on the al^lene radical. Examples are methoxymethyl, methoxyethyl, methoxypropyl, e&oxymethyl, efhoxyethyl, ethoxypropyl, propyloxypropyl, methoxybntyl, ethoxybntyl, propyloxybutyl, butyloxybutyl, r-bnt^doxybutyl, methoxypentyl, ethoxypentyl, propyloxypentyl including their isomers. The terms "hydroxyalkyl" as used herein denotes the radical R'R" where R' is an hydroxy radical and R" is alkyiene as defined herein and the attachment point of the hydroxyalkyl radical will be on the alkyiene radical The term "acyl" as used herein denotes a group of formula C(=0)R ("alkylcarbonyl") wherein R is hydrogen, unbranched or branched alkyl contaioing 1 to 6 carbon atoms, cycloalkyl containing 3 to 7 carbon atoms, an aryl, an alkoxy, or a NR'R" group. The term acyl includes a group of formula C(=0)0R' ("alkoxycarbonyl") or C(=0)NR^' ("carbamoyl") where R is an altyl group and R** and R' is defined hereinabove. The term "acylating agent" as used herein refers to a reagent which is capable of transferring an acyl moiety as defined previously to another functional group capable of reacting with the acylating agent Typically an alkylcarbonyl is introduced by reaction with an anhydride or an acyl haUde. The term "anhydride" as used herein refers to confounds of the general structure RC(0)-0-C(0)R wherein is as defmed in the previous paragraph. The term "acyl hahde" as used herein refers to the group RC(0)X wherein X is bromo or chloro. Tj'pically an alkoxycarbonyl is introduced by reaction with an alkoxycarbonyl chloride. The term "alkoxycarbonyl chloride" as used herein refers to compounds of the general structure R0C(=O)Q. Typically a carbamoyl group is introduced by reaction with an isocyanate. The term "isocyanate" as used herein refers to coirqiounds of fie general structure RN=C=0. The functional group depicted as "-XC(=Y)Z" wherein X and Y are independently O or NR^ and Z is Ci.6 alkoxy, KR*R\ alkyl or alkoxyalkjd preferable refer to "guanidines" (-MR^(=NR°) NR^R^), "imidates" (-OC(=NR^)alkyl), "amidines" (-NR*C(=NR^)aIkyl), "carbonates" (-OCC=0)OR), "carbamates" (-0C(=0) NR^' or -NR*C(=0)OR), "ureas" (-NR^CC=0)NR^R^), "amides" (-NR^C(=0)aIky]} or "esters" ('OC(=0)aIky] > where R^ and R' are as defined berem and R is an alkyl group. The functional group "C(=Y)2" as used herein refers to esters, amideE, imidates and amidines. The term "heterocyclylalkyl" as used herein means a radical -R'R" where R' is an alkyiene radical and R" is a heterocyclyl radical as defined herein. Examples of heterocyclylalfcyl radicals include, but are not limited to, tetrahydropyran-2-ylmethyl, 2-piperidinylmethyl, 3-piperidinylme±yl, morphohn-l-ylpropyl, and the like. The term "alkj'Iamino" as used herein means a radical -NR'R", wherein R' is hydrogen and R" is an alkyl radical as defined herein. The term "dialkylamiao" as used herein means a radical - NR'R", wherein R' and R" are aliyl radicals as defined herein. Examples of alkylamino radicals include, but are not limited to, methylamino, ethylamino, cyclopropyhnethylamino, dicyclopropylmethylamino, dimethylamino, methylethylamino, diethylamino, di(l-methyiethyl}anuno, and the like. The term "aryl" as used herein denotes an optionally substituted monocyclic or polycycHc-aromatic group comprising carbon and hydrogen atoms. Examples of suitable aryl groups include, but are not limited to, phenyl and naphthyl (e. g. 1-naphthyl or 2-naphthyi). Suitable substituents for aryl are selected from the group consisting of Ci^ alkyl, Ci_6 haloalkyl, Ci.6 aUfoxy, Ci^ baloalkoxy, Cj^ alkylthio, alkoxycarbonyl, CONR^', nitro, halogen and cyano. Optionally substituted phenyl in R^ can be for example 2-chloro-phenyl, 3-cbloro-phenyl, 4-chloro-phenyl, 2,3-dicblorDphenyl, 2,4-dichlDrophenyl. 2,5-dichlorophenyl, 2,6-dichlDrophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyI, 2,3.4-trichlorophenyl, 3,4,5-trichlorophenyl, 2,3,4,5,6-pentachlorophenyl, 2-cyaQo-phenyl, 3-cyano-phenyl, 4-cyano-phenyl, 2,3-dicyanopbenyl, 2,4-dicyanophenyl, 2,5-dicyanophenyl, 2,6-dicyanophenyl, 3,4-dicyanophenyl, 3,5-dicyanophenyl, 3,6-dicyanophenyl, 2-bromopheDyl, 3-bromophenyl, 4-bromophenyl, 2,3-dibromopheny!, 2,4-dibromopbenyl, 2,5-dihroniophenyl, 2,6-dibromopheayl, 3,4-dibTomophenyl, 3,5-dibromophenyl, 3,6-dibromophenyl or 3-chloro-5-cyano-phenyl, The term "heteroaryl" or "heteroaromatic" as used herein means a monocyclic or bicyclic radical of 5 to 12 ring atoms having at least one aromatic ring containing four to eight atoms per ring, incorporating one or more N, O, or S heteroatoms, the remaioing ring atoms being carbon, with the understanding that the attachment point of said heteroaryl radical will be on said aromatic ring. As well known to those sldUed in the art, heteroaryl rings have less aromatic character than their all-carbon counter parts. Thus, for the purposes of the iuventioo, a heteroarj'l group need only have some degree of aromatic character. Exanqiles of heteroaryl moieties include monocyclic aromatic heterocycles ha\'ing 5 to 6 ring atoms and 1 to 3 heteroatoms include, but is not limited to, includmg, and includes, but is not limited to, pjTidinyl, pyrimidinyl, pyrazinyl, pyridazinone, pj-rrolj'!, pyrazolyl, imidazolyl, triazoline, and oxadiaxoline which can optionally be substituted with one or more, preferably one or two substituents selected from hydroxy, cyano, alkyl, alkoxy, thio, lower baloalkoxy, alkylthio, halo, haloalkyl, alkylsulfinyl, altylsulfony], halogen, amino, allcylainino, dialkylamino, aminoalkyl, alkylaminoalkyl, and diaikylaminoalkyl, nitro, alkoxycarbonyl and carbamoyl, alkylcarbamoyl and dialkyicarbamoyl. The term "heterocyclylaUcyl" as used herein means a radical -R'R" where R' is an alkylene radical and R" is a heterocyclyl radical as defined herein. Examples of heterocyclylalkyl radicals include, but are not limited to, 2-piperidinylmetiiyl, 3-piperidinylmethyl, morpholin-l-ylpropyl, and the like. The term "heterocycje" or "heterocyclic" as used hersin means a non-aromatic monocyclic or polycyclic ring comprising carbon and hydrogen atoms and one or more N, S, or 0 hetematoms. k. heterocyclic group can have one or more carbon-carbon double bonds or carbon-heteroatom double bonds ID the ring as long as the ring is not rendered aromatic by their presence. Examples 3f heterocycloalkyl groups include pyrrolidinyl, pyrrohdino, piperidinyl, piperidiuo, piperazinyl, piperazino, moiphohnyl, morpholino, thiomorpholinyl, thiomorpholino. A heterocyclic group :an be unsubstituted or substituted with one to three suitable substituents selected from hydroxy, :yano, alkyl, alkoxy, thio, lower haloalkoxy, alkylthio, halo, haloalkyl, alkylsulfinyl, aUcylsulfonyl, halogen, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, and diaUcylaininoalkyl, nitro, alkoxycarbonyl and carbamoyl, aUcylcarbamoyl and dialkylcarbamoyl. The terms "amino", "alkylamino" and "dialkylamino" as used h^-eia refer to -NH2, -NHR and -NR2 respectively and R is alkyl as defined above. The two alkyl groups attached to a nitrogen in a dialkyi moiety can be the same or differenL The terms "aminoaikyl", "alkylaminoalkyl" and "dialk>'lammoalkyl" as used herein refer to NHzCCH^jn-, RHN(CH2)n-, and R2N(CH2)n-respectively wherein n is 1 to 6 and R is alkyl as defined above The term "acyl" or "alkylcarbonyl" as used herein denotes a radical of formula C(=0)R wherein R is hydrogen, unhranched or branched alkyl containing 1 to 6 carbon atoms or a phenyl group. The term "acylammo" as used herem denotes a radical of foranila -NH-C(=0)-R wherein R is hydrogen, unbranched or branched alkyl containing 1 to 6 carbon atoms, cycloalkyl containing 3 to 7 carbon atoms or an aiyl. The torm "halogen" as used herein means fluorine, chlorine, bromine, or iodine. Correspondingly, the meaning of the term "halo" encompass fluoro, chloro, bromo, and iodo. The term "alkylthio" or "thioaDcyl" means an -S-alkyl group, wherein alkyl is as defmed above such as meththio, ethylthio, n-propylthio, i-propylthio, »-butylthio, hexylthio, including their isomers. The term "alkylsutfinyl" as used herein means the radical -S(0)R', wherein R' is alkyl as defined herein. Examples of aUcylaminosulfonyl include, but are not hmited to methylsulfinyl and i^o-propylsulfinyl. The term "alkylsulfonyr' as used herein means the radical -S{0)2R', wherein R' is altyl as defined herein. Examples of alkylaminosulfonyl include, but are not hmited to methylsulfonyl and wo-propylsulfooyl. The term "sulfonylating agent" as used herein refers to a reagent which is capable of transferring an alkyl sulfonyl moiety as defined previously to another functional group capable of reacting with the sulfonating agent such as a sulfonyl chloride Cl-^02-R. The prefix "carbamoyl" as used herein means the radical -C0NH2, The prefix "N-alkylcabamoyl" and "N,N-dialkyIcarbamoyl" as used herein means a the radical CONJIR' or CONRU" respectively wherein the R' and R" groups are independendy alkyl as defined herein. The term "homologous" as used herein refers to a series of related conqiounds whose structure at some part of the molecule differs only by a -(CH2)- or -(CHs)^- from another member of the series 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 equihbrimn and attempts to isolate an individual tautomers usually produce a mixture whose cheinicai and physical properties are consistent with a mixture of compounds. The position of the equihbrium is dependent on chemical features within the molecule. For example, in many ahphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates while; in phenols, the enol form predominates. Common prototropic tautomers include keto/enol (-C(=0)-CH- ^ -C(-OH)=CH-), amide/imidic acid (-CC=0)-NH- ^ -C(-OH)=N-) and amidme (-C(=NR}-NH- ^ -C(-NHR)=N-) tautomers. The latter two are particularly common in heteroaryl and heterocyclic rings and the present mventiou encompasses all tautomeric forms of the confounds. 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 bke, and with organic acids (e.g. with acetic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, malic acid, saHcylic acid, citric acid, methanesuiphonic acid andp-toluenesulfoiiic acid, and the like). The tenD "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 io trace amounts. Me 1_1 tetrahydrofuran (THF) or other polar aprotic solvents such as dimethylsulfoxide (DMSO), dimethylacetamide (DMA) or N,N-dimethyIformamide (IMF) in the presence of a base such as such as n-butyl hthium, sodium hydride, or sodium tert-butoxide. The reaction is conveniently carried out under an inert atmosphere such as nitrogen or argon atmosphere at a reaction terr^ierature from 0°C to boiling tenq)erature of the reaction mixture, preferably at a reaction temperature between about 10°C and about 1S0°C. 4-AIkyl pyrazoles were prepared by reacting the aldehyde with an alkyl Grignard reagent to produce a secondary carbinol 8 and subsequendy reducing the secondary carbinol with triethylsLtane to yield 9. (SchenK 3) One skilled in the art will recognize that although the scheme is depicted with a methyl Grignard reagent other ailiyl and alkenyl Grignard reagents as well as other organometallic derivatives conunonly used in organic synthesis, including, but not limited to, hthium, zinc, cadmium, zirconium, sodium, potassium, also will suffice. The reaction is carried out at temperatures ranging from -78'C to 0°C in inert solvents which include diethyl ether, tetrahydrofuran, 1,2-diinethoxyethane, hexane. Reduction of aldehyde 7 to carbinol 12 is accomphshed with a hydride reducing agent. Typical reducing agents include sodium borohydride, lithium borohydride, and sodium triacetoxyborohydride. Alternatively catalytic hydrogenatioo or other reducing agents known in the art can be appUed. NaBHt reductions are conveniently carried out in an organic solvent for example alcoholic solvents such as methanol, ethano], propanol or ethers such as tetrahydrofuran, diethyl ether, or dimethoxyethane or a mixture of the mentioned solvents. Aprotic solvents are required for more reactive hydride transfer reagents. The reaction is carried out at a reaction temperature between about -lO^C and about 60°C, preferably at room tea5)erature. The reduction reaction can also be carried out as described in textbooks about organic chemistry e.g. from J. March (1992), "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 4* ed. John WUey & Sons. The carbinol can then be further derivatized 13 (R'^ = acyl, alkyl, arallcyl, aryl, carbamoyl). (a) RMgBr, THF; (b) EtjSiH, TFA, CH^a^; (c) NaBH^, MeOH; (d) alkylating or acylating agent; (e) FhjP*CH^CO^Me, NaH, THF, 0 °C: (f) Mg, MeOH: (g) LiEt3BH, THF, -40 °C to rt. Alteraati-v'ely, the C-4 aldehyde can be caiverted to an alkene 14 (Scheme 3) or substituted alkene with a Wittig reagent or Emmons-Wadsworth reagent (see J. W. Schulenberger and S. Archer, Organic Reactions, Wiley &. Sons, New York 1965 vol. 14, chapter 1, pp. 1-51; J. March, Advtsiced Organic Oiemistry, 4"' ed., John Wiley & Sons, New York, 1992, pp. 956-963). The olefination reaction is carried out by procedures similar to those described in the hterature, for example in the presence of a strong base such as 7?--butyl lithimn or preferably sodium hydride in an organic solvent such as anhydrous ethers such as diethyl ether, dibutyl ether, dioxane, preferably anhydrous tetrahydrofiiran under inert atmosphere such as nitrogen or argon atmosphere at a reaction temperature &om 0°C to 80°C, preferably at a reaction temperature between about 5°C and about 50°C. The olefination affords an efficient method for homologation of the C-i substituent. Optionally the resulting alkene may be reduced to 15a by catal5^c hydrogenation wi^ standard platinum, paHadimn and ruthenium catalyst on supporting materials such as activated carbon or alumina, or generally as described in textbooks about organic chemistry (e.g. J. March (1992), Advaiiced Organic Chemistry: Reactiom, Mechanisms, and Structure, 4^ ed. John Wiley & Sons, New York, 1992, pp. 771-7S0) under a pressure from 1-40 atmospheres; or, by dissolving metal reduction (Yuon et al., TetraJiedron Lett 1986 27:2409; Hudlicky et al. Tetrahedron Lett. 1987 28:5287) if desired. Appropriate solvents iar the hydrogenation reaction axe organic solvent such as alcohols (e.g. methanol, ethanol), ethers (e.g. tetrahydiofuran, 1,2-dimethoxyelhane), esters (e.g. ethyl acstate), halogenated hydrocarbons (e.g. dichlorometbane) or hydrocarbons {e.g. hexane, cyclohexane and toluene). Dissolving metal reductions are carried out with magnesium in methanol. Reduction of 15a with diisobutylaluminum hydride (DIBAL-H), lithium aluminum hydride or lithium triethylborohydride affords the diol I5b. Introduction of substituents at the C-4 can also be accon5)Iished by an acylation of the hydroxypyrazole (Scheme 4). The acyl derivative 16 (step a) wherein R^^ is alkyl, aryl or aralky! is formed by leacting the correspondiag acid chloride with a 5-hydroxy-pyrazole 2. The reaction is conveniently carried out mider conditions known from acylation reactions for exanqile in an inert solvent, such as ethers e.g. anhydrous tetrahydrofnran, diethyl ether, dibutyl ether, dioxane, or a mixture of the mentioned solvents, at a reaction temperature ftom room temperature to boiling ten5)erature of the reaction mixture in the presence of a catalyst such as Ca{0H)2, KjCOs, AlCIs, BF3, FeCh, SnCLi or ZnQ:. The 5-hydraxy pyrazole 16 is easily converted to a 5-chloropyrazole derivative 17 with a chlorinating agent such as (C0a)2, HCl, PCI5, PQs, S0a2 or POCls. The reaction is conveitiently carried out under an inert atmosphere such as nitrogen or argon atmosphere at a reaction temperature from room temperature to boiling lemperatLue of the reaction rmxture. Preferably, the reaction is carried out in the presence of phogshorus oxychloride (POCI3) at a reaction temperature between about 5Q°C and about 180°C. Optionally, the reaction can be carried out in an organic solvent such as halogenated hydrocarbons (e.g. dichloromethane or chioroform), hydrocarbons (e.g. cyclohexane, methyl cycJohexane, decaline, benzene, toluene, o-xj'lene. j;i-xylene orp-xylene) or a mixtures of the mentioned solvents. deduction of the carbonyl IS to alkane 19 (scheme 4, step d) is accomplished with alkylsilaiie in ie presence of a protic or Lewis acid. The reaction is conveniently caiiied out with trimethylsUane, triethylsilane or tripropylsilane. Trtfluoroacetic acid (IFA) is the preferred protic acid and SnCJ4 is the preferred Lewis acid (D. L. Comins et al, Tetrahedron. Lett., 1986, 27:1869) at a reaction temperature from 0°C to SO^C, preferably at a reaction teaperature between about 5°C and about SO^C. Optionally, the oxo derivative IS is directly reduced to Ihe corresponding methylene 19 using other procedures known in the art, e.g., the Qemmensen reduction, the Wolff-Kischner reduction and hydogenolysis of thioacetals or reduction. The C-3 ester or pyrazoles 5 and 25 (Scheme 5) are converted into the corresponding amides 45 by transamidation or by saponification of the ester which can be then be converted to the amide by standard methodology (J. March Advanced Organic Oiemistry. 4'*' Ed J Wiley & Sous: New York 1991; pp 419-424). A pyrazole with a nitrUe 23 is converted to the corresponding imidate 46 by treating the nitrile with an alcohol in the presence of hydrochloric acid. R. Sandler and W. Karo, Organic Functional Group Preparations, 2°^ Ed-, Academic Press, New Yort, vol, m, }S>S6, pp. 314-330). Amidines 47 are prepared by treating an imidate with a ammonia or a substituted amine or, alternatively by sequential treatment of an amide 45 with phosphorus oxychloride and ammonia or a substituted amine. The C-3 carbinol in 9 (Scheme 6) can be converted to esters (20; R" = C(=0)R^), carbonates (20; R^^ = C(=0)OR^) and carbamates (20; R^^ = C(=0)NHR^) by condensation of 9 with acid chlorides or anhydrides, alfcylchloroformates, and isocyanates respectively (J. Maich. Advanced Organic Chemistry i^ Ed J Wiley & Sons: New Ycdc, 1991; p-p 392-396 and S9I-S92; S. R. Sandler and W. Karo, Organic Functional Group Preparations, 2""* Ed., Academic Press, New York, vol. 1,1983, pp. 299-304; vol. H, 19S6, 260-271). Ethers (20; R'^ = altj'l or aralfcyl) can be prepared by the Williamson ethei synthesis or Mitsunobu reaction (March supra, pp. 386-87; S. R. Sandler and W. Karo, Organic Functioiial Group Preparations, T^ Ed., Academic Press, New York, vol. 1,1983, pp. 129-133). The Williamson ether synthesis may be preferably carried oiit in an organic solvent such as polar aprotic solvents like N,N-dimethylacetarDide or N,N-dimethylformamide (DMF), acetonitrile or tetrahydrofuran using a base such as sodium hydride, lithium hydride, potassium hydride, potassium rert-butoxide, lithium carbonate, sodium carbonate, potassium carbonate or organic amines such as triethylamine or an N-alkyl morpholine such as N-methylmorpholine ^ a reaction tenqrerature between about -10°C and about 60°C, preferably at room temperature. Alternatively, the carbinol can be conva:ted to an alkyl halide and reacted with an alkali metal phenoxide. Amines 21 WM'e prepared from the alcohol 9 by the Mitsunobu condensation (March supra^ pp. 414415). Treatment of 21 TOth acylating agents provides amides (22; R" = COR*), carbamates (22; R^^ = COsR^) and ureas (22; R'^ = C(=0)NHR^). Guanidines (22; R^^ = C(=NH)NRV) are prepared from the thiourea (22; R'^ = C(=S)NHR*) by sequential treatment with dimethylsulfate and an amine. (Y. Yamamoto et al. Synthesis arid Chemistry of Guanidines in The Chemistry of Amidines and Imidates, S, Patai and Z. Rappoport (Eds.), Wiley &. Sons, Chichester 1991, Chapter 10, pps.489-492). Condensation of the amine with a sulfonylating agent produces the corresponding sulfonamide (22; R^^ = SO2R*)- The homologous amine and carbinol derivatives are prepared by a two-step process comprising conversion of the primaiy alcohol to an alkyl halide and displacement of the halide with sodium cyanide. The resulting nitrile 23 can be reduced to the amine 24 (R}^ = H) by sequential treatment with diisobutylaluminum hydride and sodium borohydride. The resulting amine 24 (B}^ = H) can be treated with acylating, alkylating and sulfonylating agents. Hydrolysis and esterificatjon of 23 )'ielded the corresponding ester 25 (R" = Me) which was reduced to alcohol (26; R'^ = H) and further derivatized with alkylating and acylating agents as described above. Introduction of heterocyclylaityl substituents onto the C-3 position of the pyrazole was accomplished by modification of the nitrile 23 or the ester 25. Pyridazinones 28 were prepared by base-catalyzed condensation of the appropriately substituted ester orrutrile and 3,6-dichloropyridazine (Scheme 7). The condensation is accomplished efficientiy with sodium hydride and DMF. Hydrolysis of 27a or 27b under acidic conditions with aqueous hydrochloric acid and acetic acid resulted in hydrolysis, decarboxylation and concomitant hydrolj'sis of the chloropyridazine to produce pyridazinone 28. 2-Oxo-2,3-dihydro-l,3,4-oxadiazoles 30a was prepared by cyclization of an acyl hydrazide 29 with phosgene (or equivalents such as carhonyl diimidazole, alkyl chloroformates and the hke) to directly produce the desired oxadiazole. (A. Hetzheim, 1,3,4 Oxadiazoles in Houben-Weyl Metlioden der Orgamschen Chemie, Hetarene EI/Teil 3, Band E8c; Verlag, Stuttgart; 1994, pp531-536) (Scheme 7) 2-Oxo-2,3-dihydro-l,3,4-thiadiazoles 30b are prepared by condensation of an 0-aIkyl imidate 31 and methoxythiocarbonyl hydrazide which produce a 2'methoxy-3,4-thidiazole derivative 32 which was hydrolyzed to the corresponding 2-oxo-2,3-dihydro-l,3,4- ■ thiadiazole 30b unda- acidic conditions (H. Kristinsson et al. Helv. Chbn. Acta 1982 65:2606). Alternatively, cyclization of N-acyl-N'-aUcoxycarbonyl hydrazides with Lawesson's reagent can dhectly produce the thiadiazole (B, P. Rasmussen et al. Bull. Soc. Chbn. Fr. 1985 62). Triazolones 34 can be prepared by carbamoylation of an acyl hydrazide 29 with ethyl isocyanate to yield an N-acyl-N-carbamoylhydrazide 33 cyclized to the triazolone 34 upon treatment with methanohc potassium hydroxide. Other heteroaryl-contaioing side chains were accessible by exploiting variations readily accessible at the 3-position which. Halomethyi compounds {see, e.g., 37) are susceptible to nucleophilic displacement by heteroatoms which produced the imidazol-l-ylmethj'l (67), pjTazoI-l-ylmethyl (6S) and N-substituted uracUs (72) compounds, (see exan^les 41 and 42) Linkages to a carbon atom of heteroaryl substituents can be iatroduced by adding an appropriately protected organometallic compound to a pyrazole with aldehyde-containing side chains (e.g. 105) followed by reductive removal of the carbinol moiety and subsequent deprotcction if appropriate (see examples 43-44,46 and 47). Heteroaryl and heterocycles also can be introduced by [l,3]dipolarcycladditions of 1,3-dipolar compounds and to multiple bonds (see, e.g, J. yi2ach-Advmced Organic Chemistry, 4"" Ed J Wiley & Sons: New York, 1991; pp 836-839). Thus cycloaddition of azides to nitriies affords the tetrazole 73 (example 36). DOSAGE AND ADMINISTRATION Compounds of the present invention are efficacious when administered by other routes of administration including contiouous (intravenous drip) topical parenteral, intramuscular, intravenous, subcutaneous, transdermal (which may include a penetration enhancen^nt agent), buccal, nasai and suppository administration, among other routes of administration. Oral administration can be in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions, syrups, or suspensions For the manufacture of pharmaceutical preparations, the compounds, as well as their pharmaceuticaUy useable salts, can be formulated with a therapeutically inert, inorganic or organic excipient for the production of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. The compounds of formula I can be formulated in admixture with a pharmaceutically acceptable carrier. For example, the compounds of the present invention can be administered orally as pharmacologically acceptable salts. Because the compounds of the present invention are mostly water soluble, they can be administered intravenously in physiological saline solution (e.g., buffered to a pH of about 7.2 to 7.5). Conventional buffers such as phosphates, bicarbonates or citrates can be used in the present compositions. Suitable excipients for tablets, coated tablets, dragees, and hard gelatin capsules are, for example, lactose, com starch and derivatives thereof, talc, and stearic acid or its salts. If desired, the tablets or capsules may be enteric-coated or sustained release by standard techniques. Suitable excipients for soft gelatine capsules are, for exan^le, vegetable oils, waxes, fats, semi¬solid and liquid polyols. Suitable excipients for injection solutions are, for example, water, saline, alcohols, polyols, glycerin or vegetable oils. Suitable excipients for suppositories are, for example, natural and hardened oils, waxes, fats, semi-liquid or liquid polyols. Suitable excipients for solutions and symps for enteral use are, for example, water, polyols, saccharose, invert sugar and glucose. TTie pharmaceutical preparations can also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for adjustment of the osmotic pressure, buffers, masking agents or antioxidants. The pharmaceutical preparations may also contain other therapeutically active agents imown in the ait. Other suitable pharmaceutical carriers and their formulations are described in Remington: Tlie Science and Practice ofPlmnnacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Peimsj'lvania. Representative phannaceutical formulations containing a compound of the present invention are described in Examples 6-S. 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. in particular, the modification of the present compounds to render them more soluble in water or other vehicle, for example, may be easily accoii^lished 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 admiitistration and dosage regimen of a particular compound in order to manage the phaimacoldDetics of the present compoimds for maximum beneficial effect in patients. The term "therapeutically effective amount" as used herein means an amoimt required to reduce . symptoms of the disease in an individual. That dosage can vary within wide limits and will, of course, be adjusted to the individual requirements in each particular case. For oral admimstration, adaily 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 100 mg/kg body weight per day. A typical preparation will contain from about 5% to about 95% active compound (w/w). The daily dosage can be administered as a single dosage or in divided dosages, typically between 1 and 5 dosages per day. In 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 non-nucleoside reverse transcriptase inhibitor or HTV protease inhibitor. When the active compound or its derivative or salt are administered in combination with another antiviral ageot the activity may be increased over the parent compound. When the treatment is combination therapy, such administration may be concuirent 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. It will be understood that references herein to treatment extend to prophylaxis as well as to die 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 HI\^ 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 fonn can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or anq)Oules. 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 compounds of formula I may be prepared by various methods known in the ait of organic chemistry. The starting materials for the syntheses are either readily available from commercial somces 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 iimiang the scope of the invention, but merely as being illustrative and representative thereof. Example 1 5-Hydroxy-lH-pyra2ole-3-carboxylic acid ethyl ester Diethyloxalacetate, sodium salt (14.53 g, 69.15 mmol) was dissolved in 100 mL of benzene and stirred for 20 min. To the solution was added 100 inL of acetic acid and the reaction mixture was stirred for a further 30 min. Hydrazine monohydrochloride (9.47 g,13S mmol) was added and the reaction mixture was stirred for an additional 30 min. The reaction was brought to reflux at 100°C for 24 h. The reaction was then removed from heat and cooled to room tettiperature and extracted with ethyl acetate and washed with 10% hydrochloric acid, saturated sodimn bicarbonate solution, water and then brine. The solvent was removed in vacuo to yield an oily solid which was then triturated with a 2:1 mixture of diethyl etheirhexanes to yield 3 (10.00 g, 92%) as an off-white sohd LKMS (electrospray); m/z [M+H]* = 157. Example 2 5-(tert-Butj'lHdimethyl-si!anyloxy)-lH-pyrazoIe-3-carboxyIic acid ethyl ester A solution of hydroxy pyrazole 3 (1.00 g, 6.40 mmol) in 10 mL of dimethylformamide was cooled to 0°C and purged mtb nitrogen. 12.8 mL (I2.S mmol) of BDCS Silylation Reagent (Aldrich) was added and the reaction was stirred for 24 h at room temperature. The reaction was quenched by the addition of water and extracted with ethyl acetate. The combined organic layers were further washed with water and brine, dried with MgSOi and filtered. Excess solvent was removed in vacuo to yield a dark oU. The aTide product was purified via silica gel chromatography with hexanes:ethyl acetate (9:1) to afford the desired silyl ether 5 (1.64 g, 94%): LRMS (electrospray); m/z [M+H]^ = 271. Example 3 5-(fert-Butyl-dimethyl-sUanyloxy)-l-(2,2,2-trifluoro-ethyl)-lH-pyrazole-3-carboxy]ic acid ethyl ester The silylenol ether 5 (R^ = H) (1.64 g, 6.06 mmol) was dissolved in 15 mL of dimethylformamide under nitrogen and cooled to O^C. Sodium carbonate was then added to the reaction mixture and stirred for 15 min wtiile purging with nitrogen. 2-Bromo-1,1,1-trifluoroethane(1.00g, 6.06 mmol) was then added and the reaction mixture was stirred at room temperature for 24 h. The reaction was then brought to reflux for an additional 24 h. The reaction was quenched by the addition of water. The mixture was extracted with ethyl acetate and washed with saturated sodium bicarbonate solution, water and brine. The mixture was dried with MgSO^, filtered, and the solvent removed in vacuo to yield an oil. The crude mixture was purified by silica gel column chromatography with an elution of hexanes: ethyl acetate (85:15) to afford 5 (B} = CH3I 1.S4 g, 85% ), Example 4 5-Hydroxy-l-(2,2,2-trifluoro-ethyl)-lH-pyrazole-3-carboxylic acid ethyl ester The silylenol ether 5 (1.84 g, 5.22 mmol) was dissolved in 10 mL of dichloromethane and stirred under nitrogen. The mixture was cooled to 0°C and stirred for an additional 15 min. Tetrabntylammonium fluoride hydrate (1.36 g, 5.22 mrool) was then added to the reaction vessel and allowed to stir for 24 h. The reaction was quenched by the addition of saturated sodiiam bicarbonate solution and extracted with dichloromethane. The combined organic layers were further washed with water then brine, dried with MgSO* and filtered. The solvent was removed in vacuo to yield a pale yellow oil. The crude mixture was purified by sihca gel chromatography with hexanesxthyi acetate (3:1) to give the desired product 6 (R^ = CH2CF3; 1.14 g, 91%). Example 5 l-Ethyl-5-hydroxy-lH-pyTazole-3-carboxylic acid ethyl ester Acetic acid (100 mL) was added via a dropping funnel to a solution of diethyloxalacetate, sodium salt (12.8 g, 60.9 mmol) in 175 mL benzene at room tenqjerature. After the addition was complete, a solution ofethyl hydrazine, oxalate salt (9.1 g, 60.9 mmol) in 40 mL of warm water was added dropwise with stirring. After being heated at reflux for 36 h, the reaction mixture was cooled to room ten^erature, poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine and the solvent removed in vacuo to give crude product as a brown oily solid. This residue was then triturated with a 2:1 mixture of diethyl ether:hexanes to give 2b (7.7 g) as an off-white solid: LRMS (electrospray); m/z [M+H]* = 185 A round bottom flask containing 100 mL of 1,2-dichloroetiiane was cooled to 0°C and purged with nitrogen. Dimethylformamide (14.75 g, 201 mmol) was added and allowed to stir for 5 mrn it C^C. Phosphorus oxychloride (155 g, 1.0 mol) was added slowly while maintaining an internal temperature of 0°C. A solution of the hydroxy pyrazole (20.0g, 100 mmol) dissolved in lOOmLof 1,2-dichloroethanewas added slowly to the mixture of dimethylformamide and Dhosphoms oxychloride at 0°C. Upon the con^lete addition of the hydroxy pyrazole the ■eaction vessel was removed from the ice bath and stirred at room temperature for 30 min. finally the reaction was heated to 110°C for 24 h. The reaction mixture was removed from beat ind brought to room temperature. Excess 1,2-dichloroethane and phosphorus oxychloride were removed in vacuo to yield a black oil. The oU was slowly dissolved in an excess of s^turMed jodium bicarbonate solution and stirred for an additional 6 h. The mixture was extracted with a [: 1 mixture of tetrahydrofuran and ethyl acetate, and washed with water and then hrine. The organic extracts were dried CMgS04) and evaporated to yield a dark oil. The product was lurified by slUca gel chromatography with hexanes:ethyl acetate (9:1) to afford flie product ;20.34 g, 80%;). Sodium hydride (60% in mineral oil, 0.48 g. 12 mmol) was added portionwise to 3-claloropheno] (1.54 g, 12 mmol) in 40 mL of anhydrous dimethylformamide at room temperature. After the phenoxide solution stirred for 15 min, 4a (2.0 g, S.2 mmol) was added in one portion and the reaction then heated at 110°C under nitrogen for 1 h. The reaction mixture was then cooled to room temperature and then poured into 0.5 N sodium bisulfate solution. The crude product was extracted using a 1:1 mixture of hexanes: ethyl acetate and the combined organic layers washed with 0.1 N NaOH and brine, and the solvent removed in vacuo. The crude product was then purified by silica gel chromatograpby (10:1 then 5:1 bexanes:ethyl acetate) to yield 7c (2,3 g) as a white solid: LRMS (eieclrospray): m/z [M+H]*= 337. E:sample 8 5-(3,5-Dich]oro-phenoxy)-4-(l-hydToxy-ethyl)-l-isopropyl-lH-pyra2ole-3-carboxylic acid ethyl estec Slethylinagaesiambromide (3.0 M in tetrahydrofuran, 0.9 mL, 2.7 mmol) was added slowly to a iolution of die 7a in THF:diethyl ether (1:6, 30 mL) at -30°C. After the addition was complete, he reaction was stirred at Q°C for 2 h. An additional 0.3 mL of the Giignard reagent solution was then added, stirring continued for an additional 1 h. The reaction quenched by adding laturated aqueous ammomum chloride. The product was extracted into ethyl acetate and the :ombined organic layers washed with brine. The crude product was purified by silica gel :hroinatography (10:1 hexanes:ethyl acetate) to give the title compound (0.93 g) as a colorless )il: LRMS (electrospray); m/z [M+Na]*= 409. Example 9 5-(3,5-Dichloro-phenoxy)-4-ethyl-l-isopropyl-lH-pyrazole-3-carboxylic acid ethyl ester 10: R = Me, AT = 3,5-di-Cl-C5H3 H; R = Me, Ar = S.S-di-Cl-CgHj To a solution of alcohol (0.61 g, 1.6inmol) and trifluoroacetic acid (1.3 mL, 17 mmo]) in 20 mL of dichloromethane was added triethylsilane (0.28 mL, 1.7 mniol) at room temperature. After 2 h, an additional 0.28 mL triethylsilane was added and the reaction stiired overnight. A further 0.3 mL triethylsilane was then added and the reaction was complete after an additional 5 h. The solvent was removed in vacuo. The residue was taken up in ethyl acetate and washed with saturated sodium bicarbonate solution and brine. The crude product was purified by silica gel chromatography (20:1 hexanes:ethyl acetate) to give the title compound (0.55 g): LRMS (electrospray); m/z [M+H]* = 371. Lithium triethylborohydride (1.0 M in THF, 3.0 mL, 3.0 mmol) was added slowly to ester Sa (0.54 g, 1.5 nunol) in 10 mL of tetrahydrofurao at -20°C. The reaction was stured at -20°C for 30 min, then at 0°C for an additional 1 h. The reaction was then quenched by adding 4 mL of a 10% solution of acetic acid in ethanol. After 10 min, the solvents were removed in vacuo, the residue taken op in 1 M HCl and the product extracted into ethyl acetate. The combined organic layers were washed with saturated aqueous sodium bicarbonate and brine and the solvent removed in vacuo. Purification by silica gel chromatography (2:1 hexanes:e±yl acetate) gave 9a (0.42g) as a white solid: LRMS (electrospray); m/z Pv^+H]* = 329. Example 11 3 -Chloromethyl-5 -(3,5-dichloro-phenoxy)-4-ed3yI-l -isopropyl-lH-pyrazole Thioay] chloride (0.13 mL, 1.8 mmol) was added dropwise to an ice-cold solution of 9a (0.35 g, l.lmjnoI)in lOmL of dichloromethaue. After 1 h, the solvent was removed m vacwo, the 5 residue treated with saturated aqueous sodium bicarbonate, and the product extracted into ethyl acetate. The combined organic layers were washed with brine and the solvent removed in vacua to give 35 (0.37 g) in sufficient purity ihat it was not purified finther: LRMS (electrospray); m/z [M+H]^ = 347. ) Example 12 [5-(3,5 -Dicliloro-pbeDDxy)-4-etiiyl-l -isopiopyl-lH-pyTazol-3 -yl] -acetonitrite • A solution of 35 (0.37 g, I.l mmol) in 2 mL of dimefliyl sulfoxide was added to a stiiring mixture of sodium cyanide (0.11 g, 2.2 mmol) in 10 mL of dimethyl sulfoxide at room tenqjerature. After 4 h the reaction mixture was poured into 0.1 N aqueous sodium hydroxide and the product extracted into ethyl acetate. The combined organic layers were diluted with an equal volume of hexanes then v^'ashed tiiree times with walei and then brine. The solvents were I then removed in vacuo and purification by silica gel chromatography (8:1 then 5:1 hexanes:ethyl acetate) gave 23a (0.345g): LRMS (electrospray); m/z [M+H]* = 338. Example 13 2-[5-(3,5-Dichloro-phenoxy)-4-ethyH-isopropyMH-pyrazDl-3-yI]-ethyiamine Diisobutylaluminum hydride (1.5 M in toluene, 0.88 mL, 1.3 mmol) was added slowly to a solution of 23a (0.15 g, 0.44 mmol) in 5 mL of toluene at -10°C. Stirring was continued at -10°C for 30 niin, then sodium borohydride (0,10 g, 2.7 mmol) was added in one portion followed by the dropwise addition of 10 mL of methanol. After the addition was complete, the cooling bath was removed and the reaction stirred at room temperature for 30 min. The reaction mixture was then poured into aqueous sodium potassium tartrate solution and extracted with ether. The combined ether layers were then washed with brine and dried over potassium carbonate. Purification by silica gel chromatography (95:5:0.5 dichloromethane: methanol: saturated aqueous ammonium hydroxide) gave 24a (0.11 g): LRMS (electrospray); m/z [M+H]* = 342. Example 14 [5-(3,5-Dichloro-phenoxy)-^-ethyI-l-isopropyl-lH-pyrazol-3-yl]-aceticacid The nitrile 23a (0.19 g, 0.56 mmol) was heated at 100°C for 1.5 b in a mixture of 3 mL of glacial acetic acid, 3 mL of water, and 6 mL of concentrated hydrochloric acid. The reaction mixture was poured into 50 mL of water and the product extracted into ethyl acetate. The combined organic layers were washed with brine and the solvent removed in vacuo to give 2Sa (0.19 g): LRMS (electrospray); m/z [M+H]* = 357. Example 15 [5-(3,5-Dichloro-phenoxy)-4-ethyl-l-isopropyl-lH-pyrazol-3-yl]-acetic acid methyl ester Diisobatylaluminam hydride (1.5 M in toluene, 0.S8 nxL, 1.3 mmol) was added slowly to a solution of23a(0.15g, 0.44 mmol) in 5 mL of toluene at-10°C. Stirring was continued at-10°Cfor30min, then sodium borohydiide (0.10 g, 2.7 mmol) was added in one portion followed by the dropwise addition of 10 mL of methanol. After the addition was complete, the cooling bath was removed and the reaction stirred at room temperature for 30 min. The reaction mixture was then poured into aqueous sodium potassium tartrate solution and extracted with ether. The combined ether layers were then washed with brine and dried over potassium carbonate. Purification by sihca gel chromatography (95:5:0.5 dichloromethane: methanol: saturated aqueous ammonium hydroxide) gave 24a (0.11 g): LRMS (electrospray); m/z [M+H]"^ = 342. The nitrile 23a (0.19 g, 0.56 mmol) was heated at 100°C for 1.5 h in a mixture of 3 mL of glacial acetic acid, 3 roL of water, and 6 mL of concentrated hydrochloric acid. The reaction mixture was poured into 50 mL of water and the product extracted into ethyl acetate. The corobined organic layers were washed with brine and the solvent removed 171 VOCMO to give 25a (0.19 g): LRMS (electrospray); m/z [M+H]* = 357. Example 15 [5-(3,5-Dichloro-phenoxy)-4-ethyl-l-isopropyMH-pyrazol-3-yl]-acetic acid methyl ester A solution of 25a (R" = H; 0.19 g, 0.53 mmol) in 10 niL of 3 M methanolic hydrogen chloride was stirred overnight at room temperature. The reaction was then concentrated in vacuo, and the residue taken up in ethyl acetate and washed with saturated sodium bicarbonate solution and brine. Removal of the solvent in vacuo gave 25a (R'* = Me; 0.19 g) which needed no further purification: LRMS (electrospray); m/z [M+H]* = 371. A solution of hthiumtriethylborohj'dride (1.0 M in THF, 1.5 mL, 1.5 mmol) was added slowly to a solution of 25a (0.19 g, 0.51 mmol) m 5 mL of THF at -20'C. Stirring was continued at -20°C for 30 min then at 0°C for 1 h. The reaction was then quenched by adding 5 mL of a 10% acedc acid in ethanol solution. After stirring for 30 min, the solvent was removed in vacuo and the residue taken up in 1 N HCl and the products (a mixture of aldehyde and alcohol) were extracted into ethyl acetate. The combined organic layers were washed with brine and the solvent removed in vacuo. The crude product mixture was then dissolved in 10 mL of methanol and sodium borohydride (O.lOg, 2.6 mmol) was added in one portion at 0°C. Stirring was conUnuedfor 30 min then the reaction was quenched by adding 10 mL of saturated aqueous anmionium chloride. The mixhire was diluted with 50 mL of water and tiie product extracted into ethyl acetate. Purification by siUca gel chromatography (2:1 hexanes: ethyl acetate) gave 26a (0.14 g) as a coloriess oil: LRMS (electrospray); m/z {M+Hf = 343, Example 17 Carbamic acid 5-(3,5-dichloro-phenoxy)-l-isopropyl-4-me±yl-lH-pyrazol-3-yl[nethyl ester To a solution of 30a (R" = H; 0.20 g, 0.64 mmol) in 5 mL of dichloromethane at 0°C was added trichloroacetylisocyanate (91 ^L, 0.77 mmol) dropwise. After 30 min the solvent was removed i in vacuo and the residue was taken up in 4 mL of methanol and treated with 2 mL of water and 200 mg of potassium carbonate. The reaction was stirred at room temperature for 2 h. The reaction mixture was then poured into 50 mL of water and the product extracted into ethyl acetate. The combined organic layers were washed with brine and the solvent removed in vacuo. Purification by silica gel chromatography (2; 1 hexanes:ethy] acetate) followed by I recrystallization from dichloromethaneyhexanes gave 20a (R^^ = CONH:; 0.21 g) as a white solid: LRMS (electrospray); m/z pvi+H]"' = 35S. Sodium'boTobydride(80mg, 2.1 mmol) was added in one portion to a solution of 7c (0-72 g, 2.1 mmol) in 20 mL of methanol atO°C. After stirring for 30 mio, the reaction was quenched fay adding 4 mL of saturated aqueous ammonium chloride and then the bulk of the solvents were removed in vacuo. The residue was taken up in water and the product extracted into ethyl acetate. The comhined organic layers were washed with water and brine and the solvents removed in vacuo. Purification by silica gel chromatography (6:1 then 4:1 hexanes:etbyl acetate) gave the ritle compound 36 (0.64 g) as a colorless oil: LRMS (electrospray); m/z [M+Na]"^ = 361. A solution of diphosphoms tetraiodide (0.62 g, 1.1 mmol) and 40 mL of toluene was heated in the dark at 85°C for 10 min. A solutioii of 36 (0.62 g, l.S rmnol) in 4 mL of toluene was then added in one portion and the mixture stirred for 10 min. The reaction was then quenched by addhig 40 mL of 10% aqueous sodium bisulfite solution and the mixture stirred until it became colorless. The layers were then separated and the organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo- This crude product 37 was taken directly on to the next step. Example 20 5-(3-Chloro-pheiioxy)-l-isopropyl-4-mefliyl-iH-pyra2ol-3-yl]-inethanoI 'i.solutionof lithium triethylborobydride (1.0 M in THF, 5.4 mL. 5,4 mmol) was slowly added to J}ecn]deiodide37{].8iimiDl)in lOmLoftetrahydrofuraa at-20°C. After30roin, Ihe ■eaclion was wanned to 0°C and stirred for 1 h. An additional 2.7 mL of lithium riethylborohydiide solution was added and the reaction stitred for 30 min more. The reaction i vas then quenched by adding 5 mL of 10% acetic acid in ethanol and the reaction was loncentrated in vacuo. The resulting residue was taken up in 1 N HCl and the product extracted □to ethyl acetate. The combined organic layers were washed with saturated aqueous sodium jicaibonate and brine and the solvent was removed in vacuo. Purification by sihca gel ;hromatography (2:1 hexanes:ethyl acetate) gave 38 (0.46 g) as a colorless oil: LRMS electrospray); m/z [M+H]*= 2S1. Example 21 6-[5-(3-ChIoro-phenoxy)-l-isoprop3'I-4-methyl-lH-pyra2o2-3-y]methyl]-2H-pyrida2in-3-one 5odiuni hydride (60% dispersion in mineral oil, 0.14 g, 3.5 mmol) was added in one portion to a 5olutioaof 39 (0.40 g, 1.4 mmol) and 3,6-dichloropyridazine (0.42 g, 2.8 mmol) in iOmLof DMF at room temperature. The reaction was stirred for 1 h, then poured with vigorous stirring into 100 mL of 0.5 N aqueous sodium bisulfate. The resulting red oily solid was collected by SltratioE and washed with water. This solid was then dissolved into ethyl acetate and washed with brine and the solvent removed in vacuo. The residue was then taken up in a mixture of 4- mL of acetic acid, 8 mL of 12 N HCl and 4 mL of water and heated under argon at 100°C for 1 h. The reaction mixture was then cooled and carefully added to aqueous potassium carbonate md the product extracted into ethyl acetate. Purification by preparative thin layer chromatography (95:5 dichloromethane:metharioI) gave 40 {0,35 g) as a white solid: LRMS (electrospray); m/z [M+H]* = 359. Example 22 2-[5-(3-ChIoro-phenoxy)-4-ethyl-l-isopropyl-lH-pyrazol-3-yliiiethyl]-isoindole-l,3-dioiie To a roixture of 9a (220 mg, 0.746 nimol), triphenylphospbine (391 mg, 1.49 mmol) and phthalimide (220 mg, 1.49 mmol) in tetrahydrofuran (20 mL), was added diethyl azodicarboxylate (260 mg, 1.492niiQol) dropwise at room temperature under nitrogen. The resulting yellow solution was stirred under nitrogen at room temperature for 24 h. Methanol (3 mL) was added and all solvents were removed in vacuo. The residue was purified on sUica gel with hexane:ethyl acetate (4:1) to give a white soHd 41 (310 mg, 98%): LRMS (electrospray); m/z pVl+H]* = 424. To a solution of 32 (310 mg, 0.731 mmol) in methanol (10 mL) and tetrahydrofuTan (10 mL), was added anhydrous hydrazine (243 mg, 0.24 mL, 7.31 mmol) at room temperature. The reaction mixture was heated at reflux under nitrogen for 2 h. The reaction was cooled to room temperature and a 10% NaOH solution (30 mL) was added to the reaction mixture. The crude product was extracted with dicUoromethane (4 x 25 mL). The solvents were removed in vacuo. The residue was purified on silica gel with ethyl acetale:methanol (4:1) to give a pale yellow oil 21a (182 mg, 85%): LRMS (electrospray); m/z [M+H]* = 294. Example 24 N-[5-(3,5-DicIiIoro-phenoxy)-4-ethyl-l-isopropy!-lH-pyra2ol-3-ylmethylj-formaimde A solution of amine 21a (71 mg, 0.21 mmol) in ethyl formate (6 mL) was heated at reflux for 5 h. The solvent was then removed in vacuo. The residue was purified by silica gel chromatography with hexane/ethyl acetate (2:1) to give a white solid 22a (R^^ = COH; 73 mg, yield 95%): LRMS (eleclrospray); m/z [M+B]* = 356. Example 25 N-[5- A solution of the amine 21a (71 mg, 0.22 mmol) in acetic anhydride (5 mL) was stirred al room temperature for 2.5 h. Methanol (10 mL) was added to the reaction mixture and the solvents were removed in vacuo. The residue was treated with 10% NaHCOa (20 mL) and stirred for 20 min. The crude product was extracted with dichloromethane (3 x 20 mL). The organic phase was collected and washed with brine. The solvent was removed in vacuo. The residue was purified by silica gel chromatography with hexane:ethyl acetate (2:1) to give a white solid 22a (R}^ = COMe; 70 mg, yield 87.5%): LRMS (eleclrospray); m/z [M+H]* = 370. Example 26 N-[5 -(3,5-Dichloro-phenoxy)-4-e±yl-1 -isopropyl- lH-pyrazol-3-ylinethyl] -methanesulfonamide To a solution of the 21a (S3 mg, 0.25 mmol) and triethylamine (76 mg, 0.75 mmol) in anhydrous dichloromethane (5 mL), was added methanesulfonyl chloride (41 mg, 0.35 nunol). The resulting yellow slurry was stirred under nitrogen at room temperature for 20 h. Water (10 mL) was added to the reaction. The crude product was extracted with dichloromethane (3 x 10 mL). The organic layers were collected and washed with brine. The solvent was removed in vacuo. The residue was purified on silica gsl with hexane.-ethyl acetate (3:1) to give a white solid 22a (R" = S02Me; 98 mg, yield 96.5%): LRMS (eleclrospray); m/z [M+H]* = 406. Example 27 [5-(3,5 -Dichloro-phenoxy )-4-ethyH -isopropyl-lH-pyrazol-3-ylmetbyl] -urea To a solution of the 21a (S5 mg, 0.26 mmol) in tetrahydrofuran (5 mL), was added trimethylsilyl isocyanate (53 mg, 0.39 mmol) in one portion. The reaction mixture was stirre-d at room tanperatureimderidtrogenfoTlOh. The reaction was dilated with methanol (lOmL). AE solvents were then removed in vacuo. The residue was purified on silica gel with hexaneiethyl acetate (2:1) to give a white solid 22a (R" = CONH2; 80mg, 83%): LRMS (electrospray); m/z [M+H]*=371. Example 28 [5-(3 -Chloro-phenoxy)-3 -hy droxymethyl-1 -isopropyl- lH-pyra2ol-4-yl] -methanol To a solution of the 7a (110 mg, 0.327 mmol) in tetrahydrofuran (10 mL) cooled to -78°C, was added a solution of lithium aluminum hydride (1.0 M in tetrahydrofuran, 0.72 mL, 0.72 mmol). The reaction was stirred under nitrogen at -78°C for 30 ma and then stirred at 0°C for another 45 min. Methanol (0.5 mL) was added to quench the reaction. The resulting reaction mixture was stilted with a saturated sodium potassium tartrate solution (15 mL) for 2 h. The crude product was extracted with diethyl ether (4 x 25 mL) and the organic layers were collected and washed with brine. The solvents were removed 171 vacuo. The residue was pmified on siHca gel with hexane:ethyl acetate (1:2) to give 42 (95 mg, yield 97.8%): LRMS (electrospray); m/z [M+H]* = 297. Example 29 5-(3,5-Dichloro-pheuoxy)-1 -isopropyl-4-(2-methoxycarbonyI-vinyl)- lH-pyrazole-3-carboxy lie acid ethyl ester To a solution of the 7a (200 mg, 0.54 mmol) in tetrahydrofuran (10 mL) at 0°C, was added methyl(triplienylphosphoranylidene)acetate(1.30g, 3.89 nunol). The reaction was stirred under nitrogen at room temperature for 7 h. Water (40 mL) was added to the reaction mixture. The crude product was extracted with ethyl acetate (3 x 35 mL). The organic layers were collected and washed with brine. The solvents were removed in vacuo. The residue was purified on sUica gel with hexane:ethyl acetate (4:1) to give the 14a (220 mg, yield 95%): LRMS (electrospray); m/2 [M+H]* = 427. Example 30 5-(3,5-Dichloro-phenoxy)-l -isopropyl-4-(2-methoxycaiboDyl-ethyl)- lH-pyrazole-3 -carboxylic acid ethyl ester COjEt COjEt EtO^C. EtOjC. 15a To a mixture of pre-dried magnesium turnings (50 mg, 2,10 mmol) and anhydrous methanol (30 mL) atO^C, was added a solution of X4 (ISO mg. 0.42 mmol) in methanol (2 mL). Gas evolution was observed. The resulting reaction mixture was stirred at 0°C for 5 h and then at room temperature for 10 h. The reaction mixture was filtered through CELITE®. The filtrate was collected and treated with 10% sodium bisulfate solution. The crude product was extracted with ethyl acetate (3 x 25 mL). The organic layers were collected and washed with brine. The solvent was removed in vaaw. The residue was purified on sHica gel with hexane:ethyl acetate (4:1) to give the product 15a as a colorless oil (157 mg, yield 90%): LRMS (electrospray); m/z [M+H]"^ = 429. Example 31 3 -[5-(3,5 -Dichloro-phenoxy)-3-hydroxymethyl-1 -isopropyl- lH-pyrazol-4-yl]-propan-l -ol CH^OH COjEt EtO,C 15a To a solution of the 15a (100 mg, 0,24 mmol) in tetrahydrofuran (15 mL) at ^0°C, was slowly added a solution of lithium triethylborohydride (1.0 M in tetrahydroftiran, 1.25 mL, 1.25 mmol). 20 The reaction solution was stiired under nitrogen at -40°C for 10 minutes and then stirred at O^C for another 45 min. The reaction mixture was warmed up to room temperature and then stiired with 1 N HCl (20 roL) for 30 niin. The crude product was extracted with diethyl ether (3 x 25 mL). The organic layers were collected and washed with brine. The solvents were removed in vacuo. The residue was purified on silica gel with hexaiie:ethyl acetate (1:1) to give the product 15b (52 mg, yield 60%): LRMS (electrospray); m/z [M+H]^ = 359. Example 32 3-(2,4-Dietiiyl-5-liydroxymethyl-2H-pyrazQl-3-yloxy)-benzoiiitrile To a solution aryl bromide (96 mg, 0.30 mmol) in dimethylfonnamide (8 mL), was added tetrakis(triphenylphosphine)palladium(0) (173 mg, 0.15 mmol) and zinc cyanide (32 mg, 0.27 mmol) at room temperature. The resulting mixture was heated at 90°C under argon for 6 h. The reaction mixture was poured into saturated sodium bicarbonate (50 mL) and the crude pioduct was extracted into ethyl acetate (3 x 30 mL). The organic layers were collected and washed with brine. The solvents were removed in vacuo. The residue was purified on silica gel with hexaneiethyl acetate (1:1) to give the title compound (50 mg, 61.5%): LRMS (electrospray); m/z rM+H]* = 272. Example 33 5-(3,5-DicbloTO-phenoxy)-4-hydroxyniethyl-l-isopropyl-lH-pyra2:ole-3-carboxylic acid ethyl ester To a solution of 7a (559 mg, 1.51 mmol) in tetrahydrofuran (5 mL) and methanol (15 mL) at 0°C, was added sodium borohydride (5S mg, 1,52 mmol) in one portion. The reaction mixture was stirred under nitrogen at 0°C for 30 min. Saturated ammonium chloride solution (25 mL) was added to quench the reaction. The organic phase was collected. The aqueous phase was extracted with ethyl acetate (3 x 20 mL). All organic extracts were combined, washed with brine and concentrated in vflcwo. Theresidue was ptuified on sihca gel with hexane:ethyl acetate (4:1) to give the alcohol 42 (494 mg, yield 87%): LRMS (electrospray); m/z \M+H}'* = 373. Example 34 5-(3,5-DicUoro-phenoxy)-l-isopropyl-4-methoxymethyI'lH-pyra2ole-3-carboxyIic acid ethyl estear To a solution of 42 (87 mg, 0.233 nimol) in anhydrous dimethylformamide (5 mL) at 0°C, was added sodium hydride {60% dispersion in mineral on, 12 mg, 0.2S0 mmol). The reaction mixture was stirred under nitrogen at 0°C for 30 min. Methyl iodide (50 mg, 0.35 mmol) was added to the reaction solution at 0°C. The resulting reaction mi?rture was stirred under nitrogen at room temperature for 2 h. 10% sodium bisulfate solution (10 mL) was added to quench the reaction. The crude product was extracted with ethyl acetate (3 x 10 mL). The organic layers were collected, washed with brine and the solvent was removed in vacuo. The residue was purified on silica gel with hexane;eth;'l acetate (6:1) to give 43 (50 mg, yield 56%); LRMS (electrospray); m/z!>d+HI^ = 387. Example 35 [5-(3,5-Dichloro-phenoKy)-l-isopropyl-4-methoxymethyl-lH-p;Ta2;ol-3-yl]-methanol To a solution of 43 (47 mg, 0.12 mmol) in tetrahydrofuran (15 mL) at -AO°C, was slowly added hthium triethylborohydride (1.0 M inTHF, 0.25 mL, 0.25 mmol). The reaction solution was stirred under nitrogen at ~40°C for 10 min and then stirred at 0°C for 45 mta. The reaction mixrure was warmed up to room temperature and was then treated with 1 N hydrochloric acid (20 mL) for 30 minutes. The crude product was extracted with diethyl ether (3 x 25 roL). The organic layers were collected, washed with brine and the solvents were removed in vacuo. The residue was purified on silica gel with hexaneiethyl acetate (1:1) to 44 (26 mg, yield 63%): LRMS (electrospray); m/z [M+H]* = 345. Example 36 5- [5-(3,5 -Dichloro-phenoxy)-4-ethyl-l -isopropyi- lH-pyrazol-3 -ylinethyl]-2H-tetrazole To a solution of nitrile (56; 0.065 g, 0.192 mmol) in 3iiiL of xylenes was added azidotEibutyltin (0.05S niL, 0.221 mmol) and the reaction roixture heated at ISO^C for 12 h. The reaction mixture was then concentrated HI vacuo and the resulting residue partitioned between ethyl acetate and aqueous ammonium chloride. The organic layer was dried over magnesium sulfate, filtered and then concentrated in vacuo. The crude product was purified by flash chromatography on siUca gel (1:1 bexane:ethyl acetate then 9:1 ethyl acetate: methanol) to yield the desired product (73; 3.4 mg, 5%): LRMS (electrospray) m/z (MH) = 381. Example 37 l-[5-(3,5-Dichloro-phenoxy)-4-ethyM-isopropyi-lH-pyrazol-3-j'l]-propaTi-2-on To a solution of the ester (66; 0.054 g, 0.140 mmol) in 5 mL of tetrahydrofuran at 0'C under an argon atmosphere was added methylmagnesium bromide solution (1 Min diethyl ether, 1.26 mL, 1.26 mmol) The reaction was allowed to warm to room temperature and then stirred overnight. The reaction was quenched by the dropwise addition of water followed by acidification with 1 N aqueous hydrochloric acid. The product was extracted into ethyl acetate, dried over magnesium sulfate, and the solvents removed in vacuo. Purification by flash chromatography silica gel (3:1 hexane:ethyl acetate) gave the product as an oil (8 mg, 16%): LRMS (electrospray) mJz (MH) = 355. Example 3S 1 -[5-(3,5-DichlorO'phenoxy)-4-ethyl- 1-isopropyI- lH-pyrazol-3-yl] -propan-2-Dl To a solution of alcohol {36; 0.080 g, 0.233 mmol) in 7 mL of dichloromethane was added dropwise a solution of the Dess-Martin periodinane (l,l,l-triacetoxy-l,l-dihydro-l,2-beiiziodoxol-3(lB)-one; 0,09 g, 0.233 mmol) in 0.7 niL of dichloromethane. After 30 min. a solution of water (0.005 mL, 0.256 mmol) in 5 mL in dichloromethane was added and the reaction was allowed to stir overnight at room temperature. The reaction was partitioned between dichloromethane and 10% aqueous sodium bisulSte/sodiura carbonate. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude aldehyde product was dissolved in tetrahydrofuran, cooled to -24°C, and then methyhnagnesium bromide (1 M in tetrahydrofuran, 0.26 mL, 0.26 mmol) was added dropwise. After stirring for 72 h, the reaction was quenched by the dropwise addition of water and the resulting mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water and the organic layer was dried over magnesium sulfate. Purification by flash chromatography on silica gel (7:3 hexaneietbyl acetate) gave the secondary alcohol 81 as an oil (11.4 mg, 14%). Example 39 2-[5 -(3,5-Dichloro-phenoxy)-l ,4-diethyl-1 H-pyrazol-3 -yl]-N-phenyl-ac8tainide To a solutioii of the carboxylic acid (71; 0.15 g, 0.44 mmol) in 5 mL of tetrahydrofuran was added l,l'-carboDyldiiinidazoIe (0.70 g, 0.44 mmol) and this mixtuie was heated at 50°C for 30 min. Aniline (0.040 mL, 0.44 mmol) was added and the reaction mixture was maintained at 50°C for an additional 3 h and then was stirred at room temperature overnight. The reaction mixture was then poured into 30 mL of ethyl acetate and this solution was washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and brine. The solvent was then removed in vacuo and crude product was purified by preparative thin layer chromatography on silica gel (4:1 hexane:ethyl acetate) to yield the amide 86 as a white solid (0.174 g, 95%): mp 112.2^ 15.9°C; LRMS (electrospray) m/z (MH) = 418. Esample 40 5-(3,5-Dichloro-phenoxy)-l,3,4-triethyl-lH-pyrazole A solution of keto alcohol {0.16 g, 0.52 mmol) in 0.5 mL of Iriethylsilane and 0.5 mL of trifluoroacetice acid was stirred at 35°C ovemighL The reaction was concentrated in vacuo and the resulting crude product purified by preparative thin layer chromatography on silica gel (10:1 hexane:ethyl acetate) to yield the 89 as an oil (94 mg, 64%): LRMS (electrospray) m/z (MH)=313. Example 39 2- [5 -(3,5-Dichloro-phenoxy)-l ,4-dietliyMH-pyrazoI-3-yl] -N-phenyl-acetamide To a solution of the carboxylic acid (71; 0.15 g, 0.44 mmol) in 5 mL of tetrahydrofuran was added IJ'-carbonjddiimidazole {0.70 g, 0.44 inmol) and this inixtuie was heated al 50°C for 30 min. Aniline (0.040 mL, 0.44 nunol) was added and the reaction mixture was maintained at 50°C for an additional 3 h and then was stirred at room temperature overnight. The reaction mixture was then poured into 30 mL of ethyl acetate and this solution was washed with 1 N hydrochloric acid, saturated sodium bicarbonate, and brine. The solvent was then removed in vacuo and crude product was purified by preparative thin layer chromatography on silica gel (4:1 hexane:ethyl acetate) to yield the amide 86 as a white solid {0.174 g, 95%): mp 112.2-115.9'C; LRMS {electrospray) m/z (MH) = 418. Example 40 5-(3,5-Dichloro-phenoxy)-l,3,4-triethyl-lH-pyrazole A solution of keto alcohol (0.16 g, 0.52 mmol) in 0.5 mL of triettiylsilane and 0.5 mL of trifluoroacetice acid was stirred at 35C overnight The reaction was concentrated in vacuo and the resultmg crude product purified by preparative thin layer chromatography on silica gel (10:1 hexane:ethyl acetate) to yield the 89 as an oil (94 mg, 64%): LRMS (electrospray) m/z (MH)=313. Example 41 5-(3,5-Dicliloro-plienoxy )-4-ethyl-l -isopropyl-3 -pyrazol-1 -ylmethyl- lH-pyra?ole A 10 mL single neck round bottom was purged with nitrogen. The chloromethyl pyrazole (0,100 g, 0,288 mmol) was added to the reaction vessel and dissolved in 1 mL of dimethylfoimamide. Potassium carbonate and pyrazole (0.029 g, 0.431 mmol) w^e then sequentially added to the reaction vessel. The reaction was stirred for 24 h and then partitioned between water and ethyl acetate. The combined organic extracts were washed with water and brine, dried over sodium sulfate, and filtered. The solution was concentrated in vacuo to yield the crude product, which was purified by flash chromatography on sihca gel (S5:15 hexanesxthyl acetate) to yield the desired product (6S; 90%); LRMS m/z(M*) = 379. The corresponding imidazole derivative 67 was prepared by an analogous procedure substituting imidazole for pyrazole in Example 41. The desired product was isolated in 83% yield: LRMS m/z(RO = 379. Example 43 3-[5-(3,5-Dicliloro-phenoxy)-4-ethyl-I-isopropyl-lH-p>Tazol-3-ylmethyl]-lH-pyrunidine-2,4- dione A 10 mL single neck round bottom flask was purged with nitrogen. The chloromethyl pyrazole (0.100 g, 0.288 mmol) was added to the reaction vessel and dissolved in 1 mL of dimethyiformaiaide. Potassium carbonate was then added to the reaction vessel followed by uracil (0.050 g,0.43 imnol). The reaction was stirred for 24 h and then partitioned between water and ethyl acetate. The combined organic extracts were washed with water and brine, dried over sodium sulfate, and filtered. The solution was concentrated in vacuo and the crude product, was pmified by flash chromatography on silica gel (9:1 hexanes:ethyl acetate) to yield 72 in 85% yield: LRMS m/z(M:^ = 423. Example 43 5-(3,5-Dichloro-phenoxy)-4-ethyl-1 -isopropyl-lH-pyrazol-3 -yl] -tbiophen-2-yl-rQethanol A 100 niL three-neck round bottom was purged with nitrogen. The flask was charged with magnesium flakes (0.074g, 3.067iniiiol) and heated and purged under nitrogen. Tetcatiydrofuraii (5 mL) and 2-iodothiophene(0.500g,2.384inniol) were then added to the reaction vessel and heated. When the magnesium was consimied an aliquot of (0.61nil,0.611mmol) was added to tetrahydrofaran solution of aldehyde (0.200g, 0.611mmol) at 0° C. Tlie reaction was allowed to warm to room temperature then cooled to 0° C. The reaction was quenched upon the addition of saturated ammonium chloride and partitioned between water and ethyl acetate. The combined ethyl acetate extracts were washed with ammonium chloride and saturated brine. The ethyl acetate solution was dried over sodium sulfate and filtered. The solution was concentrated in vacuo and the crude product puiifie-d by flash chroamatography on silica gel chromatography (80:20 hexanes:ethyl acetate) to afford 91 in 75 % yield: LRMS M*=411. A solution of hydroxymethyl thiophene 91 ( O.lOOg, 2.431rDmol) and 3 mL of trifluoroacetic acid was cooled to 0° C. Triethylsilaoe (0.5Swl, 3.65 mmol) was added and the reaction stirred at 0° C under a nitrogen atmosphere. The reaction was allowed to warm to room temperature and stirred for an additional 24 h. The reaction was cooled to 0" C and quenched by slow addition of saturated sodium bicarbonate. The reaction was extracted with ethyl acetate and the combined ethyl acetate extracts were washed with saturated sodium bicarbonate, water and brine. The ethyl acetate solution was dried over sodium sulfate and filtered. The solutioo was concentrated in vacuo and the crude product was purified by flash chromatography on silica gel (90:10 hexanes:ethyl acetate) to yield 76 m 90% yield; LRMS IvT = 395. Example 45 5-(3,5-DichIoro-phenoxy)-l,4-diethyMH-pyrazole-3-carbaIdehyde Solid tetrapropylaminonium perrathenate (118 mg, 0.33 mmol) was added in one portion to a stirred mixture of the alcohol (17; 2.12 g, 6.72 nunol), N-methyhnorpholine N-oxide (1,18 g, lO.I mmol) and 4 A molecular sieves (3.36 g) in dichloromethane (66 mL) and acetonitrile (8 mL) at room temperature imder argon. The reaction was stirred at room temperature for 1,5 h. The reacti.on mixture was filtered through CELrTE® and the filtrate was concentrated in vacuo. The crude product was purified flash chromatography on silica gel (4:1 hexane:ethyl acetate) to afford 1.79 g (S5%) of lOS as a pale yellow oil:LRMS (electrospray) m/z(MH) = 313. step 1 DimethylchJorosulphonamide (3.8 g, 25.5 mmol) was stirred with imidazole (2.0 g, 29.4 mmol) and triethylamine (2.97 g, 29.4 mmol) in benzene (35 mL) at room temperature for 16 h. The mixture was filtered and the solid was washed with benzene (50 mL). The combined filtrate was concentrated in vacuo. The cmde product was purified by flash chromatography on silica gel{4;l hexanerethyl acetate) to afford tiie sulphonamide 106 as colorless oil (3.6 g, 69%). step 2 To a solution of the imidazojyl sulphonamide (106; 146 mg, Q.S34 mmol) in tetrafaydrofuran (8 mL) at -78°C wa£ added dropwise n-butyllithium (1.6 M in bexane, 0.521 mL, 0.834 mmol). The reaction mixture was stirred at -78'C under argon for 45 min. A solution of the aldehyde 105 (201 mg, 0.642 mmol) in tetrahydrqfuran (1 mL) was then added slowly. The resulting reaction mixture was allowed to warm up to room temperature and stirred for 19 h. The reaction was quenched with saturated aqueous animonium chloride (10 mL). The crude carbiaol 107 was exUracted with ethyl acetate (3 x 10 mL). The combined filtrates were dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on silica gel (4:1 hexane:ethyl acetate) to afford 88 as a pale yellow oil {156 mg, 50%). step 3 The carbiDol 107 was mixed with trifluoroacetic acid (1.0 roL) and triethylsilane (0.6 mL) at room temperature. The reaction mixture was heated at reflux for 3 h. The reaction mixture was cooled to room temperature and the trifluoroacetic acid and triethylsilane were removed in vacuo. The residue was purified by flash chromatography on silica gel (5% methanol in dichloromethane) to afford 88 as a white solid (90 mg, S0%); LRMS (electrospray): m/2(MH) = 365; mp 145-14S"C. stepl To a EolutioD of N,N-diinethyl-4-iodo-lH-imida2oIe-l-sulfonamide (193 mg, 0.64 mmol) in dichloromethane (3 mL) was added ethyl magnesium bromide (3 M in diethyl ether, 0.18 mL, 0.60 mmol) at room temperature under argon. The reaction mixture was stirred at room temperature for 30 minutes. A solution of the aldehyde (100 mg, 0.32 mmol) in dichloromethane (0.7 mL) was then added to the above formed Grignard reagent dropwise at room temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with saturated aqueous armnoniimi chloride solution (10 mL). The crude carbiuol was extracted with ethyl acetate (3 x 10 mL). The combined ethyl acetate extracts were dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash chromatography on sihca.gel 5% methanol in dichloromethane) to afford the carbinol 109 as colorless oil, {120 mg, 76.8%). step z. The carbinol 109 was dissolved in trifluoroacetic acid (1.0 mL) and triethylsilane (0.4 mL) at room temperature. The mixture was reflnxed at 80'C for 3 h. The crude desoxy derivative 110 was isolated after the evaporation of volatile reagents in vacuo. step 3 The crude N-protected desoxy derivative 110 was contacted with hydrochloric acid (1 M). The reaction mixture was heated at reflux for 3 h and then stirred ai room temperature for 48 h. Saturated sodium bicarbonate solution was added to the reaction mixlnre until it reached pH 8. The erode product was extracted with ethyl acetate (3 x 10 mL). The combined extracts were washed with water (1x10 mL) and brine (1x10 mL) and the solvent removed in vacuo. Tbe crude product was purified by flash chromatography on silica gel (5% methanol in dichloromethane) to afford 90 as a white solid (60 mg, 67% over two steps): LRMS(electrospray) m/z (MH) = 365; mp 142-145.2° C. 'o a solution of 105 {102 mg, 0.326 mmol) in tetrahydrofuran (10 mL) was added methyl jiphenylphosporanyUdene)acelate (1.09g, 3.26 mmol) at room temperatme under argon. The 3sulting mixture was stirred at room temperature for 24 h and tben concentrated in vacuo. The ,,p-misaturated ester 111 was purified flash chromatography on silica gel (5:1 hexane/ethyl cetate) to afford 111 as a white solid (107 mg, 88.9%). i.solutionof the 111m methanol (1.0 mL) was added to a stirred mixture of magnesium powder 42 mg, 1.74 mmol) and methanol (15 mL) at CC. The reaction was kept at O^C for 3 h and then i'anned to room temperature for 16 h. The reactioD mixture was poured into 2 M aqueous odium bisulfate (20 mL). The aude product was extracted with ethyl acetate (3 x 10 mL). The :thyl acetate was removed in. vacuo and the crude product was purified by flash chromatography m silica gel (5:1 hexane;ethy! acetate) to afford 112 as a colorless oU (75 mg, 70%). To a solution of 112 (75 mg, 0.202 mmol) m tetrahydrofuran (10 mL) was added lithium riethylborohydride (1 M in tetrahydrofuran, 0.606 mL, 0.606 mmol) at -30°C over 5 min. The eaction mixture was warmed to 0°C and stirred for 3 h. The reaction mixture was poured into 2 ■J hydrochloric acid (50 mL) and the tetrahydrofuran was removed in vacuo. The resulting ;olution was stirred at room temperature for 6 h. The crude product was extracted into lichloromethane (4 x 10 mL). athe combined extracts were dried over magnesium sulfate, "iltered and evaporated. The crude product was purified by flash chromatography over silica gel 2:1 hexane:ethyl acetate) to afford the carbinol 92 as colorless oil (58 mg, 85 %): :.RMS(eIeclrospray): m/z (MH) = 342. step 4 A solution of 114 in methanol (25mL) was deoxygenated by bubbling argon through for 20 min. Potassium hydroxide (149 mg, 2.66 imnol) was added to this solution and the resulting mixture was refluxed for 19 h. The reaction mixture was poured into 20 mL of 10% aqueous sodium bisolfate and the crude product was then extracted into ethyl acetate (3 x 10 mL). The combined extracts were evaporated and purified by flash chromatography on silica gel (5% methanol in dichloromethane) to afford 93 as a white sohd (89 mg, 77% over 4 steps):LRMS (electrospray) i m/z(MH) = 396. To a solution of the above SEM-protected (SEM = 2-(tiimethylsiiyl)ethoxymethyl) pyrazole (190 mg, 0.958 mmol) in tetrahydrofuran (5 mL) at -7S°C was added dropwise a solution of n-butyllithitim (1.6 M in hexane, 0.56 mL, 0.S96 mmol). The reaction mixture was stirred at -78'C under argon for 45 min. A solution of 105 in tetrahydrofuran (1 mL) was added slowly and the resulting reaction mixture was stiired at -7S'C for 2 b. Saturated ammonium chloride solution (10 mL) was added to quench the reaction and the crude carbinol 115 was extracted with ethyl acetate (3 x 10 mL). The combined extracts were evaporated and purified by flash chromatography over silica gel (4:1 hexanexthyl acetate) to afford 115 as a pale yellow oil (112 mg, 68%). The carbinol (115; 112 mg, 0.219 mmol) was mixed with diphosphoms tetraiodide (124 mg, 0.219 mmol) at room temperature. The reaction mixture was stirred at 80° C for 30 m. The reaction mixttffe was cooled to room ten^rature and was stitred vigorously with 10% aqueous sodium bisulfite (20 mL) until the organic layer became colorless. The crude product was extracted with ethyl acetate (3 xlO mL) and the solvent removed iji vacuo. The residue was purified by flash chromatography on silica gel (5% methanol in dichloromethane) to afford 96 as a pale yellow oil (68 mg, 85%). Example 51 3-Chioro-5-[2.4-diethyl-5-(2-hydroxy-ethyl)-2H-pyrazol-3-ylox3']-benzonitrile step 1 To a solution of Cmetlioxymethyl)triphenylphophonium chloride (928 rag, 2.7 mmo!) in tetrahydroffiran {15 mL) was added potassium bis{triiiiethylsilyl)amide (0.5 M in toluene,5.4 inL, 2.7 mmol) at -7S°C over 10 min. The resul&ig reddish slurry was stirred at -78°C for 20 min, then a solution of the aldehyde {116; 82 mg, 0.27 mmo]) in tetrabydrofuran (1,5 mL) was added slowly over 10 min. The reaction mixture was allowed to warm to room temperature and then stirred for 16 h. Acetic acid (5 mL) was added to the reaction mixture and then the mixture was adjusted to pH 7 with 10% aqueous sodium bicarbonate. The cmde product was extracted with ethyl acetate (3 x 20 mL) and the solvent then removed iii vacuo. Purification of the crude product by flash chromatography on silica gel (4:1 hexane:ethyl acetate) afforded the 1:1 mixture of the enol ethers 117 (74 mg, 83%). step 2 To a solution of 117 (74 mg, 0.223 mmol) in acetonitrile (5 mL) and water (5 mL), was added mercury(IO acetate powder (92 mg, 0.29 mmol) in one portion at room ten^erature. The reaction was complete within 1.5 h. The acetonitrile was removed from the reaction mixture in vacuo to give an aqueous solution of the mercury adduct 118. step 3 Ethanol (5 mL) was added to the above aqueous solution of 118 followed by the addition of sodium borohydride (34 mg, 0.90 mmol) at 0°C. The turbid reaction mixture was stirred at 0'C for 1,5 h- The reaction mixture was then poured into 20 mL of 10% aqueous sodium bisulfate and the resulting mixture then neutralized by adding saturated aqueous sodium bicarbonate. The crude product was extracted with ethyl acetate (3 x 10 mL) and crude product purified by flash chromatography on sUica gel (4:1 hexane:ethyl acetate) to afford 97 as a colorless oil (60 mg, 84.3% over two steps):LRMS (eIectrospray)m/z (MH) = 319. 11 52 To a solution of 11 (150 mg, 0.456 nuuol) in N,N-diniethylfoniiaimde (5 mL) was added sodium hydride (60% dispersion in mineral oil, 22 mg, 0.547 mmol) at room ten^erature. The reaction mixture was stirred until no more bubbles were observed. Methyl iodide (97 mg, 0.684 mmol) was then added to the reaction mixture and this was stirred at room temperature for 20 min. The reaction mixture was poured into 20 mL of 10% aqueous sodium bisulfate. The crude product '■■ was extracted with ethyl acetate (3 x 10 mL) and the combined organic layers were washed with water (2 x 10 mL) and then brine (1 x 10 mL). The solvent was removed ui vacuo and crude product purified by flash chromatography on silica gel (5:1 hexane:ethyl acetate) to afford pure 52product as colorless oil (110 mg, 70 %):LRMS (electrospray) m/z (MH) = 343. Example 53 HIV Reverse Transcriptase Assay: lohibitor IC-ai determination HIV-] RT assay was carried out in 96-well Millipore MidtiScreen MADVNOB50 plates using pniified recombinant enzyme and a poly(rA)/oligo(dT)i6 template-primer in a total volume of 50 pL. The assay constituents were 50 nM Tris/HQ, 50 mM NaCi, 1 mfil EDTA, 6 roM MgQs, 5 ]M dlTP, 0.15 nCi fB] dTTP, 5 jJ-g/ml poly (rA) pre annealed to 2.5 |.ig/ml oligo (dT)i6 and a range of inhibitor concentrations in a final concentration of 10% DMSO. Reactions were initiated by adding 4 nM HI\'-1 RT and after incubation at ST^C for 30 rain, 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 ^il of 10% TCA and 2 x 200 )xl 70% etbanol. Finally, the plates were dried and radioacti\ity counted in a Packard TopCounter after the addition of 25 jA scintillation fluid per well. ICso's were calculated by plotting % inhibition versus logio inhibitor concentrations. Representative IC5D data has been included in Table 2. Aativical assay method: Anti-HIV antiviral activity was assessed using an adaptation of the method of Pauwels et al. {Pauwels et al., 198S, J Virol Methods 20:309-321}. The method is based on the ability of compounds to protect HIV-infected T lymphoblastoid cells (MI4 cells) from cell-death mediated by the infection. The endpoint of the assay was calculated as the concentration of compound at which the ceU viability of the cultuie was preserved by 50% ('50% inhibitory concentration', IC50). The cell viability of a culture was determined by the uptake of soluble, yellow 3-[4,5-dimethylthia2oi-2-yI]-2,5-diphenyltetrazohum bromide (MTT) and its reduction to a purple insoluble foimazan salt. After solubilization, spectrophotometric methods were employed to measure the amount of fonnazan product. MT4 cells were prepared to be in logarithmic-phase growth and a total of 2 x 10^ cells infected with the HXB2-stram of HEV at a multiplicity of 0.0001 infectious units of vims per cell in a total volume of between 200-500 microliters. The cells were incubated with virus for one hour at 37°C before rem.ovai of virus. The cells are then washed in 0.01 M phosphate buffered saline, pH 7.2 before being resuspended in culture medium for incubation in culture with serial dilutions of test compound. The culture medium used was RPMI1640 without phenol red, supplemented with penicillin, streptomycin, L-glutanune and 10% fetal calf serum (GMIO). Test compounds were prepared as 2 mM solutions in dimethyl sulfoxide (DMSO). Four repUcate, serial 2-fold dilutions in GMIO were then prepared and 50 microliters amounts placed in 96-well plates over a final nanomolar concentration range of 625 - 1.22. Fifty microliters GMIO and 3.5 x 10'^ infected cells were then added to each well. Control cultures containing no cells (blank), iminfected cells (100% viabihty; 4 repUcates) and infected cells without compound (total \Tms-naediated cell death; 4 replicates) were also prepared. The cultures were dien incubated ai 37°C in a humidified atmosphere of 5% CO; in air for 5 days. A fresh solution of 5 mg/mL MTT was prepared in 0.01 M phosphate buffered saline, pH 7.2 and 20 microliters added £0 each culture. The cultures wens further incubated as tefore for 2 hours. They were then mixed by pipetting up and down and 170 microliters of Triton X-100 in acidified isopropanol (10% v/v Triton X-100 in 1:250 mixture of concentrated HQ in isopropanol). When the formazan deposit was Mly solubUized by further mixing, the absorbance (OD) of the cultures was measured at 540nm and 690nm wavelength (690 nm readings were used as blanks for artifacts between wells). The percent protection for each treated culture was then calculated from the equation: % Protection = (OD drug-treated cultures) - (OD untreated virus control cultures) X 100% (OD uninfected cultures) - (OD untreated virus control cultures) The ICso can be obtained fcom graph plots of percent protection versus logio drug concentration. In bothassays, conqjounds of formulas Irange in activity from an IC50 of about 0.5 to about 10000 nM or 0.5 to about 5000 nM, with preferred compounds having a range of activity &om about 0.5 to about 750 nM, more preferably about 0.5 to 300 nM, and most preferably about 0.5 5 to 50 nM. appropriate tablet machine. membrane filter and packaged under sterile conditions. 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 foregomg 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 detennined with reference to the following appended claims, along with the full scope of equivalents to which such claims are entitied. All patents, patent apphcations and pubHcations cited in this apphcation are hereby incorporated by reference in their entirety for all purposes to the same extent as if each iadividual patent, patent apphcation or publication were so indi:'iduaUy denoted. i C1.3 haloalkyl and Ci_3 alkoxy; or R" is N[(CH2)2]2W wherein W is selected from the group consisting of NR^ (CH^),, N(C=0)Z, CHOR^ CHR^ CHNHC(=0)Z and CHNR'R'; n, 0, p and q are as defined below and s is 0 or 1; R^, R^, R' and R' (i) taken independently are selected from the group consisting of hydrogen, Ci^alkyl, Ci_6hydroxyalkyl, Ci.galkoxy-Ci.jalkyl d.^alkylamino-Ci-jaUcyl and Ci,3 dialkylaimno--Ci.3aIkyl or (ii) when both R* and R^ aie attached to the same nitrogen atom they may be taken together, along with the nitrogen, to form a pyrrolidine, piperidine, pipwazine or morpholine; X, and Y are independently O or NR^; Z is hydrogen, hydroxyl, Ci-galtoxy, NR^'^, Ci^alkyl, Ci.salkoxy-Ci.salkyl wherein R^^ is R^ or phenyl optionally substituted with one to three groups independently selected from the group consisting of halogen, cyano, Ci.jalkyl, Ci.shaloalkyl and C], 3alkoxy; n is 0 to 3; o and p are independently 0 to 4 and o + p k, rl and r2 axe independently 0 to 4, and 5 > (rl + r2) > 2; and, acid addition salts, hydrates and solvates thereof; with the proviso that when R' is -(CH2)nR^'. n is 1 and R'^ is substituted phenyl, R^ is oliier than unsubstituted phenyl. 2. A compound according to claim 1 wherein: R^ is selected fi-om the group consisting of C,_6alb/1, C^shaloalkyl, C3_7cycloalkyl. Ci_ 3alko>:y-Ci.3 alkyl and optionally-substituted phenyl; R^ is optionally substituted phenyl; and, R' is C,.6 alfcyl, C3.7 cycloalkyl. (CH3)„R" or -(CH3)c-0-(CH:)pR"; wherein, said aUcyl and said cycloalkyl are optionally substituted by-OH, -OR^, -NR^R', -C(=T)Z or -X(C:=Y)Z; R" is a phenyl optionally substituted with one to three groups independently selected from the group consisting of halogen, cyano, Ci.^alkyl, Ci.jhaloalkyl and C;. 3alkox7. 3. A compound according to claim 2 wherein R^ is substituted Ci-a alkyl, Ila-c or -(CHi)nR^ wherein R^ is IHa-inh. 4. A compound according to claim 2 wherein R^ is -(CH2)oNR^R', -(CH2)i,C(=0)Z or KCH2)nXC(=0)Z. 5. A compound according to claim 1 wherein: R" is phenyl, or a heteroaxyl ring according to tonnula lUa-Ulli; hydrogen, C1.6alkyl, C1_6hydroxyalky!, C1,3 alkoxy-C1-3s alkyl, Ci.salkylainino-Ci.s aliyl and C1.3 dialkylammo-Ci.salkyl or (ii) when both R* and R' are attached to the same nitrogen atom they may be taken together, along with the nitrogen, to foim a pyrrolidine, piperidine, piperazine or morphohne; X, and Y are independently -O- or -NR*; 2 is hydrogen, hydroxy], Ci^alkoxy, NR'R", C^alkyl, Ci_3ali:oxy-Ci.3alky! wherein R" is R^ or phenyl optionaUy substituted with one to three groups independently selected from the group consistiag of halogen, cyano, C1.3 altyl, C3.3 haloalkyl and C1.3 alkoxy; n is 0 to 3; o and p are independently 0 to 4 and o + p k, rl and r2 are independently 0 to 4, and 5 > (rl + r2) > 2; and, acid addition salts, hydrates and solvates thereof; with the proviso that when R** is (CH2)BR^', n is 1 and R" is substituted phenyl, R^ is other than unsnbstituted phenyl. 12. Use of a compound of formula I for the preparation of a medicament for treating HR^ infection according to claim 11, further comprising co-admimstering at least one compound selected from the group consisting of HIV protease inlubitors, nucleoside reverse transcriptase inhibitors, non-nucleoside re^'erse transcriptase inhibitors, CCR5 inhibitors and vhal fusion inhibitors. 13. Use according to claim 12 wherein the reverse transcriptase inhibitor is selected from the group consisting of zidovudine, lamivudine, didanosine, zalcitabine and sta^Tidine, rescriptor, sustiva and viramune and/or the protease inhibited is selected from the group consisting of saquina^^r, ritonavir, nelfinavir, indinavir, an^renavir, lopinavir and atazanavir. 14. Use of a compound of formula I according to claim 11 for the preparation of a medicament for a retrovirus reverse transcriptase. 15. Use of a confound of formula 1 according to claim 11 for the preparation of a medicament for treating an HIV infection, or preventing an HIV infection, or treatiag AIDS or ARC, wherein the host is infected with a strain of HIV expressing a reverse transcriptase with at least one mutation. 16. Use ofa compound offormula I according to claim 11 for treating an HIV infection, or preventing an HIV infection, or treating AIDS or ARC, wherein said stram of HIV exMbits reduced susceptibihty to efavirenz, delavirdine or nevirapine. R"' is phenyl, or a beteroaryl ring according to tonmUa Jila-lllii; •NRV, ■C(=0)Z, -X(C=0)Z

Documents:

1947-chenp-2005 abstract.pdf

1947-chenp-2005 claims.pdf

1947-chenp-2005 correspondence-others.pdf

1947-chenp-2005 correspondence-po.pdf

1947-chenp-2005 description(complete).pdf

1947-chenp-2005 form-1.pdf

1947-chenp-2005 form-18.pdf

1947-chenp-2005 form-3.pdf

1947-chenp-2005 form-5.pdf

1947-chenp-2005 pct.pdf