CA2264064A1 - Imidazole compounds, compositions and use - Google Patents

Abstract

Novel 4,5 substituted imidazole compounds, and compositions for use in therapy as anti-inflammatory agents, and inhibitors cytokine p38/MAP kinase mediated diseases.

Description

?CA 02264064 l999-02- 19WO 98/07425 PCT/US97/14731IMIDAZOLE COMPOUNDS, COMPOSITIONS AND USEFIELD OF THE INVENTIONThis invention relates to a novel group of imidazole containingcompounds, processes for the preparation thereof, the use thereof in treating10 cytokine mediated diseases and pharmaceutical compositions for use in suchtherapy.BACKGROUND OF THE INVENTIONInterleukin-1 (IL-1) and Tumor Necrosis Factor (TNF) are biological15 substances produced by a variety of cells, such as monocytes or macrophages.IL-1 has been demonstrated to mediate a variety of biological activities thoughtto be important in immunoregulation and other physiological conditions such asin?ammation [See, e.g., Dinarello et al., Rev. Infect. Disease, _6_, 51 ( 1984)].The myriad of known biological activities of IL-1 include the activation of T20 helper cells, induction of fever, stimulation of prostaglandin or collagenaseproduction, neutrophil chemotaxis, induction of acute phase proteins and thesuppression of plasma iron levels.There are many disease states in which excessive or unregulated IL-1production is implicated in exacerbating and/or causing the disease. These25 include rheumatoid arthritis, osteoarthritis, endotoxemia and/or toxic shocksyndrome, other acute or chronic in?ammatory disease states such as thein?ammatory reaction induced by endotoxin or in?ammatory bowel disease;tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis,Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella30 arthritis, and acute synovitis. Recent evidence also links IL-1 activity todiabetes and pancreatic B cells.Dinarello, J. Clinical Immunology, 5 (5), 287-297 (1985), reviews thebiological activities which have been attributed to IL-1. It should be noted thatsome of these effects have been described by others as indirect effects of IL-1.35 Excessive or unregulated TNF production has been implicated inmediating or exacerbating a number of diseases including rheumatoid arthritis,-1-?WO 98/07425101520253035CA 02264064 l999-02- 19PCTIU S97/ 14731rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthriticconditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxicshock syndrome, adult respiratory distress syndrome, cerebral malaria, chronicpulmonary in?ammatory disease, silicosis, pulmonary sarcoisosis, boneresorption diseases, reperfusion injury, graft vs. host reaction, allograftrejections, fever and myalgias due to infection, such as in?uenza, cachexiasecondary to infection or malignancy, cachexia, secondary to acquired immunedeficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloidformation, scar tissue formation, Crohn's disease, ulcerative colitis, or pyresis.AIDS results from the infection of T lymphocytes with HumanImmunodeficiency Virus (HIV). At least three types or strains of HIV havebeen identified, i.e., HIV-1, HIV-2 and HIV-3. As a consequence of HIVinfection, T—cell mediated immunity is impaired and infected individualsmanifest severe opportunistic infections and/or unusual neoplasms. HIV entryinto the T lymphocyte requires T lymphocyte activation. Other viruses, such asHIV-l, HIV-2 infect T lymphocytes after T Cell activation and such virusprotein expression and/or replication is mediated or maintained by such T cellactivation. Once an activated T lymphocyte is infected with HIV, the Tlymphocyte must continue to be maintained in an activated state to permit HIVgene expression and/or HIV replication. Monokines, specifically TNF, areimplicated in activated T-cell mediated HIV protein expression and/or virusreplication by playing a role in maintaining T lymphocyte activation.Therefore, interference with monokine activity such as by inhibition ofmonokine production, notably TNF, in an HIV-infected individual aids inlimiting the maintenance of T cell activation, thereby reducing the progressionof HIV infectivity to previously uninfected cells which results in a slowing orelimination of the progression of immune dysfunction caused by HIV infection.Monocytes, macrophages, and related cells, such as kupffer and glial cells, havealso been implicated in maintenance of the HIV infection. These cells, likeT—cells, are targets for viral replication and the level of viral replication isdependent upon the activation state of the cells. [See Rosenberg §t_al., TheImmunopathogenesis of HIV Infection, Advances in Immunology, Vol. 57,(l989)]. Monokines, such as TNF, have been shown to activate HIV replicationin monocytes and/or macrophages [See Poli, t=,t_21l., Proc. Natl. Acad. Sci.,872782-784 ( 1990)], therefore, inhibition of monokine production or activityaids in limiting HIV progression as stated above for T-cells.-2-?WO 98/07425101520253035CA 02264064 l999-02- 19PCT/U S97/ 14731TNF has also been implicated in various roles with other viralinfections, such as the cytomegalia virus (CMV), in?uenza virus, and the herpesvirus for similar reasons as those noted.Interleukin-8 (IL-8) is a chemotactic factor first identified andcharacterized in 1987. IL-8 is produced by several cell types includingmononuclear cells, fibroblasts, endothelial cells, and keratinocytes. Itsproduction from endothelial cells is induced by IL-1, TNF, orlipopolysachharide (LPS). Human H.-8 has been shown to act on Mouse,Guinea Pig, Rat, and Rabbit Neutrophils. Many different names have beenapplied to IL-8, such as neutrophil attractant/activation protein—1 (NAP-1),monocyte derived neutrophil chemotactic factor (MDN CF), neutrophilactivating factor (NAF), and T-cell lymphocyte chemotactic factor.IL-8 stimulates a number of functions in vitro. It has been shown tohave chemoattractant properties for neutrophils, 'I‘—lymphocytes, and basophils.In addition it induces histamine release from basophils from both normal andatopic individuals as well as lysozomal enzyme release and respiratory burstfrom neutrophils. IL-8 has also been shown to increase the surface expressionof Mac—l (CD1lb/CD18) on neutrophils without de novo protein synthesis, thismay contribute to increased adhesion of the neutrophils to vascular endothelialcells. Many diseases are characterized by massive neutrophil infiltration.Conditions associated with an increased in IL-8 production (which isresponsible for chemotaxis of neutrophil into the in?ammatory site) wouldbenefit by compounds which are suppressive of IL-8 production.IL-1 and TNF affect a wide variety of cells and tissues and thesecytokines as well as other leukocyte derived cytokines are important and criticalin?ammatory mediators of a wide variety of disease states and conditions. Theinhibition of these cytokines is of benefit in controlling, reducing andalleviating many of these disease states.There remains a need for treatment, in this field, for compounds whichare cytokine suppressive anti-in?ammatory drugs, i.e. compounds which arecapable of inhibiting cytokines, such as IL-1, IL-6, IL-8 and TNF.SUMMARY OF THE INVENTIONThis invention relates to the novel compounds of Formula (I) andpharmaceutical compositions comprising a compound of Formula (I) and apharmaceutically acceptable diluent or carrier.-3-?WO 98/074251015202530CA 02264064 l999-02- 19PCT/US97/14731This invention also relates to a method of inhibiting cytokines and thetreatment of a cytokine mediated disease, in a mammal in need thereof, whichcomprises administering to said mammal an effective amount of a compound ofFormula (I).In particular the present invention relates to a method of treating aCSBP/RK/p38 kinase mediated disease, in a mammal in need thereof.This invention more specifically relates to a method of inhibiting theproduction of IL-1 in a mammal in need thereof which comprises administeringto said mammal an effective amount of a compound of Formula (I).This invention more specifically relates to a method of inhibiting theproduction of IL-8 in a mammal in need thereof which comprises administering tosaid mammal an effective amount of a compound of Formula (I).This invention more specifically relates to a method of inhibiting theproduction of TNF in a mammal in need thereof which comprises administeringto said mammal an effective amount of a compound of Formula (1).Accordingly, the present invention provides for a compound of the structure :wherein:R1 is 4-pyridyl, pyrirnidinyl, 4-pyridazinyl, 1,2,4-triazin-5-yl, quinolyl, isoquinolinyl,quinazolin-4-yl, l—imidazolyl or l-benzimidazolyl, which heteroatyl ring is optionallysubstituted independently one to three times with Y, NHRa, optionally substituted C1-4alkyl, halogen, hydroxyl, optionally substituted C 1-4 alkoxy, optionally substitutedC 1-4 alkylthio, C1-4 alkylsulfinyl, CH2OR12, amino, mono and di- C1-5 alkylsubstituted amino, N(R10)C(O)Rb, or an N—heterocyclyl ring which ring has from 5 to7 members and optionally contains an additional heteroatom selected from oxygen,sulfur;Y is X1-Ra;X1 is oxygen or sulfur;R4 is phenyl, naphth-1—yl or naphth—2—yl, or a heteroaryl, which is optionally substituted byone or two substituents, each of which is independently selected, and which, for a 4-phenyl, 4—naphth—l-yl, 5—naphth—2—yl or 6-naphth—2—yl substituent, is halogen, cyano,nitro, C(Z)NR7R17, C(Z)OR16, (CR1()R2())vCOR12, SR5, SOR5, OR12, halo--4-?WO 98/07425101520253035CA 02264064 l999-02- 19PCT/US97/14731substituted—C 1-4 alkyl, C1-4 alkyl, ZC(Z)R12, NR10C(Z)R15, or -(CR]()R2())vNR]0R20 and which, for other positions of substitution, is halogen,cyano, C(Z)NR13R 14, C(Z)OR3, (CR 1()R20)m"COR3, S(O)mR3, OR3, halo-substituted-C1-4 alkyl, C1-4 alkyl, (CR10R20)m"NR1()C(Z)R3, NR10S(O)m'R3,NR10S(O)m'NR7Rl7» ZC(Z)R3 or (CR1oR20)m"NR13R14;v is 0, or an integer having a value of 1 or 2;m is O, or the integer 1 or 2;m‘ is an integer having a value of l or 2,m" is 0, or an integer having a value of 1 to 5;n is an integer having a value of l to 10;n‘ is 0, or an integer having a value of l to 10;Z is oxygen or sulfur;R3 is C1-6all<yl, aryl, arylC1-6alkyl, heterocyclic, heterocyclylC1-6 alkyl, heteroaryl,heteroarylC1-5alkyl, wherein each of these moieties may be optionally substituted;Rb is hydrogen, C1-6 alkyl, C3_7 cycloalkyl, aryl, arylC1-4 alkyl, heteroaryl,heteroarylC1-4alkyl, heterocyclyl, or heterocyclylC1-4 alkyl;R3 is heterocyclyl, heterocyclylC1-1() alkyl or R8;R5 is hydrogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl or NR7R17, excluding themoieties —SR5 being -SNR7R17 and -SOR5 being —SOH;R7 and R17 is each independently selected from hydrogen or C 1-4 alkyl or R7 and R17together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7members which ring optionally contains an additional heteroatom selected fromoxygen, sulfur or NR 1 5;R3 is C 1.10 alkyl, halo-substituted C1-10 alkyl, C2_1() alkenyl, C2-10 alkynyl, C3_7cycloalkyl, C5-7 cycloalkenyl, aryl, arylC1-1() alkyl, heteroaryl, heteroarylC1-10 alkyl,(CR10R20)nOR11, (CR10R20)nS(0)mR18, (CR10R2o)nNHS(O)2R1s,(CR1()R2())nNR13R14; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl may beoptionally substituted;R9 is hydrogen, —C(Z)R11 or optionally substituted C1_10 alkyl, S(O)2R13, optionallysubstituted aryl or optionally substituted aryl-C 1-4 alkyl;R10 and R20 is each independently selected from hydrogen or C1-4 alkyl;R11 is hydrogen, C1-1o alkyl, C3-7 cycloalkyl, heterocyclyl, heterocyclyl C1_1()alkyl,aryl, arylC 1-10 alkyl, heteroaryl or heteroarylC 1-10 alkyl;R12 is hydrogen or R16;R13 and R14 is each independently selected from hydrogen or optionally substituted C1-4alkyl, optionally substituted aryl or optionally substituted aryl—C 1-4 alkyl, or together-5-?101520253035CA 02264064 l999-02- 19W0 98/07425 PCT/US97/14731with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 memberswhich ring optionally contains an additional heteroatom selected from oxygen, sulfur orNR9;R15 is R10 or C(Z)-C1-4 alkyl;R16 is C 1-4 alkyl, halo-substituted—C1-4 alkyl, or C3_7 cycloalkyl;R13 is C1-1() alkyl, C3_7 cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl,heterocyclyl—C1-1()alkyl, heteroaryl or heteroarylalkyl;or a pharmaceutically acceptable salt thereof.DETAILED DESCRIPTION OF THE INVENTIONIn Formula (1), suitable R1 moieties includes 4-pyridyl, 4-pyrimidinyl, 4-pyridazinyl, 1,2,4-triazin-5—yl, 4—quinolyl, 6-isoquinolinyl, 4—quinazolinyl, 1-imidazolyl and 1-benzimidazolyl rings, of which the 4-pyridyl, 4-pyrimidinyl and 4-quinolyl rings are preferred. More preferred is the 4-pyrimidinyl or 4-pyridylmoiety, and most preferred is the 4-pyrimidinyl ring.Suitably, the R1 ring is optionally substituted independently one to three times withY, NHRa, optionally substituted C 1-4 alkyl, halogen, hydroxyl, optionally substituted C1-4alkoxy, optionally substituted C1-4 alkylthio, C1-4 alkylsulfinyl, CH2OR12, amino, monoand di- C1-5 alkyl substituted amino, N(R1())C(O)Rb, or an N-heterocyclyl ring which ringhas from 5 to 7 members and optionally contains an additional heteroatom selected fromoxygen, sulfur.Suitably, Y is X1—Ra; and X1 is oxygen or sulfur, preferably oxygen.Suitably, Ra is C1-6alkyl, aryl, arylC1-5alkyl, heterocyclic, heterocyclicC1_6alkyl, heteroaiyl, or heteroarylC1-5alkyl; and wherein each of these moieties may beoptionally substituted. Preferably Ra is an optionally substituted C 1_5alkyl, aryl, oraryl C1-6alkyl group.When Ra is an aryl, it is preferably phenyl or napthyl. When Ra is arylalkyl,it it is preferably benzyl or napthylmethyl. When Ra is a heterocyclic orheterocyclic alkyl moiety, the heterocyclic portion is preferably pyrrolindinyl,piperidine, morpholino, tetrahydropyran, tetrahydrothiopyranyl,tetrahydrothipyransulfinyl, tetrahydrothio—pyransulfonyl, pyrrolindinyl, indole, orpiperonyl ring. It is noted that the heterocyclic rings herein may containunsaturation, such as in a tryptamine ring.-6-?WO 98/07425101520253035CA 02264064 l999-02- 19PCT/US97/14731When R3 is a heteroaryl ring as de?ned below, it is preferably a pyridine or _tetrazole ring.The Ra moieties may be optionally substituted one or more times, preferablyone to three times, independently with halogen; C 1-4 alkyl, such as methyl, ethyl,propyl, isopropyl, or t-butyl; halosubstituted alkyl, such as CF3; hydroxy; hydroxysubstituted C1-4 alkyl; (CR10R20)q C1-4 alkoxy, such as methoxy or ethoxy ;(CR10R20)q S(O)malkyl and ; (CR10R20)qS(O)m aryl (wherein m is 0, 1, or 2);(CR10R2Q)qC(O)OR11, such as C(O)C1_4 alkyl or C(O)OH moieties;(CR10R20)qC(O)R11; (CR10R20)qOC(O)RC; —O-(CH2)s—O-, such as in a ketal ordioxyalkylene bridge; (CR10R20)qNR13R14; (CR10R20)qN(R10)C(O)Rb;(CR1oR2o)qC(0)NR13R14: (CR10R20)qC(O)NR10RC;(CR10R20)qS(O)2NR13R14; (CR10R20)qS(O)2 NR 1QRC;(CR10R2())qN(R10)S(O)2 RC; cyano, nitro, or an N-heterocyclyl ring which ringhas from 5 to 7 members and optionally contains an additional heteroatom selectedfrom oxygen, sulfur or NR15; aryl, such as phenyl; an optionally substitutedarylalkyl, such as benzyl or phenethyl; aryloxy, such as phenoxy; or arylalkyloxysuch as benzyloxy; and wherein the aryl, alkylaklyl, aryloxy and arylalkyloxymoieties may be optionally substituted themselves one to two times by halogen;hydroxy; hydroxy substituted alkyl; C1-1() alkoxy; S(O)m alkyl; amino, NR7R 17group; C 1-4 alkyl, or halosubstituted C 1_4 alkyl.q is 0 or an integer having a value of 1 to 4.Rb is suitably hydrogen, C1-6 alkyl, C3-7 cycloalkyl, aryl, a1ylC1-4 alkyl,heteroaryl, heteroarylC 1_4a1kyl, heterocyclyl, or heterocyclylC1-4 alkyl moiety; allof which may be optionally substituted as defined below.RC is suitably an C1-6 alkyl, C3-7 cycloalkyl, aryl, arylC 1-4 alkyl,heteroaryl, heteroarylC1-4alkyl, heterocyclyl, or heterocyc1ylC1-4 alkyl moiety, allof which may be optionally substituted as defined below.Suitable Ra groups include,but are not limited to, methyl, ethyl, isopropyl,benzyl, halosubstituted benzyl, napthylmethyl, phenyl, halosubstituted phenyl,aminocarbonylphenyl, alkylphenyl, cyanophenyl, alkylthiophenyl, hydroxyphenyl,alkoxyphenyl, phenoxyphenyl, benzyloxyphenyl, phenylphenyl,methylenedioxyphenyl, tri?uoromethylphenyl, methylsulfonylphenyl, tetrazole,methyltetrazolyl, morpholinopropyl, piperonyl, piperidin-4—yl, alkyl substitutedpiperidine, such as 1~methyl piperidine, or 2,2,6,6-tetramethylpiperidin-4-yl.?WO 98/07425101520253035CA 02264064 l999-02- 19PCTIUS97/14731When the R1 optional substituent is N(R1())C(O) Rb, Rb is preferably a C1-6alkyl and R10 is preferably hydrogen. It is also recognized that the Rb moieties, inparticular the C1_5 alkyl group may be optionally substituted, preferably from one tothree times, preferably with halogen, such as ?uorine, as in tri?uoromethyl ortrifluroethyl.Preferably R, is substituted by Y, such as alkoxy, aryloxy, or arylalkyloxy,NHRa, or amino. A preferred ring placement of the R1 substituent on the 4-pyridylderivative is the 2—position, such as 2-methoxy—4—pyridyl. A preferred ringplacement on the 4—pyrimidinyl ring is also at the ?_—position, such as in 2-methoxy-pyrimidinyl.Preferably, when the substituent is an optionally substituted C1-4 alkyl. Thealkyl moiety is preferably substituted by halogen, such as ?uorine, chlorine, bromineor iodine; hydroxy, such as hydroxyethoxy; C1-10 alkoxy, such as amethoxymethoxy, S(O)m alkyl, wherein m is 0, 1 or 2; amino, mono & di-substituted amino, such as in the NR7R17 group, i.e. tert—butylarninoethoxy; orwhere the R7R17 may together with the nitrogen to which they are attached cyclizeto form a 5 to 7 membered ring which optionally includes an additional heteroatomselected from O/N/S; C1_10 alkyl, cycloalkyl, or cycloalkyl alkyl group, such asmethyl, ethyl, propyl, isopropyl, t-butyl, etc. or cyclopropyl methyl; orhalosubstituted C1-1() alkyl, such as CF3, Preferably the R1 substituents aretertbutylaminoethoxy, or hydroxyethoxy.Suitably, R4 is phenyl, naphth-l-yl or naphth-2-yl, or a heteroaryl, which isoptionally substituted by one or two substituents. More preferably R4 is a phenyl ornaphthyl ring. Suitable substitutions for R4 when this is a 4—phenyl, 4-naphth—l-yl,5-naphth-2-yl or 6—naphth—2—yl moiety are one or two substituents each of which areindependently selected from halogen, SR5, SOR5, OR12, CF3, or(CR1()R2())VNR10R20, and for other positions of substitution on these ringspreferred substitution is halogen, S(O)mR3, OR3, CF3, (CR1()R2())m"NR13R14,NR1()C(Z)R3 and NR1()S(O)m'R8. Preferred substituents for the 4—position inphenyl and naphth-l-yl and on the 5-position in naphth—2-yl include halogen,especially ?uoro and chloro and -SR5 and —SOR5 wherein R5 is preferably a C1_2alkyl, more preferably methyl; of which the fluoro and chloro is more preferred, andmost especially preferred is ?uoro. Preferred substituents for the 3—position in-3-?WO 98/07425‘I01520253035CA 02264064 l999-02- 19PCT/US97/1473 1phenyl and naphth-1-yl rings include: halogen, especially ?uoro and chloro; OR3, .especially C1-4 alkoxy; CF3, NR1()R2(), such as amino; -NR1()C(Z)R3, especiallyNHCO(C1-1() alkyl); NR1()S(O)m'Rg, especially NHSO2(C 1-10 alkyl), and SR3and —SOR3 wherein R3 is preferably a C1-2 alkyl, more preferably methyl. Whenthe phenyl ring is disubstituted preferably it is two independent halogen moieties,such as ?uoro and chloro, preferably di-chloro and more preferably in the 3, 4-position. It is also preferred that for the 3-position of both the OR3 and ZC(Z)R3moietites, R3 may also include hydrogen.Preferably, the R4 moiety is an unsubstituted or substituted phenyl moiety.More preferably, R4 is phenyl or phenyl substituted at the 4-position with ?uoroand/or substituted at the 3-position with ?uoro, chloro, C1-4 alkoxy, methane-sulfonamido or acetamido, or R4 is a phenyl di—substituted at the 3,4-positionindependently with chloro or ?uoro, more preferably chloro. Most preferably, R4is a 4-?uorophenyl.Suitably, R4 is an optionally substituted phenyl. Preferably the phenyl issubstituted one or more times independently by halogen, -SR5, -S(O)R5, -OR12,halo—substituted-C1-4 alkyl, or C1-4 alkyl.As used herein, "optionally substituted" unless specifically defined herein,shall mean such groups as halogen, such as ?uorine, chlorine, bromine or iodine;hydroxy; hydroxy substituted C 1- loalkyl; C 1- 10 alkoxy, such as methoxy orethoxy; S(O)m alkyl, wherein m is O, 1 or 2, such as methyl thio, methylsulfmyl ormethyl sulfonyl; amino, mono & di—substituted amino, such as in the NR7R17group; or where the R7R17 may together with the nitrogen to which they areattached cyclize to form a 5 to 7 membered ring which optionally includes anadditional heteroatom selected from O/N/S; C1- 10 alkyl, C3_7 cycloalkyl, or C3_7cycloalkyl alkyl group, such as methyl, ethyl, propyl, isopropyl, t—butyl, etc. orcyclopropyl methyl; halosubstituted C1-10 alkyl, such CF3; an optionallysubstituted aryl, such as phenyl, or an optionally substituted arylalkyl, such asbenzyl or phenethyl, wherein these aryl moieties may also be substituted one to twotimes by halogen; hydroxy; hydroxy substituted alkyl; C1- 10 alkoxy; S(O)m alkyl;amino, mono & di-substituted amino, such as in the NR7R17 group; alkyl, or CF3.Suitable pharmaceutically acceptable salts are well known to thoseskilled in the art and include basic salts of inorganic and organic acids, such ashydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane-9-?WO 98/074251015202530CA 02264064 l999-02- 19PCT/US97/14731sulphonic acid, ethane sulphonic acid, acetic acid, malic acid, tartaric acid, citricacid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoicacid, salicylic acid, phenylacetic acid and mandelic acid. In addition,pharmaceutically acceptable salts of compounds of Formula (I) may also beformed with a pharmaceutically acceptable cation, for instance, if a substituentgroup comprises a carboxy moiety. Suitable pharmaceutically acceptablecations are well known to those skilled in the art and include alkaline, alkalineearth, ammonium and quaternary ammonium cations.The following terms, as used herein, refer to:0 "halo" or "halogens", include the halogens: chloro, ?uoro, bromo andiodo.- "C1_10alkyl" or "alkyl" - both straight and branched chain radicals of1 to 10 carbon atoms, unless the chain length is otherwise limited, including,but not limited to, methyl, ethyl, n-propyl, iso—propy1, n—butyl, sec-butyl, iso-butyl, tert—butyl, n—pentyl and the like.- "aryl" - phenyl and naphthyl.° "cycloalkyl" is used herein to mean cyclic radicals, preferably of 3 to8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl,and the like.~ "heteroaryl" (on its own or in any combination, such as"heteroaryloxy", or "heteroaryl alkyl") - a 5-10 membered aromatic ring system_in which one or more rings contain one or more heteroatoms selected from thegroup consisting of N, O or S, such as, but not limited, to pyrrole, pyrazole,furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine,oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole.- "heterocyclic" (on its own or in any combination, such as"heterocycly1alkyl") - a saturated or partially unsaturated 4-10 membered ringsystem in which one or more rings contain one or more heteroatoms selectedfrom the group consisting of N, O, or S; such as, but not limited to, pyrrolidine,piperidine, piperazine, morpholine, tetrahydro pyran, or irnidazolidine.- The term "aralkyl" or "heteroarylalkyl" or "heterocyclicalkyl" is usedherein to mean C1-4 alkyl as defined above attached to an aiyl, heteroaryl orheterocyclic moiety as also defined herein unless otherwise indicate.-10-?WO 98/074251015202530CA 02264064 l999-02- 19PCT/US97/ 14731- "sulfinyl" — the oxide S (O) of the corresponding sulfide, the term"thio" refers to the sulfide, and the term "sulfonyl" refers to the fully oxidized S(0)2 moiety.For the purposes herein the "core" 4-pyrimidinyl moiety for R1 is refered toas the formula:H\/NExemplified compounds of Formula (I) include:4-(4-Fluorophenyl)-5-(4-pyridyl)imidazo1e4—(4-Fluorophenyl)-5-(2—methoxy—pyrimidin-4—yl)imidazole4-(4-Fluorophenyl)-5-(2-methylthio-pyrimidin—4—yl)imidazoleThe compounds of Formula (I) may be obtained by applying syntheticprocedures as described in USSN 08/091,491, published as Adams et al.W095/02575; US patent 5,593,992 Adams et al.; and USSN 08/659,102 publishedas PCT US96/40143. Synthetic chemistry for each of the variously substituted R1moieties is contained within each noted patent application. A description of theassay for inhibition of the cytokine speci?c binding protein (CSBP) is also found inW095/07922 (Attorney Docket No.: P50195—l). Each of these references isincorporated herein in their entirety.Pharmaceutically acid addition salts of compounds of Formula (I) maybe obtained in known manner, for example by treatment thereof with anappropriate amount of acid in the presence of a suitable solvent.METHODS OF TREATMEETThe compounds of Formula (I), or a pharmaceutically acceptable saltthereof can be used in the manufacture of a medicament for the prophylactic ortherapeutic treatment of any disease state in a human, or other mammal, whichis exacerbated or caused by excessive or unregulated cytokine production bysuch mammal's cell, such as but not limited to monocytes and/or macrophages.-11-?WO 98/07425101520253035CA 02264064 l999-02- 19PCT/US97/1473 1Compounds of Formula (I) are capable of inhibiting proin?ammatorycytokines, such as IL-1, IL-6, IL-8 and TNF and are therefore of use in therapy.IL-1, IL-6, IL-8 and TNF affect a wide variety of cells and tissues and thesecytokines, as well as other leukocyte-derived cytokines, are important andcritical in?ammatory mediators of a wide variety of disease states andconditions. The inhibition of these pro-in?ammatory cytokines is of benefit incontrolling, reducing and alleviating many of these disease states.Accordingly, the present invention provides a method of treating acytokine-mediated disease which comprises administering an effectivecytokine-interfering amount of a compound of Formula (1) or apharmaceutically acceptable salt thereof.Compounds of Formula (I) are capable of inhibiting inducibleproin?ammatory proteins, such as COX-2, also referred to by many othernames such as prostaglandin endoperoxide synthase-2 (PGHS-2) and aretherefore of use in therapy. These proin?ammatory lipid mediators of thecyclooxygenase (CO) pathway are produced by the inducible COX-2 enzyme.Regulation, therefore of COX-2 which is responsible for the these productsderived from arachidonic acid, such as prostaglandins affect a wide variety ofcells and tissues are important and critical in?ammatory mediators of a widevariety of disease states and conditions. Expression of COX-1 is not effectedby compounds of Formula (I). This selective inhibition of COX-2 may alleviateor spare ulcerogenic liability associated with inhibition of COX-1 therebyinhibiting prostoglandins essential for cytoprotective effects. Thus inhibition ofthese pro-in?ammatory mediators is of benefit in controlling, reducing andalleviating many of these disease states. Most notably these in?ammatorymediators, in particular prostaglandins, have been implicated in pain, such as inthe sensitization of pain receptors, or edema. This aspect of pain managementtherefore includes treatment of neuromuscular pain, headache, cancer pain, andarthritis pain. Compounds of Formula (I) or a pharmaceutically acceptable saltthereof, are of use in the prophylaxis or therapy in a human, or other mammal,by inhibition of the synthesis of the COX-2 enzyme.Accordingly, the present invention provides a method of inhibiting thesynthesis of COX-2 which comprises administering an effective amount of a-12-?WO 98/07425101520253035CA 02264064 l999-02- 19PCT/US97/14731compound of Formula (I) or a pharmaceutically acceptable salt thereof. Thepresent invention also provides for a method of prophylaxis treatment in ahuman, or other mammal, by inhibition of the synthesis of the COX-2 enzyme.A new member of the MAP kinase family, alternatively termed CSBP,p38, or RK, has been identified independently by several laboratories recently.Activation of this novel protein kinase via dual phosphorylation has beenobserved in different cell systems upon stimulation by a wide spectrum ofstimuli, such as physicochemical stress and treatment with lipopolysaccharideor proinflammatory cytokines such as interleukin-1 and tumor necrosis factor.The cytokine biosynthesis inhibitors, of the present invention, compounds ofFormula (I), have been determined to be potent and selective inhibitors ofCSBP/p38/RK kinase activity. These inhibitors are of aid in determining thesignaling pathways involvement in in?ammatory responses. In particular, forthe first time a definitive signal transduction pathway can be prescribed to theaction of lipopolysaccharide in cytokine production in macrophages.The cytokine inhibitors were subsequently tested in a number of animalmodels for anti-in?ammatory activity. Model systems were chosen that wererelatively insensitive to cyclooxygenase inhibitors in order to reveal the uniqueactivities of cytokine suppressive agents. The inhibitors exhibited significantactivity in many such in vivo studies. Most notable are its effectiveness in thecollagen-induced arthritis model and inhibition of TNF production in theendotoxic shock model. In the latter study, the reduction in plasma level ofTNF correlated with survival and protection from endotoxic shock relatedmortality. Also of great importance are the compounds effectiveness ininhibiting bone resorption in a rat fetal long bone organ culture system.Griswold et al., (1988) Arthritis Rheum. 31: 1406-1412; Badger, et al., (1989)Circ. Shock 27, 51-61; Votta et al., (1994) in vitro. Bone 15, 533-538; Lee et al.,(1993). B Ann. N. Y. Acad. Sci. 696, 149-170.Another aspect of the present invention, therefore, is the treatment of aCSBP/RK/p38 kinase mediated disease, in a mammal in need thereof, whichcomprises administering to said mammal an effective amount of a compound ofFormula (1). Suitable diseases, include those mentioned herein for IL-1, IL-6,IL-8 and TNF and more specifically those disease which are CSBP/RK/p38-13-?CA 02264064 l999-02- 19W0 98l07425 PCT/US97/14731kinase mediated diseases. These include, but are not limited to rheumatoidarthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthriticconditions, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxicshock syndrome, asthma, adult respiratory distress syndrome, stroke,5 reperfusion injury, CNS injuries, such as neurotrauma and ischemia, includingboth open and closed head injuries), psoriasis, restenosis, such as occursfollowing coronary angioplasty, cerebral malaria, chronic pulmonaryin?ammatory disease, silicosis, pulmonary sarcososis, bone resorption diseases,osteoporosis, , graft vs. host reaction, allograft rejections, Crohn's disease,10 ulcerative colitis or any other anti-in?ammatory bowel disease (IBD), orpyresis.CNS injuries as defined herein include both open or penetrating headtrauma, such as by surgery, or a closed head trauma injury, such as by an injury15 to the head region. Also included within this definition is ischemic stroke,particularly to the brain area.Ischemic stroke may be de?ned as a focal neurologic disorder thatresults from insufficient blood supply to a particular brain area, usually as a20 consequence of an embolus, thrombi, or local atheromatous closure of the bloodvessel. The role of in?ammatory cytokines in this are has been emerging andthe present invention provides a mean for the potential treatment of theseinjuries. Relatively little treatment, for an acute injury such as these has beenavailable.25TNF-ot is a cytokine with proin?ammatory actions, includingendothelial leukocyte adhesion molecule expression. Leukocytes infiltrate intoischemic brain lesions and hence compounds which inhibit or decrease levels ofTNF would be useful for treatment of ischemic brain injury. See Liu et al.,30 Stoke, Vol. 25., No. 7, pp 1481-88 (1994) whose disclosure is incorporatedherein by reference.Models of closed head injuries and treatment with mixed 5-LO/COagents is discussed in Shohami et al., J. of Vaisc & Clinical Physiology and35 Pharmacology, Vol. 3, No. 2, pp. 99-107 (1992) whose disclosure is-14-?W0 98/07/125101520253035CA 02264064 l999-02- 19PCT/US97/ 14731incorporated herein by reference. Treatment which reduced edema formation -was found to improve functional outcome in those animals treated.Another aspect of the present invention is to use of a compound of Formula(I) for the treatment of chronic in?ammatory or proliferative or angiogenic diseaseswhich are caused by excessive, inappropriate angiogenesis. Compounds of Formula(I) may also be used topically in the treatment or prophylaxis of disease statesexacerbated by excessive or inappropriate angiogenesis.Chronic diseases which have an inappropriate angiogenic component arevarious ocular neovasularizations, such as diabetic retinopathy and maculardegeneration.Other chronic diseases which have an excessive or increased proliferation ofvasculature are tumor growth and metastasis, atherosclerosis, and certain arthriticconditions. Therefore cytokine inhibitors will be of utility in the blocking of theangiogenic component of these disease states.The term "excessive or increased proliferation of vasculature inappropriateangiogenesis" as used herein includes, but is not limited to, diseases which arecharacterized by hemangiomas and ocular diseases.The term "inappropriate angiogenesis" as used herein includes, but is notlimited to, diseases which are characterized by vesicle proliferation withaccompanying tissue proliferation, such as occurs in cancer, metastasis, arthritis andatherosclerosis.The murine airpouch granuloma model of chronic in?ammation (Kimura etal., 1985, J. Pharmacobio-Dyn., 8:393—400; Colville-Nash et al.,1995, J. Pharm. andExp. Ther., 274: 1463-1472) whose disclosure is incorporated herein by reference inits entirety, is characterized by in?ammatory cell in?ux, fibrous tissue proliferationand intense angiogenesis. It is representative of in?ammatory angiogenesis anddemonstrates that the angiogenic component can be pharrnacologically modulatedindependently of granuloma growth and size. In addition, angiogenesis can beaccurately quantitated by a vascular casting method. For additional information onscreening, etc., see Winkler et al., USSN 60/013,138 now PCT/US97/03626, filed03/07/97, Attorney Docket No.: P50450-1, whose disclosure is incorporated hereinbe reference.In particular, compounds of Formula (I) or a pharmaceuticallyacceptable salt thereof are of use in the prophylaxis or therapy of any disease-15-?CA 02264064 l999-02- 19W0 98/07425 PCT/US97/14731state in a human, or other mammal, which is exacerbated by or caused byexcessive or unregulated IL-1, IL-8 or TNF production by such mammals cell,such as, but not limited to, monocytes and/or macrophages.5 Accordingly, in another aspect, this invention relates to a method ofinhibiting the production of IL-1 in a mammal in need thereof which comprisesadministering to said mammal an effective amount of a compound of Formula(I) or a pharmaceutically acceptable salt thereof.There are many disease states in which excessive or unregulated IL-110 production is implicated in exacerbating and/or causing the disease. Theseinclude rheumatoid arthritis, osteoarthritis, stroke, endotoxemia and/or toxicshock syndrome, other acute or chronic in?ammatory disease states such as thein?ammatory reaction induced by endotoxin or in?ammatory bowel disease,tuberculosis, atherosclerosis, muscle degeneration, multiple sclerosis, cachexia,15 bone resorption, psoriatic arthritis, Reiter‘s syndrome, rheumatoid arthritis,gout, traumatic arthritis, rubella arthritis and acute synovitis. Recent evidencealso links IL-1 activity to diabetes, pancreatic B cells and Alzheimer's disease.In a further aspect, this invention relates to a method of inhibiting theproduction of TNF in a mammal in need thereof which comprises administering20 to said mammal an effective amount of a compound of Formula (I) or apharmaceutically acceptable salt thereof.Excessive or unregulated TNF production has been implicated inmediating or exacerbating a number of diseases including rheumatoid arthritis,rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic25 conditions, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxicshock syndrome, adult respiratory distress syndrome, stroke, cerebral malaria,chronic pulmonary in?ammatory disease, silicosis, pulmonary sarcoisosis, boneresorption diseases, such as osteoporosis, reperfusion injury, graft vs. hostreaction, allograft rejections, fever and myalgias due to infection, such as30 in?uenza, cachexia secondary to infection or malignancy, cachexia secondary toacquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS relatedcomplex), keloid formation, scar tissue formation, Crohn's disease, ulcerativecolitis and pyresis.Compounds of Formula (I) are also useful in the treatment of viral35 infections, where such viruses are sensitive to upregulation by TNF or will elicitTNF production in vivo. The viruses contemplated for treatment herein are-16-?CA 02264064 l999-02- 19WO 98/07425 PCT/US97/14731those that produce TNF as a result of infection, or those which are sensitive toinhibition, such as by decreased replication, directly or indirectly, by the TNFinhibiting—compounds of Formula (1). Such viruses include, but are not limitedto HIV-l, HIV-2 and HIV-3, Cytomegalovirus (CMV), In?uenza, adenovirus5 and the Herpes group of viruses, such as but not limited to, Herpes Zoster andHerpes Simplex. Accordingly, in a further aspect, this invention relates to amethod of treating a mammal af?icted with a human immunodeficiency virus(HIV) which comprises administering to such mammal an effective TNFinhibiting amount of a compound of Formula (I) or a pharmaceutically10 acceptable salt thereof.Compounds of Formula (I) may also be used in association with theveterinary treatment of mammals, other than in humans, in need of inhibition ofTNF production. TNF mediated diseases for treatment, therapeutically orprophylactically, in animals include disease states such as those noted above,15 but in particular viral infections. Examples of such viruses include, but are notlimited to, lentivirus infections such as, equine infectious anaemia virus, caprinearthritis virus, visna virus, or maedi virus or retrovirus infections, such as butnot limited to feline immunodeficiency virus (FIV), bovine immunodeficiencyvirus, or canine immunodeficiency virus or other retroviral infections.20 The compounds of Formula (I) may also be used topically in thetreatment or prophylaxis of topical disease states mediated by or exacerbated byexcessive cytokine production, such as by IL-1 or TNF respectively, such asin?amed joints, eczema, psoriasis and other in?ammatory skin conditions suchas sunburn; in?ammatory eye conditions including conjunctivitis; pyresis, pain25 and other conditions associated with in?ammation.Compounds of Formula (I) have also been shown to inhibit theproduction of IL-8 (Interleukin-8, NAP). Accordingly, in a further aspect, thisinvention relates to a method of inhibiting the production of IL-8 in a mammalin need thereof which comprises administering to said mammal an effective30 amount of a compound of Formula (I) or a pharmaceutically acceptable saltthereof.There are many disease states in which excessive or unregulated IL-8production is implicated in exacerbating and/or causing the disease. Thesediseases are characterized by massive neutrophil in?ltration such as, psoriasis,35 in?ammatory bowel disease, asthma, cardiac and renal reperfusion injury, adultrespiratory distress syndrome, thrombosis and glomerulonephritis. All of these-17-?CA 02264064 l999-02- 19W0 93/07425 PCT/US97/14731diseases are associated with increased IL-8 production which is responsible forthe chemotaxis of neutrophils into the in?ammatory site. In contrast to otherin?ammatory cytokines (IL-1, TNF, and IL-6), IL-8 has the unique property ofpromoting neutrophil chemotaxis and activation. Therefore, the inhibition of5 IL-8 production would lead to a direct reduction in the neutrophil in?ltration.The compounds of Formula (I) are administered in an amount sufficientto inhibit cytokine, in particular IL-1, IL-6, IL-8 or TNF, production such that itis regulated down to normal levels, or in some case to subnormal levels, so as toameliorate or prevent the disease state. Abnormal levels of IL-1, IL-6, IL-8 or10 TNF, for instance in the context of the present invention, constitute: (i) levels offree (not cell bound) IL-1, IL-6, IL-8 or TNF greater than or equal to 1picogram per ml; (ii) any cell associated IL-1, IL-6, IL-8 or TNF; or (iii) thepresence of IL-1, IL-6, IL-8 or TNF mRNA above basal levels in cells or tissuesin which IL-1, IL-6, IL-8 or TNF, respectively, is produced.15 The discovery that the compounds of Formula (I) are inhibitors ofcytokines, speci?cally IL-1, IL-6, IL-8 and TNF is based upon the effects of thecompounds of Formulas (I) on the production of the IL-1, IL-8 and TNF in invitro assays which are described herein.As used herein, the term "inhibiting the production of IL-1 (IL-6, IL-8 or20 TNF)" refers to:a) a decrease of excessive in vivo levels of the cytokine (IL-1, IL-6, IL-8 or TNF) in a human to normal or sub-normal levels by inhibition of the inviva release of the cytokine by all cells, including but not limited to monocytesor macrophages;25 b) a down regulation, at the genomic level, of excessive in vivo levels ofthe cytokine (IL-1, IL-6, IL-8 or TNF) in a human to normal or sub-normallevels;c) a down regulation, by inhibition of the direct synthesis of the cytokine(IL-1, IL-6, IL-8 or TNF) as a postranslational event; or30 d) a down regulation, at the translational level, of excessive in vivolevels of the cytokine (IL-1, IL-6, IL-8 or TNF) in a human to normal or sub-normal levels.As used herein, the term "TNF mediated disease or disease state" refers35 to any and all disease states in which TNF plays a role, either by production ofTNF itself, or by TNF causing another monokine to be released, such as but not-13-?WO 98/07425101520253035CA 02264064 l999-02- 19PCT/US97/14731limited to IL-1, IL-6 or IL-8. A disease state in which, for instance, IL-1 is a —major component, and whose production or action, is exacerbated or secreted inresponse to TNF, would therefore be considered a disease stated mediated byTNF,As used herein, the term "cytokine" refers to any secreted polypeptidethat affects the functions of cells and is a molecule which modulatesinteractions between cells in the immune, in?ammatory or hematopoieticresponse. A cytokine includes, but is not limited to, monokines andlymphokines, regardless of which cells produce them. For instance, a monokineis generally referred to as being produced and secreted by a mononuclear cell,such as a macrophage and/or monocyte. Many other cells however alsoproduce monokines, such as natural killer cells, fibroblasts, basophils,neutrophils, endothelial cells, brain astrocytes, bone marrow stromal cells,epideral keratinocytes and B-lymphocytes. Lymphokines are generally referredto as being produced by lymphocyte cells. Examples of cytokines include, butare not limited to, Interleukin-1 (IL-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Tumor Necrosis Factor-alpha (TNF-a) and Tumor Necrosis Factor beta(TNF-B).As used herein, the term "cytokine interfering" or "cytokine suppressiveamount" refers to an effective amount of a compound of Formula (I) which willcause a decrease in the in viva levels of the cytokine to normal or sub-norrnallevels, when given to a patient for the prophylaxis or treatment of a disease statewhich is exacerbated by, or caused by, excessive or unregulated cytokineproduction.As used herein, the cytokine referred to in the phrase "inhibition of acytokine, for use in the treatment of a HIV-infected human" is a cytokine whichis implicated in (a) the initiation and/or maintenance of T cell activation and/oractivated T cell-mediated HIV gene expression and/or replication and/or (b) anycytokine-mediated disease associated problem such as cachexia or muscledegeneration.As TNF-B (also known as lymphotoxin) has close structural homologywith TNF-a (also known as cachectin) and since each induces similar biologicresponses and binds to the same cellular receptor, both TNF-a and TNF-B areinhibited by the compounds of the present invention and thus are herein referredto collectively as "TNF" unless specifically delineated otherwise.-19-?WO 98/07425101520253035CA 02264064 l999-02- 19PCT/US97/14731In order to use a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof in therapy, it will normally be Formulated into apharmaceutical composition in accordance with standard pharmaceuticalpractice. This invention, therefore, also relates to a pharmaceutical compositioncomprising an effective, non-toxic amount of a compound of Formula (I) and apharmaceutically acceptable carrier or diluent.Compounds of Formula (I), pharmaceutically acceptable salts thereofand pharmaceutical compositions incorporating such may conveniently beadministered by any of the routes conventionally used for drug administration,for instance, orally, topically, parenterally or by inhalation. The compounds ofFormula (I) may be administered in conventional dosage forms prepared bycombining a compound of Formula (I) with standard pharmaceutical carriersaccording to conventional procedures. The compounds of Formula (I) may alsobe administered in conventional dosages in combination with a known, secondtherapeutically active compound. These procedures may involve mixing,granulating and compressing or dissolving the ingredients as appropriate to thedesired preparation. It will be appreciated that the form and character of thepharmaceutically acceptable character or diluent is dictated by the amount ofactive ingredient with which it is to be combined, the route of administrationand other well-known variables. The carrier(s) must be "acceptable" in thesense of being compatible with the other ingredients of the Formulation and notdeleterious to the recipient thereof.The pharmaceutical carrier employed may be, for example, either a solidor liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc,gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like.Similarly, the carrier or diluent may include time delay material well known tothe art, such as glyceryl mono-stearate or glyceryl distearate alone or with awax.A wide variety of pharmaceutical forms can be employed. Thus, if asolid carrier is used, the preparation can be tableted, placed in a hard gelatincapsule in powder or pellet form or in the form of a troche or lozenge. Theamount of solid carrier will vary widely but preferably will be from about25mg. to about lg. When a liquid carrier is used, the preparation will be in theform of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such asan ampule or nonaqueous liquid suspension.-20-?CA 02264064 l999-02- 19WO 98/07425 PCT/US97/ 14731Compounds of Formula (I) may be administered topically, that is bynon-systemic administration. This includes the application of a compound ofFormula (I) externally to the epidermis or the buccal cavity and the instillationof such a compound into the ear, eye and nose, such that the compound does not5 significantly enter the blood stream. In contrast, systemic administration refersto oral, intravenous, intraperitoneal and intramuscular administration.Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site ofin?ammation such as liniments, lotions, creams, ointments or pastes, and drops10 suitable for administration to the eye, ear or nose. The active ingredient maycomprise, for topical administration, from 0.001% to 10% w/w, for instancefrom 1% to 2% by weight of the Formulation. It may however comprise asmuch as 10% w/w but preferably will comprise less than 5% w/w, morepreferably from 0.1% to 1% w/w of the Formulation.15 Lotions according to the present invention include those suitable forapplication to the skin or eye. An eye lotion may comprise a sterile aqueoussolution optionally containing a bactericide and may be prepared by methodssimilar to those for the preparation of drops. Lotions or liniments forapplication to the skin may also include an agent to hasten drying and to cool20 the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol oran oil such as castor oil or arachis oil.Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application. They maybe made by mixing the active ingredient in finely—divided or powdered form,25 alone or in solution or suspension in an aqueous or non-aqueous ?uid, with theaid of suitable machinery, with a greasy or non-greasy base. The base maycomprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax,a metallic soap; a mucilage; an oil of natural origin such as almond, corn,arachis, castor or olive oil; wool fat or its derivatives or a fatty acid such as30 stearic or oleic acid together with an alcohol such as propylene glycol or amacrogel. The formulation may incorporate any suitable surface active agentsuch as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or apolyoxyethylene derivative thereof. Suspending agents such as natural gums,cellulose derivatives or inorganic materials such as silicaceous silicas, and other35 ingredients such as lanolin, may also be included.-2]-?WO 98/07425101520253035CA 02264064 l999-02- 19PCT/US97/14731Drops according to the present invention may comprise sterile aqueousor oily solutions or suspensions and may be prepared by dissolving the activeingredient in a suitable aqueous solution of a bactericidal and/or fungicidalagent and/or any other suitable preservative, and preferably including a surfaceactive agent. The resulting solution may then be clarified by filtration,transferred to a suitable container which is then sealed and sterilized byautoclaving or maintaining at 98-100° C. for half an hour. Alternatively, thesolution may be sterilized by filtration and transferred to the container by anaseptic technique. Examples of bactericidal and fungicidal agents suitable forinclusion in the drops are phenylmercuric nitrate or acetate (0.002%),benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitablesolvents for the preparation of an oily solution include glycerol, diluted alcoholand propylene glycol.Compounds of formula (I) may be administered parenterally, that is byintravenous, intramuscular, subcutaneous intranasal, intrarectal, intravaginal orintraperitoneal administration. The subcutaneous and intramuscular forms ofparental administration are generally preferred. Appropriate dosage forms forsuch administration may be prepared by conventional techniques. Compoundsof Formula (I) may also be administered by inhalation, that is by intranasal andoral inhalation administration. Appropriate dosage forms for suchadministration, such as an aerosol formulation or a metered dose inhaler, maybe prepared by conventional techniques.For all methods of use disclosed herein for the compounds of Formula(I), the daily oral dosage regimen will preferably be from about 0.01 to about 80mg/kg of total body weight, preferably from about 0.1 to 30 mg/kg, morepreferably from about 0.2 mg to 15 mg. The daily parenteral dosage regimenabout 0.01 to about 80 mg/kg of total body weight, preferably from about 0.1 toabout 30 mg/kg, and more preferably from about 0.2 mg to 15mg/kg. The dailytopical dosage regimen will preferably be from 0.1 mg to 150 mg, administeredone to four, preferably two or three times daily. The daily inhalation dosageregimen will preferably be from about 0.01 mg/kg to about 1 mg/kg per day. Itwill also be recognized by one of skill in the art that the optimal quantity andspacing of individual dosages of a compound of Formula (I) or apharmaceutically acceptable salt thereof will be determined by the nature andextent of the condition being treated, the form, route and site of administration,and the particular patient being treated, and that such optimums can be-22-?WO 98/07425101520253035CA 02264064 1999-02- 19PCT/US97/14731determined by conventional techniques. It will also be appreciated by one ofskill in the art that the optimal course of treatment, i.e., the number of doses of acompound of Formula (I) or a pharmaceutically acceptable salt thereof givenper day for a defined number of days, can be ascertained by those skilled in theart using conventional course of treatment determination tests.The novel compounds of Formula (I) may also be used in associationwith the veterinary treatment of mammals, other than humans, in need ofinhibition of cytokine inhibition or production. In particular, cytokine mediateddiseases for treatment, therapeutically or prophylactically, in animals includedisease states such as those noted herein in the Methods of Treatment section,but in particular viral infections. Examples of such viruses include, but are notlimited to, lentivirus infections such as, equine infectious anaemia virus, caprinearthritis virus, visna virus, or maedi virus or retrovirus infections, such as butnot limited to feline immunodeficiency virus (FIV), bovine immunodeficiencyvirus, or canine immunodeficiency virus or other retroviral infections.The invention will now be described by reference to the followingbiological examples which are merely illustrative and are not to be construed asa limitation of the scope of the present invention.BIOLOGICAL EXAMPLESThe cytokine—inhibiting effects of compounds of the present inventionwere determined by the following in vitro assays:Interleukin - 1 (IL-1)Human peripheral blood monocytes are isolated and purified from eitherfresh blood preparations from volunteer donors, or from blood bank buffy coats,according to the procedure of Colotta et al, J Immunol, 132, 936 ( 1984). Thesemonocytes (lx106) are plated in 24-well plates at a concentration of 1-2million/ml per well. The cells are allowed to adhere for 2 hours, after whichtime non-adherent cells are removed by gentle washing. Test compounds arethen added to the cells for 1h before the addition of lipopolysaccharide (50ng/ml), and the cultures are incubated at 37°C for an additional 24h. At the endof this period, culture supematants are removed and clarified of cells and alldebris. Culture supematants are then immediately assayed for IL-1 biologicalactivity, either by the method of Simon et al,, J. Immunol. Methods, 84, 85,( 1985) (based on ability of IL-1 to stimulate a Interleukin 2 producing cell line-23-?WO 98/07425101520253035CA 02264064 1999-02- 19PCT/US97/ 14731(EL-4) to secrete IL-2, in concert with A23l87 ionophore) or the method of Leeet al., J. ImmunoTherapy, 6 (1), 1-12 (1990) (ELISA assay).Tumour Necrosis Factor (TNF):Human peripheral blood monocytes are isolated and purified from eitherblood bank buffy coats or platelet pheresis residues, according to the procedureof Colotta, R. et al., J Immunol, 132(2), 936 (1984). The monocytes are platedat a density of 1x106 cells/ml medium/well in 24-well multi-dishes. The cellsare allowed to adhere for 1 hour after which time the supernatant is aspiratedand fresh medium (lml, RPMI-1640, Whitaker Biomedical Products, Whitaker,CA) containing 1% fetal calf serum plus penicillin and streptomycin (10units/ml) added. The cells are incubated for 45 minutes in the presence orabsence of a test compound at lnM-10mM dose ranges (compounds aresolubilized in dimethyl sulfoxide/ethanol, such that the final solventconcentration in the culture medium is 0.5% dimethyl sulfoxide/0.5% ethanol).Bacterial lipopolysaccharide (E. coli O55:B5 [LPS] from Sigma Chemicals Co.)is then added (100 ng/ml in 10 ml phosphate buffered saline) and culturesincubated for 16-18 hours at 37°C in a 5% CO2 incubator. At the end of theincubation period, culture supematants are removed from the cells, centrifugedat 3000 rpm to remove cell debris. The supernatant is then assayed for TNFactivity using either a radio-immuno or an ELISA assay, as described in WO92/10190 and by Becker et al., J Immunol, 1991, 147, 4307.IL-1 and TNF inhibitory activity does not seem to correlate with theproperty of the compounds of Formula (I) in mediating arachidonic acidmetabolism inhibition. Further the ability to inhibit production of prostaglandinand/or leukotriene synthesis, by nonsteroidal anti-in?ammatory drugs withpotent cyclooxygenase and/or lipoxygenase inhibitory activity does not meanthat the compound will necessarily also inhibit TNF or IL-1 production, at non-toxic doses.In vivo TNF assay:While the above indicated assay in an in vitro assay, the compounds ofFormula (I) may also be tested in an in vivo system such as described in :(1) "Differentiation In Vivo of Classical Non—Steroidal Antiin?ammatoryDrugs from Cytokine Suppressive Antiin?ammatory Drugs and Other-24-?WO 98/07425101520253035CA 02264064 l999-02- 19PCT/US97/ 14731Pharmacological Classes Using Mouse Tumour Necrosis Factor Alpha Production",-Griswold et al., Drugs Under Exp. and Clinical Res.,XIX (6), 243-248 (1993); or in(2) Boehm, et al., 1-substituted 4-aryl—5-pyridinylimidazoles - a new class ofcytokine suppressive drugs with low 5—lipoxygenase and cyclooxygenase inhibitorypotency. Journal Of Medicinal Chemistry 39, 3929-3937 (1996) whose disclosuresare incorporated by reference herein in their entirety.Interleukin -8 (IL-8 ):Primary human umbilical cord endothelial cells (HUVEC) (CellSystems, Kirland, Wa) are maintained in culture medium supplemented with15% fetal bovine serum and 1% CS-HBGF consisting of aFGF and heparin.The cells are then diluted 20-fold before being plated (250t1l) into gelatingcoated 96-well plates. Prior to use, culture medium are replaced with freshmedium (200].ll). Buffer or test compound (25pl, at concentrations between 1and l0uM) is then added to each well in quadruplicate wells and the platesincubated for 6h in a humidified incubator at 37°C in an atmosphere of 5%CO2. At the end of the incubation period, supernatant is removed and assayedfor IL-8 concentration using an IL-8 ELISA kit obtained from R&D Systems(Minneapolis, MN). All data is presented as mean value (ng/ml) of multiplesamples based on the standard curve. IC5()'s where appropriate are generatedby non-linear regression analysis.Cytokine Speci?c Binding Protein AssayA radiocompetitive binding assay was developed to provide a highlyreproducible primary screen for structure—activity studies. This assay providesmany advantages over the conventional bioassays which utilize freshly isolatedhuman monocytes as a source of cytokines and ELISA assays to quantify them.Besides being a much more facile assay, the binding assay has been extensivelyvalidated to highly correlate with the results of the bioassay. A specific andreproducible Cytokine inhibitor binding assay was developed using solublecystosolic fraction from THP.l cells and a radiolabeled compound. PatentApplication USSN 08/123175 Lee et al., ?led September 1993, USSN; Lee etal., PCT 94/ 10529 filed 16 September 1994 and Lee et al., Nature 300, n(72),739-746 (Dec. 1994) whose disclosures are incorporated by reference herein inits entirety describes the above noted method for screening drugs to identifycompounds which interact with and bind to the cytokine specific binding-25-?W0 98l07425101520253035CA 02264064 l999-02- 19PCT/U S97/ 14731protein (hereinafter CSBP). However, for purposes herein the binding proteinmay be in isolated form in solution, or in immobilized form, or may begenetically engineered to be expressed on the surface of recombinant host cellssuch as in phage display system or as fusion proteins. Alternatively, whole cellsor cytosolic fractions comprising the CSBP may be employed in the screeningprotocol. Regardless of the form of the binding protein, a plurality ofcompounds are contacted with the binding protein under conditions sufficient toform a compound/ binding protein complex and compound capable of forming,enhancing or interfering with said complexes are detected.Representative compounds of Formula (1), Examples 1 to 3 have alldemonstrated positive inhibitory activity in this binding assay.CSBP Kinase Assay:This assay measures the CSBP-catalyzed transfer of 32P from [a—32P]ATP tothreonine residue in an epidermal growth factor receptor (EGFR)—derived peptide(T669) with the following sequence: KRELVEPLTPSGEAPNQALLR (residues661-681). (See Gallagher et al., "Regulation of Stress Induced Cytokine Productionby Pyridinyl Imidazoles: Inhibition of CSPB Kinase", BioOrganic & MedicinalChemistry, to be published 1996).Kinase reactions (total volume 30 ul) contain: 25 mM Hepes buffer, pH 7.5;10 mM MgCl2; 170 uM AT1>(1); 10 uM Na ortho vanadate; 0.4 mM T669 peptide;and 20-80 ng of yeast-expressed purified CSBP2 (see Lee et al., Nature 300, n(72),739-746 (Dec. 1994)). Compounds (5 ul from [6X] stock(2)) are pre—incubated withthe enzyme and peptide for 20 min on ice prior to starting the reactions with32P/MgATP. Reactions are incubated at 30 0C for 10 min and stopped by adding 10ul of 0.3 M phosphoric acid. 32P-labeled peptide is separated on phosphocellulose(Wattman, p81) ?lters by spotting 30 ul reaction mixture. Filters are washed 3 timeswith 75 mM phosphoric acid followed by 2 washes with H20, and counted for 32P.(1) The Km of CSBP for ATP was determined to be 170 uM. Therefore,compounds screened at the Km value of ATP.(2) Compounds are usually dissolved in DMSO and are diluted in 25 mMHepes buffer to get final concentration of DMSO of 0.17%.Prostaglandin endoperoxide synthase-2 (PGHS-2) assay:The following assay describes a method for determining the inhibitoryeffects of compounds of Formula (I) on human PGHS—2 protein expression in-26-?WO 98/07425101520253035CA 02264064 l999-02- 19PCT/US97/14731LPS stimulated human monocytes. The assay shown below is demonstratedwith compounds other than that of Formula (1) herein:Method: Human peripheral blood monocytes were isolated from buffy coatsby centrifugation through Ficoll and Percoll gradients. Cells were seeded at 2 X106/well in 24 well plates and allowed to adhere for 1 hour in RPMIsupplemented with 1% human AB serum, 20mM L-glutamine, Penicillin-Streptomycin and l0mM HEPES. Compounds were added at variousconcentrations and incubated at 37°C for 10 minutes. LPS was added at 50ng/well (to induce enzyme expression) and incubated overnight at 37°C. Thesupernatant was removed and cells washed once in cold PBS. The cells werelysed in 100ml of cold lysis buffer(50mM Tris/HCl pH 7.5, 150mM NaCl, 1%NP40, 0.5% sodium deoxycholate, 0.1% SDS, 300ug/ml DNAse, 0.1%TRITON X-100, 1mM PMSF, lmM leupeptin, lmM pepstatin). The lysate wascentrifuged ( 10,000 X g for 10 min. at 4°C) to remove debris and the solublefraction was subjected to SDS PAGE. analysis (12% gel). Protein separated onthe gel were transferred onto nitrocellulose membrane by electrophoretic meansfor 2 hours at 60 volts. The membrane was pretreated for one hour inPBS/0.1% Tween 20 with 5% non-fat dry milk. After washing 3 times inPBS/T ween buffer, the membrane was incubated with a 112000 dilution of amonospeci?c antiserum to PGHS-2 or a 1:1000 dilution of an antiserum toPGHs—1 in PBS/T ween with 1% BSA for one hour with continuous shaking.The membrane was washed 3X in PBS/T ween and then incubated with a l:3000dilution of horseradish peroxidase conjugated donkey antiserum to rabbit Ig(Amersham) in PBS/Tween with 1% BSA for one hour with continuousshaking. The membrane was then washed 3X in PBS/T ween and the ECLimmunodetection system (Amersham) was used to detect the level of expressionof prostaglandin endoperoxide synthases—2.Results: The following compounds were tested and found to be active inthis assay (i.e., inhibited LPS induced PGHS-2 protein expression in rank orderpotency similar to that for inhibiting cytokine production as noted in assaysindicated): 6-(4-Fluoro—pheny1)—2,3-dihydro-5-(4-pyridinyl)imidazo[2,1-b]thiazole; and DexamethasoneSeveral compounds were tested and found to be inactive (up to l0uM):2—(4-Methylsulfinylphenyl)-3-(4—pyridyl)-6,7—dihydro-(SH)-pyrrolo[1,2-a]imidazole; rolipram ; phenidone and NDGA. None of these compounds-27-?WO 98/07425101520253035CA 02264064 l999-02- 19PCT/US97/1473 1tested were found to inhibit PGHS-1 or cPLA2 protein levels in similarexperiments.TNF-or in Traumatic Brain Injury AssayThe present assay provides for examination of the expression of tumornecrosis factor mRNA in specific brain regions which follow experimentallyinduced lateral ?uid-percussion traumatic brain injury (TBI) in rats. AdultSprague-Dawley rats (n=42) are anesthetized with sodium pentobarbital (60mg/kg, i.p.) and subjected to lateral ?uid-percussion brain injury of moderateseverity (2.4 atm.) centered over the left temporaparietal cortex (n=18), or"sham" treatment (anesthesia and surgery without injury, n=18). Animals aresacrificed by decapitation at 1, 6 and 24 hr. post injury, brains removed, andtissue samples of left (injured) parietal cortex (LC), corresponding area in thecontralateral right cortex (RC), cortex adjacent to injured parietal cortex (LA),corresponding adjacent area in the right cortex (RA), left hippocampus (LH)and right hippocampus (RH) are prepared. Total RNA is isolated and Northernblot hybridization is performed and quantitated relative to an TNF-a positivecontrol RNA (macrophage = 100%). A marked increase of TNF— Ot mRN Aexpression is observed in LH (l04:17% of positive control, p < 0.05 comparedwith sham), LC (l05:2l%, p< 0.05) and LA (69:8%, p < 0.01) in thetraumatized hemisphere 1 hr. following injury. An increased TNF— ot mRNAexpression is also observed in LH (46i8%, p < 0.05), LC (30:3%, p < 0.01)and LA (32:3%, p < 0.01) at 6 hr. which resolves by 24 hr. following injury. Inthe contralateral hemisphere, expression of TNF— ot mRNA is increased in RH(46;*:2%, p < 0.01), RC (4:3%) and RA (22:8%) at 1 hr. and in RH (28:11%),RC (715%) and RA (26:t6%, p < 0.05) at 6 hr. but not at 24 hr. followinginjury. In sham (surgery without injury) or naive animals, no consistentchanges in expression of TNF— ot mRNA is observed in any of the 6 brain areasin either hemisphere at any times. These results indicate that followingparasagittal ?uid-percussion brain injury, the temporal expression of TNF— otmRNA is altered in specific brain regions, including those of the non-traumatized hemisphere. Since TNF— ot is able to induce nerve growth factor(NGF) and stimulate the release of other cytokines from activated astrocytes,this post—traumatic alteration in gene expression of TNF— ot plays an importantrole in both the acute and regenerative response to CNS trauma.-23-?WO 98/07425101520253035CA 02264064 l999-02- 19PCTIUS97l14731CNS Injury model for IL-B mRNAThis assay characterizes the regional expression of interleukin—lB (IL-IB) mRN A in specific brain regions following experimental lateral ?uid-percussion traumatic brain injury (TBI) in rats. Adult Sprague-Dawley rats(n=42) are anesthetized with sodium pentobarbital (60 mg/kg, i.p.) andsubjected to lateral ?uid-percussion brain injury of moderate severity (2.4 atm.)centered over the left temporaparietal cortex (n=l8), or "sham" treatment(anesthesia and surgery without injury). Animals are sacrificed at 1, 6 and 24hr. post injury, brains removed, and tissue samples of left (injured) parietalcortex (LC), corresponding area in the contralateral right cortex (RC), cortexadjacent to injured parietal cortex (LA), corresponding adjacent area in the rightcortex (RA), left hippocampus (LH) and right hippocampus (RH) wereprepared. Total RNA is isolated and Northern blot hybridization is performedand the quantity of brain tissue IL-ll3 mRNA is presented as percent relativeradioactivity of IL-18 positive macrophage RNA which is loaded on same gel.At 1 hr. following brain injury, a marked and signi?cant increase in expressionof IL-1B mRNA is observed in LC (20.0:O.7% of positive control, n=6,p < 0.05 compared with sham animal), LH (24.5:0.9%, p < 0.05) and LA(21,513. 1 %, p < 0.05) in the injured hemisphere, which remained elevated up to6 hr. post injury in the LC (4.0¢0.4%, n=6, p < 0.05) and LH (5.0il.3%,p < 0.05). In sham or naive animals, no expression of IL-1B mRNA is observedin any of the respective brain areas. These results indicate that following TBI,the temporal expression of IL-113 mRNA is regionally stimulated in speci?cbrain regions. These regional changes in cytokines, such as IL-1B play a role inthe post—traumatic pathologic or regenerative sequelae of brain injury.SYNTHETIC EXAMPLESThe invention will now be described by reference to the followingexamples which are merely illustrative and are not to be construed as alimitation of the scope of the present invention. All temperatures are given indegrees centi grade, all solvents are highest available purity and all reactions rununder anhydrous conditions in an argon atmosphere unless otherwise indicated.In the Examples, all temperatures are in degrees Centigrade (°C). Massspectra were performed upon a VG Zab mass spectrometer using fast atombombardment, unless otherwise indicated. 1H—NMR (hereinafter "NMR")spectra were recorded at 250 MHz using a Bruker AM 250 or Am 400-29-?WO 98/07425101520253035CA 02264064 l999-02- 19PCT/US97/1473 1spectrometer. Multiplicities indicated are: s=singlet, d=doublet, t=triplet,q=quartet, m=multiplet and br indicates a broad signal. Sat. indicates asaturated solution, eq indicates the proportion of a molar equivalent of reagentrelative to the principal reactant. Flash Chromatography is run over a MerckSilica gel 60 (230-400 mesh).Example 14(5)-(4-Fluorophenyl)-5(4)-(4-pyridyl)imidazolePyridine-4-carboxaldehyde (321 mg, 3.0 mmol), and THF (3 mL) were cooled to-50" and lithium bis(trimethylsilyl)amide (LiBSA) (1 M in THF) (3 mL, 3.0 mmol) wasadded dropwise (T<-40"), stirred for 45 min, and warmed to -30” for 5 min to affordSolution A.THF (3 mL), and 4-Fluorophenyl(tosyl)methy1 isocyanide (8) (see nextexperiment) (867 mg, 3.0 mmol) were cooled to -50° and LiBSA (1M in THF) (3 mL, 3.0mmol) was added dropwise at -50”, stirred 30 min to afford Solution B.Solution A was cooled to -60" and solution B was added dropwise. The resultingsolution was stirred at -70“ for 30 min, warmed to 23° over 4 h, stirred at 23° for 16 h,poured into 5% aq Na,CO3 (25 mL) and extracted with EtOAc (4 x 25 mL), dried(Na,SO,,) concentrated and ?ash chromatographed (0—8% MeOH in CH,Cl2) to afford (28)251 mg (35%). The product was crystallized from acetone/hexane: 'H NMR 8.42 (m,2),7.72 (s,l), 7.40 (m,4), 7.12 (m,2): MS (ES+) m/z = 240 (MH*): mp 245 — 246 (dec).Anal. (C,,HmFN, . 1/10 H20) C, H, N.4-Fluorophenyl(tosyl)methyl isocyanide: Toluenesul?nic acid sodium salt(150g, 0.84 mol), H20 (500 mL), and t-butylmethyl ether (TBME) (250 mL) werevigorously stirred, and concd HCl (75 mL) was added dropwise. The resulting twophases were separated and the aqueous phase was extracted with TBME (100 mL). TheTBME phases were dried (Na,SO,) and concentrated to near dryness and the white solidwas combined with hexane (350 mL) and filtered and dried in vacuo to afford 96g oftoluenesulfinic acid.The free acid (92.3 g, 0.62 mol), p-?uorobenzaldehyde (92.3 g, 0.744 mol),formamide (73.9 mL) and camphorsulfonic acid ( l4.4g, 0.062 mol) were combined,vigorously stirred and heated to 65° for 16 h. The resulting white mass was cooled to 23°,triturated with CH3OH (150 mL) and hexane (350 mL), filtered and dried in vacuo toafford 88.35 g (46%) 4—?uorophenyl tosylmethylforrnamide as a white solid: ‘H NMR8.06 (s, 1H), 7.69 (d, J = 8 Hz, 2H), 7.43 (m, 2H), 7.32 (d, J = 8 Hz, 2H), 7.08 (m, 2H),6.29 (s,lH), 2.43 (s, 3H).-30-?WO 98/07425101520253035CA 02264064 l999-02- 19PCT/US97/14731A solution of the formamide obtained above (20.2 g, 65.7 mmol), and anhydrousDME (330 mL) was cooled to -10" and POCl_, ( 18.4 mL, 197 mmol) was added dropwise.Triethylamine (45.8 mL, 329 mmol) in DME (30 mL) was added dropwise (T<—5°) andthe reaction was stirred at -5° for 2h, then poured into H20 (600 mL)and extracted withEtOAc (3 x 150 mL). The extracts were washed with satd aq NaHCO,, dried (Na2SO,)and concentrated. The colorless oil was triturated with hexane to afford a solid.Filtration and drying afforded 16.2 g (85%) of 4-?uorophenyl(tosyl)methyl isocanide asa white solid. ‘H NMR 7.62 (d, J = 8 Hz. 2H), 7.34 (m, 4H), 7.10 (m, 2H), 5.59 (s, 1H),2.48 (s, 3H).Example 24-(4—F1uorophenvl)-5-(2-methoxv-Dvrimidin-4-vhimidazolePrepared by the method of example 1 except using 2-methoxypyrimidine-2-carboxaldehyde isocyanide to afford the title compound as a light brown powder. MSES+ rn/z = 271 (MH+).Example 34—(4—Fluorophenvl)-5-(2-methvlthio-Dvrimidin-4—V1)imidazolePrepared by the method of example 1 except using 2-methoxypyrimidine-2-carboxaldehyde isocyanide to afford the title compound as a light brown powder. MSES+ rn/2 = 287 (MH+).All publications, including but not limited to patents and patent applications,cited in this specification are herein incorporated by reference as if each individualpublication were speci?cally and individually indicated to be incorporated byreference herein as though fully set forth.The above description fully discloses the invention including preferredembodiments thereof. Modifications and improvements of the embodimentsspeci?cally disclosed herein are within the scope of the following claims.Without further elaboration, it is believed that one skilled in the art can, usingthe preceding description, utilize the present invention to its fullest extent.Therefore the Examples herein are to be construed as merely illustrative and nota limitation of the scope of the present invention in any way. The embodimentsof the invention in which an exclusive property or privilege is claimed aredefined as follows.-31-

Claims (18)

WHAT IS CLAIMED IS:

1. A compound of the formula:
wherein:
R1 is 4-pyridyl, pyrimidinyl, 4-pyridazinyl, 1,2,4-triazin-5-yl, quinolyl, isoquinolinyl, quinazolin-4-yl, 1-imidazolyl or 1-benzimidazolyl, which heteroaryl ring is optionally substituted independently one to three times with Y, NHRa, optionally substituted C1-4 alkyl, halogen, hydroxyl, optionally substituted C1-4 alkoxy, optionally substituted C1-4 alkylthio, C1-4 alkylsulfinyl, CH2OR12, amino, mono and di- C1-6 alkyl substituted amino, N(R10)C(O)R b, or an N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur;
Y is XI-Ra;
X1 is oxygen or sulfur;
R4 is phenyl, naphth-1-yl or naphth-2-yl, or a heteroaryl, which is optionally substituted by one or two substituents, each of which is independently selected, and which, for a 4-phenyl, 4-naphth-1-yl, 5-naphth-2-yl or 6-naphth-2-yl substituent, is halogen, cyano, nitro, -C(Z)NR7R17, -C(Z)OR16, -(CR10R20)v COR12, -SR5, -SOR5, -OR12, halo-substituted-C1-4 alkyl, C1-4 alkyl, -ZC(Z)R12, -NR10C(Z)R16, or -(CR10R20)v NR10R20 and which, for other positions of substitution, is halogen, cyano, -C(Z)NR13R14, -C(Z)OR3, -(CR10R20)m"COR3, -S(O)mR3, -OR3, halo-substituted-C1-4 alkyl, -C1-4 alkyl, -(CR10R20)m"NR10C(Z)R3, -NR10S(O)MR8, -NR10S(O)m NR7R17, -ZC(Z)R3 or -(CR10R20)m"NR13R14;
v is 0, or an integer having a value of 1 or 2;
m is 0, or the integer 1 or 2;
m' is an integer having a value of 1 or 2, m" is 0, or an integer having a value of 1 to 5;
n is an integer having a value of 1 to 10;
n' is 0, or an integer having a value of 1 to l0;
Z is oxygen or sulfur;
Ra is aryl, arylC1-6alkyl, heterocyclic, heterocyclyl C1-6 alkyl, heteroaryl, heteroaryl C1-6alkyl, wherein each of these moieties may be optionally substituted:

Rb is hydrogen, C1-6 alkyl, C3-7 cycloalkyl, aryl, arylC1-4 alkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclyl, or heterocyclylC1-4 alkyl;
R3 is heterocyclyl, heterocyclylC1-10 alkyl or R8;
R5 is hydrogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl or NR7R17, excluding the moieties -SR5 being -SNR7R17 and -SOR5 being -SOH;
R7 and R17 is each independently selected from hydrogen or C1-4 alkyl or R7 and R17 together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR 15;
R8 is C1-10 alkyl, halo-substituted C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, aryl, arylC1-10 alkyl, heteroaryl, heteroarylC1-10 alkyl, (CR10R20)n OR11, (CR10R20)n S(O)mR18, (CR10R20)n NHA(O)2R18, (CR10R20)n NR13R14; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl may be optionally substituted;
R9 is hydrogen, C(Z)R11 or optionally substituted C1-10 alkyl, S(O)2R18, optionally substituted aryl or optionally substituted aryl-C1-4 alkyl;
R10 and R20 is each independently selected from hydrogen or C1-4 alkyl;
R11 is hydrogen, C1-10 alkyl, C3-7 cycloalkyl, heterocyclyl, heterocyclyl C1-10alkyl, aryl, arylC1-10 alkyl, heteroaryl or heteroarylC1-10 alkyl;
R12 is hydrogen or R16;
R13 and R14 is each independently selected from hydrogen or optionally substituted C1-4 alkyl, optionally substituted aryl or optionally substituted aryl-C1-4 alkyl, or together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR9;
R15 is R10 or C(Z)-C1-4 alkyl;
R16 is C1-4 alkyl, halo-substituted-C1-4 alkyl, or C3-7 cycloalkyl;
R18 is C1-10 alkyl, C3-7 cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-C1-10alkyl, heteroaryl or heteroarylalkyl;
or a pharmaceutically acceptable salt thereof.

2. The compound according to Claim 1 wherein R1 is an optionally substituted 4-pyridyl or 4-pyrimindyl.

3. The compound according to Claim 2 wherein the optional substituent is Y or NHRa.

4. The compound according to Claim 3 wherein X 1 is oxygen and Ra is optionally substituted aryl, arylalkyl or alkyl.

5. The compound according to any of Claims 2 to 4 wherein R4 is an optionally substituted phenyl.

6. The compound according to Claim 5 wherein the phenyl is substituted one or more times independently by halogen, SR5, S(O)R5, OR12, halo-substituted-C1-4 alkyl, or C1-4 alkyl.

7. The compound according to Claim 1 which is:
4-(4-Fluorophenyl)-5-(4-pyridyl)imidazole 4-(4-Fluorophenyl)-5-(2-methoxy-pyrimidin-4-yl)imidazole 4-(4-Fluorophenyl)-5-(2-methylthio-pyrimidin-4-yl)imidazole; or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a compound according to any of Claims 1 to 7 and a pharmaceutically acceptable carrier or diluent.

9. A method of treating a CSBP/RK/p38 kinase mediated disease, in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (I) according to any one of Claims 1 to 7.

10. The method according to Claim 9 wherein the mammal is afflicted with a CSBP/RK/p38 kinase mediated disease which is cytokine mediated and the disease is selected selected from psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis and acute synovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic condition, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, Alzheimer's disease, stroke, neurotrauma, asthma, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcososis, bone resorption disease, osteoporosis, restenosis, cardiac and renal reperfusion injury, thrombosis, glomerularonephritis, diabetes, graft vs. host reaction, allograft rejection, inflammatory bowel disease, Crohn's disease, ulcerative colitis, multiple sclerosis, muscle degeneration, eczema, contact dermititis, psoriasis, sunburn, and conjunctivitis.

11. The method according to Claim 10 wherein the disease is asthma, osteoporosis, or arthritis.

12. A method of treating inflammation in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (I) according to any of Claims 1 to 7.

13. A method of treating osteoporosis in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (I) according to any of Claims 1 to 7.

14. A method of treating a chronic disease in a mammal in need thereof, which disease is characterized by excessive, undesired or inappropriate angiogenesis, with an effective amount of a compound according to any of Claims 1 to 7.

15. The method according to Claim 14 wherein the disease is diabetic retinopathy and other ocular neovascularizations.

16. The method according to Claim 14 wherein the disease is tumor growth and metastosis.

17. The method according to Claim 14 wherein the disease is atherosclerosis.

18. The method according to Claims 1 to 4 wherein the disease is arthritis.