AU1539902A - Tri-substituted imidazoles having multiple therapeutic properties - Google Patents

Description

AUSTRALIA

PATENTS ACT 1990 DIVISIONAL APPLICATION NAME OF APPLICANT(S): SmithKline Beecham Corporation ADDRESS FOR SERVICE: DAVIES COLLISON CAVE Patent Attorneys 1 Little Collins Street Melbourne, 3000.

INVENTION TITLE: "Tri-substituted imidazoles having multiple therapeutic properties" The following statement is a full description of this invention, including the best method of performing it known to us: r' )I'LR' I'I)1\22N 2 39 X, q TRI-SUBSTITUTED IMIDAZOLES HAVING MULTIPLE THERAPEUTIC PROPERTIES This application is a divisional of application 44782/99 which was a divisional of patent 705568, the entire contents of which are incorporated herein by reference.

This invention retiates to a novel group of imidazole compounds, processes for the preparation thereof, the use thereof in treating cytokine mediated diseases and pharmaceutical compositions for use in such terapy.

Interleukin- I (EL- 1) and Tumor Necrosis Factor (TNF) are biological substances produced by a variety of cells, such as monocytes or macrophages. EL- I has been demonstrated to mediate a variety of biological activities thought to be important in immunoregulation and other physiological conditions such as inflammation [See, Dinarello et al., Rev- Infect- Diseas, L. 51 (1994)]. The myriad of known biological activities of IL- I include the activation of T helper cells, induction of fever, stimulation of prostaglandin or coLlagenase production, neutrophil chemotaxis, induction of acute phase proteins and the suppression of plasma iron levels.

There are many diseae states in which excessive or unregulated IL- I production is implicated in exacerbating and/or causing the disease. These include rheumatoid arthritis, osteoarthritis, endomoxemia and/or toxic shock syndrome, other acute or chronic inflammatory disease states such as the inflamimatory reaction induced by endotoxin or inflammatory bowel disease; tuberculosis, az!crosclerosis. muscle degeneration. cachexia. psoriatic arthrits. Reiter's syndrome,. rheumatoid arthritis, gout, traurnatic arthrits. rubella arthritis, and acute synovitis. Recent evidence also links DL- I activity to diabetes and pancreatic B cefls.

Dinarello, I Cinical Immunology, 5 287-297 (1985), reviews the biological activities which have been attributed to IL-I1. It should be noted that some of these effects have been described by others as indirect effects of KL-I.

Excessive or unregulated TNF production has been implicated in mediating or exacerbating a number of diseases including rheumatoid arthritis, rheumatoid spondylitis. osteoarthritis. gouty arthritis and other arthritic conditions; sepsis. septic shock, endotoxic shock. gram negative sepsis, toxic shock syndrome, adult respiratory distres syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoisosis, bone resorption diseases, repedfusion injury, graft vs. host reaction, allograft rejections, fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia. secondary to acquired immune deficiency syndrome (AIDS), AIDS. ARC (AIDS related complex), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, or pyresis.

AIDS results from the infection of T lymphocytes with Human lImmunodeficiency Virus (HIV). At least three types or strains of HIfV have been identified, ie., HIV-1, HIfV-2 and HIV-3. As a consequence of FHV infection, T-ceU mediated immunity is impaired and infected individuals manifest severe opportunistic infections and/or unusual neoplasms. HIV entry into the T lymphocyte requires T lymphocyte activation. Other viruses, such as WHV-I,. HIV-2 infect T lymnphocytes after T Cell activation and such virus protein expression and/or replication is mediated or maintained by such T cell activation. Once an activated T lymphocyte is infected with HIV, dhe T lymphocyte must continue to be maintained in an activated state to permit HIfV gene expression and/or 19V replication. Monokines, specifically TNF, are implicated in activated T-cell mediated HIIV protein expression and/or virus replication by playing a role in maintaining T lymphocyte activation. Therefore, interference with monokine activity such as by inhibition of monokine production, notably TNF, in an HI V-infected individual aids in limiting the maintenance of T cell activation. thereby reducing the progression of HIV infectivity to previously uninfected cells which results in a slowing or elimination of the progression of immune dysfunction caused by HIV infection. Monocytes, macrophages, and related cells, such as kupifer and glial cells, have also been implicated in maintenance of the HIfV infection. These cells, like T-cells are targets for viral replication and the level of viral replication i dependent upon the activation state of the cells. [See Rosenberg The Immunopathogenesis of HPV Inifection. Advances in Immunology, Vol. 57, (1989)). Monokines, such as TNF, have been shown to activate IV replication in monocytes and/or macraphages [see Poa. ctaL Proc. Nail. Acad. Sci., 87:782-784 (1990)), therefore inhibition of monokine production or activity aids in limiting IV progression as stated above for T-cells.

TNF has also been implicated in various roles with other viral infections, such as the cytomegalia virus (CMV), influenza virus, andthe herpes virus for similar reasons as those notedi.

Interleukin-8 (IL-8) is a chemotactic factor first identified and characterized in 1987. 11-8 is produced by several cell types including mononuclear cells, fibroblasts, endothelia cells, and keratinocytes. Its production from endothelial cells is induced by IL-I, TNF, or iipopolysacbharide (LPS). Human EL-S has been shown to act on Mouse, Guinea Pig, Rat, and Rabbit Neutrophils. Many different nam'es have been applicd to IL-8, such as neutrophil attractant/activation protein- I (NAP-i1), monocyte derived neutrophil chemotactic factor (MDNCF), neutrophil activating factor (NAF), and T-cell lymphocyte chemotactic factor.

LL-8 sumulates a number of functions in vitro. It has been shown to have chemoattractant properties for neutrophils, T-lymphocytes, and basophils. In addition it induces histamine release from basophils from both normal and atopic individuals as well as lysozomal enzyme release and respiratory burst from neutrophils. IL-8 has also been shown to increase the surface expression of Mac-I (CDI Ib/CD18) on neutrophis without de novo protein synthesis, this may contribute to increased adhesion of the neutrophils to vascular endothelial cells. Many diseases are characterized by massive neutrophil infiltration. Conditions associated with an increased in IL-8 production (which is responsible for chemotaxis of neutrophil into the inflammatory site) would benefit by compounds which are suppressive of IL-8 production.

IL-] and TNF affect a wide variety of cells and tissues and these cytoi'cnes as .well as other leukocyte derived cytokines are important and critical inflammatory :mediators of a wide variety of disease states and conditions. The inhibition of these cytokines is of benefit in controlling, reducing and alleviating many of these disease states.

There remains a need for treatment, in this field, for compounds which are cytokine suppressive anti-inflammatory drugs, i.e. compounds which are capable of inhibiting cytokines, such as IL-1, IL6, IL-8 and TNF.

SUMMARY OFTBE ON This invention relates to the novel compounds of Formula and pharmaceutical compositions comprising a compound of Formula and a pharmaceutically acceptable diluent or carrier.

This invention also relates to a method of inhibiting cytokines and the treatment 25 of a cytokine mediated disease, in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula This invention more specifically relates to a method of inhibiting the production of IL-I in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula This invention more specifically relates to a method of inhibiting the production of IL-8 in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula This invention more specifically relates to a method of inhibiting the production of TNF in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula Accordingly, the present invention provides a compound of Formula R,

R

2

N

R4

N

Rj is 4-pyridyl, pynimidinyl, quinolyl, isoquinolinyl, quinazolin-4-yi, l-irnidazolyl or I-benzimidazolyl, which heteroazyl ring is optionally substituted with one or two substituents each of which is independently selected from CI-4 alkcyl, halogen, hydroxyl, C 1-4 alkoxy, C 1-4 aikylthio, C 1- alkylsultinyl, CH20R 1 2 NR IOR2O, or an N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatoin selected from oxygen, sulfur or NRI *R4 is phenyl, naphth-1-yl or naphth-2-y1, 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-yI subsrtitiuent, :is halogen, cyano, nitro, -C(Z)NR7RI7, -C(Z)0Rl6, -(CRIoR2o)mCOR1 2 -SOR5, -0R12, halo-substituted.C1A4 allcyl, CIA4 alkyl. -ZC(Z)R12, -NR IOC(Z)R1 6. or -(CRIOR2O)JTNRIOR2O and which, for other positions of :substitution, is halo, cyano, -C(Z)NR1 3

RI

4 -C(Z)0R3, -(CR lOR2O)mCOR3, -S(O)MR3, -0R3, halo-substituted-C1- 4 alkyl, -Cj-4 alkyl, -(CR1 OR2)mNR LOC(Z)R3. -NRI 0S(O)mR8, -NR IOS(O)m'NR7R 17. -ZC(Z)R3 :or -(CRIOR2)MNR13R14; *R2 is ClI- 10 alkyl N3, -(CR IOR2O)n' 0R9, heteroyclyl, heterocyclylC I 10 alkyl, Cl-ialkyl, halo-substituted Cl-l aikyl, C2.1o alkeyl, C2-l alkynyl, C3..7 cycloalkyl, C3..7cycloalkytl 1.1 alkyl. C5-7 cycloalkenyl, :::,C5-7cycloalkenyi-C1..10-alkyi, aryl, arylCI-1O alkyL, heteroaryl, hetervaryl-C 1-1 0-alkyl. (CRIoR2o)noR II, (CR 10R20)nS(O)mR 18.

(CR 10R20)nNHS(Q)2R 18. (CR 10R20)nNR 13R14- (CR 10R20)nNO2.

(CR 10R20)nCN, (CR 10R20)n'SO2RI 8 (CR1OR2O)nS(O)m'NRI3R 14.

(CRIoR2o)nC(Z)Rll,'(CRIOR2O)nOC(Z)RIIL (CRIOR2)nC(Z)ORII, (CR 10R20)nC(Z)NR 13R 14. (CRIOR20)nC(Z)NRl R9, (CR 10R20)nNR IOC(Z)Rl 1, (CR 10R20)nNR IOC(Z)NR 3R 14.

(CR1 0R20)nN(0R6)C(Z)NRi 3R 14, (CR1 0R20)nN(0R6)C(Z)R 11, (CRI 0R20)nC(=N0R6)RI I, (CR 1 0R20)nNR iOC(=NR 19)NRi 3R 14.

(CR 10R20)nOC(Z)NR 13R 14, (CR loR2o)nNR 1OC(Z)NR1 3RI 4.

(CP. 1 R20)nNR 10C(Z)ORIO, 5-CRig)- 1 2,4.-oxadizaol-3-yI or 4{R42>5-(RR 1 )-4,5-dihydro-1 ,2,4-oxadiazol-3-yl; wherein the cycloalkyl, cycloalkyl alkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocycic and heterocyclic alkyl groups may be optionally substituted; n is an integer having a value of I to n' is 0, or an integer having a value of I to mn is 0, or t~he integer 1 or 2; Z is oxygen or sulfur; m' islIor 2, R3 is heterocyclyl, heterocyclylC I- 10 alkyl or RS; is hydrogen, C 1 4 alkyl, C2..4 alkenyl. C2-4 alkynyl or NR7R 17. excluding the moeities -SR5 being -SNR7R17 and -SOR5 being -SOH; R6 is hydrogen, a pharmnaceutically acceptable cation, C I 10 alkyl, C 3 7 cycloalkyl, aryl, arylC 1.4 alkyl, heteroaryl, heteroarylalkryl, heterocyclyl, aroyl, or C alkanoyl R7 and R 17 is each independently selected from hydrogen or C1.-4 alkyl or R7 and R 17 :,together with the nitrogen to which they are attached form a heterocyclic ring of to 7 members which ring optionally contains an additional heteroatom, selected from oxygen, sulfur or R8 is Ci-loalkyl, halo-substituted Cll alkyl, C2-!0 alkenylC2.10alkynY C3-.7 cycloalkyl, C5-7 cycloalkenyl, aryl. azyl1- 10 alkyl, heteroaryl, heteroarylC I alkyl, (CR 10R20)nOR 11, (CR 10R20)nS(Q)mR 1 8, (CR 10R20)nNHS(O)2R 1 8, (CRIOR2O)nNR13Ri4; wherein the aryl. arylalkyl. heteoaryL, heteroaryl alkyl may be optionally substituted; R9 is hydrogen, -C(Z)RI I or optionally substituted CI-10 alkyl, S(O)2RI8, Optionally .:substituted aryl or optionally substituted aryl-C 1- alkcyl; R 10 and R2o is each independently selected from hydrogen or C 1-4alkyl; RI I is hydrogen, Cl-jo alkyl. C3-.7 cycloalkyl. heterocyclyL, beterocyclyl CI..ioalkyl, aryl, ary1C .I -1 alkyl, heterouryl or heteroarylC I 1 alkyl-, R12 is hydrogen or RI6; R 13 and R 14 is each independently selected from hydrogen or optionally substituted C 1- alkyl, optionally substituted aryl or optionally substituted azyl-C 1-4 alkyl, or together with the nitrogen which they ame aitached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatomn selected from oxygen, sulfur or NR9 R 15 is RIO0 or C(Z)-C 1-4 alkyl; Ri 16 is C 1- alkyl, halo-substituted-C 1-4 alkyl, Or C3-.7 cycloalkyl; R 18 is C 1- 10 alkyl, C3-7 cycloalkyl, heterocyclyL, aryl, arylalkyl. uieterocyclyl, heterocyclyl-C I. oalkyl, heteroaryl or heteroarylalkyl; R 1 is hydrogen, cyano, C 1.4 alkyl, C3..

7 cycloalkyl or aryl; or a pharmaceutically acceptable salt thereof.

6 DETAILED DESCRIPTION OF THE [NVEION The novel compounds of Formula may also be used in association with the veterinary treatment of mamnmals, other than humans, in need of inhibition of cytokine inhibition or production. In particular, cytokine mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted herein in the Methods of Treatment section, but in particular viral infections.

Examples of such viruses include, but are not limited to, lentivirus infections such as, equine infectious anaemia virus, caprine arthritis virus. visna virus, or maedi virus or retrovirus infections, such as but not limited to feline immunodeficiency virus (Fly), bovine immunodeficiency virus, or canine imumunodeficiency virus or other retroviral infections.

In Formula suitable R I moieties includes 4-pyridyl, 4-pyrimidinyl, 4quinolyl, 6-isoquinolinyl, 4-quinazolinyl, 1-irnidazolyl and 1-benzimidazolyl, of which the 4-pyridyl, 4-pyriruidinyl and 4-quinolyl are preferred. More preferred is an optionally substituted 4-pyrimidinyl and an optionally substituted 4-pyridyl, and most preferred is the an optionally substituted 4-pyrzxnidinyl ring.

Suitable substituents for the R I heteroaryl rings are C 1- alkyl, halo. OH, C 1 alkoxy, C1-4 alkylthio, C1-4 alkYlsulfnYL. CH2ORl2. NR1OR2O. or an N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NRI5. A preferrdsubstittuent for all R moieties is Cl 1-4ikyL in particular methyl, and NR 1oR2o, preferably where RIO and R20 are hydrogen or methyl, more preferably RIO and R2g) are hydrogen. A more preferred substituent is the NRIOR2O moiety. Preferred ring placement of the R I substituent for on the 4-pyriclyl derivative is the 2-position, such as 2-methyl-4-pyridyl.

Preferred ring placemnent on the 4-pyrunidinyl is also at the 2-position, such as 2methyl-pyrimidine or 2-amino pyrimidine.

Suitably, R4 is phenyl. naphth-lI-yl or naphth-2-yl, or a heteroaryl, which is optionally substituted by one or two substituents. More preferably R4 is a phenyl or naphibyl ring. Suitable substitutions for R4 when this is a 4-phenyl, 4-naphth-1-yi, naphth-2-yl or 6-naphth-2-yl moiety are one or two substituets each of which are independently selected from halogen, -SR5, -SOR5, -0R6, CF3, Or -(CRlOR2O)mNRIOR2O, and for other positions of substitution on these, rings preferred substitution is halogen, -S(O)MR3, -0R3, CF3, -(CRIOR2O)mNRl3R 14, -NRIOC(Z)R3 and -NRIOS(O)mR3. Preferred substixuents for the 4-position in phenyl and naphth-lI-yl and on the 5-position in naphth-2-yl include halogen, especially fluoro and chioro and -SR5 and -SORS wherein R5 is preferably a C 1-2 alkyl, more preferably methyl; of which the fluoro and chioro is more preferred, and most especially preferred is fluoro. Preferred substituents for the 3-position in phenyl and naphth- I-yl rings include: halogen, especially fluoro and chloro; -0R3, especially C 1-4 aikoxy; CF3, NR 1OR2O, such as amino; -NRI oC(Z)R3, especially -NHCO(C I 10 alkyl); -NRIOS(O)mR8, especially -NHSO2(CI-10 alkyl), and -SR3 and -SOR3 wherein R3 is preferably a C 1-2 alkyl, more preferably methyl. When the phenyl ring is disubstituted preferably it- is two independent halogen moieties, such as fluoro and chloro, preferably di-chioro and more preferably in the 3.4-position.

Preferably, the R4 moiety is an unsubstituted or substituted phenyl moiety.

More preferably, R4 is phenyl or phenyl substituted at the 4-position with fluoro and/or substituted at the 3-position with fluoro, chioro, CI1-4 alkoxy, methane-sulfonamido or acetanuido, or R4 is phenyl di-substituted at the 3,4-position with chioro or fluoro, more preferably chioro. Most preferably R4 is a 4-fluorophenyl.

In Formula suitably Z is oxygen.

Suitably, R2is Cl-loalkyl N3, -(CRlOR2O)n' 0R9, heterocyclyl, heterocyclylCl-l0 alkyl, Cl-loalkyl, halo-substituted CI1-10 alkyl, C2-10 aLkenyl, C2- ~10 alkYnYl, C3-7 cycloalkYl, C3-7cycloalkylCI -10alkyl, C5-7 cycloalkenyl, C5-7 cycloalkenyl Cl-b alkyl, aryl, arylCi-lo alkyl, heteroaryl, heteroarylCl-li0alkyl, (CRIOR2O)nORI I, (CRIOR2)nS(O)mRl 8. (CR 10R20)nNHS(O)2Rl8, (CR1 0R20)nNR 13R14, (CR 10R20))nNO2, (CR1 0R20)nCN, (CR 10R20)flSQ2R 18.

(CR 10R20)nS(O)m'NRI 3R 14. (CRiOR2O)nC(Z)RI 1. (CR 10R20)nOC(Z)R 1, ~(CR 10R20)nC(Z)OR11. (CRlOR20)nC(Z)NR13R 14. (CRIOR2O)nC(Z)NR 11 R9, (CR IOR2O)nNR 1oC(Z)RI 1. (CRIOR2O)nNR 1OC(ZNRl3Rl4, (CRIOR2)nN(0R6)C(Z)NRl3R14. (CRIOR2O)nN(0R,6)C(Z)RI 1, (CR iOR2o)nC(=N0R6)RI 1, (CR 10R20)nNR lOC(=NR 19)NR1 3R 14.

(CR 10R20)uOC(Z)NR 13R14. (CRbOR2O)nNRIOC(Z)NR13R14.

5-(Ris)-1A4-oxadizaoI-3-yl or 4-(R12)- 5 RR)-4.5-dihydro- 1,2.4-oxadiiazol-3-yl;wherein the aryI. arylalkyl, heteroaryl, heteroarylalkyl. heterocyclic. and heterocyclicaklyl moieties may be optionally substituted; wherein n is an integer having a value of I to 10, m is 0, or the integer I or 2; n' is 0, or an integer having a value of 1 to 10; and m' is I or 2.

Preferably nis 1 to 4.

Preferably R2 is an optionally substituted heterocyclyl ring, and optionally substituted heterocyCly1C 1-10 alkyl, an optionally substituted C 1. 10 alkyl, an optionally substituted C3-7cycloalkyL, an optionally substituted C3-7cycloalkyl C 1 alkyl, (CR 10R20)nC(Z)ORI I group, (CR 10R20)nNR 13R 14, (CRlOR20)nNHS(O)2R18, (CRloR2O)nS(O)mRlS, an optionally sutstituted aryl; an optionally substituted arylCi-lo alkyl, (CRIOR2O)nORlII,(CRIOR2O)nC(Z)Rl I, or (CRIOR2)nC(N0R6)RI 1 group.

8 More preferably R2 is an optionally substituted heterocyclyl ring, and optionally substituted hewerocyclylC I 1 alkyl, optionally substituted aryl.

(CR1 IoR2o)nNR 1 3R 14. or (CRJ I0R20)nC(Z)OR I I group.

When R2 is an optionally substituted heterocyclyl the ring is preferably a rnorpholino, pyrrolidinyl, or a piperidinyl group. When the ring is optionally substituted the substituents may be directly attached to the free nitrogen, such as in the piperidinyl group or pyrrole ring, or on the ring itself. Preferably the ring is a piperidine or pyrrole, more preferably piperidine. The heterocyclyl ring may be optionally substituted one to four times independently by halogen; C 1-4 alkyl. aryl, such as phenyl; aryl alkyL, such as benzyl wherein the aryl or aryl alkyl moiet ies themselves may be optionally substitued (as in the definition section below); 11, such as the C(O)Ci1-4 alkyl or C(O)OH moicities; C(O)H, C(O)C 1-4 alkyl, .99hydroxy substituted C 1- alkyl, C 1-4 alkoxy, S(O)inClA- alkyl (wherein mn is 0, 1, or NR I OR20 (wherein RI1O and R20 are independently hydrogen or C I 4alkyl).

15 Preferably if the ring is a piperidine, the ring is attached to the iinidazole at the 4-position, and the substituents are directly on the available nitrogen, ie. a I-Forinyl-4 piperidine, l-benzyl-4-piperidine, 1 -iethyl-4-piperidine, I-etboxycarbonyl-4piperidine. If the ring is substituted by an alkyl group and the ring is attached in the 4position. it is preferably substituted in the 2 or 6 position or both, such as 2,2,6,6tetrarnethyl-4-piperidine. Simiarly, if the ring is a pyrrole, the ring is attached to the imidazole at the 3-position, and the substituents are aldo, directly on the available nitrogen.

When R2 is an optionally substituted heterocyclyl C I -i1 alkyl group, the ring is preferably a morpholino, pyrrolidinyl, or a piperidinyl group. Preferably this alkyl moiety is from I to 4. more preferably 3 or 4. and preferably 3, such as in a propyl group. Preferred heterocyclic alkyl groups include but are not limited to, morpholino ethyl. morpholino propyl, pyrrollidinyl propyl, and piperidinyl propyl moieties. The heterocyclic ring herein is also optionally substiuited in a similar mannier to that indicated above for the direct attachemnent of the heterocycyl.

When R2 is an optionally substituted C3-7cycloalkyl, or an optionally substituted C3-7cycloalkyl C 1 -10 alkyl, the cycloalkyl group is preferably a C5 to C6 ring which ring may be optionally substituted I or more times independtly by halogen, such as fluorine, chlorine, bromine or iodine; hydroxy;, C 1 -10 alkoxy. such as methoxy or ethoxy; S(O)gm alkyl, wherein mn is 0, 1, or 2, such as methyl thio. methylsulfinyl or methyl sulfonyl; amino, mono di-substituted amin~o, such as in the NR7R 17 group; or where the R7 R17 may cyclize together with the nitrogen to which they are attached to form a 5 to 7 membered ring which optionally includes an additional heteroatom selected from OINIS; C I1-10 alkyl, such as miethyl ethyl, propyl, isopropyL, or t-butyl; halosubstitued alkyl, such as C173; hydroxy substituted C I- oalkyl; C(O)OR 11, such as the free acid or methyl ester derivative; an optionally substituted aryl, such as phenyl; an optionally substituted aiyialkyl, such as benzyi of phenethyl; and further where these aryl moieties may also be substituted one to two times by halogen; hydroxy; C I alkoxy; S(O)m alkyl; amino, mono di-subsztuted amino, such as in the NR7R 1 7 group; alkyl or halosubstitued alkyl.

When R2 is (CRIwR2O)nNRI3RI4. R13 and R14 are as defined in Formula that is R13 and R14 are each independently selected from hydrogen. optionally substituted Cl -4 alkyl. optionally substituted aryl or an optionally substituted aryl-Cl1 4 alkyl, or together with the nitrogen which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatomn selected from oxygen, sulfur or NR9. It is recognized that in some instances this can yield the same moiety as a heterocyclic CI-10 alkyl moiety noted above which is also a suitable R2 variable. Preferably R13 and R14 are independently hydrogen, CI-4 alkyl, preferably :methyl, or benzyL. The n term is preferably I to 4, more preferably 3 or 4, and most preferably 3, such as in apropyl group. Preferred groups include, but are not limited to, amninopropyl, (N-methyl-N-benzyl)axninopropyl, (N-Phenylmethyl)amino- I-propyl, or diethylamino propyl.

When R2 is a (CR1OR20)nC(Z)ORI I group, RI 1 is suitably hydrogen, C 1-4 :alkyl, especially methyl. The n term is preferably I to 4, more preferably 2 or 3, such as in an ethyl or propyl group. Preferred groups include, but are not limited to, carboxymethyl- I -butyi, carboxy- I1-propyl, or 2-acetoxyethyL *.:When R2 is a (CRIOR2o)nS(O)mRl8 group m is 0. 1, or 2, and RI g is preferably aryl. especially phenyl. or C 1-10 alkyl. especially methyl. The n tenm is preferably 1 to 4, more preferably 2 or 3, such as in an ethyl or propyl group.

When R2 is a(CR IOR2O)nOR I group, RI is suitably hydrogen. aryl, especially phenyl, or C 1- 10 alkyl, especially methyl or ethyl. The n term is preferably 1 to 4.momepreferably 2or 3.such asin anethyl or propyl group.

When R2 is a (CR 10R20)nNHS(O)2R18 group. RIB is suitably alkyl.

especially methyl. Thten term is preferably 1 to 4, morm preferably 2 or 3, such as in an ethyl or propyl group.

When R2 is a optionally substituted aryl, the aryl is preferably phenyl. The aryl ring may be optionally substituted one or more times, preferably by one or two substituents independently selected from C 1-.4 alkyl, halogen, especially fluoro or chloro, (CRIOR2O)tORl 1, -(CRlOR20hXNRl0R20, especially amino or mono- or dialkylamino -(CR lOR2O)tS(O)reRl18, wherein m is 0, 1 or 2 SH-, -(CRlOR20M)NR13RI4, -NRIOC(Z)R3 (such -NHCO(CI-il alkYl)); -NRIOS(O)mR8 (such as -NHSO2(C I- 10 alkyl)); t isO0, or an integer of I to 4. Preferably the phenyl is substituted in the 3 or 4- position by -(CR I 0R20)tS(O)MR I and R 18 is preferably C 1- 10 alkyl, especially methyl.

When R2 is an optionally substituted heteroaryl or heteroarylalkyl group the ring may be optionally substituted one or more times, preferably by one or two substuents, independently selected from one or more tunes, by C 1 -4 alkyl, halogen, especially fluoro or chloro, (CR 10R20)tORl 1, -(CRlOR2O)tNRIOR2O, especially amino or mono- or di-alkylamino -(CR lOR2OhtS(OhnRl8, wherein in is 0, 1 or 2 SH-, -(CR 10R20)n-NR13Rl4, -NRIOC(Z)R3 (such -NHCO(Cpjo0 alkyl)); -NRIoS(O)inRS (such as -NHSO2(Cl-IO alkyl)); t isO0, oran integer of I to 4.

One skille in the art would readily recognize that when R2 is a (CR 10R20)nOC(Z)RI 1 or (CRIOR2)nOC(Z)NRl3RI4 moiety, or any similarly substituted group that n is preferably at least 2 which will allow for the synthesis of stable compounds.

Preferably R2 is a C 1-4 alkyl (branched and unbranched), especially methyl, a *15 rethylthio propyl, a methylsulfinyl propyl, an amino propyl, N-methyl-N-benzylamio propyl group, diethylamino propyl, cyclopropyl methyl, inorpholinyl butyl.

morpholinyl propyl, a inorpholinyl ethyl, a piperidine or a substituted piperidine.

More preferably R2 is a methyl, isopropyl, butyl, t-butyl, n-propyl, methyithiopropyl, or inethylsulfinyl propyl, morpholino propyl, morpholinyl butyl, phenyl substituted by halogen, thioalkyl or sulfinyl alkyl such as a rnethylthio, methylsulfinyl or 20 methylsulfonyl moiety; piperidinyl, I-Formyl-4-piperidine, l-benzyl-4-piperidine, 1methyl-4-piperidine, or a I1-ethoxycarbonyl-4-pipcridine.

In all instances herein where there is an alkenyl or alkynyl moiety as a substituent group, the unsaturated linkage, ie., the vinylene or acetylene linkage is preferably not directly attached to the nitrogen, oxygen or sulfur moieties, for i nstance in OR3, or for certain R2imoieties.

As used herein, -optionally substituted- unless specifically defined shall mean such groups as halogen, such as fluorine chlorine, bromine or iodine; hydroxy; hydroxy substituted C I Oalkyl; C1-l10 alkoxy, such as inethoxy or ethoxy-, S(O)m alkyl, wherein ma is 0, 1 or 2, such as methyl thio, methylsullinyl or methyl sulfonyl;, amino, mono di-substituted amino, such as in the NR7R17 group; or where the R7R17 may together with the nitrogen to which they are attached cyclize to form a 5 to 7 memnbered ring which optionally includes an additional heteroatomn selected from OINIS; Ci-loalkyl.,cycloalkyl, or cycloalkyl alkyl group, such as methyl, ethyl, propyl, isopropyl, t-butyl, etc. or cyclopropyl methyl; halosubstituted C 1- 10 alkyl, such CF3; an optionally substituted aryl, such as phenyl, or an optionally substituted ary'Aaikyl, such as benzyl or phenethyl, wherein these aryl moieties may also be substituted one to two times by halogen; hydroxy; hydroxy substituted alkyl; C 1 alkoxy; S(O)m aLkyl; amino, mono di-substituted amino, such as in the NR7R17 group; alkyl, or CF3.

In a preferred subgenus of compounds of Formula RI is 4-pyridyl, 2-alicyl- 4-pyridyl, 4-quinolyl, 4-pyrinidinyl. or 2-arnino-4-pyrirnidinyl; R2 is morpholinyl propyl, aminopropyl, piperidinyl, N-benzyl-4-piperidine, or a N-methyl-4-piperidine; and R4 is phenyl or phenyl substituted one or two times by fluoro, chioro, CI1A alkoxy, -s(O)m alkyl, methanesulfonamido or acetamido.

A preferred subgrouping of compounds of Formula are those where R2 Is other tha methyl when R I is pyridyl, and R4 is an optionally substituted phenyl.

Suitable pharmaceutically acceptable salts are well known to those skille in the art and include basic salts of inorganic and organic acids, such as hydroc:Jlonc acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane suiphonic acid, ethae suiphonic acid, acetic acid, rnalic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumnaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid. In addition, pharmaceutically- acceptable salts of compounds of Formula may also be formed with a pharmnaceutically acceptable cation, for instance, if a substituent group comprises a carboxy moiety. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, amnmoniumn and quaternary azumoniumn cations.

The following terms, as used herein, refer to: "halo" or "halogens", include the halogens: chloro, fluoro, bromo and iodo.

T I lalkyl" or "alkyl' both straight and branched chain radicals of 1 to carbon atoms, unless the chain length is otherwise limited, including, but not limited to, methyl, ethyl, n-propyl. iso-propyl, n-butyl, sec-butyl, iso-butyl, ter;-butyL, n-pentyl and the like.

The term "cycloalkyl" is used herein to mean cyclic radicals, preferably of 3 to 8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like.

The term "cycloalkenyl" is used herein to mean cyclic radicals, preferably of to 8 carbons, which have at least one bond including but not limited to cyclopentenyl, cyclohexenyl, and the like.

'MTe term "alkenyl" is used herein at all occurrences to mean straight or branched chain radical of 2-10 carbon atoms, unles the chain length is limited thereto, including, but not limited to ethenyl, I1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1butenyl. 2-butenyl and the like.

"aryl" phenyl and naphthyl; 'heteroaryl" (on its own or in any combination, such as "heteroaryloxy", or ";ieteroaryl alkyl") a 5- 10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, 0 or S, such as, but not limited, to pyrrole, pyrazole, furan, thuophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, tniazole, imidazole, or benzimidazole.

"heterocyclic" (on its own or in any combination, such as whererocyclylalkyr) -a saturated or partially unsaturated 4- 10 membered ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, 0, or S; such as, but not limited to, pyrrolidine, pipetidine, piperazine, rnorpholinc, tetrahydro pyran, or imidazolidine.

The term "aralkyl" or "heteroarylalkyl" or "heterocyclicalkyl" is used herein to mean C 1-4 alkyl as defined above attached to an aryl, heteroaryl or heterocyclic moiety As also defined herein unless otherwise indicate.

*sulfinyl -the oxide S of the corresponding sulfide, the term hio" refers to the sulfide, and the term "sulfonyl" refers to the fully oxidized S (0)2 moiety.

*"aroyl" a C(0)Ar, wherein Ar is as phenyl, naphthyl, or aryl alkyl derivative such as defined above, such group include but are note limited to benzyl and phenethyL.

*"aikanoyl" a C(0)Ci1 -1 alkyl wherein the alkyl is as defined above.

:The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in raceinic and optically active forms. All of these compounds are included within the scope of the present invention.

Exemplified compounds of Formula include: 1-[3-Morpholinyl)propyll-4-(4-fluorophenyl-5-(4-pyridy)imidazole; 1-(3-Chloropropyl)-4-(4--fluorophenyl)-5-(4-pyridyl)imidazole; 1-(3-Azidopropyl)-(4fluoophenyl)-5-4-pyrdyl)imidazole; 1-(3-Aminopropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)inidazole; 1 -(3-Methysfonmidopropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; 1 -[3-(N-Phenylmethyl)anopropyll-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; I -[3-(N-Phenylmethyl-N-methyl)aminopropyl)-4-(4-fluorophenyl)-5-(4pyridyl)imidazole; 1 1-Pyrrolidiny1)prcopyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imaidazole; I -(3-Diezhylaminopropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)inidazole; 1-Piperidinyl)propyl]-4-(4-f Iuorophenyl)-5-(4-pyridyl)imidazole; 1-[3-(Methylthio)propy1J-4-(4-fluorophenyl)-5-(4-pyridy)imidazole; 1-[2-(4-Morpholinyl)ethyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; 13 I .[3-(4-Morpholbnyl)propylI- 4 -(3-methylthiophenyl)-5-(4-pyridyl)imidazole; 1 (3-(4-Morphoiny)propyI-4-(3-methyufinypheny)(-pyridy)mdao 0 1 -[3-(N-mechyl-N- benzyl)aminopropyll-4-(3-methylthiophenyl).5(4pyridyl)irnidazole; 1 -[3-(N-methy-N-benzy)amnopropyIJ4-(3-methylsulfinylpheny1)-5.{4pyridyl)imidazole; 1 44-(Methylchio)pheny1J-4-(4--tluorophenyl)-5-(4-pyridyl)imidazole 1 -[4-(Med y~sulfml)phenyl]- 4 -(4-fluorophenyl)-5-(4-pyridyi)imidazole; 1- [3-(Methlhhio)phenyl]-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; 1 [-Mtysliy~bny]-4furpey)5-4prdliiaoe I -[2-(Methyhthio)phexzylj4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; 1 2 -(Methylsulfinyl)phenyIJ4-(4-fluorophenyl)-S-(4-pyidy)imidazo,1e; 1 -Cyclopropyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; **15 I-lsopropyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; 1 -Cyclopropylnlethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazol; 1 -te-B ii d-4-(4-fluoropbenyl)-5-(4-pyridyl)iznidazole; 1-(2,2-Diethoxyethyl)-4-(4-fluoropbenyl)-5-(4-pyricjyl)imidazole; 1-Formylmethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imiiazole; 1 -Hydroxyirninylrnethyl-4-(4-fluorophenyl)-5-(4-pyridyl)imidazole; 1 -Cynonetyl4-(4-flurophenyl)-5-(4-pyridyl)imidazole; 4-(4-Fluoropbcnyl)- 1-(3-(4-fnorpholinyl)propylJ-5-(2-chlowopyidin.4.yi) imidazole; 4-(4-Fluorophenyl)- 1 4 -morpholinyl)propylF 5-(2-axuino-4-pyridjnyl) imidazole; 1 -(4-Caboxymcthyl)propyl4-(4fluorophenyl)-pyridyl)mjclzle; 1-(4-Carboxypropyl)-4-(4-fluorophenyl)-5-(4-pyridyl)iniazole 1*3Croyehlehy .4furpey)5-4prdliiaoe 1 -(3-Carboxymy)ethyl-4-(4-fluorpbenyl)-5-(4-pyridyl)iinazole 1 -Benzylpiprdn4.ylI -(4-fluorophenyl)-5-(4-pyridyl) imiclazole; 5-(2-Aminopyrimidin-4-yi)-4-4-fluorophenyl)- I-(3-(4-Morpholinyl)propylI iinidazole; 5-(2-Azninopyrimidin-4-yl)-4-(4-fluorophenyly-. I-benzylpiperidin-4-yl)imidazole; 5-(2-Aminopyrimidin4-yl)-4-(4-fluorophenyl)- I-(2-propyl)imidazole; 5-(2-Aminopynimidin-4-yl)-4-(4-fluorophenyl)- I -(cyclopropybmethyl)imidazole; 5-(2-Aminopyrimidin-4-yl)-4-(4-fluorophenyl)- 1-(1 -carboxyethyl-4- 35 piperidinyl)imidazole; 5-(2-Aminopyrimidin-4-yl.)-4-(4-fluorophenyl)- 1-(4-piperidinyl) imidazole; 1 -MethyI-4-phenyi'-5-(4-pyridyl)iniidazole; 1 -Me Lhy-4-(3-(chlobophenyl)1-5-[4-pyridinyljixnidazole; 1 -Methyl-4-(3-methyltiophenyl)-5-(4-pyridyl)irndazole; 14.

1 -Methyl-4-(3-methyLsulnyphenyl)-5-(4-pyridyl)imidazole; (+/-)-4-(4-Fluorophenyl)- I -(3-(rnethylsulfmnyl)propylj -5-(4-pyridinyl)irnidazole; 4-(4-Fluorophenyl)- 1 -[(3-methylsulfonyl)propyl-5-(4-pyriiinyl)imidazole; 1 -(3-Phenoxypropyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)imudazole; 1 -[3-(Phenylzhio)propyl]-4-(4-fluorophenyl)--(4-pyridinyl)imidazole; 1 -(3-Phcny~sfnylpropyJ)-4-(4-fluorcophenyl)-5-(4-pyridinyl)imidazole; I -(3-Ethoxypropyl)-4-4-fluorophenyl)-5-(4-pyridinyl)imidazole; I -(3-Phenylsulfonylpropyl-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole; 1 -[3-(4-MorpholinyI)propyI]-4-(3-cbloropheny)-5(4-pyridy)imidazole; 4* 4-(4-Ruoropbenyl)- 1 (-ophlnlpopl--prmi--n4yliiaoe 4-(4-Fluorophenyl)(2-(methyhio)-4-pyrimidinylj-lI-(3-(4-znorpholinyI)propyl]..

imidazole; 4-(4-Fluorophenyl)-5-[2-(methylsulfmyl)-4-pyrimidinylj-l1-(3-(4-morpholinyl)propyllimidazole; 1.PropenyI)-4-(4-fluoropheny)-5-(4-pyridiny)imidazole; 1 2 -Propenyl)-4-(4-fluorophenyl)-5-pyridiny)imidaol; ~5-((2-N,N-Dimethylanno)pyimidin-4-yl-4-(4-fluorophenyl). 1-3-(4-morpholinyl)propyil]mdazole; 1 3 4 -Morpholiny)propy1-5-(4-pyidiny)-4-[4-(Uifluormeuiy)pbenylimidazole; -[3-(4-Morpholiny)propyJ-5-(4-pyridiny)-4-3-(tffuoromet&y)ph.ny1Jjmda le; 1 .(Cyclopropylmethyl)-4-(3,4-dicblorophenyl)-5.(4-pyidinyl)imidazole; 1 -(CyclopropylmethyI)-4-(3-trifluofomethylphenyl)-5-(4-pyridinyl)imidazole; 1 -(Cyclopropymelhy1)-4-(4-fluoropheuyI)-5-(2-methypyrid.4y1)imidazole; -(3-(4-Mophoinyl)popyJ-5-(4-pyridiny)4-(3,5-bisarifluoromethypeny)imidazole 5-(4-(2-Aminopyimidinyl)J-4-(4-tluorophenyl)- 1 -(2-carboxy-2,2dimethylethyl)uimle; 1-Formyl-4-piperidinyl)-4-4-fluorophenyl)--(4-pyridinyl)imidazoe; 5-(2-Amino4-pyrimidinyl)-4-(4-flnorophenyl)- I -methyl-4-piperidinyl)imidazole; I -(2,2-Dimnethyl-3-morpholin-4-y)propyl-4.(4-fluoropheny5(2-Amuino.4pyrimidinyl)imidazole; 4-(4-Fluorophenyl)-5-(4-pyridyl)- 1-(2-acetoxyelkiyl)imidazole.

5-(2-Aminopyrimidin-4-yl)-4-(4-fluorophenyl)- I -(Il-benzylpyrrolin-3-yl)imnidazole; 5-(2-Aminopyrimidin-4-yl)-4-4-fluorophenyl)- 1 -(2,2,6,6-tlmetbytpiperndin-4- YI)imidazole.

Preferred compounds of Formula include: 5-f4-(2-Amino)pyrinidinyl]-4-(4-fluorophenyl)- 1 -(4-N-rnurpholino- 1 propyl)imidazole; 5-II4-(2-Arninopyrimidiny1)-4-(4-fluorophenyu)- 1-(1 befzyl-4-piperidinyl)imidazole; 5-(2-Anino-4-pyrimidinyl)-4-(4-fluorophenyl)- Il-( 4 -piperidinyl)imidazole;

S-(

2 -Arnino-4-pyrimidinyl)-4-(4-fluorophenyl)-l -rethyl-4-pipenidinyl)imidazole.

Another aspect of the present invention is the compound, 4-phenyl-5-[4pyridyl)imidazole. Another aspect is of the present invention is a pharmaceutical composition comprising a carrier or diluent and effective amount of 4-phenv!-5-f4pyridyl)imidazole. Yet another aspect of the present invention is the novel method of treating a cytokine mediated disease state. in a mammal in need thereof, with an effective amount of 4-phenyl-5-[4-pyridyl)imidazolc.

9.15 For purposes herein the dosage ranges, formulation details, and methods of making are analogous to the compounds of Formula The compounds of Formula may be obtained by applying synthetic procedures, some of which are ilustrated in Schemes l and V. The synthesis provided for in these Schemes is applicable for the producing compounds of Formula having a variety of different R 1, R2, and R 4 groups which are reacted employing optional substituents which are suitably protected, to achieve compatibility with the reactions outlined herein. Subsequent deprotection, in those cases, then affords compounds of the nature generally disclosed. Once the imidazole nucleus has been established, further compounds of Formula may be prepared by applying standard techniques for so..functional group interconversion, well known in the art.

For instance: -C(O)NR 13RI4 from -CO2CH3 by heating with or without catalytic metal cyanide, e.g. NaCN, and HNRj3R14 in CH3OH; -OC(O)R3 from -OH with ClC(O)R3 in pyridine; -NRIO-C(S)NR13RI4 from -NHRIO with an alkylisothiacyante or thiocyanic acid; NR6C(O)0R6 from -NHR6 with the alkyl chioroformate; -NRIOC(O)NRl3RI4 from -NHRIO by treatent with an isocyanate, e.g. HN=-C=O or RION=C=-O; -NRIO-C(O)R8- from -NHR1O by treatment with Cl- C(O)R3 in pyridine; -C(=NRIO)NRl3RI4 from -C(NR13R14)SR3 with H3NR3+OAcby heating in alcohol; -C(NR13Rl4)SR 3 from -C(S)NR13Rl4 with R6-1 in an inert iolvent, e.g. acetone; -C(S)NRl3RI4 (where R13 or R14 is not hydrogen) from -C(S)NH-2 with HNR 13R 14-C(=NCN)-NR 1 3 Rl 4 from -C(=NR 13RI14)-SR3 with NH2CN by heating in anhydrous alcohol, alternatively from -C(=NH)-NRlI3R 14 by treatent with BrCN and NaQEt in EtOH; -NRlO.C(=NCN)SRg from -NHRlO by treatment with (R8S)2C=NCN; -NR IOSO2R3 from -NHR 10 by treatment with 16.

CISO2R3 by heating in pyridine; -NR IOC(S)R 3 from -NRIOC2(O)R 8 by treatment wi~h Lawesson's reagent [2,4-bis4-methoxyphenyl)- I .J, 2 4 -dithuadiphosphetane-2,4disulfide]; -NR IOSO2CF3 from -NHR6 with trific anhydride and base wherein R3, R6, R 1O, R 1 3 and R 14 are as defned in Form ula herein.

R

4 CHO V) ArS(% ,H I f 2

NCHO

CHC1 3 NaOH

CH

2

CI

2 H20-O P'TC

R

4

CH

2

NH

2

(VIII)

Wimyaung agent

R

4 CH12NICHO /dehydrating agent

R

4

CH

2 NC MVI 0 .0 0 6 0* 0 0 Ar-S(O)

(TV)

NHCHO

Ar S(0) 2

LI

wherein 04 Idehydrating agent 0 .0 0 0* 0 Ar-S(O)

R

4 NC RICHO R2NH 2

NR

2

SCHEMEI

Referring to Scheme I the compounds of Formula are suit-ably prepared by reacting a compound of the Formula (LI) with a compound of the Formula (Ell) wherein p is0, lor 2 ,R 1,R2 and R4 are as defed hereinor areprrsrs of tegroups R 1 R2 and R4, and Ar is an optionally substituted phenyl group, and thereafter if nece,,sary converting a precursor of R 1

R

2 and R 4 t a group R1, R2 and R 4 17 Suitably Ar is phenyl optionally subst~ituted by C l-4alkyl, C 1 4 alkoxy or halo.

Preferably Ar is phenyl or 4-methyiphenyl. Suitably the reaction is performed at ambient temperature or with cooling -S0* to 100 in an inert solvent such as methylene chloride, tetrahydrofuran, toluene or dinlethoxyethane in the presence of an appropriate base such as 1,8-diazabicyclo [5.4.0.J undec-7-ene (DB U) or a guanidine base such as 1,5,7- triazabicyclo [4.4.01 dec-5-ene (OBD). Suitably p is 0 or 2, preferably p is 0 in which cae the intermediates of formnula (11) are very stable and capable of storage for a long time.

Precursors of the groups R 1 R2 and R4 can be other R 1

R

2 and R 4 groups which can be interconverted by applying standard techniques for functional group interconversion. For example a compound of the formula wherein R 2 ;S haO o-substituted C 1 0 alkyl can be converted to the corresponding C I 0 alkYlN 3 derivative by reacting with a suitable azide salt, and thereafter if desired can be reduced to the corresponding Cl 1 ljalkylqH 2 compound, which in turn can be reacted with RI18S(0) 2 X wherein X is halo chloro) to yield the corresponding CI-1.lalkylNHS(0)2Rlg compound.

Alternatively a compound of the formula where R 2 is halo-substituted Cl..l()alkyl can be reacted with an amine R1 3

R

1 4NH to yield the corresponding :4.7 CI..

10 -alk[ylNR 1 3R 1 compound, or can be reacted with an alkali metal salt of R18SH to yield the corresponding C I jalkylSR 18 compound.

In a further aspect the present invention provides compound$ of the Formula (11) asdefined herein with the proviso that when ArS(O)p is tosyl, then R 4 is not an unsubstituted phenyl.

The compounds of Formula in Schemne 1, may be prepared by the methods of Van Lcusen et al., JCC, 42, 1153 (1977). For example a compound of the Formula may be prepared by dehydrating a compound of the Formula (IV) wherein Ar, R 4 and p are as defined herein.

Suitable dehydrating agents include phosphorus oxychioride, oxalyl chloride or tosyl chloride in the presence of a suitable base such as trnethylamine.

The compounds of formula (IV) may be prepared by reacting a compound of the formula R 4 CHO where R 4 is as defined herein, with ArS(0)pH and forinamide, under dehydrating conditions at ambient or elevated temperature e.g. 30* to 1500, conveniently at reflux, optionally in the presence of an acid catalyst. Alternatively trimethysilylchloride can be used in place of thie acid catalyst. Exam'ples of acid catalysts include camphor- IO-sulphonic acid, p-toluenesulphonic acid, hiydrogen chloride or sulphuric acid.

The compounds of the formula (UI) where p is 2 may also be prepared by reacting in the presence of a strong base a compound of the formula (VI) R 4

CH

2

NC

18-.

with a compound of the formula (VII) ArSO2LI wherein R 4 and Ar are as defined herein and L I is a leaving group such as halo, e.g. fluoro. Suitable strong bases include alkyl littuums such as butyl lithium or lithium diisopropylamide.

The compounds of formula (VI) may be prepared by reacting a compound of the formula (VIED) R 4

CH

2 NH2 with an alkyl formate ethylformate) to yield an intermediate amide which can be converted to the desired isonitrile by reacting with a dehydrating agent such as oxalyichloride, phosphorus oxychloride or tosyl chloride in the presence of a suitable base such as triethylamine.

Alternatively a compound of the formula (VIMI may be converted to a compound of dhe formula (VI) by reaction with chloroform and sodium hydroxide in aqueous dichloromethane under phase transfer catalysis.

*0000 The compounds of the formula (MI) may be prepared by reacting a compound :*see* of the formula R ICHO with a primary amine R 2

NH

2 15 The amino compounds of the formula (VMn) are known or can be prepared from the corresponding alcohols, oximes or amnides using standard functional group irnerconversions.

Be: In a further process, compounds of Formula may be prepared by coupling a suitable derivative of a compound of Formula (IX): T* N

T

4 (IX) eseO wherein Tiis hydrogen and T4 isR4, or alternaively Tj iRI and T4is Hin which Rl1, R2 and R4 are as hereinbefore defined; with: when T I is hydrogen, a suitable derivative of die heteroaryl ring R 1 H, under ring coupling conditions to effect coupling of the heteroaryl ring R I to the imidazole nucleus at position 5; (ii) when T4 is hydrogen, a suitable derivative of die aryl ring R4H, under ring coupling conditions, to effect coupling of the aryl ring R4 to the iruidazole nucleus at position 4. Such aryl/heteroaryl coupling reactions are well known to those skilled in the art. In general, an organometallic synthetic equivalent of an anion of one component is coupled with a reactive derivative of the second component, in the presence of a suitable Latalysi- The anion equivalent may be formed from either the imidazole of Foirnula in which case the aryl/heteroaryl compound provides the reactive derivative, or the aryl/heteroaryl compound in which case the imidazole provides the reactive derivative. Accordingly, suitable derivatives of the compound of Formula (IX) 19-.

or the aryi/herteroaryl rings include organornetalc derivatives such as organomagnesium, organoziric, organostanane and boronic acid derivatives and suitable reactive derivatives include the bromo, iodo, fluorosulfonate and uifluorornethanesulphonace derivatives. Suitable procedures are described in WO 9 1/19497, the disclosure of which is incorporated by reference herein.

Suitable organomagnesium and arganozinc derivatives of a compound of Formula (IX) may be reacted with a halogen, fluorosulfonate or triflaz derivative of the heteroaryl or aryl ring, in the presence of a ring coupling catalyst, such as a palladium or palladium (HI) catalyst, following the procedure of Kumada et al., Tetrahedron Letters, 22,5.319 (198 Suitable 'such catalysts include teiralds- (triphenylphosphine)paLadium and PdC12[l,4-bli-(diphenylphosphino)-butne], optionally in the presence of lithium chloride and a base, such as triethylamine. In addition, a nickel catalyst, such as Ni(U)C12(1,2-biphenylphosphino)ethane, may also be used for coupling an aryl ring, following the procedure of Pridgen, J Org Chem, 1982, 47,.4319. Suitable reaction solvents include hexamethylphosphor-aznide. When the heteroaryl ring is 4-pyridyl, suitable derivatives include 4-bromo- and 4-iodopyridine and the fluorosulfonate and tiflate esters of 4-hydroxy pyridine. Similarly, suitable derivatives for when the aryl ring is phenyl include the broino, fluorosulfonate, trillate and, preferably, the iodo-derivatives. Suitable organomnagniu and organozinc derivatives may be obtainied by treating a compound of Formula (IX) or the brorno derivative thereof with an alkyllithium compound to yield the corresponding lithium reagent by deprotonation, or umansmetallation. respectively. This; lithium intermediate may then be treated with an excess of a magnesum halide or zinc halide to yield the corresponding orgoetic reagent.

A ulalkyltin derivative of the compound of Formula (DO) may be treated with a bromide, fluorosulfonate, triflate, or, preferably, iodide derivative of an aryl or beteroaryl ring compound, in an inert solvent such as tetrahydrofuran, preferably containing 10% hemethylpbosphoramide, in the presence of a suitable coupling catalyst, such as a palladium catalyst for instance tetraki- (triphenylphosphine)palladiuxn, by the method described in by Stifle. J Amer Chem Soc, 1987, 109, 5478, US Patents 4,719,218 and 5,002,942, or by using a palladium (11) catalyst in the presence of lithium chloride optionally with an added base such as triethylarnine, in an inert solvent such as dimethyl formamnide. Thialkyltin derivatives may be conveniently obtained by metallation of the corresponding compound of Formula (IX) with a lithiating agent, such as s-butyl-lithium, or n-butyllitllium, in an ethereal solvent, such as tetrahydrofuran, or treatment of the bromio derivative of the corresponding compound of Formula OIX) with an alkyl lithium, followed, in each case, by treatment with a trialkyltin halide. Alternatively, the broino- derivative of a compound of Formula (IX) may be treated with a suitable heteroaryl or aryl trialkyl tin compound in the presence of a catalyst such as tetrakis-(triphenyl-phosphine)palladium, under conditions similar to those described above.

Boronic acid derivatives are also useful. Hence, a suitable derivative of a compound of Formula such as the bromo, iodo, triflate or fluorosulphonate derivative, may be reacted with a heteroaryl- or aryl-boronic acid, in the presence of a palladium catalyst such as tetrakir-(triphenylphosphine)-palladium or PdC2[Il,4-bis- (diphenyl-phosphino)-butane) in the presence of a base such as sodium bicarbonate, under reflux conditions, in a solvent such as dimethoxyethane (see Fischer and Haviniga, Rec. Tray. Chim. Pays Bas, 84,439,1965, Snieckus, Tetrahedron Lett., 10 29, 2135, 1988 and Terashimia, Chem. Pharm. Bull., 11, 4755, 1985). Nonaqueous conditions, for instance, a solvent such as DMF, at a temperature of about :100 0 C, in the presence of a Pd(l) catalyst may also be employed (see Thompson W J et al, J Org Chem, 49, 5237, 1984). Suitable boronic acid derivatives may be prepared by treating the magnesium or lithium derivative with a trialkylborate ester, such as triethyl, tri-iso-propyl or tributylborate, according to standard procedures.

In such coupling reactions, it will be readily appreciated that due regard must be exercised with respect to functional groups present in the compounds of Formula (IX).

Thus, in general, amino and sulfur substituents should be non-oxidised or protected.

Compounds of Formula (IX) are imidazoles and may be obtained by any of the 20 procedures herein before described for preparing compounds of Formula In particular, an a-halo-ketone or other suitably activated ketones R4COCH2Hal (for compounds of Formula (IX) in which TI is hydrogen) or R COCH2Hal (for compounds of Formula (IX) in which T4 is hydrogen) may be reacted with an amidine of the formula R2NH-C=NH, wherein R2 is as define!" in Formula or a salt thereof, in an inert solvent such as a halogenated hydrocarbon solvent, for instance chloroform, at a moderately elevated temperature, and, if necessary, in the presence of a suitable condensation agent such as a base. The preparation of suitable a-halo-ketones is described in WO 91/19497. Suitable reactive esters include esters of stro.ng organic acids such as a lower alkane sulphonic or aryl sulphonic acid, for instance, methane or p-toluene sulphonic acid. The amidine is preferably used as the salt. suitably the hydrochloride salt, which may then be converted into the free amidine in situ by employing a two phase system in which the reactive ester is in an inert organic solvent such as chloroform, and the salt is in an aqueous phase to which a solution of an aqueous base is slowly added, in dimolar amount, with vigorous stirring. Suitable amidines may be obtained by standard methods, see for instance, Garigipati R, Tetrahedron Letters, 190, 31, 1989.

Compounds of Formula may also be prepared by a process which comprises reacting a compound of Formula wherein TI is hydrogen, with an N-acyl heteroaryl salt, according to the method disclosed in US patent 4,803,279. US patent 21.

4,719,218 and US patent 5,002,942, to give an intermediate in which the heteroaryl ring is attached to the imidazole nucleus and is present as a 1,4-dihydro derivative thereof, which intermediate may then be subjected to oxidative-deacylation conditions (Scheme II). The heteroaiyl salt, for instance a pyridinuum salt, may be either preformed or, more preferably, prepared in situ by adding a substituted carbonyl halide (such as an acyl halide, an aroyl halide, an arylalkyl haloformate ester, or, preferably.

an alkyl haloforruate ester, such as acetyl bromide, benzoylchloride, benzyl chioroformate, or, preferably, ethyl chioroformate) to a solution of the compound of Formula (IX) in the heteroaryl compound R 1 H or in an inert solvent such as methylene chloride to which the heteroaryl compound has. been added. Suitable deacylating and oxidising. conditions are described in U.S. Patent Nos. 4,803,279, 4,719,218 and 5,002,942, which references are hereby incorporated by reference in their entirety.

Suitable oxidizing systems include sulfur in an inert solvent or solvent mixture, such as decalin, decalin and diglyme, p-cymene, xylene or mesitylene, under reflux conditions, or, preferably, potassium t-butoxide in t-butanol with dry air or oxygen.

*X

N

:ZONH o R) 4 SCHEME 11 In a further process, illustrated in Scheme MI below, compounds of Formula (I) may be prepared by treating a compound of Formula thermally or with the aid of a cychising agent such as phosphorus oxychioride or phosphorus pentachioride (see Engel and Steglich, Liebigs Ann Chem, 197 8, 1916 and Strzybny et al., I Org Chemn, 1963, 28, 338 Compounds of Formula may be obtained, for instance, by acylating the corresponding a-keto-amine with an activated formate derivative such as the corrsponding anhydride, under standard acylating conditions followed by formation of the imine with R 2

NH

2 The amunokewine may. be derived from the parent ketone by oxamination and reduction and the requisite ketone may in turn be prepared by decarboxylation of the beta-ketoester obtained from the condensation of an aryl (heteroaryl) acetic ester with the RICOX component.

22 R 0 X o a R )JO 0 2) HO .)NaNO,. HCOA O 0 Oi O PO reduce 2.)M 2 A, MO 4 ~P"A;R4 H R o 0 ormb oQ SCHEME M In Scheme IV illustrated below, two different routes which use ketone (formula XI) for preparing a compound of Formula A heterocyclic ketone (XI) is prepared by adding the anion of the alkyl heterocycle such as 4 -methyl-quinoline (prepared by treatment thereof with an alkyl lithium, such as n-butyl lithium) to an Nalkyl-O-alkoxybenzamide, ester, or any other suitably activated derivative of the same oxidation state. Alternatively, the anion may be condensed with a benzaldehyde, to give an alcohol which is then oxidised to the ketone (XI).

R, NHRA R P 0 4 0

H

Oa(X) Fl

R

4 O A"CH V H RR 4 4I R R4 SCHEME IV In a further process, N-substituted compounds of Formula may be prepared by treating the anion of an amide of Formula (XI): R1CH2NR2COH (XII) wherein R I and R2 with: a nitrile of the Formula (XIII): R4CN (XIII) wherein R4 is as hereinbefore defined, or an excess of an acyl halide, for instance an acyl chloride, of the Formula

(XIV):

R4COHal (XIV) i 23 wherein R4 is as hereinbefore defined and Hal is halogen, or a corresponding anhydride, to give a bis-acylated intermediate which is then =raed with a source of ammnira, such as arnmonium acetate.

R

2 HN base Ri,_CI R2 U+ -N(W0r 2 R N2 o0- 4,CNP4 C

N

.One variation of this approach isWsrtdin Scheme V above. A primary 10 amine (R2NH2) is treated with a halomethyl heterocycle of Formula RICH 2 X to give the secondary amine which is then converted Co the amnide by standard techniques.

Alternatively the amaide may be prepared as illustrated in scheme V by alkylation of the formanaide with RICH2X. Deprotonation of this arnide with a strong amnide base, such :as lithium di-is-propyl amaide or sodium, buj-(trrnethylsilYl)amide, followed by addition of an excess of an aroyl chloride yields the bis-acylated compound which is then closed to an imidazole compound of Formula by heating in acetic acd containing ammonium acetate. Alternatively, the anion of the amide, may be reacted with a substituted aryl nitrile to produce the amidazle of Formula directly.

Suitable protecting groups for use with hydroxyl group and the imidazole niutrogen ame well known in the art and described in many references, for intMe Protecting Groups in Organic Synthesis, Greene T W, Wiley-Interscience, New York, 1981. Suitable exampies of hydroxyl protecting groups include silyl ethers, such as tbutyldimethyl or t-butyldiphenyl, and alkyl ethers, such as methyl connected by an alkyl chain of variable link, (CRIOR20)n. Suitable examples of imidazole nitrogen protecting groups include tetrahydropyranyl.

PharmaCeuiall acid addition salts of compounds of Formula may be obtained in known manner, for example by treatment thereof with an appropriate amount of acid in the presence of a suitable solvent- In the Examples, all temperatures are in degrees Centigrade Mass spectra were performed upon a VG Zab mass spectrometer using fast atom bombardment, unless otherwise indicated. IH-NMR (hereinafter 'NMR") spectra were recorded at 250 M&z using a Bruker AM 250 or Am 400 spectrometer. Multiplicitie indicated are: s~inglet, d=doublet, t=triplet, q=quartet. m=muitiplet and br indicates a broad 24 signal. Sat. indicates a saturated solution. eq indicates the proportion of a molar equivalent of reagent relative to the principal reactant.

Flash chromatography is run over Merck Silica gel 60 (230 400 mesh).

SYNTHETIC EXAMPLES The invention will now be described by reference to the following examples which are merely ill ustrative and are not to be construed as a Limitation of the scope of the present invention. All temperatures are given in degrees centigrade, all solvents are highest available purity and all reactions run under anydrous: conditions in an argon atmosphere unless otherwise indicated.

I -f3-44-MomhoinvflponvI-4-(4-fluorohenfl-5-(4-pvidvI'liImidazole a) 4-fluoroolhenyl-tolylthiomethylforrnamide 15 A solution of p-fluorobenzaldehyde (13.1-milliliters (heeinaftermrL.), 122 millimoles (hereinafter mmol) thiocresol 16.64 grams (hereinafter 122 mmol), forrnamide (15.0 niL, 445 nimol), and toluene (300 mL) were combined and heated to toluene reflux with aetropic removal of H120 for 18 h- The cooled reaction was diluted wth EtOAc (500mL) and washed with satd aq Na2CO3(3 x 100 mL), said aq NaCi (100 mQL, dried (Na2SO4), and concentrated. The residue was triturated with petroleum ether, fitered and dried in vacuo to afford 28.50 g of the title compound as a white solid (85 melting point (hereinaftermrp) 119 1200.

b) .4fumhnItI~timddsofd The compound of example 1(a) (25 g, 91 remol) in CHZCI2 (300 mL) was cooled to -300 and with mechanical stirxing P0C13(11 n1L, 110 nimol) was added dropwise followed by the dropwise addition of Et3N (45 mL, 320 nimol) with the temperature maintained below -300. Stirrd at -300 for 30 min and 50 for 2 h, diluted with CH2C12 (300 mL and washed with 5% aq Na2CO3 (3 x 100 mL), dried (Na2SO4) and concentrated to 500 mL This solution was filtered through a 12 x 16 cm, cylinder of silica in a large sintered glass funnel with CH2Cl2 to afford 12-5 g, of purified isonitrile as a light brown, waxy solid. IR (CH2C12) 2130 cm- I.

c) Aydne4 .L.JL. xadhy A (4-Mtph1 rr -l"f Pyridie-4-carboxaldehyde (2.14 g, 20 romoL), 4-(3-aznunopropyl)morphohin (2.88 g, 20 nimol), toluene (50 roL) and MgSO4 (2 g) were combined and stirred under argon for 18 h. The MgSO4 was filtered off and the filtrate was conwentraied and the residue was reconcentrated from CH2C12 to afford 4.52 g of the title compound as ayellow oil containing less than 5% of aldehyde based on 1 H NMR. IH NMR (CD3Cl): d 8.69 J 4.5 Hz, 28), 8.28 1H1), 7.58 J 4.5 Hz, 28), 3.84 (in, 68), 2.44 (mn, 611), 1.91 (mn, 28).

d) 1-f3-(4-Morpholinyl')propvil-4-(4.flgorophenyl).5.(4nvri-dvflimazole The compound of example I1(b) (1.41 g, 5.5 mmol), and the compound of example I1(c) 17 g, 5.0 nimol) and CH2CI2 (10 mL) were cooled to 5 0G. 1.5.7triazabicyclo(4.4.Ojdec-5-ene, henceforth referred to as TBD, (0.71 g 5.0 mmol) was added and the reaction was kept at 5 OC for 16 h, diluted with EtOAc (80 mL) and washed with sazdaq NA2CO3 (2 x15 mL) The EtOAc was extraced with IN HCl(3 x 15 mQL, and the acid phases were washed with EtOAc (2 x 25SmL), layered with EtOAc (25 tuL) and made basic by the addition of solid K2C03 til pH 8.0 and then NaOH til pH 10. The phases were separated and the aq was extracted with additional EtOAc (3 x 25 mQL. The extracts were dried (K2C03) concentrated and the residue was crystalized from acetone/hexane to afford 0.94 g (51 of the title .compound. mp 149 150 0.

Exapl 2 .Clrgoy)-(-loohnl--(-ydliiaoe To 3-3-hlo ooro opy--(-lamrio Ha fl(15.1 g,0. 120mdoleeinfr o)adH2 (100 mL) was added pyridine-4-carboxaldehyde (9.55 tuL, 0. 100 mol), then K2C03 (8.28 g, 0.060 mol) then CH2CL2 (100 mQL and the mixtur was stirred for 40 min.

The phases were separated and the aq phase was extracted with additional CH2CI2 (2 x 50 mQL, dried (Na2SO4) and concentrated to afford 17.1 g IH NMR (CD3C1): d 8.69 J 4.5 Hz, 2H, 8.32 I 8.28 1 7.58 J =4.5 Hz, 2H1), 3.71 (in, 2H), 3.63 J 6Hz, 211), 2.24 (tzJ-= 6Hz, 2H1). The presence of 9% of the aldehyde, was evident by IH NMR.

b) I o A lA -4-lorlh IA-4 yi~liidZ The compound of example I1(b) (6.85 g, 26.6 tumol), the compound of example 2(a) (6.32g, 34.6 tumol), CHZCI2 (70 mL), and TBD (4.07 g, 28.4 tumol) were reacted by the procedure of example I(d) to afford 3.19 g nip 139 1400.

Examale To a solution of the compound of example 2(b) (250 milligram (hereinafter mig), 0.79 tumol) and DMF (5 mL) was added NaN3 (256 mug. 3.95 nimol) and NaY (12 mug, 0.08 nimol) and the mixture was heated to 900 till the reaction wzs completed based on tic analysis (19:1 CH2C12IMCQH). The cooled reaction was added to 5% aq Na2CO3 (20 niL) and extracted with EtOAc (3 x 25 niL. The combined extracts were washed with H20 (3 x 25 rnL and flash chrornatographed (2.2 x 10 cm column) with 0 1% eOH in CH2l2 to afford 254 mug (100%) of the title compound as awhite solid. mp =64 -65 0 26 Example 4 I -(3-Am inonropvfl-4-(4-t] uoroozhenvi )-5-(4--nvridvl)imidazole The compound of example 3, described above (254 mg, 0.79 mmol), was dissolved in THF (2 ruL) an added dropwise to a0 0 solutionoflI N iAIH 4 in THF (1.2 niL, 1.2 mmrol), stirred at 00 for 15 min, EtOAc (4 mQL was carefully added and the mixture was added to ice cold 10% NaOH (15 mL) and the product was extracted with EtOAc (4 x 25 ruL), dried (K2C03) and concentrate to a waxy solid, (175 mng, mp 81 820.

I -(3-Methylsulfonamidopropvl)-4-(4-fluorophenyfl-5-(4-nvyridvl)imidazoie To the compound of Example 4, descwribed above (79 rug, 0.26 mmrol) in CH2CI2 (0.5 ml) was added Et3N (72 uiL, 0.52 mmnol), and then methanesulfonyl chloride (25 uL., 0.31 rumol). The reaction exothernied to CH2C12 reflux briefly. The reaction was over within I ruin based on tlc (19: 1 CH2I2 /MeO) and was poured into 10% NaOH (5 mL) and extracted with EtOAc(3x 20ml.). The extracts were washed with H20 (10 ruL) and said aq NacI (10 mQL, dried (Na2SO4), concentrated *and flash chromatographed (Ilx 10 cm silica) with 0 MeOH in CH2C12 to afford 63 rug rup 186 1870.

.k Following the procedure of example 3 above, except using benzylainine, as the nucleoplide and purification of the crude product by trituraion with hot hexane, the title compound was prepared as a white solid (32% yield). rup 125 1260.

1 -r34N-Phenylmethvl-N-methvflamingpropyl)-4-(4-fluomphenl')-5-4- Rxy1).imidazole Following the procedure of example 3 except using N-benzylmethylamine as the nucleophile and purification of the crude product by tribxauion with hot hexane, the title compound was prepared as a white solid (42% yield). rup 90 9 35Exml8 I -f3-01 -Pvrrolidinflpropvll-4-(4-fluorohenl)-5-(4-pyridflimidazle Following the procedure of example 3 except using pyrrolidine as the nucleophile and purification of the crude product by trituration with hot hexane, the title compound was Prepared as a white solid (35% yield). up, 105 1070.

27 I -(3-Diethylamninopropvl)-4-(4-fl uoron~hen-yl)-5-(4-pyri)im idazoie Following the procedure of example 3 except using diethylarnine as thie nucleophile and isolation of the product by extraction with diethyl ether, the title compound was prepared as a white solid (21 yield). mp, 94 950.

Following the procedure of example 3 except using piperidine as the nucleophile and purification of the crude product by trituration with hot he;.ane, the title compound was prepared as a white solid (63% yield). nap 105 1080.

ExampleI 1 -f 3 -(Methvthiopropl1-4-(4fluorophen v(4p~dvIimle Following the procedure of example 3 except iung sodium tbioinethane as the nucleophile and omitting the sodium iodide followed by purification of the crude product by trituration with hot hexane, the title compound was prepared as a white solid (50% yield). nip 85 860.

Following the procedure of example 1 except using 4-(2azninoethylfmorpholine as the amine. the title compound was prepared as a light yellow oil (100%) containing less than 10% of aldehyde based on IH NMR. I H NMR (CD3CI): d 8.68 J 6 Hz, 2H1), 8.28 1H), 7.58 J 6 Hz, 2H), 3.82 (mn, 2H), 3.72 (mn, 4H). 2.72 (in. 2H1), 2.55 (mn. 4H).

Following the procedure of example 1 except using the compound of example 20(a) as the mnine, afforded the title compound as a white solid (2 1 rnp= 114- 1150.

a) N-r3-methylthiophenyl-(tolvlthiomethyllforaminde Following the procedure of example I1(a) except using inlethylthiobenzaldehyde as the aldehyde, the title compound was prepared as a white solid inp 103 -1040.

28-.

b) 3 -methyl thiop hen yI -(tol ylthio)meth ylisoc vni de Following the procedure of example 1 except using the compound of the previous step as the formarnide, the title compound was prepared as a light brown oil IR (CH2C12) 2120 cm c) I -I344-MoMholinyl)pronvl-4-(3-methy]L hiophenyfl-5-(4-pridy1)imidazoe Following the procedure of example 1 except using the compound of the previous step as the isonitrile, afforded the title compound as a white solid (31 nip 105 1060.

ExamfleI. 14 The compound of example 13(c) (200 mg. 0.49 nimol) was dissolved in HOAc (4 mL). K2S208 (151 mg, 0.56 mmol) dissolved in H20 was added and the solution was stirred for 16 h, poured into 10 aq NaOH (50 mL) (the resulting solution was pH 10) and extracted with EtOAc (3 x 25 niL). The extrcswrure 120) concentrated and the residual oil crystaized from acetonelfbexane to afford 87 mig of awhite solid. mp 117 1180.

20 .1 -I3-(N-metl-N-benzyhaminonropvll..43-methylhjophenvfl..5-4- RydbD~imidazom a) EPTidine-4-carhaxaldehyde, 3 -(N-methyl-N-benzylaminopmRopvlrnu Following the procedure of example 1(c) except using 3(-N-Methyl-Nbenzylarnino)propylamnine as the amine (UedaT.; UizakiL; Chem. Pharm. Bull.

1967, 15, 228 237.), the title compound was obtained as a light ye~1ow oil (100%) containing less than 10% of aldehyde based on IH NMR. 1 H NMR (CD3CJ): d 8.65 (d,J 7Hz. 8.21 1H).,7.54 J 4.5 Hi, 2H), 7.52 5H), 3.69 J= I11 Hz, 211), 3.48(s. 211), 2.44 J I11 Hz, 211), 2.18 3H), 1 .91 (in, 2H1).

b) I -[3-(N-methyl-N-benvfllarinoronvl1-4(3mrhvthiohenli.S-(4.

pyjdyfimdaol Following the procedure of example I1(d) except using the compound of example 13(b) as the isonitrile, and the compound prepared in the previous step as the imine afforded the title compound as a white solid nip 87 -880.

Eam&Ic16 I -f 3-(N-methv1-N-benzyl~aminopropyl14-(3-methlsufinylheni)5(4.

Following the procedure of examnple 14 except using the compound of example as the sulfide afforded the title compound as a white solid mp 84 29- I -f4-(Methylthio)phenvl l- 4 4 -fluorop~henvl)-5-( 4 -pyridvfllmidn7ole a) Pvridine-4-carboxaldehdyeC (4-methyl thiophenvllimine Following the procedure of example I1(c) except using 4-(methylthio)aniline as the amine afforded (100%) of a light yellow oil with no detectable amount of aldehyde based on IH NUR. IH NMR (CD3CI): d 8.75 (di, J 6 Hz, 211), 8.47 I 7.74 (d, J 6 Hz, 211), 7.30 I 8 Hz, 2H1), 7.22 J 8 Hz, 2H), 2.52(s, 311).

Following the procedure of example I1(d) except using the compound of the prvious step as the imine afforded the title compound as a white solid mp 172- 1730.

1 -f 4 -(Methvlsulfinvl)2henvl4(4fluomphenl)5(4DwidyI)imidazole Following the procedure of example 14 except using the compound of example 17(b) as the sulfide afforded the title compound as a white solid mp 202 2030.

Example 19 Following the procedure of example 1 except using 3-(mediylthio)aniine as the amine afforded ofalfight yellow oil with ca 2.5% of aldehyde based on I H NMR. I HNMR (CD3C): d8.76 J =6Hz, 2H),S.44 1H), 7.74 J =6Hz, 211), 7.30 J 8 Hz, 2H1), 7.34 6.98 (mi, 4H). 2.52(s. 3H).

b) I-r'-ieyti ob )Rh....II4 A IA Ic5M5-A: dlinUA Following the procedure of example 1(d) except using the compound of the previous step as the imine afforded the title compound as a white solid mp 155- 1560.

Following the procedure of example 14 except using the compound of example 19(b) as the sulfide afforded the title compound as a white solid mp 233 2340.

I -r 2 -(Medivlthio~phenXI1-4-( 4 -fluomphenlil-s-(4.py,,idylniMidAm~ a) Pyridine-4-carboxaldehd ye (2-methyl thiophenvl~imine Following the procedure of example I1(c) except using 2 -(rnethylthio)aniiine as the am ine afforded (98 of a light yellow oil with ca 8 of aidehyde based onIH NMR. I H NMR (CD3CI): d 8.75 I 6 Hz, 28). 8.41 IH), 7.79 J 6 Hz, 2H), 7.36 7.00 (in. 4H), 2.47(s. 3H).

b) 1 -f2-(methvlthio~phenyl--(4-fluorohenl--(4-oixdvnimida~ole Following the procedure of example I1(d) except using the compound of the previous step as the imine and purification by flash chromatography with 0 -1I% MeOH in CH2CI2 afforded the title compound as a non-crystalline white foam mp =59-60 0 *Ex ample2 *1 -2-(MethlsulfinXVlhenvll-4-(4-fluoronhe.nvl)-5-(4-nvridflim idazole Following the procedure of example 14 except using the compound of example 21(b) as the sulfide, and purification by flash chromatography with 0 MeOH in CH2CI2 afforded the title compound as a non-crystalline white foam mp 60 1650. (The il defned mp is probably the result of a mixture of conformtional isomers which is clearly indicated in the 1 H and 13 C NUvR spectra of this compound.) .20 (See also Example 2 above for altrntive method of preparation) 4 -Eirl~vhonxL-toyknm1hxlfomaaide To a solution of toluene suiphinic acid sodium salt hydrate (120g) in water (750 ml) was added concentrated sulphuric adid (16m1). Dic lormethane (SOil) was :::.added and the organic and aqueous layers were separated; the aqueous layers being extracted with dicbloromnedhane (2x200m1). The combined organic extracts were dried (Na2SO4) and evaporated to dryness to yield the solid sulphinic acid (71.79g, 0.46 mole). This was added to p-fluorobenzadehyde (57.04g, 0.46 mole) and formamnide (62.1 g, 1.38 mole) and the resulting mixture was stifled with camphor- lO-suiphonic: acid (21.3g, 0.092 mole) at 60.65*,'under nitrogen for 22 hours. A solution of sodium bicarbonate (33.6g, 0.40 mole) in water (400m1) was added to the ice-cooled solid product which was broken up and stirred for 30 minutes. Ile crude product was collected and washed with acetone (220m1l) and thent ether (3x220m1) and dried to yield the dervired product, 9 1.5g, 64.8%.

To a suspension of the compound of the previous step (3.22g, 10.5 rmole) in dimethoxyethane (2lml) stkring at 100 was added phosphorus oxychioride (2.36m1.

01 25.3 mrnole) dropwise over 5 minutes. Triethylamine (7.35m1. 52.5 mole) was then added dropwise over 10 minutes and the reaction mixture; was poured into saturated sodium bicarbonate solution (lO0m!) and the oily product was extracted into dichioromethane (2x30mD. The organic extracts were evaporated to yield a black oil (3.5 1Ig) which was eluted from Grade MJ basic alumoina (60g) using dichloromethane.

The combined product fractions were evaporated and ether added to crystallize the desired product, 1.735g, 57%.

c) I -(3-Chlaopropvfl-4-(4-fluomnphenfl)-5-(4-nyridfl)-imidazole To a solution of the compound of the previous step 183g. 4.O9mmol) and the compound of example 2(a) (1.122g. 6.l5mrnole) in dimethoxyethae (i5mi) at ambient temperature wips added dropwise over 10 minutes a solution of DBU (0.67M1, 4.Slmmole) in dimethoxyethane (l1in!). The reaction mixture was stirrd at ambient temperature for 1-l/2hours and then evaporated to leave an oil which was eluted from Grade Mf basic alumina (100g) to yield the desired product, 1.096g, .*Example 24 I -r4-(4-Momaholinyl~butl1--(4-fluoronhenvD)-5-(4-pvrdylimida.le a) 4-44-Morpholinombut- I -ohalimide 4-Bromobutyl-1I-pthalimide (5.0 g, 17.7 inmol) and morphioline (20 inL) were combined andstre dfor 3h, diluted with Et20 (200 niL), and fMlened The solid was washed with more Et2O and the combined filtrates were extracted with 3 N HCI (3 x niL). T7he combined acid phases were washed with Et2O (3 x50 mQL, layered with :.:EtOAc and made basic by the addition of solid K2C03 til the foaming stopped and then 10% aq NaOH was added til the pH was >10. Exuwation with EtOAc (3 x 100 inL), drying, (K 2 C03), concentration and flash filtration 1 L silica wash first with 0 -4% MeOH in CH 2 C1 2 and then elute product with 4% 'MeOH and 1% EtjN in CH 2 Cl 2 to afford 5.52 g of the title compound as a white b) 4-A-MIAhn b~j The compound of example 24 (1.0 g, 3.47 inmol), hydrazine monohydrate (190 W.,3.82 mmol) and CH 3 0H (20 niL) were combined and stirred at 230 overnight.

The CH30H was removed in vacua and the resudue was concentrated to dryness from EtOH. The residue was combined with 2N HCI (20 ruL) and stirred for 2h, filteed and the solid was washed with H20. Ile combined filtrates were concentrated in vacuo and reconcentrated from EtOH twice to give a white foam which was dissolved in 3:1

CH

2 Cl2/CH 3 OH, and stirred with solid K 2 C03 for 5 min and filtered. The filtrate was concentrated to afford 0.535 g of a brown oil. 1H NMR (CD3CI): 3.7 3.2 (m, 6H), 2.7 2.2 (mn, 1.6 1-3 (in, 6H).

C) Pvridine-4-carboxaldehvde f4-4-rnorpholinvl~huIXl1imine 32.

Following the procedure of example 1(c) except using the compound of example 24(b) as the amine the title compound was prepared as a light yellow oil (100%) containing 30% of aldehyde based on 1 H NMR. 1 H NMR (CD3CI): 8.60 J 6 Hz. 2H).

8.19 IH), 7.51 J 6 Hz, 2H), 3.7 3.2 6H), 2.5 2.2 1.7 1.4 4H).

d) I -14-(4-Morpholinvf)butvl -4-(4-fluorophenvl)-5-(4-nvridvl)imidazole Following the procedure of example 1(d) except using the compound of example 24(c) as the imine afforded the title compound mp 103 1040.

Example 1 -Cvcloropvl-4-(4-fluorophenvl-5-(4-pvridvl)imidazole a) Pvridine-4carboxaldehvde cyclopropyvlimine Following the procedure of example 1(c) except using a 100% excess of the volatile cyclopropylamine the title compound was prepared as a light yellow oil 1 H NMR (CD3CI): 8.65 J 6 Hz, 2H), 8.40 IH), 7.51 J 6 Hz, 2H), 3.07 IH), 1.01 4H) b) I -Cyclopropvl-4-(4-fluoroohenvl)-5-(4-pvridvyl)imidazole The compound of the previous step (20 mmol), the compound of example 1(b) (5.65g, 22 mmol), and CH2Cl2 (20 niL) were cooled to 00 and TBD (2.84g, 20 mmol) was added. Stirred at 50 for 2h, 230 for 48h and refluxed for 4 h. The crude reaction 20 was flash filtered through a sintered glass funnel filled with silica (IL of silica) eluting with 0 4% CH30H in CH 2 Cl 2 Crystals from hexane/acetone to afford 839 mg mp 129.0- 129.50.

'Examle 26 1 -Isopropvl-4-(4-fluorohenvl-5-(4-pyridvDlimidazole a) Pidine-4-carboxaldehyde isopropvlimine Following the procedure of example 1(c) except using isopropylamine as the amine the title compound was prepared as a light yellow oil 1 H NMR (CD3Cl): 8.67 J 4.4 Hz, 2H), 8.27 1H), 7.59 J 4.43 Hz, 2H), 3.59 (m, 1H), 1.27 J= 6.3 Hz, 6H).

b) 1 -sopropvl-4-(4-fluorophenlD-5-(4-vridvlimidazole Following the procedure of example 1(d) and substituting the imine of the previous step the compound was prepared using a modified work up of flash filtration of the crude reaction through silica (0 4% CH 3 0H in CH 2

CI

2 Two crystallizations from hexane /acetone afforded the title compound as tan needles (30 mp 179.0 179.5.

Example 27 1 -Cvcloronvlmethl-4-(4-fluoroohenvI'-5-(4-Dvridvlimidazole 33.

C.

V.

C

V

a) Eyridine-4-carboxaldehyde Cyclopropylznethyli *e Following the procedure of example I1(c) except using cycloprPYlmehyarinme as the amine the title compound was prepared as a light yellow oil 1 H NMR (CD3CI); 8.69 J 4.5 Hz, 8.27 1I), 7.61 J 4.5 Hz, 214), 3.55 J 6.7 Hz, 2H), 1. 15 (mn, IH), 0.57 (in, 2H), 0.27 (mn, 2H).

b) I -Cvclopropylrnethvl-4-(4-fluoroohenl )-5-(4-pyrddvl)im idazole Following the procedure of example I1(d) substituting the imine of the previous step the compound was prepared using a modified work up of flash filtration of the crude reaction through silica (0 CH30H in CH 2

CI

2 Crystallization from hexane /acetone afforded the title compound as white flakes (62 mp 162.0 162.5.

1 -tert-Butv1-4-(4-fluoinhenvi)-5-(4-pvndflimidazole a) ftdn--ahxlehd etblfmn 15 Following the procedure of example 1 except using tert-butylamine as the amine the title compound was prepared as a light yellow oil IH NMR (CD3CI): 8.67 AdJ 3=4.4 Hz, 2H), 8.22 1H), 7.61 J =4.4 Hz, 2H), 1.30 9H).

Following the procedure of example 1 substituting the imine of the previous 20 step the compound was prepared using a modified work up of flash filtration of the crude reaction through silica (0 CH 3 OH in CH2C12) to afford the title compound as tan powder (16 mp= 199.0 -200.0.

1 -(2.2-Diethoxyethyl)-4-(4-fluorolnhenfl-S-(4-pidylimidakzole IFollowing the procedure of example 1(c) except using 2,2-diethoxyethylamine as the amine the title compound was prepared as a light yellow oil IH NMR (CD3CI): 8.69 J 4.4 Hz, 2H), 8.28 lH), 7.60 J 3=4.4 Hz, 2H), 4.82 J 5.1 Hz, IHO, 3.82 (di, J 5.1 Hz. 1H), 3.72 (mn. 21H), 3.57 (mn, 2H), 1.21 J 7.3 Hz, 6H).

b) 1 -(2-2-Diethoxvethvl)--4-(4-fluorophenv1')-544-pvndyllmidazole Following the procedure of example I1(d) substituting the imine of the previous step, the compound was prepared using a modified work up of flash filtration of the crude reaction through silica (0 CH 3 0H in CH2CI2), followed by a flash chromatography through silica with 25 -100% EtOAc in hexane) and trituration of the resulting gum with hexane afforded the title compound as a white pcwder (47 mp 69.5 70.0.

C. C C C

V.

V. C C C

C.

CC..

V

34 I -Form Xvlmethyl-4(4-fluorophenyfl-5--Dvndvlm-id-amzle The product of exarmple 29(b) (400 mug, 1. 13 rmol), H 2 0 (10 mQL, acetone (16' mL) and concd H2S0 4 (I mL) were combined and refluxed for 24 h. Most of the acetone was removed in vacuo and the residue was combined with 5% aq Na2CO 3 and extract~ed with EtOAc, dried (Na 2

SO

4 concentrated and ciystaliyzed from acetone to afford the title compound as a white powder (47 rup 11.55- 119.0.

1 -HvdroxvdinlmethXI.4-4-fluorophenv).54v,.d)imiaole The product of example 30 (317 mg, 1. 13 rumol), hydroxylamine hydrochloride (317 mug), pyridine (317 gQL, and EtOH (3.8 niL) were combined and refluxed for 3h, poured into 5% aq Na 2

CO

3 and extracted with EtOAc, dried (Na 2

SO

4 and flash filtered in 0 MeOH in CH 2 CI2 wo afford 261 mug of the title compound as a white powder. nip 184.0 185.0.

d 4 1 -Cyanomethyl.444-fluormphenvfl.54pvridyj)im The product of example 31 (250 rmg. 0.84 inmol), and CuSO 4 were combined and refluxed for 2h. The cooled reaction was flash filtered in 0 MeOH in CH2CL 2 to afford 129 mug of the title compound as a white powder. rup 132.0 133.0.

-r 3 44 .Momholinlpropl).(4fluoopheny)-(2methvpd4vyl),gdI a) 4-Forrmvl-2-methjVlpvrdinC 4-Cyano-2-methylpyridine was prepared from 2.6-lutidine ascccrding to the literatur procedure (Yamanak.aL; AbeR.; Sakcamoto.T.; Hidetoshi, HiranuaH.; KamatakA Chem. Pharin. Bull. 25(7). 1821 1826.). A solution of 4-Cyano-2methylpyridine (0.367 g. 3.11 rumoL) and toluene (3.5 niL) was cooled to -780 and 1 M DEBAL in hexanes (3.6 niL, 3.6 mmroL) was added dropwise via syringe pump (T -650). The reaction was warmed to 50 and stirred for 5 muin, recooled to -780 and CH3H( 3 mL) wadd<-00.warm d o5and sdfor 5 mnand thn 2 5% aqRochelle'sstwasded,sted for3min and then acidifiedto< pH aq H2S0 4 The aqueous was made basic by the addition of solid K2C03 and extracted with EtOAc. The extracts were dried (Na2SO 4 concentraed and filtered thijugh silica MeOH in CH21 2 to afford 253 mug of aldehyde. HI MR (CD3CI): d 10.05 IH), 8.74 J 7Hz, 1 7.51 IH), 7.30 I 7Hz, 1H), 2.68 3H).

b) E~ie-uoadye1-4mrhlnlpcgllmn Page(s)., 7 3 were not lodged with this application 36 chromatography with 0-8% CH 3 0H tn CH2CI2 afforded 34 mg thie title compound as a white solid. mp 186 1870.

Pyridine-4-carboxaldehyde was reacted with mcthyl-4-aminobutyr=t by the procedure of example I1(c) to afford the titde compound as a yellow oil. I H NMR (CD3CI): 6 8.69 J 5.8 Hz, 2H), 8.27 I 7.56 J 5.8 Hz, 2H), 3.70. (in, 2H); 2-31 J 8.0 Hz, 2H), 2.08. (mn, 2H1).

b) I -(3-Methoxycarbolyl- I -propyl)-4-(4- tluorophenyl)-5-(4-pyridylimidazole Following the procedure of example 1 except using the compound of the previous step as the imine afforded the title compound as a white solid mp= 69.0 70.00.

too0. 000 Examl 3 I -(3-Carboxy- I -propyO-4-(4-fluoro henyI)-(-pyiyimidazoe The compound of example 36 (100 mng, 0.29 inmol), CH 3 0H (3 mL), and THF mL) were combined and the resulting soin was treated with a soln of LiOH (62 ~.20 mg, 1.5 mniol) in H 2 0 (1.5 niL) and the resulting soin was sdtied for 4h. Removal of the volatile comnpounents in vacuo, redislving in H120 and chomatograph y through EHP-20 with H 2 0 til the eluates were neutral and then with 25% aq MeOH affordied the *eg title compound as the lithium salt; 65mg ES MS We. 326 OS.. Pyridine-4-carboxaldehyde was reacted with f -alanine methyl ester by the procedure of example 1(c) to afford the title compound as a yellow oil 11 NMR (CD3CI): 868.68 J 4.5 Hz, 2H1), 8.33 1H); 7.57 J 4.5 Hz, 2H1), 3.93 J 6.7 Hz., 2H1); 3.68 3H1). 2.76 J 6.7 Hz. 2H1), b) 1 I~CI t. Following the procedure of example I1(d) except using the compound of the previo'.s step as the izrnne afforded fte title compound as a white solid (40% [romn the amine). mp 119.0 120.00.

Exml 39 The compound of example 3 8(b) was nydrolysed by the procedure Of example 37 to afford the title compound as the lithium salt; (71 ES MS m/e 312

(MH+)

LUnR&AQ I -Benglpipejdin -4-ylI)- 4 -(4-fluoohnv 4prdi mdzl a) Pvridine=4caroxaldehyde (1--be nzylPipcerin bJimine Pyridine-4-carboxaldehyde was reacted with 4 -amio-Nbenzylpiperidjne by the procedure of example I1(c) to afford the tidle compound as a yellow oil.

b) I -BenZylpj~cridin4-v444.fluomhnI5 4 d I) im iaz& Following the procedure of example I1(d) except using the compound of example the previous step as the imine afforded the title compound as a white solid from the amine). ES MS W~e 413 ~15 u kA 2 -Arninopvrimidin-4-vfl.4(4-fluorothenyl)1--4MohIin 1Uopl 2 -Aminopvrinhidine4-carboxaldehvdle dinethyl acetal Dunethylformamide dimethyl acetal (55 niL, 0.41 mol), and pyruvic aldehyde dimethyl acetal (50 mL, 0.41 mol) were combined and heated to 1000 for 18 h. Methanol was removed in vacuo to afford an oil.

A solution of NaOH (18 g, 0.45 mol) in H 2 0 (50 mL) was added to guanidine HO (43 g, 0.45 mol) in H 2 0 (100 rnL), and the resulting solution was added to the above described oil. The resulting mixtur was stirred at 230 for 48 .25 h. Filtration afforded 25g of the title compound.

The compund of the previous step (1 .69 g, 10 mmol) and 3N HCI (7.3 mL, 22 mmol) were combined and heated to 480 for 14h, cooled, layered with EtOAc (50 niL) and neutralied by the addition of NaHCO 3 1g. 25 mmol) in small portions. The sq phase was extracted with EtOAc (5 x 50 mL) and the extracts were dried (Na2SO4)and concentrated to afford 0.793 g of the title compound.

c) 2 -Aminonvrimidine-4-carboxalde-hyde, f 3 4 -MoWhoinl~tprnpyI~imine The compound of the previous step and 4 3 -aminopropyl)morpholinewere reacted by the procedure of example 1 to afford the title compound as a yellow oil.

d) 5-( 2 -Aino~fl0Vriidin~4yl)4-(44fiorohenv1)- I -fr344- Morpholinylprogyll imidazole SB 216385 Following the procedure of example 1 except using the compound of the previous step as the imine afforded the tile compound as a white solid. IH NMR (CD3C1) 5 8.15(d. J 5.4 Hz, I 7.62(s, IH), 7.46 (dd, 2H), 7.00(t, J 8.6Hz, 2H), 6.50(d, J 5.4 Hz, I 5.09(brd.s, 2H), 4.34(t, J 7.0 H7. 2H), 3.69(m, 4H), 2.35(brd.s,4H), 2.24(t, J 4.6 Hz, 2H), 1.84(mn, 2H).

Example 42 (2-Am inonvrimidin-4-yfl-4-(4-fluorophenvl)- 1-(1 -benzvlpidin-4-vlhimidazole a) 2-Aininogyrilnidine-4-carboxaidehyde (I -benzylpiRceridin-4-vl~imine 2-Aminopyriznidine-4-carboxaldehyde and 4-aminobenzylpiperidine were reacted by the procedure of example I1(c) to afford the title compound as a yellow oil.

b) 5-(2-Arninoovrim id in-4-vI)-4(4--fluoohenvl)- 1-benZylpi~crndin-4- Following the procedure of example 1 except using the compound of the previous step as the imine afforded the title compound as a white solid (3 1% from the *amine), nip 227 -2290 (dec).

5-(2-Aniinopvrimidin-4vfl-4-(4-fluorophenfl)- 1-(2-propvflimidazole a) 2-Aminopvimidine-4-carboxaldehvde (2-oropflimine 2-Axninopyimidine-4-carboxaldehyde and 2-propyl amine were reacted by the procedure of example I1(c) to afford the title compound as a yellow oil.

b) 5-(2-Aminonwimidin4.vl)-4-(4-fluorophenyll-lI-(2-proyliMidaZ&l 25Following the procedure of example 1(d) except usinig the compound of the previous step as the imine afforded the title compound as a white solid (32% from the 2-aininopyrimidine aldehyde). mp 201 2020.

Example4 5-(2-Aniinopvrimidin-4-vl')-4-(4-fluoropthenvD)- I -(cjclnpropvlmethXI~imidykzQle 2-Amninopyriinidine-4-carboxaldehyde and 2-cyclopropylmethyl amine were reacted by the procedure of example I1(c) to afford the title compound as a yellow oil.

b) 5-(2-Aminopyimidin-4-fl-4-(4-fluoroohenvll- I-(cyclopropylmehyDmiazw& Following the procedure of example 1 except using the compound of the previous step as the imine afforded the title compound as a white solid (38% from the 2-amiropyriniidine aldehyde). mp 18~7 1880.

Example 5-(2-Aminopvrimidin-4-yl)-4-(4-flurorlhefll)- I -carbovethvl-4piperidinl)imidazole a) 2-Aminopyim idine-4-carboxaldehvde (I -carboxvethvl-4-nieridinvl)irn me 2-Aminopyrimidine-4-carboxaldehyde and I -carboxyerhyl-4-amninopiperdine were reacted by the procedure of example 1(c) to afford the tite compound as a yellow oil.

b) 5-(2-Aminopyrimidin-4-vfl-4-4fluorohenvl 1 -carboxvethy-4- VjperidinjI~midazole Following the procedure of example 1(d) except using the compound of the previous step as the imine afforded the title compound as a white solid (26% from the 2-aminopyrimidine aldehyde). mp 216 2180 (dec).

:::':Examle 46 15 Aminonvrimidin4-vfl-4-(4-fluorophenvfl--(4-Oineridinvl) imidazole i. a) 2-Aminobvrimidine-4-carboxaldehvde (1 -t-butoxvcarbonvl4aminoiaerinllimine 2-Aminopyrimidine-4-carboxaldehyde prepared in Example 41 and I-tbutoxycarbonyl-4-aminopiperidine (Mach R. etal., L Med. Chem, 36, p3707- 3719, 1993) were reacted by the procedure of example I(c) to afford the title compound as a yellow oil.

b) 544-2-Amino'vriridinyl-444flnoroheny1.- I-(l-tbutoxvyarftnvjaiadin-4=1) irnidazole ~*Following the procedure of example 1(d) except using the compound of the previous step as the imine afforded the title compound as a white solid (27% from the 2-aminopyrinmidine aldehyde).

C) 5(44-(2-Aminoavrimi di-4-4-fu(mfie luo4aa imidazole SB-220025 The compound of the previous step was combined with 4N HG in dioxane (5 mL), stired 10 min, diluted wilth EtOAc and the liquid phase was decanted. The solid was twice washed with Et 2 O (25 mL) and the liquid phase was decanted. Further triturtion with EtOH (abs) and then Et 2 O and drying in vacuo at 500 for 16 h afforded the title compound as the trihydrochioride (41 mp 265 275 (dec) Exampale 47 I -Methyl-4-phenl-5-(4-nvrimdl)imidazole Following the procedure of example 48(b) except using benzonitrile the title compound as a white solid. mp 161-1620.

1 -Methyl-4-r3-(chlorophenvl)1-5-[4-pvridinyllimidazole a) N-(4-EPyridinylmethfl)-N'-methvlformaniide To a stirring, argon-purged solution of 4-picolyl chloride..HCI 15g, 91.4 rumol) and N-methylformamide (53.4 ml, 914 mmol) in 300 ml of 77-IF at roam temperature was added portionwise over a 20 minute period a suspension of 80% NaH (5.48g, 1 83mrnol). The reaction was quenched I Sh later by the addition of ice, partitioned between methylene chloride and water, washe with water and brine, dried over MgSO4, and evaporated to dryness to afford a dark oil. Flash chromatography on silica gel provided 10.5g of the titled compounds a pale yellow oil. TLC; silica gel (9:1 CHCII MeSH) Rf 0.54.

b) I -Methvl-4-(3-(chloronhenyl)1-5-f4-pvridinvl lirnidazole To a stirred, argon-covered, -780 solution of lithium diisopropylamide 15 (hereinafter LDA), (prepared from 11.2 ml of diisopropyianiine in 150 ml of tetrahydrofuran (hereinafter THF) by the addition of 31.9 ml of 2.5M n-BuLi in hexanes) was added dropwise the product of the previous reaction (l0g, 66-5 mmol) in 100 mL of THFE Stirring of the resultant reddish-brown solution was continued at -780 for 40 min at which point 3-chiorobenzonitriie (18-3g, 133 mmol) in 100 inL THF was added dropwise over 20 min. The reaction was allowed to warm to room temperature, stirred for Ilh and heated to refiux for 12 h. The reaction was cooled and worked up in a manner similar to the previous reaction. Flash chromatography on silica gel provided 2.15g of an oil which was crystallized by dissolution with heating in 10 mL of ethyl acetate. Following crystallization, the solid was collected, washed, and dried (0.4 mm Hg) to afford 1.43g of the titled compound as a light tan solid. mp 119-12l10.

I -MethyI-4-(3-metlthiophenyfl)--(4-pvridvlhMidAZgk Following the procedure of example 48(b) except using the compound of example 13(b) as the aryl nitrile the title compound was obtained as a white solid. ES NI)S We =281 (MH+) Exam I -MethyL-4-(3-methylsulflnylphenfl-5-(4pgyndvl~imidazole Following the procedure of example 14 except using the compound of example 49 as the sulfide the title compound was obtained as a white solid. ES MIS ine 297 (MH+) Exwale 1 W(1/444-Fuoropherill)- 14 -3-(medylsulflnyl'Ipopvll-544-pvridinvflimidAzal

I

41 Following the procedure of example 14 except using the compouno irorn example I I as the sulfide and quenching with saturated aq NH40H afforded the title compound as a white solid (0.87 g, rnp 122 1230.

Exampl 4-(4-FluoroihenyJ) I -f(3-rnethvlsulfonl)nronvll- 5-(4-pnvrinyl )intidazoleC The compound of Example 51 (0.5087 g. 1.48 rnmol) was dissolved in methanol (8 ml) and cooled to 09C. The addition of trifluoroacetic acid 12 nil) was followed by the dropwise addition of meta-chloroperoxybenzoic acid (0.23 g, 2.22 mmol) dissolved in CH2CI2 (10 ml). After stirring for 1 hithe solvents were evaporated. The residue was partitioned betwe en H20 and EtOAc and the aqueous phase was made basic by the addition of 2N NaOH. The organic phase was separated, dried (MgSO4) and concentrated and the residue was pruitied by flash chromatography (silica gel, 5% MeOH/CH2CI 2 to afford the title compound (0.37 g, rup 146 1470.

To a solution of the compound from example 2(b) (0.22 g, .70 mmol) in acet nitrile (10 ml) was added K2C03 (0.19g9. 1.40 remol) and phenol 10 g. mmol). After stirring at 70rC for 24 h the reaction was diluted with H20. The organic phase was separated and cocnrtdand dhe residue was purified by flash chromatography (silica gel, 5% MCOH/CH2CI2) followed by recrystalination in hexane to afford the title compound (0.02 g, as a white solid. mp 95 960.

ExamDl Pevlo~r 1--4furnb l- (-~ddnlii-ml Following the procedure for example 3 except using thophenol as the nucleophile, adding 2.2 eq K2C03 and omitting the NaL. The cooled reaction was 30 diluted with 10% NaOH and the product was exuncted with ether. Flash chromatography was followed by re~rystaIiZaI*on from hexane to afford the title compound 13 g. 53%) as white needles. mp 98 990.

a) Qung Arboxa~1ldehyd ri IA o~on~~jpj~i Quinoyl-4-carboxaldehyde and 4-(3-aminopropyl)morpholine were reacted by the procedure of example I1(c) to afford the title compound as a yellow oil.

b) I-r3- IA LU inll IA El itinrop .tvC (A 4:.inol4~~t.Z 42 Following the procedure of example 1 except using the compound of the previous step as the irnine afforded the fidle compound as a white solid (48% from the amine). mp 139.5 140.0.

-(3-Phenvlsulfinvlpropyl)-4-(4-fluoronhenv)-5-(4-ovridinvl)imidazole Following die procedure of example 14 except using the compound from example 54 as the sulfide and quenching with saturated aq NH40H afforded the title compound as a white solid. mp 146.5 1480.

I -(3-Ethoxypropyfl- 444-fluoronhenvl)-5-(4-pyridinfliniidazole To a solution of die compound of example 2(b) (0.40 g, 1.26 mmol) in ethanol ml) 'was added sodium ethoxide (0.8 nml, 21 wt% in ethanol). After refluxing 16 h *15I the mixture was cooled, diluted with H20 and extracted with EtOAc. Concentration of the solvent and purification by flash chromatography (silica gel, 5% MeOHI CH2Cl2) afforded the title compound (0.05 g. 12 mp 85 -860.

Following the procedure for example 52 except using the compound from example 56 as the sulfoxide and rectystalizing from hexane following the chromatography afforded the title compound as white solid. mp 109 -1100.

Eample 59~ 1 -r3-(4-M~rolinl)propv1--(3-chlonphenfl-5-(4-pvddlimidahmle a) 3-hoohYj-tlihimU3s Yaif Following the procedure of example l(ab) except using 3-chlorobenzaldehyde as the aldehyde component the title compound was prepared.

b) I-r2 -IA R A f'2 CIAiua Following the procedure of example 1(d) substituting the isocyanide prepared in the previous step the title compound was prepared. MS-DCI NH3 383 Following the procedure of example 1(d) substituting the isocyanide prepared in Example 67(a) the title compound was prepared. mp 1060.

43.

4-f4-(4 -fluorophenyl)- 1 3-(4-morpholinyl)propyI 1-54-1 H-pyrLMid-2-One-4-Yl )imJidA7Ole a) 2-Methylrhiopvrimidine-4-carboxaldehvde 134(4- Following the procedure of example I1(c) except using 2-methylthiopyrzmidine-4-carboxaldehyde rflredereck H. et al. Chem, Ber, 1964.,3407) afforded the title compound as a yellow oil.

b) 4A IAlu~h 1.fi IA T'mo~phlin')DrQfxl-(lHI-Uxnud2zn Concenawae aqueous ammoniumn hydroxide (2 mL) was addto 4-(4flu robeyl)-5-[2-(uetbyisulfinyl)-4-pyrimidinylj-l-3-(4-morpholiyl)propyljimidazolc (0.14g, 0.37 mniol) [prepared in Example 63J and the reacton mixture was heated to 1500C for 18 h. After cooling to ambient temperature the *amnionium hydroxide was decanted. The re-sidue was purified by flash chromatography elating successively with 4% and 10% methanol in dichloromethane followed by succesive elutions with mixtures of9010/1 and 7W3W3 chlowafommimethanol/concenwtated ammoniumn hydroxide. Tritwadon with ether afforded the title compound as an off-white solid (0.035 S, 24%).

ESMS 384 .2 44-Rambnvl -ir-(etylhoV-nmidA llrZ- HI I =bQ bz=d Following the procedure of I1(d) except using 2-methylthiopyrimidine-4carboxaldehyde -(4-rmorpbolinyl)propyImfine [prepared in Example QUMa) afforded the tidle compound as a yelow oiL IH NMR (CDQ23) 6 8.31(d,3J= 7 Hz, IH). 7.64(s,1H). 7.46 2H), 7.05(t.,J=89 Hz, 2H1), 6.81(d, J- 5 Hz, 111). 4.42(t.

J =7.5 Hz, 2H), 3.7 1(t,3J 5Hz.4H), 2-59(s,31). 37(brd. s. 4H). 2.27(t.J 6 Hz, 2H1). 1.8S(ra. 2H1).

gle 6h3 ~MMMUiuak A solution of K2S208 (0.20 g, 0.73 nimol) in water (5 niL) was added to 4-(4-fluoropenyl)-S-[2-(mcthylthio)-4-pyriinidinylJ- 1434(4cnorphoiinyl)propyljimidazole (0.20 g. 0.48 mraol) in glacial acetic acid (10 mL).

After stirrng at ambsent temperature for 72 h, the reaction miume was poured into water, neatralimd with concentrated aqueous ammonium, hydroxide and extracted four times with dihowean.Te organi phases woe combined 44and evaporat-ed. The residue was purified by flash chromatography elur~ing, successively with 4% and 10% methanol in dichioromethane to afford the title compound as a clear oil (0.15 g, lHNMIR(CDCl3)S68.57(d, J =7 Hz, 18H), 7.77(s,1IH), 7.47 (dd, 2H1), 7.18 J 5 Hz, I H)7.09(t, IJ= 9 Hz, 2H1), 4.56(m, 2H), 3.72(t, J 5Hz, 4H), 3.00(s, 3H), 2.40(brd. s, 4H), 2-33(t, J 8 Hz, 2H), 1.94(m, 2H1).

ExamDle 4 I -Propenvl)-4-(4-fluoronhenvl)-54(4-nvridinvflinidazole a) Evridine-4-carboxaldehyde (2-nmRoevimine Pyridine-4-carboxaldehyde and 2-prope ny! amine were reacted by the procedure of exarmple I1(c) to afford the title compound as a yellow oil.

b) I -Propenvf-4-(4-fluorophenvl)-5-(4-nvridinyl)imidazole Following the procedure of example 1 except using the compound of the previous step as the iinine afforded a mixture of the title compound and 1-(2- Propenyl)-4-(4-fluorophenyl)-5-(4-pyridinyl)imidazole Chromatography of the mixture with 0 -50% EzOAc in hexanes afforded the title compound nip= 173.5 174.0 Example 6 Furthur chromatography of the mixture from example 64(b) afforded the title compound nip 116.0 -117.0 ape6 54 (2-N.N-Dimethyamino~pyrimidin-4-yl1-4 44-flunomphenv1,- I-i3-(4-morholinlY- P=rD2fizmidazole Following the procedure of example 6 1(b) except using aqueous dimethylarnine afforded the title compound as a yellow glass. ESMS 411 a) 4-trifluoromethvlplhenvl-tolylthiomethsocyanide Following the procedure of examiple I(ab) except using 4-trifluoromethylbenzaldebyde as the aldehyde component the title compound was prepared.

b) 1 -r3-(4-Morpholinyl)npyll-5-(4..pyndinfl-444-4trifluoomeihyw) phenXilimidazol The umine prepared in Example 1(c) was reacted with the isocyaruide prepared in the previous step using the procedure of example I(d) to prepare the title compound was prepared. rnp 1330.

Examl6 1- !3-(4-Morphglinvl ~prnpvll- 5 -(4-pvridiny1)-4-f3-(trifluoromechyl)phbeny11imidazole Following the procedure of example I (ab) except using 3-trifluoromethyl benzaldehyde as the aldehyde component the tide compound was prepared.

b) I -r3-(4-Mophinlrol-54-ydinII-4-(ifluoroiethXI'phenyllimiazole The irnine prepared in Examrple 1 was reacted with dhe isocyanide prepared in the previous step using the procedure of example I1(d) to prepare the title compound *was prepared. ESMS 417 [M+H] Example69 a) 3.-ihoohni-allhoetviglo Following the procedure of example 1(ab) except using 3,4-dichlorobenzaldehyde as the aldehyde component the title compound was prepared.

b) I ~AAL -Clorpiety)434chegb t-SL~A~ydnl~d Following the procedure of example 1(d) substituting the imine prepared in Example 27(a) and the isocyanide prepared Wn the prmvous step t title compound was prepared. nip 145.50.

ExampIle7 Following the procedure of Example I1(d) substituting the inine prepared in Example 27(a) and the isocyanide prepared Example 68(a) the title compound was prepared. nip 105.50.

ia=Vki71 Reaction of 4-fonnyl-2-methylpyridine (prepared in Example 33(a)) and cyclopropylmethyl amine by the procedure of example I1(c) affords the title compound as a yellow oil.

b) 1 -(Cvclooopylmethyfl-444-fluorophenfl)-5-(2-methlpvrijd-4-Mmidazole Following the procedure of example 1 except using the compound of the 46 previous step as the imine afforded the title compound was as a white solid (62% from the 2-aminopyrimidine aldehyde). mp 141.0 141.50.

Example 72 1 -3-(4-Moholinyl)ropyll-S-'4-p2ddinv imidaol a) 3-5-isrifluromthyjpenl-tolylthiomethlli nd Following the procedure of example l(ab) except using 3,S-bistrifluoromethylberzaldehyde as the aldehyde component the title compound was prepared.

b) I -f-Mo phniinyl~pronvll -5-(4-pddnvl)-4 methylphenylim idzole Following the procedure of example 1(d) substituting the imine prepared in Example 1(c) and the isocyanide prepared in the previous step the title compound was prepared. mp 136.5-137.50.

Examle- 73 5-r4-(2-Aminopyiidinvl)1-4-(4-fluonhenm 1-(2-carboxvy-22-dimethvlethl).

a) 2-Aminovrimidine-4-car oxaldehyde (ethyl 3-amino-2.-2-dimethvl- .i 20 propionatehmine 2-Aminopyrimidie-4-carboxaidebyde and ethyl 3-amino-2,2-dim ethylpropionate, were reacted by the procedure of example I(c) to afford the title compound as a yellow oil b) Cfd (2-Amino rimidinl)l-444fluo hen 1A I2-carbx :I dimthylpr=Qilmilazle Following the procedure of example 1(d) except using the compound of the previous step as the imine afforded the title compound as a white solid (11% frm the amine).

c) 5-[442-Aminovrimidinyl'1-444-fluophenfl.. 1-(2-carboxy-22dimcftletthyffimidazole lithium salt The compound of example 73(c) was hydrolysed by the procedure of example 37 to afford the title compound as the lithium salt; ES MS n/c 356.

Example 74 1-(1 -Fomyl-4-pieridinyl)-4-(4-fluomnhenfl-5-4-pvrdinynimidazole i-il-Benzylpiperidin-4yl)-4-(4-fluoropenyl)-5-(4-pyridyl)imidazole (100 mg;prepared in Example 40) was dissolved in 10% formic acid/methanol under argon and palladium black (100 mg) mixed in 10% formic acid/methanol was added. The r 47 reaction was stirred under argon at room temperature for sixteen hours. The reaction mixture was evaporated and the residue mixed in H2Oletayl acetate and the pH taken to 10. The layers were separated and the aqueous phase extracted with ethyl acetate.

The combined organic layers were evaporated and the residue was flash chrornatographed (silica gel/methylene chloride/methanol) to yield the title compound, an off-white solid. ES MS Wie 351 (MH+) 5-(2-ArninO-4-pvrimidinl-4-(4-fluorophcflfl-l1-(1 -methyl-4-gpprdinXflimidazole a) 4- Amino- I-methXvliparidifle l-Methylpiperidin-4-one (4.22 g. 37 nimol) and an ice cold soin of !N HCI in (37 mi., 37 nimol) were combined. Trituration followed by evaporation of the Et2O at 230 under a streamn of argon afforded the hydrochloride. MeOH (114 mL), anhydrou~s NH.4OAc (28.7, 373 nimol) and 3A molecular sieves were added Stirred min and then NaCNBH3 (2.33 g, 37 mmol) was added, and the mixture was stirred for h:li. Acidified to pH 1 with concentrated HCI and washed with Et,2O. The resulting mixture was made basic with 50% aq NaOH and extracted with EtOAc, died (K 2 C0 3 and distilied Obp= 55 -60 0 15 mm) to afford 3.88 g of theuitle compound.

2-Aminopyriiidine-4carboxaldehyde and the compound of the previous. step were reacted by the procedure of example I1(c) to afford the title compound as a yellow oil.

5C 1 mn~jiin.AA *I1 LA4huriEbcmk....j.I- 1 XffimidamlL Following the procedure of example 1(d) exce-pt using the compound of the previous step as the imime afforded the title compound after purification by chromatography on silica with 0 10% MeOH and 0 Et3N in CH2C1 2 followed by 22.fractional preciptation from MeOH with EL2O; as a yellow solid (20% from the amine).

nip 235 2370D (dec).

Example76 1 .(2-2-Dimety-3-morpholin-4-lIpopyl-4-(4-fluorphen1')-5-(2-Amilo-4-: pyrimidn~midazot a) N -0 -Amino -2-2-dimethvLpropylimorpholine, 2,2-dimethyl-3-N-morpholinyl propionaldehyde (CheneyLL I Amer. Chem.

Soc. 1951, 73, p685 686; 855 mig, 5.0 nimol) was dissolved in Et2O (2 niL) and I N HCO in Et2O (5 niL, 5 minol) was added. Stirred 5 min and the Et2O was evaporated in a stream of Ar. The solid was dissolved in anhydrous MeOH (15 niL) followed by anhydrous NH4OAc (3.85 g, 50 inmol), and 3A molecular sieves. Stirred 5 min and then NaCNBH 3 (0.3 14 g. 4.0 nimoL) was added. Stirred 45 muin and coned HCl was added Lil the reaction mixture was pH 1. The MeOH was removed in vacuo and the residual mixture was dissolved in H 2 0 (15 mL) and extracted with Et 2 O (25 mL). The aq phase was layered with another portion Of Et2O and made basic by addition of aq NaOH til pH 10. Extraction with Et2O (3 x 40 niL), drying (K2C0 3 and concentration afforded the title compound b) 2 -Aminopvr~imidine-4-carboxaldehvde 043-(-Morpholinvl)-2.2dimehlpbopWyllimine 2-Aminopyrimidine-4-carboxaldehyie and the product of the previous step were reacted by the procedure of example I1(c) to afford the title compound as a yellow oil C) I -(2-2-Din ehyl-3-morphoin-4-y)provl.44fluorohenvi-5(2 4 in-4 Following the procedure of example 1 except using the compound of the previous step as the imine afforded the title compound as a white solid (16% from the amine). rnp 242 -2450 (dec.).

Example 7 4-(4-Fluorophenyl)-5-44-prydfl)- 1 -(2-acetoxXvetl~midazole 500 mig of 4-(4-Fluorophenyl)-5-(4-pyridyl)iznidazole was dried at 50' C overnight in :20 vacuo and added to a flask containing 20 ml of dried (sieve) dimethyl formamnide (hereinafter DMF) and treated with NaH (at 0 then stirred at room temperature, and dropwise with 2-acetoxy ethyibromide. After three days, the mixture was poured into ice water, extracted into methycene chloride. the organic phase washed with water, dried over sodium sulfate and stripped in vacuo. Flashed the residue on silica using CH2Cl2-acetone (85:15) and eluting with increasing CH30H from 0 to 10%. Two major product fractions were obtained, the pure cuts combined to give a slower eluting fraction and a faster eluting isomer. These isomers were stripped and recrystalluzed from EtOAc-bexane to give the minor isomer (slower mov~ing) and the fast, major isomer (the titled compound). NMR (250mHz, CDCl3) shows CH2CH2 as singlet at 8 4.1 ppm, very clean, H-ortho to F. triple t at 6.9 ppm. Card C:66.60, H:4.86, N: 12.92; Found 0:67.10, 67.03 11:5.07, 4.94 N: 13.08, 13.09. JR (nujol mull) shows 1740 cm-' (sharp, ester).

MEMOQS OF REAMEN The compounds of Formula or a pharmaceutically acceptable salt thereof can be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of any disease state in a human, or other mammnal, which is exacerbated or caused by excessive or unregulated cytokine production by such mammal's cell, such as but not limited to monocytes and/or macrophages.

49 Compounds of Formula are capable of inhibiting proinflammatory cy;okines, such as IL. IL-6, L-8 and TNF and are therefore of use in therapy. IL-1, 11-6, IL-8 and TNF affect a wide variety of cells and tissues and these cytokines, as well as other leukocyte-derived cytokines, are important and critical inflammatory mediators of a wide variety of disease states and conditions. The inhibition of these pro-inflammatory cytokines is of benefit in controlling, reducing and alleviating many of these disease states.

Accordingly, the present invention provides a method of treating a cytokinemediated disease which comprises administering an effective cytokine-interfering amount of a compound of Formula or a pharmaceutically acceptable salt thereof.

In particular, compounds of Formula or a pharmaceutically acceptable salt thereof are of use in the prophylaxis or therapy of any disease state in a human, or other :'mammal, which is exacerbated by or caused by excessive or unregulated IL-I, IL-8 or TNF production by such mammal's cell, such as, but not limited to, monocytes and/or 15 macrophages.

Accordingly, in another aspect, this invention relates to a method of inhibiting the production of IL-I in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula or a pharmaceutically acceptable salt thereof 20 There are many disease states in which excessive or unregulated IL I production is implicated in exacerbating and/or causing the disease. These include rheumatoid arthritis, osteoarhritis, endotoxemia and/or toxic shock syndrome, other acute or chronic inflammatory disease states such as the inflammatory reaction induced S" by endotoxin or inflammatory bowel disease, tuberculosis, atherosclerosis, muscle degeneration, multiple sclerosis, cachexia, bone resorption, psoriatic arthritis, Reiter's ol **syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis and acute *synovitis. Recent evidence also 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 the production of TNF in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula or a pharmaceutically acceptable salt thereof.

Excessive or unregulated TNF production has been implicated in mediating or exacerbating a number of diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoisosis, bone resorption diseases, such as osteoporosis, reperfusion injury, graft vs. host reaction, allograft rejections, fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis and pyresis.

Compounds of Formula are also useful in the treatment of viral infections, where such viruses are sensitive to upregulation by TNF or will elicit TNF production in vivo. The viruses contemplated for treatment herein are those that produce TNF as a result of infection, or those which are sensitive to inhibition, such as by decreased replication, directly or indirectly, by the TNF inhibiting-compounds of Formula Such viruses include, but are not limited to HIV-1, HIV-2 and HIV-3, Cytomegalovirus (CMV), Influenza, adenovirus and the Herpes group of viruses, such as but not limited to, Herpes Zoster and Herpes Simplex. Accordingly, in a further aspect, this invention relates to a method of treating a mammal afflicted with a human immunodeficiency virus (HIV) which comprises administering to such mammal an effective TNF 0* 15 inhibiting amount of a compound of Formula or a pharmaceutically acceptable salt thereof.

o* Compounds of Formula may also be used in association with the veterinary treatment of mammals, other than in humans, in need of inhibition of TNF production.

TNF mediated diseases for treatment, therapeutically or prophylactically, in animals 20 include disease states such as those noted above, but in particular viral infections.

Examples of such viruses include, but are not limited to, lentivirus infections such as, equine infectious anaemia virus, caprine arthritis virus, visna virus, or madi virus or C retrovirus infections, such as but not limited to feline immunodeficiency virus (FIV), bovine immunodeficiency virus, or canine immunodeficiency virus or-other retroviral infections.

The compounds of Formula may also be used topically in the treatment or prophylaxis of topical disease states mediated by or exacerbated by excessive cytokine production, such as by IL-1 or TNF respectively, such as inflamed joints, eczema, psoriasis and other inflammatory skin conditions such as sunburn; inflammatory eye conditions including conjunctivitis; pyresis, pain and other conditions associated with inflammation.

Compounds of Formula have also been shown to inhibit the production of IL-8 (Interleukin-8, NAP). Accordingly, in a further aspect, this invention relates to a method of inhibiting the production of IL-8 in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula or a pharmaceutically acceptable salt thereof.

There are many disease states in which excessive or unregulated IL-8 production is implicated in exacerbating and/or causing the disease. These diseases are characterized by massive neutrophil infiltration such as, psoriasis, inflammatory bowel Li:"j" r--FI 51.

disease, asthma, cardiac and renal reperfusion injury, adult respiratory distress syndrome, thrombosis and glomei-ulonephritis. All of these diseases are associaed with increased IL-8 production which is responsible for the cheinotaxis of neutropijs into the inflammratory site. In contrast to other inflammatory cytokines (IL-i, TNF, and IL-6), IL-8 has the unique property of promoting neutrophil chemocaxis and acivation. Therefore, the inhibition of IL-8 production would lead to a direct reduction in the neutrophil infiltraton.

The compounds of Formula are administered in an amount sufficient to inhibit cytokine, in particular IL-6, IL-8 or TNF, production such that it is regulated down to normal levels, or in some case to subnormal levels, so as to ameliorate or prevent the disease state. Abnormal levels of IL-I, ML-6, IL-R or TNF, for instance in the context of the present invention, constitute: levels of free (not cell bound) IL-I, IL-6, IL-8 or TNF greater than or equal to I picogram per mil; (ii) any cell See associated IL-l1, IL-6, IL-8 or TNF; or (iii) the presence of IL-I1, UL-6. IL-8 or TNF 15 ruRNA above basal levels in cells or tissues in which EL-1, IL-6, IL-8 or TNF, respectively, is produced.

discovery that the compounds of Formula are inhibitors of cytokines, specifically IL-I, IL-6. IL-8 and TNF is based upon the effects of the compounds of Formulas on the production of the IL-, 1IL-8 and TNF in in vitro assays which are described herein.

Sao* As used herein, the term "inhibiting the production of IL- I (HL-S lb'-8 or TNF)" refers to: a) a decrease of excessive in vivo levels of the cytokine (IL-I, HL-6, IL- or Os....TNF) in ahumnan to normal or sub-normal levels by inhibition of the in vo release of the cytokine by all cells, including but not limited to monocytes or macrophages; b) a down regulation, at the genomic level, of excessive in vivo levels of the cytokine (IL-i1, IL-6, IL-S or INF) in a human to normal or sub-normal levels; c) a down regulation, by inhibition of the direct synthesis of the cytokine (IL-I1, IL-6, EL 1 -8 or TNF) as a postranslational event; or d) a down regulaton, at the translational level, of excessive in vivo levels of the cytokine (UL-i1. IL-6, IL-S or TNF) in a human to normal or sub-normal levels.

As used herein, the term 'TNF mediated disease or disease state" refers to any and all disease states in which TNF plays a role, either by production of TNF itself, or by TNF causing another monokine to be released, such as but not limited to 1L-1, IL-6 or 11L-8. A disease state in which, for instance, IL- I is a major component, and whose production or action, is exacerbated or secreted in response to ThF, would therefore be considered a disease stated mediated by TNF.

52 As used herein, the term "cytokine" refers to any secreted polypepude that atfects the functions of cells and is a molecule which modulates interactions between cells in the immune, inflammatory or hematopoietic response. A cytokine includes, but is not limited to, monokines and lymphokines, regardless of which cells produce them.

For instance, a monokine is generally referred to as being produced and secreted by a mononuclear cell, such as a macrophage and/or monocyte. Many other cells however also produce 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 referred to as being produced by lymphocyte cells. Examples of cytokines include, but are not limited to, Interleukin-1 Interleukin-6 Intrleukin-8 Tumor Necrosis Factor-alpha (TNFa) and Tumor Necrosis Factor beta (TNF-B).

As used herein, the term "cytokine interfering" or "cytokine suppressive amount" refers to an effective amount of a compound of Formula which will cause a 15 decrease in the in vivo levels of the cytokine to normal or sub-normal levels, when given to a patient for the prophylaxis or treatment of a disease state which is i exacerbated by, or caused by, excessive or unregulated cytokine production.

As used herein, the cytokine referred to in the phrase "inhibition of a cytokine, for use in the treatment of a HIV-infected human" is a cytokine which is implicated in 20 the initiation and/or maintenance of T cell activation and/or activated T cellmediated HIV gene expression and/or replication and/or any cytokine-mediated disease associated problem such as cachexia or muscle degeneration.

As TNF-B (also known as lymphotoxin) has close structural homology with TNF-a (also known as cachectin) and since each induces similar biologic responses and binds to the same cellular receptor, both TNF-a and TNF-8 are inhibited by the compounds of the present invention and thus are herein referred to collectively as "TNF" unless specifically delineated otherwise.

In order to use a compound of Formula or a pharmaceutically acceptable salt thereof in therapy, it will normally be Formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice. This invention, therefore, also relates to a pharmaceutical composition comprising an effective, non-toxic amount of a compound of Formula and a pharmaceutically acceptable carrier or diluent Compounds of Formula pharmaceutically acceptable salts thereof and pharmaceutical compositions incorporating such may conveniently be administered by any of the routes conventionally used for drug administration, for instance, orally, topically, parenterally or by inhalation. The compounds of Formula may be adm'iistered in conventional dosage forms prepared by combining a compound of Formula with standard pharmaceutical carriers according to conventional procedures. The compounds of Formula may also be administered in conventional i i ll;- i 53 dosages m combination with a known, second therapeutically active compound. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation. It will be appreciated that the form and character of the pharmaceutically acceptable character or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the Formulation and not deleterious to the recipient thereof.

The pharmaceutical carrier employed may be, for example, either a solid or 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 carrer or diluent may include time delay material well known to the art, such as glyceryl mono- :5 stearate or glyceryl distearate alone or with a wax.

15 A wide variety of pharmaceutical forms can be employed. Thus, if a solid arrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25mg. to about Ig. When a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.

Compounds of Formula may be administered topically, that is by nonsystemic administration. This includes the application of a compound of Formula (I) externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream. In contrast, systemic administration refers to 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 of inflammation such as liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, for instance from 1% to 2% by weight of the Formulation.

It may however comprise as much as 10% w/w but preferably will comprise less than w/w, more preferably from 0.1% to 1% w/w of the Formulation.

Lotions according to the present invention include those suitable for application to the skin or eye. An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to ttose for the preparation of drops. Lotions or liniments for application to the skin may also include 54an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an 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 may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy base. The base may comprise 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 as steric or oleic acid together with an alcohol such as propylene glycol or a macrogeL The Formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such 15 as lanolin, may also be included.

Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent. The resulting 20 solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100' C. for half an hour.

Alternatively, the solution may be sterilized by filtration and transferred to the container by an aseptic technique. Examples of bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), 25 benzalkonium chloride and chlorhexidine acetate Suitable solvents for the preparation of an oily solution include glycerol diluted alcohol and propylene glycoL Compounds of formula may be administered parenterally, that is by intravenous, intramuscular, subcutaneous intranasal, intrarectal, intravaginal or intraperitoneal administration. The subcutaneous and intramuscular forms of parenteral administration are generally preferred. Appropriate dosage forms for such administration may be prepared by conventional techniques. Compounds of Formula may also be administered by inhalation, that is by intranasal and oral inhalation administration. Appropriate dosage forms for such administration, such as an aerosol Formulation or a metered dose inhaler, may be prepared by conventional techniques.

For all methods of use disclosed herein for the compounds of Formula the daily oral dosage regimen will preferably be from about 0.1 to about 80 mg/kg of total body weight, preferably from about 0.2 to 30 mg/kg. more preferably from about mg to 15mg. The daily parenteral dosage regimen about 0.1 to about 80 mg/kg of total body weight, preferably from about 0.2 to about 30 mg/kg, and more preferably from agout 0.5 mg to 15mg/kg. The daily topical dosage regin:n will preferably be from 0. 1 rug to 150 mug, administered one to four, preferably two or three, times daily. The daily inhalation dosage regimen will preferably be from about 0.01 rug/kg to about 1 mg/kg per day. It willalsoberecognzed by one of silin the an that the optimal quantity and spacing of individual dosages of a compound of Formula or a pharmaceuwiAlly acceptable salt thereof will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optiumurs can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment. ie., the number of doses of a compound of Formula or a pharmaceutically acceptable salt thereof given per day for a defined number of days, can be scertained by those skilled in the art using conventional course of treatment :00,1 determination tests.

The invention will now be described by reference to the following biological oo :examples which are merely illustrative and are not to be construed as a limitation of the scope of the present invention.

The cytokine-inhibiting effects of compounds of the present invention -were determined by the following in vitro assays: :Intelenkin I (RA-) Human peripheral blood monocytes were isolated and purified from either fresh blood preparations from volunteer donors, or from blood bank buffy coats, according to 25 the procedure of Colotta eal at Immunol. 132, 936 (1984)o Thiese mponocytes (Ix 10 6 were plated in 24-well plates at a concentration of 1-2 millonlml per well. The cells were allowed to adhere for 2 hours, after which tine non-adherent cells were removed by gentle washing, Test compounds were then added to the cells for lbh before the addition of ippolysaccharide (50 nglml), and the cultures were incubated at 37 0 C for an additional 24hL At the end of this period, culture super-natants were removed and clarified of cell and all debris Culture supernatants were then immediately assayed for EL- I biological activity, either by the method of Simon at al., J. ImmunoL Methods, 84, 85, (1985) (based on ability of IL- I to stimulate a Interleukin 2 producing cell line (EL-4) to secrete EL-2, in concert with A23 187 ionophore) or the method of Lee et aL, 1. lmmunoTherapy, 6 1-12 (1990) (ELISA assay). T7he compounds of Fr.rmnula as evidenced by Examples Ito 24were shown to beinhibitors of invitro UL-I produced by human monocytes.

56 Tutmour Necrosis Factor (TNF): Human peripheral blood ruonocytes were isolated and purified from either blood bank buffy coats or plateletpheresis residues, according to the procedure of Colotta, R. et al., J Immunol, 132(2). 936 (1984). The monocytes were plated at a density of 1lx 106 cells/mi medium/well in 24-well multi-dishes. The cells were allowed to adhere for I hour after which tine the supernatant was aspirated and fresh medium (I mi. RPMI-l1640, 'Whitaker Biomedical Products, Whitaker, CA) containing 1% fetal calf serum plus penicillin and streptomycin (10 units/mi) added. The cells were incubated for 45 minutes in the presence or absence of a test compound at I nM- 10mM dose ranges (compounds were solubilized in dimethyl sulfoxidelethaol, such that the final solvent concentration in the culture medium was 0.5% dimethyl ~sulfoxide/0.5% ethanol). Bacterial lipopoly-saccharide coi 055:B5 LSJ fro Sigma Chemicals Co.) was then added (100 ng/ml in 10 mi phosphate buffered saline) cultures incubated for 16-18 hours at 37*C in a 5% CO 2 incubator. At the end of the incubation period, culture supernatants were removed from'the cells, centrifuged at 3000 rpm to remove cell debris. The supeniatant was then assayed for TN4F activity using either a radio-immuno or an ELISA assay, as described in WO 92110190 and by Becker et al., J Immunol, 1991, 147, 4307. The compounds of Formula as *.:evidenced by Examples I to 24 were shown to be inhibitors of in vitro TNF produced by human monocytes.

I- and TNF inhibitory activity does not seem to coreate with the property of the compounds of Formula in mediating arachidonic acid metabolism inhibition.

Further the ability to inhibit production of prostaglandin and/or leukotriene syn thesis, by nonsteroidal anti-inflammatory drugs with potent cyclooxygenas and/or lipoxygenase inhibitory activity does not mean that the c-ompound will necessarily also inhibit TNF or IL- I production, at non-toxic doses.

Interlaikin -8 (EL4) Primary human umbilical cord endothelial cells (HUVEC) (Cell Systems, Kirlandl, Wa) are maintained in culture medium supplemented with 15% fetal bovine serum and 1% CS-HBGF consisting of aFGF and heparin. The cells are then diluted before being plated (250p±l) into gelating coated 96-well plates. Prior to use, culture medium are replaced with fresh Medium (200pl). Buffer or test compound (2Aa ocnrtosbten1ad 0i)i hnaddt ahwUi quadruplicate wells and the plates incubated for 6h in a humidified incubator at 37 0 C in an atmosphere of 5% C02. At the end of the incubation period, supernrtant is removed and assayed for IL-8 concentration using an IL-8 EUISA kcit obtained from R&D Systems (Minneapolis, MN). All data is presented as mean value (ng/rnl) of 57 multiple samples based on the standard curve. IC50's where appropriate are generated by non-linear regression analysis.

Cytokine Specific Binding Protein Assay A radiocompetitive binding assay was developed to provide a highly reproducible primary screen for structure-activity studies. This assay provides many advantages over the conventional bioassays which utilize freshly isolated human monocytes as a source of cytokines and ELISA assays to quantify them. Besides being a much more facile assay, the binding assay has been extensively validated to highly correlate with the results of the bioassay. A specific and reproducible CSAIDT

M

cytokine inhibitor binding assay was developed using soluble cystosolic fraction from THP.I cells and a radiolabeled compound. For instance, a suitable radiolabeled compound of this CSAID T cytokine inhibitor class is 4-(Fluorophenyl)-2-(4hydroxyphenyl-3,5-t2)-5-(4-pyridyl)imidazole. In brief, the THP.I cytosol was 15 routinely prepared from cell lysate obtained by nitrogen cavitation followed by a 10 K x g low speed and a 100 K x g high speed centrifugation, the supernatant of which was designated as the cytosolic fraction. THP.l cytosol was incubated with appropriately diluted radioligand at room temperature for a pre-determined time to allow the binding to achieve equilibrium. The sample was added to a G-10 column and eluted with 20 mm TRN, 50mMb mercaptoethanol, NaN 3 The fraction encompassing the void volume was collected and the radioactivity was assessed by liquid scintillation counting. This was determined to reflect bound radioligand since the radioactive signal was abrogated by the presence of excess cold ligand in the incubation mixture or when there was no cytosolic fraction present Compounds of Formula at various doses 25 were added to the binding assay to achieve inhibition of binding of the radiolabel.

IC50s as well as Ki values were determined by regression analysis and scatchard plot analysis respectively. There is generally excellent correlation between the IC50 of compounds tested in both the binding assay and the bioassay and can be used interchangeably in many cases.

Patent Application USSN 08/123175 Lee et aL, filed September 1993 whose disclosure is incorporated by reference herein in its entirey describes the above noted method for screening drugs to identify compounds which interact with and bind to the cytokine specific binding protein (hereinafter CSBP). However, for purposes herein the binding protein may be in isolated form in solution, or in immobilized form, or may be genetically engineered to be expressed on the surface of recombinant host cells such as in phage display system or as fusion proteins. Alternatively, whole cells or cytosolic fractions comprising the CSBP may be employed in the creening protocol. Regardless of the form of the binding protein, a plurality of compounds are contacted with the binding protein under conditions sufficient to form a compound/ binding protein I I 58 complex and compound capable of forming, enhancing or interfering with said complexes are detected.

More specifically, the Binding Assay is performed as follows: MA7ET[L: incubation buffer: 20 mM Tris. I TOM MgCI 2 20 mM Hepes, 0.02% NaN3, store at 4C. Elution buffer 20 mM Tris, 50 mM 2-mercapwoethanol, NaN3, store at 4*C.

Sephadex: add 100 g Sephadex G-10 (Pharmacia, Uppsala, Sweden) to 400 rnL dd H 2 0Oand allow toswell atoomfteperature for 2hours. Decan fines and wash 3 times. Add NaN3 and qs with dd H120 to 500 raLs and store at Assemble Columns: Straw column. filter frit and tip (Kontes, SP.420160-000, 420162- 002). Lowsorb tubes (Nunc) used in binding reaction. THP.1 cytosol spun at 15000 rpm for 5 muin to clarify. THP.I cytosol prepared by hypnotic treatment of cells and ~.lysis by decompression in nitrogen. Nuclei and membrane fragments removed by differential centrifugation (10,000 g for 1 hour and 100,000 g for 1 hour).

Cmpgunds: Non-radioactive Compound I with corresponding EtOH control (dilutions made in incubation buffer) and 3 H-Compound I (dilutions in incubation buffer)

O

A. Column Preparation 1. Begin 30 ruin before anticipated elution of reaction mixture.

Add 3mL of G- 10slurryto colun for bedvol of1.5 mL 3. Rinse with? 7 L elution buffer (fill to top of column) 4. Cut columns down to size.

B. Sample Incubation 1. 15 min incubation at 4C 2. Binding reaction mixture; 100 p.L cytosol, 10 ul. cold Compound I or EtOH control, 10 pL 3 H-Compound I (molar concentration depends on nature of study).

3. Freen control 100 PiL incubation buffer in lieu of cytosol preparation.

C. Sample Elution 1 Elute 2. Add total reaction volume to G- 10 column.

3. Add 400 ptJ, elution buffer to column and discard eluate.

4. Add 500 pL elution buffer to column, collecting eluted volume in ml scintillation vial.

Add 15 mL Ready Safe scintillation fluid.

6. Vortex and count in liquid scintillation counter for 5 minutes.

59 Include a "total input counts control" (10 p.L of labeled ligand).

D. Data Analysis I. Plot DPMS as ouptut in graphic form and analyze by regression analysis and 'Lundon ligand binding" software for the determination of IC 50 and KdfVi respectively.

2. Rank order the IC5Os of the tested compounds in the bioassay and compare to that generated by the binding assay and establish a correlation curve.

The binding assay was further validated by the following criteria: THP. 1 cytosol demonstrated saturable and specific binding of the radiolabeled compoundL Preparation of 4 -(Fuoropheny)-24hydroxyphenyl3,t)5-(4-pyrjdyl)imidazole, (Compound 1).

A 2.9 mg (0.0059 mmol) portion of 2-(3.5-Dibromo-4-hydroxyphenyl).4-(4.

fluorophenyl)-5-(4-pyridyl)imidazole, Compound was dissolved in 0.95 mL of dry DMF and 0.05 mL of triethylamine in a 2.4 mL round bottom flask equipped with a small magnetic stirring bar. A 1.7 mg portion of 5% Pd/C (Engelhard lot 28845) was added, and the flask was attached to the stainless steel tritium manifold. The mixture was degassed through four freeze-pump-thaw cycles, then tnium gas (5.3 Ci, 0.091 mmol) was introduced. The reaction mixture was allowed to warm to room temperature and was stirred vigorously for 20h. The mixture was froze in liquid nitrogen, the remaining tritium gas (2.4 Ci) was removed, and the flask was removed from the manifold. The reaction mixture was transferred, using 3 x I ml. of methanol as rinsings.

into a 10 mL round bottom flask. and the solvents were remnoved by static vacuum transfer. A 1.5 niL portion of methanol was added to the residue, then removed by static vacuum transfer. The latter process was repeated.* Finally, the residue was suspended in ruL of ethanol and filtered through a syringe-tip Millipore filter (0.45 micron), along with 3 x ca- I niL ethanol rinsings. The total filtrate volume was determined to be 3.9 niL, and the total radioactivity, 94.2 mCi. Solution was determined to be 3.9 miL, and the total radioactivity, 94.2 mCi. HPLC analysis of fitrate (Partiuil 5 ODS-3, 4.6 mm LD. x cm. 1 mLmi of 70:30:01 wateriacetonitrileltrifluoroacetic acid, Radiomatic Flo-One Beta radio detector with 3 mlJmin of Ecoscint-H cocktail through a 0.75 niL cell) showed the presence of Compound I (Rt 60 mini. ca. 37% of total radioactivity), and a discrete intermediate presumed to be the moriobromo derivative Compound la (Rt 11. 8 miin. ca. The filtrate solution was evaporated to near dryness with a stream of nitrogen, and the residue was dissolved in about 1.2 mL of the HPLC mobile phase. The solution was separated by HPLC as shown below, and aie peaks corresponding 1o Compounds I and la and SB collected separately.

kiELCMethod Column Airex Ulzrasphere rumInD. x Mobile Phase 70:30:0.1 waer/amtnitrile/trifluoroaceic acid Flow Rate 5 mlimin LUV detection 21 Onr Injection Volumes 0.05 0.4 m: Retention Times 7.8 muin Compound I 24 min Compound la.

The pooled Compound I fractions totaled 32 ruL in volume and the radioactive concentration was 1.52 ruCi/ruL (total 48.6 mn Ci). The pooled'SB Compound Ia 3

H

fractions (totaling 10.1 mCi) were evaporated to dryness and the residue was transferred quantitatively into a glass vial using 3.8 niL of absolute ethanol for further analysis.

An 8 ml. (12.2 mCi) portion of Compound I was evaporated to dryness in :.:vacuo at <350C, then redissolved in 0.5 ruL of mobile phase. The whole volume was injected into the HPLC system described above, and the appropriate peak was collected. Evaporation of the collected eduate in vacuo at <3rC and transfer of the yellow residue into a vial with absolute ethanol provided a solution (3.8 mL.. 2.44 mCihmL) of Compound I. The portion of this solution used for NMR analyses was first evaporated to dryness using stream of nitrogen then taken up in CD 3

OD.

Analysis of 4-(4-Ruoropenyl)-2(4-hydroxyphenyl-3,-t2)yS.(4 pyridyl)iznidazole, Compound L Radiochemical Purity by HPLC Column Ultrasphere Octyl, 5mm, 4.6 m ID. x 25 cm, Beckman Mobile Phase 3 50:150:O.5(v/vlv) waterlacetonitrletrifluoroacetic acid Flow Rate 1 .0 m~lmin Mass detection UV at 210 tim Radioactivity detection Ramona-D radioactivity flow detector Scintillator Tru-Count (Tru-Lab Supply Co.) Flow rate 5.0 mL~min Cell volume 0.75 mL Retention time 7.7 muin Rtsul2U2 6 1' Radioactive Concentration by Scinltillain Cminting Method Scirntilator Instrument Efficiency ReuX Ready Safe (Beckman Instruments, Inc.) TM Analytic model 6581 Automated DPM calculation from quench curve 2.44 mCi/rnL SpMCActvt MassSMm Method Instrument Experiment Peak Referencing Solvent Result Cl-Mg, NH 3 reagent gas 20.0 Ci/mmol 3 H Distribution: Unlabeled 4 Single Label 43% Double LAbe 13% Brunker AM 400 Proton decoupled 3 H NMR Proton non-decoupled 3 H NM Proton non-decoupled 3 H NhM SolentPea ofmethanol al 3.3 Methanol-d 4 Tritium is incorporated exclusively on the carbon atoms ortho to aromatic hvdroxyl gun An~alWAISmmaay Raiochemnical purity determined by HPLC Radioactivity concentrtion determined by scintilation counting RCM9 99.7% 2.44 mai/mL apecuic activity aewnnuaea by mass spectrometry 20.0 Ci/mmol 3 H NMR agrees with the proposed structure Representative compounds of Formula Examples 1 to 77, but for the compound of example 2- not tested and compound of Example 72, have all demonstrated a positive inhibitory activity in this binding assay.

The above description fuly discloses the invention including prefered embodiments thereof. Modificalaons and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration, it is believed that one skld in the are can, using the preceding description, utilize the present invention to its fullest extent Therefore the Examples herein are to be construed as merely ilustrative and not a limitation of the scope of the present invention in any way. The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows.

P .OPER.M2Cfl334-94 CmV 12-69b 62 Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and v ariations such as "comprises" and "Comprising", will be undierstood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

0 a 0.0..

Claims (9)

1. A compound of the formula NHCHO R I HCHO wherein R 4 is a phenyl substituted one more times independently by fluorine, SRS, SOR 5 or halo-substituted C 14 alkyl; R 5 is hydrogen, CI 4 alkyl, C 2 4 alkenyl, C2 4 alkynyl or NR7R 1 7 excluding the moieties SR 5 being SNR 7 RI 7 and SOR 5 being SOH; R 7 and R 1 7 is each independently selected from hydrogen or C-4 alkyl or R 7 and R 1 P 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, S. sulfur or NR, Ro 1 is hydrogen or C 4 alkyl; R 12 is hydrogen or R,6; Ri 5 is R 1 o or C(Z)-C_4 alkyl; R 1 6 is C1 4 alkyl, halo-substituted-C_ 4 alkyl, or C 3 7 cycloalkyl; and Z is oxygen or sulfur.

2. The compound according to claim 1 wherein the R 4 phenyl is substituted by fluorine.

3. The compound according to claim 2 wherein the phenyl is substituted in the 4- position.

4. The compound according to Claim 1 wherein the R 4 phenyl is substituted by SR 5 or S(O)R

5 P:\OPERXPDB\2209391.239 27/8Y99 The compound according to claim 4 wherein R, is a C,- 2 alyl. S

6. The compound according to claim 5 wherein the phenyl is substituted in the 4- position.

7. The compound according to claim 1 wherein the R 4 phenyl is substituted by CF 3

8. The compound according to claim 7 wherein the phenyl is substituted in the 4- position. DATED this 4 day of February 2002 SmithKline Beechanm Corporation by DAVIES COLLISON CAVE Patent Attorneys for the Applicant C C*

9* C