NZ302117A

NZ302117A - 1-cycloalkyl or cycloalkylalkyl 4,5-trisubstituted imidazole derivatives and medicaments

Info

Publication number: NZ302117A
Application number: NZ302117A
Authority: NZ
Inventors: Jerry Leroy Adams; Ravi Shanker Garigipati; John Cheung-Lun Lee
Original assignee: Smithkline Beecham Corp
Priority date: 1995-01-12
Filing date: 1996-01-11
Publication date: 1999-10-28
Also published as: CZ219597A3; MX9705296A; AU709370B2; FI972970A0; WO1996021654A1; BR9607097A; FI972970A; HUP0102677A3; JPH10512264A; EP0802908A4; NO973231D0; KR19980701374A; NO973231L; EP0802908A1; HUP0102677A2; AU4770496A; CA2210322A1; PL321292A1

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 302117 New Zealand No 302117 International No PCT/US96/01094 TO BE ENTERED AFTER ACCEPTANCE AND PUBLICATION Priority dates 12 01 1995,18 01 1995,07 06 19095, Complete Specification Filed 11 01 1996 Classification (6) C07D401/04, C07D403/04,14, C07D413/14, A61K31/44,47,415,505 Publication date 28 October 1999 Journal No 1445 HO DRAWINGS NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION Title of Invention Novel compounds Name, address and nationality of apphcant(s) as in international application form SMITHKLINE BEECHAM CORPORATION, 1 Franklin Plaza, Philadelphia 19103, Pennsylvsnia, United States of America WO 96/21654 PCT/US96/01094 5 NOVEL COMPOUNDS This invention relates to a novel group of imidazole compounds, processes lor the preparation thereof, the use thereof in treating cytokine mediated diseases and 10 pharmaceutical compositions for use in such therapy BACKGROUND OFTHE INVENTION Interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF) are biological substances produced by a variety of cells, such as monocytes or macrophages IL-1 has been 15 demonstrated to mediate a variety of biological activities thought to be important in immunoregulation ana other physiological conditions such as inflammation [See, e g , Dinarello et al Rev. Infect. Disease. 6.51 (1984)] The mynad of known biological activities of IL-1 include the activation of T helper cells, induction of fever, stimulation of prostaglandin or collagcnase producuon, neutrophil chemotaxis, induction ot acute 20 phase proteins and the suppression of plasma iron levels There are many disease states in which excessive or unregulated IL-1 production is implicated in exacerbating and/or causing the disease These include rheumatoid arthritis, osteoarthritis endotoxemia and/or toxic shock syndrome other acute or chronic inflammatory disease states such as the inflammatory reaction induced by 25 endotoxin or inflammatory bowel disease, tuberculosis atherosclerosis, muscle degeneration cachexia, psoriatic arthritis, Reitcr's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthrius, and acute synovitis Recent evidence also links IL-1 acuvity to diabetes and pancreatic B cells Dinarello, J, Clinical Immunolopv. 5 (5), 287-297 (1985), reviews the biological 30 activities which have been attributed to IL-1 It should be noted that some ol these effccts have been described by others as indirect eltects of IL-1 13 12 13 WO 96/21654 -2- PCT/US96/01094 Excessive or unregulated TNF producuon has been implicated in mcdiaung or exacerbating a number of diseases including rheumatoid arthritis, rheumatoid spondylius osteoarthritis, gouty arthritis and other arthritic conditions, sepsis, sepuc shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory 5 distress syndrome cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoisosis, bone resorption diseases, repcrfusion injury, graft vs host reacuon. allograft rejecuons, 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 formauon, 10 scar ussue lonmauon, Crohn's disease, ulcerative colitis, or pyresis AIDS results from the infection of T lymphocytes with Human Immunodeficiency Virus (HIV) At least three types or strains of HIV have been identilied i e , HIV-1, HIV-2 and HIV-3 As a consequence of HIV infccuon, T-cell mediated immunity is impaired and infected individuals manifest severe opportunisuc 15 intecuons and/or unusual neoplasms HIV entry into the T lymphocyte requires T lymphocyte activation Other viruses, such as HIV-1, HIV-2 infect T lymphocytes alter T Cell activation and such virus protein expression and/or replication ts mediated or maintained by such T cell activation Once an acuvated T lymphocyte is infected with HIV, the T lymphocyte must continue to be maintained in an activated state lo permit 20 HIV gene expression and/or HIV replicauon Monokines, specifically TNF, are implicated in activated T-cell mediated HIV 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, m an HIV-iniected individual aids in limning the maintenance of T cell activauon, thereby 25 reducing the progression of HIV infecuvily to previously uninfected cells which results in a slowing or elimination of the progression of immune dysfunction cau<icd by HIV infection Monocytes, macrophages, and related cells, such as kupffer and glial cells, have also been implicated in maintenance of the HIV infecuon These cells, like T-cells, are targets for viral replicauon and the level of viral replication is dependent 30 upon the activation state of the cells [ See Rosenberg et al , The Immunopathogenesis of HIV Infection. Advances in Immunology Vol 57, (1989)] Monokines, such as TNF ha\e been shown to activate HIV replication in monocytes and/or macrophages [See Poll et al. Proc Natl Acad Sci , 87 782-784 (1990)), therelore, inhibition ol monokine production or activity aids in limning HIV progression as stated above for 35 T-cells TNF has also been implicated in various roles with other viral mfecuons, such as the cyuimegali j virus (CMV) influenza virus and the herpes virus for similar reasons as those noted 13 12 13 wo 96/21654 pct/us96/01094 L ' Interleukin-S (XL-S) is a chemotactic tactor iirst identified and characterized in 1987 IL-8 is produced bv several cell tvpes including mononuclear cells fibroblasts endothelial cells and keratinocvtes Us production lrom endoiheh.il cells is induced b\ IL-1,TNF, or hpopolvsachhande (LPS) Human IL-S has been shown to acton Mouse 5 Guinea Pic Rat and Rabbit Neutrophils Manv ditterent names ha\e been applied to IL-S such as neutrophil attractant/acuvation protein-1 (\'A.P-1) monocyte derived neutrophil chemotactic lactor (MDNCF) neutrophil activating lactor (NA.F) and T-cell lymphocyte chemotacuc tactor IL-8 stimulates a number ol tunctions in vitro It has been shown to ha\e 10 chemoattractant properties tor neutrophils T-lymphocvtes and basophils Inaddiuonit induces histamine release lrom basophils trom both normal and atopic individuals as well as K sozomal enzyme release and resptrator\ burst trom neutrophils IL-8 has also been shown to increase the surlace expression ot Mac-1 (CD1 lb/CD 18) on neutrophils without de novo protein synthesis this may contribute to increased adhesion ot the 15 neutrophils to vascular endothelial cells Manv diseases are characterized bv massive neutrophil infiltration Conditions associated with an increased in IL-8 production (which is responsible for chemotaxis ot neutrophil into the inflammatory sue) would benefit by compounds which are suppressne of IL-S production IL-1 and TNF allect a wide variety ol cells and tissues and these cvtokanes as 20 well as other leukocyte derived cytokines are important and critical inflammatory mediators ot a wide variety ot disease states and conditions The inhibition ot these cytokines is ot benefit in controlling reducing and alleviating manv of these disease states There remains a need tor treatment, in this field tor compounds which are 25 cytokine suppressive anii-tnfiammatorv drugs le compounds which are capable ot inhibiting cytokines such as IL-1 IL-6 IL-8 and TNF SUMMARY OF THE INVENTION This invention relates to the novel compounds of Formula (I) and i0 pharmaceutical compositions comprising a compound ot Formula (I) and a pharmaceutical^ acceptable diluent or earner This invention also provides a method ot inhibiting cytokines and the tieatment ot a cytokine mediated disease in a mammal in need thereot which comprises administenng to said mammal an elective amount ot a compound of Formula (I) "o This invention more specifically provides a method ol inhibiting the producuon ot IL-1 in a mammal in need thereot which comprises administering to said mammal an etlecuve amount ot a compound ot Formula (I) WO 96/21654 -4- <«sr( pctajs96/0109-1 Thi<> invention more specilically provides a method ol inhibiting the pioduction ol IL-S in a mammal in need thereot which comprises administenng to said mammal an etlecuve amount ot a compound of Formula (I) This invention more specifically provides a method ol inhibiting the production 5 oi TNF in a mammal in need thereot which comprises administenng to said mammal an etiective amount ot a compound of Formula (I) 10 Riis4-pvndyl p\nmidinvl quinolvl isoquinohnyl quinazohn-4-yI 1-imidazolvl or l-ben7imidazolyl which ring is optionally substituted with one or two subsutuents each ot which is independently selected trom C 1.4 alkyl halogen hvdroxyl C]-4 alkoxy, Ci-4 alkvlthio C ]-4 alkvlsullinyl CH2OR12 amino mono and di- C1-6 alkvl substituted amino N(R io)C(0)Rc or an N-heterocvclvl ring which ring has 15 trom 5 to 7 members and optionally contains an additional heteroatom selected trom oxygen sulfur or NR]5 R4 is phen\ 1 naphth-1 -vl or naphth-2-yl or a heteroaryl which is optionally substituted bv one or two subsutuents, each ot which is independently selected and which tor a 4-phenvl 4-naphth-l-vl, 5-naphth-2-yl or 6-naphth-2-vl substitiuent is halogen 20 cvano nitro -C(Z)NR7Rn -C(Z)ORi6. -(CRioR20)vCOR 12 -SR5, -SOR5 -OR12, halo-substituted-Ci-4 alkyl, C1-4 alkyl -ZC(Z)Ri2 -NRioC(Z)Ri6 or -(CR ioR20)vNR 10R20 ^id which, tor other positions of substitution is halogen cvano -C(Z)NRi3Ri4 -C(Z)OR3,-(CRioR2t))m"COR3,-S(0)mR3,-OR3 halo-substituted-Ci-4 alkvl -C1-4 alkyl, -(CRioR20)m"NRioC(Z)R3 -NRioS(0)m'R8, 25 -NR]0S(O)m'NR7Ri7 -ZC(Z)R3 or -(CR]oR20)m"NRl3Rl4-v is 0, or an integer having a value of 1 or 2 m is 0, or the integer 1 or 2 nV is an integer having a value ot 1 or 2, m" is 0 or an integer having a value ol 1 to 5 30 Rc is hydrogen Ci-fialkvl Cv7cycloalkyl arvl,arylCi^ alkyl, heteroaryl heteroarvlCi-4alkvl heterocvclvl or heterocvclvlC i-4alkvl C 1.4 alkyl R2 is an optionally substituted C3-7 cycloalkyl, or C3.7cycloalkvlC1.10 alkyl R3 is heterocvciyl, hetcrocyclylCi-io alkyl or Rg, R5 is hvdrogen C1-4 alkyl C2-4 alkenyl, C2-4 alkynyl or NR7R17 excluding the 35 moeities -SRs being -SNR7R17 and -SOR5 being -SOH (I) wherein wo 96/21654 - 5 R7 and R17 is each independently selected from hydrogen or C \ -4 alkyl or R7 and R17 together with the nitrogen to which they are attached form a heterocyclic nng ot 5 to 7 members which nng optionally contains an additional heteroatoin selected trom oxygen sulturor NR15, 5 Rr isCi-10 alk\l halo-substituted Cl-io alkvl, C2-10 alkenyl, C2-10 alkvnvl C3-7 cycloalkyl C5-7 cycloalkenvl, arvl, arylCl-ioalkyl, heteroarvl heteroarvlCi-10 alkvl (CRioR20)nORil,(CRioR20)nS(0)mRi8, (CRlOR20)nNHS(0)2Rl8. (CRioR20)nNR 13R14, wherein the arvl arylalkyl, heteroarvl heteroarvl alkyl may be optionally substituted 10 n is an integer having a value ol 1 to 10, Ry is hvdrogen -C(Z)Ri ] or optionally substituted Ci -10 alkyl S(0)2R-18 opuonalh substituted arvl or optionally substituted aryl-Ci-4 alkyl, RlO and R20 is each independently selected trom hydrogen or C1-4 alkvl R1 1 is hvdrogen or R1 s 15 R12 is hvdrogen or R16 Rl3 and R]4iseach independently selected from hvdrogen or optionally substituted C1 -4 alkyl optionally substituted arvl or optionally substituted arvl-C 1 -4 alk\ 1, or together with the nitrogen which they are attached torm a heterocyclic ring ot 5 to 7 members which nng optionally contains an additional heteroatom selected trom 20 oxygen sultur or NR9 R15 is hvdrogen C1 -4 alkvl or C(Z)-C 1.4 alkyl R16 is C ] _4 alkvl halo-substituted-Ci-4 alkyl or C3 7 cycloalkyl, RlS is Ci-io alkyl C3-7 cvcloalkvl heterocvclvl, arvl arylCj-io alkyl heterocvclyl neternv. v1 vl Ci -1o^lkyl heteroarvl or heteroarvlalkvl 25 Z isowucn or a pnarmacsuucalK acceptable salt thereot DETAILED DESCRIPTION OF THE INVENTION The novel compounds of Formula (I) mav also be used in association with the vetennarv treatment ot mammals, other than humans, in need ot inhibition ot cytokine 30 inhibition or production In particular cytokine mediated diseases tor treatment, therapeutically or prophvlactically in animals include disease states such as those noted herein in the Methods of Treatment section, but in particular viral infections Examples ot such viruses include but are not limited to, lentivirus intections such as. equine intectious anaemia virus capnne arthritis virus, visna virus or maedi virus or retrovirus intections 35 such as but not limited to teline immunodeficiency virus (FTV), bovine immunodeficiency virus or canine immunodeficiency virus or other retroviral intections In Formula (I) suitable R1 moieties includes 4-pyndyl, 4-pyrimidmyl 4- quinolyl 6-isoquinolinyl 4-qumazohnyl 1-imidazolyl and 1-benzimidazolyl ot which | ''JTLLLCCIL'/. rno~iiRiy*oFricLl CF 111 2 0 AUG 1399 ! _,_RE ££l VE ^ rp.ct/us96/01094 4( v wo 96/21654 pct/us96/01094 -6- ihe 4-pyndyl. 4-pynmidinyl and 4-quinolyl are preferred More prelerred is an optionally subsututed 4-pynmidinyl or optionally substituted 4-pyridyl moiety and most preferred is an optionally subsututed 4-pyrimidinyl nng Suitable subsutuents for the R] heteroaryl rings are Cj.4 alkyl, halo, OH, Cj-4 5 alkoxy, C]_4 alkylthio, C]-4 alkylsulfinyl, CH20R]2, ammo, mono and di-C].6 alkyl substituted amino, N(R]0)C(O)Rc, or an N-heterocyclyl nng which nng has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sullur or NR15 A preferred subsutuent for all the R1 moieues is C1-4 alkyl, in particular methyl, amino, and mono- and di-Cj.fi alkylsubstituted amino, preterably 10 where the amino group is mono-substituted, more preferably with methyl The alkyl gioup in the mono- and di-Cj.fi alkylsubstituted moiety may be halo subsututed, such as in tnfluoro- 1 e , tnfluoromethyl or triflurocthyl When the R] optional subsutuent is N(R]o)C(0) Rc, wherein Rc is hydrogen, C1 alkyl 7 cycloalkyl, aryl, arylC]-4 alkyl, heteroaryl, heteroarylC | -4alkyl, 15 hetcrocyclyl or heterocyclic i-4alkyl C1.4 alkyl, Rcis preferably Ci-6 alkyl, preferably R]() is hydrogen It is also recognized that the Rc moieues, in particular the C|-6 alkyl group may be optionally substituted, preferably from one to three times, preterably with halogen, such as fluonne, as in tnfluoromethyl or trifluroethyl Preferably, the preferred subsutuent for R) is the amino or mono C|.^ alkyl 20 substituted moiety A preferred nng placement ol the R \ substituent on the 4-pyndyl derivative is the 2-position, such as 2-methyl-4-pyndyl A preferred nng placement on the 4-pynmidinyl nng is also at the 2-posiUon, such as in 2-methyl-pynmidinyl, 2-ammo pynmidinyl or 2-methylarmnopynmidinyl Suitably, R4 is phenyl, naphth-l-yl or naphth-2-yl, or a heteroaryl. which is 25 optionally substituted by one or two subsutuents More preferably R4 is a phenyl or naphthyl nnp Suitable subsututions for R4 when this is a 4-phenyl, 4-naphth-1 -yl 5-naphth-2-yl or 6-naphth-2-yl moiety are one or two subsutuents each of which are independently selected from halogen, -SR5, -SOR5, -OR 12. CF3, or -(CRioR20)vNR 10^20. 2111:1 f°r ol^er positions ol substituuon on these nngs preferred 30 substitution is halogen, -S(0)mR3, -OR3, CF3, -(CRioR20)m"NRi3R]4t -NRjoC(Z)R3 and -NRl0S(O)m'R8 Preferred subsutuents for the 4-position in phenyl and naphth-l-yl and on the 5-position in naphth-2-yl include halogen, especially fluoro and chloro and -SR5 and -SOR5 wherein R5 is preterably a Cj-2 alkyl, more preferably methvl ol which the fluoro and chloro is more preferred, and most especially prelerred is 35 fluoro Preferred subsutuents for the 3-posiuon in phenyl and naphth-l-yl nngs include halogen, especially fluoro and chloro, -OR3, especially Ci-4 alkoxy, CF3, NR10R20. such as amino, -NRioC(Z)R3, especially -NHC0(C|. 10 alkyl), -NRioSCOJm'Rg. especially -NHSO2(Ci-]0 alkyl), and -SR3 and -SOR3 wherein R3 is preferably a C j.2 13 12 13 wo 96/21654 /*>. o pctajs96/01094 I '' - 7 - I alkyl, more prelerablv meihvl When the phenvl ring is disubsututed preierabh it is iwo independent halogen moieues, such as fluoro and chloro preterably di-chloro and more preterably in the 3 4-posuion It is also prelerred that lor the 3-posiuon ol both the -OR^ and-ZC(Z)R3 moietues, R3 may also include hvdrogen 5 Prelerablv the R4 moiety is an unsubsututed or substituted phenyl moiety More prelerablv R4 is phenyl or phenyl subsututed at the 4-position with fluoro and/or substituted at the 3-posiuon with fluoro, chloro, C1-4 alkow methane-sulfonamido or acetamido or R4 is a phenvl di-substituted at the 3 4-position independentiv with chloro or fluoro more preleraolv chloro Most prelerablv R4 is a 4-fluorophenvl 10 Suitablv R2 is an opuonallv substituted C3-7cvcloalkvl or an optionallv substituted C3-7Cvdodlkvl Ci-io alkyl Prelerablv R2 is a C3-7cycloalkyl ol which the cvcloalkyl group is prelerablv a C4-7 nng more prelerablv a C4 or C6 ring most prelerablv a C^ ring, which nng is optionally subsututed 15 The C3-7cycloalkyl nng may substituted one to three times independentiv by halogen such as fluorine, chlorine, bromine or iodine hvdroxv C[-ioalkoxv such as methoxy or ethoxy S(0)m alkvl wherein m is 0 l,or2 such as methyl thio methylsulfinvl or methvl sulfonyl S(0)m aryl cyano nitro amino mono & disubsiituted amino such as in the NR7R17 group, wherein R7 and R j7 are as delined in 20 Formula (I) or where the R7R17 may cyclize together with the nitrogen to which thev are attached to form a 5 to 7 membered nng which optionally includes an additional heteroatom selected lrom oxygen, sullur or NR15 (and R15 is as delined tor Formula (I)) N(Rio)C(0)Xi(wherein Rio is as delined lor Formula (I)), and X1 is C].4 alkvl an 1 or arvlC 1-4alkvl) N(Rio)C(0) aryl C1 _ 10 alkyl such as methyl ethyl propvl 2s isopropyl or t-butvl, optionally substituted alkyl wherein the subsutuents are halogen (such as CF3), hydroxy nitro, cyano amino mono & di-substituted amino such as in the \R7R 17 group, S(0)m alkyl and S(0)m aryl wherein m is 0, 1 or 2 optionally substituted Cj-ioalkylene such as ethylene or propylene opuonally substituted Ci-io alkvne such as acetylene (ethvnvl) or 1-propynvl C(0)0R] j (wherein Ri 1 is as 30 defined in Formula (I)), such as the free acid or methyl ester derivative the group Rd -C(0)H =0 =N-OR] 1, -N(H)-OH (or substituted alkyl or arvl derivatives thereot on the nitrogen or the oxime moiety),-N(0Rb)-C(0)-R6 oxirane an optionally subsututed aryl such as phenvl an opuonally subsututed arylCi-4lkyl such as benzvl or phenethyl an opuonallv substituted heterocvcle or heterocyclic Ci-4alkyl and further 35 these aryl arvlalkvl heterocyclic and heterocyclic alkyl moieties are opuonallv subsututed one to two times by halogen hydroxy, C1 _ 10 alkoxv S(0)m alkyl cvano nitro amino, mono & di-substituted amino such as in the NR7R17 group an alkyl, halosubstituted alkyl INTELLLl', ^ CuU OfF/cF5 JjlmLlCiu 1 .1, .'LnlYOFFiccT 1 u' nz j or ui 3 bL? 1239 ~-S-Srr-!939~ WO 96/21654 -8- PCT/US96/01094 Suitably Ra is a 1,3-dioxyalkyIene group of the lormula -0-(CH2)s-0-, wherein s is 1 to 3, preferably s is 2 yielding a 1,3-dioxyethylene moiety Suitably Rfc is hydrogen, a pharmaceuUcally acceptable cauon, aroyl or a C]-io alkanovl group 5 Suitably Rfi is NR19R2] , alky] j.fi, halosubstituted alkyl ]-6. hydroxy subsututed alkyl j.fi alkenyl 2-6. ary' Qr heteroaryl optionally substituted by halogen, alkyl 1-6, halosubsututed alkylj-6. hydroxyl, or alkoxy ]-6 Suitably Rj9 is H or alkyl 1-6 Suitably R21 is H, alkyl aryl, benzyl, heteroaryl, alkyl substituted by 10 halogen or hydroxyl or phenyl substituted by a member selected from the group consisting of halo, cyano, alkyl j_i2i alkoxy j.g, halosubstituted alkylj.fi alkyllhio, alkylsulphonyl, or alkylsulfmyl, or Rjg and R21 may together with the nitrogen 10 which they are attached form a nng having 5 to 7 members, which members may be optionally replaced by a heteroatom selected from oxygen, sulfur or nitrogen The ring 15 may be saturated or contain more than one unsaturated bond Prelerably R6 is NR19R21 and Rjy and R21 are preferably hydrogen When the R2 moiety is subsututed by NR7R17 group, or NR7R17 C1 -10 alkyl group, and the R7 and R17 areas defined in Formula (I), the subsutuent is preferably an amino, amino alkyl, or an opuonally substitued pyrrohdmyl moiety 20 A preferred nng placement on the cyclohexyl nng, particularly when it is a Cfi nng, is the 4-position When the cyclohexyl ring is disubsututed it is preferably disubsututed at the 4 position, such as in 25 wherein R'* and R^' are independently the optional subsututents indicated above for R2 Preferably, R' and R- are hydrogen, hydroxy, alkyl, substituted alkyl, optionally substituted alkynyl, aryl arylalkyl, NR7R17, and N(Riq)C(0)Ri 1 Suitably, alkyl is C]-4 alkyl, such as methyl, ethyl, or isopropyl, NR7R17 and NR7R17 alkyl, such as amino, methylamino, aminomethyl, ammoethyl, substituted alkyl such as in 30 cyanomethyl, cyanoethyl, mtroethyl, pyrrolidinyl, optionally subsututed alkynyl, such as propynyl or ethynyl aryl such as in phenyl, arylalkyl, such as in benzyl, or together R'' and R2' are a kcto lunctionality As used herein, "optionally subsututed" unless specifically defined herein, shall 35 mean such groups as halogen, such as fluorine, chlonne, hromme or iodine, hydroxy, 1312 13 wo 96/21654 pct/us96/0109-i -9- hydroxy substituted Ci-ioalkyl Ci_iO aJkoxy, such as methoxy orethoxy S(0)m alkyl. wherein m is 0, 1 or 2, such as methyl thin, methylsulfinyl or methyl sulfonyl amino, mono & di-subsututcd amino, such as in the NR7R]7 group, or where the R7R 17 may together with the nitrogen to which they are attached cychzc to form a 5 to 5 7 membered ring which optionally includes an additional heteroatom selected from O/N/S Ci-io alkyl, cycloalkyl, or cycloalkyl alkyl group, such as methyl, ethyl, propyl, isopropyl t-butyl, etc or cyclopropyl methyl halosubstituted Cm0 alkyl, such CF3, an optionally substituted aryl, such as phenyl, or an optionally subsututed arylalkyl, such as benzy! or phenethyl, wherein these aryl moieues may also be 10 substituted one to two umes by halogen, hydroxy, hydroxy subsututed alkyl, Cj-jo alkoxy, S(0)m alkyl, amino, mono & di-substituted amino, such as in the NR7R17 group alkyl, or CF3 In a prelened subgenus of compounds of Formula (I), Ri is 4-pyridyl, 2-alkvM-15 pyndyl, 4 pyrimidinyl, 2-ammo-4 pynmidinyl or 2-methylamino-4-pynmidinyl, R2 is an optionally subsumed C4 or Cfi cycloalkyl and R4 is phenyl or optionally subsututed phenyl In a more preferred subgenus R4 is phenyl or phenyl substituted one or two times by fluoro chloro, Cj-4 alkoxy, -S(0)m alkyl, methanesulfonamido or acetamido, R2 is cyclohexyl subsututed by methyl, phenyl, benzyl amino acetamide, aminomcthyl, 20 aminoethyl, cyanomethyl, cyanoethyl, hydroxy, mtroethyl pyrrohdinyl, ethynyl, 1-propynyl, =0, 0-(CH2)20-, =NORi ], wherein R l j is hydrogen, alkyl or aryl NHOH, or N(0H)-C(0)-NH2. and Ri is a 4-pynmidmyl moiety, opuonally substituted by amino, or mcthylamino or R] is a 4-pyndyl opuonally subsututed by methyl 25 Suitable pharmaceutical^ acceptable salts arc well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochlonc acid, hydrobromic acid, sulphunc acid, phosphonc acid, methane sulphonic acid, ethane sulphoruc acid aceuc acid, malic acid, lartanc acid, cunc acid lactic acid, oxalic acid, succinic acid, lumanc acid, maleic acid, benzoic acid, salicylic acid, phenylaceuc acid 30 and mandehc acid In addition, pharmaceuucally acceptable salts of compounds of Formdla (I) mav also be formed with a pharmaceutical^ acceptable cauon, for instance, if a subsutuent croup compnses a carboxy moiety Suitable pharmaceuucally acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth ammonium and quaternary ammonium cauons 35 The following terms, as used herein, refer to • "halo" or "halogens", include the halogens chloro, fluoro, bromo and lodo 13 12 13 WO 96/21614 - 10- PCT7US96/010SM • "C].ioalkyl" or "alkyl" - both straight and branched chain radicals ol 1 to 10 carbon atoms, unless liic cliain length is otherwise limned, including, bui not limited lo, methyl, eihyl n-propyl m>-prupyl n-butyl, sec-butyl, no-butyl rer/-butyl. n-penlyl and the like 5 • The term "cycloalkyl" is used herein to mean cyclic radicals, preferably of 3 to 8 carbons, including but not limited to cyclopropyl, cyclopentyl, cvclohexyl, and the like • The term "cycloalkenyl" is used herein to .nean cyclic radicals, preferably of 5 to 8 carbons which have at least one bond including but not limited to cyclopentenyl, 10 cyclohexenyl and the like • The term "alkenyl" is used herein at all occurrences to mean straight or branched chain radical of 2-10 carbon atoms, u iless the chain lengtn is limited thereto, including, but not limned to ethenyl 1-propenyl, 2-k openyl, 2-methyl-l-propenyl, 1-butenvl 2-butenyl and the 111 e 15 • "aryl" - phenyl and naphthyl, • "heieroaryl" (on its own orm any combination, such as "heteroaryloxy", or "heteroaryl alkyl") - a 5-10 membered aromatic nng system in which one or more nngs contain one or more heteroatoms selected trom the group consisting of N 0 or S, such as but not limited, to pyrrole, pyrazole, furan, thiophene, quinohne, isoquinoline, 20 quinazolinyl, pyridine, pynmidine oxazolc, thiazolc, thiadiazole, tnazole, imidazole, or bcnzimidazolc • "heterocyclic" (on its own or in any combination, such as "heterocyclylalkyl") - a saturated or partially unsaturated 4-10 membered ring system in which one or more nngs contain one or more heteroatoms selected from the group consisung ot N, O, or S. 25 such as but not limited to, pyrrolidine, pipendine, piperazine, morphohne, tetrahydropyrau it imidazolidine • The term "aralkyl" or "heteroarylalkyl" or "hetcrocychcalkyl' is used herein to mean Cm alkyl as defined above attached to an aryl, heieroaryl or heterocyclic moiety as also defined herein unless otherwise indicate 30 • "sulfinyl" - the oxide S (O) of the corresponding sulfide, the term "thio" refers to the sulfide and the term "sulfonyl" refers lo the fully oxidized S(0)2 moiety • "aroyl" - a C(0)Ar, wherein Ar is as phenyl, naphthyl, or aryl alkyl denvative such as defined above, such group include bu« are no'e limited to benzyl and phenethyl • "alkanoyl" - a C(0)Ci-io alkyl wherein the alkyl is as defined above 35 It is recognized that the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms All ot these compounds are included within the scope of the present invention 13 1213 WO 96/11654 PCT/US96/01094 - I 1 - Exemplified compounds of Formula (1) mdudc 5 (2 dmino-4-pynmidinyl)-4-(4-nuorophenyl) 1-(4-(l,3-dioxycvclopentyl) cyclohexyl) imidazole, 5 5 (2-ainmo-4-pynmidinyl)-4-(4-fluoroplienyl)-l-(4-ketocyclohexyl)imidd2ole, 5-(2-amino-4-pynmidinyl)-4-(4-fluorophenyl)-l -(4-cyclohexyl oxime) imidazole, 5-(2-anuno-4-pynmidinyl)-4-(4-fluorophenyl)-1 -(4-cyclohexyl hydroxylarnine) imidazole, 5-(2-aniino-4-pyniTiidinyl)-4-(4-fluorophcnyD-l-(r7wu-4-hydroxyurcd) imidazole, 10 5-(2 amino-4-pynmidinyl)-4-(4-fluorophenyl)-l-(c/j-4-hydroxyurea) imidazole, 5-(2-amino-4-pynmidinyl)-4-(4-flunrophcnyl)-l-(4-hydroxycyclohexyl)imidazole, 5-[4-(2-N-methylamino)pynmidinyl]-4-(4-fluorophenyl)-l-(4-ketocvclohexyl)-lmidazole, 5-|4-(2-N-methyldnun(>)pynmidinyl]-4-(4-flunrophcny])-l-(rram-4-hydroxy-15 cyclohexyl)imidazoIc, 5-[4-(2-N-methylamino)pynmidinyl]-4-(4-fluorophenyl)-l-(m -4-hydroxy- cyclohexyDimidazole, 5-[4-(2-N-Mcthylamino)pynmidinyl]-4-(4-fluorophcnyl)-l-[4-(m-pyrTohdinyl)-cyclohexyl]imidazole, 20 5-(4-(2-N-methyIamino)pyrimidinyl]-4-(4-fluorophenyl)-l-l4-(;rom--l-pyrrolidinyl)-cyclohcxyl]imidazole, 5-[4-(2-N-methylanuno)pynmidinyl]-4-(4-fluorophenyl)-l-(4-ethynyl-4-hydroxy- cyclohexyl)imidazole, 5-[4-(2-N-mcthylamino)pynmidinyl]-4-(4-flui)rophenyl)-1 -(4-( 1 -propynyl)-4-25 hydroxycyclohexyl)imidazole, 5-[4-(2-N-methylamino)pynmidinyl)-4-(4-fluorophenyl)-l-(4-amino-4-methyl- cyclohexyl)imidazole, 5-[4-(2-N-methylamino)pvrimidinyl]-4-(4-fluorophenyl)-I-(4-aceiamido-4-methyl-cyclohexyl)imidazole, 30 5-[4-(2-N-mcthylaniino)pynmidinyl]-4-(4-fluorophenyl)-l-(4-hydroxy-4-methyl-cyclohexyI)imidazole, 5-[4-(2-N-methylamino)pynmidinyl]-4-(4 fluorophenyl)- l-(4-oxiranyl- cyclohexyI)imidazole, 5-|4-(2-N-Meihyldmino)pynmidinyl]-4-(4-f1uorophenyl)-l-(4-cyanomethyl-4-35 hydroxycyclohexyDimidazole, 5-[4-(2-N-Meihylamino)pynmidiny]]-4-(4-fluorophenyl)-l-(4-hydroxy-4-hydroxymcthylcyclohexly)imidazole 13 12 13 wo 96/216m pct/us96/010im - 12- 5-[4-(2-Amino)pyrimiduiyl]-4-(4-fluorophenyl)- l-[4-hydroxy-4-( 1 propynyl)- cyclohexyljimidazole, 5-[4-(2-AjTuno)pynmidinyl]-4-(4-fluorophenyl)-l-(4-hydroxy-4-methyl-cyclohexyDimidazole 5 Addiuonal compounds wiihin the scope of Formula (I) include 5-[4-(2-N-methylamino)pynmidinyl]-4-(4-fluorophenyl)-l-(4-hydroxy-4-isopropyl- Lyc]ohexyl)imidazolc, 5-14 (2-N-methylamino)pynmidinyl]-4-(4-fluorophenyl)-l-(4-hydroxy-4-phenyl-10 cyclohexyl)imidazole, 5-[4-(2-N-mcihyldmino)pynmidinyl]-4-(4-fluoropheny])-l-(4-hydroxy-4-benzyl- cyclohexyl)imidazole, 5-|4-(2-N-methylamino)pynmidiny]]-4-(4-fluorophenyl)-l-(4 hydroxy-4-cyanomelhyl cyclohexyl)imidazolc, 15 5-[4-(2-N-melhyl<iniino)pynmidinyl]-4-(4-fluorophcnyl)-l-(4-hydroxy-4-(2-cyanoeihyl)cyclohexyl)imidazole, 5-|4-(2-N-melhylamino)pynmidmyl]-4-(4-fluorophenyl)-l-(4-hydroxy-4-(2- aminoelhyl)(.yclohexyl)imidazole, <i-l4-(2-N-meihylamino)pynmidinyl]-4-(4-fluorophenyl)-l-(4-hydroxy-4-(2-niiroeihyl)-20 tyclohexyl)imidazole, 5-{4-(2-N-melhylamino)pynmidinyl]-4-(4-f]uoropheny])-l-(4-hydroxymcthyl-4-amino- cyclohexyl)imidazole 5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-l-(4-hydro\y-4-amino-cyclohexyDimidazole, 25 5-[4-(2-N-methy]amino)pynmidinyl]-4-(4-fluorophenyI)- l-(4-amino-cyclohexyl)imidazole 5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-l-(4-hydroxy-4-tluomethyl cyclohexyl)imidazole 5-[4-(2-N-methylamino)pynmidinyl]-4-(4-fluorophenyl)-l-(4-hydroxy-4-hydroxy 30 methylcyclohexyl)imidazole, 5-[4-(2-N-methylamino)pyrinudinyl]-4-(4-fluorophenyl)-l-(4-hydroxy-4-aininomeihyl- cyclohexyl)imidazole, 5-[4-(2-amino)pyrimidinyl]-4-(4-fluorophenyl)-l-(4-annno-4-melhyl-cyclohexyl)imidazole, 35 5-[4-(2-airuno)pynmidiny)]-4-(4-fluorophenyI)-l-(4-hydroxy-4-niethyl-cyclohexyl)imidazole, 5-[4-(2-amino)pynmidiny])-4-(4-nuorophenyl)-l-(4-oxiranyl-cyclohexyDimidazole 13 12 13 WO 96/216*4 - 13- PCT/US96/01094 Excmplilied and additional compounds of Formula (I) included herein include the 2-mcthylamino-4-pyrimidinvl derivatives of the 2-aminopynminid-4-yl compounds noted above noted compounds and the 2-amuio-4-pynmidinyl derivative1; of the 2-5 methylaminopyriminid-4 yl compounds noted above where not where not explicitly described The compounds of Formula (I) may he obtained by applying synthetic procedures, some ol which are illustrated in Schemes I to XI below The synthesis provided for in these Schemes is applicable for the producing compounds of Formula (I) 10 having a vanety of different R |, R2 and groups which arc reacted, employing optional subsutuents which are suitably protected, to achieve compatibility with the rcacuons outlined herein Subsequent deprotecuon, in those cases, then affords compounds ol the nature generally disclosed Once the imidazole nucleus has been established, further compounds of Formula (I) may be prepared by applying standard 15 techniques tor functional group interconvcrsion, well known in the art For instance -C(0)NR 13R14 from -CO2CH3 by heating with or without catalytic meial cyanide, e g NaCN, and HNRi3R]4 in CH3OH, -0C(0)R3 from -OH with e g , C1C(0)R3 in pyndine, -NR|0-C(S)NRi3R]4 from -NHR10 with an alkylisolhiocyante or thiocyanic acid, NRfiC(0)0R6 trom -NHRfi with the alkyl 20 chloroformate -NRioC(0)NRi3R]4 from -NHR10 by treatment with an isocyanate, e g HN=C=0 or Ri()N=C=0, -NR io-C(0)Rg from -NHR10 by treatment with Cl-C(0)R3 in pyndine -C(=NR]o)NRl3R]4 from -C(NRi3R]4)SR3 with H3NR3+0Ac_ bv heating in alcohol, -C(NRj3R|4)SR3 from -C(S)NRi3R|4 with R6-I in an inert solvent, e g acetone -C(S)NRj3Ri4 (where R13 or R14 is not hydrogen) from 25 -C(S)NH2 with HNRi3Ri4-C(=NCN)-NRi3Ri4 lrom -C(=NR 13R14VSR3 with NH2CN by heating in anhydrous alcohol, alternatively lrom -C(=NH)-NR|3R]4 by treatment with BrCN and NaOEtin EtOH, -NRjo-C(=NCN)SR8 trom -NHR10 by treatment with (RflS)2C=NCN, -NR10SO2R3 trom -NHRjo by treatment with CISO2R3 by heaung in pyridine,-NRi(|C(S)R3 lrom -NRioC(0)Rg by treatment with 30 Lawesson's reagent (2,4-£>M(4-methoxyphenyl)-1,3,2,4 dithiadiphosphetane-2,4- disulfide] -NR10SO2CF3 lrom -NHRf, with triflic anhydride and base wherein R3, Rfi, RlO, Rl3and R14 arc as defined in Formula (I) herein In a lurther aspect the present invention provides tor compounds of the Formula 35 (II) having the structure 13 12 13 wo 96/2161-1 pct/us96/01094 - 14 Ar—S(0)p (II) R4 NC wherein p is 0, or 2, R4 is as defined for Formula (I) and Ar is an opuonally subsututed aryl as defined herein Suitably, Ar is phenyl optionally substituted by Cj_4alkyl, Cj_4 alkoxy or halo Preferably Ar is phenyl or 4-methylphenyl, 1 e a tosyl 5 derivative Compounds of Formula (II) are belived novel, provided than when Ar is tosyl, and p is 0 or 2, then R4 is not an unsubstituted phenyl Precursors of the groups Rj, R2 an 4 R4 can be other Rj, R2 and R4 groups which can be interconverted by applying standard techniques for functional group interconversion For example a compound of the formula (I) wherein R2 is halo 10 -substituted C]. j q alkyl can be converted to the corresponding C j. | q alkylN3 derivative by reacting with a suitable azide salt, and thereafter if desired can be reduced to the corresponding Cj.]QdlkylNH2 compound which in turn can be reacted with RjgSfO^X wherein X is halo (e g . chloro) to yield the corresponding C]_]()alkylNHS(0)2R]8 compound 15 Allernauvely a compound of the formula (I) where R2 is halo-substituted C]_io-alkyl can be reacted with an amine R^R^NH to yield the corresponding C]_]o-alkylNR]3R]4 compound, or can be reacted with an alkali metal salt of RjgSH to yield the corresponding Cj.ioalkylSRi^ compound 13 12 13 wo 96/2165-4 - 15- pct/11s96/0i094 Referring to Scheme I the compounds of Formula (I) are suitably prepared by 5 reacting a compound of the Formula (II) with a compound of the Formula (III) wherein p is 0 or 2, R], R.2 and R4 are as defined herein, for Formula (I), or are precursors ol the croups Rj R2 and R4, and Ar is an optionally substituted phenyl group, and thereafter if necessary converting a precursor of R1, R2 and R4 to a group R |. R2 and R4 It is recognized that R2NH2 which is reacted with RiCHO to form the lmine, Formula (HI) 10 the R2 moiety when it contains a reactive functional group, such as a primary or secondary amine, an alcohol or thiol compound the group must be suitably protected Suitable protecting groups may be found in, Protecting Groups in Organic Syndesis, 13 12 13 wo 96/21654 FCT/US96/0109-1 - 16- Greene T W, Wiley-lntcrsucncc, New York, 1981, whose disclosure is incorporated herein by reference For instance, when R2 is contains as a subsutuent group a heterocyclic ring, such as a pipendine ring, the nitrogen is protected with groups such as t-Boc, CO2R1R. or a subsutucd arylalkyl moiety 5 Suitably, the reaction is performed at ambient temperature or wiLh cooling (e g -50" to 10°) orheaung in an inert solvent such as methylene chlonde DMF, tetrahydrofuran, toluene, acetonitnle, or dimcthoxycthane in the presence of an appropriate base such as 1,8-diazabicyclo [540] undec-7-ene (DBU) or a guanidine 10 base such as 1,5,7-lnaza-bicyclo [4 4 0] dec-5-ene (TBD) The intermediates ol tormula (II) have been lound to be very stable and capable of storage for a long time Preterably, p is 2 Reaction a compound of the Formula (II) wherein p = 2 with a compound ol the Formula (IID-Scheme 1 gives consistently higher yields ot compounds of Formula 15 (I) than when p=0 In addition, the reaction of Formula (II) compounds wherein p = 2 is more environmentally and economically attracuve When p=0, the preferred solvent used is methylene chlonde, which is environmentally unattractive for large scale processing, and the preferred base, TBD, is also expensive, and produces some byproducts and impunucs, than when using the commercially attractive synthesis (p=2) 20 as further described herein As noted. Scheme I utilizes the 1,3-dipoIar cycloadditions of an anion of a substituted aryl thiomethylisocyanide (when p=0) to an lmine More specifically this reaction requires a strong base, such as an amine base, to be used tor the deprotonation step The commercially available TBD is preferred although t-25 butoxide, Li+ or Na-n, or K+ hexamethyldisilazide may also be used While methylene chlonde is the prelered solvent, other halogenated solvents, such as chloroform or carbon tetrachloride, ethers, such asTHF, DME. DMF, dicthylcther, t-butyl methyl ether, as well as acetonitnle, toluene or mixtures thereof can be uuluzcd The reaction may take place from about -20'C to about, 40*C, preferably 30 from about 0"C to about 23'C, more preferably from about 0'C to about 10'C, and most preferably about 4*C for reactions involving an Rj group of pynmidine For compounds wherein R1 is pyndine, it is recognizcd that varying the reauons conditions of both temperature and solvent may be necessary, such as decreasing temperatures to about -50°C or changing the solvent to THF 35 In a further process, compounds of Formula (I) may be prepared by coupling a suitable derivative of a compound of Formula (IX) 13 12 13 WO 96/21654 - 17- PCT/US96/01094 (IX) wherein T| is hydrogen and T4 is R4 , or alternatively Tj is R1 and T4 is H in which R1, R2 and R4 are as hereinbefore defined, with (1) whenT| is hydrogen, a suitable 5 derivative ot the heteroaryl nng Ri H, under ring coupling conditions, to effect coupling of the heteroaryl nng R ] to the imidazole nucleus at position 5, (11) when T4 is hydrogen, a suitable derivative of the aryl ring R4H, under nng coupling conditions, to effect coupling of the aryl nng R4 to the imidazole nucleus at position 4 Such aryl/heteroarvl coupling reactions are well known to those skilled in the 10 art In general an organometallic synthetic equivalent ot an anion of one component is coupled with a reactive derivative of the second component in the presence of a suitable catalyst The anion equivalent may be formed from either the imidazole ot Formula (IX) m which case the aryl/heteroaryl compound provides the reacuve denvative, or the aryl/heteroaryl compound in which case the imidazole provides the 15 reactive denvative Accordingly, suitable derivatives of the compound of Formula (IX) or the aryl/heteroaryl rings include organometallic denvauves such as organomagnesium, organozinc, organostannane and boronic acid denvauves and suitable reactive denvauves include the bromo, lodo, fluorosulfonate and tnfluoromethanesulphonate denvauves Suitable procedures are desenbed in WO 20 91/19497, the disclosure of which is incorporated by reference herein Suitable organomagnesium and organozinc dcnvativcs ol a compound of Formula (IX) may be reacted with a halogen, fluorosullonate or tnflate denvative of the heteroaryl or aryl nng, in the presence of a nng coupling catalyst, such as a palladium (O) or palladium (II) catalyst, following ihe procedure of Kumada et a\, 25 Tetrahedron Letters, 22, 5319 (1981) Suitable such catalysts include terrakn-(tnphenylphosphinc)pdlladium and PdChll,4-fcis-(diphenylphosphino)-butane], optionally in the presence of lithium chloride and a base such as tnethylamine In addition, a nickel (II) catalyst, such as Ni(II)Cl2(1.2-biphenylphosphino)ethane, may also be used tor coupling an aryl nng, following the procedure of Pridgcn et al, J Org 30 Chcm, 1982,47,4319 Suitable reaction solvents include hcxamethylphosphor-amide When the heteroaryl ring is 4-pyndyl, suitable denvauves include 4-bromo- and 4-lodo-pyndine and the fluorosulfonate and tnfldte esters of 4-hydroxy pyndine Similarly, suitable denvauves for when the aryl nng is phenyl include the bromo, fluorosulfonate inflate and, preferably, the lodo-denvatives Suitable 35 organomagnesium and organozinc denvauves may be obtained by treating a compound 13 12 13 WO 96/21654 - 18- PCT/US96/01094 of Formula (IX) or the bromo derivative thereof with an alkyllnhium compound to yield the corresponding lithium reagent by deprotonaiion or transmetallauon, respectively This lithium intermediate may then be treated with an excess of a magnesium halidc or zinc halide to yield the corresponding orgdnomctallit reagent 5 A tnalkylun denvative of the compound of Formula (IX) may be treated with a bromide, fluorosulfonate, inflate, or, preferably, iodide denvative of an aryl or heieroaryl nng compound, in an inert solvent such as letrahydrofuran, preferably containing 10% hexamethylphosphoramide, in the presence of a suitable coupling catalyst, such as a palladium (0) catalyst, for instance /c/roAii-(lnphenylphosphine)-10 palladium, by the method desenbed in by Sulle, J Amer Chem Soc, 1987, 109, 5478, US Patents 4,719,218 and 5,002,942, or by using a palladium (II) catalysi in the presence ol lithium chlonde opuonally with an added base such as ineihylamine, in an inert solvent sut.h as dimethyl formamide Trialkyltin denvauves may be conveniently obtained by metallation of the corresponding compound of Formula (IX) with a 15 hthiaung agent such as jr-butyl-lithium or n-butyllithium, in an ethereal solvent, such as tetrahydroluran, or treatment of the bromo denvative of the corresponding compound of Formula (IX) with an alkyl lithium, followed, in each case, by treatment with a trialkyltin halide Alternatively, the bromo- denvative of a compound of Formula (IX) may be treated wiih a suitable heteroaryl or aryl tnalkyl tin compound in 20 the presence ol a catalyst such as /e/ra/lij-(tnphenyl-phosphine)-palladium, under conditions similar to those desenbed above Boronic acid denvauves are also useful Hence, a suitable denvative of a compound of Formula (IX), such as the bromo, lodo, inflate or fluorosulphonate denvative may be reacted wilh a heteroaryl- or dryl-boronio acid, in the presence ot a 25 palladium Ldtdlysl such as /erraJ.u-(tnphenylphosphine) palladium or PdCl2[l.4-b/\- (diphenyl-phosphino)-buiane] in the presence of a base such as sodium bicarbonate, under reflux condiuons, in a solvent such as dimethoxyethane (see Fischer and Haviniga, Rec Trav Chim Pays Bas, 84,439, 1965, Snieckus, V , Tetrahedron Lett, 29, 2135, 1988 and Terashimia, M , Chem Pharm Bull, 11,4755, 1985) Non-30 aqueous condiuons, for inctance, a solvent such as DMF, at a temperature of about 100°C in the presence of a Pd(II) catalyst may also be employed (see Thompson W J et al J Org Chem, 49,5237, 1984) Suitable boronic acid denvauves may be prepared by treating the magnesium or lithium denvative with a tnalkylborate ester such as tnethvl In-iw-propyl or tnbutylborate, according to standard procedures 35 In sui.h coupling reacuons, it will be readily appreciated that due regard must be exercised wiih respect to functional groups present m the compounds of Formula (IX) Thus in general amino and sulfur subsutuents should be non-oxidised or protected 13 12 13 WO 96/21654 - 19- PCT/US96/01094 Compounds of Formula (IX) are imidazole'; and mav be obtained by any ol ihe procedures herein before desenbed for preparing compounds of Formula (I) In particular, an cx-halo-keionc or other suitably acuvated ketones R.4COCH2Hal (for compounds of Formula (IX) in which Ti is hydrogen) or R]COCH2Hal (for 5 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 delined in Formula (I), or a salt thereof, in an inert solvent such as a halogcnalcd 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 prcparauon of suitable a-halo-ketones is 10 described in WO 91/19497 Suitable reactive esters include esters of strong 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 salL, suitably the hydrochloride salt, which may then be converted into the free amidine m situ , by employing a two phase system in whiLh the reactive ester is in an inert organic sohent 15 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, Gangipati R, Tetrahedron Letters, 190,31, 1989 Compounds of Formula (I) may also be prepared by a process which compnses 20 reacting a compound of Formula (IX) wherein T1 is hydrogen, with an N-acyl heteroaryl salt, according to the method disclosed in US patent 4,803,279 US patent 4,719,218 and US patent 5,002,942, to give an intermediate in which the heteroaryl nng is attached to the imidazole nucleus and is present as a 1 4-dihydro denvative thereol, which intermediate may then be subjected to oxidative-deacylation conditions 25 (Scheme II) The heieroaryl salt, for instance a pyndinium salt, may be either preformed or, more preterably 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 haloformate ester, such as acetyl bromide, benzoylchlonde, benzyl chloroformate, or, preferably ethyl chloroformate) to a solution of the compound of 30 Formula (IX) in the heteroaryl compound RjH or in an inert solvent such as methylene chloride to which the heteroaryl compound has been added Suitable deacylaung and oxidising conditions are desenbed 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 sultur in an inert solvent or solvent mixture, such as 35 decalin, decalin and diglyme, /?-cymene, xylene or mesitylene, under reflux conditions, or, preferably, potassium r-butoxide in r-buianol with dry air or oxygen 13 12 13 WO 96/21654 -20- PCT/US96/01094 "X P HN Tl NH i—N X'> S/dacalinA or K* (txjloxicm/aif :> SCHEME n 5 In a further process, illustrated in Scheme III below, compound1: of Formula (I) may be prepared by treating a compound of Formula (X) thermally or with the aid of a cyclismg agent such as phosphorus oxychlonde or phosphorus pentachlonde (see Engel and Steghch, Liebigs Ann Chem, 1978, 1916 and Strzybny ct al, J Org Chem, 1963, 28,3381) Compounds of Formula (X) may be obtained, for instance, by 10 acylaung the corresponding a-keto-amine with an activated formate denvative such as the corresponding anhydride, under standard acylaung condiuons followed by formation of the inune with R2NH2 The aminoketone may be derived from the parent ketone by examination and reduction and the requisite ketone may in turn be prepared by decarboxylation of the beta-ketoester obtained from the condensation of an aryl 15 (heteroaryl) acetic ester with the R]COX component. r,Y-° l!^OMC HHtNQ, HCIH.O Hy° ToL. Y°. POP, R|SI ^ 2)r«*c. R>NH, h.0 /a r/ ■of + 2.) HCI R H fonsuU (x) SCHEME III 20 In Scheme IV illustrated below, two (2) different routes which use ketone (formula XI) for preparing a compound of Formula (I) 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 alky) lithium, such as n-butyl lithium) to an N-25 alkyl-O-alkoxybenzamide, ester, or any other suitably activated denvauve of the same oxidation state Aliemauvely, the anion may be condensed with a benzaldehyde, to give an alcohol which is then oxidised to the ketone (XI) 13 12 13 wo 96/21654 FCI7US96/01094 -21 - H/ X Ao "CM, U' (XI) ■ \ R* c Br, R.^NHRj 0 R-yN R< c R,^Br r/^° HN 1) NH H^°° : SCHEME TV 5 In a further process, N-substituied compounds of Formula (1) may be prepared by treating the anion ol an amide of Formula (XII) R1CH2NR2COH (XII) wherein Ri and R2 with (a) a nitrilc ot the Formula (XIII) 0 R4CN (XIH) wherein R4 is as hereinbefore defined, or (b) an excess of an acyl halide, for instance an acyl chlonde, of the Formula (XIV) R4COHal (XIV) 5 wherein R4 is as hereinbefore defined and Hal is halogen, or a corresponding anhydnde, to give a fc/s-acylated intermediate which is then treated with a source ot ammonia, such as ammonium acetate 0 R2HN »-H base r H O (XII) SCHEME V 1 ) LI+ -N(i-Pr)2 FU FU' -CN x> r*' One \ ariauon ol this approach is illustrated in Scheme V above A pnraary amine (R2NH2) is treated with a halomethyl heterocycle of Formula R1CH2X to give the secondary amine which is then converted to the amide by standard techniques Alternatively the amide may be prepared as illustrated in scheme V by alkylauon of the formamide with R1CH2X Deprotonation of this amide with a strong amide base, such as lithium di-/w-propyl amide or sodium fcij-(tnmethylsilyl)amide, followed by 13 12 13 wo 96/21614 pct/us96/01094 - 22 - addition ol an excess of an arovl chlonde yields the fcu-acylated compound which is then closed lo an imidazole compound of Formula (I) hy heaung in acetic acid containing ammonium acetate Alternately the anion of the amide may be reacted with a substituted aryl nitnlc to produce the imidazole ol Formula (1) direcdy 5 The following descnption and schemes are further exemplification of the process as previously desenbed above in Scheme 1 Vanous pynmidine aldehyde denvauves 6, 7 and 8 as depicted in scheme VI below, can be prepared by modification of the procedures of Bredereck et al (Chem. Ber 1964, 97, 3407) whose disclosure is incorporated by 10 reference herein These pynmidine aldehydes are then utilized as intermediates in the synthesis as further desenbed herein The unprotected ammo aldehyde denvative, e g 8, can be somewhat unstable Use of an acetolysis procedure as desenbed in Scheme VI, wherein the aldehyde 7 is isolated as the acetamide denvauve (compound 3 is converted to 7 \ia the intermediate 4) and leads to a more stable compound for use in the 15 cycloaddition reaction to make compounds ol Formula (I) General acetolysis conditions, for such a reaction are employed and arc well known to those of skill in the art Suitable conditions are exemplified, for instance in Example 83 In greater detail, the reaction employs heating the 2-amino pynmidine dialkoxy acetal with acetic anhydnde in the presence of a catalytic amount of 20 concentrated sulfunc acid, which simultaneously acetylates the amine and leads to the exchange of one of the alkoxy groups for an acetoxy group The resultant compound is converted to the aldehyde by deacetylation with a catalyuc amount of an alkoxide salt and the corresponding alcohol solvent, c g Na+ methoxide and methanol Alternatively, higher yields can be obtained by first acetylaung the amine with aceuc anhydnde and 25 then affecting exchange by subsequent addition ot concentrated sulfuric acid 13 12 13 WO 96/21654 - 23- PCT/US96/01094 10 15 O MeO, MeO^ MeO^ 1 MeO —NMe2 MeO || MeO , / \ 1 thiourea NaOEt /ElOH 2 Mel NH HX H3CS $ MaO OMe acoh h2so4 HsCT T1 Hz° \ HaN^'NHR base \ R = H, alkyl RHN ACzO [" h2so4 MeO OAc NaOMe MeOH H3CS MeO OMe HCI THF/H20 RHN SCHEME VI The reaction of mimes with tosylmethyl isonunles was first reported by van Leusen (van Leusen, el a], J Org Chem 1977,42,1153 ) Reported were the following conditions ten butyl amine(/BuNH2) m dimethoxyethane (DME), K^CO^ in MeOH, and NaH in DME Upon re-examination of these conditions each was found produce low yields A second pathway involving amine exchange to produce the t-butyl lmine followed by reacuon with the isocyanide to produce a 1 -/Bu imidazole was also operating This will likely occur using any primary amine as a base The secondary amines, while not preferred may be used, but may also decompose the lsonitnle slowly Reactions will likely require about 3 equivalents of amine to go to completion resulting in approximately 50% isolated yields Hindered secondaiy amines (dnsopropylamine) while usable are very slow and generally not too effective Use of tertiary and aromatic amines, such as pyndine, and tnethylamine gave no reaction under certain test conditions, but more basic types such as DBU, and 4-dimethylamino pyridine (DMAP) while slow, did produce some yields and hence may be suitable for use herein 13 12 13 wo 96/21654 pct/us96/01094 - 24 - As depicted in Schcmcs VII and VIII below the pynmidine aldehydes of Scheme VI, can be condensed with a primary amine, 10 generate an imine, which may suitably be isolated or reacted in situ, with the desired isonitrile in the presence ol a variety ot suitable bases, and solvents as desenbed herein to afford the 5-(4-pynnndinyl)-5 imidazoles, wherein Rt and R4 are as defined herein for Formula (I) compounds One preferred method for preparing compounds of Formula (I) is shown below in Scheme VII The lmines, prepared and isolated in a separate step where often tars which were hard to handle The black color was also often earned over into the final product The yields, for making the lmines varied, and environmentally less-acceptable solvents, 10 such as CH2CI2 were olten used in their preparation This reaction wherein p=2 requires a suitable base for the reaction to proceed The reaction requires a base strong enough to deprotonate the isonitrile Suitable bases include an amine a carbonate, a hydnde, or an alkvl or aryl lithium reagent, or mixtures thereof Bases include, but are not limited to, potassium carbonate, sodium carbonate, 15 pnmary and secondary amines such as t-butylamine, dnsopropyl amine, morpholine, pipendine, pyrrolidine, and other non-nuileophilic bases such as DBU, DMAP and 1,4-diazabicyclo[2 2 2]octane (DABCO) Suitable solvents for use herein, include but are not limited to N,N-dimethyl-formamide (DMF), MeCN halogenated solvents, such as methylene chlonde or 20 chloroform, letrahydrofuran (THF), dimethylsulfoxide (DMSO), alcohols, such as methanol or ethanol, benzene, toluene, DME or EtOAc Preferably the solvent is DMF, DME, THF, or MeCN, more preferably DMF Product isolation may generally be accomplished by adding water and filtenng the product as a clean compound The mixture is non-nucleophilic thus no isonitrile decomposition occurs 25 13 12 13 WO 96/21654 -25- PCT/US96/01094 DME f-BuNH? 25 °C, 24 h ^ 43% MeHN NHMe /-fluNH, if tBu tBu MeHN N^N NHMs .SCHEME VH While not convenient for large scaJe work, addition of NaH, instead of t-butylaminc to the isonitrile, perhaps with temperatures lower than 25 °C (in THF) arc 5 likely needed Additionally, BuLi has also been reported to be an effective base for deprotonaung tosyl benzyhsomtnles at -50 °C (DiSanto, R , Cosu, R Massa, S Artico, M Synth Cnmmun 1995,25, 795) Various temperature condiuons may be uuhzed depending upon the preferred base For instance, 1BUNH2/DME, K^COVMeOH, K2CO3 in DMF, at temperatures 10 above 40 °C the yields may drop to about 20% but little difference is expected between 0"C and 25 PC Consequently, temperature ranges below 0 'C. and above 80 °C are contemplated as also being within the scope ot this invention Preferably, the temperature ranges are from about 0 "C lo about 25 "C For purposes herein, room tempature which is depicted as 25°C, but it is recognized that this may vary from 20°C to 30°C 15 As shown in Schemc VIII below, the lmine is preferably formed in situ in a solvent This preferred synthesis, is a process which occurs as a one-pot synthesis Suitably, when the primary amine is utilized as a salt, such as in the dihydrochlonde salt in the Examples, the reaction may further include a base, such as potassium carbonate prior to the addition of the isonitrile Alternatively the piperidine nitrogen 20 may be required to be protected as shown below Reacuon conditions, such as solvents, bases temperatures, etc are similar to those illustrated and discussed above for the isolated lmine as shown in Scheme VIII One skilled in the art would readily 13 12 13 WO 9W165J PCT/US96/01094 - 26- recognizc that under some circumstances the in situ formation ol the lmine may require dehydrating condiuons, or may require acid catalysis boc' nhm® boc cho i DMF 5 h NH, K N^N NHMo SCHEME vni Another method for preparing compounds of Formula (I) is shown below m Scheme Villa To avoid the difficulty associated with isolating the pynmidine aldehyde 8 it is possible to hydrolyze the acetal 3 to aldehyde 8 as desenbed herein The aldehyde 8, formed in situ, can be treated sequentially with a pnmary amine, ethyl 10 acetate, and NaHCOi to form the corresponding lmine in situ, which is extracted into the ethyl acetate Addition of the isomtnle a carbonate base and DMF allows for the formauon of the 5-(4-pynmidinyl)-imidazoles, wherein R2 and R4 are as defined herein for Formula (I) compounds 15 While it is recognized that Schemes VII, VIII, and VIII(a) are shown using a pipendine nng in the R2 position this is for illustration purposes only and any suitable R2 as defined herein may be utilized 13 12 13 WO 96/216S4 PCTYUS96/01094 27- OMo OMe 3N HO NyN NHMe iTY nYn NHMe CHO PG nh, ElOAc Yn NHMo F=* N > .pg -PG k2co3 DMF SCHEME Villa 10 The preferred method of synthesis for compounds of Formula (I) also provides for a suitable and reliable method for introduction of an S(0)malkyl moiety on the pynmidine (R | group) by using, for instance, the 2-methylthn> pynmidine aldehyde denvative, as is also described in the Examples section In scheme IX below (X=S Methyl), compound 1, while a final product may also be used as a precursor, as previously noted to make further compounds of formula (I) In this particular instance the methylthio moiety is oxidized to the methyl sulfinyl moiety which may additionally be further modified to a substituted amino group Y' forX = SCH3 h3c(0)s^ n, KgSjOg AcOH/ H20 nh2r for X = NRAc HCI 1312 13 WO 96/21654 -28- PCT/US96/01094 SCHEME IX Another embodiment of the present invention is the novel hydrolysis of 2-thiomethylpynmidme acetal to 2-thiomethylpynmidine aldehyde as shown in Scheme X below Hydrolysis of the acetal to aldehyde using various known reaction conditions, S such as formic acid did not produce a satisfactory yield of the aldehyde, <13%) was obtained The preferred synthesis involves the use of AcOH (fresh) as solvent and concentrated H2SO4 under heating conditions, preferably a catalytic amount of sulfuric acid Healing conditions include temperatures from about 60 to 85 C, preferably trom about 70' to about 80'C as higher temperatures show a darkening of the reaction mixture 10 Alter the reaction is completed the mixture is cooled lo about room temperature and the acetic acid is removed An alternative procedure lo this involves heating the acetal in 3N HCL at 40°C for about 18 hours, cooling and extracting the bicarbonate neutralized solution into ElOAc 15 OMe OMb AcOH/conc H2SO< 80 C rr1- NyS>N SCHEME X The final 2-aminopynmidin-4-yl imidazole compounds of Formula (I), as well as similar pyndine containing compounds can be prepared by one of three methods 1) direct reaction of the 2-ammopynmidine unine with the isomtnle, 2) condensation ol the 20 2-acetamidopynmidinc iminc with the isomtnle followed by removal of the acetamido group and 3) oxidation of the 2-methylthiopynmidine denvauve to the corresponding sulfoxide followed by displacement with the desired amine While these schemes herein are presented, for instance with an opuonally subsututed pipendine moiety for the resultant R2 posiuon, or a 4-fluoro phenyl for R4, 25 any suitable R2 moiety or R4 moiety may be added in this manner if it can be prepared on the pnmary amine Similarly, any suitable R4 can be added via the isomtnle route The compounds of Formula (II), in Scheme I, may be prepared by the methods of Van Leusen et al, supra For example a compound of the Formula (II) may be prepared by dehydrating a compound ol the Formula (IV)-Scheme I, wherein Ar, R4 and p are as 30 defined herein Suitable dehydrating agents include phosphorus oxychlonde, oxalyl chlonde, thionyl chlonde, phosgene, or tosyl chlonde in the presence of a suitable base such as tnethylamine or dnsopropylethylamine, or similar bases, etc such as pyndine Suitable solvents are dimethoxy ether, tetrahydrofuran, or halogenated solvents, preferably THF 131213 WO 96/21654 PCT/US96/0109-4 -29- 10 The reaction is most etficeni when the reacuon temperatures are kept between -10'C and 0"C At lower temperatures incomplete reaction occurs and ai higher temperatures, the solution turns dark and the product yield drops The compounds ol formula (IV)-Schemc 1 may be prepared bv reacting a compound ol the formula (V)-Scheme I, R4CHO where R4 is as defined herein, with ArS(0)pH and formamide with or without water removal, preferably under dehydrating conditions, at ambient or elevated temperature c g 30° to 150°, conveniently at reflux, optionally in the presence of an acid catalyst. Alternatively tnmethysilylchlonde can be used in place ol the acid catalyst Examples of acid catalysts include camphor-10-sulphonic acid formic acid, p-toluenesulphonic acid, hydrogen chlonde or sulphuric acid An optimal method of making an isonitrile of Formula (II> is illustrated below, in Scheme XI & CHO lormamide TMSCI PhMe MeCN 1 1 50 °C NHCHO NHCHO SOjTol TolSOjH XT NHCHO 90V. JO* SOjTol 05M THF NHCHO Et3N SCVTol POCI3 " ^ -10to0°C F rV NC 30 iron 70% yield 4 15 SCHEME XI The conversion of the substituted aldehyde to the tosylbenzyl formamide may he accomplished by heating the aldehyde, 1-Scheme XI, with an acid, such as p-toluene-sulfonic acid tormic acid or camphorsulfonic acid, with formamide and p-toluene-sulfinic acid [under reaction conditions of about 60'C for about 24 hours] Preferably, no 20 solvent is used The reaction, may give poor yields (< 30%) when solvents, such as DMF, DMSO toluene, acetonitnle, or excess formamide are used Temperatures less than 60"C are generally poor at producing the desired product, and temperatures in excess of 60 C may produce a product which decomposes, or obtain a benzyhc bis-formamidc 2-Scheme XI In Example 23 (a), desenbed in WO 95/02591, Adams et al, 25 synthesizes 4-Fluorophenyl-tosylmethylformamide a compound of Formula (IV) -Scheme I wherein p = 2 This procedure differs from that presently desenbed herein by the following conditions using the sodium salt of toluene sulFmic acid, neat which 13 12 13 WO 96/21654 -30- PCT7US96/U1094 proccss results in uneven hcaung. lower yields and lower reproduceabilny ihcn the present invention, as described herein which uses sulfinic acid and allows for use of non aqueous conditions Condiuons for making a-(p-Toluencsulfonyl)-4-fluorobcnzvlisoniinleas 5 desenbed in Example 23 (b), of WO 95/02591, Adams el al, used as a solvent MeCl to extract the product and DME as solvent The present invention improves upon this process by utuzing less expensive solvents, such as THF and EtOAc to extract Further higher yields are obtained by recrystahzing with an alcohol, such as 1-propanol, although other alcohols, such as methanol, ethanol and buianols are acceptable Previously, the 10 compound was partially punfed using chromatography techniques, and hazardous solvents tor additional purifications Another embodiment of the present invention is the synthesis of the tosyl benzyl tormamide compound, achieved by reacting the bisformamide intermediate 2-Scheme 15 XI with p-toluenesulfimc acid In this prelerred route, preparation ol the bis-formamide lrom the aldehyde is accomplished by heating the aldehyde with formamide, in a suitable solvent with acid catalysis Suitable solvents are toluene, acetonitnle, DMF, and DMSO or mixtures thereof Acid catalysts, are those well known in the art, and include but arc not limited to hydrogen chlonde, p-tolucnesulfonic acid, camphorsulfonic acid, and other 20 anhydrous acids The reaction can be conducted at temperatures ranging from about 25 C to 110'C, preferably about 50 C, suitably lor about 4 to about 5 hours, longer rcacuon times are also acceptable Product decomposition and lower yields may be observed at higher temperatures (>70"C) at prolonged reactions times Complete conversion of the product generally requires water removal from the reaction mixture 25 Preferred conditions for convening a bis-tormamide denvauve to the tosyl benzvl formamide arc accomplished by heating the bisformamide m a suitable solvent with an acid catalyst and p-toluenesulfinic acid Solvents for use in this reacuon include but are not limited to toluene, and acetonitnle or mixtures thereof Additional mixtures of these solvents with DMF, or DMSO may also be used but may result in 30 lower yields Temperatures may range from about 30"C to about 100*C Temperatures lower than 40*C and higher than 60 C are not prelened as the yield and rate decreases Preterably the range is trom about 40 to 60*C most preferably about 50"C The optimal time is about 4 to 5 hours, although it may be longer Preterably, acids used include but are not limited to, toluenesulfonic acid, camphorsulfonic acid, and 35 hydrogen chlonde and other anhydrous acids Most preferably the bisformamide is heated in toluene acetonitnle in a 1 1 ratio, with p-toluenesulfinic acid and hydrogen chlonde 13 12 13 wo 96/21654 pct/us96/01094 - 31 - Another embodiment of the present invention is the prelerred synthetic route lor synthesis of the losylbenzyl formamide compound which is accomplished using a one pot procedure Tins process first converts the aldehyde to the bis-fomiamide derivative and subsequently reacts the bis-formamidc derivative with toluencsulfinic acid This 5 procedure combines the optimized conditions into a single, efficient process High yields, >y()% of the aryl benTylforrnamide may he obtained in such a manner Preferred reaction conditions employ a catalyst, such as tnmethylsilyl chlonde (TMSC1), in a preferred solvent, toluene acetonitnle, prelerably in a 1 1 ratio A reagent, such as TMSCI, is preferred which reacts with water produced therein and at the same 10 time produces hydrogen chlonde to catalyze the reaction Also preferred is use of hydrogen chlonilc and p-tolucnesulfonic acid Therefore, three suitable reaction conditions for use herein include 1) use of a dehydrating agent which also provides hydrogen chlonde, such as TMSCI. or by 2) use ol a suitable dehydrating agent and a suitable source of acid source, such as but not limited to, camphorsulfonic acid hydrogen IS chloride or toluenesulfonic acid and 3) alternative dehydrating conditions, such as the azeotropic removal of water and using an acid catalyst and p-toluene sulfinic acid Compounds of the lormula (II) where p is 2 may also be prepared by reacting in the presence of a strong base a compound of the formula (VI) -Scheme 1, R4CH2NC 20 with a compound of the formula (VU)-Schemc I, ArSCbL] wherein R4 and Ar are as defined herein and Lj is a leaving group such as halo, c g fluoro Suitable strong bases include, but are not limited to, alkyl lithiums such as butyl lithium or lithium diisopropvlamidc fvan Leusen et al.. Tetrahedron Letters. No 23,2367-68 (1972)) The compounds of formula (Vl)-Schemc I may be prepared by reacting a 2S compound of the formula (Vlll)-Scheme I, R4CH2NH2 with an alkyl formate (e g eihylformate) to yield an intermediate amide which can be converted to the desired isomtnle by reacting with well known dehydrating agent, such as but not limited to oxalyl chlonde, phosphorus oxychlonde or tosyl chloride in the presence of a suitable base such as tncthylaminc 30 Alternatively a compound of the formula (VIII) - Scheme I may be convened to a compound of the formula (VI)- Scheme I by reaction with chloroform and sodium hydroxide in aqueous dichloromethane under phase transfer catalysis The compounds of the lormula (III) - Scheme I may be prepared by reacting a compound ot the tormula RjCHO with a primary amine R2NH2 35 The amino compounds of the formula (VIII) - Scheme I are known or can be prepared from the corresponding alcohols, oximes or amides using standard functional group interconvcrsions 13 12 13 WO 96/21654 PCT/US96/0MI94 -32- In Scheme XII below, the compound 5 Scheme 12 is shown in the Examples section as Example 2, the compound 6-Schcmc 12 as Example 4, compound 7-Scheme 12 as Example 5, 8-Schemc 12 as Example 6 and compound 9-Schemc 12 as Example 7 o o o HjN <5 "V- NHj Conditions a) t NHjOH'HCI, Na/IOj, HjO , u Raney Ni, H2, b) 2-aminopyrlmldinyM carboxaldhyd# CHjCI,, c) 4 lluorophenyt lotythiomelhylsocyanide TBD, CH2CIj, d) i HCI, H-.0, II NajCOs HjO e) NH2OH»HCI 5 NajC03, H?0 . 1 NaCNBHj, MeOH, 9) KNCO, DMF, Hp. HOAC SCHEME XII Cycloalkanones such as 1-Scheme XII (available from Aldnch Chemical Co, 10 Milwaukee, Wi) may be converted to cycloalkylamines such as 2-Scheme XII by conventional procedures for reductive animation such as oxime formation with hydroxylarnine m HtO followed by rcducuon of the oxime to the amine by standard conditions such as catalytic hydrogenation with Raney Ni in an Hi atmosphere The 13 12 13 W0 96/216S4 - 33- PCT/US96/01094 resulting cyclualkylanrunes such as 2-Schenie XII may be reacted with arvl aldehvdes such as 2-aminopynmidinvl-4-carboxaldhvde in non-hydroxylic organic solvents to form lmmes such as 3-Schcmc XII Depending on the degree of activation of the aldehydes towards imine lormation, catalytic acid (such as toluenesultonic acid) and 5 dehydrating conditions (such as azeotropic removal of water in refluxing benzene) may or may not he needed Imines such as 3-Scheme XII may be converted to 1 4 diaryl imidazoles alkylated with cycloalkyl groups by reacuon with isonitnles such as 4-fluorophenyl-tolylthiomethylisocvanide in the presence of a base such as 1,5,7-tnazabicycloH 4 0)-dec-5-ene (TBD) in organic solvents such as CH2CI2 In this way 10 3-Scheme XII was converted to 5 Scheme XII Cycloalkyl ketal subsututed imidazoles such as 5-Scheme XII are hydrolyzed with aqueous acids (such as aqueous HC1) followed by neutralization with base (such as aqueous NajCOO to afford ketones such as 6-Scheme VI 6-Scheme XII is converted to the oxime 7-Scheme XII with hydroxylarnine in H2O 7-Scheme XII is convened to the hydroxylarnine 8-Scheme XII 15 by reduction with sodium cyano borohvdride in methanol 8-Scheme X is converted to the hydroxyureas 9-Scheme XII by the procedure of Adams ct al (WO 91/14674 published 3 October 1991) In the above noted Scheme, the alcohol 10-Scheme 13 may be prepared by reducing the ketone of 6-Scheme 13 with a suitable reducing agent, such as NaBH4 In formula XI below, Ri is may be an optionally subsututed alkyl, aryl or a 25 heteroaryl group and Ri is either an OH, NH2 or SH, or Rj and R2 togethercan form a C3-7 cycloalkyl nng such as, for example a pyrrolidine or piperdine nng Some representative examples of such compounds arc illustrated in scheme XIV below o 20 SCHEME XIII 13 12 13 WO 96/21654 - 34- PCT/US96/01094 10 (XI) SCHEME XIV The ketone 1 can be reacted with any organomettalic reagent (RjM) to afford the corresponding alcohol 2 ( wherein Rj can be hydrogen or any optionally susbtituted alkyl aryl, arylalkyl, hetcocyclic, heterocyclic alkyl, etc moiety) The alcohol 2 can be converted to the neopentyl amine 3, by using the classical Ritter reacuon well known by those ot skill in th art The amine 3 can be acylated or sulfonylaied The ketone 1 can be can be transformed into an spirooxirane 4 by reagents suLh as dimcthylsulfonium methvlide arid dimethyl sulfoxonium methylide The oxirane 4 can be nng opened with a plethora of nucleophiles such as hydroxides, thiolates, amines, organometallic reagents (such as the well known organo-cuprate ororgano-aluminum reagents, etc ) 5, R, = CH20H,CH2SH,CH2NH;, Optionally subst Alkyl or Aryl SCHEME XIV 131213 WO 96/21654 PCT/US96/01094 -35- The ketone 1 -Schcme XV may also be sub|ected to reductive animation by any primary or secondary amines to afford amines 6 Scheme XV Ri R, R2NH/ EtOH or MeOH NaCNBH3 R, and can be any alkyl or aryl group Rt and R2 can also be a part of a nng SCHEME XV Suitable protecting groups for use with hydroxyl groups and the imidazole nitrogen are well known m the art and desenbed in many reterences, for instance Protecting Groups in Organic Synthesis, Greene T W, Wiley-Interscience, New York, 1981 Suitable examples of hydroxyl protecting groups include silyl ethers, such as t-10 butyldimethyl or t-butyldiphenyl, and alkyl ethers, such as methyl connected by an alkyl chain of variable link, (CR|oR20)n Suitable examples of imidazole nitrogen protecting groups include tetrahydropyranyl Pharmaceuucally acid addition salts of compounds of Formula (I) may be obtained in known manner, for example by treatment thereof with an appropriate 15 amount of acid in the prescncc of a suitable solvent METHODS OF TREATMENT The compounds of Formula (I) or a pharmaceutical^ acceptable salt thereof can be used in the manufacture of a medicament for the prophylactic or therapeutic 20 treatment ot any disease state in a human, or other mammal, 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 Compounds of Formula (1) are capable of inhibiting proinflammatory cytokines, such as IL-1, IL-6, IL-8 and TNF and are therefore of use in therapy IL-1, IL-6, IL-8 25 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 inhibiUon of these pro-inflammatory 13 12 13 WO 96/21654 PCT/US96/01094 36 ' / 3 ^ v ( , | cytokines is ot bend it in controlling reducing and alleviating manv ol these disease states Compounds oi Formula (I> are capable ol inhibiting inducible proinflammatory proteins such as COX-2 also relerred to b\ manv other names such as prostaglandin 5 endoperoxide svnthase-2 (PGHS-2) and are theretore ol use in therapy These proinflammatory lipid mediators ot the cvclooxygenase (CO) pathwav are produced by the inducible COX-2 enzvme Regulation, theretore of COX-2 which is responsible tor the these products derued trom arachidonic acid such as prostaglandins alfect a wide vanetv ot cells and tissues are important and critical inflammatory mediators ol a wide 10 \arietv ot disease states and conditions Expression ot COVl is not elfected by compounds ot Formula (I) This selective inhibition ot COX-2 mav alleviate or spare ulcerogenic liability associated with inhibition ot COX-1 thereby inhibiung prostoglandins essenual tor cvtoprotective eftects Thus inhibition ol these proinflammatory mediators is ot benetu in controlling reducing and alleviating manv ol 15 these disease states Most notablv these inflammatory mediators in particular prostaglandins have been implicated in pain such as in the sensitization ot pain receptors or edema This aspect ot pain management theretore includes treatment ot neuromuscular pain headache cancer pain, and arthntis pain Compounds ol Formula (1) or a pharmaceuucally acceptable salt thereot, are ol use in the prophylaxis or 20 therapy in a human or other mammal, bv inhibiuon of the synthesis ot the COX-2 enzvme Accordingly the present invention provides a method ot inhibiting the synthesis ot COX-2 which comprises administenng an effective amount ol a compound ot Formula (I) or a pharmaceuucally acceptable salt thereof The present invention also 25 provides for a method ot prophylaxis treatment in a human or other mammal, bv inhibition ot the synthesis ot the COX-2 enzyme Accordingly the present invention provides a method ot treating a cytokine-mediated disease which compnses administenng an effective cytokine-interfenng amount of a compound ol Formula (I) or a pharmaceuticals acceptable salt thereof 30 In particular compounds of Formula (I) or a pharmaceuucally acceptable salt thereot are ot use in the prophylaxis or therapv of any disease state in a human, or other mamma] which is exacerbated by or caused by excessive or unregulated EL-l, IL-8 or TNT production by such mammal's cell such as but not limited to monocytes and/or macrophages 35 Accordingly in another aspect, this invention provides a method ot inhibiting the production ot IL-1 in a mammal in need thereof which comprises administenng to said mammal an effective amount ot a compound of Formula (I) or a pharmaceutical^' acceptable salt thereot TniLLLCCTU/ u F-fiO [rjjy OFHCL OF i\'Z 2 0 AUG 1929 RECEIVFn WO 96/21654 PCT/US96/01(194 -37. , \ 'i i / w There arc manv disease states in which excessive or unregulated IL-1 production is implicated in exacerbating and/or causing the disease These include rheumatoid arthritis osteoarthritis stroke endotoxemia and/or toxic shock syndrome other acute or chronic inflammatory disease states such as the inflammatory reaction induced by 5 endotoxin or inflammatory bowel disease tuberculosis atherosclerosis muscle degeneration multiple sclerosis cachexia bone resorpuon psonauc arthritis Reuers svndrome rheumatoid arthritis gout traumatic arthritis rubella arthritis and acute svnovuis Recent evidence also links IL-1 activity to diabetes pancreatic ft cells and •\l7heimer s disease 10 In a further aspect this invention provides a method ot inhibiting the production ot TNF in a mammal in need thereot which comprises administering to said mammal an etlecuve amount ot a compound ot Formula (I) or a pharmaceutical^ acceptable salt thereot Excessive or unregulated TNF production has been implicated in mediating or 15 exacerbating a number ot diseases including rheumatoid arthritis rheumatoid spondvlius osteoarthritis gouty arthritis and other arthritic conditions, sepsis sepuc shock endotoxic shock gram negative sepsis, toxic shock syndrome adult respiratory distress svndrome stroke, cerebral maJaria chronic pulmonarv inflammatory disease silicosis pulmonary sarcoisosis, bone resorption diseases such as osteoporosis 20 rcpcrlusion miurv grift vs host reaction allograft rejections lever and mvalgias due to infection such as influenza cachexia secondary to intection 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 pvresis 25 Compounds ol Formula (I) are also useful in the treatment of viral infections where such viruses are sensitive to upregulation bv TNF or will elicit TNF production in vno The viruses contemplated tor 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 bv the TNF tnhibiting-compounds of Formula (1) 30 Such viruses include but are not limited to HIV-1 HFV-2 and HIV-3 Cytomegalovirus (CMV) Influenza adenovirus and the Herpes group ot viruses, such as but not limited to Herpes Zoster and Herpes Simplex Accordingly in a further aspect this invention provides a method ot treating a mammal afflicted with a human immunodeticiencv virus (HIV) which comprises administering to such mammal an eftecuve TNF 35 inhibiting amount ot a compound ot Formula (I) or a pharmaceutical^ acceptable salt thereot Compounds ol Formula (I) may also be used in association with the vetennarv treatment ot mammals other than in humans in need ot inhibition of TNF production f "JfU-LCClUflL Pr^PCRTYOFFiCL I or nz | 2 0 AUG t0!)9 I RECEIVCn WO 96/21654 PCT/US96/01094 -38- TNF mediated diseases for treatment, therapeutically or prophylacucally in animals include disease states such as those noted above, but in parucular viral infections Examples of such viruses include, but are not limited to, lenuvirus infections such as, equine infectious anaemia virus, caprine arthritis virus, visna virus, or maedi virus or 5 retrovirus infections, such as but not limned to feline immunodeficiency virus (F1V), bovine immunodeficiency virus, or canine immunodeficiency virus or other retroviral infections The compounds of Formula (I) may also be used topically m the treatment or prophylaxis of topical disease states mediated by or exacerbated by excessive cytokine 10 production, such as by IL-1 or TNF respectively, such as inflamed joints eczema, psonasis and other inflammatory skin conditions such as sunburn inflammatory eye condiuons including conjunctivius, pyresis, pain and other condiuons associated with inflammation Compounds of Formula (I) have also been shown to inhibit the production of IL-15 8 (lnterleukin-8, NAP) Accordingly, in a turlhcr aspcct. this invenuon 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 (I) or a pharmaceuucally acceptable salt thereof There are many disease states in which excessive or unregulated IL-8 production 20 is implicated in exacerbating and/or causing the disease These diseases are characterized by massive neutrophil infiltrauon such as, psonasis, inflammatory bowel disease, asthma, cardiac and renal reperfusion in)ury, adult respiratory distress syndrome, thrombosis and glomerulonephnus All of these diseases are associated with increased IL-8 production which is responsible for the chcmotaxis of neutrophils into 25 the inflammatory site In contrast lo other inflammatory cytokines (IL-1, TNF, and IL-6) IL-8 has the unique property of promoting neutrophil chemotaxis and activauon Theretore, the inhibition of IL-8 production would lead to a direct reduction in the neutrophil infiltrauon The compounds of Formula (I) are administered m an amount sufficient to 30 inhibit cytokine, in particular IL-1, 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-1, IL-6, IL-8 or TNF, tor instance in the conlcxt of the present invention constitute (1) levels of free (not cell bound) IL-1, IL-6, IL-8 or TNF greater than or equal to 1 picogram per ml, (11) any cell 35 associated IL-1, IL-6, IL-8 or TNF, or (in) the presence of IL-1, IL-6, IL-8 or TNF mRNA above basal levels m cells or Ussucs in which IL-1, IL-6, IL-8 or TNF, respectively, is produced 13 12 13 WO 96/21654 PCT/US96/01094 -39- The discovery that the compounds of Formula (I) are inhibitors of cytokines, specifically IL-1, IL-6, IL-8 and TNF is based upon the effects of the compounds of Formulas (I) on the production of the IL-1, IL-8 andTNF in in vitro assays which are desenbed herein 5 As used herein the term "inhibiting the production of IL-1 (IL-6, IL-8 or TNF)" reters to a) a decrease of excessive in vivo levels of the cytokine (IL-1, IL-6, IL-8 or TNF) in a human to normal or sub-normal levels by inhibition of the in vivo release of the cytokine by all cells, including but not limited to monocytes or macrophages 10 b) a down regulation, at the genomic level of excessive m vivo levels of the cytokine (IL-1, IL-6, IL-8 or TNF) in a human to normal or sub-normal levels c) a down regulation, by inhibition of the direct synthesis of ihe cytokine (IL-1, IL-6 IL-8 or TNF) as a postranslational event or d) a down regulation, at the translational level of excessive in vivo levels of the 15 cytokine (IL-1, IL-6 IL-8 or TNF) in a human to normal or sub-normal levels As used herein, the term "TNF mediated disease or disease slate" refers to any and all disease states in which TNF plays a role, either by producuon of TNF itself, or by TNF causing another monokine to be released, such as but not limited to IL-1, IL-6 20 or IL-8 A disease state in which, for instance, IL-1 is a maior component, and whose production or acuon, is exacerbated or secreted in response to TNF, would therefore be considered a disease stated mediated by TNF As used herein, the term "cytokine" refers to any secreted polypeptide that 25 affects the funcuons of cells and is a molecule which modulates interacuons between cclls 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 30 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 (IL-1), Intcrleukm-6 (IL-6), lnterleukin-8 (IL-8), Tumor Necrosis Factor-alpha (TNF-a) 35 and Tumor Necrosis Factor beta (TNF-B) As used herein, the term "cytokine interfering" or "cytokine suppressive amount" refers to an effecuve amount of a compound of Formula (I) which will causc a decrease in the in vivo levels of the cytokine to normal or sub-normal levels when given 13 12 13 WO 96/21654 -40- PCT/US96/01094 to a patient for the prophylaxis or treatment nf a disease state which is exacerbated by or caused by, excessive or unregulated cytokine producuon As used herein, the cytokine referred to in the phrase "inhibition of a cytokine, tor use in the treatment ol a HIV-inlecied human" is a cytokine which is implicated in 5 (a) the initiation and/or maintenance of T cell activation and/or activated T cell-mediated HIV gene expression and/or replication and/or (b) any cvtokine-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 10 binds to the same cellular receptor, both TNF-a and TNF-B are inhibited by the compounds of the present invention and thus are herein referred to collectively as "TNF" unless specifically delineated otherwise A new member of the MAP kinase family, alternatively termed CSBP, p38 or RK, has been identified independently by several laboratories recently Activation ol 15 this novel protein kinase via dual phosphorylation has been observed in different cell systems upon stimulation by a wide spectrum of sumult, such as physicochemical stress and treatment with hpopolysacchande or proinflammatory cytokines such as mterleukin-1 and tumor necrosis lactor The cytokine biosynthesis inhibitors, ol the present invention, compounds of Formula (I), have been determined to be potent and selective 20 inhibitors of CSBP/p3S/RK kinase activity These inhibitors are of aid in determining the signaling pathways involvement in inflammatory responses In particular, for the first time a definitive signal transduction pathway can be presenbed to the action of hpopolysacchande in cytokine production in macrophages The cytokine inhibitors were subsequently tested in a number of animal models 25 for anti-inflammatory activity Model systems were chosen that were relatively insensitive to cyclooxygenase inhibitors in order to reveal the unique activities of cytokine suppressive agents The inhibitors exhibited significant activity in many such in vivo studies Most notable are its effectiveness in the collagen-induced arthritis model and inhibiuon of TNF producuon in the endotoxic shock model In the latter 30 study, the reduction in plasma level of TNF correlated with survival and protection from endotoxic shock related mortality Also of great importance are the compounds effectiveness in inhibiting bone resorption m a rat fetal long bone organ culture system Gnswold et al, (1988) Arthritis Rheum 31 1406-1412, Badger, et al, (1989) Circ. Shock 27,51-61 Vottaetal, (1994)invitro Bone 15, 533-538, Leeet al , (1993) B 35 Ann N Y At.ad Su 696, 149-170 In order to use a compound of Formula (1) or a pharmaceutical^ acceptable salt thereof in therapy, it will normally be Formulated into a pharmaceutical composiuon in accordance with standard pharmaceuucal practice This invention, theretore, also 13 12 13 WO 96/21654 nrm)S96/01fl94 -41 - relates in a pharmaceutical composition comprising an effective non-toxic amount ol a compound of Formula (I) and a pharmaceuucally acceptable camcr or diluent Compounds ol Formula (I), pharmaceuucally acceptable salts thereof and pharmaceutical compositions incorporating such may conveniently be administered by 5 any of the routes conventionally used for drug administration for instance, orally, topically, parenterally or by inhalation The compounds of Formula (I) may be administered in conventional dosage forms prepared by combining a compound of Formula (I) with standard pharmaceutical earners according to conventional procedures The compounds of Formula (I) may also be administered in conventional dosages in 10 combinauon with a known, second therapeuucally acuvc compound These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropnate to (he desired preparation It will be appreciated that ihe form and charactcr ol the pharmaceuucally acccptable charactcr or diluent is dictated bv the amount ol active ingredient with which it is to be combined, the route ol administration and other 15 well-known variables The carner(s) must be "acceptable" in the sense of being compatible wiLh the other ingredients of the Formulation and not deletenous to the recipient Ihereol The pharmaceutical earner employed may be lor example, either a solid or liquid Exemplary of solid earners are lactose, terra alba, sucrose talc, gelatin, agar, 20 pectin, acacia, magnesium stearate, stearic acid and the like Exemplary of liquid earners are syrup, peanut oil, olive oil, water and the like Similarly, the earner or diluent may include time delay material well known to the art, such as glyceryl mono-stcarate or glyceryl dislearatc alone or with a wax A wide vanety of pharmaceutical forms can be employed Thus, il a solid 25 carrier 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 camcr will vary widely but preferably will be from about 25mg to about Ig When a liquid earner is used, the preparation will be in the form of a syrup emulsion, soft gelatin capsule, stenle mieclable liquid such as an ampule or nonaqueous liquid suspension 30 Compounds of Formula (I) may be administered topically, that is by non- systemic administration This includes the application ol 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 35 and intramuscular administration Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of lnflammauon such as liniments. lotions creams ointments or pastes, and drops suitable for administration to 13 12 13 WO 96/21654 PCT/US96/01094 -42- the eve ear or nose The active ingredient may compnse for topical administration, from 0 001% to 10% w/w, for instance from 1% to 27c hy weight of the Formulation It may however compnse as much as 10% w/w but preferably will compnse less than 5<ft w/w, more preferably from 0 1% to 19?- w/w of the Formulation 5 Lotions according to the present invention include those suitable for application to the skin or eye An eye lotion may compnse a stenle aqueous solution optionally containing a bactencide and may be prepared by methods similar to those for the preparation of drops Lotions or liniments for application to the skin may also includc an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a 10 moistunzer 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 acuve ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid ol suitable machinery, with 15 a greasy or non-greasy base The base may compnse hydrocarbons such as hard, sofl or liquid paraffin, glycerol, beeswax, a metallic soap a mucilage an oil of natural origin suih as almond com arachis, castor or olive oil. wool fat or its denvauves or a fatty acid such as stenc 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 20 an anionic cationic or non ionic surfactant such as a sorbitan ester or a polyoxyethylene denvative thereof Suspending agents such as natural gums, cellulose denvauves or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included Drops according to the present invention may compnse stenle aqueous or oily 25 soluuons or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution or a bactencidal and/or fungicidal agent and/or any other suitable preservative, aad preferably including a surface active agent The resulting solution may then be clanfied by filtration transferred to a suitable container which is then sealed and stenlized by autoclaving or maintaining at 98-100 C for half an hour 30 Altcmauvely, the solution may be stenlized by filtration and transferred to the container by an aseptic technique Examples of bactencidal and fungicidal agents suitable for inclusion in the drops are phenylmercunc nitrate or acetate (0 002%), benzalkonium chlonde (0 01%) and chlorhexidme acetate (0 019r) Suitable solvents for the preparation of an oily solution include glycerol diluted alcohol and propylene glycol 35 Compounds of formula (1) may be administered parenterally, that is by intravenous intramuscular, subcutaneous intranasal, intrarectal, intravaginal or mtrapentoneal administrauon The subcutaneous and intramuscular forms of parenteral administration are generally preferred Appropnate dosage forms for such 1312 13 WO 96/21654 -43- PCT/US96/01094 administration may be prepared by conventional techniques Compounds of Formula (I) may also be administered by inhalation, that is by intranasal and oral inhaJauon administration Appropnate dosage forms for such administration such as an aerosol Formulation or a metered dose inhaler, may be prepared by conventional techniques 5 For all methods of use disclosed herein for the compounds of Formula (I), the daily oral dosage regimen will preferably be from about 0 1 to aboul 80 mg/kg of total body weight, preferably from about 0 2 to 30 mg/kg, more preferably from about 0 5 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 10 mg/kg, and more preferably from 10 about 0 5 mg to 15mg/kg The daily topical dosage regimen will preferably be from 0 1 mg to 150 mg administered one to tour, preierably two or three times daily The daily inhalation dosage regimen will preferably be from about 0 01 mg/kg to about 1 mg/kg per day It will also be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of a compound of Formula (I) or a pharmaceutical ly 15 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 optimums can be determined by convenuonal techniques It will also be appreciated by one of skill in the an that the optimal course of treatment, i e the number of doses of a compound of Formula (I) or a pharmaceuucally acceptable i»alt 20 thereof given per day lor a defined number of days, can be ascertained by those skilled in the an using conventional course of treatment determination tests The invention will now be desenbed by reference to the following biological examples which arc merely illustrative and are not to be construed as a limitation of the scope of the present invention 25 BIOLOGICAL EXAMPLES The cytokine-inhibiting effects of compounds of the present invention were determined by the following in vitro assays Interleukin -1 (IL-1) 30 Human peripheral blood monocytes are isolated and purified from either fresh blood preparations from volunteer donors, or from blood bank buffy coats, according to the procedure of Colotta et al, J Immunol, 132,936 (1984) These monocytes (lxl 0^) are plated in 24-well plates at a concentration of 1-2 million/ml per well The cells arc allowed to adhere for 2 hours, alter which time non-adherent cells are removed by 35 gentle washing Test compounds are then added to the cells for about lhour before the addition of hpopolysacchande (50 ng/ml). and the cultures are incubated at 37°C for an additional 24 hours Al the end of this period culture super-natants are removed and clarified of cells and all debris Culture supernatants are then immediately assayed for 13 12 13 WO 96/21654 -44- PCT/US96/01094 IL-1 biological acuviiy, either by the method of Simon et al, J Immunol Methods 84 85, (1^85) (based on ability of IL-1 to stimulate a. Intcrleukin 2 producing cell line (EL-4) to secrete IL-2, in concert with A23187 lonophore) or the method of Lee etal, J ImmunoTherapv, 6(1), 1-12 (1990) (ELISA assay) 5 Tumour Necrosis Factor (TNF) Human peripheral blood monocytes are isolated and purified from either blood bank buffy coats or plateletpheresis residues, according to the procedure of Coloua, R etal, J Immunol, 132(2), 936 (1984) The monocytes arc plated al a density of lxlO6 10 cclls/ml mcdiumywell in 24-well multi-dishes The cclls are allowed to adhere for 1 hour after which lime the supernatant is aspirated and fresh medium (lml, RJPMI-1640, Whuaker Biomedical Products, Whitaker, CA) containing 1% tetal calf serum plus penicillin and streptomycin (10 units/ml) added The cells are incubated for 45 minutes in the presence or absence of a lesi compound al InM- 10mM dose ranges (compounds 15 are solubilized in dimethyl sultoxide/ethanol, such that the final solvent concentration in the culture medium is 0 5% dimethyl sulfoxide/O 5% ethanol) Bacterial hpopolysacchande (£ call 055 B5 [LPS] from Sigma Chemicals Co ) is then added (100 ng/ml in 10 ml phosphate buflered saline) and cultures incubated for 16-18 hours at 37°C in a 5% CCH incubator At the end of the incubation penod, culture supernatants are 20 removed from the cells, centnfuged at 3000 rpm to remove ccll debns The supernatant is then assayed for TNF activity using cither a radio-immuno or an ELISA assay, as desenbed in WO 92/10190 and by Becker et al, J Immunol, 1991,147,4307 IL-1 and TNF inhibitory activity does not seem to correlate with the property of 25 the compounds of Formula (I) in mediating arachidonic acid metabolism inhibition Further the ability to inhibit production of prostaglandin and/or leukotnene synthesis, by nonsteroidal anu-inflammatory drugs with potent cyclooxygcnasc and/or lipoxygenase inhibitory activity does not mean that the compound will necessanly also inhibit TNF or IL-1 producuon, at non-toxic doses 30 Interleukin -8 (IL-8) Pnmary human umbilical cord endothelial cells (HUVEC) (Cell Systems, Kirland, Wa) are maintained in culture medium supplemented with 157r fetal bovine serum and 1% CS-HBGF consisting of aFGF and hepann The cells are then diluted 35 20-fold before being plated (250[il) into gelating coated 96-well plates Prior to use, culture medium are replaced with fresh medium (200|il) Buffer or test compound (25pl, at concentrations between 1 and IOjiM) is then added to each well in quadruplicate wells and the plates incubated for 6h in a humidified incubalor at 37°C in 13 12 13 WO 96/21654 PCT/US96/01094 r, T P ' / *45- 5^ ^ H k an atmosphere ot 5t7o CO2 At ihe end ot the incubauon penod, supernatant is remov ed and assavcd tor IL-8 concentration using an IL-8 ELISA kit obtained trom R&D Systems (Minneapolis, MN) All data is presented as mean value tng/mH ot multiple samples based on the standard curve IC^o's where appropriate are generated bv non-5 linear regression analysis Cytokine Specific Binding Protein Assay A radiocompetitive binding assay was developed to provide a highly reproducible primary screen tor struuure-activitv studies This assay provides manv advantages over 10 the conventional bioassavs which uulizc treshlv isolated human monocytes as a source oi cytokines and ELISA assays to quantity them Besides being a much more tacile assav the binding assav has been extensively validated to highly correlate with the results ot the bioassav A specitic and reproducible cytokine inhibitor binding assav was developed using soluble cvstosolic traction trom THP 1 cells and a radiolabeled compound L'S 15 P itent \os > 7X"i 664 and 5 S71 ''^1 ukI 1 uo il \ •// c 300 n(72) 739-746 (Dec IUl)4) wnose disclosures are incorporated bv reierence lerein in its entirety descrine^ the aoove noted method tor screening drugs to idenuiv uomDounds which interact <vith ana bind to the c\tokine specitic binding protein (hereinatter CSBP) However tor puroosc-herein the ninding protein may be m isolated torm in solution or in immobilized rorm or 20 ma\ be genetically engineered to be exoressed on the surtace ot recomoinant host ceils such as in phage display svstem or as tusion proteins Alternatively vvnole -ells or cvtosolic tractions comprising die CSBP mav be employed in the creening Drotccol Regardless ot the torm 01 the binding protein a plurality ot compounds are contacted with the binding protein under conditions sutficient to torm a compound/ ninding ore ten 25 complex and compound caDable ot torming enhancing or mtertenng with said complexes are detected Representative tinal comDOunds ot Formula (I) ot Formula (I) Examples 4 8 10 to 21 have all demonstrated positive inhibitors' activity in this binding assav 30 Prostaglandin endoperoxide svnthase-2 (PGHS-2) assay The tollowing assav describes a method for determining the inhioitorv eriects ot compounds ot Formula (I) on human PGHS-2 protein expression in LPS stimulated human monocytes Method. 35 Human penpneal blood monocytes were isolated trom butfy coats bv cenuitugation througn Ficoll and Pcrcoll gradients Cells were seeded at 2 X 10^/well in 24 well plates and allowed m adhere tor 1 nour in RPVII supplemented with \% human AB serum F if'.F-Li EG 1 u/in TcrcriiY office I liFTJZ 2 0 AUG 1SS9 [ \ ! RECEIVED [ WO 96/21654 -46- 1,CI7US96/(U094 20mM L-glutamine, Penicillin-Streptomycin and )0mM HEPES Compounds were added at various concentrations and incubated at 37l)C for 10 minutes LPS was added at 50 ng/well (to induce enzyme expression) and incubated overnight at 37°C The supernatant was removed and cells washed once in cold PBS The cells were lysed in 5 1 OOjil of cold lysis buffer(50mM Tns/HCl pH 7 5, 150mM NaCl, 1 % NP40,0 5% sodium deoxycholate, 0 1 % SDS, 300ug/ml DNAse, 0 19J TRITON X-100, ImM PMSF, ImM leupeptin, ImM pepstaun) The lysate wascentnfuged (10,000X g for 10 mm al 4°Q to remove debris and the soluble fraction was subjected lo SDS PAGE analysis (12Vr gel) Protein separated on the gel were transferred onto nitrocellulose membrane 10 by eleurophoreuc means for 2 hours at 60 volts The membrane was pretreated for one hour in PBS/0 1% Twcen 20 with 5% non-fat dry milk After washing 3 times in PBS/Twecn buffer, the membrane was incubated with a 1 2000 dilution of a monospecific antiserum to PGHS-2 or a 1 1000 diluuon of an antiserum to PGHs-l in PBS/Tween with \% BSA for one hour with continuous shaking The membrane was 15 washed 3X in PBS/Tween and then incubated with a 1 3000 dilution of horseradish peroxidase conjugated donkey antiserum to rabbit Ig (Amersham) in PBS/Tween with 1 % BSA for one hour with continuous shaking The membrane was then washed 3X in PBS/Twecn and the ECL immunodetection system (Amersham) was used to detect the level of expression of prostaglandin endoperoxide synthases-2 20 RESULTS- The following compounds were tested and found lo be active (inhibited LPS induced PGHS-2 protein expression in rank order potency similar to that for inhibiting cytokine production as noted in assays indicated) 25 6-(4-Fluorophenyl)-2 3-dihydro-5-(4-pyndinyl)imidazoI2,l-b]thiazole and Dexamelhasone Several compounds were tested and found to be inactive (up to lOuM) 2-(4-Mcthylsulfinylphenyl)-3-(4-pyndvl)-6 7-dihydro-(5H)-pyrrolo[ 1,2-a]imidazole rolipram, phenidone and NDGA 30 None of the compounds tested was lound to inhibit PGHS-1 orcPLA2 protein levels in similar expenments SYNTHETIC EXAMPLES The invention will now be desenbed by reference to the following examples 35 whiLh are merely illustrative and are not to be construed as a limitation of the scope ot the present invention All temperatures are given in degrees centigrade, all solvents are highest available pumy and all reactions run under anydrous conditions in an argon atmosphere unless otherwise indicated 13 12 13 W0 96/216M PCT/US9f./UI094 -47- In the Examples, all temperatures ure in decrees Centigrade (°C) Muss spectra were performed upon a VG Zab mass spectrometer using fast atom bombardment, unless otherwise indicated 'H-NMR (hereinafter "NMR") spcctra were recorded al 250 MHz using a Bruker AjM 250 or Am 400 spectrometer Multiplicities indiuied are 5 s=singlet, d=doublet, t=tnplet, q=quartet, m=muluplet and br indicates a broad signal Sat indicates a saturated solution, eq indicates Ihe proportion ol a mol.ir equivalent of reagent relative to the principal reactant Flash chromatography is run over Merck Silica gel 60 (230 - 400 mesh) 10 Example 1 l-l3-(4-Morpholinyl1propv]1 4-f4-fluoronhenvl)-5-f4-pvndvnimida7.olc a) 4-fluorophenyl-tolvlthiomeihyltormamide A solution of p-fluorobenzaldehyde (13 1 milliliters (hereinafter mL), 122 milhmoles (hereinafter mmol) thiocresol (16 64 grams (hereinafter g), 122 mmol), 15 tormamide (15 0 mL, 445 mmol), and toluene (300 mL) were combined and healed to toluene reflux with azeotropic removal of H2O tor 18 h The cooled reaction was diluted with ElOAc (5()0 mL) and washed wiih said aq Na2C03(3 x 1(K) mL), satd aq NaCl (100 mL), dried (Na2S04), and conceniraied The residue was tnturatcd with petroleum ether, filtered and dried in vacuo lo afford 28 50 g of the title compound as a 20 white solid (85 %) melting point (hereinafter mp) =119- 120° b) 4 fluorophenyl-tolvl thiomelhvlisocvanide The compound of example 1(a) (25 g, 91 mmol) in CH2CI2 (300 mL) was cooled to -30° and with mechanical stirring POCI3 (11 mL, 110 mmol) was added dropwise followed by the dropwise addition of Et3N (45 mL, 320 mmol) with the 25 temperature maintained below -30° Stirred at -30° for 30 min and 5° for 2 h diluted with CH2CI? (300 mL) and washed with 59c aq Na2CC>3 (3 x 100 mL), dried (Nd2S04) 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 CH2CI2 to afford 12 5 g (53%) of punfied isonilnle as a light brown, waxy solid IR (CH2CI2) 2130 cm"' 30 c) Pvndine-4-carhoxaldehvde [4-Morpholinvlprop-3-vllimine Pyndme-4-carboxaldehyde (2 14 g, 20 mmoL), 4 (3-ammopropyI)morpholine (2 88 g, 20 mmol), toluene (50 mL) and MgS04 (2 g) were combined and stirred under argon tor 18 h The MgS04 was filtered off and the filtrate was concentrated and the residue was reconcentrated from CH2CI2 to afford 4 52 g (97%) of the uile compound 35 as a yellow oil containing less than 5% of aldehyde based on NMR ^HNMR (CD3CI) d 8 69 (d, J = 4 5 Hz, 2H), 8 28 (s, 1H), 7 58 (d, J = 4 5 Hz, 2H), 3 84 (m, 6H),2 44(m, 6H), 1 91 (m,2H) d) l-f3-(4-Morpholinvl>propvIl-4-(4-fLtioronhenvl)-5-f4-pvridvl')imida7olf! 13 1213 WO 96/216M -48 PCT/US96/01(194 The compound of example 1 (b)(1 41 g, 5,5 mrnol), and the compound of example l(c)(l 17 g, 5 0 mmol) and CH2CI2 (10 mL) were tooled 1115 "C 15 7-inuzabicyclo|4 4 0]dec-5 enc, henceforth referred U> as TBD, (0 71 g 5 0 mmol) was added and the reaction was kept at 5 °C for 16 h, diluted wiih ElOAc (80 mL) and 5 washed with said ai| NaoCO^ (2x15 mL) The EtOAc was extracted with 1 N HC1 (3 x 15 mL), and the acid phases were washed with EtOAc (2 x 25 mL), layered with EtOAc (25 mL) and made basic by the addition of solid K2CO3 til pH 8 0 und ihen 10% NaOH til pH 10 The phases were separated and the aq was extracted with additional ElOAc (3 x 25 mL) The extracts were dned (K2CO3) conceniraied and the residue was crystahzed from acetone/hexane 10 afford 0 94 g (51%) of ihe utle compound mp = 149- 150 0 Example 2 5-(2-nmino-4-pvnmidinvl)-4-(4 fluororhenvn-l-(4-(1.3-dioxvcvclopentvl) cyclohexyl) imidazole a) l-Amino-4-(1.3-dioxvcvlopenivncvclohexanc 1,4-Cyclohexanedione monoethvlene ketal (15 6 g, 0 10 mol) H2O (170 mL) and Na2C03 (27 8 g) were combined and NH2OH • HC1 (27 8 g, 0 40 mol) was added in small portions The resulung mixture was stirred tor 30 min Extraction with ElOAc, drying (Na2S04) and concentration afforded 17 lg (100%) of 4-(l,3-dioxycylopentyl) cyclohexanone oxime The oxune (6 O g, 35 mmol), Raney Ni (ca 3 mL as a suspension in pH 7 0 H2O) and EtOH (abs) were combined and shaken at 50 psi H2 for 16 h The catalyst was filtered off and ihe filtrate was concenlratcd and distilled to afford 2 4 g (60%) of the bile compound (bp = 68°, 0 18 mm) b) 2-Aminopvrimidine-4-carhoxrt)dehvile (4-ethvlene ketal-Ncvclohexvl) lmine The product ol the previous step 2 (a), and the product of Example 3 (b), prepared below, were reacted by the procedure of 1(c) except that the solvent was CH2CI2 and no drying agent (MgS04) was required to afford the title compound as a yellow oil c) 5-(2-amino-4-pvnmidinvl)-4-(4-f1uorophenvD-l-l'4-dioxycvclohexvl')imiria7.olft Following the procedure of example 1 (d) except using the compound of the previous step as the lmine altorded the title compound ESI mass spectrum MH+ = 396 Example 3 2-Aminnpvnmidinp-4-carhoxaldehvrift a) 2-Aminopvnmidine-4-carhoxaldehvde dimethyl acetal 13 1213 W0 9fi/21fiS4 FCT/US96/01094 - 49- Dimethyltormnmide dimethyl acctal (55 mL 0 41 mol), and pyruvic aldehyde dimethyl acctal (50 mL, 0 41 mol) were combined and heated to 100° tor about 18 hours Methanol was removed in vacuo to afford an oil A solution of NuOH (18 g, 0 45 mol) in H2O (50 mL) was added lo guanidine 5 HC1 (43 g. 0 45 mol) in H2O (100 mL), and ihe resulung solution was added lo the above described oil The resulting mixture was stirred at 23° for 48 h Filtration afforded 25g (50%) of the title compound b) 2-Aminopvrimidine-4-carhoxaldehvde The compound of the previous step (I 69 g, 10 mmol) and 3N HC1 (7 3 mL, 22 10 mmol) were combined and heated to 48° for 14h, cooled, layered with ElOAc (50 mL) and neutralized by the addition of NaHCOi (2 Ig, 25 mmol) in small portions The aq phase was extracted with EtOAc (5 x 50 mL) and the extracts were dried (Na2S04)and concentrated to afford 0 793 g (64%) of the title compound 15 Example 4 5-f2-aminp-4-pvnmidinvl)-4-f4-f1i)orophenvl)- l-(4-kclocvclohexvl)imida?nle The product of example 2 (1 27 g, 3 22 mmol) and 3 N HCL (12 4 mL) were combined and stirred at 23° for 16 h, combined with 10% aq Na2CC>3 (50 mL) and extracted with ElOAc The extracts were dned (Na2S04) and conceniratcd and flash 20 chromatographed (0- 4% MeOH) to afford 0 72 g (64%) of ihe utle compound as a white solid ESI mass spectrum MH+ = 352 Example 5 5-(2-amino-4-pvrimidinvl)-4-f4 fliinrnphenvl)-l-f4-cvclohexvl oximel lmirin/olr 25 The product of example 4 (351 g, 1 0 mmol) NH2OH • HC1 (278 mg, 4 0 mmol), H2O (6 mL), and CH3OH, (2 mL) were combined, Na2C03 (278 mg. 2 6 mmol) was added in small portions The mixture was stirred for 24 h, aq NaHC03 was added and the mixture was extracted with CH2CI2, concentrated and flash chromatographed with 0-8% MeOH to afford 0 248 g (677r) of the utle compound 30 Example 6 5»(2-amino-4-pvnimdinvlV4-(4-fhiornphenvlV1 -(4-cvclohexvl hvdroxvlamin^ imidazole The product ol example 5 (250 mg. 0 68 mmol), NaCNBH3 (42 mg. 0 68 mmol) 35 and MeOH (2 5 mL) were combined Methanolic HC1 (several drops) was added (pH < 3) and the mixture was surred for 1 h, diluted with 10% aq NaOH and extracted with EtOAc The extracts were dried (Na2S04) concentrated and flash chromatographed (0 -8% MeOH in CH2CI2) to afford 160mg (64%) ESI mass spectrum MH+ = 369 13 12 13 WO 96/21654 PCT/US96/01094 -50- Example 7 .S-f2-aminp-4-pvnTTnriinvn-4-(4-niinronhenv)1- l-(frfln.r-4-hvdrnxvurea') imidazole and 5-f2-amino-4-pvnrrndinvlM-f4-fliinrophenvl)-1-fcf.f-4-hvdmxvurca') imidazole 5 The product of example 6 was reacted by the procedure of Adams et al (WO 91/14674 published 3 October 1991) to afford a mixture of as and trans cyclohexyl hydroxyurea isomers Trituration of the mixture with CH2CI2 selectively dissolved the lis isomer (based on nmr) The solid was filtered off The filtrate was concentrated to afford 5-(2-amino-4-pynmiduiyl)-4-(4-fluorophenyl)-l-(cu-4-hydroxvurea) imidazole 10 SB 223768 containing ca 20% of the trans isomer based on nmr mp = 185 - 245 (dci.) The solid obtained above was redissolved m CH2Cl2/MeOH and conceniratcd til precipitation began Filtration afforded pure 5-(2-amino-4-pynmidwyl)-4-(4-fluorophenyl)-1-(/ranf-4-hydroxyurea) imidazole mp = 188 - 190° 15 Example 8 5-(2-amino-4-pvnmidinvlM-r4-fluoroph;nvl)-1-(ftYm.i-4-hvdroxvcvLlohexvn imidazole The product of example 4 (0 61 g, 1 74 mmol) and 1M NaBH4 in CH^OH were combined in CH^OH/THF (1 1,7 mL) and surred for 10 mm, the reaction was poured 20 into 10% aq NajCO^ (25 mL), extracted with EtOAc (4 x 50 mL) and dried (NaiSOj) Flash chromatography (0 - 8% CH^OH in CH2CI2) afforded 0 52 g (85%) of the title compound In methods analagous to those desenbed above and in the schematics herein the 25 following compound may be prepared Example 9 5-(2-amino-4-pynmidinyl)-4-(4-fluorophenyl)-l-(4-aminocyclohexyDimidazole Example 10 30 5-r4-(2-N-mcthvlamino)pvnmidinyn-4-C4-fluorophenvl)-l-f4-kp.tocvclohexvnimidazole a) 2-N-methvlaminopvnmidine-4-carboxaldehvde The utle compound was prepared as described in Example 3 using methyl guanidine HC1 *H NMR (CDCI3,400 MHz) 8 9 95 (s, 1H), 8 88 (d, 1H), 7 50 (, 1H), 3 54 (s 3H), 2 54 (s, 3H) 35 b) 2-N-methvlaminc>pvnmidine-4-carboxaldehvde-f4-ethvleneketal-l- lyclPhexyDimine The compound of example 10(a) (8 g 5 8 mmol) and the compound of example 2(a) ( 8 g 5 I mmol) were surred for 18 h in DMF (12 mL) Concentrauon under 13 12 13 WO 9G/216S4 PCTVUS96/01094 - 51 - vaccuum afforded the utle compound as a yellow oil 'H NMR (400 MHz, CDCI3) 5 8 34 (d, 1H), 8 15 (s, 1H). 7 13 (d lH),5 25(d 1H), 3 39 (m. 1H), 3 03 (d, 3H), 1 90 (m, 7H), 1 79 (m, 2H), 1 65 (m, 2H) c) 4-flnnrophenvl-tolvkulfnnvlmethvl formamide 5 Concentrated HC1 (15 mL) was added dropwise to a suspension of /^-toluene sulfwic acid sodium salt (30 g) in H2O (100 mL) and ?cr/-butyl methyl ether (50 mL) Alter stirring far 15 mm , the organic phase was removed and the aqueous phase was extracted with /erf-butyl methyl ether The organic phases were combined, dned (Na2S04), and concentrated almost to dryness Hexane was added and the resulting 10 solid was filtered to give the free acid (22 06 g") The free acid (140 6 mmol) was combined with p-fluorobenzaldehyde (22 mL, 206 mmol). formamide (20 mL, 503 mmol) and camphor sulfonic acid (4 g. 17 3 mmol) and stirred at 60 °C for 18 h The resulung solid was broken up and surred with methanol (35 mL), and hexane (82 mL) The mixture was filtered The large chunks were crushed and the resulting solid was 15 surred vigorously 5h in mcthanol/hcxane (200 mL, 1 3) The suspension was filtered to afford the title compound (27 08 g, 62 79r yield) ' H NMR (400 MHz, CDCI3) 5 8 13 (s, 1H), 7 71 (d, 2H), 7 43 (dd. 2H), 7 32 (d,2H),7 08 (I, 2H), 6 35 (d. 1H),2 45 (s. 3H) d) 4-fluoro-tolvlsulfonvlmethvl lstuvanide 20 A mixture of the compound from example 10(c) (2 01 g, 6 52 mmol) in ethylene glycol dimethyl ether (DME) (32 mL) was cooled to - 10°C Added dropwise was POCI3 (1 52 mL, 16 30 mmol) dissolved in DME (3 mL) keeping the internal temperature below -5°C Alter stirnng at -5°C lor 1 h , the reacuon was quenched with H2O and the product was extracted with EtOAc followed by an aqueous saturated 25 NaHCOi wash The organic phase was dned (Na2S04) and concentrated The residue was tnturated with petroleum ether and filtered affording the utle compound (1 70 g, 90% yield) as an orange brown solid IR (CH2CI2) 2135 cm-* e) 5-f4 f2-N-methvlamino)nvnmidinvll-4-f4-fluorophenvl)-1-r4-d.3-dioxvcvclopentvOcvclohexvnimidazole 30 The compound from example 10(b) (1 6 g, 5 84 mmol) was combined with the compound from example 10(d) (2 g 6 9 mmol) and powdered K2CO3 (1 2 g, 8 7 mmol) in DMF (12 mL) at 0°C for 3 h The mixture was slowly warmed to room temperature and stirred an additional 18 h EtOAc was added and the mixture was filtered, concentrated and taken up in H2O/E1OAC The resulting yellow solid was 35 filtered and purified by flash chromatography (silica gel) eluting with 5% MeOH/CH2Cl2 to afford the title compound ( 50 g, 29% yield) JH NMR (400 MHz, CDCI3) 8 8 16 (d, 1H). 7 78 (s. IH), 7 45 (q, 2H), 6 99 (t, 2H), 6 40 (d. 1H). 5 70 (m, 13 12 13 WO 96/21654 -52 - PCT/US96/01094 IH), 4 74 (m, IH), 3 99 (s, 4H), 3 05 (d, 3H). 2 20 (M, 2H), 2 04 (q, 2H), 1 89 (dd 2H), 1 68 (m, 3H) 0 5-[4-f2-N-methvlamino)pynm»linvn-4-(4-fluorophenvl)-1 -f4-kpmcvclnhpxvnimidazole 5 Following the procedure of example 4 except using the compound of example 10(e) (50 g, 22 mmol), the utle compound was obtained ( 37 g, 78% yield) mp 232 5 - 233 5°C lH NMR (400 MHz, CDCI3) 5 7 97 (d, IH). 7 69 (s. IH), 6 89 (t, 2H), 6 24 (d, IH), 5 08 (m, IH), 3 25 (s, IH), 2 91 (d, 3H), 2 39 (d, 5H). 2 08 (m. 2H), 1 92 (m, IH) 10 Example 11 5-f4-(2-N methvlaminp)pvrimidinvn-4-C4-fliiorophenvlVl-(rrfln.s-4-hydroxvcvclohexvDimidazole The utle compound was prepared following the procedure of example R exccpt 15 using the compound lrom example 11 (0 ( 49 g, 1 34 mmol) and recrystahzmg from EtOH/H20 to afford white crystals ( 38 g, 77% yield) mp 230 - 231 °c ' H NMR (400 MHz, CDCI3) 5 8 08 (m, IH), 7 70 (s, IH), 7 37 (q, 2H), 6 98 (t, 2H), 6 32 (d. IH), 4 67 (m. IH) 3 67 (m. IH), 3 00 (s, 3H), 2 18 (m, 2H), 2 07 (m, 2H), 1 75 (m, 2H), 1 37 (m, 2H) 20 Using an analagous methods to Example 11 the us isomer was also obtained 5-[4-(2-N-methylamino)pynmidinyl]-4-(4-fluorophenyl)-l-(nv 4-hydroxycyclohexyl)imidazole Example 12 5-14-(2-N-Methvlamino')pvrimidinyll-4-f4-fluorophenvl)-1-f4-(ci.T-25 pyrrohdinvl)cyclohexvllin»dazole and 5-[4-f2-N-mcthv1amino)nvnmiriinvn-4-(4-fluorophenvlVl-f4-(rrffn.y-l-nvrrolidinyncyclohexvllimidazole To a soluuon of pyrrolidine ( 3 mL, 3 6 mmol) ui MeOH (3 mL) was added 5% ethanohc HC1 ( 25 mL) The compound of example 10(f) (50 g, 1 26 mmol) was added followed by sodium cyanoborohydnde ( 05 g, 1 30 mmol) After stirring for 2 days, the 30 mixture was concentrated and the residue was suspended in H2O and brine and then extracted wtih EtOAc The organic phase was dried (Na?,S04) and concentrated The products were purified by flash chromatography (silica gel) eluting with 5% - 20% MeOH/CH2Cl2 with the en- isomer cluung from the column first to afford the title compounds 5-[4(2-N-melhylamino)pynmidinyl]-4-(r-fluorophenyl)-l-[4-cjs-35 pyrrohdinyl)cyclohcsyl]imidazole, mp 192 - 193°C, ^H NMR (400 MHz. CDCI3) 6 8 04 (s. IH), 7 95 (s IH), 7 35 (q, 2H), 6 95 (1,2H), 6 30 (d, IH), 4 59 (s, IH), 3 40 (m, IH), 2 97 (s, 3H) 2 58 (s. 4H). 2 13 (q, 2H), 2 00 (d, 2H), 1 84 (m 6H). 1 50 (t, 2H). and 5-[4-(2-N-methylamino)pynmidinyl]-4-(4-fiuoropheny])-l-[4-(wms- 1-pyrrolidinyl)- 13 12 13 WO 96/2165-1 -53 - PCT/UG96/01094 cycloh-xyUimidazole mp 155 - 156°C, lH NMR (400 MHz CDG3) 5 8 03 (d IH) 7 64 (s, IH), 7 35 (q, 2H), 6 95 (t, 2H) 6 28 (d, IH), 4 61 (t, IH) 3 12 (s IH) 2 96 (s IH) 2 58 vs. 4H), 2 25-2 05 (m 4H), 1 78 (s 4H). 1 70 (m, 2H), 1 35 (i, 2H) 5 Example 13 5-I4-r2-N-mcthvlamino)pvnmidinvn-4-f4-fluoronhcnvl)-l-(4-cthvnvl-4-hvdroxvcvclohexvDimidazole The compound from example 10(f) ( 50 g, 1 37 mmol) was suspended in dry THF (5 mL) and cooled lo -78°C Ethynylmagnesium bromide (13 4 mL, 6 17 mmol, 5 10 M in THF) was added and the mixture was surred for 2 h The reacuon was quenched with saturated aqueous NH4CI and the product was extracted with EtOAc The organic phase was dried (Na2S04) and concentrated The product was purified by flash chromatography (silica gel) eluung with 2% MeOH/CH2Cl2 to afford the title compound mp 233 5 - 234 5°C 1H NMR (400 MHz, CDCI3) 8 8 08 (d, 1H), 7 77 (s 15 IH), 7 38 (q 2H), 6 97 (t 2H), 6 31 (d, lH),4 68 (s. IH), 2 76 (s, 3H) 2 62 (s, IH) 2 10 (m, 6H) 1 63 (q 2H) Example 14 S-f4-(2 N-methvldmino^pvnmidinvn-4-r4-fluorophenvn-1 -(4-amino-4-20 melhvl(-vclohexvl)imidazole a) 5-r4-(2-N-methvlamino)pvnmidinvll-4-('4-f1uorophenvn- l-(4-hvdroxv-4-mcihvlcvclohexvl)imida/ole Following the procedure of example 13 except using methylmagnesium bromide, the utle compound was obtained (769f> yield) as a 1 1 mixture of as- and 25 trans- isomers >H NMR (400 MHz, CDCI3) 5 8 13 (s IH) 7 79 (s 5H),7 72(s, 5H) 7 43 (m 2H). 6 96 (m, 2H), 6 38 (m, IH), 5 45 (m, IH), 4 68 (m. 5H), 4 52 (m. 5H) 3 00 (d 3H), 2 30-1 40 (m, 8H), 1 36 (s, 1 5 H). 1 25 (s I 5H) b) M4 f2-N-methv]amino)pvnmidinvP-4-(4-fluorophenvl)-l-(4-amino-4-methvlcvclohexvPimtdazole 30 A mixture of the compound from example 14(a) (28 g, 75 mmol), sodium cyanide (03 g) and H2SO4 ( 5 mL) was stirred for 18 h After diluting with H2O and adding 509c NaOH the mixture was refluxed for 4 h , then cooled and extracted with EtOAc The aqueous phase was made basic with 50% NaOH and was extracted with EtOAc The organic phase was dried (Na2S04) and concentrated The residue was 35 purified by flash chromatography (silica gel) eluung with Me0H/CH2Cl2/H20 (20 80 2) to attord the utle compound mp 186 - 192°C Example 15 13 12 13 WO 96/216^4 PCT/US96/01094 -54- S-[4-f2-N-methvlaminn>pvnrTndinvn-4-f4-nuoronhenvlVl-(4-acetamido-4-methvlcvclohexvllimidazole A mixture of the compound of example 14(b) ( 02 g, 05 mmol) and DMAP ( 0012 g, 01 mmol) in pyndine (1 mL) was cooled to 0DC Acetic anhydnde ( 009 mL) 5 was added and the mixture was warmed to room temperature After sumng for 18 h , the mixture was diluted with H2O and the product was extracted with EtOAc The organic phase was dned (Na2S04) and concentrated Flash chromatohraphy (silica gel) eluting with 0% - 5% MeOH/CH2Cl2 afforded the title compound (019 g, 90% vicld) mp 175 - 176°C 'H NMR (400 MHz, CDCI3) 5 8 14 (d, IH), 7 77 (s, IH), 7 43 (4, 10 2H), 7 00 (t, 2H), 6 40 (d, IH), 4 58 (m, IH), 3 03 (d, 3H), 2 41 (d, 2H). 2 09 (m, 2H). 2 02 (s, 3H), 1 82 (m, 2H), 1 40 (c, 3H), 1 37 (m 2H) In methods analagous lo Examples 1 to 15 above the following compounds may be made 15 Example 16 5-[4-(2-N-meihylamino)pyrimidinyl]-4-(4-fluorophenyl)-l-(4-hydroxy-4-methylcyclohexyl)imidazole, mp 160-161*C Example 17 5-[4-(2-N-mcthylamino)pynmidinyl)-4-(4-fluorophenyl)-1 -(4—oxiratiyJ-cyclohexyl)imidazole, m p 229-23(TC 20 Example 18 5-14-(2-N-Methvlamino)pvnmidinvll-4-(4-fluorophenvl)-l-('4-cvanomcthv)-4-hvdroxvcvclohexvnimidazole a) 4-Fluorophcnvl-tolvlsulfonomethvlformamide To a suspension of p-toluenesulfinic acid sodium sail (30 g) in H2O (100 25 mL) was added methyl t-butyl ether (50 mL) followed by dropwise addition of conc HC1 (15 mL) Alter stirnng 5 min , the organic phase was removed and the aqueous phase was extracted with methyl t-butyl ether The organic phase was dned (Na2S04) and concentrated to near dryness Hexane was added and the free acid was filtered 30 The p-toluenesulfinic acid (22 g, 140 6 mmol), p-fluorobenzaldehyde (22 mL 206 mmol), formamide (20 mL, 503 mmol) and camphor sulphonic acid (4 g, 17 3 mmol) were combined and stirred at 60" C 18 h The resulung solid was broken up and stirred with a mixture of MeOH (35 mL) and hexane (82 mL) then Tillered The solid was resuspended in McOH/hcxane (1 3, 200 mL) and stirred 35 vigorously to break up remaining chunks Filtration afforded the title compound (27 g 62 % yield) 'H NMR (400 MHz, CDCU) 5 8 13 (s, IH), 7 71 (d, 2H), 7 43 (dd, 2H), 7 32 (d, 2H), 7 08 (t. 2H). 6 34 (d IH). 2 45 (s, 3H) b) 4-FUiorophenvl-tolvlsulfonomeihvlisocyanide 13 12 13 WO 96/21654 PCT/US96/01094 -55- The compound in ihe previous step (2 Olg, 6 25 mmol) in DME (32 mL) was cooled to -10CC POCh (1 52 mL, 16 3 mmol) was added followed by the dropwise addition of tnethylamine (4 6 mL 32 6 mmol) in DME (3mL) keeping the internal temperature below -5'C The mixture was gradually warmed over 1 5 h , qucnched in HiO and extracted with EtOAc The organic phase was washed with saturated aqueous NaHCO^ dned (NaiSO*), and concentrated The resulung residue was triturated with petroleum ether and filtered to afford the utle compound (1 7 g, 90% yield) 5H NMR (CDClj) 5 7 63 (d, 2H), 7 33 (m, 4H), 7 10 (t, 2H) 5 60 (s, IH), 2 50 (s. 3H) 10 c) l-Amino-4-H .3-dioxvcvclopcntvl)cvclnhexane To a mixture of 1,4-cyclohexanedione monoethylcne ketal (27 6g, 177 mmol) and hydroxvlammc hydrochloride (49 2 g, 708 mmol) in H^O (250 mL) was added portionwise Na^COi (49 2 g, 547 mmol) After stirring I h, the mixture was cxiracted with EtOAc The organic phase was dned (Na;S04) and 15 concentrated affording 4-(l 3-dioxycyclopentyl)-cyclohcxanone oxime (27 5 g 90% yield) The oxime (27 5 g, 161 mmol), Raney Ni (ca 13 5 mL as a suspension in EtOH) and EtOH (200 mL) were combined and shaken al 50 psi H2 for <1 h The catalyst was filtered off and the filtrate was concentrated to afford the title 20 compound as a colorless oil (23 6 g, 93% yield) 'H NMR (CDCli) 5 2 64 (m, IH), 1 75 - 1 25 (m, 12 H) d) 2-N-Methvlaminopvnmidine-4-carboxvaldehvde dimethyl acetal Pyruvic aldehyde dimethyl acetal (277 mL, 2 3 mol) and N.N-dimelthyl lormamidc dimethyl acetal (304 mL, 2 3 mol) were stirred together at 100BC for 25 18 h The mixture was cooled and concentrated This crude product was added to a well surred solution of methyl guanidine hydrochloride (112 g) and NaOEt (74 g) and the resulting mixture was refluxed for 24 h then cooled, filtered, and concentrated The resulting residue was triturated with hot EtOAc and filtered over cehte The filtrate was concentrated affording the 30 title compound as a brown oil 'H NMR (CDC13) 5 8 33 (d, IH), 6 75 (d, IH), 5 10 (s, IH), 3 40 (s, 6H), 3 00 (s 3H) e) 2-N-Mcthvlaminopvrimidine-4-carhoxaldehvde A mixture of the compound from the previous step (10 04 g, 55 mmol) in 3N HC1 (45 mL) was stirred at 47'C for 24 h After cooling EtOAc was added 35 followed by the addition of solid NaHCOj The aqueous phase was extracted with EtOAc (4 x 100 mL) The organic phases were combined, dned (Na2S04), and contrated to afford the utle compound as a yellow foam 'H NMR (CDC13) 5 9 88 (s IH). 7 33 (d. IH), 7 Ol (d. IH), 2 05 (s, 3H) 13 12 13 WO 96/21654 PCT/US96/01094 -56- f) 2-N-Methvlamino-4-carhoxjldehvdef4-pihvIcne ketal cvclohexvnimine A mixture ol the compound from the previous step (9 5 g, 6 9 mmol) and l-amino-4 (l,3-dioxvcyclopentyl)cyclohexane prepared in example 18 (c) (10 8 c 6 9 mmol) were surred in DMF (150 mL) 18 h The utle compound was used 5 without any purification 'H NMR (CDClj) 8 8 34 (d, IH), 8 15 (s, IH), 7 13 (d IH) 5 25 (d, IH), 3 39 (m, IH), 3 03 (d, 3H), 1 90 (m, 7H0. 1 79 (m 2H), 1 65 (m, 2H) g) 5-[4-(2-N-Methvlaminopvnmidinlvn-4-f4-fluorophenvl)-l-(4-ethvlene ketal cvclohexvDimidazolc 10 To the crude product from the previous example in DMF cooled to OflC was added 4-fluorophenyl-iollylsulfonomcthylisocyanide prepared in example 1 (b)(20g 69 mmol) and K:COi (12 g, 87 mmol) The mixture was stirred al0°C for 3 h then gradually warmed to room temp and stirred for 18 h EtOAc was added and the mixture was filtered washing the solid with EtOAc H;0 was added 15 to the filtrate and the organic phase was separated, dned (NaiS04), and concentrated The residue was purified by flash chromatography (Silica gel, 2% MeOH/CHiClz) to alford the title compound as a yellow solid (10 7 g 38% yield) 'H NMR (CDCN) 5 8 16 (d, IH), 7 78 (s, IH), 7 45 (q, 2H), 6 99 <t, 2H) 6 40 (d IH), 5 70 (m,!H) 4 74 (m. IH), 3 99 (s. 4H), 3 05 (d, 3H), 2 20 (m 2H), 2 04 (dq, 20 2H), 1 89 (dd, 2H). 1 68 (m, 2H) h) 5-l4-(2-N-Methvlamino)Pvnmidinvll-4-f4-fluorophenvl)-l-C4-oxocvclohexvllimidazole A mixture ol the compound from the previous step (10 73 g, 26 23 mmol) in 3N HC1 (150 mL) was stin-ed 36 h then neutralized with saturated aqueous 25 Na^COi and filtered The solid was washed with water arid the aqueous mixture was extracted with EtOAc The organic phase was dned (Na^SO^) and concentrated giving the title compound as a pale yellow solid (7 9 g, 11% yield) mp 232 5 - 233 5"C l) 5-f4-(2-N-Methvlamino)pynmidinvll-4-r4-nuorophenvl)-l-r4-30 oxiranvlcvclohexyDimidazole To a suspension ol sodium hydride (0 07 g, 1 18 mmol, 60% suspension in mineral oil) in DMSO (1 2 mL) was added tnmethylsulfoxonium iodide (0 39 g, 1 78 mmol) The mixture was surred unul gas evoluuon ceased Added to this was the compound trom the previous step (0 50 g, 1 4 mmol) in dry THF (5 mL) 35 The resulting mixture was surred 4 h then poured into H20 and filtered The resulung solid was triturated with acetone/hexane to afford the title compound (4117 g, 77% yield) mp229-230*C 13 12 13 W0 96/216S4 PCT/US96/01094 -57- ]) 5 [4-f2-N-Meihvlamino1pvnmidinvll-4-f4-nuorophenv1>-1-f4-rvannmeihvl-4-hvdroxvcvclnhexvl'limidazole To a soluuon of the compound of from the previous step in dry THF (10 mL) was added dicthylaluminum cyanide (2 mL, 1M in toluene) After stirring at 5 70 C lor 1 h the mixture was cooled and qucnched with 10% NaOH and decanted The organic phase was decanted then concentrated The residue was purified by flash chromatography (silica gel, 5% MeOH/CHiCli) and the product was recr7Stalized from Et0H/H20 affording the utle compound as white crystalc mp 152 - 154*C 10 Example 19 5-l4-f2-N-Methvlamino^pvnmidinvn-4-f4-fhiorophcnvl)-l-(4-hvdroxv-4-hvdroxvmethvlcvclohexlv)imidazole a) A solution of the compound in example 18 (i) (0 084 g, 22 mmol) and 15 887r lormic acid (3 mL) was surred 1 h The mixture was concentrated and the residue was dissolved in MeOH Excess Et-^N was added and the mixture was stirred 24 h The mixture was concentrated and purified by flash chromatography (silica gel, 2% - 10% MeOH/CHiCb) The resulting white solid was tniurated with acetone/hexane to afford the title compound as a mixture of cis and trans 20 isomers (0 047 g, 53% yield) mp 125 - 130"C Example 20 5-14-f2-Amino)nvnmidinvl"l-4-f4-fluorophenvl)-1 -l4-hvdroxv-4-( 1-25 propvnvDcvilohexvnimidazole a) 2-Amino-4-carboxaldchvdef4-ethvlcne ketal cvclohexvDimine Following the procedure of example 18 (0 subsutuung 2- aminopynmidine-4-carboxaldehyde (prepared in Example 3) afforded the utle compound 'H NMR (CDC1,) 8 8 36 (d, IH), 8 16 (s, IH), 7 21 (d lH),5,13(m, 30 1H), 3 98 (s 4H), 2 00 - 1 40 (m, 8H) b) 5-f4-(2-amino)pvrimidinvll-4-(4-fluorophenvl)-l-(4-elhvlene ketal cvclohexvnimidazole Following the procedure of example 18(g) using the compound from the previous step aftorded the utle compound *H NMR (CDC10 8 8 29 (d, IH), 7 77 35 (s, IH). 7 45 (ij, 2H), 7 00 (i. 2H), 6 50 (d, IH) 5 12 (s 2H) 4 63 (m, IH), 4 00 (s, 4H), 2 17 (m 2H), 2 05 (m, 2H), 1 90 (m, 2H), 1 73 (m 2H) c) 5-14 (2-Armno1pvrimidinvn-4-f4-fluorophenvn-l-(4 oxocvclohe\vl)imida?o)e 13 12 13 WO 96/21654 PCT/US96/01094 -58- Following the procedure of example 1(h) except using the from the previous step afforded the utle compound as a white solid 'H NMR (CDC13) 6 8 02 (d. IH), 7 74 (s, 1H),7 32 (q, 2H). 6 94 (t. 2H), 6 28 (d. IH). 5 10 (m, IH), 2 93 (s, 3H), 2 44 (m, 6H), 2 12 (m, 2H) 5 d) 5-(Amino)pynmidinyll-4-(,4-nuorophenvl)-l-f4-hvdrQXv-2-propynvDcvclohexvllimidazole To a suspension of the compound trom the previous step (0 49 g, 1 4 mmol) in dry THF (30 mL) at -786C was added propynyl magnesium bromide [15 mL, 1M sin in THF, obtained by bubbling propyne gas (4 g) into dry THF (75 10 mL) followed by the addition of methyl magnesium bromide (26 mL, 78 mmol, 3M in Et^O) and surnng the mixture until gas evolution ceascs] The resulung mixture was gradually warmed to room temperature After quenching with saturated aueous NH4CI, the mixture was extracted with EtOAc The organic phase was dried (NaiS04) and conccntratcd The resulting residue was punfied by 15 flash chromatography (silica gel, 5% MeOH/CHjCh) affording the title compound (0 068 g 12% yield) as a white solid mp 231- 232'C Example 21 5-r4-(2-Amino)pvnmidinvn-4-(4-fluorophenvl)-l-(4-hvdroxv-4-methvl- 20 cyilPlKNyDimidazpJe a) 5-14-(2-Aminp)pvnmidinyn-4-(4-fluorophenvn-l-(4-pxiranvlcvclohexvPimidazole Following the procedure of example 18 (1) except using 5-[4-(2-amino)pvnmidinyl]-4-(4-fluorophenyl)-1 -(4-oxocyclohexyl)irmdazole prepared in 25 example 20 (c) afforded the tale compound as a yellow solid *H NMR (CDCU) 88 II (d. IH), 7 78 (s, IH), 7 38 (q, 2H), 6 99 (t, 2H). 6 43 (d, IH), 4 65 (m, IH), 2 71 (s 2H), 2 26 (m, 2H), 2 03 (m, 4H), 1 39 (m, 2H) b) 5-H4-(2-Amino)pvrimidinvn-4-f4-fluorophenvl)-l-(4-hvdroxv-4-meihvlcvclohexvDimidazole 30 To a suspension of the compound from the previous step (1 24 g, 3 39 mmol) in dry THF (40 mL) was added lithium aluminum hydnde (5 mL, 5 mmol, 1M in THF) The resulung mixture was refluxed 1 h then poured into 3N HC1 (200 mL) and made basic with solid NaHCO* After extracting with EtOAc, the organic phase was dned (Na2SO,i) and concentrated The resulung residue was 35 punfied bv flash chromatography (silica gel, 5% MeOH/CH2Cl2) then crystalized from EtOH/H;0 to afford the Utle compound as a white solid (0 06 g, 4 8 % yield) mp 110- lire 13 12 13 WO 96/2165-1 PCT7US96/01094 -59- In mctliods anidagous to Examples 1 to 18 above the following compounds may be made 5-|4-(2-N-methylamino)pynmidinyl]-4-(4-fluorophenyl)-l-(4-hvdroxy-4-isopropyl-cyclohexyDimidazole, 5 5-|4-(2-N-mcthy]dmino)pynmidinyl]-4-(4-fluorophenyl)-M4-hydroxy-4-phenyl-cyclohexyDimidazole, 5-[4-(2-N-methylamino)pyrtmidinyl]-4-(4-fluorophenyl)-l-(4-hydroxy-4-benzyl- cyclohexyDimiddzole, 5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophcny])-l-(4-hydroxv-4-cyanomethyl 10 cyclohexyDimidazole, 5-[4-(2-N-methyldmino)pynmidinyl|-4-(4-fluorophenyl) l-(4-hydroxy-4-(2- cyanoethyl)cyclohexyl)imidazolc, 5-[4-(2-N-methvlamino)pyrimid!nyl]-4-(4-fluorophenyl)-l-(4-hydroxy-4-(2-aminoethyl)cyclohexyl)imidazole, 15 5-[4-(2-N-methyldmino)pynmidinyl]-4-(4-lluurophenyl)-I-(4-hydroxy-4-(2-nitroethy])-cyclohexyPimidazole, 5-[4-(2-N-methylamino)pyniDidinyl]-4-(4-fluorophenyl)-l-(4-hydroxymethyl-4-amino- cvclohexyl)imiddzole 5-(4-(2-N-methylamino)pyrimidinyl]-4-(4 nunrophenyl)-l-(4-hydroxy-4-amino-20 cyclohexyl)imidazole, 5-[4-(2-N-mcthylamino)pynniidinyl]-4-(4-fluorophenyl)-l-(4-aniino- cyclohexyl)imidazole 5-[4-(2-N-methylamino)pyrimidiny])-4-(4-fluoropheny])-l-(4-hydroxy-4-thiomethyl cyclohcxyPimidazole 25 5-[4-(2-N-methylamino)pynmidinyl)-4-(4-fiuorophenyl)-l-(4-hydroxy-4-hydroxy methylcyclohexyDimidazole, 5-(4-(2-N-mcthylamino)pyrimidinyl]-4-(4-fluorophenyD-l-(4-hydroxy-4-aminomethyl- cyclohexyOimidazole, 5-{4-(2-amino)pynmidinyl]-4-(4-fluorophcnyl)-l-(4-amino-4-methyl-30 cyclohexyDimidazole 5-(4-(2-amino)pyrimidinyl]-4-(4-fiuorophenyl)-l-(4-hydroxy-4-methyl- cyclohexyDimidazole 5-[4-(2-amino)pynmidinyl]-4-(4-fiuorophenyP-l-(4-oxiranyl-cyclohexyl)imidazole 35 The above description fully discloses the invention including preferred emboGiments thereof Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims Without 13 12 13 </div>

Claims

1. WO 96/21654 -60- PCT/US96/01094 luriher elaboration il is believed that one skilled in ihe are can using the preceding descnpuon, uulize the present invention to its fullest extent Therefore the Example1; herein arc to be construed as merely lllustrauve and not a limitation of the scope of the present invention in any way The embodiments of the invenuon in which an exclusive 5 properly or pnvilege is claimed are defined as follows 13 12 13 P50314-3 - 61 - What is Claimed Is 1 A compound of the Formula 5 wherein Rl is 4-pyndyl, pynmidinyl, quinolyl, isoquinolmyl, quinazolin-4-yl, 1-imidazolyl or 1-benziraidazolyl, which ring is optionally substituted with one or two subsutuents 10 each of which is independently selected from Ci-4 alkyl, halogen, hydroxy], Ci-4 alkoxy, Ci-4 alkylthio, Cj-4 alkylsulfinyl, CH2OR12, amino, mono and di- Ci-6 alkyl subsututed amino, N(Rio)C(0)Rc or an N-heterocyclyl ring which ring has from 5 to 7 members and opuonally contains an addiuonal heteroatom selected from oxygen, sulfur or NR15, 15 R4 is phenyl, naphth-l-yl or naphth-2-yl, or a heteroaryl, which is opuonally subsututed by one or two subsutuents, each of which is independently selected, and which, for a 4-phenyl, 4-naphth-l-yl, 5-naphth-2-yl or 6-naphtii-2-yl subsutuent, is halogen, cyano, nitro, -C(Z)NR7Ri7, -C(Z)ORi6, -(CRioR20)vCORi2, -SR5, -SOR5, -OR12, halo-subsUtuted-Ci-4 alkyl, C1.4 alkyl, -ZC(Z)Ri2, -NRioC(Z)Ri6, or 20 -(CRioR20)vNRlOR20 and which, for other posiuons of subsutuuon, is halogen, cyano, -c(z)NRi3Ri4, -c(z)OR3, -(CRioR20)m"COR3, -s(0)mR3, -OR3, halo-subsUtuted-Ci-4 alkyl, -Ci-4 alkyl, -(CRioR20)m"NRioC(Z)R3, -NRioS(0)m'R8, -NRl0S(O)m'NR7Ri7, -ZC(Z)R3 or-(CRioR20)m"NRl3Rl4> v is 0, or an integer having a value of 1 or 2, 25 m is 0, or the integer 1 or 2, m' is an integer having a value of 1 or 2, ra" is 0, or an integer having a value of 1 to 5, Rc is hydrogen, Cj.g alkyl, c3.7 cycloalkyl, aryl, arylCi.4 alkyl, heteroaryl, heteroarylCi-4alkyl, heterocyclyl, or heterocyclylCi-4alkyl Ci-4 alkyl 30 R2 is an opuonally subsututed C3-7 cycloalkyl, or C3-7cycloalkylCi-io alkyl, R3 is heterocyclyl, heterocyclylCi-io alkyl or Rg, > 1 R5 is hydrogen, Cj-4 alkyl, C2-4 alkenyl, C2-4 alkynyl or NR7R17, excluding the raoeiues -sr5 bemg -SNR7ri7 and -sors berng -SOh| i ? . / -3 I R ~ _ ,m fz <■ I 7 R7 and R17 is each independently selected lrom hydrogen or Ci-4 alkvl or R7 and R17 together with the nitrogen to which they are attached form a heterocyclic ring ot 5 to 7 members which nng optionally contains an additional heteroatom selected lrom oxygen, sulfur or NR15, RS is Ci-io alley], halo-subsututed C ]_ 10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, aryl, arylC 1 -10 alkyl, heteroarvl, heteroarylC 1 -10 alkyl, (CR]0R20)nORll, (CRioR20)nS(0)mRis, (CR]oR20)nNHS(0)2RlS, (CRioR20)nNRl3Rl4, wherein the aryl, arylalkyl, heteroaryl heteroaryl alkyl may be optionally substituted, n is an integer having a value of 1 to 10, R9 is hydrogen, -C(Z)R] 1 or optionally subsututed Ci-io alkyl, S(0)2Rl8. optionally subsututed aryl or optionally subsututed aryl-Ci-4 alkyl, RlO and R20 is each independently selected trom hydrogen or C1-4 alkyl, Rl 1 is hydrogen, or Rig. Rl2 is hydrogen or R16, Rl3 and R14 is each independently selected from hydrogen or optionally subsututed Ci-4 alkyl, opuonally subsututed aryl or opuonally subsututed aryl-Ci-4 alkyl, or together with the nitrogen which they are attached form a heterocyclic nng ot 5 to 7 members which ring opuonally contains an addiuonal heteroatom selected from oxygen, sulfur or NR9 , Rl5 is hydrogen, Ci-4 alkyl or C(Z)-Ci-4 alkyl, R16 is C1-4 alkyl, halo-substituted-Ci-4 alkyl, or C3-7 cycloalkyl, Rig s Ci-io alkyl, C3-7 cycloalkyl, heterocyclyl, aryl, arylCi-io alkyl, heterocvclvl heterocyclyl-Ci-ioalkyl, heteroaryl or heteroarylalkyl / i->o\\gen vii a pharmacouticalK acccptable salt theicof

2. The compound according to Claim 1 wherein R1 is an opuonallv subsututed 4-pyndyl or 4-pynmindyl

3. The compound according to Claim 2 wherein the optional subsutuent is methyl ami 10, or methylamino

4. The compound according to Claim 2 wherein R4 is an opuonallv suosucuted phenyl 1'j'ullcc'uai n iv^othcxt f> £ M 7 k OF fj Z 2 0 A!J3 10£9 -63- T/n ^ /- 10 35 A t

5. The compound accoiding to Claim 4 wherein the phenyl is substituted one or more tunes independently by halogen -SR, -S(0)R> -OR,:, halo-substituted-CM alkjl or CM alkyl

6. The compound accoiding to anv of Claim 1 wherein R: is selected from optionally substituted C, to C\ i_\<-loalkvl or C4 oi C„ cyeloalkylCMalkvl

7. The compound accoidmg to (. laim 6 wheiem R, is selected from optionally substituted C, or Ch c\cloalk\ 1 S The compound accoiding to Claim 6 wherein the cycloalkvl nng may be substituted one to three times independently by halogen hydroxy, C, U) alkoxy, S(0)mC, lt)alk\l, wheiein m is 0 1 oi 2 amino c\ano nitro, NR7R17 group, C, ]0 alkyl, substituted alk\l wherein the subsutuents aie selected trom halogen, hydroxy, 15 nitro, cyano NR7R(7 S(0)mCMalkyl C(0)0R,| -0-(CH:)s0- and s is 1 to 3 -C(0)H, -O =N-ORu,-N(RU))-OH -N(0Rll)-C(0)-R(,, optionally substituted aryl, or optionally substituted aiylalkyl N(R10)C(O)X| C(0)0Rn optionally substituted alkvlene, oi optionally subsisted C, H)alkynyl, wherein Rb is hydrogen, a pharmaceuucally acceptable cauon, aroyl or a C i-io 20 alkanoyl group, r6 is nr19r21, 1-6' halosubstituted alkyl i-g, hydroxy subsututed alkyl 1-6, alkenyl 2-6. aryl or heteroaryl opuonally subsututed by halogen, alkyl halosubsUtuted alkyli-g, hydroxyl, or alkoxy [-6, R[9 is H or alkyli-6, and 25 R21lS H, alkyl^.g, aryl, benzyl, heteroaryl, alkyl subsututed by halogen or hydroxyl, or phenyl subsututed by a member selected from the group consisung of halo, cyano, alkyl\.\2, alkoxy halosubsUtuted alkyl 1-6, alkylthio, alkylsulphonyl, or alkylsulfinyl, or R19 and R21 may together with the nitrogen to which they are attached form a nng having 5 to 7 members, which members may be opuonally replaced by a 3Q heteroatom selected from oxygen, sulfur or nitrogen, and Xi is Ci-4 alkyl, aryl or arylCi-4alkyi. 9 The compound according to Claim 8 wherein the opuonal subsututents are hydroxy, aryl, arylalkyl, alkyl, alkynyl, NR7R17, NR7R17 Ci_6 alkyl, =0, =NORi 1, -NH(OH), -N(0H)-C(0)-NH2, cyanoalkyl, muoalkyl, or -0-(CH2)20- 10 The compound according to Claim 1 which is ilLI ECllJnL Pit "RTY OFFICc" or ni jffij P50314-3 -64- 5-(2-amino-4-pynmidinyl)-4-(4-fluorophenyl)-l-(4-(l,3-dioxycyclopentyl) cyclohexyl) imidazole, 5-(2-amino-4-pynmidinyl)-4-(4-fluorophenyl)-l-(4-ketocyclohexyl)imidazole, 5-(2-amino-4-pynmidinyl)-4-(4-fluorophenyl)-l-(4-cyclohexyl oxime) imidazole; 5 5-(2-amino-4-pynmidinyl)-4-(4-fluorophenyl)-l-(4-cyclohexyl hydroxylarnine) imidazole, 5-(2-amino-4-pynmidinyl)-4-(4-fluorophenyl)-1 -(/ra/ty-4-hydroxyurea) imidazole, 5-(2-amino-4-pyrimidinyl)-4-(4-fluorophenyl)-l-(czv-4-hydroxyurea) imidazole, 5-(2-amino-4-pvnmidinyl)-4-(4-fluorophenyl)-l-(4-hydroxycyclohexyl)imidazole, 10 5- [4-(2-N-methy lamino)pyrimidinyl] -4-(4-fluorophenyl)-1 -(4-ketocyclohexyl)-lmidazole, 5-[4-(2-N-methylamino)pynmidinyl]-4-(4-fluorophenyl)-l-(rranj'-4-hydroxy- cyclohexyl)imidazole, 5-[4-(2-N-methylamino)pynmidinyl]-4-(4-fluorophenyl)-l-(czj -4-hydroxy-15 cyclohexyDimidazole, 5-[4-(2-N-Methylamino)pyrimidmyl]-4-(4-fluorophenyl)-l-[4-(cw-pyrrolidmyl)- cyclohexyl]imidazole, 5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-l-[4-(rran.y--l-pyrrohdinyl)-cyclohexyl]imidazole, 20 5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-l-(4-ethynyl-4-hydroxy-cyclohexyl)iraidazole, 5-[4-(2-N-methylamino)pynmidinyl]-4-(4-fluorophenyl)-1 -(4-( 1 -propynyl)-4- hydroxycyclohexyl)imidazole, 5-[4-(2-N-methylamino)pynmidinyl]-4-(4-fluorophenyl)-l-(4-amino-4-methyl-25 cyclohexyDimidazole, 5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-l-(4-acetaniido-4-methyl- cyclohexyl)imidazole, 5-[4-(2-N-methylaraino)pynraidinyl]-4-(4-fluorophenyl)-l-(4-hydroxy-4-methyl-cyclohexyl)imidazole, 30 5-[4-(2-N-methylamino)pynmidinyl]-4-(4-fluorophenyl)- l-(4-oxiranyl-c y c lohexy l)imidazole, 5-[4-(2-N-Methylamino)pyrimidinyl]-4-(4-fluorophenyl)-l-(4-cyanomethyl-4- hydroxycyclohexyl)imidazole, 5-[4-(2-N-Methylamino)pyrimidinyl]-4-(4-fluorophenyl)-l-(4-hydroxy-4-35 hydroxymethylcyclohexly)imidazole, _ ^ 5-[4-(2-Amino)pynmidinyl]-4-(4-fluorophenyl)-l-[4-hydroxyU-(l-=propynyl)- L, ,Tor,,x u ol i ' £ cyclohexyl]inndazole, f | ' 2 I ;' K33 I - 65 - A \ 7 \J> . li ' ' 5-[4-(2-Amuio)pyrimidinyll-4-(4-fluorophenyl)-l-(4-hydroxy-4-methyl-cyclohexyl)imidazole, or a pharmaccutically acceptable salt thereof 11 A pharmaceutical composition comprising a compound according to any of 5 Claims 1 to 10 and a pharmaceuucally acceptable earner or diluent 12 Use ol a compound ol Formula (1) accoiding to any ot Claims 1 to 10 in the manufacture ot a medicament loi use in Heating a cytokine mediated disease 10 13 1 he use accoiding to Claim 12 wheiein the cytokine mediated disease is selected trom iheumatoid aulnitis iheumatoid spondylitis osteoarthritis, gouty aithritis and other atthittic condition sepsis, septic shock, endotoxic shock, gram negatn e sepsis toxic shock syndiome stioke asthma adult lespiratorv distress syndrome cerebral malatia, chronic pulmonaiv mllammatoiy disease silicosis, 15 pulmonaiv saicososis bone lesoiption disease osteopoiosis, lepertusion injury, graft vs host leaction allogialt rejection Ciohn's disease ulcerative colitis or pyresis 14 The use according to Claim 12 wherein the disease state is mediated by IL-1, 11-6, IL-8, oi TNF 20 15 The use accoiding to Claim 13 wherein the cytokine mediated disease state is asthma, osteoporosis oi aithritis 16 Use ot a compound ot Formula (1) according to any ot Claims 1 to 10 in the 25 manufacture of a medicament toi use in treating inflammation 17 Use of a compound ot Formula (1) according to any of Claims 1 to 10 in the manufacture of a medicament toi use in treating osteoporosis 30 18 Use of a compound of Fotmula (I) according to any ot Claims 1 to 10 in the manufacture of a medicament tor use in heating a CSBP/RK/p38 kinase mediated disease 19 The use according to Claim 18 wherein the CSBP/RK/p38 kinase mediated 35 disease is selected from rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic condition sepsis septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, stroke, asthmas-adult— b F I'^icltECiUAL PROPERTY OFFICtl OF NZ I 2 0 AUG 1999 RECEIVED 5 10 15 20 25 30 mT (•' r ' ' .1 0 *7 JU ^ li li / respiratory distress syndrome, stroke, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcososis, bone resorption disease, osteoporosis, reperfusion injury, graft vs host reaction, allograft rejections, Crohn's disease, ulcerative colitis or pyresis 20 A process for preparing a compound ot Formula (I) as defined in Claim 1 which comprises reacting a compound of the Formula (II) • Ar—S(0)p (ii) with a compound of the Formula CM)1 FW ^NR2 H 0® wherein p is 0 or 2, and a base strong enough to deprotonate the isonitrile moiety of Formula (II), and Ri, R2 and R4 are as defined in Claim 1 or are precursors of the groups Ri, R2 and R4 and Ar is an optionally substituted phenyl group, and thereafter if necessary, converting a precursor of Rj, R2 and R4 to a group Rj, R2 and R4 21 The process according to Claim 20 wherein the reacuon, when p=0, utilizes TBD as a base 22 The process according to Claim 20 wherein, when p=2, the base is an amine, a carbonate, a hydnde, or an alkyl or aryl lithium reagent 23 The process according to Claim 20 wherein the lmine of Formula (HI), is isolated prior to reacuon with Formula (II) .J7ELLEGTUAL PfiCVEfiTY QFRCfT OF N Z ; 2 0 AUG 1999 J RECEIVED - 67- 10 15 20 25 30 24 The process according to Claim 20 wherein the mune ol Formula (111), is formed in situ prior to reaction with Formula (II) 25 The pioccss accoiding to Claim 24 wherein the imine is formed in situ by reacting an aldehyde ot the formula R(CHO, wherein R, is as defined lor Formula (I), with a primary amine of the formula R2NH2. wherein R2 is as defined for Formula (I) 26 The process according to Claim 25 wherein formation of the imine in situ utilizes dehydrating conditions 27 The process according to Claim 25 wherein the solvent is N,N-dimethyl-formaraide (DMF), halogenated solvents, teuahydrofuran (THF), dimethylsulfoxide (DMSO), alcohols, benzene, or toluene, or DME 28 The process according to Claim 25 wherein the aldehyde R,CHO is a pvnmidine aldehyde of the formula wherein X is NHRa and Xi is hydrogen, or is defined as the optional substituent group on the R, moiety in Formula (I) according to Claim 1 29 The process according to Claim 25 wherein the primary amine R2NH2 is a C3-7 cycloalkyl amine, C3.7 cycloalkyl Ci-ioalkyl amine, all of which may be optionally substituted 30 The process according to Claim 29 wherein the R, moiety of the R,NH2 is 4- hydroxycyclohexyl, 4-hydroxycycIohexyl, 4-ketocyclohexyl, 4-oxiranylcyclohexyl, 4-methyl-4-hydroxy cyclohexyl, 4-isopropyl-4-hydroxy cyclohexyl, 4-pyrrolinindyl-cyclohexyl, 4-methyl-4-aminocyclohexyl, 4-methyl-4-acetamidocyclohexyl, 4-phenyl-4-hydroxy cyclohexyl, 4-benzyl-4-hydroxy cyclohexyl, I-propenyl-4-hydroxy, 4-hydroxy-4-aramo-cyclohexyl, 4-aminomethyl-4-hydroxy cyclohexyl or 4-(l,3-dioxycyclopentyl) cyclohexyl 31 The process according to Claim 20 wherein th&.campnund of Formula (D is j IMltLLECTUAL PROPERTY OFFICE] OF NZ 2 0 AUG 1999 RECEIVED P50314-3 5-{2-arnino-4-pynmidinyl)-4-(4-fluorophenyl)-l-(4-ketocyclohexyl)imidazole, 5-{2-amino-4-pynmidinyl)-4-(4-fluorophenyl)-1 -(4-cyclohexyl oxirae) imidazole, 5-(2-amino-4-pynmidinyl)-4-(4-fluorophenyl)-l-(4-cyclohexyl hydroxylarnine) imidazole, 5 5-(2-arnino-4-pynmidinyl)-4-(4-nuorophenyl)-l-(;ronj-4-hydroxyurea) imidazole, 5-(2-arnino-4-pynmidmyl)-4-(4-fluorophenyl)-l-(ci5-4-hydroxyurea) imidazole, 5-(2-amino-4-pynmidinyl)-4-(4-fluorophenyl)-l-(4-hydroxycyclohexyl)imidazole, 5-[4-(2-N-raethylamino)pynmidinyl]-4-(4-fluorophenyl)-l-(4-ketocyclohexyl)-imidazole, 10 5-[4-(2-N-methylamino)pyiimidinyl]-4-(4-fluorophenyl)-l-(rra/w-4-hydroxy-cyclohexyl)imidazole, 5-[4-(2-N-methylaraino)pyryindinyl]-4-(4-fluorophenyl)-l-(cj.y -4-hydroxy- cyclohexyl)iroidazole, 5-[4-(2-N-Methylamino)pynmidinyl]-4-(4-fluorophenyl)-l-[4-(c/5-pyrrohdinyl)-15 cyclohexyljunidazole, 5-[4-(2-N-methylamino)pyriraidinyl]-4-(4-fluorophenyl)-l-[4-(/ra^5-l-pyiTolidinyl)- cyclohexyljunidazole, 5-[4-(2-N-methylamino)pynmidinyl]-4-(4-fluorophenyl)-l-(4-ethynyl-4-hydroxy-cyclohexyl)imidazole, 20 5-[4-(2-N-methylamino)pynmidinyl]-4-(4-fluorophenyl)-l-(4-(l-propynyl)-4-hydroxycyclohexyl)Lmidazole, 5-[4-(2-N-methylaraino)pynroidinyl]-4-(4-fluorophenyl)-l-(4-amuio-4-methyl- cyclohexyl)imidazole, 5-[4-(2-N-raethylaraino)pynraidmyl]-4-(4-fluorophenyl)-l-(4-acetamido-4-raethyl-25 cyclohexyDimidazole, 5-[4-(2-N-methylarnmo)pynmidinyl] -4-(4-fluorophenyl)-1 -(4-hydroxy-4-methyl- cyclohexyl)im idazole, 5-[4-(2-N-methylarnino)pynmidinyl]-4-(4-fluorophenyl)-l-(4-oxiranyl-cyclohexyl)imidazole, 30 5-[4-(2-N-Methylamino)pynmidinyl]-4-(4-fluorophenyl)-l-(4-cyanomethyl-4-hydroxycyclohexyl)imidazole, 5-[4-(2-N-Methylammo)pyrimidinyl]-4-(4-fluorophenyl)-l-(4-hydroxy-4- hydroxymethylcyclohexly)imidazole, 5-[4-(2-Amino)pyrimidinyl]-4-(4-fluorophenyl)-l-[4-hydroxy-4-(l-propynyl)-35 cyclohexyDimidazole, 5-[4-(2-Amino)pyrimidmyl]-4-(4-fluorophenyl)-l-(4-hydroxy-|4-methyl:v['L"7" 1 u M up, j cyclohexyDimidazole, f'z -69- T A, \ *! O v*° "52 Use ol a compound ol Foimula (I) accoiding to any of Claims 1 to 10 in the manulactuie of a medicament loi use m inhibiting synthesis oi piostaglandin 5 endopeioxide synthase-2 (PGI1S-2) 33 The use accoiding to Claim 32 wheiein inhibition ol PGHS-2 is used in the prophylaxis oi theiapeutic tieatment ol edema levei, algesia neuiomuscidar pain, headache, cancel pain, oi aithntic pain 15 END OF CLAIMS 20 25 see also COMPLETE SPECIFICATION 30 35 IfJTELLECTUATpfiOr^OFFiCE OF NZ 2 0 AUG 1999 RECEIVED P50314-3 - 70 - 5-[4-(2-N-methylammo)pynmidinyl]-4-(4-fluorophenyl)-l-(4-acetamido-4-methyl- cyclohexyl)imida2ole, 5-[4-(2-N-methylamino)pyrimidinyl]-4-(4-fluorophenyl)-l-(4-hydroxy-4-methyl-cyclohexyl)imidazole, 5 5-[4-(2-N-methylaraino)pyiamidinyl]-4-(4-fluorophenyl)-l-(4-oxiranyl-cyclohexyDimidazole, 5-[4-(2-N-raethylaraino)pyrimxdinyl]-4-(4-fluorophenyl)-l-(4-hydroxy-4-hydroxy methylcyclohexyl)iraidazole, 5-[4-(2-N-methylamwo)pynnndinyl]-4-(4-fIuorophenyl)-l-(4-hydrory-4-cyanornethyl 10 cyclohexyl)irmdazole 5-[4-(2-Araino)pynraidinyl]-4-(4-fluorophenyl)-l-[4-hydroxy-4-(l-propynyl)- cyclohexyl]irnidazole, 5-[4-(2-Araino)pynraidinyl]-4-(4-fluorophenyI)-1 -(4-hydroxy-4-ixiethyl-cyclohexyl)imidazole, 15 or a pharmaceuucally acceptable salt thereof VI | or ' L lJ* Mv. - I f:. p -<-> ~3 .j w - n