CA2242974A1 - Novel substituted imidazole compounds - Google Patents

Abstract

Novel 1,4,5-substituted imidazole compounds and compositions for use in therapy as cytokine inhibitors.

Description

WO 97t25046 PCT~USg7~00~2 NOVEL SUB~il'll U 1~ IMIDAZOLE COMPOUNDS

This invention relates to a novel group of imi~7ole compounds, processes for thepr~3~alion thereof, the use thereof in treating cytokine m~ te-l ~i~e~es and S ph~rm~elltic~l compositions for use in such therapy.

p,ACKGROUND OF THE INVENTION
Interleukin-l (IL-l) and Tumor Necrosis Factor (TNF) are biological sub~lances produced by a variety of cells, such as monocytes or macrophages. IL-l has been 10 demon~tr~t~rl to mP-1i~t- a variety of biological activities thought to be i~ u~L~lL in ;mmlm- regulation and other physiological co~Titions such as in 11~,, ....~1 ion [See, e.g., Dinarello et al., Rev. Tnfect. Disease~ 6, S1 (1984)]. The myriad of known biological activities of IL-l include the activation of T helper cells, induction of fever, s~imlll~tion of prost~gl~n-lin or collagenase production, neutrophil chemotaxis, induction of acute phase lS proteins and the suppression of plasma iron levels.
There are many disease states in which excessive or unregulated IL- 1 production is jmrli~tt~d in exacerbating and/or c~ in~ the disease. These include rh~llm~toid arthritis, osteoarthritis, endotoxemia and/or toxic shock syndrome, other ~ute or chronic infi~mm~tory disease states such as the inT~ y reaction in~ e-l by endotoxin or 20 infl~mm~tory bowel ~ e~e; tuberculosis, atherosclerosis, muscle degelleldliûn, cachexia, psoriatic arthritis, Reiter's syndrome, rhellm~t~ "iLis, gout, traumatic arthritis, rubella arthritis, and acute synovitis. Recent evidence also links IL-1 activity tO diabetes and pancreatic B cells.
Dinarello, J. C1;T1;t'~1 Immunolo~y~ 5 (5), 287-297 (1985), reviews the biological 2~ activities which have been attributed to IL- 1. It should be noted that some of these effects have been descAbed by others as indirect effects of IL-l.
Fx-~e~cive or unregulated TNF production has been impli~t.ofl in m~ tin~ or exacell,alillg a llUllll of ~ice~ces including rh~lTm~foid arthritis, rh~llm~toid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; sepsis, septic shock, endotoxic 30 shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral m~l~ri~, chronic pulmonary infl~mm~tory flice~se, silicosis, pulmonary sarcoisosis, bone resorption dice~ces, reperfusion injury, graft vs. host reaction, allograft rejections, fever and myalgias due to infection, such as infll~ 7~ cachexia secondary to infection or m~lig~n~y, cachexia, secondary to acquired immllne deficiency syndrome (AIDS), AIDS, 35 ARC (AIDS related complex), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, or pyresis.

W O 97/25046 PCT~US97/00529 AIDS results from the infection of T lymphocytes with Human Immunodeficien.~y Virus (HIV). At }east three types or strains of HIV have been identified, i.e., HIV-1, HIV-2 and HIV-3. As a consequence of HIV infection, T-cell m~ ted immnnity is impaired a~nd infected individuals manifest severe opportunistic infections and/or Imll~u~l neoplasrns.
5 EIIV entry into the T lymphocyte requires T lymphocyte activation. Other viruses, such as HIV- I, HIV-2 infect T lymphocytes after T Cell activation and such virus protein expression and/or replication is m~o~iAt~A or mAintAined by such T cell activation. Once an activated T lymphocyte is infected with HIV, the T lymphocyte must continue to be mAintAined in an activated state to permit HIV gene e~ll,ssion and/or HIV replication.
10 Monokines, ~perifir~1y TNF, are impli~t~cl in activated T-cell m~Ai~te-l HIV protein e~ es~.ion and/or virus replication by playing a role in m~int~ining T lymphocyte activation. Therefore, hltG,rGlGllce with monokine activity such as 'r.y inhibition of monokine production, notably TNF, in an HIV-infected individual aids in limitin~ the ~Ai~.t~nAnr~e of T cell activation, thereby re~ ing the progression of HIV infectivity to 15 previously uninfected cells which results in a slowing or elimin~tion of the progression of immllne dysfunction caused by HIV infection. Monocytes, macrophages, and related cells, such as kupffer and glial cells, have also been implicated in ~ An~e of the HIV
infection. These cells, like T-cells, are targets for viral replication and the level of viral replication is (lepenf~nt upon the activation state of the cells. Monokines, such as TNF, 20 have been shown to activate EIIV replication in monocytes and/or macrophages [See Poli, et ~L. Proc. Natl. Acad. Sci., 87:782-784 (1990)], Illeref~e, inhibition of monokine production or activity aids in limiting HIV progression as stated above for T-cells.
TNF has also been implicated in various roles with other viral infections, such as the cyt- ~nt-~Ali~ virus (CMV), inflllen~ virus, and the herpes virus for sirnilar reasons as those 25 noted.
Interleukin-8 (IL-8) is a chemotactic factor first id~ntified and characterized in 1987. IL-8 is produced by several cell types in- lu-lin~ mononllcl~r cells, fibroblasts, endothelial cells, and keratinocytes. Its production from endothelial cells is in~lllce(l by IL-1, TNF, or lipopolysachharide (LPS). Human IL 8 has been shown to act on Mouse, 30 Guinea Pig, Rat, and Rabbit NeuLI~hils. Many dirr~r~ l names have been applied to IL-8, such as neutrophil attractant/activation protein-l (NAP-1), monocyte derived neutrophil chemotactic factor (MDNCF), neutrophil activating factor (NAF), and T-cell lymphocyte chemotactic factor.
IL-8 stim~ tes a number of functions in vitro. It has been shown to have 3~ chemoattractant plo~ellies for neutrophils, T-lymphocytes~ and basophils. In addition it induces hic~mine release from basophils from both normal and atopic individuals as well as lysozomal enzyme release and ~t;spilalory burst from neutrophils. IL-8 has also been shown to increase the surface exples~ion of Mac-1 (CD1 lb/CD18) on neutrophils without de novo protein synth~si~, this may con~ uL~ to increased adhesion of the n~ u,~hils to vascular endothelial cells. Many (li~e~ces are char~rto,ri7ecl by massive neull~hi infiltration. Conditions associated with an increased in IL-8 production (which is 5 responsible for chemotaxis of neul ~ u~l into the infi~mm~tory site) would benefit by compounds which are suppressive of IL-8 production.
IL-l and TNF affect a wide variety of cells and tissues and these cytokines as well as other leukocyte derived cytokines are illl~.)Ull~ . and critical inflAmm~tory m~A;~tor.s of a wide variety of disease states and conditions. The inhibition of these cytokines is of benefit 10 in controlling, r~A~lcin,~ and alleviating many of these disease states.
There remains a need for l~ t, in this field, for colll~ou~ds which are cytokine suppressive anti-infl~mm~tnry drugs, i.e. compounds which are capable of inhibiting cytokines, such as IL-1, IL-6, IL-8 and TNF.

15 SUMMARY OF T~F. IN~IENTIC~N
This invention relates to the novel compounds of Formula (I) and rh~rm:~çeut~
compositions corn~)ri~in~ a compound of Formula (I) and a ph~rm~relltic~lly acceptable diluent or carrier.
This invention relates to a metnod of treating a CS~P/RK/p38 kinase m~Ai~ted Ai~e~e, in a Ill~ 1 in need thereof, which comprises ~Amini~t~,ring to said ".~.. ~1 an erre-;live ~mount of a compound of Formula (I).
This invention also relates to a method of inhibiting cytokines and the tre~tm~t of a cytokine m~Ai~ted Ai~e~e, in a m~mm~l in need thereof, which comprises ~mini~tering to said m~mm~l an effective amount of a compound of Formula (I).
This invention more specifically relates to a method of inhibiting the production of IL-l in a m~mm~l in need thereof which compri~es ~tlmini~tPring to said m~mm~l an effective amount of a compound of Formula (I).
This invention more speçific~lly relates to a method of inhibiting the production of IL-8 in a ~ 1 in need thereof which comprises ~Amini~terin~ to said m~mm~l an effective amount of a compound of Formula (I).
This invention more specifically relates to a method of inhibiting the production of TNF in a m~mm~l in need thereof which comprises ~-l...it~ e, ;..g to said m~mm~l an effective amount of a compound of Formula (I).

W O 97/25046 PCT~US97/00529 Accordingly, the present invention provides a compound of Pormula (I):
~2 N
I ~>
R4~ (I) Rl is a 4-pyridyl, or 4-pyrimidinyl ring which is substituted with a C1~ alkoxy or a C1-4 alkylthio group, and is additionally optionally sllbstitllt~sl indeFçnl1~ntly by Cl 4 aL~cyl, halogen, hydroxyl, Cl 4 alkoxy, Cl 4 alkylthio, Cl 4 alkylsulfinyl, CH20R12, .amino, mono and di- C1 6 alkyl substituted amino, N~Rlo)C(O)Rc or an N-heterocyclyl ring which ring has from 5 to 7 melllbe-~ and optionally contains an additional heteluato selected from oxygen, sulfur or NR1s;
R4 is phenyl, naphth- 1 -yl or naphth-2-yl, or a heteroaryl, which is optionally substituted by one or two subsli~ . ,Ix, each of which is indepçn~ntly S~leCtefl, and which, for a 4-phenyl, ~naphth-l-yl, 5-naphth-2-yl or 6-naphth-2-yl snbstit~lP-nt is halogen, cyano, nitro, -C(Z)NR7R17, -C(Z)OR16, -(CRloR2o)vcoRl2~ -SR5, -SORs, -OR12, halo-s~lbstitlltt~l-cl~ alkyl, Cl~ aLkyl, -ZC(Z)R12, -NRloC(Z)R16, or -(CRloR20)vNRloR20 and which, for other positions of substitution, is halogen, cyano, -C(Z)NR13R14, -C(Z)OR3, -(CRloR20)m~COR3, -S(O)mR3, -OR3, halo-~ub~ ul~d-C l 4 a1kyl, -Cl 4 aLkyl, -(cRloR2o)m~NRloc(z)R3~ -NRlos(o)mlR8 -NRlos(o)m~NR7Rl7~ -ZC(Z)R3 or-~cRloR2o)ml~NRl3Rl4;
v is 0, or an integer having a value of 1 or 2;
m is 0, or the integer 1 or 2;
20 m' is an integer having a value of 1 or 2, m" is 0, or an integer having a value of 1 to 5;
R2 is an optionally substituted heterocyclyl, or an optionally substituted heterocyclylC 1-10 alkyl moiety;
n is an integer having a value of 1 to 10;
25 Z is oxygen or sulfur;
Rc is hydrogen, C1 6 alkyl, C3 7 cycloaLkyl, aryl, arylCl ~ alkyl, helelu~
heteroarylCl 4alkyl, h~tc~u.:yclyl, or heterocyclylCl~alkyl Cl 4 alkyl;
R3 is heterocyclyl, heterocyclylcl-lo alkyl or R8;
Rs is hydrogen, C 1-4 aLkyl, C2 4 alkenyl, C2 4 alkynyl or NR7R17, eYch~lin~ the moeities -SR5 being -SNR7R17 and -SOR5 being -SOH;
R7 and R17 is each independently selected from hydrogen or Cl 4 alkyl or R7 and R17 together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 WO 97/25046 PCT~U597fO0529 m.ombe~c which ring optionally contains an ~ ition~l heteroatom 5~ ct~fl from oxygen, sulfur or NR15;
R8 is Cl lo alkyl, halo-~ub~liluLed Cl lo alkyl, C2 10 alkenyl, C2 10 alkynyL C3-7 cycloaLkyl, C5 7 cycloalkenyl, aryl, arylCl lo alkyl, heteroaryl, ht~telu~ylCl 10 alkyl, (CRloR2o)nORll, (cRloR2o)ns(o)mRl8~ (CRl0R20)nNHs(O)2Rl8~
(CRloR20)nNR13R14; wherein the aryl, atylalkyl, heteroaryl, heteroaryl alkyl may be optionally substituted;
Rg is hydrogen, -C(Z)Rll or optionally ~,ul;~LiLuLed Cl lo alkyl, S(O)2Rlg, optionally substituted aryl or optionally substituted aryl-Cl 4 alkyl;
10 R1o and R20 is each independently sel~cte~ from hydrogen or C1 4 alkyl;
Rl 1 is hydrogen, Cl 10 alkyl, C3 7 cycloaL~yl, heterocyclyl, heterocyclyl Cl loalkyl, aryl, arylCl 10 alkyl, heteroatyl or heteroarylC1 10 alkyl;
R12 is hydrogen or R16;
R13 and R14 is each indepe~lently sel~ct~d from hydrogen or optionally substituted Cl 4 alkyl, optionally substituted aryl or optionally substituted aryl-Cl 4 alkyl, or together with the nitrogen which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally cont~inc an additional heteroatom selected from oxygen, sulfur or NRg;
Rls is Rlo or C(Z)-Cl ~1 alkyl;
20 R16 is Cl~ allyl, halo-substituted-Cl 4 alkyl, or C3 7 cycloaLkyl;
Rlg is Cl lo alkyl, C3 7 cycloalkyl, heterocyclyl, aryl, aryll loalkyl, heterocyclyl, heterocyclyl-Cl 1oalkyl, heteroaryl or heteroaryl1 1oalkyl;
or a ph~rm~ euti~lly ~cep~hle salt thereof.

25 Dl~TAILED DESCRIPTION OF THE INVENTION
The novel compounds of Formula (I) may also be used in association with the veterinary tre~tm~nt of m~mm~l~, other than hllm~n~, in need of inhibition of cytokine inhibition or production. In particular, cytokine m~ te~ diseases for tre~tm~nt th~ ea Lically or plopllyl~rti(~lly, in ~nim~l~ include disease states such as those noted 30 herein in the Methods of Treatment section, but in particular viral infections. Examples of such viruses inclll~e, but are not limited to, lentivirus infections such as, equine infectious anaemia virus, caprine arthritis virus, visna virus, or maedi virus or retrovirus infections, such as but not limited to feline irnmuno-leficien~y virus (FIV), bovine irnrnunodeficiency virus, or canine immuno~1efi~iency virus or other retroviral infections.
In Formula ~I), suitable R1 moieties include a 4-pyridyl or a 4-pyrimidinyl ring.
The R1 moieties are substituted at least one time by a Cl 4 alkoxy or C1 4alkylthio moiety.
Preferably the R1 moiety is a C1 4 alkoxy group, such as n-butyl, isoproxy, ethoxy or W O 97/25046 PC~US97/00529 methoxy. A preferred ring pl~em~nt of the R~ substituent on the 4-pyridyl derivative is in the 2-position, such as 2-methoxy4-pyridyl. A pl~rc~led ring pl~ren~nt on the 4-pyrimidinyl ring is also at the 2-position, such as in 2-methoxy-pyrirnidinyl.Suitable additional ~ùb~Liluents for the R1 heteroaryl rings are Cl 4 alkyl, halo, OH, S Cl 4 alkoxy, Cl 4 alkylthio, Cl 4 aL~ylsulfinyl, CH20R12, amino, mono and di-Cl 6 alkyl substihlt~l amino, N(Rl~)C(O)RC, or an N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR15. The alkyl group in the mono- and di-Cl 6 aLkylsubsLiluled moiety may be halo ~ub~Liluled, such as in trifluoro- i.e., trifluoromethyl or trifluroethyl.
When the Rl optional substituent is N(Rlo)c(o) Rc, wll~lchl Rc is hydrogen, C1-6alkyl, C3 7 cycloalkyl, aryl, arylCl~ alkyl, heteroaryl, heteroarylCl 4aL~yl, heterocyclyl, or heterocyclylCl 4alkyl Cl~ alkyl, Rc is preferably C~1-6 alkyl; pr~relably Rlo is hydrogen.
It is also recognized that the Rc moieties, in particular the C1 6 alkyl group may be optionally s-lhstitute-l, preferably from one to three times, preferably with halogen, such as 1~ fluorine, as in trifluoromethyl or trifluroethyl.
Suitably, R4 is phenyl, naphth-1-yl or naphth-2-yl, or a heteroaryl, which is optionally substituted by one or two subsfitl~entc~ More preferably R4 is a phenyl or na~hLllyl ring. Suitable ~lbsLiLuLions 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 ~ubs~ .ent~ each of which sre20 independently selected from halogen, -SR5, -SOR5, -OR12, CF3, or -(CRloR2o)vNRl~)R2o~ and for other positions of substit~tion on these rings ~ d ~ubsLiLution is halogen, -s(o)mR3~ -OR3, CF3, -(cRIoR2o)ml~NRl3Rl4~ -NRlOC(Z)~3 and -NR~S(O)m~Rg. Preferred sub~ 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 25 and -SOR5 whel~in R5 is preferably a C1 2 alkyl, more preferably methyl; of which the fluoro and chloro is more preferred, and most especially preferred is fluoro. ~Gfelr~d ~iub.~ .nt~ for the 3-position in phenyl and naphth-l-yl rings include: halogen, especially fluoro and chloro; -OR3, especially Cl 4 alkoxy; CF3, NRloR2o~ such as amino; -NRloC(Z)R3, especially -NHCO(Cl l() alkyl); -NRlos(o)m~Rg~ especially -30 NHS02(Cl lo alkyl), and -SR3 and -SOR3 wherein E;~3 is ~lert;~Lbly a C1 2 allcyl, more preferably methyl. When the phenyl ring is disubstituted preferably it is two independent halogen moieties, such as fluoro and chloro, preferably di-chloro and more preferably in the 3,4-position. It is also plert;l,ed that for the 3-position of both the -OR3 and -ZC(Z)R3 moietitf~s, R3 may also include hydrogen.
3~ Preferably, the R4 moiety is an un~llb.stitute~l or substituted phenyl moiety. More preferably, R4 is phenyl or phenyl substituted at the 4-position with fluoro and/or ~ub~liLuLed at the 3-position with fluoro, chloro, C 14 alkoxy, methane-sulfo~mitlQ or .

6 PCT/US97~<70529 ~ce~ ln, or R4 is a phenyl di-substituted at the 3,4-position independently with chloro or fluoro, more preferably chloro. Most preferably, R4 is a 4-fluorophenyl.
In Formula (I), Z is oxygen or sulfur, preferably oxygen.
Suitably, R2 is an optionally s~ stitl-te~ heL~,u-;y~;lyl, or a heterocyclylCl lo alkyl 5 moiety.
When R2 is an optionally substituted heterocyclyl the ring is preferably a morpholino, pyrrolidinyl, or a piperidinyl group. When the ring is optionally substituted the substit~ t~ may be directly ~ eh.~cl to the free nitrogen, such as in the piperidinyl group or pyrrole ring, or on the ring itself. Preferably the ring is a piperidine or pyrrole, 10 more preferably piperillinç The heterocyclyl ring may be optionally ~l~h~ one to four times independently by halogen; C14 alkyl; aryl, such as phenyl; arylaL~yl, such as benzyl, wherein the aryl or aryl alkyl moiet;t~s themselves may be optionally ~ub~LiluLt;d (as in the definition section below~; C(O)ORl 1, such as the C(O)Cl 4 aL~yl or C(O)OH moieties, C(O)H; C(C))Cl 4 aLkyl, hydroxy substituted Cl 4 alkyl, Cl~ alkoxy, S~O)mC1 4 alkyl (wherein m is 0, 1, or 2), NRloR20 (wherein Rlo and R20 are indepçn~ 7tly hydrogen or C1 ~lalkyl).
Preferably if tne ring is a piperidine, the ring is attached to the imi~ e at the 4-position, and tne substitu~onts are ~I.,e~,Lly on the available nitrogen, i.e. al-Formyl-4-pipçriclin~o7 1-benzyl-4-pirç~i~inP 1-methyl4-piperidine, 1-etho~yc~lJollyl4-20 pir~oriciin~. If the ring is ~.u~sliLuLed by an aLkyl group and the ring is ,7tt~7~h~d in the4-position, it is preferably ~.ul~..LiLuLed in tne 2- or 6- position or both, such as 2,2,6,6-tetramethyl-4-piperidine. Similarly, if the ring is a pyrrole, tne ring is attached to the imin~7Ole at the 3-position, and the substituents are all directly on the available nitrogen.
When R2 is an optionally substituted heterocyclyl Cl lo alkyl group, tne ring ispreferably a morpholino, pyrrolidinyl, or a piperidinyl group. Preferably the alkyl moiety is from 1 to 4 carbons, more preferably 3 or 4, and most preferably 3, such as in a propyl group. Prcfell~d heterocyclic alkyl groups include but are not limited to, morpholino etnyl, morpholino propyl, pyrrolidinyl propyl, and piperidinyl propyl moieties. The heterocyclic ring herein is also optionally ~.ul~liLul~d in a similar manner to that inf~ tÇCl above for the direct ;.~ h.~ t of the heterocyclyl.
In all in.ct~n~çs herein where there is an alkenyl or alkynyl moiety as a substituent g;oup, the unsaturated linkage, i.e., the vinylene or acetylene linkage is preferably not directly ,.tt .C~hPt1 to tne nitrogen, oxygen or sulfur moieties, for in~t~nee in OR3, or for certain R2 moieties.
As used herein, "optionally substituted" unless specifically defined shall mean such groups as halogen, such as flllorine, chlorine, bromine or iodine, ~lyd~OXy; hydroxy .ubsLiLuLed Cl 1oaLI~yl; Cl lo alkoxy, such as me~oxy or ethoxy; S(~)m a~kyl, wherein m W O 97/25046 PCT~US97/005~9 is 0, 1 or 2, such as methyl tnio, methylsulfinyl or methyl sulfonyl; amino, mono & di-~.uI,~.LiluLcd amino, such as in the NR7R17 group; or where the 1~7R17 may together with the nitrogen to which they are ~tt~rhP(1 cyclize to form a 5 to 7 membered ring which optionally inchlAes an ~flAition~l heteroatom selected from O/N/S; Cl lo alkyl, cycloalkyl, or 5 cycloalkyl alkyl group, such as methyl, ethyl, propyl, isopluL,yl, t-butyl, etc. or cyclopropyl methyl; halosl1bstitlltçd Cl lo alkyl, such CF2CF2H, or CF3; halo~.ulr.!LiLuled Cl lo aLkoxy, such OCF2CF2H; an optionally substituted aryl, such as phenyl, or an optionally ~b..~ d arylalkyl, such as benzyl or ~h~ ~yl, W~ ll these aryl moieties may also be substituted one to two times by halogen; hyd~o~y; hydroxy substituted alkyl; Cl lo alkoxy; S(O)m 10 alkyl; amino, mono & di-sllbstitllt~ amino, such as in the NR7R17 group; alkyl, or CF3.
In a ~lcÇcllcd subgenus of compounds of Formula (I), Rl is 2-alkoxy-4-pyridyl or2-alkoxy-4-pyrirnidinyl; R2 is morpholinyl propyl, pipçriflinyl, N-benzyl~-piperidinyl, or N-methyl~-piperidinyl; and R4 is phenyl or phenyl substh~lte~ one or two times by fluoro, chloro, Cl 4 alkoxy, -S(O)m alkyl, mpth~npslllfonamido or ~ret~mitlo.
Suitable ph~n~relltically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sl-lrhllrir acid, phosphoric acid, m~th~.nP snlphonic acid, ethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, sllrrinic acid, film~r~r acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and m~n~1~1ic acid.
20 In addition, ph~rm~reutir~lly acceptable salts of com~oul,ds of Formula (I) may also be formed with a ph~....A~e~ll;r,~lly acceptable cation, for in~t~n~e, if a ~.ub~ t group co-ll~ es a carboxy moiety. Suitable ~ ""~rentir~lly acceptable cations are well known to t_ose skilled in the art and include zllk5~1in~, ~lk~lin~ earth, ammonium and qn~t.orn~ry ammonium cations.
The following terms, as used herein, refer to:
~ "halo" or "halogens", include the halogens: chloro, fluoro, bromo and iodo.
~ "Cl loaLI~yl" or "aLkyl" - both straight and branched chain radicals of 1 to 10 carbon atoms, unless the chain length is otherwise limite~, including, but not limited to, methyl, ethyl, n-propyl, zso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl and the like.
~ The term "cycloalkyl" is used herein to mean cyclic radicals, preferably of 3 to 8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like.
~ The term "cycloaLkenyl" is used herein to mean cyclic radicals, preferably of 5 to 8 carbons, which have at least one bond in~ ing but not lirnited to cyclopentenyl, cyclohexenyl, and the like.
~ The term "aL~enyl" is used herein at all occurrences to mean straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, inclll~ing, but WO 97/25046 PCT~US97/00529 not limited to ethenyl, 1~ ellyl, 2-propenyl, 2-methyl~ lu~,nyl, 1-butenyl, 2-butenyl and the like.
~ "aryl" - phenyl and naphthyl;
~ "hel~ alyl" (on its own or in any co,llbhl~lion, such as "h~ Lyloxy", or "hc;lel~o~yl aLkyl") - a 5-10 m~mhered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group con~ ting of N, O or S, such as, but not limitt~.-l, to pyrrole, pyrazole, furan, thiophene, quinoline, isoq-linolin~.7 quinazolinyl, pyridine, pyrimirlin~, oxazole, thiazole, thi~ 7.ole, triazole, imidazole, or l~ç,-7.i~ 7Ole.
~ "heterocyclic" (on its own or in any combination, such as "heterocyclylaL'cyl") - a saturated or partially lln~tllr~qted 4-10 lllelllb~lt;d ring system in which one or more rings contain one or more heteroatoms selected from the group co~ ting of N, O, or S; such as, but not limited to, pyrrolidine, pir~eri~lin~ e, morpholine, tetrahydro pyran, or imi~ 01i~1inP.
~ The term "aralkyl" or "h~L~loalylalkyl" or "heterocyclicalkyl" is used herein to mean Cl 4 alkyl as defined above ~tt~h~ to an aryl, heteroaryl or heterocyclic moiety as also fl~fin~-l herein unless otherwise inrlirslt~.
~ "sulfinyl" - the oxide S ~O) of the corresponding sulfide, the term "thio" refers to the sulfide, and the te~n "sulfonyl" refers to the fully oxidized S (~)2 moiety.~ "aroyl" - a C(O)Ar, wherein Ar is as phenyl, naphthyl, or aryl aLkyl deliv~live such as defined above, such group include but are not limited to benzyl and phenethyl.
~ "aLkanoyl" - a C(O)Cl lo alkyl ~hen,ill the aL~cyl is as defined above.
For the purposes herein the "core" 4-pyrimidinyl moiety for R1 or R2 is referred to N~

as the forrnula:
The compounds of the present invention may contain one or more asymm~tric carbon atoms and may exist in racemic and optically active forrns. All of these compounds are ;nslnd~l within the scope of the present invention.

Exemplifil-~l compounds of Formula (I) include:
1-(4-Piperidinyl)-4-(4-Flourophenyl)-5-(2-isopropoxy-4-pyrimidinyl) imi~l~7ole 1-(4-Piperidinyl)-4-(4-Fluorophenyl)-5-(2-methoxy-4-pyrimidinyl) imi~l~7.ole 5-(2-Hydroxy-4-pyrimidinyl)-4-(4-fluorophenyl)- 1 -(4-piperidinyl)imi-1~7.ole ~-(2-Methoxy-4-pyridinyl)-4-(4-fluorophenyl)- 1 -(4-piperidinyl)imirl~7Qle 5-(2-iso-Propoxy~pyridinyl)-4-(4-fluorophenyl) -1-(4-piperidinyl)imitl~7O1e 5-(2-Methylthio4-pyrimidinyl)-4-(4-fluorophenyl)- 1-(4-piperidinyl)imifi~7ole g WO 97/25046 PCT~US97/00529 5-(2-Methylthio4-pynrnidinyl)-4-(4-fluorophenyl)-1-[(1-methyl4-piperidinyl~imi(l~ole 5-(2-Ethoxy~-pyrimi(1inyl)-4-(4-fluorophenyl)-1-(4-piperidinyl)imi~1~7ole 1-(1-Ethylcarboxylpiperidin~yl)-3-(4-thiolll(,lhylphenyl)-5-r2-(thiomethyl)-S pyrimidin-4-yl]-im~ ole I-(1-Ethylcarbo~-yl~ idine~-yl)-4-(4-methylsulfinylphenyl)-5-[2-methylsulfinyl-pyrimidin-4-yl] imid~7ole A prefered grouping of compounds of Formula (I) have the structure:

Rt N
~r ,, R4 N (Ia) wllGlehl Rl is pyrirnidinyl substituted with a C1 4 alkoxy, and is additionally optionally substituted independently one or more times by Cl 4 alkyl, halogen, hydroxyl, C1_4 alkoxy, Cl 4 alkylthio, Cl 4 alkylsulfinyl, CH20R12, amino, mono and di- C1 6 alkyl ~u~LiLuled amino, N(Rlo)C(O)Rc or an N-heterocyclyl ring which ring has from S to 7 membersand optionally contains an additional hetelo~olll selected from oxygen, sulfur or NR15;
R2 is an optionally ~lb~LiLuL~d heterocyclyl, or an optionally substituted heterocyclylCl lo alkyl moiety;
R4 is phenyl, which is optionally substituted by halogen;
R1o is indep~n~ntly selected from hydrogen or C1 4 alkyl;
Rc is hydrogen, C1 6 alkyl, C3 7 cycloaLkyl, aryl, arylCI~ alkyl, heteroaryl, heteroarylCl~alkyl, heLe~ ;yclyl, or hc;L~ L;yclylCl 4alkyl Cl~ alkyl, all of which may be optionally substit lt~
R12 is hydrogen or Rl6;
R16 is Cl 4 allyl, halo-substituted-C14 alkyl, or C3 7 cycloalkyl;
R15 is hydrogen, C14 alkyl or C(Z)-C1 4 alkyl;
Z is oxygen or sulfur;
or a ph~ re~ltically acceptable salt thereof.
Preferably, R2 is piperidine, 1-Forrnyl-4-piperidine, l-benzyl~-piperidine, l-methyl-4-piperidine, 1-ethoxycarbonyl-4-piperidine, 2,2,6,6-tetramethyl~-piperidine, morpholino ethyl, morpholino propyl, pyrrolidinyl propyl, or piperidinyl propyl.
Another prefered grouping of c~ll.poul.ds of Formula (I) have the structure:

-WO 97/25046 PCT~US97~00529 R

R
t~ _N
I ~>
R4~ (Ib) wherein Rl is pyridyl substihlte-l with a Cl 4 alkoxy, and is ~ tions-lly optionally substituted indepç~eIltly one or more times by Cl 4 alkyl, halogen, hydroxyl, Cl ~ alkoxy, Cl 4 alkylthio, C1 4 alkylsulfinyl, CH20R12, amino, mono and di- C1 6 alkyl substituted amino, N(Rlo)c(o)Rc or an N-h~ u~yclyl ring which ring has from 5 to 7 members and optionally co~ s an additional hel~roa~ûll, se.lect~l from oxygen, sulfur or NR15;
R2 is an optionally ~u~Lilul~d heterocyclyl, or an optionally substituted heterocyclylCl lo alkyl moiety;
R4 is phenyl, which is optionally sul~sLiLuled by halogen;
Rlo is indeper rlently sel~ctt-~l from hydrogen or Cl~ alkyl;
Rc is hydrogen, C1 6 alkyl, C3 7 cycloalkyl, aryl, arylCl 1 alkyl, het~loa,yl, heteroarylCl 4alkyl, heterocyclyl, or heterocyclylCl 4alkyl Cl 4 alkyl, all of which may be optionally ~b~ e~;
R12 is hydrogen or R16;
R16 is Cl 4 aLkyl, halo-~ùbsliluLed-Cl 4 alkyl, or C3 7 cycloalkyl;
R1s is hydrogen, Cl~ alkyl or C(Z)-Cl~ aLkyl;
Z is oxygen or sulfur;
or a ph~nn~ellti~lly acc~L~le salt thereof.
Preferably, R2 is pipçri~linP, 1-Formyl-4-pipPri~lin~, 1-benzyl-4-piperidine, l-methyl-4-piperidine, 1-etho~yca,l~ollyl-4-piperidine, 2,2,6,6-tetramethyl~-pipen~linlo, morpholino ethyl, morpholino propyl, pyrrolidinyl propyl, or piperidinyl propyl.
l~he co~ oullds of Formula (I) may be obtained by applying synthetic procedures,some of which are illustrated in Schemes I to XI herein. The synthesis provided for in these Schemes is applicable for the producing compounds of Formula (I) having a variety of Lrr.,.~,nt Rl, R2, and R4 groups which are reacted, employing optional substituents which are suitably ~lote~;led~ to achieve colll~alibility with the reactions outlined herein.
Subsequent deprotection, in those cases, then affords compounds of the nature generally disclosed. Once the imi~7ole nucleus has been established, further compounds of Formula (I) may be prepared by applying standard techniques ~or functional group interconversion~
well known in the art.
For instance: -C(O)NR13R14 from -C02CH3 by heating with or without catalytic ~ metal cyanide, e.g. NaCN, and HNR13R14 in CH30H; -OC(O)R3 from -OH with e.g., ClC(O)R3 in pyridine; -NRlo-C(S)NR13R14 from -NHRlo with an alkylisothiocyante or W O 97/25046 PCTAjS97/00529 thiocyanic acid; NR6C(O)OR6 from -NHR6 with the aLkyl chlolofc..lllate; -NRloC(O)NR13R14 from -NHRlo by t-e~ t with an isocyanate, e.g. HN=C=O or R1oN=C=O; -NR10-c(o)R8 from -NHRlo by tre~tm~nt with Cl-C(O)R3 in pyridine;
C(=NRlo)NR13R14 from -C(NR13R14)SR3 with H3NR3~0Ac- by heating in alcohol;
C(NR13R14)SR3 from -C(S)NR13R14 with R6-I in an inert solvent, e.g. S~cetr~n~;
C(S)NR13R14 (where R13 or R14 is not hydrogen) from -C(S~NH2 with HNR13R14-C(=NCN)-NR13R14 from -C(=NR13R14)-SR3 with NH2CN by heating in anhydrous alcohol, ~ VCly from -C(=NH3-NR13R14 ~y tre~tm~nt with BrCN and NaOEt in EtOH; -NRlo-C(=NCN)SRg from -NHRlo by lle~ nt with (RgS)2C=NCN;
NR1oS02R3 from -NHRlo by tre~tm~nt with ClS02R3 by heating in pyridine;
NRloC(S)R3 from -NRloC(O)Rg by tre~tn~nt with Lawesson's reagent ~2,4-bis(4-methoxyphenyl)-1,3,2,4-(1ithi~iphosrhet~ne-2,4-~ ulfiflel; -NRloS02CF3 from -NHR6 with triflic anhydride and base wherein R3, R6, Rlo, R13 and R14 are as defined in Formula (~) herein.
Precurso~s of the groups Rl, R2 and R4 can be other R~!, R2 and R4 groups which can be i..tc~cc,.~vcl~ed by applying standard techniques for functional group interconversion.
For ex~mple a compound of the formula (I) wherein 1~2 is halo -substituted Cl lo alkyl can be converted to the corresponding Cl lo aLkylN3 de~;v~Live by reacting with a suitable azide salt, and thereafter if desired can be reduced to the corresponding Cl loaL~ylNH2 20 compound, which in turn can be reacted with RlgS(0)2X wll~Gin X is halo (e.g., chloro) to yield the corresponding Cl 1oaLkylNHS(0)2Rlg colllpoul-d.
~lt~ tively a compound of the formula (I) where R2 is halo-substituted Cl lo-aL~cyl can be reacted with an amine R13R14NH to yield the corresponding Cl lo-aL~cylNR13Rlq compound, or can be reacted with an alkali metal salt of RlgSH to 25 yield the cullcs~ ding Cl loalkylSE;: 18 compound.

W O 91/25046 PCT~US97/00529 R4CHO ( V) + Ar S(O)p H R4CH2NH2 (Vm) / \ r~ lau~,gagent H~CHO C~CI3 ~ ~
NaOH R4CH2NHCHO
CH2Cl2 H20, PTC \~ ~ dch~JlàLil~s agent Ar--S~O)p R4CH2NC (VI) ~1~ A~ S(0)2 L~ (V~)/

wherem p =~

RlCHO + R2NH2 d~h~a~g agent Ar--S(O)p P~1~NR2 ~ H ~) \/

SCElEME I

Referring to Scheme I the compounds of Formula (I) are suitably l~l~cd by S reacting a compound of the Formula (II) with a compound of the Formula (III) whe}ein p is O or 2, Rl, R2 and R4 are as ~e~ln~-l herein, for Formula (I), or are precursors of the groups Rl, 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 R1, R2 and R4.
Suitably, the reaction is performed at ambient le~ el~tule or with cooling (e.g. -50~
10 to 10~) or heating in an inert solvent such as methylene chloride, DMF, tetrahydrofuran, toluene, acelul~ ile, or dimethoxyethane in the presence of an a~l~liate base such as 1,8-W O 97/2S046 PCT~US97/OOS29 diazabicyclo ~.4Ø] undec-7-ene (DBU) or a guanidine base such as 1,5,7-tri~a-bicyclo [4.4.0] dec-5-ene (TBD). The int~rm.oAi~t~s of forrnula (II) have been found to be very stable and capable of storage for a long time. Preferably, p is 2. PTC is defined as a phase transfer catalyst.
Compounds of the Formula (II) have the structure:
Ar--S(O)p (II) R4/~\ NC
wherein p is 0, or 2; R4 is as defined for Formula (I) and Ar is an optionally substituted aryl as Ae~ln~A herein. Suitably, Ar is phenyl optionally S~ ?~ tG~ by 10 Cl 4allcyl, Cl 4 aLkoxy or halo. I~e~Gl~ly Ar is phenyl or 4-methyl~hen~l, i.e. a tosyl de~ivali~
Reaction of a compound of the Formula (II) wherein p = 2, with a compound of thePormula (m) in Scheme I gives con~ictçntly higher yields of compounds of Formula (I) than when p=0. In addition, the reaction of Pormula (II) com~oullds wherein p = 2 is more 15 envirorlm~nt~lly and economically attractive. When p=0, the preferred solvent used is methylene cloride, which is envirt nmP~t~lly unattractive for large scale procçs~ing, and the ~r~f~l~d base7 TBD, is also GXl~en~ive, and produces some byproducts and illl~u~iLies, than when using the culll~llcrcially attractive synthesis (p=2) as further described herein.
As noted, Sch~ o I utilizes the 1,3-dipolar cyclo~A-liti~ns of an anion of a 20 substituted aryl thiol~letl-ylisocyanide (when p=0) to an imine. More specifically, this reaction requires a strong base, such as an amine base, to be used for the dep~-3tvllation step.
The co-~ cially available TBD is preferred although t-bllto~ide, Li~ or Naf, or K~
hP.x~methylAi~ 7i~1e may also be used. While methylene chloride is the prefered solvent, other halogenated solvents, such as chloroform or carbon tetrachloride; ethers, such as 25 T~, DME, DMP, diethylether, t-butyl methyl ether; as ~,vell as acGLv.,il,ile, toluene or LIlr~s thereof can be ~tilti7~ll The reaction may take place from about -20~C to about;
40~C, preferably 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 R1 group of pyrimidine.
For compounds wherein Rl is pyridine, it is recognized that varying the reations conditions 30 of both tell~ dtulG and solvent may be n~ces~ry, such as decreasing temperatures to about -50~C or eh~ngin~ the solvent to THF.

-In a further process, compounds of Formula (I) may be prepared by coupling a suitable delivaLive of a compound of Formula (IX):

, 2 Tl N
11 /~
~--N
T4 (IX) wherein Tl is hydrogen and T4 is R4, or ~lf~-rn~tively Tl is Rl and T4 is H m which Rl, R2 and R4 are as hereinbefore defined; with: (i) when T1 is hydrogen, a suitable derivative of the helel~yl ring R1H, under ring coupling conditions, to effect coupling of the heteroaryl ring Rl to the imi~l~7Ole nucleus at position 5; (ii) when T4 is hydrogen, a 10 suitable d~,liv~tive of the aryl ring R4H, under ring coupling conditions, to effect coupling of the aryl ring R4 to the imi~ ol~ nucleus at position 4.
Such aryl/heteroaryl coupling reactions are well known to those skilled in the art.
In general, an organomPt~llic synthetic equivalent of an anion of one component is coupled with a reactive d,.iv~live of the second component, in the presence of a suitable catalyst.
15 The anion equivalent may be formed from either the imi-l~7Ole of Formula (IX), in which case the aryl/h~ 1 compound provides the reactive de~ivalivc, or the aryl/heL~
compound in which case the imicl~7.o]e. provides the reactive dcliv~l~ve. Accordingly, suitable deliv~Lives of the compound of Formula (~) or the aryl/heteroaryl rings include organomPt~,llic d~,liv~ves such as organrJm~ .,., organozinc, org~nc-st~nn~n~ and 20 boronic acid deliv~-ivcs and suitable reactive derivatives include the bromo, iodo, fluorosulfonate and trifluor~m~-th~neslllrhonate delivativ-~s. Suitable procedures are described in WO 91/19497, the disclosure of which is incorporated by reference herein.
Suitable organom~gn~ lm and org~no7inr d~ivalives of a compound of Formula ~IX) may be reacted with a halogen, fluorosulfonate or triflate de~iv~l;ve of the heteroaryl 25 or aryl ring, in the presence of a ring coupling catalyst, such as a p~ lm (O) or p~ Aillm (II) catalyst, following the procedure of Kllm~ et aL, Tetrahedron T .etters, 22, 5319 (1981). Suitable such catalysts include tetrakis-(triphenylphosphine)p~ Aillm and PdC12rl,4-bis-(diphenylphosphino)-butane], optionally in the presence of lithium chloride and a base, such as triethylamine. In z~klitio~ a nickel (II) catalyst, such as M(II)C12(1,2-30 biphenylphosphino)ethane, may also be used for coupling an aryl ring, following theprocedure of Pridgen et al., J. Org. Chem, 1982, 47, 4319. Suitable reaction solvents include h~-~c:~m~.thylphosphor-amide. When the heteroaryl ring is ~pyridyl, suitable derivatives include 4-bromo- and 4-iodo-pyridine and the fluorosulfonate and triflate esters of 4-hydroxy pyridine. Similarly, suitable derivatives for when the aryl ring is phenyl W O 97/25046 PCT~US97/00529 include the bromo, fluorosulfonate, triflate and, preferably, the iodo-derivatives. Suitable org~nom~gn~sJIlm and organozinc derivatives may be obtai.~ed by treating a compound of Formula (IX) or the bromo derivative thereof with an alkyllithium compound to yield the corresponding lithium reagent by deprotonation or tr~n~m~t~llation~ respectively. This lithium il~t~ di~t~ may then be treated with an excess of a m~necillm halide or zinc halide to yield the co~ ollding organom~t~l]ic reagent.
A triaLkyltin deliv~live of the compound of Formula (IX) may be treated with a bromide, fluorosulfonate, triflate, or, pr,fe-d~ly, iodide d~,l;vaLive of an aryl or heteroaryl ring compound, in an inert solvent such as tetrah~ r~all, preferably cont~inin~ 10~o 10 hPxamlothylphosphoramide, in the presence of a suitable coupling catalyst, such as a p~lla(1illm (O) catalyst, for inct~nce tetrakis-(triphenylphosphine)-p~ lm~ by the method described in by Stille, J. Amer. Chem. Soc, 1987, 109, 5478, US Patents 4,719,218 and 5,002,942, or by using a p~lla-lillm (Il) catalyst in the presence of lithium chloride optionally with an added base such as triethylamine, in an inert solvent such as dimethyl 15 fs,. ".~",it1~. Trialkyltin Llelivatives may be conveniently obtained by m~ot~ tion of the ujlLc;~onding compound of Formula (IX) with a lithi~ting agent, such as s-butyl-lithium or n-butyllithillm, in an ethereal solvent, such as tetrahy~vfu.~, or Llc~ of the bromo deliv~live of the corresponding compound of Formula (IX) with an alkyl lithinm, followed, in each case, by tre~tmtont with a triaLlcyltin halide. ~ltt~rn~tively, the bromo- delivalivt; of 20 a compound of Formula (IX) may be treated with a suitable heteroaryl or aryl tnaL~yl tin compound in the presence of a catalyst such as tetrakis4~iphellyl-phosphine)-p~ rlillm, under conditions similar to t_ose fiPst~ribe~l above.
Boronic acid derivatives are also useful. Hence, a suitable de~iv~liv~ of a compound of Forrnula (IX), such as the bromo, iodo, triflate or fluorosulphonate derivative, 25 may be reacted with a heteroaryl- or aryl-boronic acid, in the presence of a p~ rn catalyst such as tetrakis-(lli~hel yl~hosphine)-p~ inm or PdC12rl,4-bis-(diphenyl-phosphino)-butane] in the presence of a base such as sodium bicarbonate, under reflux conditions, in a solvent such as dimetho~y~lh~e (see Fischer and Haviniga, Rec. Trav.
Chim. Pays Bas, 84, 439, 196~, Sni~ s, V., Tetrahedron Lett., 29, 2135, 1988 and30 Ter~chimi~ M., Chem. Pharm. Bull., 11, 4755, 198~). Non-aqueous conditions, for inSt~nre, a solvent such as DMF, at a tenl~e~alulc; 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 de.ivalives may be prepared by treating the magnesium or lithium de.ivaliv~ with a trialkylborate ester, such as triethyl, tri-iso-propyl or 35 tributylborate, according to standard procedures.

W~ 47J25a46 PCTnUS97/00529 In such coupling reactions, it will be readily appreciated that due regard must be exercised with respect to functional groups present in the compounds of Forrnula (IX) Thus, in general, amino and sulfur ~ubsl ;l, IP,I~t.c: should be non-oxidised or protected Compounds of Formula (IX) are im~ 7~oles and may be obtained by any of the S procedures herein before t1es( rihe(1 for ~l~ing compounds of Formula (I) In particular, an oc-halo-ketone or other suitably activated ketones R4COC~I2Hal (for compounds of Formula (IX) in which Tl is hydrogen) or RlCOCH2Hal (for co~ ullds of Formula (IX) in which T4 is hydrogen) may be reacted with an ~mi-lint- of the formula R2NH-C=NH, wherein R2 is as (lef1n~A in Formula (I), or a salt thereof, in an inert solvent such as a 10 halogenated hydrocarbon solvent, for in~t~n-~e chloroform, at a moderately elevated lelll~e~dluie~ and, if n~cec~ry, in the presence of a suitable contl~ns~tion agent such as a base The preparation of suitable a-halo-ketones is described in WO 91/19497. Suitable reactive esters include esters of strong organic acids such as a lower aL~cane sulphonic or aryl sulphonic acid, for in~t~n~e, m~th~ne orp-toluene sulphonic acid The ~mitlin~ is 15 preferably used as the salt, suitably the hydroçhloride salt, which may then be converted into the free ~mi~in~ in situ, by employing a two phase system in which the reactive ester is in an inert organic solvent such as chloroform, and the salt is in an aqueous phase tO
which a solution of an aqueous base is slowly added, in dimolar amount, with vigorous stirrin~ Suitable ~miflin~s may be obtained by standard mPtho-1~, see for in~t~n~e, 20 Garigipati R, Tetra'nedron T ~tt~r~, 190, 31, 1989 C(i..-~ou lds of Formula (I) may also be prepared by a process which comprises reacting a compound of Formula (IX), wllel~ Tl 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 i~ I~" t~ t.o in which the heteroaryl ring is ~ft~Ch~l to the 25 imi(l~7olP nucleus and is present as a 1,4-dihydro derivative thereof, which interm~ tt~
may then be subjected to oxidative-deacylation conditions (Scheme II) The hetelu~yl salt, for in~t~n~e a pyri~inillm salt, may be either preformed or, more preferably, prepared in situ by adding a substituted carbonyl halide (such as an acyl halide, an aroyl halide, an arylaL~yl haloformate ester, or, ~lefeldbly, an aLkyl haloformate ester, such as acetyl 30 bromide, benzoy}chloride, benzyl chlororol.,ldt~, or, preferably, ethyl chloroformate) to a solution of the compound of Formula (IX) in the heteroaryl compound RlH or in an inert solvent such as methylene chloride to which the hete-~3~yl compound has been added Suitable deacylating and oXi~ ng conditions are described in U S Patent Nos 4,803,279, 4,719,218 and 5,0()2,942, which references are hereby incorporated by reference in their 35 entirety. Suitable oxidizing ~y~lellls include sulfur in an inert solvent or solvent lui~lul~, such as (l~c~lin~ decalin and diglyme, p-cymene, xylene or mesitylene, under reflux conditions, or, preferably, pot~ m t-butoxide in t-butanol with dry air or oxygen W O 97/25046 PCTrUS97/00~29 ~2 R RQJ~N
RX4l0 NH ~ N,~ p~mdine/R~COCI ~N,~ S/deralin,~ or 1~N~

SCHEMl~ II

S In a further process, illustrated in ~ch~m~ m below, compounds of Formula (I) may be prepared by treating a compound of Formula (X) th~rm~lly or with the aid of a cyclising agent such as pho..~hc~ s oxychk)ri~le or phosphorus pentachloride (see Engel and Steglich, Liebigs Ann Chem, 1978, 1916 and SLI~yl~liy et al., J Org Chem, 1963, 28, 3381).
Compounds of Formula (X) may be obtained, for in.ct~nt~e, by acylating the collG~onding 10 a-keto-amine with an activated formate derivative such as the corresponding anhydride, under standard acylating conditions followed by formation of tne imine with R2NH2. The a ninoketone may be derived from the parent ketone by o~min~tion and reduction and the requisite ketone may in turn be L~lc~ ,d by decarboxylation of the beta-ketoester obtained from the conden~tion of an aryl (heteroaryl) acetic ester with the RlCOX co~ ol1ent.
Rl~C~
X l.)NaOMe R 0 R 0 1-) ~ ~ R,2 ,R2 + 2.) HC~1~ 1 .)NaNO2~ HCI, H20 ~'F HlOJI Me ~N O poC13 Rl~f N~
R~OR R~ 2.) redure R4~NH2 2-)NH2R2~ -H20 R4~--H~H R4 N
fcrmula (X) SCHEM~ III

In Scheme IV illustrated below, two (2) different routes which use ketone (fo~nula 20 XI) for ~repali~g a compound of Formula (I). A heterocyclic ketone (XI) is ~ alcd by adding the anion of the allcyl heterocycle such as 4-methyl-quinoline (prepared by tre~tm~nt thereof with an alkyl 1ithinm, such as n-butyl lithium) to an N-aLkyl-O-alkoxybel-7~mi~
ester, or any other suitably activated deliv~ e of the same oxidation state. ~lt~rn~tJvely~
the anion may be con-len~ed with a be~7~lclehyde, to give an alcohol which is then oxidised 2~ to the ketone (XI).

WO 97~25046 PCT~US97/OOS29 Rl NHR2 R~ rH
R4~0 R ~

~X ) HN ~ r ~ R4 ~ R4 ~ R4~0 R~
SCHEME IV

In a further process, N-substituted compounds of Formula (I) may be prepared by 5 treating the anion of an amide of Formula (XII):
RlCH2NR2COH (XII) wll~ Rl and R2 with:
(a) a nitrile of the Forrnula (Xm):

10 wh~ R4 is as hereinbefore defin~l, or (b) an excess of an acyl halide, for in~t~n~e an acyl chloride, of the Forrnula (XIV):
R4COHal (XIV) wl,.~eill R4 is as helGi~ rul~ defined and Hal is halogen, or a corresponding anhydride, to give a bis-acylated int~rm~ te which is then treated with a source of ~mmoni~, such as 1~ ~mm~niilm acetate.

R2HN base R1 CI R R2 1.) LiI -N(i-Pr~ ~ R1 N
o/~H o R4~CN R ~N

(Xll) SCE~ME V

One variation ûf this approach is illustrated in Scheme V above. A ~illl~y amine(R2NH2) is treated with a halomethyl heterocycle of Pormula RlCH2X to give the secondary amine which is then converted to the amide by standard techniques.
~lt~ fively the amide may be prepared as illustrated in scheme V by alkylation of the form~mide with RlCH2X. Deprotonation of this amide with a strong arnide base, such as lithium di-iso-propyl amide or sodium bis-(trimethylsilyl)amide, followed by addition of an excess of an aroyl chloride yields the bis-acylated compound which is then closed to an imidazole compound of Formula (I), by heating in acetic acid cv..l~ini..g ammonium acetate. ~ltPrn~tively, the anion of the amide may be reacted with a s~ liLuLt;d a~l nitrile to produce the im~ 7ole of Forrnula (I) directly.
The following description and schemes are further exemplification of the process as S previously described above in Scheme I. Various pyrimi~1ine aldehyde derivatives 6 and 7 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 incc"~olated by reference herein. These pyrimi~linP. aldehydes are then utilized as ;nt~Prm~ te!s in the synthesis as further described.
MeO
o >--NMe2 MeO>~ MeO MeO>~ N
MeO 1 ~MeO 2 1. thiourea NaOEt tEtOI~
2. RI
SR ~ ~ RO~

3 N~ O(n) NaORt ROH~ ~j 5 ~ R ~3 / MeO OMe HCI MeO OMe HCI
THF / H20 n = 1 or 2 THF / H2O

6 SR ~N~3 R7~~N~

H O H O

Scl~
The reaction of imines with tosylmethyl isonitriles was first reported by van Leusen (van T ~lls~.n ~ et al., J. Org. Chem. 1977, 42, 11 53.) Reported were the following conditions: tert butyl arnine(tBuNH2) in dimethoxyethane (DME), K2C03 in MeOH, and NaH in DME. Upon re-exzlmin~tion of these conditions each was found produce low W O 97/25046 PCT~US97/~0529 yields. A second pathway involving amine exchange to produce the t-butyl imine followed by reaction with the isocyanide to produce a l-tBu imi~l~7OIe was also Opeld~illg. This will likely occur using any ~ ll~ y amine as a base. The secondary ~mines~ while not ~lefe~,~,d may be used, but may also decompose the isonitrile slowly. ~ ction~ will likely re~uire S about 3 equivalents of amine to go to completion, reslllting in appr xim~t~oly 50% isolated yields. Hindered secondary amines (diisopropylamine) while usable are very slow and generally not too effective. Use of tertiary and aromatic amines, such as pyridine, and triethylamine 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 and10 hence may be sllit~hle for use herein.
As depicted in Sch~mes VII and VIII below, the pyrimidine aldehydes of Scheme VI, can be con-l~n~e-l with a plimal y amine, to generate an imine, which may suitably be isolated or reacted in situ, with the desired isonitrile in the presence of a variety of suitable bases, and solvents as described herein to afford the 5-(4-pyrimidinyl)-substituted 15 imicl~7oles, wherein R2 and E~4 are as defined herein for Formula (I) compounds.
One preferred method for ~lG~JOlil~g compounds of Formula (I) is shown below in Scheme VII. The imines, prepared and isolated in a separate step were often tars, which were hard to handle. The black color was also often carried over into the final product.
The yield for m~king the imines varied, and envil~,.,..~.,l~lly less-acceptable solvents, such 20 as CH~Cl2 were often 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 hydride, or an alkyl or aryl lithium reagent; or ~ ul~,s thereof.
Bases inc.lt~ , but are not limited to, pot~ m carbonate, sodium carbonate, primary and 2~ secondary ~mine~, such as morpholine, piperidine, pyrrolidine, and other non-nucleophilic bases.
Suitable solvents for use herein, include but are not lirnited to N,N-dimethyl-forrn~mi~le (DMP), MeCN, halogenated solvents, such as methylene chloride or chloroform, tetrahydl~)rul~l (THF), dimethylsulfoxide (DMSO), alcohols, such as methanol 30 or ethanol, benzene, or toluene, or DME. Preferably the solvent is DMF, DME, THF, or MeCN, more preferably DMF. Product isolation may generally be accompli~h~-l by adding water and filtering the product as a clean compound.

W O 97/25046 PCTrUS97/00529 N~' Me ~ Me S~TOI ~ N

X = O, S

SCHEl~E VII
While not convenient for large scale work, addition of NaH to the isonitrile, perhaps with Lelllyelalulc;s lower than 25 ~C (in THF) are likely nPefle~ tionAlly, BuLi has also been reported to be an ~rr~cLi~e base for d~..,l(~llating tosyl benzylisonitriles at -50~C.
(DiSanto,et al., Synth. Commun. 1995, 25, 795).
Various tel~l~e.dlu,~ conditions may be utili7erl depending upon the preferred base.
For in.ct~nf~e, tBuNH2/DME, K2CO3/MeOH, K2C03 in DMF, at telll~e-aLu.Gs above 40~C, the yields may drop to about 20% but little ~lirÇ~,lGllce is e~pected between 0~C and 25 10 ~C. Consequently, Iclllpl l~tul~, ranges below 0 ~C, and above 80 ~C are con~ te~l as also being within the scope of this invention. Preferably, the temperature ranges are from about 0 ~C to about 25 ~C.
As shown in Scheme VIII below, the imine is preferably formed in situ in a solvent.
This ~rGfGlled synthf~sic, is a process which occurs as a one-pot synthesis. Suitably, when 1~ the primary amine is utilized as a salt, the reaction may further include a base, such as potassium carbonate prior to the addition of the isonitrile. ~ltern~tively, the piperidine nitrogen may be required to be protected as shown below. Reaction conditions, such as solvents, bases, LG111~)e1~lU1GS, etc. are similar to those illustrated and discussed above for the i~ol~t~ll imine as shown in Scheme VII. One skilled in the art would readily recogr~ize 20 that under some e~ u ~ es, the in situ formation of the imine may require dehydrating conditions, or may require acid catalysis.

WO 97/25046 PCT~US97~W529 N~ BOC
BOC
,,CHO ~ ~ DMF
r , 5 h ~
OR N~2 N~ N
OR

BOC N

KD~CMOF3 _RO ~N~ 3N HCI N~
SO~Tol ~ N
NC ~ F

S~F,lV~, VIII

Scheme IX, describes an ai: .:rnative process for making compounds of formula (I).
S In this particular in~t~n~e, the alkylthio moiety is oxifli7e~l to the alkylsulfinyl or sulfonly moiety which is reacted with a suitable alkoxy moiety.
RS ~ N R(~n)S~ N RO~ N

OXONE ~ ~3 ,R2 NaOR/ROH 1~3 R2 Scheme IX
Another embodiment of the present invention is the novel hydrolysis of 2-thiomethylpyrimirline acetal to 2-thiom~Lhyl~y~ i(1in~ aldehyde, as shown in Scheme X
below. Hydrolysis of the acetal to aldehyde using various known reaction conditions, such as formic acid, did not produce a s~ti~f~c~Qry yield of the aldehyde, <13%) was obtained.
15 The preferred synthesis involves the use of AcO~I (fresh) as solvent and con-centrated H2SO4 under heating conditions, preferably a catalytic amount of sulfuric acid. ~ting conditions include tGll~eldLUl~s from about 60 to 85~C, preferably from about 70 to about 80~C as higher te~ GldlulGs show a ~1~rk~ning of the reaction mixture. After the reaction PCTrUS97/00529 is complete the ~ Lul~,is cooled to about room ~Clll~J~d~lllC and the acetic acid is removed.
A more ~l~f~,~r~,d ~ltPrn~t;ve procedure to this involves heating the acetal in 3N HCl at 40~C for about 18 hours, cooling and extracting the bicarbonate neutralized solution into EtOAc.
S
OMe O

OMe AcoEvconc H2so4 ~ H

SMe SMe Ss ~ - ~ X
While these schP~Ps herein are presçntPrl, for in~t~nce, with an optionally substituted piperidine moiety for the res--lt~nt R2 position, or a 4-fluoro phenyl for R4, any 10 suitable R2 moiety or R4 moiety may be added in this manner if it can be prepared on the pl;lnal y amine. Similarly, any suitable R4 can be added via the isonitrile route.
The compounds of Formula (II), in Scheme I, may be ~r~,d by the methods of van Leusen et al., supra. For çx~mrle a compound of the Formula (II) may be ~.c~alcd by del,y~Ldti,lg a compound of the Formula (IV)-Scheme I, wherein Ar, R4 and p are as 15 defined herein.
Suitable delly~dLillg agents include phosphorus oxychloride, oxalyl chloride, thionyl chloride, phosgene, or tosyl chloride in the presence of a suitable base such as triethylamine or diiscpl.,~ylethylamine, or similar bases, etc. such as pyridine. Suitable solvents are rlimPthoxy ether, tetrahydrofuran, or halogen~teA solvents, preferably THF.
20 The reaction is most effi~ent when the reaction temperatures are kept beL~vv~en 10~C and 0~C. At lower telll~eldlu-~,s in~omrlPte reaction occurs and at higher telll~cl~lulc;s, the solution turns dark and the product yield drops.
The compounds of formula (IV)-Scheme I may be ~ ~ed by reacting a compound of the formula (V)-Scheme L R4CHO where R4 is as defined herein, with ~rS(0)pH and 2~ ~. "".",i~l.o with or without water removal, preferably under dehydrating conditions, at ambient or elevated temperature e.g. 30~ to 150~, conveniently at reflux, optionally in the presence of an acid catalyst. ~lt~rn~tively trimethysilylchloride can be used in place of the acid catalyst. E~xarnples of acid catalysts include c~mrhor-10-sulphonic acid, formic acid, p-toluenesulphonic acid, hydrogen chloride or slllphllri~ acid.

W O 97/2504~ PCT~US97J~529 An optimal method of making an isonitrile of Formula (II~ is i~ tr~ted below, inScheme XI.

rV",.d",i.l~ NHCHO SO2Tol PhMe. ~ hlHCHO TolSO2H ~e~ NHCHO

50 ~C 2 3 SO2Tol Q.5 MTHF SO2Tol ~~ NHCHO Et,qN ~ NC
10toO ~C F
70% yield 4 SCHEME XI
S The conversion of the substituted aldehyde to the tosylbenzyl fonn~mi~ may be accomr li.~h~ by heating the aldehyde, l-Scheme XI, with an acid, such as p-toluene-sulfonic acid, formic acid or c~mrhorsulfonic acid; with fo""~lllicle and ~toluene-slllfinic acid [under reaction conditions of about 60~C for about 24 hours]. Preferably, no solvent is used. The reaction, may give poor yields (< 30%) when solvents, such as DMF, DMSO, toluene, acetonitrile, or excess form~mi-lç are used. TG111~1alU~CS less than 60~C are generally poor at producing the desired product, and tel-l~e.;~lul~s in excess of 60~C may produce a product which decomposes, or obtain a benzylic bis-fc.. ".~ le, 2-Scheme XI.
Another embo~1imt-~t of the present invention is the ~ylll~esis of the tosyl benzyl form~mi-lP. compound, achieved by reacting the bi~r~. ".i...,ill~. int~rm.o.rli~t~, 2-Scheme XI
15 with p-tol~le~s~llfinic acid. In this ~l~,fe~cd route, ~lGp~dlion of the bis-fo....~.icle from the aldehyde is accomplished by heating the aldehyde with form~mi(le7 in a suitable solvent with acid catalysis. Suitable solvents are toluene, aceton,~lile, DMF, and DMSO or ules thereof. Acid catalysts, are those well known in the art, and include but are not limited to hydrogen chloride, p-tol~lçnesulfonic acid, c~mrhors~-lfonic acid, and other 20 anhydrous acids. The reaction can be cond~-~ te~1 at t~ el~lu.~s ranging from about 25~C
to 110~C, preferably about 50~C, suitably for about 4 to about 5 hours, longer reaction times are also acceptable. Product decomposition and lower yields may be observed at higher telllpeldlulcs (~70~C) at prolonged reactions times. Complete conversion of the product generally requires water removal from the reaction n~i~lulc.

W O 97/25046 PCT~US97/0052g Preferred conditions for con~e~ g a bis-form~mi-l~ deliv~tive to the tosyl benzyl rO. IIIAIIIitle are accomplished by heating the bisform~micle in a suitable solvent with an acid catalyst and p-tol~en~s~llfinic acid. Solvents for use in this reaction include but are not limited to toluene, and acetonitrile or ll~u~L~lleS thereof. Additional mixtures of these 5 solvents with DMF? or DMSO may also be used but may result in lower yields.
Temp-,.alu~._s may range from about 30~C to about 100~C. Te,ll~eralulc;s lower than 40~C
and higher than 60~C are not ~l~fe~l~d as the yield and rate decreases. Preferably the range is from about 40 to 60~C, most preferably about 50~C. The optimal time is about 4 to 5 hours, although it may be longer. Preferably, acids used include but are not limited to, 10 tc~ on~sulfonic acid, c~mphcrslllfonic acid, and hydrogen chloride and other anhydrous acids. Most preferably the bisform~micle is heated in toluene:~etonitrile in a 1:1 ratio, with p-t lllen~os~ nic acid and hydrogen chloride.
Another embodiment of the present invention is the ~lefelled synthetic route forsynthesis of the tosylbenzyl r~" .,.;...,~ compound which is accomplished using a one-pot procedure. This process first converts the aldehyde to the bis-fortn~mi-l~ de.iv~Live and subsequently reacts the biS-form~mi~lç dc~ivaLi~re with tQluen~osulfinic acid. This procedure comhin~s the optimi7~ conditions into a single, efficient process. High yields, >90% of the aryl benzylf ). " ~ may be obtained in such a manner.
PlGfc,led reaction conditions employ a catalyst, such as LlhllcLhylsilyl chloride (TMSCl), in a ~e~ll~d solvent, toluene:acetonitrile, preferably in a 1:1 ratio. A reagent, such as TMSCl, is preferred which reacts with water produced therein and at the same time produces hydrogen chloride to catalyze the reaction. Also preferred is use of hydrogen chloride and p-tolll~-n~--slllfonic acid. Therefore, three suitable reaction conditions for use herein include 1) use of a dehydrating agent which also provides hydrogen chloride, such as TMSCl; or by 2) use of a suitable delly~ g agent and a suitable source of acid source, such as but not limited to, c~mphor.sulfonic acid, hydrogen chloride or t ~hlenes~l~fonic acid;
and 3) ~It~rn~tive dehydrating conditions, such as the ~eotropic removal of water, and using an acid catalyst and p-toluene sulfinic acid.
Compounds of the formula (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 I, R4CH2NC with a compound of the formula (VII)-Scheme I, ArS02Ll wL~ ll R4 and Ar are as defined herein and Ll is a leaving group such as halo, e.g. fluoro. Suitable strong bases include, but are not limited to, alkyl lithillm~ such as butyl lithium or lithium diisopropylamide (Van Leusen çt al., Tetrahedron Letters. No. 23, 2367-68 (1972)).
The compounds of formula (VI)-Scheme I may be p~ ed by reacting a conl~,oulld of the formula (VIII)-Scheme I, R4CH2NH2 with an aLkyl formate (e.g. ethylformate) to yield an interm~ t~ amide which can be converted to the desired isonitrile by reacting with well known dehydlalillg agent, such as but not limited to oxalyl chloride, phosphorus oxychloride or tosyl chloride in the presence of a suitable base such as triethylamine.
~ lt~rnz~tively a colll~uul-d of the formula (VIII) - Scheme I may be converted to a compound of the formula ~ Scheme I by reaction with chloroform and sodium S hydroxide in aqueous dichlorom~-th~ne under phase transfer catalysis.
The compounds of the formula (m) - Scheme I may be prepared by reacting a compound of the formula RlCHO with a primary amine R2N~2.
The arnino compounds of the formula (VII~ çh.ome I are known or can be ~lc~a,ed from the co.l~s~ollding alcohols, oximes or amides using standard functional 10 group interconversions.
Suitable protecting groups for use with hydroxyl groups and the imi~1~7ole nitrogen are well known in the art and described in many references, for in.~t~nce, Protecting Groups in Organic Synthesis, Greene T W, Wiley-lnterscience, New York, 1981. Suitable exarnples of hydroxyl protecting groups include silyl ethers, such as t-buty1ciim.-thyl or t-15 butyl-lirh~nyl, and allyl ethers, such as methyl connected by an aL~yl chain of variable link, (CRloR2o)n. Suitable e~c~rnrl~s of imit1~7.ole nitrogen ~ te~ g groups include tetrahydr~,~y,~lyl.
ph~ cGulir~lly acid addition salts of compounds of For-m--ula (I) may be obtained in known manner, for ex~mrl~ by tre~tm~nt thereof with an a~r~ ;ate amount of acid in 20 the presence of a suitable solvent.

MF.THODS OF I~EATMENT
The compounds of Pormula (I) or a ph~rm~r~lltic~lly acceptable salt thereof can be used in t_e m~nllfactl-re of a m~-lic~m~nt for the pl~llylactic or therapeutic tre~tnn~nt of 25 any disease state in a human, or other m~mm~l, which is exacerbated or caused by excessive or unreg~ t~-~l cytokine prod~ ti-~n by such ~ s cell, such as but not limited to monocytes and/or macrophages.
Compounds of Formula (I) are capable of inhibiting proinfl~mm~t-~ry cytokin~s, such as IL-l, IL-6, IL-8 and TNF and are therefore of use in therapy. IL-l, IL-6, IL-8 and 30 TNF affect a wide variety of cells and tissues and these cytokin~, as well as other leukocyte-derived cyt--kinPs, are important and critical infl~mm~tory m~ tcrc of a wide variety of disease states and conditions. The inhibition of these pro-infl~mm~tQry cytokines is of benefit in controlling, re~ ing and alleviating many of these disease states.
Accordingly, the present invention provides a method of treating a cytokine-m~-.Ai~te-l disease which comprises z~-lmini~t~rin~ an effective cytokine-interfering amount of a compound of Formula (I) or a ph~rm~reutically acceptable salt thereo~.

Compounds of Formula (I) are capable of inhihitin~ in~1llcihle proinfl~mm~tQry proteins, such as COX-2, also referred to by many other names such as prost~lan~lin endoperoxide synthase~2 (PGHS-2) and are therefore of use in therapy. These proinflamm~tory lipid m.~ t~,rs of the cyclooxygenase (CO) pathway are produced by the S in~lnr.il~le COX-2 enzyme. Regulation, therefore of COX-2 which is responsibIe for the these products derived from aracnidonic acid, such as prost~ nflin.c affect a wide variety of cells and tissues are inl~G Lallt and critical infl~ rJI y m~ tors of a wide variety of disease states and conditions. Expression of COX- 1 is not effected by compounds of Formula (I). This selective inhibition of COX-2 may alleviate or spare ulcerogenic Iiability 10 associated with inhibition of COX-1 thereby inhibiting prosto~lan(1in.s çssçnti~l for ~;yLopl~tective effects. Thus inhibition of tnese pro-infl~mm~tory m~ tr)r.c is of benefit in controlling, retlllcing and alleviating many of these disease states. Most notably these infl~.. ~1ul y m~.Ai~tor.s, in particular prost~ n~lin.c, have been implicated in pain, such as in the senciti7~tion of pain receptors, or edema. This aspect of pain m~n~em~nt therefore 15 inrlucle.c ~ .nt of neuromuscular pain, h~ he, cancer pain, and arthritis pain.
Compounds of Formula (I) or a ph~rm~elltie~lly acceptable salt thereof, are of use in the u~hylaxis or therapy in a human, or other m~mm~l, by inhibition of the synthesis of the COX-2 enzyme.
Accordingly, the p;esent invention provides a metnod of inhibiting the synthesis of 20 COX-2 which comprises ~clmini.cterin~ an effective amount of a compound of Formula (I) or a ph~rm~ce~ltic~lly acceptable salt thereof. The present invention also provides for a method of prophylaxis ll~dllllen~ in a human, or other m~mm~l, by inhibition of the synthesis of the COX-2 enzyme.
In particular, compounds of Formula (I) or a ph~rm~r~eutically acceptable sait 25 thereof are of use in the prophylaxis or therapy of any disease state in a human, or other m~mm~l, which is exacerbated by or caused by excessive or unregulated IL 1, IL-8 or TNF
production by such ~ s cell, such as, but not limited to, monocytes and/or macrophages.
Accordingly, in another aspect, this invention relates to a method of inhibiting the 30 production of IL-1 in a m~mm~l in need thereof which comprises ~lmini.cte.ring to said m~mm~31 an effective amount of a compound of Formula (I) or a rh~rn ~-~e~ltic~lly acceptable salt thereof.
There are many disease states in which excess}ve or unregulated IL- 1 production is implic~t~d in exacerbating and/'or c~nsing the ~lice~ce These include rhellm~toid arthritis, 3~ osteoarthritis, stroke, endotoxemia and/or toxic shock syndrome, other acute or chronic inflamm~tory disease states such as the infl~mm~tnry reaction intll~ce~l by endotoxin or infl~mm~to;y bowel tlic~.~ce7 tuberculosis, atherosclerosis, muscle degeneration, multiple WO 97/25046 PCT~US97/00529 sclerosis, c~c}-Pxi~ bone resorption, psoriatic arthritis, Reiter's syndrome, rheum~tQid arthritis, gout, traumatic arthritis, rubella arthritis and acute synovitis. Recent evidence also links IL-l activity to diabetes, pancreatic ~ cells and Alzheimer's disease.
In a further aspect, this invention relates to a method of inhibiting the production of 5 TNP in a rn~mm~l in need thereof which comI)ri~C ~ ";ni~le, I--g to said m~mm~l an effective amount of a compound of Formula (I) or a ph~rrn~eutir~lly acceptable salt thereof.
Excessive or unregulated TNF production has been implicated in mt~ tin~ or exacell,aL~llg a number of diseases inrh~(1;n~ rh~llm~toid arthritis, rhe!-m~tQi~l spondylitis, 10 osteoarthritis, gouty art_ritis and other arthritic conditions, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, cerebral m~l~ri~, ch~onic pulmonary infl;~ e~ce~ silicosis, p~llmon~ry sarcoisosis, bone resorption ~lice.~c, such as osteoporosis, reperfusion injury, graft vs. host reaction, allograft rejections, fever and myalgias due to infection, such as i~ n~, 15 c~ch~ secondary to infection or m~lign~ncy, cachexia secondary to acquired immnnP
deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloid form~tiQIl, scar tissue formation, Crohn's disease, ulcerative colitis and pyresis.
Compounds of Formula (I) are also useful in the L~ "Irl~ of viral infections, where such viruses are sensitive to upregulation by TNF or will elicit TNF production fn vivo.
20 The viruses cont~mpl~t~ for tre~trn~nt herein are those that produce TNF as a result of infection, or those which are sensitive to inhibition, such as by decreased replication, dheclly or indhc~;Lly, by the TNF inhibiting-compounds of Formula (1). Such viruses in~lu~le, but are not lirnited to HIV-l, HIV-2 and HIV-3, Cytomegalovirus (CMV),Tnfll-lon7~ adenovirus and the Herpes group of viruses, such as but not lirnited to, Herpes 2S Zoster and Herpes Simplex. Accordingly, in a further aspect, this invention relates to a method of treating a m5~rnm~1 ~ffli~t~-l with a human immunodeficiency virus (HI~) which comrri~es ~lmini~terin~ to such m~mm~l an effective TNF inhibiting amount of a compound of Pormula (I) or a ph~ reuti~lly acceptable salt thereof.
Compounds of Formula (I) may also ~e used in association with the veterinary 30 tre~tmt~nt of mzlmm~l~, other tnan in hllm~n~, in need of inhibition of TNF production.
TNF mr~ t~ e~es for treatment, therapelltir~lly or prophylactically, in ~nim~l~ include disease states such as those noted above, but in particular viral infections. Fxamples of such viruses include, but are not limited to, lentivil~s infections such as, equine infectious ~n~r~ virus, caprine arthritis virus, visna virus, or maedi virus or retrovirus infections, 35 such as but not limited to feline imm~ln~defIciency virus (FIV), bovine immunodeficiency virus, or canine imrnunodeficiency virus or other retroviral infections.

W O 97/25046 PCT~US97/00529 The compounds of Formula (I) may also be used topically in the tre~tm~nt or prophylaxis of topical disease states m~ tçcl by or exacerbated by excessive cytokine production, such as by rL-1 or TNF respectively, such as infl~mt~.cl joints, eczema, psoriasis and other infl~Tnm~tory skin conditions such as sunburn; in~ oly eye conditions S including conjunctivitis; pyresis, pain and other conditions associated with infl~mm~tion.
Compounds of Formula (I) have also been shown to inhibit the production of IL-8 (Interleukin-8, NAP). Accordingly, in a further aspect, this invention relates to a method of inhibiting the production of IL-8 in a mAmm~l in need thereof which comprises ?~lrnini~terin~ to said mATnm~l an effective amount of a compound of Formula (I) or a 10 ph~rm~-~euti~lly acceptable salt thereof.
There are many disease states in which excessive or unregulated IL-8 production is implicated in exacerbating and/or c~llsinE the disease. These ~ e~çs are characterized by massive neutrophil infiltration such as, psoriasis, inflAmm~tory bowel ~i~c~ce~ A~thm~, cardiac and renal reperfusion inJury, adult respilatoly distress syndrome, thrombosis and 15 glomerulone~hliLis. All of these diseases are associated with increased IL-8 production which is responsible for the chemotaxis of ncuLl~hils into the inflAmm~tory site. In contrast to other inf~AmmAtQry cytokines (IL- 1, TNF, and IL-6), IL-8 has the unique . ly of promoting neutrophil chemotaxis and activation. Therefore, the inhibition of IL-8 production would lead to a direct reduction in the neulluphil infiltration.The compounds of Formula (I) are ~Amini~tered in an amount sllffic;ent to inhibit cytokine, in particular IL-1, IL-6, IL-8 or TNP, production such that it is regulated down to norrnal levels, or in some case to subnormal levels, so as to ameliorate or prevent the disease state. Abnormal levels of IL-1, II,-6, IL-8 or TNF, for in-~t~nre in the context of the present invention, consLilule: (i) levels of free (not cell bound) IL-I, IL-6, 11,-8 or TNF
2~ greater than or equal to 1 picogram per ml; (ii) any cell associated IL-l, IL-6, II,-8 or TNF; or (iii) the presence of IL-l, IL-6, IL-8 or INF mRNA above basal levels in cells or tissues in which IL-1, IL-6, IL-8 or TNF, lc*~e~;livcly~ is produced.
The discovery that the compounds of Formula (I) are inhibitors of cytokines, specifically IL- 1, IL-6, IL-8 and TNP is based upon the effects of the compounds of 30 Formulas (I) on the production of the IL-l, IL-8 and TNF in in vitro assays which are described herein.
As used herein, the term "inhibiting the production of IL-l (IL-6, IL-8 or TNF)"refers to:
a) a decrease of excessive in vivo levels of the cytokine (IL-l, IL-6, IL 8 or TNF) 35 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;

, W ~ 97/25a46 PCT~US97~00529 b) a down regulation, at the genomic level, 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;
c) a down regulation, by inhibition of the direct synthesis of the cytokine (IL- 1, IL-6, IL-8 or TNF) as a postranslational event; or d) a down regulation, at the translational level, of excessive in vivo levels of the cytokine (IL- l, IL-6, IL-8 or TNT~- ~ in a human to normal or sub-normal levels.
As used herein, the term "TNF meAiplte~l disease or disea~se state" refers to any and all disease states in which TNF plays a role, either by production of TNF itself, or by TNF
c~ in~ another monokine to be released, such as but not lirnited to IL-1, IL-6 or IL-8. A
10 disease state in which, for inst~nee~ IL-1 is a major component, and whose production or action, is exacerbated or secreted in response to TNF, would therefore be considered a disease stated m~ t~l by TNF.
As used herein, the term "cytokine" refers to any secreted polypeptide that affects the functions of cells and is a molec~ which modulates interactions between cells in the 15 immllne7 infl~mm~tory or hematopoietic response. A cytokine inrl~ es, but is not limited to, monokin~s and lymph-)kin~s, regardless of which cells produce them. For in~t~nr,e, a monokine is generally referred to as being produced and secreted by a mononuclear cell, such as a macrophage and/or monocyte. Many other cells however also produce monokines, such as natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, 20 brain astrocytes, bone marrow stromal cells, epideral keratinocytes and B-lymphocytes.
Lymphokin~s are generally referred to as being produced by lymphocyte cells. Examples of cytokines incllltle, but are not limited to, Interleukin-l (IL-l), TntPrlellkin-6 (IL-6), Tnt~rlPukin-8 (IL-8), Tumor Necrosis Factor-alpha (TNF-oc) and Tumor Necrosis Factor beta (TNF-B).
As used herein, the term "cytokine interfering" or "cytokine ~.u~ ssive amount"
refers to an effective ~mollnt of a compound of Formula (I) which will cause a decrease in the in vivo levels of the cytokine to normal or sub-norrnal levels, when given to a patient for the prophylaxis or treatment of a disease state which is exacerbated by, or caused by, excessive or unregulated cytokine production.
As used herein, the cytokine referred to in the phrase "inhibition of a cytokine, for use in the tre~tment of a HIV-infected human" is a cytokine which is implicated in (a) the initiation and/or . . .~ e of T cell activation and/or activated T cell-m~ t~l HIV
gene expression and/or replication and/or (b) any cytokine-mediated disease associated problem such as cachexia or muscle degeneration.
As TNF-~ (also known as lymphotoxin) has close structural homology with TNF-a (also known as cachectin) and since each induces similar biologic responses and binds to the same cellular receptor, both TNF-a and TNF-~ are inhibited by the compounds of the W O 97~5046 PCT~US97/00529 present invention and thus are herein referred to collectively as "TNF" unless specifirs.lly delinP~S7tPd otherwise.
A new member of the MAP kinase family, alternatively termed CSBP, p38, or RK, has been identified independently by several laboratories recently [See Lee et al., Nature, Vol. 300 n(72), 739-746 (1994)]. Activation of this novel protein kinase via dual phosphorylation has been observed in diff~G.It cell systems upon stim--lS~tion by a wide ~Ct;llulll of stimuli, such as physicochemical stress and Ll~,alll~~t with lipopolyss rchs ri~l~
or proinflS7mmS7tory cytokines such as intPrieukin-l and tumor necrosis factor. The cytokine biosynthesis inhihitors, of the present invention, compounds of Formula (I), have 10 been clet~ Pd to be potent and selective inhibitors of C~BP/p38/RK kinase activit,v.
These inhibitors are of aid in dete! ...i";l~ the ~i~ns71ing ~Jal~lW~5; involvement in inlls7mms7tory responses. In particular, for the first time a definitive signal tr;~n~duction pathway can be prescribed to the action of lipopolyss7c~çhs7ri(1e in cytokine production in macrophages. In addition to those ~lice~es already noted, treatment of stroke, neulvLIdullla, cardiac and renal lepel~usion injury, thrombosis, glomerulonephritis, ~ hetrs and pancreatic ,B cells, mnltirle sclerosis, muscle d~genPration, ec7Pm~ psoriasis, sunburn, and col~ lclivilis are also inr.l~lrlrrl The cytokine inhibitors were subsequently tested in a number of animal models for anti-inflS~mmS~tory activity. Model systems were chosen that were relativelyin.cPncitive to cyclooxygenase inhihitor.c in order to reveal the unique activities of cytokine ~u~lGs.sive agents. The inhihitors exhibited ~jgnifics7nt activity in many such in vivo studies. Most notable are its effe~ ,ness in the collagen-in~uce-l arthritis model and inhibition of TNF production in the endotoxic shock model. In the latter study, the reduction in plasma level of TNF correlated with survival and protection from endotoxic shock related mortality. Also of great i.~ oll~ce are the colllpuullds effectiveness in inhibiting bone resorption in a rat fetal long bone organ culture system. Griswold et al., (1988) Arthritis Rheum. 31:1406-1412; Badger, et al., (1989) Circ. Shock 27, 51-61;
Votta et al., (1994)in vitro. Bone 15, 533-538; Lee et al., (1993). B Ann. N. Y. Acad.
Sci. 696, 149-170.
In order to use a compound of Formula (I) or a phs7rm~reutics711y acceptable salt thereof in therapy, it will normally be Forml-ls tr~ into a phs7n~7s7relltical composition in accordance with standard phs7rms7re~ltics71 practice. This invention, therefore, also relates to a pharn-~renticS~l colll~osilion coll~ .ing an effective, non-toxic amount of a compound of Pormula (I) and a pharrnS7re~ltirS7lly acceptable carrier or diluent.
Compounds of Formula (I), phS7rn7~reutirs7lly acceptable salts thereof and phs7rms7reutical compositions incorporating such may conveniently be s7~mini~tered by any of the routes conventionally used for drug s7~1mini~tration, for inctS7nce. orally, topically, W O 97/2504~ PCT~US97/00529 pa~ f,ldlly or by inhalation. l'he compounds of Formula (I) may be ~lmini~tf~red in conventional dosage forms plGpa.~,d by combining a compound of Formula (I) with standard ph~rn ~relltical carriers according to conventional procedures. The compounds of Pormula (I) may also be ~flmini~tf-.red in conventional dosages in combination with a 5 known, second therapentif ~lly active compound. These procedures may involve mixin~, gr~n~ tin~ and colll~lessing or dissolving the ingredients as ~ ~iate to the desired cpalaLion. It will be appreciated that the form and çh~r~rtPr of the ph~rm~f e~ltic"lly acceptable character or diluent is f~ t~tf~rl by the amount of active ingredient with which it is to be combined, the route of ~1mini~tration and other well-known variables. The 10 carrier(s) must be "acceptable" in the sense of being comr~tihle with the other ingredients of the Formulation and not ~el~tf-rious to the recipient thereof.
The ph~rm~el~tical carrier employed may be, for example, either a solid or liquid.
F.xempl~ry of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, nPcium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, 15 peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may include time delay material well known to the art, such as glyceryl mono-stearate or glyceryl distearate alone or with a wax.
A wide variety of phs~rm~f elltic ~1 forms can be employed. Thus, if a solid carrier is used, the ~lG~aLion can be t~hif~tf ~l placed in a hard gelatin capsule in powder or pellet 20 form or in the form of a troche or lozenge. The amount of solid calTier will vary widely but preferably will be from about 25mg. to about lg. When a liquid carrier is used, the preparation will be in the forrn of a syrup, emulsion, soft gelatin c~rslllf, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.
Co~ ou~ds of Formula (I) may be ~Amini~tered topically, that is by non-systemic 2~ ~flmini~tration. This inf lllf'f s the application of a co~"po~nd of Formula (I) externally to the epidermis or the buccal cavity and the inctill~fion of such a compound into the ear, eye and nose, such that the co~ oulld does not .~i~nifi(~"ntly enter the blood stream. In contrast, systemic ~flmini~tration refers to oral, intravenous, inl~ ol~~~1 and il~ uscular Z~f~ on.
Form~ tif)ns suitable for topical "flmini~tration include liquid or semi-liquid ~alations suitable for penc;l~dlion through the skin to the site of ;nfl~mm~tion such as li"i...~ , lotions, creams, ointmf nt~ or pastes, and drops snit~ble for ~lmini~tration to the eye, ear or nose. The active ingredient may comprise, for topical ~-lmini~tration, from ~ 0.001% to 10% w/w, for instance from 1% to 2% by weight of the Formulation. It may however comprise as much as 10% w/w but preferably will conlprise less than 5% w/w, more preferably from 0.1% to 1% w/w of the Form~ tion.

Lotions according to the present invention include those suitable for application to the skin or eye. An eye lotion may comprise a sterile aqueous solution optionally ctmt~ining a bactericide and may be prepared by methods similar to those for the~lc~alation of drops. Lotions or liniment~ for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or ~reton~, and~or a moictnri7P~ such as glycerol or an oil such as castor oil or arachis oil.
Creams, ointm~-.nt~s or pastes according to the present invention are semi-solidForm~ tions of the active ingredient for e~tf~rn~1 application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable m~rhin~.ry, with a greasy or non-greasy base. The base may comrrice hydrocarbons such as hard, soft or liquid pdld~rlll, glycerol, beeswax, a m~ot~11iC soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol or a macrogel. The F )rm~ tinn may incolpc.ldlc any suitable surface active agent such as an anionic, cationic or non-ionic surf~t~nt such as a sorbitan ester or a polyoxyethylene delival ive thereof.
Suspending agents such as natural gums, cellulose derivatives or inorganic m~t~ri~l~ such as ~ci1ic~ceous silicas, and other ingredients such as l~nolin, may also be inc~ rle-1 Drops according to the present invention may co~ ise sterile aqueous or oily solutions or sucperlcions and may be plc~aLcd by dissolving the active ingredient in a suitable aqueous solution of a bact-rici~l~1 and/or f~1n~ici~l~1 agent and/or any other suitable preservative, and preferably including a surface active agent. The res111ting solution may then be cl~rifi~cl by filtration, transferred to a suitable container which is then sealed and steri1i~t~cl by autoclaving or ~ i"i"g at 98-lO0~ C. for half an hour. ~l~rn~tively~ the ~25 solution may be steri1i7~d by filtration and transferred to the container by an aseptic technique. Examples of bactericidal and fungicidal agents suit~hle for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), ben7~1k~.nium chloride (0.01%) and chlorh~iflin~ acetate (0.01%). Suitable solvents for the plG~dL~Lion of an oily solution include glycerol, diluted alcohol and propylene glycol.
Compounds of formula (I) may be ~-l, l .i l);.ciL.~,I ed ~a Gl,teldlly, tnat is by iL~L avGllous, h~Lld~ scular, ~.ub~;uLaneous intranasal, intrarectal, intravaginal or illLLd~Glilolleal ~lmini~tration. The subcutaneous and inL-,.111~~sc~ r forms of palGlltt;ldl ~imini~tration are generally preferred. Appropriate dosage forms for such ~lmini.ctration may be prepared by conventional techniques. Compounds of Fo~nula (I) may also be ~-lmini~tered by inh~1~tion, that is by intranasal and oral inh~1~tion ~rimini~tration Appropriate dosage forms for such ~rlminictration, such as an aerosol Formulation or a metered dose inhaler, may be prepared by conventional techniques.

_ -WO 97/25046 PCT~lJS97~0V529 For all methods of use disclosed herein for the co~ ollllds of Formula (I), the daily oral dosage regimen will preferably be from about 0.1 to about 80 mg/kg of total body weight, preferably from about 0.2 to 30 mg/kg, more preferably from about 0.5-mg to 15mg. The daily ~ lcl~l dosage regimen about 0.1 to about 80 mg/kg of total bodyS weight, preferably from about 0.2 to about 30 mg/kg, and more preferably from about 0.5 mg to l~mg/kg. The daily topical dosage regimen will preferably be from 0.1 mg to 150 mg, ~lmini.ctPred one to four, preferably two or three times daily. The daily inh~l~tion dosage regimen will pre~erably be ~rom 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 rh~rm~ceutically acceptable salt thereof will be ~l~t.-rmin~fl by the nature and extent of the condition being treated, the form, route and site of z~-1mini~tration, and the particular patient being treated, and that such o~ can be ~1ete~ by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a co~ oul~d of Formula (I) or a ph~m~ce~ltic~lly acceptable salt thereof given per day for a defined number of days, can be ascertained by those skilled in the art using convel~lional course of IlGdL~ ,nt ~l~;t~ ",;,~ on tests.
The novel compounds of Forrnula (I) may also be used in association with the vele~ll.~y tre~tmPnt of m~mm~l~, other than hllm~n~, in need of inhihition of cytokine inhibition or production. In particular, cytokine mt~rli~tecl ~ e~eS for tre~tm~.n~, t~c.,~ lly or ~r~llyl~ti~ ~lly, in ~nim~lc include disease states such as those noted herein in the Methods of Tr~tm~-nt section, but in particular viral infections. Fx~mrl~s of such viruses inf.luAe, but are not limited to, lelllivi~us infections such as, equine infectious ~n~ ni~ virus, caprine arthritis virus, visna virus, or maedi virus or l~,t~O~ us infections, such as but not limited to feline imrnuno~efteienry virus (FIV), bovine immlln~ ficiency virus, or canine i~ n~orlefie~ip~nry virus or other reL~vilal infections.
The invention will now be ~lescri~e(l by reference to the following biological exarnples which are merely illLl~lldliv~ and are not to be co~sllued as a limit~fi~ n of the scope of the present invention.
BIOLOGICAL EXAMPLES
The cytokine-inhibiting effects of compounds of the present invention were deterrnine-l by the following in vitro assays:
I~ ,,.lc ~l~in ~ 1 (IL-1) Human peripheral blood monocytes are isolated and purified from either fresh blood alations from volunteer donors, or from blood bank buffy coats, according to theprocedure of Colotta et al, J Immunol, 132, 936 (1984). These monocytes (lx106) are W O 97/25046 PCT~US97/00529 plated in 2~well plates at a concentration of 1-2 million/rnl per well. The cells are allowed to adhere for 2 hours, after which time non-adherent cells are removed by gentle washing.
Test compounds are then added to the cells for lh before the addition of lipopolys~cch~n-l~
(50 ng/rnl), and the cultures are incubated at 37~C for an additional 24h. At the end of this S period, culture supern~t~nt~ are removed and cl~rifiçcl of cells and all debris. Culture sl~pern~t~ntC are then im mt~ tely assayed for IL-l biological activity, either by the method of Simon et al., J. Tmm~lnol Methods, 84, 85, (1985) (based on ability of IL-l to stimnl~te a Tnterlt~.ukin 2 producing cell line (EL-4) to secrete IL-2, in concert with A23 187 ionophore) or the method of Lee et al., J. ImmunoTherapy, 6 (1), 1-12 (1990) (ELISA assay).~ represP.~ ive compound of Formula (I), F~r~mrle 1, demonstrated positive inhibition in this assay.
Tumour Nc~ ~ Factor (TNF):
Hurnan peripheral blood monocytes are isolated and purified from either blood bank buffy coats or pl~tç~ .heresis re~iAIlces, acco,~lulg to the procedure of Colotta, R. et al., J
~nunol, 132(2), 936 (1984). The monocytes are plated at a density of lx106 cells/ml n Pdinm/well in 24-well multi-dishes. The cells are allowed to adhere for 1 hour after which time the sup~",~tSlnt is as~i,a~d and fresh m~tljurn (lml, RPMI-1640, Whitaker Biomedical Products, Whitaker, CA) cont;~ g 1% fetal calf serum plus pçni(~.illin and ~llG~Lolllycin (10 ul~its/rnl) added. The cells are in~ b~t~l for 45 minntto.s in the presence or 20 absence of a test compound at lnM-lOmM dose ranges (co~ oullds are solubilized in dimethyl sulfoxide/eth~nol, such that the final solvent concentration in the culture m~ lm is 0.5% dimethyl sulfoxide/0.5% ethanol). Bacterial lipopoly-s~csh~ride (E. coli 055:B5 LPS~ from Sigrna ~h~mir~l~ Co.) is then added (100 ng/ml in 10 rnl phosphate buffered saline) and cultures incubated for 16-18 hours at 37~C in a 5% C02 incubator. At the end 25 of the incubation period, culture sup~rn~t~nt~ are removed from the cells, ce~ ; r~ ~ged at 3000 rpm to remove cell debris. The ~u~ t~nt is then assàyed for TNF activity using either a radio-~ll~o or an ELISA assay, as described in WO 92/10190 and by Becker et al., J Tmmllnol, 1991, 147, 4307.
IL-l and TNF inhibitory activity does not seem to correlate with the l~lu~ Ly of the 30 compounds of Formula (I) in m~ ting arachidonic acid metabolism inhibition. Further the ability to inhibit production of prost~ nflin and/or leukotriene synth~ , bynonsteroidal anti-infl~mm~tory drugs with potent cyclooxygenase and/or lipoxygenase inhibitory activity does not mean that the compound will n.ocess~rily also inhibit TNF or IL-l production, at non-toxic doses.
35 In vivo TNF ~ssay:
While the above jn~ t~c~ assay in an in vitro assay, the compounds of Formula (I) may also be tested in an in vivo system such as described in:

(1) Griswold et al., Drugs Under Exp. and Clir~ical Res..XIX (6), 243-248 (1993); or (2) Boehm, et al., Journal Of Medicinal ~hemist~y 39, 3929-3937 (1996) whose disclosures are incol~ulaled by reference herein in their entirety.
IL ~lrin -8 ~IL,-8 ):
Primary human umbilical cord e~ othPlial cells (HUVEC) (Cell Systems, Kirl~nn', Wa) are ms~int~inP-l in culture mPrlillm supplPm~tPtl with 15% fetal bovine serum and 1%
CS-HBGF c~.n~ tin~ of aFGF and hPp .rjn The cells are then diluted 20-fold before being plated (250~1) into gelating coated 96-well plates. Prior tû use, culture m~r'.inm are replaced with fresh mPf'illm (200,ul). l3uffer or test compound (25~, at con-~Pntrations 10 between 1 and lO,uM) is then added to each well in quadr lpliç~t~ wells and the plates in~,llb~t.o(l for 6h in a hnmi~;fi.o.~l in.-l-b~lol at 37~C in an ~tm~sph~e of 5% C02. At the end of the in~llb~til n period, ~u~e .~t~nt is removed and assayed for IL-8 concentration using an IL-8 ELISA kit obtained from R~D Systems ~Minneapolis, MN). All data is~lesr~ rl as mean value (ng/ml) of mllltirlP. s~mrl~P.s based on the standard curve. IC50's 15 where a~p~ iate are generated by non-linear regression analysis.
Cyto~ Specific Binding r~vlei~ Assay A radioco...pel ;l i v~ bin~ ng assay was developed to provide a highly reproducible ~'lilll~ screen for structure-activity studies. This assay provides many advantages over the con~ Lional bioassays which utilize freshly i~ok~te(~ human monocytes as a source of cytokines and ELISA assays to quantify them. Re~i-1Ps being a much more facile assay, the binding assay has been extensively v~ t~cl to highly correlate with the results of the bioassay. A specific and reproducible cytokine inhibitor binding assay was developed using soluble cystosolic fraction from TEIP. 1 cells and a radiolabeled cc,nl~o~ d. Patent Application USSN 08/123175 Lee et al., filed September 1993, USSN; Lee et al., PCT
94/10529 filed 16 September 1994 and Lee et al., Nature 300, n(72), 739-746 (Dec. 1994) whose disclosures are incol~ol~ted by reference herein in its c~ GIy describes the above noted method for screening drugs to identify compounds which illt~,.a;l with and bind to the cytokine specific binding protein (hereinafter CSBP). However, for purposes herein the bin-lin~ protein may be in isolated form in solution, or in immobilized form, or may be g~n~tic~lly e~ginPered to be expressed on the surface of recomhin~nt host cells such as in phage display system or as fusion proteins. ~ltPrn~tively, whole cells or cytosolic fractions comprising the CSBP may be employed in the screening protocol. Regardless of the form of the binding protein, a plurality of compounds are contacted with the binding protein under conditions sllfflcient to forrn a compoundl binding protein comple~c and compound capable of forming, enhancing or illtelre~ g with said complexes are detected.
Represent~tive final compounds of Pormula (I), Examples 1 to 4, and 6 have all demonstrated positive inhibitory activity of an IC~o of < SOuM in this binding assay.

W O 97/Z5046 PCTfUS97/00529 5; SRP KINASE ASSA~:
This assay measures the CSBP-catalyzed transfer Of 32p from [a-32P3ATP to threonine residue in an epi(1~-rrn~l growth factor receptor (EGFR)-derived peptrde (T669) with the following sequence: KRELVEPLTPSGEAPNQALLR (residues S G61-681). (See ~T~ gh~.r et al., "Regulation of Stress Tn~ red Cytokine Production by Pyridinyl Tm~ 7oles: Inhibition of CSPB Kinase", BioOrganic & Meflir,in~l Chemistry, to be published 1996).
Kinase reactions (total volume 30 ul) contain: 25 mM Hepes buffer, pH 7.5;
10 mM MgC12; 170 uM ATP(l); 10 uM Na ortho vanadate; 0.4 mM T669 peptide;
and 20-80 ng of yeast-e~icss~d purified CSBP2 (see Lee et al., Na~ure 300, n(72), 739-746 (Dec. 1994)). Colllpoullds (5 ul from [6X3 stock(2)) are pre-incllb~tefl with the enzyme and peptide for 20 min on ice prior to starting the reactions with 32P/MgATP. Reactions are incub~t~-~ at 30 oc for 10 min and stopped by adding 10ul of 0.3 M phosphoric acid. 32P-labeled peptide is separated on phosphocellulose (Wattman, p81) filters by spotting 30 ul reaction ~ LuLe~ Filters are washed 3 times with 75 mM ph~sphoric acid followed by 2 washes with H20, and counted for 32P.
(1) The Km of CSBP for ATP was t~ e~ l to be 170 uM. Therefore, compounds screened at the Km value of ATP.
(2) Compounds are usually dissolved in DMSO and are diluted in 25 mM
20 Hepes buffer to get final co,lcel,t,dlion of DMSO of 0.17%.
Re~,;,e~ live final compounds of Pormula (1), Examples 1,5 8, and 9 have all demonstrated ~o~iLive inhibitory activity of an ICso of < 50uM in this binding assay.
Fx~mple 10 demonstrated an IC50 of > 50uM in this assay.

25 Pl v~l~J~ c' ~ e .r oxide ~.y~lhas~-2 (PGHS-2) assay:
The following assay describes a method for ~ele....i~ g the inhibitory effects of compounds of Formula (I) on human PGHS-2 protein expression in LPS stim~ t~d human monocytes.
Method: Human periph~l blood monocytes were isolated from buffy coats by 30 centrifugation through Ficoll and Percoll gradients. Cells were seeded at 2 X 106/well in 24 well plates and allowed to adhere ~or 1 hour in RPMI supplemented with 1% human AB
serum, 20mM L-~ , ptonicillin-Streptomycin and 10mM HEPES. Compounds were added at various concentrations a~d incubated at 37~C for 10 minnte~. LPS was added at 50 ng/well (to induce enzyme expression) and in~l~b~tP-l overnight at 37~C. The 3~ supernatant was removed and cells washed once in cold PBS. The cells were lysed in lOO,ul of cold lysis buffer(50mM Tris/HCl pH 7.5, 150mM NaCl, 1% NP40, 0.5% sodium deoxycholate, 0.1% SDS, 300ug/ml DNAse, 0.1% Tl~ITON X-100, lmM PMS~, lrnM

W O 97/25046 PCT~US97/00529 leupeptin, lmM ~ atill). The lysate was centrif~ged (10,000 X g for 10 min. at 4~C) to remove debns and the soluble fraction was subjected to SDS PAGE. analysis (12% gel).
Protein separated on the gel were transferred onto nitrocellulose ,lw.)l~ e by electrophoretic means for 2 hours at 60 volts. The membrane was pretreated for one hour S in PBS/0. 1% Tween 20 with 5% non-fat dry miLk. After washing 3 times in PBS/Tween buffer, the membrane was inr~llb~tP~ with a 1:2000 dilution of a monospecific antiserum to PGHS-2 or a 1:1000 dilution of an antiserum to PGHs-l in PBS/Tween with 1% BSA for one hour with continuous ~h~kin~ The membrane was washed 3~ in PBS/Tween and then incubated with a 1:3000 dilution of horseradish peroxidase conjugated donkey antiserum to 10 rabbit Ig (~mF r.ch~m) in PBS/l ween with 1% BSA for one hour with continuous sh~king.
The m~..-.l-l,.,lF was then washed 3X in PBSlTween and the ECL imrnunodetection system (AmPr.ch~m) was used to detect the level of expression of prost~gl~nclin endoperoxide synthases-2.
Results: The following compounds were tested and found to be active in this assay (i.e., inhibited LPS in~ e-l PGHS-2 protein e~ ssion in rank order potency similar to that for inhibiting cytokine production as noted in assays in-lic~tFed):
4-(4-Fluc luphc.lyl)-2-(4-methylsulrll,ylpllenyl)-5-(4-pyridyl)imi-1~7Qle 6-(4-Fluo-v~h~lyl)-2,3-dihydro-5-(4-pyridinyl)imitl~7Ot2,1-b~thiazole; and De~mPth~one Several compounds were tested and found to be inactive (up to 10uM):
2-(4-Methylsulfinylphenyl)-3-(~pyridyl)-6,7-dihydro-(5H)-pyrrolo[ 1,2-a]imi~1~7ole;rolipram, ph~-ni~lone and NDGA.
None of the compounds tested was found to inhibit PGHS- 1 or cPLA2 protein levels in si~lar e.~ F~

TNF-a in T-~ Brain Injury Assay The present assay provides for e~min~tion of the expression of tumor necrosis factor mRNA in specific brain regions which follow e~ t~lly in~ ced lateral fluid-percussion tr~l~m~tiC brain injury (TBI) in rats. Adult Sprague-Dawley rats (n=42) are ~n~ F~.d with sodium pentobarbital (60 mg/~g, i.p.) and subjected to lateral fluid-pe,.;~lssion brain iniury of moderate severity (2.4 atm.) centered over the left te~lpo~ uietal cortex (n=18), or "sham" treatment (~npsthp~ia and surgery without injury, n=18). Animals are s~c-rifiçe~l by decapitation at 1, 6 and 24 hr. post injury, brains removed, and tissue samples of left (injured) parietal cortex (LC), corresponding area in the contralateral right cortex (RC), cortex adjacent to injured parietal cortex (LA), corresponding adjacent area in the right cortex (RA), lefthippocampus (LEI) and right hippocampus (RH) are prepared. Total RNA is isolated W O 97/25046 PCT~US97/00~29 and Northern blot hybri~li7~tion is pel~~ ed and qllAntitAt~l relative to an TNF-oc ~o~ilive control RNA (macrophage = 100%). A mArk~ll increase of TNF- a mRNA
e~lGssion is observed in LH (104+17% of positive control, p < 0.05 co~ d with sham), LC (105+21%, p< 0.05) and LA (69+8%, p c 0.01) in the tr~nm~ti~ed hemisphere 1 hr. following injury. An increased TNF- a mRNA expression is also observed in I,H (46+8%, p < 0.05), LC (30+3%, p < 0.01) and LA (32+3%, p < 0.01)at 6 hr. which resolves by 24 hr. following injury. In the contralateral h~mi~ph~o~re~
e~lession of TNF- a rnRNA is increased in RH (46~2%, p < 0.01), RC (4+3%) and RA (22+8%) at 1 hr. and in RH (28+11%), RC (7+5%) and RA (26+6%, p < 0.05) at 10 6 hr. but not at 24 hr. following injury. In sham (surgery without injury) or naive AnimAl~, no consistent changes in expression of TNF- a mRNA is observed in any of the 6 brain areas in either hemisphere at any times. These results in~ ate that following par~cAgitt~l fluid-pel~;u~sion brain injury, the t~ ol~l expression of TNF-a rnRNA is altered in specific brain regions, inrlu-1inf~ those of the non-trAnm15 hemisphere. Since TNF- a is able to induce nerve growth factor (NGF) and stimlllAt~ the release of other cytokines from activated a~,o~;yl~s, this post-trA--mAtir alteration in gene e~lcssion of TNF- a plays an important role in both the acute and regenerative response to CNS trauma.

20 ~NS Tn~iury model ~or IL-~ mRNA
This assay characterizes the regional expression of interleukin-1~ 1B) mRNA in specific brain regions following e7crerim~nt~l lateral fluid-percussion tr~ tic brain injury (IBI) in rats. Adult Sprague-Dawley rats (n=42) are ~n~sthtoti7.o(l with sodium pentobarbital (60 mg/kg, i.p.) and subjected to lateral 25 fluid-~c~;ussion brain injury of moderate severity (2.4 atm.) centered over the left temporAp~riPtAl cortex (n=18), or "sham" L.~ .l (Anesth~ci~ and surgery without injury). Animals are s~crifi~eA at 1, 6 and 24 hr. post injury, brains removed, and tissue s~n-ples of left (injured) parietal cortex (L,C), co,le~onding area in the contralateral right cortex (RC), cortex ~ A~ent to injured parietal cortex (LA),30 corresponding ~-1jAr~nt area in the right cortex (RA), left hippocarnpus (LH) and right hippoc~n-rl~ (RH) were ~rep~ed. Total RNA is isolated and Northern blot hy7Wdization is pe,~.,lled and the quantity of brain tissue IL-l~ mRNA is presented as percent relative radioactivity of IL- ~ ~ positive macrophage RNA
which is loaded on same gel. At 1 hr. following brain injury, a m~rk~fl and 35 ~ignifir~nt increase in e~ ssion of IL-lB rnRNA is observed in LC (20.0_0.7% of positive control, n=6, p < 0.05 compared with sham animal), LH (24.5_0.9%, p < 0.05) and LA (21.5+3.1%, p < 0.05) in the injured hemisphere, which remained W O 97~5046 PCT~US97/00529 elevated up to 6 hr. post injury in the LC (4.0~0.4%, n=6, p < 0.05) and LH
(5.0+1.3%, p < 0.05). In sham or naive ~nim~l~, no expression of IL-l~ mRNA is observed in any of the respective brain areas. These results indicate that following TBI, the L~ dl expression of IL-l~ mRNA is regionally stim~ t~d in specific brain regions. These regional changes in cy~okin~, such as IL-113 play a role in the post-tr~llm~ti~ pathologic or regellGld~ivG sequelae of brain injury.

SY~I l'H~':llC EXAMPLES
The invention will now be described by reference to the following examples whichare merely illu~lldlive and are not to be construed as a limitation of the scope of the present invention. All l~m~er~Lulcs are given in degrees centigrade, all solvents are highest available purity and all reactions run under anyllluus conditions in an argon atmosphere unless othenvise intlic~t~rl Mass spectra were ~ rolllled upon a VG Zab mass spectrometer using fast atom bombardment, unless otherwise in(1ir~t~(1 lH-NMR
1~ (hereinafter "NMR") spectra were recorded at 250 MHz using a Bruker AM 250 or Am 400 spectrometer. Mlllti~ ti~s in~ t~(l are: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet and br indicates a broad signal. Sat. inf~ t~:S a saturated solution, eq indicates the plupulLion of a molar equivalent of reagent relative to the principal re~t~nt Plash cllrolllatography is run over Merck Silica gel 60 (230 - 400 mesh).
Example 1 5-(2-Methoxy-4-pvrimidinyl)-4-(4-fluorophenyl)- 1 -(4-piperidinvl)irnidazole a) 2-N-Methylthio~li."iclin~carboxaldehyde dimethyl acetal Pyruvic aldehyde d1I11GI11Y1 acetal (60 rnL, 459 mmol) and N,N-dimethyl form~mifie dilllGLllyl acetal (60 rnL, 459 rnmol) were stirred together at 100 for 18 h. The ll~iAIulG
was cooled.
Methanol (300 mL), thiourea (69.6 g) and sodium methoxide (231 rnL, 25 wt% in MeOH) were added to the above mixture and stirred at 70~ for 2 h. After cooling,iodom~th~nlo (144 mL) was added dropwise and the lllix.LulG was stirred 3 h. at room temp.
After ~lilntin~ with PtOAc and H20, the organic phase was sep~r~tefl, dried (Na2S04),and concelllldted to yield the title compound as a brown oil (75.~ g, 82% yield). lH NMR
(CDC13): d 8.17 (d, lH), 6.77 (d, lH), 5.15 ~s, lH), 3.40 (s, 6H).
b) 2- Metho~y~ylhnidine-4-carboxaldehyde dimethyl acetal The product of the prece~ling example (5.0 g, 25 mmol) was dissolved in m~th~nol~ (100 mL), cooled to 4~and a solution of oxone (9.21g), in H20 (100 mL) was added dropwise (T < 15~). Warmed to 23~, stirred 2h, poured into 10 % aq NaOH (250 mL) and - extracted with EtOAc. The extracts were washed with 10% aq NaOH, dried (Na2SO4), W O 97/2~046 PCT~US97/00529 filte.~d, concentrated, and flash cnromatographed (70% hexanelEtOAc) to afford 1.66g (36%) of the title compound. ESP~ (Mass Spec) m/z 185 (MH+3.
c) 2- Metho~y~y~ line~-carboxaldehyde The product of the prece~ling example (0.54 g, 2.93 mmol), was dissolved in 3 M
S HCl (2.17 mL, 6.5 mmol) and stirred at 23~ for 3 days, cooled to 4~, layered with EtOAc and made slightly basic by the addition of solid Na2CO3. Extraction with EtOAc (5 x 40 mL) afforded 0.309 g (76%) of the title compound as a white solid. lH NMR (CDC13): d 9.96 (s,1), 8.78 (d,l), 7.46 (d, 1), 4.10 (s, 3).
d) 1-t-Bulo~yc~bullyl4-aminopiperidine 1- t-Buto~yc~l,oliyl piperidine~-one (cornmercially available from T ~n~eter Chem) (39.9 g, 0.20 mol), THF (150 mL), EI2O (300 rnL), and H2NOH HCl (55.2, 0.80 mol) were dissolved together and Na2CO3 (55.2 g, 0.53 mol) was added in small portions.
The llLi~luie was stirred at 23~ for 14 h, most of the THF was evaporated in vacuo, adjusted to pH > 10 with 50% aq NaOH, extracted with EtOAc(5 x 50 mL) and concentrated to a 15 white foam. Triturated with hexane, filtered and the solid was dried in vacuo to afford 40.31 g of the title co~ oulld.
The above residue was dissolved in EtOH (absolute, 1 L) and Raney Ni (50 mL of aslurry in EtOH) was added and the mi~ule was reduced under H2 (50 psi) for 3.5 h. The catalyst was filtered off and washed with EtOH to afford. Concentration afforde 38.44g 20 (96% overall) of the title compound as a colorless oil which solidified to a white solid upon sts~n~1in~ at-20~.
e) 4-Fluulul~rlcllyl-tolylsulfonolll~ ylro~ icle To a ~u~ ion of p-tol~ n~s~ nic acid sodium salt (30 g) in H20 (100 mL) was added methyl t-butyl ether (50 mL) followed by dropwise addition of conc HCl (15 rnL). After 25 stirring 5 min, the organic phase was removed and the aqueous phase was extr~-~teA with methyl t-butyl ether. The organic phase was dried (Na2S04) and conce,lllated to near dryness. Hexane was added and the resllltin~ preCirit~t~ collected to afford p-tolll~neslllfinic acid; yield 22 g.
p-T~ e~ s--lfinie acid (22 g, 140.6 ~nol), p-fluorobt~n7~kl.-rlyde (22 mL, 206 mmol), 30 fnrrn~mide (20 nL, 503 mmol) and camphor sulphonic acid (4 g, 17.3 mmol) were combined and stirred at 60 ~ 18 h. The resulting solid was broken up and stirred with a l~ lul~ of MeOH (35 mL) and hexane (82 mL) then filtered. The solid was resuspended in MeOH /
hexanes (1:3, 200 mL) and stirred vigorously to break up the rem~ining chunks. Filtration af~orded the title compound (27 g, 62 % yield): lH NMR (400 MHz, CDC13) d 8.13 (s, lH), 35 7.71 (d, 2H), 7.43 (dd~ 2H), 7.32 (d, 2H), 7.08 (t, 2H), 6.34 (d, lH), 2.45 (s, 3H).
f) 4-Fluorophenyl-tolylsul~ûnomethylisocyanide WO 97/25046 PCT~US97/00529 4-Fluorophenyl-tolylsulfonomelhylro~ mi~ (2.01g, 6.25 mmol~ in DME (32 mL) was cooled to -10 ~C. POC13 (1.52 m~, 16.3 mmol) was added followed by the dropwise addition of triethylamine (4.6 rnL, 32.6 mmol) in DME (3mL) keeping the internalte~ eldLul~, below -5 ~. The ll~h-Lule was gradually warmed to ambient temperature over 1 S h., poured into H20 and ~ ed with EtOAc. The orga~uc phase was washed with sat aq NaHCO3, dried (Na2S04), and concel~ t~d. The rçs~ ing residue was ~liLuldled with petroleum ether and filtered to afford the title col~uLIlld (1.7 g, 90% yield): lH NMR
(CDC13) d 7.63 (d, 2H), 7.33 (m, 4H), 7.10 (t, 2H), 5.60 (s, IH), 2.50 (s, 3H).
g) 2- Metho~y~yl; " ~;~ine-4-carboxaldehyde rl-t-blllo~syc~l,ollyl-4-aminopiperidinel 10 i ~e The product of example l(d) (0.308 g, 2.23 mmol), and the product of example l(c) (0.468 g, 2.34 mrnol) were combined in CH2C12 (50 mL) and stirred at 23~ for 16h.
Concentration afforded the title compound as a light orange foam. lH NMR (CDC13): d 8.56 (d, 1), 8.26 (s, 1), 7.57 (d, 1), 4.05 (s and m, 4), 3.5 (m, 2), 3.0 (m, 2), 1.75 (m, 4), 1.46 (s, 9).
h) 5-(2-Methoxy-4-pyrimidinyl)-4-(4-ffuorophenyl)-1-~(1-t-butoxycarbonyl)-4-piperidinyllimi-l~7Ole The product of the prece(1in~ example, DMF (5 rnL), the product of e~mple l(f) (0.708 g, 2.23 mmol) and K2C03 (0.308 g, 2.23 mmol) were combined and stirred for 2 20 days, diluted with Et20 and filtered. The filtrate was co~ . d~d under high vacuum to a brown solid. Trituration witb Et~O and hexane (1: 1, 200 mL) afforded the title compound as a tan solid. Cryst~11i7~tinn from ?-~etorl~/hexane afforded 0.50~g (64% from the product of example 4(c). ESP+ (Mass Spec) m/z 453 (MH~).
i) 5-(2-Methoxy-4-pyrimidinyl)-4-(4-fluolo~hellyl)- l-(4-piperidinyl)imi~1~7.( 1e The product of the prece~l;ng example (0.505g, 1.43 mmol), was added to ice coldTFA, under Ar. The resulting solution was warmed to 23~ and stirred 1.5 h. The TFA was removed in vacuo the residue was dissolved in EtOAc and extracted into H2O (2 x 20 mL).
The com~ined aqueous phases were layered with EtOAc and cooled to 4~, made basic by the addition of 10% aqueous NaOH and the aqueous was extracted with EtOAc (4 x 25 mL). The combined extracts were dried (Na2SO4) and concentrated to a white crystalline solid. Trituration of the solid with hexane afforded 16~ mg of white solid. Lvaporation of the above filtrate afforded an additional 133mg of slightly yellow crystals. Total yield 298 mg (~9%). For the first crop of crystals: mp 1~9-160~.

Fxample 2 5-(2-Iso-Propoxy~-pyrimidinyl)-4-(4-fluorophenyl)- 1 -(4-piperidinyl)imi~7Ole _ W O 97/250~6 PCT~US97/00529 a) ~-Methylthi~ h~idine-4-carbo~Aldehyde The product of example l(a) (9.96 g, 50 rnmol), and 3 N HCl (42 mL, 126 mmol) were combined and sti~red at 48~ for 16h, cooled to 23~, combined withEtOAc (200rnL) and made basic by the addition of solid Na2C03 (12.6 g, 150 mmol).
The aqueous phase was extracted with EtOAc (4 x 150 mL, dried ~f~Na2S04), conc~lLl~ted and the residue was filtered through a pad of silica (ca 150 rnL) with CH2C12 to afford 7.49 g (97%) of the title c~3ll~0ulld lH NMR (CDCl3): ~ 9.96 (s, l), 8.77 (d, 1), 7.44 (d, 1), 2.62 (s, 3).
b) 2-Methylthic,~ ine-4-carboxaldehyde 1-t-l~ulo~y~;~bollyl~
10 ~minopiperidine imine The product of the previous step (4.84 g, 31.4 mmol), MgSO4 (ca 2 g), the product of example l(d) (6.51 g, 32.6 mmol) and CH2Cl2 (100 ml) were combined and stirred at 23 ~ for 16 h. Filtration and concentration of the filtrate afforded the title compound as a yellow oil. lH NMR (CDCl3): ~ 8.57 (d, 1), 8.27 (s, 1), 7.58 (d, 1), 15 4.05 (m, 2), 3.55 (m, 1), 3.00 (m, 2), 2.60 (s, 3), 1.75 (m, 4), 1.48 (s, 9).
c) 5-(2-Methylthio-4-pyrimi-linyl)-4-(4-fluorophenyl)-1-r(l-t-butoxycarbonyl)~-piperidinyllimid~ole T~he product of the previous çx~mrle and the product of example l(f~ (9.41 g, 32.6 mmol), DMF (64 mL) and K2CO3 (4.43 g, 32.4 mmol) were reacted by the procedure of 20 e~mple l(h) to afford 9.07 g of product (62% from the product of example l(a). MS ES+
rn/z = 470 f~MH+).
d) 5-(2-M~-tl~ylsulfinyl-4-pyrimidinyl)~(4-fluorophenyl)- 1 -rt 1 -t-butoxycarbonyl~4-piperidinyllimidazole The product of the previous example (4.69g, 10 mmol) was dissolved in THF, 25 cooled to -10~ and oxone (6.14g, 10 ~nol) in H2O (50 rnL) was added dropwise (T < 5~).
The resllltin~ , was warmed to 20~ over ca 50 min, poured into a vigorously stirred Ul~ of 10% aq NaOH (300 mL), ice (100 rnL), and EtOAc (300 mT ). The EtOAc was separated, dried (Na2SO4), and concenl~dl~d to a yellow oil. Flash ehlolllaLography (0-2%
MeOH in CH2C12) afforded 3.58g (74%). ESP+ (Mass Spec) m/z 486 (MH+).
30 e) 5-f2-iso-Propoxy~-pyrirnidinyl)4-(4-fluorophenyl)- 1 --r~ 1 -t-butoxycarbonyl)-4-piperidinyllimitl~7ole NaH (60% in mineral oil) was washed with dry THF and layered with more THF (5 mL) and anhydrous iso-propanol (1.15 mL) was added. When the bubbling subsided the reslllting soln was recooled to 23~ and the product of the previous example (0.58 g, 1.19 mmol) in THF (5 mL) was added dropwise. After 5 min the reaction 35 was shaken with EtOAc (ca 100 mL) and H20 (50 mT ~) and the phases were separated and W O 97~250~6 PCTAU597~00529 the EtOAc was dried and conce"l~ d. The residue was cryst~lli7~-1 from ~cetQn~rhexane to afford 335 mg of the title compound (58~). MS ES+ m/z = 482 (MH~).
f) 5-(2-iso-Propoxy-4-pyrir~udinyl)4-(4-fluorophenyl)- 1 -(4-piperidinyl)irnidazole The product of the preceeding example (325 mg, 0.68 mmol) was treated with TFA
S by the procedure of example l(i). The crude product was crystallized from 13t20/hexane to afford 106 mg (41%) of white crystals. mp = 121 - 122~.

Example 3 5-(2-Hydroxy-4-pyrimidinyl)-4-(4-fluorophenyl)- 1 -(4-piperidinyl)imicl~7-)le 10 trifln- roacetate _ a) 5-(2-Methylsulfonyl~-pyrimidinyl)-4-(~fluorophenyl~- 1 -r( l -t-butoxycarbonyl)-4-piperidinyllimi~l~7~1e The product of example 2(c) (9.07 g, 19.3 mmol), dissolved in 1~ was cooled to -10~ and oxone (28.5g, 46.4 mmol)in H20 (250 rnL)was added dropwise. The resulting 15 lLUYlwc was stirred at 23~ for 24h, combined with ice (100 mL) and CH2C12 and washed with brine (l00 mL), dried (Na2S04), concelllLdled and dried in vacuo to afford 8.27 g (85%). MS ES+ m/z = 502 (MH+).
b) 5-(2-Hydroxy4-pyrimidinyl) 4-(4-fluorophenyl)-1-r(l-t-butoxycarbonyl)~
piperidinyl~imitl~zole The product of the previous example (141 mg, 0.28 rnmol) was dissolved in THF ~5rnL) to which was added 50~o aq NaOH (150 uL, ca 1.8 mmol). The soln was stirred for 3 days and a precipitate foImed. The solid was filtered off, washed with THF, and dried in vacuo to afford the title compound. MS ES~ m/z = 440 (MlI+).
5-(2-Hydroxy4-pyrimidinyl)-4-(4-fluorophenvl)- 1 -(4-piperidinyl)imi~1~7olP
25 c) The product of the previous example and TFA (3 mL) were combined and stirred for 30 rnin, conc~ ed and the residue was triturated with ~t20 and filtered and the white solid was washed with Et2O, dried in vacuo to afford 114 mg (90% of monoTFA salt from the product of çx~mple 3(a). mp = 80 - l 10~ (dec).

Example 4 5-(2-Methoxy~-pyridinyl~l (4-fluorophenvl)-1-(4-piperidinyl)imitl~7Ole a) 2-Chlo~ ylidine4-carboxaldehyde 1-t-l,ulokyca,l~onyl~aminopiperidine ;min~, 2-Chloropyridine-4-carboxaldehyde was yle~al~d as described in the patent liLcldlulc (VVPI Acc. No. 88-258820/37) whose disclosure is incorporated by reference in 35 its entirety herein. This aldehyde was reacted with the product of example l(d) by the procedure of example l(g) to afford the title compound as a yellow oil, d~alenlly a lulc of imine isomers based on NMR. . lH NMR (CD3Cl): o 8.49, 8.35 (2d, lH), W O 97/25046 PCTrUS97/00529 8.22, 8,21 (2s, 1), 7.57, 7.29 (2s, lH), 7.45,7.12 (2d, lH), 2.93 (m, 1), 2.70 (m, 3), 1.64 (m, 3), 1.42, 1.40 (2s, 9), 1.17 (m, 2).
b) 5-(2-Chloro-4-pyridinyl) 4-(4-fluorophenyl)- 1 -(1 -t-buto~yc~l,onylpiperidin-4-yl)irnidazole The product of examp}e 4(a) was reacted with the product of example 1 (f~
by the procedure of example 1 (h). The crude product was filtered through silicaeluting with 0 - 2% MeOH in CH2C12 to afford the title compound as a light yellow solid. MS ES+ m/z = 457, 459 (MH+).
c) 5-(2-Methoxv-4-pyridinyl) 4-(4-fluorophenyl~- 1 -(1 -t-butoxycarbonyl 10 piperidin4-yl)irnidazole The product of the precee~in~ example (l.Og, 2.19 rnrnol) was dissolved in 25% NaOMe in MeOH (20 mL) and heated to reflux for 1 h, cooled and combined with H20 and extracted with EtOAc (2x). The extracts were dried (Na2S04) and concentrated. The residue was flash cl~omalographed (0 - 30% EtOAc in hexane) 15 afforded 300 mg (32%) of the title co~ oulld as a brown solid.
Crystals from acetone/h~Y~nP- MS ES~ mlz = 453 (MH+).
d) 5-(2-Methoxy~pyridinyl~-4-14-fluorophenyl) - 1 -(4-piperidinyl)irnidazole The product of the previous example was reacted by the procedure of ex~mrlel(i). The crude product was l~ dled with 1:10 Et20/hexane filtered and 20 dried in vacuo to afford the title compound as a white solid. mp=136 - 137.

Px~ S
5-(2-iso-PropQxv-4-pyridinyl)-4-(4-fluolo~he~ (4-piperidinyl)imi-1~7,ole The product was ~lc~ared by the procedure of Example 4 sub~ ; . ,g sodium 25 isopropoxide and is.,~r~allol for sodium methoxide and methanol. MS ES~ m/z = 381 (MH+).

F.y~m~le 6 5-~2-Methylthio-4-pyrimi~linyl)-4-(4-fluorophpnyl)- 1 -(4-piperidinyl)imidai!;ole The product of example 2(c) was reacted by the procedure of example l(i) to afford the title compound. mp = 182 - 183~.

Ex~m~1e 7 5-(2-Methylthio-4-pyrimi~1inyl)-4-(4-fluorophenyl)- 1 -r(1 -methyl)-4-3~ piperidinyl]imi~l~7Ole a) 2-Methylthiopvrimicline-4-carboxaldehyde 1-methyl-4-arninopiperidine irnine _ W~ 97~25046 PCTAUS97/aO529 The product of example 2(a) was reacted with 1-methyl 4-amino piperidine by the procedure of ç~mple 2(b) to afford the title co.,-~ound b) 5-(2-Methylthio4-pyrirnidinyl)-4-~4-fluu~ yl)- 1 -r( 1 -methyl)-4-piperidinvll;mi-1~7,Qle The product of the previous example was reacted with the product of example 1 (f) by the procedure of example 1 ~i) to afford the title compound. mp =
181 - 182~.
Fx~m,l?le g 5-(2-Ethoxv4-pyrimidinyl)-4-(4-fluorophenyl)- 1 -(4-piperidinyl)imidazole 10 a) 5-(2-Fthoxy~-pyrimidinyl)-4-(4-fluoropheny~ rf l-t-b~lL~yc~lJollyl)~-piperi~ yllimi~l~7ole The title colll~uulld was ~ ,d by the method of example 2(e) except that anhydrous EtOH was used in place of 2-propanol.
b) 5-(2-Ethoxy-4-pyrimi~linyl)~-(4-fluoroph~nyl)-1-(4-piperidinyl~imi~ ole The product of the precee~lin~ example was treated with TFA by the procedure of e~c~mrle 1 (i) to afford the title compound as white crystals. mp - 128 - 129.

F.x~mple 9 1-(1 -Ethylcarbo~ylyiyGlidin-4-yl)-3-(4-thiomethylphenyl)-5-r2-~thiomethyl)pyri-m--idin 4-yll-imi~ .7Ole 20 a) 4-Thiom~f hyl~he~lyl-tolysulfon~ Iylisocyanide The titled compound was prepared using the proceedures 1 (e) & (f) sll~s~ .li.,g 4-thiomethylben7~k1hyde for 4-fluorob~n7~ hyde.
b) 2-Thiomethylpyrimi-lin~-carboxaldehyde[1-ethoxycarbonyl-4-aminopiperidine~imine The titled co~ oulld was prepared using the proccedure of example 2 (b) subslill.lillg the 25 commercially available 1-ethoxycarbonyl4-aminopireri~lin~ for 1-t-bulo~ycalbonyl4-aminopiperidine c) 1-( l-Ethylcarbo~yl~i~elidin-4-yl)-3-(4-thiomethylphenyl)-5-[2-(thiomethyl)pyrimidin-4-yl]-imi(1~7Ole4-thiomethylphenyl-tolysulfonomethylisocyanide (9.0g, 29.2 mmol)and2-thiomrll.yl~y,;l..i~lin~-4-carboxaldehyde[l-ethoxycarbonyl-4-aminopireri~line] imine (7.0g, 22.1 mmol) allowed to react ~cording to the proceedure of example 1 (h). Upon completion of the reaction most of the DMF was eva~olal~d in high vacuo, the lGIII~ i"g solution poured into water and extracted with EtOAc. The extracts were washed with water, brine, dried (Na2SO4), filtered, concentrated, and flash chromatographed (60%
EtOAc/hexane) to yield the titled compound (4.0g, 38.5% yield). ESP+ (Mass Spec) m/z 471 (MH+).

W O 97/25046 PCT~US97/00529 Example 10 Ethylcarbonyl~ ,idine~-yl)-4-(4-methylsul~lllyl~llenyl)-5-r2-methylsulfinyl-pyrimi~1in~-yll imidazole The product of the previous example (2g, 4.26mmol) was dissolved in TH~ cooled to -10~ and OXONE (3.3g, 8.52mmol) in water (10 ml) was added dropwise (T < 5~). The r~,slllting mixture was warmed to 20~ over ~0 mins, poured into a vigorously stirred e of 10% aq NaOH (1~0 ml), ice (100 ml), and E~tOAc was separated, dried (Na2S04), and concentrated to a yellow solid. ~Pçrict~lli7erl from EtOAc/h~xh~nP
(1:10) to afford the titled compound (80mg). ESP+ (Mass Spec~ m/z 502 (M~+).
All publications, inr,ll-rling but not limited to patents and patent applications, cited in this specific~tion are herein incol~G,ated by lefelcnce as if each individual publication were specifically and individually intlic~tecl to be incol~ol~ted by reference herein as though fully set forth.
The above description fully discloses the invention inrlllrlin~ preferred emborlim~nt~ thereof. Mo-lific~tinn~ and improv~"lents of the embor~ tSnl!i specifically disclosed herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the are can, using the prece~ing description, utilize the present invention to its fullest extent. Therefore the P,x~mI)le,c herein are to be construed as 20 merely illusLI~tive and not a lirnitation of the scope of the present invention in any way.
The embo~ of the i,l~.,lion in which an exclusive plu~clly orprivilege is claimed are defined as follows.

Claims (29)

1. A compound represented by the formula:

R1 is a 4-pyridyl, or 4-pyrimidinyl ring which is substituted with a C1-4 alkoxy group, and is additionally optionally substituted independently by C1-4 alkyl, halogen, hydroxyl.
C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylsulfinyl, CH2OR12, amino, mono and di- C1-6 alkyl substituted amino, N(10)C(O)Rc or an N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR15;
R4 is phenyl, naphth-1-yl or naphth-2-yi, or a heteroaryl, which is optionally substituted by one or two substituants, each of which is independently selected, and which, for a 4-phenyl, 4-naphth-1-yl, 5-naphth-2-yl or 6-naphth-2-yl substituant, is halogen, cyano, nitro, -C(Z)NR7R17, -C(Z)ORl6, -(CR10R20)vCOR12, -SR5, -SOR5, -OR12. halo-substituted-C1-4 alkyl, C1-4 alkyl, -ZC(Z)R12, -NR10C(Z)R16, or -(CR10R20)vNR10R20 and which, for other positions of substitution, is halogen, cyano, -C(Z)NR13R14, -C(Z)OR3, -(CR10R20)m"COR3, -S(O)m'R3, -OR3, halo-substituted-C1-4 alkyl, -C1-4 alkyl, -(CR10R20)m"NR10C(Z)R3, -NR10S(O)m'R8, -NR10S(O)m'NR7R17, -ZC(Z)R3 or-(CR10R20)m"NR13R14;
v is 0, or an integer having a value of 1 or 2;
m is 0, or the integer 1 or 2;
m' is an integer having a value of 1 or 2, m" is 0, or an integer having a value of 1 to 5;
R2 is an optionally substituted heterocyclyl, or an optionally substituted heterocyclylC1-10 alkyl moiety;
Z is oxygen or sulfur;
is hydrogen, C1-6 alkyl, C3-7 cycloalkyl, aryl, arylC1-4 alkyl, heteroaryl, heteroarylC1-4alkyl, heterocyclyl, or heterocyclylC1-4alkyl C1-4 alkyl;
R3 is heterocyclyl, heterocyclylC1-10 alkyl or R8;
R5 is hydrogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl or NR7R17, excluding the moieties -SR5 being -SNR7Rl7 and -SOR5 being -SOH;
R7 and R17 is each independently selected from hydrogen or C1-4 alkyl or R7 and R17 together with the nitrogen to which thev are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR15;
R8 is C1-10 alkyl, halo-substituted C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, aryl, arylC1-10 alkyl, heteroaryl, heteroarylC1-10 alkyl, (CR10R20)nOR11, (CR10R20)nS(O)mR18, (CR10R20)nNHS(O)2R18, (CR10R20)nNR13R14; 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)R11 or optionally substituted C1-10 alkyl, S(O)2R18, optionally substituted aryl or optionally substituted aryl-C1-4 alkyl;
R10 and R20 is each independently selected from hydrogen or C1-4alkyl;
R11 is hydrogen, C1-10 alkyl, C3-7 cycloalkyl, heterocyclyl, heterocyclyl C1-10alkyl, aryl, arylC1-10 alkyl, heteroaryl or heteroarylC1-10 alkyl;
R12 is hydrogen or R16;
R13 and R14 is each independently selected from hydrogen or optionally substituted C1-4 alkyl, optionally substituted aryl or optionally substituted aryl-C1-4 alkyl, or together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR9 ;
R15 is R10 or C(Z)-C1-4 alkyl;
R16 is C1-4 alkyl, halo-substituted-C1-4 alkyl, or C3-7 cycloalkyl;
R18 is C1-10 alkyl, C3-7 cycloalkyl, heterocyclyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-C1-10alkyl, heteroaryl or heteroarylalkyl;
or a pharmaceutically acceptable salt thereof.

2. The compound according to Claim 1 wherein R1 is a 4-pyridyl or 4-pyrimindyl substituted with an isopropoxy, ethoxy, or methoxy group.

3. The compound according to Claim 1 or 2 wherein R4 is an optionally substituted phenyl.

4. The compound according to Claim 3 wherein the phenyl is substituted one or more times independently by halogen,-SR5, -S(O)R5, -OR12, halo-substituted-C1-4 alkyl, or C1-4 alkyl.

5. The compound according to Claim 1 or 2 wherein R2 is morpholino propyl, piperidine, N-methylpiperidine, N-benzylpiperidine, or 2,2,6,6-tetramethylpiperidine.

6. The compound according to Claim 1 which is:
1-(4-Piperidinyl)-4-(4-Fluorophenyl)-5-(2-isopropoxy-4-pyrimidinyl) imidazole 1-(4-Piperidinyl)-4-(4-Fluorophenyl)-5-(2-methoxy-4-pyrimidinyl) imidazole 5-(2-Methoxy-4-pyridinyl)-4-(4-fluorophenyl)-1-(4-piperidinyl)imidazole 5-(2-iso-Propoxy-4-pyridinyl)-4-(4-fluorophenyl)-1-(4-piperidinyl)imidazole 5-(2-Ethoxy-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(4-piperidinyl)imidazole; or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising a compound according to any of Claims1 to 6 and a pharmaceutically acceptable carrier or diluent.

8. A method of treating a cytokine mediated disease, in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (I) according to any of Claims 1 to 6.

9. The method according to claim 14 wherein the mammal is afflicted with a cytokine mediated disease selected from psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis and acute synovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic condition, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, Alzheimer's disease, stroke, neurotrauma, asthma, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcososis, bone resorption disease, osteoporosis, restenosis, cardiac and renal reperfusion injury, thrombosis, glomerularonephritis, diabetes, graft vs. host reaction, allograft rejection, inflammatory bowel disease, Crohn's disease, ulcerative colitis, multiple sclerosis, muscle degeneration, eczema, contact dermititis, psoriasis, sunburn, and conjunctivitis.

10. The method according to Claim 9 wherein the disease state is mediated by IL-1, Il-6, IL-8, or TNF.

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

12. A method of treating inflammation in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (I) according to any of Claims 1 to 6.

13. A method of treating osteoporosis in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (I) according to any of Claims 1 to 6.

14. A method of inhibiting the synthesis of prostaglandin endoperoxide synthase-2 (PGHS-2) in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (I) according to any of Claims 1 to 6.

15. The method according to Claim 14 wherein inhibition of PGHS-2 is used in theprophylaxis or therapeutic treatment of edema, fever, algesia, neuromuscular pain, headache, cancer pain, or arthritic pain.

16. A method of treating a CSBP/RK/p38 kinase mediated disease, in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (I) according to any of Claims 1 to 6.

17. The method according to claim 16 wherein the mammal is afflicted with a CSBP/RK/p38 kinase medicated disease which is psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, gouty arthritis, traumatic arthritis, rubella arthritis and acute synovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic condition, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, Alzheimer's disease, stroke, neurotrauma, asthma, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcososis, bone resorption disease, osteoporosis, restenosis, cardiac and renal reperfusion injury, thrombosis, glomerularonephritis, diabetes, graft vs. host reaction, allograft rejection, inflammatory bowel disease, Crohn's disease, ulcerative colitis, multiple sclerosis, muscle degeneration, eczema, contact dermititis, psoriasis, sunburn, and conjunctivitis.

18. A process for preparing a compound of Formula (I) as defined in Claim 1 which comprises reacting a compound of the Formula (II):

with a compound of the Formula (III):

wherein p is 0 or 2; and a base strong enough to deprotonate the isonitrile moiety of Formula (II); and R1, R2 and R4 are as defined in Claim 1 or are precursors of the groups R1, 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 R1, R2 and R4.

19. The process according to Claim 18 wherein the reaction, when p=0, utilizes TBD as a base.

20. The process according to Claim 18 wherein the reaction, when p=2, the base is an amine, a carbonates, a hydride, or an alkyl or aryl lithium reagent.

21. The process according to Claim 18 wherein the imine of Formula (III), is isolated prior to reaction with Formula (II).

22. The process according to Claim 21 wherein the imine of Formula (III), is formed in situ prior to reaction with Formula (II).

23. The process according to Claim 22 wherein the imine is formed in situ by reacting an aldehyde of the formula R1 CHO, wherein R1 is as defined for Formula (I), with a primary amine of the formula R2NH2, wherein R2 is as defined for Formula (I).

24. The process according to Claim 23 wherein formation of the imine in situ utilizes dehydrating conditions.

25. The process according to Claim 24 wherein the solvent is N,N-dimethyl-formamide (DMF), halogenated solvents. tetrahydrofuran (THF), dimethylsulfoxide (DMSO), alcohols. benzene, or toluene, or DME.

26. The process according to Claim 23 wherein the aldehyde R1CHO is a pyrimidinealdehyde of the formula:
wherein X is C1-4 alkoxy or C1-4 alkyl thio, and X1 is defined as the optional substituent group on the R1 moiety in Formula (I) according to Claim 1, to yield a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

27. The process according to Claim 23 wherein the aldehyde R1CHO is a pyridine aldehyde of the formula:

wherein X is C1-4 alkoxy or C1-4 alkyl thio, X1 is defined as the optional substituent group on the R1 moiety in Formula (I) according to Claim 1, to yield a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

28. The process according to Claim 23 wherein the primary amine R2NH2 is R2 ispiperidine, 1-Formyl-4-piperidine, 1-benzyl-4-piperidine, 1-methyl-4-piperidine,1-ethoxycarbonyl-4-piperidine, 2,2,6,6-tetramethyl-4-piperidine, morpholino ethyl, morpholino propyl, pyrrolidinyl propyl, or piperidinyl propyl.

29. The compound according to Claim 18 which is:
1-(4-Piperidinyl)-4-(4-Fluorophenyl)-5-(2-isopropoxy-4-pyrimidinyl) imidazole 1-(4-Piperidinyl)-4-(4-Fluorophenyl)-5-(2-methoxy-4-pyrimidinyl) imidazole 5-(2-Methoxy-4-pyridinyl)-4-(4-fluorophenyl)-1-(4-piperidinyl)imidazole 5-(2-iso-Propoxy-4-pyridinyl)-4-(4-fluorophenyl)-1-4-piperidinyl)imidazole 5-(2-Ethoxy-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(4-piperidinyl)imidazole; or a pharmaceutically acceptable salt thereof.