AU9333301A - Novel substituted imidazole compounds - Google Patents

Description

23-11-01; 4:33PM;DAVIES COLLISON CAVE A FutScr /8 I I PAut t S e c u r e f a x 7/ 83

AUSTRALIA

PATENTS ACT 1990 DIVISIONAL APPLICATION NAME OF APPtfCANT: SmithKline 13eecham Corporation ADDRESS FOR SERVICE- DAVIES COLLISON CAVE Patent Attorneys 1 Little Collins Street Melbourne, 3000.

INVENTION TITLE: "Novel substituted imidazolc compounds" The following statement is a full description of this invention, including the best method of performing it known to us: RECEIVED TIME 23. NOV. 16:42 PITTM 3 O.1: PRINT TIME 23. NOV. 16 5 23-11-01; 4:33PM;DAVIES COLLISON CAVE A IPutScr fx#8/3 I 1PAust Secure fax 8/ 83 NOVEL SUBSTITUTED IMIDAZOLE

COMPOUNDS

This application is a divisional of Australian Patent Application No. 83815/98, the entire contents of which are incorporated herein by reference.

FIELD OF THE INVENTION This invention relates to a novel ropf mdzeco ousrosses for the preparation thereof, the use thereof in treating CSBP/p38 mediated diseases and pharmaceutical compositions for use in such therapy.

BACKGROUND -OF THE MINVEN Intacelulr ignl raxisduction is the means by which cells resond to extracellular stimuli. Regardless of the nanure of the cell surface receptor a, protein tyrosine kinase or seven-transmembae G-procein coupled), protein kinases and 1 phosphatases along with phopholipases are the essential machinery by which the signal is further transmitted within the cell [Marshall, J. C. -rjl 80, 179-278 (1995)).

Protein kinases can be categorized into five classes with the two major classes bein, tyrosine kinases and serine threonmne Icinases depending upon whether the enzyme phosphorylates its substrate(s) on specific tyrosine(s) or serine thronine(s) residues [Hunter, T.,4hod s in Enzrn1tog Pmoein Kinase Clssification) p: 3, Hunter, T.; Sefton, B. eds. vol. 200, Academic Press; San Diego, 1991].

For most biological responses, multiple intracellfular kinases are involved and an individual kinase can be involved in more than one signaling event. These kinases are often cytosolic and can translocate to the nucleus or the ribosomes where they can *.25 affect tmascriptional and translational events, respectively. The involvement of kinases in trancriptional control is presently much better understood than their effect on translation as illustrated by the studies on growth factor induced signal transduction involving MAP/ERK kinase [Marshall, C. 1. Cell .80, 179 (1995); Herskcowitz. L fel-, 80, 187 (1995); Hunter, T. CfL. 80, 225 19 95);Seger. and Krebs. E. G. FASE-B 726-735 (1995)].

While many signaling pathways are part of cell homeostasis, numerous cytokines UL- I and TNF) and certain other mediators of inflammation COX-2, and iNOS) are produced only as a response to stress signals such as bacterial ~~lippopolysaccharide (LPS). The first indications suggetn hatheiga transduction pathway leading to LPS-induced cytokine biosynthesis involved protein kinases camne from studies of Weinstein (Weinstein, er al., J.Imrnm~oo. 1.51.

RECEIVED TIME 23.NOV. 16:42 RECIVD IM 23 NV. 1642PRINT TIME 23. NOV. 16 '23-11-01; 4:33PMDAVIES COLLISON CAVE AIPutSurfx#9/3 I 1PAust Secure fax 9/ 83 3829(1993)] but the specific protein kinases involved were not identified. Working from a similar perspective, Han [Han, er al.. Science 265, 808(1994)] identified murine p38 as a kinase which is tyrosine phosphorylated in response to LPS_ Definitive proof of the involvement of the p38 kinase in LPS-stixnulated signa trndcIopahy leading to the initiation of proinflamniatory cytokine biosynthesis was provided by the independent discovery of p38 kinase by Lee [Lee; et al., Naur 372, 739(1994)] as the molecular target for a novel class of andi-inflammatory agents. The discovery of p38 (termed by Lee as CSBP I and 2) provided a mechanism of action of a class of antiinflarmmatory compounds for which SK&F 86002 was the prototypic example- These compounds inhibited ILAI and TNF synthesis in human monocyres at concentrations in the low rn.M range [Lee, et al., Im. J. Immunopharmac. 10(7), 835(1988)] and exhibited activity in animal models which are refractory to cyclooxygenase inhibitors [Lee; er al., Annals N. Y. Acad. Sci., 696, 149(1993)].

MITOGEN AND STRESS ACTIVATED PROTEIN KINASE CASCADES (ja FSK1--k sKM SAPK1a,c SAPK aPK2

AK

(JNKr,,y (csPg 3g6 p8~[~ oxidative

STRESS

F+_PK6 I SP27 Figure I It is now firrmly established that CSBP/p38 is a one of several kinases involved in a stress-response signal transduction pathway which is parallel to and largely independent of the analogous mzitogen-activated protein kinase (MAP) kinase cascade 2- RECEIVED TIME 23.NOV, 16:42 RECIVD IM 23 NV. 1642PRINT TIME 23. NOV. 16: 23-11-01; 4:33PM;DAVIES COLLISON CAVE A I~s euefx#1/8 A 1PAust Secure fax 1 0/ 83 (Figure Stress signals, including LPS, pro-inflammatory cytokines. oxidants, UV light and osmotic stress, activate kinases upstream from CSBP/p38 which in turn phosphorylate CSBP/p38 at threonine 180 and tyrosine 182 resulting in CSBP/p38 activation. MAPKAP kinase-2 and MAPKAP kinase-3 have ben identified as downstream substrates of CSBP/p38 which in rurn phosphorylate heat shock protein lHsp 27 (Figeure It is not yet known whether MAPKAP-2, MAPKAP-3, WnkI or Mnk2- are involved in. cytokine biosynthesis or alternatively that inhibitors of CSBP/p38 kinase might regulate cytokine biosynthesis by blocking a yet unidentified substrate downstream from CSBP/p38 (Cohen, P. Trends CelBiol., 353-361(1997)).

p38 Kinase Pathway LPSIIL-IfTNF stress=U SKK2(MKK3) SKK3 (MKK6) a a. a.

a Figure 2 What is known, however, is that in addition to inhibiting IL- I and TNF, CSBP/p38 kinase inhibitors (SK&F 86002 and SB 203580) also decrease the synthesis 15 Of a wide variety of pro-inflammatory proteins including. IL-6, ftL-8, GM-CSF and COX-2. Inhibitors of CSBP/p38 kinase have also been shown to suppress the TNFinduced expression of VCA.M- I on endothelial cells, the TNF-induced phosphorylation and activation of cytosolic PLA2 and the EL- I -stimulated synthesis of collagenase and -3- RECEIVED TIME 23.NOV, 16:42 RECIVD IM 23 NV. 1642PRINT TIME 23. NOV. 16:5 23-11-01; 4:33PM;DAVIES COLLISON CAVE I 1Aust Secure fix 11/ 83 stromelysin. These and additional data demonstrate that CSBP/p38 is involved not only cytokine synthesis, but also in cytokine signaling [CSBP/P38 kinase reviewed in Cohen, P. Trends Cell Biol., 353-361(1997)].

Interleukin- (IL- 1) and Tumor Necrosis Factor (TNF) are biological substances produced by a variety of cells, such as monocytes or macrophages. IL-1 has been demonstrated to mediate a variety of biological activities thought to be important in immunoregulation and other physiological conditions such as inflammation [See, DinareUo et al., Rev. Infect Disease, 6, 51 (1984)]. The myriad of known biological activities of ILI- include the activation of T helper cells.

induction of fever, stimulation of prostaglandin or collagenase production, neutrophil chemotaxis, induction of acute phase proteins and the suppression of plasma iron levels.

There are many disease states in which excessive or unregulated IL-1 production is implicated in exacerbating and/or causing the disease. These include Is rheumatoid arthritis, osteoarthritis. endotoxemia and/or toxic shock syndrome, other acute or chronic inflammatory disease states such as the inflammatory reaction induced by endotoxin or inflammatory bowel disease; tuberculosis, atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis, and acute synovitis. Recent evidence also links IL-1 activity to diabetes and pancreatic B cells [review of the biological activities which have been attributed to IL-1 Dinarello, J. Cinical Immunology, 5 287-297 (1985)].

Excessive or unregulated TNF production has been implicated in mediating or exacerbating a number of diseases including rheumatoid arthritis, rheumatoid 25 spondylitis. osteoarthritis, goury arthritis and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoisosis, bone resorption diseases, reperfusion injury, graft vs. host reaction, allograft rejections, fever and myalgias due to infection, such as influenza.

cachexia secondary to infection or malignancy, cachexia, secondary to acquired immune deficiency syndrome (AIDS). AIDS, ARC (AIDS related complex), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, or pyresis.

Inerleukin-8 (IL-8) is a chemotactic factor produced by several cell types including mononuclear cells, fibroblasts, endothelial cells, and keratinocytes. Its 35 production from endothelial cells is induced by IL-1, TNF, or lipopolysachharide (LPS). 1L-8 stimulates a number of functions in vitro. It has been shown to have -4- RECEIVED TIME 23. NOV. 16:42 PRINT TIME 23. NOV. 16:55 23-11-01; 4:33PM;DAVIES COLLISON CAVE I PAust Secure fax 12/ 83 chemoattractant properties for neutrophils. T-lymphocytes, and basophils. In addition it induces histamine release from basophils from both normal and atopic individuals as well as lysozomal enzyme release and respiratory burst from neutrophils. IL-8 has also been shown to increase the surface expression of Mac-I (CDI lb/CD18) on neutrophils without de novo protein synthesis, this may contribute to increased adhesion of the neutrophils to vascular endothelial cells. Many diseases are characterized by massive neutrophil infiltration. Conditions associated with an increased in IL-8 production (which is responsible for chemotaxis of neutrophil into the inflammatory site) would benefit by compounds which are suppressive of IL-8 production.

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

Inhibition of signal transduction via CSBP/p38. which in addition to IL-1, TNF and IL-8 described above is also required for the synthesis and/or action of several additional pro-inflammatory proteins IL-6. GM-CSF, COX-2. collagenase and stromelysin), is expected to be a highly effective mechanism for regulating the excessive and destructive activation of the immune system. This expectation is supported by the potent and diverse anti-inflammatory activities described for CSBP/p38 kinase inhibitors [Badger, et al., J. Pharm. Exp. Thera 279 1453- 1461.(1996); Griswold, et al, Pharmacol. Comm. 7, 323-229 (1996)].

There remains a need for treatment, in this field, for compounds which are cytokine suppressive anti-inflammatory drugs, i.e. compounds which are capable of 25 inhibiting the CSBP/p38/RK kinase.

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

This invention relates to 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 This invention also relates to a method of inhibiting cytokines and the 35 treatment of a cytokine mediated disease, in a mammal in need thereof, which RECEIVED TIME 23. NOV. 16:42 PRINT TIME 23. NOV. 16:55 23-11-01; 4:33PM;DAVIES COLLISON CAVE A FutSeuefx#3/3 I I PAus t S e c u r e f a x 13/ 83 comprises administering to said mammal an effective amount of a compound of Formula This invention more specifically relates to a method of inhibiting the production of IL- I in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula This invention more specifically relates to a method of inhibiting the production of IL-8 in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula This invention more specifically relates to a method of inhibiting the production of TNF in a mammal in need thereof which comprises administering to said mnammal an effective amount of a compound of Formula Accordingly, the present invention provides a compound of Formula

R

2 R4

(N

wherein Ri is 4-pyridyl, pyrn-iidinyl. 4-pyridazinyi, 1,2,4-triazin-5-yl. quinolyl, isoquinolinyl, or quinazolin-4-yl ring, which ring is substituted with Y-Ra and optionally with an additional independent substituent selected from C 1 -4 alkyl, halogen, hydroxyl, C1_4 alkoxy, C1_4 alkylthio, C1_4 alkylsulfinyl, CH2ORI2, amino, mono and di- C 1-6 alkl substituted amino, an N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR 15, N(RlIO)C(O)Rb or NHRa; Y is oxygen or sulfur; R4 is phenyl, naphth- I-yl or raaphth-2-yl, or a heteroaryl, which is optionally substituted by one or two substituents, each of which is independently selected, and which, for a 4-phenyl, 4-naphth-1-yl. 5-riaphth-2-yl or 6-naphth-2-yl substituent is halogen, cyano, nitro, C(Z)NR7R 17, C(Z)0R 16, (CRioR2O0vCOR12, SR5, SORS. 0R12. halo-substituted-Cj- alkyl, C1_4 alkyl, ZC(Z)RI2. NRloC(Z)Rl6. or (CR1OR2O)vNRIOR 2 O and which, for other positions of substitution, is halo-en, cyano, C(Z)NR13Rp 1 4, C(Z)0R3.

(CR1I 0R2))m"-CQR3. S(O)mR3. 0R,3, halo-substituted-C 1-4 alkyl, C 1-4 alkcyl, (CR1 0R20)m-NR I OCZ)R3, NRl0 S(O)mR8. NR I OS(O)m'NR7R 17, ZC(Z)R3 or (CRIOR2O)m"NR 13R14; Z is oxygen or sulfur- -6- RECEIVED TIME 23.NOV. 16:42 RECIVD IM 23 NV. 1642PRINT TIME 23. NOV. 16 :5 23-11-01; 4:33PM;DAVIES COLLISON CAVE A utSerefx#1/8 A I P A ii s t S e c u r e f a x 14/ 83 n is an integer having a value of 1 to rn is 0, or the integer I or 2; m' is an integer havinga a value of I or 2, mn is 0, or an integer having a value of I to v is 0. or an integer having a value of I or 2; R2 is A is an optionally substituted aryl, heterocycly-l, or heteroaryl ring, or A is a substitulted C I -1alkyl; R2 2 is an optionally substituted C I.- 10 alkyl; Ra is aryl, ary1i6alkyI, heterocyclic, heterocyclylC 16 alkyl, beteroaryl, or heteroarylC I .6alkyl, wherein each of these moieties may be optionally substituted; Rb is hydrogen. C1-6 alkyl, C3-7 cycloalkyl, aryl, arylC 1-4 alkyl, heteroaryl, heteroarylC 1 4 alkyl, heterocyclyl. or heterocyclylCl14 alkyl; and wherein each is of these moieties may be optionally substituted; R3 is heterocyclyl, heterocyclylC I 1 alkyl or R8; is hydrogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl or NR7R 17, excluding the moieties SR5 being SNR7R17 and SOR5 being SOH; R7 and R 17 is each independently selected from hydrogen or Ci 1-4 alkyl or R7 and R17 together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatorn selected from oxygen, sulfur or RS is Cl..

10 alkyl. halo-substituted CI-1iO alkyl, C2-10 alkenyl, C2-10 alkynyl. C3-7 *cycloaikyl, C5-7 cycloalkenyl. aryl; axylC-l 1 lky0 heteroaryl, eroyl-o ak (CR I R2)n R 1, and I0R20)nS(O)rnR 18, (CR1 I0R20)nNHS(O)2R 18.

(CR ORO~nN I 14;andwherin he aylarylalkyl. heteroaryl. heteroaryl *alkyl may be optionally substituted; R9 is hydrogen, C(Z)RI 1 or optionally substituted Cl 1 alkyl, S(O)2RI8, optionally substituted aryl or optionally substituted aryl-C 1-4 alkyl; RIO and RIO are each independently selected from hydrogen or C1-4 alkyl; R 11 is hydrogen, C I 10 alkyl, C3-7 cycloalkyl, heterocyclyl. heterocyclyl ~Cj..oalkyl, aryl, arylCI-..j alkyl, heteroaiyl or heteroarylC j.lo ailcyl. wherein these moieites may be optionally substituted; R 12 is hydrogen orR 16; R 13R and Rl14 is each independently selected from hydrogen or optionally substituted Ci 1 4 alkyl, optionally substituted aryl or optionally substituted aryl-C 1-4~ alkcyl, -7- RECEIVED TIME 23. NOV. 16:42 PITTM 3 O.1: PRINT TIME 23. NOV. 16 5 23-11-01; 4:33PM;DAVIES COLLISON CAVE A PusSeuefx#1/8 A I PAu s t S e c u r e f a x 1 5/ 83 or together with the nitrogen which they are attached form a heterocyclic ring of to 7 members which ring optionally contains an additional hereroatorn selected from oxygen, sulfur or NR9; is Ri1o or C(Z)-.C 1 4 alkyl; R1 is CI-4 alkyl, halo-substituted-C 1 4 alkyl. or C3-7 cycloalkyl;, R18 is CI1.i alkyl, C3-7 cycloalkyl, bererocyclyl, aryl, amy] I-lalkyl, heterocyclyl, heterocyclyl-C I- I Oalkyl, heteroazyl or heteroaryl I -1 oailcyl; or a pharmaceutically acceptable salt thereof.

DETAILED-DESCRIMTON OF IM INVFN-flON In Formula suitable R I moieties includes 4-pyridyl, 4-pyrimidinyl, 4pyridazinyl, 1 .2,4-triazin-5-yl, 4-quinolyl, 6-isoquinolinyl. or 4-quinazolinyl rings, of which the 4-pyridyl, 4-pyrimidinyl and 4-quinolyl ring's are preferred. More preferred is the 4-pyrimidinyl or 4-pyridyl moiety, and most preferred is the 4pyrimidinyl ring.

The Rl moiety is substituted with the Y-Ra group wherein Y is oxygen or sulfur, and Ra is aryl, arylC1-6alkyl, heterocyclic, heterocycicCl-6 alkyl, heteroaryl. or heteroaryiC 1-.6alkyl; and wherein each of the Ra moieties may be optionally substituted as defined below.

When Ra is aryl, it is preferably phenyl or napthyl. When Ra is arylalkyl, it it is preferably benzyl or napthylmethyl. When Ra is a heterocyclic or heterocyclic alkyl moiety, the heterocyclic portion is preferably pyrrolindinyl, piperidinyl, rorpholino, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothipyransuifinyl, tetrahydrothio-pyransulfonyl, pyrrolindinyl, indole, or piperonyl ring. It is noted that the heterocyclic rings herein may contain unsaturation, such as in a tryptamine When Ra is a heteroaryl ring as defined below, it is preferably a pyridine or tetraole ring.

The Ra aryl, heterocyclic and heteroaryl rings may be optionally substituted oeomoetimes, preferably one to three times, independently with halogen; C 1-4 alkyl, such as methyl, ethyl, propyl, isopropyl. or t-butyl-; halosubstituted alkyl, such as CF3; hydroxy; hydroxy substituted CI1- alkyl; (CR I R 2 0 )q C 1 4 alkoxy, such as methoxy or ethoxy: (CRI 1 0

R

2 0 )q S(O)malkyl and,; (CR 1OR2o)qS(O)6 aryl (wherein m is 0, 1, or (CR jOR20)qC(O)OR 1 11. such as C(O)CI-4 alkyl or .35 C(O)OH moieties; (CR I R20)qC(O)R 1 1 (CR I R 2 0 )qOC(O)Rc; O-(CH2)s-O;

~(CR

1 QR2 0 )qNRJ 3 R l (CR 1 OR2 0 )qN(R lo)C()Rb; (CR 1 0R 2 0 )qC(O)NRl13R 14; RECEIVED TIME 23. NOV. 16:42 PRINT TIME 23. NOV. 16:54 23-11-01; 4:33PM;DAVIES COLLISON CAVE A I~s euefx#1/8 A I PAu s t S e c U r e f a x 1 6/ 83 1 oRc; (CR 1 OR20)qS(O)2NR 13R 14; I Rl0R)qS(O) 2

NR

1 0Rc: (CR 1 0R 2 0)qN(R l )S(O)2Rc; cyano, nitro, an N-heterocyclyl ring which ringc has from 5 to 7/ members and optionally contains an additional heteroarom, selected from oxygen, sulfur or NR 15; aryl, such as phenyl, an optionally substituted arylalkyl, such as benzyl or phenerhyl; aryloxy, such as phenoxy; or arylalicyloxy such as benzyloxy; and wherein the aryl, alkylalkvl, aryloxy and arylalkyloxy containing moieties may be optionally substituted themselves one to two times by halogen, hydroxy, hydroxy substituted alkyl, C I.i -0 alkoxy, S(O)m alkyl, amino, NR7RI7 group, CIA alkyl, or halosubstituted Cl-4 io alkyl.

Suitably, s is an integer having a value of 1, 2, or 3. Preferably s is 2 yielding a I.3-dioxyethylene moiety, or ketal functionality.

Suitably, q is 0 or an integer having a value of I to 4.

Suitably, Rb is hydrogen, C 1-6 alkyl, C3-7 cycloalkyl, aryIl, arylC 1-4 ailkyl, heteroaryl, heteroarylC 1-4alcyl, heterocyc lyl, or heterocyclylC 1 4 alkyl moiety; all of which moieties may be optionally substituted as defined below.

Suaitably, Rc is an C 1 ailkyl, C3-.7 cycloalkyl, aryl, arylC 1 alkyl, heteroaxyl. beteroarylC 1 -alkyl, heterocyclyl, or heterocyclylC 1 alkcyl moiety, all of which moieties may be optionally substituted as defined below.

Suitable Ra groups include, but are not limited to. benzyl, hialosubstituted benzyl, naprthylmetbyl, phenyl, halosubstiruted phenyl. arninocarbonyiphenyl, alkyiphenyl, cyanophenyl, alcylthiophenyl, hydroxyphenyl, alkoxyphenyl, phenoxyphenyl, benzyloxyphenyl, phenyiphenyl. methylenedioxyphenyl, :25 trifluoromethylphenyl, methylsulfonylphenyl, tetrazole, methylitraolyl, morpholinopropyl. piperonyl, piperidin-4.yl, alkyl substituted piperidine. such as 1-methyl piperidine, or 2 2 6 6 -tetraehypiperidin.4yl- Preferred ring substitution on the benzyl or phenyl rings is in the 4-position- Preferred substitution on the phenyl or phenyl alkyl groups is halogen, halosubstituted alkl or alkyl groups. such as fluoro or chioro. or methyl.

It is recognized that the R I group may additionally be substituted one or more times independently by C1-4 alkyl, halo, OH, CIA4 alkoxy, C.14 alkylthio, Ci- 4 alkylsulfinyl, CH2OR 12. amino, mono- and di-CI-6 alkyl substituted amino, N(R IO)C(O)Rb, NHRa or an N-heterocyclyl ring which ring has from 5 to 7 -9- RECEIVED TIME 23.NOV, 16:42 RECIVD IM 23 NV. 1642PRINT TIME 23. NOV. 16 :54 ~end2 3-11-01; 4:42PM;DAVIES COLLISON CAVE A FAust Secuire fax 17/ 83 members and optionally contains an additional heteroatom Selected from oxygen, sulfur or NR 1 When the additional RI optional substituent is N(RIO)C(O)Rb. Rb is preferably CI-6 alkyl; preferably RIO is hydrogen. It is also recognized that the Rb moieties, in particular the C1-6 alkyl group may be opconallsustueperay from one to three times, prefera~ly with halogen suhalorinaintflomethyl or trifluroethyl.

The preferred ring placement for YRa moiety on the 4-pyndyl derivative is in the 2-position, and a preferred* ring placement on the 4-pyrimidinyl ring, is also at io the 2-position.

Suitably, R4 is phenyl, naphth-1-yl or naphth-2-yl, or a heteroaryl, which is optionally substituted by one or two substicuents. More preferably R4 is a phenyl or naphchyl ring. Suitable substitutions for R4 when this is a 4-phenyl, 4-naphth-1-yl, 5-naphth-2-yl or 6-riaphrth-2-yl rxoiety are one or two substituents each of which are independently selected from halogen, SR5, SOR5, OR 12. CF3, or (CRI OR2o)vNR IoR 2 o, and for 91ther positions of substitution on these rings preferred substitution is halogen, S(O)mR3, 0R3. CF3. (CR I 0R20)m'NRl3I1 4 NRlOC(:Z)R3 and NRjOS(O)m'R8.

When R 4 is a heteroaryl r'ing, the ring is substituted in a similar ring substitution pattern as for the phtnyl ring, i.e. halogen, SR5, SOR 5 i, OR 12, CF3, or (CRI 0R20>vNR 10R20.

Preferred substituents for Ithe 4-position in phenyl and naphth-1-yl and on the in naphth-2-yl include 'halogen. especially fluoro and chloro and SR5 and OR5 wherein R5 is preterably CI2alkyl, more preferably merthyl; of which the fluoro and chioro is more preferred, and most especially preferred is fluoro- Preferred substituents for the 3-position in phenyl and naphth-lI-yl rings include: halogen, especially fluor'o and chioro: 0R3, especially CI1A- aflcoxy, CF3, NRlOR2O, such as amino; NRIOC(Z)R 3 especially NHCO(C 1 1 0 alkyl); .NRlO)S(O)mRg. especially NHSiD2(CI- 1 0 ailkyl), and SR3 and SOR3 wherein R3 is preferably a Cl12 alkyl, more preferably methyl. When the phenyl ring is disubstituted preferably it is two independent halogen moieties, such as fluoro and chloro, preferably di-chioro and more preferably in the 3,4-position. It is also preferred that for the 3-position cfboth the 0R3 and ZCZ)R 3 rnoietites, R3 May also include hydrogen.

Preferably, the R4 Tnoiety is an unsubstixuted or substituted phenyl moiety.

More preferably, R4 is phenyl or pheny! substituted at the 4 -position with fluoro RECEIVED TIME 23.NOV. 16:51 RECIVD IM 23 NV. 16~1PRINT TIME 23. NOV. 17: 12 Resend23-11-01; 4:42PM;DAVIES COLLISON CAVE A Auist Secure fax 18/ 83 and/or substituted at the 3-position with fluoro. chloro, C1_4 alkoxy, methanesulfonamido or acetamido, or R4 is a phenyl di-substituted at the 3,4-position independently with chloro, or fluoro, more preferably chioro. Most prefer-ably, R4 is a 4-fluorophenyl.

Suitably, Z is oxygen or sulfur, preferably oxygen.

Suitably, R3 is heterocyclyl. heterocyclylCj.I.-10 alkyl or R8.

Suitably, R5 is hydrogen. C 1- alkyl, C24 alkenyl, C 2 4 alkynyl or NR7RI17 excluding the moieties SR5 being SNR7R17 and SOR5 beingv SOH-.

Suitably, R6 is hydrogen, a pharmaeutically acceptable cation, C 1 I -10 alkyl,

C

3 7 cycloalkyl, aryl, arylC 1- alkyl, heteroaryl, heteroarylC 1 4alkyl, heterocyclyl, aroyl, or C 1.-10 alkanoyl.

Suitably, R7 and R.17 is each independently selected from hydrogen or C 1 -4 alkyl or R7 and R17 together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatomn selected from oxygen, sulfur or NR 1 Suitably, R8 is C I -1 alkyl,- halo-substituted C 1.-10 alkyl, C2- 1O alkenyl, alkynyl, C3-7 cycloalkyl, CS.7 cycloalkenyl. aryl, arylCIi alkcyl, heteroaryl, heteroazylC 10 alkyl. (CR I OR2O)nOR 11, (CRi I0R20)nS(OhnR 18, (CR1 0R20)nNl{S(0)2R 1 8, (CR1 oR2o)nNR! 3R 14; wherein the aryl, arylalkyl, heteroaryl, and heteroarylalicyl containing inoieites may be qptionaLfly substituted.

Suitably, Rg is hydrogen, C(Z)R I or optionally su 'bstituted CI-1iO alkyl, S(0)2R l8, optionally substituted aryl or an optionally substituted aryl-CI-4 alkyl.

Suitably, RIO and R20 are each independently selected from hydrogen or C1.4 alkyl.

Suitably, Ri I is hydrogen, C 1 -1O alkcyl,C3ccolk.heroyy, heterocyclyl ClI.-.I alkyl, aryl, arylC I 1 alkyl, heteroaxyl or heteroarylC I 10 alkyl; and wherein all of these moieties may be optionally substituted.

Suitably, R 12 is hydrogen or RI 6; and R 16 is suitably, C1_4 alkyl, halosubstituted-C 1 alkcyl, or Ct3.7 cycloalkyl.

Suitably, R 13 and R 14 is each independently selected from hydrogen or optionally substituted C 1-4 alkyl, optionally substituted aryl or optionally substituted aryl-C 1 4 alkyl, or together with the nitrogen which they are attached .form a heterocyclic ring of 5 to 7 -members which ring optionally contains an additional hereroatorn selected from oxygen, sulfur or NR9- Suitably, RIS is RIO or C(Z)-Cj-4 alkyl.

RECEIVED TIME 23.NOV'. 16:51 RECIVD IM 23 NV. 1651PRINT TIME 23. NOV. 17 :11 Resend'23-11-O1; 4:42PMDAVIES COLLISON CAVE A IA~ euefx#1/8 I I PAjst Sevire fax 19/ 83 Suitably, R 18 is C I- 10 alkyl, C3-7 cycloalkyl, heterocyclyl, aryl, aryl1-1 Oalkyl, heterocyclyl, heterocyclyl-C 1- oalkyl, heteroaiyl or heteroaryl 1- I Oalkyl.

Suitably, v is 0, or an integer having a value of I or 2.

Suitably, mn-is 0, or the ineger I or 2.

Suitably, mn' is an integer having a value of I or 2.

Suitably, mn" is 0, or an integer having a value of I to Suicably, n is an integer having a value of I to

R

2 is a substituted alkyl derivative. It is recognized that the first methylene carbon in this chain is a tertiary carbon, and it will contain one hydrogen moiety. This methylene group will have has two additional substituents, an R 2 2 moiety and an A moiety, C(H)(A)(R 2 2 Both A and R 2 2 may not be unsubstituted C 1 10 alkyl moieties.

In a preferred embodiment, R2 is a C(AAl)(A) moiety, wherein AA I is the R22 moiety, but is specifically the side chain residue of an amino acid, as is further described herein.

Suitably, A is an optionally substituted C3-7cYCloalyl, aryl, heteroaryl, or heterocyclic ring, or A is a substituted C 1

I.-

10 alkyl moiety.

When A is'an aryl, heteroaryl and heterocyclic ring, the ring may be substituted ~0 independently one or more times, preferably, I to 3 times by C I 1 alkyl; halogen; halo substituted C 1 1 alkyl. such as CF 3 (CR IOR2OhtOR 11; (CR IoR2o)tNR I3Rl4, especially amino or mono- or di-C 1- alkylaino; (CR I OR2O)tS(O)mR 18, wherein mn .is 0, 1 or 2; SH: NR IOC(Z)R 3 (such NHCO(C I 1 0 alkyl)); or NR I OS(O)mR8 (such as Suitably, is 0. or an integer of I to 4.

When A is an optionally substituted cycloalkyl it is as defined below in the R' 2 2 substitution.

When A is an optionally substituted heterocyclyl ring, the ring is preferably a niorpholino, pyrrolidinyl, piperazinyl or A piperidinyl ring.

When A is an optionally substituted aryl moiety, it is preferably a phenyl ring When A is an optionally substituted heteroaryl ring, the beteroaryl term is as defined below in the definition section.

When A is a substituted C 1 10 alkyl moiety, the alkyl chain may be straight or branched. The chain is substituted independently I or more times, preferably I to 3 times by halogen, such as fluorine, chlorine, bromine or Iodine; halosubsticuted C 1 12 RECEIVED TIME 23.NOV, 16:51 RECIVD IM 23 NV. 1651PRINT TIME 23. NOV. 17: 11 Resend23-11-01; 4:42PM;DAVIES COLLiSON CAVE A IPAust Secure fax 20/ 83 alkyl, such as CE 3 C3..7cycloalkyl, CI-10 alkoxy, such as methoxy or ethoxy; hydroxy substituted C I 10 alkoxy; halosubstituted C 1 alkoxy, such as OCF 2

CF

7 -I OR 11, S(O)mR 1 8 (wherein m is 0, 1 or NR 13Rl14; C(Z)NR I A1 4 S (O)mNR13 R14; NR,)3C(Z)R 1 1; NHS(Oy2R 18 C(Z)R 11; OC(Z)R 1 1 (Z)0R 1 11;

C(Z)NR

1 0R9; N(0R6)C(Z)NR 13R14. N(0R6)C(Z)R I: C(=-NOR6)Rl 1; NR23C(=NRI 9)NRI 3R 14; OC(Z)NRi 3R 14; NR-23C(Z)NR 1 3R1 4; or NR23C(Z)OR Prefer-ably, A is a C 3 7 cycloallcyl, or a C 1 6 ailkyl, more preferably aC1alkyl, i.e. a mnethylene or ethylene moiety, more preferably a mnethylene moiety which is substituted by one of the above noted groups.

Preferably, when A is an alkyl derivative, it is substituted by OR I 1 where R 1 1 is preferably hydrogen, aryl or arylalkyl; NRj3RI4; OC(Z)R 1 i; or C(Z)0R 1 1- More preferably, A is substituted by OR I 1 where R 1 I is hydrogen.

Suitably, R 2 2 is a CI.-.

10 alkyl chain, which chain may be straight or branched and which may be optionally substituted independently, one or more times, preferably I to 3 times, by halogen, such as fluorine, chlorine, bromine or iodine; halo substituted alkyl: C 1 10 alkoxy. such as methoxy or ethoxy; hydroxy substituted Ci- alkoxy; haosubstituted C .I 1 alkoxy, such as OCF2CF 2 H: OR 11; S(O)mR 18; NRI3RW4 C(Z)NR 13R14; S(O)m'NR13R 14; NR23C(Z)RlI; NHSCO)2RI 8; C(Z)R 11; OC(Z)R i;C(Z)OR 11; C(Z)NR I1 I0R9: N(0R6)C(Z)NR I AR14; N(0R6)C(Z)R 11; C(=NOR,6)R 11; NR23C(=NR I 9)NRJ I3A 1 4; OC(Z)NR 13 R 14; NR23C(Z)NR 3k 14; NR23C(Z)OR 10; optionally substituted C 3 7 cycloalkyl; ~:optionally substituted aryl, such as phenyl; optionally substituted heteroaryl; or an ~:optionally substituted heterocyclic moiety. The optional substitucents on these cycloalkyl, aryl, beteroaryl, and heterocyclic moieties are as defined herein below.

It is noted that those R 2 2 substituent groups which contain carbon as the first connecting group, i.e. C(Z)OR 1 C(Z)NRj I10R9, C(Z)Rl 1, C(Z)NR 13R C(=NOR6)R 11, may be the sole carbon in alkyl chain. Therefore, R22 may, for o. o instance, be a carboxy, an aldebyde, an amide, as well as being a substituent off a *30 methylene unit, such as carbamoylmethyl. or aceramidomethyl. In other words, R 2 2 can be an optionally substituted alkyl group as defined above- or R 2 2 can be C(Z)ORi 11. C(Z)NR1 1 iOR9, C(Z)R 11. C(Z)NR I3A 4 or C(=NOR6)RI

I

Preferably R22 is a Cl-6 unsubstituted or substituted alkyl group, such as a C 1 3 alkylene, such as methyl, ethyl or isopropyl. or a merhylene or ethylene moiety .35 substituted by one of the'above noted moieties, or as noted above those substituent groups which contain a carbon may substicureri for the first methylene unit of the alkyl 13- RECEIVED TIME 23. NOV. 16:51PRN TIE 2.OV 171 PR I NT T I ME 23. NOV. 17 I I Resend23-11-01; 4:42PM;DAVIES COLLISON CAVE A I~s euefx#2/8 I I PAu s t S e c u r e f x 2 1 83 chain, such as carboxy, C(O)0R 1 1 C(O)NR I 3 R 1 or R 2 2 is an optionally substitued aryl group. such as a benzyl or phenethyl.

Preferably R 2 2 is a C 1 6 unsubstituted or substituted alkyl group, more preferably a C 1 -2 alkylene chain, such as a methylene or ethylene moiety, more preferably methylene.

Preferably the R 22 alkyl chain is substituted by OR 1 1 where R 1 I is preferably hydrogen, aryl or arylalkyl; S(O)rmR 18 where mn is 0 and R 18 is a C 1 6 alkyl; or an optionally substituted aryl, i.e. a benzyl or phenethyl moiety.

More preferably, R22 is methyl, phenyl, benzyl, CH 2 OH. or CH 2 -O-aryl.

Preferably, one or both of A and R 2 2 contain hydroxy moieties, such as in C 1 -6 alkcyl OR 1 1 wherein R I is hydrogen, i.e.CH 2

CH

2

OI{

Suitably, when AA 1 is the side chain residue of an amino acid, itE is a C 1 -6 alkyl group, which may be straight or branched. This means the R group off the core amino acid of the structure R-C(H)(COOH)(NH 2 The R residue term is for example,

CH

3 for alanine, (CH 3 2 C11- for valine, (CH 3 2 CH-CH-2-for leucine. phenyl-CH'- for phenylalanine, CH 3 -S-CJ1 2

-CH

2 for methionine, etc. All generally recognized primary amino acids are included in this groups, such as but not limited to, alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamnic acid, glycine, histidine, isoleucine, leixcine, lysine, methionine, phenylalanine, serine, threonine, tryptophan, tyrosine, valine, hydroxylysine. inethyihistidine, and other naturally occurring amino acids not found in proteins, such as b-alanine, g-aminobutyric acid. homocystcine, homoserine, citmilline, ornithine, canavanine, djenkolic: aci&L and b-cyanoalanine, or .*other naturally occurring non-mammalian amino acids.

Preferably AAI is the residue.of phenylalanine, or aiaziine.

When R22 is an optionally substituted heterocyclic moiety, the ring is preferably a inorpholino, pyrrolidinyl, piperazinyl. or a piperidinyl group. When the heterocyclic ring is optionally substituted the substirtuents may be directly attached to the free nitrogen, such as in the piperidinyl group or pyrrole ring, or on the ring itself.

Preferably the ring is a piperidine, or pyrrole, more preferably piperidine.

The R22 herterocyclyl ring may be optionally substituted one to four times independently by halogen; Cl1.-4 alkyl: aryl, such as phenyl; arylalkyl, such as benzyl, (and wherein the aryl or aryl alkyl moieties themselves may be optionally substituted *as defined in the definition section below); C(O)OR 11, such as the C(O)CI-4 ailkyl or C(O)OH moieties; C(O)H; C(O)C 14 alkyl; hydroxy substituted C 1-4 alkyl; C 1alkoxy; S(O)mC 1- alkyl (wherein in isO0, 1, or orNR IOR20 (wherein RIO and are independently hydrogen or C1 I 4alklcy).

-14- RECEIVED TIME 23. NOV. 16:51PRN TIE 2.OV 171 PR I NT T I ME 23. NOV. 17 I I Resend13-11-O1; 4:42PM;DAVIES COLLISON CAVE A I~s euefx#2/8 I 1PAust Seclire fax 22/ 83 Preferably if the ring is a piperidine, the substituents are attached directly on the available nitrogen, i-e. a 1-Forrnyl-4-piperidine, l-benzyl- 4 -piperidine, I.-methyl-4piperidine, l-ethoxycarbonyl-4-piperidine. If the ring is substituted by an alkyl group and the ring, is attached in the 4-position. it is preferably substituted in the 2- or 6position or both, such as 2 2 6 ,6-Eetrarncrhyl-4-piperidine. Similarly, if the ring is a1 pyrole, the substituents are all directly on the available nitrogen.

When the R22 optional substituent is an optionally substituted aryl, it IS.

preferably a phenyl; or when R 2 2, is an optionally substituted heteroaryl ring (as defined in the definition section below), the rings may be optionally substituted independently one or more times, preferably by one to three times by Ci Ilo1 alkyl: halogen, especially fluoro or chioro; (CR IOR20)tORI 1; (CRI OR2O)tNRl13Rl1 4 especially amino or mono- or di-CI1A- alkylamino; (CRlIoR20)tS (O)mR 18, wherein m isO0, 1 or 2: SH; OR 1 1; NRI OC(Z)R3 (such NHCO(C I 10 alkyl)); or NR I S(O)mRS (such as NHS0s(Cl.

10 alkyl)).

When A or R22 is an (optionally) substituted C3-7cycloalcyl group, it is preferably a C3 or C6 ring, most preferably a C3 ring, which ring may be optionally substituted one or more time, preferably I to 3 times, independently by halogen, such as fluorine, or chlorine; (CR1OR2O)tORl 1: S(O)rnRI 8 cyano, (CRIoR2o0WR1 3 R1 4 especially amino or mono- or di--C 1 alkylarnino; N(RlIO)C(O)X I and X I is C 1alkyl, aryl or arylCI-4alcyl; C I-10 alkyl, such as methyl, ethyl, propyl, isopropyl, or t-butyl;, an optionally substituted alkyl wherein the substituents are halogen, (such as CF3), hydroxy. nitro, cyano, amino, NR13RI4, or S(O)mR 18 an optionally *~.substituted alkylene. such as ethylene or propylene. an optionally substituted alkyne, such as ethyne; C(O)0R 11; the group Re; =N-OR 11; N(H)-OH (or :25 substituted alkcyl or aryl derivatives thereof on the nitrogen or the oxime moiety); or N(ORd)-C(Oy-Rf.

OV Suitably Rdj is hydrogen, a pharmaceutically acceptable cation. aroyl or a CI-1O alkanoyl group.

Suitably Re is a I ,3"dioxyalkylene group of the formnula wherein 30 s is I to 3, preferably s is 2 yielding a I .3-dioxyethylene moiety, or ketal functionality.

Suitably Rf is NR2 1

R

24 alkyl 1-6; halosubstituted alkyl 1-6; hydroxy coo.*:substinuted alkyl alkenyl 2-6; aryl or heteroaryl optionally substituted by halogen, alkyl 1-6, halosubstituted alkyl 1 hydroxyl. or alkoxy 1-6.

Suitably R 2 1 is hydrogen. or alicyll-..

Suitably Rt 24 is hydrogen, alkyl 1-6, aryl, benzyl, heteroaryl, alkyl substituted :by halogen or hydroxyl, or phenyl substituted by a member selected from the group RECEIVED TIME 23.NOV. 16:51 RECIVD IM 23 NV. 1651PRINT TIME 23. NOV. 17 :11 Resend23-11-O1; 4:42PM;DAVIES COLLISON CAVE PutSeuefx# 3/8 I I PAus t S e c u r e f a x 23/ 83 consisting of halo, cyano, alky1 1 6 alkoxy 1-6. halosubstituted alkyll1 S(O)m alkylI16; or and R 24 may together with the nitrogen to which they are attached form a ring having 5 to 7 members, which members may be optionally replaced by a heteroatorn selected from oxygen, sulfur or nitrogen. The ring may be saturated or contain more than one unsaturated bond. Preferably Rf is NR2 I R24, and more preferably R21~ and R24 are both hydrogen.

When the A or R22, optional substituent is NRI3RI4 it is recognized that in some instances this can yield the same moiety as -a heterocyclic moiety noted above which is also a suitable variable. Preferably R 13 and R 14 are independently hydrogen, C1-4 alkyl, preferably methyl, or benzyl.

When the A or R2,_ optional substituent is a C()R group, R I is suitably hydrogen, Ci 1-4 alkyl. especially methyl.

When the A or R77 optional substituent is a S (O)nR 18 group, R 18 is preferably aryl, especially phenyl, or a C1I.-.10 alkyl, especially methyl, or ethyl- When the A or PR22 optional substituent is a ORi 1 group, RI 1 is preferably hydrogen, aryl, especially phenyl, or C I1-10 alkyl. especially methyl or ethyl.

When the A or R22 optional substituent is a NHS(O)2R I g group, R 18 is suitably alkyl, especially methyl.

In a preferred subgenus of compounds of Formula R I is 2-phenoxy-4a pyridyl or 2-phenoxy-4-pyrimidinyl. R4 is phenyl or phenyl substituted one or two times by fluoro, chioro, C 1 4 alkoxy, 5 S(O)m alkyl, methanesulfonamido or acetarnido.

:0 0 4 :kis CH 2 QI-. CH 3 benzyl, phenyl, CH2NH(methyl) or CH~Ndimethyl); and R22 is methyl, ethyl, methaol, or CH2-O-phenyl; or alternatively the R 2 group is 1-hydroxy- *0 So25 3-phenylprop-2-yl. 1-hydroxyprop-2-yl, l-hydroxybut-2-yl, L.3-dihydroxyprop-2-yl, or 0 0* I -hydroxy-2-phenyethy-2-y1.

0 *0 Ashyroy usdrei, sub ptio lld susittd unes spcfial de1e shal *0.630 hyroy Cyrx susiue -i.oakl C.10 alkoxy. such as methoxy or erhoxy: halosubstituted CI-1lO alkoxy; S(O)m alkyl, such as methyl thio, methylsulfinyl or fee&*:methyl siilfonyl; NR7R 17, such as amino or mono or -disubstituted C 1- alkyl or wherein the R 7 R 17 can cyclize together with the nitrogen to which they are attached to form a 5 to 7 membered ring which optionally contains an additional heteroatorn selected from OINlS: Cl- 10 alkyl. C3-7cycloalkyl, or C3-7cycloalkyl CI-10 alkyl group, such as methyl, ethyl, propyl, isopropyl, t-butyl, etc. or cyclopropyl methyl; -16- RECEIVED TIME 23. NOV. 16:51 PRINT TIME 23. NOV. 17:11 Resend23-11-O1; 4:42PM;DAVIES COLLISON CAVE A PutScr I IPAjst Secure fax 24/ 83 halosubstituted C 1 10 alkyl. such CF2CFAH or CF3; an optionally substituted aryl, such as phenyl, or an optionally substituted arylalkyl, such as benzyl or phenethyl.

wherein these aryl moieties may also be substituted one to two times by halogen; hydroxy;, hydroxy substituted alkyl; C I 10o alkoxy; S(O)malkyl; armino, mono dis substituted C 1 4 alkyl amino, such as in the NR7R 17 group; Cj1 4 alkyl, or CF3.

Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobrorrii acid, sulphuric acid, phosphoric acid, methane suiphonic acid, ethane suiphonic acid, acetic acid. malic acid. tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid. fumaric acid, rnaleic acid, benizoic acid, salicylic acid, phenylacetic acid and mandelic acid.

In addition, pharmaceutically acceptable salts of compounds of Formula (I) may also be formed with a pharmaceutically acceptable cation, for instance, if a substiruent group comprises a cax-boxy moiety. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, amnmoniumn and quaternary amnmonium cations.

The term "halo" or "halogens" is used herein to mean the halogens. chloro, **.fluoro, bromo and iodo.

The rerm"Cl-ljoalkyl or "alkyl" is used herein to mean both straight and branched chain radicals of I to 10 carbon atoms, unless the chain length is otherwise limited. including, but not limited to, methyl, ethyl. n'-propyl. iso-propyl, n-butyl, sec-butyl, iso-butyl, teri-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 cyciopropyl, cyclopentylcyclohexyl, and the like.

The term "cycloalkenyl .is used herein to mean cyclic radicals, preferably of .:30 5 to 8 carbons, which have at least one bond including but not limited to cyclopentenyl, cyclohexenyl, and the like.

The term "alkenyl" is used herein at all occurrences to mean straight or *.**branched chain radical of 2- 10 carbon atoms, -unless the chain lengrth is limited thereto, including, but not limited to ethenyl. I -propenyl. 2-propenyl, 2-methyl- 1 propeny, 1.1-butenyl, 2-butenyl and the like.

The term "aryl" is used herein to mean phenyl and naphthyl; 17- RECEIVED TIME 23. NOV. 16 51 PRINT TIME 23. NOV. 17 :11 Resend'43-11-O1; 4:42PMDAVIES COLLISON CAVE A IPutScr a I I PAu s t S e c u r e f a x 25/ 83 The term "heteroaryl" (on its own or in any combination, such as "heteroaryloxy", or 'heteroaryl alkyl'") is used herein to mean a 5-10 mnembered aromatic ring system in which one or more rings contain one or more heteroatozns selected from the group consisting, of N, 0 or S, such as, but not limited, to pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, rhiadiazole, tetrazole, triazole, imidazole, or benzinbdazole.

The term "heterocyclic" (on its own or in any combination, such as "heterocyclylalkyl") is used herein to mean a saturated or partially unsaturated 4- mnembered ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, 0, or S, such as, but not limited to, pyrrolidine, piperidine, piperazine, 'norpholine, tecrahydro pyran, or imnidazolidine.

The term "aralkyl" or "heteroarylalkyl" or 'heterocyclicalkyI" is used herein to mean C1-4 alkyl as defined above attached to an aryl, heteroaryl or heterocyclic mnoiety as also defined herein unless otherwise indicate.

The term "sulfinyl" is used herein to mean the oxide S of the corresponding sulfide, the term "thio" refers to the sulfide, and the term "sulfonyl" refers to the fully oxidized S (0)2 moiety.

The term "aroyl" is used herein to mean C(0)Ar, wherein Ar is as phenyl, naphthyl, or aryl ailkyl derivative such as defined above. such group include but are not limited to benzyl and phenethyl.

:The term "alkanoyl 4 is used herein to mean C(O)C I -10 1 wherein the alkyl is as defined above.

It is recognized that the compounds of the present invention may exist as stereoisomers, regioisomers, or diastereiomers. These compounds may contain one or more asymmetric carbon atoms and may exist in racerriic and optically active forms. All of these compounds are included within the scope of the present invention.

Exemplified compounds of Formula include: -Hydroxyprop-2-yy..4-(4..fluorophenyl)5- 2 4 -fluorophenoxy)pyrimidin-4 yl]imidazole I l.

3 -Dihydroxyprop-2-yl)-4..(4..nuorophenyl 5- 2 4 -fluorophenoxy)pyrlmidin4.

yllirnidazole -18- RECEIVED TIME 23.NOV. 16:51 RECIVD IM 23 NV. 1651PRINT TIME 23. NOV. 17 :11 Resend23-11-O1; 4:42PM;DAVIES COLLISON CAVE I 1Aust Secure fax 2 6/ 83 1 -Phenoxyprop-2-yl .4-(4fluorophenyI 2 -phenoxypyrimidin-4-yl)mjdaole -Hydroxy-3-phenylprop-2-y )-44-florophenyl)-5-(2-p henoxypyrimi yl)irnidazole I Hydroxybut-2-yl)-4-4f 1-(1 .3-Dihydroxyprop-2-yI 4 4 -fluorophenyl)-5-(2-phenoxypyrimidin-4yl)inidazole 1 -Hydroxy-2-phenyleth-2-yl)-4.(4.fluorophenyl).S- 2 -phenoxypyrimidin-4yl)imidazole 1 -Hydroxyprop-2-yl)-4-(fluorophenyl)-[2-(4-chlorophenox yl~irnidazole 1-(1 -Hydroxybut 2 -y1).4-((4fluorophenyl1)-5-[2-(4-chorophenoxy )pyriidin4yljimidazole 1-(1 -Hydroxyprop-2-yl)-4-(4-fluoropheny))-5-[2-(4-methylphenoxy)pyrimidil4 yljimidazole 1 -Hydroxybut-2-y)-4-(4-fluorophenyl)--[2- )pyrimidin-4yl]imidazole -Dihydroyprop-2-yl)-4-fluoropenyl)-5-[2-(4-methylphenoxy)pyri idin- 4-yl]iidazole 1-(4N-Morpholinyl-2-but-yl )-(4-fluorophenyl)-5 -(2-phenoxypyriridinyyl)imdazole The compounds of Formula may be obtained by applying synthetic procedures, some of which are illustrated in Schemes I to XII herein. The synthesis provided for in these Schemes is applicable for the producing compounds of Formula having a variety of different RI. R2, and R4 groups which are reacted, employing optional substituents which are suitably protected, to achieve compatibility with the reactions outlined herein. Subsequent deprotection, in those cases, ,hen affords compounds of the nature generally disclosed. While the schemes describe compounds of Formula with Y as Oxygen, one skilled in the art would readily be 30 able to make compounds of Formula wherein Y is sulfur using similar reaction processes as exemplified herein.

Once the imidazole nucleus has been established, further compounds of Formula may be prepared by applying standard techniques for functional group interconversion, well known in the art. For instance: C(O)NR 13R 14 from CO2CH3 by heating with or without catalytic metal cyanide, e.g. NaCN, and HNR13R14 in OC(O)R3 from OH with CIC(O)R 3 in pyridine; NRIO-C(S)NR13R -19- RECEIVED TIME 23. NOV. 16:51 PRINT TIME 23. NOV. 17 I Resend23-11-01; 4:42PM;DAVIES COLLISON CAVE A us Serefx#7/8 I I P A u Q t S e c u r e f a x 27/ 83 from NHR 1o with an alkylisothiocyante or thiocyanic acid: NR6C(O)0R 6 from NHR6 with the alkyl chloroforrnate; NR1IOC(O)NR

I

3 R 1 4 from NHRi1O by treatment with an isocyanate, e.g. HN=C=O or R ioN=CC=O; NR IO-C(O)R 8 from NI-R 10 by treatment with CI-C(O)R3 in pyridine; C(=NR1O)NRl 3

RI

4 from C(NR13RI 4

)SR

3 with H3NR3+OAc- by heatinga. in alcohol; C(NR I3R 14)SR 3 from C(S)NR13 R 14 with R6-1 in an inert solvent, e.g. acetone; C(S)NR I3R 14 (where R 13 or R 14 is not hydrogen) from C(S)NH2) with HNR I3R 14-C(=NCN)-NR 13 R 14 from C(=NR]3R 1 4)-SR 3 with NH2-CN by heating in anhydrous alcohol, alternatively from C(=NH)-NR l 3

R

14 by treatment with BrCN and NaOEr in EtOH;, NRl &C(=NCN)SR 8 from NHR 10 by treatment with (R8S)2C=NCN: NP, I SO-R 3 from NHRIO by treatmenE with CISO2R3 by heating in pyridine; NRIOC(S)R 3 from -NRIOC(O)R8 by treatment with Lawesson's reagenE 2 ,-bis(4-methoxyphenyl)l.

3 2 ,4-diriadiphosphetane-2,4disulfide]. NR I QSO27CF 3 from NHR6 with triflic anhydride and base wherein R3, R6, R 10, R 13 and Rl14 are as defined in Formula (1) Z~herein.

Precursors of the. groups R 1. R2 and P4can be other R 1 and R 4 groups which can be interconverted by applying standard techniques for functional group intercoriversjon. For example a compound of the formula wherein is halo substiruted C I 10 alkyl can be converted to the corresponding C I.- 10 alkylN 3 derivative by reacting with a suitable azide salt, and thereafter if desired can be reduced to the corresponding C I I aikyiNH', compound, which in tumn can be reacted with R I 8

S(O)

2 X wherein X is halo chioro) to yield the corresponding oalkylNHS(O) 2

R

1 8 compound.

Alternatively a compound oftefrua(1) where is halo-substituted C.I -I 0 .alkyi can be reacted with an amine R1 3 R 14NH to yield the corresponding Cj..lQ-alkyINR 1 3

R

1 4 compound, or can be reacted with an alkali metal salt of

*R

1 I SH to yield the corresponding C 1 1 alkylSR 1 8 compound.

*0 RE EI E TI E 2 .NV.6 5 R N I E 2 .N V 7 1 Resend23-11-01; 4:42PM;DAVIES COLLISON CAVE A I~s euefx#2/8 A 1PAust Secure fax 28/ 83 4 CHO Ar S(O H

H

2

NCHO

Y

CK.C1 3 NaOH cH2-7 2

I

H

2 0, FTC Ar-S(O),

(IV)

R

4

NHCHO

R

4 CH- NH 2

(VIMI

onyladi,- agni

R

4

CH

2

NHCHO

7/dehydrating agct

R

4 CHiNC (VI) R ICHO R2N11 2 Ar L I -bcrin p 2 I dehydradne went

Y

Ar-S(O)p R4 NC R r NF1 2

H

(Ml) Scheme I Referring to Scheme I the compounds of Formula are suitably prepared by reacting, a compound of the Formula (11) with a compound of the Formula (IMI wherein p is 0 or 2. R 1

R

2 and R 4 are as defined herein, for Formula or are precursors of the groups R 1

R

2 and R 4 and Ar is an optionally substituted pheniyl group, and thereafter if necessary converting a precursor of R 1, R 2 and R 4 to a group R I, R 2 and R 4 It is recognized that R2NH-, which is reacted with RI CHO to form 21 RECEIVED TIME 23. NOY, 16:51PRN TIE 2.OV 11 D PRINT TIME 23, NOV. 17: 10 Resend23-11-01; 4:42PM;DAVIES COLLISON CAVE A I PUjs Secijre fax 29/ 83 the imine, Formula (III) the R2 moiety when it contains a reactive functional group, such as a primary or secondary amine, an alcohol, or thiol compound the group must be suitably protected. Suitable protecting groups may be found in, Protecting Groups in Organic Synthesis, Greene T W, Wiley-Interscience. New York, 1981.

whose disclosure is incorporated herein by reference. For instance, when R2 is a heterocyclic ring, such as a piperidine ring, the nitrogen is protected with groups such as t-Boc, CO2R 18, or a substitued arylalkyl moiety.

Suitably, the reaction is performed at ambient temperature or with cooling -50° to 10") or heating in an inert solvent such as methylene chloride, DMF, tetrahydrofuran, toluene, acetonitrile, or dimethoxyethane in the presence of an appropriate base such as K2C03, t-buNH2, 1,8-diazabicyclo undec-7-ene (DBU), or a guanidine base such as 1,5, 7 -triaza-bicyclo dec-5-ene (TBD).

The intermediates of formula (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 for use herein.

Compounds of the Formula (II) have the structure: Ar-S(O)p R4 NC wherein p is 0, or 2; R4 is as defined for Formula and Ar is an optionally substituted aryl as defined herein. Suitably, Ar is phenyl optionally substituted by 20 C-4alkyl, C-4 alkoxy or halo. Preferably Ar is phenyl or 4-methylphenyl, i.e. a tosyl derivative.

Reaction a compound of the Formula (II) wherein p 2, with a compound of the Formula (nI)-Scheme I gives consistently higher yields of compounds of Formula than when p-O. In addition, the reaction of Formula (II) compounds wherein p 2 is more environmentally and economically attractive. When p=O, the S: preferred solvent used is methylene chloride, which is environmentally unattractive for large scale processing, and the preferred base, TBD, is also expensive, and produces some byproducts and impurities, than when using the commercially attractive synthesis (p= 2 as further described herein.

S* 30 As noted. Scheme I utilizes the. 1,3-dipolar cycloadditions of an anion of a substituted aryl thiomethylisocyanide (when p=0) to an imine. More specifically, this reaction requires a strong base, such as an amine base, to be used for the deprotonation step. The commercially available TBD is preferred although -22- RECEIVED TIME 23. NOV. 16:51 PRINT TIME 23. NOV. 17 Resend23-11-O1; 4:42PM;DAVIES COLLISON CAVE A I~s euefx#3/8 I I P A ij c t S e c u r e f a x 3 0/ 83 t-butoxide, Li+ or Na-i, or K+ hexarnethyldisilazide may also be us ed. While methylene chloride is the prefered solvent, other halogenated solvents, such as chloroform or carbon tetrachloride: ethers, such as THF, DME, DMF, dierhylether, t-butyi methyl ether; as well as acetonitrile, toluene or mnitures thereof can be uciltized. The reaction may cake place from about -200C to about; 40 0 C, preferably from about 0 0 C to about 230C, more preferably from about OO'C Co about I10 0 C, and most preferably about 40C for reactions involving an RI group of pyrin'udine. For compounds wherein RI is pyridine, it is recognized that'varying the reations conditions of both temperature and solvent may be necessary. such as decreasing temperatures to about -500C or changing the solvent to THF- In a further process, compounds of Formula may be prepared by coupling a suitable derivative of a compound of Formula (IX): wherein T I is hydrogen and T4 is R4 or alternatively T I is R I and T4 is H in which R 1, R2 and R4 are as hereinibefore defined; with: when Ti is hydrogen. a suitable V. derivative of the heteroaryl rin R I ndrin couplingconditionst effect coupling *.of the heteroaiyl ring Rl to the irnidazole nucleus at position 5; (ii) when T4 is hydrogen, a suitable derivative of the aryl ring R4R, under ring coupling conditions.

to effect coupling of the aryl ring R4 to the itnidazole nucleus at position 4.

Such aryllheteroaryl coupling reactions are well known to chose skilled in the art. In general, an organometallic synthetic equivalent of an anion of one component C is coupled with a reactive derivative of the second component, in the presence of a suitable catalyst. The anion equivalent may be formed from either the irnidazole of Formula in which case the arylflieteroaxyl compound provides the reactive derivative, or the aryL/heteroaryl compound in which case the imnidazole provides the reactive derivative. Accordingly, suitable derivatives of the compound of Formula (IX) or the aryL/heceroaryl rings include orgaoealc eIvaieuha 7. 30 organoniagnesium, organozinc, organostannane and borontic acid derivatives and suitable reactive derivatives include the brorno, iodo, tluorosulfonate and trifluoromethanesulphonate derivatives. Suitable procedures are described in WO 91/19497, the disclosure of which is incorporated by reference herein.

-23- RECEIVED TIME 23. NOV. 16:51 PITTM 3 O. 1:i PRINT TIME 2 3. NOV. 17 Resend23-11-O1; 4:42PM;DAVIES COLLISON CAVE A I~s euefx#3/8 I 1PAust Secure fay 31/ 83 Suitable organomagnesiurn and organo zinc derivatives of a compound of Formula (DC) may be reacted with a halogen, fluorosulfonare or triflate derivative of the heteroaryl or aryl ring, in the presence of a ring coupling catalyst, such as a palladium or palladium (11) catalyst, following the procedure of Kumada er al., Letters, 22, 5319 (198 Suitable such catalysts include tezrakis- (triphenylphosphine)palladium and PdCl2114-bis-(diphenylphosphino-buae), optionally in the presence of lithium chloride and a base, such as triechylaxnine: In addition, a nickel (I1) catalyst, such as Ni(U)Cl2(1,2-biphenyphospio)ethane, may also be used for coupling an aryl ring, following the procedure of Pridgen et al., J.

Org. Chemn, 1982, 47, 4319. Suitable reaction solvenrs include hexamethylphosphor-mide. When the heteroaryl ring is 4-pyridyl, suitable derivatives include 4-brorno- and 4-iodo-pyridine and the fluorosulfonate and triflate esters of 4-hydroxy pyridine. Similarly, suitable derivatives for when the aryl ring is phenyl include the brorno, fluorosulfonate, triflate and, preferably. the iododerivatives. Suitable organornagnesium and organozinc derivatives may be obtained by treating a compound of Formula (D0) or the bromo derivative thereof with an alkyllithium compound to yield the corresponding lithium reagent by deprotonation or transretallAtion. respectively. This lithium intermediate may then be treated with an excess of a magnesium halide or zinc halide to yield the corresponding organometallic reagent A trialkyltin derivative of the compound of Formula (IX) may be treated with a bromide, fluorosulfonate, trillate. or, preferably, iodide derivative of an aryl or heteroaryl ring compound, in an inert solvent such as tetrahydrofuran, preferably containing 10% hexamethylphosphoramide, in the presence of a suitable coupling catalyst, such as a palladium catalyst. for instance teirakis-(triphenylphosphine).

palladium. by the method described in by Stifle, J. Amer. Chem. Soc, 1987, 109,.

5478, US Patents 4,719,218 and 5 002 ,941, or by using a palladium (11) catalyst in the presence of lithium chloride optionally with an added base such as uriethylamine, in an inert solvent such as dimethyl fornmide. Triaficyltin derivatives may be conveniently obtained by metallation of the corresponding compou 'nd of Formula (DX) with a lithiating agent, such as s-butyl-Iithjum or n-butyllithium, in an ethereal solvent, such as teraydrofuran, or treatment of the brorno derivative of the *corresponding compound of Formula (IX) with an alkyl1 lithium, followed, in each ease, by treatment with a trialkyltin halide. Alternatively, the bromo- derivative of a compound of Formula (IX) may be treated with a suitable heteroaryl or aryl trialkyl -24.- RECEIVED TIME 23. NOV. 16:51 PRINT TIME 23. NOV. 1?:10D Resend23-11-O1; 4:42PM;DAVIES COLLISON CAVE A Pus Serefx#3/3 I I PAuc t S e c u r e f a x 32/ 83 tin compound in the presence of a catalyst such as tezrakis-(triphenyl-phosphine).

palladium. under conditions similar to those described above.

Boronic acid derivatives are also useful. Hence, a suitable derivative of a compound of Formula such as the brorno, iodo, triflate or fluorosuiphonate derivative, may be reacted with a heteroaryl- or aryl-boronic acid, in the presence of a palladium catalyst such as tertra ds.(tiiphenylphosphine)-pallaiium or PdCl2[I,4bis-(diphenyl..phosphino)-.buae] in the presence of a base such as sodium bicarbonate, under reflux conditions, in a solvent such as dimethoxyethane (see Fischer and Haviniga, Rec. Tray. Chim. Pays Bas, 84. 439. 1965, Snieckus,

V.,

Tetrahedron Lett., 29, 2135, 1988 and Terasbirnia, Chemn. Pharm. Bull.. 11, 4755, 1985). Non-aqueous conditions, for instance, a solvent such as DMF, at a temperature of about 1006C, in the presence of a PdW1) catalyst may also be employed (see Thompson W J et al, J Org Chein, 49, 5237. 1984). Suitable boronic acid derivatives may be prepared by treating the magnesium or lithium derivative with a trialkylborawe ester, such as triethyl, tri-iso-propyl or tributylborate, according to standard procedures.

In such coupling reactions, it will be readily appreciated that due regard must be exercised with respect to functional groups present in the compounds of Formula Thus, in general, amino and sulfur substituents should be non-oxidised or protected.

Compounds of Formula (IX) are imidazoles and may be obtained by any of the procedures herein before described for preparing compounds of Formula In **particular, an a-halo-ketone or other suitably activated ketones R4COCH2HaI (for com po unds of Formula (IX) in which T I is hydrogen) or R ICOCH2HaI (for compounds of Formula (IX) in which T4 is hydrogen) may be reacted with an amidine of the formula R2NH-C-NiI, wherein R2 is as defined in Formula or a salt thereof, in an inert solvent such as a halogenated hydrocarbon solvent, for instance chloroform, at a moderately elevated temperature, and, if necessary, in the presence of a suitable condensation agent such as a base- The preparation of suitable a-halo-ketones is described in WO 91/19497. Suitable reactive esters include esters of strong organic acids such as a lower alkane suiphonic or aryl sulphonic acid, for instance, methane or p-toluene suiphonic acid. The ainidine is preferably used as the salt, suitably the hydrochloride salt, which may then be converted into the free ainidine 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 RECEIVED TIME 23.NOV. 16:51 RECIVD IM 23 NV. 16~iPRINT TIME 23. NOV. 17?: Resend23-11-O1; 4:42PM;DAVIES COLLISON CAVE I~s euefx#3/8 A PAust Secure fax 33/ 83 vigorous stirring. Suitable anhidies may be obtained by standard Methods. see for instance, Garigipad R, Tetrahedron Letters, 190, 31. 1989.

Compounds of Formula may also be prepared by a process which comprises reacting a compound of Formula wherein Ti is hydrogen, with an N-acyl heteroaryl salt, according Co the method disclosed in US patent 4,803,279, US patent 4,719,218 and US patent 5,002,941, to give an intermediate in which the heteroaryl ring is attached to the imidazole nucleus and is present as a I ,4-dihYd-o derivative thereof, which irnernediate may then be subjected to oxidativedeacylation conditions (Scheme 11). The heteroaxyl salt, for instance a pyridinium salt. may be either preformed or, more preferably, prepared in situ by adding a substituted carbonyl halide (such as an acyl halide, an aroyl halide, an arylalkyl haloformate ester, or, preferably, an alkcyl haloformate ester, such as acetyl bromide, befizoylchioride, benzyl chioroformate, or, preferably, ethyl chioroformare) to a solution of the compound of Formrula (DX) in the heteroaryl compound RIH or in an u~ inert solvent such as methylene chloride to which the heteroaryl compound has been added. Suitable deacylating and oxidising conditions are descnibed in U.S. Patent Nos. 4,803,279, 4,719,218 and 5,002,94 1, which references are hereby incorporated by reference in their entirety. Suitable oxidizing systems include sulfur in an inert solvent or solvent mixture, such as decajin, decalin and diglyme, p-cymene, xylene or mesitylene, under reflux conditions, or, preferably, potassium r-butoxide in r- V. butanol with dry air or oxygen.

H*

R

2.

NW 1w.O> S~ft..Nah r~ Scheme II In a further process, illustrated in Scheme Ml below, compounds of Formula may be prepared by treating a compound of Formnula thermally or with the C. **aid of a cyclising agent such as phosphorus oxychionide or phosphorus pentachioride (see Engel and -Steglich, Liebigs Ann Chew, 1978p- 1916 and Strzybny eta. Org Chemn, 1963, 28, 338 Compounds of Formula WX may be obtained, for instance, by acylating the corresponding a-keto-amaine with an activated formate derivative such as the corresponding anhydride, under standard acylating conditions followed 26 RECEIVED TIME 23. NOV. 16:51 PRINT TIME 23. NOV. 1710 i Resend23-11-O1; 4:42PM;DAVIES COLLISON CAVE A PAust Secure fax 34/ 83 by formation of the irnine with R2NH2. The arninoketone may be derived from the parent ketone by oxamiriation and reduction and the requisite ketone may in turn be prepared by decarboxylation of the bera-keroester obtained from the condensation of an aryl (heteroaryl) acetic ester with the RICOX component.

A, 0.

X .)NaC~e F1 0 A 0 )Oo 0 R MI1.)NaNO.c,% a. ~o OS AN.1 OR2)+e 2.NH O R 0(ormwa

IX)

Scheme HIl In Scheme IV illustrated below, two different routes which use ketone (formula XI) for preparing a compound of Formula WI. A heterocyclic ketone (XI) is prepared by adding the anion of the alkyl heterocycle such as 4 -rnethyJ-quinoline -(prepared by treatment thereof with an alky! lithium, such as n-butyl lithium) to an N-alkyl-O-alkoxybenzande, ester, or any other suitably activated derivative of the same oxidation state. Alternatively, the anion may be condensed with a benzaldehyde, to give an alcohol which is then oxidised to the ketone (XI).

A. 1 4R SL r"1 2

*R

X R, ,RI B R. 2-U Io B 0N .R 4

CH

2 -2NBr 2 CO

NHI

whereinScem R n R ih prepare by trei the aino nieo Formula (XII): R4CN

(XIII)

wherein R~ 4 is as hereinbefore defined, or 27.

RECEIVED TIME 23. NOV. 16:51PRN TIE 2.OV 171 PR I NT T I ME 23, NOV. 17: Resend23-11-01; 4:4'ZPM;DAVIES COLLISON CAVEIPutSerefx#3/ 3 I I PAu c t S e c u r e f a x 35/ 83 an excess of an acyl halide, for instance an acyl chloride, of the Formu .la R4CQHaI

(XIV)

wherein R4 is as hereinbefore defined and Hal is halogen, or a corresponding anhydride, to give a bis-acylated intermediate which is Then treated with a source of ammonia, such as ammonium acetate.

F4H bs R11.) U+ -N(.Prj !R

H

2 H b as YR iR Ri F 1 ~.N CN

N

(X11) Scheme V One vaiation of this approach is illustated in Scheme V above. A primary -amine (R2NH2) is treated with a halomethyl het~erocycle of Formula R ICH2X TO gicve the secondary amine which is Then converted to the amide by standard techniques. Alternatively the amide 'may be prepared as illustrated in scheme V by 1s alkylation of the formrnide with R I CH2X. Deprotonaion of this amide with a strong amide base, such as lithium di-iso-propyl arnide or sodium bis- (trirnethylsilyl)ayude, followed by addition of an excess of an aroyl chloride yields the bis-acylated compound which is then closed to an imidazole compound of Formula by heating in acetic acid containing ammnoriium acetate. Alternatively, 20 the anion of the armide may be reacted with a substituted aryl nitrile to produce the iridazole of Formula directly.

The following description and schemes are further exemplification of the process as previously described above in Schemne L. Various pyrinjiidine aldehyde derivatives 6, as depicted in Scheme VI below, can be prepared by modification of the procedures of Bredereck et al. (Chem. Ber. 1964, 97,3407) whose disclosure is incorporated by reference herein. These pyrimidine aldehydes are then utilized as intermediates in the synthesis as further described herein.

RECEIVED TIME 23. NOV. 16:51PRN TIE 2.OV 1:i PRINT TIME 23. NOV. 17 Resend23-11-O1; 4:42'PM;DAVIES COLLISON CAVE A FutScr u I I PAus t See u r e f ax 3 6/ 83 0~1 thiourea S MeO\L MoO c e 0NaE/tO MO MeO 2aE /0 Meo. OMe 0(n) 11 Na0R, ROH

HOI

dz-E1-N N -THF/H20 N' 41 Mo W~e MeO 0Me n= or2 Scheme VI The reaction of irnines with tosylmethyl isonitriles was first reported by van Leusen (van Leusen, et al. 1. Org. Chem. 1977, 42. 1 153-) Reported were the following conditions: tert buryl axnine(IBUNH2)) in dimethoxyethane

(DMNE),

'K.'CO3 in MeOH, and NaH in DME. Upon re-exanination of these conditions each was found to produce low yields. A second pathway involving amine exchange to produce the t-butyl imine followed by reaction with the isocyanide to produce a 1l-zBu imidazole was also operating. This will likely occur using any primary amine as a base. The secondary amines, while not preferred may be used, but may also decompose the isonitnile slowly. Reactions will likely require about 3 equivalents of amine to go to completion, resulting in approximately 50% isolated yields. Hindered secondary amines (diisopropylamine) while usable are very slow and generally not .15 too effective. Use of tertiary and aromatic amiunes, such as pyridine, and 0, tootriethyanie gave no reaction iunder certain test conditions. but more basic types to. .*such as DBU, and 4-dimethylanmno pyridine (DMA?) while slow, did produce some yields and hence may be suitable for use herein.

As depicted in Schemes V11 and VMI below, the pyrimidine aldehydes of Scheme VI, can be condensed with a primary 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-(4pyzimidinyl)-substicuted imidazoles, wherein R2 and R4 are as defined herein for Formula compounds.

One prefere method for preparing compounds of Formula is shown to. below in Scheme VU, in which the irmine is prepared and isolated in a separate step prior to the addtion of the isonitrile. The yield for making the irnines varied, and 29 *RECEIVED TIME~ 23. NOV. 16:51 PR INT TIME 2 3. NOV. 17: Resend23-11-01; 4:42PM;DAVIES COLLISON CAVE A FutScr u I 1PAust Secure fax 37/ 83 environmentally less-acceptable solvents, such as CH2CI2 were often used in their preparation.

This reaction, wherein 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 mixtures thereof. Bases include, but are not limited to, potassium carbonate, sodium carbonate, primary and secondary amines, such as t-butvlanriine.

diisopropyl amine, morpholine, piperidine, pyrrolidine, and other non-nucleophilic bases, such as DBU. DMAP and I 4 -diazabicyco[222otne

(DABCO).

Suitable solvents for use herein, include but are not limited to the organic solvents of N.N-dinethyl-formarnide (DMF), MeCN, halogenated solvents, such as methylene chloride or chloroform, tetrahydrofuran (THF), dimethylsulfoxide (DMSO), alcohols, such as methanol or ethanol, benzene, toluene, DME or EtOlAc.

Preferably the solvent is DMF, DME. THF, or MeCN, more preferably

DMF.

Product isolation may generally be accomplished by adding water and filtering the product as a clean compound. In scheme VII below, Ra is as defined for Formula (1) comounds. and X is oxygen or sulfur- Ra, DMF

HN

Ra N- -N N 1 0_1_

K

2

CO

3 ""iImine is isolated prior to cycloaddi~on SchemeVfl *While not convenient for large scale work. addition of NaH* to the isonitrile.

perhaps with temperatures rower than 25 OC (in TUF) are likely needed.

Additionally, BuLi has also been reported to be an effective base for deprotonating 5525 tosyl benzyfisonrriles, at -50 OC. (DiSanto, et al-, Synth. Comnmun. 1995,25,795).

Various temperature conditions may be utilized depending upon the preferred base. For instance, t.BuNH'_JDME, K2)CO3IMeOH, K2C03 in DMF, at temperatures above 40 OC, the yields may drop to about 20% but little difference is expected between 0 0 C and 25 OC. Consequently, temperature ranges below 0 0

C,

and above 80 0 C are contemplated as also being within the scope of this invention.

Preferably, the temperature ranges are fromn about QOC to about 25 0 C. For purposes RECEIVED TIME 23. NOV. 16:51 PRINT TIME 23. NOV. 17:10D Resend23-1 1-01; 4:42PM;DAVIES COLLISON CAVE A Pu tScefa I I PAjs t S e c u r e f a x 38/ 83 herein. room temperature, is generally depicted as 250C, but it is recognized that this may vary from 20 0 C to 300C.

As shown in Scheme VIII below, the imine is preferably formed in situ in a solvent. This preferred synthesis, is a process which occurs as a one-pot synthesis_ Suitably, when the primary amine is utilized as a salt, such as in the dihydrochloride salt in the Examples, the reaction may further include a base, such as Potassium carbonate, prior to the addition of the isonitrile. For hydroxy-concaning, amnines a protected group(PG) may be required in the irnrine forming and cycloaddirion reactions; suitably the PG is silyl (such as triethyl, diphenyl-t-butyl, dimethyl-tburyl) or C(0)2R, wherein R is preferably alkyl, aryl. arylalkyl moieties well known to those skilled in the art. Reaction conditions, such as solvents, bases, temperatures, etc. are similar to those illustrated and discussed above for the isolated irnine as shown in Scheme V11. One skilled in the art would readily recognize that under some circumstances. the in situ formation of The imine may require dehydraring il conditions, or may require acid catalysis.

Ra XAN_~ H

K

0 DMF Ra,. I~OJ X NO, -N

DMF

*NH

2 Imnenot olated bectd n u XQ,0.S V1111 Scheme IX, describes an alternative process for making compounds of see 0.:formula In this particular instance, the alkyllthio moiety is oxidized to the 0methyl sulfinyl or sulfonyl moiety which is reacted with a suitable.Y~a moiety.

RS N RO) a 9:4:XN OXONE

IP

2 NaYRa N LN

-N

N

N

n =1,2 X Y

S

Scheme IX -31- RECEIVED TIME 23. NOV. 16 5 1 PRINT TIME 23. NOV. 17 :0 9 Resend23-11-01; 4:42PM;DAVIES COLLISON CAVE A IPAust Secure fax 39/ 83 Another embodiment of the present invention is the novel hydrolysis of 2thioalkylpyrimidine acetal to 2 -thioalkylpyrimidine 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 satisfactory yield of the aldehyde, was obtained. The preferred synthesis involves the use of AcOH (fresh) as solvent and con-centrated H2S0 4 under heating conditions, preferably a catalytic amount of sulfuric acid. Heating conditions include temperatures from about 60 to 0 C, preferably from about 70 to about 80 0 C as higher temperatures show a darkening of the reaction mixture. After the reaction is completeed the mixture is cooled to about room temperature and the acetic acid is removed. A more preferred alternative procedure to this involves heating the acetal in 3N HCI at 40 0 C for about 18 hours, cooling and extracting the bicarbonate neutralized solution into EtOAc N 3NHCI/oC

N-

SN H SN

H

0 0 S= alkyl Scheme X The final 2-(RaY)pyrimidin-4-yl imidazole compounds of Formula as well as similar pyridine containing compounds can be prepared by one of three methods: 1) direct reaction of the 2 -(RaY)pyrimidine imine with the isonitrile; 2) oxidation of the 2 -alkylthiopyrimidine derivative to the corresponding sulfoxide 20 followed by displacement with the desired HYRa under basic conditions, for example using a metal salt of HYRa or in the presence of a non-nucleophilic amine or alkali metal base; or 3) reaction of the 2 -halopyrimidine or pyridine imine with the isonitrile followed by displacement with HYRa under basic conditions described in the second method, see also Adams et al., USSN 08/659.102 filed 3 June 1996, Scheme XI, whose disclosure is incorporated herein by reference in its entirety.

While these schemes herein art presented, for instance, with R2 2 0 and methyl in the R2 position, and 4-fluorophenyl for R4, any suitable R2 moiety or R4 moiety may be added in this manner if it can be prepared on the primary amine. Similarly, any suitable R4 can be added via the isonitrile route.

30 The compounds of Formula in Scheme I. may be prepared by the methods of van Leusen et al., supra. For example, a compound of the Formula

(II)

may be prepared by dehydrating a compound of the Formula (IV)-Scheme I, wherein Ar. R 4 and p are as defined herein.

-32- RECEIVED TIME 23. NOV. 16:51 PRINT TIME 23. NOV. 17:09 Resend23-11-01; 4:42PM;DAVIES COLLISON CAVE A IA~tScr a I I PAu s t S e c u r e f a x 40/ 83 Suitable dehydrating agents include phosphorus oxychloride, oxalyl chloride.

thionyl chloride, phosgene, or tosyl chloride in the presence of a suitable base such as Eriethylamine or diisopropylethylamjine, or similar bases, etc. such as pyridine.

Suitable solvents are dimethoxy ether, tetrahydrofuran, or halogenated solvents, preferably TI-F. The reaction is most efficent when the reaction temperatures are kept between -I10 0 C and 0 0 C. At lower temperatures incomplet e reaction occurs and at higher temperatures, the solution turns dark and the product yield drops.

The compounds of formula (IV)-Scheme I may be prepared by reacting a compound of the formula (V)-Scheme 1, R 4 CHO where R 4 is as defined herein, with- ArS(O)pH and formamide with or without water removal, preferably under dehydrating conditions. at ambient or elevated temperature e.g. 3O* to 1500, conveniently at reflux, Optionally in the presence of an acid catalyst- Alternatively ruiinethysilylchloride can be used in place of the acid catalyst. Examples of acid catalysts include camnphor-lI0-sulphonic acid, formic acid. p -toluenesulphonic acid, is. hydrogen chloride or sulphuric acid.

An optimal method of making an isonitrile of Formula (11) is illustrated below, in Scheme XL .formamide NHCHO SO Tol CH -T SC NHCHO ToS H

NHCHO

F0PhMe:

SIM%

so a Oc 2 3 S*To

H

PO.1 S0.O NH H .3

NC

.1 too.

SC EE

NC

Th co v ri no.h u siu e l e yd ot et s l e z lf r a nd a be acomlihe by0 heain th leye 0 -cmXLwtancishas toluene-sulfonic 3 acdmom cai rc m h r ufo i cd ihf r a i ea dp tolu ne-sulf nic aci [und erreactio co di ion ef a ou 0 C fo b u 2 o r .3 RECEIVED TIME 23.NOV. 16:51 RECIVD IM 2 1651PRINT TIME 23. NOV. 17 09 Resend23-11-01; 4:42PM;DAVIES COLLISON CAVE I IPAj~t Secure fax 41/ 83 Preferably, no solvent is used. The reaction, may give poor yields 30%) when solvents, such as DMF, DMSO, toluene, acetonitrile, or excess formamide are used.

Temperatures less than 60oC are generally poor at producing the desired product, and temperatures in excess of 60 0 C may produce a product which decomposes, or obtain a benzylic bis-formamide, 2-Scheme

XI.

Another embodiment of the present invention is the synthesis of the tosyl benzyl formamide compound, achieved by reacting the bisformamide intermediate, 2-Scheme XI with p-toluenesulfinic acid. In this preferred route, preparation of the bis-formamide from the aldehyde is accomplished by heating the aldehyde with formamide, in a suitable solvent with acid catalysis. Suitable solvents are toluene, acetonitrile. DMF, and DMSO or mixtures thereof. Acid catalysts, are those well known in the art, and include but are not limited to hydrogen chloride, p-toluenesulfonic acid, camphorsulfonic acid, and other anhydrous acids. The reaction can be conducted at temperatures ranging from about 25 0 C to 11 OC. preferably about 50 0 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 temperatures (>70 0 C) at prolonged reactions times. Complete conversion of the product generally requires water removal from the reaction mixture.

Preferred conditions for converting a bis-formamide derivative to the tosyl benzyl formamide are accomplished by heating the bisformamide in a suitable solvent with an acid catalyst and p-toluenesulfinic acid. Solvents for use in this reaction include but are not limited to toluene, and acetonitrile or mixtures thereof.

Additional mixtures of these solvents with DMF, or DMSO may also be used but may result in lower yields. Temperatures may range from about 30 0 C to about 100 0 C. Temperatures lower than 40oC and higher than 60 0 C are not preferred as the yield and rate decreases. Preferably the range is from about 40 to 60 0 C. most preferably about 50 0 C. The optimal time is about 4 to 5 hours, although it may be longer. Preferably, acids used include but are not limited to, toluenesulfonic acid, camphorsulfonic acid, and hydrogen chloride and other anhydrous acids. Most preferably the bisformamide is heated in toluene:acetonitrile in a 1:1 ratio, with ptoluenesulfinic acid and hydrogen chloride.

Another embodiment of the present invention is the preferred synthetic route for synthesis of the tosylbenzyl formamide compound which is accomplished using a one-pot procedure. This process first converts the aldehyde to the bis-formamide 35 derivative and subsequently reacts the bis-formamide derivative with toluenesulfinic acid. This procedure combines the optimized conditions into a single, efficient -34- RECEIVED TIME 23. NOV. 16:51 PRINT TIME 23. NOV. 17:09 Resend'43-11-O1; 4:42PM;DAVIES COLLISON CAVE A '~tSuefx I IPAjct Secure fax 42/ 83 proes. ig yels.>90% of the aryl benzylforxnarnide may be obtained in such a mnanner- Preferred reaction conditions employ a Catalyst, such as trimethylsilyl chloride (TMSCI), in a preferred solvent, toluene:aceonruzile, preferably in a 1: 1 ratio. A reagent, such as TMSCI is preferred which reacts with water produced therein and at the same time produces hydrogen chloride to catalyze the reaction.

Also prefer-red is use of hydrogen chloride and p-toiuenesulfonic acid. Therefore, three suitable reaction condition 's for use herein include 1) use of a dehydratin g agent which also provides hydrogen chloride, such as TMSCI; or by 2) use of a suitable dehydrating agent and a suitable source of acid source, such as but not limited to, camphorsulfonic acid, hydrogen chloride or toluenesulfonic acid: and 3) alternative dehydrating conditions. such as the azeotropic removal of water, and using an acid catalyst and p-toluene sulfinic acid.

Compounds of the formula (H1) where p is 2 may also be prepared by reacting is in the presence of a strong base a compound of the formula (VI) -Scheme 1,

R

4

CH

2 NC with a compound of the formula (VID-Scheme L, ArSO 2 L I wherein

R

4 -And Ar are as defined herein and L I is a leaving group such as hao,. e. g. fluoro.

Suitable strong bases include, but are not limited to, alkyl Jithiums such as butyl lithium or lithium diisopropylamide (Van Leusen etL.. Tetrahedron Letters, No. 23, 2367-68 (1972))..

The compounds of formula (VI)-Schemne I may be prepared by reacting a compound of the formula (VIU)-Scheme I, R 4 CH2)NH 2 with an alkyl formate erthylformnate) to yield an intermediate amnide which can be converted to the desired isonitrile by reacting with well known dehydrating agent, such as but not limited to oxalyl chloride, phosphorus oxychloride Or toSyl chloride in the presence of a o suitable base such as triethylarmne.

Alternatively a compound of the formula (VIII) Scheme I.may be converted to a compound of the formula Schemne I by reaction with chloroform and ::::*sodium hydroxide in aqueouis dichlorornethane under phase transfer catalysis.

The compounds of the formula (IM! Scheme I may be prepared by reacting a compound of the formula R ICHIO with a primary armine R 2

NH

2 The amio compounds of the formula (VII) Scheme I are known or can be prepared from the corresponding alcohols, oximes or amide-s using standard .functional group interconversions.

~*35 The amnino compounds used to prepare the irnines of formula (MI) Scheme

I

are known or can be prepared using Standard functional group interconversions 35 RECEIVED TIME 23. NOV. 16:51PITTIE 2.OV 70 PRINT TIME 23, NOV. 17 0 9 I A Resenuto-ii-oi; 4.4ZM;flVItZ C.ULLISON AVE PAUst Secuire fax; 43/ 83 (Scheme XII). A particularly useful and general method to prepare these amines is from the a amino acids, which are readily available or if not can be prepared from the corresponding aldehyde using standard amino acid synthesis, such as the Strecker synthesis. The free amino acids or the corresponding amino protected compounds (CBZ, fMOC, or t-BOC) many of which are commercially available can be reduced to the carbinol under standard conditions. For example, borane on the .carboxtylic acid or if the ester, hydride agents may be employed in the reduction. The protected amino alcohols may be used as intermediates to fu~rther elaborate the side chain- Furtherrmore, protecting groups may be used to mask reactive functionality and thereby facilitate the formation of the imine and subsequent cycloaddition reaction to form the imidazole.

An example of this is the use of a silyl protecting group on a alcohol.

A

Stigcker Syesm NsN c0I4 r90=i CompOWtdg -%00t Wo MOMai aloehyd 10- WOm M e O~t tanm~e (111) in Schwne i

H

2 N><J NRN>< n doproisa

I

0

H

H

P~R

14~ Wj.tWAe tef o anim eyfd or ft~og

R

ft H *0 ~0 Scheme X11 Suitable protecting groups for, use With hydroxyl groups and the imidazole nitrogen are well known in the art and described in many references, for instance.

-36- RECEIVED TIME 23-NOV. 16:51 RECIVD IM 23 NV. 1651PRINT TIME 23. NOV. 17 09 Resend23-11-01; 4:42PM;DAVIES COLLISON CAVE I IAust Secure fax 44/ 83 Protecting Groups in Organic Synthesis, Greene T W, Wiley-Interscience, New York, 1981. Suitable examples of hydroxyl protecting groups include silyl ethers, such as t-butyldimethyl or t-butyldiphenyl, and alkyl ethers, such as methyl connected by an alkyl chain of variable link, (CRIOR20)n- Suitable examples of imidazole nitrogen protecting groups include tetrahydropyranyl.

Pharmaceutically acid addition salts of compounds of Formula may be obtained in known manner, for example by treatment thereof with an appropriate amount of acid in the presence of a suitable solvent.

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

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

Accordingly, the present invention provides a method of treating a cytokinemediated disease which comprises administering an effective cytokine-interfering 25 amount of a compound of Formula or a pharmaceutically acceptable salt thereof.

Compounds of Formula are capable of inhibiting inducible proinflammatory proteins, such as COX-2. also referred to by many other names such as prostaglandin endoperoxide synthase-2 (PGHS-2) and are therefore of use in S. therapy. These proinflammatory lipid mediators of the cyclooxygenase

(CO)

pathway are produced by the inducible COX-2 enzyme. Regulation, therefore of COX-2 which is responsible for the these products derived from arachidonic acid, such as prostaglandins affect a wide variety of cells and tissues are important and critical inflammatory mediators of a wide variety of disease states and conditions.

Expression of COX-1 is not effected by compounds of Formula This selective 35 inhibition of COX-2 may alleviate or spare ulcerogenic liability associated with inhibition of COX-1 thereby inhibiting prostoglandins essential for cytoprotective -37- RECEIVED TIME 23. NOV. 16:51 PRINT TIME 23. NOV. 17:09 Resend23-11-01; 4:42PM;DAVIES COLLISON CAVE I IP u e S ec ure fax 45/ 83 effects. Thus inhibition of these pro-inflammatory mediators is of benefit in controlling, reducing and alleviating many of these disease states. Most notably these inflammatory mediators, in particular prostaglandins, have been implicated in pain, such as in the sensitization of pain receptors, or edema. This aspect of pain management therefore includes treatment of neuromuscular pain, headache, cancer pain, and arthritis pain. Compounds of Formula or a pharmaceutically acceptable salt thereof, are of use in the prophylaxis or therapy in a human, or other mammal, by inhibition of the synthesis of the COX-2 enzyme.

Accordingly, the present invention provides a method of inhibiting the synthesis of COX-2 which comprises administering an effective amount of a compound of Formula or a pharmaceutically acceptable salt thereof. The present invention also provides for a method of prophylaxis treatment in a human, or other mammal, by inhibition of the synthesis of the COX-2 enzyme.

In particular, compounds of Formula or a pharmaceutically acceptable salt thereof are of use in the prophylaxis or therapy of any disease state in a human, or other mammal, which is exacerbated by or caused by excessive or unregulated IL-1.

IL-6, IL-8 or TNF production by such mammal'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 production of IL-1 in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula or a pharmaceutically acceptable salt thereof.

There are many disease states in which excessive or unregulated IL-1 production is implicated in exacerbating and/or causing the disease. These include 25 rheumatoid arthritis, osteoanhritis, stroke, endotoxemia and/or toxic shock syndrome, other acute or chronic inflammatory disease states such as the inflammatory reaction induced by endotoxin or inflammatory bowel disease, tuberculosis, atherosclerosis, muscle degeneration, multiple sclerosis, cachexia, bone resorption, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis and acute synovitis. Recent evidence also links IL-1 activity to diabetes, pancreatic 8 cells disease, and Alzheimer's disease.

In a further aspect, this invention relates to a method of inhibiting the production of TNF in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula or a 35 pharmaceutically acceptable salt thereof.

-38- RECEIVED TIME 23. NOV. 16:51 PR INT TIME 23. NOV. 17 0 Resend23-11-01; 4:42PM;DAVIES COLLISON CAVE I I Aus t Sec u re fax 46/ 83 Excessive or unregulated TNF production has been implicated in mediating or exacerbating a number of diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis. gouty arthritis and other arthritic conditions, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, stroke, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoisosis, bone resorption diseases, such as osteoporosis, reperfusion injury, graft vs. host reaction, allograft rejections, fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis and pyresis.

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

Compounds of Formula may also be used in association with the 25 veterinary treatment of mammals, other than in humans, in need of inhibition of TNF production. TNF mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted above, but in particular viral infections. Examples of such viruses include, but are not limited to, lentivirus infections such as, equine infectious anaemia virus, caprine arthritis virus, visna virus, or maedi virus or retrovirus infections, such as but not limited to feline i mmunodeficiency virus (FIV), bovine immunodeficiency virus, or canine immunodeficiency virus or other retroviral infections.

The compounds of Formula may also be used topically in the treatment or prophylaxis of topical disease states mediated by or exacerbated by excessive 35 cytokine production, such as by IL-I or TNF respectively, such as inflamed joints, eczema, psoriasis and other inflammatory skin conditions such as sunburn; -39- RECEIVED TIME 23. NOV. 16:51 PRINT TIME 23. NOV. 17:09 Resend23-11-O1; 4:42PM;DAVIES COLLISON CAVE A PutScr a I I P A u s t Secure fax 47/ 83 inflammatory eye conditions including conjunctiviEis; pyresis, pain and other conditions associated with inflammation.

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

There are many disease states in which excessive or unregulated J.L-8 production is implicated in exacerbating and/or causing the disease- These diseases are characterized by massive neutrophil infiltration such as, psoriasis, inflammnatry bowel disease, asthma, cardiac and renal reperfusion injury. adult respiratory distress syndrome, thrombosis and glomerulonephritis. All of these diseases are associated with increased IL-8 production which is responsible for the chemotaxis of neutrophils into the inflammatory site. In contrast to other inflammatory cytokines (IL-I1, TNF, and IL-6), IL-8 has the unique property of promoting neurrophil chemocaxis and activation. Therefore, the inhibition of IL-8 production would lead to a direct reduction in the neutrophil infiltration.

The compounds of Formula are administered in an amount sufficient to inhibit cytokine, in particular EL-i1. IL-6, IL-8 or TNF, production such that it is regulated down to normal levels, or in some case to subnormal levels, so as to ameliorate or prevent the disease state. Abnormal levels of IL-1, IL-6. IL-8 or TNF, for instance in the context of the present invention, constitute: levels of free (not cell bound) IL-i1, lL-6, IL-8 or TNF greater than or equal to I picogramn per ml; (ii) any cell associated 1, EL-6, IL-8 or TNF; or (iii) the presence of IL- 1. E1-6, IL-8 or TNF mRNA above basal levels in cells or tissues in which IL-I, EL-6, EL-8 or TNF, respectively. is produced.

9 The discovery that the compounds of Formula are inhibitors of cytokines, specifically it-I, IL-6, U1-8 and TINF is based upon the effects of the compounds of Formulas on the production of the IL IL-8 and TNF in in virro assays which are described herein.

As used herein, the term "inhibiting the production of IL-1 (IL-6, IL-8 or TNF)" refers to: a) a decrease of excessive in vivo levels of the cytokine I EL-6, JL-8 or TNF) in a human to normal or sub-normal levels by inhibition of the in vivo release **35 of the cytokine by all cells, including but not lirnited to monocytes, or macrophages; RECEIVED TIME 23. NOV. 16:51PRN TIE 2.OV 7D PR I NT TIME 23. NOV. 17 0 9 Resend23-11-01; 4:42PM;DAVIES COLLISON CAVE A IPAjc t S ec ure f ax 48/ 83 b) a down regulation, at the genomic level, of excessive in vivo levels of the cytokine (IL- 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-I, IL-6, IL-8 or TNF) in a human to normal or sub-normal levels.

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

As used herein, the term "cytokine" refers to any secreted polypeptide that affects the functions of cells and is a molecule which modulates interactions between cells in the immune, inflammatory or hematopoietic response. A cytokine includes, but is not limited to, monokines and lymphokines, regardless of which cells produce them. For instance, a monokine is generally referred to as being produced and secreted by a mononuclear cell, such as a macrophage and/or monocyte. Many other cells however also produce monokines, such as natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, bone marrow stromal cells.

epideral keratinocytes and B-lymphocytes. Lymphokines are generally referred to as being produced by lymphocyte cells. Examples of cytokines include, but are not limited to, Interleukin-1 Interleukin-6 Interleukin-8 Tumor Necrosis Factor-alpha (TNF-a) and Tumor Necrosis Factor beta (TNF-B).

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

As used herein, the cytokine referred to in the phrase "inhibition of a cytokine.

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

35 As TNF-8 (also known as lymphotoxin) has close structural homology with TNF-a (also known as cachectin) and since each induces similar biologic responses -41- RECEIVED TIME 23. NOV. 16:51 PRINT TIME 23. NOV. 17:08 Resend23-11-01; 4:42PM;DAVIES COLLISON CAVE I I Au st S e cu re f ax 49/ 83 and binds to the same cellular receptor, both TNF-a and TNF-8 are inhibited by the compounds of the present invention and thus are herein referred to collectively as "TNF" unless specifically delineated otherwise.

A new member of the MAP kinase family, alternatively termed CSBP, p38, or RK, has been identified independently by several laboratories. Activation of this novel protein kinase via dual phosphorylation has been observed in different cell systems upon stimulation by a wide spectrum of stimuli, such as physicochemical stress and treatment with lipopolysaccharide or proinflammatory cytokines such as interleukin-I and tumor necrosis factor. The cytokine biosynthesis inhibitors, of the present invention, compounds of Formula have been determined to be potent and selective inhibitors of CSBP/p38/RK kinase activity. These inhibitors are of aid in determining the signaling pathways involvement in inflammatory responses. In particular, for the first time a definitive signal transduction pathway can be prescribed to the action of lipopolysaccharide in cytokine production in macrophages. In addition to those diseases already noted, treatment of stroke, neurotrauma, cardiac and renal reperfusion injury, congestive heart failure, chronic renal failure, angiogenesis related processes, such as cancer, thrombosis, glomerulonephritis, diabetes and pancreatic b cells, multiple sclerosis, muscle degeneration eczema, psoriasis, sunburn, and conjunctivitis are also included.

The CSBP inhibitors were subsequently tested in a number of animal models for anti-inflammatory activity. Model systems were chosen that were relatively insensitive to cyclooxygenase inhibitors in order to reveal the unique activities of cytokine suppressive agents. The inhibitors exhibited significant activity in many such in vivo studies. Most notable are its effectiveness in the collagen-induced 25 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 importance are the compounds 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., (1 9 94)in vitro. Bone 15, 533-538; Lee et al., (1993). B Ann. N. Y Acad. Sci. 696, 149-170.

C* Chronic diseases which have an inappropriate angiogenic component are various ocular neovasularizations, such as diabetic retinopathy and macular S. degeneration. Other chronic diseases which have an excessive or increased 35 proliferation of vasculature are tumor growth and metastasis, atherosclerosis, and -42 RECEIVED TIME 23. NOV. 16:51 PRINT TIME 23. NOV. 17:08 Resend23-11-01; 4:42PM;DAVIES COLLISON CAVE I IPAu st S e cu re f ax 50/ 83 certain arthritic conditions. Therefore CSBP kinase inhibitors will be of utility in the blocking of the angiogenic component of these disease states.

The term "excessive or increased proliferation of vasculature inappropriate angiogenesis" as used herein includes, but is not limited to, diseases which are S characterized by hemangiomas and ocular diseases- The term "inappropriate angiogenesis" as used herein includes, but is not limited to. diseases which are characterized by vesicle proliferation with accompanying tissue proliferation, such as occurs in cancer, metastasis, arthritis and atherosclerosis.

Accordingly, the present invention provides a method of treating a CSBP kinase mediated disease in a mammal in need thereof, preferably a human, which comprises administering to said mammal, an effective amount of a compound of Formula or a pharmaceutically acceptable salt thereof.

It has now been found that the branching of the R 2 moiety, such as in the Rterm provides for improved activity against the CSBP enzyme, and for improved in vivo activity versus the unbranced R2 alkyl chain, such as disclosed in US Patent 5,593,992.

In order to use a compound of Formula or a pharmaceutically acceptable salt thereof in therapy, it will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice. This invention.

therefore, also relates to a pharmaceutical composition comprising an effective, nontoxic amount of a compound of Formula and a pharmaceutically acceptable S* carrier or diluent.

Compounds of Formula pharmaceutically acceptable salts thereof and 25 pharmaceutical compositions incorporating such may conveniently be administered by any of the routes conventionally used for drug administration, for instance, orally.

topically, parenterally or by inhalation. The compounds of Formula may be administered in conventional dosage forms prepared by combining a compound of Formula with standard pharmaceutical carriers according to conventional procedures. The compounds of Formula may also be administered in conventional dosages in combination with a known, second therapeutically active compound. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation. It will be appreciated that the form and character of the pharmaceutically acceptable character 35 or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables. The carrier(s) -43- RECEIVED TIME 23. NOV. 16:51 PRINT TIME 23. NOV. 17:08 Resend23-11-01; 4:42PM;DAVIES COLLISON CAVE A IPAust Secure fax 51/ 83 must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

The pharmaceutical carrier employed may be, for example, either a solid or liquid. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar.

S pectin, acacia, magnesium stearate, stearic acid and the like. Exemplary of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may include time delay material well known to the art, such as glyceryl mono-stearate or glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be employed. Thus, if a solid i0 carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25mg. to about Ig. When a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatin capsule. sterile injectable liquid such as an ampule or nonaqueous liquid suspension.

Compounds of Formula may be administered topically, that is by nonsystemic administration. This includes the application of a compound of Formula (1) externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not signicantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

Formulations suitable for topical administ-ation include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such liniments, lotions, creams, ointments or pastes, and drops suitable for 25 administration to the eye, ear or nose. The active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, for instance from 1% to 2% by weight of the formulation. It may however comprise as much as 10% w/w but preferably will comprise less than 5% w/w. more preferably from 0. 1% to 1% w/w of the fFormulation.

Lotions according to the present invention include those suitable for application to the skin or eye. An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops. Lotions or liniments for application to the skin may .also include an agent to hasten drying and to cool the skin, such as an alcohol or o" 35 acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.

-44- RECEIVED TIME 23. NOV, 16:51 PRINT TIME 23. NOV. 17:08 Resend23-11-01; 4:42PM;DAVIES COLLISON CAVE A I Au sct S e cu re f ax 52/ 83 Creams. ointments or pastes according to the present invention are semi-solid Formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form. alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable s machinery, with a greasy or non-greasy base. The base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol or a macrogel. The formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.

Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent. The resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100*C. for half an hour. Alternatively, the solution may be sterilized by filtration and transferred to the container by an aseptic technique. Examples of bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate benzalkonium chloride and chlorhexidine acetate Suitable solvents for the preparation of an oily 25 solution include glycerol, diluted alcohol and propylene glycol.

Compounds of Formula may be administered parenterally, that is by intravenous, intramuscular, subcutaneous intranasal. intrarectal, intravaginal or intraperitoneal administration. The subcutaneous and intramuscular forms of parenteral administration are generally preferred. Appropriate dosage forms for such administration may be prepared by conventional techniques. Compounds of Formula may also be administered by inhalation, that is by intranasal and oral inhalation administration. Appropriate dosage forms for such administration, such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional S: techniques.

35 For all methods of use disclosed herein for the compounds of Formula the daily oral dosage regimen will preferably be from about 0.1 to about 80 mg/kg of RECEIVED TIME 23. NOV, 16:51 PRINT TIME 23, NOV. 17:08 Resend23-11-01; 4:42PM;DAVIES COLLISON CAVE I I kj t Sec u re fax 53/ 83 total body weight, preferably from about 0.2 to 30 mg/kg, more preferably from about 0.5 mg to 15mg. The daily parenteral dosage regimen about 0.1 to about mg/kg of total body weight, preferably from about 0.2 to about 30 mg/kg, and more preferably from about 0.5 mg to 15mg/kg. The daily topical dosage regimen will preferably be from 0.1 mg to 150 mg, administered one to four, preferably two or three times daily. The daily inhalation dosage regimen will preferably be from about 0.01 mg/kg to about 1 mg/kg per day. It will also be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of a compound of Formula or a pharmaceutically acceptable salt thereof will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, the number of doses of a compound of Formula or a pharmaceutically acceptable salt thereof given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.

The novel compounds of Formula may also be used in association with the veterinary treatment of mammals, other than humans, in need of inhibition of CSBP/p38 or cytokine inhibition or production. In particular, CSBP/p38 mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted herein in the Methods of Treatment section, but in particular viral infections. Examples of such viruses include, but are not limited to, lentivirus infections such as, equine infectious anaemia virus, caprine arthritis virus, visna virus, or maedi virus or retrovirus infections, such as but not limited to feline immunodeficiency virus (FIV), bovine immunodeficiency virus, or canine immunodeficiency virus or other retroviral infections.

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

BIOLOGICAL EXAMPLES The cytokine-inhibiting effects of compounds of the present invention may be determined by the following in vitro assays: :0 Assays for Interleukin 1 Interleukin -8 (IL-8 and Tumour Necrosis 0. 35 Factor (TNF) are well known in the art, and may be found in a number of publications.

-46- RECEIVED TIME 23. NOV. 16:51 PRINT TIME 23, NOV. 17:08 Resend23-11-01; 4:42PM;DAVIES COLLISON CAVE IPutScr u I I Pks t Se c u r e f a x 54/ 83 and patents. Representative suitable assays for use herein are described in Adams et al., US 5,593,992, whose disclosure is incorporated by reference in its entirety, In vivo TNF assay: Griswold et al., Drugs Under Exp. and Clinical Res.,XiX(6). 243-248 (1993); or Boehm. er al., Journal Of Medicinal Chemisry 39, 3929-3937 (1996) whose disclosures are incorporated by reference herein in their entirety.

LPS-induced TN~a Production in Mice and Rats In order to evaluate in vivo inhibition of LPS-induced TNFa production in rodents, both mice and rats are injected with LPS.

Mouse Method Male Balb/c midce from Charles River Laboratories are pretreated minutes) with compound or vehicle. After the 30 min. pretreat time, the mice are given LPS (lipopolysaccharide from Eshenichia coli Serotype 055-85, Sigma Chemical Co., St Louis, MO) 25 ug/mouse in 25 ul phosphate buffered saline (pH intraperitoneally. Two hours later the mice are killed by C01' inhalation and blood samples are collected by exsang-uination into heparinized bloo d collection tubes and stored on ice. The blood samples are centrifuged and the plasma collected and stored at -200C until assayed for TNFot by EUISA.

@0 0 Rat Method 25 Male Lewis rats fromh Charles River Laboratories are pretreated at various times with compound or vehicle. After a determined pretreat time, the rats are given LPS (lipop'olysaccharide from Esherichia coi Serotype 055-85, Sigma Chemical Co., St Louis, MO) 3.0 mg/kg intra peritoneally. The rats are kiled by CO 2 0~.*inhalation and hepaninized wvhole blood is collected from each rat by cardiac 000.30 puncture 90 minutes after the LPS injection. The blood samples are centrifuged and the plasma collected for analysis by ELISA for TN"Fa levels.

ELISA Method TNFci levels were measured using, a sandwich ELISA, as described in Olivera et al., Circ. Shock, 37, 301-306, (1992), whose disclosure is incorporated by reference in its entirety herein, using a hamster mnonoclonal antimurine TNFCI (Genzyme, Boston, MA) as the capture antibody and a polyclonal rabbit antimurine TNFa 47 RECEIVED TIME 23. NOV. 16:51 PRINT TIME 23. NOV. 17 08 Resend23-11-O1; 4:42PM;DAVIES COLLISON CAVE IPutScr a I I PAus t S e c u r e f a x 55/ 83 (Genzyrne) as the second antibody. For detection, a peroxidase-conjugated coat antirabbit antibody (Pierce, Rockcford, IL) was added, followed by a substrate for peroxidase (I mg/mi orthophenylenediarnine with I% urea peroxide). TNFct levelIs in the plasma samples from each animal were calculated from a.-standard curve generated with recombinant mw-inc TNFa (Genzyme).

LPS-Stixnulated Cytokine Production in Human Whole Blood Assy: Test compound concentrations were prepared at 10 X concentrations and LI'S prepared at I ug/mi (final conc. of 50 ng/nil LI'S) and added in 50 uL, volumes.

to 1.5 mL eppendoff tubes. Jieparinized human whole blood was obtaned from healthy volunteers and was dispensed into eppendorf tubes containing compounds and L.PS in 0.4 rnL volumes and the tubes incubated at 37 C. Following a 4 hour incubation, the tubes were centrifuged at 5000 rpm for 5 minutes in a TOMY microfuge, plasma was withdrawn and frozen at -80 C.

Cyrokine measurement: IL-I and/or TNF were quantified using a standardized

ELISA

technology. An in-house ELISA kit was used to detect human EL- I and TNF.

Concentrations of IL- I or TNF were determined from standard curves of the appropriate cytokine and IC50 values for test compound (concentration that inhibited 50% of LI'S-stimulated cytokine production) were calculated by linear regression analysis.

*.CSBP/p3g Kinase Assay: This assay measures the CSBP/p38-catalyzed transfer of 32p from [a- 25 3 2 PJATP to threonine residue in an epidenijal growth factor receptor (EGFR)-derjved peptide (T669) with the following sequence:

KRELVEPLTPSGEAPNQAJ.JR

(residues 661-68 (See Gallagher et al., "Regulation of Stress Induced Cytokine Production by Pyridinyl. Imidazoles: Inhibition of CSBP Kinase", BioOrganic Medicinal Chemistry, 1997, 5, 49-64).

Reactions were carried in round bottom 96 well plate (from Cowing) in a 0 nial volume. Reactions contained (in final concentration): 25 mM Hepes, p117.5: 8 0 mM MgCI 2 0. 17 mM ATP' (the K9(ATp] of p38 (see Lee et al., Nature 300, n72 pg 639-746 (Dec. 1994)); 2.5 uCi of [g-32PIJATP; 0.2 mM sodium orthovanadate;

I

*m1M DTT; 0. 1% BSA; 10% glycerol; 0.67 m.M T669 peptide; and 2-4 nM of yeastexpressed. activated and purified p38. Reactions were initiated by the addition of [garnma-32P]Mg/ATP, and incubated for 25 min. at 37 inhbitors (dissolved in DMS0) were incubated with the reaction mixture on ice for 30 minutes prior to -48.

RECEIVED TIME 23. NOV. 16 :5 1 PRINT TIME 23. NOV. 17: 08 Resend23-11-01; 4:42PM;DAVIES COLLISON CAVE I 1Aust Secure fax; 56/ 83 adding the 32P-ATP. Final DMSO concentration was 0.16%. Reactions were terminated by adding 10 ul of 0.3 M phosphoric acid. and phosphorylated peptide was isolated from the reactions by capturing it on p81 phosphocellulose filters.

Filters were washed with 75 mM phosphoric acids, and incorporated 32P was S quantified using beta scintillation counter. Under these conditions, the specific activity of p38 was 400-450 pmol/pmol enzyme, and the activity was linear for up to 2 hr of incubation. The kinase activity values were obtained after subtracting values generated in the absence of substrate which were 10-15% of total values.

Representative final compounds of Formula Examples 1 to 23 have to demonstrated positive inhibitory activity of an IC 5 0 of 50uM in this binding assay or a similar assay.

Prostoglandin endoperoxide synthase-2 (PGHS-2) assay: This assay describes a method for determining the inhibitory effects of IS compounds of Formula on human PGHS-2 protein expression in LPS stimulated human monocytes. A suitable assay for PGHS-2 protein expression may be found in a number of publications, including US Patent 5.593,992 whose disclosure is incorporated herein by reference.

TNF-a in Traumatic Brain Injury Assay This assay provides for examination of the expression of tumor necrosis factor mRNA in specific brain regions which follow experimentally induced lateral fluidpercussion traumatic brain injury (TBI) in rats. Since TNF- a is able to induce nerve growth factor (NGF) and stimulate the release of other cytokines from activated 25 astrocytes, this post-traumatic alteration in gene expression of TNF- a plays an important role in both the acute and regenerative response to CNS trauma. A suitable assay may be found in WO 97/35856 whose disclosure is incorporated herein by reference.

CNS Injury model for IL-b mRNA This assay characterizes the regional expression of interleukin-1B (IL-1B) mRNA in specific brain regions following experimental lateral fluid-percussion traumatic brain injury (TBI) in rats. Results from these assays indicate that following TBI, the temporal expression of IL-18 mRNA is regionally stimulated in specific brain 35 regions. These regional changes in cytokines, such as IL-16 play a role in the post- -49- RECEIVED TIME 23. NOV. 16:51 PRINT TIME 23. NOV. 17:08 Resend'/3-1i-O1; 4:42PM;DAVIES COLLISON CAVEIPus Serefx#5/3 I I PAlis t S e c u r e f a x 57/ 83 traurnatic pathologic or regenerative sequelae of brain injury- A suitable assay-may be found in WO 97/35856 whose disclosure is incorporated herein by reference.

Angiogenesis Assay: Described in WO 97/32583, whose disciosrue is incorporated herein by reference, is an assay for determination of inflammatory angiogenesis which may be used to show that cytokine inhibition will stop the tissue destruction of excessive or inappropriate proliferation of blood vessels.

io SYNTHETIC

EXAMPLES

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

In the Examples, all temperatures are in degrees Centigrade Mass spectra were performed upon a VG Zab mass spectrometer using fast atom bombardment or on a micromass platformn electrospray ionization mass spectrometer in the positive ion mode using 95:5 CH3CN/CH 3 oH with 1% formic acid as the carrier solvent, unless otherwise indicated. I H-NMR (hereinafter "NMR") spectra were recorded at 250 M1-z using a Bruker AM 250 or Am 400 spectrometer.

Multiplicities indicated are: s=singlet. ddoublet, t=triplet, q=quaxtet, m--multiplet and br indicates a broad signal. Sat. indicates a saturated solution, eq indicates the proportion of a molar equivalent of reagent relative to the principal reactant.

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

vilimidazole a) 4 -Fluoropheni-kolyslfofomeflhy.fonmde To a suspension of p-toluenesulfinic acid sodium salt (30 grams, hereinafter in H20 (100 milliliters (hereinafter was added methyl t-butyl ether mL) followed by dropwise addition of conc. HCl (15 fiL). After stirring 5 min- the organic phase was removed and the aqueous phase was extracted with methyl tbury! ether. The organic phase was dried (Na2SO 4 and concentrated to near dryness. Hexane was added and the free acid was filtered. The p-toluenesulfinic 50 RECEIVED TIME 23.NOV. 16:51 RECIVD IM 23 NV. 1651PRINT TIME 23. NOV. 17 07 Resend23-11-0j; 4:42PM;DAVIES COLLISON CAVE A IPutScefx A I PAjs t S e c u r e f a x 58/ 83 acid (22 g,140.6 millimole (hereinafter p-fluorobenzaldehyde (22 rnL, 206 mmol), formamnide (20 mL, 503 minol) and camphor suiphonic acid (4 g, 17.3 rnmol) were combined and stirred at 60 0 DC for about 18 hours (hereinafter"h) The resulting solid was broken up and stirred with a mixture of MeQEi (35 mL) and hexane (82 rnL then filtered. The solid was resuspended in MeOH/hexane (1:3, 200 ML) and stirred vigorously to break up remaining chunks. Filtration afforded the tidle compound (27 g, 62 yield). I H NMR (400 MHz, CDCJ 3 d 8.13 (s, 1H), 7.71 2H), 7.43 (dd, 211), 7.32 2H), 7.08 2H1), 6.34 1H), 2.45 (s, 3H1).

b) 4-loohnirlrcll2 t~i~lnd The compound in the previous step (2.0 1ia, 6.25 mrnol) in ethyleneglycol dimethylether (DME) (32 ML) was cooled to -I O-C. POC1 3 (1.52 nil 16.3 inmol) was added followed by the dropwise addition of triethylaniine (4.6 niL. 32.6 mnrol) in DME (3mL) keeping-. the internal temperature below The mixture was gradually warmed over I quenched in H20 and extracted with EtOAc. The organic phase was washed with saturated aqueous NaHCO3, dried (Na2-SO 4 and concentrated. The resulting residue was triturated with petroleum ether and filtered to afford the title compound (1.7 g, 909o yield). 1 H NMR (CDC13): d 7.63 2.H), 7.33 (in, 4H), 7. 10 211). 5.60 1IH), 2.50 3H) c) 2 -Propylthigpyriridine.4--caxadhediehlcea Charge a I L 3-necked flask equipped with a stir bar, thermometer, 100 ML addition funnel and reflux condezisor with N.N-diznethylforma nide dimethyl acecal (88.7 S, 98.9 m.L, 700 minol) and pyruvaldehyde dirnethyl acetal (85.3 86.8 niL, 700 nunbI) and heat in an oil bath at 1 10 *C for 3-4 h. Cool the solution to 85 0

C

25 and add Uhourea (48.9 g, 636.4 rnrol) and NaOMe (25 wt in MeOH. 151.2 g, 160 inL, 700 mrnol) and stir at 85 *C for 3-4 h. Cool the solution to 65 *C and charge

I-

bromoropane (86.9 g. 64.4 rnL, 700 mmnol) to the addition funnel and add slowly over 10-1 IS mn to the reaction, bringing the solution to a mild reflux. After I h, add 100 niL of EtOAC to the reaction and bring the oil bath temperature to 95 0

C.

Replace the reflux condensor with a distillation head and distill *150-200 MiL of solvent from the reaction. Add an additional 400 niL of EtOAc and 120 MnL of H.0 and stir at 50 *C for 5 min. Transfer to a separatory funnel and separate the aqueous phase. Add 60 mL of FLO0, agitate. and separate the aqueous phase. A sample was concentrated to give a yellow oil: 'H NNM (300 MHz, CDCI 3 d 8.53 (lH, d, J 35 Hz), 7-16 (1 H. d, J 5.0 Hz), 5.17 (11H, 3.42 3.14 (2H, t, J 7.3 Hz), 1.76 (211, mn), 1.05 (3H. t, J =7.3 Hz).

-51- *9 0 *0 0 *0 *0 RECEIVED TIME 23. NOV. 16:51 ITTME 2.OV 17D PRINT TIME 23. NOV. 17 0 7 Resend23-11-01; 4:42PM;DAVIES COLLISON CAVE A IPutScr fx I I PAjs t S e c u r e f a x 53/ 83 Alternatively, brornopropane can be replaced with any suitable alkyl halide and the alkylation process can occur at about 0 to about 100 *C.

d) 2 -Propvlthiooyrimidine-4-carboxaldehyde The product of the previous step (24 g, 105 rnunol) was dissolved in THF s rL) and 3N HCL (150 mi) was added. The resulting mixturewastreude argon and heated to 57 'C for 4 h. The THF was stripped off and the mixture wa s cooled in an ice bath. EtOAc (300 m-L) was added followed by the addition of'solid NaHCO. ,Additional H.0 was added to dissolve all the solid, and the aqueous phase was extracted with EtOAc (3 x 150 mL). The organic phases were combined, dried, (NaSq) and concentrated to give a brown Oil. The crude product was purified by flash chromatography (sil ica gel, 0- 1% MeOH/CHCL) to give the title compound as a yelowoil.~H MR 400 ~z.CDC 3 d 9.95 IH), 8.78 1Hi), 7.45 1H), 3.21 2H), 1.82 2H), 1. 1 3H).

e) 2-Npvtjprmdn--cfxlgye()2aio I -i ronanoiimine To a solution of 2 -propylthiopyrnidine-4carboxalehyde (10.9 g, 60 nunol) in CILCl. (200 mL) was added amnino-l-propanol (5.85 S, 78 mxnol). The solution was stirred at room temperature under argon for 16 h. The solution was concentrated to give the title compound. ES MS m/e =240 (NM) f) 141-yrx~o-:~~L-loo~enl--2(2o1vtioprmdn 4 -yflimidazole The product of the previous step (14.7 g,-60 mmrol) was dissolved in DMF (200 niL) and stirred under argon. Potasium carbonate (6.6 g, 48 inmol) was added followed by the addition of the product of example I1(b) (12-14 g. 42 mrnol). ,The mixture was stirred at rt for 72 hi. The DMF was pumped off and the residue was :25 partitioned between EtOAc and water. The organic phase was separated, washed with brine, dried (Na.SO), and concentrated. The crude product was purified by flash chromatography (silica gel, 0-4% MeOH/CH-4CL) to give the. title compound as a yellow solid. ES MS ro/e 373 (MW) tS)- 1-(1 -Hvdroxyvnro2:yvl_4(4-fluoropheny)5[2-(Dogsulfonyl);.

pvyrimdinAv1)irrdazole The product of example I1(f) 4 g, I.

7 5rnmol) was dissolved in methanol (100 mL) and cooled in an ice bath while stirring under argon. OXONE (8.26g.

13.44) nmnol in KtO (60 mL) was added and the mixture was stirred at rt for 12 h.

The MeOH was stripped and the residue partitioned between EtOAc and M~O- The mixture was made basic by the addition of solid K.CQ, and extracted with EtOAc.

52 RECEIVED TIME 23. NOV. 16:51PRN TIE 2.OV 17D PRINT TIME 23. NOV. 17 0 7 Resend23-11-01; 4:42PM;DAVIES COLLISON CAVE I~s euefx#6/8 A PAust Secure fax 60/ 83 the combined organic extracts were washed with brine, dried (Na.S0 4 and concentrated to give the title cormpound as a yellow solid.

ES MSnWe =405 (MR-) h) Si l-l.ydroxyvrop2l).4.(4 .fuoronhenvl5r2 ___ghox pvyrirnidin-4y1]irndazole NaH (252 mg, 10 mmnol) was added in small portions to a solution of 4-fluorophenol (2.21 g, 19.8 inmol) in dry THF (50 niL). After the vigorous reaction bad subsided, this solution was added to a solution of the product of example I1(g) (2 S, 4.95 romol) dissolved in dry TFIF (200 mL). The reaction i0 mnixture was stirred at rt under argon for 1 h. The reaction mixture was concentrated.

and the residue partitioned between EtOAc and HLO. The organic phase was washed with IN NaQOl, brine, dried (NaS0., and concentrated. The crude product was purified by flash chromatography (silica gel. 0-4% MeOH/CR.CL) to give the title compound as a light yellow solid.

ES MS nile 409 (NMW) Exam&~ 2 I-(1 yd~yrt--XL-_1-~qohny)5f:4fuLWhnx~y~dn4 yilirnidazole Following the procedures of examples 1 except using amino- I propanol in place of amino- I-propanol in step I1(e) afforded the title compound as an off-white solid. ES MS rn/c 409 (MW) V Exmle3 yilirnidazole Following the procedures of examples 1 except using 2-amino-1,3propanediol in place of ammno-1I-propanol in step 1 afforded the title compound as an off-white solid. ES MS ni/e =425 (NM) hHWi~pe 4 Following the procedures of examples I1(e) except using amino- I propanol in place of amino-1-propanol in step 1 and using phenol in place 53 !-RECEIVED TIME, p23. NOV. 16: 51 PRN-IE 2.NV 70 PRINT TIME 23. NOV. 17 0 7 Resend23-11-O1; 4:4'4PM;DAVIES COLLISON CAVE A PAust Secure fax 61/ 83 of 4-fluorophenol in step 1 afforded the title compound as light yellow crystals.

ES W+ MS rn/e =391 (Mli) Exgmpke 14-( vrxpop2xj 4 2~mdn4 Following the procedure Of example I except using phenol in place Of 4fluorophenol, afforded the title compound as light yellow crystals.

ES MS mn/e =391 (NM) Exampe 6 Following the procedures of examples I except using amino- 1 -propanol in place of amino- I1-propanol in step I and using phenol in place of 4-fluorophenol in step I afforded the title compound as light yellow crystals.

ES MSr/e 391 (MM) Xl~irnidazole Following the procedures of examples -1 except using pherioxy-2-arniinopropane in place of amino- 1-propanol in. step I and using phenol in place of 4-fluorophenol in step I afforded the title compound as a light yellow solid. ES MS m/e 467 (NM) Examgple8 Yflimidazole Following the procedures of examples I except using amnino-3- 30 phenyl-1I.propanol in place of amino.-1-propanol in step 1 and using' phenol in place of 4-fluorophenol in step I afforded the title compound as yellow solid.

ES MS m/e 467 (MW-) 35 (S)-lI l-HydroxX- 3 -johenvlp o I 14.(4..nuorop n;~.(2hnxprmid in-4- -54- RECEIVED TIME 23. NOV. 16:51PRN TIE 2.OV l7D PRINT TIME 23. NOV. 17 0 7 Resend23-11-O1; 4:42PM;DAVIES COLLISON CAVE P Aust Secure fax 62/ 83 Following the procedures of examples 1 except using arnrino-3phenyl- I-propanol in place of arnino-lI propanol in step 1 and using phenol in place of 4-fluorophenol in step I afforded the title compound as a .yellow solid.

ES MS Wie 467 (MH-) Examnple I-(I Hydroxvbut2- yI)4fluorOh henv5-2-rh5(2xpenox.divI')imidazole Following the procedures of examples 1 except using ar-ino-1butanol in place of amino- I-propanol in step I and using phenol in place of 4 -fluorophenol in step I afforded the title compound as white solid.

ES MS xt/e 405 (MWH) EXamRIC I I I -(I-vdovu-yj 4uoobel 5 2-ho yflirnidazole Following the procedures of examples I except using amino-I butanol in place of aznino-1-propanol in step I and using phenol in place of 4-fluorophenol in step I afforded the title compound as white solid. ES MS nile 405 (No) Example 12 3 Dihydroxv~or---yi v1.4-fl fenl)-5-ro henoxlp5(2hidi-4 y-Umidazole Following the procedures of examples 1 except using 2-axnino-1,3propanediol in place of amino.-1-propanol in step I and using phenol in place of 4-fluorophenol in step 1 afforded the title compound as a white solid. ES (+MS nie =407 (MM~ E&aMple] 3 YIlimnidazole Following the procedures* of examnples I except using (R)-2-aino,- ~2 -phenylethanol in place of amnino I1-propanol in step I and using phenol in **35 Place of 4-fluorophenol in step I afforded the title compound as a white solid.

ES MS rn/e =453 (Mir) RECEIVED TIME 23.NOV. 16:51 RECIVD IM 23 NV. 1651PRINT TIME 23. NOV. 17 07 Resend23-11-01; 4:42PM;DAVIES COLLISON CAVEI ustSuefa I I P A u s t S e c u r e f a x 63/ 83 ExamRnle-14 -Hydroxy-2phenleth2vlYI) 4..(4-fluoropJbenvl)S2heno midrmjin-4- VI' iN-idazole the procedures of examples I except using (S)-2-amino-2phenylethanol in place of amino-l-propanol in step I and using phenol in place of 4-fluorophenol in step I afforded the title compound as a white solid- ERS MS ni/e 453 (MO-) Example- I-Hydroxv~roD-2avl)--4fumhnl--2(-hoghnx)~ in4 vilimidazole Following the procedure of example 1 except using 4-chiorophenol in place of 4-fluorophenol, afforded the title compound as a white solid.

U~ ES MSni/e =425 (M1f) Example 16 ylliinidazole Following the procedures of examples I1(e) except using amino- Ibutanol in place of amino- I -propanol in step I and using 4-chlorophenol in place of 4-fluorophenol in step 1 afforded the title, compound as a white solid.

ES ES MS nile 439 (NM) Example 17 I-Hydroxybut-2-yI 4 4 -fluomRohenv

-S-

2 4 4 -chigorohenoxv~~iijjl yilimnidazole Following the procedures of examples I except using amnino- I butanol in place of amino-l1-propanol in step I and using 4-chiorophenol in place of 4-fluorophenol in step I afforded the title compound as white solid. ES W+ MS nWe 439 (NM) Examole 18 1410 -Hvdiroxy~rou..2-i4)..4-(4-fluomphenyl

)-I

2 merbylphenoxy')pyrimjdin- !Ly limi~dazole -56- RECEIVED TIME 23.NOV. 16:51 RECIVE TME 3. OV 1651PRINT TIME 23. NiOV. 17: 07 Resend23-11-01; 4:42PM;DAVIES COLLISON CAVE A PutSerefx#4/3 I I PAus t S e c u r e f a x 64/ 83 Following the procedure Of example I except using 4-methylphenol in place of 4-fluorophenol, afforded the title compound as a white solid.

IES MS ride 405 (MW') Example 19 (R)-I(-vdoyu--)--4fooh I _5r( Yllimidazole Followin g the procedures of examples 1 except using amino-I butanol in place of amlino-i -propanol in step I and using 4-methyiphenol in place of 4-fluorophenol in step I afforded the title compound as white solid. ES MS rn/e =419 (MH-) Exarrile 1-(1 -Hvdroxybut-2vl).4.(4fluorophenvI

F

2 1-( 4 -meth]henoxv)pyrimidi-4- Is- Yllirnidazole Following the procedures of -examples 1 except using aino 1butanol in place of amino-1I-propanol in step I and using 4-methyiphenol in place of 4-fluorophenol in step I afforded the title compound as white solid. ES MS m/e =419 (MW) a 4 (l im d xR--2- I r- o p h e--n v i v ip 12 -m e vln Y ip v f l m id in 4 -liiiazole Folwn the procedures of examples I except using 2-amno-1,3- :25 propanediol in place of amino-lI-propanol in step I and using 4methylphenol in place of 4-fl uorophenol in step I afforded the title compound as a white solid. ES MS rn/c 421 (NM) Ex apDle 22 01-14 4 N-M opinyl-2.but.v; 4(-lg~hly)5(2TheoyvrriiX vl~ir-idazole a) (S)-3-(r-butoxyqarbonvlai~jno);. -utanol Methyl (S)-3-(t-butoxycarbonylarnino). I -butyrate prepared according to (McIntosh and Acquaah, Can. Chem 66, 1752 (1988)) (3 g, 13.8 Mmnol) was dissolved in dry THF (100 mL) and cooled in an ice bath while stirring under argon.

Lithium borohydride (305 mgo, 13.9 minol) was added and the mixture allowed to 57 RECEIVED TIME 23.NOV. 16:51 RECIVD IM 23 NV. 1651PRINT TIME 23. NOV. 17 07 Resend23-11-01; 4:42PM;DAVIES COLLISON CAVE I 1PAust Secure fax 65/ 83 warm to room temperature and stir for 16 hours. The solvent was evaporated and the residue taken up in EtOAc, washed with brine, dried (NaS.S0), and concentrated- The crude product was purified by flash chromatography (silica gel, 0-20% EtOAc/ hexane) to give the title compound as a white solid. ES MS rn/e 190 (MW-) b) 3 z4t-butoxvcarbonvl inobI._-buaol mesvlate Teproduct of example 22 (1.06 g, 5.6 mniol) was dissolved in CHKC1, ml) and cooled in an ice bath while stirring under argon. Triethylanaine (0.667 g, 6.6 mnmol) was added followed by the dropwise addition of znethanesulfonyl chloride (0.687 g, 6 inmol). After 10 mninutes the ice bath was removed and-the i0 mixture stirred at rt for 2 h. The solvent was stripped off and the title compound was isolated as a yellow oil. ES MS rn/e 268 (MM, 290 (MNa) c) 4 R~S)-3-(t-butoxvcarbon -amino~but -yfropoi The crude product of exaple 22 mrool) was dissolved in morpholine mL) and heated to 57 'C while stirrin g under argon for I h. The solvent was pumped off. and the residue was partitioned between EtOAc and water. The organic phase was washed with brine, dried (Na 2 and concentrated. The crude product was purified by flash chromatography (silica ael, 2-5% MeOWICH,C],) to give the title compound as a white solid. ES M4S in/c 259 (Mir) d) 4 -(3-aninobut- I-yP~mor~holine The product of example 22 (0.41 g. 1.59 nitol) was dissolved in CILC.

mL) -and cooled in an ice bath while stirring under argon. A solution'of trifluoroacetic acid (5 mQL in CKLCL (5 rnL) was added and the mixture allowed to warm to room temperature for I h. The solvents were evaporated to give the title compound as an oil. ES MS rn/e 159 (MH*) e) S) 4-N-Mo pholiri -2-but-vt uoro ~e~j-5 :2phenov~rmidinv4vIin~daole Following the procedures of examples 1 except using the crude product of 22 plus excess triethylamine in place of amnino- I-propanol in step I and using phenol in place of 4 -fluorophenol in step I afforded the title compound as a pink solid ES ()MS rale 474 (MWr) *8 RE EI E TI E 2 .NV.6 5 R NT TM 3 O 1 Resend23-11-O1; 4:42PM;DAVIES COLLISON CAVE A PutScr a A I PAus t S e c u r e f a x 66/ 83 By analag-ous methods to those indicated above the following compounds may be prepared: 23 24

I

methyl -ethyl R2 hvdroxxmethyl hydroxynethyl hydroxymerhyl isopro,v1 27 28 29 31 I 2-(methy1poV I phenyl benzyl i hydroxyrnethyl Ii hydroxymechvl hydroxyrnethyl methl 32 j isopnopyI hydroxymeth I dzehyroxymethyl, dimnethylanlinomethyl dirnethylaminomejbyl dimethylaminomethyl a. 9 a 9* 99 9* 9 9 9 a a a. 2-(methyl~provyl 34 vhenvi vhevL "Al 5M1iI101CY 35 benzyl dimsthylarninomethyl 36 phenetbyl dimethylaininomethyl 37 retbyl carboxy 38 ethyl abx 39 isoproeyI carboxy 2-(methyl)propyl carboxy 41 j phenyl carboxy 42_ beayL carboxy 43 phenethyl carboxy_ 999a*9 a a. 9.

a a *9 a a 9.

-59- RECEIVED TIME 23,NOV. 16:51 RECIVD IM 23 NV. 1651PRINT TIME 23. NOV. 17 07 Resend23-11-O1; 4:42PM;DAVIES COLLISON CAVE PutScr a I I PAlis t Secure fax 67/ 83 44 46 47

RI

methyl methyl methyl_ R2

-CONH

2 -CONIIme CONMe 2 mehoxvniechyl 48 methyl 49 so 51 52 53 methyl methyl 54 methyl 54 methyl 56 methyl 57 methyl phenoxymethyl carbaxnylmethyl metehyesuifonomethyI -benzenesulfonamidoinethyl

S

S

S

*5

S

S

*5 a S S 9* 58 59 I methyl methvl 60 mty 61 methyl 62 metyl 63 methyl 64 mehl methyl 66 methyl 67 methyl phenylmethyIsulfonamiudornethyI NV'-ethYlurcidomethyl N'-phenylureidometbyl -CH2OCH2CH~h -CONUPh -CONH]Bn -CH2OCH2(4-MePh) -CH2OCH2(4-Fph) -Cfl2OCH2(4-ClPh) *CH20CH2(3-O~Ph) -CH2O(4-MePh) -CH2O(4-FPh) 68 69 71 methyl mekhlmethyl RECEIVED TIME 23.NOV. 16:51 RECEVED IME 3. NV. 1:51PRINT TIME 23. NOV. 17:06 HesenOiJ-1i-Ui; 4:42-PM;DAVIES COLLISON CAVE A IPutSur fx I I PAus t S e c u r e f a x 6 8/ 831 72 73 74 76 77 78 79 81 82 83 84 85 86 87 88 89 91 92 93 94 96 R1 methyl methyl ethyl -ethyl ethvl ethyl ethyl ethyl et hyl ethyl ethyl ethyl ethyl ethylethyl _Ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl R'2? -CH2O(4-CIPh) -CH2O(3-ClPh) -CONH2 -CONHMe CONWe 2 methoxymiethyl Phenoxymezki benzyloxyznethyj carbamnoyl carbainoylmethyl aminornethyl N-(methyl)aznnomethyl N-(biezvl)aninomethyl acetamidomethyl aetzamidornethyl behaesnzadoethvl benzenesulfonamnidomethyl Phenyhnethylsulfonaraidomethyl -CH2OCH2CH2Ph -CONHPh -CONHBn S.

S

S

*5 S S S *5 -CH2OCH2(4-MePh) -61- RECEIVED TIME 23. NOV. 16:51 PRINT TIME 2 3. NOV. 17 06 Resend23-11-01; 4:42PM;DAVIES COLLISON CAVE A IPAust Secure fax 63/ 83 97 98 99 100 101 102 103 ethyl ethyl ethyl ethy I ethyl ethyl ethyl -CH20CH2(4-FPh) -CH20CH2(4-CIPh) -CH20CH2(3-ClPh) -CH20(4-MePh) -CH20(4-FPh) CH20(4-QCIPh) -CH20(3-CIPh) e o e C 0* me *See o

C

see.

S

See...

S

Ce *e C a 50 0

*O

be All publications, includingbut not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.

10 The above description fully discloses the invention including preferred embodiments thereof. Modifications and improvements of the embodiments 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 preceding description, utilize the present invention to its fullest extent. Therefore, the 15 Examples herein are to be construed as merely illustrative and not a limitation of the scope of the present invention in any way. The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows.

62 RECEIVED TIME 23. NOV. 16:51 PRINT TIME 23. NOV. 17:06

Claims (21)

1. A compound represented by the formula: R2 R,I) wherein RI is 4-pyridyl, pyrimidinyl, 4-pyridazinyl, l,2,4--riazin-5-yl, quinoly), isoquinolinyl, or quinazolin-4-yl ring, which ring is substituted with Y-Ra and optionally with an additional independent substituent selected from C14 alkyl, halogen, hydroxyl, Ci.. 4 alkoxy, C1-.4 alkylthio, C1-.4 alkylsulfinyl, CH2OR12, amino, mono and di- C1-6 alkyl substituted amino, an N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatomn selected from oxygen, sulfur or N(RIO)C(O)Rb or NHRa; Y is oxygen or sulfur, R4 is phenyl, naphth-l -yl or naphth-2-yl, or a heteroazyl, which is optionally substituted by one or two substituents, each of which is- independently selected, and which, for a 4-phenyl, 4-naphth-1-yl, 5-naphth-2-yl or 6-naphth-2-yl substitueni; is halogen, cyano, nitro, C(Z)NR7R17, C(Z)0R16, (CRIOR2O)vCOR12, SR5, 0R12, halo-substituted-C1..4 alkyl, 01.4 alkcyl, ZC(Z)Rl2, NRIOC(Z)R16, or 0, (CRloR2o)vNRloR20 and which, for other positions of substitution, is halogen, cyano, C(Z)NR13R14, C(Z)0R3, (CR1OR2O)mn"COR3, S(O)rnR3, 0R3, halo- *eoo substituted-C 1-4 alkyl, C1-4 alkyl, (CR1OR2O)mnNRl OC(Z)R3, NRIOS(O)mn'R8, 0 NRlOS(O)rn'NR7RJ 7, ZC(Z)R3 or (CRlOR20)m",NRl3R1 4;2 0 Z is oxygen or sulfuri, n is an integer having avalue of 1 to 0. 0 m is 0, or the integer I or 2; n' is an integer having a value of 1 or 2, in" is 0, or an integer having a value of I to v is 0, or an integer having a value of 1 or 2;, R2 is (R 2 2 A is an optionally substituted aryl, heterocyclyl, or heteroaryl ring, or A is a substituted CI- 1 0 alkyl; 00. R 22 is an optionall~y substituted C 1 10 alkyl; Ra is aryl, arylCI-6alkyl, heterocyclic, heterocyclylI-i.. alkyl, heleroaiyl, hctcroarylCl-6alkyl, wherein each of these moieties may be optionally substituted; -63- RECEIVED TIME 23. NOV. 16:51 PRINT TIME 23. NOV. 17 06 Resend/3-11-01; 4:42PM;DAVIES COLLISON CAVE FutScr u I I PAu s t S e c u r e f a x 71/ 83 R 2 2 is an oio~nally substituted C I 10 alkyl; tais sty!. atYIC 1 .6alyl, heterocyclic, heteracyclylc 1 6 alkyl, heteroaryl heteroAtyC I--akYl, wherein each of these moieties may be optionally substituted; Rab is hydrogen, C 1.6 alkYl, C3-7 cycloalkyl, aiyl, aryCIA4 alkyl, heteroaryi, heroarylC 1-akyl, heterocyclyl, Or heterocyrlYlC 1 4 alk, wherein each of these moieties may be optionally substituted; IR3 is heterocyclyl, heterocyclyCIC- Io mikyl or RS is hydrogen C 1- 4 alkyl, C2-4 alkenyl, C2. alkynyl or NR7RI 7, excluding the moieties SRS being SNRL7Rl7 and SORs being SOH- R6 is hydrogen, a pharmaceutically acceptable Cation, CI-10i alkyl, C3-.7 cycloakyl, aryl. arylC 1- alkyl, heteroaryl, hctcroaryl1jak heterocyclyl, aroy], or C I1_10 alkanoyl; R7 and R)17 is each independently selected from hydrogen or C 1- alkyl or R7 and R1 7 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, sulfu~r or NR IS; Ra is Ci.io alkyl, halo-substituted CI..io alkyl, C2-10o aikewiYl, C2- 1 0 allcynyL C 3 7 cYrcloalklA C5-.7 cycloalkenyl, aryl, arylCI..i0 alkyL, heteroaryl, haterioarylCl..o alkyl. (CRIOR2O) 12 0RI L (CR1oR2o)nS(O)rnRl8, (CRloR2o)nNHS()Rls, (C~i0R20)nNRl3RI4, wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl *.may be optionally substituted, X9 is hydrogen, C(Z)R 1 or optionally substituted C1..lo alkyl, S(0)2R 1 9, optionally substituted aryl or optionally substituted azyl-C 1-4 alkyl; RI. o:n R20 is each independently selected from hydrogen or C~ 1.4 aikyl, RI I is hydrogen, CI-10 ailcYl, C3.7 cycloalkyl, heterocyclyl, heterocyclyl Cl-i oalkyl, aryl, avyiC 1 -10 alkyl, hetei-oaryl or heteroaryiC 1 -10 alkl wherein these moieties may be optionally substituted, Rl 2 is hydrogen or RI 6; R13 and Rl 4 is each independently selected from hydrogen or optionally substituted C 1 4 alkyl, optionally substituted aryl or optionally substituted aryl-CI-4 allcyl, or together with the nitrogen which they arc attached form a hetcrocyclic ring of to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfu~r or NR9; :R5 is Rio or C(Z)-C 1- alkyl; RECEIVED TIME' 23. NOV. 16:51 PRINT TIME 23. NOV. 17:0 6 Resend'43-11-O1; 4:42PM;DAVIES COLLISON CAVE A IPutSur fx I IPAus t Secure fax 72/ 83 R 1 6 is C 1-4 alkyl, halo-substituted..C 1- alkyl, or C3-.7 cycloalkyl; IR1 is CI-10o aikyl. C3-.7 cyCloalkyl. heterocylw aryL. aryli-ioafcyl, haterocyclyj, heterocyclyl-C I I 0aikyL 'heteroaryl or heteroazyJ 1 -1 0lkyl; or a pharmasceutically acceptable sak thereof

2. The Compound acoording to Claim 1 wherein RI is a substituted 4-pyridyl or

4-pyriinindyl. 3. The compound according to Claim 2 wherein the Ra moiety is optionally substituted aryl. or atylalcyl. 4. The compound according to Claim I wherein the R. Moiety is substitued one or more times with halogen; Cl- ailkyl; halosubstituted afty); hydroxy; hydroxy substituted CI- 4 alky; (CR- 1 0 R. 20 )q cl-4 ulkoxcy; (CRIOR 2 0 )q S(O)malkyl; (CRjoR2 0 )qS(O)m aryl, (CPRIoR.2)qC(O)oR 1 1; (CR. 1 oRCo qC(OJR Ij; (CR- 1 FR 2 0 )qOC(O)RkC, (CR 1 oR 2 0 )NR 3 R 1 4; (CR 1 oR~o)qjN(R1o)C(O)Rb; (CR1OR 2 o)qC(O)NR 1 3R14; (CR 1 OR2 0 )qC(O)NR 1 oRe; (C 1 R 2 0 )qS(O) 2 NRl 3Rl4. (CR 1 0R'20)qS(O) 2 NRI oRe, (CRI OR2ij)qN(- O)S(O) 2 Rc, cyano, nitro, N-hcteocyrlyl ring which rin~g has from 5 to 7 members and optionally contains an additional hcteroatom selected from oXygen, SUlfUr or NR IS; axyl; arylalkyl, ayloxy; or arylalkyloxy; and wheruin the aryl, alkcylalyl, azyloxy and azylalkyoxy may be optionally substituted themselves one to two tines by halogen; hydroxy; hydroxy substituted alkyl; C I -10 akOXcy; S(O)m alkyl; amino. NR7R 1-7 group; C 1 4 alkyl, or lialosubstituted C 1 -4 alky q is0Of or2n integer having a value of I to 4; Rb is hydrosen,, C1-.6 alkyl, C3-7 cycloalkyl, aryl, hzylCI.4 alkyl, heteroaryl, heteroarylCl..4alkyl. heterocyclyl, or a heterocyclylCl..4 alkcyl moiety; and Rc is C 1.-6 ai, C3 -7 cycloalkyl, ary). arylC 1 4 alkyl, hateroaryl, hctcroarylC I -alkyl, heterocyclyl, or a heterocyclyiC 1.-4 alkyl moiety, -wherein all of these moieties may be optionally substituted- The compound according to Claimn4 wherein the substituent group on thc Ra moicty is halogen, halosubstituted alkyl, hydroxy, cyano, alkyl. aryl, alkoxry, RECEIVED TIME 23. NOV. 16:5 1 PRINT TIME 23. NOV, 17:0 6 Resend23-11-01; 4:42PMDAVIES COLLISON CAVE IPAu,,t Secure fax 73/ 83 arYlaXY, arylalkYloXcy, a&ikylthio, aikcylsulfonyl, azninocarbonyl, acetamido, propionarnido. rncthylenedioxy, tetrazole, methyltetrazolyl.

6. The compound according to Claim 2 wherein R4 is an optionally substituted pheziyl.

7. The compound according to Claim 6 wherein the Phenyl is SubStitUted one or moire times independently by halogen, SRS, S(O)RS, OR 12. halo-subsitUted.C 1 &Ukyl, OF C 1- a1Jl- a. The compound according to any one of Claims I to?7 whercin A is an optionally substituted aryl, heteroaryl or heteoryclic ring.

9. The compound according to any one of Clams i to 7 wherein A is a substituted C 1 10 aLkyl. The compound according to Claim 9 wherein A is a hydroxy mibgtituted C 1 10 allkyl. The compound according to Claim I wherein R22 is a C 1 10 alky or a hydroxy substituted C 1 I.- 10 alkyl.

12. The compound according to Claim I which is: 1-(4-N-MorpholinyI-2-but-yl).<4-flurophcnyl)-5-(2.phenoxpyriajdiny.q. yl)imidazole 1 l-Hydroxprop-2-yl)4(4luorophenyl)S.(-(4-4luorophnoxy)pyriniin.4. ylimidazole ,3-Diydroxyprop--y)-4-(4-fluorophenyl)-5-[2-(4-fluoropherxoxy)pyrjrnidjn.4- yl]imnidazole I -(I-Hydroxprop--y)-4(4fluorophelyt)-s.{2..phenoxypyrindn4.yl)irrgdaz 0 1 3S 1 hnxpo--l-4(-loohnl-S(-hnxprmdi--Iirdz 1 ydroxy.3phenypro p..2..y4-4-l)4{4feluero(pheI..s.(py~r..n- yI)imnidazolc 1 -Hydroxybut-2-y)-4-(4-fluorophenyl)-S-(2 -phenoxypyrimidin-4-yi)irnidazole 1 l3-Dihydroxyprop-.2-y)-4-(4-4uoropherlyl). 5-(2-phenoxypyrimidin4-y)imnidazole 1 -T-ydroxy-2-phenylcth.2..yli.4.(4-fluofopheny).5-. (2-phenoxypyrirniidin.4. yI)imnidazole RECEIVED TIME 23. NOV. 16:51PRN TIE 2.OV 7C PRINT TIME 23,NOV. 17:06 Resend23-11-O1; 4:42PM;DAVIES COLLISON CAVE I I A s S e cu re f ax 74/ 83 s 1-(1 14ydroxyprop-2-yl)-4-(4-fluarapheny yl]imidazole 1 -4-chlorophe)oxy-pyrin-eyd)n-4. yl]imidazole 1-(l -Hyydroxyprop-2-yl)-4-(4-fluorophnyl)-5 -[2-(4-mcthylponoxy)pyriidin-4- ylimidazole 1-(1 -Hdroxybut-2-yi)-4--(4-fluorophnyl)-S-[2-(4-methylphcnxy)pyritnidin-4 yl]imidazol I-(1,3-DI yd roxypr--l)4-(4fuorophen yl]imidazole; or a pharamnceutically acceptable salt thereof

13. A pharmaceutical composition comprising an effective amount of a compound according to Claim I and a pharmaceutically acceptable carrier or diluent.

14. A method of treating inflammation in a mammal in need thereog which comprises administering to said mammal an efcti v amount of a compound of Formula according to Claim 1. A method of trating a CSBP/RK/p3 8 Idnase mediated disease in a mammal in :25 need thereof, which method comprises administering to said mammal an effective amount of a compound of Formula according to Claim 1.

16. The method according to Claim 15 wherein the CSBP/RK/p38 kinase mediated disease is psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis and acute syrovitis, rheumatoikd-a iditj, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic condition, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, Alzheineres disease, stroke, neurotrauma, asthma, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, 97 RECEIVED TIME 23. NOV. 16 5 1 PRINT TIME 23. NOV. 17 0 6 Resend23-11-D1; 4:42PM;DAVIES COLLISON CAVE euefx#7/8 A IPAust Seclire fax 75/ 83 pulmonary sarcososis, bone resorption disease, osteoporosis, restenosis, stroke. caLrdiac and renal reperftasion injury, chronic renial failure, congestive heart failure, angiogenic diseases, thrombosis, giomerulanepbritis, diabetes, graft vs. host reaction, allograIt rejection, inflammatory bowel disease, Crohn's disease, ulcrative colitis, multiple sclerosis, muscle degeneration, eczema, contact dermititis, psoriasis, sunburn, or conajunctivitis.

17. A process fbr preparing a compound of Forrula as defined in Claim 1 which comprises reacting a compound of the Formula (11) with a compound of the Formula (MI): 20 wherein p is 0 or 2; and a base strong eno ugh to deprotonate the isonitri~e moiety of Formula and R I, R 2 and R 4 anc as defincd in Claim 1 or are precursors of the groups Rl, R 2 and R 4 and Ar is an optionally substituted phcnyl group, and thereafter if necessaxy, converting a precursor of R 1 R 2 and R4~ to a group R 1 R 2 andR4

18. The process according to Claim 17 wherein p-0-

19- The proccss according to Claim 17 wherein pp; 2 z0. The process according to Claim 19 wherein the base is an arnine a carbonate, a hydride, or an alkyld or aryl lithium reagent.

21. The process according to Claim 19 wherein the irnine of Formula is isolated prior to reaction with Formula (II). 68 RECEIVED TIME 23. NOV. 16:51 ITTME 2.OV 17C PRINT TIME 23, NOV. 17 0 6 Resend23-11-01; 4:42PM;DAVIES COLLISON CAVE A IPAust Secure fax 76/ 83

22. The process according to Claim 19 wherein the imine of Formula (111), is formed in situ prior to reaction with Formula (11).

23. The process according to Claim 22 wherein the inine is formed in situ by reacting an aldehyde of the formula RICHO, wherein RT is as defined for Formula with a primary amine of the formula R2NH2, wherein R 2 is as defined for Formula

24. The process according to Claim 23 wherein formation of the imine in situ utilizes dehydrating conditions. The process according to Claim 23 or 24 wherein the st Ivent is N,N- dirnethylformamide (DMF), a halogenated solvent, tetrahydrofuran (THP), dimethylsulfoxide (DMSO), an alcohol, benzene, toluene, MeCN, or DME.

26. The process according to Claim 23 wherein the aldehyde RICHO is a pyrimidine aldehyde of the formula: X CHO X wherein X is YRa, and Xl is hydrogen, or is an optional substituent group on the RI moiety in Formula according to Claim 1, to yield a compound of Formula or a 25 pharmaceutically acceptable salt thereof.

27. The process according to Claim 24 wherein the aldehyde RICHO is a pyridine aldehyde of the formula: 30 wherein X is YRa, and X1 is hydrogen, or is an optional substituent group on the RI moiety in Formula according to Claim 1, to yield a compound of Formula or a pharmaceutically acceptable salt thereof

69- RECEIVED TIME 23, NOV. 16:51 PRINT TIME 23. NOV. 17:06 Resend23-11-01; 4:42PM;DAVIES COLLISON CAVE A PutScr a A I PAust Secure fax 77/ 83 28. The process according to Claim 27 wherein the compound is: 1-4NMrhlnl2bty)4(-loohnl--2peoyyiiiy4 yl)imidazole; yllirn-Ldazole 1-(I 3 Dhydrorox-yrop42- 1)4.(orropheny1)S( 2 4 fluoophe o).dn4 yliridazole I -Phenoxyprop2 y1)-4-florohenl)oro2phenoyr(2Phn-4iil)iidzle yl )imidazole 1 3 -Dihydroxyprop-2y)(4 .for ophenyl)5( 2 phnoxpeniidinj4 yI)imidazole I-Hydroxy-2-phenyleh2y).4.(4fluorophenyI)- 5 2 -phenoxypyrimdin-.- yI)iinidazole y1]imidazole I -Hdoyu--i--4fumhnl--2(-hoohnx~yidn4 yljirnidazole 1 -yrxpo--l--4furpey)--2(-ntypeoyprmdn4 yl]imidazole l-IHydroxybt-2y)-4fumnl--2-y1).(4luophen1 l52(enetyyih)di-4 yljimidazole 4 -yl]irtnidazole or a pharamaceutically acceptable salt thereof. 999*99 RE EI E TI E 2 .NV96 5 T TM 3 O 17 0 Resend23-11-O1; 4:42PM;DAVIES COLLISON CAVE I~s euefx#7/8 A I PAu s t S e c u r e f a x 7 8 1.13 29. A compound, or pharmaceutically acceptable salt thereof, which is: N R1 0 N N R1 methyl ethyl iSOprOpylI 2-(methvl) ropy) phentyl benzyl phenethyl methyl isopropyl 2-(rnethyl)propyl phenyl benzyl, phenethyl R2 hydroxyinethyl hydroxyrnethyl hydroxymethyl hydroxymethyl hydroxymethyl hydroxymethyl dirnethylaminomethyl diehlarinomehy diehJlanomethyl dimehlar-noejy dime thylaminonezbyJ dimethylaminomethyl a. a. a a a *aa.a. a a. a. a a. a. dimethylarminomethyi carboxy carboxy carboxy carboxy carboxy carboxy carboxy -CONH 2 methyl methyl methyl -CONHMe -CONMe 2 -71 RECEIVED TIME 23.NOV. 16:51 RECEVED IME 3. NV. 1:~1PRINT TIME 23. NOV. 17:05 Resend23-11-Q1; 4:42PM;DAVIES COLLISON CAVE A FPAust Secure fax 79/ 83 A compound, or pharmaceutically acceptable salt thereof, which is: Ni I \R2 K-j N 'neIh/) methyl bezyoxymnethyi methyl Craylehyl mnethyl anyoxmethy methylc' oy methyl atahyl methy inethvI N-(bniylorniethyl methyl acernxtlamiomethvi methyl benzamidomethyl mehy zethanesulfonaridomethyl "h~l benzenesulfonamidoinethyI methyl phenyl ethylsulfonarnidornethyl mehy N-ethylureidomethyl methy I CH2OCH2C2H2Ph methy1 -CONIIPh methyl -CONHBn methyl CH2OCH2(4-MePh) *methyl -CH2OCH2(4-FPh) mnethyl -CH2OCH2(4..ClPh) methy -CH2OCH2(3-ClPh) *methyI -CH20(4-MePh) methyl -CH20(4-FPh) me.h. -CH2O(4-CIPh)

72- RECEIVED TIME 23. NOV. 16:51 PRINT TIME 23. NOV. 17:05 Resend23-11-Q1; 4:42PM;DAVIES COLLISON CAVE I IPAuc t S ec u re f ax -CH20(3-ClPh) 80/ 83 methyl ethyl ethll ethyl ethyl ethyl ethyl ethyl -CQNR 2 ethyl ethyl, ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethyl ethvI ethyl ethyl -CONHMe CONWe 2 rnethox rnethyI Rhenoxymethyl benzyloxymethyl carbamoylmethyl carbamoyImeth I aminomethyl N-(methjyI)aminomethyl Y-(dimethyI)anhnomethyl N-(benzyl )arninomethyl acetamidomethyl bexzamidornethyl metbmesulfonamidomethyl benzenesulfonamhLdomethyI phenylxnehylsufonarjdomethvl IV'tylureidonethyl AP phenlureidomeEhyl a a. a a a a. -CH2OCH2CH2Ph -CONHPh -CONI]Bn -CH2OCH-2(4-MePh) -CH2OCH2(4-FPh) -CH2OCH2(4-ClPh) -CH2OCH2(3-ClPh) -CH2Q(4-MePh) -CH20(4-FPh) -CH2O(4-ClPh) -CH2O(3-CIPh) 73 RECEIVED TIME 23. NOV. 16:51 RN IE 2.NV 7D PRINT TIME 23, NOV. 17 0 Resend23-11-O1; 4:42PM;DAVIES COLLISON CAVE A IPA ust S e cu re f ax; 8 1/ 83 31. A pharmaceutical composition comprising a compound according to Claim 29 or 30, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent. 32. A method of treating a CSBP/RK/p38 kinase mediated disease in a mammnal in need thereof, which method comprises administering to said mammal an effective amount of a compound according to Claim 29 or 33. The method according to claim 32 wherein the CSBP/R.K/p38 kinase mediated disease is psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis. gout. traumatic arthritis, rubella arthritis and acute synovitis, rheumatoid-arthfitid, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic condition, sepsis, septic shock, endocoxic shock, gram negative sepsis. toxic shock syndrome, Alzheimer's disease, stroke, neurotraurna, asthma, adult respiratory distress syndrome, cerebral malaria, chronic pulmnonary inflammatory disease, silicosis, pulmonary sarcososis, bone resorption disease, osteoporosis, restenosis, stroke, cardiac and renal reperfusion injury, chronic renal failure, con gestive heart failure, angiogenic diseases, thrombosis, glomnerulrrnephritis, diabetes, graft vs. host reaction, allograft rejection, inflammatory bowel disease, Crohn's disease, ulcerative colitis, multiple sclerosis, muscle degeneration, eczema. contact dermititis, psoriasis, sunburn, or conjunctivitis. The process according to Claim 17 wherein the compound of formula is defined in Claim 29 or a. a.- RECEIVED TIME 23. NOV. 16:51 PRINT TIME 23. NOV. 17:05 Resend23-11-01; 4:42PM;DAVIES COLLISON CAVE A I PAu st S e cu re fa x; 82/ 83 P.O II7167di 3/1 1/01 75 1 3 -dihydroxyprop-2-yl)-4-(4-fluorophenyl)-5-(2-phenoxypyrimidin-4. yl)imidazole or a pharmaceutically acceptable salt thereof. 36. A method of preparing l-(l 3 -dihydroxyprop-2-yl)-4-(4-fluorophenyl)-5(2. phenoxypyrimidin-4-yl)imidazole or a pharmaceutically acceptable salt thereof comprising methods generically disclosed herein, but where the reactants and conditions are selected to provide said compound or salt. 37. A method according to claim 36, substantially as hereinbefore described with reference to the Examples. DATED this 23rd day of November, 2001 SmithKline Beecham Corporation By DAVIES COLLISON CAVE Patent Attorneys for the Applicants 0* 4 4* 4 *4 .4 4 4. 4 4 *44* 4 *44* 4**4*4 4 0 *444*4 4. 4* C 4 44 4 4. 44 RECEIVED TIME 23. NOV. 16:51 PRINT TIME 23. NOV. 17 0