AU747427B2 - Novel angiogenesis inhibitors - Google Patents

Description

WO 00/02871 PCT/US99/15200 TITLE OF THE INVENTION NOVEL ANGIOGENESIS INHIBITORS BACKGROUND OF THE INVENTION The present invention relates to compounds which inhibit tyrosine kinase enzymes, compositions which contain tyrosine kinase inhibiting compounds and methods of using tyrosine kinase inhibitors to treat tyrosine kinase-dependent diseases/conditions such as neoangiogenesis, cancer, tumor growth, atherosclerosis, age related macular degeneration, diabetic retinopathy or inflammatory diseases, in mammals.

Tyrosine kinases are a class of enzymes that catalyze the transfer of the terminal phosphate of adenosine triphosphate to tyrosine residues in protein substrates. Tyrosine kinases are believed, by way of substrate phosphorylation, to play critical roles in signal transduction for a number of cell functions. Though the exact mechanisms of signal transduction is still unclear, tyrosine kinases have been shown to be important contributing factors in cell proliferation, carcinogenesis and cell differentiation.

Solid tumors which are treated by the present invention are cancers such as cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung. These include histiocytic lymphoma, lung adenocarcinoma and small cell lung cancers. Additional examples include cancers in which overexpression or activation of Raf-activating oncogenes Kras, erb-B) is observed. More particularly, such cancers include pancreatic and breast carcinoma.

Accordingly, inhibitors of these tyrosine kinases are useful for the prevention and treatment of proliferative diseases dependent on these enzymes.

-1- WO 00/02871 PCT/US99/15200 For example, a method of treatment described herein relates to neoangiogenesis. Neoangiogenesis occurs in conjunction with tumor growth and in certain diseases of the eye.

It is characterized by excessive activity of vascular endothelial growth factor.

Vascular endothelial growth factor (VEGF) binds the high affinity membrane-spanning tyrosine kinase receptors KDR and Flt-1. Cell culture and gene knockout experiments indicate that each receptor contributes to different aspects of angiogenesis.

KDR mediates the mitogenic function of VEGF whereas Fit-1 appears to modulate non-mitogenic functions such as those associated with cellular adhesion. Inhibiting KDR thus modulates the level of mitogenic VEGF activity.

Vascular growth in the retina leads to visual degeneration culminating in blindness. VEGF accounts for most of the angiogenic activity produced in or near the retina in diabetic retinopathy. Ocular VEGF mRNA and protein are elevated by conditions such as retinal vein occlusion in primates and decreased pO2 levels in mice that lead to neovascularization.

Intraocular injections of anti-VEGF monoclonal antibodies or VEGF receptor immunofusions inhibit ocular neovascularization in both primate and rodent models. Regardless of the cause of induction of VEGF in human diabetic retinopathy, inhibition of ocular VEGF is useful in treating the disease.

Expression of VEGF is also significantly increased in hypoxic regions of animal and human tumors adjacent to areas of necrosis. VEGF is also upregulated by the expression of the oncogenes ras, raf, src and mutant p53 (all of which are relevant to targeting cancer). Monoclonal anti-VEGF antibodies inhibit the growth of human tumors in nude mice. Although these same -2tumour cells continue to express VEGF in culture, the antibodies do not diminish their mitotic rate. Thus tumour-derived VEGF does not function as an autocrine mitogenic factor. Therefore, VEGF contributes to tumour growth in vivo by promoting angiogenesis through its paracrine vascular endothelial cell chemotactic and mitogenic activities.

These monoclonal antibodies also inhibit the growth of typically less well vascularised human colon cancers in athymic mice and decrease the number of tumours arising from inoculated cells. Viral expression of a VEGF-binding construct of Flk-1, Flt-1 the mouse KDR receptor homologue, truncated to eliminate the cytoplasmic tyrosine kinase domains but retaining a membrane anchor, virtually abolishes the growth of a transplantable glioblastoma in mice presumably by the dominant negative mechanism of heterodimer formation with membrane spanning endothelial cell VEGF receptors. Embryonic stem cells, which normally grow as solid tumours in nude mice, do not produce detectable tumours if both VEGF alleles are knocked out. Taken together, these data indicate the role of VEGF in the growth of solid tumours. Inhibition of KDR or Flt-1 is implicated in is pathological neoangiogenesis, and these receptors are useful in the treatment of diseases S*in which neoangiogenesis is part of the overall pathology, inflammation, diabetic o. retinal vascularisation, as well as various forms of cancer. The compounds of the instant invention represent novel structures for the inhibition of KDR kinase.

Summary of the Invention 20 The first aspect of the invention is a compound in accordance with formula I: *R 3 R N

X

04 R1

I

or a pharmaceutically acceptable salt, hydrate or prodrug thereof, wherein X is O or S; R' is methyl or CF 3

R

2 is H, C1- 6 alkyl, C 5 1 0 aryl, C5- 1 0 heteroaryl, C3-6 cycloalkyl; said alkyl, aryl, heteroaryl or cycloalkyl being optionally substituted with from one to three members selected from Ra; or R' and R 2 are connected to form a 5-membered lactam; [I:\DAYLB\libh]00792.doc:sak

R

3 is C1- 6 alkyl, C5- 1 0 aryl, Cs-lo heteroaryl, C3- 6 cycloalkyl; said alkyl, aryl, heteroaryl or cycloalkyl being optionally substituted with one to three members selected from Ra;

R

4 is H, C-o 1 0 alkyl, C3- 6 cycloalkyl, C1- 6 alkoxy, C2- 1 0 alkenyl, C2-10 alkynyl, aryl, C3- 1 0 heterocyclyl, C 16 alkoxyNR 7

R

8

NO

2 OH, -NH 2 or C5- 1 0 heteroaryl, said alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with one to three members selected from Ra; Ra is H, CI-lo alkyl, halogen CF 3

NO

2 NHC(O)R*, OR, NR 7 R, C5- 10 aryl, C5- 1 0 aralkyl, C5- 1 0 heteroaryl or C3- 1 0 heterocyclyl, said aralkyl, aryl and heteroaryl optionally being substituted with one or two groups of NO 2 halo, C5-10 aryl, C1- 6 alkoxy, C1- 6 alkyl or CF 3 R* is H, or C1- 6 alkyl, NHC(O)CHR(C5-lo araklyl), wherein the aryl ring of the V aralkyl may be optionally substituted with one, two or three groups selected from OH, C1- 6 alkyl, or halo, S° 15 R is H, or C 1 -6 alkyl; and e* R 7

R

8 are independently selected from H, C-o 1 0 alkyl, C3- 6 cycloalkyl, COR, COOR, C5- 1 0 aryl, C3- 1 0 heterocyclyl, or C5- 10 heteroaryl or NR 7

R

8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated ring containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group 20 consisting of N, 0 and S.

The second aspect of the invention is a pharmaceutical composition including or consisting of an effective amount of at least one compound in accordance with the first aspect, together with a pharmaceutically acceptable carrier, diluent or adjuvant therefor.

s" The third aspect of the invention is a method for treating cancer in a mammal requiring said treatment, which method includes or consists of administering to said mammal an effective amount of at least one compound in accordance with the first or second aspect.

The fourth aspect of the invention is a method for the treatment of disease in which neoangiogenesis is implicated in a mammal requiring said treatment, which method includes or consists of administering to said mammal an effective amount of at least one compound in accordance with the first or second aspect.

The fifth aspect of the invention is a method for the treatment of retinal vascularisation in a mammal requiring said treatment, which method includes or consists RA, of administering to said mammal an effective amount of at least one compound in 5 accordance with the first aspect.

)accordance with the first aspect.

[1:\DAYLIB\Iibh]00792.doc:sak The sixth aspect of the invention is a method for the treatment of diabetic retinopathy in a mammal requiring said treatment, which method includes or consists of administering to said mammal an effective amount of at least one compound in accordance with the first or second aspect.

The seventh aspect of the invention is a method for the treatment of age related macular degeneration in a mammal requiring said treatment, which method includes or consists of administering to said mammal an effective amount of at least one compound in accordance with the first aspect.

The eighth aspect of the invention is a method for the treatment of inflammatory disease in a mammal requiring said treatment, which method includes or consists of administering to said mammal an effective amount of at least one compound in accordance with the first or second aspect.

The ninth aspect of the invention is a method for the treatment of inhibiting tyrosine kinase in a mammal requiring said treatment, which method includes or consists of 15 administering to said mammal an effective amount of at least one compound in accordance with the first or second aspect.

The tenth aspect of the invention is a method for the prophylaxis of cancer in a mammal requiring said treatment, which method includes or consists of administering to said mammal an effective amount of at least one compound in accordance with the first or 20 second aspect.

The eleventh aspect of the invention is a method for the prophylaxis of disease in which neoangiogenesis is implicated in a mammal requiring said prophylaxis, which method includes or consists of administering to said mammal an effective amount of at least one compound in accordance with the first or second aspect.

The twelfth aspect of the invention is a method for the prophylaxis of retinal vascularisation in a mammal requiring said prophylaxis, which method includes or consists of administering to said mammal an effective amount of at least one compound in accordance with the first or second aspect.

The thirteenth aspect of the invention is a method for the prophylaxis of diabetic retinopathy in a mammal requiring said prophylaxis, which method includes or consists of administering to said mammal an effective amount of at least one compound in accordance with the first or second aspect.

The fourteenth aspect of the invention is a method for the prophylaxis of age related Rmacular degeneration in a mammal requiring said prophylaxis, which method includes or [I:\DAYLIB\libh]00792.doc:sak consists of administering to said mammal an effective amount of at least one compound in accordance with the first or second aspect.

The fifteenth aspect of the invention is. a method for the prophylaxis of inflammatory diseases in a mammal requiring said prophylaxis, which method includes or consists of administering to said mammal an effective amount of at least one compound in accordance with the first or second aspect.

The sixteenth aspect of the invention is the use of a compound in accordance with the first aspect, in the manufacture of a medicament for treating or preventing cancer.

The seventeenth aspect of the invention is a use of a compound in accordance with the first aspect in the manufacture of a medicament for treating or preventing a disease in which neoangiogenesis is implicated.

The eighteenth aspect of the invention is the use of a compound in accordance with the first aspect in the manufacture of a medicament for treating or preventing retinal Svascularisation.

The ninteenth aspect of the invention is the use of a compound in accordance with the first aspect in the manufacture of a medicament for treating or preventing diabetic retinopathy.

The twentieth aspect of the invention is the use of a compound in accordance with the first aspect in the manufacture of a medicament for treating or preventing age related macular degeneration.

The twenty-first aspect of the invention is the use of a compound in accordance the first aspect in the manufacture of a medicament for treating or preventing inflammatory diseases.

The twenty-second aspect of the invention is the use of a compound in accordance 9 with the first aspect for inhibiting tyrosine kinase.

The twenty-third aspect of the invention is a compound in accordance with the first aspect when used to treat or prevent cancer.

The twenty-fourth aspect of the invention is a compound in accordance with the first aspect when used to treat or prevent a disease in which neoangiogenesis is implicated.

The twenty-sixth aspect of the invention is a compound in accordance with the first aspect when used to treat or prevent retinal vascularisation.

The twenty-seventh aspect of the invention is a compound in accordance with the first aspect when used to treat or prevent diabetic retinopathy.

SThe twenty-eighth aspect of the invention is a compound in accordance with the rst aspect when used to treat or prevent age related macular degeneration.

[I:\DAYLIB\fibh]00792.doc:sak The twenty-ninth aspect of the invention is a compound in accordance with the first aspect when used to treat or prevent inflammatory diseases.

The thirtieth aspect of the invention is a compound in accordance with the first aspect when used to inhibit tyrosine kinase.

These and other aspects of the invention will be apparent from the teachings contained herein.

Detailed Description of the Invention The invention is described herein in detail using the terms defined below unless otherwise specified.

The term "alkyl" refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 10 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cycloheptyl, cyclopentyl and cyclohexyl.

0 [I:\DAYLB\ibh]00792.doc:sak WO 00/02871 PCT/US99/15200 When substituted alkyl is present, this refers to a straight, branched or cyclic alkyl group as defined above, substituted with 1-3 groups of R a described herein.

The term "alkenyl" refers to a non-aromatic hydrocarbon radical, straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond.

Preferably one carbon to carbon double bond is present, and up to four non-aromatic carbon-carbon double bonds may be present.

Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted with one to three groups of R a when a substituted alkenyl group is provided.

The term "alkynyl" refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond. Up to three carboncarbon triple bonds may be present. Preferred alkynyl groups include ethynyl, propynyl and butynyl. As described above with respect to alkyl, the straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted with 1-3 groups of R a when a substituted alkynyl group is provided.

Aryl refers to 5-10 membered aromatic rings e.g., phenyl, substituted phenyl and like groups as well bicyclic rings such as naphthyl. Aryl thus contains at least one ring having at least 5 atoms, with up to two such rings being present, containing up to 10 atoms therein. The preferred aryl groups are phenyl and naphthyl. Aryl groups may likewise be substituted with 1-3 groups ofRa as defined herein. Preferred substituted aryls include phenyl and naphthyl substituted with one or two groups.

8- WO 00/02871 PCT/US99/15200 As used herein, "aralkyl" is intended to mean an aryl or heteroaryl moiety, as defined herein, attached through a C1-6 alkyl linker, where alkyl is defined above. Examples of aralkyls include, but are not limited to, benzyl, naphthylmethyl, phenylpropyl, 2-pyridylmethyl, 2-imidazolylethyl, 2quinolinylmethy, 2-imidazolylmethyl and the like.

The term heterocycle, heteroaryl or heterocyclic, as used herein except where noted, represents a stable 5- to 7membered mono- or 7- to 10-membered bicyclic heterocyclic ring system, any ring of which may be saturated or unsaturated, aromatic or non-aromatic, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O and S. The nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Heterocycles include any bicyclic group in which any of the above-defined rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. The heterocycle, heteroaryl or heterocyclic may be substituted with 1-3 groups of R a Examples of such heterocyclic elements include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thiophenyl, imidazopyridinyl, tetrazolyl, -9- WO 00/02871 PCT/US99/15200 triazinyl, thienyl, benzothienyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl.

The term "alkoxy" refers to a substituent with an alkyl group of the designated length in either a straight or branched configuration, and may include a double or a triple bond, which is attached via an oxygen molecule. Examples of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy allyloxy, propargyloxy, vinyloxy and the like.

The term "halo" or "halogen" is intended to include the halogen atoms fluorine, chlorine, bromine and iodine.

Tyrosine kinase dependent diseases or conditions refers to hyperproliferative disorders which are initiated/maintained by aberrant expression of the activating ligands VEGF) of the tyrosine kinases. Examples include psoriasis, cancer, immunoregulation (graft rejection), atherosclerosis, rheumatoid arthritis, angiogenesis tumor growth, diabetic retinopathy), age related macular degeneration, etc.

One aspect of the invention is realized when X is O and all other variables are as originally described.

Another aspect of the invention is realized when X is S and all other variables are as originally described.

Still another aspect of the invention is realized when

R

3 and R 4 independently, are C 5 1 0 aryl or C 5 1 0 heteroaryl optionally substituted with 1-3 groups of R a Yet another aspect of the invention is realized when:

R

1 is H, C1- 1 0 alkyl, C 5 10 aryl, halo, CF3, or C5- 1 0 heteroaryl; said alkyl, aryl, and heteroaryl being optionally substituted with from one to three members selected from Ra; I 2 s 1, CI6 akylor C5-10 aryl, sadalk .yl or aryl ptionaiiy substituted with one to three members selected from R a; O&R are independently CI-1iO alkyl, C 5 10 aryl, orC51 heteroaryl, said alkyl, aryl and heteroaryl being optionally substituted with from one to three :::members selected from Ra;and all other variables are as described above.

Examples of the compounds of this invention are: 2.(2-(3-hydroxy)napthyl)4-pheny-5-trifluoroacetamdooxazle; 2..(2-43.hydroxy)napthyl)-4-(3-tbiophenyl)-5-acetamidooxazole; 2..(2-(3-hydroxy)napthyl)-4-pheny-5-acetamifdooxazole; 2..(2.(3.hydroxy)napthyl)..4-(3-tbiophenyl)-5-trifluoroacetafludooxazole; hydroxy-4-methoxy)phenyl' 24(2-1 -hydroxy-4-niethyl)pheny] 9-hydroxy)phenyl 2-(5-isoquinolinyl)-4-phenyl-5-acetamidooxazole; 2..(2.(3..ydroxy)napthyl).4-(3-thiophelyl)-5aCetmidooxazole; 2..(2.(3.hydroxy)napthyl)-4-phenyl-5-acetamidooxazole; 2-(3-(5-phenyl)pyrzidyl)-4-phenyl-5--acetamiooxazole; 2 (8.(5(3.nitro)phenyl~pyridyl)-4-phenyl-5-acetamidooxazole; -11- 12 2-(3 -naphthyl)phenyl)pyridyl)-4-phenyl-5 -acetamidooxazole; -(4-methyl)phenyl)pyridyl)-4-phenyl-5-acetamidooxazole; -(4-methoxy)phenyl)pyridyl)-4-phenyl-5 -acetamidooxazole; 2-(3 2-(3 -methoxy)phenyl)pyridyl)-4-phenyl-5 -acetamidooxazole; 2-(3 -(3-fluoro)phenyl)pyridyl)-4-phenyl-5-acetamidooxazole; 2-(3 -(2-naphthyl)phenyl)pyridyl)-4-phenyl-5 -acetamidooxazole; -(2-trifluoromethyl)phenyl)pyridyl)-4-phenyl-5-acetamidooxazole; 2-(2-hydroxy)phenyl-4-phenyl-5-acetamidooxazole; 0 2-(2-hydroxy-4-phenyl)-phenyl-4-phenyl-5-acetamidooxazole; 2-(2-hydroxy-(4-(3 -nitro)-phenyl))-phenyl-4-phenyl-5 -acetamidooxazole; 2-(2-hydroxy-(4-( 1 2-(2-hydroxy-(4-(4 2-(2-hydroxy-(4-(4 2-(2-hydroxy-(4-(3 2-(2-hydroxy-(4-(3 2-(2-hydroxy-(4-(3 2-(2-hydroxy-(4-(2-naphthyl)-phenyl))-phenyl-4-phenyl-5-acetamidooxazole; 2-(2-hydroxy-(4-(2-trifluoromethyl) -phenyl))-phenyl-4-phenyl-5 -acetamidooxazole; 2-(2-hydroxy-4-phenyl)-phenyl-4-thiophenyl-5-acetamidooxazole; .*oy-4(-ir)-hnl)penl4tiphnl5aeamdoaoe 2-(2-hydroxy-(4-(3 2-(2-hydroxy-(4-( 1 2-(2-hydroxy'-(4-(4 252-(2-hydroxy'-(4-(4 '-mhlox)-phenyl))-phenyl-4-thiophenyl-5 -acetamidooxazole; 252-(2-hydroxy-(4-(3 2-(2-hydroxy-(4-(3 2-(2-hydroxy-(4-(3 2-(2-hydroxy-(4-(2-naphuomthyl)-phenyl))-phenyl-4-thiophenyl-5-acetamidooxazole; 2-(2-hydroxy-(4-2tilmeh)-phenyl))-phenyl-4-thiophenyl-5-acetamidooxazole; 302-(2-hydroxy-(4-3t-phenyl))-phenyl-4-(3 -pyridyl)-5 -acetamidooxazole; 2-(2-hydroxy-(4-3l-nt l)-phenyl))-phenyl-4-(3 2-(2-hydroxy-(4-( 1 -napthyl)-phenyl))-phenyl-4-(3 2-(2-hydroxy-(4-(4 '-methoy)-phenyl))-phenyl-4-(3 [1:\DAYLIB\libh]00792.doc:sak 13 2-(2-hydroxy-(4-3 '-chloro)-phenyl))-phenyl-4-(3-pyridyl)-5 -acetamnidooxazole; 2-(2-hydroxy-(4-3 '-methoxy)-phenyl))-phenyl-4-(3 -pyridyl)-5 -acetamidooxazole; 2-(2-hydroxy-(4-(3 '-fluoro)-phenyl))-phenyl-4-(3-pyridyl)-5 -acetamnidaooxazole; 2-(2-hydroxy-(4-(2-naphthyl)-phenyl))-phenyl-4(3 -pyridyl)-5 -acetamidooxazole; 2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl))-phenyl-4-(3-pyridyl)-5-acetamidooxazole; 2-(2-hydroxy-4-phenyl)-phenyl-4-(3 2-(2-hydroxy-(4-(3 -nitro)-phenyl))-phenyl-4-(3 2-(2-hydroxy-(4-( 1 -naphthyl)-phenyl))-phenyl-4-(3 2-(2-hydroxy-(4-(4 '-methyl)-phenyl))-phenyl-47(3 2-(2-hydroxy-(4-(4 '-methoxy)-phenyl))-phenyl-4-(3-chlorophenyl)-5 -acetamidooxazole; 2-(2-hydroxy-(4-(3 '-chloro)-phenyl))-phenyl-4-(3-chlorophenyl)-5-acetamidooxazole; 2-(2-hydroxy-(4-(3 '-methoxy)-phenyl))-phenyl-4-(3 2-(2-hydroxy-(4-(3 '-fluoro)-phenyl))-phenyl-4-(3 2-(2-hydroxy-(4-(2-naphthyl)-phenyl))-phenyl-4-(3 -chlorophenyl)-5 -acetamidooxazole; 15 2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl))-phenyl-4-(3-chlorophenyl)-5- 000 acetamidooxazole; .00. o. 2-(2-hydroxy-4-phenyl)-phenyl-4-(2-chlorophenyl)-5 -acetamidooxazole; o2-(2-hydroxy-(4-(3 -nitro)-phenyl))-phenyl-4-(2-chlorophenyl)-5-acetamidooxazole; 000. 2-(2-hydroxy-(4-(1-naphthyl)-phenyl))-phenyl-4-(2-chlorophenyl-5-acetamiooxazolo.

000.90 20 2-(2-hydroxy-(4-(4 '-methyl)-phenyl))-phenyl-4-(2-chlorophenyl)-5-acetamidooxazole; :0000.2-(2-hydroxy-(4-(4 '-methoxy)-phenyl))-phenyl-4-(2-chlorophenyl)-5-acetamidooxazole; 2-2hdoy(.30clr)-hnl)pey--2clrohnl--ctmdoaoe 0000. 2-(2-hydroxy-(4-(3 '-mhox)-phenyl))-phenyl-4-(2-chlorophenyl)-5-acetamidooxazole; 2-2hdoy(o3'fur)pey)-hny--2clrpey)5-ctmdoaoe 252-(2-hydroxy-(4-(2'-napthoy)-phenyl))-phenyl-4-(2-chlorophenyl)-5-acetamidooxazole; .000.. ~2-(2-hydroxy-(4-(2'-fluoromy)-phenyl))-phenyl-4-(2-chlorophenyl)-5-mdoaoe octmioxaoe 2-(2-hydroxy-(4-(-hh-phenyl))-phenyl-4-(-chlorophenyl)-5-acetamidooxazole; 2-(2-hydroxy-(4-(3 2(-yrx-4(1-ahhl-hnl)pey--4clrpey)5acetamidooxazole; 2-(2-hydroxy-(4(4'-yl-phenyl))-phenyl-4-(4-chlorophenyl)-5 -acetamidooxazole; 2-(2-hydroxy-(4-(4 '-mto)-phenyl))-phenyl-4-(4-chlorophenyl)-5 -acetamidooxazole; 2-(2-hydroxy-(4-(3 '-cahl)-phenyl))-phenyl-4-(4-chlorophenyl)-5-acetamidooxazole; ~RA~i~ 2-(2-hydroxy-(4-(3 '-methoy)-phenyl))-phenyl-4-(4-chlorophenyl)-5 -acetaidooxazole; 3,2-(2-hydroxy-(4-(3 '-fluoo)-phenyl))-phenyl-4-(4-chlorophenyl)-5-acetamidooxazole; [1:\DAYLIB\1ibh100792.doc:sak 14 2-(2-hydroxy-(4-(2-naphthyl)-phenyl))-pheny 1 -4-(4-chlorophenyl)-5 -acetamidooxazole; 2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl))-phenyl-4-(4-chlorophenyl)-5acetamidooxazole; 2-(2-hydroxy-4-phenyl)-phenyl-4-(4-trifluoromethylphenyl)-5-acetamidooxazole, 2-(2-hydroxy-(4-(3 -nitro)-phenyl))-phenyl-4-(4-trifluoromethylphenyl)-5 acetamidooxazole; 2-(2-hydroxy-(4-( 1 -naphthyl)-phenyl))-phenyl-4-(4-trifluoromethylphenyl)-5acetamidooxazole; 2-(2-hydroxy-(4-(4 '-methyl)-phenyl))-phenyl-4-(4-trifluoromethylphenyl)-5acetamidooxazole; 2-(2-hydroxy-(4-(4 '-methoxy)-phenyl))-phenyl-4-(4-trifluoromethylphenyl)-5acetamidooxazole; :2-(2-hydroxy-(4-(3 '-chloro)-phenyl))-phenyl-4-(4-trifluoromethylphenyl)-5acetamidooxazole; 15 2-(2-hydroxy-(4-(3 '-methoxy)-phenyl))-phenyl-4-(4-trifluoromethylphenyl)-5acetamidooxazole; 2-(2-hydroxy-(4-(3 '-fluoro)-phenyl))-phenyl-4-(4-trifluoromethylphenyl)-5- 2-(2-hydroxy-(4-(2-naphthyl)-phenyl))-phenyl-4.(4-trifluoromethylphenyl)-5- 20 acetamidooxazole; 2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl))-phenyl-4-(4-trifluoromethylphenyl)-5acetamidooxazole; 2-(2-hydroxy-4-phenyl)-phenyl-4-(3 2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(3 2-(2-hydroxy-(4-( 1-naphthyl)-phenyl))-phenyl-4-(3 -methoxyphenyl)-5 acetamidooxazole; 2-(2-hydroxy-(4-(4 '-methyl)-phenyl))-phenyl-4-(3-methoxyphenyl)-5-acetamidooxazole; 2-(2-hydroxy-. '-methoxy)-phenyl))-phenyl-4-(3-methoxyphenyl)-5acetamidooxazole; 2-(2-hydroxy-(4-(3 '-chloro)-phenyl))-phenyl-4-(3 2-(2-hydroxy-(4-(3 '-methoxy)-phenyl))-phenyl-4-(3 -methoxyphenyl)-5 acetamidooxazole; 2-(2-hydroxy-(4-(3 '-fluoro)-phenyl))-phenyl-4-(3 -methoxyphenyl)-5 -acetamidooxazole; pgA.Al-~ -(2-hydroxy-(4-(2-naphthyl)-phenyl))-phenyl-4-(3 -methoxyphenyl)-5 j etamidooxazole; [I:\DAYLIB\libh]00792.doc:sak 2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl))-phenyl-4-(3 acetamidooxazole; 2-(2-hydroxy-4-phenyl)-phenyl-4-(3-thiophenyl)-5 -acetamidooxazole; 2-(2-hydroxy-(4-(3 -nitro)-phenyl))-phenyl-4-(3 2-(2-hydroxy-(4-( 1 -naphthyl)-phenyl))-phenyl-4-(3 2-(2-hydroxy-(4-(4 '-methyl-phenyl))-phenyl-4-(3 2-(2-hydroxy-(4-(4 '-methoxy)-phenyl))-phenyl-4-(3 2-(2-hydroxy-(4-(3 '-chloro)-phenyl))-phenyl-4-(3-thiophenyl)-5-acetamidooxazole; 2-(2-hydroxy-(4-(3 '-methoxy)-phenyl))-phenyl-4-(3 -thiophenyl)-5 -acetamidooxazole; 2-(2-hydroxy-(4-(3 '-fluoro)-phenyl))-phenyl-4-(3 -thiophenyl)-5 -acetamidooxazole; 2-(2-hydroxy-(4-(2-naphthyl)-phenyl))-phenyl-4-(3 2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl))-phenyl-4-(3 :acetamidooxazole; 2-(2-hydroxy-4-phenyl )-phenyl-4-(2-thiophenyl)-5 -acetamidooxazole; 2-(2-hydroxy-(4-(3 -nitro)-phenyl))-phenyl-4-(2-thiophenyl)-5-acetamidooxazole; 2-(2-hydroxy-(4-( 1 -naphthyl)-phenyl))-phenyl-4-(2-thiophenyl)-5-acetamidooxazole; 2-(2-hydroxy-(4-(4 '-methyl)-phenyl))-phenyl-4-(2-thiophenyl)-5 -acetamnidooxazole; 2-(2-hydroxy-(4-(4 '-methoxy)-phenyl1))-phenyl-4-(2-thiophenyl)-5-acetamidooxazole; *doy(-3-clr)pey)-hny--2tipey)--ctmdoaoe 2-(2-hydroxy-(4-(3 '-choo)-phenyl))-phenyl-4-(2-thiophenyl)-5-acetamidooxazole; 2-(2-hydroxy-(4-(3 '-metox)-phenyl))-phenyl-4-(2-thiophenyl)-5 -acetamidooxazole; *2-(2-hydroxy-(4-(3 -fluoroy)-phenyl))-phenyl -4-(2-thiophenyl)-5-acetamidooxazole; 2-(2-hydroxy-(4-(2-napthl)-phenyl))-pheny-4-(2-thioophenyl)-5 -acetamidooxazole; 2-(2-hydroxy-(4-(2'-rfumethyl)-phenyl))-phenyl-4-(2-hiophenyl)-5acetamidooxazole; 2-(2-hydroxy-(4-('mo-phenyl))-phenyl-4-(2,6-dichlorophenyl)-5--ctmdoaoe 2-2hdoy(-3-ir)pey)-hnl4(,-ihoohnl- acetamidooxazole; 2-(2-hydroxy-(4-(4 '-mhl)-phenyl))-phenyl-4-(2,6-dichlorophenyl)-5-actmdoaoe 2-(2-hydroxy-(4-(4 '-methoxy)-phenyl))-phenyl-4-(2,6-dichlorophenyl)-5 3 'Uacetamidooxazole; [1:\DAYLIB\libh]00792.doc:sak 16 2-(2-hydroxy-(4-(3'-fluoro)-phenyl))-phenyl-4-(2,6-dichlorophenyl)-5-acetamidooxazole; 2-(2-hydroxy-(4-(2-naphthyl)-phenyl))-phenyl-4-(2,6-dichlorophenyl)-5acetamidooxazole; 2-(2-hydroxy-(4-(2-trifluoromethyl))-phenyl)-phenyl-4-(2,6-dichlorophenyl)-5acetamidooxazole; 2-(2-(3-hydroxy)-naphthyl)-4-phenyl-5-trifluoracetamidooxazole; 2-(2-(3-hydroxy)-naphthyl)-4-(3-thiophenyl)-5-trifluoracetamidooxazole; 1-[2-(2-amino-quinolin-3-yl)-4-phenyl-oxazol-5-yl)]-pyrrolidin-2-one; 1 -[4-phenyl-2-(5-thiophen-3-yl-pyridin-3-yl)-oxazol-5-yl)]-pyrrolidin-2-one; 1-[2-(hydroxy-5-methoxy-phenyl)-4-phenyl-oxazol-5-yl)]-pyrrolidin-2-one Schemes 1-3 for preparing the novel compounds of this invention are presented below. The examples which follow the schemes illustrate the compounds that can be synthesised by these schemes. The schemes, however, are not limited by the compounds listed nor by any particular substituents employed for illustrative purposes. The examples ,is specifically illustrate the application of the following schemes to specific compounds.

Schemes 1 and 2 demonstrate to generalised protocols for the preparation of the required oxazoles from nitriles and diamides respectively. Scheme 3 exemplifies the synthesis of a lactam substituted compound. The reaction conditions employed are apparent from the specific examples that follow. Alternative conditions and protocols would be apparent to those skilled in the art.

[I:\DAYLIB\libh]00792.doc:sak 17-33 is THESE PAGES ARE INTENTIONALLY LEFT BLANK S

S

S

S* S S S

S.

S

5955

S

S

5* S S

S

S

S

S

555 S S

S

SSSS

[1:\DAYLIB\libh]00792.doc:sak WO 00/02871PCJS9150 PCT[US99/15200 SCHEME 1 Oxazoles from amide nitriles

H-

2 N O -N 0 HO

R

2 Coupling R, 0 ,NgetNC

N~R

2 R, 0 CH 3 CI~/MeSO 3

H

NC W''R2CC2 H 2 C 2

I

HN

-34- WO 00/02871 WO 0002871PCTIUS99/1 5200 SCHEME 2 Oxazoles from diamides NHFmnoc piperidine_ 0-NH2

DMF

coupling RNHFmoc IJV YNHFmoc piperidine.

H RDMF 0

H

coupling agentfl N

R

2

CO

2

H

0

__IYNH

2 H R1 32TFAAITFA 0H 2 01 2

R

HN 0 R 0CF3

R

3 00CI/D IPEA solvent 0 -indicates a polymeric support WO 00/02871 WO 0002871PCTJLJS99/15200 SCHEME 3 0

HO

O N

H

2 N ON R 0

NC

C N R N

-N

H

2 N 0 0T R H 2

N

N -N N1 /1 0 The amino thiazoles can be prepared as described in "Reactions of xc-amino- and c-acylaminothioamides with aluminum chloride. Synthesis of some imidazole and thiazole derivatives." Nyitrai, Jozsef, Lempert, Karoly. Acta Chim.

-36- WO 00/02871 PCT/US99/15200 (Budapest) (1972), 73(1), 43-61, or "Cyclization of o-chloro-oacylamido acetophenones." Drach,B. Dolgushina, I. Yu.; Sinitsa, A. D. Inst. Org. Khim., Kiev, USSR. Khim.

Geterotsikl. Soedin. (1974), 928-31. Conversion of the aminothiazoles to the lactam thiazoles can proceed in a similar manner described above for the corresponding amino oxazoles.

The invention described herein includes a pharmaceutical composition which is comprised of a compound of formula I or a pharmaceutically acceptable salt, hydrate or prodrug thereof in combination with a carrier. As used herein the terms "pharmaceutically acceptable salts" and "hydrates" refer to those salts and hydrated forms of the compound which would be apparent to the pharmaceutical chemist, those which favorably affect the physical or pharmacokinetic properties of the compound, such as solubility, palatability, absorption, distribution, metabolism and excretion. Other factors, more practical in nature, which are also important in the selection, are the cost of the raw materials, ease of crystallization, yield, stability, solubility, hygroscopicity and flowability of the resulting bulk drug.

When a compound of formula I is present as a salt or hydrate which is non-pharmaceutically acceptable, this can be converted to a salt or hydrate form which is pharmaceutically acceptable in accordance with the present invention.

When the compound is negatively charged, it is balanced by a counterion, an alkali metal cation such as sodium or potassium. Other suitable counterions include calcium, magnesium, zinc, ammonium, or alkylammonium cations such as tetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium, meglumine, triethanolhydroammonium, etc. An appropriate number of counterions is -37- WO 00/02871 PCT/US99/15200 associated with the molecule to maintain overall charge neutrality.

Likewise when the compound is positively charged, e.g., protonated, an appropriate number of negatively charged counterions is present to maintain overall charge neutrality.

Pharmaceutically acceptable salts also include acid addition salts. Thus, the compound can be used in the form of salts derived from inorganic or organic acids or bases. Examples include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth. Also, the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.

Other pharmaceutically acceptable salts include the sulfate salt ethanolate and sulfate salts.

-38- WO 00/02871 PCT/US99/15200 The compounds of the present invention, may have asymmetric centers and occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention. When any variable aryl, heteroaryl, R 1 etc)occurs more than one time in any constituent or in Formula I, its definition on each occcurence is independent of its definition at every other occurrence, unless otherwise stated.

The compounds of the invention can be formulated in a pharmaceutical composition by combining the compound with a pharmaceutically acceptable carrier. Examples of such compositions and carriers are set forth below.

The compounds may be employed in powder or crystalline form, in solution or in suspension. They may be administered orally, parenterally (intravenously or intramuscularly), topically, transdermally or by inhalation.

Thus, the carrier employed may be, for example, either a solid or liquid. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Examples of liquid carriers include syrup, peanut oil, olive oil, water and the like. Similarly, the carrier for oral use may include time delay material well known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.

Topical applications may be formulated in carriers such as hydrophobic or hydrophilic bases to form ointments, creams, lotions, in aqueous, oleaginous or alcoholic liquids to form paints or in dry diluents to form powders. Such topical formulations can be used to treat ocular diseases as well as inflammatory diseases such as rheumatoid arthritis, -39- WO 00/02871 PCT/US99/15200 psoriasis, contact dermatitis, delayed hypersensitivity reactions and the like.

Examples of oral solid dosage forms include tablets, capsules, troches, lozenges and the like. The size of the dosage form will vary widely, but preferably will be from about 25 mg to about 500mg.

Examples of oral liquid dosage forms include solutions, suspensions, syrups, emulsions, soft gelatin capsules and the like. Examples of injectable dosage forms include sterile injectable liquids, solutions, emulsions and suspensions. Examples of injectable solids would include powders which are reconstituted, dissolved or suspended in a liquid prior to injection.

In injectable compositions, the carrier is typically comprised of sterile water, saline or another injectable liquid, e.g., peanut oil for intramuscular injections. Also, various buffering agents, preservatives and the like can be included.

For the methods of treatment disclosed herein, dosages can be varied depending upon the overall condition of the patient, the nature of the illness being treated and other factors.

An example of a suitable oral dosage range is from about 0.1 to about 80 mg/kg per day, in single or divided doses. An example of a suitable parenteral dosage range is from about 0.1 to about mg/kg per day, in single or divided dosages, administered by intravenous or intramuscular injection. An example of a topical dosage range is from about 0.1 mg to about 150 mg, applied externally from about one to four times a day. An example of an inhalation dosage range is from about 0.01 mg/kg to about 1 mg/kg per day.

The compounds may be administered in conventional dosages as a single agent or in combination with other therapeutically active compounds.

WO 00/02871 PCT/US99/15200 EXAMPLE 1 2-(2-(3-hvdroxv)napthvl)-4-phenl-5-trifluoracetamidooxazole Step 1 Ph NC NH 2

HCI

OH

H0 Ph 0 NC N N N

HO

3 2 -amino-2-phenylacetonitrile hydrochloride (3.0 g, 18mmol) and 2- hydroxy-3-napthoic acid (5.1 g, 27mmol) were dissolved in 50mL of dimethylformamide. To this solution was added benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate (14 g, 27mmol) and diisopropylethylamine (14 ml, 8mmol) and the reaction allowed to proceed with stirring overnight. The reaction was then concentrated and the oil taken up into ethylacetate and washed with water NaC1 solution and the organics dried over sodium sulfate. Flash chromatography provided the desired product 1H NMR (CDCl3) d 7.95 1H), 7.24-7.7 10H), 7.15 (brd, 1H), 6.38 (d, 1H).

-41- WO 00/02871 PCT/US99/15200 The amide nitrile from above (1.9 g, 6.3mmol) was treated with trifluoraceticanhydride (8.9 ml, 63mmol) in dichloroethane containing 2% trifluoracetic. After 30 minutes the reaction was concentrated. Residue was taken up into toluene and concentrated, process was repeated to furnish slightly impure which was used in the next step without further purification. 1H NMR (CDC13) d 8.4 1H), 7.7-7.9 4H), 7.3-7.5 6H), 3.0 (brs, 1H).

EXAMPLE 2 2-(2-(3-hydroxv)napthyl)-4-phenvl-5-acetamidooxazole

P

N

HN-

CH3 HO

HO

The 2 -(2-(3-hydroxy)napthyl)-4-phenyl-5trifluoracetamidooxazole from above (2.5g, 6.3mmmol) was dissovled in toluene (65ml) and treated sequentially with diisopropylethylamine (2.2ml, 12.6mmol) and acetylchloride (0.90ml, 12.6mmol) and stirred at room temperature for 2 hours. The reaction was diluted with Ethylacetate and washed with H20 NaCl and dried over Na2SO4.

After recrystallization from MeOH/EtOAc a white solid was obtained.

1H NMR (DMSO-d6) d 8.5 1H), 8.2 J 8.2Hz, 1H), 7.83 3H), 7.38- 7.54 6H), 2.18 (brs, 3H). MS 345.

-42- 43 EXAMPLE 3 2-(2-(3-hydroxy)napthyl)-4-(3-thiophenyl)-5-trifluoroacetamido-oxazole

S

000 0 CF 3

HO

8 Stepi1 2-amino-2-(3 -thiophenyl) acetonitrile hydrochloride *CHOP HCI NH 2 A6 Sodium caie(3.77g, 77mmol) was 6isle in wtr(40m1) folwdby ammonium chloride (4.53g, 84.7mmol). Thiophene-3-carboxaldehyde (Aldrich, 8.66g, 77mmol) was dissolved in MeOH (60m1) and added via addition funnel to the rapidly :0 :stirring solution in a steady stream. The reaction was Goes 0009 .000 [I:\DAYLIB\Iibh]00792.doc:sak WO 00/02871 PCT/US99/15200 allowed to proceed at room temperature overnight. The reaction was diluted with saturated NaHCO3 and extracted with diethylether (3X100ml). Organics were combined and washed with saturated NaCI and dried over Na2SO4. Organics were concentrated and the in a minimum amount of ether and filtered.

The filtrate was satured with HCI gat at o0C. The solids that formed were filtered and washed with ether to give after drying a yellow solid which was used without further purification.

1H NMR (DMSO-d6) d 9.8 (brs,3H), 7.91 1H), 7.70 1H), 7.43 1H), 6.04 1H).

Step 2

S

NC NC NCOH Nc i HCI NH 2 HO

HO

6 2 7 The 2-amino-2-(3-thiophenyl) acetonitrile hydrochloride (6) (1.6g, 9.17 mmol) was dissolved in DMF (90ml) from above was treated with 2- hydroxy-3-napthoic acid (2.58g, 13.8mmol), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (7.2 g, 13.8mmol), 1hydroxybenzotriazole (1.9g, 13.8mmol) and diisopropylethylamine (7 ml, 40mmol) the reaction was stirred overnight at room temperature. After 18hours the DMF was removed, the residue was taken up into EtOAc and washed successively with 1N HC1, H20, saturated NaHCO3 and saturated NaCI. After purification by chromatography, product was isolated.

-44- WO 00/02871 PCT/US99/15200 H NMR (CDC13) d 10.8 s, 1H), 7.99 1H), 7.64-7.76 3H), 7.47-7.53 2H), 7.22-7.36 4H), 7.04 (brd, J 7.7 Hz, 1H), 6.49 J 8 Hz, 1H).

Step 3 The amide nitrile from above (280mg, 0.93mmol) was dissolved in CH2C12 and treated with trifluoraceticanhydride (2ml) and trifluoracetic (0.5ml). The reaction was allowed to proceed for 4 hours at which point it was concentrated. The solids that remained were filtered with the aid of CH2C12 and washed further with CH2C12 to give the desired product.

H NMR (CDC1 3 d 10.7 1H), 8.37 1H), 7.96 (brs, 1H), 7.82 J= 8.4 Hz, 1H), 7.72 J 8.3 Hz, 1H), 7.68 1H), 7.3-7.52 6H).

EXAMPLE 4 3 -hvdroxv)napthvl)-4-(3-thiophenvl)-5-acetamidooxazole

S

N

HO

CH

3 9 The oxazole (271mg, 0.67mmol) from above was suspended in toluene (10ml) and treated with acetyl chloride (0.14ml, 2 .01mmol), and diisopropylethylamine (0.35ml, 2.01mmol). The reaction was allowed to stir overnight at room temperature. Reaction was diluted with ethylacetate and washed with saturated NaHCO3 and saturated NaCI and dried over MgSO4. The crude product was suspended in MeOH and treated with 1IN NaOH (3m1) for 15 minutes. Cloudy solution was filtered and the filtrate was neutralised with IN HC1. The solids that formed were filtered washed with MeOH and dried under vacuum to yield the desired product HRMS found 351.0803 calculated 351.0803 for C 19

H

15

N

2 0 3

S.

Example 1- [2-(2-Amino-quinolin-3-yI)-4-phenyl-oxazol-5-ylJ-pyrrolidin-2-one 0

NN

*H

2 N Step 1 S 10 2-chloro-quinoline-3-carboxylic acid 0S0 sees &0 .4 S.

CS O [1:\DAYL1B\libh]00792.doc:sak WO 00/02871 PCT/S99/1 5200 To a cold solution LDA (60mL, 120mmol, 2M solution) in THF (400mL) was added 2-chloroquinoline in THF(100mL) at such a rate to maintain temperature <70oC. The reaction was stirred for 2 hours at which point CO2 was bubbled through the solution until the internal temperature reached -78oC (-690C to -78oC). The reaction was then allowed to gradually warm to room temperature overnight. After concentration to dryness, the residue taken up into diethylether and water. The layers were then separated, the aqueous phase acidified with 6N HC1 and the solids collected. This material was used without further purification.

Step 2 N CI

H

N CN 0 Quinoline acid from above was suspended in CH2C12 (100mL) and cooled to -100C. Diphenyl phosphinic chloride was then added followed by dropwise addition of Et3N. The reaction was allowed to proceed with warming to OoC for one hour. The amino nitrile, suspended in CH2C12 (50mL) containing Et3N (1 equiv.), was added to the solution and reaction stirred overnight with warming to room temperature. The reaction was then concentrated to a semisolid and the residue partitional between EtOAc and water. The layers were separated and the organics washed -47- WO 00/02871 PCT/US99/15200 with 0.5N HC1, water, NaHCO3 (sat) water, and dried (MgSO4). After the volatiles had been removed, NMR indicated that starting material remained in the residue. Therefore, the solids were stirred in NaHCO3 (sat). The solids were then refiltered and taken up into EtOAc, washed with water, and dried (MgSO4). The desired material was obtained by flash chromatography (10% EtOAc/CH2C12).

Step 3 N-[2-(2-Chloro-quinolin-3-yl)-4-phenvl-oxazol-5-vl1-2,2,2-trifluoroacetamide N CI

O-CF

3 T

-N

H

Amide nitrile from Step 2 was dissolved in a mixture of CH2Cl2/trifluoroacetic anhydride/trifluoroacetic acid (58/40/2) and stirred at room temperature overnight. The reaction was then concentrated and the residue taken up into EtOAc. This EtOAc solution was then washed with water, aqueous NaHCO3 (sat) and brine. The organics were dried with MgSO4 and concentrated to afford the desired product as a solid that was used without further purification.

-48- WO 00/02871 PCT/US99/15200 Step 4 4- Chloro-N-[2-(2-chloro-quinolin-3-vl)-4-phenvl-oxazol-5-vyl-butyramide The requisite oxazole was dissolved in CH2C12 (100mL) and treated with 4-chloro-butyrl chloride and diisopropylethyl amine. After 3 hours of reflux, TLC indicated that starting material still present. An additional eqiuvalent of acid chloride and base were added and the reaction refluxed for an additional two hours. The reaction was then cooled to room temperature and concentrated to a yellow gum. The residue was taken up into EtOAc and water. The layers were then separated and the organics washed with aqueous NaHCO3 (sat), brine, and dried (MgSO4).

Flash LC EtOAc/ CH2Cl2) gave the desired product.

Step 1- 2-( 2 -chloro-quinolin-3-v)-4-phenvl-oxazol-5-vll -Dvrrolidin-2-one -49- N Cl 0 N--z' The amide was dissolved in CHC13/Et 3 N 30mL) and heated to reflux overnight.

The reaction was then concentrated to a yellow gum and the residue taken up into EtOAc and water. The layers were then separated and the organics washed with brine and dried (MgSO 4 The material was used without further purification.

Step 6 1-[2-(2-Amino-quinolin-3-yl)-4-phenyl-oxazol-5-yl]-pyrrolidin-2-one 0

N

H

2 N N The chloroquinoline derivative from above was suspended in NH3 in a glass 10 bomb. The cap was placed on the vessel and the mixture heated to 80 0 C overnight. The reaction was cooled to -78 0 C and contents poured into a beaker to facilitate evaporation of the NH3 The solid residue *000 [I:\DAYLIB\ibh]00792.doc:sak WO 00/02871 WO 0002871PCT/US99/1 5200 that remained was partitioned between EtOAc and water. The organics were washed with brine and dried (MgSO4). Flash LC EtOAc/CH2Cl2) gave the desired product plus an amount of recovered starting material.

EXAMPLE 6 1- [4-Phenvl-2-( 5-thiophen-3-yl-pvridin-3-l)-oxazol-5-yl-pvyrrolidin-2-one Ste 1 5-Thiophen-3-vl-nicotinic acid methyl ester Methyl-3-bromo-nicotinate and 3-thiophene boronic acid were dissolved in degassed dioxane (25mL). To the homogeneous solution was added Pd((Ph3)4P)). The reaction was heated to 900C for 18 hours and then -51- WO 00/02871 PCT/US99/15200 cooled to room temperature and concentrated. The residue was taken up into EtOAc and water. The layers were then separated and the organics washed with brine and dried (MgSO4). Flash LC (60% Hexanes/EtOAc) gave the desired product.

Step 2 5-Thiophen-3-vl-nicotinic acid The ester from above was suspened in MeOH (20mL), treated with 1N NaOH and stirred at room temperature for 1 hr. The reaction was then concentrated to dryness and the residue dissolved in water and neutralized with 1N HC1. The solids were filtered and dried over P205 at 500C for 10 hours. This material was used without further purification.

Step 3 N-(Cvano-phenl-methvl)- 5-thiophen-3-vl-nicotinamide -52- WO 00/02871 PCT/US99/15200 The acid from above and the benzyl amino nitrile were treated with EDC- HC1 and HOAt in DMF (10mL). The reaction was allowed to proceed overnight at room temperature. The reaction was then concentrated and the residue taken up into EtOAc and water. The layers were separated and the organics washed with aqueous NaHCO3 (sat), water, and dried (MgSO4). Flash LC (50% CH2Cl2/EtOAc) gave the desired product.

Step 4 4-Phenvl-2-(5-thiophen-3-vl-pvridin-3-vl)-oxazol-5-vlamine

N

NH

The amide nitrile (0.064mg, 0.2mmol) was partially dissolved in dichlorethane (5mL). MeSO3H (0.039mL, 0.6mmol) was then added and the reaction allowed to proceed overnight at room temperature. The reaction was diluted with CH2Cl2 and extracted with aqueous NaHCO3 -53- WO 00/02871 PCT/US99/15200 (sat), water and then dried (MgSO4). The desired product was isolated by flash LC (40% EtOAc/ CH2C12) to give a pale yellow solid. The material was triturated with Et20, filtered and dried over P205.

Step 4-Chloro-N-[4-Phenvl-2-(5-thiophen-3-vl-pyridin-3-vl)-oxazol-5-yllbutyramide N 0 0 N

H

Amino oxazole (319mg, 1.0mmol) from above was suspended in CHCl3 and treated with DMAP (24mg, 0.02mmol), Et3N (0.280mL, 2.0mmol), and 4-chloro-butyrlchloride (0.22mL, 2.0mmol). The reaction was then heated to 80oC for 6hr wherein TLC indicated starting material still present. Two equivalents of acid chloride and Et3N were then added and the reaction heated for an additional two hours. The reaction was then cooled to room temperature and concentrated to dryness. The residue was partitioned between EtOAc and NaHCO3. The layers were then separated and organics washed with water and dried over MgSO4.

Flash LC with CH2C12 followed by 2% EtOAc/CH2Cl2 yield the product as a yellow gum which was used directly in the next step.

Step 6 1- 4 -Phenvl- 2 -(5-thiophen-3-vl-pyridin-3-vl)-oxazol-5-vl1-pvrrolidin-2-one -54- WO 00/02871 PCTIUS99/15200 Chloro amide from above (0.38g, 0.896mmol) was treated with Et3N (5mL) and a small amount of CHC13 until homogeneous. The reaction was heated to 900C for 2hr. The reaction was then cooled to room temperature and concentrated to dryness. The residue was partitioned between EtOAc and aqueous HCI The organics were washed further with water, brine, and dried (MgSO4). Flash LC CH2C12 gave an off white solid that was triturated with diethylether and dried over P205.

EXAMPLE 7 1-[ 2 -(Hvdroxv-5-methoxv-phenvl)-4-phenvl-oxazol-5-vll-pyrrolidin-2-one This compound was prepared in a manner analogous to that described above.

2N S OCH 3

HO

WO 00/02871 PCT/US99/15200 Kinase inhibition is demonstrated in accordance with the following protocol.

VEGF RECEPTOR KINASE ASSAY VEGF receptor kinase activity is measured by incorporation of radio-labeled phosphate into polyglutamic acid, tyrosine, 4:1 (pEY) substrate. The phosphorylated pEY product is trapped onto a filter membrane and the incorporation of radiolabeled phosphate quantified by scintillation counting.

MATERIALS

VEGF receptor kinase The intracellular tyrosine kinase domains of human KDR (Terman, B.I. et al. Oncogene (1991) vol. 6, pp. 1677-1683.) and Flt-1 (Shibuya, M. et al. Oncogene (1990) vol. 5, pp. 519-524) were cloned as glutathione S-transferase (GST) gene fusion proteins.

This was accomplished by cloning the cytoplasmic domain of the KDR kinase as an in frame fusion at the carboxy terminus of the GST gene. Soluble recombinant GST-kinase domain fusion proteins were expressed in Spodoptera frugiperda (Sf21) insect cells (Invitrogen) using a baculovirus expression vector (pAcG2T, Pharmingen).

Lvsis buffer mM Tris pH 7.4, 0.5 M NaC1, 5 mM DTT, 1 mM EDTA, 0.5% triton X-100, 10 glycerol, 10 mg/ml of each leupeptin, pepstatin and aprotinin and ImM phenylmethylsulfonyl fluoride (all Sigma).

-56- WO 00/02871 PCT/US99/15200 Wash buffer mM Tris pH 7.4, 0.5 M NaCI, 5 mM DTT, 1 mM EDTA, 0.05% triton X-100, 10 glycerol, 10 mg/ml of each leupeptin, pepstatin and aprotinin and ImM phenylmethylsulfonyl fluoride.

Dialysis buffer mM Tris pH 7.4, 0.5 M NaCI, 5 mM DTT, 1 mM EDTA, 0.05% triton X-100, 50 glycerol, 10 mg/ml of each leupeptin, pepstatin and aprotinin and ImM phenylmethylsuflonyl fluoride.

X reaction buffer 200 mM Tris, pH 7.4, 1.0 M NaC1, 50 mM MnC1 2 mM DTT and 5 mg/ml bovine serum albumin (Sigma).

Enzyme dilution buffer mM Tris, pH 7.4, 0.1 M NaCl, 1 mM DTT, 10 glycerol, 100 mg/ml BSA.

10 X Substrate 750 gg/ml poly (glutamic acid, tyrosine; 4:1) (Sigma).

Stop solution trichloroacetic acid, 0.2 M sodium pyrophosphate (both Fisher).

Wash solution trichloroacetic acid, 0.2 M sodium pyrophosphate.

Filter plates Millipore #MAFC NOB, GF/C glass fiber 96 well plate.

-57- WO 00/02871 PCT/US99/15200

METHOD

A. Protein purification 1. Sf21 cells were infected with recombinant virus at a multiplicity of infection of 5 virus particles/ cell and grown at 27 °C for 48 hours.

2. All steps were performed at 4 0 C. Infected cells were harvested by centrifugation at 1000 X g and lysed at 4 oC for minutes with 1/10 volume of lysis buffer followed by centrifugation at 100,000Xg for 1 hour. The supernatant was then passed over a glutathione Sepharose column (Pharmacia) equilibrated in lysis buffer and washed with 5 volumes of the same buffer followed by volumes of wash buffer. Recombinant GST-KDR protein was eluted with wash buffer/10 mM reduced glutathione (Sigma) and dialyzed against dialysis buffer.

B. VEGF receptor kinase assay 1. Add 5 ptl of inhibitor or control to the assay in

DMSO.

2. Add 35 gl of reaction mix containing 5 pl of 10 X reaction buffer, 5 pl 25 mM ATP/10 gCi [33p]ATP (Amersham), and 5 gl 10 X substrate.

3. Start the reaction by the addition of 10 pl of KDR nM) in enzyme dilution buffer.

4. Mix and incubate at room temperature for minutes.

Stop by the addition of 50 pl stop solution.

6. Incubate for 15 minutes at 4 0

C.

7. Transfer a 90 il aliquot to filter plate.

-58- WO 00/02871 PCT/US99/15200 8. Aspirate and wash 3 times with wash solution.

9. Add 30 gl of scintillation cocktail, seal plate and count in a Wallac Microbeta scintillation counter.

Human Umbilical Vein Endothelial Cell Mitogenesis Assay Expression of VEGF receptors that mediate mitogenic responses to the growth factor is largely restricted to vascular endothelial cells. Human umbilical vein endothelial cells (HUVECs) in culture proliferate in response to VEGF treatment and can be used as an assay system to quantify the effects of KDR kinase inhibitors on VEGF stimulation. In the assay described, quiescent HUVEC monolayers are treated with vehicle or test compound 2 hours prior to addition of VEGF or basic fibroblast growth factor (bFGF). The mitogenic response to VEGF or bFGF is determined by measuring the incorporation of 3 H]thymidine into cellular DNA.

Materials HUVECs HUVECs frozen as primary culture isolates are obtained from Clonetics Corp. Cells are maintained in Endothelial Growth Medium (EGM; Clonetics) and are used for mitogenic assays at passages 3-7.

Culture Plates NUNCLON 96-well polystyrene tissue culture plates (NUNC #167008).

Assay Medium -59- WO 00/02871 PCT/US99/15200 Dulbecco's modification of Eagle's medium containing 1 g/ml glucose (low-glucose DMEM; Mediatech) plus 10% fetal bovine serum (Clonetics).

Test Compounds Working stocks of test compounds are diluted serially in 100% dimethylsulfoxide (DMSO) to 400-fold greater than their desired final concentrations. Final dilutions to IX concentration are made directly into Assay Medium immediately prior to addition to cells.

Growth factors Solutions of human VEGF165 (500 ng/ml; R&D Systems) and bFGF (10 ng/ml; R&D Systems) are prepared in Assay Medium.

3 HIThvmidine [Methyl- 3 H]Thymidine (20 Ci/mmol; Dupont-NEN) is diluted to 80 uCi/ml in low-glucose DMEM.

Cell Wash Medium Hank's balanced salt solution (Mediatech) containing 1 mg/ml bovine serum albumin (Boehringer-Mannheim).

Cell Lysis Solution 1 N NaOH, 2% Na2C03.

Method 1. HUVEC monolayers maintained in EGM are harvested by trypsinization and plated at a density of 4000 cells per WO 00/02871 PCT/US99/15200 100 ul Assay Medium per well in 96-well plates. Cells are growtharrested for 24 hours at 37 0 C in a humidified atmosphere containing 5% CO2.

2. Growth-arrest medium is replaced by 100 ul Assay Medium containing either vehicle (0.25% DMSO) or the desired final concentration of test compound. All determinations are performed in triplicate. Cells are then incubated at 37 0 C02 for 2 hours to allow test compounds to enter cells.

3. After the 2-hour pretreatment period, cells are stimulated by addition of 10 ul/well of either Assay Medium, VEGF solution or 10X bFGF solution. Cells are then incubated at 37 0 C/5% CO2.

4. After 24 hours in the presence of growth factors, 3 H]Thymidine (10 ul/well) is added.

5. Three days after addition of [3H]thymidine, medium is removed by aspiration, and cells are washed twice with Cell Wash Medium (400 ul/well followed by 200 ul/well). The washed, adherent cells are then solubilized by addition of Cell Lysis Solution (100 ul/well) and warming to 37 0 C for 30 minutes. Cell lysates are transferred to 7-ml glass scintillation vials containing 150 ul of water. Scintillation cocktail (5 ml/vial) is added, and cellassociated radioactivity is determined by liquid scintillation spectroscopy.

Based upon the foregoing assays the compounds of formula I are inhibitors of VEGF and thus are useful for the inhibition of neoangiogenesis, such as in the treatment of occular disease, diabetic retinopathy and in the treatment of cancers, solid tumors. The instant compounds inhibit VEGF- -61- WO 00/02871 PCT/US99/15200 stimulated mitogenesis of human vascular endothelial cells in culture with IC50 values between 0.01 5.0 gM. These compounds also show selectivity over related tyrosine kinases FGFR1 and the Src family).

-62-

Claims (6)

1. A compound in accordance with formula I: R 3 ^N R2 R 4 R1 I or a pharmaceutically acceptable salt or hydrate thereof, wherein X is O or S; R' is methyl or CF 3 R 2 is H, CI- 6 alkyl, C5- 1 0 aryl, Cs- 1 0 -heteroaryl, C3- 6 cycloalkyl, said alkyl, aryl, to heteroaryl or cycloalkyl being optionally substituted with one to three members selected a, from Ra, or R and R 2 are connected to form a 5-membered lactam; R is C 1 -6 alkyl, C5- 0 o aryl, Cs.lo-hetoroaryl, C3- 6 cycloalkyl, said alkyl, aryl, i heteroaryl or cycloalkyl being optionally substituted with one to three members selected S 15 from Ra; R 4 is H, C-o 1 0 alkyl, C3- 6 cycloalkyl, C1- 6 alkoxy, C2- 1 0 alkenyl, C2- 10 alkynyl, C5- 1 0 I'i. aryl, C3-10 heterocyclyl, C1- 6 alkoxy, NR 7 R 8 NO 2 OH, -NH 2 or C5- 1 0 heteroaryl, said alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with one to three members selected from Ra; 20 Ra is H, C-o 1 0 alkyl, halogen, CF 3 NO 2 NHC(O)R*, OR, -NR 7 R 8 C5- 10 aryl, C5- 1 0 aralkyl, C5- 1 0 heteroaryl or C 3 1 0 heterocyclyl, said aralkyl, aryl and heteroaryl optionally substituted with one or two groups selected from NO 2 halo, C5- 1 0 aryl, C1- 6 alkoxy, C 1 -6 alkyl, and CF 3 R* is H, or CI- 6 alkyl, NHC(O)CHR(C5_-o aralkyl), wherein the aryl ring of the aralkyl may be optionally substituted with one, two or three groups selected from OH, C1- 6 alkyl, and halo; R is H, or Ci- 6 alkyl; and R 7 and R 8 are independently selected from: H, Cl- 1 l alkyl, C3- 6 cycloalkyl, COR, -COOR, C5- 1 0 aryl, C3- 1 0 heterocyclyl, or 10 heteroaryl or NR 7 R 8 can be taken together to form a heterocyclic 5-10 membered q saturated or unsaturated ring containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, -O and S. [1:\DAYLIB\1ibh100792.doc:sak 64

2. A compound in accordance with Claim 1 wherein: R 1 is methyl or CF 3 R 2 is H, C 16 alkyl, or C 5 10 aryl, said alkyl or, aryl, optionally substituted with one to three members selected from Ra, or R 1 and R 2 are connected to form a 5-membered lactam; R 3 and R 4 are independently C 110 alkyl, C 5 10 aryl, or C 5 -Io heteroaryl, said alkyl, aryl and heteroaryl being optionally substituted with one to three members selected from Ra; and all other variables are as described above.

3. A compound according to claim 1 or 2 wherein X is 0 and all other variables io are as originally described.

4. A compound according to claim 1 or 2 wherein X is S and all other variables are as originally described. A compound according to any one of claims 1, 3 and 4 wherein R 3 and R 4 independently, are C 5 -jo aryl or C 5 -Io heteroaryl, said aryl or heteroaryl being optionally substituted with one to three members selected from Ra.

6. A compound according to any one of claims I to 5, selected from the group hconsisting ofy 2 -hydroxy)napthyl)-4-phenylpn-trifluoro acetamidooxazole; -hydroxy)napthyl)-4-(3-thiophenyl)-5 -acetamidooxazole; -hydroxy)napthyl)-4-phenyl- -hydroxy)napthyl)-4-(3 -thiophenyl)-5 -trifluoroacetamido-oxazole; 2-(2-hydroxy-4-methoxy)phenyl-4-phenyl-5 -acetamidooxazole; 2-(2-hydroxy-4-methyl)phenyl-4-phenyl-5 -acetamidooxazole; 2-(2-hydroxy)phenyl-4-phenyl-5 -acetamidooxazole; 2-(5-isoquinolinyl)-4-phenyl-5-acetamidooxazole; 2-(2-(3-hydroxy)napthyl)-4-(3 -thiopheny)-5 -acetamidooxazole; -phenyl)pyridyl)-4-phenyl-5 -acetamidooxazole; 2-(3-(5-(3-nitro)phenyl)pyridyl)-4-phenyl-5 -acetamidooxazole; 2-(3 -naphthyl)phenyl)pyridyl)-4-phenyl-5 -acetamidooxazole; 2-(3-(5-(4-methyl)phenyl)pyridyl)-4-phenyl-5-acetamidooxazole; -(4-methoxy)phenyl)pyridyl)-4-phenyl-5 -acetamidooxazole; -chloro)phenyl)pyridyl)-4-phenyl-5 -acetamidooxazole; SRA( -methoxy)phenyl)pyridyl)-4-phenyl-5 -acetamidooxazole; 2-(3-(5-(3-fluoro)phenyl)pyridyl)-4-phenyl-5-acetamidooxazole; [IADAYLIB\ibh]00792.doc:sak -(2-naphthyl)phenyl)pyridyl)-4-phenyl-5 -acetamidooxazole; -(2-trifluoromethyl)phenyl)pyridyl)-4-phenyl-5-acetamidooxazole; 2-(2-hydroxy)phenyl-4-phenyl-5-acetamidooxazole; 2-(2-hydroxy-4-phenyl)-phenyl-4-phenyl-5 -acetamidooxazole; 2-(2-hydroxy-(4-(3 2-(2-hydroxy-(4-( 1 2-(2-hydroxy-(4-(4 2-(2-hydroxy-(4-(4 2-(2-hydroxy-(4-(3 0 2-(2-hydroxy-(4-(3 2-(2-hydroxy-(4-(3 '-fluoro)-phenyl))-phenyl-4-phenyl-5 -acetamidooxazole; 2-(2-hydroxy-(4-(2-naphthyl)-phenyl))-phenyl-4-phenyl-5 -acetamnidooxazole; :2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl))-phenyl-4-phenyl-5-acetamidooxazole; :e 2-(2-hydroxy-4-phenyl)-phenyl-4-thiophenyl-5-acetamidooxazole; 2-(2-hydroxy-(4-(3 2-2hdox-4* .npty)pey)-hnl4tipey--ctmdoaoe 2-(2-hydroxy-(4-( 1 2-(2-hydroxy'-(4-(4 2-(2-hydroxy'-(4-(' -hox)-phenyl))-phenyl-4-thiophenyl-5 -acetamidooxazole; 2-(2-hydroxy-(4-(3 2-(2-hydroxy-(4-(3 '-metox)-phenyl))-phenyl-4-thiophenyl-5 -acetamidooxazole; 2-2hdoy(-.-ahhl V. ~2-(2-hydroxy-(4-(3 2-(2-hydroxy-(4-(-ahh-phenyl))-phenyl-4- 2-(2-hydroxy-(4-(2-ntrlorty)-phenyl))-phenyl-4- h iophel-5-acetamidooxazole; :2-(2-hydroxy-(4-(-hh-phenyl))-phenyl-4-(3-pyridyl)-5-acetamidooxazole;

252-(2-hydroxy-(4-3 -it)-phenyl))-phenyl-4-(3-pyridyl)-5-acetamidooxazole; 2-(2-hydroxy-(4-( 1 -napthoy)-phenyl))-phenyl-4-(3 -pyridyl)-5 -acetamidooxazole; [1:\DAYLIB\libh]00792.doc:sak 66 2-(2-hydroxy-(4-3 '-chloro)-phenyl))-phenyl-4-(3-pyridyl)-5-acetamidooxazole; 2-(2-hydroxy-(4-3 '-methoxy)-phenyl))-phenyl-4-(3-pyridyl)-5-acetamidooxazole; 2-(2-hydroxy-(4-(3 '-fluoro)-phenyl))-phenyl-4-(3-pyridyl)-5-acetamidaooxazole; 2-(2-hydroxy-(4-(2-naphthyl)-phenyl))-phenyl-4(3 -pyridyl)-5 -acetamidooxazole; 2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl))-phenyl-4-(3 2-(2-hydroxy-4-phenyl)-phenyl-4-(3 2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(3 -chlorophenyl)-5 -acetamnidooxazole; 2-(2-hydroxy-(4-( 1 -naphthyl)-phenyl))-phenyl-4-(3 2-(2-hydroxy-(4-(4 '-methyl)-phenyl))-phenyl-4-(3 2-(2-hydroxy-(4-(4 '-methoxy)-phenyl))-phenyl-4-(3-chlorophenyl)-5-acetamidooxazole; 2-(2-hydroxy-(4-(3 '-chloro)-phenyl))-phenyl-4-(3 -chlorophenyl)-5 -acetamidooxazole; 2-(2-hydroxy-(4-(3 '-methoxy)-phenyl))-phenyl-4-(3-chlorophenyl)-5 -acetamidooxazole; 2-(2-hydroxy-(4-(3 '-fluoro)-phenyl))-phenyl-4-(3 2-(2-hydroxy-(4-(2-naphthyl)-phenyl))-phenyl-4-(3 15 2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl))-phenyl-4-(3 acetamidooxazole; 2-(2-hydroxy-4-phenyl)-phenyl-4-(2-chlorophenyl)-5-acetamidooxazole; 2-(2-hydroxy-(4-(3 -nitro)-phenyl))-phenyl-4-(2-chlorophenyl)-5 -acetamidooxazole; 20 2-(2-hydroxy-(4-(1-naphthyl)-phenyl))-phenyl-4-(2-chlorophenyl-5-acetamiooxazolo. 00000 20 2-(2-hydroxy-(4-(4 '-methyl)-phenyl))-phenyl-4-(2-chlorophenyl)-5-acetamidooxazole; 6 6 o.2-(2-hydroxy-(4-(4 '-methoxy)-phenyl))-phenyl-4-(2-chlorophenyl)-5-acetamidooxazole; 2.0hdoy(-3'clr)-hnl)pey--2clrohnl--ctmdoaoe '0 2-(2-hydroxy-(4-(3 '-mhox)-phenyl))-phenyl-4-(2-chlorophenyl)-5-acetaidooxazole; o:o 2-(2-hydroxy-(4-(3 '-fluoo)-phenyl))-phenyl-4-(2-chlorophenyl)-5 -acetamidooxazole; 2-(2-hydroxy-(4-(2'-naphthy)-phenyl))-phenyl-4-(2-chlorophenyl)-5 -acetamidooxazole; 2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl))-phenyl-4-(2-chlorophenyl)-5 acetamidooxazole; 2-(2-hydroxy-4-phenyl)-phenyl-4-(4-chlorophenyl)-5-acetamidooxazole; 2-(2-hydroxy-(4-(3 -nitro)-phenyl))-phenyl-4-(4-chlorophenyl)-5-acetamidooxazole; 2-(2-hydroxy-(4-( 1 -naphthyl)-phenyl))-phenyl-4-(4-chlorophenyl)-5-acetamidooxazole; 2-(2-hydroxy-(4-(4 '-methyl)-phenyl))-phenyl-4-(4-chlorophenyl)-5 -acetamidooxazole; 2-(2-hydroxy-(4-(4' -methoxy)-phenyl))-phenyl-4-(4-chlorophenyl)-5 -acetamidooxazole; 2-(2-hydroxy-(4-(3 '-chloro)-phenyl))-phenyl-4-(4-chlorophenyl)-5-acetamidooxazole; 2-(2-hydroxy-(4-(3 '-methoxy)-phenyl))-phenyl-4-(4-chlorophenyl)-5-acetamidooxazole; V5,2-(2-hydroxy-(4-(3 '-fluoro)-phenyl))-phenyl-4-(4-chlorophenyl)-5-acetamidooxazole; [1:\DAYLIB\libh]00792.doc:sak 67 2-(2-hydroxy-(4-(2-naphthyl)-phenyl))-phenyl -4-(4-chlorophenyl)-5-acetamidooxazole; 2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl))-phenyl-4-(4-chlorophenyl)-5- acetamidooxazole; 2-(2-hydroxy-4-phenyl)-phenyl-4-(4-trifluoromethylphenyl)-5-acetamnidooxazole, 2-(2-hydroxy-(4-(3 -nitro)-phenyl))-phenyl-4-(4-trifluoromethylphenyl)-5- acetamidooxazole; 2-(2-.hydroxy-(4-( 1 -naphthyl)-phenyl))-phenyl-4-(4-trifluoromethylphenyl)-5 acetamidooxazole; 2-(2-hydroxy-(4-(4 '-methyl)-phenyl))-phenyl-4-(4-trifluoromethylphenyl)-5- acetamidooxazole; 2-(2-hydroxy-(4-(4 '-methoxy)-phenyl))-phenyl-4-(4-trifluoromethylphenyl)-5- acetamidooxazole; 2-(2-hydroxy-(4-(3 '-chloro)-phenyl))-phenyl-4-(4-trifluoromethylphenyl)-5- acetamidooxazole; 2-(2-hydroxy-(4-(3 '-methoxy)-phenyl))-phenyl-4-(4-trifluoromethylphenyl)-5- acetamidooxazole; 2-(2-hydroxy-(4-(3 '-fluoro)-phenyl))-phenyl-4-(4-trifluoromethylphenyl)-5 acetamidooxazole; 2-(2-hydroxy-(4-(2-naphthyl)-phenyl))-phenyl-4. acetamidooxazole; 2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl))-phenyl-4-(4-trifluoromethylphenyl)-5- acetamidooxazole; 2-(2-hydroxy-4-phenyl)-phenyl-4-(3-methoxyphenyl)-5-acetamidooxazole; 2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(3 2-(2-hydroxy-(4-( 1-naphthyl)-phenyl))-phenyl-4-(3 acetamidooxazole; 2-(2-hydroxy-(4-(4 '-methyl)-phenyl))-phenyl-4-(3 2-(2-hydroxy- '-methoxy)-phenyl))-phenyl-4-(3-methoxyphenyl)-5- acetamidooxazole; 2-(2-hydroxy-(4-(3 '-chloro)-phenyl))-phenyl-4-(3 2-(2-hydroxy-(4-(3 '-methoxy)-phenyl))-phenyl-4-(3-methoxyphenyl)-5- acetamidooxazole; 2-(2-hydroxy-(4-(3 '-fluoro)-phenyl))-phenyl-4-(3 E4AL,~ 2-(2-hydroxy-(4-(2-naphthyl)-phenyl))-phenyl-4-(3 -methoxyphenyl)-5 -3 acetamnidooxazole; [I:\DAYLIB\Iibh]00792.doc:sak 68 2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl))-phenyl-4-(3 acetamidooxazole; 2-(2-hydroxy-4-phenyl)-phenyl-4-(3-thiophenyl)-5-acetamidooxazole; 2-(2-hydroxy-(4-(3 -nitro)-phenyl))-phenyl-4-(3-thiophenyl)-5-acetamidooxazole; 2-(2-hydroxy-(4-( 1 -naphthyl)-phenyl))-phenyl-4-(3 2-(2-hydroxy-(4-(4 '-methyl-phenyl))-phenyl-4-(3 2-(2-hydroxy-(4-(4 '-methoxy)-phenyl))-phenyl-4-(3-thiophenyl)-5 -acetamidooxazole; 2-(2-hydroxy-(4-(3 '-chloro)-phenyl))-phenyl-4-(3-thiophenyl)-5-acetamnidooxazole; 2-(2-hydroxy-(4-(3 '-methoxy)-phenyl))-phenyl-4-(3-thiophenyl)-5 -acetamidooxazole; 2-(2-hydroxy-(4-(3 '-fluoro)-phenyl))-phenyl-4-(3 -thiophenyl)-5 -acetamidooxazole; 2-(2-hydroxy-(4-(2-naphthyl)-phenyl))-phenyl-4-(3 2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl))-phenyl-4-(3-thiophenyl)-5- :acetamidooxazole; 2-(2-hydroxy-4-phenyl )-phenyl-4-(2-thiophenyl)-5-acetamidooxazole; 2-(2-hydroxy-(4-(3 -nitro)-phenyl))-phenyl-4-(2-thiophenyl)-5-acetamidooxazole; 2-(2-hydroxy-(4-( 1 -naphthyl)-phenyl))-phenyl-4-(2-thiophenyl)-5 -acetamidooxazole; 2-(2-hydroxy-(4-(4 '-methyl)-phenyl))-phenyl-4-(2-thiophenyl)-5-acetamidooxazole; 2-2hdoy(-( 9toy-hny)-hnl4(2tipey)5a9tmdoaoe 9 ~2-(2-hydroxy-(4-(4 '-mhox)-phenyl ))-phenyl-4-(2-thiophenyl)-5 -acetamidooxazole; 9-2hdoy(-3-ehx)pey)-hnl4(-hohnl--ctmdoaoe 20 2-(2-hydroxy-(4-(3 '-loro)-phenyl))-phenyl -4-(2-thiophenyl)-5 -acetamidooxazole; 2-(2-hydroxy-(4-(3 '-mepthy)-phenyl))-phenyl -4-(2-thiophenyl)-5 -acetamnidooxazole; 2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl))-phenyl-4-(2-thiophenyl)-5 acetamidooxazole; 2-(2-hydroxy-4-phenyl)-phenyl-4-(2,6-dichlorophenyl)-5-acetamidooxazole; 2-(2-hydroxy-(4-(3 -nitro)-phenyl))-phenyl-4-(2,6-dichlorophenyl)-5-acetamidooxazole; 2-(2-hydroxy-(4-( 1-naphthyl)-phenyl))-phenyl-4-(2,6-dichlorophenyl)-5 acetamidooxazole; 2-(2-hydroxy-(4-(4 '-methyl)-phenyl))-phenyl-4-(2,6-dichlorophenyl)-5 acetamidooxazole; 2-(2-hydroxy-(4-(4 '-methoxy)-phenyl))-phenyl-4-(2,6-dichlorophenyl)-5 acetamidooxazole; 2-(2-hydroxy-(4-(3 '-chloro)-phenyl))-phenyl-4-(2,6-dichlorophenyl)-5-acetamidooxazole; RA42-(2-hydroxy-(4-(3 '-methoxy)-phenyl))-phenyl-4-(2,6-dichlorophenyl)-5- "ctamidooxazole; [1:\DAYLIB\libh]00792.doc:sak 69 2-(2-hydroxy-(4-(3'-fluoro)-phenyl))-phenyl-4-(2,6-dichlorophenyl)-5-acetamidooxazole; 2-(2-hydroxy-(4-(2-naphthyl)-phenyl))-phenyl-4-(2,6-dichlorophenyl)-5- acetamidooxazole; 2-(2-hydroxy-(4-(2-trifluoromethyl))-phenyl)-phenyl-4-(2,6-dichlorophenyl)-5- acetamidooxazole; 2-(2-(3-hydroxy)napthyl)-4-phenyl-5-trifluoracetamidooxazole; 2-(2-(3-hydroxy)napthyl)-4-(3-thiophenyl)-5-trifluoroacetamido-oxazole; 1-[2-(2-Amino-quinolin-3-yl)-4-phenyl-oxazol-5-yl]-pyrrolidin-2-one; 1-[4-Phenyl-2-(5-thiophen-3-yl-pyridin-3-yl)-oxazol-5-yl]-pyrrolidin-2-one; 1-[2-(Hydroxy-5-methoxy-phenyl)-4-phenyl-oxazol-5-yl]-pyrrolidin-2-one. 7. A compound in accordance with any one of claims 1 to 6, said compound being substantially as hereinbefore described with reference to any one of the examples. 8. A compound in accordance with any one of claims 1 to 7 produced by a Sprocess, said process being substantially as hereinbefore described with reference to any 15 one of the examples. o 9. A pharmaceutical composition including or consisting of an effective amount of at least one compound according to any one of claims 1 to 8, together with a pharmaceutically acceptable carrier, diluent or adjuvant therefor. 10. A method for the treatment of cancer in a mammal requiring said treatment, 20 which method includes or consists of administering to said mammal an effective amount of at least one compound according to any one of claims 1 to 8, or of a composition according to claim 9. 11. A method of treating cancer in accordance with claim 10 wherein the cancer is selected from cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung. 12. A method in accordance with claim 10 wherein the cancer is selected from histiocytic lymphoma, lung adenocarcinoma, small cell lung cancers, pancreatic cancer, gioblastomas and breast carcinoma. 13. A method for the treatment of disease in which neoangiogenesis is implicated in a mammal requiring said treatment, which method includes or consists of administering to said mammal an effective amount of at least one compound according to any one of claims 1 to 8, or of a composition according to claim 9. 14. A method in accordance with claim 13 wherein the disease is an ocular A disease. [1:\DAYLIB\libh]00792.doc:sak A method for the treatment of retinal vascularisation in a mammal requiring said treatment, which method includes or consists of administering to said mammal an effective amount of at least one compound according to any one of claims 1 to 8, or of a composition according to claim 9. 16. A method for the treatment of diabetic retinopathy in a mammal requiring said treatment, which method includes or consists of administering to said mammal an effective amount of at least one compound according to any one of claims 1 to 8, or of a composition according to claim 9. 17. A method for the treatment of age related macular degeneration in a mammal lo requiring said treatment, which method includes or consists of administering to said mammal an effective amount of at least one compound according to any one of claims 1 to 8, or of a composition according to claim 9. :18. A method for the treatment of inflammatory disease in a mammal requiring said treatment, which method includes or consists of administering to said mammal an effective amount of at least one compound according to any one of claims 1 to 8, or of a composition according to claim 9. 19. A method according to claim 18 wherein the inflammatory disease is selected from rheumatoid arthritis, psoriasis, contact dermatitis and delayed hypersensitivity reactions. 20 20. A method for the treatment of inhibiting tyrosine kinase in a mammal oooo requiring said treatment, which method includes or consists of administering to said o *mammal an effective amount of at least one compound according to any one of claims 1 °ooo to 8, or of a composition according to claim 9. 21. A method for the prophylaxis of cancer in a mammal requiring said treatment, which method includes or consists of administering to said mammal an effective amount of at least one compound according to any one of claims 1 to 8, or of a composition according to claim 9. 22. A method of preventing cancer in accordance with claim 21 wherein the cancer is selected from cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung. 23. A method in accordance with claim 21 wherein the cancer is selected from histiocytic lymphoma, lung adenocarcinoma, small cell lung cancers, pancreatic cancer, gioblastomas and breast carcinoma. RA 24. A method for the prophylaxis of disease in which neoangiogenesis is plicated in a mammal requiring said prophylaxis, which method includes or consists of L[h -oA 0[I:\DAY LIB\libh]00792 .doc:sak 71 administering to said mammal an effective amount of at least one compound according to any one of claims 1 to 8, or of a composition according to claim 9. A method in accordance with claim 24 wherein the disease is an ocular disease. 26. A method for the prophylaxis of retinal vascularisation in a mammal requiring said prophylaxis, which method includes or consists of administering to said mammal an effective amount of at least one compound according to any one of claims 1 to 8, or of a composition according to claim 9. 27. A method for the prophylaxis of diabetic retinopathy in a mammal requiring said prophylaxis, which method includes or consists of administering to said mammal an effective amount of at least one compound according to any one of claims 1 to 8, or of a composition according to claim 9. 28. A method for the prophylaxis of age related macular degeneration in a mammal requiring said prophylaxis, which method includes or consists of administering to said mammal an effective amount of at least one compound according to any one of Sclaims 1 to 8, or of a composition according to claim 9. 29. A method for the prophylaxis of inflammatory diseases in a mammal requiring said prophylaxis, which method includes or consists of administering to said mammal an effective amount of at least one compound according to any one of claims 1 20 to 8, or of a composition according to claim 9. oo .30. A method according to claim 29 wherein the inflammatory disease is selected from rheumatoid arthritis, psoriasis, contact dermatitis and delayed hypersensitivity oo9• reactions. 31. Use of a compound in accordance with any one of claims 1 to 8 in the 9 9 manufacture of a medicament for treating or preventing cancer. 32. Use of a compound in accordance with claim 31, wherein the cancer is selected from cancers of the brain genitouriuary tract, lymphatic system, stomach, larynx and lung. 33. Use of a compound in accordance with claim 31, wherein the cancer is selected from cancers of the brain genitouriuary tract, lymphatic system, stomach, larynx and lung. 34. Use of a compound in accordance with any one of claims 1 to 8 in the manufacture of a medicament for treating or preventing a disease in which I neoangiogenesis is implicated. [I:\DAYLIB\fibh]00792.doc:sak 72 Use of a compound in accordance with claim 33, wherein the disease is an ocular disease. 36. Use of a compound in accordance with any one of claims 1 to 8 in the manufacture of a medicament for treating or preventing retinal vascularisation. 37. Use of a compound in accordance with any one of claims 1 to 8 in the manufacture of a medicament for treating or preventing diabetic retinopathy. 38. Use of a compound in accordance with any one of claims 1 to 8 in the manufacture of a medicament for treating or preventing age related macular degeneration. 39. Use of a compound in accordance with any one of claims 1 to 8 in the manufacture of a medicament for treating or preventing inflammatory diseases. Use of a compound in accordance with claim 39, wherein the disease is selected for the prophylaxis of inflammatory diseases in a mammal requiring said prophylaxis, which method includes or consists of administering to said mammal an effective amount of at least one compound according to any one of claims 1 to 8, or of a s15 composition according to claim 9. 41. Use of a compound in accordance with any one of claims 1 to 8, for inhibiting tyrosine kinase. 42. A compound in accordance with any one of claims 1 to 8 when used to treat ~or prevent cancer. 43. A compound in accordance with claim 42 wherein the cancer is selected from *,,cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung. 44. A compound in accordance with claim 42 wherein the cancer is selected from 0 •histiocytic lymphoma, lung adenocarcinoma, small cell lung cancers, pancreatic cancer, gioblastomas and breast carcinoma. 45. A compound in accordance with any one of claims 1 to 8 when used to treat or prevent a disease in which neoangiogenesis is implicated. 46. A compound in accordance with claim 45, wherein the disease is an ocular disease. 47. A compound in accordance with any one of claims 1 to 8 when used to treat or prevent retinal vascularisation. 48. A compound in accordance with any one of claims 1 to 8 when used to treat or prevent diabetic retinopathy. 49. A compound in accordance with any one of claims 1 to 8 when used to treat R or prevent age related macular degeneration. t T 0[I:\DAYLIB\libh]00792.doc:sak 73 A compound in accordance with any one of claims 1 to 8 when used to treat or prevent inflammatory diseases. 51. A compound in accordance with claim 50, wherein the inflammatory disease is selected from rheumatoid arthritis, psoriasis, contact dermatitis and delayed hypersensitivity reactions. 52. 52. A compound in accordance with any one of claims 1 to 8 when used to inhibit tyrosine kinase. Dated 6 March, 2002 Merck Co., Inc. 1o Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON 00 0 [I:\DAYLIB\ibh]00792.doc:sak