WO2000002871A1 - Novel angiogenesis inhibitors - Google Patents

Novel angiogenesis inhibitors Download PDF

Info

Publication number
WO2000002871A1
WO2000002871A1 PCT/US1999/015200 US9915200W WO0002871A1 WO 2000002871 A1 WO2000002871 A1 WO 2000002871A1 US 9915200 W US9915200 W US 9915200W WO 0002871 A1 WO0002871 A1 WO 0002871A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
hydroxy
acetamidooxazole
valeramidooxazole
benzamidooxazole
Prior art date
Application number
PCT/US1999/015200
Other languages
French (fr)
Inventor
Mark E. Fraley
Randall W. Hungate
William F. Hoffman
William R. Huckle
Richard L. Kendall
Kenneth A. Thomas, Jr.
Original Assignee
Merck & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9822700.2A external-priority patent/GB9822700D0/en
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU52082/99A priority Critical patent/AU747427B2/en
Priority to JP2000559102A priority patent/JP2002520324A/en
Priority to EP99937204A priority patent/EP1097147A4/en
Priority to CA002336848A priority patent/CA2336848A1/en
Publication of WO2000002871A1 publication Critical patent/WO2000002871A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/48—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • 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 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.
  • cancers include histiocytic lymphoma, lung adenocarcinoma and small cell lung cancers. Additional examples include cancers in which overexpression or activation of Raf-activating oncogenes (e.g., K- ras, erb-B) is observed. More particularly, such cancers include pancreatic and breast carcinoma.
  • Raf-activating oncogenes e.g., K- ras, erb-B
  • tyrosine kinases are useful for the prevention and treatment of proliferative diseases dependent on these enzymes.
  • 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.
  • VEGF Vascular endothelial growth factor binds the high affinity membrane-spanning tyrosine kinase receptors KDR and Flt-1.
  • KDR mediates the mitogenic function of VEGF
  • Flt-1 appears to modulate non-mitogenic functions such as those associated with cellular adhesion. Inhibiting KDR thus modulates the level of mitogenic VEGF activity.
  • VEGF 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 p ⁇ 2 levels in mice that lead to neovascularization.
  • 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 tumor cells continue to express VEGF in culture, the antibodies do not diminish their mitotic rate.
  • VEGF tumor-derived VEGF does not function as an autocrine mitogenic factor. Therefore, VEGF contributes to tumor growth in vivo by promoting angiogenesis through its paracrine vascular endothelial cell chemotactic and mitogenic activities.
  • monoclonal antibodies also inhibit the growth of typically less well vascularized human colon cancers in athymic mice and decrease the number of tumors arising from inoculated cells.
  • 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 tumors in nude mice, do not produce detectable tumors if both VEGF alleles are knocked out. Taken together, these data indicate the role of VEGF in the growth of solid tumors.
  • KDR or Flt-1 are implicated in pathological neoangiogenesis, and these receptors are useful in the treatment of diseases in which neoangiogenesis is part of the overall pathology, e.g., inflammation, diabetic retinal vascularization, as well as various forms of cancer.
  • the compounds of the instant invention represent novel structures for the inhibition of KDR kinase.
  • a compound is disclosed in accordance with formula I :
  • X is O or S
  • R is H, Ci _ ⁇ o alkyl, C3-6 cycloalkyl, C5.10 aryl, halo, CF3, C3.10 heterocyclyl, or C5.10 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R is H, C ⁇ _6 alkyl, C5.10 aryl, C5.10 heteroaryl, C3-6 cycloalkyl; said alkyl, aryl, heteroaryl or cycloalkyl optionally substituted with from one to three members selected from R ;
  • R is C ⁇ _6 alkyl, C5.10 aryl, C5.10 heteroaryl, C3-6 cycloalkyl; said alkyl, aryl, heteroaryl or cycloalkyl optionally substituted with from one to three members selected from R ;
  • R is H, C ⁇ _ ⁇ o alkyl, C3.6 cycloalkyl, C .Q alkoxy, C2-10 alkenyl, C2-10 alkynyl, C5.10 aryl, C3.10 heterocyclyl, C1-6 alkoxyNR R ⁇ , N0 2 , OH, -NH 2 or C5.10 heteroaryl, said alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from R a ;
  • R a is H, C ⁇ _ ⁇ o alkyl, halogen, CF 3) NO 2 , NHC(O)R*, OR, - NR NR7R8, R7R8, C5.10 aryl, C5.10 aralkyl, C 5 . 10 heteroaryl or C3.10 heterocyclyl, said aralkyl, aryl and heteroaryl optionally substituted with 1-2 groups of NO2, halo, C5.10 aryl, Ci-6 alkoxy, Cl-6 alkyl or CF3,
  • R* is H, or C ⁇ _ 6 alkyl, NHC(O)CHR(C 5 . 10 aralkyl), the aryl ring of the aralkyl being optionally substituted with 1-3 groups of OH, Cl-6 alkyl, or halo,
  • R is H, or C ⁇ _g alkyl
  • R7&R8 are independently H, C .IQ alkyl, C3-6 cycloalkyl, COR,
  • COOR, CO2, C5.10 aryl, C3.10 heterocyclyl, or C5.10 heteroaryl or NR7R8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated rin containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, O and S.
  • a pharmaceutical composition which is comprised of a compound represented by the formula I:
  • R , R , R and R are described as above or a pharmaceutically acceptable salt or hydrate or prodrug thereof in combination with a carrier.
  • Also included is a method of treating a tyrosine kinase dependent disease or condition in a mammal which comprises administering to a mammalian patient in need of such treatment a tyrosine kinase dependent disease or condition treating amount of a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof. Also included is a method of treating cancer in a mammalian patient in need of such treatment which is comprised of admininstering to said patient an anti-cancer effective amount of a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof.
  • Also included in the present invention is a method of treating diseases in which neoangiogenesis is implicated, which is comprised of administering to a mammalian patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof in an amount which is effective for reducing neoangiogenesis. More particularly, a method of treating ocular disease in which neoangiogenesis occurs is included herein, which is comprised of administering to a mammalian patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt hydrate or pro-drug thereof in an amount which is effective for treating said ocular disease.
  • a method of treating retinal vascularization is included herein, which is comprised of administering to a mammalian patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof in an amount which is effective for treating retinal vascularization.
  • Diabetic retinopathy is an example of a disease in which neoangiogenesis or retinal vascularization is part of the overall disease etiology.
  • a method of treating age-related macular degeneration is also included.
  • 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. 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.
  • 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.
  • 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 carbon- carbon 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 of R a as defined herein.
  • Preferred substituted aryls include phenyl and naphthyl substituted with one or two groups.
  • aralkyl is intended to mean an aryl or heteroaryl moiety, as defined herein, attached through a Cl-6 alkyl linker, where alkyl is defined above.
  • alkyl is defined above.
  • aralkyls include, but are not limited to, benzyl, naphthylmethyl, phenylpropyl, 2-pyridylmethyl, 2-imidazolylethyl, 2- quinolinylmethy, 2-imidazolylmethyl and the like.
  • heterocycle, heteroaryl or heterocyclic represents a stable 5- to 7- membered 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, 2- oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazoly
  • 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.
  • alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy allyloxy, propargyloxy, vinyloxy and the like.
  • 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 (e.g. VEGF) of the tyrosine kinases.
  • the activating ligands e.g. VEGF
  • Examples include psoriasis, cancer, immunoregulation (graft rejection), atherosclerosis, rheumatoid arthritis, angiogenesis (e.g. tumor growth, diabetic retinopathy), age related macular degeneration, etc.
  • X is O and all other variables are as originally described.
  • Still another aspect of the invention is realized when
  • R and R are C5.10 aryl or C5.10 heteroaryl
  • R is H, C ⁇ _ ⁇ o alkyl, C5.10 aryl, halo, CF3, or C5.10 heteroaryl; said alkyl, aryl, and heteroaryl being optionally substituted with from one to three members selected from R a ;
  • R is H, C ⁇ .g alkyl or C5.10 aryl, sai alkyl or aryl optionally substituted with one to three members selected from R ;
  • R & R are independently C .IQ alkyl, C5.10 aryl, or C5.10 heteroaryl, said alkyl, aryl and heteroaryl being optionally substituted with from one to three members selected from R a ;and all other variables are as described above.
  • 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 synthesized by these schemes.
  • the schemes are not limited by the compounds listed nor by any particular substituents employed for illustrative purposes.
  • the examples specifically illustrate the application of the following schemes to specific compounds.
  • Schemes 1 and 2 demonstrate to generalized 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.
  • amino thiazoles can be prepared as described in
  • 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.
  • pharmaceutically acceptable salts and “hydrates” refer to those salts and hydrated forms of the compound which would be apparent to the pharmaceutical chemist, i.e., 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.
  • 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.
  • a counterion e.g., an alkali metal cation such as sodium or potassium.
  • suitable counterions include calcium, magnesium, zinc, ammonium, or alkylammonium cations such as tetramethylammonium, tetrabutylammonium, choline, triethylhydroammonium, meglumine, triethanol- hydroammonium, etc.
  • An appropriate number of counterions is associated with the molecule to maintain overall charge neutrality.
  • an appropriate number of negatively charged counterions is present to maintain overall charge neutrality.
  • Pharmaceutically acceptable salts also include acid addition salts.
  • 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-hydroxy- ethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate
  • 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.
  • 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.
  • 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.
  • any variable e.g., aryl, heteroaryl, R , etc
  • 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.
  • the carrier employed may be, for example, either a solid or liquid.
  • solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • liquid carriers include syrup, peanut oil, olive oil, water and the like.
  • 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, psoriasis, contact dermatitis, delayed hypersensitivity reactions and the like.
  • oral solid dosage forms examples 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.
  • oral liquid dosage forms include solutions, suspensions, syrups, emulsions, soft gelatin capsules and the like.
  • injectable dosage forms include sterile injectable liquids, e.g., solutions, emulsions and suspensions. Examples of injectable solids would include powders which are reconstituted, dissolved or suspended in a liquid prior to injection.
  • 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.
  • 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 80 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.
  • the amide nitrile (7) from above (280mg, 0.93mmol) was dissolved in CH2CI2 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 CH2CI2 and washed further with CH2CI2 to give the desired product.
  • Step 2 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 MgS04 and concentrated to afford the desired product as a solid that was used without further purification. Step 4
  • the amide was dissolved in CHCl3/ ⁇ t3N (1:1, 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 seperated and the organics washed with brine and dried (MgSO4). The material was used without further purification.
  • 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 90oC for 18 hours and then 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 (MgS ⁇ 4). Flash LC (60% Hexanes/EtOAc) gave the desired product.
  • the amide nitrile (0.064mg, 0.2mmol) was partially dissolved in dichlorethane (5mL). MeS ⁇ 3H (0.039mL, O. ⁇ mmol) was then added and the reaction allowed to proceed overnight at room temperature. The reaction was diluted with CH2CI2 and extracted with aqueous NaHCO3 (sat), water and then dried (MgS04). The desired product was isolated by flash LC (40% EtOAc/ CH2CI2) to give a pale yellow solid. The material was triturated with Et2O, filtered and dried over P2 ⁇ -
  • Step 6 l-F4-Phenyl-2-(5-thiophen-3-yl-pyridin-3-yl)-oxazol-5-yll-pyrrolidin-2-one
  • Chloro amide from above (0.38g, 0.896mmol) was treated with Et3N (5mL) and a small amount of CHCI3 until homogeneous. The reaction was heated to 90f>C for 2hr. The reaction was then cooled to room temperature and concentrated to dryness. The residue was partitioned between EtOAc and aqueous HCl (0.5N). The organics were washed further with water, brine, and dried (MgS ⁇ 4). Flash LC 5%EtOAc/ CH2CI2 gave an off white solid that was triturated with diethylether and dried over P2O5.
  • This compound was prepared in a manner analogous to that described above.
  • 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 radio- labeled phosphate quantified by scintillation counting.
  • 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.
  • GST glutathione S-transferase
  • Soluble recombinant GST-kinase domain fusion proteins were expressed in Spodoptera frugiperda (Sf21) insect cells (Invitrogen) using a baculovirus expression vector (pAcG2T, Pharmingen).
  • Sf21 cells were infected with recombinant virus at a multiplicity of infection of 5 virus particles/ cell and grown at
  • VEGF receptors that mediate mitogenic responses to the growth factor is largely restricted to vascular 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.
  • 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.
  • 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.
  • EGM Endothelial Growth Medium
  • NUNC #167008 NUNCLON 96-well polystyrene tissue culture plates
  • Assay Medium Dulbecco's modification of Eagle's medium containing 1 g/ml glucose (low-glucose DMEM; Mediatech) plus 10% (v/v) fetal bovine serum (Clonetics).
  • HUVEC monolayers maintained in EGM are harvested by trypsinization and plated at a density of 4PPP cells per 100 ul Assay Medium per well in 96-well plates. Cells are growth- arrested for 24 hours at 37°C in a humidified atmosphere containing 5% C02-
  • Growth- arrest medium is replaced by 100 ul Assay Medium containing either vehicle (0.25% [v/v] DMSO) or the desired final concentration of test compound. All determinations are performed in triplicate. Cells are then incubated at 37 C/5% CO2 for 2 hours to allow test compounds to enter cells.
  • [ 3 H]Thymidine (10 ul/well) is added. q 5. Three days after addition of [ HJthymidine, 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
  • 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, e.g., diabetic retinopathy and in the treatment of cancers, e.g., solid tumors.
  • the instant compounds inhibit VEGF- stimulated mitogenesis of human vascular endothelial cells in culture with IC50 values between 0.01 - 5.0 ⁇ M.
  • These compounds also show selectivity over related tyrosine kinases (e.g. FGFRl and the Src family).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

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 and conditions such as angiogenesis, cancer, atherosclerosis, diabetic retinopathy or autoimmune diseases, in mammals.

Description

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 (e.g., K- ras, 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. 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 Flt-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 pθ2 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 tumor cells continue to express VEGF in culture, the antibodies do not diminish their mitotic rate. Thus tumor-derived VEGF does not function as an autocrine mitogenic factor. Therefore, VEGF contributes to tumor 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 vascularized human colon cancers in athymic mice and decrease the number of tumors 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 tumors in nude mice, do not produce detectable tumors if both VEGF alleles are knocked out. Taken together, these data indicate the role of VEGF in the growth of solid tumors. Inhibition of KDR or Flt-1 is implicated in pathological neoangiogenesis, and these receptors are useful in the treatment of diseases in which neoangiogenesis is part of the overall pathology, e.g., inflammation, diabetic retinal vascularization, 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
A compound is disclosed in accordance with formula I :
Figure imgf000006_0001
I or a pharmaceutically acceptable salt, hydrate or prodrug thereof,
wherein
X is O or S;
R is H, Ci _ιo alkyl, C3-6 cycloalkyl, C5.10 aryl, halo, CF3, C3.10 heterocyclyl, or C5.10 heteroaryl; said alkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;
0 R is H, Cι_6 alkyl, C5.10 aryl, C5.10 heteroaryl, C3-6 cycloalkyl; said alkyl, aryl, heteroaryl or cycloalkyl optionally substituted with from one to three members selected from R ;
Q R is Cι_6 alkyl, C5.10 aryl, C5.10 heteroaryl, C3-6 cycloalkyl; said alkyl, aryl, heteroaryl or cycloalkyl optionally substituted with from one to three members selected from R ; R is H, Cι_ιo alkyl, C3.6 cycloalkyl, C .Q alkoxy, C2-10 alkenyl, C2-10 alkynyl, C5.10 aryl, C3.10 heterocyclyl, C1-6 alkoxyNR Rδ, N02, OH, -NH2 or C5.10 heteroaryl, said alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with from one to three members selected from Ra;
Ra is H, Cι_ιo alkyl, halogen, CF3) NO2, NHC(O)R*, OR, - NR NR7R8, R7R8, C5.10 aryl, C5.10 aralkyl, C5.10 heteroaryl or C3.10 heterocyclyl, said aralkyl, aryl and heteroaryl optionally substituted with 1-2 groups of NO2, halo, C5.10 aryl, Ci-6 alkoxy, Cl-6 alkyl or CF3,
R* is H, or Cι_6 alkyl, NHC(O)CHR(C5.10 aralkyl), the aryl ring of the aralkyl being optionally substituted with 1-3 groups of OH, Cl-6 alkyl, or halo,
R is H, or Cι_g alkyl; and
R7&R8 are independently H, C .IQ alkyl, C3-6 cycloalkyl, COR,
COOR, CO2, C5.10 aryl, C3.10 heterocyclyl, or C5.10 heteroaryl or NR7R8 can be taken together to form a heterocyclic 5-10 membered saturated or unsaturated rin containing, in addition to the nitrogen atom, one to two additional heteroatoms selected from the group consisting of N, O and S. Also disclosed is a pharmaceutical composition which is comprised of a compound represented by the formula I:
Figure imgf000008_0001
wherein R , R , R and R are described as above or a pharmaceutically acceptable salt or hydrate or prodrug thereof in combination with a carrier.
Also included is a method of treating a tyrosine kinase dependent disease or condition in a mammal which comprises administering to a mammalian patient in need of such treatment a tyrosine kinase dependent disease or condition treating amount of a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof. Also included is a method of treating cancer in a mammalian patient in need of such treatment which is comprised of admininstering to said patient an anti-cancer effective amount of a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof. Also included in the present invention is a method of treating diseases in which neoangiogenesis is implicated, which is comprised of administering to a mammalian patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof in an amount which is effective for reducing neoangiogenesis. More particularly, a method of treating ocular disease in which neoangiogenesis occurs is included herein, which is comprised of administering to a mammalian patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt hydrate or pro-drug thereof in an amount which is effective for treating said ocular disease.
More particularly, a method of treating retinal vascularization is included herein, which is comprised of administering to a mammalian patient in need of such treatment a compound of formula I or a pharmaceutically acceptable salt, hydrate or pro-drug thereof in an amount which is effective for treating retinal vascularization. Diabetic retinopathy is an example of a disease in which neoangiogenesis or retinal vascularization is part of the overall disease etiology. Also included is a method of treating age-related macular degeneration.
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. When substituted alkyl is present, this refers to a straight, branched or cyclic alkyl group as defined above, substituted with 1-3 groups of Ra, 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 Ra, 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 carbon- carbon 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 Ra, 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 of Ra as defined herein. Preferred substituted aryls include phenyl and naphthyl substituted with one or two groups. As used herein, "aralkyl" is intended to mean an aryl or heteroaryl moiety, as defined herein, attached through a Cl-6 alkyl linker, where alkyl is defined above. Examples of aralkyls include, but are not limited to, benzyl, naphthylmethyl, phenylpropyl, 2-pyridylmethyl, 2-imidazolylethyl, 2- quinolinylmethy, 2-imidazolylmethyl and the like.
The term heterocycle, heteroaryl or heterocyclic, as used herein except where noted, represents a stable 5- to 7- membered 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 Ra. Examples of such heterocyclic elements include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolodinyl, 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, 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 (e.g. VEGF) of the tyrosine kinases. Examples include psoriasis, cancer, immunoregulation (graft rejection), atherosclerosis, rheumatoid arthritis, angiogenesis (e.g. 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
O A R and R , independently, are C5.10 aryl or C5.10 heteroaryl
optionally substituted with 1-3 groups of R .
Yet another aspect of the invention is realized when:
R is H, Cι_ιo alkyl, C5.10 aryl, halo, CF3, or C5.10 heteroaryl; said alkyl, aryl, and heteroaryl being optionally substituted with from one to three members selected from Ra;
2 R is H, Cχ.g alkyl or C5.10 aryl, sai alkyl or aryl optionally substituted with one to three members selected from R ;
R & R are independently C .IQ alkyl, C5.10 aryl, or C5.10 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-trifluoroacetamidooxazole;
2-(2-(3-hydroxy)napthyl)-4-(3-thiophenyl)-5-acetamidooxazole;
2-(2-(3-hydroxy)napthyl)-4-pheny-5-acetamidooxazole;
2-(2-(3-hydroxy)napthyl)-4-(3-thiophenyl)-5-trifluoroacetamido- oxazole;
2-(2-(2-hydroxy-4-methoxy)phenyl)-4-phenyl-5-acetamidooxazole;
2-(2-(2-hydroxy-4-methyl)phenyl)-4-phenyl-5-acetamidooxazole;
2-(2-(2-hydroxy)phenyl)-4-phenyl-5-acetamidooxazole;
2-(5-isoquinolinyl)-4-phenyl-5-acetamidooxazole; 2-(2-(3-hydroxy)napthyl)-4-(3-thiophenyl)-5-acetamidooxazole;
2-(2-(3-hydroxy)napthyl)-4-phenyl-5-acetamidooxazole;
2-(3-(5-phenyl)pyridyl)-4-phenyl-5-acetamidooxazole;
2-(3-(5-(3-nitro)phenyl)pyridyl)-4-phenyl-5-acetamidooxazole;
2-(3-(5-(l-naphthyl)pyridyl)-4-phenyl-5-acetamidooxazole; 2-(3-(5-(4-methyl)phenyl)pyridyl)-4-phenyl-5-acetamidooxazole;
2-(3-(5-(4-methoxy)phenyl)pyridyl)-4-phenyl-5-acetamidooxazole;
2-(3-(5-(3-chloro)phenyl)pyridyl)-4-phenyl-5-acetamidooxazole;
2-(3-(5-(3-methoxy)phenyl)pyridyl)-4-phenyl-5-acetamidooxazole; 2-(3-(5-(3-fluoro)phenyl)pyridyl)-4-phenyl-5-acetamidooxazole;
2-(3-(5-(2-naphthyl)pyridyl)-4-phenyl-5-acetamidooxazole;
2-(3-(5-(2-trifiuoromethyl)phenyl)pyridyl)-4-phenyl-5- acetamidooxazole;
2-(2-hydroxy)phenyl-4-pheny-5-acetamidooxazole; 2-(2-hydroxy)phenyl-4-pheny-5-benzamidooxazole;
2-(2-hydroxy)phenyl-4-pheny-5-valeramidooxazole;
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-(l-naphthyl))-phenyl-4-phenyl-5-acetamidooxazole; 2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-phenyl-5-acetamidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-ρhenyl-5- acetamidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-phenyl-5-acetamidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-phenyl-5- acetamidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-phenyl-5-acetamidooxazole;
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;
2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-thiophenyl-5- acetamidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-thiophenyl-5-acetamidooxazole; 2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-thiophenyl-5- acetamidooxazole;
2-(2-hydroxy-(4-(4 -methoxy)-phenyl)-phenyl-4-thiophenyl-5- acetamidooxazole 2-(2-hydroxy-(4-(3 -chloro)-phenyl)-phenyl-4-thiophenyl-5- acetamidooxazole 2-(2-hydroxy-(4-(3' methoxy)-phenyl)-phenyl-4-thiophenyl-5- acetamidooxazole 2-(2-hydroxy-(4-(3 -fluoro)-phenyl)-phenyl-4-thiophenyl-5- acetamidooxazole 2-(2-hydroxy-(4-(2- naphthyl)-phenyl)-phenyl-4-thiophenyl-5- acetamidooxazole 2-(2-hydroxy-(4-(2- trifluoromethyl)-phenyl)-phenyl-4-thiophenyl-5- acetamidooxazole; 2-(2-hydroxy-4-phenyl)-phenyl-4-(3-pyridyl)-5-acetamidooxazole;
2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(3-pyridyl)-5- acetamidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(3-pyridyl)-5-acetamidooxazole;
2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(3-pyridyl)-5- acetamidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(3-pyridyl)-5- acetamidooxazole;
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- acetamidooxazole;
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-chlorophenyl)-5-acetamidooxazole
2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(3-chlorophenyl)-5- acetamidooxazole;
2-(2-hydroxy-(4-(l- naphthyl))-phenyl-4-(3-chlorophenyl)-5- acetamidooxazole 2-(2-hydroxy-(4-(4 methyl)-phenyl)-phenyl-4-(3-chlorophenyl)-5- acetamidooxazole 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-chlorophenyl)-5- acetamidooxazole 2-(2-hydroxy-(4-(2- naphthyl)-phenyl)-phenyl-4-(3-chlorophenyl)-5- acetamidooxazole 2-(2-hydroxy-(4-(2. trifluoromethyl)-phenyl)-phenyl-4-(3-chlorophenyl)-5- 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; 2-(2-hydroxy-(4-( l-naphthyl))-phenyl-4-(2-chlorophenyl)-5- acetamidooxazole;
2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(2-chlorophenyl)-5- acetamidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(2-chlorophenyl)-5- acetamidooxazole; 2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(2-chlorophenyl)-5- acetamidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(2-chlorophenyl)-5- acetamidooxazole; 2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(2-chlorophenyl)-5- acetamidooxazole;
2-(2-hydroxy-(4-(2-naphthyl)-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-(l- naphthyl))-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 2-(2-hydroxy-(4-(3 -fluoro)-phenyl)-phenyl-4-(4-chlorophenyl)-5- acetamidooxazole 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- acetamidooxazole;
2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(4-trifluoromethylphenyl)-5- acetamidooxazole; 2-(2-hydroxy-(4-(l-naphthyl))-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-(4-trifluoromethylphenyl)-
5-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-methoxyphenyl)-5- acetamidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(3-methoxyphenyl)-5- acetamidooxazole;
2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(3-methoxyphenyl)-5- acetamidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(3-methoxyphenyl)-5- acetamidooxazole; 2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(3-methoxyphenyl)-5- acetamidooxazole;
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;
2-(2-hydroxy-(4-(2-naphthyl)-ρhenyl)-phenyl-4-(3-methoxyphenyl)-5- acetamidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(3-methoxyphenyl)- 5-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-(l -naphthyl))-phenyl-4-(3-thiophenyl)-5- acetamidooxazole 2-(2-hydroxy-(4-(4' -methyl)-phenyl)-phenyl-4-(3-thiophenyl)-5- acetamidooxazole 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- 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-thiophenyl)-5- acetamidooxazole 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-(l- n: aphthyl))-phenyl-4-(2-thiophenyl)-5- acetamidooxazole 2-(2-hydroxy-(4-(4' methyl)-phenyl)-phenyl-4-(2-thiophenyl)-5- acetamidooxazole 2-(2-hydroxy-(4-(4' -methoxy)-phenyl)-phenyl-4-(2-thiophenyl)-5- acetamidooxazole 2-(2-hydroxy-(4-(3 -chloro)-phenyl)-phenyl-4-(2-thiophenyl)-5- acetamidooxazole 2-(2-hydroxy-(4-(3 methoxy)-phenyl)-phenyl-4-(2-thiophenyl)-5- acetamidooxazole 2-(2-hydroxy-(4-(3' -fluoro)-phenyl)-phenyl-4-(2-thiophenyl)-5- acetamidooxazole 2-(2-hydroxy-(4-(2- naphthyl)-phenyl)-phenyl-4-(2-thiophenyl)-5- acetamidooxazole;;
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-(l-naphthyl))-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; 2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(2,6-dichlorophenyl)-5- acetamidooxazole;
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-hydroxy-4-phenyl)-phenyl-4-phenyl-5-benzamidooxazole; 2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-phenyl-5-benzamidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-phenyl-5-benzamidooxazole;
2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-phenyl-5-benzamidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-phenyl-5- benzamidooxazole; 2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-phenyl-5-benzamidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-phenyl-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-phenyl-5-benzamidooxazole;
2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-phenyl-5- benzamidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-phenyl-5- benzamidooxazole;
2-(2-hydroxy-4-phenyl)-phenyl-4-thiophenyl-5-benzamidooxazole
2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-thiophenyl-5- benzamidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-thiophenyl-5-benzamidooxazole;
2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-thiophenyl-5- benzamidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-thiophenyl-5- benzamidooxazole; 2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-thiophenyl-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-thiophenyl-5- benzamidooxazole; 2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-thiophenyl-5- benzamidooxazole;
2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-thiophenyl-5- benzamidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-thiophenyl-5- benzamidooxazole;
2-(2-hydroxy-4-phenyl)-phenyl-4-(3-pyridyl)-5-benzamidooxazole;
2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(3-pyridyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(3-pyridyl)-5-benzamidooxazole; 2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(3-pyridyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(3-pyridyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(3-pyridyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(3-pyridyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(3-pyridyl)-5- benzamidooxazole; 2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(3-pyridyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(3-pyridyl)-5- benzamidooxazole;
2-(2-hydroxy-4-phenyl)-phenyl-4-(3-chlorophenyl)-5-benzamidooxazole; 2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(3-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(3-chlorophenyl)-5- benzamidooxazole; 2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(3-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(3-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(3-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(3-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(3-chlorophenyl)-5- benzamidooxazole; 2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(3-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(3-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-4-phenyl)-phenyl-4-(2-chlorophenyl)-5-benzamidooxazole; 2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(2-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(2-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(2-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(2-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(2-chlorophenyl)-5- benzamidooxazole; 2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(2-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(2-chlorophenyl)-5- benzamidooxazole; 2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(2-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(2-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-4-phenyl)-phenyl-4-(4-chlorophenyl)-5-benzamidooxazole 2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(4-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(4-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(4-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(4-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(4-chlorophenyl)-5- benzamidooxazole; 2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(4-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(4-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(4-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(4-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-4-phenyl)-phenyl-4-(4-trifluoromethylphenyl)-5- benzamidooxazole; 2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(4-trifluoromethylphenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(4-trifluoromethylphenyl)-5- benzamidooxazole; 2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(4-trifluoromethylphenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(4-trifluoromethylphenyl)-
5-benzamidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(4-trifluoromethylphenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(4-trifluoromethylphenyl)-
5-benzamidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(4-trifluoromethylphenyl)-5- benzamidooxazole; 2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(4-trifluoromethylphenyl)-
5-benzamidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(4- trifluoromethylphenyl)-5-benzamidooxazole;
2-(2-hydroxy-4-phenyl)-phenyl-4-(3-methoxyphenyl)-5-benzamidooxazole; 2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(3-methoxyphenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(3-methoxyphenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(3-methoxyphenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(3-methoxyphenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(3-methoxyphenyl)-5- benzamidooxazole; 2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(3-methoxyphenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(3-methoxyphenyl)-5- benzamidooxazole; 2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(3-methoxyphenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(3-methoxyphenyl)-
5-benzamidooxazole;
2-(2-hydroxy-4-phenyl)-phenyl-4-(3-thiophenyl)-5-benzamidooxazole; 2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(3-thiophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(3-thiophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(3-thiophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(3-thiophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(3-thiophenyl)-5- benzamidooxazole; 2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(3-thiophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(3-thiophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(3-thiophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(3-thiophenyl)-5- benzamidooxazole;
2-(2-hydroxy-4-phenyl)-phenyl-4-(2-thiophenyl)-5-benzamidooxazole
2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(2-thiophenyl)-5- benzamidooxazole; 2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(2-thiophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(2-thiophenyl)-5- benzamidooxazole; 2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(2-thiophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(2-thiophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(2-thiophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(2-thiophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(2-thiophenyl)-5- benzamidooxazole; 2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(2-thiophenyl)-5- benzamidooxazole;
2-(2-hydroxy-4-phenyl)-phenyl-4-(2,6-dichlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(2,6-dichlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(2,6-dichlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(2,6-dichlorophenyl)-5- benzamidooxazole; 2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(2,6-dichlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(2,6-dichlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(2,6-dichlorophenyl)-5- benzamidooxazole; 2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(2,6-dichlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(2,6-dichlorophenyl)-5- benzamidooxazole; 2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(2,6- dichlorophenyl)-5-benzamidooxazole;
2-(2-hydroxy-4-phenyl)-phenyl-4-phenyl-5-valeramidooxazole;
2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-phenyl-5-valeramidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-phenyl-5-valeramidooxazole; 2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-phenyl-5- valeramidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-phenyl-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-phenyl-5-valeramidooxazole; 2-(2-hydroxy-(4-(3'-rnethoxy)-phenyl)-phenyl-4-phenyl-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-ρhenyl)-phenyl-4-phenyl-5-valeramidooxazole;
2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-phenyl-5- valeramidooxazole; 2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-phenyl-5- valeramidooxazole;
2-(2-hydroxy-4-phenyl)-phenyl-4-thiophenyl-5-valeramidooxazole;
2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-thiophenyl-5- valeramidooxazole; 2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-thiophenyl-5-valeramidooxazole;
2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-thiophenyl-5- valeramidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-thiophenyl-5- valeramidooxazole; 2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-thiophenyl-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-thiophenyl-5- valeramidooxazole; 2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-thiophenyl-5- valeramidooxazole;
2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-thiophenyl-5- valeramidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-thiophenyl-5- valeramidooxazole;
2-(2-hydroxy-4-phenyl)-phenyl-4-(3-pyridyl)-5-valeramidooxazole
2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(3-pyridyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(3-pyridyl)-5-valeramidooxazole; 2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(3-pyridyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(3-pyridyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(3-pyridyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(3-pyridyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-fiuoro)-phenyl)-phenyl-4-(3-pyridyl)-5- valeramidooxazole; 2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(3-pyridyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(3-pyridyl)-5- valeramidooxazole;
2-(2-hydroxy-4-phenyl)-phenyl-4-(3-chlorophenyl)-5-valeramidooxazole; 2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(3-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(3-chlorophenyl)-5- valeramidooxazole; 2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(3-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(3-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(3-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(3-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(3-chlorophenyl)-5- valeramidooxazole; 2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(3-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(3-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-4-phenyl)-phenyl-4-(2-chlorophenyl)-5-valeramidooxazole; 2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(2-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(2-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(2-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(2-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(2-chlorophenyl)-5- valeramidooxazole; 2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(2-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(2-chlorophenyl)-5- valeramidooxazole; 2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(2-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(2-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-4-phenyl)-phenyl-4-(4-chlorophenyl)-5-valeramidooxazole; 2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(4-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(4-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(4-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(4-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(4-chlorophenyl)-5- valeramidooxazole; 2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(4-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(4-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(4-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(4-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-4-phenyl)-phenyl-4-(4-trifluoromethylphenyl)-5- valeramidooxazole; 2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(4-trifluoromethylphenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(4-trifluoromethylphenyl)-5- valeramidooxazole; 2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(4-trifluoromethylphenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(4-trifluoromethylphenyl)-
5-valeramidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(4-trifluoromethylphenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(4-trifluoromethylphenyl)-
5-valeramidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(4-trifluoromethylphenyl)-5- valeramidooxazole; 2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(4-trifluoromethylphenyl)-
5-valeramidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(4- trifluoromethylphenyl )- 5 -valeramidooxazole ;
2-(2-hydroxy-4-phenyl)-phenyl-4-(3-methoxyphenyl)-5-valeramidooxazole; 2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(3-methoxyphenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(3-methoxyphenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(3-methoxyphenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(3-methoxyphenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(3-methoxyphenyl)-5- valeramidooxazole; 2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(3-methoxyphenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(3-methoxyphenyl)-5- valeramidooxazole; 2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(3-methoxyphenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(3-methoxyphenyl)-
5-valeramidooxazole;
2-(2-hydroxy-4-phenyl)-phenyl-4-(3-thiophenyl)-5-valeramidooxazole; 2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(3-thiophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(3-thiophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(3-thiophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(3-thiophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(3-thiophenyl)-5- valeramidooxazole; 2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(3-thiophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(3-thiophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(3-thiophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(3-thiophenyl)-5- valeramidooxazole;
2-(2-hydroxy-4-phenyl)-phenyl-4-(2-thiophenyl)-5-valeramidooxazole;
2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(2-thiophenyl)-5- valeramidooxazole; 2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(2-thiophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(2-thiophenyl)-5- valeramidooxazole; 2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(2-thiophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(2-thiophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(2-thiophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(2-thiophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(2-thiophenyl)-5- valeramidooxazole; 2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(2-thiophenyl)-5- valeramidooxazole;
2-(2-hydroxy-4-phenyl)-phenyl-4-(2,6-dichlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(2,6-dichlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(2,6-dichlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(2,6-dichlorophenyl)-5- valeramidooxazole; 2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(2,6-dichlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(2,6-dichlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(2,6-dichlorophenyl)-5- valeramidooxazole; 2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(2,6-dichlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(2,6-dichlorophenyl)-5- valeramidooxazole and 2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(2,6- dichlorophenyl)-5-valeramidooxazole.
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 synthesized by these schemes. The schemes, however, are not limited by the compounds listed nor by any particular substituents employed for illustrative purposes. The examples specifically illustrate the application of the following schemes to specific compounds. Schemes 1 and 2 demonstrate to generalized 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.
SCHEME 1
Oxazoles from amide nitriles
Figure imgf000036_0001
SCHEME 2
Oxazoles from diamides
Figure imgf000037_0001
O coupling agent TFAA/TFA
N R
R CO H π I // CH C
M Ri O
Figure imgf000037_0002
φ -indicates a polymeric support
SCHEME 3
Figure imgf000038_0001
Figure imgf000038_0002
Figure imgf000038_0003
The amino thiazoles can be prepared as described in
"Reactions of α-amino- and α-acylaminothioamides with aluminum chloride. Synthesis of some imidazole and thiazole derivatives." Nyitrai, Jozsef; Lempert, Karoly. Acta Chim. (Budapest) (1972), 73(1), 43-61, or "Cyclization of ω-chloro-ω- acylamido acetophenones." Drach,B. S.; Dolgushina, I. Yu.; Sinitsa, A. D. Inst. Org. Khim., Kiev, USSR. Khim. Geterotsikl. Soedin. (1974), (7), 928-31. Conversion ofthe 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, i.e., 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, e.g., 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, triethanol- hydroammonium, etc. An appropriate number of counterions is 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-hydroxy- ethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, 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. 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 (e.g., aryl, heteroaryl, R , 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, 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, e.g., 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 80 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. EXAMPLE 1
2-(2-(3-hydroxy)napthyl)-4-phenyl-5-trifluoracetamidooxazole
Figure imgf000043_0001
Step l
Figure imgf000043_0002
2-amino-2-phenylacetonitrile hydrochloride (1) (3.0 g,
18mmol) and 2- hydroxy-3-napthoic acid (2) (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, 81mmol) 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 (3X), NaCl solution and the organics dried over sodium sulfate. Flash chromatography provided the desired product (3). IH NMR (CDCI3) d 7.95 (s, IH), 7.24-7.7 (m, 10H), 7.15 (brd, IH), 6.38 (d, IH). Step 2
The amide nitrile (3) 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 (4) which was used in the next step without further purification. 1H NMR (CDCI3) d 8.4 (s, IH), 7.7-7.9 ( , 4H), 7.3-7.5 (m, 6H), 3.0 (brs, IH).
EXAMPLE 2
2-(2-(3-hydroxy)napthyl)-4-phenyl-5-acetamidooxazole
Figure imgf000044_0001
The 2-(2-(3-hydroxy)napthyl)-4-phenyl-5- trifluoracetamidooxazole (4) 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 H2O (2X), NaCl and dried over Na2S04. After recrystallization from MeOH/EtOAc a white solid was obtained.
1H NMR (DMSO-d6) d 8.5 (s, IH), 8.2 (d, J = 8.2Hz, IH), 7.83 (m, 3H), 7.38- 7.54 (m, 6H), 2.18 (brs, 3H). MS (M++l) 345. EXAMPLE 3
2-(2-(3-hydroxy)napthyl)-4-(3-thiophenyl)-5-trifluoroacetamido- oxazole
Figure imgf000045_0001
Step l
2-amino-2-(3-thiophenyl) acetonitrile hydrochloride
Figure imgf000045_0002
Sodium cyanide (3.77g, 77mmol) was dissolved in water (40ml) followed by ammonium chloride (4.53g, 84.7mmol). Thiophene-3-carboxaldehyde (Aldrich, 8.66g, 77mmol) was dissolved in MeOH (60ml) and added via addition funnel to the rapidly stirring solution in a steady stream. The reaction was allowed to proceed at room temperature overnight. The reaction was diluted with saturated NaHCθ3 and extracted with diethylether (3X100ml). Organics were combined and washed with saturated NaCl and dried over Na2SO4. Organics were concentrated and the in a minimum amount of ether and filtered. The filtrate was satured with HCl gat at 0°C. The solids that formed were filtered and washed with ether to give after drying a yellow solid (6) which was used without further purification. IH NMR (DMSO-d6) d 9.8 (brs,3H), 7.91 (m, IH), 7.70 (rn, IH), 7.43 (m, IH), 6.04 (s, IH).
Step 2
Figure imgf000046_0001
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-yloxy- tripyrrolidinophosphonium hexafluorophosphate (7.2 g, 13.8mmol), 1- hydroxybenzotriazole (1.9g, 13.8mmol) and diisopropylethylamine (7 ml, 40mmol) the reaction was stirred overnight at room temperature. After lδhours the DMF was removed, the residue was taken up into EtOAc and washed successively with IN HCl, H2O, saturated NaHCθ3 and saturated NaCl. After purification by chromatography, product (7) was isolated. XH NMR (CDCI3) d 10.8 ( s, IH), 7.99 (s, IH), 7.64-7.76 (m, 3H), 7.47-7.53 (m, 2H), 7.22-7.36 (m, 4H), 7.04 (brd, J = 7.7 Hz, IH), 6.49 (d, J = 8 Hz, IH).
Step 3
The amide nitrile (7) from above (280mg, 0.93mmol) was dissolved in CH2CI2 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 CH2CI2 and washed further with CH2CI2 to give the desired product.
1H NMR (CDCI3) d 10.7 (s, IH), 8.37 (s, IH), 7.96 (brs, IH), 7.82 (d, J= 8.4 Hz, IH), 7.72 (d, J = 8.3 Hz, IH), 7.68 (m, IH), 7.3-7.52 (m, 6H).
EXAMPLE 4
2-(2-(3-hydroxy)napthyl)-4-(3-thiophenyl)-5-acetamidooxazole
Figure imgf000047_0001
The oxazole (8) (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 NaHCθ3 and saturated NaCl and dried over MgS04. The crude product was suspended in MeOH and treated with IN NaOH (3ml) for lδminutes. Cloudy solution was filtered and the filtrate was neutralized with IN HCl. The solids that formed were filtered washed with MeOH and dried under vacuum to yield the desired product (9). HRMS (M++l) found 351.0803 calculated 351.0803 for C19H15N2O3S.
EXAMPLE 5
l-[2-(2-Amino-quinolin-3-yl)-4-phenyl-oxazol-5-yl1-pyrrolidin-2-one
Figure imgf000048_0001
Step l 2-chloro-quinoline-3-carboxylic acid
Figure imgf000048_0002
To a cold solution LDA (60mL, 120mmol, 2M solution) in THF (400mL) was added 2-chloroquinoline in THF(lOOmL) at such a rate to maintain temperature <70°C. 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 HCl and the solids collected. This material was used without further purification. Step 2
Figure imgf000049_0001
Quinoline acid from above was suspended in CH2CI2 (lOOmL) and cooled to -10°C. Diphenyl phosphinic chloride was then added followed by dropwise addition of Et3N. The reaction was allowed to proceed with warming to 0oC for one hour. The amino nitrile, suspended in CH2CI2 (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 with 0.5N HCl, 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/CH2Cl2).
Step 3
N-r2-(2-Chloro-quinolin-3-yl)-4-phenyl-oxazol-5-yll-2.2.2-trifluoro- acetamide
Figure imgf000050_0001
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 MgS04 and concentrated to afford the desired product as a solid that was used without further purification. Step 4
4- Chloro-N-f2-(2-chloro-quinolin-3-yl)-4-phenyl-oxazol-5-yl1-butyramide
Figure imgf000051_0001
The requisite oxazole was dissolved in CH2CI2 (lOOmL) and treated with 4-chloro-butyrl chloride and diisopropyl ethyl 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 (MgS04). Flash LC (5% EtOAc/ CH2CI2) gave the desired product.
Step 5
l-f2-(2-chloro-quinolin-3-yl)-4-phenyl-oxazol-5-yll-pyrrolidin-2-one
Figure imgf000052_0001
The amide was dissolved in CHCl3/Εt3N (1:1, 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 seperated and the organics washed with brine and dried (MgSO4). The material was used without further purification.
Step 6
l-[2-(2-Amino-quinolin-3-yl)-4-phenyl-oxazol-5-yll-pyrrolidin-2-one
Figure imgf000052_0002
The chloroquinoline derivative from above was suspended in NH3 (1) in a glass bomb. The cap was placed on the vessel and the mixture heated to 80°C overnight. The reaction was cooled to -78oC and contents poured into a beaker to facilitate evaporation of the NH3 (1). The solid residue that remained was partitioned between EtOAc and water. The organics were washed with brine and dried (MgSO4). Flash LC (20% EtOAc/CH2Cl2) gave the desired product plus an amount of recovered starting material.
EXAMPLE 6
l-[4-Phenyl-2-(5-thiophen-3-yl-pyridin-3-yl)-oxazol-5-yll-pyrrolidin-2-one
Figure imgf000053_0001
Step l
5-Thiophen-3-yl-nicotinic acid methyl ester
Figure imgf000053_0002
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 90oC for 18 hours and then 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 (MgSθ4). Flash LC (60% Hexanes/EtOAc) gave the desired product.
Step 2
5-Thiophen-3-yl-nicotinic acid
Figure imgf000054_0001
The ester from above was suspened in MeOH (20mL), treated with IN 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 IN HCl. The solids were filtered and dried over P2O5 at
50°C for 10 hours. This material was used without further purification.
Step 3
N-(Cyano-phenyl-methyl)- 5-thiophen-3-yl-nicotinamide
Figure imgf000055_0001
The acid from above and the benzyl amino nitrile were treated with EDC- HC1 and HO At in DMF (lOmL). 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 NaHC03 (sat), water, and dried (MgSO4). Flash LC (50% CH2Cl2/ΕtOAc) gave the desired product.
Step 4 4-Phenyl-2-(5-thiophen-3-yl-pyridin-3-yl)-oxazol-5-ylamine
Figure imgf000055_0002
The amide nitrile (0.064mg, 0.2mmol) was partially dissolved in dichlorethane (5mL). MeSθ3H (0.039mL, O.βmmol) was then added and the reaction allowed to proceed overnight at room temperature. The reaction was diluted with CH2CI2 and extracted with aqueous NaHCO3 (sat), water and then dried (MgS04). The desired product was isolated by flash LC (40% EtOAc/ CH2CI2) to give a pale yellow solid. The material was triturated with Et2O, filtered and dried over P2θδ-
Step 5
4-Chloro-N-r4-Phenyl-2-(5-thiophen-3-yl-pyridin-3-yl)-oxazol-5-yl]- butyramide
Figure imgf000056_0001
Amino oxazole (319mg, l.Ommol) from above was suspended in CHCI3 (75mL) 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 80°C 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 NaHCθ3. The layers were then separated and organics washed with water and dried over MgSθ4. Flash LC with CH2CI2 followed by 2% EtOAc/CH2Cl2 yield the product as a yellow gum which was used directly in the next step.
Step 6 l-F4-Phenyl-2-(5-thiophen-3-yl-pyridin-3-yl)-oxazol-5-yll-pyrrolidin-2-one
Figure imgf000057_0001
Chloro amide from above (0.38g, 0.896mmol) was treated with Et3N (5mL) and a small amount of CHCI3 until homogeneous. The reaction was heated to 90f>C for 2hr. The reaction was then cooled to room temperature and concentrated to dryness. The residue was partitioned between EtOAc and aqueous HCl (0.5N). The organics were washed further with water, brine, and dried (MgSθ4). Flash LC 5%EtOAc/ CH2CI2 gave an off white solid that was triturated with diethylether and dried over P2O5.
EXAMPLE 7
l-[2-(Hydroxy-5-methoxy-phenyl)-4-phenyl-oxazol-5-yll-pyrrolidin-2-one
This compound was prepared in a manner analogous to that described above.
Figure imgf000057_0002
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 radio- labeled 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).
Lysis buffer
50 mM Tris pH 7.4, 0.5 M NaCl, 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). Wash buffer
50 mM Tris pH 7.4, 0.5 M NaCl, 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
50 mM Tris pH 7.4, 0.5 M NaCl, 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. 10 X reaction buffer
200 mM Tris, pH 7.4, 1.0 M NaCl, 50 mM MnCl2, 10 mM DTT and 5 mg/ml bovine serum albumin (Sigma).
Enzyme dilution buffer
50 mM Tris, pH 7.4, 0.1 M NaCl, 1 M DTT, 10 % glycerol, 100 mg/ml BSA.
10 X Substrate
750 μg/ml poly (glutamic acid, tyrosine; 4:1) (Sigma).
Stop solution
30% trichloroacetic acid, 0.2 M sodium pyrophosphate (both Fisher). Wash solution
15% trichloroacetic acid, 0.2 M sodium pyrophosphate.
Filter plates Millipore #MAFC NOB, GF/C glass fiber 96 well plate. 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 C. Infected cells were harvested by centrifugation at 1000 X g and lysed at 4 °C for 30 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 5 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 μl of inhibitor or control to the assay in 50% DMSO. 2. Add 35 μl of reaction mix containing 5 μl of 10 X reaction buffer, 5 μl 25 mM ATP/10 μCi [ P]ATP (Amersham), and 5 μl 10 X substrate.
3. Start the reaction by the addition of 10 μl of KDR (25 nM) in enzyme dilution buffer. 4. Mix and incubate at room temperature for 15 minutes.
5. Stop by the addition of 50 μl stop solution.
6. Incubate for 15 minutes at 4 C.
7. Transfer a 90 μl aliquot to filter plate. 8. Aspirate and wash 3 times with wash solution.
9. Add 30 μl 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 Dulbecco's modification of Eagle's medium containing 1 g/ml glucose (low-glucose DMEM; Mediatech) plus 10% (v/v) 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.
IPX Growth factors
Solutions of human VEGFχ65 (500 ng/ml; R&D Systems) and bFGF (10 ng/ml; R&D Systems) are prepared in Assay Medium.
IPX r3HlThvmidine
[Methyl-3H]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% (w/v) Na2Cθ3. Method
1. HUVEC monolayers maintained in EGM are harvested by trypsinization and plated at a density of 4PPP cells per 100 ul Assay Medium per well in 96-well plates. Cells are growth- arrested for 24 hours at 37°C in a humidified atmosphere containing 5% C02-
2. Growth- arrest medium is replaced by 100 ul Assay Medium containing either vehicle (0.25% [v/v] DMSO) or the desired final concentration of test compound. All determinations are performed in triplicate. Cells are then incubated at 37 C/5% CO2 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, 10X VEGF solution or 10X bFGF solution. Cells are then incubated at
37°C/5% CO2.
4. After 24 hours in the presence of growth factors, 10X
[3H]Thymidine (10 ul/well) is added. q 5. Three days after addition of [ HJthymidine, 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°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 cell- associated 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, e.g., diabetic retinopathy and in the treatment of cancers, e.g., solid tumors. The instant compounds inhibit VEGF- stimulated mitogenesis of human vascular endothelial cells in culture with IC50 values between 0.01 - 5.0 μM. These compounds also show selectivity over related tyrosine kinases (e.g. FGFRl and the Src family).

Claims

WHAT IS CLAIMED IS:
1. A compound in accordance with formula I:
Figure imgf000065_0001
I or a pharmaceutically acceptable salt or hydrate thereof,
wherein
X is O or S;
R1 is H, Cι_ιo alkyl, C3-6 cycloalkyl, C5.10 aryl, halo, CF3,
C3. 0 heterocyclyl, or C5. 0 heteroaryl, said alkyl, aryl, heteroaryl and heterocyclyl being optionally substituted with one to three members selected from
Ra;
2 R is H, Cχ_6 alkyl, C5.10 aryl, C5.10 heteroaryl, C3-6 cycloalkyl, said alkyl, aryl, heteroaryl or cycloalkyl being optionally substituted with one to three members selected from R , or R 1 and R 2 are connected to form a 5- or 6-membered lactam, said lactam being optionally substituted with one or more substitutents selected from Ra;
3 R is Cχ.g alkyl, C5.10 aryl, C5.10 heteroaryl, C3-6 cycloalkyl, said alkyl, aryl, heteroaryl or cycloalkyl being optionally substituted with one to three members selected from R ;
R is H, Cχ_ιo alkyl, C3-6 cycloalkyl, Cχ-6 alkoxy, C2.10 alkenyl, C2-1P alkynyl, C5.10 aryl, C3.10 heterocyclyl, Cl-6 alkoxyNR7R8, N02, OH, -NH2 or C5.10 heteroaryl, said alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl being optionally substituted with one to three members selected from Ra;
Ra is H, Cι_ιo alkyl, halogen, CF ; N02, NHC(0)R*, OR,
NRγRδ, C5.10 aryl, C5.10 aralkyl, C5.10 heteroaryl or C3_χø heterocyclyl, said aralkyl, aryl and heteroaryl optionally substituted with one or two groups selected from NO2, halo, C5. 0 aryl, Cχ-6 alkoxy, Cl-6 alkyl, and CF3;
R* is H, or Cι_6 alkyl, NHC(O)CHR(C5.10 aralkyl), wherein the aryl ring of the aralkyl may be optionally substituted with one, two or three groups selected from OH, C -6 alkyl, and halo;
R is H or Cχ_6 alkyl; and
R7 and R8 are independently selected from:
H, Cι_ιo alkyl, C3-6 cycloalkyl, COR, COOR, C5.10 aryl, C3. 0 heterocyclyl, or C5. 0 heteroaryl or NR7R8 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 consisting of N, O and S.
2. A compound in accordance with Claim 1 wherein:
R is H, Cχ_χo alkyl, C5. 0 aryl, halo, CF3, or C5. 0 heteroaryl, said alkyl, aryl, and heteroaryl being optionally substituted with one to three members selected from Ra;
2 R is H, Cχ.g alkyl, or C5. 0 aryl, said alkyl or aryl, optionally substituted with one to three members selected from R , or R 1 and R 2 are connected to form a 5- or 6-membered lactam, said lactam being optionally substituted with one or more substitutents selected from Ra;
R and R are independently Cχ_χo alkyl, C5. 0 aryl, or
C5.X0 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 wherein X is O and all other variables are as originally described.
4. A compound according to Claim 1 wherein X is S and all other variables are as originally described.
5. A compound according to Claim 1 wherein R 3
and R , independently, are C5. 0 aryl or C5. 0 heteroaryl, said aryl or heteroaryl being optionally substituted with one to three members selected from Ra.
6. A compound selected from the group consisting of:
2-(2-(3-hydroxy)napthyl)-4-pheny-5-trifluoroacetamidooxazole; 2-(2-(3-hydroxy)napthyl)-4-(3-thiopheny)-5-acetamidooxazole; 2-(2-(3-hydroxy)napthyl)-4-pheny-5-acetamidooxazole; 2-(2-(3-hydroxy)napthyl)-4-(3-thiopheny)-5-trifluoroacetamido- oxazole; 2-(2-(2-hydroxy-4-methoxy)phenyl)-4-phenyl-5-acetamidooxazole;
2-(2-(2-hydroxy-4-methyl)phenyl)-4-phenyl-5-acetamidooxazole;
2-(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;
2-(2-(3-hydroxy)napthyl)-4-phenyl-5-acetamidooxazole;
2-(3-(5-phenyl)pyridyl)-4-phenyl-5-acetamidooxazole;
2-(3-(5-(3-nitro)phenyl)pyridyl)-4-phenyl-5-acetamidooxazole;
2-(3-(5-(l-naphthyl)pyridyl)-4-phenyl-5-acetamidooxazole; 2-(3-(5-(4-methyl)phenyl)pyridyl)-4-phenyl-5-acetamidooxazole;
2-(3-(5-(4-methoxy)phenyl)pyridyl)-4-phenyl-5-acetamidooxazole;
2-(3-(5-(3-chloro)phenyl)pyridyl)-4-phenyl-5-acetamidooxazole;
2-(3-(5-(3-methoxy)phenyl)pyridyl)-4-phenyl-5-acetamidooxazole;
2-(3-(5-(3-fluoro)phenyl)pyridyl)-4-phenyl-5-acetamidooxazole; 2-(3-(5-(2-naphthyl)pyridyl)-4-phenyl-5-acetamidooxazole;2-(3-(5-(2- trifluoromethyl)phenyl)pyridyl)-4-phenyl-5-acetamidooxazole;
2-(2-hydroxy)phenyl-4-pheny-5-acetamidooxazole;
2-(2-hydroxy)phenyl-4-pheny-5-benzamidooxazole;
2-(2-hydroxy)phenyl-4-pheny-5-valeramidooxazole; 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-(l-naphthyl))-phenyl-4-phenyl-5-acetamidooxazole;
2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-phenyl-5-acetamidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-phenyl-5- acetamidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-phenyl-5-acetamidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-phenyl-5- acetamidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-phenyl-5-acetamidooxazole; 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;
2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-thiophenyl-5- acetamidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-thiophenyl-5-acetamidooxazole;
2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-thiophenyl-5- acetamidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-thiophenyl-5- acetamidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-thiophenyl-5- acetamidooxazole; 2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-thiophenyl-5- acetamidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-thiophenyl-5- acetamidooxazole;
2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-thiophenyl-5- acetamidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-thiophenyl-5- acetamidooxazole;
2-(2-hydroxy-4-phenyl)-phenyl-4-(3-pyridyl)-5-acetamidooxazole;
2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(3-pyridyl)-5- acetamidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(3-pyridyl)-5-acetamidooxazole;
2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(3-pyridyl)-5- acetamidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(3-pyridyl)-5- acetamidooxazole; 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- acetamidooxazole;
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-chlorophenyl)-5-acetamidooxazole
2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(3-chlorophenyl)-5- acetamidooxazole;
2-(2-hydroxy-(4-(l- naphthyl))-phenyl-4-(3-chlorophenyl)-5- acetamidooxazole 2-(2-hydroxy-(4-(4' -methyl)-phenyl)-phenyl-4-(3-chlorophenyl)-5- acetamidooxazole 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-chlorophenyl)-5- acetamidooxazole 2-(2-hydroxy-(4-(2- naphthyl)-phenyl)-phenyl-4-(3-chlorophenyl)-5- acetamidooxazole 2-(2-hydroxy-(4-(2- trifluoromethyl)-phenyl)-phenyl-4-(3-chlorophenyl)-5- 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;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(2-chlorophenyl)-5- acetamidooxazole; 2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(2-chlorophenyl)-5- acetamidooxazole;2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(2- chlorophenyl)-5-acetamidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(2-chlorophenyl)-5- acetamidooxazole; 2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(2-chlorophenyl)-5- acetamidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(2-chlorophenyl)-5- acetamidooxazole;
2-(2-hydroxy-(4-(2-naphthyl)-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-(l-naphthyl))-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; 2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(4-chlorophenyl)-5- acetamidooxazole;
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- acetamidooxazole;
2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(4-trifluoromethylphenyl)-5- acetamidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-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-(4-trifluoromethylphenyl)-
5-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-methoxyphenyl)-5- acetamidooxazole; 2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(3-methoxyphenyl)-5- acetamidooxazole;
2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(3-methoxyphenyl)-5- acetamidooxazole; 2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(3-methoxyphenyl)-5- acetamidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(3-methoxyphenyl)-5- acetamidooxazole;
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;2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(3- methoxyphenyl)-5-acetamidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(3-methoxyphenyl)- 5-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-(l-naphthyl))-phenyl-4-(3-thiophenyl)-5- acetamidooxazole;
2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(3-thiophenyl)-5- acetamidooxazole;
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- 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-thiophenyl)-5- acetamidooxazole;
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-(l-naphthyl))-phenyl-4-(2-thiophenyl)-5- acetamidooxazole; 2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(2-thiophenyl)-5- acetamidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(2-thiophenyl)-5- acetamidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(2-thiophenyl)-5- acetamidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(2-thiophenyl)-5- acetamidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(2-thiophenyl)-5- acetamidooxazole; 2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(2-thiophenyl)-5- acetamidooxazole;;
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-(l-naphthyl))-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;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(2,6-dichlorophenyl)-5- acetamidooxazole;
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-hydroxy-4-phenyl)-phenyl-4-phenyl-5-benzamidooxazole;
2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-phenyl-5-benzamidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-phenyl-5-benzamidooxazole;
2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-phenyl-5-benzamidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-phenyl-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-phenyl-5-benzamidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-phenyl-5- benzamidooxazole;2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-phenyl-5- benzamidooxazole; 2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-phenyl-5- benzamidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-phenyl-5- benzamidooxazole;
2-(2-hydroxy-4-phenyl)-phenyl-4-thiophenyl-5-benzamidooxazole 2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-thiophenyl-5- benzamidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-thiophenyl-5-benzamidooxazole;
2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-thiophenyl-5- benzamidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-thiophenyl-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-thiophenyl-5- benzamidooxazole; 2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-thiophenyl-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-thiophenyl-5- benzamidooxazole;
2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-thiophenyl-5- benzamidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-thiophenyl-5- benzamidooxazole;
2-(2-hydroxy-4-phenyl)-phenyl-4-(3-pyridyl)-5-benzamidooxazole;
2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(3-pyridyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(3-pyridyl)-5-benzamidooxazole;
2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(3-pyridyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(3-pyridyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(3-pyridyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(3-pyridyl)-5- benzamidooxazole; 2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(3-pyridyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(3-pyridyl)-5- benzamidooxazole; 2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(3-pyridyl)-5- benzamidooxazole;
2-(2-hydroxy-4-phenyl)-phenyl-4-(3-chlorophenyl)-5-benzamidooxazole;
2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(3-chlorophenyl)-5- benzamidooxazole; 2-(2-hydroxy-(4-( l-naphthyl))-phenyl-4-(3-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(3-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(3-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(3-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(3-chlorophenyl)-5- benzamidooxazole; 2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(3-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(3-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(3-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-4-phenyl)-phenyl-4-(2-chlorophenyl)-5-benzamidooxazole;
2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(2-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(2-chlorophenyl)-5- benzamidooxazole; 2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(2-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(2-chlorophenyl)-5- benzamidooxazole; 2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(2-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(2-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(2-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(2-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(2-chlorophenyl)-5- benzamidooxazole;2-(2-hydroxy-4-phenyl)-phenyl-4-(4-chlorophenyl)-5- benzamidooxazole
2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(4-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(4-chlorophenyl)-5- benzamidooxazole; 2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(4-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(4-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(4-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(4-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(4-chlorophenyl)-5- benzamidooxazole; 2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(4-chlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(4-chlorophenyl)-5- benzamidooxazole; 2-(2-hydroxy-4-phenyl)-phenyl-4-(4-trifluoromethylphenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(4-trifluoromethylphenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(4-trifluoromethylphenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(4-trifluoromethylphenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(4-trifluoromethylphenyl)-
5-benzamidooxazole; 2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(4-trifluoromethylphenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(4-trifluoromethylphenyl)-
5-benzamidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(4-trifluoromethylphenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(4-trifluoromethylphenyl)-
5-benzamidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(4- trifluoromethylphenyl)-5-benzamidooxazole; 2-(2-hydroxy-4-phenyl)-phenyl-4-(3-methoxyphenyl)-5-benzamidooxazole;
2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(3-methoxyphenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(3-methoxyphenyl)-5- benzamidooxazole; 2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(3-methoxyphenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(3-methoxyphenyl)-5- benzamidooxazole; 2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(3-methoxyphenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(3-methoxyphenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(3-methoxyphenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(3-methoxyphenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(3-methoxyphenyl)-
5-benzamidooxazole; 2-(2-hydroxy-4-phenyl)-phenyl-4-(3-thiophenyl)-5-benzamidooxazole;
2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(3-thiophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(3-thiophenyl)-5- benzamidooxazole; 2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(3-thiophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(3-thiophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(3-thiophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(3-thiophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(3-thiophenyl)-5- benzamidooxazole; 2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(3-thiophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(3-thiophenyl)-5- benzamidooxazole; 2-(2-hydroxy-4-phenyl)-phenyl-4-(2-thiophenyl)-5-benzamidooxazole
2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(2-thiophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(2-thiophenyl)-5- benzamidooxazole; 2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(2-thiophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(2-thiophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(2-thiophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(2-thiophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(2-thiophenyl)-5- benzamidooxazole; 2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(2-thiophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(2-thiophenyl)-5- benzamidooxazole;
2-(2-hydroxy-4-phenyl)-phenyl-4-(2,6-dichlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(2,6-dichlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(2,6-dichlorophenyl)-5- benzamidooxazole; 2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(2,6-dichlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(2,6-dichlorophenyl)-5- benzamidooxazole; 2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(2,6-dichlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(2,6-dichlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(2,6-dichlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(2,6-dichlorophenyl)-5- benzamidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(2,6- dichlorophenyl)-5-benzamidooxazole; 2-(2-hydroxy-4-phenyl)-phenyl-4-phenyl-5-valeramidooxazole;
2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-phenyl-5-valeramidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-phenyl-5-valeramidooxazole;
2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-phenyl-5- valeramidooxazole; 2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-phenyl-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-phenyl-5-valeramidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-phenyl-5- valeramidooxazole; 2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-phenyl-5-valeramidooxazole;
2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-phenyl-5- valeramidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-phenyl-5- valeramidooxazole; 2-(2-hydroxy-4-phenyl)-phenyl-4-thiophenyl-5-valeramidooxazole;2-(2- hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-thiophenyl-5-valeramidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-thiophenyl-5-valeramidooxazole;
2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-thiophenyl-5- valeramidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-thiophenyl-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-thiophenyl-5- valeramidooxazole; 2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-thiophenyl-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-thiophenyl-5- valeramidooxazole;
2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-thiophenyl-5- valeramidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-thiophenyl-5- valeramidooxazole;
2-(2-hydroxy-4-phenyl)-phenyl-4-(3-pyridyl)-5-valeramidooxazole
2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(3-pyridyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(3-pyridyl)-5-valeramidooxazole;
2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(3-pyridyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(3-pyridyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(3-pyridyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(3-pyridyl)-5- valeramidooxazole; 2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(3-pyridyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(3-pyridyl)-5- valeramidooxazole; 2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(3-pyridyl)-5- valeramidooxazole;
2-(2-hydroxy-4-phenyl)-phenyl-4-(3-chlorophenyl)-5-valeramidooxazole;
2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(3-chlorophenyl)-5- valeramidooxazole; 2-(2-hydroxy-(4-( l-naphthyl))-phenyl-4-(3-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(3-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(3-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(3-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(3-chlorophenyl)-5- valeramidooxazole; 2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(3-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(3-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(3-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-4-phenyl)-phenyl-4-(2-chlorophenyl)-5-valeramidooxazole;
2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(2-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(2-chlorophenyl)-5- valeramidooxazole; 2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(2-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(2-chlorophenyl)-5- valeramidooxazole; 2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(2-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(2-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(2-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(2-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(2-chlorophenyl)-5- valeramidooxazole; 2-(2-hydroxy-4-phenyl)-phenyl-4-(4-chlorophenyl)-5-valeramidooxazole;2-
(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(4-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(4-chlorophenyl)-5- valeramidooxazole; 2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(4-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(4-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(4-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(4-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-ρhenyl)-phenyl-4-(4-chlorophenyl)-5- valeramidooxazole; 2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(4-chlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(4-chlorophenyl)-5- valeramidooxazole; 2-(2-hydroxy-4-phenyl)-phenyl-4-(4-trifluoromethylphenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(4-trifluoromethylphenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(4-trifluoromethylphenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(4-trifluoromethylphenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(4-trifluoromethylphenyl)-
5-valeramidooxazole; 2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(4-trifluoromethylphenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(4-trifluoromethylphenyl)-
5-valeramidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(4-trifluoromethylphenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(4-trifluoromethylphenyl)-
5-valeramidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(4- trifluoromethylphenyl)-5-valeramidooxazole; 2-(2-hydroxy-4-phenyl)-phenyl-4-(3-methoxyphenyl)-5-valeramidooxazole;
2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(3-methoxyphenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(3-methoxyphenyl)-5- valeramidooxazole; 2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(3-methoxyphenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(3-methoxyphenyl)-5- valeramidooxazole; 2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(3-methoxyphenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(3-methoxyphenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(3-methoxyphenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(3-methoxyphenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(3-methoxyphenyl)-
5-valeramidooxazole; 2-(2-hydroxy-4-phenyl)-phenyl-4-(3-thiophenyl)-5-valeramidooxazole;2-(2- hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(3-thiophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(3-thiophenyl)-5- valeramidooxazole; 2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(3-thiophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(3-thiophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(3-thiophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(3-thiophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(3-thiophenyl)-5- valeramidooxazole; 2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(3-thiophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(3-thiophenyl)-5- valeramidooxazole; 2-(2-hydroxy-4-phenyl)-phenyl-4-(2-thiophenyl)-5-valeramidooxazole;
2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(2-thiophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(2-thiophenyl)-5- valeramidooxazole; 2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(2-thiophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(2-thiophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(2-thiophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(2-thiophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(2-thiophenyl)-5- valeramidooxazole; 2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(2-thiophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(2-thiophenyl)-5- valeramidooxazole;
2-(2-hydroxy-4-phenyl)-phenyl-4-(2,6-dichlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3-nitro)-phenyl))-phenyl-4-(2,6-dichlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(l-naphthyl))-phenyl-4-(2,6-dichlorophenyl)-5- valeramidooxazole; 2-(2-hydroxy-(4-(4'-methyl)-phenyl)-phenyl-4-(2,6-dichlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(4'-methoxy)-phenyl)-phenyl-4-(2,6-dichlorophenyl)-5- valeramidooxazole; 2-(2-hydroxy-(4-(3'-chloro)-phenyl)-phenyl-4-(2,6-dichlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-methoxy)-phenyl)-phenyl-4-(2,6-dichlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(3'-fluoro)-phenyl)-phenyl-4-(2,6-dichlorophenyl)-5- valeramidooxazole;
2-(2-hydroxy-(4-(2-naphthyl)-phenyl)-phenyl-4-(2,6-dichlorophenyl)-5- valeramidooxazole and
2-(2-hydroxy-(4-(2-trifluoromethyl)-phenyl)-phenyl-4-(2,6- dichlorophenyl)-5-valeramidooxazole.
7. A pharmaceutical composition which is comprised of a compound in accordance with Claim 1 and a pharmaceutically acceptable carrier.
8. A method of treating cancer in a mammal in need of such treatment which is comprised of admininstering to said mammal a therapeutically effective amount of a compound of Claim 1.
9. A method of treating cancer in accordance with
Claim 8 wherein the cancer is selected from cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung.
10. A method in accordance with Claim 8 wherein the cancer is selected from histiocytic lymphoma, lung adenocarcinoma, small cell lung cancers, pancreatic cancer, gioblastomas and breast carcinoma.
11. A method of treating a disease in which neoangiogenesis is implicated, which is comprised of administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1.
12. A method in accordance with Claim 11 wherein the disease is an ocular disease.
13. A method of treating retinal vascularization which is comprised of administering to a mammal in need of such treatment a therapeutically effective amount of compound of Claim 1.
14. A method of treating diabetic retinopathy which is comprised of administering to a mammalin need of such treatment a therapeutically effective amount of compound of Claim 1.
15. A method of treating age-related macular degeneration which is comprised of administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1.
16. A method of treating inflammatory diseases which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1.
17. A method according to Claim 16 wherein the inflammatory disease is selected from rheumatoid arthritis, psoriasis, contact dermatitis and delayed hypersensitivity reactions.
18. A method for inhibiting tyrosine kinase which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1.
19. A method of preventing cancer in a mammal in need of such treatment which is comprised of admininstering to said mammal a therapeutically effective amount of a compound of Claim 1.
20. A method of preventing cancer in accordance with Claim 19 wherein the cancer is selected from cancers of the brain, genitourinary tract, lymphatic system, stomach, larynx and lung.
21. A method in accordance with Claim 20 wherein the cancer is selected from histiocytic lymphoma, lung adenocarcinoma, small cell lung cancers, pancreatic cancer, gioblastomas and breast carcinoma.
22. A method of preventing a disease in which neoangiogenesis is implicated, which is comprised of administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1.
23. A method in accordance with Claim 22 wherein the disease is an ocular disease.
24. A method of preventing retinal vascularization which is comprised of administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1.
25. A method of preventing diabetic retinopathy which is comprised of administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1.
26. A method of preventing age-related macular degeneration which is comprised of administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1.
27. A method of preventing inflammatory diseases which is comprised of administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1.
28. A method according to Claim 27 wherein the inflammatory disease is selected from rheumatoid arthritis, psoriasis, contact dermatitis and delayed hypertensitivity reactions.
PCT/US1999/015200 1998-07-10 1999-07-06 Novel angiogenesis inhibitors WO2000002871A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU52082/99A AU747427B2 (en) 1998-07-10 1999-07-06 Novel angiogenesis inhibitors
JP2000559102A JP2002520324A (en) 1998-07-10 1999-07-06 Novel angiogenesis inhibitors
EP99937204A EP1097147A4 (en) 1998-07-10 1999-07-06 Novel angiogenesis inhibitors
CA002336848A CA2336848A1 (en) 1998-07-10 1999-07-06 Novel angiogenesis inhibitors

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US9228598P 1998-07-10 1998-07-10
US60/092,285 1998-07-10
GBGB9822700.2A GB9822700D0 (en) 1998-10-16 1998-10-16 Novel angiogenesis inhibitors
GB9822700.2 1998-10-16

Publications (1)

Publication Number Publication Date
WO2000002871A1 true WO2000002871A1 (en) 2000-01-20

Family

ID=26314531

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1999/015200 WO2000002871A1 (en) 1998-07-10 1999-07-06 Novel angiogenesis inhibitors

Country Status (5)

Country Link
EP (1) EP1097147A4 (en)
JP (1) JP2002520324A (en)
AU (1) AU747427B2 (en)
CA (1) CA2336848A1 (en)
WO (1) WO2000002871A1 (en)

Cited By (93)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002096397A1 (en) * 2001-05-29 2002-12-05 Chemokine Therapeutics Corporation Bicyclic aromatic chemokine receptor ligands
US6596746B1 (en) 1999-04-15 2003-07-22 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
US6706717B2 (en) 2000-12-21 2004-03-16 Bristol-Myers Squibb Company Thiazolyl inhibitors of Tec family tyrosine kinases
WO2006060318A2 (en) 2004-11-30 2006-06-08 Amgen Inc. Quinolines and quinazoline analogs and their use as medicaments for treating cancer
US7081454B2 (en) 2001-03-28 2006-07-25 Bristol-Myers Squibb Co. Tyrosine kinase inhibitors
US7105530B2 (en) 2000-12-21 2006-09-12 Smithkline Beecham Corporation Pyrimidineamines as angiogenesis modulators
US7125888B2 (en) 2002-05-02 2006-10-24 Merck & Co., Inc. Tyrosine kinase inhibitors
US7125875B2 (en) 1999-04-15 2006-10-24 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
WO2007089445A2 (en) 2006-01-27 2007-08-09 Amgen Inc. Ang2 and vegf inhibitor combinations
US7265134B2 (en) 2001-08-17 2007-09-04 Merck & Co., Inc. Tyrosine kinase inhibitors
US7312215B2 (en) 2003-07-29 2007-12-25 Bristol-Myers Squibb Company Benzimidazole C-2 heterocycles as kinase inhibitors
WO2008079291A2 (en) 2006-12-20 2008-07-03 Amgen Inc. Substituted heterocycles and methods of use
WO2008086014A2 (en) 2007-01-09 2008-07-17 Amgen Inc. Bis-aryl amide derivatives useful for the treatment of cancer
WO2008090382A1 (en) * 2007-01-25 2008-07-31 The University Of Sheffield Thiazole and oxazole derivatives for use in the treatment of prion diseases, cancer and conditions of the central nervous system as well as in the regulation of stem cells
WO2008103277A2 (en) 2007-02-16 2008-08-28 Amgen Inc. Nitrogen-containing heterocyclyl ketones and their use as c-met inhibitors
EP2107054A1 (en) * 2008-04-01 2009-10-07 Università Degli Studi Di Milano - Bicocca Antiproliferative compounds and therapeutic uses thereof
EP2341067A1 (en) 2003-07-18 2011-07-06 Amgen, Inc Specific binding agents to hepatocyte growth factor
US7989631B2 (en) 2006-02-10 2011-08-02 Amgen Inc. Hydrate forms of AMG706
WO2011161217A2 (en) 2010-06-23 2011-12-29 Palacký University in Olomouc Targeting of vegfr2
WO2012129344A1 (en) 2011-03-23 2012-09-27 Amgen Inc. Fused tricyclic dual inhibitors of cdk 4/6 and flt3
EP2578583A1 (en) 2006-07-14 2013-04-10 Amgen Inc. Fused heterocyclic derivatives and methods of use
EP2589610A1 (en) 2007-08-21 2013-05-08 Amgen, Inc Human c-fms antigen binding proteins
EP2603216A1 (en) * 2010-08-11 2013-06-19 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
US8481564B2 (en) 2006-04-20 2013-07-09 Janssen Pharmaceutica, N.V. Inhibitors of c-fms kinase
US8497376B2 (en) 2007-10-17 2013-07-30 Janssen Pharmaceutica N.V. Inhibitors of c-fms kinase
WO2013132044A1 (en) 2012-03-08 2013-09-12 F. Hoffmann-La Roche Ag Combination therapy of antibodies against human csf-1r and uses thereof
US8557847B2 (en) 2005-06-10 2013-10-15 Janssen Pharmaceutica, N.V. Synergistic modulation of FLT3 kinase using a FLT3 inhibitor and a farnesyl transferase inhibitor
US8648199B2 (en) 2005-12-23 2014-02-11 Amgen Inc. Process for making a solid-state form of AMG 706
CN103596938A (en) * 2011-05-23 2014-02-19 默克专利有限公司 Thiazole derivatives
WO2014036022A1 (en) 2012-08-29 2014-03-06 Amgen Inc. Quinazolinone compounds and derivatives thereof
US8697716B2 (en) 2006-04-20 2014-04-15 Janssen Pharmaceutica Nv Method of inhibiting C-KIT kinase
US8765746B2 (en) 2010-10-13 2014-07-01 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
US8796314B2 (en) 2009-01-30 2014-08-05 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
US8796268B2 (en) 2010-08-11 2014-08-05 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
US8859602B2 (en) 2006-04-20 2014-10-14 Janssen Pharmaceutica Nv Inhibitors of c-fms kinase
US9029411B2 (en) 2008-01-25 2015-05-12 Millennium Pharmaceuticals, Inc. Thiophenes and uses thereof
US9029352B2 (en) 2012-08-07 2015-05-12 Janssen Pharmaceutica Nv Process for the preparation of C-FMS kinase inhibitors
US9062038B2 (en) 2010-08-11 2015-06-23 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
US9090601B2 (en) 2009-01-30 2015-07-28 Millennium Pharmaceuticals, Inc. Thiazole derivatives
CN104860885A (en) * 2014-02-24 2015-08-26 中国科学院上海药物研究所 Naphthylamide compound, and preparation method and use thereof
US9139589B2 (en) 2009-01-30 2015-09-22 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
US9303046B2 (en) 2012-08-07 2016-04-05 Janssen Pharmaceutica Nv Process for the preparation of heterocyclic ester derivatives
WO2016112111A1 (en) 2015-01-08 2016-07-14 The Board Of Trustees Of The Leland Stanford Junior University Factors and cells that provide for induction of bone, bone marrow, and cartilage
WO2016202935A1 (en) 2015-06-19 2016-12-22 Bayer Pharma Aktiengesellschaft Glucose transport inhibitors
EP3170824A1 (en) 2008-01-15 2017-05-24 Amgen, Inc 6-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethyl)-1,6-naphthyridin-5(6h)-one derivatives as c-met inhibitors
US9745288B2 (en) 2011-08-16 2017-08-29 Indiana University Research And Technology Corporation Compounds and methods for treating cancer by inhibiting the urokinase receptor
WO2018119183A2 (en) 2016-12-22 2018-06-28 Amgen Inc. Kras g12c inhibitors and methods of using the same
WO2018217651A1 (en) 2017-05-22 2018-11-29 Amgen Inc. Kras g12c inhibitors and methods of using the same
WO2019051291A1 (en) 2017-09-08 2019-03-14 Amgen Inc. Inhibitors of kras g12c and methods of using the same
WO2019213516A1 (en) 2018-05-04 2019-11-07 Amgen Inc. Kras g12c inhibitors and methods of using the same
WO2019213526A1 (en) 2018-05-04 2019-11-07 Amgen Inc. Kras g12c inhibitors and methods of using the same
WO2019217691A1 (en) 2018-05-10 2019-11-14 Amgen Inc. Kras g12c inhibitors for the treatment of cancer
WO2019232419A1 (en) 2018-06-01 2019-12-05 Amgen Inc. Kras g12c inhibitors and methods of using the same
WO2019241157A1 (en) 2018-06-11 2019-12-19 Amgen Inc. Kras g12c inhibitors for treating cancer
WO2020050890A2 (en) 2018-06-12 2020-03-12 Amgen Inc. Kras g12c inhibitors and methods of using the same
WO2020102730A1 (en) 2018-11-16 2020-05-22 Amgen Inc. Improved synthesis of key intermediate of kras g12c inhibitor compound
WO2020106647A2 (en) 2018-11-19 2020-05-28 Amgen Inc. Combination therapy including a krasg12c inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers
WO2020106640A1 (en) 2018-11-19 2020-05-28 Amgen Inc. Kras g12c inhibitors and methods of using the same
WO2020132653A1 (en) 2018-12-20 2020-06-25 Amgen Inc. Heteroaryl amides useful as kif18a inhibitors
WO2020132651A1 (en) 2018-12-20 2020-06-25 Amgen Inc. Kif18a inhibitors
WO2020132649A1 (en) 2018-12-20 2020-06-25 Amgen Inc. Heteroaryl amides useful as kif18a inhibitors
WO2020132648A1 (en) 2018-12-20 2020-06-25 Amgen Inc. Kif18a inhibitors
WO2020180770A1 (en) 2019-03-01 2020-09-10 Revolution Medicines, Inc. Bicyclic heterocyclyl compounds and uses thereof
WO2020180768A1 (en) 2019-03-01 2020-09-10 Revolution Medicines, Inc. Bicyclic heteroaryl compounds and uses thereof
WO2021026100A1 (en) 2019-08-02 2021-02-11 Amgen Inc. Pyridine derivatives as kif18a inhibitors
WO2021026101A1 (en) 2019-08-02 2021-02-11 Amgen Inc. Kif18a inhibitors
WO2021026099A1 (en) 2019-08-02 2021-02-11 Amgen Inc. Kif18a inhibitors
WO2021026098A1 (en) 2019-08-02 2021-02-11 Amgen Inc. Kif18a inhibitors
WO2021081212A1 (en) 2019-10-24 2021-04-29 Amgen Inc. Pyridopyrimidine derivatives useful as kras g12c and kras g12d inhibitors in the treatment of cancer
WO2021092115A1 (en) 2019-11-08 2021-05-14 Revolution Medicines, Inc. Bicyclic heteroaryl compounds and uses thereof
WO2021091982A1 (en) 2019-11-04 2021-05-14 Revolution Medicines, Inc. Ras inhibitors
WO2021091967A1 (en) 2019-11-04 2021-05-14 Revolution Medicines, Inc. Ras inhibitors
WO2021091956A1 (en) 2019-11-04 2021-05-14 Revolution Medicines, Inc. Ras inhibitors
WO2021097212A1 (en) 2019-11-14 2021-05-20 Amgen Inc. Improved synthesis of kras g12c inhibitor compound
WO2021097207A1 (en) 2019-11-14 2021-05-20 Amgen Inc. Improved synthesis of kras g12c inhibitor compound
WO2021108683A1 (en) 2019-11-27 2021-06-03 Revolution Medicines, Inc. Covalent ras inhibitors and uses thereof
WO2021142026A1 (en) 2020-01-07 2021-07-15 Revolution Medicines, Inc. Shp2 inhibitor dosing and methods of treating cancer
WO2021257736A1 (en) 2020-06-18 2021-12-23 Revolution Medicines, Inc. Methods for delaying, preventing, and treating acquired resistance to ras inhibitors
US11236091B2 (en) 2019-05-21 2022-02-01 Amgen Inc. Solid state forms
WO2022060836A1 (en) 2020-09-15 2022-03-24 Revolution Medicines, Inc. Indole derivatives as ras inhibitors in the treatment of cancer
WO2022060583A1 (en) 2020-09-03 2022-03-24 Revolution Medicines, Inc. Use of sos1 inhibitors to treat malignancies with shp2 mutations
WO2022140427A1 (en) 2020-12-22 2022-06-30 Qilu Regor Therapeutics Inc. Sos1 inhibitors and uses thereof
US11426404B2 (en) 2019-05-14 2022-08-30 Amgen Inc. Dosing of KRAS inhibitor for treatment of cancers
WO2022235866A1 (en) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Covalent ras inhibitors and uses thereof
WO2022235870A1 (en) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Ras inhibitors for the treatment of cancer
WO2022235864A1 (en) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Ras inhibitors
WO2023060253A1 (en) 2021-10-08 2023-04-13 Revolution Medicines, Inc. Ras inhibitors
WO2023114954A1 (en) 2021-12-17 2023-06-22 Genzyme Corporation Pyrazolopyrazine compounds as shp2 inhibitors
EP4227307A1 (en) 2022-02-11 2023-08-16 Genzyme Corporation Pyrazolopyrazine compounds as shp2 inhibitors
WO2023172940A1 (en) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Methods for treating immune refractory lung cancer
WO2023240263A1 (en) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Macrocyclic ras inhibitors
WO2024081916A1 (en) 2022-10-14 2024-04-18 Black Diamond Therapeutics, Inc. Methods of treating cancers using isoquinoline or 6-aza-quinoline derivatives
US11993597B2 (en) 2022-03-10 2024-05-28 Amgen Inc. Inhibitors of KRAS G12C and methods of using the same

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10021246A1 (en) * 2000-04-25 2001-10-31 Schering Ag New N-substituted benzamide derivatives are tyrosine kinase KDR and FLT inhibitors useful e.g. for treating tumors, psoriasis, rheumatoid arthritis, diabetic retinopathy or liver sclerosis
SI1569907T1 (en) * 2002-12-13 2016-06-30 Ym Biosciences Australia Pty Ltd Nicotinamide-based kinase inhibitors
JP5046950B2 (en) * 2004-10-22 2012-10-10 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ Inhibitors of C-FMS kinase

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4122183A (en) * 1973-12-17 1978-10-24 Lilly Industries Limited Oxazole derivatives
US4946855A (en) * 1987-12-14 1990-08-07 Sawai Pharmaceutical Co., Ltd. Carboxamide derivatives having tetrazole and thiazole rings and their use

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6339868A (en) * 1986-08-04 1988-02-20 Otsuka Pharmaceut Factory Inc Di (lower alkyl) phenol derivative

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4122183A (en) * 1973-12-17 1978-10-24 Lilly Industries Limited Oxazole derivatives
US4946855A (en) * 1987-12-14 1990-08-07 Sawai Pharmaceutical Co., Ltd. Carboxamide derivatives having tetrazole and thiazole rings and their use

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1097147A4 *

Cited By (155)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7091223B2 (en) 1999-04-15 2006-08-15 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
US6596746B1 (en) 1999-04-15 2003-07-22 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
US9382219B2 (en) 1999-04-15 2016-07-05 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
US8716323B2 (en) 1999-04-15 2014-05-06 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
US8993567B2 (en) 1999-04-15 2015-03-31 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
US7189854B2 (en) 1999-04-15 2007-03-13 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
US6979694B2 (en) 1999-04-15 2005-12-27 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
US7153856B2 (en) 1999-04-15 2006-12-26 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
US7125875B2 (en) 1999-04-15 2006-10-24 Bristol-Myers Squibb Company Cyclic protein tyrosine kinase inhibitors
US7037926B2 (en) 2000-12-21 2006-05-02 Bristol-Myers Squibb Company Thiazolyl inhibitors of Tec family tyrosine kinases
US6953795B2 (en) 2000-12-21 2005-10-11 Bristol-Myers Squibb Company Thiazolyl inhibitors of Tec family tyrosine kinases
US7105530B2 (en) 2000-12-21 2006-09-12 Smithkline Beecham Corporation Pyrimidineamines as angiogenesis modulators
US7858626B2 (en) 2000-12-21 2010-12-28 Glaxosmithkline Llc Pyrimidineamines as angiogenesis modulators
US8114885B2 (en) 2000-12-21 2012-02-14 Glaxosmithkline Llc Chemical compounds
US6706717B2 (en) 2000-12-21 2004-03-16 Bristol-Myers Squibb Company Thiazolyl inhibitors of Tec family tyrosine kinases
US6956045B2 (en) 2000-12-21 2005-10-18 Bristol-Myers Squibb Company Thiazolyl inhibitors of Tec family tyrosine kinases
US7241781B2 (en) 2000-12-21 2007-07-10 Bristol-Myers Squibb Company Thiazolyl inhibitors of Tec family tyrosine kinases
US7262203B2 (en) 2000-12-21 2007-08-28 Smithkline Beecham Corporation Pyrimidineamines as angiogenesis modulators
US7223757B2 (en) 2001-03-28 2007-05-29 Bristol-Myers Squibb Company Tyrosine kinase inhibitors
US7081454B2 (en) 2001-03-28 2006-07-25 Bristol-Myers Squibb Co. Tyrosine kinase inhibitors
WO2002096397A1 (en) * 2001-05-29 2002-12-05 Chemokine Therapeutics Corporation Bicyclic aromatic chemokine receptor ligands
US6693134B2 (en) 2001-05-29 2004-02-17 Chemokine Therapeutics Corporation Bicyclic aromatic chemokine receptor ligands
US7265134B2 (en) 2001-08-17 2007-09-04 Merck & Co., Inc. Tyrosine kinase inhibitors
US7125888B2 (en) 2002-05-02 2006-10-24 Merck & Co., Inc. Tyrosine kinase inhibitors
EP2341067A1 (en) 2003-07-18 2011-07-06 Amgen, Inc Specific binding agents to hepatocyte growth factor
US7312215B2 (en) 2003-07-29 2007-12-25 Bristol-Myers Squibb Company Benzimidazole C-2 heterocycles as kinase inhibitors
WO2006060318A2 (en) 2004-11-30 2006-06-08 Amgen Inc. Quinolines and quinazoline analogs and their use as medicaments for treating cancer
US8557847B2 (en) 2005-06-10 2013-10-15 Janssen Pharmaceutica, N.V. Synergistic modulation of FLT3 kinase using a FLT3 inhibitor and a farnesyl transferase inhibitor
US8648199B2 (en) 2005-12-23 2014-02-11 Amgen Inc. Process for making a solid-state form of AMG 706
WO2007089445A2 (en) 2006-01-27 2007-08-09 Amgen Inc. Ang2 and vegf inhibitor combinations
US7989631B2 (en) 2006-02-10 2011-08-02 Amgen Inc. Hydrate forms of AMG706
US9296726B2 (en) 2006-04-20 2016-03-29 Janssen Pharmaceutica Nv Inhibitors of c-fms kinase
US9394289B2 (en) 2006-04-20 2016-07-19 Janssen Pharmaceutica Nv Inhibitors of c-fms kinase
US9403804B2 (en) 2006-04-20 2016-08-02 Janssen Pharmaceutica Nv Inhibitors of c-fms kinase
US9526731B2 (en) 2006-04-20 2016-12-27 Janssen Pharmaceutica Nv Method of inhibiting C-KIT kinase
US8697716B2 (en) 2006-04-20 2014-04-15 Janssen Pharmaceutica Nv Method of inhibiting C-KIT kinase
US9266866B2 (en) 2006-04-20 2016-02-23 Janssen Pharmaceutica Nv Inhibitors of C-FMS kinase
US8481564B2 (en) 2006-04-20 2013-07-09 Janssen Pharmaceutica, N.V. Inhibitors of c-fms kinase
US8759347B2 (en) 2006-04-20 2014-06-24 Janssen Pharmaceutica Nv Inhibitors of C-FMS kinase
US8933091B2 (en) 2006-04-20 2015-01-13 Janssen Pharmaceutica Nv Method of inhibiting C-KIT kinase
US8859602B2 (en) 2006-04-20 2014-10-14 Janssen Pharmaceutica Nv Inhibitors of c-fms kinase
US8895584B2 (en) 2006-04-20 2014-11-25 Janssen Pharmaceutica Nv Inhibitors of c-fms kinase
EP3093289A1 (en) 2006-07-14 2016-11-16 Amgen, Inc [1,2,4]triazolo[4,3-a]pyridine derivatives useful as inhibitors of the hepatocyte growth factor receptor
EP2578583A1 (en) 2006-07-14 2013-04-10 Amgen Inc. Fused heterocyclic derivatives and methods of use
WO2008079291A2 (en) 2006-12-20 2008-07-03 Amgen Inc. Substituted heterocycles and methods of use
WO2008086014A2 (en) 2007-01-09 2008-07-17 Amgen Inc. Bis-aryl amide derivatives useful for the treatment of cancer
WO2008090382A1 (en) * 2007-01-25 2008-07-31 The University Of Sheffield Thiazole and oxazole derivatives for use in the treatment of prion diseases, cancer and conditions of the central nervous system as well as in the regulation of stem cells
WO2008103277A2 (en) 2007-02-16 2008-08-28 Amgen Inc. Nitrogen-containing heterocyclyl ketones and their use as c-met inhibitors
EP2592093A1 (en) 2007-08-21 2013-05-15 Amgen, Inc Human c-fms antigen binding proteins
EP2589610A1 (en) 2007-08-21 2013-05-08 Amgen, Inc Human c-fms antigen binding proteins
EP3330292A1 (en) 2007-08-21 2018-06-06 Amgen, Inc Human c-fms antigen binding proteins
US8497376B2 (en) 2007-10-17 2013-07-30 Janssen Pharmaceutica N.V. Inhibitors of c-fms kinase
EP3170824A1 (en) 2008-01-15 2017-05-24 Amgen, Inc 6-([1,2,4]triazolo[4,3-a]pyridin-3-ylmethyl)-1,6-naphthyridin-5(6h)-one derivatives as c-met inhibitors
US9029411B2 (en) 2008-01-25 2015-05-12 Millennium Pharmaceuticals, Inc. Thiophenes and uses thereof
WO2009121535A2 (en) * 2008-04-01 2009-10-08 Universita`Degli Studi Di Milano - Bicocca Antiproliferative compounds and therapeutic uses thereof
WO2009121535A3 (en) * 2008-04-01 2010-01-07 Universita`Degli Studi Di Milano - Bicocca Antiproliferative compounds and therapeutic uses thereof
EP2107054A1 (en) * 2008-04-01 2009-10-07 Università Degli Studi Di Milano - Bicocca Antiproliferative compounds and therapeutic uses thereof
US8796314B2 (en) 2009-01-30 2014-08-05 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
US9139589B2 (en) 2009-01-30 2015-09-22 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
US9090601B2 (en) 2009-01-30 2015-07-28 Millennium Pharmaceuticals, Inc. Thiazole derivatives
WO2011161217A2 (en) 2010-06-23 2011-12-29 Palacký University in Olomouc Targeting of vegfr2
US9062038B2 (en) 2010-08-11 2015-06-23 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
EP2603216A1 (en) * 2010-08-11 2013-06-19 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
EP2603216A4 (en) * 2010-08-11 2013-12-18 Millennium Pharm Inc Heteroaryls and uses thereof
US8859768B2 (en) 2010-08-11 2014-10-14 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
US8796268B2 (en) 2010-08-11 2014-08-05 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
US8796271B2 (en) 2010-08-11 2014-08-05 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
US8765746B2 (en) 2010-10-13 2014-07-01 Millennium Pharmaceuticals, Inc. Heteroaryls and uses thereof
WO2012129344A1 (en) 2011-03-23 2012-09-27 Amgen Inc. Fused tricyclic dual inhibitors of cdk 4/6 and flt3
EP2937349A1 (en) 2011-03-23 2015-10-28 Amgen Inc. Fused tricyclic dual inhibitors of cdk 4/6 and flt3
US9249114B2 (en) 2011-05-23 2016-02-02 Merck Patent Gmbh Thiazole derivatives
CN103596938B (en) * 2011-05-23 2016-12-28 默克专利有限公司 Thiazole
CN103596938A (en) * 2011-05-23 2014-02-19 默克专利有限公司 Thiazole derivatives
US9745288B2 (en) 2011-08-16 2017-08-29 Indiana University Research And Technology Corporation Compounds and methods for treating cancer by inhibiting the urokinase receptor
WO2013132044A1 (en) 2012-03-08 2013-09-12 F. Hoffmann-La Roche Ag Combination therapy of antibodies against human csf-1r and uses thereof
US9303046B2 (en) 2012-08-07 2016-04-05 Janssen Pharmaceutica Nv Process for the preparation of heterocyclic ester derivatives
US9029352B2 (en) 2012-08-07 2015-05-12 Janssen Pharmaceutica Nv Process for the preparation of C-FMS kinase inhibitors
WO2014036022A1 (en) 2012-08-29 2014-03-06 Amgen Inc. Quinazolinone compounds and derivatives thereof
US9914707B2 (en) 2014-02-24 2018-03-13 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences Naphthylamide compound, preparation method and use thereof
CN104860885B (en) * 2014-02-24 2017-11-17 中国科学院上海药物研究所 Naphthoyl aminated compounds, preparation method and use
CN104860885A (en) * 2014-02-24 2015-08-26 中国科学院上海药物研究所 Naphthylamide compound, and preparation method and use thereof
RU2655607C2 (en) * 2014-02-24 2018-05-29 Шанхай Инститьют Оф Матириа Медика, Чайниз Экэдеми Оф Сайэнсиз Naphthylamide compound, preparation method and use thereof
WO2015124101A1 (en) * 2014-02-24 2015-08-27 中国科学院上海药物研究所 Naphthylamide compound, preparation method and use thereof
WO2016112111A1 (en) 2015-01-08 2016-07-14 The Board Of Trustees Of The Leland Stanford Junior University Factors and cells that provide for induction of bone, bone marrow, and cartilage
WO2016202935A1 (en) 2015-06-19 2016-12-22 Bayer Pharma Aktiengesellschaft Glucose transport inhibitors
EP4001269A1 (en) 2016-12-22 2022-05-25 Amgen Inc. Benzoisothiazole, isothiazolo[3,4-b]pyridine, quinazoline, phthalazine, pyrido[2,3-d]pyridazine and pyrido[2,3-d]pyrimidine derivatives as kras g12c inhibitors for treating lung, pancreatic or colorectal cancer
WO2018119183A2 (en) 2016-12-22 2018-06-28 Amgen Inc. Kras g12c inhibitors and methods of using the same
US11285135B2 (en) 2016-12-22 2022-03-29 Amgen Inc. KRAS G12C inhibitors and methods of using the same
US10532042B2 (en) 2016-12-22 2020-01-14 Amgen Inc. KRAS G12C inhibitors and methods of using the same
WO2018217651A1 (en) 2017-05-22 2018-11-29 Amgen Inc. Kras g12c inhibitors and methods of using the same
EP3974429A1 (en) 2017-05-22 2022-03-30 Amgen Inc. Precursors of kras g12c inhibitors
US10519146B2 (en) 2017-05-22 2019-12-31 Amgen Inc. KRAS G12C inhibitors and methods of using the same
US11905281B2 (en) 2017-05-22 2024-02-20 Amgen Inc. KRAS G12C inhibitors and methods of using the same
WO2019051291A1 (en) 2017-09-08 2019-03-14 Amgen Inc. Inhibitors of kras g12c and methods of using the same
US11306087B2 (en) 2017-09-08 2022-04-19 Amgen Inc. Inhibitors of KRAS G12C and methods of using the same
EP4141005A1 (en) 2017-09-08 2023-03-01 Amgen Inc. Inhibitors of kras g12c and methods of using the same
US10640504B2 (en) 2017-09-08 2020-05-05 Amgen Inc. Inhibitors of KRAS G12C and methods of using the same
WO2019213516A1 (en) 2018-05-04 2019-11-07 Amgen Inc. Kras g12c inhibitors and methods of using the same
US11766436B2 (en) 2018-05-04 2023-09-26 Amgen Inc. KRAS G12C inhibitors and methods of using the same
US11090304B2 (en) 2018-05-04 2021-08-17 Amgen Inc. KRAS G12C inhibitors and methods of using the same
US11045484B2 (en) 2018-05-04 2021-06-29 Amgen Inc. KRAS G12C inhibitors and methods of using the same
WO2019213526A1 (en) 2018-05-04 2019-11-07 Amgen Inc. Kras g12c inhibitors and methods of using the same
US10988485B2 (en) 2018-05-10 2021-04-27 Amgen Inc. KRAS G12C inhibitors and methods of using the same
WO2019217691A1 (en) 2018-05-10 2019-11-14 Amgen Inc. Kras g12c inhibitors for the treatment of cancer
WO2019232419A1 (en) 2018-06-01 2019-12-05 Amgen Inc. Kras g12c inhibitors and methods of using the same
US11096939B2 (en) 2018-06-01 2021-08-24 Amgen Inc. KRAS G12C inhibitors and methods of using the same
WO2019241157A1 (en) 2018-06-11 2019-12-19 Amgen Inc. Kras g12c inhibitors for treating cancer
EP4268898A2 (en) 2018-06-11 2023-11-01 Amgen Inc. Kras g12c inhibitors for treating cancer
WO2020050890A2 (en) 2018-06-12 2020-03-12 Amgen Inc. Kras g12c inhibitors and methods of using the same
US11285156B2 (en) 2018-06-12 2022-03-29 Amgen Inc. Substituted piperazines as KRAS G12C inhibitors
US11299491B2 (en) 2018-11-16 2022-04-12 Amgen Inc. Synthesis of key intermediate of KRAS G12C inhibitor compound
EP4234546A2 (en) 2018-11-16 2023-08-30 Amgen Inc. Improved synthesis of key intermediate of kras g12c inhibitor compound
WO2020102730A1 (en) 2018-11-16 2020-05-22 Amgen Inc. Improved synthesis of key intermediate of kras g12c inhibitor compound
US11918584B2 (en) 2018-11-19 2024-03-05 Amgen Inc. Combination therapy including a KRASG12C inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers
WO2020106647A2 (en) 2018-11-19 2020-05-28 Amgen Inc. Combination therapy including a krasg12c inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers
US11439645B2 (en) 2018-11-19 2022-09-13 Amgen Inc. Combination therapy including a KRASG12C inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers
WO2020106640A1 (en) 2018-11-19 2020-05-28 Amgen Inc. Kras g12c inhibitors and methods of using the same
US11053226B2 (en) 2018-11-19 2021-07-06 Amgen Inc. KRAS G12C inhibitors and methods of using the same
WO2020132651A1 (en) 2018-12-20 2020-06-25 Amgen Inc. Kif18a inhibitors
US11236069B2 (en) 2018-12-20 2022-02-01 Amgen Inc. KIF18A inhibitors
WO2020132649A1 (en) 2018-12-20 2020-06-25 Amgen Inc. Heteroaryl amides useful as kif18a inhibitors
WO2020132653A1 (en) 2018-12-20 2020-06-25 Amgen Inc. Heteroaryl amides useful as kif18a inhibitors
WO2020132648A1 (en) 2018-12-20 2020-06-25 Amgen Inc. Kif18a inhibitors
WO2020180770A1 (en) 2019-03-01 2020-09-10 Revolution Medicines, Inc. Bicyclic heterocyclyl compounds and uses thereof
WO2020180768A1 (en) 2019-03-01 2020-09-10 Revolution Medicines, Inc. Bicyclic heteroaryl compounds and uses thereof
US11426404B2 (en) 2019-05-14 2022-08-30 Amgen Inc. Dosing of KRAS inhibitor for treatment of cancers
US11827635B2 (en) 2019-05-21 2023-11-28 Amgen Inc. Solid state forms
US11236091B2 (en) 2019-05-21 2022-02-01 Amgen Inc. Solid state forms
WO2021026101A1 (en) 2019-08-02 2021-02-11 Amgen Inc. Kif18a inhibitors
WO2021026098A1 (en) 2019-08-02 2021-02-11 Amgen Inc. Kif18a inhibitors
WO2021026100A1 (en) 2019-08-02 2021-02-11 Amgen Inc. Pyridine derivatives as kif18a inhibitors
WO2021026099A1 (en) 2019-08-02 2021-02-11 Amgen Inc. Kif18a inhibitors
WO2021081212A1 (en) 2019-10-24 2021-04-29 Amgen Inc. Pyridopyrimidine derivatives useful as kras g12c and kras g12d inhibitors in the treatment of cancer
WO2021091967A1 (en) 2019-11-04 2021-05-14 Revolution Medicines, Inc. Ras inhibitors
WO2021091982A1 (en) 2019-11-04 2021-05-14 Revolution Medicines, Inc. Ras inhibitors
WO2021091956A1 (en) 2019-11-04 2021-05-14 Revolution Medicines, Inc. Ras inhibitors
WO2021092115A1 (en) 2019-11-08 2021-05-14 Revolution Medicines, Inc. Bicyclic heteroaryl compounds and uses thereof
WO2021097212A1 (en) 2019-11-14 2021-05-20 Amgen Inc. Improved synthesis of kras g12c inhibitor compound
WO2021097207A1 (en) 2019-11-14 2021-05-20 Amgen Inc. Improved synthesis of kras g12c inhibitor compound
WO2021108683A1 (en) 2019-11-27 2021-06-03 Revolution Medicines, Inc. Covalent ras inhibitors and uses thereof
WO2021142026A1 (en) 2020-01-07 2021-07-15 Revolution Medicines, Inc. Shp2 inhibitor dosing and methods of treating cancer
WO2021257736A1 (en) 2020-06-18 2021-12-23 Revolution Medicines, Inc. Methods for delaying, preventing, and treating acquired resistance to ras inhibitors
WO2022060583A1 (en) 2020-09-03 2022-03-24 Revolution Medicines, Inc. Use of sos1 inhibitors to treat malignancies with shp2 mutations
WO2022060836A1 (en) 2020-09-15 2022-03-24 Revolution Medicines, Inc. Indole derivatives as ras inhibitors in the treatment of cancer
WO2022140427A1 (en) 2020-12-22 2022-06-30 Qilu Regor Therapeutics Inc. Sos1 inhibitors and uses thereof
WO2022235864A1 (en) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Ras inhibitors
WO2022235870A1 (en) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Ras inhibitors for the treatment of cancer
WO2022235866A1 (en) 2021-05-05 2022-11-10 Revolution Medicines, Inc. Covalent ras inhibitors and uses thereof
WO2023060253A1 (en) 2021-10-08 2023-04-13 Revolution Medicines, Inc. Ras inhibitors
WO2023114954A1 (en) 2021-12-17 2023-06-22 Genzyme Corporation Pyrazolopyrazine compounds as shp2 inhibitors
EP4227307A1 (en) 2022-02-11 2023-08-16 Genzyme Corporation Pyrazolopyrazine compounds as shp2 inhibitors
WO2023172940A1 (en) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Methods for treating immune refractory lung cancer
US11993597B2 (en) 2022-03-10 2024-05-28 Amgen Inc. Inhibitors of KRAS G12C and methods of using the same
WO2023240263A1 (en) 2022-06-10 2023-12-14 Revolution Medicines, Inc. Macrocyclic ras inhibitors
WO2024081916A1 (en) 2022-10-14 2024-04-18 Black Diamond Therapeutics, Inc. Methods of treating cancers using isoquinoline or 6-aza-quinoline derivatives

Also Published As

Publication number Publication date
CA2336848A1 (en) 2000-01-20
AU747427B2 (en) 2002-05-16
AU5208299A (en) 2000-02-01
EP1097147A1 (en) 2001-05-09
JP2002520324A (en) 2002-07-09
EP1097147A4 (en) 2001-11-21

Similar Documents

Publication Publication Date Title
WO2000002871A1 (en) Novel angiogenesis inhibitors
US6235741B1 (en) Angiogenesis inhibitors
WO1998054093A1 (en) Novel angiogenesis inhibitors
AU760020B2 (en) Novel angiogenesis inhibitors
AU744939B2 (en) Novel angiogenesis inhibitors
US6465484B1 (en) Angiogenesis inhibitors
US6162804A (en) Tyrosine kinase inhibitors
JP7082446B2 (en) Sulfoxyimine glycosidase inhibitor
US6265403B1 (en) Angiogenesis inhibitors
AU781506B2 (en) Integrin expression inhibitors
KR100646486B1 (en) Indole-3-carboxamides as glucokinasegk activators
KR20050038631A (en) Pyrrole based inhibitors of glycogen synthase kinase 3
CA2513631A1 (en) Cyclic urea derivatives, preparation method thereof and pharmaceutical use of same as kinase inhibitors
US6380203B1 (en) Angiogenesis inhibitors
US20230025301A1 (en) Novel Heterocyclic Derivatives with Cardiomyocyte Proliferation Activity for Treatment of Heart Diseases
JP2010540628A (en) N-substituted oxyindoline derivatives as calcium channel blockers
KR20050044852A (en) Benzotriazepines as gastrin and cholecystokinin receptor ligands
US6228871B1 (en) Angiogenesis inhibitors
TWI835770B (en) Cardiac sarcomere inhibitors
JP2000080086A (en) Retinoid-associated receptor function-adjusting agent
US20230312583A1 (en) 1h-imidazo [4,5-h] quinazoline compound as novel selective flt3 inhibitors
KR20240028959A (en) Compounds as autotaxin inhibitors and pharmaceutical compositions comprising the same
JP2024521141A (en) Fused isoxazolyl compounds as KAT6A inhibitors
TW201940471A (en) Cardiac sarcomere inhibitors

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AL AM AU AZ BA BB BG BR BY CA CN CU CZ EE GD GE HR HU ID IL IN IS JP KG KR KZ LC LK LR LT LV MD MG MK MN MX NO NZ PL RO RU SG SI SK TJ TM TR TT UA US UZ VN YU ZA

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SL SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 09701993

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: 1999937204

Country of ref document: EP

ENP Entry into the national phase

Ref country code: JP

Ref document number: 2000 559102

Kind code of ref document: A

Format of ref document f/p: F

WWE Wipo information: entry into national phase

Ref document number: 52082/99

Country of ref document: AU

ENP Entry into the national phase

Ref document number: 2336848

Country of ref document: CA

WWP Wipo information: published in national office

Ref document number: 1999937204

Country of ref document: EP

WWG Wipo information: grant in national office

Ref document number: 52082/99

Country of ref document: AU

WWW Wipo information: withdrawn in national office

Ref document number: 1999937204

Country of ref document: EP