BISARYLCARBINOL DERIVATIVES AS INHIBITORS OF LEUKOTRIENE BIOSYNTHESIS

Abstract: Compounds having the formula (I): R<1>R<2>C(OR<3>)-Ar<1>-X-Ar<2>-Ar<3> are inhibitors of leukotriene biosynthesis. These compounds are useful as anti-asthmatic, anti-allergic, anti-inflammatory, and cytoprotective agents. They are also useful in treating angina, cerebral spasm, glomerular nephritis, hepatitis, endotoxemia, uveitis, and allograft rejection and in preventing the formation of atherosclerotic plaques.

Description: TITLE OF THE INVENTION BISARYLCARBINOL DERIVATIVES AS INHIBITORS OF LEUKOTRIENE BIOSYNTHESIS BACKGROUND OF THE INVENTION The leukotrienes constitute a group of locally acting hormones, produced in living systems from arachidonic acid. The major leukotrienes are Leukotriene B4 (abbreviated at LTB4), LTC4, LTD4 and LTE4. The biosynthesis of these leukotrienes begins with the action of the enzyme 5-lipoxygenase on arachidonic acid to produce the epoxide known as Leukotriene A4 (LTA4), which is converted to the other leukotrienes by subsequent enzymatic steps. Further details of the biosynthesis as well as the metabolism of the leukotrienes are to be found in the book Leukotrienes and Lipoxygenases, ed. J. Rokach, Elsevier, Amsterdam (1989). The actions of the leukotrienes in living systems and their contribution to various diseases states are also discussed in the book by Rokach. EP 385,662 (published Sept. 5, 1990) discloses 5- lipoxygenase inhibitors of the formula in which a heterocyclic moiety, Q, is linked to Ar, which may be phenylene, via A-X. The group CR2R3 attached to Ar represents a 0-, S- or N-containing heterocyclic ring, whereas the CR R2 of the present invention does not form a ring. The Ar3 unit of the present invention is absent from the above formula. EP 462,812 (published December 27, 1991) discloses 5- lipoxygenase inhibitors of the formula OR 1 Ar^-XW-C-R 2 I R 3 in which a phenyl, naphthyl or a bicyclic heterocycle (Aχl) is linked to a 5-membered heterocycle (Ar2) via Al-Xl. The group CR2R3 attached to Ar2 represents a O- or S-containing heterocyclic ring. The present compounds lack such a ring. EP 462,830 (published December 27, 1991) discloses 5- lipoxygenase inhibitors of the formula in which a phenyl, naphthyl or a bicyclic heterocycle (Arl) i s linked to a phenylene or pyridylene (Ar2) via Al-Xl. The group CR2R3 attached to Ar represents a O or S-containing heterocyclic ring; Rl is for example H, alkyl, alkyocarbonyl, or alkylthio. In contrast, CRlR 2 of the present compounds does not define a ring, and OR3 on the present compounds is different from R^ of the above formula. WO94/00444 (published January 6, 1994) discloses leukotriene biosynthesis inhibitors which are aryl substituted naphthalenes of the formula The present compounds differ from those of the above formula in that they lack the ring containing χl and χ2. Crawley et al (J. Med. Chem. 1992, 35, 2600-2609) discloses the 5-lipoxygenase inhibitor of the formula below. The compounds of the present invention differ in that they lack the tetrahydropyran ring, and that they possess an aromatic substituent on the bicyclic ring moiety. SUMMARY OF THE INVENTION The present invention relates to compounds having activity as leukotriene biosynthesis inhibitors, to methods for their preparation, and to methods and pharmaceutical formulations for using these compounds in mammals (especially humans). Because of their activity as leukotriene biosynthesis inhibitors, the compounds of the present invention are useful as anti- asthmatic, anti-allergic, anti-inflammatory, and cytoprotective agents. They are also useful in treating angina, cerebral spasm, glomerular nephritis, hepatitis, endotoxemia, uveitis, and allograft rejection and in preventing the formation of atherosclerotic plaques. DETAILED DESCRIPTION OF THE INVENTION The present invention provides compounds of Formula I RlR2C(OR3)-Arl-X-Ar2-Ar3 I wherein: Arl is a 6-membered aromatic ring containing 0-3 N, substituted with one or two of the same or different R4 groups; Ar2 is a 10-membered bicyclic ring, substituted with one or two of the same or different R5 groups, wherein said bicyclic ring is a bicyclic aromatic ring containing 0-4 ring N, 2H-l-benzopyran-2-one, or 2H-2- thioxo- 1 -benzopyran; A_3 and Ar 4 are indepedently a 5-membered aromatic ring containing one O or S and 0-3 N; a 5-membered aromatic ring containing 1-4 N; or a 6-membered aromatic ring containing 0-3 N; wherein said aromatic ring is substituted with one or two of the same or different R^ groups; X is OCH2, CH20, O, S, S(O), or S(0)2; Ri is H, lower alkyl, lower perfluoroalkyl or Aι * 4; R is H, lower alkyl or lower perfluoroalkyl; R3 is H or lower alkyl; R4 is H, lower alkyl, lower alkoxy, lower alkylthio, Nθ2, CN, CF3, CF3O or halogen; R5 is R4, oxo or thioxo; R6 is R 4 , lower alkylsulfinyl, lower alkylsulfonyl or C02R ; R7 is H or lower alkyl; or a pharmaceutically acceptable salt thereof. A preferred embodiment of the present invention provides compounds of Formula I wherein: Ar is Phe or Pye, each of which is substituted with one or two of the same or different R4 groups; Ar3 is Ph, Py, Fu, Th, Tz, Im, or Pyr, each of which is substituted with one or two of the same or different R6 groups; X is OCH2, CH2O, S, S(O), or S(0)2; Rl is H, lower alkyl, lower perfluoroalkyl, Ph, Py, Im, Fu or Tz; and the remaining substitutents are as defined above for Formula I. A more preferred embodiment of the present invention provides compounds of Formula I wherein: Ar* is Phe or Pye each of which is unsubstituted or substituted with halogen; Ar2 is naphthyl, quinolinyl, isoquinolinyl or 2H-l-benzopyran-2- one, wherein said naphthyl and quinolinyl are optionally substituted with CN; Ar3 is Ph, Py, Fu, Th, Tz, Im, or Pyr each of which is substituted with one or two of the same or different R6 groups; Alkyl means linear, branched and cyclic structures and combinations thereof. "Lower alkyl" means alkyl groups of from 1 to 7 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, s- and t-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclohexyl and the like. "Lower perfluoroalkyl" includes lower alkyl groups in which all the hydrogen atoms are replaced by fluorine. Examples are -CF3, -CF2CF3, c-Pr-F5, c-Hex-Fi 1 and the like. "Lower alkoxy" means alkoxy groups of from 1 to 7 carbon atoms of a straight, branched, or cychc configuration. Examples of lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like. "Lower alkylthio" means alkylthio groups of from 1 to 7 carbon atoms of a straight, branched or cyclic configuration. Examples of lower alkylthio groups include methylthio, propylthio, isopropylthio, cycloheptylthio, etc. By way of illustration, the propylthio group signifies -SCH2CH2CH3. "Lower alkylsulfinyl" means those alkylsulfinyl groups of from 1 to 7 carbon atoms of a straight, branched or cyclic configuration. Examples of lower alkylsulfinyl groups are methylsulfinyl, 2-butyl- sulfinyl, cyclohexylmethylsulfinyl, etc. By way of illustration the 2- butylsulfinyl group signifies -S(0)CH(CH3)CH2CH3. "Lower alkylsulfonyl" means those alkylsulfonyl groups of from 1 to 7 carbon atoms of a straight, branched or cyclic configuration. Examples of lower alkylsulfonyl groups are methylsulfonyl, 2-butyl- sulfonyl, cyclohexylmethylsulfonyl, etc. By way of illustration the 2- butylsulfonyl group signifies -S(0)2CH(CH3)CH2CH3. Halogen includes F, Cl, Br, and I. Examples of "6-membered aromatic ring containing 0-3 N" include benzene, pyridine, pyridazine, pyrimidine, pyrazine, 1,2,3- triazine, 1,2,4-triazine and 1,3,5-triazine. Examples of "10-membered bicyclic aromatic ring containing 0-4 N" include naphthalene, quinoline, isoquinoline, cinnoline, quinazoline, quinoxaline, naphthyridine, and pteridine. Examples of "5-membered aromatic ring containing one O or S and 0-3 N" include furan, oxazole, isoxazole, 1,2,5- oxadiazole, 1,3,4-oxadiazole, thiophene, thiazole, isothiazole, 1,2,4- thiadiazole and 1,3,4-thiadiazole. Examples of "5-membered aromatic ring containing 1-4 N" include pyrrole, pyrazole, imidazole, 1,2,3-triazole, 1,2,4-triazole and tetrazole. Optical Isomers - Diastereomers - Geometric Isomers Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention is meant to comprehend such possible diastereomers as well as their racemie and resolved, enantiomerically pure forms and pharmaceutically acceptable salts thereof. Salt The pharmaceutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N--dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like. When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids. It will be understood that in the discussion of methods of treatment which follows, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts. Utilities The ability of the compounds of Formula I to inhibit biosynthesis of the leukotrienes makes them useful for preventing or reversing the symptoms induced by the leukotrienes in a human subject. This inhibition of the mammalian biosynthesis of leukotrienes indicates that the compounds and pharmaceutical compositions thereof are useful to treat, prevent, or ameliorate in mammals and especially in humans: 1) pulmonary disorders including diseases such as asthma, chronic SUBSTITUTE SHEET < RULE 26) bronchitis, and related obstructive airway diseases, 2) allergies and allergic reactions such as allergic rhinitis, contact dermatitis, allergic conjunctivitis, and the like, 3) inflammation such as arthritis or inflammatory bowel disease, 4) pain, 5) skin disorders such as atopic eczema, and the like, 6) cardiovascular disorders such as angina, formation of atherosclerotic plaques, myocardial ischemia, hypertension, platelet aggregation and the like, 7) renal insufficiency arising from ischaemia induced by immunological or chemical (cyclosporin) etiology and 8) migraine or cluster headache, 9) ocular conditions such as uveitis, 10) hepatitis resulting from chemical, immunological or infectious stimuli, 11) trauma or shock states such as burn injuries, endotoxemia and the like, 12) allograft rejection, 13) prevention of side effects associated with therapeutic administration of cytokines such as Interleukin II and tumor necrosis factor, 14) chronic lung diseases such as cystic fibrosis, bronchitis and other small- and large-airway diseases, 15) cholecystitis, 16) multiple sclerosis, and 17) proliferation of myoblastic leukemia cells. Thus, the compounds of the present invention may also be used to treat or prevent mammalian (especially, human) disease states such as erosive gastritis; erosive esophagitis; diarrhea; cerebral spasm; premature labor; spontaneous abortion; dysmenorrhea; ischemia; noxious agent-induced damage or necrosis of hepatic, pancreatic, renal, or myocardial tissue; liver parenchymal damage caused by hepatoxic agents such as CCI4 and D-galactosamine; ischemic renal failure; disease- induced hepatic damage; bile salt induced pancreatic or gastric damage; trauma- or stress-induced cell damage; and glycerol-induced renal failure. The compounds also act as inhibitors of tumor metastasis and exhibit cytoprotective action. The cytoprotective activity of a compound may be observed in both animals and man by noting the increased resistance of the gastrointestinal mucosa to the noxious effects of strong irritants, for example, the ulcerogenic effects of aspirin or indomethacin. In addition to lessening the effect of non-steroidal anti-inflammatory drugs on the gastrointestinal tract, animal studies show that cytoprotective compounds will prevent gastric lesions induced by oral administration of strong acids, strong bases, ethanol, hypertonic saline solutions, and the like. Two assays can be used to measure cytoprotective ability. These assays are; (A) an ethanol-induced lesion assay and (B) an indomethacin-induced ulcer assay and are described in EP 140,684. Dose Ranges The magnitude of prophylactic or therapeutic dose of a compound of Formula I will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound of Formula I and its route of administration. It will also vary according to the age, weight and response of the individual patient. In general, the daily dose range for anti-asthmatic, anti-allergic or anti-inflammatory use and generally, uses other than cytoprotection, lie within the range of from about 0.001 mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg to about 10 mg per kg, and most preferably 0.1 to 1 mg per kg, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases. For use where a composition for intravenous administration is employed, a suitable dosage range for anti-asthmatic, anti- inflammatory, or anti-allergic use is from about 0.001 mg to about 25 mg (preferably from 0.01 mg to about 1 mg) of a compound of Formula I per kg of body weight per day and for cytoprotective use from about 0.1 mg to about 100 mg (preferably from about 1 mg to about 100 mg and more preferably from about 1 mg to about 10 mg) of a compound of Formula I per kg of body weight per day. In the case where an oral composition is employed, a suitable dosage range for ant-asthmatic, anti-inflammatory or anti-allergic use is, e.g. from about 0.01 mg to about 100 mg of a compound of Formula I per kg of body weight per day, preferably from about 0.1 mg to about 10 mg per kg and for cytoprotective use from 0.1 mg to about 100 mg (preferably from about 1 mg to about 100 mg and more preferably from about 10 mg to about 100 mg) of a compound of Formula I per kg of body weight per day. For the treatment of diseases of the eye, ophthalmic preparations for ocular administration comprising 0.001-1% by weight solutions or suspensions of the compounds of Formula I in an acceptable ophthalmic formulation may be used. The exact amount of a compound of the Formula I to be used as a cytoprotective agent will depend on, inter alia, whether it is being administered to heal damaged cells or to avoid future damage, on the nature of the damaged cells (e.g., gastrointestinal ulcerations vs. nephro tic necrosis), and on the nature of the causative agent. An example of the use of a compound of the Formula I in avoiding future damage would be co-administration of a compound of the Formula I with an NSAID that might otherwise cause such damage (for example, indomethacin). For such use, the compound of Formula I is administered from 30 min. prior up to 30 minutes after administration of the NSAID. Preferably it is administered prior to or simultaneously with the NSAID, (for example, in a combination dosage form). Pharmaceutical Compositions Any suitable route of administration may be employed for providing a mammal, especially a human with an effective dosage of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. The pharmaceutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids. The compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy. For administration by inhalation, the compounds of the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or nebulisers. The compounds may also be delivered as powders which may be formulated and the powder composition may be inhaled with the aid of an insufflation powder inhaler device. The preferred delivery system for inhalation is a metered dose inhalation (MDI) aerosol, which may be formulated as a suspension or solution of a compound of Formula I in suitable propellants, such as fluorocarbons or hydrocarbons. Suitable topical formulations of a compound of Formula I include transdermal devices, aerosols, creams, ointments, lotions, dusting powders, and the like. In practical use, the compounds of Formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. In addition to the common dosage forms set out above, the compounds of Formula I may also be administered by controlled release means and/or delivery devices such as those described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200 and 4,008,719, the disclosures of which are hereby incorporated herein by reference. Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Desirably, each tablet contains from about 1 mg to about 500 mg of the active ingredient and each cachet or capsule contains from about 1 to about 500 mg of the active ingredient. The following are examples of representative pharma¬ ceutical dosage forms for the compounds of Formula I: Combinations With Other Drugs In addition to the compounds of Formula I, the pharmaceutical compositions of the present invention can also contain other active ingredients, such as cyclooxygenase inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), peripheral analgesic agents such as zomepirac diflunisal and the like. The weight ratio of the compound of the Formula I to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the Formula I is combined with an NSAID the weight ratio of the compound of the Formula I to the NSAID will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1 :200. Combinations of a compound of the Formula I and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. NSAIDs can be characterized into five groups: ( 1 ) propionic acid derivatives ; (2) acetic acid derivatives; (3) fenamic acid derivatives; (4) oxicams; and (5) biphenylcarboxylic acid derivatives, or a pharmaceutically acceptable salt thereof. The propionic acid derivatives which may be used comprise: alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, prano-profen, suprofen, tiaprofenic acid, and tioxaprofen. Structurally related propionic acid derivatives having similar analgesic and anti-nflammatory properties are also intended to be included in this group. Thus, "propionic acid derivatives" as defined herein are non- narcotic analgesics/non-steroidal anti-inflammatory drugs having a free -CH(CH3)COOH or -CH2CH2COOH group (which optionally can be in the form of a pharmaceutically acceptable salt group, e.g., -CH(CH3)COO-Na+ or -CH2CH2COO " Na+), typically attached directly or via a carbonyl function to a ring system, preferably to an aromatic ring system. The acetic acid derivatives which may be used comprise: indomethacin, which is a preferred NSAID, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofεnac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, and zomepirac. Structually related acetic acid derivatives having similar analgesic and anti-inflammatory properties are also intended to be encompassed by this group. Thus, "acetic acid derivatives" as defined herein are non- narcotic analgesics/non-steroidal anti-inflammatory drugs having a free -CH2COOH group (which optionally can be in the form of a pharmaceutically acceptable salt group, e.g. -CH2COO _ Na+), typically attached directly to a ring system, preferably to an aromatic or heteroaromatic ring system. The fenamic acid derivatives which may be used comprise: flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid. Structurally related fenamic acid derivatives having similar analgesic and anti-inflammatory properties are also intended to be encompassed by mis group. Thus, "fenamic acid derivatives" as defined herein are non- narcotic analgesics/non-steroidal anti-inflammatory drugs which contain d e basic structure: which can bear a variety of substituents and in which the free -COOH group can be in the form of a pharmaceutically acceptable salt group, e.g., -COO'Na+. The biphenylcarboxylic acid derivatives which can be used comprise: diflunisal and flufenisal. Structurally related biphenyl¬ carboxylic acid derivatives having similar analgesic and anti- inflammatory properties are also intended to be encompassed by this group. Thus, "biphenylcarboxylic acid derivatives" as defined herein are non-narcotic analgesics/non-steroidal anti-inflammatory drugs which contain the basic structure: which can bear a variety of substituents and in which the free -COOH group can be in the form of a pharmaceutically acceptable salt group, e.g., -COO"Na + . The oxicams which can be used in the present invention comprise: isoxicam, piroxicam, sudoxicam and tenoxican. Structurally related oxicams having similar analgesic and anti-inflammatory properties are also intended to be encompassed by this group. Thus, "oxicams" as defined herein are non-narcotic analgesics/non-steroidal anti-inflammatory drugs which have the general formula: wherein R is an aryl or heteroaryl ring system. The following NSAIDs may also be used: amfenac sodium, aminoprofen, anitrazafen, antrafenine, auranofin, bendazac lysinate, benzydanine, beprozin, broperamole, bufezolac, cinmetacin, ciproquazone, cloximate, dazidamine, deboxamet, delmetacin, detomidine, dexindoprofen, diacerein, di-fisalamine, difenpyramide, emorfazone, enfenamic acid, enolicam, epirizole, etersalate, etodolac, etofenamate, fanetizole mesylate, fenclorac, fendosal, fenflumizole, feprazone, floctafenine, flunixin, flunoxaprofen, fluproquazone, fopirtoline, fosfosal, furcloprofen, glucametacin, guaimesal, ibuproxam, isofezolac, isonixim, isoprofen, isoxicam, lefetamine HCl, leflunomide, lofemizole, lonazolac calcium, lotifazole, loxoprofen, lysin clonixinate, meclofenamate sodium, meseclazone, nabumetone, nictindole, nimesulide, o anoxin, oxametacin, oxapadol, perisoxal citrate, pimeprofen, pimetacin, piproxen, pirazolac, pirfenidone, proglumetacin SUBSTITUTE SHEET (RULE 2β) maleate, proquazone, pyridoxiprofen, sudoxicam, talmetacin, talniflumate, tenoxicam, thiazolinobutazone, thielavin B, tiaramide HCl, tiflamizole, timegadine, tolpadol, tryptamid, and ufenamate. The following NSAIDs, designated by company code number (see e.g., Pharmaprojects), may also be used: 480156S, AA861, AD1590, AFP802, AFP860, AI77B, AP504, AU8001, BPPC, BW540C, CHINOIN 127, CN100, EB382, EL508, F1044, GV3658, ITF182, KCNTEI6090, KME4, LA2851, MR714, MR897, MY309, ON03144, PR823, PV102, PV108, R830, RS2131, SCR152, SH440, SIR133, SPAS510, SQ27239, ST281, SY6001, TA60, TAI-901 (4-benzoyl-l-indancarboxylic acid), TVX2706, U60257, UR2301, and WY41770. Finally, NSAIDs which may also be used include the salicylates, specifically acetyl salicylic acid and the phenylbutazones, and pharmaceutically acceptable salts thereof. In addition to indomethacin, other preferred NSAIDs are acetyl salicylic acid, diclofenac, fenbufen, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, phenylbutazone, piroxicam, sulindac, and tolmetin. Pharmaceutical compositions comprising the Formula I compounds may also contain inhibitors of the biosynthesis of die leukotrienes such as are disclosed in EP 138,481 (April 24,1985), EP 115,394 (August 8, 1984), EP 136,893 (April 10, 1985), and EP 140,709 (May 8, 1985), which are hereby incorporated herein by reference. The compounds of the Formula I may also be used in combination with leukotriene antagonists such as those disclosed in EP 106,565 (April 25, 1984) and EP 104,885 (April 4, 1984) which are hereby incorporated herein by reference and others known in the art such as those disclosed in EP Application Nos. 56,172 (July 21, 1982) and 61,800 (June 10, 1982); and in U.K. Patent Specification No. 2,058,785 (April 15, 1981), which are hereby incorporated herein by reference. Pharmaceutical compositions comprising the Formula I compounds may also contain as the second active ingredient, prostaglandin antagonists such as those disclosed in EP 11,067 (May 28, 1980) or thromboxane antagonists such as those disclosed in U.S. Pat. 4,237,160. They may also contain histidine decarboxylase inhibitors such as α-fluoromethylhistidine, described in U.S. Pat. 4,325,961. The compounds of die Formula I may also be advantageously combined with an Hi or H2-receptor antagonist, such as for instance acetamazole, aminothiadiazoles disclosed in EP 40,696 (December 2, 1981), benadryl, cimetidine, famotidine, framamine, histadyl, phenergan, ranitidine, terfenadine and like compounds, such as those disclosed in U.S. Patent Nos. 4,283,408; 4,362,736; and 4,394,508. The pharmaceutical compositions may also contain a K + /H + ATPase inhibitor such as omeprazole, disclosed in U.S. Pat. 4,255,431, and the like. Compounds of Formula I may also be usefully combined with most cell stabilizing agents, such as l,3-bis(2-carboxychromon-5-yloxy)-2- hydroxypropane and related compounds described in British Patent Specifications 1,144,905 and 1,144,906. Another useful pharmaceutical composition comprises the Formula I compounds in combination with serotonin antagonists such as methysergide, the serotonin antagonists described in Nature, !i£, 126-131 (1985), and the like. Each of the references referred to in this paragraph is hereby incorporated herein by reference. Other advantageous pharmaceutical compositions comprise the Formula I compounds in combination with anti-cholinergics such as ipratropium bromide, bronchodilators such as the beta agonist salbutamol, metaproterenol, terbutaline, fenoterol and the like, and the anti-asthmatic drugs theophylline, choline theophyllinate and enprofylline, the calcium antagonists nifedipine, diltiazem, nitrendipine, verapamil, nimodipine, felodipine, etc. and the corticosteroids, hydrocortisone, methylprednisolone, betamethasone, dexamethasone, beclomethasone, and the like. SUBSTITUTE SHEET (RULE 26. Methods Of Synthesis Compounds of Formula I of the present invention may be prepared according to the synthetic routes outlined in Schemes 1 to 13 and by the following methods described herein. Scheme 1 Compounds of Formulas IA and IB can be synthesized using the route described in Scheme 1. Bromophenol II can be acetylated by treating a mixture of II and acetyl chloride in the presence of a base such as pyridine in a solvent such as dichloromethane to yield the corresponding acetate which, upon heating neat with a Lewis acid such as aluminum chloride, gives the acyl derivative III. Reaction of III with first an inorganic base such as sodium hydride in an organic solvent such as benzene followed by addition of a carbonate such as diethylcarbonate furnishes the intermediate IV. The intermediate IV is then transformed using trifluoromethanesulfonic anhydride, in the presence of an amine such as triethylamine, in a neutral solvent such as dichloromethane, to the corresponding triflate V. Cross coupling of this material with an aryl lithium species resulting from reaction of an aryl halide (Br or I) with an alkyl lithium such as n-BuLi in a mixture of THF/hexanes, in the presence of trimethyl borate and catalyzed by a Pd(0) species such as (Ph3P)4Pd, in a mixture of THF/water as solvent, affords derivatives VI. Compounds of Formula 1 A can be obtained by heating a mixture of VI and a thiophenol of general structure VII (Scheme 10) in a polar solvent such as N-methyl-2-pyrτolidinone with an inorganic base like potassium carbonate. Compounds of Formula IB can be obtained by treating compounds of general structure 1 A in the presence of a peracid such as mCPBA in an organic solvent such as dichloromethane. Scheme 2 Compounds of Formula IC can be synthesized using die route described in Scheme 2. The meta-cresol Vm is converted in several steps to the Compound IX using the same protocol as described in Scheme 1 for the conversion of II to VI. Intermediate IX is dien brominated by heating in d e presence of a brominating reagent such as NBS in an organic solvent such as carbon tetrachloride in the presence of a catalytic amount of a radical initiator such as AIBN, giving access to Compound X. Bromide displacement can be accomplished using a phenol of a general structure XI (Scheme 9) in the presence of an inorganic base such as cesium carbonate in an aprotic dipolar solvent such as DMF to afford compounds of Formula IC. Scheme 3 Compounds of Formula ID can be prepared as shown in Scheme 3. The aromatic bromide VI can be reacted by heating in the presence of trime thylsilylethane thiol and an inorganic base such as potassium carbonate in a polar solvent such as N-methyl-2-pyrrolidinone to afford derivative XII. The thiol derivatives XIII can be obtained by treating XII with B114NF in an organic solvent such as DMF. Sulfur linked compounds may be obtained by heating tiiiol XIII with an aromatic bromide of general formula XIV (Scheme 13) in die presence of an inorganic base such as potassium carbonate in a polar solvent such as N-methyl-2-pyrrolidinone to yield compounds of Formula ID. Scheme 4 Compounds of Formula IE, IF and IG can be obtained using the route described in Scheme 4. Naphthalene XV (U.S. 5,308,852, Merck Frosst) can be transformed to the corresponding triflate XVII using trifluoromethanesulfonic anhydride in die presence of a tertiary amine such as triethylamine in a neutral solvant such as dichloro¬ methane. The resulting triflate can be reacted witii a palladium (II) species such as palladium acetate, a catalyst such as l,l '-bis(diphenyl- phosphino)ferrocene, an organic base (e.g. Et3N) and methanol in a dipolar aprotic solvent (for example DMSO) under an atmosphere of carbon monoxide to yield XVIII. The ester function in XVIII can be selectively reduced to the primary alcohol XIX using lithium borohydride in an organic solvent such as THF. Coupling products of structures IE and IF can be obtained by reacting the phenol XV with compounds of the general structure XVI (Schemes 11 and 12), and die alcohol XIX witii compounds of general structure XI (Scheme 2), respectively, using a phosphine such as triphenylphosphine in die presence of an azodicarboxylate (e.g. dimetiiylazodicarboxylate) in an organic solvent such as THF. The coupling reaction between alcohol XIX and the general structure XIV (Scheme 13) to obtain compound IG can be effected using a base such as sodium hydroxide and 18-crown-6 in a hot organic solvent such as toluene. Scfrerne ,5 Compounds of Formula IH can be obtained using the route described in Scheme 5. The triflate XVII can be transformed to the trimethyltin derivative XX using a ditin such as hexamediylditin in the presence of palladium (0) species such as tetrakis(triphenylphosphine) palladium and in the presence of lid ium chloride. Iodination of XX to the corresponding iododerivative XXI can be done by treating XX witii iodine in an organic solvent such as chloroform. Final products of the general structure IH can be obtained by coupling the iododerivative XXI witii die diiophenol of die general structure VII (Scheme 10) in the presence of a base such as potassium tert-butoxide, and a palladium (0) species such as tetrakis(triphenyl-phosphine) palladium, in a hot solvent such as ethanol. Scheme 6 Compounds of the Formula IJ can be synthesized as shown in Scheme 6. The iododerivative XXI can be treated with trimethylsilyl- ethanethiol in the presence of potassium tert-butoxide and a palladium (0) species such as tetrakis(triphenylphosphine) palladium in a hot protic solvent such as edianol giving compounds XXII. Deprotection of XXII using a fluoride source such as tetrabutylammonium fluoride in an organic solvent such as THF gives the corresponding tiiiol XXIII. Coupling reaction between the tiiiol XXHI and die bromo derivative of the general structure XIV (Scheme 13) in the presence of an inorganic base such as potassium carbonate in an organic solvent such as DMF and N- medιyl-2-pyrrolidinone gives Compound IJ. Scheme 7 The quinoline IK of Scheme 7 may be prepared in a multi- step sequence from an appropriately dihalogenated quinoline XXIV. The quinoline XXIV is firstly converted into the quinoline XXV by a regioselective reaction with an appropriate metalated aromatic such as dimethyl 3-furyl borate in the presence of a catalyst such as tetrakis (triphenylphosphine) palladium. The conversion to the quinoline XXVI is achieved by treatment of XXV with a metalated memyl reagent such as metiiyl magnesium bromide in die presence of a catalyst such as [1,3- bis(diphenylphosphino)propane]nickel (II) chloride. The quinoline XXVI is converted into the quinoline XXVII by first treatment with an oxidizing reagent such as m-chloroperoxybenzoic acid in an organic solvent followed by reaction of the intermediate N-oxide with an acylating reagent such as dialkylcarbamyl chloride, and a cyanating agent such as trimethylsilyl cyanide. Bromination of XXVII is achieved upon treatment with a bromine source, such as N-bromosuccinimide and light. Coupling of die benzylic halide XXVIII with the appropriate phenol of die general structure XI (Scheme 9) in an organic solvent such as DMF using an inorganic base such as CS2CO3 provides compounds of formula IK of the present invention. Scheme 8 The isoquinoline IL of Scheme 8 may be prepared in a multi-step sequence from an appropriately substituted anisole XXIX. The amine XXIX is converted into the sulfonamide XXX by a two-step procedure involving sulfonylation using a sulfonylating agent such as p- toluenesulfonyl chloride in die presence of a base such as pyridine, followed by alkylation witii an appropriate aryl halo methyl ketone such as a bromomethyl aryl ketone in the presence of a base such as CS2CO3 in an organic solvent such as acetone. The cyclization of die sulfonamide XXX to provide XXXI is achieved by heating in an acid such as trifluoroacetic acid. The demethylation of isoquinoline XXXI is achieved under acidic conditions, such as heating witii pyridine hydrochloride, leading to XXXII. The phenol XXXII is then converted into the iodide XXXHI by procedures similar to those described for the sequence XV - XVI I- XX - XXI in Schemes 4 and 5. Coupling of die iodide XXXϋl and die appropriate thiophenol of the general structure VII (Scheme 10) in an organic solvent such as butanol in the presence of a base such as potassium t-butoxide and a catalyst such as (Ph3P)4Pd provides compounds of Formula IL of the present invention. Scheme 9 The phenols of structure XI can be obtained following die route described in Scheme 9. The protected bromophenol XXXIV can be transformed to the tertiary alcohol XXXV by first a transmetallation using magnesium in an organic solvent such as THF or by using an alkyllidiium such as n-butyllithium, followed by addition of the appropriate ketone. Alternatively, fluoroketone XXXVI can be transformed to the corresponding benzyl ether XXXVII by treating widi die benzyloxy sodium salt in an organic solvent such as DMF. Treatment of compound XXXVII witii alkyl lithium such as methyl lithium or with a Grignard reagent such as methyl magnesium bromide provides compound XXXV. The tertiary alcohol XXXV can be alkylated to XXXIII with an alkyl halide such as mediyl iodide in die presence of base such as potassium hydride in an organic solvent such as DMF. Removal of the protecting group by treating XXXV with hydrogen in the presence of a catalyst such as Pd/ C (P = Bn or 3,4-DMB) or by using a fluoride source such as tetrabutylammonium fluoride in an organic solvent such as THF (P = TBDMS or TBDPS) provides the phenols of structure XI. Scheme 10 The thiophenols of the general Formula VII can be obtained using a multi-step sequence shown in Scheme 10. The bromofluoro- benzene XXXIX can be first transmetallated with magnesium in an organic solvent such as THF followed by the addition of the appropriate ketone to obtain the corresponding tertiary alcohol of the general Formula XL. The introduction of the tiiiol function can be effected by treating the fluoro derivatives XL with a tiiiol source such as trimethylsilylethane tiiiol in the presence of an hydride such as sodium hydride in an aprotic solvent such as DMF. The resulting Compound XLI can be converted to die tiiiol VII by treatment with a fluoride source such as tetrabutyl¬ ammomum fluoride in an organic solvent such as THF. Alternatively, thiol VII can be obtained by treating the fluoroketone XXXVII with sodium metiiylthiolate giving XLIII and followed by treating XLIII with the appropriate Grignand reagent. Then cleavage of the methyltiiio ether group can be effected by first oxidizing die sulfur to the sulfoxide using an oxidizing reagent such as mCPBA and then by treating it with trifluoroacetic anhydride. Compounds of Formula VII (R3 = lower alkyl) can be obtained by treating a compound of Formula XLI or XLIV witii an alkyl halide such as alkyl iodide and a base such as potassium hydride, to provide compounds of Formula XLII or XLV, respectively; conversion of XLII and XLV into VII (R3 = lower alkyl) may be effected using methods discussed above. Scheme 11 Compounds of Formula XVI (Z=CH) can be obtained according to the reaction sequence depicted in Scheme 11. Protection of the bromo alcohol XL VI witii a silylating agent such as tertbutyldimethylsilyl chloride in the presence of a base such as triethylamine in an organic solvent such as dichloromethane give compounds XL VII. The formation of the corresponding tertiary alcohols XL VIII can be effected following the same protocol as described for die preparation of compounds XXXV in Scheme 9 followed by treatment with a fluoride source such as tetrabutylammonium fluoride in an organic solvent such as THF to provide compounds XVI (Z=CH). Scheme 12 The corresponding pyridine alcohol XVI (Z=N) can be synthesized using 2,6-dibromopyridine as starting material. First a transmetallation with an alkyllithium such as butyllitiiium in an organic solvent such as THF followed by addition of dry ice gives Compound L. Reduction of the acid function by treating the acid L witii a chloroformate agent such as ethyl chloroformate in a protic solvent such as ethanol followed by a treatment with an hydride source such as lithium aluminum hydride or sodium borohydride gives the corresponding alcohol LI. Compounds XVI (Z=N) can be obtained following the same sequence as described for the transformation of XL VI to XVI (Z=CH) in Scheme 11. Sche e 13 The bromopyridines of the general Formula XIV can be obtained starting with 2,6-dibromopyridine and using die same protocol as described for the transformation of Compound XXXIV to XXXV in Scheme 9. SCHEME 1 IB (n = 1,2) 29 SCHEME 2 VIII IX IC 30 SCHEME 3 ID SCHEME 4 SCHEME IH SCHEME 6 XIV IJ 8 -34 SCHEME 7 XXIV 1)mCPBA 2)CIC(0)N(ALK 3) Me 3 SiCN (ALK=lower alk XXVIII XXVII XI -35 SCHEME 8 SCHEME 9 PREPARATION OF PHENOLS XXXVI -37 SCHEME 10 PREPARATION OF TMOPHENOLS XLIII SCHEME 1 1 PREPAR ATION OF ALCOHOLS XLIX (R 3 =lower alkyl) SCHEME 12 PREPARAΉON OF ALCOHOLS XVI (Z=N) SUBSTITUTE SHEET (RΛE 26) SCHEME 13 PREPARAΉON OF BROMOPYRIDINES XIV (R 3 =hydrogen) KH, R 3 I Representative Compounds Table I illustrates compounds of Formula Ia, which are representative of the present invention. TABLE I Table II illustrates compounds of Formula lb which are further representative of the present invention. TABLE II Table III illustrates compounds of Formula Ic which are further representatives of the present invention. Ic TABLE III SUBSTITUTE SHEET ( αE 26) Table IV illustrates compounds of Formula Id which are representative of the present invention Id TABLE IV Assays For Determining Biological Activity Compounds of Formula I can be tested using the following assays to determine tiieir mammalian leukotriene biosynthesis inhibiting activity. Human 5-Lipoxygenase Inhibitor Screen Objective of the Assay: The objective of the assay is to select agents which specifically inhibit the activity of human 5- lipoxygenase using a 100,000 x g supernatant fraction prepared from insect cells infected with recombinant baculovirus containing the coding sequence for human 5-lipoxygenase. Enzyme activity is measured spectrophotometrically from the optimal rate of conjugated diene formation (A234) measured after the incubation of the enzyme with arachidonic acid in the presence of ATP, calcium ions and phosphatidylcholine. SUBSTITUTE SHEET 0M.E 26) Description of Procedure: The activity of 5-lipoxygenase is measured using a spectrophotometric assay and recombinant human 5- lipoxygenase as a source of enzyme. The 100,000 x g fraction from S19 cells infected witii the recombinant baculovirus rvH5LO(8-l) containing the coding region sequence for human 5-lipoxygenase is prepared as described by Denis et al., (J. Biol. Chem., 2£& 5072-5079 (1991)). The enzymatic activity is measured, using a spectrophotometric assay from the optimal rate of conjugated diene formation (A234) using the procedure described by Riendeau et al., (Biochem. Pharmacol. 2i_, 2323- 2321, (1989)) witii minor modifications. The incubation mixture contains 50 mM sodium phosphate pH 7.4, 0.2 mM ATP, 0.2 mM CaCl2, 20 μM arachidonic acid (5 μL from a 100-fold concentrated solution in ethanol), 12 μg/mL phosphatidylcholine, an aliquot of the 100,000 x g fraction (2-10 μL) and inhibitor (0.5 mL final volume). Inhibitors are added as 500-fold concentrated solutions in DMSO. Reactions are initiated by die addition of an aliquot of die enzyme preparation and die rate of conjugated diene formation is followed for 2 min. at r.t.. The reactions are performed in semi-micro cuvettes (0.7 mL capacity, 10 mm path lengtii and 4 mm internal width) and the absorbance changes are recorded with a Hewlett-Packard diode array spectrophotometer (HP 8452 A) connected to the ChemStation using UV/VIS Kinetics Software. Enzymatic activity is calculated from the optimal rate of the reaction by a linear fit of the variation of A234 during the first twenty seconds using the least square method for the equation A234=V 0 t + A° where V 0 is the rate, t is the time, and Ao is the absorbance at zero time. The results are expressed as percentages of inhibition of the reaction rate relative to controls (typically between 0.15-0.21 AU/min) containing the DMSO vehicle. Human Pol vmorphonuclear (PMN . Leukocyte LTB4 Assay A. Preparation of Human PMN. Human blood is obtained by antecubital venepunc ture from consenting volunteers who have not taken medication witiiin me previous 7 days. The blood is immediately added to 10% (v/v) trisodium citrate (0.13 M) or 5% (v/v) sodium heparin (1000 IU/mL). PMNs are isolated from anticoagulated blood by dextran sedimentation of erythrocytes followed by centrifugation through Ficoll-Hypaque (specific gravity 1.077), as described by Boyum (Scand. J. Clin. Lab. Invest., 21 (Supp 97), 77 (1968)). Contaminating erythrocytes are removed by lysis following exposure to ammonium chloride (0.16 M) in Tris buffer (pH 7.65), and the PMNs are resuspended at 5 x IO 5 cells/mL in HEPES (15 mM)- buffered Hanks balanced salt solution containing Ca2+ (1.4 mM) and Mg2+ (0.7 mM), pH 7.4. B. Generation and Radioimmunoassay ofLTB4. PMNs (0.5 mL; 2.5 x 10^ cells) are placed in plastic tubes and incubated (37°C, 2 min) witii test compounds at die desired concentration or vehicle (DMSO, final concentration 0.2%) as control. The synthesis of LTB4 is initiated by die addition of calcium ionophore A23187 (final concentration 10 μM) or vehicle in control samples and allowed to proceed for 5 min. at 37°C. The reactions are tiien terminated by the addition of cold metiianol (0.25 mL) and samples of die entire PMN reaction mixture are removed for radioimmunoassay of LTB4. Samples (50 μL) of authentic LTB4 of known concentration in radioimmunoassay buffer (RIA) buffer (potassium phosphate 1 mM; disodium EDTA 0.1 mM; Thimerosal 0.025 mM; gelatin 0.1%, pH 7.3) or PMN reaction mixture diluted 1:1 witii RIA buffer are added to reaction tubes. Thereafter [3H]-LTB4 (10 nCi in 100 μL RIA buffer) and LTB4-antiserum (100 μL of a 1:3000 dilution in RIA buffer) are added and the tubes vortexed. Reactants are allowed to equilibrate by incubation overnight at 4°C. To separate antibody-bound from free LTB4, aliquots (50 μL) of activated charcoal (3% activated charcoal in RIA buffer containing 0.25% Dextran T-70) are added, die tubes vortexed, and allowed to stand at r.t. for 10 min. prior to centrifugation (1500 x g; 10 min; 4°C). The supematants containing antibody-bound LTB4 are decanted into vials and Aquasol 2 (4 mL) is added. Radioactivity is quantified by liquid scintillation spectrometry. The specificity of ti e antiserum and die sensitivity of the procedure have been described by Rokach et al., Prostaglandins Leukotrienes and Medicine, 12, 21 (1984). The amount of LTB4 produced in test and control samples is calculated. Inhibitory dose-response curves are constructed using a four-parameter algorithm and from these the IC50 values are determined. Human Whole Blood Assay In Vitro For Ltb4 Production Fresh blood is collected in heparinized tubes by venipuncture from human volunteers. A 500 μL aliquot is incubated witii one of the test compounds at final concentrations varying from 3 nM to 3 mM at 37°C for 15 min. Drug stock solutions are made up in DMSO and 1 μL of the stock solution is added to each assay tube. The blood is then incubated with A23187 (in 5 μL autologous plasma, 25 μM final concentration) at 37°C for 30 min. At die end of incubation, plasma is obtained (12,000 x g, 15 min) and a 100 μL aliquot is added to 400 μL methanol for protein precipitation. The mixture is vortexed, centrifuged and the supernatant stored at -70°C until assayed for LTB4 by standard RIA. Pulmonary Mechanics In Trained Conscious Squirrel Monkeys - A Non- Invasive Technique Objective of the Assav: To assess pulmonary mechanics changes in the airways of conscious squirrel monkeys with the use of a double plethysmograph instead of thoracic catheterization of the pie ural space as in the former invasive technique to measure airway resistance (RL) and dynamic compliance (Cdyn)- The non-invasive technique measures changes in the pulmonary parameter "specific airway resistance" (sRaw) which is defined as airway resistance x thoracic gas volume. Agonists like LTD4, 50 μg/mL oτAscaris suum antigen (1:25 dilution) aerosol challenge cause an increase in sRaw values, i.e. bronchoconstriction, and consequently allow die evaluation of specific antagonists against these agonists. For evaluation of compounds in tiiis model, monkeys are fasted overnight and dosed die following morning. The compound is dissolved in 1% methocel solution and given orally at doses ranging from 1 to 0.003 mg/kg in a volume of 1 mL/kg in the home cage. Three h later the monkeys are placed in a chair within a thoracic plethysmograph whilst the muzzle of die monkey is placed into a nasal plethysmograph dirough which he breathes. Baseline values for sRaw (cm H2O x sec.) are taken and at 4 h post compound administration, die monkeys are challenged with an aerosol of the specific agonist. The aerosol is generated by an ultrasonic DeVilbiss nebulizer and administered to the monkeys in the nasal plediysmograph at a rate of 2 litres/minute with the aid of a Pulmo-Aide pump (DeVilbiss, 561 series) for 10 min.. For data collection, a Buxco Electronics Inc. respiratory computer is utilized which facilitates continuous recording of pulmonary function changes and derives a value for sRaw for each animal. Following challenge, each minute of data is calculated as a percent change from control values for specific airway resistance (sRaw). The results for each test compound are subsequently obtained for a minimum period of 60 minutes post challenge which are then compared to previously obtained historical baseline control values for tiiat monkey. In addition, the overall values for 60 minutes post-challenge for each monkey (historical baseline values and test values) are averaged separately and are used to calculate the overall percent inhibition of LTD4 or Ascaris antigen response by the test compound. For statistical analysis, paired t-test is used (Reference: Pennock, B.E. et al., J. Appl. Physiol: Respirat. Environ. Exercise Physiol. 4£ (2) 399-406, 1979. DOG MODEL: Whole Blood (ex vivo) LTB4 and Urinary LTE4_Excretion Assays Normal male dogs are anaesthetised, bronchially intubated and catheterised for drug administration and urine collection. After the first urine voiding (15 min.), blood is collected into anticoagulant to define die baseline LTB4 biosynthetic capacity of whole dog blood, and to determine die in vitro potency of diis compound in dog blood. Compounds are dissolved in PEG 2OO/H2O to a concentration of 0.3 mg/mL. In tubes #1-4, 10 μL of PEG 200 (vehicle) is added to serve as controls. Compounds are titrated from 0.0015 μM - 0.37μM (final concentration). Compounds are added in a volume of 10 μL in ascending concentrations in duplicate (tubes #5-16). The highest drug concentration is also added to tube #17 as a drug blank. To each tube, 500 μL venous blood is added, followed by incubation for 15 minutes at room temperature, without shaking. Tubes #1 & 17, then receives 5 μL of autologous plasma containing 10% DMSO (blanks). 5 μL of autologous plasma containing 10% DMSO and 5 mM A23187 (final 50 μM) are added to tubes #2 to 16 to stimulate LTB4 synthesis. Samples are incubated for 30 min. at 37°C, and the reaction terminated by centrifugation. Aliquots of plasma is added to 4 volumes of MeOH, and centrifuged to precipitate proteins prior to analysis of LTB4 content by RIA. A bolus dose of compounds (0.1, 0.05 or 0.025 mg/kg in PEG2OO/H2O) is then administered intravenously, followed by a continuous infusion (via a 21 gauge IV catheter) of the compounds (2.5, 0.8 or 0.25 μg/kg/min). Urine is continuously collected for 1 hour intervals. Sample volumes are recorded, and urinary LTE4 stabilised with ION NaOH solution (10 μL/mL), prior to freezing (-70°C). Venous blood is similarly collected (into anticoagulant) contralateral to die IV at hourly intervals. All blood samples are immediately aliquoted (500 μL). To one aliquot, 5 μL of autologous plasma containing 10% DMSO is added as a blank. To otiier aliquots, 5 μL of autologous plasma containing 10% DMSO and 5 mM A23187 is added (final 50 μM) to stimulate LTB4 syndiesis as described above. Aliquots (10 mL) of thawed urine are centrifuged (10,000 x g), and die supernatant adjusted to pH 5.4 witii 100 μL glacial acetic acid. As a recovery standard, 3 nCi of [14,15,19,20-3H]-LTC4 (12 pg) is added. Samples are applied to a 3 μm particle Cl8 precolumn, and washed witii 2 volumes of 0.1 % NH4OAC buffer pH 5.4. Peptide leukotrienes are then eluted onto a C18 analytical HPLC column, and separated with a 66% MeOH/34% 0.1 % NH4AC pH 5.4 (v/v) mobile phase containing 1 mM EDTA. Fractions eluting with the retention time of synthetic LTC4 (obtained from daily calibration witii standards) are collected for estimation of [3H]-LTC recovery by scintillation counting. Prior experiments established that recoveries of [3H]-LTC4 and [3H]- SUBSTITUTE SHEET (RULE 26T LTE4 from dog urine after RP-HPLC are comparable (86.8 ± 1.9% and 83.1 ± 6.1% respectively). In some experiments synthetic LTE4 (0.5 ng/mL) and/or 0.1 nCi [3HJ-LTE4 (0.4 pg) are added to certain samples to identify the exact retention time of LTE4. Fractions (0.75 min, 0.75 mL) eluting before, during and after die predicted retention time of syndietic LTE4 (from daily calibration) are collected into sequential wells in a polypropylene microtitre plate, aliquots (200 μL) are removed to identify the retention time of added [3H]-LΗ_4), and die remainder frozen to -70°C and lyophilised in a vacuum centrifuge. Fractions are redissolved in 50 μL of 20 mM Na2Pθ4 pH 7.2 containing 0.9% NaCl, 0.02% sodium azide, 0.1 mM phenyl methyl sulphonyi fluoride and 1 % gelatin and mixed witii 2-3 nCi of [14,15,19,20-3H]-LTE4 (5.2 - 7.8 pg) and an anti-LTC4 mouse monoclonal antibody (21% cross-reactivity with LTE4; final dilution 1/150,000) and incubated for 2h at 21°C. Free ligand is precipitated by addition of dextran coated charcoal and centrifugation. An aliquot of die supernatant is removed and die concentration of LTE4 immunoactive material estimated by comparison of the unknown bound [3H]-LTE4 against a standard curve derived by serial dilution of a synthetic LTE4 stock solution (4000 - 7.8 pg/tube). LTE4 concentration is calculated as the immunoreactive material (pg) in n co-eluting fractions - n x average background immunoreactive material (pg) in pre- and post-LTE4 fractions, corrected for [3H]-LTC4 recovery, and the fraction volume removed for estimating the retention time of added [3H]-LTE4. Urinary LTE4 excretion (ng/hour) is then calculated from the concentration and excretion volume, and related to values obtained during the first collection on a case by case basis. % inhibition of baseline L TE4 is calculated for the 5-6 and 6-7h time points, and die mean value obtained for the treatment group. An ED50 is then calculated using these values and the infusion dose by non-linear regression analysis (4 parameter fit). Aliquots (50 μL) of MeOH supematants of plasma are similarly diluted into 50 μL of the above RIA buffer and mixed with 5-8 nCi of [5,6,8,9,11,12,14,15-3H]-LTB4 (1.7 - 2.7 pg) and an anti-LTB4 sheep antiserum (final dilution 1/7500). LTB4 is quantified as above against a standard curve derived by serial dilution of a synthetic LTB4 stock solution (1000 - 1.95 pg/tube). LTB4 generation stimulated by 50 μM A23187 is derived by subtraction of the blank value (DMSO alone) and values are related to those obtained in the first (pre-tr eatment) sample. An ED50 is then calculated using the maximum values for ex vivo inhibition, and the infusion dose, by non-linear regression analysis. For the calculation of in vitro IC50 values, blank values for LTB4 production are subtracted from each subsequent value, and the % inhibition calculated for each drug concentration (compared with PEG/H20). The IC50 is then calculated by non-linear regression analysis. The invention will now be illustrated by the following non- limiting examples in which, unless stated otiierwise: (i) all operations were carried out at room or ambient temperature, that is, at a temperature in the range 18-25°C, (ii) evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 pascals: 4.5- 30 mm. Hg) witii a bath temperature of up to 60°C, (iii) die course of reactions was followed by thin layer chromatography (TLC) and reaction times are given for illustration only; (iv) melting points are uncorrected and s d' indicates decomposition; die melting points given are those obtained for the materials prepared as described; polymorphism may result in isolation of materials with different melting points in some preparations; (v) the structure and purity of all final products were assured by at least one of the following techniques: TLC, mass spectrometry, nuclear magnetic resonance (NMR) spectrometry or micr oanalytical data; (vi) yields are given for illustration only; (vii) when given, NMR data is in the form of delta (δ) values for major diagnostic protons, given in parts per million (ppm) relative to te tramethylsilane (TMS) as internal standard, determined at 300 MHz or 400 MHz using the indicated solvent; conventional abbreviations used for signal shape are: s. singlet; d. doublet; t. triplet; m. multiplet; q. quartet; br. broad; etc.: in addition "Ar" signifies an aromatic signal; (viii) chemical symbols have their usual meanings; the following abbreviations have also been used v (volume), w (weight), b.p. (boiling point), m.p. (melting point), L (liter(s)), mL (milliliter(s)), μL (microliter(s)), g (gram(s)), mg (milligrams(s)), mol (mole(s)), mmol (millimole(s)), eq (equivalent(s)). PREPARAΉON OF PHENOLS PHENOL 1: 5-- __oro-3-ri-hvdroxv-l-rthi_zol-2-v1.propyl1phe ol Step 1: 1 -CThiazol-2-yl) propanone To a solution of thiazole (10 g, 0.12 mol) in dry THF (100 mL) at -78°C was added BuLi (50 mL, 2.47 M in hexane). The resulting reaction mixture was stirred 30 min. men ethyl propionate (18.8 mL, 0.16 mol) in THF was added and die cooling bath was removed. After 30 min. an aqueous solution of NH4OAC (25%) was added and the THF evaporated. Ether was added and washed successively with H2O, brine, dried over MgSθ4 and evaporated. The residue was distilled under vacuum to give 12.1 g (73%) of die title compound. Step 2: 5-Fluoro-3-[l -hydroxy- 1-( ______ l-2-yl)propyl] (O-benzyl)- phenol A solution of 3-benzyloxy-l-bromo-5-fluorobenzene (EP: 0385662, ICI, Pharma) (5.4 g, 19.4 mmol) in dry THF (30 mL) containing magnesium (941 mg, 38.7 mmol) was heated until die Grignard reagent was formed then die reaction mixture was stirred at r.t. for 30 min. and transferred to a solution of l-(thiazol-2-yl)propanone in dry THF at 0°C. The reaction mixture was stirred for 30 min. then an aqueous solution of NH4OAC (25%) was added and the THF evaporated. The residue was diluted with EtOAc and washed successively witii H2O, brine, dried over MgS04 and evaporated. The residue was purified by chromatography using hexane:EtOAc 9:1 to give 2.2 g, (50%) of the title product. Step 3: 5-Fluoro-3-r 1 -hvdroxy- 1 -fthiazol-2-yl .propyllphenol To a solution of 5-fluoro-3-[l -hydroxy- l-(thiazol-2- yl)propyl](0-benzyl)phenol (200 mg, 0.58 mmol) in MeOH (9 mL) was added 10% Pd on charcoal (200 mg) and ammonium formate (180 mg, 2.9 mmol). The reaction mixture was refluxed for 2 h and tiien filtrated tiirough a pad of celite and washed with EtOAc. After evaporation of the solvent, the residue was purified by chromatography on silica gel using a mixture of hexane:EtOAc 7:3 to give 116 mg (79%) of the title compound. iH NMR (400 MHz, CDCI3); δ 0.89 (t, 3H); 2.32 (m, 2H); 3.44 (s, IH); 5.59 (s, IH); 6.42 (dd, IH); 6.83 (m, 2H); 7.28 (d, IH); 7.69 (d, IH). PHENOL 2: 5-Fluoro-3-(3-hydroxypent-3-yl.phenol Step 1: l-Bromo-3-(3.4-dimetiιoxybenzyloxy)-5-fluorobenzene Sodium hydride (80% disp. in oil; 933 mg, 31.1 mmol) was added, all at once, to 3,4-dimedιoxybenzyl alcohol (3.48 g, 20.7 mmol) in DMF (40 mL) at 0°C and under Ar. After 5 min., die mixture was allowed to warm to r.t. After 1 h, l-bromo-3,5-difluorobenzene (4 g, 20.7 mmol) in DMF (5 mL) was added dropwise at r.t. The resulting mixture was kept at this temperature for 16 h and slowly poured into H2θ (500 mL). It was extracted with EtOAc (3x) and die combined organics were washed witii 25% NH4OAC buffer (lx), H2O (2x) and brine. The solution was dried (MgS04) and concentrated to give a pale yellow solid diat was purified by column chromatography on silica gel (EtOAc :hexane, 10:90 - 15:85) to afford the title compound as a white solid (5.85 g, 83%). Step 2: 5-Fluoro-3-(3-hydroxypent-3-yl)[0-(3,4-dimethoxy- benzyl.lphenol To a solution of l-bromo-3-(3,4-dimetiιoxybenzyloxy)-5- fluorobenzene (Step 1) (1.02 g) in THF (10 mL) at -78°C was added n- BuLi (1.5 mL of a 2.2 M solution) dropwise. After 30 min. 3-pentanone (0.33 mL) was added and after 30 min. d e bath was removed and the mixture stirred for 10 min. The reaction mixture was quenched widi NH4OAC buffer and extracted with EtOAc. The organics were dried (MgS04) and concentrated. Chromatography of the residue (silica gel; hexane/EtOAc (3:1) provided the title compound as a colorless oil. Step 3: 5-Fhιoro-3-f3-hvdroxypent-3-yl .phenol Following the procedure described for Phenol 1, Step 3, but substituting 5-fluoro-3-(3-hydroxypent-3-yl)[0-(3,4-dimethoxy- benzyl)]phenol from Step 2 for 5-fluoro-3-[l-hydroxy-l-(dιiazol-2- yl)propyl](0-benzyl)phenol the title compound was obtained as a solid. iH NMR (300 MHz, Acetone-d6); δ 0.72 (t, 6H); 1.78 (m, 4H); 3.61 (s, IH); 6.41 (dd, IH); 6.67 (dd, IH); 6.76 (s, IH); 8.50 (s, IH). PHENOL 3: 5-Fluoro-3-(hexafluoro-2-hvdroxyprop-2-yl.ρhenol Following the procedure described for Phenol 2, Step 2, and Phenol 1, Step 3, but substituting hexafluoroacetone (Aldrich) for 3- pentanone, die title compound was obtained. iH NMR (300 MHz, Acetone-d6); δ 6.75 (dd, IH); 7.0 (d, IH); 7.12 (s, IH); 8.2 (s, IH). PHENOL 4: 3-Diphenylhvdroxymethyl-5-fluorophenol Following the procedure described for Phenol 2, Step 2 and die procedure described for Phenol 1, Step 3 but substituting benzophenone for 3-pentanone, the title compound was obtained. iH NMR (300 MHz, Acetone-d6); δ 5.34 (s, IH); 6.48 (m, IH); 6.55 - 6.60 (m, 2H); 7.23 - 7.35 (m, 10H); 8.64 (s, IH). PHENOL 5: 5-Fluoro-3-π-hvdroxypentyl .phenol SUBSTITUTE SHEET- (RULE 26) Following the procedure described for Phenol 2, Step 2 and for Phenol 1, Step 3, but substituting valeraldehyde for 3-pentanone, die title compound was obtained. iH NMR (300 MHz, Acetone-d6); δ 0.9 (t, 3H); 1.2 - 1.4 (m, 4H); 1.6 - 1.7 (m, 2H); 4.6 (t, IH); 6.45 (d, IH); 6.6 (d, IH); 6.7 (s, IH); 7.95 (s, IH). PHENOL 6: 5-Fluoro-3- { 1 -hydroxy- 1 -[N-(2-trimethylsilylethoxy- mediyl)imidazol-2-yllpropyl ) phenol Step 1: 3-Benzvloxv-5-fluoropropiophenone Following the procedure described for Phenol 2, Step 1, but substituting 3,5-difluoropropiophenone for l-bromo-3,5-difluorobenzene and benzyl alcohol for 3,4-dimethoxybenzyl alcohol as starting material, the title compound was obtained. Step 2: 5-Fluoro-3- { 1 -hydroxy- 1 -[N-(2-trimethylsilylethoxy- methvttimidazol-2-vnpropvl ) (O-benzvDphenol To a stirred solution of SEM-imidazole, {Jet. Lett.26, 6273, 1985) (252 mg, 1.27 mmol) in THF (5 mL) at -78°C under N2 BuLi (857 μl, 1.4 M, 1.27 mmol) was added dropwise. The reaction mixture was stirred at -78°C for 20 min. and d e ketone from Step 1 (274 mg, 1.06 mmol) was added dropwise. The reaction mixture was stirred at -78 °C for 30 min. and then quenched witii a 25% solution of NH4OAC, concentrated and extracted with EtOAc. The organic phase was washed with brine, dried over MgSθ4, filtered and evaporated to give an oil as the crude compound. The oil was purified by a flash silica column using hexane and EtOAc 9: 1 as the eluant. The titie compound was obtained as a transparent oil (188 mg, 39%) and used as such for the next step. Step 3: 5-Ruoro-3- { 1 -hydroxy- 1 -[N-(2-trimethylsilylethoxy- methvnimidazol-2-vnpropvl ) phenol Following the procedure described for Phenol 1, Step 3 but substituting 5-fluoro 3-{ 1 -hydroxy- l-[N-(2-trimethylsilylethoxymethyl)- imidazol-2-yl]propyl}(0-benzyl)phenol from Step 2 for 5-fluoro-3-[l- hydroxy-l-(thiazol-2-yl)ρropyl](0-benzyl)phenol, the titie compound was obtained as an oil. iH NMR (400 MHz, CDCI3); δ 0.03 (s, 9H); 0.7 - 0.8 (It, 3H); 0.8 - 0.9 (It, 2H); 1.9 - 2.25 (m, IH); 2.30 - 2.40 (m, IH); 3.12-3.22 (m, IH); 3.30 - 3.40 (m, IH); 4.08 (s, IH); 4.95 (s, 2H); 6.04 (s, IH); 6.45 - 6.52 (d, IH); 6.65 (s, IH); 6.99 (s, IH); 6.72 - 7.0 (d, IH). PHENOL 7: 3-. 1 -Hvdroxy- 1 -( _hiazol-2-yl.propyllp_.enol Step 1: 3-Bromo-(O-tert-butyldimethylsilyl .phenol To a solution of 3-bromophenol (50 g, 289 mmol) in 340 mL DMF was added Et3N (35 g, 347 mmol) and tert-butyldimethylsilyl chloride (52 g, 347 mmol). The mixture was stirred for 0.5 h, and then diluted with Et2θ (2 L). The organic phase was washed witii 5% aqueous HCl and brine, and dried over MgS04. Flash chromatography using hexane:EtOAc (95:5) gave 80.1 g (96%) of product. Step 2: 3-[l -Hydroxy- l-(thi_zol-2-yl)ρropyl]-(0-tert-butyldimetiιyl- silvDphenol Following the procedure described for Phenol 2, Step 2, but substituting 3-bromo-(0-tert-butyldimethylsilyl)phenol from Step 1 for 1- bromo-3-(3,4-dimetiιoxybenzyloxy)-5-fluoro benzene and l-(thiazol-2- yl)propanone from Phenol 1, Step 1, for 3-pentanone, the title compound was obtained. Step 3: 3-ri-Hvdroxv-l-(thiazol-2-yl)propynphenol To a solution of compound from Step 2 (5.57 g, 15.96 mmol) in THF (40 mL) there was added n-Bu4NF IM in THF (18 mL); the mixture was stirred at r.t. for 30 min., tiien H2θ (10 mL) was added. The mixture was concentrated to a small volume, die residue extracted with EtOAc, the extract washed twice with brine, dried and evaporated to a residue which was chromatographed on silica gel, eluting with a 1 : 1 mixture of EtOAc and hexane, to afford the title product as a white solid (2.59 g) m.p. 145-146°C. PHENOL 8: 3-fl-Hvdroxv-l-phenvlpropvl .phenol Step 1: 3-Bromo(Q-tert-butvldiphenvlsilvl.phenol Following the procedure described for Phenol 7, Step 1 but substituting tert-butyldiphenylsilyl chloride for tert-butyldimethylsilyl chloride die title compound was obtained. Step 2: 3-fl -Hvdroxypropyl .(O-tert-butyldiphenylsilyl .phenol Following the procedure described for Phenol 2, Step 2 but substituting 3-bromo(0-tert-butyldiphenylsilyl)phenol from Step 1 for 1- bromo-3-(3,4-dimetiιoxybenzyloxy)-5-fluorobenzene and propion- aldehyde for 3-pentanone, the title compound was obtained. « Step 3: 3-(tert-Butyldiphenylsilyloxy)propiophenone To a solution of 3-(l-hydroxypropyl)(0-tert-butyldiphenyl- silyl)phenol (11.7 g, 30 mmol) in CH2CI2 (300 mL) at 0°C was added molecular sieves powder (8g, flame dried) followed by PCC (18 g, 84 mmol). The reaction mixture was stirred at r.t. for 1 h then poured on a silica gel column and eluted witii Et2θ to give die title compound as an oil (10.8 g, 93%). Step 4: 3-( 1 -Hydroxy- 1 -phenylpropyl)(0-tert-butyldiphenyl- silyl.phenol To a solution of 3-(tert-butyldiphenylsilyloxy)propiophen- one (410 mg, 1.06 mmol) in THF (6 mL) at -20°C was added PhMgBr (2M in Et2θ, 2.0 mL, 4 mmol) dropwise. The reaction mixture was stirred at r.t. for the night, then quenched with saturated NH4CI at 0°C. The organic phase was extracted with EtOAc washed with H2O, brine, dried (MgSθ4) and the solvent evaporated to afford the title compound as an oil which was used as such in the next step. Step 5: 3-( 1 -Hvdroxy- 1 -phenylpropy phenol Following the procedure described for Phenol 7, Step 3, but substituting 3-( 1 -hydroxy- 1 -phenylpropyl)(0-tert-butyldiphenylsilyl)- phenol from Step 4 for 3-[l-hydroxy-l-(thiazol-2-yl)propyl](0-tert- butyldimethylsilyl)phenol, the title compound was obtained. iH NMR (300 MHz, CDCI3); δ 0.85 (t, 3H); 2.3 (q, 2H); 6.65 (m, IH); 6.9 (m, 2H); 7.1 - 7.4 (m, 6H). PHENOL 9: 3-f3-Hvdroxy-2-methylpentyl.phenol Following the procedure for Phenol 8, Step 4 and for Phenol 7, Step 3 but substituting isopropylmagnesium chloride in THF (Aldrich) for phenylmagnesium bromide, die titie compound was obtained. H NMR (300 MHz, Acetone-d6); δ 0.64 - 0.69 (m, 6H); 0.93 (d, 3H); 1.83 (m, 2H); 1.97 (m, IH); 3.27 (s, IH); 6.64 (dd, IH); 6.84 (d, IH); 6.95 (m, IH); 7.10 (t, IH); 7.99 (s, IH). PHENOL 10: 3-f2_2-Dimethvl-3-hvdroxvpentyl.pheno1 Following the procedure described for Phenol 8, Step 4 and Phenol 7, Step 3 but substituting tert-butylmagnesium chloride in THF (Aldrich) for phenylmagnesium bromide, d e titie compound was obtained. iH NMR (300 MHz, Acetone-d6); δ 0.67 (t, 3H); 0.90 (s, 9H); 1.83 (m, IH); 2.17 (m, IH); 3.29 (s, IH); 6.66 (dd, IH); 6.87 (d, IH); 6.97 (s, IH); 7.09 (t, IH); 8.00 (s, IH). PHENOL 11: 3-f 1 -Hydroxy- 1 -(pyridin-2-yl .propyl .phenol Step 1: 3-[l-Hydroxy- 1 -(pyridin-2-yl)proρyl](0-tert-butyldiphenyl- silyl.phenol n-BuLi (2.4 M in hexane, 674 μL, 1.62 mmol) was added dropwise (15 min.) to 2-bromopyridine (147 μL, 1.54 mmol) in THF (5 mL) at -78°C and under Ar. The solution was stirred for 40 min. at this temperature. The 3-(tert-butyldiphenylsilyloxy)propiophenone (499 mg, 1.28 mmol) from Phenol 8, Step 3 in THF (2 mL) was then added dropwise (10 min.). The mixture was kept at -78°C for 30 min. and allowed to warm to 0°C. After 20 min. d e reaction was quenched witii a saturated NH4CI solution and extracted with EtOAc (3x). The combined organics were washed witii 25% NH4OAC buffer, H2O, brine, dried (MgSθ4) and concentrated to give an off-white gum, tiiat was purified by column chromatography on silica gel (EtOAc/hexane 1:9), affording die titie compound as a colorless gum (563 mg, 94%). Step 2: 3-ri-Hvdroxy-l-(pyridin-2-yl.propyllphenol Following the procedure described for Phenol 7, Step 3 but substituting 3- [ 1 -hydroxy- 1 -(pyridin-2-yl)pr opyl] (O-tert-butyldiphenyl- silyl)phenol from Step 1 for 3-[l -hydroxy- l-(thiazol-2-yl)propyl](0-tert- butyldime thylsilyl)phenol, the title compound was obtained. iH NMR (300 MHz, Acetone-d6); δ 0.80 (t, 3H); 2.30 (q, 2H); 5.47 (s, IH); 6.63 (m, IH); 7.04 - 7.10 (m, 3H); 7.22 (m, IH); 7.60 (d, IH); 7.75 (m, IH); 8.08 (s, IH); 8.50 (d, IH). PHENOL 12: 3-T1 -Hvdrox v- 1 -(furan-3- yl .propynphenol Following the procedure described for Phenol 11, Step 1, and Phenol 7, Step 3, but substituting 3-bromofuran for 2-bromopyridine the title compound was obtained. iH NMR (300 MHz, Acetone-d6); δ 0.82 (t, 3H); 2.13 (q, 2H); 4.15 (s, IH); 6.35 (d, IH); 6.66 (dd, IH); 6.93 (m, IH); 7.00 (m, IH); 7.10 (t, IH); 7.40 - 7.43 (m, 2H); 8.06 (s, IH). PHENOL 13: 3-f2-Hvdroxyprop-2-yl .phenol Step 1: Methyl 3-ftert-butyldiphenylsilyloxy.benzoate Following the procedure described for Phenol 7, Step 1, but substituting methyl-3-hydroxybenzoate for bromophenol the titie compound was obtained. Step 2: 3-(2-Hvdroxvprop-2-vtt(Q-tert-butyldiphenylsilvnphenol To a solution of methyl 3-(tert-butyldiphenylsiloxy)benzoate (Step 1 ) ( 1.1 g) in toluene (20 mL) at 0°C was added MeMgBr in THF (Aldrich) (5.8 mL). After 1 h, additional MeMgBr (1.9 mL) was added and die mixture was stirred at r.t. for 1 h. Saturated NH4CI was added and die mixture was extracted with EtOAc. The organics were dried (MgS04), concentrated and chromatographed (silica gel; hexane/EtOAc (4: 1 ) to provide the title compound as an oil. Step 3: 3-(2-Hvdroxyprop-2-vDphenol Following the procedure described for Phenol 7, Step 3 but substituting 3-(2-hydroxyprop-2-yl)(0-tert-butyldiphenylsilyl)phenol from Step 2 for 3-[ 1 -hydroxy- 1 -(thiazol-2-yl)propyl)(0-tert-butyl- dimetiιylsilyl)phenol, the title compound was obtained. iH NMR (300 MHz, Acetone-d6); δ 1.48 (s, 6H); 3.88 (s, IH); 6.65 (dd, IH); 6.95 (dd, IH); 7.03 (dd, IH); 7.10 (t, IH); 8.04 (s, IH). PHENOL 14: 3-f3-Hvdroxypent-3-yl.phenol Following the procedure described for Phenol 13, Step 2 and for Phenol 7, Step 3 but substituting EtMgBr in THF (Aldrich) for MeMgBr, die title compound was obtained. iH NMR (300 MHz, Acetone-d6); δ 0.71 (t, 6H); 1.78 (m, 4H); 3.40 (s, IH); 6.64 (dd, IH); 6.85 (dd, IH); 6.95 (dd, IH); 7.10 (t, IH); 8.00 (s, IH). PREPARAΉON OF THIOPHENOLS THIOPHENOL 1: 5-Fluoro-3-(hexafluoro-2-hydroxyprop-2-yl)- thiophenol Step 1: 1.3-Difluoro-5-(hexafluoro-2-hvdroxyprop-2-yl .benzene To a solution of l-bromo-3,5-difluorobenzene (4 g, 20.7 mmol) in dry THF (50 mL) containing magnesium (1 g, 41.5 mmol) was reflux until the Grignard reagent started to form. Then the reaction mixture was stirred at r.t. for 30 min.. Hexafluoroacetone was then bubbled in at 0°C until approximately 3.4g was added. The mixture was stirred for 10 min. and quenched with 25% NH4OAC. The resulting mixture was extracted with EtOAc and the combined organic phase was washed with H2O, brine, dried over MgSθ4 and evaporated to give a residue which was chromatographed on silica gel, eluting with 9:1 mixture of hexane:EtOAc to afford the title compound (4.1 g, 71%) as a white solid. Step 2: 5-Fluor o-3-(hexafluoro-2-hydroxyprop-2-yl)- 1 -(2- trimethyl- silylethylthio.benzene 2-Trimethylsilylethane thiol (2.9 g, 21.9 mmol) was added dropwise to a suspension of NaH (1.8g, 43.8 mmol) in dry DMF (60 mL) and stirred for 20 min.. Then l,3-difluoro-5-(hexafluoro-2-hydroxyprop- 2-yl)benzene (Step 1) was added in dry DMF and the resulting reaction mixture was heated at 70°C for 16 h. The reaction mixture was tiien added carefully to H2θ and extracted with EtOAc. The combined organic phases were washed witii brine, dried and evaporated to give a residue which was chromatographed on silica gel, eluting with 95:5 mixture of hexane:EtOAc to afford the title compound (3.2g, 55%). Step 3: 5-Fluoro-3-fhexafluoro-2-hydroxyprop-2-yl)thiophenol To a solution of 5-fluoro-3-(hexafluoro-2-hydroxyprop-2- yl)-l-(2-trimedιylsilyletiιylthio)benzene (1 g, 2.54 mmol Step 2) in dry DMF (20 mL) was added tetrabutylammonium fluoride (IM in THF) (Aldrich) (6.4 mL, 6.4 mmol) and the reaction mixture was heated at 60°C for 30 min.. The reaction mixture was then added to H2θ and extracted with EtOAc. The combined organic phase were washed with brine, dried and evaporated to give a residue which was chromatographed on sihca gel eluting with 8:2 mixture of hexane.EtOAc to afford the title compound (330 mg, 44%). iH NMR (400 MHz, CDCI3); δ 3.7 (s, IH), 7.1 (d, IH); 7.2 (d, IH); 7.4 (s, IH). THIOPHENOL 2: 5-Fluoro-3-[3-hydroxy-3-(thiazol-2-yl)propen-3- yllthiophenol Step 1: 3.5-Difluoro-α-(thiazol-2-yl)benzenemethanol Following die procedure described for Thiophenol 1, Step 1, but substituting the 2-thiazole carboxaldehyde (Synthesis, 2S___, 1987) for hexafluoroacetone as starting material, the titie compound was obtained as a liquid. Step 2: f3.5-Difluorophenyl.fthiazol-2-yl.methanone To a suspension of C1O3 (l.lg, 11 mmol) in CH2CI2 at r.t. was added pyridine (1.8 mL, 22 mmol) and the resulting mixture was stirred for 20 min.. The alcohol from Step 1 in CH2CI2 was added and the resulting mixmre was stirred for 16 h. Then Et2θ was added and the resulting mixmre was filtered through silica gel and washed with Et2θ. After evaporation the residue was chromatographed on silica gel eluting with 7:3 mixture of hexane:EtOAc to give 1.66g (90%) of the title compound. Step 3: l,3-Difluoro-5-[3-hydroxy-3-(thiazol-2-yl)propen-3-yl]- benzene To a solution of (3,5-difluorophenyl)(thiazol-2-yl)- methanone (lg, 4.4 mmol, Step 2) in dry THF (40 mL) was added at 0°C (4.4 mL, 4.4 mmol) of a 1.0 M THF solution of vinyl magnesium bromide (Aldrich). The reaction mixmre was stirred for 30 min. and then transferred to a IN aqueous HCl solution. The resulting mixmre was extracted with EtOAc and the combined organic phase were washed with brine, dried over MgS04 and evaporated to give a residue which was chromatographed on silica gel eluting with 85:15 mixmre of hexane: EtOAc to afford 635 mg (56%) of the title compound. Step 4: 5-Fluoro-3-[3-hydroxy-3-(thiazol-2-yl)propen-3-yl]- l-(2- trimethylsilylethylthio .benzene Following the procedure described for Thiophenol 1 , Step 2, but substimting the l,3-difluoro-5-[3-hydroxy-3-(thiazol-2-yl)propen-3- yljbenzene from Step 3 for l,3-difluoro-5-(hexafluoro-2-hydroxyprop-2- yl)benzene as starting material, the tide compound was obtained as an oil. Step 5: 5-Fluoro-3-[3-hydroxy-3-(tbiazol-2-yl)propen-3-yl]thio- phenol Following die procedure described for Thiophenol 1, Step 3, but substimting the 5-fluoro-3-[3-hydroxy-3-(thiazol-2-yl)propen-3-yl]-l- (2-trimethylsilylethylthio)benzene from Step 4 for 5-fluoro-3-(hexa- fluoro-2-hy droxyprop-2-yl)- 1 -(2-trime_ιylsilylethylthio)benzene as starting material, the title compound was obtained. THIOPHENOL 3: 5-Fluoro-3-r3-hvdroxypent-3-vDthiophenol Step 1: 3-Bromo-5-fluor o- 1 -_2-trimethylsil ylethylthio)benzene Following die procedure described for Thiophenol 1, Step 2, but substimting l-bromo-3,5-difluorobenzene (Aldrich) for 1,3-difluoro- 5-(hexafluoro-2-hydroxyprop-2-yl)benzene as starting material, the title compound was obtained. Step 2: 5-Fluoro-3-(3-hydroxypent-3-yl)- 1 -(2-trimethylsilylethyl- thio.benzene Following the procedure described for Thiophenol 1, Step 1, but substimting the 3-bromo-5-fluoro-l-(2-trimethylsilylethylthio)- benzene from Step 1, for l-bromo-3,5-difluorobenzene and 3-pentanone for hexafluoroacetone as starting material the titie compound was obtained. Step 3: 5-Fluoro-3-G-hvdroxypent-3-vDtiιiophenol Following the procedure described for Thiophenol 1, Step 3 but substimting the 5-fluoro-3-(3-hydroxypent-3-yl)-l-(2-trimethylsilyl- ethylthio)benzene from Step 2 for 5-fluoro-3-(hexafluoro-2-hydroxyprop- 2-yl)-l-(2-trimethylsilyethylthio)benzene as starting material, the title compound was obtained. SUBSTITUTE SHEET (RULE 26. iH NMR (300 MHz, Acetone-d6); δ 0.71 (t, 6H); 1.79 (m, 4H); 3.71 (s, IH); 4.49 (s, IH); 6.92 - 6.98 (m, 2H); 7.19 (m, IH). THIOPHENOL 4: 5-Fluoro-3-( 1 -hydroxy- 1 -phenyl-2,2,2-trifluoro- ethynthiophenol Step 1: 1 ,3-Difluoro-5-( 1 -phenyl- 1 -trimethylsilyloxy-2,2,2- trifluoroethyDbenzene To a solution of 3,5-difluorobenzophenone (2.27g, 10.4 mmol) in THF (5 mL) at 0°C was added trime_ιyl(trifluoromethyl)silane (0.5 M in THF, 26 mL, 13.0 mmol) and a pinch of solid n-B_4NF. The mixture was stirred at r.t. for 17 h. Sat. aqueous NH4CI was added, die layers were separated and die organic phase was extracted with EtOAc (3x 20 mL). The combined organic layers were washed with brine and dried over anhydrous MgS04. Removal of die solvent and chromato¬ graphy using hexane:EtOAc (95:5) gave 3.06 g of die title compound. Step 2: 5-Fluoro-3-(l -hydroxy- l-phenyl-2,2,2-trifluoroethyl)- thiophenol Following the procedure described for Thiophenol 1, Steps 2 and 3 but substimting the product from Step 1 for l,3-difluoro-5-(hexa- fluoro-2-hydroxyprop-2-yl)benzene as starting material, the title compound was obtained. THIOPHENOL 5: 5-Fluoro-3-(thiazol-2-ylcarbonyl.thiophenol Step 1: G-Methylthio-5-fluorophenyl.(thiazol-2-yl)methanone To a solution of (3,5-difluorophenyl)(thiazol-2-yl)- metiianone from Thiophenol 2, Step 2, (1.09 g, 4.84 mmol) in DMF (4.8 mL) was added sodium thiomethoxide (0.34 g, 4,84 mmol). The mixmre was stirred for 4 h at r.t., then added to sat. aqueous NH4CI (100 mL) and extracted with EtOAc. The combined organic layers were washed with brine and dried over anhydrous MgSθ4. Evaporation of the solvent and chromatography using hexane:EtOAc (90: 10) gave 0.80 g of the titie product. Step 2: -Methvlsulfinvl-5-fluorophenynfdιiazol-2-vttmethanone To a solution of sulfide from Step 1 (0.76 g, 2.99 mmol) in MeOH (1.5 mL) and CH2CI2 (6 mL) at 0°C was added the magnesium salt of monoperoxyphthalic acid (1.11 g, 1.80 mmol). The mixmre was stirred at 0°C for 1.25 h and then sat. aqueous NaHC03 was added. The layers were separated and the aqueous phase was extracted with CH2CI2. The combined organic layers were washed with H2O and dried over anhydrous MgS04. Evaporation of the solvent and chromatography using toluene:EtOAc (25:75) gave 0.70 g of die titie compound. Step 3: 5-πuoro-3-fthiazol-2-vlcarbonvl.thioρhenol To a solution of the sulfoxide from Step 2 (0.35 g, 1.29 mmol) in dichloroethane (2.6 mL) was added TFAA (2.6 mL). The mixmre was stirred at 80°C for 0.5 h, cooled and evaporated. The residue was dissolved in MeOH: Et3N (1:1, 5 mL). The solvent was evaporated and taken up again in MeOH/Et3N. After evaporation of the solvent and chromatography using hexane.EtOAc (70:30) 0.28 g of the titie compound was obtained. lH NMR (300 MHz, Acetone-d6); δ 7.5 (dd, IH); 8.0 (d, IH); 8.0 - 8.3 (2d, 3H). THIOPHENOL 6: 5-Fluoro-3-[ 1 -hydroxy- l-(thiazol-2-yl)ethyll- thiophenol Following die procedure described for Thiophenol 2, Step 3 and Thiophenol 5, Steps 2 and 3 but substimting the ketone from Thiophenol 5, Step 1 for (3,5-difluorophenyl)(thiazol-2-yl)-methanone and methylmagnesium bromide (Aldrich) in THF for vinylmagnesium bromide as starting material, the title compound was obtained. THIOPHENOL 7: 5-Huoro-3-[l-hydroxy-2-methyl-l-(thiazol-2-yl)- propyllthiophenol Following the procedure described for Thiophenol 2, Step 3 and Thiophenol 5, Steps 2 and 3 but substimting the ketone from Thiophenol 5, Step 1 for (3,5-difluorophenyl)(ti iazol-2-yl)-metiιanone and isopropylmagnesium bromide (Aldrich) in THF for vinylmagnesium bromide as starting material the titie compound was obtained. THIOPHENOL 8: 5-Ruoro-3-[l -hydroxy- l-(thiazol-2-yl)propyl]- thipphgPQ) Following the procedure described for Thiophenol 2, Step 3 and tiiiophenol 5, Steps 2 and 3 but substimting the ketone from Thiophenol 5, Step 1 for (3,5-difluorophenyl)(dιiazol-2-yI) metiianone and ethylmagnesium bromide in THF (Aldrich) for vinylmagnesium bromide as starting material the titie compound was obtained. Mass spec. 270 (MH+). THIOPHENOL 9: 5-Huoro-3-(l-hvdroxy-l-phenylpropynthiophenol Following the procedure described for Thiophenol 2, Step 3 and Thiophenol 1, Steps 2 and 3 but substimting 3,5-difluoropropio- phenone (Lancaster) for (3,5-difluoroρhenyl)(thiazol-2-yl)methanone and phenylmagnesium bromide in THF (Aldrich) for vinylmagnesium bromide as starting material the titie compound was obtained. THIOPHENOL 10: 5-Huoro-3-(decafluoro-3-hydroxypent-3- vDthio-phenol Step 1: 3.5-Difluoro- 1 -(decafluoro-3-hvdroxypent-3 vDbenzene A tiiree-necked flash was charged with 9.61 g (39.1 mmol) of pentafluoroethyl iodide at -78°C under a dry nitrogen atmosphere. 50 mL of Et2θ was added followed by 1.38 g (7.82 mmol) of 3,5-difluoro- benzoyl chloride (Aldrich). To die stirred solution was added 27.9 mL (39.1 mmol) of a 1.4 M solution of methyllithium lithium bromide complex in diethyl ether. The reaction mixmre was stirred for 0.5 h and then poured into a separating funnel containing 100 mL of a 5% aqueous hydrochloric acid solution and 50 mL of die tiiyl ether. After the layers were shaken and separated, die aqueous layer was further extracted witii 25 mL of dietiiyl ether, and die combined extracts were dried over anhydrous magnesium sulfate. After filtration and solvent removal on a rotary evaporator, the product was distilled under reduced pressure to give 2.44 g (82%) of the tertiary alcohol, bp 70°-75°C (5 mm). Step 2: 5-Fluoro-3-rdecafluoro-3-hvdroxypent-3-vDthiophenol Following the procedure described for Thiophenol 1, Step 2 and 3, but substimting 3,5-Difluoro-l-(decafluoro-3-hydroxypent-3- yl)benzene from Step 1 for 1 ,3-difluoro-5-(hexafluoro-2-hydroxyprop-2- yl)benzene, the titie compound was obtained. PREPARAΗON OF ALCOHOLS Alcohol 1 : 3-ri-Hvdroxy-l-. thiazol-2-yl.p.opynbenzyl alcohol Step 1: 3-Bromo(0-tert-butvldiphenvlsilvl.benzyl alcohol Following the procedure described for Phenol 7, Step 1 but substimting 3-bromo-benzyl alcohol for 3-bromophenol and tert-butyl- diphenylsilyl chloride for tert-butyldimethylsilyl chloride the titie compound was obtained. Step 2: 3-ri-Hvdroxy-l-(thiazol-2-yl.propynbenzyl alcohol Following the procedure described for Phenol 2, Step 2 and for Phenol 7, Step 3 but substimting the compound from Step 1 for 1- bromo-3-(3, 4-dimetiιoxybenzyloxy)-5-fluorobenzene and l-(thiazol-2- yl)propanone (from Phenol 1, Step 2) for 3-pentanone the titie compound was obtained. iH NMR (400 MHz, CDCI3); δ 0.9 (t, 3H); 2.4 (m, 2H); 3.82 (s, IH), 4.7 (s, 2H); 7.3 (m, 3H); 7.52 (dd, IH); 7.63 (s, IH); 7.7 (d, IH). Alcohol 2: 6-(3-Hvdroxypent-3-vl.pvridin-2-methanol Step 1: 6-Bromopicolinic acid To a suspension of 2,6-dibromopyridine (59 g, 0.25 mol) in Et2θ (600 mL) at -70°C there was added slowly n-BuLi 2.12 M in hexanes (118 mL, 0.25 mol); the resulting mixmre was stirred in the cold until a solution was obtained (45 min.); this mixmre was poured onto a slurry of crushed dry ice (200 g) in Et2θ (500 mL). The resulting suspension was allowed to warm up, then it was extracted with H2O (500 mL, then 250 mL). The combined aqueous extracts were extracted with Et2θ, then acidified with 12 N HCl, affording a precipitate which was filtered. This beige solid was washed with H2θ and dried to afford the title acid (32 g), m.p. 186-189°C. Step 2: Ethyl 6-Bromo-2-picolinate To a solution of 6-bromopicolinic acid from Step 1 (92 g, 0.455 mol) and Et3N (69 g, 0.68 mol) in THF (1.1 L) at 0°C there was slowly added etiiyl chloroformate (61.6 g, 0.57 mol). The resulting suspension was stirred at 0°C for 15 min., EtOH (250 mL) was added, and the mixmre was stirred at r.t. overnight. After filtration, the filtrate was evaporated down, the residue was taken up in Et2θ (1 L) and filtered again. The filtrate on evaporation of the solvents afforded die title compound as an oil which was immediately used as such. Step 3: 6-Bromopyridin-2-methanol The ester from Step 2 was dissolved in THF (1.2 L), the solution cooled to 0°C, and under a N2 atmosphere, tiiere was slowly added LLAIH4 (20 g) over 1 h. After a further 30 min., the mixmre was quenched carefully with sat'd aqueous NH4CI (250 mL). The granular salts were filtered off, washed witii EtOAc, and die filtrate was dried over MgSθ4, and evaporated to afford the title alcohol (85 g) as an oil. Step 4: 6-Bromo(Q-tert-butyldiphenylsilyPpyridin-2-methanol Following the procedure described for Phenol 7, Step 1 but substituting tert-butyldiphenylsilyl chloride for tert-butyldimethylsilyl chloride and 6-bromopyridin-2-methanol from Step 1 for 3-bromo- phenol, the title compound was obtained as a yellow oil. Step 5: 6-f3-Hvdroxvpent-3-vl)pvridin-2-methanol Following the procedure described for Phenol 2, Step 2 and for Phenol 7, Step 3, but substimting 6-bromo(0-tert-butyldiphenyl- silyl)pyridin-2-methanol form Step 4 for l-bromo-3-(3, 4-dimethoxy- benzyloxy)-5-fluorobenzene, die title compound was obtained. iH NMR (300 MHz, Acetone-d6); δ 0.63 (t, 6H); 1.81 (m, 4H); 4.58 (s, IH); 4.71 (s, 2H), 4.91 (s, IH), 7.46 (dd, 2H); 7.78 (t, IH). Alcohol 3: 6-(Ηexafluoro-2-hydroxyprop-2-yl.pyridin-2-methanol Following the procedure described for Phenol 2, Step 2 and for Phenol 7, Step 3 but substimting 6-bromo-(0-tert-butyldiphenyl- silyl)pyridin-2-medιanol (from Alcohol 2, Step 4) for l-bromo-3-(3,4- dimetiιoxybenzyloxy)-5-fluorobenzene and hexafluoroacetone for 3- pentanone, the title compound was obtained, m.p.: 62 0 -63°C. Alcohol 4: 6-f _ -Hvdroxy- 1 -Cdιiazol-2-yl)propyllpyridin-2-methanol Following the procedure described for Phenol 2, Step 2 and for Phenol 7, Step 3 but substimting 6-bromo(0-tert-butyldiphenyl- silyl)pyridin-2-yl_nethanol (from Alcohol 2, Step 4) for l-bromo-3-(3,4- dimethoxy)beι__yloxy-5-fluorobenzene and l-(thiazol-2-yl)propanone (from Phenol 1, Step 2) for 3-pentanone die title compound was obtained. Alcohol 5: 6-T1 -Methoxy- 1 -( thiazol-2-yl .propyπpyridin-2-methanol Step 1: 6-[ 1 -Hydroxy- 1 -(thiazol-2-yl)propyl](0-tert-butyldimethyl- silyl)pyridin-2-methanol Following the procedure described for Phenol 2, Step 2 but substimting 6-bromo-(0-tert-butyldimedιylsilyl)pyridin-2-ylmethanol for l-bromo-3-(3,4-dimethoxybenzyloxy)-5-fluorobenzene and l-(thiazol-2- yl)propanone (from Phenol 1, Step 2) for 3-pentanone, the title compound was obtained. Step 2: 6-( 1 -Metiioxy- 1 -(thiazol-2-yl)propyl)(0-tert-butyldime tiiyl- silyl.pyridin-2-methanol To a solution of alcohol from Step 1 (740 mg, 2.03 mmol) in 20 mL THF at 0°C was added KH (466 mg, 4.06 mmol, 35% in oil). After 10 min. Mel (1.44 g, 10.1 mmol) was added dropwise. The solution was stirred for 30 min. at 0°C, then poured into an aqueous saturated NH4CI. The aqueous layer was extracted with EtOAc (3x25 mL) and the combined organic layers were washed with brine and dried over anhydrous MgSθ4. Evaporation of the solvent and flash chromato- graphy on silica gel (hexane:EtOAc = 9: 1) gave the title compound (1.2 g) which was used directly in the next step. Step 3: 6-fl -Methoxy- 1 - (thi azol-2-yl .propyl .pyridin-2-ylmethanol Following the procedure described for Phenol 7, Step 3 but substimting the silyl ether from Step 2 for 3-(l-hydroxy- l-(thiazol-2- yl)propyl)(0-tert-butyldimedιylsilyl)phenol die title compound was obtained. PREPARAΉON OF BROMOPYRIDINES Bromopvridine 1: 2-Bromo-6-(hexafluoro-2-hvdroxyprop-2-yl.pyridine Following the procedure described for Alcohol 2, Step 1 but substimting hexafluoroacetone for Cθ2, the titie compound was obtained. m.p.: 67-69°C. Bromopyridine 2: 2-Bromo-6-f3-hvdroxypent-3-yl .pyridine Following the procedure described for Alcohol 2, Step 1 but substimting 3-pentanone for C02, die titie compound was obtained. iH NMR (300 MHz, CDCI3); δ 0.70 (t, 6H); 1.81 (m, 4H); 4.29 (s, IH); 7.21 (d, IH); 7.35 (d, IH); 7.56 (t, IH). Bromopyridine 3: 2-Bromo-6-[ 1 -hydroxy- 1 -(thiazol-2-yl)propyl]- pyritjine Following the procedure described for Alcohol 2, Step 1, but substimting l-(thiazol-2-yl)-l-propanone (from Phenol 1, Step 2) for Cθ2, the title compound was obtained. iH NMR (400 MHz, CDCI3); δ 0.83 (t, IH); 2.25 and 2.37 (2m, 2H); 5.97 (s, IH, OH); 7.22 (d, IH); 7.39 (d, IH); 7.58 (t, IH); 7.74 (d, IH); 7.81 (d, IH). PREPARAΗON OF COUMARINS Coumarin 1: 7-Bromomethyl-4-ffuran-3-yl.coumarin Step 1: 3-Acetoxvtoluene To a solution of m-cresol (Aldrich) (80 g, 0.74 mol) in dry CH2CI2 (300 mL) was added pyridine (71 mL, 0.89 mol) and at 0°C was added dropwise acetyl chloride (58 mL, 0.81 mol). The reaction mixture was stirred for 1 h and then diluted with more CH2CI2. The organic phase was washed successively witii HCl IN (3x), brine, dried over MgSθ4 and evaporated. The residue was distilled under vacuum to give 108 g (97%) of the title compound. Step 2: 2-Hvdroxy-4-methylacetophenone To 50 g (0.33 mol) of 3-acetoxytoluene from Step 1 was added AICI3 (60 g, 0.45 mol) and the resulting mixmre was heated at 165°C for 20 min., then cooled at 0°C and HCl IN was carefully added followed by Et2θ. The aqueous phase was extracted 5x with Et2θ and the combined organic phase wash washed witii brine, dried over MgS04 and evaporated. The residue was distilled under vacuum to give 42.2 (84%) of the titie compound. Step 3: 4-Hydroxy-7-methylcoumarin A solution of 42 g (0.28 mol) of 2-hydroxy-4-methyl- acetophenone in benzene (150 mL) was added over 30 min. to a suspension of NaH (50% oil), 30 g, 0.63 mol) in 400 mL of benzene at reflux. Then, diethylcarbonate (67.8 mL, 0.56 mol) in benzene (500 mL) was added over 15 min.. The reaction mixmre was refluxed for 16 h and more NaH (13 g, 0.28 mol) was added followed by more diethyl¬ carbonate (33 g, 0.28 mol). After another 6 h at reflux the reaction mixture was cooled to r.t. and HCl (2N) was added (1.5 L) to form a white precipitate. The solid was then filtered and added to a solution of NaOH (4N) (800 mL). The resulting basic solution was then extracted with Et2θ (2 x 500 mL) and the basic solution acidified witii HCl cone, to give a white solid which after filtration and dried gave 38.7 g (79%) of the titie compound. Step 4: 7-Methyl-4-trifluoromethanesulfonyloxycoumarin To a solution of 4-hydroxy-7-me_ιylcoumarin (10 g, 56.8 mmol) in CH2CI2 (250 mL) was added Et3N (9.5 mL, 68.2 mmol) and at 0°C was added trifluoromethanesulfonic anhydride (11.5 mL, 68.2 mmol). The reaction mixmre was stirred for 16 h. Then more CH2CI2 was added and the reaction mixmre washed with HCl IN (3x), brine dried over MgS04 and evaporated. The residue was purified by flash chromatography on silica gel using hexane:EtOAc 9:1 to give 10.6 g (61 %) of the title compound. Step 5: 4-.Furan-3-vl.-7-methvlcoumarin To a solution of 3-bromofuran (1.9 g, 12.7 mmol) in dry Et2θ (30 mL) at -70°C was added BuLi in hexane (1.9 M, 6.7 mL, 12.7 mmol) and die resulting mixmre was stirred for 20 min.. Trimethyl borate (Aldrich) (1.4 mL, 12.7 mmol) was added dropwise and the mixmre stirred for 20 min.. A solution of the triflate from Step 4 in THF: H2O (24 mL: 6 mL) containing (Ph3P)4Pd (1.1 g, 0.97 mmol) was added and the reaction was heated to reflux for 16 h. The reaction mixture was cooled to r.t. and EtOAc was added and the organic phase washed with H2O (3x), brine, dried over MgSθ4 and evaporated to give a white solid. A swish in EtOAc gave after filtration 1.8 g (82%) of the title compound. Step 6: 7-Bromomethyl-4-(f_ιran-3-yl>coumarin To a solution of 4-(furan-3-yl)-7-methylcoumarin (1.2 g, 5.3 mmol) in CCI4 (40 mL) was added NBS (1 g, 5.8 mmol) followed by AIBN (87 mg, 0.53 mmol). The resulting mixmre was refluxed for 4 h, then cooled to r.t. filtered and evaporated. Purification by chromatro- graphy on silica gel gave 682 mg (42%) of the title compound. iH NMR (400 MHz, CDCI3); 4.51 (s, 2H); 6.41 (s, IH); 6.66 (s, IH); 7.31 (d, IH); 7.39 (s, IH); 7.59 (s, IH); 7.73 (d, IH); 7.79 (s, IH). Coumarin 2: 7-BromomethvI-4-f4-fluorophenyl)coumarin Following the same procedure described for Coumarin 1 , Steps 5 and 6 but substimting 4-fluoroiodobenzene for 3-bromofuran the title compound was obtained. Coumarin 3: 7-Bromomethyl-4-(thien-3-v coumarin Following the same procedure described for Coumarin 1, Steps 5 and 6 but substimting 3-bromothiophene for 3-bromofuran the title compound was obtained. Coumarins 4 to 10 were prepared following the procedure described for Coumarin 1, Steps 1 to 5 but substimting 3-bromophenol for m-cresol and substimting respectively in Step 5, 3-bromofuran, 3- bromothiophene, iodobenzene, 4-fluoroiodobenzene, 4- chloroiodobenzene, 2-trimethyl-silyl-thiazole (Huka), 2-chloro-3- bromothiophene for 3-bromofuran, the Coumarins 4 to 10 were obtained. Coumarin 4: 7-Bromo-4-(furan-3-y coumarin Coumarin 5: 7-BrQmo-4-(thi-?n-3-yl)PQum_ n Coumarin 6: 7-Bromo-4-phenylcoumarin Coumarin 7: 7-Bromo-4-( r 4-fluorophenyl.coumarin iH NMR (400 MHz, CDCI3); δ 6.35 (s, IH); 7.20 (d, 2H); 7.30 (d, IH); 7.35 (d, IH); 7.41 (m, 2H); 7.6 (s, IH). Coumarin 8: 7-Bromo-4-f4-chlorophenyl)coumarin Coumarin 9: 7-Bromo-4-(thiazol-5-vDcoumarin iH NMR (400 MHz, CDCI3); 6.52 (s, IH); 7.52 - 7.55 (d, IH); 7.58 7.62 (t, 2H); 8.14 (s, IH); 9.0 (s, IH). Coumarin 10: 7-Bromo-4-f2-chlorothien-3-vncoumarin iH NMR (400 MHz, Acetone-d6); δ 6.5 (s, IH); 7.4 (d, IH); 7.5 - 7.6 (dd, IH); 7.65 (d, IH); 7.7 (d, IH); 7.8 (d, IH). Coumarin 11 : 7-Bromo-4-(2.4-dichlorophenyI)coumarin Step 1: 7-Bromo-4-ftrifluoromethanesulfonyloxy.coumarin Following the procedure described for Coumarin 1, Steps 1 to 4 but substimting 3-bromophenol for m-cresol the title compound was obtained. Step 2: 7-Bromo-4-(2.4-dichloropheny coumarin To a solution of the triflate from Step 1 (712 mg, 1.91 mmol) in 15 ml THF was added 2,4-dichlorophenyl boronic acid (400 mg, 2.10 mmol), (Ph3P)4Pd (110 mg, 0.095 mmol) and aqueous Na2∞3 (1.91 mL, 3.82 mmol). The mixmre was heated at 70°C for 2 h, cooled and partitioned between aqueous NH4CI and EtOAc (50 mL each). The layers were separated and the aqueous phase was extracted with EtOAc (3x25 mL). The combined organic layers were dried over anhydrous MgSθ4. The solvent was evaporated and die residue chromatographed on sihca gel (hexane: EtOAc 9: 1) to give 480 mg (68%) of the titie compound. Coumarin 12: 7-Bromo-4-(3-chloro-4-fluorophenyl)coumarin iH NMR (400 MHz, Acetone-d6); δ 6.5 (s, IH); 7.4 - 7.5 (dd, IH); 7.5 (dd, IH); 7.5 - 7.6 (d, IH); 7.6 (dq, IH); 7.6 - 7.7 (d, IH); 7.7 - 7.8 (dd, IH). Coumarin 13: 7-Bromo-4-< / 3-nitrophenyl)coumarin iH NMR (400 MHz, Acetone-d6); δ 7.4 (d, IH); 7.5 (dd, IH); 7.7 (d, IH); 7.9 - 8.0 (d, IH); 8.0 - 8.1 (m, IH); 8.4 (dt, 2H). Coumarin 14: 7-Bromo-4-( -trifluoromethoxyphenyDcoumarin iH NMR (400 MHz, Acetone-d6); 7.4 (d, IH); 7.5 (dd, IH); 7.5 - 7.6 (dt, 2H); 7.6 - 7.7 (dt, IH); 7.7 (d, IH); 7.7 (d, IH); 7.7 - 7.8 (ddd, IH). Coumarins 12 to 14 were prepared following the procedure described for Coumarin 11, Step 2 but substimting respectively 3-chloro- 4-fluorophenyl boronic acid, 3-nitrophenyl boronic acid, and 3-trifluoro- methoxyphenyl boronic acid for 2,4-dichlorophenyl boronic acid. Coumarin 15: 7-Bromo-4-(pyridin-3-v coumarin To a solution of 3-bromopyridine (0.10 mL) in THF (3 mL) stirred at -100°C was added a solution of n-BuLi in hexanes (1.4 M; 0.71 mL), after 10 min., the resulting yellow-green solution was treated witii a solution of zinc chloride in THF (0.5 M; 2 mL) and die cold batii was removed. After another 10 min., triflate from Coumarin 11, Step 1 (376 mg) and (Ph3)4Pd (46 mg) were added and the reaction mixmre was stirred at r.t. for 1 h. Ethyl acetate was then added and die organic phase was washed successively with samrated aqueous NaHCθ3, H2θ and brine dried (MgS04), and evaporated. Flash chromatography of the residue (silica gel; hexane/EtOAc (1:3)) afforded die title compound as a MHz, CDC13); δ 6.40 (s, IH); 7.25 (m, IH); 7.35 (d, IH); 7.50 (m, IH); 7.60 (s, IH); 7.75 (m, IH); 8.70 (s, IH), 8.80 (d, IH). Coumarin 16: 7-Bromo-4-(pyridin-4-yl)coumarin Following the procedure described for Coumarin 15, but substimting 4-bromopyridine for 3-bromopyridine, the title compound was obtained. iH NMR (400 MHz, CDCI3); δ 6.36 (s, IH); 7.18 - 7.26 (d, IH); 7.30 7.40 (m, 4H); 7.58 - 7.70 (m, 2H); 8.80 (d, 2H). Coumarin 17: 7-Bromo-4-fpyridin-2-v coumarin Following the procedure described for Coumarin 15, but substimting 2-bromopyridine for 3-bromopyridine, the title compound was obtained. iH NMR (CDC13, 400 MHz); δ 6.50 (s, IH), 7.35 (s, IH); 7.45 (m, IH), 7.55 (m, 2H), 7.65 (d, IH); 7.90 (t, IH); 8.80 (d, IH). Coumarin 18: 7-Bromo-4-trifluoromedιylcoumarin To a solution of 48% HBr (4.5 g, 26.7 mmol) (3 mL) containing 7-amino-4-trifluoromethylcoumarin (Aldrich) (2.0 g, 8.8 mmol) at -10°C was added NaNθ2 (670 mg in 1 mL of H2O) then Cu powder 35 mg was added. The reaction mixmre was stirred at r.t. for 30 min., men heated to 100°C for 30 min.. The reaction mixmre was cooled to 0°C and H2O (25 mL) was added. The mixmre was extracted with EtOAc (400 mL) and die combined organic phase was washed with brine (200 mL) dried over MgSθ4 and evaporated. The crude solid was purified by chromatography on silica gel using hexane:EtOAc 8:2 as eluent, to give 1.5 g (58%) of the title compound as a white solid. iH NMR (400 MHz, Acetone-d6); δ 7.0 (s, IH); 7.6 - 7.8 (m, 3H). Coumarin 19: 7-Bromo-4-(imidazol- 1 -yl .coumarin The triflate from Coumarin 11, Step 1 (373 mg, 1 mmol) was mixed witii imidazole (68 mg, 1 mmol) and K2CO3 (330 mg, 2.5 mmol) in n-methylpyrrolidone (4.0 mL) and the reaction was heated at 120°C for 30 min.. The reaction mixmre was diluted witii EtOAc, washed witii brine dried over MgS04. filtered and evaporated to give an oil which was purified on a silica gel column using hexane:EtOAc 9: 1 as the eluent. The title compound was obtained as a white solid, (40 mg, 15%). iH NMR (400 MHz, CDCI3); δ 6.48 (s, IH); 7.24 (s, IH); 7.30 (s, IH); 7.36 - 7.40 (d, IH); 7.46 - 7.48 (d, IH); 7.6 (s, IH); 7.8 (s, IH). Coumarin 20: 7-Bromo-4-. l-methylpyrrol-3-yl .coumarin Step 1: 7-Bromo-4-π-triisopropylsilyl-lH-pyrrol-3-yl)coumarin The triflate from Coumarin 11, Step 1 (298 mg, 0.8 mmol) was mixed with l-(triisopropylsilyl)-3-(tributylstannyl)pyrrole (451 mg, 0.88 mmol) (J. Org. Chem., 5_7, 1653, 1992) (Ph3P)4Pd (37 mg, 0.032 mmol) and LiCl (101.7 mg, 2.4 mmol) in dioxane (2.0 mL) and the mixmre was heated at reflux for 2.5 h. The reaction mixture was diluted in EtOAc, washed with brine, dried over MgS04, filtered and evaporated to give an oil which was purified on a silica column using toluene as the eluent. The title compound was obtained as an oil (100 mg) (28%). Step 2: 7-Bromo-4-( 1 -methvlpvrrol-3-vDcoumarin To a solution of the silyl compound from Step 1 (42 mg, 0.094 mmol) in THF (1 mL) was added n-Bu4NF (1 M) in THF (94 μL, 0.094 mmol) and the reaction mixmre was stirred at r.t. for 15 min.. The mixmre was diluted with EtOAc, washed with brine, dried over MgS04, filtered and evaporated to give an oil (27 mg, 100%) which was dissolved in DMF (1 mL). Sodium hydride (97%, 2.8 mg, 0.11 mmol) was added at r.t. and stirred for 15 min.. Then Mel (7 μL, 0.11 mmol) was added. The reaction mixmre was stirred for 30 min. and tiien heated at 60°C for 30 min.. The reaction mixmre was then poured into H2θ and extracted with EtOAc. The combined organic phase was washed with brine, dried over MgSθ4, filtered and evaporated to give the titie compound as an oil 29 mg (100%). iH NMR (400 MHz, CDCI3); δ 3.75 (s, 3H); 6.3 (s, IH); 6.4 (d, IH); 6.72 (d, IH); 6.95 (s, IH); 7.2 (m, 2H); 7.92 (d, IH). Coumarin 21: 7-Bromo-4- thiazol-4-yl)coumarin Step 1: 7-Bromo-4-( 1 -ethox vvinv coumarin A mixmre of triflate (from Coumarin 11, Step 1) (2.88 g), (1 -ethoxy vinyl) tributyltin (3.06 g), (Ph3P)4Pd (0.36 g) and LiCl (0.98 g) in dioxane (20 mL) was refluxed for 4 h. Ethyl acetate was then added and die organic phase was washed widi H2O and brine, dried (MgS04) and evaporated. Flash chromatrography of the residue (silica gel; hexane/EtOAc (9:1)) afforded the titie compound as a yellow solid. Step 2: 7-Bromo-4-f2-bromoacetvPcoumarin To a solution of vinyl ether from Step 1 (1.02 g) in CH3CN:H2θ 4:1 (25 mL) were successively added NBS (0.82 g) and concentrated HBr (20 μL). After being stirred at r.t. for 4 h, the reaction mixmre was treated with 5% aqueous NaHSθ3 (1 mL). Ethyl acetate was then added and die organic phase was washed witii samrated aqueous NaHC03, H2θ and brine, dried (MgS04) and evaporated. Flash chromatography of the residue (silica gel; hexane/EtOAc (85:15)) afforded the title compound as a white solid. Step 3: 7-Bromo-4-fthiazol-4-yl .coumarin Freshly prepared thioformamide (Helv. Chim. Acta, 31, 2065, 1948) (160 mg) was added to a solution of α-bromoketone from Step 2 (200 mg) in THF (5 mL) and the reaction mixmre was stirred at r.t. for 2 h. Etiiyl acetate was tiien added and the organic phase was washed witii samrated aqueous NH4CI, H2O and brine, dried (MgS04) and evaporated. Flash chromatography of the residue (silica gel; hexane/EtOAc (65:35) afforded the titie compound as a white solid. iH NMR (400 MHz, CDCI3); δ 6.65 (s, IH); 7.40 (d, IH); 7.55 (s, IH); 7.75 (s, IH); 8.0 (d, IH); 9.0 (s, IH). Coumarin 22: 7-Mercapto-4-(_uran-3-vPcoumarin Step 1: 7-f2-Trimethylsilylethylthio)-4-(furan-3-ylkoumarin A mixmre of 7-bromo-4-(furan-3-yl)coumarin (Coumarin 4) (1.5 g, 5.15 mmol), 2-(trimethylsilyl)ethanethiol (830 mg, 6.18 mmol), and K2CO3 (1.77 g, 12.9 mmol) in l-methyl-2-pyrrolidinone (12 mL) was heated at 105 Q C for 4 h. After cooling, there was added saturated aqueous NH4CI (10 mL), then H2O (50 mL) and the mixmre was extracted twice with EtOAc. The organic extracts were washed 4 times with H2O, dried over MgSθ4 and evaporated to a residue which was chromatographed on silica gel eluting with a 1:3 mixmre of EtOAc and hexane, to afford the title compound (963 mg) as a tan solid. Step 2: 7-Mercapto-4-ffuran-3-vDcoumarin The coumarin from Step 1 (963 mg) was dissolved in DMF (25 mL) and to this solution there was added n-Bu4NF (1 M) in THF (8.4 mL). The mixture was stirred at r.t. for 2 h, poured onto IN aqueous HCl (50 mL), diluted with H2θ (50mL) and filtered to afford the title compound (620 mg) as a tan solid, m.p.: 167-170°C. PREPARATION OF NAPHTHALENES Naphthalene 1: 3-Cyano-l-(furan-3-yl)-6-naphthol (US 5,308,852, Merck Frosst) SUBSTITUTΕ SHEET (RULE 26) Naphthalene 2: 3-Cyano-l-phenyl-6-naphthol (US 5,308,852, Merck Frosst) Naphthalene 3: 3-Cyano- 1 - _furan-3-yl)-6-hvdrox vmethylnaphthalene Step 1: 3-Cyano- 1 -(furan-3-yl)-6-(trifluoromethanesulfonyloxy)- naphthalene To a solution of the Naphthalene 1 (565 mg, 2.40 mmol) in CH2C12 (16 mL) at 0°C was added pyridine (380 mg, 4.80 mmol, 389 μL) and triflic anhydride (813 mg, 2.88 mmol, 485 μL). The solution was stirred at 0°C for 2.5 h and then poured into sat. aq. NH4CI. The layers were separated and the aq. phase extracted with EtOAc (3x 30 mL). The combined organic layers were washed witii 5% aq. HCl, 5% aq. NaHCθ3, brine, and dried over anhydrous MgS04. Evaporation of the solvent gave a solid (810 mg) which was used directly in die next step. Step 2: 6-Carbomethoxy-3-cyano- 1 -Cfuran-3-yl .naphthalene The crude triflate from Step 1 was dissolved in MeOH (8 mL) and DMSO (14 mL). To the mixmre was added E_3N (4.8 mmol, 486 mg, 670 μL), Pd (OAc)2 (0.24 mmol, 54 mg) and l,l'-bis(diphenyl- phosphino)ferrocene (0.48 mmol, 266 mg) and stirred under CO atmosphere at 65 °C for 15 h. The mixmre was poured into aq. sat. NH4CI, extracted with EtOAc (3x 50 mL) and the combined organic layers washed with brine and dried over anhydrous MgSθ4. Evaporation of the solvent and flash chromatography (4% EtOAc in toluene) gave 450 mg of the titie methyl ester. Step 3: 3-Cyano- 1 -( furan-3-yl)-6-hvdrox vmeth ylnaphthalene To a solution of the ester from Step 2 (450 mg, 1.62 mmol) in THF (10 mL) and MeOH (10 mL) was added L1BH4 (3.24 mmol, 1.62 mL, 2.0 M in THF). The mixmre was stirred for 5h at r.t. and then poured into 100 mL 5% aq. HCl solution . The layers were separated and the aqueous phase was extracted with EtOAc (3x 50 mL). The combined organic layers were washed with brine and dried over anhydrous MgSθ4. Evaporation of the solvent and flash chromatography (50% EtOAc in hexane) gave 300 mg of the title product. Naphthalene 4: 3-Cyano- 1 -Cfuran-3- yl)-6-iodonaphthalene Step 1: 3-Cvano- 1 -(furan-3-ylV7-trimethyltinnaphthalene Following die procedure described for Coumarin 21, Step 1 but substimting l-(3-furyl)-3-cyano-6-(trifluoromethanesulfonyloxy)- naphthalene (from Naphthalene 3, Step 1) for the Coumarin 11, Step 1 and hexamethylditin for (1-ethoxyvinyl) tributyltin as starting material, the titie compound was obtained as a white solid. Step 2: 3-C vano- 1 -(furan-3-yl . -6-iodonaρhthalene A saturated solution of iodine in chloroform was added to a solution of compound from Step 1 (0.58 g) in CHCI3 (2 mL) until a persistant purple coloration was obtained. The reaction mixmre was stirred at r.t. for 1 h before it was washed with 10% aqueous NaHSθ3, H2O and brine, dried (MgS04) and evaporated. Flash chromatography of the residue (sihca gel; hexane:EtOAc (95:5)) afforded the title compound as a white solid. iH NMR (400 MHz, CDCI3); δ 6.65 (s, IH); 7.60 (d, 2H); 7.65 (s, IH); 7.85 (m, 2H); 8.05 (s, IH); 8.30 (s, IH). Naphthalene 5: 3-Cvano- 1 -( furan-3-yl)-6-naphthalenethiol Step 1: 3-Cyano- l-(f-iran-3-yl)-6-[2-trimethylsilylethylthio]- naphthalene A mixmre of 3-cyano-l-(furan-3-yl)-6-iodonaph_ιalene (2.5 g, 7.25 mmol), 2-(trimethylsilyl)ethanethiol (974 mg, 7.25 mmol), potassium tert-butoxide (1.624 g, 14.5 mmol) and (Ph3P)4Pd (200 mg, 0.17 mmol) in EtOH (250 mL) was refluxed for 6.5 h. After evaporation of the EtOH, the residue was partitioned between Et2θ and H2O. The crude product from the organic phase was chromatographed on silica gel, eluting with a 1:9 mixmre of EtOAc and hexane to afford the title product (1.8 g) as an amber oil. Step 2: 3-Cvano- 1 -( furan-3-yl)-6-naphthalenethiol The product from Step 1 (1.8 g) was dissolved in DMF (40 mL) and there was added n-Bu4NF (IM) in THF (15 mL). The resulting mixmre was stirred at r.t. for 1.5 h, diluted with IN aqueous HCl (40 mL) then H2θ (300 mL) and filtered to afford the titie thiol (1.06 g) as a light orange solid m.p.: 144-146°C. PREPARAΗON OF QUINOLINE INTERMEDIATE Quinoline 1: 7-Bromomethyl-2-cvano-4- (furan-3- yl .quinoline Step 1: 7-Chloro-4-iodoquinoline 4,7-Dichloroquinoline (50 g) (Aldrich) was added in small portions to HI (425 mL) at r.t. and then heated at 130°C for 5 h. The mixture was cooled, poured into ice/H2θ (600 mL), made basic (pH 10) with 10 N NaOH, and extracted with CHCI3. The combined organics were washed with NH4OAC buffer, 10% Na2S2θ3, brine, dried (Na2S04) and concentrated providing die titie compound which was used as such. Step 2: 7-Chloro-4-ffuran-3-vl.quinoline To a solution of 3-bromofuran (30 g) in Et2θ (400 mL) at -78°C was added n-BuLi (89.3 mL, 2.4 M in hexane). After stirring for 40 min., (MeO)3B (25.5 mL) was added and die mixture was stirred at -78°C for 30 min. followed by 30 min. at 0°C. Na2Cθ3 (196 mL of a 2M solution) was then added and the mixmre stirred at 0°C for 3 h. The Et2θ was evaporated and replaced by THF (730 mL); 7-chloro-4- iodoquinoline (53.7 g) and (Ph3P)4Pd (10.7 g) were added and the mixmre was heated at reflux for 12 h. The mixture was cooled to r.t., the layers were separated and the THF phase was concentrated. The aqueous phase was extracted with EtOAc, which was combined witii the residue from the THF phase. The organics were washed witii H2O, brine, dried (MgS04) and concentrated. Chromatography (silica gel; EtOAc/hexane (1:9)) provided die title compound as a beige solid. Step 3: 4-fFuran-3-yl.-7-methylquinoline To a mixmre of 7-_hloro-4-(furan-3-yl)quinoline (30.2 g) and [l,3-bis(diphenylphosphino)ρropane]nickel (II) chloride (7.1 g) in Et2θ (950 mL) was added MeMgBr (141 mL, 1.4 M in 3:1 THF:toluene) at such a rate to maintain a temperature of 30°C. The mixmre was refluxed for 30 min., cooled to 0°C and saturated NH4CI (200 mL) was added followed by H2O (100 mL). The layers were separated and die aqueous phase was extracted with EtOAc. The combined organics were washed witii NH4OAC buffer, brine, dried (MgS04) and concentrated. Chromatography (silica gel.EtOAc/hexane (3:7)) provided the title compound as a beige oil. Step 4: 2-Cyano-4-ffuran-3-yl.-7-methylquinoline To a solution of 4-(furan-3-yl)-7-methylquinoline (24.9 g) in CHCI3 (900 mL) was added mCPBA (30.8 g; 80%) portionwise. After 1 h, samrated NaHCθ3 was added followed by H2O (150 mL). The aqueous phase was extracted with CHCI3 and the combined organics were washed with samrated NaHCθ3, brine, dried (Na2S04) and concentrated. The residue was dissolved in CH2CI2 (900 mL) and TMSCN (19 mL) was added. After 5 min., dimethylcarbamyl chloride (13.1 mL) was added and die mixmre was stirred for 12 h at r.t. Potassium carbonate (10%; 400 mL) was slowly added and die aqueous layer was extracted witfi CH2CI2. The combined organics were washed with 10% K2CO3, NH4OAC buffer, brine, dried (Na2Sθ4) and concentrated. Chromatography (sihca gel; EtOAc/hexane (1:9 to 2:3) provided die title compound as a solid. Step 5: 7-Bromomethyl-2-cvano-4-( r furan-3-yl .quinoline To a solution of 2-cy_no-4-(f_ran-3-yl)-7-methylquinoline (4.2 g) in refluxing CCI4 (400 mL) was added NBS (3.3 g) and AIBN (150 mg) portionwise. After 90 min., the mixmre was cooled to r.t. filtered through a pad of silica gel washing with CH2CI2. The filtrate was concentrated and swished with Et2θ for 15 h. The solid precipitate was collected and was 85% of the title compound. This material was used as such in the subsequent reactions. Quinoline 2: 7-Bromomethyl-2-cvano-4-f4-fluorophenyl. quinoline Step 1: 7-Chloro-4-(4-fluorophenyl.quinoline To a solution of 4-fluorophenylmagnesium bromide (5.2 mL, 10.4 mmol) 2 M in Et2θ) in THF (8 mL) at r.t., was added dropwise a solution of 4,7-dichloroquinoline (Aldrich) (2.07 g, 10.47 mmol) and (Ph3P)4Pd (0.48 g, 0.42 mmol) in THF (10 mL). After 18 h, more 4- fluorophenyl magnesium bromide (1.5 mL) was added. The solution was stirred for 5 h, at r.t., then quenched with a samrated NH4CI solution. The aqueous phase was extracted with EtOAc (3x). The combined organic phase were dried (MgS04) and concentrated. Flash chromato¬ graphy with EtOAc/hexane (1:5.6) provided the title compound (1.4 g 53%) as a solid. Step 2: 7-Bromomethyl-2-cvano-4-(4-fluorophenyl .quinoline Following die procedure described for Quinoline 1, Steps 3 to 5 but substimting 7-chloro-4-(4-fluorophenyl)quinoline from Step 1 for 7-chloro-4-(furan-3-yl)quinoline, the titie compound was obtained. iH NMR (300 MHz, CDCI3); δ 4.66 (s, 2H); 7.23 - 7.29 (m, 2H); 7.43 - 7.48 (m, 2H); 7.60 - 7.69 (m, 2H); 7.91 (d, IH); 8.18 (d, IH). Preparation of Isoquinolines Isoquinoline 1: 7-Iodo-4-phenylisoquinoline Step 1: 7-Methoxy-4-phenylisoquinoline To a solution of 3-methoxybenzylamine (15 g) and pyridine (15 mL) in CH2CI2 (100 mL) at 0°C was added p-toluenesulfonyl chloride (21 g) portionwise. After addition was complete, the mixmre was stirred at r.t. for 2 h and then saturated NH4CI was added. The mixture was extracted with Et2θ and the extracts were washed with H2O, brine, dried (MgSθ4) and concentrated. The residue, 2-bromo- acetophenone (23 g) and CS2CO3 (45 g) in acetone (400 mL) were stirred at r.t. for 20 h. The acetone was evaporated and saturated NH4CI was added. The mixmre was extracted with EtOAc and the organics were washed with H2O, brine, dried (MgSθ4) and concentrated. The residual solid was swished in Et2θ for 3 h and then mixed witii TFA (17 mL). After heating at 75°C for 2.5 h, the mixmre was cooled to r.t., EtOAc and H2O were added and the aqueous phase was made basic by die careful addition of solid K2CO3. The organic phase was washed witii samrated NaHCθ3, H2O, brine and dried (MgSθ4). Concentration and chromato¬ graphy (silica gel; hexane/EtOAc (3:2 to 1 :1) provided die titie compound as a solid. Step 2: 7-Trifluoromethanesulfonyloxy-4-phenylisoquinoline A mixmre of 7-methoxy-4-phenylisoquinoline (8.8 g) and pyridine hydrochloride (30 g) was heated at 195-200°C for 4.5 h. The mixmre was cooled and H2O was added. After stirring for 30 min., the precipate that formed was isolated by filtration, and washed with H2O. The residual solid was swished with EtOAc for 90 min. To a portion of this material (3 g) and pyridine (5.5 mL) in CH2CI2 (100 mL) at 0°C was added triflic anhydride (2.8 mL) and die mixmre was stirred at 0°C for 30 min and tiien at r.t. for 90 min. Samrated NH4CI was added and the mixmre extracted with CH2CI2. The organics were washed with H2O, brine, dried (MgSθ4) and concentrated. Chromatography (silica gel; hexane/EtOAc (4:1)) provided the title compound as a solid. Step 3: 7-Iodo-4-phenvlisoquinoline A mixmre of 7-trifluoromethanesulfonyloxy-4-phenyl- isoquinohne (2.7 g), hexametiiylditm (7.4 g), LiCl ( 1.9 g) and (Ph3P)4Pd (500 mg) in dioxane (50 mL) was heated at 90°C for 1 h. The mixmre was cooled, filtered through celite and die filtrate was concentrated. The residual material was dissolved in CHCI3 (50 mL) and 12 (1.8 g) was added. After 1 h, 10% NaHS03 was added and the mixmre was extracted with CHCI3. The organics were washed with H2O, brine, dried (MgS04) and concentrated. Chromatography (sihca gel; hexane/EtOAc (10:1 to 7:3)) provided the titie compound as an oil. iH NMR (300 MHz, Acetone-d6); δ 7.45 - 7.58 (m, 5H); 7.64 (d, IH); 7.96 (d, IH); 8.46 (s, IH); 8.58 (d, IH); 9.22 (s, IH). Isoquinohne 2: 7-Iodo-4-(furan-3-yl)isoquinoline Step 1: 3-Chloroacetylfuran Under N2, 3-furoic acid (25 g, 0.22 mmol) was dissolved in CH2CI2 (200 mL) and DMF (few drops) then oxalyl chloride (23.9 mL, 0.27 mmol) was added at 0°C. The resulting solution was stirred at 0°C for 15 min. and at r.t. for 30 min. The solvent was evaporated. To the acid chloride (3.1 g, 24 mmol) in Et2θ (20 mL) at r.t. was added an ethereal solution of diazomethane until the reaction was completed by T.L.C. The reaction mixmre was cooled to 0°C and HCl (g) was bubbled in for 20 min.. Excess HCl (g) was removed by bubbling N2 into the solution for 2 h. The resulting solution was washed with a samrated solution of NaHCθ3 (2x), brine, dried over MgSθ4 and then concentrated. Flash chromatography of me residue witii hexane:EtOAc 9: 1 as eluent afforded the titie compound as a white solid. Step 2: 7-Iodo-4-_f ran-3-yl)isoquinoline Following die same procedure as described for Isoquinohne 1, but substimting 3-chloroacetylfuran from Step 1 for 2-bromoaceto- phenone, the title compound was obtained. iH NMR (300 MHz, CDCI3); δ 6.61 (d, IH); 7.54 (s, IH); 7.62 (s, IH); 7.71 (d, IH); 7.80 (m, IH); 8.27 (s, IH); 8.46 (s, IH); 8.99 (s, IH). EXAMPLE 1 7-[5-Ruoro-3-(3-hydroxypent-3-yl)phenoxymemyl]-4-(furan-3- yl.coumarin To a solution of Coumarin 1 (77 mg, 0.25 mmol), Phenol 2 (50 mg, 0.25 mmol) in dry DMF (5 mL) was added CS2CO3 (99 mg, 0.3 mmol) and die resulting mixmre was stirred at r.t. for 2 h. Then the reaction mixture was added to an aqueous solution of HCl (IN) and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgS04 and evaporated. Purification by flash chromatography using toluene:EtOAc (9:1) gave 95 mg (89%) of the titie product. iH NMR (400 MHz, CDCI3,); δ 0.74 (t, J=7.5 Hz, 6H); 1.57 (s, IH); 1.78 (m, 4H); 5.1 (s, 2H); 6.41 (s, IH) 6.53 (dt, J=10.2 Hz, IH); 6.66 (s, IH); 6.67 (dt, IH); 6.81 (s, IH); 7.33 (m, IH), 7.45 (s, IH), 7.60 (s, IH); 7.78 (m, 2H). EXAMPLE 2 7-r5-Ruoro-3-(3-hvdroxypent-3-yl.phenylthiol-4-(fiιran-3-yl.coumarin The Thiophenol 3 (81 mg, 0.378 mmol), the Coumarin 4 (143 mg, 0.491 mmol) and K2CO3 (130 mg, 0.945 mmol) were heated at 145°C in N-metiιyl-2-pyrrohdinone (2 mL) for 1 h. The mixmre was allowed to cool to r.t. poured into H2O (20 mL), and extracted with EtOAc (3x). The combined extracts were washed with 25% NH4OAC buffer (lx), H2O (2x), brine (lx), dried (MgSθ4) and concentrated. The brown residue obtained was purified by column chromatography on silica (EtOAc/hexane 1:4) to give a yellow foam (66 mg, 41%). iH NMR (300 MHz, Acetone-d6); δ 0.74 (t, 6H), 1.84 (m, 4H), 3.87 (s, IH), 6.39 (s, IH), 6.90 (m, IH), 7.12-7.20 (m, 3H), 7.30 (m, IH), 7.47 (t, IH), 7.80-7.84 (m, 2H), 8.16 (s, IH). EXAMPLES 12-13 7-[5-Ruoro-3-(hexafluoro-2-hydroxyprop-2-yl)phenylsulfonyl]-4-(4- fluorophenyl)coumarin (Ex. 12) and 7-[5-fluoro-3-(hexafluoro-2- hvdroxyprop-2-yl .phenylsulfinvP-4-( -fluorophenvPcoumarin (Ex. 13. To a solution of Example 4 (100 mg, 0.19 mmol) in CH2CI2 (5 mL) at 0°C was added mCPBA (65 mg) and the reaction mixmre was stirred for 1 h. Then CH2CI2 was added and washed witii an aqueous solution of 10% NaOH, H2O and brine, dried over MgS04 and evaporated. Purification by flash chromatography using toluene:EtOAc 85: 15 gave 72 mg of the corresponding sulfone and 20 mg of the sulfoxide. Example 12; Mass spec; 565 (MH + ); Example 13; Mass spec; 549 (MH+). EXAMPLE 22 7- { 5-Ruoro-3-[ 1 -hydroxy- 1 -(tMazol-2-yl)-2,2,2-trifluoroethyl]phenyl- thio l-4-f4-fluorophenylfcoumarin Step 1: 7- [5-Ruoro-3-(thiazol-2-ylcarbonyl)phenylthio]-4-(4- fluorophenyl .coumarin Following the procedure described for Example 2 but substimting Thiophenol 5 for Thiophenol 3 and Coumarin 7 for Coumarin 4 as starting material the titie compound was obtained. Step 2: 7- { 5-Ruoro-3-[ 1 -hydroxy- 1 -(thiazol-2-yl)-2,2,2-trifluoro- ethyllphenylthio 1 -4-f 4-fluorophenyl'. coumarin Following the procedure described for die preparation of Thiophenol 4, Step 1 but substituting the ketone from Step 1 for 3,5- difluorobenzophenone as starting material the titie compound was obtained, m.p.: 72-73°C. EXAMPLE 26 7- { 5-Ruoro-3- [ 1 -hydroxy- 1 -(imidazol-2-yl)propyl]phenoxymethyl } -4- (furan-3-vPcoumarin Step 1: 7-(5-Ruoro-3- { 1 -hydroxy- 1 -[N-(2-trimethylsilylethoxy- methyl)imidazol-2-yl]propyl }phenoxymethyl)-4-(furan-3- yπcoumarin Following the procedure described for Example 1, but substimting Phenol 6 for Phenol 2 as starting material, the title compound was obtained. Step 2: 7- { 5-Ruoro-3-[l -hydroxy- 1 -(imidazol-2-yl)propyl]- phenoxymethyl ) -4-f furan-3-vDcoumarin Under N2 the compound from Step 1 (94 mg, 0.159 mmol) was dissolved in THF (2 mL). Tetrabutylammonium fluoride was added ((795 μL, 0.795 mmol) and the reaction was stirred at 55°C for 1 h. Ethyl acetate was added and the organic phase was washed with brine, dried over MgSθ4, filtered and evaporated to give an oil which was purified by a flash sihca column using EtOAc tiien 5% MeOH in CH2CI2 as the eluent. The title compound was obtained: 12.8 mg (17%). Mass spec: 461 (MH+). EXAMPLE 44 7- [5-Ruoro-3-(hexafluoro-2-methoxyprop-2-yl)phenylthio]-4-(furan-3 - yPcoumarin Following the procedure described for Alcohol 5, Step 2 but substimting compound from Example 3 for 6-[l -Hydroxy- l-(thiazol-2- yl)propyl]-(0-tertbutyldimethylsilyl)pyridin-2-yl methanol as starting material the titie compound is obtained. EXAMPLE 45 7-[5-Ruoro-3-(hexafluoro-2-methoxyprop-2-yl)phenylthio]-4-(4-fluoro- p epyPcQu arjn Following the procedure described for Alcohol 5, Step 2 but substimting compound from Example 4 for 6-[l -Hydroxy- l-(ti____ol-2- yl)propyl]-(0-tertbutyldimethylsilyl)pyrdidin-2-yl methanol as starting material the title compound is obtained. EXAMPLE 4$ 3-Cyano-l-(furan-3-yl)-6-[6-(3-hydroxypent-3-yl)pyridin-2-ylmethoxy]- naphthalene To a mixmre of Naphthalene 1 (125 mg, 0.53 mmol), Alcohol 2 (94.3 mg), 0.48 mmol) and triphenylphosphine (164 mg, 0.62 mmol) in THF (10 mL) was added di-tert-butylazodicarboxylate (144 mg, 0.62 mmol) and die mixmre was stirred at r.t. for 1 h. After evaporation of the TΗF, the residue was chromatographed on a column of silica gel, eluting with hexane:EtOAc (4:1) as eluant to give 166 mg of the title compound, m.p.: 115-116°C. EXAMPLE 53 3-Cyano- 1 -(fur an-3-yl)-6- { 5-fl uoro-3-[ 1 -hydroxy- 1 -(thiazol-2-yl)- propyllphenylthio 1 naphthalene Following the procedure described for Naphthalene 5, Step 1, but substimting Thiophenol 8 for 2-(trimethylsilyl)ethanethiol as starting material, the title compound was obtained, m.p.: 120-122°C. EXAMPLE 54 3-Cyano- l-(furan-3-yl)-6-{ 6-[ 1 -hydroxy- 1 -(thiazol-2-yl)propyl]pyridin- 2- yloxymethvπ naphthalene A mixmre of the Bromopyridine 3 (108 mg, 0.38 mmol), Naphthalene 3 (104 mg, 0.42 mmol) 18-crown-6 (4.0 mg, 0.015 mmol) and NaOH (64 mg, 1.14 mmol) in 7 mL toluene was heated at reflux witii a Dean-stark trap for 2 h. Additional NaOH (32 mg, 0.57 mmol) was added and the mixmre was further heated at reflux for 3 h. The cooled solution was partitioned between aq. NH4CI and EtOAc and the aq. phase was extracted with EtOAc (2x 30 mL). The combined organic layers were washed with brine and dried over anhydride MgSθ4. The solvent was evaporated and die residue chromatographed on silica gel using hexane EtOAc (7:3) to give 72 mg ot the title product. Analysis calc'd for C, 69.36; H, 4.53; N, 8.99. Found: C, 69.43; H, 4.53; N, 8.85. EXAMPLE 58 3-Cyano-l-(furan-3-yl)-6-{3-[l-methoxy-l-(thiazol-2-yl)propyl]- phenoxymethvU naphthalene Following the procedure described for Example 46 but substimting Naphthalene 3 for Naphthalene 1 and 3-[l -methoxy- 1- (dιiazol-2-yl)propyl]phenol (/. Med. Chem 1991, 24, 2176) as starting material, the title compound was obtained, m.p.: 156-157°C. EXAMPLE 64 7-[5-Ruoro-3-(hexafluoro-2-memoxyprop-2-yl)phenoxymethyl]-2- cyano-4-ffiιran-3-vDquinoline Following the procedure described for Example 1 and for Alcohol 5, Step 2 but substimting Quinoline 1 for Coumarin 1 and Phenol 3 for Phenol 2 as starting material, the title compound is obtained. The following examples have been prepared according to the example referenced in each case, by coupling the identified components. Compounds of the following examples were prepared using the starting materials and according to general procedures described in me examples specified within the parenthesis. Characterizing properties are also provided for each compound. Example 3: (Ex. 2; Thiophenol 1, Coumarin 4); Mass spec: 505 (MH + ). Example 4: (Ex. 2; Thiophenol 1, Coumarin 7); iH NMR (400 MHz, CDC13); δ 3.69 (s, IH); 6.30 (s, IH); 7.07 (m, IH); 7.2 (m, 4H); 7.4 (m, 4H); 7.6 (s, IH). Example 5: (Ex. 2; Thiophenol 1, Coumarin 15); Mass spec: 516 (MH+). Example 6: (Ex. 2; Thiophenol 1, Coumarin 9); Mass spec: 522 (MH+). Example 7: (Ex. 2; Thiophenol 1, Coumarin 21); Mass spec: 522 (MH+). Example 8: (Ex. 2; Thiophenol 1, Coumarin 16); Mass spec: 516 (MH+). SUBSTITUTE SHEET (RULE 261 Example 9: (Ex. 1; Phenol 3, Coumarin 2); m.p.: 172-173°C. Example 10: (Ex. 2; Bromopyridine 1, Coumarin 22); H NMR (400 MHz, Acetone-d6); δ 6.55 (s, IH); 6.96 (s, IH); 7.05 (br-s, IH); 7.56 (m, 2H); 7.66 (s, IH); 7.70 (d, IH), 7.86 (s, IH), 8.03 (m, 2H), 8.23 (s, IH). Example 11 : (Ex. 1 ; Phenol 5, Coumarin 2); m.p. 86-87.5°C. Example 14: (Ex. 2; Thiophenol 1, Coumarin 8); m.p.: 165-167°C; Mass spec: 550 (MH+). Example 15: (Ex. 2; Thiophenol 1, Coumarin 11); Mass spec: 583 (MH+). Example 16: (Ex. 2: Bromopyridine 1, Coumarin 7); m.p.: 108- 111°C. Example 17: (Ex. 2; Thiophenol 1, Coumarin 17); m.p.: 132- 134°C. Example 18: (Ex. 2, Thiophenol 1, Coumarin 20); Mass spec: 518 (MH+). Example 19: (Ex. 2; Thiophenol 1, Coumarin 6); Mass spec: 515 (MH+). Example 20: (Ex. 2; Thiophenol 1, Coumarin 19); Mass spec: 505 (MH+). Example 21: (Ex. 2; Thiophenol 4, Coumarin 4); Mass spec: 513 (MH+). Example 23: (Ex. 2; Thiophenol 9, Coumarin 4); Mass spec: 473 (MH+). Example 24: (Ex. 2; Thiophenol 6, Coumarin 4); m.p.: 75-76°C. Example 25: (Ex. 2; Thiophenol 7, Coumarin 4); m.p.: 72-73°C. Example 27: (Ex. 1; Phenol 11, Coumarin 1); Mass spec: 454 (MH+). Example 28: (Ex. 1; Phenol 1, Coumarin 3); Mass spec: 494 (MH+). Example 29: (Ex. 1; Phenol 1, Coumarin 1); iH NMR (400 MHz, CDC13); δ 0.88 (t, J=7.3 Hz, 3H); 2.33 (m, 2H); 3.51 (s, IH); 5.12 (s, 2H); 6.41 (s, IH), 6.54 (d, J=10.1 Hz, IH); 6.66 (s, IH); 6.95 (d, J=9.8 Hz, IH); 7.05 (s, IH); 7.26 (d, J=3.1 Hz, IH); 7.31 (d, J=8.1 Hz, IH); 7.42 (s, IH); 7.59 (s, IH); 7.69 (d, J=3.1 Hz, IH); 7.75 (d, J=8.3 Hz, IH); 7.79 (s, IH). Example 30: (Ex. 1 ; Phenol 1, Coumarin 2); iH NMR (400 MHz, CDCI3); δ 0.88 (t, J=7.3 Hz, 3H); 2.33 (m, 2H); 3.52 (s, IH); 5.11 (s, 2H); 6.34 (s, IH), 6.55 (d, IH); 6.95 (d, J=9.8 Hz, IH); 7.05 (s, IH); 7.24 (m, 4H); 7.44 (m, 4H); 7.69 (d, J=3.1 Hz, IH). Example 31: (Ex. 12; Thiophenol 8, Coumarin 4); Mass spec: 512 (MH+). Example 32: (Ex. 2; Thiophenol 8, Coumarin 10); m.p.: 73-74°C. Example 33: (Ex. 2; Thiophenol 8, Coumarin 5); Mass spec: 496 (MH+). Example 34: (Ex. 2; Thiophenol 8, Coumarin 6); Mass spec: 490 (MH+). Example 35: (Ex. 2; Thiophenol 8, Coumarin 4); Mass spec: 480 (MH+). Example 36: (Ex. 2; Thiophenol 8, Coumarin 7); Mass spec: 508 (MH+). Example 37: (Ex. 1; Phenol 7, Coumarin 1); m.p.: 103-104°C. Example 38: (Ex. 1; Phenol 7, Coumarin 3); m.p. 97-98°C. Example 39: (Ex. 2; Thiophenol 1, Coumarin 13); m.p.: 89-90°C. Example 40: (Ex. 2; Thiophenol 1, Coumarin 12); Mass spec: 567 (MH+). Example 41: (Ex. 2; Thiophenol 10, Coumarin 7); Mass spec: 633 (MH+). Example 42: (Ex. 2; Thiophenol 1, Coumarin 18); m.p.: 119- 120°C. Example 43: (Ex. 2; Thiophenol 1, Coumarin 14); m.p.: 56-57°C. Example 47: (Ex. 46; Phenol 2, Naphthalene 3); Mass spec: 430 (MH+). Example 48: (Ex. 2; Bromopyridine 2, Naphthalene 5); Mass spec. 415 (MH+). Example 49: (Ex. 46; Alcohol 3, Naphthalene 1); m.p.: 161-162°C. Example 50: (Ex. 46; Alcohol 3, Naphthalene 2); m.p.: 157-159°C. Example 51: (Ex. 2; Bromopyridine 1, Naphthalene 5); iH NMR (400 MHz, Acetone-d6); δ 6.93 (s, IH), 6.97 (s, IH); 7.47 (d, IH); 7.66 (d, IH); 7.87 (m, 3H); 8.00 (t, IH); 8.05 (s, IH); 8.38 (d, IH); 8.50 (d, 2H). Example 52: (Ex. 2; Bromopyridine 3, Naphthalene 5); Mass spec 470 (MH+). Example 55: (Ex. 46; Alcohol 4; Naphthalene 1); m.p.: 130-132°C. Example 56: (Ex. 46; Alcohol 5, Naphthalene 1); m.p.: 155-156°C. Example 57: (Ex. 46; Phenol 7, Naphthalene 3); Analysis calc'd for C; 72.08; H, 4.75; N, 6.00; found C, 72.13; H, 4.82; N, 5.82. Example 59: (Ex. 46; Alcohol 1, Naphthalene 1); m.p.: 140-142°C. Example 60: (Ex. 1; Phenol 13, Quinoline 1); m.p.: 116-117°C. Example 61: (Ex. 1; Phenol 14, Quinoline 1); m.p.: 90-91°C. Example 62: (Ex. 1; 3-Hydroxylbenzyl alcohol, Quinoline 1); m.p. 136-139°C. Example 63: (Ex. 1; Phenol 9, Quinoline 1); Mass spec: 427 (MH+). Example 65: (Ex. 1; Phenol 10, Quinoline 1); Mass spec: 441 (MH+). Example 66: (Ex. 1; Phenol 14, Quinoline 1); m.p.: 112-113°C. Example 67: (Ex. 1; Phenol 3, Quinoline 1); m.p.: 173-174°C. Example 68: (Ex. 1; Phenol 3, Quinoline 2); m.p.: 169-170°C. Example 69: (Ex. 1; Phenol 4, Quinoline 1); Mass spec: 527 (MH+). Example 70: (Ex. 1; Phenol 11, Quinoline 1); Mass spec: 462 (MH+). Example 71: (Ex. 1; Phenol 12, Quinoline 1); iH NMR (300 MHz, Acetone-d6); δ 0.80 (t, 3H); 2.16 (q, 2H); 4.28 (s, IH); 5.41 (s, 2H), 6.35 (d, IH), 6.93 (dd, IH); 7.06 (s, IH), 7.08 (d, IH), 7.22-7.27 (m, 2H); 7.38 (m, IH); 7.43 (s, IH); 7.88 (s, IH); 7.91 (d, IH); 7.95 (s, IH); 8.24 (m, 2H); 8.38 (d, IH). Example 72: (Ex. 1; Phenol 8, Quinoline 1); m.p. 123-125°C; Mass spec: 443 (MH+). Example 73: (Ex. 1; Phenol 1, Quinoline 1); Mass spec: 486 (MH+). Example 74: (Ex. 1; Phenol 7, Quinoline 1); m.p.: 136-137°C. Example 75: (Ex. 2; Thiophenol 1, Isoquinohne 1); iH NMR (300 MHz, Acetone-d6,); δ 6.88 (dd, IH); 7.30 (dq, IH); 7.44 (brd, IH); 7.61 (s, IH); 7.76-7.83 (m, 2H); 7.99 (s, 2H); 8.20 (d, IH); 8.29 (d, IH); 8.56 (s, IH); 9.22 (s, IH). Example 76: (Ex. 2; Thiophenol 1, Isoquinohne 2); iH NMR (300 MHz, Acetone-d6,); δ 7.29 (m, IH); 7.44 (d, IH); 7.48-7.62 (m, 6H); 7.73 (dd, IH), 7.94 (d, IH); 8.09 (s, IH); 8.30 (s, IH); 8.46 (s, IH); 9.28 (s, IH). Example 77: (Ex. 2; Thiophenol 8, Isoquinohne 1); m.p.: 134- 135°C; Mass spec: 463 (MH+).

Claims: - I l l - WHAT IS CLAIMED IS: 1. A compound having the formula RlR2C(OR3)-Arl-X-Ar2-Ar3 wherein Arl is a 6-membered aromatic ring containing 0-3 N, substimted witii one or two of the same or different R4 groups; A_2 is a 10-membered bicyclic ring, substimted witii one or two of die same or different R^ groups, wherein said bicyclic ring is a bicychc aromatic ring containing 0-4 ring N, 2H-1- benzopyran-2-one, or 2H-2- tiiioxo- 1 -benzopyran; Ar3 and Aι * 4 are indepedendy a 5-membered aromatic ring containing one O or S and 0-3 N; a 5-membered aromatic ring containing 1-4 N; or a 6-membered aromatic ring containing 0-3 N; wherein said aromatic ring is substimted with one or two of the same or different R6 groups; X is OCH2, CH2θ, O, S, S(O), or S(0)2; Rl is H, lower alkyl, lower perfluoroalkyl or Ar * *; R2 is H, lower alkyl or lower perfluoroalkyl; R3 is H or lower alkyl; R4 is H, lower alkyl, lower alkoxy, lower alkylthio, Nθ2, CN, CF3, CF3O or halogen; R5 is R4, oxo or thioxo; R6 is R4, lower alkylsulfinyl, lower alkylsulfonyl or Cθ2R^; R7 is H or lower alkyl; or a pharmaceutically acceptable salt thereof. 2. A compound of Claim 1 wherein Arl is Phe or Pye, each of which is substimted with one or two of the same or different R^ groups; Ar3 is Ph, Py, Fu, Th, Tz, Im, or Pyr, each of which is substimted witii one or two of the same or different R6 groups; X is OCH2, CH20, S, S(O), or S(0)2; Rl is H, lower alkyl, lower perfluoroalkyl, Ph, Py, Im, Fu or Tz; and die remaining substimtents are as defined in Claim 1. 3. A compound of Claim 1 wherein: Ar is p e or Pye each of which is unsubstimted or substimted with halogen; A_2 is naphthyl, quinolinyl, isoquinolinyl or 2H-l-benzopyran-2- one, wherein said naphthyl and quinolinyl are optionally substimted with CN; Ar3 is Ph, Py, Fu, Th, Tz, Im, or Pyr each of which is substimted with one or two of the same or different R6 groups; X is OCH2, CH20, S, S(O) or S(0)2; Rl is H, lower alkyl, lower perfluoroalkyl, Ph, Py or Tz; R6 is R4; and the remaining substimtents are as defined in Claim 1. 4. A compound of Claim 1 having the Formula Ia wherein: Ar3is Fu, Py, Tz, Im, Th optionally substimted with halogn, Pyr optionally substimted with lower alkyl, Ph optionally substimted with one or two of the same or different halogen atoms, or with one nitro group; Xis OCH2, S, S(0)2, S(O); Yis HorF; Zis NorCH; Rlis lower alkyl, perfluoro lower alkyl, Ph, Tz, Im, or Py; R2is H, lower alkyl, or lower perfluoroalkyl. A compound of Claim 1 having the Formula lb wherein: Ar3 is Fu or Ph; X is CH2θ, OCH2 or S; Yis HorF; Z is N or CH; Rl is lower alkyl, perfluoro lower alkyl or Tz; R2 is lower alkyl or perfluoro lower alkyl; R3 is H or lower alkyl. SUBSTITUTE SHEET RULE 26) A compound of Claim 1 having the Formula Ic Ic wherein: Ar3 is Fu or Ph; Y is H or F; Rl is H, lower alkyl, lower perfluoroalkyl Ph, Py, Fu or Tz; R2 is H, lower alkyl or lower perfluoroalkyl; R3 is H or lower alkyl. 7. A compound of Claim 1 having die Formula Id Id wherein: A_3 is Fu or Ph; R! is lower perfluoroalkyl or Tz; R is lower alkyl or lower perfluoroalkyl. 8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Claim 1 and a pharmaceutically acceptable carrier. 9. The pharmaceutical composition of Claim 8 additionally comprising an effective amount of a second active ingredient selected from the group consisting of non-steroidal anti-inflammatory drugs; peripheral analgesic agents; cyclooxygenase inhibitors; leukotriene antagonists; leukotriene biosynthesis inhibitors; Hi- or H2-receptor antagonists; antihistaminic agents; prostaglandin antagonists; and ACE agonists. 10. A pharmaceutical composition according to Claim 9, wherein the second active ingredient is a non-steroidal anti-inflammatory drug. 11. A pharmaceutical composition of Claim 10, wherein the weight ratio of said compound of Claim 1 to said second active ingredient rangexs from about 1000:1 to 1:1000. 12. A method of preventing die synthesis, the action, or die release of SRS-A or leukotrienes in a mammal which comprises administering to said mammal an effective amount of a compound of Claim 1. 13. The method of Claim 12 wherein die mammal is man. 14. A metiiod of treating asthma in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1. 15. A method ol * treating inflammatory discuses of the ey in a mammal which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1. 16. The method of Claim 15 wherein the mammal is man. 17. A pharmaceutically acceptable salt of a compound of formula (1) as defined in Claim 1, 2, 3, 4, 5, 6 or 7. 18. A compound of formula (I) as defined in Claim 1, 2, 3, 4, 5, 6 or 7, or a pharmaceutically acceptable salt thereof, for use in preventing synthesis, action or release of SRS-A or leukotrienes. 19. Use of a compound of formula (I) as defined in Claim 1, 2, 3, 4, 5, 6 or 7 or a pharmaceutically acceptable sail thereof, in the manufacture of a medicament for die treatment of asthma. 20. Use of a compound of formula (I) as defined in Claim 1 , 2, 3, 4, 5, 6 or 7 or a pharmaceutically acceptable salt thereof, as a leukotriene biosyndicsis inhibitor. 21. A leukotriene biosynthesis iniiib itor pharmaceutical composition comprising an acceptable leukotriene biosynthesis inliibiting amount of a compound of formula (I), as defined in Claim 1 , 2, 3, 4, 5, 6 or 7, in association with a pharmaceutically acceptable carrier.

Inventors: DELORME DANIEL, DUBE DANIEL, DUCHARME YVES, FRIESEN RICHARD, GRIMM ERICH L, LEPINE CAROLE, DELORME, DANIEL, DUBE, DANIEL, DUCHARME, YVES, FRIESEN, RICHARD, GRIMM, ERICH, L., LEPINE, CAROLE
Applicants: DELORME DANIEL, DUBE DANIEL, DUCHARME YVES, FRIESEN RICHARD, GRIMM ERICH L, LEPINE CAROLE, MERCK FROSST CANADA INC, DELORME, DANIEL, DUBE, DANIEL, DUCHARME, YVES, FRIESEN, RICHARD, GRIMM, ERICH, L., LEPINE, CAROLE, MERCK FROSST CANADA INC.
Application year: 1995
Main classification: C07D407
IPC codes: A61K31, A61P25, A61P29, A61P43, C07D277, C07D311, C07D405, C07D407, C07D409, C07D417, C07D521