WO2002022584A1

WO2002022584A1 - Thrombin inhibitors

Info

Publication number: WO2002022584A1
Application number: PCT/US2001/028791
Authority: WO
Inventors: Richard C. Isaacs; Peter D. Williams; Terry A. Lyle; Donnette D. Staas; Kelly L. Savage
Original assignee: Merck & Co., Inc.
Priority date: 2000-09-11
Filing date: 2001-09-11
Publication date: 2002-03-21
Also published as: AU2001294557A1

Abstract

Compounds of the invention are useful in inhibiting thrombin and treating blood coagulation and cardiovascular disorders and have the following structure: where R1 is hydrogen, or C¿1-4? alkyl, (CH2)0-1CN, C(O)R?14, (CH¿2)0-1CO2R14, CF3, OR14, halogen, SR?14, S(O)R14¿, S(O)¿2?R?14, NR14R15¿.

Description

TITLE OF THE INVENTION THROMBIN INHIBITORS

BACKGROUND OF THE INVENTION Thrombin is a serine protease present in blood plasma in the form of a precursor, prothrombin. Thrombin plays a central role in the mechanism of blood coagulation by converting the solution plasma protein, fibrinogen, into insoluble fibrin.

Edwards et al, J. Amer. Chem. Soc, (1992) vol. 114, pp. 1854-63, describes peptidyl a-ketobenzoxazoles which are reversible inhibitors of the serine proteases human leukocyte elastase and porcine pancreatic elastase. European Publication 363 284 describes analogs of peptidase substrates in which the nitrogen atom of the scissile amide group ofthe substrate peptide has been replaced by hydrogen or a substituted carbonyl moiety. Australian Publication 86245677 also describes peptidase inhibitors having an activated electrophilic ketone moiety such as fluoromethylene ketone or a-keto carboxyl derivatives. R. J. Brown et al., J. Med. Chem., Vol. 37, pages 1259-1261 (1994) describes orally active, non-peptidic inhibitors of human leukocyte elastase which contain trifluoromethylketone and pyridinone moieties. H. Mack et ah, J. Enzyme Inhibition, Vol. 9, pages 73-86 (1995) describes rigid amidino-phenylalanine thrombin inhibitors which contain a pyridinone moiety as a central core structure.

SUMMARY OF THE INVENTION

The invention includes a composition for inhibiting loss of blood platelets, inhibiting formation of blood platelet aggregates, inhibiting formation of fibrin, inhibiting thrombus formation, and inhibiting embolus formation in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier. These compositions may optionally include anticoagulants, antiplatelet agents, and thrombolytic agents. The compositions can be added to blood, blood products, or mammalian organs in order to effect the desired inhibitions.

The invention also includes a composition for preventing or treating unstable angina, refractory angina, myocardial infarction, transient ische ic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, ocular build up of fibrin, and reocclusion or restenosis of recanalized vessels, in a mammal, comprising a compound of the invention in a pharmaceutically acceptable carrier. These compositions may optionally include anticoagulants, antiplatelet agents, and thrombolytic agents.

The invention also includes a method for reducing the thrombogenicity of a surface in a mammal by attaching to the surface, either covalently or noncovalently, a compound ofthe invention. DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

Compounds of the invention are useful for inhibiting thrombin and treating blood coagulation and cardiovascular disorders. The invention includes compounds having the structure

Ft³-. /U^ ^R¹ \^W

X-Y-Z-R²

where u, v and w, same or different, are CH or N;

X is O, S, S(O), S(0)2, NH, C alkenyl, C(O), C(0)NH, -C(O)O-,CR10R11, -OfeNH-, CH2O-, or

CF₂; Y is (CH₂)0-l(CR⁴R5)(CH₂)o-i; Z is O, S, S(0), S(0)₂, C(O), NR*2, CR12R13, ₀r CF or a bond;

Rl is hydrogen, or C_1-4 alkyl, (CH2)θ-lCN, C(0)Rl4, (CH2)θ-lCθ2Rl⁴, CF3, OR¹⁴, halogen, SR ⁴, S(0)Rl⁴ S(0)₂R¹⁴, NRl⁴R 5;

R2 IS

1) phenyl, unsubstituted or substituted with one or two substituents independently selected from R6 and R7,

2) a 6-membered heterocyclic unsaturated ring wherein 1 or 2 ring atoms selected from N, wherein the ring is unsubstituted or substituted with R6, or

3) a 5-membered heterocyclic unsaturated ring having 1 heteroatom selected from the group consisting of N, O, and S, 2 N atoms, 2 S atoms, or 2 heteroatoms comprising 1 N and 1 S atom, wherein the ring is unsubstituted or monosubstituted with C1.4 alkyl;

R3 i IS

1) phenyl, unsaturated ring system, unsubstituted, monosubstituted, disubstituted, or trisubstituted, same or different, with C1-8 alkyl, -(CH2)o-4C3_7 cycloalkyl, or CO2R²⁰, 2) a 6-membered heterocyclic saturated ring system wherein 1 or 2 ring atoms are independently selected from the group of heteroatoms consisting of N, O and S, wherein the ring is unsubstituted, monosubstituted, disubstituted, or trisubstituted, same or different, with C s alkyl,

3) a 5- or 6-membered heterocyclic unsaturated ring having i) 1 heteroatom selected from N, S and O, ii) 2 heteroatoms selected from 1 N atom and 1 S atom, 1 N atom and 1 O atom, 1 S atom and 1 O atom, 2 N atoms, and 2 S atoms, iii) 3 heteroatoms selected from 3 N atoms and 2 N atoms and 1 S atom, or iv) 4 N atoms, wherein the ring is unsubstituted, monosubstituted, or disubstituted, same or different, with Ci-8 alkyl, C3-7 cycloalkyl, -(CH2)θ-4C3-7 cycloalkyl, NH2, or (CH2)θ- 4Xl(CH₂)0-3CH3, wherein χ is a bond, S, S(0), S(0)2, O, or NH,

, where R ,⁹ i.s hydrogen or Cι_-8alkyl,

wherein R²¹ is H, C ₆ alkyl, or C₃.₇ cycloalkyl, or

or C3.7 cycloalkyl;

R²²

R⁴ and R5 are independently hydrogen or Cχ.4 alkyl; R6 and R8 are independently

1) halogen,

2) (C(R ⁶R¹⁷))ι_2NH2, where each Rⁱ⁶ and R¹⁷ can be the same or different; 3) a 5-membered heterocylcic unsaturated ring having 3 or 4 N atoms, wherein the ring is unsubstituted, monosubstituted, or disubstituted, same or different, with C\.% alkyl, C3-7 cycloalkyl, -(CH2)θ-4C3-7 cycloalkyl, NH2, or (CH2)θ-4X²(CH2)θ-3CH3, wherein X² is a bond, S, S(O), S(0)2, O, or NH

R⁷ is halogen; RlO, RU, Rl2, Rl3, R14, R15, R16, R17, R18, R19 _an R20 _are independently hydrogen or C1.4 alkyl, or a pharmaceutically acceptable salt thereof.

In a class of compounds of the invention, Rl is hydrogen, CH3, CN or Cl; R is hydrogen or CH3, R5 is hydrogen or CH3; X is -0-, -C(0)NH-, -C(0)0-, -CH2NH- or -CH2O-; Y is - CH2CH2-, -CH₂CH(CH3)-, or -CH2"; and Z is -NH-, -0-, or a bond.

In a subclass of this class of compounds, R² is selected from the group consisting of 1) a 5-membered unsaturated heterocyclic ring containing 2 N ring atoms, substituted with Cl-4 alkyb 2) a 6-membered unsaturated heterocyclic ring containing 1 or 2 N ring atoms unsubstituted or substituted with one or two substituents independently selected from R6, and 3) phenyl, unsubstituted or substituted with one or two substituents independently selected from δ.

In a group of this subclass of compounds, R is selected from the group consisting of

In a subgroup of this group, R3 is selected from the group consisting of

Examples of this family are listed below. Inhibitory activity, as measured by the in vitro assay described in the specification, where indicated, is represented by "*", indicating Ki greater than or equal to 20 nM, or "**", indicating Ki less than 20 nM.

-7-

10-

-12-

and pharmaceutically acceptable salts thereof.

A subset of examples of the invention includes

17-

-18-

and pharmaceutically acceptable salts thereof. Particular examples of this subset are

and pharmaceutically acceptable salts thereof. The compounds of the present invention may have chiral centers and occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention. The compounds of the present invention may also have polymorphic crystalline forms, with all polymorphic crystalline forms being included in the present invention. The compounds of the present invention also include tautomeric forms, with all tautomeric forms being included in the present invention.

When any variable occurs more than one time in any constituent or in formula I, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

Some abbreviations that may appear in this application are as follows.

ABBREVIATIONS

AcOH acetic acid

CHC1₃ chloroform

CH₂C1₂ dichloromethane

DCE 1 ,2-dichloroethane

DEAD diethylazodicarboxylate

DME 1,2 dimethoxyethane

DMF dimethylformamide dppf diphenylphosphinoferrocene

DTBMP 2,6-di-tert-butyl-4-methylpyridine

EDC l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride

Et₂0 diethyl ether

EtOAc ethyl acetate

EtOH ethanol

HCl hydrochloric acid

HOBT 1-hydroxybenzotriazole hydrate iPrPhsPI isopropyltriphenylphosphonium iodide

KHSO4 potassium hydrogen sulfate

KOH potassium hydroxide

LAH lithium aluminum hydroxide

LiOH lithium hydroxide

MeOH methanol

MgS0₄ magnesium sulfate NaBH, sodium borohydride

NaHC0₃ sodium hydrogen carbonate

NaN₃ sodium azide

Na₂C0₃ sodium carbonate

Na₂S0₄ sodium sulfate nBuLi n-butyllithium

NCS N-chlorosuccinimide

NH₄0H ammonium hydroxide

NMM N-methylmorpholine

Pd-C palladium on activated carbon catalyst

PG protecting group

PI1CH₃ toluene

Ph3P triphenylphosphine

TEA triethylamine Tf2θ trifluoromethane sulfonic anhydride

TFA trifluoroacetic acid THF tetrahydrofuran

TMSCN trimethylsilyl cyanide

As used herein except where noted, "alkyl" includes both branched- and straight- chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms (Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl); "substituted" alkyl groups refer to groups having one or more defined substituents. The term "alkenyl" includes both branched- and straight-chain unsaturated aliphatic hydrocarbon groups having the specified number of carbon atoms (e.g. ethenyl, propenyl, 1- butenyl, 2-butenyl); "substituted" alkenyl groups refer to groups having one or more defined substituents. "alkoxy" represents a linear or branched alkyl group of indicated number of carbon atoms attached through an oxygen bridge; "Halo", as used herein, means fluoro, chloro, bromo and iodo; and "counterion" is used to represent a small, single negatively-charged species, such as chloride, bromide, hydroxide, acetate, trifluoroacetate, perchlorate, nitrate, benzoate, maleate, sulfate, tartrate, hemitartrate, benzene sulfonate, and the like.

The term "C3-7cycloalkyl" is intended to include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and the like.

The term "C7-12 bicyclic alkyl" is intended to include bicyclo[2.2.1]heptyl

(norbornyl), bicyclo[2.2.2]octyl, l,l,3-trimethyl-bicyclo[2.2.1]heptyl (bornyl), and the like. The term "aryl" as used herein except where noted, represents a stable 6- to 10- membered mono- or bicyclic ring system such as phenyl, or naphthyl. The aryl ring can be unsubstituted or substituted with one or more of Cι_4 lower alkyl; hydroxy; alkoxy; halogen; amino.

The terms "heterocycle", "heterocyclic", and " heterocyclyl" as used herein except where noted, represent a stable 5- to 7-membered monocyclic- or stable 8- to 11-membered fused bicyclic or stable 11- to 15-membered tricyclic ring system, any ring of which may be saturated, such as piperidinyl, partially saturated, or unsaturated, such as pyridinyl, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. Bicyclic unsaturated ring systems include bicyclic ring systems which may be partially unsaturated or fully unsaturated. Partially unsaturated bicyclic ring systems include, for example, cyclopentenopyridinyl, benzodioxan, methylenedioxyphenyl groups. Especially useful are rings containing one oxygen or sulfur, one to four nitrogen atoms, or one oxygen or sulfur combined with one or two nitrogen atoms. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic groups include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, moφholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, tetrazole, thienyl, benzothienyl, thiamoφholinyl, thiamorpholinyl sulfoxide, thiamoφholinyl sulfone, and oxadiazolyl. Morpholino is the same as morpholinyl. Unless otherwise specified, "substituted" heterocycle, heterocyclic, and heterocyclyl rings refer to rings having one or more defined substituents

In this specification methyl substituents may be represented by

I - CH₃ or i — . _r For examp ,le, t .he structures

The term "pyridyl-N-oxide" refers to a moiety having the structure

The pharmaceutically-acceptable salts of the compounds of Formula I (in the form of water- or oil-soluble or dispersible products) include the conventional non-toxic salts such as those derived from inorganic acids, e.g. hydrochloric, hydrobromoic, sulfuric, sulfa ic, phosphoric, nitric and the like, or the quaternary ammonium salts which are formed, e.g., from inorganic or organic acids or bases. Examples of acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, pamoate, pectinate, persulfate, 3-phenylproρionate, picrate, pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, tosylate, and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth. Also, the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.

Thrombin Inhibitors - Therapeutic Uses- Method of Using

Anticoagulant therapy is indicated for the freatment and prevention of a variety of thrombotic conditions, particularly coronary artery and cerebrovascular disease. Those experienced in this field are readily aware of the circumstances requiring anticoagulant therapy. The term "patient" used herein is taken to mean mammals such as primates, including humans, sheep, horses, cattle, pigs, dogs, cats, rats, and mice.

Thrombin inhibition is useful not only in the anticoagulant therapy of individuals having thrombotic conditions, but is useful whenever inhibition of blood coagulation is required such as to prevent coagulation of stored whole blood and to prevent coagulation in other biological samples for testing or storage. Thus, the thrombin inhibitors can be added to or contacted with any medium containing or suspected of containing thrombin and in which it is desired that blood coagulation be inhibited, e.g., when contacting the mammal's blood with material selected from the group consisting of vascular grafts, stents, orthopedic prosthesis, cardiac prosthesis, and extracorporeal circulation systems.

Compounds of the invention are useful for treating or preventing venous thromboembolism (e.g. obstruction or occlusion of a vein by a detached thrombus; obstruction or occlusion of a lung artery by a detached thrombus), cardiogenic thromboembolism (e.g. obstruction or occlusion of the heart by a detached thrombus), arterial thrombosis (e.g. formation of a thrombus within an artery that may cause infarction of tissue supplied by the artery), atherosclerosis (e.g. arteriosclerosis characterized by irregularly distributed lipid deposits) in mammals, and for lowering the propensity of devices that come into contact with blood to clot blood. Examples of venous thromboembolism which may be treated or prevented with compounds of the invention include obstruction of a vein, obstruction of a lung artery (pulmonary embolism), deep vein thrombosis, thrombosis associated with cancer and cancer chemotherapy, thrombosis inherited with thrombophilic diseases such as Protein C deficiency, Protein S deficiency, antithrombin III deficiency, and Factor V Leiden, and thrombosis resulting from acquired thrombophilic disorders such as systemic lupus erythematosus (inflammatory connective tissue disease). Also with regard to venous thromboembolism, compounds ofthe invention are useful for maintaining patency of indwelling catheters.

Examples of cardiogenic thromboembolism which may be treated or prevented with compounds of the invention include thromboembolic stroke (detached thrombus causing neurological affliction related to impaired cerebral blood supply), cardiogenic thromboembolism associated with atrial fibrillation (rapid, irregular twitching of upper heart chamber muscular fibrils), cardiogenic thromboembolism associated with prosthetic heart valves such as mechanical heart valves, and cardiogenic thromboembolism associated with heart disease.

Examples of arterial thrombosis include unstable angina (severe constrictive pain in chest of coronary origin), myocardial infarction (heart muscle cell death resulting from insufficient blood supply), ischemic heart disease (local anemia due to obstruction (such as by arterial narrowing) of blood supply), reocclusion during or after percutaneous transluminal coronary angioplasty, restenosis after percutaneous transluminal coronary angioplasty, occlusion of coronary artery bypass grafts, and occlusive cerebrovascular disease. Also with regard to arterial thrombosis, compounds of the invention are useful for maintaining patency in arteriovenous cannulas.

Examples of atherosclerosis include arteriosclerosis.

Examples of devices that come into contact with blood include vascular grafts, stents, orthopedic prosthesis, cardiac prosthesis, and extracorporeal circulation systems

The thrombin inhibitors of the invention can be administered in such oral forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixers, tinctures, suspensions, syrups, and emulsions. Likewise, they may be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non- toxic amount of the compound desired can be employed as an anti-aggregation agent. For treating ocular build up of fibrin, the compounds may be administered intraocularly or topically as well as orally or parenterally.

The thrombin inhibitors can be administered in the form of a depot injection or implant preparation which may be formulated in such a manner as to permit a sustained release of the active ingredient. The active ingredient can be compressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as depot injections or implants. Implants may employ inert materials such as biodegradable polymers or synthetic silicones, for example, Silastic, silicone rubber or other polymers manufactured by the Dow-Corning Coφoration.

The thrombin inhibitors can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

The thrombin inhibitors may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The thrombin inhibitors may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinlypyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the thrombin inhibitors may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross linked or amphipathic block copolymers of hydrogels.

The dosage regimen utilizing the thrombin inhibitors is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.

Oral dosages of the thrombin inhibitors, when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 30 mg/kg/day, preferably 0.025-7.5 mg/kg/day, more preferably 0.1-2.5 mg/kg/day, and most preferably 0.1-0.5 mg/kg/day (unless specificed otherwise, amounts of active ingredients are on free base basis). For example, an 80 kg patient would receive between about 0.8 mg/day and 2.4 g/day, preferably 2-600 mg day, more preferably 8-200 mg/day, and most preferably 8-40 mg/kg/day. A suitably prepared medicament for once a day administration would thus contain between 0.8 mg and 2.4 g, preferably between 2 mg and 600 mg, more preferably between 8 mg and 200 mg, and most preferably 8 mg and 40 mg, e.g., 8 mg, 10 mg, 20 mg and 40 mg. Advantageously, the thrombin inhibitors may be administered in divided doses of two, three, or four times daily. For administration twice a day, a suitably prepared medicament would contain between 0.4 mg and 4 g, preferably between 1 mg and 300 mg, more preferably between 4 mg and 100 mg, and most preferably 4 mg and 20 mg, e.g., 4 mg, 5 mg, 10 mg and 20 mg.

Intravenously, the patient would receive the active ingredient in quantities sufficient to deliver between 0.025-7.5 mg/kg/day, preferably 0.1-2.5 mg/kg/day, and more preferably 0.1-0.5 mg/kg/day. Such quantities may be administered in a number of suitable ways, e.g. large volumes of low concentrations of active ingredient during one extended period of time or several times a day, low volumes of high concentrations of active ingredient during a short period of time, e.g. once a day.

Typically, a conventional intravenous formulation may be prepared which contains a concentration of active ingredient of between about 0.01-1.0 mg/ml, e.g. 0.1 mg/ml, 0.3 mg/ml, and 0.6 mg/ml, and administered in amounts per day of between 0.01 ml/kg patient weight and 10.0 ml/kg patient weight, e.g. 0.1 ml/kg, 0.2 ml/kg, 0.5 ml/kg. In one example, an 80 kg patient, receiving 8 ml twice a day of an intravenous formulation having a concentration of active ingredient of 0.5 mg/ml, receives 8 mg of active ingredient per day. Glucuronic acid, L-lactic acid, acetic acid, citric acid or any pharmaceutically acceptable acid/conjugate base with reasonable buffering capacity in the pH range acceptable for intravenous administration may be used as buffers. Consideration should be given to the solubility of the drug in choosing an The choice of appropriate buffer and pH of a formulation, depending on solubility of the drug to be administered, is readily made by a person having ordinary skill in the art.

The compounds can also be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, or course, be continuous rather than intermittent throughout the dosage regime.

The thrombin inhibitors are typically administered as active ingredients in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier" materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixers, syrups and the like, and consistent with convention pharmaceutical practices. For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, distintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn-sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch methyl cellulose, agar, bentonite, xanthan gum and the like.

The invention also includes a method for treating an inflammatory disease in a patient which comprises treating the patient with a composition comprising a compound of the present invention. Such diseases include but are not limited to nephritis, systemic lupus erythematosus, rheumatoid arthritis, glomerulonephritis, and sacoidosis.

The invention is also a method for treating an inflammatory disease in a patient that comprises treating the patient with a combination comprising a compound of the invention and an NSAID, e.g., a COX-2 inhibitor. Such diseases include but are not limited to nephritis, systemic lupus, erythematosus, rheumatoid arthritis, glomerulonephritis, vasculitis and sacoidosis.

The present invention is a method for relieving pain, fever and inflammation of a variety of conditions including nephritis, systemic lupus erythematosus, rheumatoid arthritis, glomerulonephritis, sacoidosis, rheumatic fever, symptoms associated with influenza or other viral infections, common cold, low back and neck pain, dysmenorrhea, headache, toothache, sprains and strains, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, bursitis, burns, injuries, following surgical and dental procedures in a patient by administering to the patient a therapeutically effective amount of a compound of the invention. Thrombin inhibitors may also be useful for the treatment of dementia including pre-senile and senile dementia, and in particular, dementia associated with Alzheimer Disease.

In inflammatory diseases wherein fibrin formation is prominent, the fibrin may be a determinant of the pathology. Fibrin serves as a matrix onto which inflammatory cells can migrate and adhere, (see Sherman et al., 1977 J. Exp. Med. 145:76-85; Altieri et al., 1986 J. Clin. Invest. 78:968- 976; Wright et al., 1983 Proc. Natl. Acad. Sci, 85:7734-7738; Altieri et al., 1993 J. Biol. Chem. 268;1847-1853). Fibrin also enhances expression of the inflammatory cytokine IL-lbeta and decreases expression of IL-1 receptor antagonist by human peripheral blood mononuclear cells (see Perez 1995 J. Immunol. 154: 1879-1887). The anticoagulants warfarin and heparin attenuate delayed-type hypersensitivity reactions and experimental nephritis in animals, (see Jasain et al., Immunopathogenesis of Rheumatoid Arthritis Eds. G.S. Panayi et al., Surrey, UK, Reedbooks, Ltd. and Halpern et al., 1965 Nature 205:257-259). Enzymatic defibrination with ancrod diminishes the degree of experimental nephritis (Naish et al., 1972 Clin. Sci. 42:643-646) , systemic lupus erythematosus (Cole et al., 1990 Kidney Int. 37:29-35, and rheumatoid arthritis (see Busso et al., 1998 J. Clin. Invest. 102:41-50) in animals, and glomerulonephritis in man (see Kim et al., 1988 Q. J. Med. 69:879-905). Additionally, infra articular injection of fibrin induces arthritis in rabbits immunized with fibrin Dumonde et al., 1961 British Journal of Experimental Pathology XLIII:373-383), and antigen-induced arthritis in mice is exacerbated in urokinase-deficient mice wherein fibrinolysis synovial fibrin is compromised (see Busso et al., 1998 J. Clin. Invest. 102:41-50).

In diseases where fibrin deposition is prominent such as, but not limited to, rheumatoid arthritis, systemic lupus erythematosus, glomerulonephritis, vasculitis and sacoidosis, lowering the steady state concentration of fibrin by administration of a compound of the invention will, according to the instant invention, diminish the pathological inflammatory responses associated with these diseases.

Similarly, compounds of the invention will be useful as a partial or complete substitute for conventional NSAIDs in preparations wherein they are presently co-administered with other agents or ingredients. Thus in further aspects, the invention encompasses pharmaceutical compositions for treating inflammatory diseases as defined above comprising a non-toxic therapeutically effective amount of a compound of the invention as defined above and one or more ingredients such as another pain reliever including acetaminophen or phenacetin; a potentiator including caffeine; an H2-antagonist, aluminum or magnesium hydroxide, simethicone, a decongestant including phenylephrine, phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxyephedrine; an antiitussive including codeine, hydrocodone, caramiphen, carbetapentane, or dextramethoφhan; a diuretic; a sedating or non- sedating antihistamine. In addition the invention encompasses a method of treating inflammatory diseases comprising administration to a patient in need of such treatment a non-toxic therapeutically effect amount of a compound of the invention, optionally co-administered with one or more of such ingredients as listed immediately above.

The instant invention also involves a novel combination therapy comprising the administration of a therapeutically effective amount of an NSAID such as a COX-2 inhibitor in combination with a therapeutically effective amount of a compound of the invention to a mammal, and more particularly, to a human. The combination therapy is used to treat inflammatory diseases.

The instant pharmaceutical combinations comprising a compound of the invention in combination with an NSAID such as a COX-2 inhibitor include administration of a single pharmaceutical dosage formulation which contains both a compound of the invention and the NSAID, as well as administration of each active agent in its own separate pharmaceutical dosage formulation. Where separate dosage formulations are used, the compund of the invention and the NSAID can be administered at essentially the same time, i.e., concurrently, or at separately staggered times, i.e, sequentially. The "instant pharmaceutical combination" is understood to include all these regimens. Administration in these various ways are suitable for the present invention as long as the beneficial pharmaceutical effect of the compound of the invention and the NSAID are realized by the patient at substantially the same time. Such beneficial effect is preferably achieved when the target blood level concentrations of each active drug are maintained at substantially the same time. It is preferred that the compound of the invention and the NSAID be co-administered concurrently on a once-a-day dosing schedule; however, varying dosing schedules, such as the compound of the invention once per day and the NSAID once, twice or more times per day, or the NSAID once per day and the compound of the invention once, twice or more times per day, is also encompassed herein. A single oral dosage formulation comprised of both the compound of the invention and the NSAID is preferred. A single dosage formulation will provide convenience for the patient. The instant invention also provides pharmaceutical compositions comprised of a therapeutically effective amount of an NSAID, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. One embodiment ofthe instant compositions is a single composition adapted for oral administration comprised of a therapeutically effective amount of a COX-2 inhibitor in combination with a therapeutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. The combination can also be administered in separate dosage forms, each having one of the active agents. If administered in separate dosage forms, the separate dosage forms are administered such that the beneficial effect of each active agent is realized by the patient at substantially the same time. Common NSAIDs include salicylates such as aspirin, sodium salicylate, choline salicylate, salicylsalicylic acid, diflunisal, and salsalate; indoleacetic acids such as indomethacin and sulindac; pyrazoles such as phenylbutazone, oxyphenbutazone; pyrrolealkanoic acids such as tolmetin; phenylacetic acids such as ibuprofen, feroprofen, flurbiprofen, and ketoprofen; fenamates such as mefanamic acid, and meclofenamate; oxicams such as piroxicam; and naphthaleneacetic acids such as naproxen. Cyclo-oxygenase inhibitors such as COX-1 and COX-2 inhibitors are also NSAIDs. Employing the human whole blood COX-1 assay and the human whole blood COX-2 assay described in C. Brideau et al, Inflamm. Res. 45: 68-74 (1996), herein incoφorated by reference, preferably, the compounds have a cyclooxygenase-2 IC50 of less than about 2 μM in the human whole blood COX-2 assay, yet have a cyclooxygenase-1 IC50 of greater than about 5 μM in the human whole blood COX-1 assay. Also preferably, the compounds have a selectivity ratio of cyclooxygenase-2 inhibition over cyclooxygenase-1 inhibition of at least 10, and more preferably of at least 40. The resulting selectivity may indicate an ability to reduce the incidence of common NS AID-induced side effects.

The inhibitor of cyclooxygenase-2 may be administered at a dosage level up to conventional dosage levels for NSAIDs. Suitable dosage levels will depend upon the antiinflammatory effect of the chosen inhibitor of cyclooxygenase-2, but typically suitable levels will be about 0.001 to 50 mg/kg per day, preferably 0.005 to 30mg/kg per day, and especially 0.05 to lOmg/kg per day. The compound may be administered on a regimen of up to 6 times per day, preferably 1 to 4 times per day, and especially once per day. The dosage regimen utilizing a compound of the invention in combination with the

NSAID is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition ofthe patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt or ester thereof employed. Since two different active agents are being used together in a combination therapy, the potency of each of the agents and the interactive effects achieved by combining them together must also be taken into account. A consideration of these factors is well within the purview of the ordinarily skilled clinician for the puφose of determining the therapeutically effective or prophylactically effective dosage amounts needed to prevent, counter, or arrest the progress of the condition. Administration of the drug combination to the patient includes both self- administration and administration to the patient by another person.

Additional active agents may be used in combination with the compound of the invention in a single dosage formulation, or may be administered to the patient in a separate dosage formulation, which allows for concurrent or sequential administration. Examples of additional active agents which may be employed include HMG-CoA synthase inhibitors; squalene epoxidase inhibitors; squalene synthetase inhibitors (also known as squalene synthase inhibitors), acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitors; probucol; niacin; fibrates such as clofibrate, fenofibrate, and gemfibrizol; cholesterol absorption inhibitors; bile acid sequestrants; LDL (low density lipoprotein) receptor inducers; vitamin Bό (also known as pyridoxine) and the pharmaceutically acceptable salts thereof such as the HCl salt; vitamin B 12 (also known as cyanocobalamin); β-adrenergic receptor blockers; folic acid or a pharmaceutically acceptable salt or ester thereof such as the sodium salt and the methylglucamine salt; and anti-oxidant vitamins such as vitamin C and E and beta carotene.

The thrombin inhibitors can also be co-administered with suitable anti-platelet agents, including, but not limited to, fibrinogen receptor antagonists (e.g. to treat or prevent unstable angina or to prevent reocclusion after angioplasty and restenosis), anticoagulants such as aspirin, thrombolytic agents such as plasminogen activators or streptokinase to achieve synergistic effects in the treatment of various vascular pathologies, or lipid lowering agents including antihypercholesterolemics (e.g. HMG CoA reductase inhibitors such as lovastatin and simvastatin, HMG CoA synthase inhibitors, etc.) to treat or prevent atherosclerosis. For example, patients suffering from coronary artery disease, and patients subjected to angioplasty procedures, would benefit from coadministration of fibrinogen receptor antagonists and thrombin inhibitors. Also, thrombin inhibitors enhance the efficiency of tissue plasminogen activator-mediated thrombolytic reperfusion. Thrombin inhibitors may be administered first following thrombus formation, and tissue plasminogen activator or other plasminogen activator is administered thereafter. Typical doses of thrombin inhibitors of the invention in combination with other suitable anti-platelet agents, anticoagulation agents, or thrombolytic agents may be the same as those doses of thrombin inhibitors administered without coadministration of additional anti-platelet agents, anticoagulation agents, or thrombolytic agents, or may be substantially less that those doses of thrombin inhibitors administered without coadministration of additional anti-platelet agents, anticoagulation agents, or thrombolytic agents, depending on a patient's therapeutic needs.

The following examples and methods are illustrative of the invention as contemplated by the inventors and should not be construed as being limits on the scope or spirit of the instant invention. Unless otherwise stated, all NMR determinations were made using 400 MHz field strength. The following schemes and examples are illustrative of the invention as contemplated by the inventors and should not be construed as being limits on the scope or spirit of the instant invention. In the schems, the protecting group "PG" can be, for example, benzyl, trialkylsilyl, or acetyl or other suitable protecting group useful for protecting the relevant portion of the molecule from the indicated reaction step.

The most convergent route to this class of compounds is a metal mediated coupling reaction between two suitably functionalized and where necessary, protected components. For example, in General Scheme 1, the key step is the palladium mediated Suzuki coupling reaction of an aryl borate ester or boronic acid with an aryl or heteroaryl halide or triflate. In General Scheme 2, the roles of the two coupling fragments have been reversed. While the Suzuki reaction was used exclusively, it should be understood that any metal mediated coupling reaction which effects a similar single bond construction from appropriately functionalized components (e.g., Stille, Negishi, Buchwald reactions) could be employed where possible based upon availability of the required components.

In both these schemes, the ether linkage is installed late in the sequence via either a Mitsunobu reaction or a simple alkylation. It is understood that where appropriate, this step may be performed prior to the organometallic coupling step.

General Scheme 3 is typically employed when an amide or ester linkage to the central ring is preferable to an ether.

As shown in General Scheme 4, in cases where a lack of availability or reactivity of a suitable coupling partner precludes a direct two component coupling approach, the second aryl or heteroaryl ring of the biaryl moiety may be elaorated from suitably attached functional groups residing on one of the fragments.

Unless otherwise indicated, all variables in the schemes correspond with the variables defined in the general formula.

General scheme 1

(Mitsunobu reaction)

S1-3 (alkylation)

R' is Ci-8 alkyl, -(CH2)θ-4C3-7 cycloalkyl, or COOR20, _an(j _S serving as part of a protecting group, is, for example, Cj.4 alkyl or benzyl. General scheme 2

reaction)

S1-3 PG removal

R' is Ci-8 alkyl, -(CH2)θ-4C3-7 cycloalkyl, or COOR20, and R, serving as part of a protecting group, is, for example, Ci .4 alkyl or benzyl.

General scheme 3

(Rθ)₂B— B(OR)₂ Suzuki coupling Suzuki coupling

B(OR)₂ Hydrolysis

Suzuki coupling

R'is Cι_8 alkyl, -(CH2)θ-4C3-7 cycloalkyl, or COOR20, and R, serving as part of a protecting group, is, for example, Cι_4 alkyl or benzyl. Y is O or NH, and Y' is OH or NH2-

General scheme 4

construct heterocycle

1. HO. 2. RO„

'ZFf or ^*ZR*

Mitsunobu reaction T alkylation

R' is Ci_8 alkyl, -(CH2)θ-4C3-7 cycloalkyl, or COOR20, and the ring containing W,

X, Y and Z corresponds with the 5-membered ring defined in the general formula for R^. R, serving as part of a protecting group, is, for example, C1..4 alkyl or benzyl. Q is hydrogen or Cχ.4 alkyl. Specific scheme 1

Specific scheme 2

Specific scheme 3

EXAMPLE I

Preparation of 5-[2-(2'-Isobutyl-5-methylbiphenyI-3-yloxy)-ethyl]-4-methyl-lH-imidazole

Step A: 3-Benzyloxy-5-methylphenol

Benzyl bromide (24 mL, 200 mmol) was added to a well stirred mixture of orcinol

(25 g, 200 mmol), cesium carbonate (66 g, 200 mmol), and tetrabutylammonium iodide (4 g, 10 mmol) in DMF (400 mL). After stirring for 4 h, the reaction mixture was poured onto ice. 6 M HCl (100 mL) was added and the resulting mixture extracted with several portions of ether. The combined organic extracts were washed three times with ice cold water and dried over sodium sulfate. Filtration and concentration gave an orange oil which was purified by chromatography (9:1 - 5:1 - 4:1 hexane / EtOAc). Upon prolonged pumping in vacuo, the resulting pale orange oil crystallized as a waxy peach colored solid. Step B: 3-Benzyloχy-5-methylphenyl trifluoromethanesulfonate

Trifluoromethanesulfonic anhydride (2.6 mL, 15.5 mmol) was added slowly to a solution of 3-benzyloxy-5-methylphenol (2.6 g, 12 mmol) and 2,6-di-tert-butyl-4-methylpγridine (3.2 g, 15.6 mmol) in dichloromethane (100 mL) at -30°C. The reaction mixture was allowed to warm gradually to room temperature. It was diluted with a threefold excess of pentane. The precipitated solids were removed via filtration and the filtrate concentrated almost to dryness. Ether was added and the mixture filtered once more. The filtrate was concentrated once more and then dissolved in 19:1 hexane / ether. This solution was allowed to percolate through a small plug of silica gel which was then washed well with additional quantities of the same solvent system. Concentration of the filtrate in vacuo yielded the pure triflate as a pale yellow oil. Step C: 3'-Benzyloxy-5'-methylbiphenyl-2-carbaldehvde

A solution of 3-benzyloxy-5-methylρhenyl trifluoromethanesulfonate (2 g, 5.8 mmol), 2-formylphenylboronic acid (1.3 g, 8.7 mmol), tetrakistriphenylphosphine-palladium (0) (0.5 g, 0.32 mmol) and potassium carbonate (2 g, 14.5 mmol) in a mixture of acetone (10 mL) and water (5 mL) was heated at 100°C for exactly 2 h. The reaction mixture was cooled to room temperature and the acetone removed under reduced pressure. The residue was extracted with ethyl acetate and dried over sodium sulfate. Filtration and concentration gave a brown oil which was purified by chromatography (19:1 hexane / ether) to give the biphenyl aldehyde as a viscous yellow oil. Step D: l-(3'-Benzyloxy-5'-methylbiphenyl-2-ylV2-methylpropan-l-ol

Isopropylmagnesium chloride (2M in ether, 1,5 mL, 3 mmol) was added to a solution of 3'-benzyloxy-5'-methyIbiphenyl-2-carbaldehyde (357 mg, 1.2 mmol) in ether (5 mL) at 0°C. The reaction mixture was allowed to warm gradually to room temperature over 4 h following which time it was quenched with aqueous ammonium chloride. The reaction mixture was then extracted with ethyl acetate and the combined extracts washed with brine and dried over sodium sulfate. Filtration and concentration gave a residue which was a 1:1 mixture of the title compound and 3'-benzyloxy-5'- methylbiphenyl-2-methanol. The mixture was separated by flash chromatography eluting with 19:1 - 9:1 - 5:1 - 4:1 hexane / ethyl acetate. The title compound eluted first (colorless oil) followed by the biproduct.

Step E: 2'-Isobutyl-5-methylbiphenyl-3-ol

A solution of l-(3'-benzyloxy-5'-methylbiphenyl-2-yl)-2-methylpropan-l-ol (168 mg, 0.48 mmol) in methanol (6 mL) containing 10% Pd C (100 mg) was stirred at room temperature under an atmosphere of hydrogen overnight. The catalyst was removed via filtration through Celite. Concentration of the filtrate gave the title compound as a colorless oil.

Step F: (5-Methyl-3-trityl-3_ft-imidazol-4-yl)acetonitrile and (5-methyl-l-trityl-l-tf-imidazol-

4-yl^')acetonitrile

A solution of Tosmic (8.4 g, 44 mmol) in DME (40 mL) was added to a-50°C suspension of KOtBu (9.2 g, 80 mmol) in DME (40 mL) to give a wine red solution. A suspension of trityl 4-methylimidazole-5-carboxaldehydr (1:1 mixture) (14 g, 40 mmol) in DME (80 mL) was added in portions (with a final 20 mL wash). The reaction mixture remained homogenous and wine red in color. The reaction mixture was allowed to warm gradually until a precipitate formed at -20°C (about 1.5 h). Methanol (80 mL) was then added and the cold bath removed. The red solution was heated at reflux for 20 min. After cooling to room temperature the solvents were rotavapped off then water and a few mLs of acetic acid were added. A white ppt formed. The mixture was extracted three times with dichloromethane and the extracts then washed neutral with aqueous NaHC0₃ to which had been added some NaαC0₃. Drying (Na₂S0₄) and concentration gave a yellow oil which was purified by chromatography (1:1 — 1:2 — 1:4 hexane / EtOAc). Yield 1 : 1 mixture of isomers. Step G: Methyl (5-methyl-3-trityl-3H-imidazol-4-yl')acetate and methyl (5-methyl-l-trityl-lH- imidazol-4-vDacetate

6M HCl (50 mL) was added to a solution of the nitrile (9 g, 25 mmol) in dioxane (50 mL) and the resulting mixture heated at 100°C for 24 h. The reaction mixture was then stripped to dryness. The residue was triturated with ether, then EtOAc, then chloroform to give the imidazole acid as a mustard colored solid (4.8 g). This solid was suspended in dichloromethane (100 mL). Triethylamine (17 mL, 120 mmol) and trityl chloride (8.4 mg, 30 mmol) were then added and the reaction mixture stirred for 3 h. The suspension was poured into a 1:1 mixture of ether and EtOAc containing some methylene chloride. The mixture was washed 2x with 1M citric acid and once with brine. Drying (Na₂S0 ) and concentration gave an orange sponge (9 g). This material was dissolved in 3:1 methylene chloride / methanol (200 mL) and titrated with a slight excess of trimethylsilyldiazomethane (2M solution in hexanes). The reaction mixture was stripped and the trityl ester was purified by chromatography (98:2 chloroform / methanol), providing an orange oil. Step H: 2-(5-Methyl-3-trityl-3ff-imidazoI-4-vnethanol and 2-(5-methyl-l-trityl-lff-imidazol-

4-vf)ethanol

A solution of the ester (4.6 g, 1.6 mmol) in ether (100 mL) and THF (20 mL) was treated with 1M LAH in ether (12 mL) at -15°C. The reaction mixture was allowed to warm gradually to 0°C following which it was quenched sequentially with EtOAc (10 mL), water (0.5 mL), 15% NaOH (0.5 mL), and water (1.5 mL). The solids were filtered off and the filtrate concentrated. The residue was purified by chromatography (19:1 chloroform / methanol) to give the alcohol as a white foam. Step I: 2-(5-Methyl-3-trityl-3/_t-imidazol-4-yl ethyl methanesulfonate and 2-(5-methyl-l- trityl- l /-imidazol-4-yl^')ethyl methanesulfonate

A solution of the alcohol (255 mg, 0.66 mmol) in methylene phloride (10 mL) at 0°C was treated with triethylamine (0.16 mL, 1.15 mmol) and mesyl anhydride (160 mg, 0.92 mmol). The reaction mixture was allowed to warm gradually to room temperature and stirred there for 2 h. The reaction mixture was diluted with an excess of EtOAc and washed with aq NaHC0₃. Drying and concentration gave the mesylate as a foam.

Step J: 5-r2-(2'-Isobutyl-5-methyl-biphenyl-3-yloxy)-ethvn-4-methyl-lfl^r-imidazole

A mixture of 2-(5-methyl-3-trityl-3_fϊ-imidazol-4-yl)ethyl methanesulfon-ate and 2-(5- methyl-l-trityl-l /-imidazol-4-yl)ethyl methanesulfonate (257 mg, 0.58 mmol), 2'-isobutyl-5- methylbiρhenyl-3-ol (117 mg, 0.49 mmol) and cesium carbonate (360 mg, 1.10 mmol) in DMF (2 mL) was heated at 80°C overnight. The reaction mixture was cooled, diluted with water and extracted repeatedly with ether. The combined extracts were washed well with ice cold water and then dried over sodium sulfate. The solvents were removed in vacuo and the residue dissolved in methylene chloride (2 mL). TFA (2 mL) was added followed by triethylsilane (until the yellow color was discharged) and the resulting mixture stirred overnight. The solvent were removed and the residue partitioned between ethyl acetate and 10% aqueous sodium carbonate. The organic phase was dried over sodium sulfate and then concentrated. The residue was purified by flash chromatography eluting with 19:1 chloroform / methanol. Η NMR (CDC1₃) δ 7.45 (s, IH), 7.10-7.27 (m, 4H), 6.69 (s, 2H), 6.62 (s, IH), 4.16 (t, 2H, 6.3 Hz), 3.00 (t, 2H, 6.3 Hz), 2.45 (d, 2H, 7.3 Hz), 2.33 (s, 3H), 2.21 (s, 3H), 1.69 (m, IH), 0.73 (d, 6H, 6.6 Hz); Mass Spec (M+l) 349.6. EXAMPLE II

Preparation of 5-[2-(2'-Isopropyl-5-methylbiphenyl-3-yloxy)-l-methyl-ethyl]-pyridin-4-yl-amine

Step A: 2-(2-Isopropylphenyl)-4,4.5,5-tetramethyl-π,3,21dioxaborolane

A solution of 2-isopropylphenyl iodide (4 g, 16 mmol), bis(pinacolato)-diboron (5 g, 20 mmol), potassium acetate (4.7 g, 48 mmol), and (diρhenylphosρhino-ferrocene)palladium dichloride (0.35 g, 0.48 mmol)in DMF (80 mL) was heated at 80°C for 24 h. The reaction mixture was cooled to room temperature and the solvent removed under reduced pressure. The residue was purified by flash chromatography (19:1 hexane / ether) to give the title compound as an almost colorless, highly crystalline solid.

Step B: 3-Benzyloxy-2'-isopropyl-5-methylbiphenyl

A solution of 2-(2-isopropylphenyl)-4,4,5,5-tetramethyl-[l,3,2]-dioxaborolane (0.43 g, 1.75 mmol), 3-benzyloxy-5-methylphenyl trifluoromethane-sulfonate (0.6 g, 1.75 mmol), 2M aqueous sodium carbonate (4.4 mL), and (diphenylphosphinoferrocene)palladium dichloride (80 m g, 0.1 mmol) in DMF (9 mL) was heated at 80°C overnight. The reaction mixture was cooled to room temperature and the solvents removed under reduced pressure. The residue was partitioned between ethyl acetate and water and the organic layer removed and dried (Na₂S0₄). The solvent was removed and the residue purified by flash chromatography to give the title compound as a colorless oil. Step C: 2'-Isoρropyl-5-methylbiphenyl-3-ol

A solution of 3-benzyloxy-2'-isopropyl-5-methylbiphenyl (742 mg) in 1:1 ethyl acetate / ethanol (40 mL) containing 10% Pd/C (500 mg) was stirred at room temperature under an atmosphere of hydrogen overnight. The catalyst was removed via filtration through Celite. Concentration of the filtrate gave the title compound as a colorless oil.

Step D: -r2-(2'-Isopropyl-5-methylbiphenyl-3-yloxyVl-methyl-ethvn-ρyridin-4-yl-amine

Diethyl azodicarboxylate (0.21 mL, 1.3 mmol) was added in a dropwise manner to a mixture of 2'-isopropyl-5-methylbiphenyl-3-ol (270 mg, 1.2 mmol), _S-2-(pyridin-4-ylamino)propan-l- ol (WO 00/20394)(200 mg, 1.3 mmol) and triphenylphosphine (345 mg, 1.3 mmol) in toluene (5 mL). The urea biproduct was removed via filtration. Concentration gave a residue which was purified by flash chromatography eluting with 19:1 - 9:1 chloroform / 10% NH₄OH in MeOH. The product was further purified by HPLC and isolated as the TFA salt. Η NMR (CD₃OD) δ 8.46 (br d, IH, 7.8 Hz), 8.09 (d, 3H, 7.2 Hz), 7.96 (d, IH, 7.2 Hz), 7.34 (m, IH), 7.28 (m, IH), 7.14 (m, IH), 7.06 (m, IH), 6.86 (m, IH), 6.73 (s, IH), 6.66 (s, IH), 6.55 (s, IH), 4.26 (br m, IH), 4.15 (m, IH), 3.99 (m, IH), 2.97 (m, IH), 2.33 (s, 3H), 1.38 (d, 3H, 6.6 Hz), 1.11 (dd, 6H, 3.2, 6.8 Hz); Mass Spec (M+l) 361.8.

EXAMPLE III Preparation of 1 - { 2- [2-(2'-Isopropyl-5-methyl-biphenyl-3-yloxy)-ethyl]-phenyl } - 1 H-tetrazole

Step A: 2-(2-Nitrophenyl ethyl acetate

Acetic anhydride (4 mL, 42 mmol) was added at 0°C to a solution of 2- nitrophenethanol (5 mL, 36 mmol) and pyridine (3.5 mL, 43 mmol) in dichloromethane (100 mL). The reaction mixture was allowed to warm gradually to room temperature overnight. The reaction mixture was diluted with ether and washed with 1M HCl. Drying over sodium sulfate and concentration gave a peach colored oil.

Step B: 2-(2-Aminophenyl^')ethyl acetate The sample of 2-(2-nitrophenyl)ethyl acetate from the previous step was hydrogenated at 50 psi in EtOAc (250 mL) in the presence of 10% Pd/C to give a pink oil. Step C: 2-(2-Tetrazol-l-ylphenvDethyl acetate

A mixture of the 2-(2-aminoρhenyl)ethyl acetate from the previous step, sodium azide (3.6 g, 55 mmol), and triethyl orthoformate (9.2 mL, 55 mmol) in glacial acetic acid (200 mL) was heated at 120°C overnight. The reaction mixture was then allowed to cool and poured onto ice. The pH was raised to 7 by addition of 50% NaOH. The mixture was then extracted with EtOAc and the extracts washed with brine and then saturated NaHC0₃. Drying (Na2S04) and concentration yielded a brown oil which was purified by flash chromatography (3:2 - 1:1 - 2:3 hexane / EtOAc) to give the title compound as a yellow oil.

Step D: 2-(2-Tetrazol- l-ylphenvDethanol

A mixture of the 2-(2-tetrazol-l-ylρhenyl)ethyl acetate from the previous step , methanol (15 mL) and 15% NaOH (5 mL) was stirred at room temperature for 1.5 h. The methanol was removed under reduced pressure and the residue diluted with water. The product was extracted with methylene chloride and dried (Na2S04). Concentration and chromatography (19: 1 chloroform / methanol) gave the product as a colorless oil. Step E: l-{2-[2-(2'-Isopropyl-5-methyl-biphenyl-3-yloxy^')-ethyll-phenyl)-lH-tetrazole

The title compound was prepared essentially according to the Mitsunobu protocol for Example II, Step D using 2-(2-tetrazol-l-ylphenyl)ethanol and 2'-isopropyl-5-methylbiphenyl-3-ol as the coupling partners. Η NMR (CDC1₃) 6 8.96 (s, IH), 7.10-7.59 (m, 8H), 6.69 (s, IH), 6.61 (s, IH), 6.54 (s, IH), 4.15 (m, 2H), 3.01 (m, IH), 2.92 (m, 2H), 2.34 (s, 3H), 1.14 (d, 6H, 7.1 Hz); Mass Spec (M+l) 399.2.

EXAMPLE IV Preparation of 5-[2-(2'-Isopropyl-5-methylbiphenyl-3-yloxy)-ethyl]-4-methyl-liϊ-imidazole

The title compound was prepared essentially according to the Mitsunobu protocol for Example II, Step D using 2'-isopropyl-5-methylbiρhenyl-3-ol and a mixture of 2-(5-methyl-3-trityl-3H- imidazol-4-yl)ethanol and 2-(5-methyl-l-trityl-lr7-imidazol-4-yl)ethanolas the coupling partners. The trityl group was then removed essentially according to the procedure for Example I, Step J. The product was purified by HPLC and isolated as the TFA salt. *H NMR (CD₃OD) δ 8.69 (s, IH), 7.37 (m, IH), 7.31 (m, IH), 7.17 (m, IH), 7.09 (m, IH), 6.75 (s, IH), 6.68 (s, IH), 6.59 (s, IH), 4.22 (t, 2H, 5.9 Hz), 3.16 (t, 2H, 5.9 Hz), 3.02 (m, IH), 2.35 (s, 3H), 2.34 (s, 3H), 1.14 (d, 6H, 7.1 Hz); Mass Spec (M+l) 335.2.

EXAMPLE V Preparation of 5-[2-(2'-Isobutyl-5-methyl-biphenyl-3-yloxy)-ethyl)-4-methyl-lH-imidazole Step A: 3-Benzyloxy-5-methylphenol

Benzyl bromide (24 mL, 200 mmol) was added to a well stirred mixture of orcinol (25 g, 200 mmol), cesium carbonate (66 g, 200 mmol), and tetrabutylammonium iodide (4 g, 10 mmol) in DMF (400 mL). After stirring for 4 h, the reaction mixture was poured onto ice. 6 M HCl (100 mL) was added and the resulting mixture extracted with several portions of ether. The combined organic extracts were washed three times with ice cold water and dried over sodium sulfate. Filtration and concentration gave an orange oil which was purified by chromatography (9:1 - 5:1 - 4:1 hexane / EtOAc). Upon prolonged pumping in vacuo, the resulting pale orange oil crystallized as a waxy peach colored solid. Step B: 3-Benzyloxy-5-methylphenyl trifluoromethanesulfonate

Trifluoromethanesulfonic anhydride (2.6 mL, 15.5 mmol) was added slowly to a solution of 3-benzyloxy-5-methylphenol (2.6 g, 12 mmol) and 2,6-di-tert-butyl-4-methylpyridine (3.2 g, 15.6 mmol) in dichloromethane (100 mL) at -30°C. The reaction mixture was allowed to warm gradually to room temperature. It was diluted with a threefold excess of pentane. The precipitated solids were removed via filtration and the filtrate concentrated almost to dryness. Ether was added and the mixture filtered once more. The filtrate was concentrated once more and then dissolved in 19: 1 hexane / ether. This solution was allowed to percolate through a small plug of silica gel which was then washed well with additional quantities ofthe same solvent system. Concentration ofthe filtrate in vacuo yielded the pure triflate as a pale yellow oil. Step C: 3'-Benzyloxy-5'-methylbiphenyl-2-carbaldehvde

A solution of 3-benzyloxy-5-methylphenyl trifluoromethanesulfonate (2 g, 5.8 mmol), 2-formylρhenylboronic acid (1.3 g, 8.7 mmol), tetrakistriphenylphosphine-palladium (0) (0.5 g, 0.32 mmol)and potassium carbonate (2 g, 14.5 mmol) in a mixture of acetone (10 mL) and water (5 mL) was heated at 100°C for exactly 2 h. The reaction mixture was cooled to room temperature and the acetone removed under reduced pressure. The residue was extracted with ethyl acetate and dried over sodium sulfate. Filtration and concentration gave a brown oil which was purified by chromatography (19:1 hexane / ether) to give the biphenyl aldehyde as a viscous yellow oil. Step D: 1 -(3 '-Benzyloxy-5'-methylbiphenyl-2-ylV2-methylproρan- 1 -ol

Isopropylmagnesium chloride (2M in ether, 1,5 mL, 3 mmol) was added to a solution of 3'-benzyloxy-5'-methylbiphenyl-2-carbaldehyde (357 mg, 1.2 mmol) in ether(5 mL) at 0°C. The reaction mixture was allowed to warm gradually to room temperature over 4 h following which time it was quenched with aqueous ammonium chloride. The reaction mixture was then extracted with ethyl acetate and the combined extracts washed with brine and dried over sodium sulfate. Filtration and concentration gave a residue which was a 1:1 mixture of the title compound and 3'-benzyloxy-5'- methylbiphenyl-2-methanol. The mixture was separated by flash chromatography eluting with 19:1 — 9:1 - 5:1 - 4:1 hexane / ethyl acetate. The title compound eluted first (colorless oil, 168 mg) followed by the biproduct. Step E: 2'-Isobutyl-5-methylbiphenyl-3-ol

A solution of l-(3 -benzyloxy-5'-methylbiphenyl-2-yl)-2-methylpropan-l-ol (168 mg, 0.48 mmol) in methanol (6 mL) containing 10% Pd/C (100 mg) was stirred at room temperature under an atmosphere of hydrogen overnight. The catalyst was removed via filtration through Celite. Concentration of the filtrate gave the title compound as a colorless oil.

Step F: (5-Methyl-3-trityl-3ff-imidazol-4-yl acetonitrile and (5-methyl- l-trityl-lfl'-imidazol-

4-vπacetonitrile

A solution of Tosmic (8.4 g, 44 mmol) in DME (40 mL) was added to a -50°C suspension of KOtBu (9.2 g, 80 mmol) in DME (40 mL) to give a wine red solution. A suspension of the aldehyde (14 g, 40 mmol) in DME (80 mL) was added in portions (with a final 20 mL wash). The reaction mixture remained homogenous and wine red in color. The reaction mixture was allowed to warm gradually until a precipitate formed at -20°C (about 1.5 h). Methanol (80 mL) was then added and the cold bath removed. The red solution was heated at reflux for 20 min. After cooling to room temperature the solvents were rotavapped off then water and a few mLs of acetic acid were added. A white ppt formed. The mixture was extracted three times with dichloromethane and the extracts then washed neutral with aqueous NaHC0₃ to which had been added some Na₂C0₃. Drying (Na₂S0₄) and concentration gave a yellow oil which was purified by chromatography (1:1 - 1:2 - 1:4 hexane / EtOAc). Step G: Methyl (5-methyl-3-trityl-3fl-imidazol-4-vnacetate and methyl (5-methyl-l-trityl-lff- imidazol-4-yl)acetate

6M HCl (50 mL) was added to a solution of the nitrile (9 g, 25 mmol) in dioxane (50 mL) and the resulting mixture heated at 100°C for 24 h. The reaction mixture was then stripped to dryness. The residue was triturated with ether, then EtOAc, then chloroform to give the imidazole acid as a mustard colored solid (4.8 g). This solid was suspended in dichloromethane (100 mL). Triethylamine (17 mL, 120 mmol) and trityl chloride (8.4 mg, 30 mmol) were then added and the reaction mixture stirred for 3 h. The suspension was poured into a 1:1 mixture of ether and EtOAc containing some methylene chloride. The mixture was washed 2x with 1M citric acid and once with brine. Drying (Na₂S0 ) and concentration gave an orange sponge (9 g). This material was dissolved in 3:1 methylene chloride / methanol(200 mL) and titrated with a slight excess of trimethylsilyldiazomethane (2M solution in hexanes). The reaction mixture was stripped and the trityl ester was purified by chromatography (98:2 chloroform / methanol) providing an orange oil. Step H: 2-(5-Methyl-3-trityl-3ry-imidazol-4-yl)ethanol and 2-(5-methyl-l-trityl-lH-imidazol-

4-yl)ethanol

A solution of the ester (4.6 g, 1.6 mmol) in ether (100 mL) and THF (20 mL) was treated with 1M LAH in ether (12 mL) at -15°C. The reaction mixture was allowed to warm gradually to 0°C following which it was quenched sequentially with EtOAc (10 mL), water (0.5 mL), 15% NaOH (0.5 mL), and water (1.5 mL). The solids were filtered off and the filtrate concentrated. The residue was purified by chromatography (19:1 chloroform / methanol) to give the alcohol as a white foam.

Step I: 2-(5-Methyl-3-trityl-3H-imidazol-4-vπethyl methanesulfonate and 2-(5-methyl-l- trityl-l/_t-imidazol-4-yl^')ethyl methanesulfonate A solution of the alcohol (255 mg, 0.66 mmol) in methylene chloride (10 mL) at 0°C was treated with triethylamine (0.16 mL, 1.15 mmol) and mesyl anhydride (160 mg, 0.92 mmol). The reaction mixture was allowed to warm gradually to room temperature and stirred there for 2 h. The reaction mixture was diluted with an excess of EtOAc and washed with aq NaHC0₃. Drying and concentration gave the mesylate as a foam. Step J: 5-r2-(2'-Isobutyl-5-methyl-biphenyl-3-yloxy)-ethyll-4-methyl-l J^r-imidazole .

A mixture of 2-(5-methyl-3-trityl-3/-'-imidazol-4-yl)ethyl methanesulfon-ate and 2-(5- methyl-l-trityl-lH-imidazol-4-yl)ethyl methanesulfonate (257 mg, 0.58 mmol), 2'-isobutyl-5- methylbiphenyl-3-ol (117 mg, 0.49 mmol) and cesium carbonate (360 mg, 1.10 mmol) in DMF (2 mL) was heated at 80°C overnight. -The reaction mixture was cooled, diluted with water and extracted repeatedly with ether. The combined extracts were washed well with ice cold water and then dried over sodium sulfate. The solvents were removed in vacuo and the residue dissolved in methylene chloride (2 mL). TFA (2 mL) was added followed by triethylsilane (until the yellow color was discharged) and the resulting mixture stirred overnight. The solvent were removed and the residue partitioned between ethyl acetate and 10% aqueous sodium carbonate. The organic phase was dried over sodium sulfate and then concentrated. The residue was purified by flash chromatography eluting with 19:1 chloroform / methanol. Η NMR (CDC1₃) δ 7.45 (s, IH), 7.10-7.27 (m, 4H), 6.69 (s, 2H), 6.62 (s, IH), 4.16 (t, 2H, 6.3 Hz), 3.00 (t, 2H, 6.3 Hz), 2.45 (d, 2H, 7.3 Hz), 2.33 (s, 3H), 2.21 (s, 3H), 1.69 (m, IH), 0.73 (d, 6H, 6.6 Hz); Mass Spec (M+l) 349.6.

EXAMPLE VI Preparation of S-[2-(2'-Isopropyl-5-methylbiphenyl-3-yloxy)-l-methyl-ethyl]-pyridin-4-yl-amine

Step A: 2-(2-Isopropylphenyl)-4.4.5.5-tetramethyl-ri,3.21dioxaborolane

A solution of 2-isopropylphenyl iodide (4 g, 16 mmol), bis(pinacolato)-diboron (5 g,

20 mmol), potassium acetate (4.7 g, 48 mmol),and (diphenylphosphino-ferrocene)palladium dichloride (0.35 g, 0.48 mmol)in DMF (80 mL) was heated at 80°C for 24 h. The reaction mixture was cooled to room temperature and the solvent removed under reduced pressure. The residue was purified by flash chromatography (19:1 hexane / ether) to give the title compound as an almost colorless, highly crystalline solid.

Step B: 3-Benzyloxy-2'-isopropyI-5-methylbiphenyl A solution of 2-(2-isopropylphenyl)-4,4,5,5-tetramethyl-[ 1 ,3,2]-dioxaborolane (0.43 g, 1.75 mmol), 3-benzyloxy-5-methylρhenyl trifluoromethane-sulfonate (0.6 g, 1.75 mmol), 2M aqueous sodium carbonate (4.4 mL),and (diphenylphosphinoferrocene)palladium dichloride (80 m g, 0.1 mmol)in DMF (9 mL) was heated at 80°C overnight. The reaction mixture was cooled to room temperature and the solvents removed under reduced pressure. The residue was partitioned between ethyl acetate and water and the organic layer removed and dried (Na₂S0₄). The solvent was removed and the residue purified by flash chromatography to give the title compound as a colorless oil. Step C: 2'-Isopropyl-5-methylbiphenyl-3-ol

A solution of 3-benzyloxy-2'-isopropyl-5-methylbiphenyl (742 mg) in 1:1 ethyl acetate / ethanol (40 mL) containing 10% Pd/C (500 mg) was stirred at room temperature under an atmosphere of hydrogen overnight. The catalyst was removed via filtration through Celite. Concentration of the filtrate gave the title compound as a colorless oil. Step D: __?-r2-(^'2'-Isopropyl-5-methylbiphenyl-3-yloxy^')-l-methyl-ethvn-pyridin-4-yl-amine

Diethyl azodicarboxylate (0.21 mL, 1.3 mmol) was added in a dropwise manner to a mixture of 2'-isopropyl-5-methylbiphenyl-3-ol (270 mg, 1.2 mmol), 2-(pyridin-4-ylamino)propan-l-ol (200 mg, 1.3 mmol) and triphenylphosphine (345 mg, 1.3 mmol) in toluene (5 mL). The urea biproduct was removed via filtration. Concentration gave a residue which was purified by flash chromatography eluting with 19:1 - 9:1 chloroform / 10% NH₄OH in MeOH. The product was further purified by

HPLC and isolated as the TFA salt. 'H NMR (CD₃OD) δ 8.46 (br d, IH, 7.8 Hz), 8.09 (d, 3H, 7.2 Hz), 7.96 (d, IH, 7.2 Hz), 7.34 (m, IH), 7.28 (m, IH), 7.14 (m, IH), 7.06 (m, IH), 6.86 (m, IH), 6.73 (s, IH), 6.66 (s, IH), 6.55 (s, IH), 4.26 (br m, IH), 4.15 (m, IH), 3.99 (m, IH), 2.97 (m, IH), 2.33 (s, 3H), 1.38 (d, 3H, 6.6 Hz), 1.11 (dd, 6H, 3.2, 6.8 Hz); Mass Spec (M+l) 361.8. EXAMPLE VII

Preparation of l-{2-[2-(2'-Isopropyl-5-methyl-biphenyl-3-yloxy)-ethyl]-phenyl}-lH-tetrazole

Step A: 2-(2-Nitrophenyl^')ethyl acetate

Step B: 2-(2-Aminoρhenyl')ethyl acetate The sample of 2-(2-nitrophenyl)ethyl acetate from the previous step was hydrogenated at 50 psi in EtOAc (250 mL) in the presence of 10% Pd/C to give a pink oil.

Step C: 2-(2-Tetrazol- 1 -ylphenvDethyl acetate

A mixture of the 2-(2-aminophenyI)ethyl acetate from the previous step, sodium azide

(3.6 g, 55 mmol), and triethyl orthoformate (9.2 mL, 55 mmol) in glacial acetic acid (200 mL) was heated at 120°C overnight. The reaction mixture was then allowed to cool and poured onto ice. The pH was raised to 7 by addition of 50% NaOH. The mixture was then extracted with EtOAc and the extracts washed with brine and then saturated NaHC0₃. Drying (Na₂S0₄) and concentration yielded a brow oil which was purified by flash chromatography (3:2 - 1:1 - 2:3 hexane / EtOAc) to give the title compound as a yellow oil.

Step D: 2-(2-Tetrazol- 1 -ylphenyllethanol

A mixture of the 2-(2-tetrazol-l-ylphenyl)ethyl acetate from the previous step , methanol (15 mL) and 15% NaOH (5 mL) was stirred at room temperature for 1.5 h. the methanol was removed under reduced pressure and the residue diluted with water. The product was extracted with methylene chloride and dried (Na₂S0₄). Concentration and chromatography (19:1 chloroform / methanol) gave the product as a colorless oil.

Step E: l-{2-r2-(2'-Isopropyl-5-methyl-biphenyl-3-yloxyVethyn-phenyl -ltf-tetrazole The title compound was prepared essentially according to the Mitsunobu protocol for

Example VI, Step D using 2-(2-tetrazol-l-ylphenyl)ethanol and 2^,-Isoproρyl-5-methylbiphenyl-3-ol as the coupling partners. *H NMR (CDC1₃) δ 8.96 (s, IH), 7.10-7.59 (m, 8H), 6.69 (s, IH), 6.61 (s, IH),

6.54 (s, IH), 4.15 (m, 2H), 3.01 (m, IH), 2.92 (m, 2H), 2.34 (s, 3H), 1.14 (d, 6H, 7.1 Hz); Mass Spec

(M+l) 399.2. Example VIII

Preparation of 5-[2-(2'-Isopropyl-5-methylbiphenyl-3-yloxy)-ethyl]-4-methyl-lH-imidazole

The title compound was prepared essentially according to the Mitsunobu protocol for Example VI, Step D using 2'-isopropyl-5-methylbiphenyl-3-ol and a mixture of 2-(5-methyl-3-trityl-3H-imidazol-4- yl)ethanol and 2-(5-methyl-l-trityl-li_t-imidazol-4-yl)ethanol as the coupling partners. The trityl group was then removed essentially according to the procedure for Example V, Step J. The product was purified by HPLC and isolated as the TFA salt. ^lR NMR (CD₃OD) δ 8.69 (s, IH), 7.37 (m, IH), 7.31 (m, IH), 7.17 (m, IH), 7.09 (m, IH), 6.75 (s, IH), 6.68 (s, IH), 6.59 (s, IH), 4.22 (t, 2H, 5.9 Hz), 3.16 (t, 2H, 5.9 Hz), 3.02 (m, IH), 2.35 (s, 3H), 2.34 (s, 3H), 1.14 (d, 6H, 7.1 Hz); Mass Spec (M+l) 335.2.

Example IX Preparation of l-{4-Chloro-2-[2-(2'-isopropyl-5-methylbiphenyl-3-yloxy)-ethyl]-phenyl}-lH- [l,2,4]triazole

Step A: 5-Chloro-2-n.2,41triazol-l-yl-benzonitrile

A mixture of 2,5-dichlorobenzonitrile (25 g, 145 mmol), cesium carbonate (60 g, 184 mmol), 1,2,4-triazole (13 g, 190 mmol) and fefra-n-butylammonium iodide (5 g, 14 mmol) in DMF (200 mL) was heated at 90°C for 24 h. After cooling to room temperature the reaction mixture was poured onto crushed ice. The resulting solid was transferred to a Buchner funnel and washed well firstly with water then with ether. The residual solid was dried in vacuo to give the title compound as a pale pink solid.

Step B: 5-Chloro-2-[T.2.41triazol-l-yl-benzoic acid A suspension of 5-chloro-2-[l,2,4]triazol-l-yl-benzonitrile (8.4 g) in concentrated hydrochloric acid (50 mL) was brought to 100°C and the resulting yellow solution stirred there for 96 h. After cooling to room temperature, the solution was poured onto crushed ice. The resulting white suspension was made alkaline by addition of a 50% aqueous sodium hydroxide solution. The resulting solution was extracted twice with dichloromethane and once with ethyl acetate. The aqueous phase was cooled in ice and acidified with concentrated hydrochloric acid. The resulting white precipitate was filtered off, washed well with water and dried. Step C: 5-Chloro-2-n,2.41triazol-l-yl-benzyl alcohol

A suspension of 5-chloro-2-[l,2,4]triazol-l-yl-benzoic acid (10 g, 45 mmol) in a mixture of chloroform (50 mL) and methanol (50 mL) was titrated with trimethylsilyldiazomethane (2M in hexanes). Most ofthe starting material was consumed and went into solution The solvents were removed in vacuo and the residue dissolved in a 1:1 mixture of chloroform and ethyl acetate. The solution was dried over sodium sulfate and then evaporated to give the methyl ester as an orange solid (8 g). The ester was dissolved in THF (200 mL) and cooled to 0°C. Lithium aluminum hydride (50 mL, IM in THF) was added slowly and the reaction mixture stirred at 0°C for 0.75 h. Excess hydride was destroyed by slow addition of ethyl acetate (5 mL). The reaction mixture was subjected to the Fieser work up procedure and the crude product thus isolated was purified by flash chromatography (19:1 chloroform / methanol) to afford a yellow oil. Trituration with 1:1 dichloromethane / ether furnished the alcohol as a white solid. Step D: 5-Chloro-2-IT.2.41triazol-l-yl-benzyl bromide

Thionyl bromide (2.2 g, 10.6 mmol) was added to a suspension of 5-chloro-2- [l,2,4]triazol-l-yl-benzyl alcohol (1.5 g, 7.2 mmol) in dichloromethane (50 mL) at room temperature. A yellow solution resulted. After 0.5 h, a yellow solid precipitated from the reaction mixture. After stirring for 2 h, the reaction mixture was poured onto ice and then extracted with ethyl acetate. The organic extracts were washed with water then aqueous sodium bicarbonate and finally dried over sodium sulfate. Concentration gave the bromide as a white powder Step E: (5-Chloro-2-r 1 ,2.41triazol- 1-yl-phenylVacetonitrile

A mixture of 5-chloro-2-[l,2,4]triazol-l-yl-benzyl bromide (2 g), sodium cyanide (1 g), dioxane (15 mL) and water (5 mL) was heated at 90°C for 3 h. After cooling to room temperature the reaction mixture was extracted with ether. The extracts were washed with brine and dried over sodium sulfate. Concentration yielded the product as a mustard powder. Step F: Methyl (5-chloro-2-n.2,41triazol-l-yl-phenyl)-acetate

(5-Chloro-2-[l,2,4]triazol-l-yl-phenyl)-acetonitrile (1.7 g) was heated in a mixture of 6M HCl (10 mL) and dioxane (10 mL) at 90°C for 36 h. All solvents were removed in vacuo and the residue was then dissolved in methanol (30 mL) and titrated with trimethylsilyldiazomethane (2M in hexanes). Evaporation of the solvents and purification of the residue by flash chromatography (2: 1 :2 hexane / chloroform / ethyl acetate) gave the title compound as an orange oil. Step G: 2-(5-Chloro-2-r 1.2.41triazol- 1-yl-phenylVethanol

This compound was prepared by reduction of methyl (5-chloro-2-[l,2,4]triazol-l-yl- phenyl)-acetate with lithium aluminum hydride essentially according to the procedure employed in Step C above. Step H: l-f4-Chloro-2-r2-(2'-isopropyl-5-methylbiphenyl-3-yloxy)-ethvn-phenyll-l_g- ll,2,4ltriazole

The title compound was prepared essentially according to the Mitsunobu protocol for Example VI, Step D using 2-isopropyl-5-methylbiphenyl-3-ol and 2-(5-chloro-2-[l,2,4]triazol-l-yl- phenyl)-ethanol as the coupling partners. ^rH NMR (CDC1₃) δ 8.37 (s, IH), 8.07 (s, IH), 7.50 (m, IH), 7.10-7.36 (m, 6H), 6.75 (s, IH), 6.62 (s, IH), 6.56 (s, IH), 4.12 (m, 2H), 2.95 (m, 3H), 2.33 (s, 3H), 1.14 (d, 6H, 6.8 Hz); Mass Spec (M+l) 432.4.

EXAMPLE X Preparation of 2-[2-(2'-Isoproρyl-5-methyl-biphenyl-3-yloxy)-ethyl]-benzylamine

Step A: Acetic acid 2-(2-bromo-phenyl^")-ethyl ester

Acetic anhydride (1.7 mL, 18 mmol) was added to a mixture of 2-(2-bromo-phenyl)- ethanol (3 g, 15 mmol) and triethylamine (2.9 mL, 15 mmol) in methylene chloride (10 mL) at 0°C. The reaction mixture was allowed to warm to room temperature whereupon it was diluted with ethyl acetate and extracted with saturated sodium bicarbonate. Drying over sodium sulfate and then concentration yielded a pale yellow oil (3.75 g). The crude material was dissolved in dry DMF (10 mL) along with zinc cyanide (1.21 g, 10.2 mmol) and tetrakistriphenylphosphinepalladium (0) (1.78 g, 1.54 mmol) and the resulting mixture heated at 100°C overnight. The reaction mixture was then cooled to' room temperature and the DMF removed under reduced pressure. The residue was subjected to flash chromatography eluting with 9:1 hexane / ethyl acetate to give the title compound as a colorless oil. Step B: 2-(2-Hvdroxy-ethyl)-benzonitrile

Potassium hydroxide (5.3 mL, 1 M solution) was added to a solution of acetic acid 2- (2-bromo-phenyl)-ethyl ester (1 g, 5.3 mmol) in a mixture of methanol (3 mL) and THF (3 mL). After stirring for 1 h, the reaction mixture was neutralized with HCl (5.3 mL, 1 M solution). The organic solvents were removed under reduced pressure and the residue extracted with dichloromethane. The extracts were dried (sodium sulfate) and concentrated and the desired product then isolated as a colorless oil via flash chromatography eluting with 5:1 hexane / ethyl acetate. Step C: 2-[2-(2'-Isopropyl-5-methyl-biphenyl-3-yloxy)-ethvn-benzonitrile

The title compound was prepared essentially according to the Mitsunobu protocol for Example VI, Step D using 2'-isopropyl-5-methylbiphenyl-3-ol and 2-(2-hydroxy-ethyl)-benzonitrile as the coupling partners.

Step D: 2-F2-(2'-Isopropyl-5-methyl-biphenyl-3-yloxyVethyl -benzylamine The Mitsunobu product (38 mg) from the previous step was hydrogenated at 45 psi in ethanol containing cone. HCl (3 eq.) in the presence of 10% Pd/C to give the HCl salt of the title compound as a white solid. Η NMR (CD₃OD) δ 7.27-7.42 (m, 6H), 7.03-7.13 (m, 2H), 6.70 (s, IH), 6.63 (s, IH), 6.53 (s, IH), 4.30 (s, 2H), 4.23 (1, 2H, 6.0 Hz), 3.19 (1, 2H, 6.0 Hz), 2.97 (m, IH), 2.31 (s, 3H), 1.10 (d, 6H, 6.8 Hz); Mass Spec (M+l) 360.2.

Example XI

Preparation of 2-Isopropyl-5-methyl-biphenyl-3-carboxylic acid 5-chloro-2-[l,2,4]triazol-l-yl- benzylamide

Step A: 2-(2-Isopropyl-phenylV4.4,5,5-tetramethyl-11.3,21dioxaborolane

A mixture of l-iodo-2-isopropylbenzene (4 g, 16 mmol), pinacol diboron (5 g, 20 mmol), potassium acetate (4.7 g, 48 mmol) and PdCl₂(dppf) (350 mg) in DMF (80 mL) was heated at 80°C for 24 h. The reaction mixture was then cooled and the DMF removed under reduced pressure. The residue was chromatographed directly (19:1 hexane / ether) to give the borate as a crystalline solid. Step B: 3-Methyl-5-trifluoromethanesulfonyloxy-benzoic acid methyl ester

Trifluoromethanesulfonic anhydride (4.5 mL, 27 mmol) was added slowly to a solution of 3-hydroxy-5-methyl-benzoic acid methyl ester (Turner & Gearien, JOC 1959 p. 1952)(3.3 g, 20 mmol) and 2,6-di-tert-butyl-4-methylpyridine (5.5 g, 27 mmol) in dichloromethane (100 mL) at - 15°C. The reaction mixture was allowed to warm gradually to room temperature and was then diluted with pentane. The resulting white solid was filtered off and the filtrate concentrated to one quarter of the initial volume. It was diluted with ether and filtered once again through the original residue. The filtrate was then concentrated completely and the resulting brown oil purified by flash chromatography to give the triflate as a colorless oil. Step C: 2'-Isopropyl-5-methyl-biphenyl-3-carboxylic acid methyl ester A mixture of 3-methyl-5-trifluoromethanesulfonyloxy-benzoic acid methyl ester (1 g,

3.4 mmol), 2-(2-isopropyl-phenyl)-4,4,5,5-tetramethyl-[l,3,2]dioxaborolane (844 mg, 3.4 mmol), aqueous sodium carbonate (8.6 mL, 2M solution) and PdCl₂(dppf) (146 mg) in DMF (10 L) was heated at 100°C for 1 h. The reaction mixture was then cooled and the solvents removed under reduced pressure. The residue was chromatographed directly (19:1 hexane / ethyl acetate) to give the biaryl ester.

Step D: 2'-Isopropyl-5-methyl-biphenyl-3-carboxylic acid

A mixture of 2'-isopropyl-5-methyl-biphenyl-3-carboxylic acid methyl ester (150 mg, 0.56 mmol), and IM KOH (1.12 ml) in THF (2.5 mL) and methanol (2.5 mL) was stirred at room temperature overnight. IM HCl (1.12 mL) was then added and all the solvents were removed in vacuo. Dichloromethane was added to the residue and the resulting mixture then filtered to remove inorganic salts. Concentration of the filtrate gave the acid. Step E: 2'-Isopropyl-5-methyl-biphenyl-3-carbonyl chloride Oxalyl chloride (0.06 mL, 0.63 mmol) was added to a solution of 2'-isopropyl-5- methyl-biphenyl-3-carboxylic acid (140 mg, 0.55 mmol) in dichloromethane (5 mL) containing a few drops of at 0°C. the cold bath was removed and the reaction mixture allowed to warm gradually to room temperature and then stir there overnight. All volatile components were then removed and the residual acid chloride used directly.

Step F: Isopropyl-5-methyl-biphenyl-3-carboxylic acid 5-chloro-2-ri.2,41triazol-l-yl- benzylamide

A mixture of 2'-isopropyl-5-methyl-biphenyl-3-carbonyl chloride (75 mg, 0.27 mmol), 5-chloro-2-[l,2,4]triazol-l-yl-benzylamine (56 mg, 0.27 mmol), triethylamine (0.06 mL, 0.41 mmol) and a catalytic quantity of DMAP in dichloromethane (5 mL) was stirred at 0°C for 2 h. the reaction mixture was then diluted with ether and washed with saturated aqueous sodium bicarbonate. The organic phase was dried over sodium sulfate and then concentrated. The residue was purified by flash chromatography (5:1 to 1:1 hexane / ethyl acetate. The product was isolated as an oil. ^:H NMR (CDC1₃) δ 8.42 (s, IH), 8.18 (s, IH), 7.79 (s, IH), 7.63 (s, IH), 7.50 (s, IH), 7.15-7.50 (m, 6H), 4.49 (d, 2H, 6.3 Hz), 3.01 (m, IH), 2.46 (s, 3H), 1.14 (d, 6H, 6.8 Hz); Mass Spec (M+l) 445.2.

Example XII

Preparation of 2'-Isopropyl-5-methyl-biphenyl-3-carboxylic acid 5-chloro-2-[l,2,4]triazol-l-yl-benzyl ester

This compound was prepared essentially according to the procedure for Example XI by substituting 5- chloro-2-[l,2,4]triazol-l-yl-benzyl alcohol for 5-chloro-2-[l,2,4]triazol-l-yl-benzylamine in step F. Η NMR (CDC1₃) δ 8.43 (s, IH), 8.16 (s, IH), 7.79 (s, IH), 7.76 (s, IH), 7.69 (s, IH), 7.22-7.49 (m, 6H), 5.31 (s, 2H), 2.99 (m, IH), 2.47 (s, 3H), 1.18 (d, 6H, 6.8 Hz); Mass Spec (M+l) 446.2.

Example XIII

Preparation of (5-Chloro-2-[l,2,4]triazol-l-yl-benzyl)-(2'-isopropyl-5-methyl-biρhenyl-3-ylmethyl)- amine

Step A: (2'-Isopropyl-5-methyl-biphenyl-3-yl")-methanol Lithium aluminum hydride (2.85 mL, 1 M in THF) was added to a solution ofthe 2'- isopropyl-5-methyl-biphenyl-3-carboxylic acid methyl ester (765 mg, 2.85 mmol) in dichloromethane (10 mL) at 0°C. The reaction mixture was stirred for 0.45 h then excess reductant was destroyed via slow addition of ethyl acetate (2 mL). Following Fieser work up and drying over sodium sulfate, the product was isolated as an oil and used without further purification. Ste B: 2'-Isopropyl-5-methyl-biphenyl-3-carbaldehvde Tetra-n-propylammonium perruthenate (73 mg, 0.2 mmol) was added to a mixture of (2-isopropyl-5-methyl-biphenyl-3-yl)-methanol (500 mg, 2.1 mmol), NMO (365 mg, 3.1 mmol) and powdered 4A molecular sieves (500 mg) in dichloromethane (10 mL) at 0°C. After 10 min, the cold bath was removed and the reaction allowed to warm to room temperature. When consumption of the starting material was complete, the reaction mixture was filtered through Celite. The filtrate was concentrated and purified by column chromatography (100:0 to 98:2 to 95:5 hexane / ether) to afford the aldehyde as an oil.

Step C: (5-Chloro-2-ri,2.41triazol-l-yl-benzyl)-(2'-isopropyl-5-methyl-biphenyl-3-ylmethyl')- amine A mixture of 2'-isoρropyl-5-methyl-biphenyl-3-carbaldehyde (290 mg, 1.22 mmol),

5-chloro-2-[l,2,4]triazol-l-yl-benzylamine (254 mg, 1.22 mmol), acetic acid (0.06 mL, 1.22 mmol) and NaHB(OAc)₃ (309 mg, 1.46 mmol) in dichloroethane (5 mL) was stirred at room temperature for 6 h. the reaction mixture was quenched with aqueous sodium bicarbonate and the product extracted with ether. Upon standing the produce precipitated from the extracts and was therefore isolated via filtration as a white solid. ^]H NMR (CDC1₃) δ 8.58 (s, IH), 8.07 (s, IH), 7.58 (m, IH), 7.11-7.40 (m, 8H), 7.02 (s, IH), 3.78 (s, 2H), 3.64 (s, 2H), 3.03 (m, IH), 2.39 (s, 3H), 1.15 (d, 6H, 6.8 Hz); Mass Spec (M+l) 431.3.

Example XIV

Preparation of l-[4-Chloro-2-(2'-isopropyl-5-methyl-biphenyl-3-ylmethoxymethyl)-phenyl]-lH- [l,2,4]triazole

Sodium hydride (7 mg, 0.17 mmol) was added to a solution of (2'-isopropyl-5-methyl-biphenyl-3-yl)- methanol (40 mg, 0.17 mmol) in DMF (2.5 mL) at room temperature. After stirring for 10 min, chloro- 2-[l,2,4]triazol-l-yl-benzyl bromide (69 mg, 0.26 mmol) was added and the reaction mixture then heated at 100°C overnight. Following removal of the DMF, the residue was worked up via extraction with ethyl acetate and sodium bicarbonate. The extracts were dried over sodium sulfate and the product isolated via flash chromatography eluting with 5:1 hexane / ethyl acetate. Η NMR (CDC1₃) δ 8.46 (s, IH), 8.12 (s, IH), 7.66 (m, IH), 7.13-7.45 (m, 8H), 7.07 (m, IH), 4.56 (s, 2H), 4.46 (s, 2H), 3.05 (m, IH), 2.42 (s, 3H), 1.15 (d, 6H, 6.8 Hz); Mass Spec (M+l) 432.2.

Example XV

Preparation of 3-(4-Isopropyl-pyridin-3-yl)-5-methyl-benzoic acid 5-chloro-2-[l,2,4]triazol-l-yl-benzyl ester

Step A: 3-Methyl-5-( ,4,5.5-tetramethyl-ri,3,21dioxaborolan-2-vf)-benzoic acid methyl ester A mixture of 3-methyl-5-trifluoromethanesulfonyloxy-benzoic acid methyl ester (1.4 g, 4.7 mmol), pinacol diboron (1.4 g, 5.6 mmol), potassium acetate (1.4 g, 14 mmol) and PdCl₂(dpρf) (103 mg) in DMF (20 mL) was heated at 90°C for 1.5 h. The reaction mixture was then cooled and the DMF removed under reduced pressure. The residue was chromatographed directly (19:1 hexane / ethyl acetate) to give the borate as a white crystalline solid.

Step B: 3-(4-Isopropyl-pyridin-3-yl)-5-methyl-benzoic acid methyl ester

A mixture of 3-methyl-5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester (280 mg, 1 mmol), 3-bromo-4-isopropylpyridine (200 g, 1 mmol), cesium carbonate (390 mg, 1.2 mmol), tricyclohexyphosphine (10 mg) and Pd₂(dba)₃ (14 mg) in dioxane (2 mL) was heated at 105°C in a sealed tube for 24 h. The reaction mixture was then cooled, filtered and concentrated under reduced pressure. The residue was chromatographed (7:3 hexane / ethyl acetate) to give the title compound as a yellow oil. Step C: 3-(4-Isoproρyl-pyridin-3-yl -5-methyl-benzoic acid

A mixture of 3-(4-isopropyl-pyridin-3-yl)-5-methyl-benzoic acid methyl ester (13 mg, 0.42 mmol) and IM LiOH (1 mL) in THF (3 mL) was stirred at room temperature overnight. The THF was removed under reduced pressure and IM HCl was then added. Following extraction with chloroform and ethyl acetate, drying and concentration gave the acid as a white solid. Step D: 3-(4-Isoproρyl-pyridin-3-yl)-5-methyl-benzoic acid 5-chloro-2-ri,2.41triazol-l-yl- benzyl ester To a solution of 3-(4-isopropyl-pyridin-3-yl)-5-methyl-benzoic acid (90 mg) in acetonitrile (2 L) at room temperature was added DBU (0.07 mL) followed by 5-chloro-2-[l,2,4]triazol-l-yl-benzyl bromide (120 mg). The reaction mixture was allowed to stir overnight. The solvent was then removed and the residue chromatographed (7:3 to 1:1 to3:7 hexane / ethyl acetate) to give the product as a white solid. Η NMR (CDC1₃) δ 8.53 (d, IH, 5.3 Hz), 8.38 (s, IH), 8.35 (s, IH), 8.13 (s, IH), 7.80 (s, IH), 7.71 (s, IH), 7.65 (m, IH), 7.23-7.47 (m, 4H), 5.29 (s, 2H), 2.97 (m, IH), 2.45 (s, 3H), 1.15 (d, 6H, 6.8Hz); Mass Spec (M+l) 447.3.

Example XVI

Preparation of 3-(4-Isopropyl-l-N-oxo-pyridin-3-yl)-5-methyl-benzoic acid 5-chIoro-2-[l,2,4]triazol-l- yl-benzyl ester

Methyltrioxorhenium (a smidgen) was added to a solution of 3-(4-isopropyl-pyridin-3-yl)-5-methyl- benzoic acid 5-chloro-2-[l,2,4]triazol-l-yl-benzyl ester (67 mg, 0.15 mmol) in dichloromethane (2 mL) containing 30% aqueous hydrogen peroxide (0.05 mL). The reaction mixture was stirred for 2 h then excess oxidant destroyed by very careful addition of manganese dioxide (a spatula tip). The reaction mixture was then washed with brine, dried (sodium sulfate) and concentrated to give the title compound as a white solid. ^lU NMR (CDC1₃) δ 8.39 (s, IH), 8.16 (m, IH), 8.13 (s, IH), 8.03 (s, IH), 7.84 (s, IH), 7.69 (s, IH), 7.64 (m, IH), 7.24-7.48 (m, 4H), 5.31 (s, 2H), 2.93 (m, IH), 2.46 (s, 3H), 1.15 (d, 6H, 6.8 Hz); Mass Spec (M+l) 463.3.

EXAMPLE XVII Preparation of l-(4-chloro-2-{2-[3-(5-isobutyl-l,3-oxazol-4-yl)phenoxy]ethyl}phenyl)-lfl'-l,2,4- triazole

Step A: Ethyl S-Cbenzyloxy enzoate

A mixture of ethyl 3-hydroxybenzoate (8.4 g, 51 mmol), benzyl bromide (6.1 mL, 51 mmol) and anhydrous K₂C0₃ (7.1 g, 51 mmol) in acetone (150 mL) was heated at reflux for 16 h. Filtration and concentration gave a yellow oil which was purified by chromatography (93:7 - 90: 10 hexanes/EtOAc) to give a clear oil. Step B: 3-(Benzyloxy^')benzoic acid

A mixture of ethyl 3-(benzyloxy)benzoate (11.6 g, 51 mmol) and NaOH (4.1 g, 102 mmol) in absolute EtOH (80 mL) and water (40 mL) was heated at 60 °C for 16 h. The solvent was removed in vacuo, the solid residue dissolved in water (200 mL) and the solution washed with ether (100 mL). The aqueous layer was acidified to pH 2 by addition of concentrated HCl and the mixture was extracted with EtOAc (300 mL). The aqueous layer was saturated with NaCl and further extracted with EtOAc (200 mL) and THF (200 mL). The combined extracts were dried over MgS0₄, filtered and concentrated to give a white fluffy solid. Step C: 3-(Benzyloxy)-N-methoxy-N-methylbenzamide

To a stirred suspension of 3-(benzyloxy)benzoic acid (4.6 g, 20 mmol) in CH₂C1₂ (61 mL) was added sequentially Λ,0-dimethylhydroxylamine hydrochloride (2.4 g, 24 mmol), TEA (9.8 mL, 70 mmol) and benzotriazol-l-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent, 9.7 g, 22 mmol) The mixture was stirred at room temperature for 16 h and was then diluted with CH₂C1₂ (240 mL). The solution was washed successively with 1 N HCl, saturated aqueous

NaHC0₃, water and brine. The organic layer was dried over MgS0 . Filtration and concentration gave a light yellow oil which was purified by chromatography (80:20 - 45:55 - 30:70 hexanes/EtOAc) to afford the product as a nearly colorless oil. Step D: l-13-(Benzyloxy^phenyl1-4-methylpentan-l-one A solution of isobutylmagnesium bromide (prepared from magnesium turnings (790 mg), l-bromo-3-methylbutane (3.6 mL )and catalytic I₂ in 25 mL anhydrous ether) was added via cannula to a cold (0 °C) solution of 3-(benzyloxy)-N-methoxy-N-methylbenzamide (2.77 g, 10 mmol) in anhydrous THF (30 mL). The mixture was stirred at 0 °C for 90 min and was then poured into a mixture of 5% HCl and ice. The mixture was extracted with several portions of ether and the combined extracts washed with aqueous NaHC0₃ and brine and dried over MgS0 . Filtration and concentration gave a yellow oil which was purified by chromatography (9:1 hexanes/EtOAc) to afford a light yellow oil. Step E: l-r3-(Benzyloxy phenyll-2-bromo-4-methylpentan-l-one

Bromine (620 μL) was added dropwise to a stirred solution of l-[3- (benzyloxy)phenyl]-4-methylρentan-l-one (2.4 g, 8.6 mmol) in Et₂0 (330 mL). The orange solution was stirred at room temperature for 50 min and was then poured into water. The organic layer was washed successively with saturated aqueous NaHC0₃ and water and was dried over MgS0 . Filtration and concentration afforded an orange oil. Step F: 4-r3-(Benzyloxy')phenvn-5-isobutyl-1.3-oxazole

A solution of l-[3-(benzyloxy)phenyl]-2-bromo-4-methylpentan-l-one (3.19 g, 8.8 mmol) in formamide (124 mL) was heated at 180 °C for 4 h. The solvent was removed in vacuo and the dark residue was dissolved in 3 N HCl. The solution was diluted with water and treated portionwise with solid Na₂C0₃ until gas evolution ceased. The mixture was extracted with CHC1₃ and the aqueous layer was saturated with NaCl and further extracted with several portions of EtOAc. The combined organic extracts were dried over MgS0₄. Filtration and concentration afforded the crude product as an orange oil which comprised a 1:3 mixture ofthe title compound and 4-[3-(benzyloxy)phenyl]-5- isobutyl-lW-imidazole. The mixture was separated by chromatography (100:0 - 95:5 CHCl₃/MeOH). The title compound eluted first (light orange oil) followed by the imidazole (dark orange oil). Step G: 3-(5-Isobutyl-1.3-oxazol-4-yl phenol

To a degassed solution of 4-[3-(benzyloxy)phenyl]-5-isobutyl-l,3-oxazole (607 mg, 2.0 mmol) in anhydrous CH₂C1₂ was added β-bromocatecholborane (1.4 g, 6.9 mmol). The mixture was stirred under nitrogen atmosphere for 16 h. The product was isolated by flash chromatography

(9:1:0.1 CHCl₃/MeOH/NH OH) as a brown oil which solidified to a tan solid after prolonged drying in vacuo.

Step H: l-(4-chloro-2-{2-r3-(5-isobutyl-l,3-oxazol-4-yl)phenoxylethyllphenyl -lfl^r-l,2,4- triazole A mixture of 3-(5-isobutyl-l,3-oxazol-4-yl)phenol (108 mg, 0.50 mmol), 2-[5-chloro-

2-(l#-l,2,4-triazol-l-yi)phenyl]ethanol (112 mg, 0.50 mmol), diisopropyl azodicarboxylate (140 μL, 0.70 mmol) and triphenylphosphine (184 mg, 0.70 mmol) in CH₂C1₂ was stirred at room temperature for 3 days. The crude product was purified by reverse phase preparative HPLC and the resulting TFA salt was neutralized with aqueous K₂C0₃. The product was extracted into CH₂C1₂ and the organic extract was dried over Na₂S0₄, filtered and concentrated to an oil. Treatment with 1 M HCl-Et₂0 resulted in precipitation of the product which was collected by filtration (tan solid). *H NMR (CD₃OD) δ 9.12 (br s, IH), 8.40 (s, IH), 8.17 (s, IH), 7.68 (s, IH), 7.46 (br m, 2H), 7.31 (m, IH), 7.17 (d, / = 8.0 Hz, IH), 7.10 (s, IH), 6.82 (dd, J = 2.0 Hz, 8.4 Hz, IH), 4.19 (t, J = 6.4 Hz, 2H), 3.04 (t, / = 6.4 Hz, 2H), 2.78 (d, J = 7.2 Hz, 2H), 2.08 (m, IH), 0.95 (d, J = 6.8 Hz, 6H). Mass spec (M+l) 423.2.

EXAMPLE XVIII Preparation of l-(4-chloro-2-{2-[3-(l-isobutyl-l t-imidazolyl)phenoxy]ethyl}phenyl)-lJϊ-l,2,4-triazole

Step A: 3-d -isobutyl- lH-imidazolv-5-vf.phenol

This compound was prepared from 3-hydroxybenzaldehyde and isobutylamine essentially according to the procedure of Kuwano, E.; Tomomi, H.; Eto, M. Agric. Biol. Chem. 1991, 55, 2999-3004. Step B: l-(-4-chloro-2-(2-r3-(l-isobutyl-lH-imidazolvnphenoxylethyllphenyl^')- -1.2.4- triazole

The title compound was prepared essentially according to the Mitsunobu protocol described in Example XVII, Step H, with 3-(l-isobutyl-lH-imidazoly-5-yl)phenol and 2-[5-chloro-2- ( -l,2,4-triazol-l-yl)phenyl]ethanol as the coupling partners. ^JH NMR (CD₃OD) δ 8.98 (br s, IH), 8.80 (s, IH), 8.19 (s, IH), 7.66 (s, IH), 7.59 (br s, IH), 7.43 (br m, 3H), 7.05 (br m, 2H), 6.99 (s, IH), 4.20 (t, J = 6.4 Hz, 2H), 4.07 (d, J = 7.6 Hz, 2H), 3.04 (t, J = 6.4 Hz, 2H), 1.83 (m, IH), 0.79 (d, J = 6.6 Hz, 6H). Mass spec (M+l) 422.2. EXAMPLE XIX

Preparation of 5-(3- { 2-[5-chloro-2-( IH- 1 ,2,4-triazol- 1 -yl)phenyl]ethoxy } -5-methylphenyl)- 1 -isobutyl- lH-tetrazole

Step A: 3-Hvdroxy-5-methylbenzoic acid To a solution of methyl 3-hydroxy-5-methylbenzoate (5.0 g, 30 mmol) in EtOH (32 mL) was added sodium hydroxide (1.2 g, 30 mmol). The reaction was heated to 60 °C for 18 h. The mixture was concentrated to dryness and was then suspended in saturated HCl MeOH with stirring for 15 min.

The resulting precipitate was filtered off and washed with MeOH. The filtrate was concentrated to dryness to afford the acid as a white powder. Step B: 3-Hvdroxy-JV^"-isobutyl-5-methylbenzamide

To a mixture of 3-hydroxy-5-methylbenzoic acid (1.0 g, 6.6 mmol) and isobutylamine (481 mg, 6.6 mmol) in dry DMF (7 mL) was added l-hydroxy-7-azabenzotriazole (447 mg, 3.3 mmol) followed by EDC (1.89 g, 9.9 mmol). The reaction was stirred at 25 °C for 18 h, and the thick solution was diluted to three times its volume with water. The resulting precipitate was _: collected by filtration, washed with water and dried in vacuo to afford the product as tan crystalline needles.

Step C: 3-(Benzyloxy)-AMsobutyl-5-methyrbenzamide

To a solution of 3-hydroxy-ZV-isobutyl-5-methylbenzamide (966 mg, 4.7 mmol) in

THF (7 mL) at 0 °C was added sodium hydride (112 mg, 4.7 mmol) followed by benzyl bromide (555 μL, 4.7 mmol) in THF (3 mL). The reaction was allowed to warm to 25 °C and was stirred for 4 h under inert atmosphere. The solvent was removed in vacuo and the resulting residue was dissolved in

CHC1₃ and washed successively with 10% citric acid solution, water, and brine. The organic layer was dried over Na₂S0 , filtered and concentrated to dryness. Flash column chromatography (4:1 - 1:1 hexanes/EtO c) afforded the benzyl ether as a white powder.

Step D: 5-r3-(Benzyloxy -5-methylphenyll-l-isobutyl-lH-tetraazole

To a solution of 3-(benzyloxy)-Λf-isobutyl-5-methylbenzamide (500 mg, 1.7 mmol) in toluene (3.4 mL) was added phosphorous pentachloride (385 mg, 1.9 mmol). The solution was heated to reflux for 4 h. Toluene was removed in vacuo and the remaining residue was dissolved in DMF (5 mL). The solution was added dropwise to a suspension of sodium azide (318.5 mg, 3.4 mmol) and lithium chloride (143 mg, 3.4 mmol) in DMF (3.4 mL). The reaction was heated to 100 °C for 18 h.

The solution was poured into water (100 mL) and the resulting suspension was extracted with several portions of EtOAc. The organic layers were combined, dried over Na₂S0₄, filtered and concentrated.

Flash column chromatography (3:1 - 1:1 hexanes/EtOAc) afforded the tetrazole as an off-white solid.

Step E: 3-α-Isobutyl-lff-tetraazol-5-yiy5-methylphenol

The title compound was prepared from 5-[3-(benzyloxy)-5-methylphenyl]-l-isobutyl- lH-te raazole essentially according to the procedure described in Example III, Step G. The product was isolated by flash column chromatography (2:1 - 1:1 hexanes/EtOAc to EtOAc) as a clear oil.

Step F: S-G-l∑-rS-Chloro^-dg-l^^-triazol-l-yllphenyllethoxyl-S-methylphenvn-l- isobutyl- lH-tetraazole The title compound was prepared essentially according to the procedure described in

Example II, Step D, with 3-(l-isobutyl-lH-tetraazol-5-yl)-5-methylphenol (81 mg, 0.35 mmol) and 2- [5-chloro-2-(lfl^r-l,2,4-triazol-l-yl)phenyl]ethanol (78 mg, 0.35 mmol) as the coupling partners.

Purification by flash column chromatography (7:3 EtOAc/hexanes to EtOAc) followed by precipitation from saturated HCl/EtOAc afforded the coupled product as a white solid. Η NMR (CD₃OD) δ 9.15

(s, IH), 8.42 (s, IH), 7.68 (s, IH), 7.48-7.46 (m, 2H), 7.07 (s, 2H), 6.95 (s, 2H), 4.31 (d, J= 7.2 Hz,

2H), 4.22 (t, / = 6.2 Hz, 2H), 3.05 (t, /= 6.2 Hz, 2H), 2.40 (s, 3H), 2.17-2.14 (M, IH), 0.85 (d, /= 6.4 Hz, 6H); Mass Spec (M+l) 438.1810.

EXAMPLE XX Preparation of 5-(3-{2-[5-Chloro-2-(lrϊ-l,2,4-triazol-l-yl)phenyl]ethoxy}phenyl)-l-isobutyl-l/_t- tetraazole

Step A: 3-Hvdroxy-iV-isobutylbenzamide

The title compound was prepared from 3-hydroxybenzoic acid (5.00 g, 36 mmol) essentially according to the procedure described in Example XIX, Step (B). The amide was obtained as a white powder.

Ste B: 3-(Benzyloxy^")-JV-isobutylbenzamide The title compound was prepared from S-hydroxy-iV-isobutylbenzatnide (6.93 g, 36 mmol) essentially according to the procedure described Example XIX, Step (C). Flash column chromatography (2:3 EtOAc/hexanes to 3:2 EtOAc/hexanes) afforded the benzyl ether as a white powder.

Step C: 5-r3-(Benzyloxy phenyll-l-isobutyl-lH-tetraazole

The title compound was prepared from 3-(benzyloxy)-Λf-isobutylbenzamide (5.4 g, 19 mmol) essentially according to the procedure described in Example XIX, Step (D). Flash column chromatography (1:4 EtOAc/hexanes to 1:1 EtOAc/hexanes) afforded the tetrazole as an off-white solid.

Step D: 3-(T-Isobutyl-lff-tetraazol-5-yl)phenol

The title compound was prepared from 5-[3-(Benzyloxy)phenyl]-l-isobutyl-lH-tetraazole (5.4 g, 19.1 mmol) essentially according to the procedure described in Example XVII, Step (G). Flash column chromatography (1:4 EtOAc/hexanes to 1:1 EtOAc/hexanes to EtOAc) afforded the phenol as a white solid.

Step E: 5-(3-{2-r5-chloro-2-( -1.2.4-triazol-l-yl^')phenyllethoxy)phenyl^')-l-isobutyl-l /- tetraazole The title compound was prepared essentially according to the Mitsunobu protocol described in

Example XVII, Step H, with 3-(l-isobutyl-lH-tetraazol-5-yl)phenol (300 mg, 1.4 mmol) and 2-[5- chloro-2-(lH-l,2,4-triazol-l-yl)phenyl]ethanol (308 mg, 1.4 mmol) as the coupling partners. The crude product was purified by reverse phase HPLC. The sticky solid was partitioned between EtOAc and saturated K₂C0₃ solution, and the organic layer was dried over MgS0₄and concentrated to dryness. The residue was suspended in 4.0M HCl/Et₂0 and the solvent was removed in vacuo. Drying under high vacuum afforded the coupled product as a tan crystalline powder. *H NMR (CDC1₃) δ 9.52 (s,

IH), 8.46 (s, IH), 7.56 (s, IH), 7.47-7.43 (m, 3H), 7.27-7.16 (m, 2H), 7.06-7.04 (m, IH), 4.24-4.22 (m,

4H), 3.06 (t, 7 = 5.8 Hz, 2H), 2.28-2.46 (m, IH), 0.89 (d, J = 5.2 Hz, 6H); Mass Spec (M+l) 424.1654.

EXAMPLE XXI

Preparation of 5-[3-chloro-5-{2-[5-chloro-2-(lfl^r-l,2,4-triazol-l-yl)phenyl]ethoxy}phenyl)-l-isobutyl- lH-tetraazole

Step A: Methyl 3-(benzyloxy -5-chlorobenzoate To a solution of methyl 3-chloro-5-hydroxybenzoate (Takahashi, K.; Shimizu, S.;

Ogata, M. Heterocycles 1985, 23, 1483-1491)(810 mg, 4.3 mmol) in acetone (6 mL) at 0 °C was added K₂C0₃ (600 mg, 4.3 mmol) followed by benzyl bromide (742 mg, 4.3 mmol). The reaction was allowed to warm to 25 °C and was then heated to reflux under inert atmosphere for 4 h. The solvent was removed in vacuo and the residue was dissolved in CHC1₃ and washed successively with 10% citric acid solution, water, and brine. The organic layer. was dried over Na₂S0₄ and concentrated to dryness. Flash column chromatography (hexane to 1:4 EtOAc/hexanes) gave the product as a white solid. Step B: 3-(Benzyloxy -5-chlorobenzoic acid

The title compound was prepared from methyl 3-(benzyloxy)-5-chlorobenzoate (1.2 g, 4.3 mmol) essentially according to the procedure outlined in Example XIX, Step (A). The solids were suspended in saturated HCl/EtOAc, and the insolubles were filtered off and washed with more EtOAc. The filtrate was concentrated to dryness to afford the acid as a white solid. Step C: 3-(Benzyloxy)-5-chloro-A^-isobutylbenzamide

The title compound was prepared from 3-(benzyloxy)-5-chlorobenzoic acid (453 mg, 1.7 mmol) essentially according to the procedure described in Example XIX, Step B. The reaction was diluted to three times its volume with water and extracted into EtOAc. The organic layers were dried over Na₂S0₄ and concentrated to afford the amide as a light yellow solid.

Step D: 5-r3-(Benzyloxy -5-chlorophenyll-l-isobutyl-l//-tetraazole

The title compound was prepared from 3-(benzyloxy)-5-chloro-._V-isobutylbenzamide (576 mg, 1.8 mmol) essentially according to the procedure described in Example XIX, Step D. Flash column chromatography (1:2 EtOAc/hexanes to 1:1 EtOAc/hexanes) afforded the tetrazole as an off-white solid.

Step E: 3-Chloro-5-( 1-isobutyl- lH-tetraazol-5-yl^")phenol

The title compound was prepared from 5-[3-(benzyloxy)-5-chlorophenyl]-l-isobutyl-l//- tetraazole (305 mg, 0.89 mmol) essentially according to the procedure found in Example XVII, Step (G). Flash column chromatography (hexanes to 1:9 EtOAc/hexanes to 1:4 EtOAc/hexanes to 1:2 EtOAc/hexanes) afforded the phenol as a white solid.

Step F: 5-(3-chloro-5-{2-r5-chloro-2-(lH-l,2.4-triazol-l-yl)phenyllethoxy)phenylVl- isobutyl- lH-tetraazole The title compound was prepared essentially according to the procedure of Example XVII, Step H, with 3-chloro-5-(l-isobutyl-l#-tetraazol-5-yl)phenol (75 mg, 0.30 mmol) and 2-[5-chloro-2- (1H-1, 2 ,4-triazol-l-yl)phenyl] ethanol (65 mg, 0.30 mmol) as the coupling partners. The crude product was purified by reverse phase HPLC. The resulting sticky solid was partitioned between EtOAc and saturated K₂C0₃ solution, and the organic layer was dried over MgS0₄ and concentrated to dryness. The residue was suspended in 4.0M HCl/Et₂0 and the solvent was removed in vacuo. Drying under high vacuum afforded the coupled product as a hygroscopic, yellow solid. ^!H NMR (CDC1₃) δ 9.62 (s, IH), 8.48 (s, IH), 7.59-7.55 (m, IH), 7.49-7.36 (m, 2H), 7.23-7.04 (m, 3H), 4.24-4.11 (m, 4H), 3.06- 3.01 (m, 2H), 2.28-2.23 (m, IH), 0.90 (d, J = 6.8 Hz, 6H); Mass Spec (M+l) 458.1252.

EXAMPLE XXII Preparation of l-(4-chloro-2-{2-[3-(l-isobutyl-lfl^r-tetraazol-5-yl)phenoxy]ethyl}phenyl)methanamine

Step A: 2-(2-Bromo-5-chlorophenyl^")ethanol To a solution of 2-bromo-5-chlorophenylacetic acid (3.00 g, 12 mmol) in anhydrous THF (70 mL) at 0 °C under inert atmosphere was added borane/dimethyl sulfide complex (6.84 mL, 72 mmol) over 5 min. The reaction was allowed to warm to 25 °C while stirring for 18 h. MeOH (15 mL) was added slowly to the reaction solution and the solvents were then removed in vacuo. MeOH (15 mL) was added to the remaining viscous material and was again removed in vacuo. Flash column chromatography (1:1 EtOAc/hexanes) provided the alcohol as a clear oil. Step B: l-Bromo-4-chloro-2-[2-(methoxymethoxy)ethyllbenzene

To a solution of 2-(2-bromo-5-chlorophenyl)ethanol (1.59 g, 6.8 mmol) in anhydrous THF (40 mL) at 0 ° C was added sodium hydride (405 mg, 10 mmol) followed by chloromethyl methyl ether (840 μL, 11 mmol). The reaction was allowed to warm to 25 °C while stirring for 18 h. The solvent was removed in vacuo, and the remaining residue was dissolved in CHC1₃ and washed successively with 10% citric acid solution, water, and brine. The organic layer was dried over Na₂S0₄ and concentrated to dryness. Flash column chromatography (hexanes to 1:9 EtOAc/hexanes to 1:4 EtOAc/hexanes) afforded the product as a clear oil. Step C: 4-Chloro-2-r2-(methoxymethoxy^')ethvHbenzaldehyde

To a solution of l-bromo-4-chloro-2-[2-(methoxymethoxy)ethyI]benzene (1.42 g, 5.1 mmol) in Et₂0 (10 mL) at 0 °C under inert atmosphere was added n-butyl lithium (2.5 M solution in hexanes, 2.0 mL, 5.1 mmol). The reaction was stirred at 0 °C for 10 min followed by rapid addition of DMF (470 μL, 6.1 mmol). The solution was stirred under inert atmosphere while warming to 25 °C over 18 h. The reaction was quenched by addition of water followed by extraction into Et₂0 three times. The organic layers were combined, dried over Na₂S0₄, filtered and concentrated. Flash column chromatography (hexanes to 1:9 EtOAc/hexanes to 3:17 EtOAc/hexanes) provided the aldehyde as a yellow oil.

Step D: (4-Chloro-2-r2-(methoxymethoxy)ethyllphenyl}methanol To a solution of 4-chloro-2-[2-(methoxymethoxy)ethyl]benzaldehyde (500 mg, 2.2 mmol) in

MeOH (3 mL) at 0 °C was added sodium borohydride (165 mg, 4.4 mmol). The reaction was stirred under inert atmosphere while warming to 25 °C over 4 h. The solution was diluted with water and extracted into EtOAc three times. The organic layers were combined, dried over Na₂S0₄, filtered and concentrated. Flash column chromatography (1:2 EtOAc/hexanes to 1:1 EtOAc/hexanes) afforded the alcohol as a clear oil.

Step E: l-(Azidomethyl)-4-chloro-2-r2-(methoxymethoxy)ethyllbenzene

To a solution of {4-chloro-2-[2-(methoxymethoxy)ethyl]phenyl}methanol (170 mg, 0.74 mmol) in dry THF (2 mL) at 0 °C was added diphenylphosphoryl azide (243 mg, 0.88 mmol) followed by l,8-diazabicyclo[5.4.0]undec-7-ene (135 mg, 0.88 mmol). The reaction was stirred for 18 h while warming to 25 °C. The solution was diluted with EtOAc and washed with water followed by extraction of the aqueous layer into EtOAc twice. The organic layers were combined, dried over Na₂S0₄, filtered and concentrated. Flash column chromatography (1:4 EtOAc/hexanes to 1:1 EtOAc/hexanes) provided the azide as a clear oil.

Step F: 1 - { 4-Chloro-2- r2-(^'methoxymethoxy^')ethyllphenyl } methanamine

To a solution of l-(azidomethyl)-4-chloro-2-[2-(methoxymethoxy)ethyl]benzene (197 mg, 0.77 mmol) in THF (3 mL) at 0 °C was added triphenylphosphine (212 mg, 0.81 mmol). The solution was stirred for Ih while warming to 25 °C. Water (280 μL, 15.4 mmol) was then added and the reaction was then heated to 55 °C for 5 h. Flash column chromatography (EtOAc to 1:9 MeOH/CHCl₃ to 8:1:1 EtOAc/MeOH NH_tOH) gave the amine as an orange oil.

Step G: 2-f2-(AminomethylV5-chlorophenvnethanol To a solution of l-{4-chloro-2-[2-(methoxymethoxy)ethyl]phenyl}methanamine (153 mg, 0.67 mmol) in THF (2 mL) was added 6 N HCl (1 mL). The reaction was stirred for 5 h and was then concentrated to yield the deprotected product as a clear oil.

Step H: tert- utyl 4-chloro-2-f2-hvdroxyethyl)benzylcarbamate

To a solution of 2-[2-(aminomethyl)-5-chlorophenyl]ethanol (124 mg, 0.67 mmol) in CH₂C1₂ (4 mL) were added triethylamine (90 μL, 0.67 mmol), di-rørt-butyldicarbonate (176 mg, 0.80 mmol), and 4-dimethylaminopyridine (8 mg, 0.07 mmol), sequentially. The reaction was stirred at 25 °C for 18 h. The mixture was diluted with EtOAc and washed once each with 10% citric acid, water, and brine.

The organic layer was dried over Na₂S0 and concentrated to dryness. Flash column chromatography

(1:9 EtOAc/hexanes to 3:7 EtOAc/hexanes to 1:1 EtOAc/hexanes) afforded the protected material as a cloudy oil.

Step I: fe^Butyl 4-chloro-2-{2-r3-α-isobutyl-lff-tetraazol-5- vDphenoxylethyl Ibenzylcarbamat The title compound was prepared essentially according to the procedure described in

Example XVII, Step H, with 3-(l-isobutyl-l//-tetraazol-5-yl)phenol (88 mg, 0.31 mmol) and tert- butyl-4-chloro-2-(2-hydroxyethyl)benzylcarbamate (88 mg, 0.31 mmol) as the coupling partners.

Purification by flash column chromatography (1:4 EtOAc/hexanes to 7:13 EtOAc/hexanes) afforded the coupled product as a yellow solid.

Step J: l-(4-Chloro-2-{2-r3-(l-isobutyl- -tetraazol-5-vDphenoxyl- ethyl IphenvDmethanamine ferf-Butyl 4-chloro-2-{2-[3-(l-isobutyl-l -tetraazol-5-yl)phenoxy]ethyl}benzylcarbamate

(134 mg, 0.28 mmol) was dissolved in concentrated HCl/EtOAc and stirred at 25 °C for 18 h.

Purification by reverse phase HPLC afforded a clear oil. The material was dissolved in EtOAc and washed with saturated K₂C0₃ solution. The organic layer was dried over Na₂S0₄, filtered and concentrated to dryness. The residue was then suspended in saturated HCl EtOAc and the solvent removed in vacuo. The resulting sticky solid was recrystallized from EtOAc to provide the title compound as a white powder. Η NMR (CD₃OD) δ 7.58-7.54 (m, 2H), 7.46-7.43 (m, IH), 7.40-7.37 (m, IH), 7.32-7.22 (m, 3H), 4.36-4.34 (m, 6H), 3.29-3.26 (m, 2H), 2.20-2.17 (m, IH), 0.88-0.86 (m, 6H); Mass Spec (M+l) 386.1742.

Typical tablet cores suitable for administration of thrombin inhibitors are comprised of, but not limited to, the following amounts of standard ingredients:

Suggested Excipient Ranges in Uncoated Tablet Core Compositions

Excipient General Range (%) Preferred Range (%) Most Preferred Range (%) mannitol 10-90 25-75 30-60 microcrystalline cellulose 10-90 25-75 30-60 magnesium stearate 0.1-5.0 0.1-2.5 0.5-1.5

Mannitol, microcrystalline cellulose and magnesium stearate may be substituted with alternative pharmaceutically acceptable excipients.

In vitro assay for determining proteinase inhibition

Assays of human α-thrombin and human trypsin were performed by the methods substantially as described in Thrombosis Research, Issue No. 70, page 173 (1993) by S.D. Lewis et al. The assays were carried out at 25°C in 0.05 M TRIS buffer pH 7.4, 0.15 M NaCl, 0.1% PEG. Trypsin assays also contained 1 mM CaCl2- In assays wherein rates of hydrolysis of a p-nitroanilide (pna) substrate were determined, a Thermomax 96-well plate reader was used was used to measure (at 405 nm) the time dependent appearance of p-nitroaniline. sar-PR-pna was used to assay human α-thrombin (K_m=125 μM) and bovine trypsin (K_m=125 μM). p-Nitroanilide substrate concentration was determined from measurements of absorbance at 342 nm using an extinction coefficient of 8270 cm^" IM^"1.

In certain studies with potent inhibitors (Ki < 10 nM) where the degree of inhibition of thrombin was high, a more sensitive activity assay was employed. In this assay, the rate of thrombin catalyzed hydrolysis of the fluorogenic substrate benzyloxycarbonyl-Gly-Pro-Arg-7-amino-4- trifluoromethylcoumarin (Z-GPR-afc, Lewis S.D. et al. (1998) J. Biol. Chem. 273, pp. 4843-4854) (K_m=27 μM) was determined from the increase in fluorescence at 500 nm (excitation at 400 nm) associated with production of 7-amino-4-trifluoromethyl coumarin. Concentrations of stock solutions of Z-GPR-afc were determined from measurements of absorbance at 380 nm of the 7-amino-4- trifluoromethyl coumarin produced upon complete hydrolysis of an aliquot of the stock solution by thrombin. Activity assays were performed by diluting a stock solution of substrate at least tenfold to a final concentration < 0.1 K_m into a solution containing enzyme or enzyme equilibrated with inhibitor. Times required to achieve equilibration between enzyme and inhibitor were determined in control experiments. Initial velocities of product formation in the absence (V₀) or presence of inhibitor (V ) were measured. Assuming competitive inhibition, and that unity is negligible compared K_m/[S],

[I]/e, and [I]/e (where [S], [I], and e respectively represent the total concentrations, of substrate, inhibitor and enzyme), the equilibrium constant (Ki) for dissociation of the inhibitor from the enzyme can be obtained from the dependence of V₀/Vi on [I] shown in the equation V₀/Vi = 1 + [I]/Ki-

The activities shown by this assay indicate that the compounds of the invention are therapeutically useful for treating various conditions in patients suffering from unstable angina, refractory angina, myocardial infarction, transient ischemic attacks, atrial fibrillation, thrombotic stroke, embolic stroke, deep vein thrombosis, disseminated intravascular coagulation, and reocclusion or restenosis of recanalized vessels. The inhibitory activity of compounds of the invention against human thrombin, represented by Ki, is less than 24 nM. These are selective compounds, as evidenced by their inhibitory activity against human trypsin (represented by Ki), which is at least 1000 nM.

EXAMPLE XXIII Tablet Preparation

Tablets containing 25.0, 50.0, and 100.0 mg., respectively, of the following active compounds are prepared as illustrated below (compositions A-I), Active I is 5-[2-(2'-Isobutyl-5- methyl-biphenyl-3-yloxy)-ethyl]-4-methyl-lH-imidazole; Active II is _S-[2-(2 -Isopropyl-5- methylbiphenyl-3-yloxy)-l-methyl-ethyl]-pyridin-4-yl-amine; Active III is l-{2-[2-(2 -Isopropyl-5- methyl-biphenyl-3-yloxy)-ethyl]-phenyl}-H_f-tetrazole.

Compositions containing from 25-100 mg of active compound (mg amounts)

Component A B C D E F G H I

Active I 25 50 100 - - -

Active II - - - 25 50 100 - Active III - - . . . 25 50 100 Microcrystalline

Cellulose 37.25 100 200 37.25 100 200 37.25 100 200 Modified food corn starch 37.25 4.25 8.5 37.25 4.25 8.5 37.25 4.25 8.5 Magnesium stearate 0.5 0.75 1.5 0.5 0.75 1.5 0.5 0.75 1.5

All of the active compound, cellulose, and a portion of the corn starch are mixed and granulated to 10% corn starch paste. The resulting granulation is sieved, dried and blended with the remainder of the corn starch and the magnesium stearate. The resulting granulation is then compressed into tablets containing 25.0, 50.0, and 100.0 mg, respectively, of active ingredient per tablet.

EXAMPLE XXIV Tablet Preparation Exemplary compositions of 5-[2-(2'-Isopropyl-5-methylbiphenyl-3-yloxy)- ethyl]-4-methyl-lfl-imidazole (Active IV) tablets are shown below:

Component 0.25 mg 2 mg 10 mg 50 mg

Active IV 0.500% 1.000% 5.000% 14.29% Mannitol 49.50% 49.25% 47.25% 42.61%

Microcrystalline cellulose 49.50% 49.25% 47.25% 42.61%

Magnesium stearate 0.500% 0.500% 0.500% 0.500%

2, 10 and 50 mg tablets were film-coated with an aqueous dispersion of hydroxypropyl cellulose, hydroxypropyl methylcellulose and titanium dioxide, providing a nominal weight gain of 2.4%.

Tablet preparation via direct compression

Active IV, mannitol and microcrystalline cellulose were sieved through mesh screens of specified size (generally 250 to 750 μm) and combined in a suitable blender. The mixture was subsequently blended (typically 15 to 30 min) until the drug was uniformly distributed in the resulting dry powder blend. Magnesium stearate was screened and added to the blender, after which a precompression tablet blend was achieved upon additional mixing (typically 2 to 10 min). The precompression tablet blend was then compacted under an applied force, typically ranging from 0.5 to 2.5 metric tons, sufficient to yield tablets of suitable physical strength with acceptable disintegration times (specifications will vary with the size and potency of the compressed tablet). In the case of the 2, 10 and 50 mg potencies, the tablets were dedusted and film-coated with an aqueous dispersion of water- soluble polymers and pigment.

Tablet preparation via dry granulation Alternatively, a dry powder blend is compacted under modest forces and remilled to afford granules of specified particle size. The granules are then mixed with magnesium stearate and tabletted as stated above.

EXAMPLE XXV Intravenous Formulations Intravenous formulations of 5-[2-(2 -Isopropyl-5-methylbiphenyl-3-yloxy)-ethyl]-4- methyl-lrϊ-imidazole (Active IV) were prepared according to general intravenous formulation procedures.

Component Estimated range

Active lV 0.12 - 0.61 mg D-glucuronic acid* 0.5 - 5 mg

Mannitol NF 50-53 mg

1 N Sodium Hydroxide q.s. pH 3.9 - 4.1

Water for injection q.s. 1.0 mL

Exemplary compositions A-C are as follows:

Component A B C

Active IV 0.50 mg 0.25 mg 0.12 mg

D-glucuronic acid* 1.94 mg 1.94 mg 1.94 mg

Mannitol NF 51.2 mg 51.2 mg 51.2 mg

1 N Sodium Hydroxide q.s. pH 4.0 q.s. pH 4.0 q.s. pH 4.0

Water for injection q.s. 1.0 mL q.s. 1.0 mL q.s. 1.0 mL

Various other buffer acids, such as L-lactic acid, acetic acid, citric acid or any pharmaceutically acceptable acid/conjugate base with reasonable buffering capacity in the pH range acceptable for intravenous administration may be substituted for glucuronic acid.

Claims

WHAT IS CLAIMED IS:

A compound having the formula:

where u, v and w, same or different, are CH or N;

X is O, S, S(O), S(0)2, NH, Cι_4alkenyl, C(O), C(0)NH, -C(O)O-,CR10R11, -CH2NH-, CH2O-, or

CF₂; Y is (CH₂)0-l(CR⁴R5)(CH₂)0-i; Z is O, S, S(O), S(0)2, C(O), N 1 , CR12R13, or CF₂ or a bond;

Rl is hydrogen, or Cι_4 alkyl, (OH_2)θ-lCN, C(0)Rl4, (CH2)θ-lCθ2Rl⁴, CF3, OR14, halogen,

SR14, S(0)Rl4, S(0)2Rl4, NR14R1 _;

R i is

1) phenyl, unsubstituted or substituted with one or two substituents independently selected

3) a 5-membered heterocyclic unsaturated ring having 1 heteroatom selected from the group consisting of N, O, and S, 2 N atoms, 2 S atoms, or 2 heteroatoms comprising 1 N and 1 S atom, wherein the ring is unsubstituted or monosubstituted with Cχ-4 alkyl;

R3 IS

1) phenyl, unsaturated ring system, unsubstituted, monosubstituted, disubstituted, or trisubstituted, same or different, with Ci-8 alkyl, -(CH2)0-4C3-7 cycloalkyl, or CO2R²⁰, 2) a 6-membered heterocyclic saturated ring system wherein 1 or 2 ring atoms are independently selected from the group of heteroatoms consisting of N, O and S, wherein the ring is unsubstituted, monosubstituted, disubstituted, or trisubstituted, same or different, with Ci-8 alkyl,

3) a 5- or 6-membered heterocyclic unsaturated ring having i) 1 heteroatom selected from N, S and O, ii) 2 heteroatoms selected from 1 N atom and 1 S atom, 1 N atom and 1 O atom, 1 S atom and 1 0 atom, 2 N atoms, and 2 S atoms, iii) 3 heteroatoms selected from 3 N atoms and 2 N atoms and 1 S atom, or iv) 4 N atoms, wherein the ring is unsubstituted, monosubstituted, or disubstituted, same or different, with Ci .g alkyl, C3..7 cycloalkyl, -(CH2)θ- C3-7 cycloalkyl, NH2, or (CH2)θ- 4Xl(CH2)0-3CH3, wherein χl is a bond, S, S(O), S(0)2, 0, or NH,

, where R is hydrogen or C_1-8alkyl,

wherein R is H, C_1-6 alkyl, or C_3-7 cycloalkyl, or

or C_3-7 cycloalkyl;

R²²

R⁴ and R^ are independently hydrogen or Ci-4 alkyl; R6 and R°> are independently

1) halogen,

2) (C(Rl⁶Rl⁷))i-2NH2, where each l6 and Rl7 can be the same or different; 3) a 5-membered heterocylcic unsaturated ring having 3 or 4 N atoms, wherein the ring is unsubstituted, monosubstituted, or disubstituted, same or different, with Cι_8 alkyl, C3.7 cycloalkyl, -(CH2)θ-4C3-7 cycloalkyl, NH2_; or (CH2)θ-4X²(CH2)θ-3CH3, wherein X² is a bond, S, S(O), S(0)2, 0, or NH

⁴⁾ ^ NH₂

NH ' ^or

R⁷ is halogen; RlO, Rll, Rl2_; R13, R14, R15, R16, R17_; R18, R19 _and R20 are independently hydrogen or Cι _4 alkyl, or a pharmaceutically acceptable salt thereof.

2. A compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein

Rl is hydrogen, CH3, CN or Cl; R4 is hydrogen or CH3, R5 is hydrogen or CH3; X is -0-, -C(0)NH-, -C(0)0-, -CH2NH- or -CH2O-; Y is -CH2CH2-, -CH₂CH(CH3)-, or -CH2"; and Z is -NH-, -O-, or a bond.

3. A compound of Claim 2, or a pharmaceutically acceptable salt thereof, wherein

R is selected from the group consisting of

1) a 5-membered unsaturated heterocyclic ring containing 2 N ring atoms, substituted with Cl-4 alkyl.

2) a 6-membered unsaturated heterocyclic ring containing 1 or 2 N ring atoms unsubstituted or substituted with one or two substituents independently selected from R6, and

3) phenyl, unsubstituted or substituted with one or two substituents independently selected from R6.

4. A compound of Claim 3, or a pharmaceutically acceptable salt thereof, wherein R is selected from the group consisting of

5. A compound of Claim 4, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from the group consisting of

6. A compound of Claim 5, or a pharmaceutically acceptable salt thereof, selected from the group consisting of

-76-

•79-

^•80-

and pharmaceutically acceptable salts thereof.

7. A compound of Claim 6, or a pharmaceutically acceptable salt thereof, selected from the group consisting of

84-

^■ 85-

and pharmaceutically acceptable salts thereof.

8. A compound of Claim 7, or a pharmaceutically acceptable salt thereof, selected from the group consisting of

9. A composition comprising a compound of Claim 1 and a pharmaceutically acceptable carrier.

10. A method for inhibiting thrombin in a patient comprising administering a composition of Claim 9 to the patient.

11. A method for inhibiting thrombus formation in a patient comprising administering a composition of Claim 9 to the patient.

12. The use of a compound of Claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting thrombin, inhibiting thrombus formation, treating thrombus formation, or preventing thrombus formation in a mammal.

13. A method for treating or preventing venous thromboembolism and pulmonary embolism in a patient comprising administering to the patient a composition of Claim 9.

14. A method for treating or preventing deep vein thrombosis in a patient comprising administering to the patient a composition of Claim 9.

15. A method for treating or preventing thromboembolic stroke in a patient comprising administering to the patient a composition of Claim 9.

16. A method for lowering the propensity of a device which contacts blood to clot blood, which comprises coating the device with a composition of Claim 9.