GB2307683A - HIV protease inhibitors useful for the treatment of AIDS - Google Patents

Abstract

Compounds of formula: n=0,1,2; wherein A is 1) aryl unsubstituted or substituted with one or more of a) C 1-4 lower alkyl; b) hydroxy; c) halo; d) C 1-4 lower or branched alkoxy; e) C 1-4 lower branched thioalkyl; f) COOR 1 ; g) CONHR 1 ; h) SO 2 NHR 1 ; i) SO 2 R 1 ; or j) C 1-4 lower hydroxyalkyl; or 2) a 5- to 10-membered mono or bicyclic heterocycle in which one or both heterocyclic rings contain an atom selected from N, O, or S, which heterocycle is unsubstituted or substituted with one or more of a) C 1-4 lower alkyl; b) hydroxy; c) halo; d) C 1-4 lower or branched alkoxy; e) C 1-4 lower branched thioalkyl; f) COOR 1 ; g) CONHR 1 .

Description

TITLE r: OF THE INVENTION HIV PROTEASE INHIBITORS USEFUL FOR THE TREATMENT OF AIDS This application is related to U.S. 5,413,999.

The present invention is concerned with compounds which inhibit the protease encoded by human immunodeficiency virus (HIV) or pharmaceutically acceptable salts thereof and are of value in the prevention of infection by HIV, the treatment of infection by HIV and the treatment of the resulting acquired immune deficiency syndrome (AIDS). It also relates to pharmaceutical compositions containing the compounds and to a method of use of the present compounds and other agents for the treatment of AIDS and viral infection by HIV.

BACKGROUND OF THE INVENTION A retrovirus designated human immunodeficiency virus (hit) is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. This virus was previously known as LAV, HTLV-III, or ARV. A common feature of retrovirus replication is the extensive post-translational processing of precursor polyproteins by a virally encoded protease to generate mature viral proteins required for virus assembly and function. Inhibition of this processing prevents the production of normally infectious virus. For example, Kohl, N.E. et al., Proc. Nat'l Acad.Sci., 85, 4686 (1988) demonstrated that genetic inactivation of the HIV encoded protease resulted in the production of immature, non-infectious virus particles. These results indicate that inhibition of the HIV protease represents a viable method for the treatment of AIDS and the prevention or treatment of infection by HIV.

The nucleotide sequence of HIV shows the presence of a pol gene in one open reading frame [Ratner, L. et al., Nature, 313 277(1985)]. Amino acid sequence homology provides evidence that the pol sequence encodes reverse transcriptase, an endonuclease and an H1V protease [Toh, H. ., al., EMBO J., 4, 1267 (1985); Power, M.D. et awl., Science, 231, 1567 (1986); Pearl, L.H. et al., Nature, 329, 351 (1987)].

Applicants demonstrate that the compounds of this invention are inhibitors of HIV protease.

BRIEF DESCRIPTION OF THE INVENTION Compounds of Formula I, as herein defined, are disclosed.

These compounds are useful in the inhibition of HIV protease, the prevention of infection by HIV, the treatment of infection by HIV and in the treatment of AIDS, either as compounds, pharmaceutically acceptable salts, pharmaceutical composition ingredients, whether or not in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS, methods of preventing infection by HIV, and methods of treating infection by HIV are also disclosed.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS This invention is concerned with compounds of Formula I, combinations thereof, or pharmaceutically acceptable salts thereof, in the inhibition of HIV protease, the prevention or treatment of infection by HIV and in the treatment of the resulting acquired immune deficiency syndrome (AIDS).Compounds of Formula I are defined as follows:

n=O, 1,2; Wherein A is 1) aryl unsubstituted or substituted with one or more of a) C1-4 lower alkyl; b) hydroxy; c) halo; d) C1-4 lower or branched alkoxy; e) Cl -4 lower branched thioalkyl; f) COOR1; g) CONHR1; h) SO2NHR1; i) SO2R1;or j) C1-4 lower hydroxyalkyl; or 2) a 5- to 10-membered mono or bicyclic heterocycle in which one or both heterocyclic rings contain an atom selected from N, O, or S, which heterocycle is unsubstituted or substituted with one or more of a) C 1-4 lower alkyl; b) hydroxy; c) halo; d) Ci -4 lower or branched alkoxy; e) C1-4 lower branched thioalkyl; f) COOR; g) CONHR; h) S02NHRI; i) SO2RI; or j) C 1-4 lower hydroxyalkyl; and R is 1) aryl, unsubstituted or substituted with C1-4 lower alkyl, C1-4 lower alkoxy, or halo, or 2) C37 cycloalkyl; and R1 is C14 lower alkyl, C3 7cycloalkyl or H; and Jigs:

or pharmaceutically acceptable salt(s) thereof.

Within formula I, one preferred embodiment of the present invention covers compounds of the formula:

Xis COOR1; CONHR; SO2NHR 1, or S02R1; or a pharmaceutically acceptable salt thereof.

Within formula I, another preferred embodiment of the present invention covers compounds of the formula:

X is CONHR1 or S02NHR1, or pharmaceutically acceptable salt thereof.

Preferred compounds of the present invention include, but are not limited to: Compound A:

or pharmaceutically acceptable salts thereof; Compound B:

or pharmaceutically acceptable salts thereof; Compound C.

or pharmaceutically acceptable salts thereof.

The compounds of the present invention may be prepared as pharmaceutical compositions comprising any compound of the present invention and a pharmaceutically acceptable carrier. Such pharmaceutical compositions are useful in the treatment of and the delaying of the onset of AIDS, in the prevention of infection by HIV, in the treatment of infection of HIV, or in the inhibition of HIV protease.

A method of treating and delaying the onset of AIDS, a method of preventing infection by HIV, a method of treating infection by HIV, and a method of inhibiting HIV protease are also disclosed. Also disclosed is a combination of compounds, which is compound A, B or C, and any of AZT or ddI or ddC.

The compounds of the present invention, may have asymmetric centers and occur as racemates, racemic mixtures and as individual diastereomers, or enantiomers with all isomeric forms being included in the present invention.

When any variable (e.g., aryl, heterocycle, R, Rl, n, etc.) 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.

As used herein except where noted, "alkyl" is intended to include 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); "alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge; and "cycloalkyl" is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl (Cyh) and cycloheptyl. "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, trifluroacetate, perchlorate, nitrate, benzoate, maleate, tartrate, hemitartrate, benzene sulfonate, and the like.

As used herein, with exceptions as noted, "aryl" is intended to mean phenyl (Ph) or naphthyl.

The term heterocycle or heterocyclic, as used herein except where noted, represents a stable 5- to 7-membered mono- or bicyclic or stable 7- to 1 0-membered bicyclic heterocyclic ring system, any ring of which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, 0 and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quatemized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.

Examples of such heterocyclic elements include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazoyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl.

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 or the quatemary ammonium salts which are formed, e.g., from inorganic or organic acids or bases.

Examples of such acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropi onate, di glu conate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, ni cotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate.Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-Dglucamine, and salts with amino acids such as arginine, lysine, and so forth. Also, the basic nitrogen-containing groups may be quatemized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others. Other pharmaceutically acceptable salts include the sulfate salt ethanolate and sulfate salts.

Schemes I-In for preparing the novel compounds of this invention are presented below. Tables I and Il which follow the schemes illustrate the compounds that can be synthesized by Schemes 1- m, but Schemes I-m are not limited by the compounds in the tables nor by any particular substituents employed in the schemes for illustrative purposes. The examples specifically illustrate the application of the following schemes to specific compounds.

Amide couplings used to form the compounds of this invention are typically performed by the carbodiimide method with reagents such as dicyclohexylcarbodiimide, or 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide. Other methods of forming the amide or peptide bond include, but are not limited to the synthetic routes via an acid chloride, azide, mixed anhydride or activated ester. Typically, solution phase amide coupling are performed, but solid-phase synthesis by classical Merrifield techniques may be employed instead. The addition and removal of one or more protecting groups is also typical practice.

Additional related information on synthetic background is contained in EPO 0337714.

One method for producing Formula I compounds is provided by Scheme I.

SCHEME I

In the synthesis of the compounds of this invention, epoxide B is reacted with lithiated end group A to give an acetonide intermediate. Subsequent acid hydrolysis gives C. The reaction of epoxide with A is carried out in the presence of a mild Lewis acid such as BF3. In this Scheme I, the stereochemical integrity of the carbon B is substantially retained. Epoxide B is synthesized by known procedures, e.g. Examples 1-5, U.S 5,413,999, or WO 95/02583.

SCHEME II

Scheme II employs a bromine derivative D as a starting material. Reaction with n-BuLi or other lithiating agents readily lithiates the end group. Subsequent reaction with epoxide B in the presence of a mild Lewis acid, followed by acid hydrolysis of the acetonide group, gives F.

SCHEME m

1. sec-BuLThMEDA/THF -700 - -15 C R 2. Ph CHH3 0 ,J.

G 3. Separate 4. CSA/MeOH R Ph OH H N, 2 H R is C1 4 alkyl, hydroxy, halo, CiA lower or branched alkoxy, CI -4 lower branched thioalkyl, COOR, CONHR 1, S02NHR 1, S02R or C 1-4 lower hydroxyalkyl.

In Scheme m the aldehyde J is used instead of epoxide B.

Ortho-metalation of the benzamide G, followed by reaction with aldehyde J gives acetonide. Acid hydrolysis provides end product H.

Aldehyde J is prepared ozonolysis of allyl acetonide of Example 1.

The compounds of this invention are useful in the preparation and execution of screening assays for antiviral compounds.

For example, the compounds of this invention are useful for isolating enzyme mutants, which are excellent screening tools for more powerful antiviral compounds. Furthermore, the compounds of this invention are useful in establishing or determining the binding site of other antivirals to HIV protease, e.g., by competitive inhibition. Thus the compounds of this invention are commercial products to be sold for these purposes.

The compounds of the present invention are useful in the inhibition of HIV protease the prevention or treatment of infection by the human immunodeficiency virus (mix) and the treatment of, and delaying of the onset of consequent pathological conditions such as AIDS. Treating AIDS or preventing or treating infection by HIV is defined as including, but not limited to, treating a wide range of states of HIV infection: AIDS, ARC (AIDS related complex), both symptomatic and asymptomatic, and actual or potential exposure to HIV. For example, the compounds of this invention are useful in treating infection by HIV after suspected past exposure to HIV by, e.g., blood transfusion, organ transplant, exchange of body fluids, bites, accidental needle stick, or exposure to patient blood during surgery.

For these purposes, the compounds of the present invention may be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques), by inhalation spray, or rectally, in dosage unit formulations containing conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles.

Thus, in accordance with the present invention there is further provided a method of treating and a pharmaceutical composition for treating HIV infection and AIDS. The treatment involves administering to a patient in need of such treatment a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

These pharmaceutical compositions may be in the form of orally-administrable suspensions or tablets; nasal sprays; sterile injectable preparations, for example, as sterile injectable aqueous or oleagenous suspensions or suppositories.

When administered orally as a suspension, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may contain microcrystalline cellulose for imparting bulk, alginic acid or sodium alginate as a suspending agent, methylcellulose as a viscosity enhancer, and sweetners/flavoring agents known in the art. As immediate release tablets, these compositions may contain microcrystalline cellulose, dicalcium phosphate, starch, magnesium stearate and lactose and/or other excipients, binders, extenders, disintegrants, diluents and lubricants known in the art.

When administered by nasal aerosol or inhalation, these compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.

The injectable solutions or suspensions may be formulated according to known art, using suitable non-toxic, parenterallyacceptable diluents or solvents, such as mannitol, 1 ,3-butanediol, water, Ringer's solution or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, bland, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid.

When rectally administered in the form of suppositories, these compositions may be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but liquidify and/or dissolve in the rectal cavity to release the drug.

Dosage levels of the order of 0.02 to 5.0 or 10.0 gramsper-day are useful in the treatment or prevention of the above-indicated conditions, with oral doses two-to-five times higher. For example, infection by HIV is effectively treated by the administration of from 1.0 to 50 milligrams of the compound per kilogram of body weight from one to four times per day. In one preferred regimen, dosages of 100400 mg every six hours are administered orally to each patient.It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

The present invention is also directed to combinations of the HIV protease inhibitory compounds with one or more agents useful in the treatment of AIDS. For example, the compounds of this invention may be effectively administered, whether at periods of preexposure and/or post-exposure, in combination with effective amounts of the AIDS antivirals, immunomodulators, anti-infectives, or vaccines known to those of ordinary skill in the art.

TABLE C ANTIVIRALS Drug Name Manufacturer Indication AL-721 Ethigen ARC, PGL (Los Angeles, CA) HIV positive, AIDS Recombinant Human Triton Biosciences AIDS, Kaposi's Interferon Beta (Almeda, CA) sarcoma, ARC Acemannan Carrington Labs ARC (loving, TX) (See also immunomodulators) Cytovene Syntex sight threatening CMV Ganciclovir (Palo Alto, CA) peripheral CMV retinitis d4T Bristol-Myers AIDS, ARC Didehydrodeoxy- (New York, NY) thymidine ddI Bristol-Myers AIDS, ARC Dideoxyinosine (New York, NY) EL10 Elan Corp, PLC HIV infection (Gainesville, GA) (See also immunomodulators) Trisodium Astra Pharm. CMV retinitis, HIV Phosphonoformate Products, Inc infection, other CMV (Westborough, MA) infections Dideoxycytidine; Hoffman-La Roche AIDS, ARC ddC (Nutley, NJ) Novapren Novaferon Labs, Inc.HIV inhibitor (Akron, OH) Diapren, Inc.

(Roseville, MN, marketer) Peptide T Peninsula Labs AIDS octapeptide (Belmont, CA) Sequence Zidovudine; AZT Burroughs Wellcome AIDS, adv, ARC AIDS, adv, ARC (Rsch. Triangle Park, pediatric AIDS, NC) Kaposi's sarcoma, asymptomatic HIV infection, less severe HIV disease, neurological involvement, in combination with other therapies.

Ansamycin LM 427 Adria Laboratories ARC (Dublin, OH) Erbamont (Stamford, CT) Dextran Sulfate Ueno Fine Chem. AIDS, ARC, HIV Ind. Ltd. positive asymptomatic (Osaka, Japan) Virazole Viratek/lCN asymptomatic HIV Ribavirin (Costa Mesa, CA) positive, LAS, ARC Alpha Interferon Burroughs Wellcome Kaposi's sarcoma, (Rsch. Triangle HIV in combination Park, NC) w/Retrovir Acyclovir Burroughs Wellcome AIDS,ARC, asymptomatic HIV positive, in combination with AZT.

Antibody which Advanced Biotherapy AIDS, ARC neutralizes pH Concepts labile alpha aberrant (Rockville, MD) Interferon in an immuno-adsorption column IMMUNO-MODULATORS Drug Name Manufacturer Indication AS-lOl Wyeth-Ayerst Labs. AIDS (Philadelphia, PA) Bropirimine Upjohn advanced AIDS (Kalamazoo, MI) Acemannan Carrington Labs, Inc. AIDS, ARC (See also (Irving, TX) anti-virals) CL246,738 American Cyanamid AIDS, Kaposi's (Pearl River, NY) sarcoma Lederle Labs (Wayne, NJ) JELLO Elan Corp, PLC HIV infection (Gainesville, GA) (See also anti virals) Gamma Interferon Genentech ARC, in combination (S.San Francisco, w/TNF (tumor CA) necrosis factor) Granulocyte Genetics Institute AIDS Macrophage Colony (Cambridge, MA) Stimulating Sandoz Factor (East Hanover, NJ) Granulocyte Hoeschst-Roussel AIDS Macrophage Colony (Sommerville, NJ) Stimulating Immunex Factor (Seattle, WA) Granulocyte Schering-Plough AIDS Macrophage Colony (Madison, NJ) Stimulating Factor AIDS, in combination w/AZT HIV Core Particle Rorer seropositive HIV Immunostimulant (Ft.Washington, PA) IL-2 Cetus AIDS, in combination Interleukin-2 (Emeryville, CA) w/AZT IL-2 Hoffman-La Roche AIDS, ARC, HIV, in Interleukin-2 (Nutley, NJ) combination w/AZT Immunex Immune Globulin Cutter Biological pediatric AIDS, in Intravenous (Berkeley, CA) combination w/AZT (human) IMREG-1 Imreg AIDS, Kaposi's (New Orleans, LA) sarcoma, ARC, PGL IMREG-2 Imreg AIDS, Kaposi's (New Orleans, LA) sarcoma, ARC, PGL Lmuthiol Diethyl Merieux Institute AIDS, ARC Dithio Carbamate (Miami, FL) Alpha-2 Schering Plough Kaposi's sarcoma Interferon (Madison, NJ) w/AZT: AIDS Methionine- TNI Pharmaceutical AIDS, ARC Enkephalin (Chicago, L) MTP-PE Ciba-Geigy Corp. Kaposi's sarcoma Muramyl- (Summit, NJ) Tripeptide Granulocyte Amgen AIDS, in combination Colony Stimulating (Thousand Oaks, CA) w/AZT Factor rCD4 Genentech AIDS, ARC Recombinant (S. San Francisco,CA) Soluble Human CD4 rCD4-IgG AIDS, ARC hybrids Recombinant Biogen AIDS, ARC Soluble Human CD4 (Cambridge, MA) Interferon Hoffinan-La Roche Kaposi's sarcoma Alfa 2a (Nutley, NJ) AIDS, ARC, in combination w/AZT SK & 106528 Smith, Kline & HIV infection Soluble T4 French Laboratories (Philadelphia, PA) Thymopentin Immunobiology HIV infection Research Institute (Annandale, NJ) Tumor Necrosis Genentech ARC, in combination Factor; TNF (S.San Francisco, w/gamma Interferon CA) ANTI-INFECTTVES Drug Name Manufacturer Indication Clindamycin with Upjohn PCP Primaquine (Kalamazoo, MI) Fluconazole Pfizer cryptococcal (New York, NY) meningitis, candidiasis Pastille Squibb Corp. prevention of Nystatin Pastille (Princeton, NJ) oral candidiasis Ornidyl Merrell Dow PCP Eflornithine (Cincinnati, OH) Pentamidine LyphoMed PCP treatment Isethionate (IM & IV) (Rosemont, IL) Trimethoprim antibacterial Trimethoprim/sulfa antibacterial Piritrexim Burroughs Wellcome PCP treatment (Rsch.Triangle Park, NC) Pentamidine Fisons Corporation PCP prophylaxis isethionate for (Bedford, MA) inhalation Spiramycin Rhone-Poulenc cryptosporidial Pharmaceuticals diarrhea (Princeton, NJ) Intraconazole- Janssen Pharm. histoplasmosis; R51211 (Piscataway, NJ) cryptococcal meningitis Trimetrexate Warner-Lambert PCP OTHER Drug Name Manufacturer Indication Recombinant Human Ortho Pharm. Corp. severe anemia Erythropoietin (Raritan, NJ) assoc. with AZT therapy Megestrol Acetate Bristol-Myers treatment of (New York, NY) anorexia also.

w/AIDS Total Enteral Norwich Eaton diarrhea and Nutrition Pharmaceuticals malabsorption (Norwich, NY) related to AIDS It will be understood that the scope of combinations of the compounds of this invention with AIDS antivirals, immunomodulators, anti-infectives or vaccines is not limited to the list in the above Table, but includes in principle any combination with any pharmaceutical composition useful for the treatment of AIDS.

The synthesis of ddC, ddl and AZT are also described in EPO 484071.

Preferred combinations are simultaneous or alternating treatments of an inhibitor of HIV protease and a nucleoside inhibitor of HIV reverse transcriptase, such as AZT, ddC or ddl.

Assay for Inhibition of Microbial Expressed HIV Protease Inhibition studies of the reaction of the protease expressed in Eschericia coli with a peptide substrate [Val-Ser-Gln-Asn (betanapthyl)Ala-Pro-Ile-Val, 0.5 mg/mL at the time the reaction is initiated] were in 50 mM Na acetate, pH 5.5, at 300C for 1 hour.

Various concentrations of inhibitor in 1.0 ml DMSO were added to 25 ml of the peptide solution in water. The reaction is initiated by the addition of 15 ml of 0.33 nM protease (0.11 ng) in a solution of 0.133 M Na acetate pH 5.5 and 0.1% bovine serum albumin. The reaction was quenched with 160 ml of 5% phosphoric acid. Products of the reaction were separated by HPLC (VYDAC wide pore 5 cm C-18 reverse phase, acetonitrile gradient, 0.1% phosphoric acid). The extent of inhibition of the reaction was determined from the peak heights of the products.

HPLC of the products, independently synthesized, proved quantitation standards and confirmation of the product composition. Compounds A, B and C showed IC50 values in the range of about 1 nM - 6 nM.

INHIBITION OF VIRUS SPREAD A. Preparation of MIV-infected MT4 cell Suspension.

MT cells were infected at Day 0 at a concentration of 250,000 per ml with a 1:1000 dilution of HIV-1 strain Ilib stock (final 125 pg p24/ml; sufficient to yield < 1% infected cells on day 1 and 25100% on day 4). Cells were infected and grown in the following medium: RPMI 1640 (Whittaker BioProducts), 10% inactivated fetal bovine serum, 4 mM glutamine (Gibco Labs) and 1:100 Penicillin Streptomycin (Gibco Labs).

The mixture was incubated ovemight at 37"C in 5% C02 atmosphere.

B. Treatment with Inhibitors A matrix of nanomolar range concentrations of the pairwise combinations was prepared. At Day 1, aliquots of 125 ml of inhibitors were added to equal volumes of HlV-infected MT-4 cells (50,000 per well) in a 96-well microtiter cell culture plate. Incubation was continued for 3 days at 370C in 5% CO2 atmosphere.

C. Measurement of Virus Spread Using a multichannel pipettor, the settled cells were resuspended and 125 ml harvested into a separate microtiter plate. The supernatant was assayed for HIV p24 antigen.

The concentration of HIV p24 antigen was measured by an enzyme immunoassay, described as follows. Aliquots of p24 antigen to be measured were added to microwells coated with a monoclonal antibody specific for HIV core antigen. The microwells were washed at this point, and at other appropriate steps that follow. Biotinylated HIVspecific antibody was then added, followed by conjugated strepavidinhorseradish peroxidase. A color reaction occurs from the added hydrogen peroxide and tetramethylbenzidine substrate. Color intensity is proportional to the concentration of HIV p24 antigen. The C1C95 of Compounds A and B were 800 nM and 1500 nM, respectively.

EXAMPLE 1 Conversion of Acetonide to Allvl Acetonide

Acetonide Allyl acetonide Acetonide 32.1 g Allyl bromide 12.70 g Lithiumhexamethyldisilazide (LHMDS) 1.0 M in TMF 105 mL Tetrahydrofuran (THF) 200 mL The acetonide was dissolved in 200 mL TMF in a 100 mL 3 neck flask equipped with an addition funnel and degassed by bubbling in nitrogen for 20 min. The mixture was cooled to -25 C and the allyl bromide was added via a weighed syringe. The LHMDS was transferred to the addition funnel under nitrogen pressure via cannula.

The LHMDS was allowed to slowly drop into the magnetically stirred reaction mixture over 20 min. The internal temperature reached -14 C while the cooling bath was at -30 C. The mixture was aged at -20 to -15 C for 30 min. Water (100 mL) and IPAC (100 mL) were added and the temperature rose to 50C. The lower aqueous phase was discarded and the organic phase was washed with 100 mL of 0.2 M HCI in 3% aq. NaCI, 30 mL brine, and 30 mL 0.5 M sodium bicarbonate.

The organic phase was evaporated (55 C, 100 Torr) to an oil, another 40 mL of IPAC were added, and the mixture was again evaporated to an oil. At this point the crude allyl acetonide may be taken directly on to the next step or purified by crystallization from 30:1 hexane-IPAC or 30:1 methylcyclohexane-IPAC to give the allyl acetonide as a white crystalline solid in 87% yield.

Allyl acetonide 13C NMR data for major rotamer (62.5 MHz) 171.0 140.4 140.2 134.S 129.6 128.6 128.2 127.1 126.6 125.6 124.0 117.9 96.S 78.9 65.6 47.5 38.6 38.0 36.1 26.6 24.1 ppm EXAMPLE 2 Conversion of Allyl Acetonide to lodohyrin and Cyclization to Epoxide with NIS

Allyl acetonide lodohydrin

Ph Base7 K"'' 8 0 ~~ Epoxide Allyl acetonide (crude from above preparation) ca 0.1 mol N-iodosuccinimide (NIS) 29.24 g Aqueous sodium bicarbonate (0.5 M) 350 mL Isopropyl acetate (IPAC) 300 mL The crude allyl acetonide was dissolved in IPAC and stirred with the aqueous sodium bicarbonate and NIS for 17 h. Aqueous sodium bisulfite (38-40%) solution was added and the upper organic phase was separated.The organic phase was washed with 300 mL water and 2 x 100 mL brine. At this point the crude iodohydrin solution in IPAC can be directly taken on to the next step or the solution could be evaporated and crystallized from methylcyclohexane-IPAC to give the iodohydrin as a pale yellow crystalline solid, 13C NMR: , m.p.

rotation.

Iodohydrin (IPAC solution crude from above preparation) ca 0.1 mol Lithium hydroxide monohydrate 50 g Water 200 mL Iodohydrin 1 3C NMR data for major rotamer (62.5 MHz) 172.2 140.6 140.4 139.3 129.5 128.8 128.2 127.2 126.8 125.7 124.0 96.9 79.1 68.7 65.8 43.7 40.6 39.0 36.2 26.5 24.3 16.3 ppm EXAMPLE 3 Conversion of Allyl Acetonide to Iodohyrin and Cyclization to Epoxide with NCS/Nal The iodohydrin in IPAC was stirred with the lithium hydroxide in water for 3 h at 25-30"C. The upper organic phase was washed with 200 mL water and 200 mL brine and was dried over ca 2 g of magnesium sulfate.The IPAC solution was filtered and evaporated (50-600C, 100 Torr) down to ca 50 mL when the epoxide began to crystallize. The mixture was allowed to cool to 250C over 30 min and 75 mL of methylcyclohexane were added in 10 mL portions with stirring over 30 min. The mixture was aged for 1 h and the crystals were filtered off and washed with 2 x 20 mL methylcyclohexane and dried to give 24.10 g (64%) of the epoxide as a white crystalline solid of 99.9 A% purity by HPLC. The mother liquor and washes were evaporated to an oil and dissolved in 40 mL IPAC. The solution was treated with 10 g of Darco G60 carbon for 2 h at 25"C and filtered through a pad of Solkafl"C. The filtrate was evaporated down to ca 20 mL and 40 mL of methylcyclohexane were added.The crystalline epoxide was filtered off and washed with 2 x 10 mL methylcyclohexane to afford another 4.96 g (13%) of epoxide 96.2 A% by HPLC. The conversion of the iodohydrin to epoxide may also be accomplished by the addition of 1.7 M potassium-tert-butoxide in TMF (0.70 mL, 1.2 mmol) or 5 M potassium hydroxide in methanol (0.24 mL, 1.2 mmol) or DIEA (155 mg, 1.2 mmol) to a solution of the iodohydrin (505 mg, 1.0 mmol) in IPAC (2-3 mL) followed by washing with 2 x 2 mL water and crystallization from methyl cyclohexane-IPA C.

Allyl acetonide 26.15 g N-chlorosuccinamide (NCS) 22.7 g Sodium iodide 25.5 g Aqueous sodium bicarbonate (0.5 M) 350 mL lsopropyl acetate (IPAC) 300 mL The NCS and Nal were stirred together in 200 mL of water for 20 min. The mixture turned dark brown then immediately a black solid separated out. The solid dissolved and the color faded to clear yellow with further aging. The crude allyl acetonide was dissolved in IPAC and stirred with the aqueous sodium bicarbonate and the clear yellow solution prepared above for 17 h. Aqueous sodium bisulfite (38-40%) solution was added and the upper organic phase was separated. The organic phase was washed with 300 mL water and 2 x 100 mL brine.At this point the crude iodohydrin solution in IPAC can be directly taken on to the next step or the solution could be evaporated and crystallized from methylcyclohexane-IPAC to give the iodohydrin as a pale yellow crystalline solid.

EXAMPLE 4 Preparation of Amide 1

A solution of (-)-cis-l-aminoindan-2-ol (884 g, 5.93 mol) in 17.8 L of dry THF (KF = 55 mg/mL) (KF stands for Karl Fisher titration for water) and triethylamine (868 mL, 6.22 mol) in a 50 L round bottom flask equipped with a thermocouple probe, mechanical stirrer, and a nitrogen inlet adapter and bubbler, was cooled to 15"C.

Then, 3-phenylpropionyl chloride (1000 g, 5.93 mol) was added over 75 minutes, while the internal temperature between 14-24"C with an ice-water cooling batch. After addition, the mixture was aged at 18 to 20"C for 30 minutes and checked by HPLC analysis for the disappearance of (-)-cis-l -aminoindan-2-ol.

Progress of the reaction is monitored by high performance liquid chromatography (HPLC) analysis: 25 cm Dupont CR-RX column, 60:40 acetonitrile/lOmM (KH2P04/K2HP04), 1.0 mL/min., injection volume = 20 mL, detection = 200 nm, sample preparation = 500 X dilution. Approximate retention times: retention time (min.) identitv 6.3 cis-aminoindanol The reaction was treated with pyridinium p-toluenesulfonate (241 g, 0.96 mol, 0.16 equiv.) and stirred for 10 minutes (the pH of the mixture after diluting 1 mL sample with an equal volume of water is between 4.3-4.6). Then, 2-methoxypropene (1.27 L, 13.24 mol, 2.2 equiv.) was added and reaction was heated to 38-40 C for 2 h.

The reaction mixture was cooled to 200C and partitioned with ethyl acetate (12 L) and 5% aqueous NaHCO3 (10 L). The mixture was agitated and the layers were separated. The ethyl acetate extract was washed with 5% aqueous NaHCO3 (10 L) and water (4 L). The ethyl acetate extract was dried by atmospheric distillation and solvent switched to cyclohexane (total volume of -30L). At the end of the distillation and concentration (20 volume % of ethyl acetate extraction volume), the hot cyclohexane solution was allowed to slowly cool to 25"C to crystallize the product. The resulting slurry was further cooled to 1 00C and aged for 1 h.The product was isolated by filtration and the wet cake was washed with cold (10"C) cyclohexane (2 X 800 mL). The washed cake was dried under vacuum (26" of Hg) at 400C to afford 1.65 kg of acetonide 1(86.4%, 98 area% by HPLC), 1H NMR (300.13 MHz, CDC13, major rotamer) 3 7.36-7.14 (m, 9 H), 5.03 (d, J=4.4, 1 H), 4.66 (m, 1 H) 3.15 (m, 2 H), 3.06(burs, 2 H), 2.97 (m, 2 H), 1.62 (s, 3 H), 1.37 (s, 3 H); 13C NMR (75.5 MHz, CDC13, major rotamer) dc 168.8, 140.9, 140.8, 140.6, 128.6, 128.5, 128.4, 127.1, 126.3, 125.8, 124.1, 96.5, 78.6, 65.9, 38.4, 36.2, 31.9, 26.5, 24.1. Anal. Calcd for C21H23No2: C, 78.47; H, 7.21; N, 4.36. Found: C, 78.65; H, 7.24; N, 4.40.

EXAMPLE 5 Preparation of Epoxide 3 Tosylate Method

0 (S) /\ 0 ooth H B2ase 0: N9 3 oĬ A solution of acetonide 1(1000 g, 3.11 mol) and 2(S)glycidyl tosylate 2 (853 g, 3.74 mol, 1.2 equiv.) in 15.6 L of THF (KF = 22 mg/mL) in a 50 L 4-neck round bottom flask, equipped with a thermocouple, mechanical stirrer, addition funnel and nitrogen inlet adapter was degassed 3 times via vacuum-nitrogen purge and cooled to -56 C. Then, lithium hexamethyldisilazide (LiN[(CH3)3Si]2)(2.6 L, 1.38 M, 1.15 equiv.) was added over 2 h, while keeping the internal temperature between -50 to -45 C. The reaction mixture was stirred at -45 to -40 C for 1 h and then allowed to warm to -250C over I h. The mixture is stirred between -25 to -220C for 4 h (or until the starting acetonide is 3.0 area %).

Progress of the reaction is monitored by HPLC analysis: 25 cm X 4.6 nm Zorbax Silica column, 20% ethyl acetate in hexane, 2.0 mL/min, injection volume = 20 mL, detection = 254 nm, sample preparation = 100 X dilution. Approximate retention times: retention time (min.) identitv 5.5 amide 1 6.5 glycidyl tosylate 2 13.5 epoxide 3 The reaction mixture was quenched with DI water (6.7 L) at -15 C and partitioned with ethyl acetate (10 L). The mixture was agitated and the layers were separated. The ethyl acetate extract was washed with a mixture of 1 % aqueous NaHCO3 (5 L) and saturated NaCl (0.5 L).The ethyl acetate extract (28.3 L) was concentrated by vacuum distillation (28" of Hg) and additional ethyl acetate was added to complete the solvent switch to ethyl acetate (final volume = 11.7 L).

The ethyl acetate concentrate was further solvent switched to MeOH to crystallize the product and concentrated to a final volume of 3.2 L. The residual ethyl acetate solvent was removed by charging 10 L of methanol and collecting 10 L of distillate. The resulting slurry was stirred at 220C for 1 h, then cooled to 5"C and aged for 0.5 h.The product was isolated by filtration and the wet cake was washed with cold methanol (2 X 250 mL). The washed cake was dried under vacuum (26" of Hg) at 25"C to afford 727 g of epoxide 3 (61.2%, 98.7 area % of the major epoxide by HPLC): 13C NMR (300 MHz, CDCl3) 6 171.1, 140.6, 140.5, 139.6, 129.6, 128.8, 128.2, 127.2, 126.8, 125.6, 124.1, 96.8, 79.2, 65.8, 50.0,48.0, 44.8, 39.2, 37.4, 36.2, 26.6, 24.1. EXAMPLE 6

To a OOC solution of N-tert-butylbenzamide (531 mg, 3.0 mmol) in 10 mL of THF was added 2.44 mL (6.1 mmol) of n-BuLi (2.5 M in hexanes).The yellow solution was stirred at this temperature for 2 h before cooling to -700C. The resulting dianion was then treated with epoxide 3 (377.5 mg, 1.0 mmol) in 2 mL of THF followed immediately with 0.37 mL (3.1 mmoL) of BF30Et2. The reaction mixture was stirred for 40 min and quenched with 5 mL of sat'd NaHCO3 and diluted with 5 mL of Et2O. The aqueous phase was extracted with 3 x 5 mL of Et2O. The combined organic extracts were washed with brine and dried over MgSO4. The yellow oil was subjected to flash chromatography (SiO2; gradient 1:4, 1:3, 1:1 EtOAc/Hex) to afford compound 4a.

The above acetonide (49.1 mg, 0.08X5 mmol) was dissolved in 1 mL of 2-propanol and cooled to OOC. The solution was treated with 0.27 mL of 8 N HCl and was allowed to stir to ambient temperature over 4 h. The pH of the solution was then adjusted to 12 by the dropwise addition of 50 % NaOH at 0 C. The aqueous solution was extracted with 3x 5mL portions of CH2C12 and the combined organic extracts were washed with brine (2 x 5 mL) and dried (MgSO4).

Column chromatography (7:3 EtOAc/Hex) afforded 45.4 mg (92%) of Sa as a white solid.

1H NMR (CDC13) 6 1.47 (s, 9H), 1.76 (t, J=11.2 Hz, 1H), 2.10 (t, J=10.4 Hz, 1H), 2.70-3.01 (m, 5H), 3.93 (bs, 1H), 4.26 (bs, 1H), 5.29 (dd, J=5.1, 6.9 Hz, 1H), 5.45 (d, J=4.9 Hz, 1H), 5.96 (d, J=Rs.l Hz, 1H), 5.98 (s, 1H), 7.0-7.4 (m, 13 H).

MS (FAB) M+l = 515.

Anal calc'd for C32H38N2O4#0.8 H20: C, 72.64; H, 7.54, N, 5.30.

Found: C, 72.62; H, 7.68; N, 5.09.

EXAMPLE 7

A -70 C solution of N-(tert-butyl) benzene sulfonamide (639 mg, 3.0 mmol) in 10 mL of THF was treated with 2.44 mL (6.1 mmol) of n-BuLi (2.5 M in hexanes). The yellow solution was stirred at this temperature for 10 min then 0 C for 90 min. The solution was recooled to -700C and epoxide 3 (377.5 mg, 1.0 mmol) in 3 mL of THF was added followed by the addition of 0.37 mL (3.1 mmoL) of BF30Et2. The reaction mixture was stirred for 1 h and quenched with 2 mL of sat'd NaHCO3 and diluted with 5 mL of Et20. The aqueous phase was extracted with 3 x 5 mL of EtOAc. The combined organic extracts were washed with brine and dried over MgSO4.The yellow oil was subjected to flash chromatography (SiO2; gradient 4:1, 1:1 EtOAc/Hex) to afford 224 mg (38%) of 4b.

Acetonide 4b (121 mg, 0.205 mmol) was dissolved in 2 mL of 2-propanol and 4 mL of THE and cooled to OOC. The solution was treated with 0.64 mL of 8 N HCI and was allowed to stir to ambient temperature over 4.5 h. The solution was neutralized by the dropwise addition of 50 % NaOH at 0 C. The aqueous solution was extracted with 3x SniL portions of EtOAc and the combined organic extracts were washed with brine (2 x 5 mL) and dried (MgSO4). Column chromatography (7:3 EtOAc/Hex) afforded 28 mg (25%) of 5b mp = 185-187 C and 25 mg (25%) of 6b as a white solid; mp = 194-197 C.

Compound Sb 1H NMR (CDCl3) 6 1.33 (s, 9H), 1.66 (t, J=11.2 Hz, 1H), 2.05 (t, J=10.4 Hz, 1H), 2.80-3.10 (m, 5H), 3.35 (dd, J=2, 14 Hz, 1H), 3.60 (m, 2H), 3.98 (bs, 1H), 4.26 (bq, J=4.6 Hz, 1H), 5.32 (dd, J=4.5, 8.2 Hz, 1H), 5.96 (d, J=8.2 Hz, 1H), 7.05-7.60 (m, 12 H), 7.90 (d, J=7.5 Hz, 1H).

MS (FAB) M+l = 551.

Anal calc'd for C31H38N2SO5#0.05 H2O: C, 67.49; H, 6.96, N, 5.08.

Found: C, 67.11; H, 6.91; N, 5.09.

Compound 6b 1H NMR (CDCl3) 8 1.66 (t, J=11.2 Hz, 1H), 1.85 (t, J=10.4 Hz, 1H), 2.85-3.10 (m, SH), 3.85 (bs, 2H), 4.26 (bq, J=4.6 Hz, 1H), 5.18 (t, J=8Hz, 1H), 5.21 (dd, J=4.5, 8.2 Hz, 1H), 6.00 (d, J=8.2 Hz, 1H), 7.057.60 (m, 12 H), 7.80 (d, J=7.5 Hz, 1H).

MS (FAB) M+1 = 495.

Anal calc'd for C27H30N2SO5-0.3 CHC13: C, 61.81; H, 5.76, N, 5.22.

Found: C, 61.55; H, 5.90; N, 5.24.

EXAMPLE 8

A 0 C solution of N-(tert-butyl)-l-naphthalenamide (681 mg, 3.0 mmol) in 10 mL of THF was treated with 2.44 mL (6.1 mmol) of n-BuLi (2.5 M in hexanes). The red solution was stirred at this temperature for 100 min, cooled to -70 C. and traeted with epoxide 3 (377.5 mg, 1.0 mmol) in 3 mL of THF. After 1 min, 0.37 mL (3.1 mmoL) of BF30Et2 was added. The reaction mixture was stirred for 1 h and quenched with 2 mL of sat'd NaHCO3 and diluted with 5 mL of Et20. The aqueous phase was extracted with 3 x 5 mL of EtOAc.The combined organic extracts were washed with brine and dried over Mg SO4. The yellow oil was subjected to flash chromatography (six2; 1:1 EtOAc/Hex) to afford 289 mg (48%) of 4c.

Acetonide 4c (168.3 mg, 0.278 mmol) was dissolved in 6 mL of methanol and treated with 179 mg (0.771 mmol) of CSA and was allowed to stir to ambient temperature over 3 h. The solution was rotovaped and the residue was dissolved in EtOAc and extracted with 3x 5mL portions of NaHCO3. The organic phase was washed with brine (2 x S mL) and dried (MgSO4). Column chromatography (1:1 EtOAc/Hex) afforded 101 mg (64%) of Sc as a mixture of rotomers mp = 111-121 C.

1H NMR (CDCl3) # 1.46 and 1.61 (each s, 9H), 1.76 (m, 2H), 2.40-3.30 (m, 5H), 3.53 (bs, 1H), 4.18 (d, J=4.4 Hz, 1H), 4.20 (d, J=3.7 Hz, 1H), 5.25 (m, 1H), 5.84 (d, J=7.9 Hz, 1H), 5.94 (d, J=7.1 Hz, 1H), 7.0-8.0 (m, 15 H).

MS (FAB) M+l =565.

Anal calc'd for C36H40N2O4#1.1 H20: C, 73.96; H, 7.25, N, 4.79.

Found: C, 73.66; H, 6.95; N, 4.75.

Acetonide 4c (200 mg, 0.33 mmol) was dissolved in 4 mL of 2-propanol and 2 mL of THF and cooled to OOC. The solution was treated with 1.2 mL of 8 N HCl and was allowed to stir to ambient temperature over 4.5 h. The solution was basified(pH = 11) by the dropwise addition of 50 % NaOH at 0 C. The aqueous solution was extracted with 3x 5mL portions of EtOAc and the combined organic extracts were washed with brine (2 x 5 mL) and dried (MgSO4).

Column chromatography (1:1 EtOAc/Hex) afforded 149 mg (89%) of 6c as a white solid; mp = 220-222 C.

1H NMR (5% DMSO-d6 / CDC13) 6 1.73 (t, J=10.4 Hz, 1H), 2.10 (t, J=10.4 Hz, 1H), 2.80-3.05 (m, 5H),3.44 (m, 1H), 3.80 (m, 1H), 4.00 (bs, 1H), 4.28 (bs, 1H), 4.85 (d, J=4.1 Hz, 1H), 5.32 (dd, J=5.1, 5.3 Hz, 1H), 7.0-8.3 (m, 15 H).

Anal calc'd for C32H32N204-0.25 H20: C, 71.93; H, 6.04, N, 5.20.

Found: C, 71.68; H, 6.15; N, 5.33.

EXAMPLE 9

A. Compound 8a

To a 0 C solution of 2-methylthiophene (0.14 mL, 1.5 mmol) in 7 mL of Et2O was added 0.60 mL (1.5 mmol) of n-BuLi (2.5 M in hexanes). The yellow solution was stirred at this temperature for 2 h before cooling to -700C. The resulting anion was then treated with epoxide 3 (188 mg, 0.50 mmol) in 2 mL of ThF followed immediately with 0.15 mL (1.5 mmoL) of BF30Et2. The reaction mixture was stirred for 30 min and quenched with 5 mL of sat'd NaHCO3 and diluted with S mL of Et20. The aqueous phase was extracted with 3 x 5 mL of Et2O. The combined organic extracts were washed with brine and dried over MgSO4.The yellow oil was subjected to flash chromatography (SiO2; 1:1 EtOAc/Hex) to afford 160 mg (68%) of acetonide 7a.

The above acetonide (47.5 mg, 0.10 mmol) in 6 mL of methanol was treated with 232 mg (1.0 mmol) of camphorsulfonic acid and the whole was stirred for 4 h. The solvent was removed with reduced pressure and the residue was taken up in 10 mL of EtOAc and was washed with sat'd NaHCO3 (3x 2 mL). The organic extracts were washed with brine (2 x 2 mL) and dried (MgSO4). Column chromatography (gradient; 2:1, 1:1 EtOAc/Hex) afforded 35 mg (80%) of 8a as a white solid.

1H NMR (CDC13) 6 1.76 (t, J=11 1.2Hz, 1H), 2.08 (t, J=10.4 Hz, 1H), 2.41 (s, 3H), 2.70-3.01 (m, 5H), 3.98 (bs, 1H), 4.22 (bs, 1H), 5.25 (m, lH), 5.50 (d, J=8.l Hz, 1H), 6.60 (s, 1H), 6.64 (s, 1H), 7.0-7.4 (m, 9 H).

Anal calc'd for C26H29NS03-0.25 H20: C, 70.95; H, 6.76, N, 3.18.

Found: C, 70.98; H, 6.54; N, 3.31.

B. Compound 8b

To a 0 C solution of thianaphthalene (402 mg, 3.0 mmol) in 10 mL of Et2O was added 1.2 mL (3.0 mmol) of n-BuLi (2.5 M in hexanes). The yellow solution was stirred at this temperature for 2 h before cooling to -70 C. The resulting anion was then treated with epoxide 3 (377.5 mg, 1.0 mmol) in 5 mL of THF followed immediately with 0.37 mL (3.0 mmoL) of BF30Et2. The reaction mixture was stirred for 30 min and quenched with 5 mL of sat'd NaHCO3 and diluted with 5 mL of Et2O. The aqueous phase was extracted with 3 x 5 mL of Et2O. The combined organic extracts were washed with brine and dried over MgSO4. The yellow oil was hydrolysed directly without further purification.

The above acetonide (102 mg, 0.20 mmol) in 12 mL of methanol was treated with 232 mg (1.0 mmol) of camphorsulfonic acid and the whole was stirred for 4.1 h. The solvent was removed with reduced pressure and the residue was taken up in 10 mL of EtOAc and was washed with sat'd NaHCO3 (3x 2 mL). The organic extracts were washed with brine (2 x 2 mL) and dried (MgSO4). Column chromatography (1:2, EtOAc/Hex) afforded 75 mg (79%) of 8b as a white solid; mp = 166-168 C).

H NMR (CDCl3) # 1.76 (t,J=11.2 Hz, 1H), 2.11 (t,J=10.4Hz, 1H), 2.44 (s, 1H), 2.78-3.20 (m, SH), 4.08 (bs, 1H), 4.12 (bs, 1H), 5.25 (m, 1H), 5.77 (d, J=5.l Hz, 1H), 7.0-7.4 (m, 12 H), 7.72 (d, J=5 Hz, 1H), 7.80 (d, J=8Hz, 1H).

Anal calc'd for C29H29NSO3: C, 73.86; H, 6.20, N, 2.97.

Found: C, 73.72 H, 6.21; N, 3.15.

C. Compound 8c

Compound 8b (35 mg, 0.074 mmol) in 1.0 mL of CH2C12 was treated with 77 mg (0.223 mmol) of mCPBA (60%) and the whole was stirred for 100 min. The reaction mixture was quenched with I mL of sat'd Na2S203 and was washed with Et2O (3 x 5 mL). The combined organic extracts were washed with sat'd NaHCO3 (3x 2 mL), brine then dried (MgSO4). Column chromatography (1:2, EtOAc/Hex) afforded 33 mg (89%) of 8c as a white solid; mp = 148-151 C).

1H NMR (CDC13) 6 1.79 (t,J=11.2 Hz, 1H), 2.08 (t, J=10.4 Hz, 1H), 2.70-3.05 (m, 5H), 4.12 (m, 2H), 5.23 (m, 1H), 6.06 (d, J=8.1 Hz, 1H), 6.96 (s, 1H), 7.0-7.4 (m, 12 H), 7.77 (d, J=8 Hz, 1H).

IR (CC14) 3551, 3425, 1643, 1519,1296, 1148 cm 1.

MS (FAB) M+1 = 504.

Anal calc'd for C29H29NS05-0.40 H20: C 68.18; H, 5.88, N, 2.74.

Found: C, 68.19; H, 5.95; N, 2.67.

D. Compound 8d

To a 0 C solution of N-(methoxymethyl) indole (161 mg, 1.0 mmol) in 2 mL of Et2O was added 0.7 mL (1.2 mmol) of t-BuLi (2.5 M in pentane). The solution was stirred at this temperature for 10 min before warming to room temperature. After 45 min, the solution was cooled to -70 C and there resulting anion was then treated with epoxide 3 (125 mg, 0.33 mmol) in 1 mL of THF followed immediately with 0.12 mL (1.0 mmoL) of BF3OEt2. The reaction mixture was stirred for 10 min and quenched with 5 mL of sat'd NaHCO3 and diluted with 5 mL of EtOAc. The aqueous phase was extracted with 3 x 5 mL of EtOAc. The combined organic extracts were washed with brine and dned over MgSO4. The yellow oil was subjected to flash chromatography (SiO2; 1:1 EtOAc/Hex) to afford 113 mg (64%) of acetonide.

The above acetonide (113 mg, 0.21 mmol) in 2 mL of methanol and 1 mL of THF was treated with 146 mg (0.63 mmol) of camphorsulfonic acid and the whole was stirred for 4 h. The solvent was removed with reduced pressure and the residue was taken up in 10 mL of EtOAc and was washed with sat'd NaHCO3 (3x 2 mL). The organic extracts were washed with brine (2 x 2 mL) and dried (MgSO4). Column chromatography (1:2, EtOAc/Hex) afforded 95 mg (91%) of 8d as a foam.

1H NMR (CDC13) 6 1.95 (t, J=11.2 Hz, 1H), 2.40 (t,J=10.4 Hz, 1H), 2.60-3.01 (m, SH), 3.25 (s, 3H), 4.01 (t, 1H), 4.18 (m, 1H), 5.25 (m, 1H), 5.40 (ABq, 5=8 Hz, 2H), 5.79 (d, 5=8.1 Hz, 1H), 7.02 (s, 1H), 7.05-7.5 (m, 13 H).

Anal calc'd for C31H34N204: C, 74.67 H, 6.87, N, 5.62.

Found: C, 75.03; H, 6.97; N, 5.72.

E. Compound 8e

To a -70 C solution of 2-bromobiphenyl (0.34 mL, 1.99 mmol) in 6 mL of THF was added 0.82 mL (2.05 mmol) of n-BuLi (2.5 M in hexanes). The yellow solution was stirred at this temperature for 1 h when the resulting anion was treated with epoxide 3 (250 mg, 0.66 mmol) in 2 mL of THF followed immediately with 0.25 mL (2.05 mmoL) of BF3OEt2. The reaction mixture was stirred for 20 min and quenched with 5 mL of sat'd NaHCO3 and diluted with 5 mL of Et2O.

The aqueous phase was extracted with 3 x 5 mL of Et2O. The combined organic extracts were washed with brine and dried over MgSO4. The resulting oil was used directly without further purification.

The crude acetonide was dissolved in 6 mL of methanol was treated with 232 mg (1.0 mmol) of camphorsulfonic acid and the whole was stirred for 4.25 h. The solvent was removed with reduced pressure and the residue was taken up in 10 mL of EtOAc and was washed with sat'd NaHCO3 (3x 2 mL). The organic extracts were washed with brine (2 x 2 mL) and dried afforded 8e as a white solid; mp = 129-130"C).

1H NMR (CDC13) 6 1.58 (t, J=11.2 Hz, 1H), 1.85 (m, 1H), 2.51-3.06 (m, SH), 3.80 (bs, 1H), 4.20 (bs, 1H), 5.23 (dd, 1H), 5.66 (d, J=5.1 Hz, 1H), 7.0-7.4 (m, 18 H)..

Anal calc'd for C33H33N03e0.25 H20: C, 79.88; H, 6.51, N, 2.52.

Found: C, 79.55; H, 6.64; N, 2.89.

F. Compound 8f

To a -70 C solution of (2-bromophenyl)-5,5-dimethyl-2- oxazoline (1.52 g, 6.0 mmol) in 10 mL of THF was added 2.4 mL (6.1 mmol) of n-BuLi (2.5 M in hexanes). The yellow solution was stirred at this temperature for 40 min when epoxide 3 (755 mg, 2.0 mmol) in 4.2 mL of THF followed by 0.75 mL (6.0 mmoL) of BF3OEt2 was added. The reaction mixture was stirred for 10 min and quenched with 5 mL of sat'd NaHCO3 and diluted with 5 mL of Et20. The aqueous phase was extracted with 3 x 5 mL of Et2O. The combined organic extracts were washed with brine and dried over MgSO4. The yellow oil was subjected to flash chromatography (six2; 1:4 EtOAc/Hex) to afford 1.06 g (96%) of acetonide.

1H NMR (CDC13) 6 1.20 (s, 3H), 1.30 (s, 3H), 1.40 (s, 3H), 1.64 (s, 3H), 1.84 (m,lH), 2.00 (m, 1H), 2.80-3.50 (m, SH), 3.57 (m, 1H), 4.04 (ABq, 2H), 5.99 (d, J=2 Hz, 1H), 6.44 (dd, 1H), 6.99 (t, IH), 7.2-7.5 (m, 11 H), 7.70 (d, J=S Hz, 1H).

The above acetonide (552 mg, 1.0 mmol) in 5 mL of CH2C12 and 5 mL of pyridine was treated with excess Ac2O and 12.2 mg (0.1 mmol) of DMAP. The solution was heated at 35 C for 15 h under nitrogen. The reaction mixture was quenched with sat'd NaHCO3 (2 mL) and diluted with ether. The organic extract was washed with NaHCO3 (3 x 2 mL), H2O (3 x 2 mL), and brine (2 x 2 mL) then dried with MgSO4. Column chromatography (1:4 EtOAc/Hex) gave material which was used directly in the next step.

1H NMR (CDC13) 6 1.30 (s, 6H), 1.60 (s, 3H), 1.90 (s, 3H), 2.00 (m, 2H), 2.R0-3.50 (m, SH), 4.04 (s, 2H), 4.66 (s, 1H), 4.99 (d, J=2Hz, 1H), 5.29 (m, 1H), 6.11 (d, J=8.1 Hz, 1H), 6.89 (t, 1H), 7.0-7.5 (m, 11 H), 7.79 (d, J=5 Hz, 1H).

The above acetonide (260 mg, 0.47 mmol) in 5 mL of methanol was treated with 436 mg (1.88 mmol) of camphorsulfonic acid and the whole was stirred for 1 h. The solvent was removed with reduced pressure and the residue was taken up in 10 mL of EtOAc and was washed with sat'd NaHCO3 (3x 2 mL). The organic extracts were washed with brine (2 x 2 mL) and dried (MgSO4). Column chromatography (1:1 EtOAc/Hex) gave material which was used directly in the next step.

1H NMR (CDC13) 6 1.26 (s, 3H), 1.35 (s, 3H), 1.76 (t, J=l1.2 Hz, 1H), 2.15 (t, J=10.4 Hz, 1H), 2.50-3.50 (m, SH), 4.1R (s,2H), 4.20 (bs, 1H), 5.25 (m, 1H), 5.39 (m, 1H), 6.00 (d, J=8.1 Hz, 1H), 7.0-7.5 (m, 12 H), 7.50 (d, J=5 Hz, 1H).

The above acetate (27.7 mg, 0.050 mmol) in 1.0 mL of methanol was treated with 13.8 mg (0.lOmmol) of K2C03 and the whole was stirred at room temperature for S h. The solvent was removed with reduced pressure and the residue was taken up in 10 mL of Et2O and the organic phase was washed with water then brine (2 x 2 mL) and dried (MgSO4). Column chromatography (1:1 EtOAc/Hex) afforded 23.1 mg (90%) of 8f mp; 65-75 C.

1H NMR (CDC13) 6 1.40 (s, 6H), 1.76 (t, J=11.2 Hz, 1H), 2.05 (t, J=10.4 Hz, 1H), 2.80-3.20 (m, 5H), 4.02 (bs, 1H), 4.15 (s,2H), 4.23 (bs, 1H), 5.29 (m, 1H), 6.10 (d, J=8.1 Hz, IH), 6.88 (s, 1H), 7.0-7.5 (m, 11 H), 7.50 (d, J=8 Hz, lH).

Anal calc'd for C32H36N204-0.50 H20: C, 73.67; H, 7.15, N, 5.37.

Found: C, 73.83; H, 6.97; N, 5.40.

G. Compound 8g

A solution of the oxazoline acetonide of Example 9, Section f, above, (468 mg, 0.847 mmol) was dissolved in 5.3 mL of 2-propanol and cooled to 0 C. The solution was treated with 2.65 mL of 8 N HCI and was allowed to stir to ambient temperature over 2.5 h. The resulting white precipitate which formed was filtered to give 233 mg (62%) of lactone.

H NMR (CDC13) 2.00 (t,1H), 2.30 (t, 1H), 2.80-3.09 (m, 5H), 4.10 (t, 1H), 4.60 (dt, 1H), 5.21 (dd, 1H), 5.95 (d, J=7Hz, 1H), 6.9-7.6 (m, 12 H), 8.1 (d,J=5Hz, 1H).

The above lactone (220 mg, 0.50 mmol) was dissolved in 10 mL of EtOH, 5 mL of CH2C12 and 2.5 mL of H2O and treated with 220 mg (5.S mmol) of NaBH4 and the whole was stined for 1.5 h. The reaction mixture was quenched with 10 mL of EtOAc and was washed with sat'd NH4CI (3x 2 mL). The organic extracts were washed with brine (2 x 2 mL) and dried (MgSO4). The residue left after evaporation was recrystallized from MeOH and Et2O to afford 180mg (81%) of 8g as a white solid; mp = 160-161 C).

1H NMR (CDCl3) 6 1.86 (t, J=10.2 Hz, 1H), 2.08 (t, J=10.4 Hz, 1H), 2.70-3.01 (m, 5H), 4.04 (bt, 1H), 4.21 (m, 1H), 4.54 (d, J=14 Hz, lH), 4.79 (d, J=14 Hz, 1H), 5.23 (m, 1H), 5.96 (d, J=5.1 Hz, 1H), 7.0-7.4 (m, 13 H).

MS (FAB) M+1 = 546.

Anal calc'd for C28H31NO4#0.50 H20: C, 73.98; H, 7.10, N, 3.08.

Found: C, 73.89; H, 6.82; N, 3.12.

H. Compound 8h

To a 0 C solution of 2-bromoanisole (0.37 mg, 3.0 mmol) in 10 mL of Et2O was added 1.2 mL (3.0 mmol) of n-BuLi (2.5 M in hexanes). The yellow solution of 2-lithioanisole precipitates and the slurry was stirred at this temperature for 1 h before cooling to -700C The resulting anion was treated with epoxide 3 (377.5 mg, 1.0 mmol) in 3 mL of TMF followed immediately with 0.35 mL (3.1 mmoL) of BF30Et2. The reaction mixture was stirred for 10 min and quenched with 4 mL of sat'd NaHCO3 and diluted with 5 mL of Et20. The aqueous phase was extracted with 3 x 5 mL of Et2O. The combined organic extracts were washed with brine and dried over MgSO4.The yellow oil was subjected to flash chromatography (six2; gradient 1:4, 1:1 EtOAc/Hex) to afford 200 mg (41.5%) of acetonide.

The above acetonide (200 mg, 0.415 mmol) was dissolved in 5 mL of 2-propanol and cooled to OOC. The solution was treated with 1.3 mL of 8 N HCI and was allowed to stir to ambient temperature over 3 h. The pH of the solution was then adjusted to 9 by the dropwise addition of 50 % NaOH at OOC. The aqueous solution was extracted with 3x 5mL portions of CH2C12 and the combined organic extracts were washed with brine (2 x 5 mL) and dried (MgSO4). Column chromatography (7:3 EtOAc/Hex) afforded 385 mg (87%) of 8h as a white solid; mp = 140-142"C).

IH NMR (CDC13) 8 1.66 (t, J=10.2 Hz, 1H), 2.08 (t, J=10.4 Hz, 1H), 2.70-3.01 (m, SH), 3.80 (s, 3H), 4.04 (bt, 1H), 4.21 (m, IH), 5.26 (m, 1H), 5.80 (d, J=5.1 Hz, IH), 6.80-7.40 (m, 13 H).

MS (FAB) M+1 = 446.

Anal calc'd for C2gH31NO4-0.25 H2O: C, 74.72; H, 7.05, N, 3.11.

Found: C, 74.43; H, 6.90; N, 3.31.

I. Compound 8i

To a -70 C solution of 2,5-Dimethyl -N-tert-butylbenzamide (410 mg, 2.0 mmol) in 10 mL of THE was added 0.6 mL (4.0 mmol) of TMEDA and 3.0 mL (4.0 mmol) of sec-BuLi (1.3 M in cyclohexane).

The red solution was stirred at this temperature for 15 min before warming to -150C. After stirring at this temperature for 30 min, 181.5 mg (0.50 mmol) of aldehyde J in 2 mL of THF was added. The reaction mixture was stirred for 25 min and quenched with 5 mL of H2O and diluted with 5 mL of Et2O. The aqueous phase was extracted with 3 x 5 mL of Et20. The combined organic extracts were washed with brine and dried over MgSO4. The yellow oil was subjected to flash chromatography (six2; gradient: 1:2, 1:1 EtOAc/Hex) to afford 213 mg (75%) of acetonide.

The acetonide (28.4 mg, 0.05 mmol) was dissolved in 2 mL of MeOH and was treated with 36.3 mg (0.15 mmol) of camphorsulfonic acid and the whole was stirred for 3 h. The solvent was removed with reduced pressure and the residue was taken up in 10 mL of EtOAc and was washed with sat'd NaHCO3 (3x 2 mL). The organic extracts were washed with brine (2 x 2 mL) and dried (MgSO4). Column chromatography (gradient; 1:2, 1:1 EtOAc/Hex) afforded 25 mg (98%) of 8i as a white solid; mp = 99-109"C).

1H NMR (CDC13) 6 1.40 (s, 9H), 1.76 (t, J=11.2 Hz, 1H), 2.10 (t, J=10.4 Hz, 1H), 2.35 (s, 3H), 2.70-3.01 (m, SH), 3.88 (bs, 1H), 4.16 (m, 1H), 5.21 (dd, J=5.1, 6.9 Hz, 1H), 5.45 (d, J=5.1 Hz, 1H), 6.02 (m, 2H), 7.0-7.4 (m, 12 H).

Anal calc'd for C33H40N20361.5 H20: C, 71.32; H, 7.80, N, 5.04.

Found: C, 71.05; H, 7.41; N, 5.08.

J. Compound 8j

To a 0 C solution of 2-ethoxybromobenzene (400 mg, 1.98 mmol) in 6.6 mL of Et2O was added 0.79 mL (1.98 mmol) of n-BuLi (2.5 M in hexanes). The yellow solution was stirred at this temperature for 1 h before cooling to -70 C. The resulting dianion was then treated with epoxide 3 (250 mg, 0.66 mmol) in 2 mL of THF followed immediately with 0.24 mL (1.98 mmoL) of BF30Et2. The reaction mixture was stirred for 30 min, quenched with sat'd NaHCO3 and diluted with EtOAc. The organic extract was washed with water and brine and dried over Na2SO4. The yellow oil was subjected to flash chromatography (SiO2; 15:85 EtOAc/Hex) to afford 230 mg (70%) of acetonide.

The above acetonide (180 mg, 0.36 mmol) in 7.2 ml of methanol was treated with camphorsulfonic acid (230 mg, 0.97 mmol) and the whole was stirred for 2 h. The solvent was removed with reduced pressure, the residue taken up in EtOAc and washed with sat'd NaHCO3 x 2. The organic extract was washed with brine and dried over Na2S04. Column chromatography (SiO2; 35% EtOAc/Hex) and trituration with EtOAc/Hex afforded 68 mg (42%) of 8j as a white solid; mp = 117-119"C.

1H NMR (CDC13) 6 0.85 (d, 1H), 1.43 (t, 3H, J=6.8 Hz), 1.70 (t, 1H), 2.09 (t, 1H), 2.66 (d, 1H), 2.82 (m, 4H), 3.00 (m, 3H), 4.08 (m, 3H), 4.23 (m, 1H), 5.29 (m, 1H), 5.76 (d, J=8.4 Hz, 1H), 6.88-7.33 (m, 13H).

Anal calc'd for C29H33NO4: C, 75.78; H, 7.25, N, 3.05.

Found: C, 75.66; H, 7.21; N, 3.17.

K. Compound 8k

To a solution of 8g (75 mg, 0.17 mmol) and copper(I) chloride (16.8 mg, 0.17 mmol) in 1 ml of DMF was added tert -butyl isocyanate (20 ml, 0.17 mmol). The reaction was stirred at ambient temperature for 2 h and tert -butyl isocyanate (10 ml) and copper(I) chloride (8 mg) were added. After stirring an additional 4h, the reaction mixture was diluted with EtOAc, washed with water and brine and dried over Na2SO4. Column chromatography (six2; 55% EtOAc/Hex) afforded 31 mg (33%) of 8k as a white solid; mp=144 147 C.

1H NMR (CDC13) 6 1.20 (s, 9H), 1.72 (t, 1H), 2.01 (t, 1H), 2.82 (m, 5H), 3.05 (m, 3H), 3.44 (bs, 1H), 3;.70 (bs, 1H), 4.04 (bs, IH), 4.38 (m,lH), 4.63 (m, 2H), 5.18 (bs, 1H), 5.51 (m, 1H), 6.08 (d, 1H), 7.037.36 (m, 13H).

L. Compound 81

To a 0 C solution of 1 -bromo-2,5-dimethoxybenzene (0.30 ml, 1.98 mmol) in 6.6 mL of Et2O was added 0.79 mL (1.98 mmol) of n-BuLi (2.5 M in hexanes). The yellow solution was stirred at this temperature for 1 h before cooling to -700C. The resulting dianion was then treated with epoxide 3 (250 mg, 0.66 mmol) in 2 mL of THF followed immediately with 0.24 mL (1.98 mmoL) of BF3OEt2. The reaction mixture was stirred for 45 min, quenched with sat'd NaHCO3 and diluted with EtOAc. The organic extract was washed with water and brine and dried over Na2SO4. The yellow oil was subjected to flash chromatography (six2; 1:4 EtOAc/Hex) to afford 260 mg (76%) of acetonide.

The above acetonide (260 mg, 0.50 mmol) in 10 ml of methanol was treated with camphorsulfonic acid (310 mg, 1.35 mmol) and the whole was stirred for 3 h. The solvent was removed with reduced pressure, the residue taken up in EtOAc and washed with sat'd NaHCO3 x 2. The organic extract was washed with brine and dried over Na2SO4. Column chromatography (six2; 2:3 EtOAc/Hex) and trituration with EtOAc/Hex afforded 89 mg (37%) of 81 as a white solid; mp = 148-150"C.

1H NMR (CDCl3) # 0.89 (d,lH), 1.70 (t, 1H), 2.08 (t, 1H), 2.61 (d, 1H), 2.79 (m, 4H), 2.95 (m, 3H), 3.76 (s, 3H), 3.80 (s, 3H), 4.04 (m, 1H), 4.22 (m, 1H), 5.29 (m, 1H), 5.78 (d, 1H), 6.75 (m, 2H), 6.82 (m, 1H), 7.03-7.31 (m, 9H).

M. Compound 8m

To a -70 C solution of the acetonide of Example 9, Section H, above (500 mg, 1.0 mmol) in 10 mL of CH2C12 was added dropwise 1.4 ml (1.4 mmol) of BBr3 (1.0 M in CH2Cl2). The reaction was allowed to stir to ambient temperature overnight, quenched with cold water and stirred for 30 minutes. The aqueous phase was extracted with CH2C12 x 2 and the combined organic extracts were dried over Na2S04. Column chromatography (SiO2; 35% EtOAc/Hex) and recrystallization from EtOAc/Hex afforded 240 mg (56%) of 8m as a white solid; mp=186-1880C.

1H NMR (CDC13) 0.71 (d, 1H), 1.94 (m, 2H), 2.80 (m, 4H), 2.91 (m, 1H), 3.04 (m, 3H), 4.18 (m, 1H), 4.41 (m, 1H), 5.23 (m, 1H), 5.79 (d, J=6.4 Hz, 1H), 6.06 (bs, 1H), 6.82-7.;37 (m, 13H), S.90 (s, 1H).

N. Compound 8n

To a 0 C solution of 1 -bromo-2,4-dimethoxybenzene (0.28 ml, 1.98 mmol) in 6.6 mL of Et2O was added 0.79 mL (1.98 mmol) of n-BuLi (2.5 M in hexanes). The yellow solution was stirred at this temperature for 1 h before cooling to -70 C. The resulting dianion was then treated with epoxide 3 (250 mg, 0.66 mmol) in 2 mL of THF followed immediately with 0.24 mL (1.98 mmoL) of BF30Et2. The reaction mixture was stirred for 1 h, quenched with sat'd NaHCO3 and diluted with EtOAc. The organic extract was washed with water and brine and dried over Na2S04. The yellow oil was subjected to flash chromatography (SiO2; 1:4 EtOAc/Hex) to afford 0.27 g (79%) of acetonide.

The above acetonide (270 mg, 0.52 mmol) in 10 ml of methanol was treated with camphorsulfonic acid (330 mg, 1.4 mmol) and the whole was stirred for 6 h. The solvent was removed with reduced pressure, the residue taken up in EtOAc and washed with sat'd NaHCO3 x 2. The organic extract was washed with brine and dried over Na2SO4. Column chromatography (SiO2; 2:3 EtOAc/Hex) and recrystallization from EtOAc/Hex afforded 66 mg (26%) of 8n as a white solid; mp = 184-186"C.

1H NMR (CDC13) 60.87 (d, 1H), 1.6fez (t, 1H), 2.08 (t, 1 H), 2.40 (d, 1H), 2.67-3.01 (m, 7H), 3.82 (s, 6H), 4.00 (m, 1H), 4.24 (m, lH), 5.30 (m, 1H), 5.77 (d, J=8.8 Hz, 1H), 6.50 (m, 2H), 7.04-7.33 (m, 10H). Anal calc'd for C29H33NO5: C, 73.23; H, 7.01, N, 2.94.

Found: C, 73.11; H, 6.92; N, 3.00.

P. Compound 8p

To a solution of tert -butylamine (0.49 ml, 0.46 mmol) in 0.6 ml of toluene, cooled to -250C, was added 0.46 ml (0.23 mmol) bromine (0.5 M in CH2C12). The mixture was cooled to -700C and 8m (100 mg, 0.23 mmol) was added. The reaction was stirred at ambient temperature for 2 h and diluted with CH2C12. The organic phase was washed with water and dried over Na2SO4.

Column chromatography (SiO2; 35% EtOAc/Hex) and recrystallization from EtOAc/Hex afforded 20 mg (14%) of 8p as a white solid; mp=197-199"C 1H NMR (CDC13) 0.72 (d, 1H), 1.90 (m, 2H), 2.92 (m, 7H), 4.19 (m, 1H), 4.41 (bs, 1H), 5.23 (m, 1H), 5.83 (d, J=8.4 Hz, 1H), 6.44 (s, 1H), 7.12-7.38 (m, 10H), 7.55 (s, 1H), 9.53 (s, 1H).

Anal calc'd for C27H27Br2N04: C, 55.02; H, 4.63, N, 2.38.

Found: C, 54.79; H, 4.69; N, 2.37.

Q. Compound 8q

To a 0 C solution of 2-isobutoxybromobenzene (300 g, 1.32 mmol) in 4.4 mL of Et2O was added 0.53 mL (1.32 mmol) of n BuLi (2.5 M in hexanes). The yellow solution was stirred at this temperature for 1 h before cooling to 700 C. The resulting dianion was then treated with epoxide 3 (250 g, 0.66 mmol) in 2 mL of THF followed immediately with 0.16 mL (1.32 mmoL) of BF3OEt2. The reaction mixture was stirred for 1 h, quenched with sat'd NaHCO3 and diluted with EtOAc. The organic extract was washed with water and brine and dried over Na2S04. The yellow oil was subjected to flash chromatography (SiO2; 15% EtOAc/Hex) to afford 83 mg (24%) of acetone.

The above acetonide (83 mg, 0.16 mmol) in 3 ml of methanol was treated with camphorsulfonic acid (100 mg, 0.43 mmol) and the whole was stirred for 6 h. The solvent was removed with reduced pressure, the residue taken up in EtOAc and washed with sat'd NaHCO3 x 2. The organic extract was washed with brine and dried over Na2S04. Column chromatography (six2; 30% EtOAc/Hex) and trituration with EtOAc/Hex afforded 24 mg (31 %) of 8q as a white solid; mp = 107-108"C.

1H NMR (CDC13) 6 0.81 (d, 1 H), 1.04 (d, J=6.4 Hz, 6H), 1.71 (t, I H), 2.10 (m, 2H), 2.54 (m, 1H), 2.89 (m, 7H), 3.76 (d, J=6.4 Hz, 2H), 4.07 (m, 1H), 4.22 (m, 1H), 5.27 (m, 1H), 5.74 (d, J=8.4 Hz, 1H), 6.88-7.32 (m, 13H).

R. Compound 8r

To a 0 C solution of 2-bromothioanisole (0.26 ml, 1.98 mmol) in 6.6 mL of Et2O was added 0.79 mL (1.98 mmol) of n-BuLi (2.5 M in hexanes). The yellow solution was stirred at this temperature for 1 h before cooling to -700C. The resulting dianion was then treated with epoxide 3 (250 g, 0.66 mmol) in 2 mL of THF followed immediately with 0.24 mL (1.98 mmoL) of BF30Et2. The reaction mixture was stirred for 30 min, quenched with sat'd NaHCO3 and diluted with EtOAc. The organic extract was washed with water and brine and dried over Na2S04. The yellow oil was subjected to flash chromatography (six2; 20% EtOAc/Hex) to afford 0.26 g (79%) of acetonide.

The above acetonide (260 mg, 0.52 mmol) in 10 ml of methanol was treated with camphorsulfonic acid (320 mg, 1.4 mmol) and the whole was stirred for 4 h. The solvent was removed with reduced pressure, the residue taken up in EtOAc and washed with sat'd NaHCO3 x 2. The organic extract was washed with brine and dried over Na2S04. Column chromatography (six2; 2:3 EtOAc/Hex) and trituration with EtOAc/Hex afforded 71 mg (30%) of 8r as a white solid; mp = 139-141"C.

1H NMR (CDC13) 6 0.90 (d, 1H), 1.78 (t, 1H), 2.16 (m, 2H), 2.47 (s, 3H), 2.78-3.06 (m, 8H), 4.15 (m, 1H), 4.24 (m, 1H), 5.30 (m, 1H), 5.78 (d, 1H), 7.08-7.35 (m, 13H).

S. Compound 8s

To a solution of phenyllithium (1.1 ml, 1.98 mmol, 1.8 M in cyclohexane-ether) in 5 ml of THE, cooled to -700C, was added dropwise a solution of epoxide 3 (250 mg, 0.66 mmol). BF3OEt2 (0.24 ml, 1.98 mmol) was added and the whole was stirred at -700C for lh.

The reaction was quenched with sat'd NaHCO3 and diluted with EtOAc.

The organic phase was washed with water and brine, dried over Na2S04 and concentrated under reduced pressure to afford 300 mg (100%) of acetonide 7 of Example 9.

A solution of acetonide 7 (300 mg, 0.66 mmol) and ptoluenesulfonic acid (380 mg, 2.0 mmol) in 5 ml of benzene was stirred at ambient temperature for lh. The reaction mixture was diluted with EtOAc, washed with sat'd NaHCO3 x2, water and brine and dried over Na2S04. Column chromatography (six2 35% EtOAc/Hex) and trituration with EtOAc/Hex afforded 93 mg (34%) of 8s as a white solid; mp=160-162"C.

1H NMR (CDC13) 6 0.80 (d, 1H), 1.73 (t, 1H), 2.00 (s, IH), 2.15 (t, 1H), 2.69-3.05 (m, 7H), 4.02 (bs, 1H), 4.22 (m, 1H), 5.30 (m, 1H), 5.75 (d, J=S Hz, 1H), 7.01-7.37 (m, 14H).

T. Compound 8t

A solution of 8r (59 mg, 0.13 mmol) and potassium peroxymonosulfate (0.12g, 0.2 mmol) in 6 ml of ethanol and 2.6 ml of water was stirred at ambient temperature overnight. The reaction mixture was quenched with sat'd NaHCO3 and diluted with EtOAc. The organic phase was washed with water x 2, brine and dried over Na2S04. Column chromatography (SiO2; 3:2 EtOAc/Hex) and trituration with EtOAc/Hex afforded 50 mg (78%) of 8t as a white solid; mp= 155- 157 C.

1H NMR (CDC13) 6 1.06 (bs, 1 H), 1.81 (t, 1 H), 2.16 (t, 1H), 2.78-3.29 (m, 8H), 3.11 (s, 3H), 4.04 (m, 1H), 4.24 (m, lH), 5.27 (m, 1H), 5.84 (d, J=8.4 Hz, 1H), 7.01-7.63 (m, 12H), 8.07 (d, J=8 Hz, 1H).

Anal calc'd for C28H3lNO5S: C, 68.12; H, 6.34, N, 2.84.

Found: C, 68.08; H, 6.27; N, 3.05.

U. Compound 8u

To a 0 C solution of 2-(methoxymethoxy)-bromobenzene (430 mg, 1.9fez mmol) in 6.6 mL of Et20 was added 0.79 mL (1.98 mmol) of n-BuLi (2.5 M in hexanes). The yellow solution was stirred at this temperature for I h before cooling to -70 C. The resulting dianion was then treated with epoxide 3 (250 mg, 0.66 mmol) in 2 mL of THF followed immediately with 0.24 mL (1.98 mmoL) of BF3oEt2.

The reaction mixture was stirred for 2 hrs, quenched with sat'd NaHCO3 and diluted with EtOAc. The organic extract was washed with water and brine and dried over Na2SO4. The yellow oil was subjected to flash chromatography (SiO2; 1:5 EtOAc/Hex) to afford 61 mg (18%) of acetonide.

The above acetonide (61 mg, 0.12 mmol) was dissolved in 30 ml acetic acid solution (60 % in water) and allowed to stir at ambient temperature for 7 days. The reaction mixture was diluted with water, neutralized with NaHCO3 and extracted with EtOAc x 3. The combined organic extracts were washed with brine and dried over Na2SO4.

Column chromatography (six2; 2:3 EtOAc/Hex) afforded 18 mg (32%) of 8u as a white solid; mp=l 15-1 17"C.

1H NMR (CDC13) 6 0.87 (bs, 1H), 1.73 (t, 1H), 2.11 (t, 1H), 2.82 (m, 5H), 2.97 (m, 3H), 3.47 (s, 3H), 4.07 (m, 1H), 4.23 (m, IH), 5.20 (s, 2H), 5.27 (m, lH), 5.78 (d, 1H), 6.98-7.34 (m, 13H).

V. Compound 8 v

To a 0 C solution of 2-methoxy-4-phenoxybromobenzene (360 mg, 1.3 mmol) in 4.3 mL of Et2O was added 0.52 mL (1.3 mmol) of n-BuLi (2.5 M in hexanes). The yellow solution was stirred at this temperature for I h before cooling to -700C. The resulting dianion was then treated with epoxide 3 (250 mg, 0.66 mmol) in 2 mL of THF followed immediately with 0.16 mL (1.3 mmoL) of BF30Et2. The reaction mixture was stirred for 45 min, quenched with sat'd NaHCO3 and diluted with EtOAc. The organic extract was washed with water and brine and dried over Na2SO4. The crude acetonide product was taken on to the next reaction.

The above acetonide (380 mg, 0.66 mmol) in 13 ml of methanol was treated with camphorsulfonic acid (420 mg, 1.R mmol) and the whole was stirred for 6 h. The solvent was removed with reduced pressure, the residue taken up in EtOAc and washed with sat'd NaHCO3 x 2. The organic extract was washed with brine and dried over Na2S04. Column chromatography (six2; 2:3 EtOAc/Hex) and recrystallization from EtOAc/Hex afforded 80 mg (23%) of 8v as a white solid; mp = 175-177"C.

1H NMR (CDC13) 6 0.90 (d, 1H), 1.70 (t, 1H), 2.10 (t, 1H), 2.40 (d, 1H), 2.71-3.01 (m, 7H), 3.79 (s, 3H), 4.03 (m, 1H), 4.24 (m, 1H), 5.30 (m, IH), 5.79 (d, J=R.4 Hz, 1H), 6.54 (dd, 1H, J=2.0, 8.0 Hz, 1H), 6.63 (d, J=2 Hz, 1H), 7.02-7.37 (m, l5H).

Anal calc'd for C34H35NO5: C, 75.94 H, 6.57, N, 2.60.

Found: C, 75.69; H, 6.54; N, 2.65.

EXAMPLE 10 A. 2-Ethoxvbromobenzene To a solution of 2-bromophenol (1.3 ml, 0.012 mol) in 50 ml acetone was added K2CO3 (4.1 g, 0.03 mol) and iodoethane (1.0 ml, 0.013 mol). The reaction mixture was heated to reflux for 8h, cooled to ambient temperature and filtered. The solvent was removed under reduced pressure and the residue was taken up in EtOAc. The organic phase was washed with 1N NaOH x 2, water and brine. Drying over Na2S04 afforded 2.1 g (88%) of 2-ethoxybromobenzene.

1H NMR (CDC13) 6 1.48 (t, 3H), 4.09 (q, 2H), 6.80 (t, 1H), 6.88 (d, 1H), 7.23 (m, 1H), 7.52 (d, 1H).

B. 2-lsobutoxvbromobenzene To a solution of 2-bromophenol (0.67 ml, 5.8 mmol) in 25 ml acetone was added K2CO3 (2.0 g, 14.5 mmol) and I-iodo-2methylpropane (0.75 ml, 6.4 mmol). The reaction mixture was heated to reflux for 19h, cooled to ambient temperature and filtered. The solvent was removed under reduced pressure and the residue was taken up in EtOAc. The organic phase was washed with iN NaOH x 2, water and brine. Drying over Na2SO4 afforded 330 mg (25%) of 2isobutoxybromobenzene.

1H NMR (CDCl3) 5 1.09 (d, 6H), 2.17 (m, 1H), 3.78 (d, 2H), 6.80 (t, 1H), 6.87 (d, 1H), 7.22 (t, 1H), 7.52 (d, 1H).

C. 2-(Methoxymethoxv)-bromobenzene To a solution of 2-bromophenol (0.67 ml, 5.8 mmol) and diisopropylethylamine (1.1 ml, 6.4 mmol) was added chloromethyl methyl ether (0.49 ml, 6.4 mmol). The reaction mixture was stirred at ambient temperature for 2h, quenched with sat'd NaHCO3 and diluted with CH2C12. The organic phase was washed with water and dried over Na2S04 to afford 700 mg (58%) of the title compound.

1H NMR (CDC13) 63.52 (s, 3H), 5.24 (s, 2H), 6.88 (t, 1H), 7.15 (d, 1H), 7.25 (m, 1H), 7.54 (d, 1H).

D. 2-Bromo-5-phenoxyphenol To a solution of t-butylamine (1.1 ml, 10.7 mmol) in 13 ml toluene, cooled to -30 C was added bromine (0.28 ml, 5.35 mmol). The mixture was cooled to -700C and was treated with 3-phenoxyphenol (2.0 g, 10.7 mmol) dissolved in 2 ml CH2C12. The reaction was stirred to ambient temperature over 5h, quenched with water and diluted with CH2C12. The organic phase was washed with water and brine and dried over Na2SO4. Column chromatography (six2; 5:95 EtOAc/Hex) afforded 380 mg (14%) of 2-bromo-5-phenoxyphenol.

1H NMR (CDC13) 5 5.48 (s, 1H), 6.49 (dd, 1H), 6.67 (d, 1H), 7.01 (d, 2H), 7.13 (t, 1H), 7.35 (m, 3H).

E. 2-Methoxv-4-phenoxybromobenzene To a solution of 2-bromo-5-phenoxyphenol (0.38 g, 1.4 mmol) in 6 ml acetone was added K2CO3 (0.58 g, 4.2 mmol) and iodomethane (0.26 ml, 4.2 mmol). The reaction mixture was heated to reflux for Sh, cooled to ambient temperature and filtered. The solvent was removed under reduced pressure and the residue was taken up in EtOAc. The organic phase was washed with 1N NaOH, water and brine. Drying over Na2SO4 afforded 0.36 g (92%) of 2-methoxy-4phenoxybromobenzene.

1H NMR (CDC13) 6 3.83 (s, 3H), 6.45 (dd, 1H), 6.62 (d, 1H), 7.00 (d, 2H), 7.12 (t, 1H), 7.34 (t, 2H), 7.43 (d, 1H).

While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention emcompasses all of the usual variations, adaptations, or modifications, as come within the scope of the following claims and its equivalents.

Claims (13)

WHAT IS CLAIMED IS:

1. A compound of the formula

n = 0,1,2; Wherein A is I ) aryl unsubstituted or substituted with one or more of a) C1 4 lower alkyl; b) hydroxy; c) halo; d) C1-4 lower or branched alkoxy; e) C1-4 lower branched thioalkyl; f) COOR; g) CONHR1; h) S02NHR1; i) SO2R1;or j) Ci-4 lower hydroxyalkyl; or 2) a 5- to 10-membered mono or bicyclic heterocycle in which one or both heterocyclic rings contain an atom selected from N, O, or S, which heterocycle is unsubstituted or substituted with one or more of a) C1-4 lower alkyl; b) hydroxy; c) halo; d) C1-4 lower or branched alkoxy; e) C1-4 lower branched thioalkyl; f) COOR; g) CONHR1; h) SO2NHR; i) SO2R1;or j) C1 4 lower hydroxyalkyl; and R is 1) aryl, unsubstituted or substituted with C 1-4 lower alkyl, C1-4 lower alkoxy, or halo, or 2) C3 7 cycloalkyl; and R1 is C1-4 lower alkyl, C3 7cycloalkyl or H; and Jigs:

or pharmaceutically acceptable salt(s) thereof.

2. A compound according to Claim 1, of the formula:

Xis COOR; CONHR1; SO2NHR1, orSO2R1; or a pharmaceutically acceptable salt thereof.

3. A compound according to Claim 1, of the formula

X is CONHR1 or S02NHR1, or pharmaceutically acceptable salt thereof.

4. The compound, which is

or pharmaceutically acceptable salts thereof.

5. The compound, which is

or phannaceutically acceptable salts thereof.

6. The compound, which is

or pharmaceutically acceptable salts thereof.

7. A pharmaceutical composition comprising the compound of any of Claims 1-6 and a pharmaceutically acceptable carrier.

S. The pharmaceutical composition of Claim 7 for use in the treatment of and the delaying of the onset of AIDS, in the prevention of infection by HIV, in the treatment of infection of HIV, or in the inhibition of HIV protease.

9. A method of treating and delaying the onset of AIDS, comprising administering to a mammal in need of such treatment an effective amount of a compound of any of Claims 1-6.

10. A method of preventing infection by HIV, comprising administering to a mammal in need of such treatment an effective amount of a compound of any of Claims 1-6.

ii. A method of treating infection by HIV, comprising administering to a mammal in need of such treatment an effective amount of a compound of any of Claims 1-6.

12. A method of inhibiting HIV protease, comprising administering to a mammal in need of such treatment an effective amount of a compound of any of Claims 1-6.

13. A combination of compounds, which is compound C, and any of AZT or ddl or ddC.