GB2282808A

GB2282808A - 3-substituted heterocyclic indoles as inhibitors of HIV reverse transcriptase

Info

Publication number: GB2282808A
Application number: GB9420287A
Authority: GB
Inventors: Susan F Britcher; Jr William C Lumma; Steven D Young; Vanessea E Grey; Lekhanh O Tran
Original assignee: Merck and Co Inc
Current assignee: Merck and Co Inc
Priority date: 1993-10-14
Filing date: 1994-10-07
Publication date: 1995-04-19
Also published as: GB9420287D0

Abstract

Certain 3-substituted heterocyclic indoles are useful in the inhibition of HIV reverse transcriptase (including its resistant varieties), the prevention or treatment of infection by HIV and 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 and methods of preventing or treating infection by HIV are also described.

Description

TITLE OF THE INVENTION 3-SUBSTITUTED HETEROCYCLIC INDOLES AS INHIBITORS OF HIV REVERSE TRANSCRIPTASE BACKGROUND OF THE INVENTION This case is related to Merck case 18947, U.S.S.N.

08/021,925, filed February 24, 1993, which is a continuation-in-part of 18518IB, U.S.S.N. 07/866,765, filed April 9,1992, which is a continuation-in-part of 18518IA, U.S.S.N. 07/832,260, filed February 7, 1992, which is a continuation-in-part of 18518, U.S.S.N. 07/756,013, filed September September 6, 1991.

A retrovirus designated human immunodeficiency virus (HIV) 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 reverse transcription of the RNA genome by a virally encoded reverse transcriptase to generate DNA copies of HIV sequences, a required step in viral replication. It is known that some compounds are reverse transcriptase inhibitors and are effective agents in the treatment of AIDS and similar diseases, e.g., azidothymidine or AZT.

Nucleotide sequencing 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 HIV protease [Toh, H. et al., EMBO J. 4, 1267 (1985); Power, M.D. et al., 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 reverse transcriptase.

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

These compounds are useful in the inhibition of HIV reverse transcriptase (and its resistant varieties), the prevention of infection by HIV, the treatment of infection by HIV and in the treatment of AIDS and/or ARC, either as compounds, phannaceutically acceptable salts (when appropriate), pharmaceutical composition ingredients, whether or not in combination with other antivirals, anti-infectives, 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 reverse transcriptase and its resistant varieties, 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:

wherein: X is halo, G is halo, nitro, CN, C1-4 alkoxy, C1 4 alkylamino, sulfonamido, or C1 4alkyl substituted 0-3 times with halo; n= 0-5;

is a stable 4- to 6-membered monocyclic heterocyclic ring which is either saturated, partially unsaturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, S and P, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, said monocyclic heterocyclic ring being unsubstituted or substituted one or more times with H, amino, C1 4 alkylamino, halo, sulfonamido, cyano, C3-5 cycloalkyl, or Cl -4 alkyl substituted one to three times with halo; or a pharmaceutically acceptable salt thereof.

One preferred embodiment is compounds further limited to compounds of formula II:

wherein: X is halo; R1 and R2 are each independently H, ClAalkyl, C3 5 cycloalkyl, amino, cyano, or halo; or, R1 and R2 are connected together to form an unsubstituted cycloalkyl.

A second embodiment is compounds of formula I further limited to compounds of formula m:

wherein: X is halo; R1 and R2 are each independently H, C1-4alkyl, C3-5 cycloalkyl, amino, cyano, or halo; or, R1 and R2 are connected together to form an unsubstituted cycloalkyl.

Preferred compounds include the following: 1. 5-chloro-2-(4(5H)-imidazol-2-yl)-3-phenylsulfonylindole (L-747,655, compound 2) of the structure

or pharmaceutically acceptable salt thereof; 2. 5-chloro-2-(5(4)-methylimidazol-2-yl)-3- phenylsulfonylindole (L-750,023, compound 3) of the structure

or pharmaceutically acceptable salt thereof.

The compounds of the present invention are specifically illustrated in Table I below.

TABLE 1

3 Compound Structure LX MP I 4 NH ,797 267- 20nM > 20ûnM 2 747,655 > 27000 3.6nM 1.5nM HN 3 4 750,023 22225700 4.7nM 12nM OH3 CH7 750,005 216- 9.4nM 50nM 4 3 HN 005 21800 OH3 3 5 N1 OH3 748,558 234- 1 OnM 50nM HN CH3 236"C *indicates point of attachment

Compound Structure L# AL ME ~~ 6 > Hz 748,539 > 250 C 8.1nM 50nM HI > t 221 C 220- 5.lnM l2nM CH3 OH3 8 // 747,654 > 270 C s30nM N.D. X NtN 743,745 526nM N 9 743,745 > 28500 526nM N-NH 9 10 NN 747,608 22337800 2385nM N.D. ii 748,435 115- 16.6nM N.D. N 11700 12 Ny 750043 22336800 6.5nM N.D. HN 13 y N 750,182 249- 2288nM N.D. HN 25100

Compound Structure Lss ME "NA 14 + 750,183 249- 50nM N.D. OH3 15 H 750,184 > 2500C 29nM N.D. H

The compounds of the present invention may have asymmetric centers and may occur, except when specifically noted, as racemates, racemic mixtures or as individual diastereomers, or enantiomers, with all isomeric forms being included in the present invention. The term (+1-) is intended to encompass (+) optical isomers or (-) optical isomers or mixtures thereof.

When any variable (e.g., Rl) 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 "alkvl" is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.

"Halogen" or "halo" as used herein, means fluoro, chloro, bromo and iodo.

The term heterocycle or heterocyclic, as used herein except where noted, represents a stable 5- to 7-membered monocyclic or heterocyclic ring which is either saturated, partially unsaturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, 0 and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized. 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-oxopyrrolidinyl, pyrrolyl, 4piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, pyridyl, pyrazinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, thiadiazoyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, and oxadiazolyl.

The compounds of the present invention can be synthesized by the following methods. It will be understood that, in the schemes that follow, the particular illustrations do not limit the scope and applicability of any particular scheme, as is also apparent to a skilled artisan.

SCHEME 1

i) m-Chlorophenylthiosuccinimide, BF3 etherate ii) m-Chloroperbenzoic acid, CHC13 iii) NH4OH, NH4Cl, 100 C, sealed tube iv) POCl3, benzene, reflux v) NaN3, NH4CI, DMF, 10000 Commercially available 5-chloroindole-2-carboxylic acid is used prepare the ester l, X = Cl, by first converting to the corresponding acid chloride with oxalyl chloride in refluxing chloroform, then reacting with ethanol to give 1 As shown in scheme I, compound 1 is converted to 2 by reaction with m-chlorophenylthiosuccinimide in, e.g., chloroform at room temperature with a Lewis acid, such as boron trifluoride etherate, as catalyst.Oxidation in the ensuing step to give 3 is accomplished with a suitable oxidizing agent, such as m-chloro-perbenzoic acid (m-CPBA), sodium periodate, or hydrogen peroxide in an appropriate solvent such as MeOH, CHCl3, or acetic acid, or potassium persulfate in a solvent such as MeOH/H2O.

Reaction with ammonia while heating results in amide 4, which is then converted to nitrile 5 by reaction with phosphorous oxychloride.

Formation of the tetrazole 6 by ring synthesis is readily performed by heating 5 in azide in a solvent such as N,N-dimethylformamide, as also described by Finnegan, W.G. et al., J.Am.Chem.Soc. 80, 3908 (1958).

For the alpha-bromination of ketone 7, the brominating agent phenyltrimethylammonium tribromide (PTAB) is typically used in conventional fashion. Thiazole 9 is formed by the Hantzsch method of ring synthesis by reaction of alpha-halocarbonyl 8 with the appropriate thiourea.

SCHEME 3

Reduction of ester 10 to the corresponding alcohol 1 1 is accomplished by reaction eith. e.g., lithium aluminum hydride.

Subsequent oxidation of 11 is conveniently carried out with pyridinium dichromate (PDC) to give 12. Ring synthesis of the imidazole derivative 13 occurs by reaction with the appropriate glyoxal.

SCHEME 4

Irnidazole derivatives can be synthesized according to Scheme 4. The known sleep-inducer 5-chlorooxindole 14 X = Cl, is prepared by conventional methods, see, e.g., U.S. Patent 4,160,032, herein incorporated by reference for these purposes. Synthesis of the alpha-sulphenyl carbonyl 15 is accomplished in excess n-BuLi with the appropriate disulfide, a reaction illustrated in Example 10, Step 1, and generally described by Trost, B.M. et al., Chem. Rev. 18. 363 (1978).

Oxidation of the next step to give 16 is carried out with a suitable oxidizing agent, such as m-CPBA, like the second step of Scheme 1.

Reaction with phosphorous oxychloride, then with imidazole or other appropriate heterocycle gives 18 and its 2-heterocylic derivatives.

Formation of amide 20 is readily achieved by those skilled in the art, here reaction of methylamine with the acid chloride 19.

Reaction of the amide 20 with Lawesson's reagent [2,4-bis(4 mthoxyphenyl)-1,3 -dithia-2,4 -diphosphetane- ,4-disulfide] results in thiation of the amide to give thioamide 21. In the next step, alkylation of isothiocarboxamide 22 occurs by reaction with either methyl iodide or trimethyloxonium tetrafluoroborate. Ring synthesis of 23 results from reaction with the appropriate diamine. The thiazoline 24 is formed by reaction with 2-aminoethanethiol.

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 reverse transcriptase, 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 inventions are useful in the inhibition of HIV reverse transcriptase, the prevention or treatment of infection by human immunodeficiency virus (HIV) and the treatment 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, 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 therapeuticallyeffective amount of a compound of the present invention.

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 sweeteners/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.

The compounds of this invention can be administered orally to humans in a dosage range of 1 to 100 mg/kg body weight in divided doses. One preferred dosage range is 0.1 to 10 mg/kg body weight orally in divided doses. Another preferred dosage range is 0.1 to 20 mgRg body weight orally in divided doses. For combination therapy with nucleoside analogs, a preferred dosage range is 0.1 to 20 mg/kg body weight for the compounds of this invention administered orally in divided doses, and 50 mg to 5 g/kg body weight for nucleoside analogs administered orally in divided doses.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 reverse transcriptase inhibitor 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 pre-exposure and/or post-exposure, in combination with effective amounts of the AIDS antivirals, immunomodulators, antiinfectives, or vaccines, such as those in the following Table.

TABLE 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 (See also (Irving, TX) 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) Drug Name Manufacturer Indication 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 (Rsch. Triangle Park, pediatric AIDS, NC) Kaposi's sarcoma, asymptomatic HIV infection, less severe HIV disease, neurological involvement, in combination with therapies.

Drug Name Manufacturer Indication 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/ICN asymptomatic HIV Ribavirin (Costa Mesa, CA) positive, LAS, ARC Alpha Interferon Burroughs Well come Kaposi's sarcoma, HIV (Rsch. Triangle in combination Park, NC) w/Retrovir Acyclovir Burroughs Well come AIDS, ARC, asymptomatic HIV positive, in combination with AZT.

Antibody which Advanced Biotherapy AIDS, ARC neutralizes pH labile Concepts alpha aberrant Rockville, MD) Interferon in an immuno-adsorption column Drug Name Manufacturer Indication L-697,661 Merck (Rahway, NJ) AIDS, ARC, asymptomatic HIV positive, also in combination with AZT.

L-743,726 Merck AIDS, ARC, (Rahway, NJ) asymptomatic HIV positive, also in combination with AZT.

L-735,524 Merck (Rahway, NJ) AIDS, ARC, asymptomatic HIV positive, also in combination with AZT.

RO-31-8959 Hoffmann-La Roche AIDS, ARC, (Nutley, NJ) asymptomatic HIV positive, also in combination with AZT.

IMMUNO-MODULATORS Drug Name Manufacturer Indication AS-101 Wyeth-Ayerst Labs. AIDS (Philadelphia, PA) Bropirimine Upjohn advanced AIDS (Kalamazoo, MI) Acemannan Carrington Labs, Inc. AIDS, ARC (Irving, TX) (See also antivirals) Drug Name Manufacturer Indication CL246,738 American Cyanamid AIDS, Kaposi's (Pearl River, NY) sarcoma Lederle Labs (Wayne, NJ) EL10 Elan Corp, PLC HIV infection (Gainesville, GA) (See also antivirals) Gamma Interferon Genentech ARC, in combination (S. San Francisco, CA) w/TNF (tumor necrosis factor) Granulocyte Genetics Institute AIDS Macrophage Colony (Cambridge, MA) Stimulating Factor Sandoz (East Hanover, NJ) Granulocyte Hoeschst-Roussel AIDS Macrophage Colony (Somerville, NJ) Stimulating Factor Lmmunex (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) Drug Name Manufacturer Indication 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 (human) (Berkeley, CA) combination w/AZT IMREG-1 Imreg AIDS, Kaposi's New Orleans, LA) sarcoma, ARC, PGL IMREG-2 Imreg AIDS, Kaposi's (New Orleans, LA) sarcoma, ARC, PGL Imuthiol 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, IL) MTP-PE Ciba-Geigy Corp. Kaposi's sarcoma Muramyl-Tripeptide (Summit, NJ) Granulocyte Amgen AIDS, in combination Colony Stimulating (Thousand Oaks, CA) w/AZT Factor Drug Name Manufacturer Indication rCD4 Genentech AIDS, ARC Recombinant (S.San Francisco, CA) Soluble Human CD4 Rocombinant Biogen AIDS, ARC Soluble Human CD4 (Cambridge, MA) Interferon Hoffman-La Roche Kaposi's sarcoma Alfa 2a (Nutley, NJ) AIDS, ARC, in combination w/AZT SK & 106528 Smith, Kline & French HIV infection Soluble T4 Laboratories (Philadelphia, PA) Thymopentin Immunobiology HIV infection Research Institute (Annandale, NJ) Tumor Necrosis Genentech ARC, in combination Factor; TNF (S.San Francisco, CA) w/gamma Interferon ANTI-INFECTIVES Drug Name Manufacturer Indication Clindamycin with Upjohn PCP Primaquine (Kalamazoo, MI) Fluconazolec Pfizer cryptococcal (New York, NY) meningitis, candidiasis Pastille Squibb Corp prevention of oral Nystatin Pastille (Princeton, NJ) candidiasis Ornidyl Merrell Dow PCP Eflornithine (Cincinnati, OH) Pentamidine LyphoMed PCP treatment Isethionate (IM & IV) (Rosemont, IL) Piritrexim Burroughs Well come 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; R5121 1 (Piscataway, NJ) cryptococcal meningitis Trimetrexate Warner-Lambert PCP OTHER Druz Name Manufacturer Indication Recombinant Human Ortho Pharm. Corp. severe anemia assoc.

Erythropoietin (Raritan, NJ) with AZT therapy Drug Name Manufacturer Indication Megestrol Acetate Bristol-Myers treatment of anorexia (New York, NY) assoc.w/AIDS Total Enteral Norwich Eaton diarrhea and Nutrition Pharmaceuticals malabsorption related (Norwich, NY) 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. For example, a compound of Formula I or Formula U may be suitably administered in combination with a nucleoside analog having known biological activity against HIV reverse transcriptase.Appropriate nucleoside analogs are generally chain terminators and include AZT, ddC, ddI, D4T, HEPT and 3'-fluoro-2',3'-dideoxythymidine.

AZT is synthesized by the methods of J.P. Horwitz et al.. J.

Org. Chem. 29, 2076 (1964); R.P. Glinski et al., J. Org. Chem. 38.

4299 (1973); C.K. Chu et al., Tetrahedron Letters 29, 5349 (1988).

Application of AZT as a therapeutic drug in the treatment of AIDS is disclosed in U.S. 4,724,232.

The compound ddC is synthesized by the methods of J.P.

Horwitz et al., J. Org. Chem. 32, 817 (1967); R. Marumoto, Chem.

Pharm. Bull. 22, 128 (1974); and T.-S. Lin et al., J. Med. Chem. 30, 440 (1987).

D4T is synthesized by the methods of Herdewijn, P. et al., J. Med. Chem. 30, 1270 (1987).

HEPT is synthesized by the methods of Miyasaka, T. et. al.

J. Med. Chem. 32, 2507 (1989); and A. Rosowsky, J. Med. Chem. 24, 1177 (1981). The synthesis of ddC, ddI and AZT are also described in EPO 484071.

The compound 3 '-fluoro-2',3 '-dideoxythymidine is synthesized by the procedures of Herdewijn, P. et al., J. Med. Chem. 30, 1270 (1987). The compound RO-31-8959 is synthesized by the procedures of EP 346847, herein incorporated by reference for these purposes. The compound L-735,524 is N-(2(R)-hydroxy-1 (5)-indanyl)- 2(R)-phenylmethyl-4-(S)-hydroxy-5-( 1 -(4-(3-pyridylmethyl) 2(S)-N'-(t-butyl carboxamido)-piperazinyl))-pentaneamide , or pharmaceutically acceptable salt thereof. L-697,661 or'661' is 3-([4,7dichloro- 1,3 -benzoxazol-2-yl)methyl] amino)-5-ethyl-ethyl-6-methyl- pyridin-2(1H)-one. The synthesis of L-697,661 is described in EPO 484071, and EPO 462800, both herein incorporated by reference.

L-743 ,726 is (-6)chloro-4(S)-trifluoromethyl- 1 ,2-dihydro-4(H)-3, 1 - benzoxazin-2-one and is synthesized by the methods of EP0530994, herein incorporated by reference.

Preferred combinations are simultaneous, intermittent, or alternating treatments of L-747,655 with or without an inhibitor of HIV protease. An optional third component in the combination is a nucleoside inhibitor of HIV reverse transcriptase, such as AZT, ddC or ddI. A preferred inhibitor of HIV protease is L-735,524. Other preferred inhibitors of HIV reverse transcriptase include L-743,726.

These combinations may have synergistic effects on limiting the spread of HIV. Preferred combinations include the following: (1) L-747,655 with L-735,524, and, optionally any of L-743,726, AZT, ddI or ddC; (2) L-747,655 and any of L-743,726, AZT, ddI or ddC.

Pharmaceutically acceptable salts of these combinations are also included.

EXAMPLE 1 2-(2-Amino-4-thiazolyl)-5-chloro-3-phenylsulfonylindole hvdrobromide (L-743.797) Step A: 2-Bromoacetyl-5 -chloro-3-phenvlsulfonvlindole: A solution containing 0.64 g (1.9 mmol) of 2-acetyl-5chloro-3-phenylsulfonylindole and 0.865 g (2.3 mmol) of phenyl trimethylammonium tribromide in 15 mL of THF was stirred at 25"C under argon for 24 hours. The reaction mixture was concentrated to dryness in vacuo and the residue was partitioned between a mixture of ether, ethyl acetate and water. The organic phase was washed with aqueous sodium bisulfite solution, brine and was dried (MgSO4).Upon removal of the solvents, the solid residue was triturated with a few drops each of ether and acetonitrile, affording the title compound in 58% yield (460 mg). 1H NMR (CDCl3): 6 4.82 (s, 2H), 7.34 (dd, J = 2, 8.8 Hz, 1H), 7.45-7.59 (m, 4H), 7.96-8.03 (m, 2H), 8.25 (d, J = 2 Hz, 1H), 12.08 (s, 1H).

Step B: 2-(2-Amino-4-thiazolyl)-5 -chloro-3-phenylsulfonylindole hvdrobromide: Warming a mixture of the bromoketone from Step A (56 mg, 0.13 mmol) and thiourea (13 mg, 0.17 mmol), suspended in 5 mL of 2-propanol to 40"C produced a clear solution. Upon heating the solution at 80"C for 30 min, a white solid precipitated. The mixture was cooled in an ice bath and the solid collected by suction filtration and washed with cold 2-propanol. The solid, the title compound had mp 267-270"C, dec. 1H NMR (DMSO-d6): 6 4.5 (br s, 3H), 7.32 (dd, J = 2, 8.7 Hz, lH), 7.52-7.65 (m, 5H), 7.85-7.91 (m, 2H), 8.08 (d, J = 2 Hz, 1H).

EXAMPLE 2 5 -Chl oro-2- (4 (SH)-imidaz~ol-2-vl )-3-ohenvl sulfonvlindole (L-747.655) Step A: 5 -Chloro-2-hydroxymethyl-3 -phenylsulfonylindole: To a 500 ml oven dried round bottom flask with argon inlet, stir bar, and addition funnel was added 5-chloro-2ethoxycarbonyl-3-phenylsulfonylindole (10.0g, 27.5 mmol) and dry THF (200 mL). This stirred solution was cooled to OOC with an ice bath and lithium aluminum hydride in THF (1M solution, 30.3 mL) was added dropwise over 30 min. When the addition was complete, the ice bath was removed and the yellow reaction mixture was allowed to stir at ambient temperature for 2 h. The completed reaction was quenched by slow addition of saturated Rochelle salt solution (100 mL) and stirring was continued overnight.The two-phase mixture was diluted with water and EtOAc, the layers were separated, and the aqueous phase was extracted with EtOAc (2x). The combined organic layers were washed with brine (2x) and then dried (MgSO4). Upon removal of the drying agent and solvents, the residue was triturated with ether-hexane to afford 8.00 g of the title compound as a pinkish solid; 1H NMR (CDCl3): 8 4.59 (t, J = 6 Hz, lH), 5.14 (d, J = 6 Hz, 2H), 7.17 (dd, J = 2, 8.6 Hz, 1H), 7.33 (d, J = 8.6 Hz, 1H), 7.44-7.56 (m, 3H), 7.96-7.99 (m, 3H), 10.79 (s, 1H).

Step B: 5 -Chloro-2-formvl -3 -phenylsulfonylindole: To a 500 ml oven dried round bottom flask with a stir bar and argon inlet was suspended pyridinium dichromate (14.03g, 37.3 mmolj in dry CHC12(100 ml). With stirring, a suspension of 5-chloro2-hydroxymethyl-3-phenylsulfonylindole (8.0cur, 24.9 mmol) in dry CH2Cl2 (150 ml) was added to the mixture and the reaction was allowed to stir at ambient temperature for 6 h. The completed reaction was diluted with a 1:1 mixture of Et?O:EtOAc. This mixture was filtered through silica gel/glass filter to remove the PDC.The solvents were removed in vacuo and the residue was triturated with CHCl3 to afford 5.57g of the title compound as an off-white solid; 1H NMR (DMSO- d6): 8 7.44(dd, J = 2, 8.2 Hz, 1H), 7.56-7.68(m, 5H), 7.98(s, 1H), 8.14(d, J = 6.8 Hz, 1H), 8.29(br s, 1H), 10.57(s, 1H).

Step C: 5-Chloro-2-(4(5H)-imidazol-2-vl)-3-phenvlsulfonvlindole: To a 10 ml round bottom flask with a stir bar and argon inlet was added 5-Chloro-2-formyl-3-phenylsulfonylindole (1.0g, 3.1 mmol) and THF (5 mL). The stirred solution was chilled to -10 C and the glyoxal (40% soln., 0.5 mL, 3.4 mmol) was added. Concentrated NH40H (28%, 1.5 ml, 15.2 mmol) was added dropwise via syringe to the chilled solution. The ice bath was removed and the reaction was allowed to stir at ambient temperature for 3 h. The dark brown mixture was concentrated in vacuo and the residue was taken up into EtOAc and H20. The layers were separated and the organic phase was washed with H20 and brine, dried (MgSO4), filtered, concentrated in vacuo, and chromatographed on 45 g of silica gel using NH3 saturated CHCl3 as eluant.The chromatographed material was recrystallized from boiling n-butyl chloride to give 0.25 g (22%) of the title compound as beige crystals, mp > 270 C (HCl salt, mp > 270 C). 1H NMR (DMSO-d6): 6 7.34(d, J = 8 Hz, 1H), 7.49-7.63(m, 6H), 7.86(d, J = 7.2 Hz, 2H), 7.91(s, 1H), 8.29(s, 1H), 12.23(br s, 1H).

EXAMPLE 3 5-Chloro-2-(5(4)-methylimi dazol-2-yl)-3-phenylsulfonylindole (L-750.023) This compound was prepared in 26% (overall yield) as a white solid (mp 225"-227"C) following the same procedure as for 5 chloro-2-(4(5H)-imidazol-2-yl)-3-phenylsulfonylindole, from 5-chloro 2-formyl -3 -phenylsulfonylindole and pyruvic aldehyde. 1 H NMR (DMSO-d6): 6 2.23(s, 2H), 2.36(s, 1H), 6.95(s, 0.25H), 7.25(d, J = 8.6 Hz, 0.75H), 7.46-7.61(m, 4H), 7.87(d, J = 8 Hz, 2H), 7.91(s, 1H), 8.29(s, 1H), 11.98(s, 0.75H), 12.88(s, 0.25H).

EXAMPLE 4 5 -Chloro-2-(4(5)-methyl-5 (4)-propylimidazol-2-yl)-3 - phenylsulfonylindole (L-750.005 This compound was prepared in 40% (overall yield) as a white solid (mp 216"-218"C) following the same procedure as for 5chloro-2-(4(5H)-imidazol-2-yl)-3 -phenylsulfonylindole, from 5-chloro- 2-formyl-3-phenylsulfonylindole and 2,3-hexanedione. 1H NMR (DMSO-d6): 6 0.92(t, J = 7.2, 3H), 1.60-1.66(m, 2H), 2.26(s, 3H), 2.61(s, 2H), 7.24(d, J = 8.6, 1H), 7.46-7.60(m, 4H), 7.81(d, J = 6.9 Hz, 1H), 7.86(s, 2H), 8.29(s, 1H), 11.81(s, 0.50H), 12.82(s, 0.50H).

EXAMPLE 5 5 -Chloro-2-(4,5 -diethylimidazol-2-yl)-3-phenylsulfonylindole (L-748 *5584 This compound was prepared in 29% (overall yield) as white crystals (mp 234 -236 C) following the same procedure as for 5 chloro-2-(4(5H)-imidazol-2-yl)-3-phenylsulfonylindole, from 5-chioro- 2-formyl -3 -phenylsulfonylindole and 3 ,4-hexanedione. 1H NMR (DMSO-d6): 6 l.21(s, 6H), 2.54(dd, J = 2, 6 Hz, 2H), 2. 69(dd, J = 2, 6 Hz, 2H), 7.25(dd, J = 2, 8 Hz, 1H), 7.48-7.59(m, 4H), 7.84(d, J = 8 Hz, 2H), 7.89(s, 1H), 8.29(s, 1H), 11.82(s, 0.50H), 12.82 (s, 0.50H).

EXAMPLE 6 5-Chloro-2-(4,5,6,7-hexahydrobenzimidazol-2-yl)-3 phenylsulfonylindole (L-748*539) This compound was prepared in 40% (overall yield) as a white solid (mp > 250 C) following the same procedure as for 5-chloro2-(4(5H)-imidazol-2-yl)-3-phenylsulfonylindole, from 5-chloro-2 formyl-3-phenylsulfonylindóle and 1 ,2-cyclohexanedione. one. 1H NMR (DMSO-d6) 6 1.82(s, 4H), 2.60(s, 2H), 2.75(s, 2H), 7.24(dd, J = 2, 8 Hz, 1H), 7.48(d, J = 8.6, 1H), 7.53-7.63(m, 3H), 7.86(d, J = 8 Hz, 1H), 7.89(d, J = 8 Hz, 2H), 8.30(s, 1H), 11.82(s, 0.50H), 12.82(s, 0.50H).

EXAMPLE 7 5-Chloro-2-(4,5 -dimethylimidazol-2-yl)-3 -phenylsulfonylindole (L-748.443) To a 50 mL round bottom flask with stir bar and argon inlet, 5-chloro-2-formyl-3-phenylsulfonylindole (1.0g, 3.1 mmol) was added and dissolved in THF (15 mL). 2,3-Butanedione (1.1 mL, 6.3 mmol) was added and the yellow solution was chilled to -50C. With stirring, the concentrated NH40H (28%, 3.15 mL, 31.5 mmol) was added dropwise to the chilled solution. The ice bath was removed and the reaction was allowed to stir at ambient temperature for 2.5 h.The red solution was concentrated in vacuo and the residue was taken up in EtOAc and H20. The layers were separated and the organic phase was washed with H20 (2x) and brine (Ix), dried (MgSO4), filtered, concentrated in vacuo, and chromatographed using 80g of silica gel with NH3 saturated CHC13 as eluant. The chromatographed material was recrystallized from boiling n-butyl chloride to give 0.74g (62%) of the title compound as a white solid, mp 220 -221 C (HCl salt, mp > 250).

111 NMR (DMSO-d6): 5 2.16(s, 3H), 2.30(s, 3H), 7.23(d, J = 8.7 Hz, 1H), 7.45-7.60(m, 4H), 7.85 (d, J = 6.9 Hz, 3H), 8.27 (d, J = 1.0 Hz, 1H), 11.85 (s, 0.50H), 12.79(s, 0.50H).

EXAMPLE 8 5-Chloro-2-(l .3-oxazol-5-vl)-3 -Dhenvlsulfonvlindole (L-747.654) To a 15 mL round bottom flask with stir bar, reflux condenser, and argon inlet was added 5-chloro-2-formyl-3phenylsulfonylindole (400 mg, 1.3 mmol), Tosylmethyl isocyanide (273 mg, 1.4 mmol), and K2C03 (273 mg, 2.8 mmol) in MeOH (5 mL).

With stirring, this mixture was refluxed for 1.5 h at 80 C. The reaction was concentrated in vacuo and taken up in EtOAc and H20. The layers were separated and the organic phase was washed with H20 (1 x) and brine (lox), dried (MgSO4), filtered, and chromatographed using 20g of silica gel with NH3 saturated CHCl3 as eluant. The chromatographed material was recrystallized from boiling EtOAc and hexane to give 400 mg (85%) of the title compound as small, white crystals, mp > 270 C.

1H NMR (DMSO-d6): 6 7.31(dd, J = 8.6 Hz, 1H), 7.51-7.61(m, 5H), 7.88 (d, J = 7.7 Hz, 2H), 8.04 (d, J = 5.2 Hz, 2H), 8.71 (s, 1H).

EXAMPLE 9 3-(3-Chlorophenvlsulfonvl)-5-chloroindole-2-tetrazole (L -743.745) Step A: 3-(3-Chlorophenvlsulfonvl )-5-chl oroindole-2-nitri le: To a solution of 3-(3-chlorophenylsulfonyl)-5chloroindole-2-carboxamide (1.5g, 4.0 mmol) in 30 ml over sieve dried benzene was added (3.8 ml, 40 mmol) of POC13. The reaction was heated at 100so for 15 hours. The reaction mixture was cooled to room temperature and 20 ml of saturated NaHCO3 was added, stirred for several hours during which time a solid precipitated. This solid was collected by suction filtration and washed with CH2Cl2.Yield 1.1 8g (84who) of the title compound as an off white solid. 1H NMR (DMSOd6): 6 7.50 (dd,J=2,8.8 Hz, 1H); 7.61-7.69 (m, 2H); 7.80 (d, J=7.17 Hz, 1H); 7.97-8.03 (m, 4H).

Step B: 3-(3-Chlorophenvlsulfonvl )-5-chloroindole-2-tetrazole: To the solution of nitrile from step A (175 mg, 0.5 mmol) in 8 ml of dry DMF stirring at 50"C was added (130 mg, 2 mmol) of sodium azide and (107 mg, 2 mmol) of NHACI. The suspension was heated to 100 C for over 48 hours under argon. The reaction mixture was cooled to room temperature and diluted with crushed ice, then acidified with 1 ml concentrated HCI. A white solid precipitated as the acid was added. The solid was collected via suction filtration and washed with warm water and CHCl3.Collected 112mg (57%) of the title compound which had mp > 285 C. 1H NMR (DMSO-d6) 6 7.417.43(dd, J=2, 8.9 Hz, 1H); 7.60-7.64(m, 211); 7.73-7.75 (d, J=8.05 1H); 8.03-8.05(d, J=10.07 2H); 8.10 (s, 1H).

EXAMPLE 10 2-(Imidazol- 1 -yl-5-chlorn-3 -phenvlsulfonvlindole (L-747.608) Step 1: (+/-) 5-Chloro-3-phenylthiooxindole: A solution of 5-chlorooxindole (2.5g, 14.92 mmol) and TMEDA (4.61 mL, 30.58 mmol) in dry THF (50 mL), under argon,was cooled to -78 C and a solution of n-butyllithium (12.23 mL, 30.58 mmol of a 2.5 M solution in hexane) was added dropwise with a syringe over 30 min. (T < -65 C). This solution was aged 1h at -780C then solid diphenyldisulfide (3.26g, 14.92 mmol) was added in one portion. The mixture was warmed to 200C and stirred for 2h. The reaction was quenched with 5% aqueous HCl. The mixture was diluted with EtOAc and washed with additional HCl, H2O, and brine.Drying (MgSO4), filtration and removal of the solvent in vacuo , gave a brown solid.

This material was recrystallized from boiling EtOAc to give 845 mg of pure (+/-) 5-chloro-3-phenylthiooxindole, mp: 154-156 C. 1 H-NMR (CDCl3): 6 4.55 (111,s); 6.68 (1H, d, J=8.24 Hz); 7.15-7.41 (7H, m); 8.49 (1H, br s).

Step 2: (+1-) 5-Chloro-3-phenvl sulfonyloxindole: To a cold (0 C) solution of anhydrous m-CPBA (1.52g, 8.81 mmol) in dry chloroform (50 mL) was added 5-chloro-3phenylthiooxindole (810 mg, 2.94 mmol) in one portion. The mixture was warmed to 200C and stirred overnight. The mixture was diluted with EtOAc and washed with 15% aqueous NaHSO3 solution, H2O, and brine. Drying (MgSO4), filtration, and removal of the solvent in vacuo gave a tan solid. The solid was washed with several portions of Et20 and dried in vacuo.This material was recrystallized from EtOAchexane to give 451 mg of (+/-) 5-chloro-3-phenylsulfonyloxindole as a white solid, mp: 223-225 C. 1H-NMR (DMSO-d6): 65.75 (1H, s); 6.77 (1H, d, J=8.4Hz); 7.25-7.80 (7H, m); 10.87 (1H, br s).

Step 3: 25-Dichloro-3-phenvlsulfonvlindole: To a 25 mL round bottomed flask with a stirring bar and a drying tube was added (+/-) 5-chloro-3-phenylsulfonyloxindole (500 mg, 1.62 mmol) and phosphorous oxychloride (5.0 mL, 53.64 mmol).

This mixture was heated at 110 C for 2.5h. The cooled reaction mixture was poured into 350 mL of stirred aqueous NaHCO3 solution.

The mixture was stirred 6h then extracted with EtOAc (2 x 150 mL).

Drying (MgSO4), filtration, and removal of the solvent in vacuo gave 450 mg of a black gum. This material was chromatographed on 50g of silica gel using 35% EtOAc-hexane as eluant. The chromatographed material was recrystallized from EtOAc-hexane to give 144 mg of 2,5dichloro-3-phenylsulfonylindole as a white solid. 1H-NMR (CDCl3): 6 7.25 (2H, m); 7.51 (3H, m); 8.06 (2H, m); 8.09 (1H, s); 8.85 )lH, br s).

Step 4: 2-(Imidazol-1-vl)-5-chloro-3-phenvlsulfonvlindole: To a 5 mL round bottomed flask was added 2,5-dichloro-3phenylsulfonylindole (28 mg, 0.09 mmol) and imidazole (250 mg, 3.67 mmol). This mixture was heated in a 140"C oil bath for 6h. The mixture was cooled to room temperature and diluted with H2O. This mixture was extracted with EtOAc. Drying (Na2SO4), filtration, and removal of the solvent in Isacuo followed by chromatography on silica gel using 5% MeOH in CHCl3 as eluant gave the title compound as a white solid. An analytical sample was prepared by recrystallization from EtOAc-hexane. mp: 237-238 C. 111-NMR (CDCl3): 6 7.15 (1H, s); 7.31 (2H, m); 7.39 (2H, mj; 7.48 (1H, m); 7.57 (1H, s); 7.69 (2H,d, J=7.9 Hz); 7.82 (1H, s); 8.88 (1H, d, J=2.0 Hz).

EXAMPLE 11 5-chloro-3-phenvlsulfonvl-2-fthiazoline-2-vl)indole (L-748 435) Step A: N-methvl -5-chloro-3-phenvl sulfonvlindole-2-carboxamide: To a solution of 5-chloro-3 -phenylsulfonylindole-2carbonyl chloride (2.1g, 5.92 mmol) in THF (20 mL) was added N methyl amine gas via a pipette over 5 minutes. The reaction mixture was stirred at ambient temperature for 5 more minutes and then the white salt was eliminated by suction filtration.The filtrate was concentrated in vacuo and the solid residue was triturated with ethyl acetate to afford the title compound in 99% yield (2.00 g).1H NMR (CDC13) 6 3.12 (d, J = 4.9 Hz, 3 H), 7.34 (dd, J = 2, 8.8 Hz, 1H), 7.4 (dd, J = 0.7, 8.7 Hz, 1H), 7.48-7.57 (m, 3H), 7.91 (d, J = 1.3 Hz, 1H), 7.93 (br s, 1H), 8.2 (d, J = 1.9 Hz, 1H), 9.5 (br s, 1H).

Step B: N-methyl -5-chloro-3-phenylsulfonylindole-24hioamide: To a 100 mL oven dried round bottom flask with an argon inlet and a stir bar was added a solution of N-methyl -5-chloro-3phenylsulfonylindole-2-carboxamide (1,4 g, 4 mmol) in dry dioxane (100 mL) and 1.95 g of Lawesson's reagent. With stirring, the reaction mixture was heated at 60"C over night. Upon removal of the solvent, the solid residue was chromatographed on silica gel using chloroform as eluant. The chromatographed material was recrystallized from EtOAc to give 1.2 g (82%) of the title compound as yellow crystals. 1H NMR (CDC13) 6 3.46 (d, J = 4.9 Hz, 3 H), 7.34 (dd, J = 2, 8.8 Hz, 1H), 7.4 (d, J = 8.9 Hz, 1H), 7.47-7.57 (m, 3H), 7.83-7.86 (m, 2H), 8.27 (s, 1H).

Step C: (E,Z)N,S -Dimethyl -5-chloro-3 -phenylsulfonylindole-2- isothiocarboxamide: To a 10 mL ACE glass pressure tube with a stirring bar was added the N-methyl -5-chloro-3 -phenylsulfonylindole-2-thioamide (1.1 g, 3.01 mmol) and 10 mL of dry THF. This solution was cooled to 0 C with an ice bath and methyl iodide (4.13 mL, 60.2 mmol) was added. The tube was sealed and the reaction mixture was stirred at ambient temperature for 2 weeks. The mixture was diluted with CHCl3 (200 mL) and this solution was washed with saturated NaHCO3, saturated NaHSO3, brine, dried (MgSO4) and filtered. The solvent was concentrated in vacuo and the yellow residue chromatographed on silica gel using ethyl acetate and hexane (1:1) as eluant.The chromatographed material was recrystallized from EtOAc and hexane to give 435 mg (38%) of the title compound as a white solid, mp 224-226"C. 1H NMR (CDCl3) major isomer: 8 2.2 (s, 3 H), 3.51 (s, 3), 7.15 (dd, J = 2, 8.7 Hz, 1H), 7.29-7.31 (m, 1H), 7.48-7.57 (m, 3H), 8.02-8.05 (m, 2H), 8.07-8.1 (m, 1H) minor isomer: 6 2.51 (s, 3), 3.24 (s, 3), 6.87 (d, J = 8.7 Hz, 1H), 7.297.31 (m, 111), 7.48-7.57 (m, 3H), 8.02-8.05 (m, 2H), 8.07-8.1 (m, 1H) Alternate Step C:Second method of preperation of (E,Z)N,S-Di methyl-5-chloro-3-phenylsulfonylindole-2 isothiocarboxamide: To a 50 mL round bottom flask with a stirring bar and an argon inlet was added N-methyl -5-chloro-3-phenylsulfonylindole-2- thioamide (653 mg, 1.79 mmol), chloroform (20 mL) and trimethyloxonium tetrafluoroborate (1.32 g, 8.95 mmol). The reaction mixture was refluxed for 1 hour then cooled to ambient temperature.

The mixture was diluted with CHIC13 (100 mL) and this solution was washed with saturated NaHCO3 (2x), H20, brine, dried (MgSO4) and filtered. The solvent was concentrated in vacuo and the residue recrystallized from EtOAc and hexane to give 520 mg (74%) of the title compound as a white solid, mp 224-2260C. 1H NMR (CDC13) major isomer: 3 2.2 (s, 3 H), 3.51 (s, 3), 7.06 (br dd, J = 9.1 Hz, 1H), 7.29 (t, J = 2.7 1H), 7.47-7.56 (m, 3H), 8.00-8.05 (m, 2H), 8.07-8.1 (m, 1H) minor isomer : 6 2.51 (s, 3), 3.24 (s, 3), 6.7 (br d, J = 9.1 Hz, 1H), 7.29 (t, J = 2.7, 1H), 7.47-7.56 (m, 3H), 8.02-8.05 (m, 2H), 8.07-8.1 (m, 1H) Step D: 5-chloro-3-phenvlsulfonvl-2-(thiazoline-2-vl)indole: To a 50 mL round bottom flask with a stirring bar and an argon inlet was added (E,Z)N,S -Dimethyl -5-chloro-3-phenylsulfonylindole-2-isothiocarboxamide (200 mg, 0.528 mmol) dry DMF (5 mL).

2-aminoethanethiol (66 mg, 0.580 mmol) and triethylamine (73.6 mL, 0.528 mmol) were added and the resulting solution was stirred at 600C for 12 hours. The mixture was diluted with EtOAc and this solution was washed with H20 (2x), brine (lox) and then dried (MgSO4). Upon removal of the drying agent and solvent, the residue was chromatographed on silica gel using EtOAc/Hexane (7:3) as eluant. The chromatographed material was recrystallized in EtOAc/Hexane to afford 120 mg (60%) the title compound as white crystals, mp 115 117"C. 111 NMR (CDCl3) 5 3.48 (t, J = 8.6 Hz, 2 11), 4.4 (t, J = 8.6 Hz, 2 H), 7.32 (d, J = 1.35 Hz, 2H), 7.46-7.54 (m, 3H), 8.11-8.14 (m, 2H), 8.35 (t, J = 1.26 Hz, 1H), 9.6 (br s, 1H).

EXAMPLE 12 5-chloro-3 -phenylsulfonyl-2-((4,5)dihydroimidazol-2-yl)indole (L-750.043 To a 50 mL round bottom flask with a stirring bar and an argon inlet was added (E,Z)N,S -Dimethyl -5-chloro-3phenylsulfonylindole-2-isothiocarboxamide (200 mg, 0.528 mmol) and dissolved in dry DMF (5 mL). Ethylenediamine (35.3 mL, 0.528 mmol) and triethylamine (a drop) were added and the resulting solution was stirred at 60"C for 3 hours. The mixture was diluted with EtOAc and this solution was washed with H20 (2x), brine (lx),and then dried (MgSO4).The solvent was removed in vacuo and the residue was recrystallised in MeOH/EtOAc to give 90 mg (47.3%) of white crystals, mp 236-238"C. 1H NMR (CDC13) 6 3.98 (s, 4 H), 7.15 (dd, J = 2, 8.7 Hz, 1 H), 7.26 (t, J = 4.3 Hz, 1H), 7.44-7.53 (m, 3H), 7.91-7.94 (m, 2H), 8.12 (dd, J = 0.5, 2 Hz, 1H).

EXAMPLE 13 5 -chloro-3 -phenylsulfonyl-2-(( 1,4,5 ,6)tetrahydropyrimidine-2-yl)indole (L-750.1 82) This compound was prepared in 43% yield as a white solid (mp 249-251 OC) following the same procedure as for 5-chloro-3phenylsulfonyl-2-(thiazoline-2-yl)indole, from (E,Z)N,S -Dimethyl -5chloro-3 -phenylsulfonylindole-2-isothiocarboxamide (50 mg, 0.13 mmol), 1,3-diaminopropane (11 mL, 0.13 mmol) and a drop of triethylamine. The crude compound was chromatographed on silica gel using a mixture of CHCl3, MeOH and AcOH (90/10/1) as eluant. 1H NMR (CDC13) 6 2.16 (m, 2 H), 3.68 (t, J = 5.8 Hz, 4 H), 7.12 (dd, J = 2.2, 8.9 Hz, 1H), 7.39-7.50 (m, 4H), 7.80-7.82 (m, 2H), 7.99 (dd, J = 0.5, 2.18 Hz, 1H).

EXAMPLE 14 5-chloro-3 -phenylsulfonyl-2-(5 ,5 -dimethyl-(4,5) dihydroimidazol-2vl)indole (L-750,1 83) This compound was prepared in 56% yield as a white solid (mp 249-251"C) following the same procedure as for 5-chloro-3phenylsulfonyl-2-(thiazoline-2-yl)indole, from (E,Z)N,S -Dimethyl -5chloro-3-phenylsulfonylindole-2-isothiocarboxamide (50 mg, 0.13 mmol), 1,2-diamino 2-methyl propane (18.83 mL, 0.13 mmol) and a drop of triethylamine. The crude compound was chromatographed on silica gel using a mixture of CHCl3, MeOH and AcOH (180/10/1) as eluant.lH NMR (CDCl3) 6 1.53 (s, 6 H), 3.76 (s, 2 H), 7.24-7.28 (m, 1 H), 7.45-7.57 (m, 4 H), 7.84-7.86 (m, 2 H), 8.16 (d, J = 1.85 Hz, 1 H).

EXAMPLE 15 5-chloro-3 -phenylsulfonyl-2-(trans-hexahydrobenzimidazol-2-yl)indole (L-750.1 84) This compound was prepared in 14% yield as a white solid (mp > 250"C) following the same procedure as for 5-chloro-3phenylsulfonyl-2-(thiazoline-2-yl)indole, from (E,Z) N,S -dimethyl -5chloro-3-phenylsulfonylindole-2-isothiocarboxamide (50 mg, 0.13 mmol), trans 1,2 diaminocyclohexane (15.8 mL, 0.13 mmol) and a drop of triethylamine. The crude compound was chromatographed on silica gel using a 1:1 mixture of EtOAc:hexane as eluant. 1H NMR (CDCl3) 6 1.38-1.43 (m, 2 H), 1.61-1.66 (m, 2 H), 1.90-1.95 (m, 2 H), 2.29-2.35 (m, 2 H),3.37-3.41 (m, 2 H), 7.18 (dd, J = 1.7, 8.7 Hz, 1 H), 7.33 (d, J = 8.7 Hz, 1H), 7.44-7.54 (m, 3H), 7.91-7.94 (m, 2H), 8.08 (d, J = 2 Hz, 1H).

REVERSE TRANSCRIPTASE ASSAY The assay measures the incorporation of tritiated deoxyguanosine monophosphate by recombinant HIV reverse transcriptase (HIV RTR) (or other RT) into acid-precipitable cDNA at the Km values of dGTP and poly r(C).oligo d(G)12-18. The inhibitors of the present invention inhibit this incorporation.

The assays were carried out in 55 mM Tris (pH 8.2)-30 mM KCl-30 mM MgC12-1 mM dithiothreitol-20 sslg of rc:dGl2-l8 (Pharmacia) per ml-8 mM [3H]dGTP (New England Nuclear)-0.01 % Triton X-100-50 mM ethylene glycol-bis(B-amino-ethyl ether) N,N,N',N'-tetraacetic acid (EGTA)-1 mg of bovine serum albumin per ml. After 60 min of incubation at 370C, acid-precipitable material was collected onto glass fiber filters by using a semiautomatic cell harvester.

Bacterial cell extracts containing RT were diluted to within the linear range of the assay, and activity was determined in the presence and absence of inhibitor. Purified HIV-l RT heterodimer produced in E.

coli also served as a control. Results are determined as inhibitor concentration to give 50% inhibition (iso), in nanomoles/liter.

CELL SPREAD ASSAY Inhibition of the spread of HIV in cell culture was measured according to Nunberg, J. H. et al., J. Virol. 65, 4887 (1991).

In this assay, MT-4 T-lymphoid cells were infected with HIV-1 (wildtype, unless otherwise indicated) by using a predetermined inoculum, and cultures were incubated for 24h. At this time, < 1% of the cells were positive by indirect immunofluorescence. Cells were then extensively washed and distributed into 96-well culture dishes. Serial twofold dilutions of inhibitor were added to the wells, and cultures were continued for 3 additional days. At 4 days postinfection, 100% of the cells in control cultures were infected. HIV-1 p24 accumulation was directly correlated with virus spread. The cell culture inhibitory concentration was defined as the inhibitor concentration in nanomoles/liter which reduced the spread of infection by at least 95%, or CIC95.

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 encompasses all of the usual variations, adaptions, or modifications, as come within the scope of the following claims and its equivalents.

Claims

WHAT IS CLAIMED IS:

1. A compound of the formula:

wherein: Xis halo, G is halo, nitro, CN, C1-4 alkoxy, C1-4 alkylamino, sulfonamido, or C 1-4 alkyl substituted 0-3 times with halo; n= 0-5;

is a stable 4- to 6-membered monocyclic heterocyclic ring which is either saturated, partially unsaturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O, S and P, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, said monocyclic heterocyclic ring being unsubstituted or substituted one or more times with H, amino, C1-4 alkylamino, halo, sulfonamido, cyano, C3-5 cycloalkyl, or C 1-4 alkyl substituted one to three times with halo, or pharmaceutically acceptable salt thereof.

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

wherein Xis halo; R1 and R2 are each independently H, Cl 4alkyl, C3-5 cycloalkyl, amino, cyano, or halo; or, R1 and R2 are connected together to form an unsubstituted cycloalkyl.

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

wherein: X is halo; R1 and R2 are each independently H, C1-4 alkyl, C35 cycloalkyl, amino, cyano, or halo; or R1 and R2 are connected together to form an unsubstituted cycloalkyl.

4. A compound, which is 5-chloro-2-(4(5H)-imi dazol-2-yl)-3 -phenylsulfonylindole, or, 5-chloro-2-(5 (4)-methylimidazol-2-yl)-3 -phenyl- sulfonylindole, or pharmaceutically acceptable salt thereof.

5. A method of inhibiting HIV reverse transcriptase, comprising administering to a mammal an effective amount of a compound of Claim 1.

6. A method of preventing infection of HIV, or of treating infection by HIV or of treating AIDS or ARC, comprising administering to a mammal an effective amount of a compound of Claim 1.

7. A pharmaceutical composition useful for inhibiting HIV reverse transcriptase, comprising an effective amount of a compound of Claim 1 and a pharmaceutically acceptable carrier.

8. A pharmaceutical composition useful for preventing or treating infection of HIV or for treating AIDS or ARC, comprising an effective amount of a compound of Claim 1, and a pharmaceutically acceptable carrier.

8. A combination of a compound of Formula I or Formula II with a nucleoside analog having biological activity against HIV reverse transcriptase.

9. A synergistic combination of AIDS antiviral compounds, which is L-747,655 and L-735,524, and, optionally, one or more of the HIV inhibitors selected from the group consisting of L-743,726, AZT, ddI or ddC.

10. A synergistic combination of AIDS antiviral compounds, which is L-747,655 and one or more of the HIV inhibitors selected from the group consisting of L-743,726, AZT, ddI, or ddC.