Title of Invention	"A HETEROCYCLIC SUBSTITUTED PHENYL CONTAINING SULFONAMIDE COMPOUND"
Abstract	A heterocyclic substituted phenyl containing sulfonamide compound having the formula wherein R1, R2, R3 and R4 are as described in the specification.

Full Text

The present invention relates to heterocyclic substituted phenyl containing sulfonamides, their use as aspartic protease inhibitors, in particular as broad spectrum HIV protease inhibitors, processes for their preparation as well as pharmaceutical compositions and diagnostic kits comprising them. The present invention also concerns combinations of the present substituted phenyl containing sulfonamides with another anti-retroviral agent. It further relates to their use in assays as reference compounds or as reagents. The virus causing the acquired immunodeficiency syndrome (AIDS) is known by different names, including T-lymphocvte virus III (HTLV-III) or lymphadenopathy-associated virus (LAV) or AIDS-related virus (ARV) or human immunodeficiency virus (HIV). Distinct families have been identified, such as HIV-1 and HIV-2. Hereinafter, HIV will be used to genetically denote these viruses. One of the critical pathways in a retroviral life cycle is the processing of polyprotein precursors by aspartic protease. For instance with the HIV virus the gag-pol protein is processed by HIV protease. The correct processing of the precursor polyproteins by the aspartic protease is required for the assembly of infectious virions, thus making the aspartic protease an attractive target for antiviral therapy. In particular for HIV treatment, the HIV protease is an attractive target. HIV protease inhibitors (Pis) are commonly administered to AIDS patients in combination with other anti-HIV compounds such as, for instance nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs) or other protease inhibitors. Despite the fact that these antiretrovirals are very useful, they have a common limitation, namely, the targeted enzymes in the HIV virus are able to mutate in such a way that the known drugs become less effective, or even ineffective against these mutant HIV viruses. Or, in other words, the HIV virus creates an ever increasing resistance against the available drugs. Resistance of retroviruses, and in particular the HIV virus, against inhibitors is a major cause of therapy failure. For instance, half of the patients receiving anti-HIV combination therapy do not respond fully to the treatment, mainly because of resistance of the virus to one or more drugs used. Moreover, it has been shown that resistant virus is carried over to newly infected individuals, resulting in severely limited therapy options for these drug-naive patients. Therefore, there is a need in the art for new compounds for retrovirus therapy, more particularly for AIDS therapy. The need in the art is particularly acute for compounds that are active not only on wild type HIV virus, but also on the increasingly more common resistant HIV viruses. Known antiretrovirals, often administered in a combination therapy regimen, will eventually cause resistance as stated above. This often may force the physician to boost the plasma levels of the active drugs in order for said antiretrovirals to regain effectivity against the mutated HFV viruses. The consequence of which is a highly undesirable increase in pill burden. Boosting plasma levels may also lead to an increased risk of non-compliance with the prescribed therapy. Thus, it is not only important to have compounds showing activity for a wide range of HIV mutants, it is also important that there is little or no variance in the ratio between activity against mutant HIV virus and activity against wild type HIV virus (also defined as fold resistance or FR) over a broad range of mutant HIV strains. As such, a patient may remain on the same combination therapy regimen for a longer period of time since the chance that a mutant HIV virus will be sensitive to the active ingredients will be increased. Finding compounds with a high potency on the wild type and on a wide variety of mutants is also of importance since the pill burden can be reduced if therapeutic levels are kept to a minimum. One way of reducing this pill burden is finding anti-HIV compounds with good bioavailability, i.e. a favorable pharmacokinetic and metabolic profile, such that the daily dose can be minimized and consequently also the number of pills to be taken. Another important characteristic of a good anti-HIV compound is that plasma protein binding of the inhibitor has minimal or even no effect on its potency. Thus, there is a high medical need for protease inhibitors that are able to combat a broad spectrum of mutants of the HIV virus with little variance in fold resistance, have a good bioavailability and experience little or no effect on their potency due to plasma protein binding. Furthermore there is a continued need for compounds with an improved therapeutic index. Up until now, several protease inhibitors are on the market or are being developed. One particular core structure (depicted below) has been disclosed in a number of references, such as, WO 95/06030, WO 96/22287, WO 96/28418, WO 96/28463, WO 96/28464, WO 96/28465 and WO 97/18205. The compounds disclosed therein are described as retroviral protease inhibitors. (Figure Remove) WO 99/67254 discloses 4-substituted-phenyl sulfonamides capable of inhibiting multi-drug resistant retroviral proteases. (Figure Remove) JP 9124630 and WO 96/33184 also disclose substituted phenyl sulfonamides as inhibitors of the HIV protease. Surprisingly, the heterocyclic substituted phenyl containing sulfonamides of the present invention are found to have a favorable pharmacological and pharmacokinetic profile. Not only are they active against wild-type HIV virus, but they also show a broad spectrum activity against various mutant HIV viruses exhibiting resistance against known protease inhibitors. The present invention concerns heterocyclic substituted phenyl containing HIV protease inhibitors, having the formula (Figure Remove) RI may also be a radical of formula (Figure Remove) wherein R9, Rioa and Riob are, each independently, hydrogen, CMalkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(Ci-4alkyl)aminocarbonyl, C3.7cycloalkyl, Ca-ealkenyl, C2^alkynyl or Chalky 1 optionally substituted with aryl, Het1, Het2, C3.7cycloalkyl, CMalkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(CMalkyl)aminocarbonyl, aminosulfonyl, Ci4alkylS(O)t, hydroxy, cyano, halogen or amino optionally mono- or disubstituted where the substituents are selected from Ci-4alkyl, aryl, arylCMalkyl, C3.7cycloalkyl, C3.7cycloalkylCMalkyl, Het1, Het2, Het'CMalkyI and Het2CMalkyl; whereby Rg, RIOS and the carbon atoms to which they are attached may also form a C3.7cycloalkyl radical; RIU is hydrogen, Ca-galkenyl, C2-6alkynyl, C3.7cycloalkyl, aryl, aminocarbonyl optionally mono- or disubstituted, aminoCi-4alkylcarbonyloxy optionally mono- or disubstituted, Ci_4alkyloxycarbonyl, aryloxycarbonyl, Het'oxycarbonyl, Het2oxycarbonyl, aryloxycarbonyld-4alkyl, arylCMalkyloxycarbonyl, Ci^alkylcarbonyl, Cs-Tcycloalkylcarbonyl, Ca^cycloalkylC i-4alkyloxycarbonyl, Ca-vcycloalkylcarbonyloxy, carboxylCi-4alkylcarbonyloxy, CMalkylcarbonyloxy, arylC|-4alkyl-carbonyloxy, arylcarbonyloxy, aryloxycarbonyloxy, Het'carbonyl, Het'carbonyloxy, Het'CMalkyloxycarbonyl, Het2carbonyloxy, Het2CMalkylcarbonyloxy, Het2CMalkyloxycarbonyloxy orCi^alkyl optionally substituted with aryl, aryloxy, Het2 or hydroxy; wherein the substituents on the amino groups are each independently selected from Ci^alkyl, aryl, arylCMalkyl, Cs^cycloalkyl, Cs^cycloalkylCi^alkyl, Het1, Het2, Het'CMalkyI and Het2CMalkyl; Rub is hydrogen, Cs^cycloalkyl, Ca^alkenyl, C2.ealkynyl, aryl, Het1, Het2 or Chalky! optionally substituted with halogen, hydroxy, Ci-4alkylS(=O)t, aryl, Cs-ycycloalkyl, Het1, Het2, amino optionally mono- or disubstituted where the substituents are selected from CMalkyl, aryl, arylCMalkyl, C3.7cycloalkyl, C3.7cycloalkylCMalkyl, Het1, Het2, Het'CMalkyl and Het2CMalkyl; whereby RI ib may be linked to the remainder of the molecule via a sulfonyl group; R2 is hydrogen or Ci^alkyl; L is -C(=0)-, -O-C(-O)-, -NRg-C(=0)-, -O-Ci.6alkanediyl-C(=O)-, -NR8-Ci-6alkanediyl-C(=O)-, -S(=0)2-, -O-S(=O)2-, -NR8-S(=O)2 whereby either the C(=O) group or the S(=O)2 group is attached to the NR2 moiety, R3 is Ci-ealkyl, aryl, C3.7cycloalkyl, C3.7cycloalkylCi.4alkyl, or arylCMalkyl; R4 is hydrogen, d-4alkyloxycarbonyl, carboxyl, optionally mono- or disubstituted aminocarbonyl, C3.7cycloalkyl, C^alkenyl, C2.6alkynyl or Ci^alkyl, whereby C3.7cycloalkyl, C^alkenyl, C2_6alkynyl and Ci-ealkyl may optionally be substituted with a substituent selected from aryl, Het1, Het2, C3.7cycloalkyl, Ci-4alkyloxycarbonyl, carboxyl, optionally mono- or disubstituted aminocarbonyl, optionally mono- or disubstituted aminosulfonyl, Ci-4alkylS(=O)t, hydroxy, cyano, optionally mono- or disubstituted amino and halogen, and whereby the optional substituents on any amino function are independently selected from Cualkyl, aryl, arylCMalkyl, C3-7cycloalkyl, C3-7cycloalkyl-CMalkyl, Het1, Het2, Het'Cualkyl and Het2Cualkyl; t is zero, 1 or 2; each t independently selected is zero, 1 or 2; Haryl is an aromatic monocyclic, bicyclic or tricyclic heterocycle having 3 to 14 ring members which contains one or more heteroatom ring members selected from nitrogen, oxygen and sulfur and which may optionally be substituted on (i) one or more carbon atoms by Ci^alkyl, halogen, hydroxy, optionally mono- or disubstituted amino, nitro, cyano, haloCi^alkyl, carboxyl, Cs^cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl, -(R7a)n-M-R7b, Het1 and Het2; whereby the optional substituents on any amino function are independently selected from Rs and -A-Re; and on (ii) a nitrogen atom if present by hydroxy or -A-Rg; A is C|.6alkanediyl, -C(=O)-, -C(=S)-, -S(=O)2-, Ci.6alkanediyl-C(=O)-, Ci-6alkanediyl-C(=S)- or Ci^alkanediyl-S(=O)2-; whereby for those groups containing a Ci^alkanediyl moiety, the Ci-ealkanediyl moiety is attached to the amino group; Rs is hydroxy, Chalky!, Het'Ci^alkyl, Het2Ci-6alkyl, aminoCi^alkyl whereby the amino group may optionally be mono- or di-substituted with Chalky!; Re is hydrogen, Ci^alkyloxy, Het1, Het'oxy, Het2, Het2oxy, aryl, aryloxy or amino; and in case -A- is other than Ci^alkanediyl then R6 may also be Ci^alkyl, Het'CMalkyl, Het'oxyCMalkyl, Het2CMalkyl, Het2oxyCMalkyl, arylCMalkyl, aryloxyC|_4alkyl or aminoCMalkyl; whereby each of the amino groups in the definition of R* may optionally be substituted with one or two substituents selected from Cualkyl, CMalkylcarbonyl, CMalkyloxycarbonyl, aryl, arylcarbonyl, aryloxycarbonyl, Het1, Het2, arylCMalkyl, HetlCMalkyl or Het2CMalkyl; is C i_8 alkanediyl optionally substituted with one or more substituents selected from, halogen, Ci-»alkylcarbonyl, CMalkyloxycarbonyl, aryl, arylcarbonyl, aryloxycarbonyl, Het' or Het2; is Ci_g alkyl optionally substituted with one or more substituents selected from halogen, CMalkylcarbonyl, CMalkyloxycarbonyl, aryl, arylcarbonyl, aryloxycarbonyl, Het1 or Het2; M is defined by-C(=O)-, -O-C(=O)-, -C(=0)-0-, -CH2-CHOH-, -CHOH-CH2-, -NRg-C(=O)-, -(C=0)-NRr, -S(=0>2-, -O-, -S-, -O-S(=O)r, -S(=O)2-O-, -NRg- S(=0)2or-S(=0)2-NR8-; n is zero or 1. This invention also envisions the quaternization of the nitrogen atoms of the present compounds. A basic nitrogen can be quaternized with any agent known to those of ordinary skill in the art including, for instance, lower alkyl halides, dialkyl sulfates, long chain halides and aralkyl halides. Whenever the term "substituted" is used in defining the compounds of formula (I), it is meant to indicate that one or more hydrogens on the atom indicated in the expression using "substituted" is replaced with a selection from the indicated group, provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent. As used herein, the term "halo" or "halogen" as a group or part of a group is generic for fluoro, chloro, bromo or iodo. The term "Chalky!" as a group or part of a group defines straight and branched chained saturated hydrocarbon radicals having from 1 to 4 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, 2-methyl-propyl, and the like. The term "Ci-ealkyl" as a group or part of a group defines straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as the groups defined for Ci^alkyl and pentyl, hexyl, 2-methylbutyl, 3-methylpentyl and the like. The term "Ci-galkyl" as a group or part of a group defines straight and branched chained saturated hydrocarbon radicals having from 1 to 8 carbon atoms, such as, those defined for Chalky! and heptyl, octyl, 2-methyl-hetyl, 3-ethyl-hexyl and the like. The term "Ci-ealkanediyl" as a group or part of a group defines bivalent straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methylene, ethan-l,2-diyl, propan-l,3-diyl, propan-l,2-diyl, butan-1,4-diyl, pentan-l,5-diyl, hexan-l,6-diyl, 2-methylbutan-l,4-diyl, 3-methylpentan-1,5-diyl and the like. The term "Ci.8alkanediyl" as a group or part of a group defines bivalent straight and branched chained saturated hydrocarbon radicals having from 1 to 8 carbon atoms such as, those defied for C^alkanediyl and 2-ethyl-hexan-l,6-diyl, 3-methyl-heptan-1,7-diyl, and the like. The term "Ca^alkenyl" as a group or part of a group defines straight and branched chained hydrocarbon radicals having from 2 to 6 carbon atoms containing at least one double bond such as, for example, ethenyl, propenyl, butenyl, pentenyl, hexenyl and the like. The term "Cz-ealkynyl" as a group or part of a group defines straight and branched chained hydrocarbon radicals having from 2 to 6 carbon atoms containing at least one triple bond such as, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like. The term "Ca^cycloalkyl" as a group or part of a group is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. The term "aryl" as a group or part of a group is meant to include mono-, bi-, and tricyclic aromatic carbocycles such as phenyl and naphtyl which both may be optionally substituted with one or more substituents independently selected from Ci-ealkyl, Ci^alkyloxy, halogen, hydroxy, optionally mono- or disubstiruted amino, nitro, cyano, hydroxyCi-salkyl, haloCi^alkyl, carboxyl, Ci^alkoxycarbonyl, C3-7cycloalkyl, Het1, optionally mono- or disubstiruted aminocarbonyl, methylthio, methylsulfonyl, and phenyl optionally substituted with one or more substituents selected from Ci^alkyl, Ci-ealkyloxy, halogen, hydroxy, optionally mono- or disubstiruted amino, nitro, cyano, haloCuealkyl, carboxyl, Ci-ealkoxycarbonyl, C3-7cycloalkyl, Het1, optionally mono- or disubstituted aminocarbonyl, methylthio and methylsulfonyl; whereby the optional substituents on any amino function are independently selected from Chalky!, Ci.6alkyloxy-A-, Het'-A-, Het'Ci^alkyl, Het'd^alkyl-A-, Het'oxy-A-, Het'oxyCMakyl-A-, phenyl-A-, phenyl-oxy-A-, phenyl-oxyC|.4alkyl-A-, phenylC|^alkyl-A-, Ci^alkyloxycarbonylamino-A-, amino-A-, aminoCi^alkyl and aminoCj^alkyl-A- whereby each of the amino groups may optionally be mono- or where possible disubstituted with CMalkyl and whereby A is as defined above. An interesting subgroup of "aryl" as a group or part of a group is meant to include mono-, bi-, and tricyclic aromatic carbocycles such as phenyl and naphtyl which both may be optionally substituted with one or more substituents independently selected from C|.6alkyl, Ci^alkyloxy, halogen, hydroxy, optionally mono- or disubstituted amino, nitro, cyano, haloCualkyl, carboxyl, Ci-ealkoxycarbonyl, C3-?cycloalkyl, Het1, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, and phenyl optionally substituted with one or more substituents selected from Chalky!, Ci^alkyloxy, halogen, hydroxy, optionally mono- or disubstituted amino, nitro, cyano, haloCi^alkyl, carboxyl, Ci^alkoxycarbonyl, Cj.vcycloalkyl, Het1, optionally mono- or disubstituted aminocarbonyl, methylthio and methylsulfonyl; whereby the optional substituents on any amino function are independently selected from Ci^alkyl, Ci.6alkyloxy-A-, Het'-A-, Het'Ci^alkyl, Het'Ci-ealkyl-A-, Het'oxy-A-, Het'oxyCMakyl-A-, phenyl-A-, phenyl-oxy-A-, phenyl-oxyCi_4alkyl-A-, phenylCi^alkyl-A-, Ci-ealkyloxycarbonylamino-A-, amino-A-, aminoCi-ealkyl and aminoCi^alkyl-A- whereby each of the amino groups may optionally be mono- or where possible disubstituted with Ci^alkyl and whereby A is as defined above. The term "haloCi.6alkyl" as a group or part of a group is defined as Ci^alkyl substituted with one or more halogen atoms, preferably, chloro or fluoro atoms, more preferably fluoro atoms. Preferred haloCi^alkyl groups include for instance trifluoro-methyl and difluoromethyl. The term "hydroxyCi^alkyl" as a group or part of a group is defined as CuaUeyl substituted with one or more hydroxy atoms. The term "Het1" as a group or part of a group is defined as a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle having preferably 3 to 14 ring members, more preferably 5 to 10 ring members and more preferably 5 to 8 ring members, which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and which is optionally substituted on one or more carbon atoms by CMalkyl, Ci^alkyloxy, halogen, hydroxy, oxo, optionally mono- or disubstituted amino, nitro, cyano, hydroxyd-ealkyl, haloCi^alkyl, carboxyl, C|. 6alkoxycarbonyl, C3_7cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl and a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle having 3 to 14 ring members which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and whereby the optional substituents on any amino function are independently selected from C,. 6alkyl, Ci^alkyloxy-A-, Het2-A-, Het^Ci^alkyl, Het'Ci-ealkyl-A-, Het2oxy-A-, Het2oxyCi-4akyl-A-, aryl-A-, aryloxy-A-, aryloxyCMalkyl-A-, arylCi^alkyl-A-, Ci.6alkyloxycarbonylamino-A-, amino-A-, aminoCi-fialkyl and aminoC|^alkyl-A-whereby each of the amino groups may optionally be mono- or where possible di-substituted with CMalkyl and whereby A is as defined above. An interesting subgroup of "Het1" as a group or part of a group is defined as a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle having preferably 3 to 14 ring members, more preferably 5 to 10 ring members and more preferably 5 to 8 ring members, which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and which is optionally substituted on one or more carbon atoms by CMalkyl, Cj-ealkyloxy, halogen, hydroxy, oxo, optionally mono- or disubstituted amino, nitro, cyano, haloCi^alkyl, carboxyl, Ci^alkoxycarbonyl, Cj.Tcycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl and a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle having 3 to 14 ring members which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and whereby the optional substituents on any amino function are independently selected from CMalkyl, Ci.6alkyloxy-A-, Het2-A-, Het2Ci.6alkyl, Het2Ci. salkyl-A-, Het2oxy-A-, Het2oxyCi4akyl-A-, aryl-A-, aryloxy-A-, aryloxyCi^alkyl-A-, arylCi-ealkyl-A-, Ci-ealkyloxycarbonylamino-A-, amino-A-, aminoCi-ealkyl and aminoCi^alkyl-A- whereby each of the amino groups may optionally be mono- or where possible di-substituted with Chalky! and whereby A is as defined above. The term "Het2" as a group or part of a group is defined as an aromatic monocyclic, bicyclic or tricyclic heterocycle having preferably 3 to 14 ring members, more preferably 5 to 10 ring members and more preferably 5 to 6 ring members, which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and which is optionally substituted on one or more carbon atoms by CMalkyl, Ci-galkyloxy, halogen, hydroxy, optionally mono- or disubstituted amino, nitro, cyano, hydroxyCi-ealkyl, haloCi.6alkyl, carboxyl, Ci^alkoxycarbonyl, Cs^cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl, Het1 and an aromatic monocyclic, bicyclic or tricyclic heterocycle having 3 to 14 ring members; whereby the optional substituents on any amino function are independently selected from C^alkyl, Ci^alkyloxy-A-, Het'-A-, Het'Ci^alkyl, Het'd^alkyl-A-, Het'oxy-A-, Het'oxyCi-4akyl-A-, aryl-A-, aryloxy-A-, aryloxyCi-4alkyl-A-, arylCi. ealkyl-A-, Ci^alkyloxycarbonylamino-A-, amino-A-, aminoCi^alkyl and aminoCi. ealkyl-A- whereby each of the amino groups may optionally be mono- or where possible di-substituted with d ^alkyl and whereby A is as defined above. An interesting subgroup of "Het2" as a group or part of a group is defined as an aromatic monocyclic, bicyclic or tricyclic heterocycle having preferably 3 to 14 ring members, more preferably 5 to 10 ring members and more preferably 5 to 6 ring members, which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and which is optionally substituted on one or more carbon atoms by Ci^alkyl, Ci^alkyloxy, halogen, hydroxy, optionally mono- or disubstituted ammo, nitro, cyano, haloCi^alkyl, carboxyl, Ci^alkoxycarbonyl, C3-7cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl, Het1 and an aromatic monocyclic, bicyclic or tricyclic heterocycle having 3 to 14 ring members; whereby the optional substituents on any amino function are independently selected from Ci^alkyl, Ci^alkyloxy-A-, Het'-A-, Het'Ci^alkyl, Het'Ci^alkyl-A-, Het'oxy-A-, Het'oxy-CMakyl-A-, aryl-A-, aryloxy-A-, aryloxyCi^alkyl-A-, arylCi^alkyl-A-, Ci-ealkyloxy-carbonylamino-A-, amino-A-, aminoCi^alkyl and aminoCi^alkyl-A- whereby each of the amino groups may optionally be mono- or where possible di-substituted with Ci_4alkyl and whereby A is as defined above. As used herein, the term (=O) forms a carbonyl moiety with the carbon atom to which it is attached. The term (=O) forms a sulfoxide with the sulfur atom to which it is attached. The term (=0)2 forms a sulfonyl with the sulfur atom to which it is attached. As used herein, the term (=S) forms a thiocarbonyl moiety with the carbon atom to which it is attached. As used herein before, the term "one or more" covers the possibility of all the available C-atoms, where appropriate, to be substituted, preferably, one, two or three. When any variable (e.g. halogen or CMalkyl) occurs more than one time in any constituent, each definition is independent. The term "prodrug" as used throughout this text means the pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug as defined in the compounds of formula (I). The reference by Goodman and Oilman (The Pharmacological Basis of Therapeutics, 8th ed, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", p 13-15) describing prodrugs generally is hereby incorporated. Prodrugs of a compound of the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy group, for instance the hydroxy group on the asymmetric carbon atom, or an amino group is bonded to any group that, when the prodrug is administered to a patient, cleaves to form a free hydroxyl or free amino, respectively. Typical examples of prodrugs are described for instance in WO 99/33795, WO 99/33815, WO 99/33793 and WO 99/33792 all incorporated herein by reference. Prodrugs are characterized by excellent aqueous solubility, increased bioavailability and are readily metabolized into the active inhibitors in vivo. For therapeutic use, the salts of the compounds of formula (I) are those wherein the counter-ion is pharmaceutically or physiologically acceptable. However, salts having a pharmaceutically unacceptable counter-ion may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound of formula (I). All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention. The pharmaceutically acceptable or physiologically tolerable addition salt forms which the compounds of the present invention are able to form can conveniently be prepared using the appropriate acids, such as, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methane-sulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids. Conversely said acid addition salt forms can be converted by treatment with an appropriate base into the free base form. The compounds of formula (I) containing an acidic proton may also be converted into their non-toxic metal or amine addition salt form by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl, -D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely said base addition salt forms can be converted by treatment with an appropriate acid into the free acid form. The term "salts" also comprises the hydrates and the solvent addition forms which the compounds of the present invention are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like. The W-oxide forms of the present compounds are meant to comprise the compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called //-oxide. The present compounds may also exist in their tautomeric forms. Such forms, although not explicitly indicated in the above formula are intended to be included within the scope of the present invention. The term stereochemically isomeric forms of compounds of the present invention, as used hereinbefore, defines all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds of the present invention may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms which said compound may possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of the present invention both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention. Pure stereoisomeric forms of the compounds and intermediates as mentioned herein are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates. In particular, the term 'stereoisomerically pure' concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i. e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e. 100% of one isomer and none of the other), more in particular, compounds or intermediates having a stereoisomeric excess of 90% up to 100%, even more in particular having a stereoisomeric excess of 94% up to 100% and most in particular having a stereoisomeric excess of 97% up to 100%. The terms 'enantiomerically pure1 and 'diastereomerically pure' should be understood in a similar way, but then having regard to the enantiomeric excess, respectively the diastereomeric excess of the mixture in question. Pure stereoisomeric forms of the compounds and intermediates of this invention may be obtained by the application of art-known procedures. For instance, enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids. Alternatively, enantiomers may be separated by chromatographic techniques using chiral stationary phases. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials. The diastereomeric racemates of formula (I) can be obtained separately by conventional methods. Appropriate physical separation methods which may advantageously be employed are, for example, selective crystallization and chromatography, e.g. column chromatography. It is clear to a person skilled in the art that the compounds of formula (I) contain at least one asymmetric center and thus may exist as different stereoisomeric forms. This asymmetric center is indicated with a asterisk (*) in the figure below. The absolute configuration of each asymmetric center that may be present in the compounds of formula (I) may be indicated by the stereochemical descriptors R and S, this R and S notation corresponding to the rules described in Pure Appl. Chem. 1976, 45,11-30. The carbon atom marked with the asterisk (*) preferably has the R configuration. The present invention is also intended to include all isotopes of atoms occurring on the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14. Whenever used hereinafter, the term "compounds of formula (I)", or "the present compounds" or similar term is meant to include the compounds of general formula (I), their Af-oxides, salts, stereoisomeric forms, racemic mixtures, prodrugs, esters and metabolites, as well as their quaternized nitrogen analogues. A particular subgroup of compounds are those compounds of formula (I), and JV-oxides, salts, stereoisomeric forms, racemic mixtures, prodrugs, esters and metabolites thereof, wherein RI and Rg are, each independently, hydrogen, Ci^alkyl, Cz^alkenyl, arylCi-ealkyl, C3.7cycloalkyl, C3.7cycloalkylCi.6alkyl, aryl, Het1, HetlC|^alkyl, Het2, Het2Cualkyl; RI may also be a radical of formula (Figure Remove) wherein Rg, Rioa and Riob are, each independently, hydrogen, CMalkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(Ci-4alkyl)aminocarbonyl, Cj^cycloalkyl, C2^alkenyl, Ca-salkynyl or CMalkyl optionally substituted with aryl, Het1, Het2, C3.7cycloalkyl, Ci^alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(Ci^alkyl)aminocarbonyl, aminosulfonyl, CMalkylS(O)t, hydroxy, cyano, halogen or amino optionally mono- or disubstituted where the substiruents are selected from Chalky!, aryl, ary!CMalkyl, C3.7cycloalkyl, C3.7cycloalkylCMalkyl, Het1, Het2, Het'CMalkyI and Het2Ci^alkyl; whereby Rg, RIO« and the carbon atoms to which they are attached may also form a C3.7cycloalkyl radical; RIU is hydrogen, Cj^alkenyl, C2.6alkynyl, C3.7cycloalkyl, aryl, aminocarbonyl optionally mono- or disubstituted, aminoCMalkylcarbonyloxy optionally mono- or disubstituted, CMalkyloxycarbonyl, aryloxycarbonyl, Het'oxy-carbonyl, Het2oxycarbonyl, aryloxycarbonylCMalkyl, arylCMalkyloxy-carbonyl, CMalkylcarbonyl, C3.7cycloalkylcarbonyl, C3.7cycloalkyl-Ci-4alkyloxycarbonyl, C3.7cycloalkylcarbonyloxy, carboxylCMalkyl-carbonyloxy, CMalkylcarbonyloxy, arylCi^alkylcarbonyloxy, arylcarbonyloxy, aryloxycarbonyloxy, Het'carbonyl, Het'carbonyloxy, Het'CMalkyloxycarbonyl, Het2carbonyloxy, Het2CMalkylcarbonyloxy, Het2C|_4alkyloxycarbonyloxy or CMalkyl optionally substituted with aryl, aryloxy, Het2 or hydroxy; wherein the substituents on the amino groups are each independently selected from CMalkyl, aryl, arylCMalkyl, C3.7cycloalkyl, C3.7cycloalkylCMalkyl, Het1, Het2, Het'CMalkyl and Het2CMalkyl; Rub is hydrogen, C3.7cycloalkyl, C^alkenyl, C2.«alkynyl, aryl, Het1, Het2 or CMalkyl optionally substituted with halogen, hydroxy, Ci-4alkylS(=O)t, aryl, C3.7cycloalkyl, Het1, Het2, amino optionally mono- or disubstituted where the substituents are selected from CMalkyl, aryl, arylCMalkyl, C3.7cycloalkyl, C3.7cycloalkylCMalkyl, Het1, Het2, Het'CMalkyl and Het2CMalkyl; whereby Ri ib may be linked to the remainder of the molecule via a sulfonyl group; R2 is hydrogen or CMalkyl; L is -C(=0)-, -0-C(=0)-, -NR8-C(=0)-, -O-Ci.6alkanediyl-C(=O)-, -NRg-C|.6alkanediyl-C(=O)-, -S(=0)2-, -O-S(=O)2-, -NR8-S(=O)2 whereby either the C(=O) group or the S(=O)2 group is attached to the NR2 moiety, R3 is Ci-ealkyl, aryl, C3.7cycloalkyl, C3.7cycloalkylCMalkyl, or arylCMalkyl; R4 is hydrogen, CMalkyloxycarbonyl, carboxyl, optionally mono- or disubstituted aminocarbonyl, Ca^cycloalkyl, C2^alkenyl, C2^alkynyl or Ci^alkyl, whereby C3.7cycloalkyl, C^alkenyl, C^alkynyl and CMalkyl may optionally be substituted with a substituent selected from aryl, Het1, Het2, C3.7cycloalkyl, CMalkyloxycarbonyl, carboxyl, optionally mono- or disubstituted aminocarbonyl, optionally mono- or disubstituted aminosulfonyl, CMalkylS(=O)t, hydroxy, cyano, optionally mono- or disubstituted amino and halogen, and whereby the optional substituents on any amino fiinction are independently selected from CMalkyl, aryl, arylCMalkyl, C3.7cycloalkyl, C3.7cycloalkyl-CMalkyl, Het1, Het2, Het'CMalkyl and Het^Malkyl; t is zero, 1 or 2; each t independently selected is zero, 1 or 2; Haryl is an aromatic monocyclic, bicyclic or tricyclic heterocycle having 3 to 14 ring members which contains one or more heteroatom ring members selected from nitrogen, oxygen and sulfur and (i) which is optionally substituted on one or more carbon atoms by Ci^alkyl, Ci^alkyloxy, halogen, hydroxy, optionally mono- or disubstituted amino, nitro, cyano, haloCi_6alkyl, carboxyl, Ci^alkoxycarbonyl, Ci^alkylcarbonyloxy, C3.7cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl, -(R7a)n-M-R7b, Het1 and Het2; whereby the optional substituents on any amino function are independently selected from RS and -A-R«; and (ii) which is optionally substituted on a nitrogen atom by hydroxy or -A-R^; and A is C,.6alkanediyl, -C(=O)-, -C(=S)-, -S(=O)2-, Ci^alkanediyl-C(=O>, Ci-6alkanediyl-C(=S)- or C|.6alkanediyl-S(=O)2-; whereby for those groups containing a Ci^alkanediyl moiety, the Ci^alkanediyl moiety is attached to the amino group; RS is hydroxy, Ci^alkyl, Het'Cj^alkyl, Het2C|.6alkyl, aminoCi^alkyl whereby the amino group may optionally be mono- or di-substituted with Chalky!; Re is hydrogen, Ci^alkyloxy, Met1, Het'oxy, Het2, Het2oxy, aryl, aryloxy or amino; and in case -A- is other than Ci^alkanediyl then R6 may also be Chalky], Het'CMalkyl, Het'oxyCMalkyl, Het2CMalkyl, Het2oxyCMalkyl, arylC(.4alkyl, aryloxyCMalkyl or aminoCMalkyl; whereby each of the amino groups in the definition of Re may optionally be substituted with one or two substituents selected from Cualkyl, Ci-4alkylcarbonyl, CMalkyloxycarbonyl, aryl, arylcarbonyl, aryloxycarbonyl, Het1, Het2, arylCMalkyl, Het'Ci^alkyl or Het2CMalkyl; R?a is C i.g alkanediyl; optionally substituted with one or more substituents selected from, halogen, CMalkylcarbonyl, C|_4alkyloxycarbonyl, aryl, arylcarbonyl, aryloxycarbonyl, Het1 or Het2; Rvb is Cj.g alkyl; optionally substituted with one or more substituents selected from halogen, CMalkylcarbonyl, Ci_4alkyloxycarbonyl, aryl, arylcarbonyl, aryloxycarbonyl, Het1 or Het2; M is defined by -C(=O)-, -O-C(=O)-, -C(=O)-O-, -CH2-CHOH-, -CHOH-CH2-, -NRg-C(=0)-, -(C=0)-NRg-, -S(=0)2-, -O-, -S-, -O-S(=O)r, -S(=O)2-O-, -NR8-S(=0)2or-S(=0)2-NR8-; n is zero or 1 . A particular group of compounds are those compounds of formula (I) wherein one or more of the following restrictions apply: RI is hydrogen, Het1, Het2, aryl, Het'd^alkyl, Het2Ci^alkyl, arylC|.6alkyl, more in particular, RI is hydrogen, a saturated or partially unsaturated monocyclic or bicyclic heterocycle having 5 to 8 ring members, which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and which is optionally substituted, phenyl optionally substituted with one or more substituents, an aromatic monocyclic heterocycle having 5 to 6 ring members, which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and which is optionally substituted on one or more carbon atoms, or Chalky! substituted with an aromatic monocyclic heterocycle having 5 to 6 ring members, which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and which is optionally substituted on one or more carbon atoms; R2 is hydrogen; L is -C(=O)-, -O-C(=O)-,-O-Ci-6alkanediyl-C(=O)-, more in particular, L is -C(=O)-, -O-C(=O)-,-O-CH2-C(=O)-, whereby in each case the C(=O) group is attached to the NR2 moiety; R.3 is arylCi^alkyl, in particular, arylmethyl, more in particular phenylmethyl; R» is optionally substituted Chalky!, in particular Ci^alkyl optionally substituted with aryl, Het1, Het2, Ca^cycloalkyl or amino optionally mono- or disubstituted where the substituents are selected from Ci^alkyl, aryl, Het1 and Het2; A is Q-ealkanediyl, -C(=O)- or C|^alkanediyl-C(=O)-, in particular, A is methylene, 1,2-ethanediyl, 1,3-propanediyl, -C(=O)-or-CH2-C(=O)-; Rs is hydrogen, Chalky!, Het'Ci^alkyl, aminoCugalkyl whereby the amino group may optionally be mono- or di-substituted with CMalkyl; RS is Ci^alkyloxy, Het1, aryl, amino; and in case -A- is other than Ci^alkanediyl then Re may also be CMalkyl, Het'CMalkyl, aryloxyCMalkyl or aminoCi^alkyl; whereby each of the amino groups may optionally be substituted; or Rs and -A-R6 taken together with the nitrogen atom to which they are attached may also form Het1; Haryl is an aromatic mono- or bicyclic heterocycle having 3 to 8 ring members, which contain one or more heteroatoms selected from N, O or S and (i) which Haryl is optionally substituted on one or more carbon atoms by CMalkyl, Ci-galkyloxy, halogen, hydroxy, optionally mono- or disubstituted amino, nitro, cyano, halo-C|_6alkyl, carboxyl, Cj^alkoxycarbonyl, Ci^alkylcarbonyloxy, Cj.7cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl, (R7a)n- M-Ryb, Het1 and Het2; whereby the optional substituents on any amino function are independently selected from RS and -A-Re; and (ii) which Haryl is optionally substituted on a nitrogen atom by hydroxy or -A-Re. A special group of compounds are those compounds of formula (I) wherein RI is Het1, aryl, Het2C|.6alkyl; R2 is hydrogen; L is -C(=O)-, -0-C(=O)-, -O-CH2-C(=O)-, whereby in each case the C(=O) group is attached to the NR2 moiety; RS is phenylmethyl; and R4 is CMalkyl. Another interesting group of compounds are those compounds of formula (I) wherein RI hydrogen, C^alkyl, C2.6alkenyl, arylCualkyl, C3-7cycloalkyl, C3.7cycloalkylC|. ealkyl, aryl, Het1, Het'Ci^alkyl, Het2, Het2Ci^alkyl; wherein Het1 is a saturated or partially unsaturated monocyclic heterocycle having 5 or 6 ring members, which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and which is optionally substituted on one or more carbon atoms. Another interesting group of compounds are those compounds of formula (I) wherein RI is arylCualkyl, Het'Ci^alkyl, He^d-ealkyl or Het1 having at least 5 carbon atoms. Another interesting group of compounds are those compounds of formula (I) wherein L is -O-Ci^alkanediyl-C(=O)-. In interesting group of compounds are those compounds of formula (I), wherein the Haryl substituent on the phenyl is in para position vis-a-vis the sulfonamide moiety. An interesting group of compounds are those compounds of formula (I), wherein the Haryl substituent comprises at least one nitrogen atom, preferably said Haryl substituent comprises at least a nitrogen atom at an alpha position to the Haryl-phenyl bond. Another interesting group of compounds are those compounds of formula (I) wherein RI is selected from the group consisting of a disubstituted aryl, a trisubstituted aryl, Het2Ci^alkyl or a Het1; Haryl is monosubstituted or disubstituted; wherein if Haryl is disubstituted at least one substituent is selected from methyl, halogen or amino. Another interesting group of compounds are those compounds of formula (I), wherein the Haryl moiety is selected from the group comprising thiazolyl, imidazolyl, oxazolyl, oxadiazolyl, pyrazolyl, pyrazinyl, imidazolinonyl, quinolinyl, isoquinolinyl, indolyl, pyridazinyl, pyridinyl, pyrrolyl, pyranyl, pyrimidinyl, furanyl, triazolyl, tetrazolyl, benzofuranyl, benzoxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, thiophenyl, tetrahydrofurofuranyl, tetrahydropyranofuranyl, benzothiophenyl, carbazolyl, imidazolonyl, oxazolonyl, indolizinyl, triazinyl or quinoxalinyl; whereby the Haryl moiety may be optionally further substituted on one or more ring members; preferably the Haryl moiety is selected from the group consisting of thiazolyl, imidazolyl, oxazolyl, oxadiazolyl, pyrazolyl or pyridinyl, optionally substituted on one or more ring members. 6Another interesting group of compounds are those compounds of formula (I), wherein the Haryl moiety is thiazolyl substituted with an optionally mono or disubstituted amino group; preferably said amino group is not substituted or monosubstituted. Another interesting group of compounds are those compounds of formula (I), wherein the Haryl moiety is pyrazolyl substituted on a nitrogen atom. Another interesting group of compounds are those compounds of formula (I), wherein the Haryl moiety is oxazolyl substituted with methyl or amino, preferably said substituent is at the 2 position of the oxazolyl moiety. Another interesting group of compounds are those compounds of formula (I), wherein the Haryl moiety is oxadiazolyl substituted at the 5 position of the oxadiazolyl moiety. A suitable group of compounds are those compounds of formula (I) as a salt, wherein the salt is selected from trifluoroacetate, fumarate, chloroacetate and methanesulfonate. An interesting group of compounds are those compounds of formula (I) having a fold resistance, determined according to the methods herein described, in the range of 0.01 to 100 against HIV species having at least one mutation in the HIV protease as compared to the wild type sequence (e.g. genbank accession M38432, K03455, gi 327742) at a position selected from 10, 71 and 84; in particular at least two mutations selected from 10, 71 and 84 are present in the HIV protease; in particular the compounds have a fold resistance in the range of 0.1 to 100, more in particular in the range 0.1 to 50. An interesting group of compounds are compounds N° 1-6,24, 32-33, 35, 23-24, 38-40,42-44,46,48-52, and 57 as disclosed in the present invention. A suitable group of compounds are compounds N° 1-6,24,32,35, 23-24,38 and 40 as disclosed in the instant invention. In one aspect RS may be Ca-ealkenyl, such -CH2-CH=CH2; aryl such as phenyl or Het2 such as pyridine. In one aspect the Haryl moiety may also be substituted by Cj-ealkylcarboxylic acid such as-CH2-CH2-COOH. The invention also concerns a pharmaceutical composition consisting of a solid dispersion comprising, (a) a compound of formula (I), (b) one or more pharmaceutically acceptable water-soluble polymers. In particular, the compound is selected from compound N° 1-6,24,32-33,35,23-24, 38-40,42-44,46,48-52, and 57. Conveniently, a water soluble polymer includes hydroxypropylmethylcellulose, polyvinylpyrrolidone copolymer with vinyl acetate (PVP-VA). The invention also relates to a process for the manufacture of a composition comprising at least one compound of formula (I) or exemplified in tables 1 to 6. The invention further relates to a compound of formula (I) or exemplified in tables 1 to 6characterized in that said compound is synthesized according to any of schemes 1 to 6. The invention further relates to intermediates as described in the present invention in synthesis of a compound according to formula (I). Interesting intermediates include those of formula B-l, B-2 or K. The invention further relate to a compound of formula (I) or exemplified in tables 1 to 6 in the manufacture of a medicament for treating, preventing or combating infection or disease associated with retrovirus infection in a mammal, preferably a human. Compounds having interesting pharmacokinetic properties are those of formula (I), containing at least one substituent independently selected from thiazolyl, imidazolyl and pyridinyl. The compounds of formula (I) can generally be prepared using procedures analogous to those procedures described in WO 95/06030, WO 96/22287, WO 96/28418, WO 96/28463, WO 96/28464, WO 96/28465 and WO 97/18205. Particular reaction procedures to make the present compounds are described below. In the preparations described below, the reaction products may be isolated from the medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, triruration and chromatography. (Figure Remove) Reaction of a a-substituted-a-bromoacetophenone with thiourea or substituted thiourea, at elevated temperatures may give gave an intennediate Gl. Suitably, this reaction may be performed under refluxing conditions in the presence of DMF (dimethylformamide). This intennediate (Gl) may be reacted with chlorosulfonic acid to yield the sulfonyl chloride B-l. For example 2-bromopropiophenone may be reacted with thiourea to yield 2-amino-5-methyl-4-phenylthiazole, which can be further transformed to 4-(2-amino-5-methylthiazol-4-yl)phenyl sulfonyl chloride. When phenylacetylbromide was used to yield intermediate Gl. this latter was first brominated using techniques known in the art, before reaction with chlorosulfonic acid, yielding for example 4-(2-amino-5-bromothiazol-4-yl)phenyl sulfonyl chloride. Ra, Rb and RC are each independently Haryl substituents. (Figure Remove) Intermediate C may be prepared by reacting at low temperature intermediate A, obtained according to the procedure described in patent WO97/18205, with intermediate B in a reaction-inert solvent in the presence of a base. For example, the reaction may be performed at about 0°C in dichloromethane the presence triethylamine (Et3N). The aminoterminal protective group in the intermediates may be a protective group (PG) known in the art such as tert-butyloxycarbonyl group. This protective group may conveniently be replaced by another suitable protective group such as phtalimido, dibenzyl or benzyloxycarbonyl. Intermediate C may be deprotected using an acid, such as trifluoroacetic acid, in a suitable solvent such as dichloromethane, yielding an intermediate D. In one embodiment, a 4-(2-substituted amino-5-bromothiazol-4-yl)phenyl sulfonamide derivative C maybe denominated by catalytic hydrogenation for example, prior to protective group removal. The aminoterminal group of intermediate D may subsequently be substituted by procedures known in the art to generate E. Alternatively, intermediates may be deprotected with a strong acid such as hydrochloric acid in isopropanol, in a suitable solvent such as a mixture of ethanol and dioxane. In a preferred embodiment the protecting group may be selected from Fmoc, acetyl, terf-butyloxycarbonyl, benzyloxycarbonyl-, and dibenzyl-. (Figure Remove) Intermediate A may be generated as described in Synthesis 2. A may be reacted with 4-acetyl-phenylsulfonyl chloride to generate H. Suitable conditions for this reaction include a polar aprotic solvent such as dichlormethane and the use of a base such as EtsN. The protecting group may be removed and exchanged for another protecting group and the acetyl moiety of the phenyl ring is halogenated using techniques known in the art such as Bra. The exchange of protecting group may improve the bromination reaction. The heterocycle on the phenyl-moiety may be introduced using reactions as described in synthesis 1. Following introduction of said heterocycle, the aminoterminal group may be deprotected under conditions known in the art and the free aminomoiety may subsequently be substituted using procedures known to the person skilled in the art. (Figure Remove) Examples of this reaction include the phenylsubstituted thiazoles. Thiourea or optionally substituted thiourea may be reacted with intermediate K to generate 2-amino-substituted thiazole derivatives. The reaction may be performed in organic solvents at elevated temperatures. For example, reaction conditions may include ethanol under refluxing conditions. Ra and Rb are each independently Haryl substituents. In another example thioamides may be reacted with K to yield 2-substituted thiazoles. (Figure Remove) Oxazoles may be prepared starting from K which may be reacted with urea or substituted urea molecules to obtain 2-aminosubstituted oxazoles. The reaction may be performed in organic solvents at elevated temperatures. For example, reaction conditions include ethanol under refluxing conditions. R» and Rb are each independently Haryl substituents. 2-alkyl substituted oxazoles are prepared by reacting K with amides of formula R-C(=O)-NH2, wherein R is a Haryl substituent. (Figure Remove) This reaction procedure yields 2-aminosubstituted-imidazole derivatives. In another approach K may be reacted with amidines to generate 2-substituted imidazoles. The reaction can be performed in organic solvents at elevated temperatures, for example in the presence of THF (tetrahydrofurane) under refluxing conditions. In one embodiment the imine function of the guanidine-derivative may be incorporated in a cycle, such as 2-aminothiazole. This may yield e.g. imidazo[2,l-b]thiazole. In one embodiment the intermediate K may be reacted with salts of alkylcarboxylic acids to yield acetyl oxycarbonyl substituents. This reaction may be performed at elevated temperatures in organic solvents, for example at about 60°C in DMF (dimethylformamide). The obtained intermediate may be further reacted with ammonia acetate to yield 2-substituted imidazoles. R, Ra and Rb are each independently Haryl substituents. (Figure Remove) Intermediate H may be reacted with N,N-dimethyIformamide dimethyl acetal, in an organic solvent such as toluene. This reaction may be performed at elevated temperatures, to yield an intermediate as a mixture of cis and trans isomers. This latter intermediate may be further reacted with hydrazine or substituted hydrazine. The reaction may be performed at elevated temperatures in an organic solvent in the presence of a base. For example, the reaction may be performed in the presence of a base such as potassium carbonate, with ethanol as a solvent, under reflux conditions. The obtained product is a mixture of isomers. R is an Haryl substituent. (Figure Remove) A may be reacted with 4-cyano-phenylsulfonyl chloride to give intermediate K-S. The reaction may be performed at lower temperatures in organic solvents under alkaline conditions. For example, the reagents may be mixed at about 0°C in dichloromethane (DCM) in the presence of triethylamine. The temperature may then be allowed to increase to about room temperature. Intermediate K-5 may be further reacted with hydroxylamine to produce intermediate L. For example, intermediate K-5 may be reacted with hydroxylamine in ethanol in the presence of a base such as potassium carbonate under elevated temperatures. Refluxing conditions may be used. (5-R-oxadiazol-3-yl)phenylsulfonamide derivatives may be obtained after reaction of intermediate L with an acyl chloride of formula RC(=O)C1. In one embodiment, the latter reaction may be performed with pyridine as a solvent at elevated temperatures, for example at about 110°C. R is an Haryl substituent. The amino-protecting group may be removed following the generation of the heterocycle-phenyl moiety using conditions known in the art. Subsequently, the amino-moiety may be substituted with other groups using conditions known in the art. A preferred amino-substituent may be a bis-THF ester moiety. Synthesis scheme 5 (Figure Remove) Intermediate A may be reacted with 4-bromo-phenylsulfonyl chloride to yield intermediate M. The reaction may be performed at lower temperatures in organic solvents under alkaline conditions. For example, the reagents may be mixed at about 0°C in dichloromethane in the presence of triethylamine. The temperature may then be allowed to increase to about room temperature. The protecting group of intermediate M may be exchanged for another protecting group. For example, PGi is a boc group and PGz is a bis-tetrahydrofurane group. Intermediate M may be further reacted with a tributyltin derivative of formula RSn(nBu)3, in organic solvents in the presence of a base and catalyst at elevated temperature. For example, the reaction may be performed in dioxane, in the presence of a base such as triethylamine, and a catalyst such as [l,l'-bis(diphenylphosphino) ferrocene]palladium(II) dichloromethane adduct, at about 85°C. R is Haryl optionally substituted as defined above. In one embodiment, the protective group may be replaced by another one, preferably a bisTHF ester, prior to the reaction with a tributyltin derivative. (Figure Remove) Intermediate Ajnay be prepared by reacting compound F with an arnine, in a suitable solvent such as isopropanol. It is clear from scheme 6 that the stereochemistry of intermediate F, determines the stereochemistry of intermediate A. The compounds of formula (I) may also be converted to the corresponding TV-oxide forms following art-known procedures for converting a trivalent nitrogen into its TV-oxide form. Said TV-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chloro-benzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. ter/-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents. The present compounds can thus be used in animals, preferably in mammals, and in particular in humans as Pharmaceuticals per se, in mixtures with one another or in the form of pharmaceutical preparations. Furthermore, the present invention relates to pharmaceutical preparations which as active constituents contain an effective dose of at least one of the compounds of formula (I) in addition to customary pharmaceutically innocuous excipients and auxiliaries. The pharmaceutical preparations normally contain 0.1 to 90% by weight of a compound of formula (I). The pharmaceutical preparations can be prepared in a manner known per se to one of skill in the art. For this purpose, at least one of a compound of formula (I), together with one or more solid or liquid pharmaceutical excipients and/or auxiliaries and, if desired, in combination with other pharmaceutical active compounds, are brought into a suitable administration form or dosage form which can then be used as a pharmaceutical in human medicine or veterinary medicine. Pharmaceuticals which contain a compound according to the invention can be administered orally, parenterally, e.g., intravenously, rectally, by inhalation, or topically, the preferred administration being dependent on the individual case, e.g., the particular course of the disorder to be treated. Oral administration is preferred. The person skilled in the art is familiar on the basis of his expert knowledge with the auxiliaries which are suitable for the desired pharmaceutical formulation. Beside solvents, gel-forming agents, suppository bases, tablet auxiliaries and other active compound carriers, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers, agents for achieving a depot effect, buffer substances or colorants are also useful. Due to their favorable pharmacological properties, particularly their activity against multi-drug resistant HIV protease enzymes, the compounds of the present invention are useful in the treatment of individuals infected by HIV and for the prophylaxis of these individuals. In general, the compounds of the present invention may be useful in the treatment of warm-blooded animals infected with viruses whose existence is mediated by, or depends upon, the protease enzyme. Conditions which may be prevented or treated with the compounds of the present invention, especially conditions associated with HIV and other pathogenic retroviruses, include AIDS, AIDS-related complex (ARC), progressive generalized lymphadenopathy (PGL), Kaposi's syndrome, thrombocytopenia purpurea, as well as chronic CNS diseases caused by retroviruses, such as, for example HIV mediated dementia and multiple sclerosis. The compounds of the present invention are also useful in case of actual or potential exposure to HIV, tropical parapesis, and also anti-HIV antibody positive and HIV-positive conditions, including such conditions in asymptomatic patiens. The compounds of the present invention or any subgroup thereof may therefore be used as medicines against above-mentioned conditions. Said use as a medicine or method of treatment comprises the systemic administration to HIV-infected subjects of an amount effective to combat the conditions associated with HIV and other pathogenic retroviruses, such as HIV-1. Consequently, the compounds of the present invention can be used in the manufacture of a medicament useful for treating conditions associated with HIV and other pathogenic retroviruses, in particular medicaments useful for treating patients infected with multi-drag resistant HIV virus. The compounds of this invention may be employed in a conventional manner for the treatment of viruses, such as HIV and HTLV, which depend on aspartyl proteases for obligatory events in their life cycle. Although this invention focuses on the use of the compounds disclosed herein for preventing and treating HIV infection, the compounds of this invention can also be used as inhibitory agents for other viruses which depend on similar aspartyl proteases for obligatory events in their life cycle. These viruses include other AlDS-like diseases caused by retroviruses, such as simian immunodeficiency viruses, HTLV-I andHTLV-II. In addition, the compounds of this invention may also be used to inhibit other aspartyl proteases, and in particular, other human aspartyl proteases, including renin and aspartyl proteases that process endothelin precursors. In one embodiment, the invention relates to the use of a compound of formula (I) or any subgroup thereof in the manufacture of a medicament for treating, preventing or combating infection or disease associated with multi-drug resistant retrovirus infection in a mammal, such as HFV-1 infection. Thus, the invention also relates to a method of treating a retroviral infection, or a disease associated with multi-drug resistant retrovirus infection comprising administering to a mammal in need thereof an effective amount of a compound of formula (I) or a subgroup thereof. Preventing or prevention is meant to include prophylaxis of HIV infection and prophylaxis of the evolution of HIV infection to AIDS. In another embodiment, the present invention relates to the use of formula (I) or any subgroup thereof in the manufacture of a medicament for inhibiting a protease of a multi-drug resistant retrovirus in a mammal infected with said retrovirus, in particular HFV-1 retrovirus. In another embodiment, the present invention relates to the use of formula (I) or any subgroup thereof in the manufacture of a medicament for inhibiting multi-drug resistant retroviral replication, in particular HIV-1 replication. The compounds of the present invention may also find use in inhibiting ex vivo samples containing HIV or expected to be exposed to HIV. Hence, the present compounds may be used to inhibit HIV present in a body fluid sample which contains or is suspected to contain or be exposed to HIV. Also, the combination of an antiretroviral compound and a compound of the present invention can be used as a medicine. Thus, the present invention also relates to a product containing (a) a compound of the present invention, and (b) another antiretroviral compound, as a combined preparation for simultaneous, separate or sequential use in the prevention or treatment of retroviral infections, in particular, in the treatment of infections with multi-drug resistant retroviruses. Thus, to combat, prevent or treat HIV infections, or the infection and disease associated with HIV infections, such as Acquired Immunodeficiency Syndrome (AIDS) or AIDS Related Complex (ARC), the compounds of this invention may be co-administered in combination with for instance, binding inhibitors, such as, for example, dextran sulfate, suramine, polyanions, soluble CD4, PRO-542, BMS-806; fusion inhibitors, such as, for example, T20, T1249, RPR 103611, YK-FH312,1C 9564, 5-helix, D-peptide ADS-J1; co-receptor binding inhibitors, such as, for example, AMD 3100, AMD-3465, AMD7049, AMD3451 (Bicyclams), TAK 779, T-22, ALX40-4C; SHC-C (SCH351125), SHC-D, PRO-140, RPR103611; RT inhibitors, such as, for example, foscarnet and prodrugs; nucleoside RTIs, such as, for example, AZT, 3TC, DDC, DDI, D4T, Abacavir, FTC, DAPD (Amdoxovir), dOTC (BCH-10652), fozivudine, DPC 817; nucleotide RTIs, such as, for example, PMEA, PMPA (tenofovir); NNRTIs, such as, for example, nevirapine, delavirdine, efavirenz, 8 and 9-C1TIBO (tivirapine), loviride, TMC-125, dapivirine, MKC-442, UC 781, UC 782, Capravirine, QM96521, GW420867X, DPC 961, DPC963, DPC082, DPC083, TMC-125, calanolide A, SJ-3366, TSAO, 4"-deaminated TSAO, MV150, MV026048, PNU-142721; RNAse H inhibitors, such as, for example, SP1093V, PD126338; TAT inhibitors, such as, for example, RO-5-3335, K12, K37; integrase inhibitors, such as, for example, L 708906, L 731988, S-1360; protease inhibitors, such as, for example, amprenavir and prodrug GW908 (fosamprenavir), ritonavir, nelfinavir, saquinavir, indinavir, lopinavir, palinavir, BMS 186316, atazanavir, DPC 681, DPC 684, tipranavir, AG1776, mozenavir, DMP-323, GS3333, KNI-413, KNI-272, L754394, L756425, LG-71350, PD161374, PD173606, PD177298, PD178390, PD178392, PNU 140135, TMC-114, maslinic acid, U-140690; glycosylation inhibitors, such as, for example, castanospermine, deoxynojirimycine; entry inhibitors CGP64222. rhe compounds of this invention may be administered as single agents or in combination with other agents. Combination therapies may exert an additive or iynergistic effect in inhibiting HIV replication because each compound of the combination may act on a different site of HIV replication or may act on a different site >f the target protein. The use of such combination therapies may also advantageously •educe the dosage of a given conventional anti-retroviral agent which would be •equired for a desired therapeutic or prophylactic effect, as compared to when that igent is administered as a monotherapy. Such combinations may reduce or eliminate he side effects of conventional single antiretroviral agent therapies, while not nterfering with the anti-retroviral activity of those agents. These combinations reduce potential of resistance to single agent therapies, while minimizing any associated :oxicity. These combinations may also increase the efficacy of the conventional agent without increasing the associated toxicity. Examples of combinations include multiple combinations comprising from 2 to 6 agents. In one embodiment, the combination may arovide a synergistic effect, whereby viral infectivity and its associated symptoms may 3e prevented, substantially reduced, or eliminated completely. For each combination, lie combination index (CI) may determined according to a method described by Chou and Talalay (Adv. Enzyme Regul. 22: 27-55,1984). A CI value from about 0.8 to about 1.2 reflects additive inhibition of combined compounds, a value below 0.8 indicates a synergy between two molecules, whereas a value greater than 1.2 is indicative of antagonism. rhe compounds of the present invention may also be administered in combination with immunomodulators (e.g., bropirimine, anti-human alpha interferon antibody, IL-2, tnethionine enkephalin, interferon alpha, HE-2000 and naltrexone), antibodies (e.g. monoclonal antibody Hu-5A8), vaccines (e.g. AG-1661, Aidsvax B/B), antibiotics [e.g., pentamidine isothiorate) cytokines (e.g. Th2), modulators of cytokines, chemokines or the receptors thereof (e.g. CCR5) or hormones (e.g. growth hormone, filgrastim) to ameliorate, combat, or eliminate HIV infection and its symptoms. Such combination therapy in different formulations, may be administered simultaneously, separately or sequentially. Alternatively, such combination may be administered as a single formulation, whereby the active ingredients are released from the formulation simultaneously or separately. The compounds of the present invention may also be administered in combination with modulators of the metabolization following application of the drug to an individual. These modulators include compounds that interfere with the metabolization at cytochromes, such as cytochrome P450. Some modulators inhibit cytochrome P450. It is known that several isoenzymes exist of cytochrome P450, one of which is cytochrome P450 3A4. Ritonavir is an example of a modulator of metabolization via cytochrome P450. Other useful inhibitors of cytochrome P4so include ketoconazole, cimetidine or bergamottin. Another group of cytochrome P+so inhibitors include itraconazole, clarithromycine, erythromycine, nefazodone, delavirdine or troleandomycine. Said modulator may also be an HIV protease inhibitor and is for example selected from the group comprising indinavir, nelfinavir, saquinavir, amprenavir, lopinavir, lasinavir, palinavir, telinavir, tipranavir, mozenavir, atazanavir. Such combination therapy in different formulations, may be administered simultaneously, separately or sequentially. Alternatively, such combination may be administered as a single formulation, whereby the active ingredients are released from the formulation simultaneously or separately. Such modulator may be administered at the same or different ratio as the compound of the present invention. Preferably, the weight ratio of such modulator vis-a-vis the compound of the present invention (modulator: compound of the present invention) is 1:1 or lower, more preferable the ratio is 1:3 or lower, suitably the ratio is 1:10 or lower, more suitably the ratio is 1:30 or lower. For an oral administration form, compounds of the present invention are mixed with suitable additives, such as excipients, stabilizers or inert diluents, and brought by means of the customary methods into the suitable administration forms, such as tablets, coated tablets, hard capsules, aqueous, alcoholic, or oily solutions. Examples of suitable inert carriers are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, or starch, in particular, corn starch. In this case the preparation can be carried out both as dry and as moist granules. Suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil or cod liver oil. Suitable solvents for aqueous or alcoholic solutions are water, ethanol, sugar solutions, or mixtures thereof. Polyethylene glycols and polypropylene glycols are also useful as further auxiliaries for other administration forms. For subcutaneous or intravenous administration, the active compounds, if desired with the substances customary therefor such as solubilizers, emulsifiers or further auxiliaries, are brought into solution, suspension, or emulsion. The compounds of formula (I) can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection or infusion preparations. Suitable solvents are, for example, water, physiological saline solution or alcohols, e.g. ethanol, propanol, glycerol, in addition also sugar solutions such as glucose or mannitol solutions, or alternatively mixtures of the various solvents mentioned. Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the compounds of formula (I) or their physiologically tolerable salts in a pharmaceutically acceptable solvent, such as ethanol or water, or a mixture of such solvents. If required, the formulation can also additionally contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers as well as a propellant. Such a preparation customarily contains the active compound in a concentration from approximately 0.1 to 50%, in particular from approximately 0.3 to 3% by weight. In order to enhance the solubility and/or the stability of the compounds of formula (I) in pharmaceutical compositions, it can be advantageous to employ a-, p- or y-cyclo-dextrins or their derivatives. Also co-solvents such as alcohols may improve the solubility and/or the stability of the compounds of formula (I) in pharmaceutical compositions. In the preparation of aqueous compositions, addition salts of the subject compounds are obviously more suitable due to their increased water solubility. Appropriate cyclodextrins are a-, P- or y-cyclodextrins (CDs) or ethers and mixed ethers thereof wherein one or more of the hydroxy groups of the anhydroglucose units of the cyclodextrin are substituted with Ci^alkyl, particularly methyl, ethyl or isopropyl, e.g. randomly methylated P-CD; hydroxyCi^alkyl, particularly hydroxy-ethyl, hydroxypropyl or hydroxybutyl; carboxyCi-galkyl, particularly carboxymethyl or carboxyethyl; Ci-ealkyl-carbonyl, particularly acetyl; Ci-^alkyloxycarbonylCi^alkyl or carboxyCi^alkyloxyCi-fialkyl, particularly carboxymethoxypropyl or carboxyethoxy-propyl; Ci^alkylcarbonyloxyCi-ealkyl, particularly 2-acetyloxypropyl. Especially noteworthy as complexants and/or solubilizers are P-CD, randomly methylated P-CD, 2,6-dimethyl-p-CD, 2-hydroxyethyl-p-CD, 2-hydroxyethyl-y-CD, 2-hydroxypropyl-y-CD and (2-carboxymethoxy)propyl-p-CD, and in particular 2-hydroxypropyl-p-CD (2-HP-p-CD). The term mixed ether denotes cyclodextrin derivatives wherein at least two cyclodextrin hydroxy groups are etherified with different groups such as, for example, hydroxy-propyl and hydroxyethyl. An interesting way of formulating the present compounds in combination with a cyclodextrin or a derivative thereof has been described in EP-A-721,331. Although the formulations described therein are with antifungal active ingredients, they are equally interesting for formulating the compounds of the present invention. The formulations described therein are particularly suitable for oral administration and comprise an antifungal as active ingredient, a sufficient amount of a cyclodextrin or a derivative thereof as a solubilizer, an aqueous acidic medium as bulk liquid carrier and an alcoholic co-solvent that greatly simplifies the preparation of the composition. Said formulations may also be rendered more palatable by adding pharmaceutically acceptable sweeteners and/or flavors. Other convenient ways to enhance the solubility of the compounds of the present invention in pharmaceutical compositions are described in WO-94/05263, PCT application No. PCT/EP98/01773, EP-A-499,299 and WO 97/44014, all incorporated herein by reference. More in particular, the present compounds may be formulated in a pharmaceutical composition comprising a therapeutically effective amount of particles consisting of a solid dispersion comprising (a) a compound of formula (I), and (b) one or more pharmaceutically acceptable water-soluble polymers. The term "a solid dispersion" defines a system in a solid state (as opposed to a liquid or gaseous state) comprising at least two components, wherein one component is dispersed more or less evenly throughout the other component or components. When said dispersion of the components is such that the system is chemically and physically uniform or homogenous throughout or consists of one phase as defined in thermodynamics, such a solid dispersion is referred to as "a solid solution". Solid solutions are preferred physical systems because the components therein are usually readily bioavailable to the organisms to which they are administered. The term "a solid dispersion" also comprises dispersions which are less homogenous throughout than solid solutions. Such dispersions are not chemically and physically uniform throughout or comprise more than one phase. The water-soluble polymer in the particles is conveniently a polymer that has an apparent viscosity of 1 to 100 mPa.s when dissolved in a 2 % aqueous solution at 20°C solution. Preferred water-soluble polymers are hydroxypropyl methylcelluloses or HPMC. HPMC having a methoxy degree of substitution from about 0.8 to about 2.5 and a hydroxypropyl molar substitution from about 0.05 to about 3.0 are generally water soluble. Methoxy degree of substitution refers to the average number of methyl ether groups present per anhydroglucose unit of the cellulose molecule. Hydroxy-propyl molar substitution refers to the average number of moles of propylene oxide which have reacted with each anhydroglucose unit of the cellulose molecule. The particles as defined hereinabove can be prepared by first preparing a solid dispersion of the components, and then optionally grinding or milling that dispersion. Various techniques exist for preparing solid dispersions including melt-extrusion, spray-drying and solution-evaporation, melt-extrusion being preferred. It may further be convenient to formulate the present compounds in the form of nanoparticles which have a surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than 1000 nm. Useful surface modifiers are believed to include those which physically adhere to the surface of the antiretroviral agent but do not chemically bond to the antiretroviral agent. Suitable surface modifiers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and anionic surfactants. Yet another interesting way of formulating the present compounds involves a pharmaceutical composition whereby the present compounds are incorporated in hydrophilic polymers and applying this mixture as a coat film over many small beads, thus yielding a composition with good bioavailability which can conveniently be manufactured and which is suitable for preparing pharmaceutical dosage forms for oral administration. Said beads comprise (a) a central, rounded or spherical core, (b) a coating film of a hydrophilic polymer and an antiretroviral agent and (c) a seal-coating polymer layer. Materials suitable for use as cores in the beads are manifold, provided that said materials are pharmaceutically acceptable and have appropriate dimensions and firmness. Examples of such materials are polymers, inorganic substances, organic substances, and saccharides and derivatives thereof. Another aspect of the present invention concerns a kit or container comprising a compound of formula (I) in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit HIV protease, HIV growth, or both. This aspect of the invention may find its use in pharmaceutical research programs. The compounds of the present invention can be used in phenotypic resistance monitoring assays, such as known recombinant assays, in the clinical management of resistance developing diseases such as HIV. A particularly useful resistance monitoring system is a recombinant assay known as the Antivirogram™. The Antivirogram™ is a highly automated, high throughput, second generation, recombinant assay that can measure susceptibility, especially viral susceptibility, to the compounds of the present invention. (Hertogs K, de Bethune MP, Miller V et al. Antimicrob Agents Chemother, 1998; 42(2):269-276, incorporated by reference). Interestingly, the compounds of the present invention may comprise chemically reactive moieties capable of forming covalent bonds to localized sites such that said compound have increased tissue retention a,nd half-lives. The term "chemically reactive group" as used herein refers to chemical groups capable of forming a covalent bond. Reactive groups will generally be stable in an aqueous environment and will usually be carboxy, phosphoryl, or convenient acyl group, either as an ester or a mixed anhydride, or an imidate, or a maleimidate thereby capable of forming a covalent bond with functionalities such as an ammo group, a hydroxy or a thiol at the target site on for example blood components such as albumine. The compounds of the present invention may be linked to maleimide or derivatives thereof to form conjugates. The dose of the present compounds or of the physiologically tolerable salt(s) thereof to be administered depends on the individual case and, as customary, is to be adapted to the conditions of the individual case for an optimum effect. Thus it depends, of course, on the frequency of administration and on the potency and duration of action of the compounds employed in each case for therapy or prophylaxis, but also on the nature and severity of the infection and symptoms, and on the sex, age, weight and individual responsiveness of the human or animal to be treated and on whether the therapy is acute or prophylactic. Customarily, the daily dose of a compound of formula (I) in the case of administration to a patient approximately 75 kg in weight is 1 mg to Ig, preferably 3 mg to 0.5 g. The dose can be administered in the form of an individual dose, or divided into several, e.g. two, three, or four, individual doses. The following tables list the compounds of formula (I) which were prepared following one of the above reaction schemes. ,/ Experimental Part 1. Preparation of the compounds of formula (B) and their intermediates Example 1 (Figure Remove) A mixture of 2 g of 2-bromopropiophenone and 0.71 g of thiourea in 50 mL of ethanol was refluxed overnight. After solvent evaporation, the residue was redissolved in 50 mL of ethyl acetate and treated by 50 mL of a 2% sodium carbonate solution in water. The organic layer was dried and evaporated to yield 1.77 g (99%) of intermediate G 5-methyl-4-phenyl-2-thiazolamine. Mass spectral data: m/z =191 (M+H). 2.11 g of chlorosulfonic acid was added to 0.77 g of intermediate G in 20 mL of DCM (dichloromethane). The mixture was heated to about 50°C during 1 hour. After cooling down to room temperature, the mixture was poured on ice and extracted with ethyl acetate. The organic layer was separated, dried over MgSO4 and evaporated to yield 0.74 g (63%) of compound B 4-(2-amino-5-methylthiazol-4-yl)benzene sulfonyl-chloride. Mass spectral data: m/z = 289 (M+H). Example 2 (Figure Remove) A mixture of 2 g of phenacylbromide and 0.76 g of thiourea in 50 mL ethanol was refluxed overnight. After solvent evaporation, the residue was redissolved in 50 mL DCM and treated by 50 mL of a 2% sodium carbonate solution in water. The organic layer was dried and evaporated to yield 1.45 g (82%) of 4-phenyl-2-thiazolamine (intermediate GJ. Mass spectral data: m/z = 177 (M+H). 0.71 g of Br2 was added to 0.77 g of intermediate G in 10 mL of DCM, at 0°C. The reaction mixture was allowed to warm up to room temperature and was stirred during 30 minutes. A 2% solution of Na2C(>3 in water was then added. The organic layer was separated, dried over MgSC>4 and evaporated to yield 1.07 g (95%) of intermediate N 5-bromo-4-phenyl-2-thiazolamine. Mass spectral data: m/z = 255 (M+H). 1.2 mL of chlorosulfonic acid was added to 0.75 g of intermediate N in 5 mL of DCM. The mixture was heated to about 50°C during 2 hours. After cooling down to room temperature, the mixture was poured on ice and extracted with ethyl acetate. After removal of the organic phase, a saturated solution of NazCCh in water was added to the aqueous phase and extracted with ethyl acetate. This organic layer was separated, dried over MgSC>4 and evaporated to yield 0.67 g of intermediate O 4-(2-amino-5-bromothiazol-4-yl)benzene sulfonylchloride. Mass spectral data: m/z = 394 (M+H). 2, Preparation of the compounds of formula (C) and their intermediates (Figure Remove) A mixture of 0.48 g of intermediate A [2R-hydroxy-3-[(2-methylpropyl)amino]-lS-(phenylmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester (PG = Boc) and 0.36 g of triethylamine in 25 ml of dichloromethane was stirred at about 0°C. Then 0.67 g of intermediate O, was added and the reaction mixture was stirred during 2h at room temperature. After washing with water, the organic layer was separated, dried over MgSC>4 and the solvent evaporated, yielding 1.06 g (100 %) of intermediate P [(lS,2R)-3-[7/-[4-(2-amino-5-bromothiazol-4-yl)phenylsulfonyl]-Ar-(2-methylpropyl) amino]-2-hydroxy-l-(phenylmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester. Mass spectral data: m/z = 653 (M+H). Pd/C and hydrogen was added to a mixture of 1.06 g of intermediate P in 25 mL of methano. The reaction mixture was stirred overnight, then filtered over decalite and evaporated to yield 0.94 g of compound C [(lS,2R)-3-[JV-[4-(2-amino-thiazol-4-yl)phenylsulfonyl]-A^-(2-methylpropyl)amino]-2-hydroxy-l-(phenylmethyl)propyl] carbamic acid, 1,1-dimethylethyl ester. Mass spectral data : m/z = 575 (M+H). Example 3; Preparation of the compounds of formula (K-l) and their intermediates (Figure Remove) A mixture of 20 g of intermediate A (PG = Boc) and 6.61 g of triethylamine in 500 ml of dichloromethane was stirred at about 0°C. Then 13.6 g of 4-acetylbenzene sulfonyl chloride, was added and the reaction mixture stirred during 3h at room temperature. After washing with water, the organic layer was separated, dried over MgSO4 and the solvent evaporated, yielding 30.9 g (100 %) of intermediate fl [(lS,2R)-3-[N-(4-acetyl-phenylsulfonyl)-N-(2-methylpropyl)amino]-2-hydroxy-l-(phenylmethyl)propyl] carbamic acid, 1,1-dimethylethyl ester. Mass spectral data : m/z = 519 (M+H). 100 ml of HC1 (5 to 6 N in isopropanol) was added to 30.9 g of intermediate H in 400 ml of dichloromethane. The reaction was stirred at room temperature for 4 hours. After solvent evaporation, intermediate I was obtained as an HC1 salt N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(2-methylpropyl)-4-acetylphenylsulfonamide, hydrochloride (26.9 g, 99%)(I). Mass spectral data : m/z = 419 (M+H). 2.85 g of 9-fluorenylmethylchloroformate Fmoc-Cl and 2.23 g of triethylamine were added to 5 g of intermediate I in 150 mL of dichloromethane. The reaction mixture was stirred overnight at room temperature, then washed with water, dried over MgSC>4 and evaporated to yield 7.2 g of intermediate J-l [(lS,2R)-3-[N-(4-acetylphenylsulfonyl)-N-(2-methylpropyl)amino]-2-hydroxy-1 -(phenylmethyl)propyl]carbamic acid, 9-fluorenylmethylester. Mass spectral data: m/z = 641 (M+H). 2.11 g bromine was added to 6.5 g of intermediate J-l in 200 mL of dichloromethane. The reaction mixture was stirred at room temperature during Ihour, then washed with a saturated solution of NaHCOs in water, dried over MgSC^ and evaporated. The crude product was purified on silica gel eluting with 20% ethyl acetate in hexane, yielding 3.6 g (50%) of intermediate Itl [(lS,2R)-3-[N-[(4-bromoacetylphenyl) sulfonyl]-N-(2-methylpropyl) amino]-2-hydroxy-1 -(phenylmethyl)propyl]carbamic acid, 9-fluorenylmethylester. Mass spectral data: m/z = 719 (M+H). Example 4: Preparation of the compounds of formula (K-2) and their Intermediates (Figure Remove) 3.33 g triethylamine was added to 5 g of intermediate I in 100 mL of dichloromethane. After cooling to about 0°C, 0.94 g of acetylchloride was added. The reaction mixture was stirred overnight at room temperature, then washed with water, dried over MgSC>4 and evaporated to yield 5 g (99%) of intermediate ,fc2 [(lS,2R)-3-[N-(4-acetylphenyl sulfonyl)-N-(2-methylpropyl)amino]-2-hydroxy-l-(phenylmethyl)propyl]acetamide. Mass spectral data: m/z = 461 (M+H). To 10 g of intermediate JJ in 250 mL of dichloromethane was added dropwise a solution of bromine (3.78 g in 20 mL of dichloromethane) over one hour. After overnight stirring at room temperature, 1 mL of HC112 N was added. The reaction mixture was stirred during 3 days, then washed with a saturated solution of NaHCOs in water, dried over MgSO4 and evaporated. The crude product was purified on silica gel eluting with 60% ethyl acetate in hexane, yielding 5.9 g (50%) of intermediate K-2 [(lS,2R)-3-[N-[4-(bromoacetyl)phenylsulfonyl]-N-(2-methylpropyl)amino]-2-hydroxy-l-(phenylmethyl) propyl]acetamide. Mass spectral data : m/z = 539 (M+H). Example 5: Preparation of the compounds of formula (K-3) and their intermediates (Figure Remove) A mixture of 8.3 g of intermediate A (PG = diBenzyl), [(lR,2S)-2-[bis(phenylmethyl) amino]-l-[(2-methylpropyl)amino]methyl]benzenepropanol, and 2.12 g of triethylamine in 200 ml of dichloromethane (DCM) was stirred at 0°C. Then 4.5 g of 4-acetylbenzene sulfonyl chloride dissolved in 100 mL of DCM, were added dropwise and the reaction mixture stirred overnight at room temperature. After washing with water, the organic layer was separated, dried over MgSC>4 and the solvent evaporated, yielding 12.07 g (100 %) of intermediate HAr-[(2R,3S)-3-(Ar^V-dibenzyl)amino-2- hydroxy-4-phenylbutyl]-W-(2-memylpropyl)-4-acetylphenylsulfonamide. Mass spectral data : m/z = 599 (M+H). 2.40 g of bromine and 0.6 g of acetic acid was added to a mixture of 5 g of intermediate H in 100 mL dichloromethane. The reaction mixture was stirred at room temperature during 6 hours, then 0.25 mL bromine were added and the mixture stirred for 1 hour. The mixture was then washed with a saturated solution of NaHCOj in water, dried over MgSO4 and evaporated. The crude product was purified on silica gel eluting with 20% hexane in DCM, yielding 2.25 g (40%) of intermediate K-3 JV-[(2R,3S)-3-(AT^V-diberizyl)amino-2-hydroxy-4-phenylbutyl]-Af-(2-methylpropyl)-4-bromoacetylphenylsulfonamide. Mass spectral data: m/z = 679 (M+H). Example 6: Preparation of the compounds of formula (K-4) and their intermediates (Figure Remove) 2.67 g of triethylamine, 2.38 g of (2,6-dimethylphenoxy)-acetic acid, 1.78 g of 1-hydroxybenzotriazole and 2.77 g of l-(3-dimemylaminopropyl)-3-ethylcarbodiimide hydrochloride were added to 6 g of intermediate I in 200 mL of dichloromethane. The mixture was stirred overnight, washed with water, dried over MgSO4 and concentrated to yield 7.67 g (100%) of the desired intermediate H-4 [(lS,2R)-3-[A/-(4-acetylphenylsulfonyl)-N-(2-niethylpropyl)aniino]-2-hydroxy-l-(phenylmethyl)-propyl]-(2,6-dimethylphenoxy)acetamide. Mass spectral data: m/z = 581 (M+H). To a mixture of 4 g of the previous intermediate in 100 mL of dichloromethane was added dropwise a solution of bromine (1.66 g in 20 mL of dichloromethane) over 15 minutes. The reaction mixture was stirred during 2,5 hours, then washed with a saturated solution of NaHCCh in water, dried over MgSO4 and evaporated. The crude product was purified on silica gel eluting with 3% ethyl acetate in DCM, yielding 2 g (45%) of intermediate K-4 [(lS,2R)-3-[^-(4-bromoacetylphenylsulfonyl)-jV-(2-methylpropyl)amino]-2-hydroxy-1 -(phenylmethyl) propyl]-(2,6-dimethylphenoxy)acetamide. Mass spectral data : m/z = 659 (M+H). (Figure Remove) To 2 g of intermediate H-4 in 100 mL toluene was added 0.45 g ofN,N-Dimethylformamide dimethylacetal. The mixture was refluxed overnight, then 0.2 g of A/'.JV-Dimethylformamide dimethylacetal was added again. After overnight stirring under reflux, the same procedure was repeated (0.2 g of reactant and overnight reflux). The mixture was then concentrated and the crude product was purified on silica gel eluting with 40% ethyl acetate in hexane. The fractions comprising the desired compound were collected and evaporated. The residue was then dissolved in 100 mL of methanol containing 1.43 g of potassium carbonate. The mixture was stirred during 1 hour at room temperature and finally evaporated to yield 1.74 g of the intermediate 1-4. as a mixture of two isomers cis and trans [(lS,2R)-3-[W-[4-(3-(dimethylamino)-l-oxo-2-propenyl)phenylsulfonyl]-JV-(2-methyl propyl) amino]-2-hydroxy-1 -(phenylmethyl)-propyl]-(2,6-dimethylphenoxy)acetamide. Mass spectral data: m/z = 636 (M+H). To 95 mg of intermediate M in 5 mL ethanol was added 62 mg of potassium carbonate and 10 mg of hydrazine hydrochloride. The mixture was refluxed during 18 hour and evaporated. The crude mixture was purified by preparative HPLC, yielding 21 mg (23%) of the desired pyrazole [(lS,2R)-2-hydroxy-3-[JV-(2-methylpropyl)-7V-(4-pyrazol-3(5)-ylphenylsulfonyl)-amino]-l-(phenylmethyl)propyl]-(2,6-dimethyl phenoxy) acetamide. Mass spectral data: m/z = 605 (M+H). Example 8: Synthesis of thiazoles Preparation of the compounds of formula (L-l) (Figure Remove) To 0.5 g of intermediate K-l in 40 mL ethanol was added 0.063 g of methylthiourea. The reaction mixture was heated to reflux during 1 hour and evaporated, yielding 0.55 g of intermediate L-l [(lS,2R)-2-hydroxy-3-[A'-[4-(2-methylaminothiazol-4- yl)phenylsulfonyl]-A'-(2-methylpropyl)amino]-l-(phenylmethyl)propyl]carbamicacid, 9-fluorenylmethylester. Mass spectral data : m/z = 645 (M+H). Example 9: Preparation of the compounds of formula (M-l) - Preparation of compound 9 (Figure Remove) To 0.49 g intermediate L-l in 40 mL DMF was added 0.59 g of piperidine. The reaction mixture was stirred at room temperature during 2 hours. After solvent evaporation, the crude compound was purified on silica gel eluting with 2% methanol in dichloromethane until 4% methanol, yielding 0.21 g (62%) of intermediate M-l JV-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-2V-(2-memylpropyl)-[4-(2-methylaminothiazol-4-yl)phenyl] sulfonamide. Mass spectral data : m/z = 489 (M+H). (Figure Remove) To 0.74 mL of benzoyl isothiocyanate in 30 mL tetrahydrofuran was added 0.64 mL Af,A/-dimethylaminopropylamine. The mixture was stirred at room temperature overnight. 0.6 mL of a 50% solution of sodium hydroxide in water was then added and the mixture heated to reflux overnight. The reaction mixture was then filtered and the filtrate evaporated. The residue thus obtained was redissolved in 30 mL of DCM, washed with a saturated solution of sodium bicarbonate in water, dried over MgSC>4 and evaporated to yield 0.46 g (57%) of the intermediate thiourea (3-dimethylamino-propyl)thiourea. Mass spectral data : m/z =162 (M+H). To 0.14 g intermediate K-l in 40 mL ethanol was added 0.063 g of the previous intermediate thiourea. The reaction mixture was heated to reflux overnight and evaporated. 0.06 g (56%) of intermediate L-l 7V-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-A^-(2-methylpropyl)-[4-[2-(3-dimethylaminopropylamino)thiazol-4-yljphenyl] sulfonamide was obtained after purification by preparative HPLC. Mass spectral data : m/z = 560 (M+H). (Figure Remove) To 0.1 g of intermediate K-4 in 2 mL ethanol was added 13.7 mg methylthiourea. The reaction mixture was heated to reflux during 1 hour and evaporated. The crude compound was purified by preparative HPLC, yielding 50 mg of final compound [(lS,2R)-2-hydroxy-3-[Ar-[4-[2-(methylamino)thiazol-4-yl]phenylsulfonyl]-JV-(2-methyl propyl)amino]-l-(phenylmethyl)propyl]-(2,6-dimethylphenoxy)acetamide. Mass spectral data: m/z = 651 (M+H). Example 10; Synthesis ofoxazoles - Preparation of the compounds of formula (L-2) (Figure Remove) To 0.2 g of intermediate K-2 in 10 mL dimethylformamide was added 0.26 g acetamide. The reaction mixture was heated to 140 °C during 2 hour. After solvent evaporation, the crude compound was purified on silica gel eluting with 5% methanol in dichloromethane, yielding 0.09 g (45%) of intermediate 1X2 [(lS,2R)-2-hydroxy-3-[A?-[4-(2-methyloxazol-4-yl)phenylsulfonyl]-JV-(2-methylpropyl)amino]-l-(phenylmethyl)propyl] acetamide. Mass spectral data : m/z = 500 (M+H). Example 11: Preparation of the compounds of formula (M-2) (Figure Remove) 0.09 g of intermediate L-2 were dissolved in 10 mL of HC15 N in isopropanol. The reaction mixture was heated at 70 °C overnight. After solvent evaporation, the residue was redissolved in 20 mL of DCM and washed with a 2% solution of sodium carbonate in water. The organic layer was dried over MgSCXi and evaporated, yielding 0.05 g (62%) of intermediate M-2 A4(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-A/- (2-methylpropyl)-[4-(2-methyloxazol-4-yl)phenyl]sulfonamide. Mass spectral data : m/z = 458 (M+H) Example 12; Synthesis ofimidazoles - Preparation of the compounds of formula (L-1) (Figure Remove) To 0.100 g intermediate K-l in 5 mL of DMF was added 0.015 g of potassium acetate. The mixture was heated at 60°C during 2 days then evaporated, yielding 98 mg (94%) of the desired intermediate [(lS,2R)-3-[A^-[4-(acetyloxyacetyl)phenylsulfonyl]-//-(2-methylpropyl)amino]-2-hydroxy-l-(phenylmethyl)propyl]carbamic acid, 9-fluorenylmethylester. Mass spectral data: m/z = 699 (M+H). To 0.098 g of the previous intermediate in 5 mL acetic acid was added 0.043 g ammonium acetate. The mixture was heated overnight at 95°C, then evaporated and purified by preparative HPLC, yielding 0.015 g of intermediate L-3 [(1S,2R)- 2-hydroxy-3-[7V-[4-(2-methylimidazol-4-yl)phenylsulfonyl]-A^-(2-methylpropyl)amino]-1 -(phenylmethyl) propyl]carbamic acid, 9-fluorenylmethylester. Mass spectral data : m/z = 679 (M+H). (Figure Remove) To 0.215 g of intermediate K-l in 20 mL ethanol was added 0.040 g 2-aminothiazole. The mixture was heated at 90°C overnight then evaporated, yielding 216 mg (100%) of the desired intermediate [(lS,2R)-3-[//-[4-(imidazo[2,l-b]thiazol-6-yl)phenylsulfonyl]-W-(2-methylpropyl)amino]-2-hydroxy-1 -(phenylmethyl)propyl]carbamic acid, 9-fluorenylmethylester. Mass spectral data: m/z = 721 (M+H). Example 13; Preparation of the compounds of formula (L-3) (Figure Remove) To 0.5 g of intermediate K-3 in 50 mL THF was added 0.075 g acetylguanidine. After overnight heating at reflux, 0.15 g acetylguanidine were added and the reflux was continued during 3h. The solvent was evaporated and the residue dissolved in DCM, washed with water, dried over MgSC>4 and evaporated. The crude compound was purified on silica gel eluting with 20% ethyl acetate in dichloromethane, yielding 0.2 g (45%) of intermediate L-3 A4(2R,3S)-3-(W JV-dibenzyl)amino-2-hydroxy-4-phenylbutyl]-A^-(2-methylpropyl)-4-[2-(acetylamino)imidazol-4-yl]phenylsulfonamide. Mass spectral data: m/z = 680 (M+H). Example 14; Preparation of the compounds of formula (M-3) (Figure Remove) To a mixture of 0.2 g of intermediate L-3 in MeOH and potassium acetate was added 0.1 g of Pd/C 10%. The mixture was stirred with H2 overnight, then 0.1 g of PoVC 10% was again added. After stirring overnight with Ha, the mixture was filtered over celite and evaporated. The residue was redissolved in DCM, washed with water, dried over MgSO4 and evaporated to yield 0.05 g (33%) of intermediate M-3 JV-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-A/-(2-methylpropyl)-[4-(2-acetylaniinoimidazol-4-yl)-phenyl]sulfonamide. Mass spectral data : m/z = 500 (M+H). Example 15: Preparation of the compounds of formula (E) - Preparation of compound 1 and compound 36 (Figure Remove) To a mixture of 0.21 g of intermediate M-1 in 25 mL of DCM was added 0.248 g of 1-[[(3R,3aS,6aR)-hexahydrofuro[2>3-b]furan-3-yl]oxycarbonyloxy]-2,5-pyrrolidinedione (prepared analogously to the procedure described in WO9967417) and 0.048 g of triethylamine. The reaction mixture was stirred at room temperature overnight and evaporated. The crude compound was purified on silica gel eluting with 2% methanol in dichloromethane, yielding 0.19 g (68%) of the desired final compound [(lS,2R)-2-hydroxy-3-[A^[4-(2-methylaminothiazol-4-yl)phenylsulfonyl]-JV-(2-methylpropyl)amino]-l-(phenylmethyl) propyl]carbamic acid, [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]ester. Mass spectral data : m/z = 645 (M+H). (Figure Remove) To a mixture of 0.015 g of 5-hydroxvmethylthiazole in 5 mL of DCM were added 0.034 g of disuccinimidylcarbonate and 0.018 mL of triethylamine. The mixture was stirred at room temperature during 2 hours, then 0.050 g of intermediate M-2 was added and the mixture stirred overnight. The mixture was diluted with 5 mL of DCM, washed with a 2% solution of sodium carbonate in water, then brine, dried over MgSCU and evaporated. The crude compound was purified on silica gel eluting with 5% methanol in dichloromethane, yielding 0.026 g (36%) of the desired final compound [(lS,2R)-2-hydroxy-3-[^-[4-(2-methyloxazol-4-yl)phenylsulfonyl]-7/-(2-methylpropyl)amino]-1 -(phenylmethyl)propyl]carbamic acid, (thiazol-5-ylmethyl)ester. Mass spectral data: m/z = 599 (M+H). Example 16; synthesis of compound 38 (Figure Remove) To a mixture of 13.44 g of intermediate ^ (PG : Boc) in 400 mL of DCM was added 8.08 g of triethylamine. The mixture was then cooled down to 0°C and 8.87 g of 4-cyanobenzene sulfonylchloride dissolved in 100 mL of DCM were added dropwise. The mixture was then allowed to warm up to room temperature, stirred overnight and washed with water. The organic layer was dried over MgSO4 and concentrated to yield 19.4 g (96%) of the desired sulfonamide [(lS,2R)-3-[Ar-(4-cyanophenylsulfonyl)-Af-(2-methylpropyl)amino]-2-hydroxy-l-(phenyl methyl)propyl]carbamic acid, 1,1-dimethylethyl ester. (Figure Remove) To a mixture of 9 g of the previous intermediate in 100 mL of DCM was added dropwise 20.5 g of trifluoroacetic acid, at 0°C. The mixture was stirred overnight at room temperature, washed with a saturated solution of sodium carbonate, then brine, dried over MgSO4 and concentrated to yield 6.4 g (88%) of the desired amine N-[(2R,3S)-3-ammo-2-hydroxy-4-phenylbutyl]-W-(2-methylpropyl)-4-cyanophenylsulfonamide (K-5). (Figure Remove) To a mixture of 6.4 g of the previous intermediate in 100 mL of DCM was added 4.75 g of l-[[[[(3R,3aS)6aR)-hexahydroruro[2,3-b]ruran-3-yl]oxy]carbonyl]oxy]-2,5-pyrrolidinedione (prepared analogously to the procedure described in WO9967417) and 1.77 g of triethylamine. The reaction mixture was stirred at room temperature overnight and evaporated. The crude compound was purified on silica gel eluting with 30% ethyl acetate in dichloromethane, yielding 4.86 g (55%) of the desired compound [(lS,2R)-3-[JV-(4-cyanophenylsulfonyl)-JV-(2-methylpropyl)amino]-2-hydroxy-l-(phenylmethyl)-propyl]carbamic acid, [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]ester. (Figure Remove) To a mixture of 4.8 g of the previous intermediate in 100 mL of ethanol were added 7.12 g of potassium carbonate and 2.98 g of hydroxylamine chlorhydrate. The mixture was refluxed overnight and concentrated. The residue was dissolved in ethyl acetate and washed with water, dried over MgSO4 and concentrated to yield 4.88 g (96%) of the desired compound [(lS,2R)-2-hydroxy-3-[A/-[4-[(hydroxyimino)aminomethyl]-phenylsulfonyl]-7v"-(2-methylpropyl)amino]-l-(phenylmethyl)propyl]carbamicacid, [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]ester. (Figure Remove) To a mixture of 0.5 g of the previous intermediate in 10 mL of pyridine was added 0.11 g of 2-furanoyl chloride. The mixture was refluxed during 4 hours and concentrated. The residue was dissolved in ethyl acetate, washed with water, dried over MgSO4 and concentrated to yield 0.28 g (49%) of the desired oxadiazole derivative [(lS,2R)-3-[M[4-(5-(furan-2-yl)oxadiazol-3-yl)phenylsulfonyl]-W-(2-methylpropyl)amino]-2-hydroxy-l-(phenylmethyl) propyl]carbamic acid, [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]ester. Mass spectral data: m/z = 667 (M+H). Example 17; synthesis of compound 56 (Figure Remove) To a mixture of 12 g of intermediate A (PG : Boc) in 300 mL of DCM were added 6 mL of triethylamine and 9.6 g of 4-bromobenzene sulfonyl chloride, at 0°C. The mixture was stirred during 3 hours, washed with water, dried over MgSCU and concentrated to yield 20 g (100%) of the desired intermediate [(lS,2R)-3-[A^-(4-bromophenylsulfonyl)-A/;-(2-methylpropyl)amino]-2-hydroxy-1 -(phenylmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester. Mass spectral data : m/z - 556 (M+H). (Figure Remove) To a mixture of 10 g of the previous intermediate in 150 mL of DCM was added 13.9 mL of trifluoroacetic acid at 08C. The mixture was stirred overnight and concentrated. The residue was treated with a mixture of DCM and a saturated solution of sodium carbonate in water. The organic layer was separated, dried over MgSC>4 and concentrated to yield 6.8 g (85%) of the deprotected compound N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-AH2-methylpropyl)-4-bromophenylsulfonamide. Mass spectral data : m/z = 456 (M+H). (Figure Remove) To a mixture of 6.8 g of the previous intermediate in 300 mL of DCM was added 4 g of l-[[[[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]oxy]carbonyl]oxy]-2,5-pyrrolidine-dione (prepared analogously to the procedure described in WO9967417) and 2.7 mL of triethylamine. The reaction mixture was stirred at room temperature overnight, washed with a saturated solution of sodium bicarbonate in water, dried over MgSCU and evaporated. The crude compound was purified on silica gel eluting with 2% methanol in dichloromethane, yielding 6 g (65%) of the desired compound [(lS,2R)-3-[M(4-bromophenylsulfonyl)-7V-(2-methylpropyl)amino]-2-hydroxy-l-(phenylmethyl)propyl]-carbamic acid, [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]ester. Mass spectral data : m/z = 612 (M+H). (Figure Remove) To a mixture of 61 mg of the previous intermediate in 5 mL of dioxane were added 41 mg of 2-pyrazinyltributyltin, 10 mg of triethylamine and 7 mg of PdCl2(dppf)CH2Cl2dichloro[l,r-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct. The reaction mixture was stirred overnight at 85°C and evaporated. The crude mixture was purified by preparative HPLC to yield 4 mg of the desired compound [(1 S,2R)-2-hydroxy-3-[Ar-(2-methylpropyl)-AT-[4-(pyrazin-2-yl)-phenylsulfonyl]amino]-l-(phenylmethyl)propyl] carbamic acid, [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]ester. Mass spectral data: m/z =611 (M+H). The compounds in the following tables were prepared according to one of the above disclosed methods. In the tables below (Table 1-6) the column "synthesis", indicates the general pathway through which a compound may be prepared. (Table Remove) Antiviral analyses: The compounds of the present invention were examined for anti-viral activity in a cellular assay. The assay demonstrated that these compounds exhibited potent anti-HIV activity against a wild type laboratory HIV strain (HIV-1 strain LAI). The cellular assay was performed according to the following procedure. Cellular Assay Experimental Method; HIV- or mock-infected MT4 cells were incubated for five days in the presence of various concentrations of the inhibitor. At the end of the incubation period, all HIV-infected cells have been killed by the replicating virus in the control cultures in the absence of any inhibitor. Cell viability is measured by measuring the concentration of MTT, a yellow, water soluble tetrazolium dye that is converted to a purple, water insoluble formazan in the mitochondria of living cells only. Upon solubilization of the resulting formazan crystals with isopropanol, the absorbance of the solution is monitored at 540nm. The values correlate directly to the number of living cells remaining in the culture at the completion of the five day incubation. The inhibitory activity of the compound was monitored on the virus-infected cells and was expressed as ECjo and ECgo- These values represent the amount of the compound required to protect 50% and 90%, respectively, of the cells from the cytopathogenic effect of the virus. The toxicity of the compound was measured on the mock-infected cells and was expressed as CCso, which represents the concentration of compound required to inhibit the growth of the cells by 50%. The selectivity index (SI) (ratio CCso/ECso) is an indication of the selectivity of the anti-HIV activity of the inhibitor. Wherever results are reported as e.g. pECso or pCCso values, the result is expressed as the negative logarithm of the result expressed as ECSo or CCso respectively. Antiviral spectrum: Because of the increasing emergence of drug resistant HIV strains, the present compounds were tested for their potency against clinically isolated HIV strains harboring several mutations (Table 7 and 8). These mutations are associated with resistance to protease inhibitors and result in viruses that show various degrees of phenotypic cross-resistance to the currently commercially available drugs such as for instance saquinavir, ritonavir, nelfinavir, indinavir and amprenavir. Table 7 List of mutations present in the protease gene of the HIV strains (A to F) used . (Table Remove) Results; As a measure of the broad spectrum activity of the present compounds, the fold resistance (FR), defined as FR = ECSo(mutant strain)/EC5o(HIV-l strain LAI), was determined. Table 8 shows the results of the antiviral testing in terms of fold resistance. As can be seen in this table, the present compounds are effective in inhibiting a broad range of mutant strains: Column A: FR value towards mutant A; Column B: FR towards mutant B; Column C: FR towards mutant C; Column D: FR towards mutant D; Column E: FR towards mutant E; Column F: FR towards mutant F. The toxicity (Tox) is expressed as the pCC50 value as determined with mock transfected cells. Column WT displays the pECso value against wild type HIV-LAI strain. Table 8. Results of the toxicity testing and the resistance testing against strain A to F (expressed as FR). NA indicates not available (Table Remove) Biovailabilitv: The bioavailability of the present compounds was measured in rats. The compounds were administered orally or intraperitoneally. Animals were sacrificed at different time points after administration, whole blood was collected and serum prepared by standard methods. Concentration of the compound in serum was determined by titrating the anti-HIV activity present in the sample according to the procedure described above. Serum concentrations were also measured by HPLC-MS. Protein Binding analyses; Human serum proteins like albumin (HSA) or alpha-1 acid glycoprotein (AAG) are known to bind many drugs, resulting in a possible decrease in the effectiveness of those compounds. In order to determine whether the present compounds would be adversely effected by this binding, the anti-HIV activity of the compounds was measured in the presence of human serum, thus evaluating the effect of the binding of the protease inhibitors to those proteins. Formulation Active ingredient, in casu a compound of formula (I), was dissolved in organic solvent such as ethanol, methanol or methylene chloride, preferably, a mixture of ethanol and methylene chloride. Polymers such as polyvinylpyrrolidone copolymer with vinyl acetate (PVP-VA) or hydroxypropylmethylcellulose (HPMC), typically 5 mPa.s, were dissolved in organic solvents such as ethanol, methanol methylene chloride. Suitably the polymer was dissolved in ethanol. The polymer and compound solutions were mixed and subsequently spray dried. The ratio of compound/polymer was selected from 1/1 to 1/6. Intermediate ranges were 1/1.5 and 1/3. A suitable ratio was 1/6. The spraydried powder, a solid dispersion, is subsequently filled in capsules for administration. The drug load in one capsule ranges between SO and 100 mg depending on the capule size used. Film-coated Tablets Preparation pf.Tablet Core A mixture of 100 g of active ingredient, in casu a compound of formula (I), 570 g lactose and 200 g starch was mixed well and thereafter humidified with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone in about 200 ml of water. The wet powder mixture was sieved, dried and sieved again. Then there was added 100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil. The whole was mixed well and compressed into tablets, giving 10.000 tablets, each comprising 10 mg of the active ingredient. Coating To a solution of 10 g methylcellulose in 75 ml of denaturated ethanol there was added a solution of 5 g of ethylcellulose in 150 ml of dichloromethane. Then there were added 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 g of polyethylene glycol was molten and dissolved in 75 ml of dichloromethane. The latter solution was added to the former and then there were added 2.5 g of magnesium octadecanoate, 5 g of polyvinylpyrrolidone and 30 ml of concentrated color suspension and the whole was homogenated. The tablet cores were coated with the thus obtained mixture in a coating apparatus. We claim: 1. A heterocyclic substituted phenyl containing sulfonamide compound having the Formula (Formula Removed) an N-oxide, salt, stereoisomeric form, racemic mixture, or ester thereof, wherein R1 and R8 are, each independently, hydrogen, C1-6alkyl, C2-6alkenyl, arylC1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl, aryl, Het1, Het1C1-6alkyl, Het2, Het2C1-6alkyl; R1 may also be a radical of formula (Formula Removed) wherein R9, R10a and R10b are, each independently, hydrogen, C1-4alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(C1-4alkyl)aminocarbonyl, C3-7cycloalkyl, C2-6alkenyl, C2-6alkynyl or C1-4alkyl optionally substituted with aryl, Het1, Het2, C3-7cycloalkyl, C1-4alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(C1-4alkyl)aminocarbonyl, aminosulfonyl,C1-4alkylS(0)t, hydroxy, cyano, halogen or amino optionally mono- or disubstituted where the substituents are selected from C1-4alkyl, aryl, arylC1-4alkyl, C3-7cycloalkyl, C3-7cycloalkylCC1-4alkyl, Het1, Het2, Het1C1-4alkyl and Het2C1-4alkyl; whereby R9, R10a and the carbon atoms to which they are attached may also form a C3-7cycloalkyl radical; R11a is hydrogen, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, aryl, aminocarbonyl optionally mono- or disubstituted, aminoC1-4alkylcarbonyloxy optionally mono- or disubstituted, C1-4alkyloxycarbonyl, aryloxycarbonyl, Hett1xycarbonyl, Het2oxycarbonyl, aryloxycarbonyC1-4alkyl, arylC1-4alkyloxycarbonyl, C1- 4alkylcarbonyl, C3-7cycloalkylcarbonyl, C3-7cycloalkylC1-4alkyloxycarbonyl, C3- 7cycloalkylcarbonyloxy, carboxylC1-4alkylcarbonyloxy, C1-4alkylcarbonyloxy, arylC1- 4alkylcarbonyloxy, arylcarbonyloxy, aryloxycarbonyloxy, Het1carbonyl, Het1carbonyloxy, Het1C1-4alkyloxycarbonyl, Het2carbonyloxy, Het2C1- 4alkylcarbonyloxy, Het2C1-4alkyloxycarbonyloxy or C1-4alkyl optionally substituted with aryl, aryloxy, Het2 or hydroxy; wherein the substituents on the amino groups are each independently selected from C1-4alkyl, aryl, arylC1-4alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, Het1, Het2, Het1C1-4alkyl and Het2C1-4alkyl; R11b ishydrogen, C3-7cycloalkyl, C2-6alkenyl, C2-6alkynyl, aryl, Het1, Het2 or C1-4alkyl optionally substituted with halogen, hydroxy, C1-4alkylS(=0)t, aryl, C3-7cycloalkyl, Het1, Het2, amino optionally mono- or disubstituted where the substituents are selected from C1-4alkyl, aryl, arylC1-4alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, Het1, Het2, Het1C1-4alkyl and Het2C1-4alkyl; whereby Rub may be linked to the remainder of the molecule via a sulfonyl group; R2 is hydrogen or Ci-ealkyl; Lis-C(=0)-, -0-C(=0)-, -NR8-C(=0)-, -0-C1-6alkanediyl-C(=0)- , -NR8-C1-6alkanediyl-C(=0)-, -S(=0)2-, -0-S(=0)2-, -NR8-S(=0)2 whereby either the C(=0) group or the S(=0)2 group is attached to the NR2 moiety; R3 isC1-6alkyl, aryl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, or arylC1-4alkyl; R4 ishydrogen, C1-4alkyloxycarbonyl, carboxyl, optionally mono- or disubstituted aminocarbonyl, C3-7cycloalkyl, C2-6alkenyl, C2-6alkynyl or C1-6alkyl, whereby C3-7cycloalkyl, C2-6alkenyl, C2-6alkynyl and Ci-ealkyl may optionally be substituted with a substituent selected from aryl, Het1, Het2, C3-7cycloalkyl, C1-4alkyloxycarbonyl, carboxyl, optionally mono- or disubstituted aminocarbonyl, optionally mono- or disubstituted aminosulfonyl, C1-4alkylS(=0)t, hydroxy, cyano, optionally mono- or disubstituted amino and halogen, and whereby the optional substituents on any amino function are independently selected fromC1-4alkyl, aryl, arylC1-4alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, Het1, Het2, Het1C1-4alkyl and Het2C1-4alkyl; t is zero, 1 or 2; each t independently selected is zero, 1 or 2; Haryl is an aromatic monocyclic, bicyclic or tricyclic heterocycle having 3 to 14 ring members which contains one or more heteroatom ring members selected from nitrogen, oxygen and sulfur and which may optionally be substituted on (i) one or more carbon atoms by C1-6alkyl, halogen, hydroxy, optionally mono- or disubstituted amino, nitro, cyano, haloC1-6alkyl, carboxyl, C3-7cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl, -(R7a)n-M-R7b, Het1 and Het2; whereby the optional substituents on any amino function are independently selected from Rs and -A-R6; and on (ii) a nitrogen atom if present by hydroxy or -A-R6; A isC1-6alkanediyl, -C(=0)-, -C(=S)-, -S(=0)2-, C1-6alkanediyl-C(=0)-, C1-6alkanediyl-C(=S)- or C1-6alkanediyl-S(=0)2-; whereby for those groups containing a C1-6alkanediyl moiety, the C1-6alkanediyl moiety is attached to the amino group; Rs is hydroxy, C1-6alkyl, Het1C1-6alkyl, Het2Ci-6alkyl, arninoC1-6alkyl whereby the amino group may optionally be mono- or di-substituted with C1-4alkyl; R6 ishydrogen, C1-6alkyloxy, Het1, Het1oxy, Het2, Het2oxy, aryl, aryloxy or amino; and in case -A- is other than C1-6alkanediyl then R6 may also be C1-6alkyl, Het1C1-6alkyl, Het1oxyC1-4alkyl, Het2C1-4alkyl, Het20xyC1-4alkyl, arylC1-4alkyl, aryloxyC1-4alkyl or arninoC1-4alkyl; whereby each of the amino groups in the definition of Re may optionally be substituted with one or two substituents selected from C1-4alkyl, C1-4alkylcarbonyl, C1-4alkyloxycarbonyl, aryl, arylcarbonyl, aryloxycarbonyl, Het1, Het2, arylC1-4alkyl, Het1C1-4alkyl or Het2C1-4alkyl; R7a is C1-8 alkanediyl optionally substituted with one or more substituents selected from, halogen, C1-4alkylcarbonyl, C1-4alkyloxycarbonyl, aryl, arylcarbonyl, aryloxycarbonyl, Het1 or Het2; R7b is C1-8 alkyl optionally substituted with one or more substituents selected from halogen, C1-4alkylcarbonyl, C1-4alkyloxycarbonyl, aryl, arylcarbonyl, aryloxycarbonyl, Het1 or Het2; M is defined by -C(=0)-, -0-C(=0)-, -C(=0)-0-, -CH2-CHOH-, -CHOH-CH2-, -NR8-C(=0)-, -(C=0)-NR8-, -S(=0)2-, -O-, -S-, -0-S(=0)2-, -S(=0)2-0-, -NR8-S(=0)2 or -S(=0)2-NR8-; n is zero or 1, and wherein Het1 as a group or part of a group is defined as a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle having preferably 3 to 14 ring members, more preferably 5 to 10 ring members and more preferably 5 to 8 ring members, which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and which is optionally substituted on one or more carbon atoms by C1-6alkyl, C1-6alkyloxy, halogen, hydroxy, oxo, optionally mono- or disubstituted amino, nitro, cyano, hydroxyC1-6alkyl, haloC1-6alkyl, carboxyl, C1-6alkoxycarbonyl, C3-7cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl and a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle having 3 to 14 ring members which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and whereby the optional substituents on any amino function are independently selected from C1-6alkyl, C1-6alkyloxy-A-, Het2-A-, Het2C1-6alkyl, Het2C1-6alkyl-A-, Het2oxy-A-, Het2oxyC1-4akyl-A-, aryl-A-, aryloxy-A-, aryloxyC1-4alkyl-A-, arylC1-6alkyl-A-, C1-6alkyloxycarbonylamino-A-, amino-A-, aminoC1-6alkyl and aminoC1-6alkyl-A- whereby each of the amino groups may optionally be mono- or where possible di-substituted with C1-4alkyl and whereby A is as defined above and wherein Het2 as a group or part of a group is defined as an aromatic monocyclic, bicyclic or tricyclic heterocycle having preferably 3 to 14 ring members, more preferably 5 to 10 ring members and more preferably 5 to 6 ring members, which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and which is optionally substituted on one or more carbon atoms by C1-6alkyl, C1-6alkyloxy, halogen, hydroxy, optionally mono- or disubstituted amino, nitro, cyano, hydroxyC1-6alkyl, haloC1-6alkyl, carboxyl, C1-6alkoxycarbonyl, C3-7cycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl, Het1 and an aromatic monocyclic, bicyclic or tricyclic heterocycle having 3 to 14 ring members; whereby the optional substituents on any amino function are independently selected from C1-6alkyl, C1-6alkyloxy-A-, Hetx-A-, Het1C1-6alkyl, Het1C1-6alkyl-A-, Het1oxy-A-, Het1oxyC1-6akyl-A-, aryl-A-, aryloxy-A-, aryloxyC1-4alkyl-A-, arylC1-6alkyl-A-, C1-6alkyloxycarbonylamino-A-, amino-A-, aminoC1-6alkyl and aminoC1-6alkyl-A- whereby each of the amino groups may optionally be mono-" or where possible di-substituted withC1-4alkyl and whereby A is as defined above. 2. A compound as claimed in claim 1, wherein the Haryl substituent is an aromatic mono- or bicyclic heterocycle having 3 to 8 ring members, which contain one or more heteroatoms selected from N, O or S and (i) which Haryl is optionally substituted on one or more carbon atoms by halogen, optionally mono- or disubstituted amino, nitro, cyano, C3-7cycloalkyl, optionally mono- or disubstituted aminocarbonyl, -(R7a)n-M-R7b, Het1 and Het2; whereby the optional substituents on any amino function are independently selected from Rs and -A-R6; and (ii) which Haryl is optionally substituted on a nitrogen atom by hydroxy or -A-R6. 3. A compound as claimed in any of claims 1 or 2, wherein the Haryl moiety is selected from thiazolyl, imidazolyl, oxazolyl, oxadiazolyl, pyrazolyl, pyrazinyl, imidazolinonyl, quinolinyl, isoquinolinyl, indolyl, pyridazinyl, pyridinyl, pyrrolyl, pyranyl, pyrimidinyl, furanyl, triazolyl, tetrazolyl, benzofuranyl, benzoxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, thiophenyl, tetrahydrofurofuranyl, tetrahydropyranofuranyl, benzothiophenyl, carbazolyl, imidazolonyl, oxazolonyl, indolizinyl, triazinyl or quinoxalinyl, and i) which is optionally substituted on one or more carbon atoms by halogen, optionally mono- or disubstituted amino, nitro, cyano, C3-7cycloalkyl, optionally mono- or disubstituted aminocarbonyl, -(R7a)n-M-R7b, Het1 and Het2; whereby the optional substituents on any amino function are independently selected from R5 and -A-R6; and (ii) which is optionally substituted on a nitrogen atom by hydroxy or -A-Re. 4. A compound as claimed in any of. claims 1 or 3, wherein R1 is hydrogen, C1- 6alkyl, C2-6alkenyl, arylC1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl, aryl, Het1, Het1C1-6alkyl, Het2, Het2C1-6alkyl; wherein Het1 is a saturated or partially unsaturated monocyclic heterocycle having 5 or 6 ring members. 5. A compound as claimed in any of claims 1 to 4, wherein R1-L- is Het1-0- C(=0)-. 6. A compound as claimed in any of claims 1 to 4, wherein R1-L- is Het2-0-C1-6alkanediyl-C(=0)-, aryl-0-C1-6alkanediyl-C(=0)- or aryl-C(=0)-. 7. A compound as claimed in any one of claims 1 to 4, wherein R1 is Het2 or Het2C1-6alkyl; wherein said Het2comprises at least one heteroatom independently selected from nitrogen, oxygen and sulfur; and L is -C(=0)-, -0-C(=0)- or 0-C1-6alkyl-C(=0)-. 8. A compound as claimed in any one of claims 1 to 4, wherein R1 is Het2 or Het2C1-6alkyl; wherein said Het2 comprises at least two heteroatoms each independently selected from nitrogen, oxygen and sulfur; and L is -C(=0)-, -0-C(=0)- or 0C1-6alkyl-C(=0)-. 9. A compound as claimed in any one of claims 1 to 4, wherein, R1 is 2-thiazolylmethyl-; and L is -0-C(=0)-. 10. A compound as claimed in any of claims 1 to 4, wherein R1 is Het1 or Het1C1-6alkyl, wherein said Het1 comprises at least one heteroatom independently selected from nitrogen, oxygen and sulfur; and L is -C(=0)-, -0-C(=0)- or -0-C1-6alkyl-C(=0)-. 11. A compound as claimed in any of claims 1 to 10, having a fold resistance in the range of 0.01 to 100 against HIV species having at least one mutation in the HIV protease at a position selected from 10, 71 and 84 as compared to the wild type sequence. 12. A compound as claimed in any of the claims 1 to 11 selected from [(lS,2R)-2-hydroxy-3-[N44-(2-methylaminothiazol-4-yl)phenylsulfonyl]- N-(2-methylpropyl)amino]- l-(phenylmethyl) propyl] carbamic acid, [(3R,3aS,6aR)- hexahydrofuro[2,3-b]furan-3-yl]ester [(1 S,2R)-2-hydroxy-3-[N-[4-(2-aminothiazol-4-yl)phenylsulfonyl]- N-(2-methylpropyl)amino]-l-(phenylmethyl)propyl]carbamic acid, [(3R,3aS,6aR)-hexahydrofuro [2,3-b]furan-3-yljester [(lS,2R)-2-hydroxy-3-[N-[4-(2-acetylamino-thiazol-4-yl)phenylsulfonyl]-N-(2-methylpropyl)amino]- l-(phenylmethyl)propyl]carbamic acid, [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]ester [(lS,2R)-2-hydroxy-3-[N-[4-(2-(2-pyrrolidin-l-yl-ethylamino)-thiazol-4-yl)-phenylsulfonyl]-N-(2-me1nylpropyl)amino]-1 -(phenylmethyl)propyl]carbamic acid, [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]ester [(1 S,2R)-2-hydroxy-3-[N-[4-(2-(pyridin-4-ylamino)-thiazol-4-yl)phenylsulfonyl] -N-(2-methylpropyl)amino]-l-(phenylmethyl)propyl]carbamic acid, [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]ester [(lS,2R)-2-hydroxy-3-[N-[4-(2-(3-dimethylammo-propylamino)-thiazol-4-yl)-phenylsulfonyl]-N-(2-niethylpropyl)amino]-1 -(phenylmethyl)propyl]carbamic acid, [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]ester [(lS,2R)-2-hydroxy-3-[N-[4-(2-(2-Methoxy-phenylamino)-thiazol-4-yl)-phenylsulfonyl] -N- (2 -methylpropyl) amino] -1 - (phenylmethyl)propyl] - (4-bromo-2,6- dimethylphenoxy) acetamide [(lS,2R)-2-hydroxy-3-[N-(2-methylpropyl)-N-(4-pyrazol-3-yl-phenylsulfonyl)-amino]-1 -(phenylmethyl)propyl]-(2,6-dimethylphenoxy)acetamide [(lS,2R)-3-[N-[4-(2-(acetylamino)-imidazol-4-yl)phenylsulfonyl]-N-(2-methylpropyl)amino]-2-hydroxy-l-(phenylmethyl)propyl]carbamic acid, [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]ester 4-[4-[N-(2-methylpropyl)-N-[(2R,3S)-2-hydroxy-3-[[hexahydro-furo[2,3-b]furan-3-yl]-oxycarbonylarnino]-4-phenylbutyl]aminosulphonyl]phenyl]-imidazol-2-yl-carbamic acid, [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]ester [(lS,2R)-2-hydroxy-3-[N-[4-(2-methyloxazol-4-yl)phenylsulfonyl]-N-(2-methylpropyl)amino]-l-(phenylmethyl)propyl]carbamic acid, [(3R,3aS,6aR)-hexahydrofuro [2,3-b]furan-3-yl] ester [(lS,2R)-3-[N-[4-(5-(furan-2-yl)-[l,2,4]oxadiazol-3-yl)phenylsulfonyl]-N-(2-methylpropyl)amino]-2-hydroxy- l-(phenylmethyl)propyl]carbamic acid, [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]ester [(lS,2R)-3-[N-[4-(5-benzyloxymethyl-[l,2,4]oxadiazol-3-yl)phenylsulfonyl]-N-(2-methylpropyl)amino]-2-hydroxy-l-(phenylmethyl)propyl]carbamic acid, [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]ester [(1 S,2R)-3-[N-[4-(5-propyl-[ 1,2,4]oxadiazol-3-yl)phenylsulfonyl]-N-(2-methylpropyl)amino]-2-hydroxy- l-(phenylmethyl)propyl]carbamic acid, [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]ester [(1 S,2R)-3-[N-[4-(5-(ethoxycarbonylethyl)-[ 1,2,4]oxadiazol-3-yl)phenylsulfonyl]-N-(2-methylpropyl)amino] -2-hydroxy-1 -(phenylmethyl)propyl]carbamic acid, [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]ester [(lS,2R)-3-[N-[4-(5-(4-nitro-phenyl)-[l,2,4]oxadiazol-3-yl)phenylsulfonyl]-N-(2-methylpropyl)amino]-2-hydroxy- l-(phenylmethyl)propyl]carbamic acid, [(3R, 3aS, 6aR) -hexahydrofuro[2,3 -b]furan-3 -yljester [(1 S,2R)-3-[N-[4-(5-(3-methoxy-phenyl)-[ 1,2,4]oxadiazol-3-yl)phenylsulfonyl]-N-(2-methylpropyl)amino]-2-hydroxy- l-(phenylmethyl)propyl]carbamic acid, [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]ester [(1 S,2R)-3-[N-[4-(5-(5-methyl-isoxazol-3-yl)-[ 1,2,4]oxadiazol-3-yl)phenylsulfonyl]-N-(2-methylpropyl) amino]-2-hydroxy-l-(phenylmethyl)propyl]carbamic acid, [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]ester [(1 S,2R)-3-[N-[4-(5-[(methylcarbonyloxy)phenylmethyl]-[ 1,2,4]oxadiazol-3-yl)phenylsulfonyl] -N- (2-methylpropyl) amino] -2-hydroxy-1 -(phenylmethyl) -propyl]carbamic acid, [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]ester [(1 S,2R)-3-[N-[4-(5-isobutyl-[ 1,2,4]oxadiazol-3-yl)phenylsulfonyl]-N-(2-methylpropyl)amino]-2-hydroxy- l-(phenylmethyl)propyl]carbamic acid, [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]ester [(lS,2R)-3-[N-[4-(5-(tbiophen-2-yl)-[l,2,4]oxadiazol-3-yl)phenylsulfonyl]-N-(2-methylpropyl)amino]-2-hydroxy- l-(phenylmethyl)propyl]carbamic acid, [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]ester [(lS,2R)-3-[N-[4-(5-(4-bromo-phenyl)-[l,2,4]oxadiazol-3-yl)phenylsulfonyl]-N-(2-methylpropyl)amino]-2-hydroxy-l-(phenylmethyl)propyl]carbamic acid, [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]ester [(lS,2R)-3-[N-[4-(5-(4-cyano-phenyl)-[l,2,4]oxadiazol-3-yl)phenylsulfonyl]-N-(2-methylpropyl)amino]-2-hydroxy- l-(phenylmethyl)propyl]carbamic acid, [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]ester [(lS,2R)-2-hydroxy-3-[N-(2-methylpropyl)-N-[4-(pyridin-4-yl)-phenylsulfonyl]-amino]-l-(phenylrnethyl)propyl] carbamic acid, [(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3 -yl] ester 13. A pharmaceutical composition comprising 0.1 to 90% by weight of a compound as claimed in any one of claims 1 to 12 and a pharmaceutical tolerable excipient or auxiliaries or pharmaceutically acceptable water soluble polymers of the kind such as herein described.

Documents:

1777-DELNP-2004-Abstract-(12-06-2008).pdf

1777-delnp-2004-abstract.pdf

1777-DELNP-2004-Claims-(12-06-2008).pdf

1777-delnp-2004-claims-(26-06-2008).pdf

1777-delnp-2004-claims.pdf

1777-DELNP-2004-Correspondence-Others-(12-06-2008).pdf

1777-delnp-2004-correspondence-others-(26-06-2008).pdf

1777-delnp-2004-correspondence-others.pdf

1777-delnp-2004-description (complete)-12-06-2008.pdf

1777-delnp-2004-description (complete)-26-06-2008.pdf

1777-delnp-2004-description (complete).pdf

1777-DELNP-2004-Form-1-(12-06-2008).pdf

1777-delnp-2004-form-1.pdf

1777-delnp-2004-form-18.pdf

1777-DELNP-2004-Form-2-(12-06-2008).pdf

1777-delnp-2004-form-2.pdf

1777-delnp-2004-form-3.pdf

1777-delnp-2004-form-5.pdf

1777-DELNP-2004-GPA-(12-06-2008).pdf

1777-delnp-2004-pct-304.pdf

1777-delnp-2004-pct-306.pdf

1777-delnp-2004-pct-401.pdf

1777-delnp-2004-pct-409.pdf

1777-delnp-2004-pct-416.pdf

1777-delnp-2004-pct-search report.pdf

abstract.jpg