WO2011020913A2 - Cyclodepsipeptide antiviral compounds - Google Patents

Abstract

A compound of general formula (I), wherein X, Y, n, p, q, and R₁-R₁₇ take various meanings, for use in the treatment of HIV infections, AIDS and ARC.

Description

CYCLODEPSIPEPTIDE ANTIVIRAL COMPOUNDS

FIELD OF THE INVENTION

The present invention relates to the use of cyclodepsipeptide compounds, specifically didemnin and tamandarin compounds, as antiretroviral agents, and in particular as anti-HIV agents. Additionally, the present invention relates to new cyclodepsipeptide compounds which are closely related to didemnin and tamandarin compounds, pharmaceutical compositions containing them and their use as antiretroviral agents, and in particular as anti-HIV agents.

BACKGROUND OF THE INVENTION

Infection by the human immunodeficiency virus (HIV) can lead to the Acquired Immunodeficiency Syndrome (AIDS), a disease characterized by the destruction of the immune system, and its precursor AIDS-related complex (ARC), a syndrome characterized by symptoms such as persistent generalised lymphadenopathy, fever and weight loss. It is estimated that thirty- three million people are currently infected with HIV worldwide, and as of 2007, 26 million people worldwide have died of AIDS. HIV is a lentivirus belonging to the Retroviridae family. Two species of this retrovirus infect human beings: HIV- I and HIV-2. HIV sustains itself through release of viral RNA and multiple viral enzymes into host CD4+ T cells, macrophages, and microglial cells. Its life cycle consists of six steps: binding/ fusion, reverse transcription, integration, transcription, translation, and viral assembly and mutation (Halligan et al. Dent. Clin. North Am. 2009, 53(2), 31 1-322).

Various classes of anti-HIV medications have been developed to combat the virus at different stages of its lifecycle. The targets that have been envisaged most intensively are: reverse transcription, catalysed by reverse transcriptase (RT) (RNA-dependent DNA polymerase), a specific viral enzyme that retrotranscribes the viral single-stranded RNA genome to double-stranded proviral DNA; and proteolytic processing by the viral protease, which cleaves the precursor viral polyprotein into smaller mature (both structural and functional) viral proteins. Other targets that have been recognised more recently as sites for therapeutic intervention are viral entry, particularly virus-cell fusion and interaction of the virus with its (co-)receptors, and integration of the proviral DNA into the host cell genome, a process carried out by a specific viral enzyme (integrase) which determines whether the HIV-infected cell and all daughter cells stemming thereof will permanently carry the pro virus. Therefore, among the antiretroviral therapies currently approved in US and Europe there are nucleoside reverse transcriptase inhibitors (NRTI) such as zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, tenofovir, and emtricitabine; non-nucleoside reverse transcriptase inhibitors (NNRTI) such as nevirapine, delavirdine, efavirenz, and etravirine; protease inhibitors such as saquinavir, ritonavir, indinavir, nelfinavir, atazanavir, fosamprenavir, tipranavir, and darunavir; entry inhibitors such as maraviroc; integrase inhibitors such as raltegravir; fusion inhibitors such as enfuvirtide; and combination therapies such as lamivudine + zidovudine, abacavir + zidovudine + lamivudine, abacavir + lamivudine, tenofovir + emtricitabine, efavirenz + emtricitabine + tenofovir, and lopinavir + ritonavir (De Clercq, Int. J. Antimicrob. Agents, 2009, 33(4), 307-320; Wainberg et al. BMC Medicine, 2008, 6:31).

Cyclodepsipeptides, together with natural cyclic peptides, emerge as a broad family of natural products characterized by the occurrence of at least one ester linkage. The great interest that this class of natural compounds has elicited in the scientific community is explained by the diverse range of biological activities that they can exhibit, including antitumoral, antibiotic, antifungi, immunosuppressant, and antiinflammatory activities, in conjunction with intriguing mechanisms of action and attractive molecular architectures (Sarabia et al. Curr. Med. Chem.2004, 11, 1309-1332; Lemmens-Gruber et al. Curr. Med. Chem. 2009, 16, 1122-1137). Didemnin and tamandarin compounds are members of this class of compounds which have showed a broad spectrum of biological activity such as antitumoral, immunosuppressant, and antiviral activity. Natural didemnins were first isolated from marine tunicates, specifically from Trididemnum solidum, and tamandarin A and B were first isolated from a Brazilian ascidian of the family Didemnidae. Additional didemnin and tamandarin congeners have been subsequently obtained by synthesis (Vera et al. Med. Res. Rev. 2002, 22(2), 102-145; WO 02/02596; WO 01/76616; WO 2004/084812).

Rinehart et al. reported that didemnin A and B and some derivatives thereof were able to inhibit several DNA and RNA viruses, specifically HSV-I, HSV-2 (herpes simplex virus, types 1 and 2), vaccinia virus, PR8 (influenza virus), HA-I (parainfluenza-3 virus), COE (Coxsackie A-21 virus), and ER (equine rhinovirus) (Rinehart et al. Science, 1981, 212, 933-935; US 4,493,796; US 4,548,814). In addition, didemnin A and B were both found to exhibit significant activity against the Rift Valley fever virus (RVF), Venezuelan equine encephalomyelitis virus, and yellow fever virus. As compared with these three test viruses, Pichinde virus, a representative arenavirus, was less sensitive to the in vitro antiviral effect of both didemnins. In vivo, didemnin B at a dose of 0.25 mg/kg daily in mice infected with RVF gave a 90% survival rate and didemnin A at a dose of 1.25 to 5 mg/kg daily gave a 50% survival rate (Canonico et al. Antimicrob. Agents Chemother. 1982, 22(4), 696-697). Maldonado et al. reported the inhibitory effect of didemnin A against the replication of three types of Dengue viruses in vitro (Maldonado et al. P. R. Health Sci. J. 1982, 1 , 22-25). Weed et al. reported the activity of didemnin A and B in mice infected cutaneously with type 1 herpes simplex virus and the lack of activity against a Semliki Forest virus (SMV) infection. In addition, although both didemnin A and B were ineffective in protecting mice from HSV- I encephalitis when both virus and drug were injected intracranially, both compounds protected female mice from genital HSV-2 infection (Weed et al. Antiviral Res. 1983, 3, 269-274; Rinehart et al. Pure & Appl. Chem. 1982, 54(12), 2409-2424). Didemnin B was also found to be ineffective against the rabies virus in mice and foxes (Bussereau et al. Acta Virol. 1988, 32, 33-49) and the AIDS virus HTLV- 3 (Rinehart KL. Peptides, Chemistry and Biology, 1988, Ed. GR Marshall, pages 626-631). Finally, the antiviral activity of 21 didemnin congeners was examined against the RNA virus vesicular stomatitis virus and the DNA virus HSV- I , and some congeners were effective at inhibiting the replication of said viruses, but none of them inhibited proliferation of HIV (Sakai et al. J. Med. Chem. 1996, 39, 2819-2834).

Despite recent progress in the development of anti-HIV therapeutic options, there remains a need for drugs having different or enhanced anti-HIV properties. The problem to be solved by the present invention is to provide compounds that are useful in the treatment of

HIV infections, AIDS and ARC. SUMMARY OF THE INVENTION

In one aspect, the present invention is directed to a compound of general formula I, or a pharmaceutically acceptable salt or stereoisomer thereof,

wherein X is selected from O and NH; Y is selected from CO and -COCH(CH₃)CO-; each n and p is independently selected from 0 and 1 , and q is selected from 0, 1 and 2; each R₁, R3, R5, R9, Rn, and R15 is independently selected from hydrogen, substituted or unsubstituted C₁-CO alkyl, substituted or unsubstituted C2-C6 alkenyl, and substituted or unsubstituted C2-C6 alkynyl; R2 is selected from hydrogen , CORa, COOR_a, substituted or unsubstituted C₁-CO alkyl, substituted or unsubstituted C2-C6 alkenyl, and substituted or unsubstituted C2-C6 alkynyl; each R₄, Re, Rio, R12, and R16 is independently selected from hydrogen and substituted or unsubstituted C₁-CO alkyl; each R₇ and R13 is independently selected from hydrogen, substituted or unsubstituted C₁-CO alkyl, substituted or unsubstituted C2-C6 alkenyl, and substituted or unsubstituted C2-C6 alkynyl; each Re and R14 is independently selected from hydrogen and substituted or unsubstituted C₁-CO alkyl; or Re and R7 and/or R13 and Ri₄ together with the corresponding N atom and C atom to which they are attached may form a substituted or unsubstituted heterocyclic group;

Ri₇ is selected from hydrogen, COR_a, COORa, CONHRb, COSRc, (C=NRb)ORa, (C=NRb)NHRb, (C=NR_b)SR_c, (C=S)ORa, (C=S)NHRb, (C=S)SRc, SO2RC, SOβRc, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group, with the proviso that when n, p, and q are 0 then R17 is not hydrogen; and each R_a, Rb, and R_c is independently selected from hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group; for use in the treatment of HIV infections and associated conditions, such as AIDS and ARC.

In another aspect, the present invention is directed to a compound of general formula II, or a pharmaceutically acceptable salt or stereoisomer thereof,

wherein X, Y, n, p, q, R_a, Rb, Rc, Ri, R2, and R5-R17 are as defined above in general formula I. In another aspect, the present invention is directed to a compound of general formula III, or a pharmaceutically acceptable salt or stereoisomer thereof,

(HI) wherein X, Y, p, q, R_a, Rb, Rc, R₁-R₁O and R12-R17 are as defined above in general formula I, with the exception of the compound with the following structure:

In another aspect, the present invention is also directed to a compound of general formula II or III, or a pharmaceutically acceptable salt or stereoisomer thereof, for use as a medicament.

In another aspect, the present invention is also directed to a compound of general formula II or III, or a pharmaceutically acceptable salt or stereoisomer thereof, for use in the treatment of HIV infections and associated conditions, such as AIDS and ARC.

In another aspect, the present invention is directed to a pharmaceutical composition comprising a compound of general formula II or III, or a pharmaceutically acceptable salt or stereoisomer thereof, together with a pharmaceutically acceptable carrier.

In another aspect, the present invention is also directed to a pharmaceutical composition comprising a compound of general formula I, II or III, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier, for use in the treatment of HIV infections and associated conditions, such as AIDS and ARC. In another aspect, the present invention is directed to the use of a compound of general formula I, II or III, or a pharmaceutically acceptable salt or stereoisomer thereof, in the manufacture of a medicament for the treatment of HIV infections and associated conditions, such as AIDS and ARC.

In another aspect, the present invention is directed to a method for treating any mammal, notably a human, affected by an HIV infection or an associated condition, such as AIDS and ARC, which comprises administering to the affected individual a therapeutically effective amount of a compound of general formula I, II or III, or a pharmaceutically acceptable salt or stereoisomer thereof.

BRIEF DESCRIPTION OF THE FIGURES

Fig. 1. Graphical representation of the antiviral activity (-♦- RLUs) and toxicity (-•- Viability) of several concentrations (μM) of compound 3 in MT-2 cells (Fig. IA) and in preactivated PBMCs (Fig. IB), both infected with a recombinant virus (NL4.3 Luc). Graphical representations are at least mean of two independent experiments for MT-2 cells and four for PBMCs.

Fig. 2. Graphical representation of the antiviral activity (-♦- RLUs) and toxicity (-•- Viability) of several concentrations (μM) of compound 8 in MT-2 cells (Fig. 2A) and in preactivated PBMCs (Fig. 2B), both infected with a recombinant virus (NL4.3 Luc). Graphical representations are at least mean of two independent experiments for MT-2 cells and four for PBMCs.

Fig. 3. Graphical representation of the antiviral activity (-♦- RLUs) and toxicity (-■- Viability) of several concentrations (μM) of compound 9 in

MT-2 cells (Fig. 3A) and in preactivated PBMCs (Fig. 3B), both infected with a recombinant virus (NL4.3 Luc). Graphical representations are at least mean of two independent experiments for MT-2 cells and four for PBMCs. Fig. 4. Graphical representation of the antiviral activity (-♦- RLUs) and toxicity (-■- Viability) of several concentrations (μM) of compound 10 in MT-2 cells (Fig. 4A) and in preactivated PBMCs (Fig. 4B), both infected with a recombinant virus (NL4.3 Luc). Graphical representations are at least mean of two independent experiments for MT-2 cells and four for PBMCs.

Fig. 5. Graphical representation of the antiviral activity (-♦- RLUs) and toxicity (-■- Viability) of several concentrations (μM) of compound 1 1 in MT-2 cells (Fig. 5A) and in preactivated PBMCs (Fig. 5B), both infected with a recombinant virus (NL4.3 Luc). Graphical representations are at least mean of two independent experiments for MT-2 cells and four for PBMCs.

Fig. 6: p24-gag protein measurement in supernatants obtained from MT-2 cells infected with wild type NL4.3 in the presence or absence of compound 9 (Fig. 6A), 10 (Fig. 6B), and 1 1 (Fig. 6C).

Fig. 7. Classic antiviral assay in MT-2 cells infected or not with wild type NL4.3 in the presence of different concentrations of compounds 9 (Fig. 7A), 10 (Fig. 7B), 1 1 (Fig. 7C), zidovudine (Fig. 7D), and nelfmavir (Fig. 7E). In graphs, -♦- line represents cell viability of non-infected MT-2 cells and -■- line represents cell viability of MT-2 cells infected with wild type NL4.3. Fig. 8. Anti-HIV activity of compounds 9, 10, and 1 1 in MT-2 cells (Fig. 8A, 8C, and 8E, respectively) and in PBMCs (Fig. 8B, 8D, and 8F, respectively)) infected with X4 tropic recombinant HIV (NL4.3 Luc, X4), R5 tropic (JR Renilla, R5) and VSV pseudotyped HIV (NL4.3 delta env VSV Luc, Delta Luc). Graphics are mean of at least four independent experiments for PBMCs and just one experiment for MT-2 cells.

Fig. 9. Activity over HIV retrotranscriptase of compounds 9 (-■-), 10 (- A-), and 1 1 (-♦-). Enzimatic assay in which tryphosphate thymidine is incorporated into the DNA by viral retrotranscriptase. Compounds concentrations are expressed in μg/ml. Values obtained are expressed as cpm percentages as compared to a non-treated control ( 100%). Values are the mean of three independent experiments.

Fig. 10. Inhibition of the amount of viral DNA by compounds 9, 10, and 1 1. The assay was performed by real time PCR by amplifying R/U5-LTR- gag fragment. Compounds were evaluated at a concentration of 100 nM and Zidovudine (AZT) at a concentration of 1 μM was used as control.

Fig. 11. Transcriptional activity of several concentrations (μM) of compounds 9, 10, and 1 1 as compared to PMA (0. 1 μM) and aplidine (0.5 μM) in PBMCs resting. Luciferase activity was measured 48 hours post-transfection.

Fig. 12. Transcriptional activity of several concentrations (μM) of compounds 9, 10, and 1 1 as compared to aplidine (0.5 μM) in PBMCs resting. Luciferase activity was measured 1 , 2 or 1 6 hours post- transfection.

Fig. 13. Percentage of expression of CD69 in PBMCs resting treated for 16 hours with compounds 9, 10, and 1 1.

Fig. 14. Antiviral activity of compounds 9 (Fig. 14A), 10 (Fig. 14B), and 1 1 (Fig. 14C), Nelfmavir (Fig. 14D), and Zidovudine (AZT) (Fig. 14E) in

PBMCs infected with recombinant viruses carrying NRTIs resistances (9D), multiresistance complex (4D) or wild type (NL4.3-Renilla). In graphs, -♦- line represents cell viability of PBMCs infected with 4D, -■- line represents cell viability of PBMCs infected with 9D, and -A- line represents cell viability of PBMCs infected with NL4.3-Renilla. Data are at least mean of three independent experiments.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds of general formula I, II and III as defined above.

In these compounds the groups can be selected in accordance with the following guidance:

Alkyl groups may be branched or unbranched, and preferably have from 1 to about 12 carbon atoms. One more preferred class of alkyl groups has from 1 to about 6 carbon atoms. Even more preferred are alkyl groups having 1 , 2, 3 or 4 carbon atoms. Methyl, ethyl, n- propyl, isopropyl and butyl, including n-butyl, tert-butyl, sec-butyl and isobutyl are particularly preferred alkyl groups in the compounds of the present invention. As used herein, the term alkyl, unless otherwise stated, refers to both cyclic and noncyclic groups, although cyclic groups will comprise at least three carbon ring members.

Preferred alkenyl and alkynyl groups in the compounds of the present invention may be branched or unbranched, have one or more unsaturated linkages and from 2 to about 12 carbon atoms. One more preferred class of alkenyl and alkynyl groups has from 2 to about 6 carbon atoms. Even more preferred are alkenyl and alkynyl groups having 2, 3 or 4 carbon atoms. The terms alkenyl and alkynyl as used herein, unless otherwise stated, refer to both cyclic and noncyclic groups, although cyclic groups will comprise at least three carbon ring members.

Suitable aryl groups in the compounds of the present invention include single and multiple ring compounds, including multiple ring compounds that contain separate and/ or fused aryl groups. Typical aryl groups contain from 1 to 3 separated or fused rings and from 6 to about 18 carbon ring atoms. Preferably aryl groups contain from 6 to about 10 carbon ring atoms. Specially preferred aryl groups include substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted biphenyl, substituted or unsubstituted phenanthryl, and substituted or unsubstituted anthryl.

Suitable heterocyclic groups include heteroaromatic and heteroalicyclic groups containing from 1 to 3 separated or fused rings and from 5 to about 18 ring atoms. Preferably heteroaromatic and heteroalicyclic groups contain from 5 to about 10 ring atoms, most preferably 5, 6 or 7 ring atoms. Suitable heteroaromatic groups in the compounds of the present invention contain one, two or three heteroatoms selected from N , O or S atoms and include, e . g. , coumarinyl including 8-coumarinyl, quinolyl including 8-quinolyl, isoquinolyl, pyridyl, pyrazinyl, pyrazolyl including pyrazol-3-yl, pyrazol- 4-yl and pyrazol-5-yl, pyrimidinyl, furanyl including furan-2-yl, furan-3- yl, furan-4-yl and furan-5-yl, pyrrolyl, thienyl, thiazolyl including thiazol-2-yl, thiazol-4-yl and thiazol-5-yl, isothiazolyl, thiadiazolyl including thiadiazol-4-yl and thiadiazol-5-yl, triazolyl, tetrazolyl, isoxazolyl including isoxazol-3-yl, isoxazol-4-yl and isoxazol-5-yl, oxazolyl, imidazolyl, indolyl, isoindolyl, indazolyl, indolizinyl, phthalazinyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, pyridazinyl, triazinyl, cinnolinyl, benzimidazolyl, benzofuranyl, benzofurazanyl, benzothiophenyl including benzo[b]thiophen-2-yl and benzo[b]thiophen-3-yl, benzothiazolyl, benzoxazolyl, imidazo[l ,2- a]pyridinyl including imidazo [1 ,2 -a] pyridine- 2 -yl and imidazo[l ,2- a] pyridine- 3 -yl, quinazolinyl, quinoxalinyl, naphthyridinyl and furopyridyl. Suitable heteroalicyclic groups in the compounds of the present invention contain one, two or three heteroatoms selected from N, O or S atoms and include, e.g., pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydrothiopyranyl, piperidinyl including piperidin-3-yl, piperidin-4-yl and piperidin-5-yl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1 ,2,3,6-tetrahydropyridyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydropyrrolyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1 ,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3-azabicyclo[3.1.0]hexyl, 3- azabicyclo[4.1.0]heptyl, 3H-indolyl, and quinolizinyl.

In the above mentioned groups one or more hydrogen atoms may be substituted by one or more suitable groups such as OR', =O, SR',

SOR', SO₂R', NO₂, NHR', NR'R', =N-R', NHCOR', N(COR')₂, NHSO₂R',

NR'C(=NR')NR'R', CN, halogen, COR', COOR', OCOR', OCONHR',

OCONR'R', CONHR', CONR'R', substituted or unsubstituted Ci-Ci₂ alkyl, substituted or unsubstituted C₂-Ci₂ alkenyl, substituted or unsubstituted C₂-Ci₂ alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group, wherein each of the R' groups is independently selected from the group consisting of hydrogen,

OH, NO₂, NH₂, SH, CN, halogen, COH, COalkyl, CO₂H, substituted or unsubstituted Ci-Ci₂ alkyl, substituted or unsubstituted C₂-Ci₂ alkenyl, substituted or unsubstituted C₂-Ci₂ alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group. Where such groups are themselves substituted, the substituents may be chosen from the foregoing list. When a substituent group terminates with a double bound (such as =O and =N-R') it replaces 2 hydrogen atoms in the same carbon atom.

Suitable halogen substituents in the compounds of the present invention include F, Cl, Br and I.

The term "pharmaceutically acceptable salts" refers to any salt which, upon administration to the patient is capable of providing (directly or indirectly) a compound as described herein. It will be appreciated that non-pharmaceutically acceptable salts also fall within the scope of the invention since those may be useful in the preparation of pharmaceutically acceptable salts. The preparation of salts can be carried out by methods known in the art. For instance, pharmaceutically acceptable salts of compounds provided herein are synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. Generally, such salts are, for example, prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two. Generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred. Examples of the acid addition salts include mineral acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulphate, nitrate, phosphate, and organic acid addition salts such as, for example, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate and p-toluenesulfonate. Examples of the alkali addition salts include inorganic salts such as, for example, sodium, potassium, calcium and ammonium salts, and organic alkali salts such as, for example, ethylenediamine, ethanolamine, N,N-dialkylenethanolamine, triethanolamine and basic aminoacids salts.

The compounds of the invention may be in crystalline form either as free compounds or as solvates (e.g. hydrates, alcoholates, particularly methanolates) and it is intended that both forms are within the scope of the present invention. Methods of solvation are generally known within the art. The compounds of the invention may present different polymorphic forms, and it is intended that the invention encompasses all such forms.

Any compound referred to herein is intended to represent such specific compound as well as certain variations or forms. In particular, compounds referred to herein may have asymmetric centres and therefore exist in different enantiomeric or diastereomeric forms. Thus any given compound referred to herein is intended to represent any one of a racemate, one or more enantiomeric forms, one or more diastereomeric forms, and mixtures thereof. Likewise, stereoisomerism or geometric isomerism about the double bond is also possible, therefore in some cases the molecule could exist as (£)-isomer or (Z)- isomer (trans and cis isomers). If the molecule contains several double bonds, each double bond will have its own stereoisomerism, that could be the same or different than the stereoisomerism of the other double bonds of the molecule. Furthermore, compounds referred to herein may exist as atropisomers. All the stereoisomers including enantiomers, diastereoisomers, geometric isomers and atropisomers of the compounds referred to herein, and mixtures thereof, are considered within the scope of the present invention. In compounds of general formula I and II, particularly preferred

Ri, R5, R9, Rn, and R15 are independently selected from hydrogen and substituted or unsubstituted C₁-CO alkyl. More preferred R₁, Rs, R9, Rn, and Ri5 are independently selected from hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl and substituted or unsubstituted butyl, including substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl, and substituted or unsubstituted sec-butyl. Preferred substituents of said groups are OR', =O, SR', SOR', SO₂R ' , N O₂, N H R ', N R 'R ' , = N-R', NHCOR', N(COR')₂, NHSO₂R', NR'C(=NR')NR'R', CN, halogen, COR', COOR', OCOR', OCONHR', OCONR'R', CONHR', CONR'R', substituted or unsubstituted Ci-Ci₂ alkyl, substituted or unsubstituted C₂-Ci₂ alkenyl, substituted or unsubstituted C₂-Ci₂ alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group, wherein each of the R' groups is independently selected from the group consisting of hydrogen, OH, NO₂, NH₂, SH, CN, halogen, COH, COalkyl, CO₂H, substituted or unsubstituted Ci-Ci₂ alkyl, substituted or unsubstituted C₂-Ci₂ alkenyl, substituted or unsubstituted C₂-Ci₂ alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group. Where such groups are themselves substituted, the substituents may be chosen from the foregoing list. Hydrogen, methyl, n-propyl, isopropyl, isobutyl, sec-butyl, 4-aminobutyl, 3-amino-3-oxopropyl, benzyl, p-methoxybenzyl, p-hydroxybenzyl, and cyclohexylmethyl are the most preferred R₁, R5, R9, Rn, and R15 groups. Specifically, particularly preferred Ri is selected from sec-butyl and isopropyl, being sec-butyl the most preferred. Particularly preferred R5 is selected from isobutyl and 4-aminobutyl, being isobutyl the most preferred. Particularly preferred Rn is methyl and isobutyl. Particularly preferred Rg is selected from p-methoxybenzyl, p-hydroxybenzyl, and cyclohexylmethyl, being p-methoxybenzyl the mo st preferred . Particularly preferred R15 is selected from methyl, n-propyl, and benzyl, being methyl and benzyl the most preferred.

In compounds of general formula III, particularly preferred R₁, Rs, Rg, and R15 are independently selected from hydrogen and substituted or unsubstituted C₁-CO alkyl. More preferred R₁, R5, R9, and R15 are independently selected from hydrogen, substituted or unsubstituted methyl , sub stitute d or unsub stituted ethyl , sub stituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl and substituted or unsubstituted butyl, including substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl, and substituted or unsubstituted sec-butyl. Preferred substituents of said groups are OR', =O, SR', SOR', SO₂R ' , N O₂, N H R ', N R 'R ' , = N-R', NHCOR', N(COR')₂, NHSO₂R', NR'C(=NR')NR'R', CN, halogen, COR', COOR', OCOR', OCONHR', OCONR'R', CONHR', CONR'R', substituted or unsubstituted Ci-Ci₂ alkyl, substituted or unsubstituted C₂-Ci₂ alkenyl, substituted or unsubstituted C₂-Ci₂ alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group, wherein each of the R' groups is independently selected from the group consisting of hydrogen, OH, NO₂, NH₂, SH, CN, halogen, COH, COalkyl, CO₂H, substituted or unsubstituted Ci-Ci₂ alkyl, substituted or unsubstituted C₂-Ci₂ alkenyl, substituted or unsubstituted C₂-Ci₂ alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group. Where such groups are themselves substituted, the substituents may be chosen from the foregoing list. Hydrogen, methyl, n-propyl, isopropyl, isobutyl, sec-butyl, 4-aminobutyl, 3-amino-3-oxopropyl, benzyl, p-methoxybenzyl, p-hydroxybenzyl, and cyclohexylmethyl are the most preferred R₁, R5, R9, and R15 groups. Specifically, particularly preferred Ri is selected from sec-butyl and isopropyl, being sec-butyl the most preferred. Particularly preferred R5 is selected from isobutyl and 4-aminobutyl, being isobutyl the most preferred. Particularly preferred Rg is selected from p-methoxybenzyl, p-hydroxybenzyl, and cyclohexylmethyl, being p-methoxybenzyl the most preferred. Particularly preferred R15 is selected from methyl, n-propyl, and benzyl, being methyl and benzyl the most preferred.

In compounds of general formula I, II and III, particularly preferred Re, Rio, R12, and R16 are independently selected from hydrogen and substituted or unsubstituted Ci-Cβ alkyl. More preferred Re, Rio, R12, and R16 are independently selected from hydrogen, methyl, ethyl, n- propyl, isopropyl and butyl, including n-butyl, tert-butyl, isobutyl and sec-butyl, and even more preferred they are independently selected from hydrogen and methyl. Specifically, particularly preferred Re, Rio and R12 are methyl, and particularly preferred R16 is hydrogen. In compounds of general formula I and III, particularly preferred

R3 and R₄ are independently selected from hydrogen and substituted or unsubstituted Ci-Cβ alkyl. More preferred R3 and R₄ are independently selected from hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n- propyl, substituted or unsubstituted isopropyl, and substituted or unsubstituted butyl, including substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl and substituted or unsubstituted sec-butyl. Preferred substituents of said groups are OR', =O, SR', SOR', SO₂R', NO₂, NHR', NR'R', =N-R', NHCOR', N(COR')₂, NHSO₂R', NR'C(=NR')NR'R', CN, halogen, COR', COOR', OCOR', OCONHR', OCONR'R', CONHR', CONR'R', substituted or unsubstituted Ci-Ci₂ alkyl, substituted or unsubstituted C₂-Ci₂ alkenyl, substituted or unsubstituted C₂-Ci₂ alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group, wherein each of the R' groups is independently selected from the group consisting of hydrogen, OH, NO₂, NH₂, S H , C N , halo ge n , C O H , C O alkyl , C O₂H, substituted or unsubstituted Ci-Ci₂ alkyl, substituted or unsubstituted C₂-Ci₂ alkenyl, substituted or unsubstituted C₂-Ci₂ alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group. Where such groups are themselves substituted, the substituents may be chosen from the foregoing list. Hydrogen, methyl, isopropyl, and sec-butyl are the most preferred R3 and R₄ groups. Specifically, particularly preferred R3 is selected from methyl and isopropyl and particularly preferred R₄ is methyl or hydrogen.

In one embodiment of compounds of general formula I, II and III, particularly preferred Re and R7 are independently selected from hydrogen and substituted or unsubstituted C₁-CO alkyl. More preferred R₇ is selected from hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n- propyl, substituted or unsubstituted isopropyl and substituted or unsubstituted butyl, including substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl, and substituted or unsubstituted sec-butyl. Preferred substituents of said groups are OR', =O, SR', SOR', SO₂R', NO₂, NHR', NR'R', =N-R', NHCOR', N(COR¹J₂, NHSO₂R', NR'C(=NR')NR'R', CN, halogen, COR', COOR', OCOR', OCONHR', OCONR'R', CONHR', CONR'R', substituted or unsubstituted Ci-Ci₂ alkyl, substituted or unsubstituted C₂-Ci₂ alkenyl, substituted or unsubstituted C₂-Ci₂ alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group, wherein each of the R' groups is independently selected from the group consisting of hydrogen, OH, NO₂, NH₂, S H , C N , halo ge n , C O H , C O alkyl , C O₂H, substituted or unsubstituted Ci-Ci₂ alkyl, substituted or unsubstituted C₂-Ci₂ alkenyl, substituted or unsubstituted C₂-Ci₂ alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group. Where such groups are themselves substituted, the substituents may be chosen from the foregoing list. More preferred Re is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl and butyl, including n-butyl, tert-butyl, isobutyl and sec-butyl. Most preferred Re is selected from hydrogen and methyl and most preferred R₇ is methyl.

In another embodiment of compounds of general formula I, II and III, it is particularly preferred that Re and R₇ together with the corresponding N atom and C atom to which they are attached form a substituted or unsubstituted heterocyclic group. In this regard, preferred heterocyclic group is a heteroalicyclic group containing one, two or three heteroatoms selected from N, O or S atoms, most preferably one N atom, and having from 5 to about 10 ring atoms, most preferably 5, 6 or 7 ring atoms. A pyrrolidine group is the most preferred.

In one embodiment of compounds of general formula I, II and III, particularly preferred R13 and R14 are independently selected from hydrogen and substituted or unsubstituted Ci-Cβ alkyl. More preferred Ri3 is selected from hydrogen, substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n- propyl, substituted or unsubstituted isopropyl and substituted or unsubstituted butyl, including substituted or unsubstituted n-butyl, substituted or unsubstituted tert-butyl, substituted or unsubstituted isobutyl, and substituted or unsubstituted sec-butyl. Preferred substituents of said groups are OR', =O, SR', SOR', SO₂R', NO₂, NHR', NR'R', =N-R', NHCOR', N(COR')₂, NHSO₂R', NR'C(=NR')NR'R', CN, halogen, COR', COOR', OCOR', OCONHR', OCONR'R', CONHR', CONR'R', substituted or unsubstituted Ci-Ci₂ alkyl, substituted or unsubstituted C₂-Ci₂ alkenyl, substituted or unsubstituted C₂-Ci₂ alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group, wherein each of the R' groups is independently selected from the group consisting of hydrogen, OH, NO2, NH₂, S H , C N , halo ge n , C O H , C O alkyl , C O₂H, substituted or unsubstituted Ci-Ci₂ alkyl, substituted or unsubstituted C₂-Ci₂ alkenyl, substituted or unsubstituted C₂-Ci₂ alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group. Where such groups are themselves substituted, the substituents may be chosen from the foregoing list. More preferred Ri₄ is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl and butyl, including n-butyl, tert-butyl, isobutyl and sec-butyl. Most preferred R13 is selected from hydrogen, methyl, isopropyl, isobutyl, and 3-amino-3-oxopropyl and most preferred Ri₄ is hydrogen.

In another embodiment of compounds of general formula I, II and III, it is particularly preferred that R13 and Ri₄ together with the corresponding N atom and C atom to which they are attached form a substituted or unsubstituted heterocyclic group. In this regard, preferred heterocyclic group is a heteroalicyclic group containing one, two or three heteroatoms selected from N, O or S atoms, most preferably one N atom, and having from 5 to about 10 ring atoms, most preferably 5, 6 or 7 ring atoms. A pyrrolidine group is the most preferred.

In compounds of general formula I, II and III, particularly preferred R₂ is selected from hydrogen, substituted or unsubstituted Ci- CO alkyl, and COR_a, wherein R_a is a substituted or unsubstituted Ci-Cβ alkyl, and even more preferred R_a is methyl, ethyl, n-propyl, isopropyl and butyl, including n-butyl, tert-butyl, sec-butyl and isobutyl. More preferably R₂ is hydrogen.

In compounds of general formula I, II and III, particularly preferred Ri₇ is selected from hydrogen, COR_a, COOR_a, CONHRb,

(C=S)NHRb, and SO₂Rc, wherein each R_a, Rb, and R_c is preferably and independently selected from substituted or unsubstituted C₁-CO alkyl, sub stituted or unsub stituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group. Preferred substituents of said groups are OR', =0, SR', SOR', SO₂R', NO₂, NHR', NR'R', =N-R', NHCOR', N(COR')₂, NHSO₂R', NR'C(=NR')NR'R', CN, halogen, COR', COOR', OCOR', OCONHR', OCONR'R', CONHR', CONR'R', substituted or unsubstituted Ci-Ci₂ alkyl, substituted or unsubstituted C₂-Ci₂ alkenyl, substituted or unsubstituted C₂-Ci₂ alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group, wherein each of the R' groups is independently selected from the group consisting of hydrogen, OH, NO₂, NH₂, SH, CN, halogen, COH, COalkyl, CO₂H, substituted or unsubstituted Ci-Ci₂ alkyl, substituted or unsubstituted C₂-Ci₂ alkenyl, substituted or unsubstituted C₂-Ci₂ alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group. Where such groups are themselves substituted, the substituents may be chosen from the foregoing list. Hydrogen, COR_a, COOR_a, and SO₂Rc are the most preferred R17 groups, and hydrogen, COObenzyl, CObenzo[b]thiophen-2-yl, SO₂(p- methylphenyl), COCOCH₃ and COOC(CHa)₃ are even most preferred.

In another embodiment of compounds of general formula I, II and III, it is particularly preferred that Y is CO. In another embodiment, it is particularly preferred that Y is -COCH(CH₃)CO-.

In another embodiment of compounds of general formula I, II and III, it is particularly preferred that X is O. In another embodiment, it is particularly preferred that X is NH. In another embodiment of compounds of general formula I and II, it is particularly preferred that n, p and q are O. In another embodiment, it is particularly preferred that n is 1 and p and q are 0. In another embodiment, it is particularly preferred that n and p are 1 and q is 0. In another embodiment, it is particularly preferred that n, p, and q are 1. In another embodiment, it is particularly preferred that n and p are 1 and q is 2.

In another embodiment of compounds of general formula III, it is particularly preferred that p and q are 0. In another embodiment, it is particularly preferred that p is 1 and q is 0. In another embodiment, it is particularly preferred that p and q are 1. In another embodiment, it is particularly preferred that p is 1 and q is 2.

In additional preferred embodiments, the preferences described above for the different substituents are combined. The present invention is also directed to such combinations of preferred substitutions of formula I, II and III above.

In the present description and definitions, when there are several groups R_a, Rb, and R_c present in the compounds of the invention, and unless it is stated explicitly so, it should be understood that they can be each independently different within the given definition, i.e. R_a does not represent necessarily the same group simultaneously in a given compound of the invention. In compounds of general formula I, II and III when q takes a value of 2 there are two groups R15 and two groups R16 in the compound. It is hereby clarified that each R15 and each R16 group in a given compound may be independently selected among the different possibilities described above for such groups. A particularly preferred stereochemistry for compounds of general formula I is

wherein X, Y, n, p, q, and R1-R17 are as defined above, and when Y is COCH(CH₃)CO- it has the following stereochemistry:

A particularly preferred stereochemistry for compounds of general formula II is

wherein X, Y, n, p, q, R₁, R2, and R5-R17 are as defined above, and when Y is -COCH(CH₃)CO- it has the following stereochemistry:

A particularly preferred stereochemistry for compounds of general formula III is

wherein X, Y, p, q, R1-R10, and R12-R17 are as defined above, and when Y is COCH(CH₃)CO- it has the following stereochemistry:

Particularly preferred compounds of the invention are the following:

or pharmaceutically acceptable salts or stereoisomers thereof.

The compounds of general formula I, II and III may be prepared following any of the synthetic processes disclosed in Vera et al. Med. Res. Rev. 2002, 22(2), 102-145, WO 02/02596, WO 01/76616, and WO 2004/084812, which are incorporated herein by reference.

The present invention involves the use of compounds of general formula I, II and III in the treatment of HIV infections and associated conditions, such as AIDS and ARC. All forms of HIV are potentially treatable with the compounds of the present invention. The term HIV includes mutant strains of HIV including "drug resistant" or "multiple drug resistant" strains of the HIV virus which have been mutated to be resistant to one or more clinically approved anti-HIV agents, including, in particular, HIV strains which are resistant to one or more nucleoside reverse transcriptase inhibitors and/ or non-nucleoside reverse transcriptase inhibitors and/ or protease inhibitors. The terms ARC and AIDS refer to syndromes of the immune system caused by the HIV, which are characterized by susceptibility to certain diseases and T cell accounts which are depressed compared to normal accounts.

As used herein, the terms "treat", "treating", and "treatment" refer to one or more of the following: 1) reduction in the number of infected cells; 2) reduction in the number of virions present in the serum; 3) inhibition (i.e., slowing to some extent, preferably stopping) of rate of HIV replication; and 4) relieving or reducing to some extend one or more of the symptoms associated with HIV. Compounds of the invention may be used in pharmaceutical compositions having biological/ pharmacological activity for the treatment of the above mentioned infections and associated conditions. These pharmaceutical compositions comprise a compound of the invention together with a pharmaceutically acceptable carrier. The term "carrier" refers to a diluent, adjuvant, excipient or vehicle with which the active ingredient is administered. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by E. W. Martin, 1995. Examples of pharmaceutical compositions include any solid (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions, emulsions, etc.) compositions for oral, topical or parenteral administration. Pharmaceutical compositions containing compounds of the invention may be delivered by liposome or nanosphere encapsulation, in sustained release formulations or by other standard delivery means. The specific dosage and treatment regimen for any particular patient may be varied and will depend upon a variety of factors, including the activity of the specific compound employed, the particular formulation being used, the mode of application, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, reaction sensitivities, and the severity of the particular disease or condition being treated.

The compounds of general formula I, II and III may be used in combination with one or more additional therapeutic agents for the treatment of the above mentioned infections and associated conditions. The drugs in said combination therapies may be administered simultaneously in either the same or different pharmaceutical compositions or sequentially in any order. The amounts of each drug and the relative timing of administration will be selected in order to achieve the desired combined therapeutic effect. Examples of said therapeutic agents include agents that are effective for the treatment of HIV infections, such as nucleoside reverse transcriptase inhibitors (such as zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, tenofovir, and emtricitabine), non-nucleoside reverse transcriptase inhibitors (such as nevirapine, delavirdine, efavirenz, and etravirine), protease inhibitors (such as saquinavir, ritonavir, indinavir, nelfinavir, atazanavir, fosamprenavir, tipranavir, and darunavir), entry inhibitors (such as maraviroc), integrase inhibitors (such as raltegravir), fusion inhibitors (such as enfuvirtide), and combination therapies (such as lamivudine + zidovudine, abacavir + zidovudine + lamivudine, abacavir + lamivudine , tenofovir + emtricitabine, efavirenz + emtricitabine + tenofovir, and lopinavir + ritonavir).

The present invention also involves a me d i cal ki t fo r administering a compound of the invention, comprising printed instructions for administering this compound according to the uses and methods of treatment set forth herein, and a pharmaceutical composition comprising the compound together with a pharmaceutically acceptable carrier. To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term "about". It is understood that, whether the term "about" is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including equivalents and approximations due to the experimental and/ or measurement conditions for such given value.

The following examples further illustrate the invention. They should not be interpreted as a limitation of the scope of the invention.

EXAMPLES

The following abbreviations have been used in the examples:

Ac - acetyl Bn - benzyl

Boc - tert-Butyloxycarbonyl

Cbz - Carboxybenzyl

DCC - l ^-Dicyclohexylcarbodiimide

DIPCDI - N,N'-Diisopropylcarbodiimide

DIPEA - N,N-Diisopropylethylamine

DMF - Dimethylformamide

DTT - Dithiothreitol

EGTA - ethylene glycol-bis(2-aminoethylether)-N,N,N',N'-tetraacetic acid i-Pr - isopropyl

HATU - 2-(l//-7-Azabenzotriazol- l-yl)-N,N,N',N'-tetramethyluronium hexa-fluorophosphate

HBTU - O-(benzotriazol- l-yl)-N,N,N',N'-tetramethyluronium hexafluoro- phosphate

HOBt - N-Hydroxybenzotriazole

MTBE - Methyl tert-butyl ether

MTT - 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide

PHA - Phytohemagglutinin

TBS - tert-butyldimethylsilyl

TCA - Trichloroacetic Acid

TCID50 - 50% Tissue Culture Infective Dose

PBMC - Peripheral Blood Mononuclear Cell

PMA - Phorbol 12-myristate 13-acetate

VSV -Vesicular Stomatitis Virus

EXAMPLE 1 : SYNTHESIS OF COMPOUNDS OF THE INVENTION

Compounds 1-4 were obtained following the procedures already disclosed in WO 02/02596 and further disclosed below: Synthesis of intermediate 3AJBAPA4

3AΪBAPA4

To a mixture of HBTU (3.44 g, 9.07 mmol) and HOBt (1.17 g, 8.71 mmol) was added a solution of 2-(tert-butoxycarbonylamino)-2- methylpropanoic acid (2.0 g, 8.71 mmol) in CH₂Cl₂ (29 mL) at 0 ⁰C. The reaction mixture was stirred at 0⁰ C fo r 2 5 m i nu te s a n d 4- methylmorpholine (0.8 mL, 7.26 mmol) was added at 0⁰C. A solution of H-Leu-Pro-OBn HCl (2.58 g, 7.26 mmol) in DMF ( 10 mL) was cooled to 0⁰C and 4-methylmorpholine (2.15 mL, 19.6 mmol) was added at 0⁰C and stirred 10 minutes at this temperature. This second solution was added to the reaction mixture 5 minutes after the addition of the 4- methylmorpholine and the reaction mixture was warmed at 23°C overnight. The reaction mixture was concentrated in vacuum, dissolved in Hexane: EtOAc (1 :4) and extracted with H₂O. The combined organic layers were sequentially washed with 10% aqueous solution of KHSO₄, an aqueous saturated solution of NaHCO3, and aqueous saturated solution of NaCl. The combined organic layers were dried over Na₂SO₄, filtered, and evaporated. The crude yield was purified by column chromatography on silica gel with Hexane:EtOAc (from 9: 1 to 1 :2) as eluent to give pure 3AiBAPA4 (3.54 g, 97% yield) as a white solid.

¹H NMR (CDCl₃, 300 MHz) δ: 7.26 (m, 5H), 6.88 (d, IH, J = 8.3 Hz), 5.12 (d, IH, J = 12.2 Hz), 5.00 (d, IH, J = 12.2 Hz), 4.70 (m, IH), 4.46 (m, IH), 3.73 (m, IH), 3.55 (m, IH), 2.14 (m, IH), 1.98- 1.86 (m, 3H), 1.66 (m, IH), 1.42 (s, 3H), 1.25 (s, 12H), 1.35- 1.25 (m, 2H), 0.89 (d, 3H, J = 6.3 Hz), 0.81 (d, 3H, J = 6.6 Hz).

MS (ES) m/z 504.2 [M+H]⁺, 526.2 [M+Na]⁺. Synthesis of intermediate 3AΪBAPA3

To a solution of 3AiBAPA4 (300 mg, 0.59 mmol) in anhydrous dioxane (1.2 mL) was dropwise added a solution of HCl (4 mL, 5.9 N in dioxane, 23.6 mmol) at 23°C. The reaction mixture was stirred 2 hours and concentrated in vacuum. The residue obtained was sequentially coevaporated with Et₂O, CH₂Cl₂, and Hexane to yield 3AiBAPA3 (260 mg, 99% yield) as a white solid which was used in the following step without further purification.

¹H NMR (CDCl₃, 300 MHz) δ: 8.80 (br s, 2H), 7.91 (d, IH, J = 7.3 Hz), 7.37-7.26 (m, 5H), 5.17 (d, IH, J = 12.2 Hz), 5.04 (d, IH, J = 12.2 Hz), 4.70 (m, I H), 4.59 (m, I H), 3.76 (m, IH), 3.58 (m, IH), 2.21 (m, IH), 2.01- 1.80 (m, 3H), 1.72 (s, 3H), 1.67 (m, 2H), 1.63 (s, 3H), 1.45 (m, IH), 0.90 (d, 3H, J = 5.6 Hz), 0.89 (d, 3H, J = 6.3 Hz).

MS (ES) m/z 404.3 [M+H]⁺, 426.3 [M+Na]⁺. Synthesis of intermediate 3AJBAPA2

To a solution of 3AΪBAPA3 (260 mg, 0.59 mmol) in CH₂Cl₂ (6 mL) was added 4-methylmorpholine (98 μL, 0.89 mmol) at 0⁰C. The reaction mixture was stirred for 25 minu t e s a n d ( 3S,4R,5S)-4-(tert- butoxycarbonylamino) -3 - ( tert-butyldimethylsilyloxy) - 5 -methylheptanoic acid (288 mg, 0.74 mmol), DCC (151 mg, 0.73 mmol), and HOBt (71 mg, 0.71 mmol) were sequentially added at 0⁰C. The reaction mixture was warmed at 23°C and stirred overnight. The solids were removed by filtration and the organic layer was washed with 10% aqueous solution of KHSO₄, an aqueous saturated solution of NaHCO3, and aqueous saturated solution of NaCl. The combined organic layers were dried over Na₂SO₄, filtered, and evaporated. The crude yield was purified by column chromatography on silica gel with Hexane: EtOAc (from 4: 1 to 1 : 1) as eluent to afford pure 3AiBAPA2 (389 mg, 84% yield) as a white solid.

¹H NMR (CDCl₃, 300 MHz) δ: 7.29 (br s, 5H), 5.19 (m, IH), 5.00 (d, IH, J = 12.5 Hz), 4.92-4.83 (m, 2H), 4.52-4.44 (m, IH), 4.05 (m, IH), 3.88 (m, IH), 3.66-3.46 (m, 2H), 2.39-2.14 (m, 3H), 2.00- 1.59 (m, 8H), 1.51 (s, 9H), 1.33 (s, 3H), 1.23 (s, 3H), 0.95-0.79 (m, 21H), 0.06 (s, 6H).

MS (ES) m/z 775.9 [M+H]⁺, 797.8 [M+Na]⁺.

Synthesis of intermediate 3AiBAPAl

3AiBAPAl To a solution of 3AΪBAPA2 (389 mg, 0.50 mmol) in anhydrous dioxane (0.8 rtiL) was dropwise added a solution of HCl (3.4 mL, 5.9 N in dioxane, 20.0 mmol) at 23°C. The reaction mixture was stirred 2 hours and concentrated in vacuum. The residue obtained was sequentially coevaporated with Et₂O, CH₂Cl₂, and Heptane to yield 3AiBAPAl (308 mg, 103% yield) as a white solid which was used in the following step without further purification.

¹H NMR (CDCl₃, 300 MHz) δ: 8.09 (br s, 3H), 7.29-7.26 (m, 5H), 5.17- 5.02 (m, 2H), 4.62 (m, IH), 4.45-4.36 (m, IH), 3.84 (m, IH), 3.54 (m,

IH), 3.37 (m, IH), 2.63 (m, IH), 2.47 (m, IH), 2.15 (m, IH), 2.01- 1.88

(m, 3H), 1.65 (m, 2H), 1.56 (s, 3H), 1.43 (s, 3H), 1.23 (s, 3H), 1.07 (s,

3H), 0.85 (s, 9H).

MS (ES) m/z 561.3 [M+H]⁺, 583.3 [M+Na]⁺.

Synthesis of intermediate 3AJBAP7

To a solution of 3AiBAPAl (308 mg, 0.50 mmol) in CH₂Cl₂ (8 mL) was added HBTU (200 mg, 0.53 mmol) and HOBt (68 mg, 0.50 mmol) at 0⁰C. The reaction mixture was stirred 5 minutes at 0⁰C and a solution of Boc-Thr(Cbz-NMe-Tyr(OMe))-OH (273 mg, 0.50 mmol) in DMF (4 mL) was added at 0⁰C. Finally, after 10 minutes DIPEA (0.35 mL, 2.01 mmol) was added at 0⁰C. The reaction mixture was warmed at 23°C and stirred overnight. CH₂Cl₂ was added and the organic layer was washed with 10% aqueous solution Of KHSO₄, an aqueous saturated solution of NaHCO₃, and aqueous saturated solution of NaCl. The combined organic layers were dried over Na₂SO₄, filtered, and evaporated. The crude yield was purified by column chromatography on silica gel with Hexane: EtOAc (from 1 : 1 to 0: 100) as eluent to yield pure 3AiBAP7 (355 mg, 65% yield) as a white solid.

¹H NMR (CDCl₃, 300 MHz) δ: 7.49 (m, IH), 7.30 (m, 10H), 7.15 (m, IH),

7.02-6.99 (m, 2H), 6.77-6.71 (m, 3H), 5.60-5.30 (m, 2H), 5.17-4.98 (m, 4H), 4.73-4.49 (m, 4H), 3.89-3.80 (m, 3H), 3.73 (s, 3H), 3.59 (s, I H),

3.19 (m, IH), 3.96 (m, IH), 2.77 (s, 3H), 2.40-2.05 (m, 3H), 2.00- 1.88

(m, 4H), 1.69 (m, IH), 1.54- 1.40 (m, 3H), 1.42 (s, 9H), 1.34- 1.21 (m,

9H), 0.90-0.85 (m, 12H).

MS (ES) m/z 1088.3 [M+H]⁺, 1 1 10.0 [M+Na]⁺.

Synthesis of intermediate 3AJBAP6

3AiBAP6 To a solution of 3AiBAP7 (355 mg, 0.33 mmol) in i-PrOH:H₂O (2 : 1 , 24 mL) was added Pd(OH)₂ (7 1 mg, 20% w/w) at 23°C. The reaction mixture was stirred overnight at 23°C under hydrogen atmosphere, filtered over Celite^®, washed with i-PrOH and concentrated under vacuum. The residue obtained was precipitated with Heptane to give 3AiBAP6 (290 mg, quantitative) as a white solid which was used in the following step without further purification. ¹H NMR (CDCl₃, 300 MHz) δ: 7.26 (m, 2H), 6.79 (m, 2H), 5.54 (m, 2H), 5.25 (m, IH), 4.92 (m, IH), 4.67 (m, IH), 4.51 (m, IH), 4.38 (m, IH), 4.20-3.97 (m, 3H), 3.81 (m, IH), 3.73 (s, 3H), 3.61-3.53 (m, 2H), 3.19- 3.08 (m, 2H), 2.87-2.66 (m, 6H), 2.31- 1.71 (m, 7H), 1.47 (s, 9H), 1.17- 1.05 (m, 1 1 H), 0.84 (m, 9 H).

MS (ES) m/z 864.0 [M+H]⁺, 885.7 [M+Na]⁺.

Synthesis of compound 1

To a solution of 3AiBAP6 (90 mg, 0. 10 mmol) in CH₃CN (30 mL) was added HATU (95 mg, 0.25 mmol) at 0⁰C. The reaction mixture was stirred for 10 minutes at 0⁰C and 4-methylmorpholine (46 μL, 0.42 mmol) was added at this temperature. The reaction mixture was warmed at 23°C and stirred overnight. The solvent was concentrated under vacuum and the precipitated obtained was dissolved in EtOAc, and filtered. The organic layer was washed with 10% aqueous solution of KHSO₄, an aqueous saturated solution of NaHCO₃, and aqueous saturated solution of NaCl. The combined organic layers were dried over Na2SO4, filtered, and evaporated. The resultant crude was purified by column chromatography on silica gel with EtOAc as eluent to obtain pure compound 1 (70 mg, 80% yield) as a white solid. ¹H NMR (CDCl₃, 300 MHz) δ: 7.42 (d, IH, J = 10.0 Hz), 7.29 (d, IH, J = 9.3 Hz), 7.08 (d, 2H, J = 8.5 Hz), 6.83 (d, 2H, J = 8.5 Hz), 6.27 (s, IH), 5.05 (m, IH), 4.94 (d, IH, J = 9.5 Hz), 4.79 (t, IH, J = 10.3 Hz), 4.62 (m, IH), 4.35 (dd, IH, J = 2.7, 9.5 Hz), 4.10 (m, IH), 3.94 (m, IH), 3.79 (s, 3H), 3.77-3.52 (m, 3H), 3.38 (m, IH), 3.21 (m, IH), 2.79 (s, 3H), 2.54 (s, 3H), 2.35 (dd, IH, J = 6.1 , 17.3 Hz), 2.20-2.04 (m, 5H), 1.92 (m, IH), 1.73 (m, IH), 1.44 (s, 9H), 1.36- 1.15 (m, 8H), 0.98-0.86 (m, 14H).

MS (ES) m/z 845.3 [M+H]⁺, 868.4 [M+Na]⁺. Synthesis of intermediate 3AΪBAP4

3AiBAP4

To a solution of compound 1 (55 mg, 0.058 mmol) in anhydrous dioxane (1.0 rtiL) was dropwise added a solution of HCl (1.6 mL, 5.9 N in dioxane, 9.28 mmol) at 23°C. The reaction mixture was stirred 2 hours and concentrated in vacuum. The residue obtained was sequentially coevaporated with MTBE to yield 3AiBAP4 (50 mg, quantitative) as a white solid which was used in the following step without further purification.

¹H NMR (CDCl₃, 300 MHz) δ: 7.05 (d, IH, J = 8.1 Hz), 6.83 (d, IH, J = 8.3 Hz), 5.45 (m, IH), 4.74 (m, 2H), 4.10 (m, 2H), 3.94 (m, IH), 3.79 (m, 3H), 3.77-3.63 (m, 3H), 3.21 (m, 2H), 2.63 (s, 3H), 2.20-2.04 (m, 5H), 1.61- 1.18 (m, 15H), 0.95-0.88 (m, 14H).

MS (ES) m/z 745.2 [M+H]⁺, 767.2 [M+Na]⁺. Synthesis of compound 2

Compound 2 To a solution of HATU (27 mg, 0.07 mol) and Z-D-MeLeu-OH (20 mg, 0.07 mmol) in CH₂Cl₂ (4 mL) was added a solution of 3AiBAP4 (50 mg, 0.058 mmol) in DMF (2 mL) at 0⁰C. The reaction mixture was stirred for 15 minutes at 0⁰C and 4-methylmorpholine (16 μL, 0.15 mmol) was added at this temperature. The reaction mixture was warmed at 23°C and stirred overnight. The solvent was concentrated under vacuum and the precipitated obtained was dissolved in Hexane:EtOAc (1:4, 40 mL) and washed with 10% aqueous solution of KHSO₄, an aqueous saturated solution of NaHCO3, and aqueous saturated solution of NaCl. The combined organic layers were dried over Na₂SO₄, filtered, and evaporated. The resultant crude was purified by column chromatography on silica gel with Hexane: EtOAc (from 1:1 to 1:10) as eluent to obtain pure compound 2 (30 mg, 52% yield) as a white solid.

¹H NMR (CDCl₃, 300 MHz) δ: 7.51 (d, IH, J= 10.3 Hz), 7.38-7.27 (m, 5H), 7.09 (d, 2H, J= 8.5 Hz), 6.94 (br s, IH), 6.84 (d, 2H, J= 8.5 Hz), 5.24 (d, IH, J= 12.4 Hz), 5.15 (d, IH, J= 12.4 Hz), 5.06 (m, IH), 4.82 (m, IH), 4.65-4.54 (m, 2H), 4.05 (m, IH), 3.92 (m, IH), 3.79 (s, 3H), 3.68-3.55 (m, 2H), 3.37 (dd, IH, J= 3.9, 14.4 Hz), 3.16 (dd, IH, J = 11.2, 14.4 Hz), 2.89 (s, 3H), 2.85 (m, IH), 2.62 (m, IH), 2.56 (s, 3H), 2.40- 1.67 (m, 8H), 1.67- 1.25 (m, HH), 1.16 (d, 6H, J = 6.3 Hz), 0.93-

0.86 (m, 18H).

MS (ES) m/z 1006.8 [M+H]⁺, 1028.7 [M+Na]⁺. Synthesis of compound 3

Compound 3

To a solution of compound 2 (30 mg, 0.03 mmol) in i-PrOH:H₂O (2: 1 , 6 mL) was added Pd(OH)₂ ( 12 mg, 40% w/w) at 23°C. The reaction mixture was stirred overnight at 23°C under hydrogen atmosphere, filtered over Celite^®, washed with i-PrOH and concentrated under vacuum. The residue obtained was precipitated with Heptane to yield a white solid which was dissolved in CH₂Cl₂ (30 mL) and washed with 5% aqueous solution of Na₂CO3 (10 mL). The combined organic layers were dried over Na₂SO₄, filtered, and evaporated to obtain compound 3 (20 mg, 77% yield) as a white solid which was used in the following step without further purification.

¹H NMR (CDCl₃, 300 MHz) δ: 7.75-7.62 (m, 3H), 7.08 (d, 2H, J = 8.3 Hz), 6.83 (d, 2H, J = 8.3 Hz), 5.12 (m, IH), 4.83 (m, IH), 4.64 (m, IH), 4.49 (m, IH), 4.09 (m, IH), 3.93 (m, IH), 3.79 (s, 3H), 3.69 (m, IH), 3.58 (m, IH), 3.37 (dd, IH, J = 4.2, 14.2 Hz), 3.16 (dd, IH, J = 10.7, 14.2 Hz), 2.91 (m, IH), 2.58 (s, 3H), 2.38 (s, 3H), 2.30- 1.80 (m, 7 H), 1.80- 1.43 (m, HH), 1.37-1.09 (m, 8H), 0.98-0.82 (m, 18H).

MS (ES) m/z 873.0 [M+H]⁺. Synthesis of compound 4

Compound 4

To a solution of l-(l ,2-dioxopropyl)-S-proline (2 1 mg, 0. 1 15 mmol) in CH₂Cl₂ (0.2 mL) was added DIPCDI ( 10 μL, 0.064 mmol) at 0⁰C. The reaction mixture was stirred for 1 hour at 0⁰C and a solution of compound 3 (20 mg, 0.023 mmol) in CH₂Cl₂ (0.1 mL) was added at this temperature. The reaction mixture was stirred for 60 hours at 0⁰C and washed with 10% aqueous solution Of KHSO₄, an aqueous saturated solution of NaHCO3, and aqueous saturated solution of NaCl. The combined organic layers were dried over Na₂SO₄, filtered, and evaporated. The resultant crude was purified by semipreparative HPLC (Hypersyl, isocratic CH₃CNiH₂O (85: 15), flow 7 mL/min, UV detection) to afford pure compound 4 (16 mg, 69% yield) as a white solid.

¹H NMR (CDCl₃, 300 MHz) δ: 7.55 (d, IH, J = 4.9 Hz), 7.45-7.35 (m, 2H), 7.07 (d, 2H, J = 8.5 Hz), 7.02-6.98 (m, IH), 6.84 (d, 2H, J = 8.5 Hz), 5.38 (m, IH), 5.25 (m, IH), 5.13 (m, IH), 4.80 (m, IH), 4.70 (m, IH), 4.60 (m, IH), 4.00 (m, IH), 4.15-3.80 (m, 3H), 3.79 (s, 3H), 3.79-3.45 (m, 3H), 3.35 (dd, IH, J = 3.9, 14.2 Hz), 3.18 (m, IH), 3.16 (s, 3H), 3.1 1 (s, 3H), 2.85 (m, IH), 2.75 (t, IH, J = 16.5 Hz), 2.56 (s, 3H), 2.40- 1.82 (m, 9H), 1.80- 1.61 (m, 8H), 1.34 (t, 4H, J = 6.8 Hz), 1.25 (s, 6H), 0.98- 0.82 (m, 18H). MS (ES) m/z 1039.8 [M+H]⁺, 1061.8 [M+Na]⁺.

EXAMPLE 2: SYNTHESIS OF COMPOUNDS OF THE INVENTION

Compounds 5-7 were obtained following the procedures already disclosed in WO 02/02596 and further disclosed below:

Synthesis of compound 5

SAPL4 Compound 5

To a solution of HATU (1 17 mg, 0.30 mol) and Z-D-MeAIa-OH (39 mg, 0.16 mmol) in anhydrous DMF (0.5 mL) was added a solution of SAPL4 (92 mg, 0.1 1 mmol, obtained as disclosed in WO 02/02596) in anhydrous CH2CI2 (1.5 mL) at 0⁰C. The reaction mixture was stirred for 10 minutes at 0⁰C and 4-methylmorpholine (49 μL, 0.44 mmol) was added at this temperature. The reaction mixture was warmed at 23°C and stirred overnight. The solvent was concentrated under vacuum and the precipitated obtained was dissolved in Hexane:EtOAc (1 :4, 50 mL) and washed with 10% aqueous solution Of KHSO₄, 5% aqueous solution of Na2CO3, and aqueous saturated solution of NaCl. The combined organic layers were dried over Na2SO₄, filtered, and evaporated. The resultant crude was purified by column chromatography on silica gel with Hexane: EtOAc (from 2: 1 to 1 :2) as eluent to obtain pure compound 5 (70 mg, 62% yield) as a white solid.

¹H NMR (CDCl₃, 300 MHz) δ: 7.84 (d, IH, J = 8.8 Hz), 7.36-7.23 (m, 5H), 7.06 (d, 2H, J = 8.3 Hz), 6.83 (d, 2H, J = 8.3 Hz), 5. 17 (s, IH), 4.98 (m, IH), 4.81-4.74 (m, 2H), 4.59-4.55 (m, IH), 4.02 (m, IH), 3.77 (s, 3H), 3.76-3.59 (m, 2H), 3.34 (dd, IH, J = 4. 1 , 14.3 Hz), 3.16 (dd, IH, J = 10.9, 14.0 Hz), 3.06 (m, IH), 2.94 (m, IH), 2.88 (br s, 2H), 2.78 (s, 3H), 2.53 (s, 3H), 2.47 (m, IH), 2.32 (m, IH), 2.13 (m, IH), 1.77 (m, 2H), 1.61- 1.35 (m, 5H), 1.32- 1.16 (m, HH), 0.93-0.79 (m, 18H).

¹³C NMR (CDCl₃, 75 MHz) δ: 205.1 , 172.5, 172.4, 171.5, 170.6, 170.0, 169.5, 168.6, 158.9, 130.6, 130.0, 128.8, 128.1 , 1 14.4, 81.7, 71.0, 68.1 , 67.9, 66.4, 60.6, 57.5, 55.8, 55.5, 53.6, 49.9, 49.8, 47.3, 41.3, 38.9, 34.3, 31.8, 31.4, 29.9, 28.1 , 27.2, 25.3, 25.1 , 23.9, 22.8, 21.1 , 18.8, 17.0, 15.4, 15.2, 15.0, 14.4, 14.3, 1 1.8.

MS (ES) m/z 1036.0 [M+H]⁺, 1057.9 [M+Na]⁺.

Synthesis of compound 6

Compound 6

To a solution of compound 5 (60 mg, 0.058 mmol) in i-PrOH:H2θ (2: 1 , 4.5 mL) was added Pd(OH)₂ (25.2 mg, 42% w/w) at 23°C. The reaction mixture was stirred for 24 hours at 23°C under hydrogen atmosphere, filtered over Celite^®, washed with i-PrOH and concentrated under vacuum. The residue obtained was dissolved in CH2CI2 (80 mL) over Na2SO4, filtered, and evaporated to obtain compound 6 (53 mg, quantitative) as a white solid which was used in the following step without further purification.

¹H NMR (CDCl₃, 300 MHz) δ: 8.1 1 (d, IH, J = 8.8 Hz), 7.74 (d, IH, J = 8.8 Hz), 7.37 (d, IH, J = 8.8 Hz), 7.07 (d, 2H, J = 8.3 Hz), 6.83 (d, 2H, J = 8.6 Hz), 5.16 (d, IH, J = 3.4 Hz), 5.00 (m, IH), 4.83 (dd, IH, J = 3.1 , 9.2 Hz), 4.77 (m, IH), 4.59 (m, IH), 4.12-3.97 (m, 3H), 3.78 (s, 3H), 3.70 (m, IH), 3.58 (m, IH), 3.35 (dd, IH, J = 4.4, 14.1 Hz), 3.16 (dd, IH, J = 10.7, 14.0 Hz), 3.05 (m, IH), 2.54 (s, 3H), 2.40 (s, 3H), 2.13- 1.74 (m, 6H), 1.61- 1.36 (m, 10H), 1.32- 1.21 (m, 5H), 1.17 (d, 3H, J = 6.2 Hz), 0.93-0.80 (m, 21H).

1³C NMR (CDCl₃, 75 MHz) δ: 205.4, 175.6, 172.5, 171.6, 170.7, 170.2, 169.8, 168.8, 158.9, 130.6, 130.0, 1 14.4, 81.7, 71.2, 67.8, 66.4, 59.9, 57.6, 55.7, 55.5, 55.0, 53.6, 50.0, 49.6, 47.3, 41.3, 38.9, 35.1 , 34.3, 34.2, 31.3, 28.1 , 27.2, 25.3, 25.0, 23.9, 21.1 , 18.8, 18.5, 17.0, 15.6, 15.1 , 1 1.8.

MS (ES) m/z 901.9 [M+H]⁺, 923.5 [M+Na]⁺.

Synthesis of compound 7

Compound 7 To a solution of l-(l ,2-dioxopropyl)-S-proline (48 mg, 0.26 mmol) in CH₂Cl₂ (0.4 mL) was added DIPCDI ( 19 μL, 0. 145 mmol) at 0⁰C. The reaction mixture was stirred for 1 hour at 0⁰C and a solution of compound 6 (47 mg, 0.052 mmol) in CH₂Cl₂ (0.6 mL) was added at this temperature. The reaction mixture was stirred for 60 hours at 0⁰C, diluted with CH₂Cl₂ (30 mL), and washed with 10% aqueous solution of KHSO₄ (20 mL), an aqueous saturated solution of NaHCO3 (20 mL), and aqueous saturated solution of NaCl (20 mL) . The combined organic layers were dried over Na₂SO₄, filtered, and evaporated. The resultant crude was purified by semipreparative HPLC (Hypersyl, isocratic CH₃CNiH₂O (85: 15), flow 7 mL/min, UV detection) to afford pure compound 7 (40 mg, 72% yield) as a white solid. ¹H NMR (CDCl₃, 300 MHz) δ: 7.85 (d, IH, J = 9.0 Hz), 7.79 (d, IH, J = 9.0 Hz), 7.64 (d, IH, J = 6.3 Hz), 7.21 (m, IH), 7.07 (d, 2H, J = 8.5 Hz), 6.84 (d, 2H, J = 8.4 Hz), 5.43 (m, IH), 5.30 (m, 2H), 5.17 (m, 3H), 5.05 (m, IH), 4.79 (m, IH), 4.69 (m, IH), 4.60 (m, IH), 4.20 (m, IH), 4.09 (m, IH), 3.88-3.68 (m, 3H), 3.79 (s, 3H), 3.58 (m, IH), 3.35 (dd, IH, J = 3.9, 13.8 Hz), 3.20 (m, IH), 3.17 (s, 3H), 3.12 (s, 3H), 2.56 (s, 3H), 2.37 (m, IH), 2.13- 1.76 (m, 9H), 1.60- 1.17 (m, 1 1H), 1.14 (d, 6H, J = 6.3 Hz), 0.96-0.84 (m, 18H).

MS (ES) m/z 1068.4 [M+H]⁺, 1090.3 [M+Na]⁺, 1 106.2 [M+K]⁺. EXAMPLE 3: SYNTHESIS OF COMPOUNDS OF THE INVENTION

The following compounds were additionally obtained in accordance with the procedures disclosed in WO 02/02596 and further disclosed in the previous examples:

Compound 8

¹H NMR (CDCl₃, 300 MHz) δ: 8.56 (d, IH, J= 6.7 Hz), 7.92 (d, IH, J =

9.6 Hz), 7.68 (d, IH, J= 8.8 Hz), 7.32 (m, IH), 7.08 (d, 2H, J= 8.7 Hz), 6.84 (d, 2H, J= 8.6 Hz), 6.54 (d, IH, J= 9.1 Hz), 5.22 (m, 2H), 5.07 (m,

IH), 4.88-4.75 (m, 2H), 4.58 (m, IH), 4.12-3.58 (m, 5H), 3.79 (s, 3H),

3.38 (m, IH), 3.18 (m, IH), 2.95 (s, 3H), 2.72 (s, 3H), 2.55 (s, 3H), 2.40

(d, 3H, J= 11.4 Hz), 2.35 (m, IH), 2.37-1.46 (m, 14H), 1.41 (d, 3H, J =

6.2 Hz), 1.35 (d, 3H, J= 6.8 Hz), 1.32-1.19 (m, 10H), 1.14 (d, 6H, J = 6.5 Hz), 0.99-0.82 (m, 18H).

MS (ES) m/z 1111.0 [M+H]⁺, 1133.0 [M+Na]⁺.

¹H NMR (CDCl₃, 300 MHz) δ: 7.91 (br s, IH), 7.73 (d, IH, J= 9.4 Hz), 7.21-7.18 (m, 5H), 7.10 (d, 2H, J= 8.7 Hz), 6.91 (br s, IH), 6.85 (d, 2H, J = 8.6 Hz), 5.60 (m, IH), 5.32 (m, 2H), 5.17 (d, IH, J = 3.4 Hz), 4.83- 4.54 (m, 4H), 4.42 (m IH), 4.26 (q, IH, J = 7.1 Hz), 4.06 (m, IH), 3.81 (s, 3H), 3.71 (m, IH), 3.60 (m, IH), 3.43 (m, IH), 3.31-3.14 (m, 2H), 3.10 (s, 3H), 2.99 (d, IH, J = 7.5 Hz), 2.61 (m, IH), 2.53 (s, 3H), 2.34 (m, IH), 2.19- 1.98 (m, 12H), 1.83- 1.76 (m, 6H), 1.64 (s, 3H), 1.34 (s, 9H), 1.30 (d, 3H, J = 6.8 Hz), 1.21 (d, 3H, J = 6.1 Hz), 1.12 (d, 3H, J = 7.3 Hz), 0.92-0.83 (m, 18H).

MS (ES) m/z 1358.6 [M+H]⁺, 1380.5 [M+Na]⁺.

Compound 10

¹H NMR (CDCl₃, 300 MHz) δ: 7.94-7.80 (m, 3H) , 7.58-7.48 (m, 2H), 7.41-7.37 (m, 3H), 7.09 (d, 2H, J = 8.5 Hz), 6.84 (d, 2H, J = 8.5 Hz), 5.30 (m, IH), 5.14 (m, IH), 4.98-4.90 (m, IH), 4.95 (d, IH, J = 6.2 Hz), 4.60 (m, IH), 4.53 (m, IH), 3.98-3.85 (m, 2H), 3.79 (s, 3H), 3.69-3.58 (m, 2H), 3.37 (dd, IH, J = 4.4, 14.3 Hz), 3.16 (m, IH), 2.90 (d, IH, J = 16.6 Hz), 2.84 (s, 3H), 2.58 (s, 3H), 2.26-2.03 (m, 8H), 1.91 (m, 2H), 1.79- 1.49 (m, 6H), 1.32 (d, 3H, J = 6.2 Hz), 1.02-0.87 (m, 24H).

MS (ES) m/z 1047.7 [M+H]⁺, 1069.6 [M+Na]⁺.

Compound 11

¹H NMR (CDCl₃, 300 MHz) δ: 7.74 (d, 2H, J = 8.3 Hz), 7.67 (d, IH, J = 10.2 Hz), 7.48 (d, IH, J= 9.4 Hz), 7.37 (d, 2H, J= 8.0 Hz), 7.08 (d, 2H, J= 8.8 Hz), 6.84 (d, 2H, J= 8.5 Hz), 6.47 (d, IH, J= 8.3 Hz), 4.96 (d, IH, J= 5.1 Hz), 4.85 (m, 2H), 4.59 (dd, IH, J= 4.3, 7.9 Hz), 4.51 (dd, IH, J= 5.4, 9.3 Hz), 4.39 (dd, IH, J= 2.9, 8.3 Hz), 3.97 (dt, IH, J= 3.9, 9.6 Hz), 3.86 (IH, t, IH, J = 7.8 Hz), 3.79 (s, 3H), 3.76-3.62 (m, 2H), 3.58 (dd, IH, J= 4.4, 10.6 Hz), 3.58 (dd, IH, J= 4.4, 14.2 Hz), 3.14 (dd, IH, J= 10.6, 14.3 Hz), 2.93 (dd, IH, J= 1.8, 17.1 Hz), 2.80 (s, 3H), 2.56 (s, 3H), 2.46 (s, 3H), 3.37 (dd, IH, J= 7.8, 16.9 Hz), 2.22-2.00 (m, 6H), 1.91 (m, 2H), 1.79-1.67 (m, 1OH), 1.50-1.30 (m, 6H), 1.24-1.09 (m, 4H), 1.05 (d, 3H, J= 6.5 Hz), 0.99 (d, 6H, J=7.0 Hz), 0.96-0.88 (m, 15H). MS (ES) m/z 1041.3 [M+H]⁺, 1063.4 [M+Na]⁺. EXAMPLE 4

Following the procedures described in WO 02/02596 and in the specification, and further disclosed in the previous examples, the following compounds are obtainable:

EXAMPLE 5

Following the procedures described in WO 02 / 02596 and in the specification, and further disclosed in the previous examples, the following compounds are obtainable:

EXAMPLE 6: BIOASSAYS FOR THE DETECTION O F ANTI-HIV ACTIVITY The aim of these assays was to evaluate the anti-HIV activity and the mechanism of action of the compounds of the invention. a. MTT and gag-p24 detection assays

MTT assay was performed as described by Pauwels et al. (J. Virol. Methods. 1988, 20, 309-321). Briefly, 10⁴ MT-2 cells infected with 100

TCID50 of HIV- I NL4.3 wild type were seeded in 96 microwell plates with 1 00 μl of culture medium (RPMI+ 10%FCS) and different concentrations of the compounds to be tested were added. After 7 days, cell viability was measured by adding the MTT reagent. Briefly, 20 μl of MTT solution (7.5 mg/ml in PBS) were added to each well and left in culture for 1 hour (37°C, 5% C O₂) . Afterwards, 150 μl of culture supernatant were carefully removed avoiding cell disturbance. Formazan crystals were produced and dissolved by adding 100 μl Triton X- 100 al 10% (V/ V) in acidified isopropanol (0.04 M HCl isopropanol). The viability was then measured in a UV spectrometer microplate reader.

The antiviral assay based in the p24-gag protein determination lead us to evaluate the exact amount of viral proteins in the supernatants produced by the infection. To that end, the assay was performed as MTT assay, but measurement of p24-gag protein in the culture infected supernantants was performed following the manufacturer instructions (InnotestTM HIVAg mAb, Innogenetics). b. Recombinant virus assay (antiviral activity)

The recombinant virus assay was performed in both, MT-2 cells and PBMCs previously activated with PHA + IL-2. Cells were infected with supernatants obtained from 293t cells transfected with full-length infectious HIV- I plasmids pNL4.3-Luc (X4 tropic virus), pNL4.3-Renilla (X4 tropic virus able to develop more than one round of replication), pNL4.3-Δenv-Luc plus pVSV-env (HIV pseudotyped with the G protein of VSV) or pJR-Renilla (R5 tropic virus able to develop more than one round of replication). Resistant viruses were obtained cloning in NL4.3- Renilla the pol gene of viruses from different infected donors. Virus 9D carry the following mutations:

41L,67N,70R,98G, 1 18I, 184V,215F,219Q,74I and virus 4D: K65R, K70R, V75I, F77L, F1 16Y, Q 151 M, M 1841, Ll OI. The assay was then performed in 96 well microplates seeded with 100 μl containing 250.000 (PBMCs) or 100.000 (MT-2) cells/ well. The compounds to be tested were added to the culture in concentrations ranging from 50 to 0.0016 μg/ml (100 μl/well) . Finally, cell culture was infected with supernatants obtained form transfection of the different plasmids described above. After 48 hours, cell culture supernatant was removed and cells were lysed with Luciferase assay system or Renilla assay system (both from Promega) following the specifications of the manufacturer, and the luciferase-renilla activity was measured in a luminometre (Berthold Detection systems). All the experiments were controlled with cells treated with the vehicle (DMSO) and non-treated cells.

HIV- I replication inhibition was evaluated by measuring the reduction of luciferase-renilla activity or RLUs (Relative light units) in a luminometre, being the 100% the infection of non-treated cells. c. Toxicity evaluation

MTT assay is per se a toxicity evaluation method. Thus, for recombinant virus assay an alternative method must be used. Therefore, toxicity was measured by treating non infected cells with the tested compounds in the same concentrations and conditions described above for antiviral assays. To that end, MT-2 and PBMCs were treated with the compounds, and 48 hours later culture supernatant was removed and cells were subjected to two different methods:

1. Propidium iodide addition ( 1 μg/ml) and analysis by flow cytometry.

2. CellTiter GIo reagent addition and RLUs quantification in a luminometre.

In both methods, cells treated with the vehicle (DMSO) and non-treated cells (100% viability) were used as controls.

Inhibitory Concentration 50 (IC50), Cytotoxic Concentration 50 (CC50) and specificity index (SI) were calculated for each compound using GraphPad software, non linear regression fit and sigmoidal dose- response curves. d. Retrotranscriptase activity

Retrotranscriptase (RT) activity is a potential target for compounds with antiviral activity, since this enzyme is characteristic for the Retroviridae family. To evaluate the activity on RT of the compounds of the invention, thymidine incorporation method was used. To that end, 10 μl/well of mix 1 (Triton X- 100 0.5%, KCl 0.5 M and DTT 125 mM) were added to a 96 microplate. Afterwards, 50 μl of viral supernatants, the compounds to be tested at active concentrations and 40 μl of mix 2 (EGTA 5 mM in Tris HCl 0.5M pH 7.8, MgCl₂ 0.5M, Metil ³H Thymidine 5' triphosphate and Poly(rA).p(dT)) were added to the microplate and left in culture for 1 hour at 37°C. Afterwards, reaction was stopped with 20 μl of Na₂P₂O? 120 mM in TCA 60% and the mixture was incubated at 4°C for 15 minutes. Then, the mixture was filtered with TCA 5% and results were obtained in a β-counter. e. Viral DNA quantification

One way to evaluate the first steps of the infectious cycle is the quantification of viral DNA by real time PCR. Thus, preactivated PBMCs were infected with a wild type HIV (NL4.3) in the presence or absence of the compounds to be tested (at a concentration of 100 nM) or zidovudine (at a concentration of 1 μM) for 24 hours. Afterwards, cells were lysed and genomic DNA was extracted with Qiagen DNA Blood minikit (Qiagen). Real time PCR was then performed with SYBR Green PCR Master Mix (Applied Biosystem) following the recommendations of the manufacturer in an ABI Prism7000 (Applied Biosystem). DNA amplification was performed with specific primers for a LTR-gag fragment of the viral genome: R/U5 (forward), 5^'-GGC TAA CTA GGG AAC CCA CTG-3^' and LTR/gag (reverse), 5^'-CCT GCC TCG AGA GAG CTG CTC TGG-3^'. β-actin amplification was used as control. f . Transcriptional activity

Transcription should be one of the more important targets for antiretroviral therapy, since viral latency is a crucial fact that lead to the establishment of the chronic infection. Thus, PBMCs resting were transfected in an Equibio electroporator with a luciferase construct under the control of the complete HIV proviral genome (NL4.3-Luc). Briefly, 5O 10⁶ of PBMCs were transfected with 50 μg of pNL4.3-Luc, and left in culture in the presence or absence of the compounds to be tested during different times (at a concentration of 100 nM). Afterwards, luciferase activity was measured in lysed cells.

CD69 expression was measured in PBMCs resting treated with the compounds for 18 hours. Afterwards, cells were subjected to single- colour immunophenotyping and analyzed with a FACScalibur flow cytometer (Becton Dickinson, Belgium). Background staining was assessed with the appropriate isotype- and fluorochrome-matched control mAb and subtracted. Results are shown as percentage of cells expressing the receptor. g. Results

The recombinant virus assay was performed by measuring luciferase activity in infected cells. To rule out non specific inhibition of luciferase activity, a previous assay in HeLa-Tet-On-Luc cell line was performed with all compounds to be tested. In this cell line, luciferase activity was expressed by treating the culture with doxicyclin, switching on the Tet On system (Table 1).

Table 1. Luciferase specificity assay on HeLa-Tet-On-Luc cells

ND: Not determined

Six compounds showed non specific inhibition of luciferase activity at 50 μM. However, when lower concentrations were used, three of them (compounds 3, 7 and 8) were specific at 10 μM and compounds 9, 10 and 1 1 were specific at 1 μM.

All of them were subjected to antiviral evaluation in MT-2 cells with increasing concentrations ranking from 0 to 50 μM. Results are shown in Table 2.

Table 2. Antiviral activity of the compounds in MT-2 cells infected with NL4.3-LUC.

All the compounds were active in the recombinant virus assay. Eight compounds (compounds 3, 5, 6, 7, 8, 9, 10 and 1 1) showed a specificity index greater than 10, and thus were selected for further research. Compounds 9, 10 and 1 1 were the most potent as antiviral agents, and, although toxicity values were also high, specificity index was greater than 10.

When tested in PBMCs, as shown in Table 3, the profile of antiviral activity was very positive. Indeed, five compounds (compounds 3, 8, 9, 10, and 1 1) displayed stronger antiviral activity (nanomolar range) on HIV-infected PBMCs than in MT-2 cells. Compound 1 did not show antiviral activity in PBMCs infections while in MT-2 cells infections it did. Compounds 5 and 6 were active in MT-2 cells infections, but they were less potent in PBMCs. Compounds 3 and 8 inhibited viral replication in both MT-2 cells and PBMCs, although specificity index was lower in PBMCs. In addition, compounds 9 and 10 were less potent in MT-2 cells (IC50 values higher) and, which is more interesting, less toxic in PBMCs. In fact, these two compounds have better profiles in PBMCs, with specificity index of 6907 (compound 10) and 31825 (compound 9).

Table 3. Anti-HIV activity of the compounds in PBMCs infected with NL4.3-LUC.

NR: Not reached

In conclusion, these compounds display strong potency as inhibitors of the viral cycle. Eight compounds in MT-2 cells and six compounds in PBMCs were active with SI greater than 10. Five compounds (compounds 3, 8, 9, 10 and 1 1) were selected for further investigations.

Compound 3 (Figure IA and IB) showed antiviral activity in both MT-2 cells and PBMCs (ICso 1.39 μM and 0. 16 μM, respectively). This compound was more toxic in PBMCs, as shown in Figure 1. Toxic concentrations were not reached at 57.3 μM in MT-2 cells, while in PBMCS CC50 value was about 27 μM.

Compound 8 (Figure 2A and 2B) showed also antiviral activity in both MT-2 cells and PBMCs. Although at concentrations of 50 μM it was nonspecific, at 10 μM it was specific, with an IC50 value 100 fold lower.

Compounds 9 (Figure 3A and 3B), 10 (Figure 4A and 4B), and 1 1 (Figure 5A and 5B) were the most potent compounds of all tested compounds. Compounds 9, 10, and 1 1 showed IC50S values in the nanomolar range in PBMCs (0.63, 0.86, and 69.4 nM, respectively), and they are among the most potent of the antiviral compounds in vitro existing in the literature. Compound 9 is specially interesting, with a specificity index greater than 31800.

To corroborate the antiviral activity showed in the recombinant virus assay, MT-2 cells were infected with a wild type HIV (NL4.3) in the presence or absence of compounds 9, 10 and 1 1. After 7 days, MTT was added to the culture and viability evaluated in a microplate UV- Vis reader or by p24-gag viral protein measurement in culture supernants. In Figure 6, it is represented the inhibition of p24-gag protein in culture supernatants.

Antiviral activity of these compounds was confirmed with active concentrations ranging the nanomolar scale. In Figure 7 it is represented the MTT classic assay. In MTT assay, the antiviral activity of the compounds was not showed as clear as in the other assays. This fact could be explained since the potential toxicity of the compounds would be greater after 7 days of treatment. Moreover, HIV in the MTT assay could escape from the antiviral activity, since degradation of compounds is more probable when cultures are treated for such long periods of time. However, an incipient antiviral activity is showed with the treatment at concentrations of 1 or 10 nM.

Once it was clearly established that the compounds of the invention were potent inhibitors of HIV infection, it was important to determine exactly the step of the viral cycle interfered by these compounds. With this aim, the antiviral activity of the compounds was also tested in infections performed with recombinant viruses displaying different tropism. Therefore, active concentrations of compounds were tested against infection produced by X4, R5 or VSV pseudotyped HIV that enters host cells by a receptor independent mechanism. The results of this assay are shown in Table 4 and Figure 8.

Table 4. Results of antiviral assays in MT-2 cells or PBMCs infected with X4 (NL4.3-Renilla), R5 (JR Renilla) or VSV pseudotyped HIV (NL4.3Delta-env-VSV-Luc).

The results show the degree of inhibition of the replication of X4, R5 and VSV pseudotyped in both MT-2 cells and PBMCs exerted by the three compounds, which is of similar potency, suggesting that the target of the compounds of the invention is not the viral entry. Note that MT-2 cells lack of CCR5 receptor so it cannot became infected with an R 5 tropic virus.

The next step was to evaluate the activity of compounds on the viral retro transcription. For this purpose, an enzimatic assay was performed wherein the supernatants containing HIV retrotranscriptase were treated with the compounds of the invention and triphosphate thymidine incorporation was measured. As shown in Figure 9, none of the tested compounds was able to inhibit the retrotranscriptase activity.

To corroborate these results, viral DNA was directly quantified in cell lysates by real time PCR. To that end, wild type HIV (NL4.3) infected PBMCs were treated with active concentrations of the compounds of the invention for 18 hours. Afterwards, cells were lysed and genomic DNA extracted and subjected to a real time PCR. Surprisingly, the three tested compounds were able to decrease the amount of viral DNA (Figure 10), suggesting that the activity of these compounds could be related to a target subsequent to the viral entry but previous to the retro transcription and/ or integration, without having any direct effect on the reverse transcriptase.

Although the main target of the compounds of the invention seems to be prior to integration, the activity on retrotranscription was studied by transfection of a luciferase construct under the control of the complete

HIV genome (NL4.3-Luc) and treating the cultures at different times post- transfection. As shown in Figure 11, there were no important modifications of transcripcional activity when treated with the compounds of the invention, while with PMA a 5 fold increase on luciferase activity was obtained. Moreover, aplidine used as control showed a surprising inhibitory effect.

Since the effect of the compounds of the invention could be related to the time of exposure to the treatment, transcriptional activity was evaluated at different times. The data shown in Figure 12 seem to corroborate the lack of activity of the compounds of the invention on viral transcription. Aplidine was able to inhibit HIV transcription at 16 hours of treatment. These effects were corroborated when expression of a typical marker of activation in lymphocytes (CD69) was measured after treatment with the compounds (Figure 13).

Lastly, the activity of these compounds was also evaluated in HIV carrying different patterns of resistances. Recombinant viruses carrying resistances to NRTIs or with multiresistance complex were used to infect PBMCs as compared to a standard (NL4.3-Renilla). As shown in Table 5 and Figure 14, the activity of the compounds was similar in all the viruses tested. In addition, it was confirmed that the compounds of the invention do not target HIV RT. Protease activity can also be discarded, since potency of the three compounds on resistant viruses to nelfinavir (4D) was also similar. Moreover, the activity of these compounds in infections with viruses able to develop one single round of replication (NL4.3-Luc) suggests that their target should be previous to transcription.

Table 5. Antiviral activity (IC50 (nM)) of the compounds in PBMCs infected with recombinant viruses carrying NRTIs resistances (9D) or multiresistance complex (4D) or wild type (NL4.3-Renilla)

Claims

1. A compound of general formula I

(I) wherein X is selected from O and NH;

Y is selected from CO and -COCH(CH₃)CO-; each n and p is independently selected from 0 and 1 , and q is selected from 0, 1 and 2; each Ri, R3, R5, R9, Rn, and R15 is independently selected from hydrogen, substituted or unsubstituted Ci-Cβ alkyl, substituted or unsubstituted C2-C6 alkenyl, and substituted or unsubstituted C2-C6 alkynyl;

R2 is selected from hydrogen , CORa, COOR_a, substituted or unsubstituted Ci-Cβ alkyl, substituted or unsubstituted C2-C6 alkenyl, and substituted or unsubstituted C2-C6 alkynyl; each R₄, Re, Rio, R12, and R16 is independently selected from hydrogen and substituted or unsubstituted Ci-Cβ alkyl; each R₇ and R13 is independently selected from hydrogen, substituted or unsubstituted C₁-CO alkyl, substituted or unsubstituted C2-C6 alkenyl, and substituted or unsubstituted C2-C6 alkynyl; each Re and Ri4 is independently selected from hydrogen and substituted or unsubstituted C₁-CO alkyl; or Re and R₇ and/or R13 and R14 together with the corresponding N atom and C atom to which they are attached may form a substituted or unsubstituted heterocyclic group;

Ri₇ is selected from hydrogen, COR_a, COORa, CONHRb, COSRc, (C=NRb)ORa, (C=NRb)NHRb, (C=NR_b)SR_c, (C=S)ORa, (C=S)NHRb, (C=S)SRc,

SO2RC, SOβRc, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group, with the proviso that when n, p, and q are 0 then Ri₇ is not hydrogen; and each R_a, Rb, and R_c is independently selected from hydrogen, substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C2-C12 alkenyl, substituted or unsubstituted C2-C12 alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group; or a pharmaceutically acceptable salt or stereoisomer thereof, for use in the treatment of HIV infections, AIDS or ARC.

2. A compound according to claim 1 , wherein R3 and R₄ are independently selected from hydrogen and substituted or unsubstituted Ci-C₆ alkyl.

3. A compound according to claim 2, wherein R3 is isopropyl and R₄ is hydrogen.

4. A compound according to claim 2, wherein R3 and R₄ are methyl.

5. A compound of general formula II

wherein X, Y, n, p, q, R_a, Rb, Rc, Ri, R2, and R5-R17 are as defined in claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof.

6. A compound according to any preceding claim, wherein Rn is selected from hydrogen and substituted or unsubstituted C₁-CO alkyl.

7. A compound according to claim 6, wherein Rn is methyl or isobutyl.

8. A compound of general formula III

(III) wherein X, Y, p, q, R_a, Rb, Rc, Ri-Rio and R12-R17 are as defined in claim 1 , or a pharmaceutically acceptable salt or stereoisomer thereof, with the exception of the compound with the following structure:

9. A compound according to claim 8, wherein R3 and R₄ are independently selected from hydrogen and substituted or unsubstituted Ci-C₆ alkyl.

10. A compound according to claim 9, wherein R3 is isopropyl and R₄ is hydrogen.

1 1. A compound according to any preceding claim, wherein Ri, R5, R9, and Ri5 are independently selected from hydrogen and substituted or unsubstituted C₁-CO alkyl.

12. A compound according to claim 1 1 , wherein Ri is selected from sec-butyl and isopropyl, Rs is isobutyl, Rg is p-methoxybenzyl, and R15 is selected from methyl and benzyl.

13. A compound according to any preceding claim, wherein Re, Rio, Ri2, and Riβ are independently selected from hydrogen and substituted or unsubstituted C₁-CO alkyl.

14. A compound according to claim 13, wherein Re, Rio and R12 are methyl, and R16 is hydrogen.

15. A compound according to any preceding claim, wherein Re and Ri4 are independently selected from hydrogen and substituted or unsubstituted C₁-CO alkyl.

16. A compound according to claim 15, wherein Re is selected from hydrogen and methyl, and R14 is hydrogen.

17. A compound according to any preceding claim, wherein R₇ and Ri3 are independently selected from hydrogen and substituted or unsubstituted C₁-CO alkyl.

18. A compound according to claim 17, wherein R₇ is methyl and Ri 3 is selected from hydrogen, methyl, isopropyl, isobutyl, and 3-amino-3- oxopropyl.

19. A compound according to any of claims 1 to 14, wherein Re and R₇ and/ or R13 and Ri₄ together with the corresponding N atom and C atom to which they are attached form a substituted or unsubstituted pyrrolidine group.

20. A compound according to any preceding claim, wherein R2 is selected from hydrogen, substituted or unsubstituted C₁-CO alkyl, and CORa, and wherein R_a is a substituted or unsubstituted C₁-CO alkyl.

21. A compound according to claim 20, wherein R2 is hydrogen.

22. A compound according to any preceding claim, wherein R17 is selected from hydrogen, COR_a, COORa, CONHRb, (C=S)NHRb, and

SO2RC, and wherein each R_a, Rb, and R_c is independently selected from substituted or unsubstituted C ₁-CO alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic group.

23. A compound according to claim 22, wherein R17 is selected from hydrogen, COObenzyl, CObenzo[b]thiophen-2-yl, Sθ2(p-methylphenyl), COCOCH₃ and COOC(CHa)₃.

24. A compound according to any preceding claim, wherein X is NH.

25. A compound according to any of claims 1 to 23, wherein X is O.

26. A compound according to any preceding claim wherein Y is CO.

27. A compound according to any of claims 1 to 25, wherein Y is - COCH(CH₃)CO-.

28. A compound according to claim 1 having the following structure:

or pharmaceutically acceptable salts or stereoisomers thereof.

29. A compound having the following structure:

or pharmaceutically acceptable salts or stereoisomers thereof.

30. A pharmaceutical composition comprising a compound according to claim 5, 8 or 29, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier.

31. A compound according to claim 5, 8 or 29, or a pharmaceutically acceptable salt or stereoisomer thereof, for use as a medicament.

32. A pharmaceutical composition comprising a compound as defined in any of claims 1 to 29, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier, for use in the treatment of HIV infections, AIDS or ARC.

33. Use of a compound as defined in to any of claims 1 to 29, or a pharmaceutically acceptable salt or stereoisomer thereof, in the manufacture of a medicament for the treatment of HIV infections, AIDS or ARC.

34. A method of treating any mammal, notably a human, affected by an HIV infection, AIDS or ARC, which comprises administering to the affected individual a therapeutically effective amount of a compound as defined in any of claims 1 to 29, or a pharmaceutically acceptable salt or stereoisomer thereof.