WO2005105843A2

WO2005105843A2 - Hiv protease inhibitors

Info

Publication number: WO2005105843A2
Application number: PCT/DK2005/000296
Authority: WO
Inventors: Christian Eeg Jensen; Jon Bondebjerg; Lars Naerum
Original assignee: Arpida A/S
Priority date: 2004-04-30
Filing date: 2005-04-29
Publication date: 2005-11-10
Also published as: WO2005105843A3

Abstract

Phosphinate compounds of general formula (I) or pharmaceutically acceptable salts or esters thereof, that are capable of potently inhibiting proteases such as, e.g., metallo proteases or aspartate proteases, especially HIV protease including HIV-1 proteases. A compound of the invention is therefore useful as an active substance in the treatment of HIV related diseases such as AIDS.

Description

HIV PROTEASE INHIBITORS

The present invention relates to novel chemical compounds useful as protease inhibitors or prodrugs thereof, a process for their manufacture, pharmaceutical compositions comprising these compounds and their use in medicine and therapy. More specifically, the invention relates to phophinate compounds useful as inhibitors of protease, even more specifically aspartic proteases or metallo proteases, especially HIV-1 protease which is an essential enzyme in the replication of Human Immunodeficiency Virus (HIV).

BACKGROUND OF THE INVENTION

HIV (human immunodeficiency virus) infection remains a major medical problem.

According to estimates from the Joint United Nations programme on HIV/AIDS (UNAIDS) and the World Health Organization (WHO), 37 million adults (men and women aged 15-49) and 2.5 million children were living with HIV at the end of 2003.

This is more than 50% higher than the figures projected by WHO in 1991. During 2003, some 5 million people became infected with the human immunodeficiency virus (HIV), which causes AIDS. The year also saw 3 million deaths from HIV/AIDS - a high global total, despite antiretroviral therapy, which reduced AIDS and AIDS related deaths in thedeveloped countries.

An increasingly important type of antiretroviral drugs is the group of Protease Inhibitors (Pis), which were first approved in 1995. The protease is a member of the aspartic protease family and is required for viral maturation by processing of the polyprotein precursors into active forms, thus making the protease an attractive target for antiviral therapy. Currently available drugs for the treatment of HIV include a number of Pis: Amprenavir, Indinavir, Lopinavir, Ritonavir, Saquinavir, Nelfinavir, Atazanavir and Tipranavir. Current clinical practice is to use Pis in combination therapy, typically with reverse transcriptase (RT) inhibitors. However, a major increasing therapeutic problem is the emergence of drug resistant viral strains.

The emergence of resistant virus can be attributed to errors induced by the HIV reverse transcriptase, in conjunction with a high viral replication rate. It is likely that mutations that lead to resistant virus occur spontaneously but remains undetectable until initiation of therapy leads to a selective pressure for the emergence of virus with replicative advantage over the wildtype population. Accumulation of mutations that lead to a reduction in inhibitor binding while maintaing sufficient substrate turnover can lead to drug resistance. Although the onset of drug resistance can be delayed to some extent by the use of combination therapy, there remains a need for more effective HIV protease inhibitors (Pis) that retain activity against Pl-resistant and multi-PI resistant viral strains.

The object of the present invention is, accordingly, to provide novel compounds, which are potent inhibitors of HIV protease and are efficacious in the treatment of HIV related diseases. Thus, compounds of this invention may be capable of inhibiting the replication of viral strains resistant to commonly used Pis. Further objects will become apparent from the following description.

SUMMARY OF THE INVENTION

The present invention relates to compounds of the general formula (I)

or a pharmaceutically acceptable salt or ester thereof, wherein one of R-i and R₂ is hydrogen and the other is R_y, -COR_y, -COOR_y, -CONR_y or -SO₂R_y, in which R_y is selected from the group consisting of Cι_₆alkyl, C₂.₆alkenyl, C₃.

₁₀cycloalkyl, C₃.₇heterocycloalkyl, aryl, heteroaryl, biaryl, C-i-salkyl-aryl, Cι-₅alkyl- heteroaryl, aryl-C-i-salkyl, heteroaryl-C^alkyl, C^alkyl-Cs-_T-cycloalkyl, and C^alky!-^- ₇heterocycloalkyl, optionally substituted with one or two substituents selected from the group consisting of halogen, hydroxy, C^alkyl, C^alkoxy, amino, cyano, thioC-i-e-alkyl, trifluoromethyl, trifluoromethylthio and phenyl;

R₃ is selected from Ci-salkyl-aryl, C^salkyl-heteroaryl, Cι-₅alkyl-biaryl, C.,-₅alkyl-C₃- cycloalkyl and Ci-salkyl-Cs-_T-heterocycloalkyl, optionally substituted with one or two substituents selected from the group consisting of halogen, hydroxy, Cι-₅alkyl, d-

₃alkoxy, amino, cyano, thioCι-₆-alkyl, trifluoromethyl, trifluoromethylthio and phenyl;

R₄ is hydrogen or Ci-₆-alkyl; R₅ is selected from hydrogen, C^alkyl, C₂-₆alkenyl, C₃-₇cycloalkyl, C₃-₇heterocycloalkyl, Ci-_δalkyl-Cs-_T-cycloalkyl, C-ι-5alkyl-C₃.₇heterocycloalkyl, C-i-₅alkyl-aryl, Ci-salkyl-heteroaryl, Cι-₅alkyl-biaryl, C₂.₆alkenyl-aryl, C₂.₆alkenyl-heteroaryl, and a side chain of a natural amino acid, optionally - if R₃ is different from hydrogen and a side chain of a natural amino acid - substituted with one or two substituents selected from the group consisting of halogen, hydroxy, C^alkyl, C^alkoxy, amino, cyano, thioC-i-e-alkyl, trifluoromethyl, trifluoromethylthio and phenyl;

R₇ is selected from hydrogen, C₂-₆alkenyl, C^alkyl-aryl, Cι.₅alkyl-heteroaryl, C^alkyl- biaryl,

C₂-₆alkenyl-aryl, C₂- ₆alkenyl-heteroaryl, C₂.₆alkenyl-biaryl, and a side chain of a natural amino acid, optionally - if R₃ is different from hydrogen and a side chain of a natural amino acid - substituted with one or two substituents selected from the group consisting of halogen, hydroxy, C^alkyl, C^alkoxy, amino, cyano, thioCi-β-alkyl, trifluoromethyl, trifluoromethylthio and phenyl;

R₈ is selected from hydroxy, methoxy, ethoxy, propoxy, amino, hydrazine, aminohydroxyl, aminoaryl, aminoheteroaryl, amino-C^-alkyl, C^alkyl-aryl, and C-i- ₅alkyl-heteroaryl.

Further objects of the present invention will become apparent from the following description.

The compounds provided by the present invention are, in particular, useful in combating HIV disease states such as AIDS.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

The terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either both of those included limits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described.

It must be noted that as used herein and in the appended claims, the singular forms "a," "and" and "the" include plural references unless the context clearly dictates otherwise.

The term "human immunodeficiency virus" or "HIV" as used herein is intended to mean a human retrovirus causing AIDS. HIV may be either type 1 (HIV-1 ) or type 2 (HIV-2). HIV-1 is found in relative abundance throughout the world and is responsible for the global HIV pandemic, whereas the geographic distribution of HIV-2 is much more limited. HIV-2 is found primarily in West Africa and several other African countries. In all regions, the proportion of HIV-1 infections is considerably larger than that of HIV-2 infections.

The term "treatment" is defined as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of a compound of the present invention to prevent the onset of the symptoms or the complications, or alleviating the symptoms or the complications, or eliminating the disease, condition, or disorder.

In the method of the present invention, the term "antiviral effective amount" means the total amount of each active component of the method that is sufficient to show a meaningful patient benefit, i.e., healing of acute conditions characterized by inhibition of the HIV infection. When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously. The terms "treat, treating, treatment" as used herein and in the claims means preventing or ameliorating diseases associated with HIV infection.

As used herein, alone or in combination, the term "Cι-₆ alkyl" denotes a straight or branched, saturated hydrocarbon chain having from one to six carbon atoms. C^ alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, 2-methyl butyl, 1-methylbutyl, n-hexyl, iso-hexyl, 3-methylpentyl, neopentyl, 3,3-dimethylbutyl and the like. It is to be understood that the term includes unsubstituted or substituted C-ι-₆ alkyl.

As used herein, alone or in combination, the term "C₂-₆ alkenyl" denotes a straight or branched, unsaturated hydrocarbon chain having from two to six carbon atoms and at least one double bond. C₂-₆ alkenyl groups include, but are not limited to, vinyl, 1- propenyl, allyl, iso-propenyl, n-butenyl, n-pentenyl, n-hexenyl and the like. It is to be understood that the term includes unsubstituted or substituted C₂.₆ alkenyl.

The term "C-ι-₃ alkoxy" or "C^ alkoxy" in the present context designates a group -O-Ci-s alkyl or -O-C^ alkyl used alone or in combination, wherein Cι-₃ alkyl and d-₆ alkyl are as defined above. Examples of linear alkoxy groups are methoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy. Examples of branched alkoxy are iso-propoxy, sec- butoxy, tert-butoxy, iso-pentoxy and iso-hexoxy.

The term "thiod-₆-alkyl" in the present context designates a group

wherein C-i-e-alkyl is as defined above. Representative examples include, but are not limited to, methylthio, ethylthio, n-propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, n-pentylthio, isopentylthio, neopentylthio, tert-pentylthio, n-hexylthio, isohexylthio and the like.

The term "C₃.₁₀ cycloalkyl" as used herein denotes a radical of one or more saturated mono-, bi-, tri- or spirocyclic hydrocarbon having from three to ten carbon atoms. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclo[3.2.1]octyl, spiro[4.5]decyl, norpinyl, norbonyl, norcaryl, adamantyl and the like. It is to be understood that the term includes unsubstituted or substituted C₃.₁₀ cycloalkyl. The term "C₃-₇ heterocycloalkyl" as used herein denotes a radical of a totally saturated heterocycle like a cyclic hydrocarbon containing one or more heteroatoms selected from nitrogen, oxygen and sulphur independently in the cycle. Examples of heterocycles include, but are not limited to, pyrrolidine (1-pyrrolidine, 2-pyrrolidine, 3- pyrrolidine, 4-pyrrolidine, 5-pyrrolidine), pyrazolidine (1-pyrazolidine, 2-pyrazolidine, 3- pyrazolidine, 4-pyrazolidine, 5-pyrazolidine), imidazolidine (1-imidazolidine, 2- imidazolidine, 3-imidazolidine, 4-imidazolidine, 5-imidazolidine), thiazolidine (2- thiazolidine, 3-thiazolidine, 4-thiazolidine, 5-thiazolidine), piperidine (1-piperidine, 2- piperidine, 3-piperidine, 4-piperidine, 5-piperidine, 6-piperidine), piperazine (1- piperazine, 2-piperazine, 3-piperazine, 4-piperazine, 5-piperazine, 6-piperazine), morpholine (2-morpholine, 3-morpholine, 4-morpholine, 5-morpholine, 6-morpholine), thiomorpholine (2-thiomorpholine, 3-thiomorpholine, 4-thiomorpholine, 5- thiomorpholine, 6- thiomorpholine), 1 ,2-oxathiolane (3-(1 ,2-oxathiolane), 4-(1 ,2- oxathiolane), 5-(1 ,2-oxathiolane)), 1 ,3-dioxolane (2-(1 ,3-dioxolane), 3-(1 ,3-dioxolane), 4-(1 ,3-dioxolane)), tetrahydrofuran (2- tetrahydrofuran, 3- tetrahydrofuran, 4- tetrahydrofuran, 5- tetrahydrofuran), tetrahydropyrane (2- tetrahydropyrane, 3- tetrahydropyrane, 4- tetrahydropyrane, 5- tetrahydropyrane, 6- tetrahydropyrane), hexahydropyradizine, (1 -(hexahydropyradizine), 2-(hexahydropyradizine), 3- (hexahydropyradizine), 4-(hexahydropyradizine), 5-(hexahydropyradizine), 6- (hexahydropyradizine)). It is to be understood that the term includes unsubstituted or substituted C₃-₇ heterocycloalkyl.

The term

as used herein refers to a cycloalkyl group as defined above having the indicated number of carbon atoms attached through an alkyl group as defined above having the indicated number of carbon atoms. It is to be understood that the term includes unsubstituted or substituted C-i-salkyl-Cs-_T-cycloalkyl.

The term "C^salkyl-Cs-_T-heterocycloalkyl" as used herein refers to a heterocycloalkyl group as defined above having the indicated number of carbon atoms attached through an alkyl group as defined above having the indicated number of carbon atoms. It is to be understood that the term includes unsubstituted or substituted Cι-₅alkyl-C₃- ₇heterocycloalkyl.

The term "aryl" as used herein is intended to include carbocyclic aromatic ring systems. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated below. The term "heteroaryl" as used herein includes heterocyclic unsaturated ring systems containing one or more heteroatoms selected among nitrogen, oxygen and sulphur, such as furyl, thienyl, pyrrolyl, and is also intended to include the partially hydrogenated derivatives of the heterocyclic systems enumerated below.

The terms "aryl", "biaryl" and "heteroaryl" as used herein refers to an aryl or biaryl, which optionally is unsubstituted or substituted with one or two substituents, or a heteroaryl, which optionally is unsubstituted or substituted with one or two substituents. Examples of useful substituents are: halogen (fluoro, chloro, bromo, iodo), hydroxy, cyano, amino, trifluoromethoxy, trifluoromethyl, trifluoromethylthio, C-ι-₆alkyl, C-i-ealkoxy, thioC₁.₆-alkyl, and phenyl. Examples include, but are not limited to, phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N-hydroxytriazolyl, N- hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), phenanthrenyl, fluorenyl, pentalenyl, azulenyl, biphenylenyl, thiophenyl (1 -thienyl, 2- thienyl), furyl (1-furyl, 2-furyl), furanyl, thiazinyl, isoxazolyl, isothiazolyl, 1 ,2,3-triazolyl, 1 ,2,4-triazolyl, pyranyl, pyridinyl, pyridazinyl, pyrazinyl, pyrrolinyl, 1 ,2,3-triazinyl, 1 ,2,4- triazinyl, 1 ,3,5-triazinyl, 1 ,2,3-oxadiazolyl, 1 ,2,4-oxadiazolyl, 1 ,2,5-oxadiazolyl, 1 ,3,4- oxadiazolyl, 1 ,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl, 1 ,2,5-thiadiazolyl, 1 ,3,4-thiadiazolyl, tetrazolyl, thiadiazinyl, isoindolyl, benzofuranyl, benzothiophenyl (thianaphthenyl), oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, benzisoxazolyl, purinyl, quinazolinyl, quinolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, phteridinyl, azepinyl, diazepinyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1 -imidazolyl, 2-imidazolyl, 4-imidazolyl, 5- imidazolyl), imidazolinyl, triazolyl (1 ,2,3-triazol-1-yl, 1 ,2,3-triazol-2-yl, 1 ,2,3-triazol-4-yl, 1 ,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl), thiazolyl (2-thiazolyl, 4- thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl, 4- pyridazinyl, 5-pyridazinyl), isoquinolyl (1 -isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5- isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), quinolyl (2-quinolyl, 3-quinolyl, 4- quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), benzo[b]furanyl (2- benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl, 5-benzo[b]furanyl, 6- benzo[b]furanyl, 7-benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro- benzo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl), 5- (2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl), 7-(2,3-dihydro- benzo[b]furanyl)), benzo[b]thiophenyl (2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4- benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl (2-(2,3-dihydro-benzo[b]thiophenyl), 3-(2,3-dihydro- benzo[b]thiophenyl), 4-(2,3-dihydro-benzo[b]thiophenyl), 5-(2,3-dihydro- benzo[b]thiophenyl), 6-(2,3-dihydro-benzo[b]thiophenyl), 7-(2,3-dihydro- benzo[b]thiophenyl)), indolyl (1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazolyl (1-indazolyl, 2-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6- indazolyl, 7-indazolyl), benzimidazolyl, (1-benzimidazolyl, 2-benzimidazolyl, 4- benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8- benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1- benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl). Non-limiting examples of partially hydrogenated derivatives are 1 ,2,3,4- tetrahydronaphthyl, 1 ,4-dihydronaphthyl, 2,3-dihydrobenzofuranyl, pyrrolinyl, pyrazolinyl, indolinyl, oxazolidinyl, oxazolinyl, oxazepinyl and the like.

The term "d-salkyl-aryl" as used herein refers to an aryl group as defined above attached through a d-₅ alkyl group as defined above having one, two, three, four or five carbon atoms; it is to be understood that the term includes unsubstituted or substituted Cι-₅alkyl-aryl.

The term "d-salkyl-heteroaryl" as used herein refers to a heteroaryl group as defined above attached through a C-ι-₅ alkyl group as defined above having one, two, three, four or five carbon atoms; it is to be understood that the term includes unsubstituted or substituted C^salkyl-heteroaryl.

The term "d-salkyl-biaryl" as used herein refers to a biaryl group as defined above attached through a C-ι-₅ alkyl group as defined above having one, two, three, four or five carbon atoms; it is to be understood that the term includes unsubstituted or substituted d-salkyl-biaryl.

The term "C₂.₆alkenyl-aryl" as used herein refers to an aryl group as defined above attached through a C₂.₆ alkenyl group as defined above having two, three, four, five or six carbon atoms; it is to be understood that the term includes unsubstituted or substituted C₂.₆alkenyl-aryl. The term "C₂-₆alkenyl-heteroaryl" as used herein refers to an heteroaryl group as defined above attached through a C₂.₆ alkenyl group as defined above having two, three, four, five or six carbon atoms; it is to be understood that the term includes unsubstituted or substituted C₂.₆alkenyl-heteroaryl.

The term "C₂-₆alkenyl-biaryl" as used herein refers to a biaryl group as defined above attached through a C₂-e alkenyl group as defined above having two, three, four, five or six carbon atoms; it is to be understood that the term includes unsubstituted or substituted C₂-₆alkenyl-biaryl.

The term "aryl-d-salkyl" as used herein refers to a d-5 alkyl group as defined above having one, two, three, four or five carbon atoms attached through an aryl group as defined above; it is to be understood that the term includes unsubstituted or substituted aryl-Cι-₅alkyl.

The term "heteroaryl-d-₅alkyl" as used herein refers to a d-₅ alkyl group as defined above having one, two, three, four or five carbon atoms attached through a heteroaryl group as defined above; it is to be understood that the term includes unsubstituted or substituted heteroaryl-d-₅alkyl.

"Halogen" designates an atom selected from the group consisting of F, Cl, Br and I.

The terms "aminohydroxyl", "aminoaryl", "aminoheteroaryl" and "amino-d-₆-alkyl" as used herein refer to a hydroxyl, an aryl, a heteroaryl or d-₆-alkyl group attached through amino, i.e. -NH-OH, -NH-aryl, -NH-heteroaryl or -NH-d-₆-alkyl.

The terms "unsubstituted" or "substituted" as used herein means that the groups in question are optionally unsubstituted, or substituted with one or two of the substituents specified or substituted with one or more, for example one, two, three or four, substituents selected from halogen, hydroxy, d-₅alkyl, Cι-₃alkoxy, amino, cyano, thiod-₆-alkyl, trifluoromethyl, trifluoromethylthio and phenyl. When the groups in question are substituted with more than one substituent the substituents may be the same or different.

The terms "amino acid", "amino acid residue", "natural amino acid" and "natural amino acid residue" as used herein all refer to the D- or L- isomers of the 20 standard amino acid residues: alanine (Ala), arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine (Cys), glutamine (Gin), glutamic acid (Glu), glycine (Gly), histidine (His), isoleucine (lie), leucine (Leu), lysine (Lys), methionine (Met), phenylalanine (Phe), proline (Pro), serine (Ser), threonine (Thr), tryptophan (Trp), tyrosine (Tyr) and valine (Val). An amino acid is a monomer containing an amino group and a carboxyl group that can be polymerized to form peptide and protein chains. Typically, peptide/protein- forming amino acids have the amino and carboxyl groups attached to the same carbon atom (the alpha carbon) and are designated alpha amino acids. The term "side chain of an alpha amino acid" denotes the substituent on the alpha carbon. Variable substituents generate different amino acids with different chemical properties. An amino acid residue is the portion of the amino acid that remains after incorporation into a polypeptide chain. The residue includes the alpha-carbon and the nitrogen/carbonyl moieties.

The terms "unnatural amino acid" and "non-natural amino acid residue" as used herein refer to non-standard or modified or unnatural amino acid residues. Examples of non- standard amino acid residues are 4-hydroxyproline, 6-A/-methyl lysine, alpha- aminoisobutyric acid, isovaline, homophenylalanine, 2-naphthyl alanine and alpha- methyl serine. Unnatural amino acid residues have been modified after protein synthesis, and/or have a chemical structure in their side chain(s) different from that of the standard amino acid residues; they can be chemically synthesized or may be commercially available. Examples of unnatural amino acid residues are pipecolic acid, thiazolidine carboxylic acid, dehydroproline, 3- and 4-methylproline, 3,3- dimethylproline, diphenyl-L-alanine, 4-phenyl-L-phenylalanine, 3-(3-benzothiophene)-L- alanine, 2-naphthyl-L-alanine, p-chloro-phenyl-L-alanine, m-methoxy-phenyl-L-alanine, m-fluoro-phenyl-L-alanine, styryl-L-alanine, cyclopropyl-alanine, cyclohexyl-alanine, 3- (4-pyridyl)-L-alanine, homophenylalanine, L-allyl-glycine, 2-amino-butanoic acid, and norvaline.

Certain of the above defined terms may occur more than once in the structural formulae, and upon such occurrence each term shall be defined independently of the other.

As used herein, the phrase "a functional group which can be converted to hydrogen in vivo" is intended to include any group which upon administering the present compounds to the subjects in need thereof can be converted to hydrogen e.g. enzymatically or by the acidic environment in the stomach. Non-limiting examples of such groups are acyl, carbamoyl, monoalkylated carbamoyl, dialkylated carbamoyl, alkoxycarbonyl, alkoxyalkyl groups and the like such as d-₆-alkylcarbonyl, aroyl, C-ι-₆- alkylcarbamoyl, di-d-₆ alkyl-alkylcarbamoyl, Cι-₆-alkoxycarbonyl and d-e-alkoxy- d-₆- alkyl.

As used herein, the phrase "HIV mediated diseases " is intended to include any disease or disorder in which an effect, preferably an inhibiting effect, on HIV protease is beneficial, especially on AIDS.

The term "IC₅₀" as used herein denotes the concentration required for 50% inhibition of HIV protease in a binding assay.

Abbreviations and symbols commonly used in the peptide and chemical arts are used herein to describe the compounds of the present invention. In general, the amino acid abbreviations follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature as described in Eur. J. Biochem., 158, 9 (1984).

Certain radical groups are abbreviated herein. t-Bu refers to the tertiary butyl radical, Boc refers to the t-butyloxycarbonyl radical, Fmoc refers to the fluorenylmethoxycarbonyl radical, Ph refers to the phenyl radical, Cbz refers to the benzyloxycarbonyl radical.

The compounds The present invention relates to compounds of the general formula (I)

or a pharmaceutically acceptable salt or ester thereof, wherein one of R-i and R is hydrogen and the other is R_y, -COR_y, -COOR_y, -CONR_y or -SO₂R_y, in which R_y is selected from the group consisting of d-₆alkyl, C₂.₆alkenyl, C₃-₁₀cycloalkyl, C₃- ₇heterocycloalkyl, aryl, heteroaryl, biaryl, d-₅alkyl-aryl, d-₅alkyl-heteroaryl, aryl-d- ₅alkyl, heteroaryl-C_t-₅alkyl, d-₅alkyl-C₃-₇cycloalkyl, and d-salkyl-d-_T-heterocycloalkyl, optionally substituted with one or two substituents selected from the group consisting of halogen, hydroxy, d-₅alkyl, Cι-₃alkoxy, amino, cyano, thiod-₆-alkyl, trifluoromethyl, trifluoromethylthio and phenyl; R₃ is selected from d-₅alkyl-aryl, d-₅alkyl-heteroaryl, d-salkyl-biaryl, d-₅alkyl-C₃-₇cycloalkyl and d-salkyl-C₃-₇heterocycloalkyl, optionally substituted with one or two substituents selected from the group consisting of halogen, hydroxy, C^alkyl, Cι-₃alkoxy, amino, cyano, thioCι-₆-alkyl, trifluoromethyl, trifluoromethylthio and phenyl; and R₄ is hydrogen or d-₆-alkyl;

R₅ is selected from hydrogen, d-₆alkyl, C₂-₆alkenyl, C₃-₇cycloalkyl, C₃-₇heterocycloalkyl, d-₅alkyl-C₃- cycloalkyl, d-salkyl-d-_T-heterocycloalkyl, C^salkyl-aryl, d-salkyl-heteroaryl, d-₅alkyl-biaryl, C₂.₆alkenyl-aryl, C₂.₆alkenyl-heteroaryl, and a side chain of a natural amino acid, optionally - if R₃ is different from hydrogen and a side chain of a natural amino acid - substituted with one or two substituents selected from the group consisting of halogen, hydroxy, d-₅alkyl, Cι-₃alkoxy, amino, cyano, thioC-ι-₆-alkyl, trifluoromethyl, trifluoromethylthio and phenyl; R₇ is selected from hydrogen, C₂-

₆alkenyl, d-₅alkyl-aryl, d-₅alkyl-heteroaryl, d-₅alkyl-biaryl, d-₅alkyl-C₃.₇cycloalkyl, d- ₅alkyl-C₃-₇heterocycloalkyl, C₂.₆alkenyl-aryl, C₂-₆alkenyl-heteroaryl, C₂-₆alkenyl-biaryl, and a side chain of a natural amino acid, optionally - if R₃ is different from hydrogen and a side chain of a natural amino acid - substituted with one or two substituents selected from the group consisting of halogen, hydroxy, d-₅alkyl, d-₃alkoxy, amino, cyano, thiod-₆-alkyl, trifluoromethyl, trifluoromethylthio and phenyl; and R₈ is selected from hydroxy, methoxy, ethoxy, propoxy, amino, hydrazine, aminohydroxyl, aminoaryl, aminoheteroaryl, amino-d-e-alkyl, d-salkyl-aryl, and d-₅alkyl-heteroaryl.

In a preferred embodiment of the invention, one of Ri and R₂ is hydrogen and the other is R_y, -COR_y, -COOR_y, -CONR_y or -SO₂R_y, in which R_y is selected from the group consisting of C₃.₁₀cycloalkyl, C₃.₇heterocycloalkyl, aryl, heteroaryl, biaryl, d-salkyl-aryl, Cι-₅alkyl-heteroaryl, aryl-d-salkyl, heteroaryl-d-₅alkyl, Cι-salkyl-C₃-₇cycloalkyl and d- ₅alkyl-C₃-₇heterocycloalkyl, optionally substituted with one or two substituents selected from the group consisting of halogen, hydroxy, C^alkyl, d-₃alkoxy, amino, cyano, thiod-6-alkyl, trifluoromethyl, trifluoromethylthio, and phenyl. In a more preferred embodiment, R_yis selected from the group consisting of C₃-₇heterocycloalkyl, aryl, heteroaryl, d-salkyl-aryl, and Cι.₅alkyl-heteroaryl, optionally substituted with one or two substituents selected from the group consisting of halogen, hydroxy, C^alkyl, Ci- ₃alkoxy, thiod-₆-alkyl, and trifluoromethyl. In another preferred embodiment of the invention one of ^ or R₂ is hydrogen and the other is R_y, -COR_y, -COOR_y, -CONR_y or -SO₂R_y, in which R_y is selected from the group consisting of phenyl, benzyl, thiophenyl, thiophenylmethyl, quinolinyl, naphthyl, naphthylmethyl, furanyl, pyridinyl and tetrahydrofuranyl, optionally substituted with one or two substituents selected from the group consisting of halogen, hydroxy, d-₅alkyl, Cι-₃alkoxy, thiod-₆-alkyl, and trifluoromethyl. In a more preferred embodiment the one or two substituents may be selected from the group consisting of fluoro, chloro, bromo, hydroxy, methyl, tert-butyl, methoxy, methylthio, and trifluoromethyl.

In a further prefered embodiment of the invention one of R-_\ or R₂ is hydrogen and the other is selected from the group consisting of 8-quinolinesulfonyl, 2-naphtoyl, 2-furoyl, 4-^-butylbenzenesulfonyl, 3-fluorobenzoyl, 4-methoxybenzenesulfonyl, 2-thiophenoyl, 2-naphthylacetyl, 2-chlorobenzoyl, 2-fluorobenzoyl, benzyloxycarbonyl, 4- methoxyphenylacetyl, 3-methylthio-phenylacetyl, 2-chloro-3-pyridinoyl, 5-methyl-2- thiophenoyl, 5-bromo-2-furoyl, 3-chlorobenzoyl, 3-bromobenzoyl, 3- trifluoromethylbenzoyl, 3-methoxybenzoyl, 3-methylbenzoyl, 4-fluorobenzoyl, 2- hydroxy-3-methylbenzoyl, 2-thiophenacetyl, and tetrahydro-2-furanyloxycarbonyl.

In another preferred embodiment of the invention one of R-i or R₂ is hydrogen and the other may be benzoyl substituted with one or two substituents selected from the group consisting of fluoro, chloro, bromo, hydroxy, methyl, tert-butyl, methoxy, methylthio, and trifluoromethyl.

In a preferred embodiment of the invention R₃ is selected from the group consisting of Cι-₅alkyl-aryl and C-i-₅alkyl-heteroaryl, optionally substituted with one or two substituents selected from the group consisting of halogen, hydroxy, d-₅alkyl, Ci- ₃alkoxy, amino, cyano, thiod-₆-alkyl, trifluoromethyl, trifluoromethylthio, and phenyl. In more preferred embodiment R₃ is Ci-₅alkyl-aryl, optionally substituted with one or two substituents selected from the group consisting of halogen, hydroxy, d-₅alkyl, d- ₃alkoxy, amino, cyano, thiod-₆-alkyl, trifluoromethyl, trifluoromethylthio, and phenyl.

In another preferred embodiment of the invention R₃ is benzyl, optionally substituted with one or two substituents selected from the group consisting of halogen, hydroxy, Cι- alkyl, Cι-₃alkoxy, amino, cyano, thiod-₆-alkyl, trifluoromethyl, trifluoromethylthio and phenyl. Preferably, R₃ is benzyl. In certain cases, however, R₃ may be a straight d-₆ alkyl chain.

R₄is preferably selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec- butyl, tert-butyl, n-pentyl and n-hexyl; and more preferably R₄ is hydrogen.

In a preferred embodiment of the invention R₅ is selected from the group consisting of d-₆alkyl, C₃-₇cycloalkyl, d-₅alkyl-C₃-₇cycloalkyl, d-salkyl-aryl, Ci-₅alkyl-heteroaryl, Ci- ₅alkyl-biaryl, C₂.₆alkenyl-aryl, optionally substituted with one or two substituents selected from the group consisting of halogen, hydroxy, d-₅alkyl, d-₃alkoxy, amino, cyano, thiod-₆-alkyl, trifluoromethyl, trifluoromethylthio, and phenyl. In a more preferred embodiment, the one or two substituents is selected from the group consisting of halogen, d-₃alkoxy, and phenyl.

In another preferred embodiment of the invention R₅ is selected from the group consisting of benzothiophenylmethyl, (E)-3-phenyl-2-propenyl, ethyl, cyclohexylmethyl, iso-butyl, benzyl, fluoro substituted benzyl, methoxy substituted benzyl, 3H- imidazolylmethyl, 1 H-indolylmethyl, methyl, pyridinylmethyl, phenylethyl, 1 ,1- diphenylmethyl, cyclopropyl, hydrogen, methyl, iso-propyl, propyl, sec-butyl, cyclopropylmethyl, isopentyl, butyl, cyclohexylethyl, napthylmethyl and biphenylmethyl.

In a further preferred embodiment of the invention R₅ is d-₆ alkyl. Preferably, R₅ is selected from the group concisting of methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, iso-butyl and isopentyl.

In yet another preferred embodiment of the invention R₅ is d- alkyl. Preferably, R₅ is selected from the group consisting of butyl, iso-butyl, sec-butyl and tert-butyl. More preferably R₅ is iso-butyl.

In a preferred embodiment R₇ is selected from the group consisting of C₂.₆alkenyl, d- ₅alkyl-aryl, d-₅alkyl-heteroaryl, d-salkyl-biaryl, C₂.₆alkenyl-aryl, C₂.₆alkenyl-heteroaryl, and C₂.₆alkenyl-biaryl, optionally substituted with one or two substituents selected from the group consisting of halogen, hydroxy, d-₅alkyl, d-₃alkoxy, amino, cyano, thiod-e- alkyl, trifluoromethyl, trifluoromethylthio and phenyl.

In another preferred embodiment of the invention R₇ is selected from the group consisting of 3H-imidazolyl-methyl, phenylethyl, benzyl, (E)-3-phenyl-2-propenyl, naphthylmethyl, 1 H-indolylmethyl, biphenylmethyl, allyl, benzothiopenylmethyl, phenylpropyl, and cyclopropylmethyl, optionally substituted with one or two substituents selected from the group consisting of halogen, hydroxy, d-₅alkyl, Cι-₃alkoxy, amino, cyano, thiod.₆-alkyl, trifluoromethyl, trifluoromethylthio and phenyl. In a more preferred embodiment R₇ is selected from the group consisting of 3H-imidazolyl-methyl, phenylethyl, benzyl, fluoro substituted benzyl, chloro substituted benzyl, hydroxy substituted benzyl, (E)-3-phenyl-2-propenyl, naphthylmethyl, 1 H-indolylmethyl, biphenylmethyl, allyl, benzothiopenylmethyl and phenylpropyl. In a even more preferred embodiment R₇ is selected from the group consisting of 3H-imidazol-4-yl-methyl, 2- phenylethyl, benzyl, 3-fluoro-benzyl, 4-chloro-benzyl, 4-hydroxy-benzyl, (E)-3-phenyl-2- propenyl, naphth-2-ylmethyl, 1 H-indol-3-ylmethyl, biphenylmethyl, allyl, benzothiopen- 3-ylmethyl and 3-phenylpropyl. In a most preferred embodiment R₇ is (E)-3-phenyl-2- propenyl.

In a preferred embodiment of the invention R₈ is selected from the group consisting of hydroxy, methoxy, ethoxy, propoxy and amino. In a more preferred embodiment R₈ is selected from the group consisting of hydroxy, methoxy and amino; and in a even more preferred embodiment R₈ is amino.

Preferred compounds of the invention are: {[(S)-1 -((S)-2-Benzo[b]thiophen-2-yl-1 -carbamoyl-ethylcarbamoyl)-2-(3H-imidazol-4-yl)- ethylcarbamoyl]-methyl}-[2-phenyl-1-(quinoline-8-sulfonylamino)-ethyl]-phosphinic acid;

({(S)-1-[(S)-1-Carbamoyl-2-(3H-imidazol-4-yl)-ethylcarbamoyl]-3-phenyl- propylcarbamoyl}-methyl)-{1-[(naphthalene-2-carbonyl)-amino]-2-phenyl-ethyl}- phosphinic acid; {[(S)-1 -((S)-1 -Carbamoyl-3-phenyl-propylcarbamoyl)-propylcarbamoyl]-methyl}-{1 -

[(furan-2-carbonyl)-amino]-2-phenyl-ethyl}-phosphinic acid;

[1 -(4-tert-Butyl-benzenesulfonylamino)-2-phenyl-ethyl]-({(S)-1 -[(S)-1 -carbamoyl-2-(3- fluoro-phenyl)-ethylcarbamoyl]-2-cyclohexyl-ethylcarbamoyl}-methyl)-phosphinic acid;

{[(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamoyl]- methyl}-[1-(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

{[(S)-1-((S)-1-Carbamoyl-2-naphthalen-2-yl-ethylcarbamoyl)-2-(3-methoxy-phenyl)- ethylcarbamoyl]-methyl}-[1-(4-methoxy-benzenesulfonylamino)-2-phenyl-ethyl]- phosphinic acid;

({(S)-1-[(S)-1-Carbamoyl-2-(4-hydroxy-phenyl)-ethylcarbamoyl]-3-methyl- butylcarbamoyl}-methyl)-{1-[(naphthalene-2-carbonyl)-amino]-2-phenyl-ethyl}- phosphinic acid; {[(S)-1-((S)-1-Carbamoyl-3-phenyl-propylcarbamoyl)-2-(3-methoxy-phenyl)- ethylcarbamoyl]-methyl}-[2-phenyl-1-(quinoline-8-sulfonylamino)-ethyl]-phosphinic acid;

{[(S)-1-[(S)-1-Carbamoyl-2-(3H-imidazol-4-yl)-ethylcarbamoyl]-2-(3H-imidazol-4-yl)- ethylcarbamoyl]-methyl}-[2-phenyl-1-(quinoline-8-sulfonylamino)-ethyl]-phosphinic acid; {[(S)-1 -[(S)-1 -Carbamoyl-2-(3H-imidazol-4-yl)-ethylcarbamoyl]-2-(3H-imidazol-4-yl)- ethylcarbamoyl]-methyl}-{1-[(naphthalene-2-carbonyl)-amino]-2-phenyl-ethyl}- phosphinic acid;

({(S)-1 -[(S)-1 -Carbamoyl-2-(1 H-indol-3-yl)-ethylcarbamoyl]-3-methyl-butylcarbamoyl}- methyl)-{2-phenyl-1-[(thiophene-2-carbonyl)-amino]-ethyl}-phosphinic acid; {[(S)-2-Benzo[b]thiophen-3-yl-1 -((S)-1 -carbamoyl-3-phenyl-propylcarbamoyl)- ethylcarbamoyl]-methyl}-[1-(2-naphthalen-2-yl-acetylamino)-2-phenyl-ethyl]-phosphinic acid;

({(S)-1-[(S)-1-Carbamoyl-2-(3H-imidazol-4-yl)-ethylcarbamoyl]-2-cyclohexyl- ethylcarbamoyl}-methyl)-[1-(2-chloro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid; (1 -Benzoylamino-2-phenyl-ethyl)-{[(S)-1 -((S)-1 -carbamoyl-3-phenyl-propylcarbamoyl)-

2-(3H-imidazol-4-yl)-ethylcarbamoyl]-methyl}-phosphinic acid;

{[(S)-1-[(S)-1-Carbamoyl-2-(3H-imidazol-4-yl)-ethylcarbamoyl]-2-(3-fluoro-phenyl)- ethylcarbamoyl]-methyl}-{2-phenyl-1-[(thiophene-2-carbonyl)-amino]-ethyl}-phosphinic acid; {[(S)-1 -((E)-(S)-1 -Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamoyl]- methyl}-[2-phenyl-1-(quinoline-8-sulfonylamino)-ethyl]-phosphinic acid;

({(S)-1-[(S)-1-Carbamoyl-2-(3H-imidazol-4-yl)-ethylcarbamoyl]-3-methyl- butylcarbamoyl}-methyl)-{1-[(naphthalene-2-carbonyl)-amino]-2-phenyl-ethyl}- phosphinic acid; ({(S)-2-Biphenyl-4-yl-1 -[(S)-1 -carbamoyl-2-(4-chloro-phenyl)-ethylcarbamoyl]- ethylcarbamoyl}-methyl)-{2-phenyl-1-[(S)-(tetrahydro-furan-3-yl)oxycarbonylamino]- ethyl}-phosphinic acid;

({(S)-2-Biphenyl-4-yl-1-[(S)-1-carbamoyl-2-(4-hydroxy-phenyl)-ethylcarbamoyl]- ethylcarbamoyl}-methyl)-[1-(4-tert-butyl-benzenesulfonylamino)-2-phenyl-ethyl]- phosphinic acid;

({(S)-1 -[(S)-1 -Carbamoyl-2-(1 H-indol-3-yl)-ethylcarbamoyl]-2-cyclohexyl- ethylcarbamoyl}-methyl)-[1-(2-naphthalen-2-yl-acetylamino)-2-phenyl-ethyl]-phosphinic acid;

[1 -(4-tert-Butyl-benzenesulfonylamino)-2-phenyl-ethyl]-({(S)-1 -[(S)-1 -carbamoyl-2-(3- fluoro-phenyl)-ethylcarbamoyl]-3-methyl-butylcarbamoyl}-methyl)-phosphinic acid; (1 -Benzyloxycarbonylamino-2-phenyl-ethyl)-{[(S)-1 -((S)-2-biphenyl-4-yl-1 -carbamoyl- ethylcarbamoyl)-2-(1 H-indol-3-yl)-ethylcarbamoyl]-methyl}-phosphinic acid;

{[(S)-1 -[(S)-1 -Carbamoyl-2-(1 H-indol-3-yl)-ethylcarbamoyl]-2-(3H-imidazol-4-yl)- ethylcarbamoyl]-methyl}-{2-phenyl-1-[(thiophene-2-carbonyl)-amino]-ethyl}-phosphinic acid;

{[(S)-1 -((S)-1 -Carbamoyl-but-3-enylcarbamoyl)-ethylcarbamoyl]-methyl}-[1 -(2- naphthalen-2-yl-acetylamino)-2-phenyl-ethyl]-phosphinic acid;

({(S)-1-[(S)-1-Carbamoyl-2-(3-fluoro-phenyl)-ethylcarbamoyl]-2-pyridin-4-yl- ethylcarbamoyl}-methyl)-[1-(2-naphthalen-2-yl-acetylamino)-2-phenyl-ethyl]-phosphinic acid;

{[(S)-1-((S)-1-Carbamoyl-3-phenyl-propylcarbamoyl)-3-phenyl-propylcarbamoyl]- methyl}-[1-(4-methoxy-benzenesulfonylamino)-2-phenyl-ethyl]-phosphinic acid;

{[(S)-1-((S)-2-Benzo[b]thiophen-3-yl-1-carbamoyl-ethylcarbamoyl)-2,2-diphenyl- ethylcarbamoyl]-methyl}-[1-(4-methoxy-benzenesulfonylamino)-2-phenyl-ethyl]- phosphinic acid;

{[(S)-1-[(S)-1-Carbamoyl-2-(3a,7a-dihydro-benzo[b]thiophen-3-yl)-ethylcarbamoyl]-2-

(3H-imidazol-4-yl)-ethylcarbamoyl]-methyl}-{1-[(naphthalene-2-carbonyl)-amino]-2- phenyl-ethyl}-phosphinic acid;

{[(S)-1-((S)-1-Carbamoyl-2-naphthalen-2-yl-ethylcarbamoyl)-2-phenyl-ethylcarbamoyl]- methyl}-{1 -[2-(4-methoxy-phenyl)-acetylamino]-2-phenyl-ethyl}-phosphinic acid;

{[(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamoyl]- methyl}-{1-[(furan-2-carbonyl)-amino]-2-phenyl-ethyl}-phosphinic acid;

{[(S)-1 -((S)-1 -Carbamoyl-3-phenyl-propylcarbamoyl)-propylcarbamoyl]-methyl}-[1 -(3- fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid; {[(S)-1 -((E)-(S)-1 -Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-propylcarbamoyl]-methyl}-

{1 -[(furan-2-carbonyl)-amino]-2-phenyl-ethyl}-phosphinic acid;

{[(S)-1-((S)-1-Carbamoyl-3-phenyl-propylcarbamoyl)-3-methyl-butylcarbamoyl]-methyl}-

[1-(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

{[(S)-1-((S)-1-Carbamoyl-3-phenyl-propylcarbamoyl)-3-methyl-butylcarbamoyl]-methyl}- {1-[(furan-2-carbonyl)-amino]-2-phenyl-ethyl}-phosphinic acid;

{[(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-propylcarbamoyl]-methyl}-

[1-(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

({[(S)-((S)-1-Carbamoyl-4-phenyl-butylcarbamoyl)-cyclohexyl-methyl]-carbamoyl}- methyl)-[1-(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid; {[1 -((S)-1 -Carbamoyl-2-naphthalen-2-yl-ethylcarbamoyl)-cyclopropylcarbamoylj- methyl}-[1-(3-methylsulfanyl-benzoylamino)-2-phenyl-ethyl]-phosphinic acid; ({[(S)-((R)-1-Carbamoyl-4-phenyl-butylcarbamoyl)-cyclohexyl-methyl]-carbamoyl}- methyl)-{1-[(2-chloro-pyridine-3-carbonyl)-amino]-2-phenyl-ethyl}-phosphinic acid;

{[(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamoyl]- methyl}-{2-phenyl-1-[(thiophene-2-carbonyl)-amino]-ethyl}-phosphinic acid; {[(S)-1 -((E)-(S)-1 -Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamoyl]- methyl}-{1-[(5-methyl-thiophene-2-carbonyl)-amino]-2-phenyl-ethyl}-phosphinic acid;

{1 -[(5-Bromo-furan-2-carbonyl)-amino]-2-phenyl-ethyl}-{[(S)-1 -((E)-(S)-1 -carbamoyl-4- phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamoyl]-methyl}-phosphinic acid;

{[(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamoyl]- methyl}-[1-(3-chloro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

[1 -(3-Bromo-benzoylamino)-2-phenyl-ethyl]-{[(S)-1 -((E)-(S)-1 -carbamoyl-4-phenyl-but-

3-enylcarbamoyl)-3-methyl-butylcarbamoyl]-methyl}-phosphinic acid;

{[(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamoyl]- methyl}-[2-phenyl-1-(3-trifluoromethyl-benzoylamino)-ethyl]-phosphinic acid; {[(S)-1 -((E)-(S)-1 -Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamoyl]- methyl}-[1-(3-methoxy-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

{[(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamoyl]- methyl}-[1-(3-methyl-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

{[(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamoyl]- methyl}-[1 -(2-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

{[(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamoyl]- methyl}-[1-(4-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

{[(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamoyl]- methyl}-[1-(2-hydroxy-3-methyl-benzoylamino)-2-phenyl-ethyl]-phosphinic acid; {[(S)-1 -((S)-1 -Carbamoyl-4-phenyl-butylcarbamoyl)-3-methyl-butylcarbamoyl]-methyl}-

[1 -(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

({[((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-methyl]-carbamoyl}-methyl)-[1-

(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

{[1 -((E)-(S)-1 -Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-ethylcarbamoyl]-methyl}-[1 -(3- fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

{[1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-2-methyl-propylcarbamoyl]- methyi}-[1-(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

{[1 -((E)-(S)-1 -Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-butylcarbamoyl]-methyl}-[1 -(3- fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid; {[1 -((E)-(S)-1 -Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-2-methyl-butylcarbamoyl]- methyl}-[1-(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid; {[1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-2-cyclopropyl- ethylcarbamoyl]-methyl}-[1-(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

{[1-((E)-(^s)-¹-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-2-cyclohexyl-ethylcarbamoyl]- methyl}-[1-(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid; {[1 -((E)-(S)-1 -Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-4-methyl-pentylcarbamoyl]- methyl}-[1-(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

{[1 -((E)-(S)-1 -Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-pentylcarbamoyl]-methyl}-[1 -

(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

{[1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-cyclohexyl- propylcarbamoyl]-methyl}-[1-(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

({(S)-1-[(S)-1-Carbamoyl-2-(4-hydroxy-phenyl)-ethylcarbamoyl]-3-phenyl- propylcarbamoyl}-methyl)-[1-(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

{[(S)-1-((S)-1-Carbamoyl-but-3-enylcarbamoyl)-2-cyclopropyl-ethylcarbamoyl]-methyl}-

[1-(2-naphthalen-2-yl-acetylamino)-2-phenyl-ethyl]-phosphinic acid; {[(S)-1 -((S)-1 -Carbamoyl-2-cyclopropyl-ethylcarbamoyl)-2-pyridin-4-yl-ethylcarbamoyl]- methyl}-[2-phenyl-1-(2-thiophen-2-yl-acetylamino)-ethyl]-phosphinic acid;

{[(S)-1-((S)-1-Carbamoyl-2-phenyl-ethylcarbamoyl)-2,2-diphenyl-ethylcarbamoyl]- methyl}-{2-phenyl-1-[(thiophene-2-carbonyl)-amino]-ethyl}-phosphinic acid;

({(S)-1-[(S)-1-Carbamoyl-2-(4-chloro-phenyl)-ethylcarbamoyl]-2-naphthalen-2-yl- ethylcarbamoyl}-methyl)-[1 -(2-chloro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

{[(S)-1-((S)-1-Carbamoyl-2-phenyl-ethylcarbamoyl)-2-phenyl-ethylcarbamoyl]-methyl}-

[1 -(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid; and stereoisomers thereof.

From the list above, more preferred compounds of the invention are:

{[(S)-1 -((S)-1 -Carbamoyl-3-phenyl-propylcarbamoyl)-propylcarbamoyl]-methyl}-[1 -(3- fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid; {[(S)-1 -((E)-(S)-1 -Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-propylcarbamoyl]-methyl}- [1-(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

{[(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamoyl]- methyl}-[1-(3-chloro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid; [1 -(3-Bromo-benzoylamino)-2-phenyl-ethyl]-{[(S)-1 -((E)-(S)-1 -carbamoyl-4-phenyl-but- 3-enylcarbamoyl)-3-methyl-butylcarbamoyl]-methyl}-phosphinic acid; {[(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamoyl]- methyl}-[1-(2-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid; {[(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamoyl]- methyl}-[1-(4-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid; {[1 -((E)-(S)-1 -Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-ethylcarbamoyl]-methyl}-[1 -(3- fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

{[1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-2-methyl-propylcarbamoyl]- methylH"1-(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid; {[1 -((E)-(S)-1 -Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-butylcarbamoyl]-methyl}-[1 -(3- fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

{[1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-2-methyl-butylcarbamoyl]- methyl}-[1-(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid; {[1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-2-cyclopropyl- ethylcarbamoyl]-methyl}-[1-(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid; {[1 -((E)-(S)-1 -Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-pentylcarbamoyl]-methyl}-[1 - (3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid; and stereoisomers thereof.

An even more prefered selection of compounds from the above list is: {[1 -((E)-(S)-1 -Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-ethylcarbamoyl]-methyl}-[1 -(3- fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

{[1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-2-methyl-propylcarbamoylj- methyl}-[1-(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

{[1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-2-methyl-butylcarbamoyl]- methyl}-[1 -(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

{[1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-2-cyclopropyl- ethylcarbamoyl]-methyl}-[1-(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid; and stereoisomers thereof.

The compounds of the invention may exist as geometric isomers or optical isomers or stereoisomers as well as tautomers. Accordingly, the invention includes all geometric isomers and tautomers including mixtures and racemic mixtures of these and a pharmaceutically acceptable salt thereof, especially all R- and S- isomers. The compounds of the invention may also exist as solvent complexes as well as in different morphological forms.

The present invention also encompasses pharmaceutically acceptable salts of the present compounds. Such salts include pharmaceutically acceptable acid addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts. Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 1977, 66, 2, which is incorporated herein by reference. Examples of metal salts include lithium, sodium, potassium, magnesium salts and the like. Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like.

Also intended as pharmaceutically acceptable acid addition salts are the hydrates and solvent complexes, which the present compounds are able to form.

The acid addition salts may be obtained as the direct products of compound synthesis. In the alternative, the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.

The compounds of the present invention may form solvates with standard low molecular weight solvents using methods well known to the person skilled in the art. Such solvates are also contemplated as being within the scope of the present invention. The invention also encompasses prodrugs of the present compounds, which on administration undergo chemical conversion by metabolic processes before becoming active pharmacological substances. In general, such prodrugs will be functional derivatives of the present compounds, which are readily convertible in vivo into the required compound of the Formula I. Prodrugs are any covalently bonded compounds, which release the active parent drug according to Formula I in vivo. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

If a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein. Inventive compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone. Individual enantiomers or diastereomers obtained by separation or by direct synthesis may in certain cases show an improved inhibition compared to the corresponding enantiomeric or diastereomeric mixtures. Accordingly, IC₅₀ values observed for racemic mixtures may be larger than those observed for the enantiomer or diastereomer alone. As shown in the examples herein, a reduction of about 50% of the IC₅₀ may be expected. In cases in which compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of this invention. In cases wherein compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.

The invention also encompasses active metabolites of the present compounds.

The present invention includes all complexes of the compounds of this invention.

The meaning of any substituent at any one occurrence in Formula I or Formula II or any subformula thereof is independent of its meaning, or any other substituent's meaning, at any other occurrence, unless specified otherwise.

In a preferred embodiment of this invention, the compounds of Formula I exhibit an IC₅₀ value of less than 500 μU, preferably less than 100 μM, more preferably less than 50 μM, even more preferably less than 1 μM, especially less than 500 nM, particularly less than 100 nM, such as, e.g., 75 nM or less, 50 nM or less, or 25 nM or less when subjected to an HIV protease inhibition assay as described herein.

Synthetic Method of Preparation

The compounds of the present invention having the general Formula I may be prepared by the method set forth in the scheme A below, where X is oxygen (O).

Synthesis of compounds of common structure A-VI (method A): Stepl :

30-1 OOmg of an appropriate resin (POEPOP, PEGA, TENTA-GEL, HYDRA or POEPS) with an appropriate linker such as Rink amide linker or no linker (POEPOP) was weighed off to a plastic syringe fitted with a Teflon filter. The resin was swollen in DMF and washed with DMF (3 times). The linker was deprotected if necessary (Rink amide linker) and washed DMF (10 times). To the resins was added a solution of an Fmoc protected amino acid, an appropriate base (TEA, DIEA, NEM, Melm) and an appropriate coupling reagent (MSNT, TBTU, HATU, BTC, DCI, GDI, DCC, EDC, PyBrop) in an appropriate solvent (DCM, DCE, CHCI_3, THF or DMF). The acid was activated 5-15 minutes in advance of addition to the resin. After complete reaction the resin was washed with DMF (10 times) and used directly in step 2.

Step 2:

The resins were treated with 20% piperidine/DMF (10 + 20 minutes) and washed DMF (10 times). To the resins was added a solution of an Fmoc protected amino acid, an appropriate base (TEA, DIEA, NEM, Melm) and an appropriate coupling reagent

(MSNT, TBTU, HATU, BTC, DCI, GDI, DCC, EDC, PyBrop) in an appropriate solvent

(DCM, DCE, CHCI_3,THF or DMF). The acid was activated 5-15 minutes in advance of addition to the resin. After complete reaction the resin was washed with DMF (10 times) and used directly in step 3.

Step 2

Scheme A

R ΝCO R_rBr Step 5

Step 6

X = OorNH;Y = linker; W = CO, SO₂, COO, CONH, CH₂

Scheme A (continued)

Step 3:

The resins were treated with 20% piperidine/DMF (10 + 20 minutes) and washed DMF (10 times) and an appropriate dry solvent (MeOH, 1 ,4-dioxane, THF, DMF or mixtures hereof) (5 times). Solutions of aldehyde, AcOH, Bt and an appropriate reducing agent (NaBH₃CN or (CH₃COO)₃BHNa) in an appropriate dry solvent (MeOH, 1 ,4-dioxane, THF, DMF or mixtures hereof) was added.

After complete reaction the resins were washed with DMF (10 times) and used directly in step 4.

Step 4:

To the resins was added a solution of the Fmoc protected phosphinate building block (Formula B-VII), an appropriate base (TEA, DIEA, NEM, Melm) and an appropriate coupling reagent (MSNT, TBTU, HATU, BTC, DCI, GDI, DCC, EDC, PyBrop) in an appropriate solvent (DCM, DCE, CHCI₃, THF or DMF). The acid was activated 5-15 minutes in advance of addition to the resin. Heating to 50°C was sometimes necessary. After complete reaction the resin was washed with DMF (10 times) and used directly in step 5.

Step 5: The resins were treated with 20% piperidine in DMF (10min. + 20 min.) at room temperature and then rinsed with DMF (8 times). To the resins were added solutions of acid chlorides, sulphonyl chlorides, isocyanates or formates in an appropriate solvent

(DCM, DCE, THF or DMF) with an appropriate base (TEA, DIEA or NEM).

Alternatively, solutions of carboxylic acids in an appropriate solvent (DCM, DCE, CHCI₃, THF or DMF) with an appropriate base (TEA, DIEA or NEM) and an appropriate coupling reagent (TBTU, HATU, PyBrop, DIC, BTC, GDI, DCC or EDC) was added after appropriate activation time.

After complete reaction the resins were washed with DMF (10 times) and DCM (5 times) and used directly in step 6.

Step 6:

The discrete resin-bound compounds were treated with a solution of 66.5:20:5:5:2.5:1

TFA:DCM:water:PhSMe:(CH₂SH)₂:TIPS to remove the adamantyl protection from the phosphinate and various protective groups from the amino acid side chains. In case of the Rink amide linker this cleaving solution was combined with washings from subsequent treatments with 95% TFA (aq) and concentrated in vacuo to give the crude carboxamides. Otherwise the resins were washed AcOH (3 times), DCM (3 times), DMF (6 times) dry MeOH (6 times). The compounds were then cleaved from the resin by treatment of 0.1 M NaOMe in methanol (kept over basic AI₂O₃) to give the crude methyl esters. Cleavage from the resin could also be achieved by the use of another nucleophilic base such as NaOH, NH₂NH₂, NH₂-OH or RNH₂ in an appropriate solvent (THF, DCE, DCM, CHCI₃, H₂O) to give the crude carboxylic acids, carbohydrazides, hydroxamic acids or substituted carboxamides, respectively. The crude products were collected, neutralized and lyophilized. Purification was performed by preparative HPLC. Analysis of the products was made by LC-MS (Liquid Chromatography-Mass Spectrometry).

Acid addition salts of the compounds of Formula I are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, acetic, trifluoroacetic, maleic, succinic or methanesulfonic. Certain of the compounds form inner salts or zwitterions, which may be acceptable. Cationic salts are prepared by treating the parent compound with an excess of an alkaline reagent, such as a hydroxide, carbonate or alkoxide, containing the appropriate cation; or with an appropriate organic amine. Cations such as Li⁺, Na⁺, K⁺, Ca⁺⁺, Mg⁺⁺ and NH₄ ⁺ are specific examples of cations present in pharmaceutically acceptable salts. Halides, sulfate, phosphate, alkanoates (such as acetate and trifluoroacetate), benzoates, and sulfonates (such as mesylate) are examples of anions present in pharmaceutically acceptable salts.

Pharmaceutical compositions In one aspect of this invention, there is provided a pharmaceutical composition comprising, as an active ingredient, a compound of the present invention together with a pharmaceutically acceptable carrier or diluent for use in the treatment or prevention of HIV mediated diseases, preferably diseases caused or mediated by HIV-1 proteases, especially diseases caused or mediated by multi-drug resistant mutant HIV- 1 proteases. This composition may be in unit dosage form and may comprise from about 1 μg to about 1000 mg, such as, e.g., from about 10 μg to about 500 mg, from about 50 μg to about 500 mg, preferably from about 0.05 to about 100 mg, more preferably from about 0.1 to about 100 mg and even more preferably from about 0.1 to about 50 mg of the compound of the invention or a pharmaceutically acceptable salt or ester thereof. The composition of the invention may be used for oral, nasal, transdermal, pulmonal or parenteral administration. It is contemplated that the pharmaceutical composition of the invention is useful for treatment of bacterial and/or parasitic infections.

The compounds of the invention may be administered alone or in combination with pharmaceutically acceptable carriers, diluents or excipients, in either single or multiple doses. Accordingly, the compounds of Formula I may be used in the manufacture of a medicament. The pharmaceutical compositions according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 19.sup.th Edition, Gennaro, Ed., Mack Publishing Co., Easton, Pa., 1995.

The pharmaceutical compositions may be specifically formulated for administration by any suitable route such as the oral, rectal, nasal, pulmonary, topical (including buccal and sublingual), transdermal, intracisternal, intraperitoneal, vaginal and parenteral

(including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route, the oral route being preferred. It will be appreciated that the preferred route will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated and the active ingredient chosen.

Pharmaceutical compositions for oral administration include solid dosage forms such as capsules, tablets, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings or they can be formulated so as to provide controlled release of the active ingredient such as sustained or prolonged release according to methods well known in the art.

Liquid dosage forms for oral administration include solutions, emulsions, suspensions, syrups and elixirs.

Pharmaceutical compositions for parenteral administration include sterile aqueous and non-aqueous injectable solutions, dispersions, suspensions or emulsions as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also contemplated as being within the scope of the present invention. Other suitable administration forms include suppositories, sprays, ointments, cremes, gels, inhalants, dermal patches, implants etc.

A typical oral dosage is in the range of from about 0.001 to about 50 mg/kg body weight per day, preferably from about 0.01 to about 30 mg/kg body weight per day, and more preferred from about 0.05 to about 20 mg/kg body weight per day administered in one or more dosages such as 1 to 3 dosages. The exact dosage will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.

The formulations may conveniently be presented in unit dosage form by methods known to those skilled in the art. A typical unit dosage form for oral administration one or more times per day such as 1 to 3 times per day may contain from about 1 μg to about 1000 mg, such as, e.g., from about 10 μg to about 500 mg, from about 50 μg to about 500 mg, preferably from about 0.05 to about 100 mg, more preferably from about 0.1 to about 100 mg and even more preferably from about 0.1 to about 50 mg of a compound according to the invention.

For parenteral routes, such as intravenous, intrathecal, intramuscular and similar administration, typically doses are in the order of about half the dose employed for oral administration.

The compounds of this invention are generally utilized as the free substance or as a pharmaceutically acceptable salt thereof. One example is an acid addition salt of a compound having the utility of a free base. When a compound of the Formula (I) contains a free base such salts are prepared in a conventional manner by treating a solution or suspension of a free base of the Formula (I) with a chemical equivalent of a pharmaceutically acceptable acid, for example, inorganic and organic acids. Representative examples are mentioned above. Physiologically acceptable salts of a compound with a hydroxy group include the anion of said compound in combination with a suitable cation such as sodium or ammonium ion.

For parenteral administration, solutions of the novel compounds of the Formula (I) in sterile aqueous solution, aqueous propylene glycol or sesame or peanut oil may be employed. Such aqueous solutions should be suitable buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. The aqueous solutions are particularly suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.

Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene or water.

Similarly, the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. The pharmaceutical compositions formed by combining the novel compounds of the Formula (I) and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations may conveniently be presented in unit dosage form by methods known in the art of pharmacy.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include a suitable excipient. These formulations may be in the form of powder or granules, as a solution or suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion. If a solid carrier is used for oral administration, the preparation may be tableted, placed in a hard gelatine capsule in powder or pellet form or it can be in the form of a troche or lozenge. The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatine capsule or sterile injectable liquid such as an aqueous or non- aqueous liquid suspension or solution.

A typical tablet, which may be prepared by conventional tabletting techniques, may contain: Core: Active compound (free compound or salt) 5.0 mg Lactosum Ph. Eur. 67.8 mg Cellulose, microcryst. (Avicel) 31.4 mg Amberlite 1.0 mg Magnesii stearas q.s. Coating: Hydroxypropyl methylcellulose approx. 9 mg Acylated monoglyceride approx. 0.9 mg

If desired, the pharmaceutical composition of the invention may comprise the compound of the Formula (I) in combination with further pharmacologically active substances such as those described in the foregoing.

Use of the invention

It is contemplated that the compounds of Formula I are useful in medicine, particularly as protease inhibitors, more particularly as inhibitors of metallo or aspartic proteases, even more particularly as inhibitors of HIV proteases such as HIV-1 proteases. Examples of aspartic protease inhibited by the compounds of the invention are pepsin, cathepsin D and cathepsin E. Examples of metallo protease inhibited by the compounds of the invention are MMP-9, MMP-12, MMP-14 and TACE. The compounds of the invention may also inhibit serine proteases, for example cathepsin G, chymotrypsin or neutrophil elastase. The compounds of the invention may also be useful as a prodrug. Further, the present invention provides useful compositions and formulations of these compounds, including pharmaceutical compositions and formulations of said compounds. Accordingly, the present compounds may be especially useful for the treatment or prevention of diseases caused by HIV, preferably HIV-1 proteases, especially multi-drug resistant mutant HIV-1 proteases. Examples include treatment or prevention of AIDS.

Examples of mutant HIV-1 proteases are CB-1960 and CB-1983 having the following amino acid sequences: CB-1960: NH2-PQITLWQRPF VTVKIGGQIK EALIDTGADD TVFEDLNLPG RWKPKLIGGI GGFVKVREYE EVPIEICGHK AIGTWVGPT PANIIGRNML TQIGCTLNF-COOH

CB1983:

NH2-PQITLWQRPV VKVKIGGQLR EALLDTGADD TVFEDIELPG RWTPKIIGGI GGFVRVRQYD QVPIEVCGHK AIGSVLVGPT PANIIGRNLM TRLGFTLNF-COOH Thus, in one aspect the present invention relates to a method for the treatment of ailments, the method comprising administering to a subject in need thereof an effective amount of a compound or a composition of this invention.

In a preferred aspect the invention relates to a method for the treatment of diseases caused or mediated by HIV proteases, including HIV-1 proteases, the method comprising administering to a subject in need thereof an effective amount of a compound or a composition of this invention.

It is contemplated that an effective amount of a compound or a composition of this invention corresponds to an amount of active ingredient, i.e. active compound or a pharmaceutically acceptable salt or ester thereof, in the range of from about 1 μg to about 1000 mg, such as, e.g., from about 10 μg to about 500 mg, from about 50 μg to about 500 mg, preferably from about 0.05 to about 100 mg, more preferably from about 0.1 to about 100 mg or even more preferably from about 0.1 to about 50 mg per day.

In yet another aspect, the present invention relates to use of a compound of this invention for the preparation of a medicament, preferably a medicament for the treatment or prevention of HIV mediated diseases.

In yet another aspect, there is provided a medicament for the treatment or prevention of HIV mediated diseases, for example AIDS.

The precise amount of an inventive compound which is therapeutically effective, and the route by which such compound is best administered, is readily determined by one of ordinary skill in the art by comparing the blood level of the agent to the concentration required to have a therapeutic effect.

For example, the compounds of this invention may be administered orally to the patient, in a manner such that the concentration of drug is sufficient to inhibit HIV protease or to achieve any other therapeutic indication as disclosed herein. Typically, a pharmaceutical composition containing the compound is administered at an oral dose of between about 0.1 to about 50 mg/kg in a manner consistent with the condition of the patient. Preferably the oral dose would be about 0.5 to about 20 mg/kg. Typically, the compound is generally administered at a dosage of 600 to 1200 mg, preferably about 800 mg, three times a day. The compounds of this invention may also be administered intravenously, i.e. as an intravenous infusion of the compound in 5% dextrose in water or normal saline, or a similar formulation with suitable excipients, is most effective, although an intramuscular bone injection is also useful. Typically, the parenteral dose will be about 0.01 to about 100 mg/kg; preferably between 0.1 and 20 mg/kg, in a manner to maintain the concentration of drug in the plasma at a concentration effective to inhibit HIV protease. The compounds may be administered one to four times daily at a level to achieve a total daily dose of about 0.4 to about 400 mg/kg/day.

No unacceptable toxicological effects are expected when compounds of the present invention are administered in accordance with the present invention.

Accordingly, in another aspect the present invention relates to a compound of the general Formula (I) or any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof for use as a pharmaceutical composition.

The invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one compound of the Formula (I) or any optical or geometric isomer or tautomeric form thereof including mixtures of these or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers or diluents. The present invention is also directed to combinations of the compounds with one or more agents useful in the treatment of AIDS. For example, the compounds of this invention may be effectively administered, whether at periods of pre-exposure and/or post-exposure, in combination with effective amounts of other, known or novel, AIDS antivirals, immunomodulators, antiinfectives, or vaccines. Additionally, the compounds of the invention herein may be used in combination with another class of agents for treating AIDS, which are called HIV entry inhibitors.

It will be understood that the scope of combinations of the compounds of this invention with AIDS antivirals, immunomodulators, anti-infectives, HIV entry inhibitors or vaccines includes in principle any combination with any pharmaceutical composition useful for the treatment of AIDS. In such combinations the compound of the present invention and other active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).

In the following synthetic examples, all of the starting materials were obtained from commercial sources unless otherwise indicated. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. These examples are given to illustrate the invention, not to limit its scope.

EXAMPLES

Materials and Methods The starting materials used herein are commercially available or can be prepared according to procedures previously reported in the literature. Unless otherwise stated commercial starting materials were used without further purification. All solvents were

HPLC grade. Anhydrous solvents were obtained by storing over 4 A activated molecular sieves. Synthetic methods to prepare the compounds of this invention might employ protective groups to mask a reactive functionality or minimize unwanted side reactions. Such protective groups are described generally in Green (1981).

Room temperature is approx. 20 degrees centigrade (°C). Mass spectra (ES-MS spectra) were obtained on a Micromass Quattro micro™ instrument in the positive mode unless otherwise noted.

Materials and abbreviations

AcOH Acetic acid

Ad Adamantyl

ATT 6-Aza-2-Thiothymine (from Aldrich; 99%) Bt Benzotriazole

BTC Bis-trichloromethylcarbonate (from Fluka; 99%)

Cbz Benzyloxy carbonyl

CDI 1 ,1 '-Carbonyldiimidazole (from Fluka; 97%)

DCC Λ/,/V-dicyclohexylcarbodiimide (from Fluka; 99%) DCE 1 ,2-Dichloroethane

DCM Dichloromethane DIG N,N^'-Diisopropylcarbodiimide (from Fluka; 98%)

DIEA Diisopropylethyl amine

Dhbt-OH 3-Hydroxy-1 ,2,3-benzotriazin-4(3H)-one

DMF N,N-Dimethyl formamide DMSO Dimethyl sulfoxide

EDC N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide (from Fluka; 97%)

Fmoc 9-Fluorenylmethoxycarbonyl

HATU O-(7-Azabenzotriazol-1-yl)-N,N,N^',N^'tetramethyluroniumhexafluoro- phosphate (from Aldrich; 97%) HMBA p-Hydroxymethylbenzoic acid (from Bachem; 99%)

HMDS Hexamethyldisilazane

HOAt 1-Hydroxy-7-azabenzotriazole (from Aldrich; 98%)

Melm Λ/-methyl imidazole

MSNT 2,4,6-mesitylenesulfonyl-3-nitro-1 ,2,4-triazolide (from Nova-Biochem) NEM N-Ethyl morpholine (from Fluka; 98%)

PEGA Poly(ethylene glycol)-poly(acryl amide) copolymer

POEPOP Polyoxyethylene-polyoxypropylene copolymer

Pfp Pentafluorophenyl

TBTU O-Benzotriazol-1-yl-N,N,N^',N^'-tetramethyluronium tetrafluoroborate (from Fluka; 98%)

TFA Trifluoroacetic acid

THF Tetrahydrofurane

TIPS Triisopropyl silane

TMS Trimethylsilyl Trt Trityl

Z Benzyloxy carbonyl

Aminodiphenylmethane (96%), hypophosphorous acid (50 w%), phenylacetaldehyde (90+%), 3-fluoro-4-nitrobenzoic acid (98%), NaOMe (95%) were all obtained from Aldrich.

Benzyl chloroformate, N-(9-fluorenylmethoxycarbonyloxy)succinimide, di-tert-butyl dicarbonate, palladium on activated charcoal (10%), hydrobromic acid (48%), 1- bromoadamantane, silver-(l)-oxide, hexamethyldisilazane, methyl bromoacetate, piperidine (98%), SnCI₂ (98%) and borane THF complex solution (~1 M) were all obtained from Fluka. Dess-Martin periodinane was obtained from Relakem. All used amines were obtained from Aldrich or Fluka (purity 95-98%). All used amino acids were obtained from Neosystem, Bachem or Fluka (purity 95- 99%).

All used sulphonyl chlorides were obtained from Aldrich or Fluka (purity 95-99%). All used acid chlorides were obtained from Aldrich, Fluka or Maybridge (purity 95-99%). All used formates were obtained from Aldrich, Fluka or Maybridge (purity 95-99%). All used isocyanates were obtained from Aldrich, Fluka or Maybridge (purity 95-99%). All used inorganics were obtained from Aldrich, Fluka or Riedel de-Haen (purity 95- 99%).

POEPOP resin was synthesized as disclosed in Renil et al. (1996). PEGA resin was obtained form Polymer Labs. TENTA-GEL resin was obtained from Nova-Biochem.

Synthesis of Compounds of the Invention

The illustrative general method for the synthesis of the compounds of the invention is described above in Scheme A. Synthesis of phospinate-carboxylic building blocks (B- VI), (B-VII), (B-VIII) is illustrated below in Scheme B.

Step 1 :

Commercially available hypophosphorous acid 50w/w% (aq) was concentrated in vacuo to approximately 90w/w%. Aminodiphenylmethane (128mmol, 23.4g, 1 eq.) was mixed with hypophosphorous acid (194mmol, 10ml, 1.5 eq.) in a 1 L round bottomed flask along with 400ml 1 ,4-dioxane, flushed with argon. The mixture was heated to 120°C and 1 ,4-dioxane/water was distilled off slowly during the dropwise addition of phenylacetaldehyde (154mmol, 18.0ml, 1.2 eq.) as a 1 :1 mixture with 1 ,4-dioxane. After the addition of the aldehyde, distillation ceased and the temperature was raised to 130°C to distill off half of the remaining 1 ,4-dioxane. The mixture was cooled to room temperature and left overnight after addition of 150ml EtOH. The precipitate was filtered off and washed with EtOH and Et₂O (twice each) and dried in vacuo to yield 25,4g (56%) of a white solid. [M+H]⁺ = 352.1 (calculated: 351.1) ΗBr

Scheme B

Step 2 and 3:

Compound I (35.6mmol, 12.5g, 1 eq.) was transferred to a round-bottomed flask and refluxed at 120°C with 50ml aqueous HBr (48%) for 2 hours. The mixture was concentrated in vacuo and resolvated in 100ml water. The aqueous layer was washed with DCM (3 times) before adjustment of pH to 7 with 10M NaOH (aq). NaHCO₃ (71.2mmol, 7.5g, 2.0 eq.) was added and the mixture was stirred vigorously while Cbz- CI (42.7mmol, 6.0ml, 1.2 eq.) was added dropwise. After 30 minutes the reaction was complete according to LC-MS and pH was adjusted to 1 with 10M HCI (aq). NaCI was added to saturate the mixture before extraction with EtOAc (10 times). The combined organic layers were dried over MgSO₄, filtered and concentrated in vacuo to yield a white solid 12.3g (100%). Due to solubility problems the compound was used crude for the next reaction (purity: -90%; by HPLC/LC-MS). [M+H]⁺ = 320.1 (calculated: 319.1) Step 4:

The crude compound (35.6mmol, 11.4g, 1 eq.) was transferred to a round-bottomed flask fitted with a Claisen adapter and a condenser. The system was flushed with argon. HMDS (178mmol, 37.1ml, 5 eq.) was added and the mixture was heated to 115°C for 2 hours to give a suspension. The temperature was lowered to 95°C and methyl bromoacetate (46.3mmol, 4.3ml, 1.3 eq.) was added dropwise over 30 minutes. After 3 hours the temperature was lowered to 65°C and stirring was continued for 16 hours. The mixture was concentrated in vacuo and the residue resolvated in 600ml EtOAc. The organic layer was washed with 1 M HCI (aq), water and brine (twice each). The aqueous layers were back-extracted once each with EtOAc. The combined organic layers were dried over Na₂SO₄, filtered and concentrated in vacuo, to yield a white solid, 11.5g (82%). The compound was used with no further purification. [M+H]⁺ = 392.1 (calculated: 391.1)

Step 5:

The crude compound was split into 3 portions (9.8mmol, 3.82g, 1 eq.) each of which were suspended in 20ml CHCI₃ in 2-necked round bottomed flasks. The flasks were flushed with argon and Ag₂O (19.6mmol, 4.54g, 2 eq.) was added. The suspensions were refluxed under argon for 15 minutes before the dropwise addition of 1- bromoadamantane (10.8mmol, 2.32g, 1.1 eq.) in 10ml CHCI₃ over 30 minutes. The mixtures were refluxed for another hour before the heating was turned off and the reactions stirred at room temperature for 16 hours. Reactions were complete according to LC-MS. The mixtures were filtered through Celite into the same flask and concentrated in vacuo. The residue was solvated in CHCI₃ and washed with 2.5%

NaHCO₃ (aq), brine and water (twice each). The organic layer was dried over Na₂SO , filtered and concentrated in vacuo to yield 16.2g (100%) of a brownish oil. The product was used for the next step without any further purification. [M+H]⁺ = 526.1 (calculated: 525.2)

Step 6:

The crude compound (30mmol, 15.5g, 1 eq.) was solvated in 200ml MeOH, and 30ml 4M NaOH (aq) was added dropwise over 30 minutes. After 1 hour the hydrolysis was complete according to LC-MS and the mixture was concentrated in vacuo. 200ml Water and 200ml EtOAc was added to the residue and pH of the mixture adjusted to 1 with 10M HCI (aq). The aqueous layer was extracted with EtOAc (3 times). The combined organic layers were dried over Na₂SO₄, filtered and concentrated in vacuo to yield 13.3g (86%) of a pale yellow solid. The product was used for the next step without any further purification. [M+H]⁺ = 512.1 (calculated: 511.2)

Step 7:

The crude compound (9.78mmol, 5.00g, 1 eq.) was suspended in 170ml 32:18:1 EtOAc:MeOH:H₂O. Palladium on activated charcoal (0.98mmol, 1.06g, 0.1 eq.), NaHCO₃ (48.9mmol, 4.11g, 5 eq.) and N-(9-fluorenylmethoxycarbonyloxy)succinimide (14.67mmol, 4.95g, 1.5 eq.) was added and the flask fitted with a balloon filled with H₂. After 16 hours LC-MS showed full conversion. The mixture was filtered through a plug of Celite and concentrated in vacuo to yield a sticky yellow solid. Purification by preparative HPLC yielded 4.2g (72%) of a white solid. [M+H]⁺ = 600.2 (calculated: 599.2)

Step 8:

The crude compound (0.98mmol, 500mg, 1 eq.) was suspended in 30ml 32:18:1 EtOAc:MeOH:H₂O. Palladium on activated charcoal (O.IOmmol, 106mg, 0.1 eq.), NaHCO₃ (4.89mmol, 411g, 5 eq.) and di-tert-butyl dicarbonate (1.47mmol, 321 mg, 1.5 eq.) was added and the flask fitted with a balloon filled with H₂. After 16 hours LC-MS showed full conversion. The mixture was filtered through a plug of Celite and concentrated in vacuo to yield a sticky yellow solid. Purification by preparative HPLC yielded 255mg (55%) of a white solid. [M+H]⁺ = 478.1 (calculated: 477.2)

EXAMPLES 1-66 were all prepared according to method A using TENTAGEL resin derivatized with Rink amide linker. Cleavage of the products from the resin was achieved using TFA:DCM 1 :1 with 2% TIPS.

EXAMPLE 1

(r(S)-1-((S)-2-Benzorb1thiophen-2-yl-1-carbamoyl-ethylcarbamoyl)-2-(3H-imidazol-4-vn- ethylcarbamovn-methylH2-phenyl-1-(quinoline-8-sulfonylamino)-ethvn-phosphinic acid

The title compound can be prepared according to method A using L-histidine in step 1 , 3-(3-benzothiazine)-L-alanine in step 2, no aldehyde in step 3 and 8-quinolinesulfonyl chloride /DCE/DIEA in step 5.

HPLC purity: 84%

Found mass (LC-MS): [M+H]⁺ = 774.3, calculated mass: M = 773.2

EXAMPLE 2 fflS)-1-r(S)-1-Carbamoyl-2-(3H-imidazol-4-vn-ethylcarbamoyll-3-Dhenyl- propylcarbamoyl)-methyl)-{1-r(naphthalene-2-carbonyl)-aminol-2-phenyl-ethyl)- phosphinic acid

The title compound can be prepared according to method A using L-histidine in step 1 , L-styrylalanine in step 2, no aldehyde in step 3 and 2-naphtoyl chloride /DCE/DIEA in step 5.

HPLC purity: 90%

Found mass (LC-MS): [M+H]⁺ = 707.4, calculated mass: M = 706.3

EXAMPLE 3 (IYSV1 -((S)-1 -Carbamoyl-3-phenyl-propylcarbamoyl)-propylcarbamoyll-methylH1 - r(furan-2-carbonyl)-amino1-2-phenyl-ethyl}-phosphinic acid

The title compound can be prepared according to method A using L- homophenylalanine in step 1 , L-2-aminobutyric acid in step 2, no aldehyde in step 3 and 2-furoyl chloride /DCE/DIEA in step 5.

HPLC purity: 98% Found mass (LC-MS): [M+H]⁺ = 583.4, calculated mass: M = 582.2

EXAMPLE 4

H -(4-tert-Butyl-benzenesulfonylamino)-2-phenyl-ethyll-(((S)-1 -f (S)-1 -carbamoyl-2-(3- fluoro-phenyl)-ethylcarbamovn-2-cvclohexyl-ethylcarbamoyl)-methyl)-phosphinic acid

The title compound can be prepared according to method A using m-Fluoro-L- phenylalanine in step 1 , 3-cyclohexyl-L-alanine in step 2, no aldehyde in step 3 and 4- tert-butylbenzenesulfonylchloride /DCE/DIEA in step 5.

HPLC purity: 98%

Found mass (LC-MS): [M+H]⁺ = 757.4, calculated mass: M = 756.3

EXAMPLE 5 {r(S)-1-((E)-(SV1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamovπ- methyl)-ri-(3-fluoro-benzoylamino)-2-phenyl-ethyn-phosphinic acid

The title compound can be prepared according to method A using L-styrylalanine in step 1 , L-leucine in step 2, no aldehyde in step 3 and 3-fluorobenzoyl chloride /DCE/DIEA in step 5.

HPLC purity: 99%

Found mass (LC-MS): [M+H]⁺ = 651.4, calculated mass: M = 650.3

EXAMPLE 6

{r(S)-1-((S)-1-Carbamoyl-2-naphthalen-2-yl-ethylcarbamoyl)-2-(3-methoxy-phenyl)- ethylcarbamovπ-methyl)-π-(4-methoxy-benzenesulfonylamino)-2-phenyl-ethyl1- phosphinic acid

The title compound can be prepared according to method A using 3-(2-naphthyl)-L- alanine in step 1 , 3-methoxy-L-phenylalanine in step 2, no aldehyde in step 3 and 4- methoxy-1-sulfonyl chloride /DCE/DIEA in step 5.

HPLC purity: 99%

Found mass (LC-MS): [M+H]⁺ = 787.4, calculated mass: M = 786.3

EXAMPLE 7 (((^,SV1-r(S)-1-Carbamoyl-2-(4-hvdroxy-phenvπ-ethylcarbamoyll-3-methyl- butylcarbamoyl)-methyl)-(1-r(naphthalene-2-carbonyl -aminol-2-phenyl-ethyl|- phosphinic acid

The title compound can be prepared according to method A using L-tyrosine in step 1 , L-leucine in step 2, no aldehyde in step 3 and 2-naphtoyl chloride /DCE/DIEA in step 5.

HPLC purity: 90% Found mass (LC-MS): [M+H]⁺ = 673.4, calculated mass: M = 672.3

EXAMPLE 8

{r(S)-1-((S)-1-Carbamoyl-3-phenyl-propylcarbamoyl)-2-(3-methoxy-phenyl)- ethylcarbamoyll-methyl)-r2-phenyl-1-(quinoline-8-sulfonylamino)-ethyll-phosphinic acid

The title compound can be prepared according to method A using L- homophenylalanine in step 1 , 3-methoxy-L-phenylalanine in step 2, no aldehyde in step 3 and 8-quinolinesulfonyl chloride /DCE/DIEA in step 5.

HPLC purity: 96%

Found mass (LC-MS): [M+H]⁺ = 772.4, calculated mass: M = 771.3

EXAMPLE 9 fr(S)-1-r(S)-1-Carbamoyl-2-(3H-imidazol-4-yl)-ethylcarbamoyll-2-(3H-imidazol-4-vn- ethylcarbamovn-methyl>-r2-phenyl-1-(quinoline-8-sulfonylamino)-ethyll-phosphinic acid

The title compound can be prepared according to method A using L-histidine in step 1 , L-histidine in step 2, no aldehyde in step 3 and 8-quinolinesulfonyl chloride /DCE/DIEA in step 5.

HPLC purity: 86% Found mass (LC-MS): [M+H]⁺ = 708.4, calculated mass: M = 707.2

EXAMPLE 10

{r(S)-1-r(S)-1-Carbamoyl-2-(3H-imidazol-4-yl)-ethylcarbamoyll-2-(3H-imidazol-4-vn- ethylcarbamoyll-methyl)-(1-r(naphthalene-2-carbonyl)-aminol-2-phenyl-ethyl)- phosphinic acid

The title compound can be prepared according to method A using L-histidine in step 1 , L-histidine in step 2, no aldehyde in step 3 and 2-naphtoyl chloride /DCE/DIEA in step 5.

HPLC purity: 95%

Found mass (LC-MS): [M+H]⁺ = 671.4, calculated mass: M = 670.2

EXAMPLE 11

(KSV-1 -r(S)-1 -Carbamoyl-2-(1 H-indol-3-yl)-ethylcarbamovπ-3-methyl-butylcarbamoyl)- methylH2-phenyl-1-r(thiophene-2-carbonyl)-aminol-ethyl)-phosphinic acid

The title compound can be prepared according to method A using L-tryptophan in step 1 , L-leucine in step 2, no aldehyde in step 3 and 2-thiophenecarbonyl chloride /DCE/DIEA in step 5.

HPLC purity: 97%

Found mass (LC-MS): [M+H]⁺ = 652.4, calculated mass: M = 651.2

EXAMPLE 12

{r(S)-2-Benzorblthiophen-3-yl-1-((S)-1-carbamoyl-3-phenyl-propylcarbamoyl)- ethylcarbamoyll-methyl)-π-(2-naphthalen-2-yl-acetylamino)-2-phenyl-ethyll-phosphinic acid

The title compound can be prepared according to method A using L- homophenylalanine in step 1 , 3-(3-benzothiazine)-L-alanine in step 2, no aldehyde in step 3 and 2-(2-naphtyl)acetyl chloride /DCE/DIEA in step 5.

HPLC purity: 95%

Found mass (LC-MS): [M+H]⁺ = 775.4, calculated mass: M = 774.3

EXAMPLE 13 (((S 1-f(S)-1-Carbamoyl-2-(3H-imidazol-4-yl)-ethylcarbamovn-2-cvclohexyl- ethylcarbamoyl)-methyl)-ri-(2-chloro-benzoylamino)-2-phenyl-ethyll-phosphinic acid

The title compound can be prepared according to method A using L-histidine in step 1 , 3-cyclohexyl-L-alanine in step 2, no aldehyde in step 3 and o-CI-benzoylchloride /DCE/DIEA in step 5.

HPLC purity: 98% Found mass (LC-MS): [M+H]⁺ = 671.5, calculated mass: M = 670.2

EXAMPLE 14

(1 -Benzoylamino-2-phenyl-ethylHr(S)-1 -((S)-1 -carbamoyl-3-phenyl-propylcarbamovD-

2-(3H-imidazol-4-yl)-ethylcarbamoyll-methyl)-phosphinic acid

The title compound can be prepared according to method A using L- homophenylalanine in step 1 , L-histidine in step 2, no aldehyde in step 3 and o-CI- benzoylchloride /DCE/DIEA in step 5.

HPLC purity: 94%

Found mass (LC-MS): [M+H]⁺ = 679.4, calculated mass: M = 678.2

EXAMPLE 15 r(S 1-r(S)-1-Carbamoyl-2-(3H-imidazol-4-yl)-ethylcarbamoyll-2-(3-fluoro-phenyl)- ethylcarbamoyll-methylH2-phenyl-1-r(thiophene-2-carbonyl)-aminol-ethyl}-phosphinic acid

The title compound can be prepared according to method A using L-histidine in step 1 , m-Fluoro-L-phenylalanine in step 2, no aldehyde in step 3 and 2-thiophenecarbonyl /DCE/DIEA in step 5.

HPLC purity: 96%

Found mass (LC-MS): [M+H]⁺ = 655.4, calculated mass: M = 654.2

EXAMPLE 16

{f(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamovn- methylH2-phenyl-1-(quinoline-8-sulfonylamino)-ethyll-phosphinic acid

The title compound can be prepared according to method A using L-styrylalanine in step 1 , L-leucine in step 2, no aldehyde in step 3 and 8-quinolinesulfonyl chloride /DCE/DIEA in step 5.

HPLC purity: 99%

Found mass (LC-MS): [M+H]⁺ = 720.5, calculated mass: M = 719.3

EXAMPLE 17 ({(S)-1-r(S)-1-Carbamoyl-2-(3H-imidazol-4-yl)-ethylcarbamoyll-3-methyl- butylcarbamoyl)-methylH1-f(naphthalene-2-carbonyl)-aminol-2-phenyl-ethyl)- phosphinic acid

The title compound can be prepared according to method A using L-histidine in step 1 , L-leucine in step 2, no aldehyde in step 3 and 2-naphtoyl chloride /DCE/DIEA in step 5.

HPLC purity: 80% Found mass (LC-MS): [M+H]⁺ = 647.5, calculated mass: M = 646.3

EXAMPLE 18

({(S)-2-Biphenyl-4-yl-1-r(S)-1-carbamoyl-2-(4-chloro-phenyl)-ethylcarbamoyll- ethylcarbamoyl)-methyl)-{2-phenyl-1-[(S)-(tetrahvdro-furan-3-yl)oxycarbonylamino1- ethvD-phosphinic acid

The title compound can be prepared according to Method A, using TENTA-GEL resin with a Rink amide linker, L-phenylalanine in step 1 , 4-phenyl-phenyl-L-alanine in step 2, no aldehyde in step 3 and (S)-(+)-3-hydroxytetrahydrofuranyl succidinylcarbonate/DCE/DIEA in step 5.

EXAMPLE 19

({(S)-2-Biphenyl-4-yl-1-f(S)-1-carbamoyl-2-(4-hvdroxy-phenyl)-ethylcarbamoyll- ethylcarbamoyl)-methyl)-π-(4-tert-butyl-benzenesulfonylamino)-2-phenyl-ethvn- phosphinic acid

The title compound can be prepared according to Method A, using TENTA-GEL resin with a Rink amide linker, L-tyrosine in step 1 , 4-phenyl-phenyl-L-alanine in step 2, no aldehyde in step 3 and 4-tert-butylbenzenesulfonyl chloride/DCE/DIEA in step 5.

EXAMPLE 20

(|(S)-1-r(S)-1-Carbamoyl-2-(1H-indol-3-yl)-ethylcarbamoyll-2-cvclohexyl- ethylcarbamoyl)-methyl)-π-(2-naphthalen-2-yl-acetylamino)-2-phenyl-ethyll-phosphinic acid

The title compound can be prepared according to method A using L-tryptophan in step 1 , 3-cyclohexyl-L-alanine in step 2, no aldehyde in step 3 and 2-(2-naphtyl)acetyl chloride /DCE/DIEA in step 5.

HPLC purity: 95%

Found mass (LC-MS): [M+H]⁺ = 750.6, calculated mass: M = 749.3

EXAMPLE 21 π -(4-tert-Butyl-benzenesulfonylamino)-2-phenyl-ethvn-(f (S)-1 -IYS)-1 -carbamoyl-2-(3- fluoro-phenv0-ethylcarbamoyll-3-methyl-butylcarbamoyl)-methyl)-phosphinic acid

The title compound can be prepared according to method A using m-Fluoro-L- phenylalanine in step 1 , L-leucine in step 2, no aldehyde in step 3 and 4-tert- butylbenzenesulfonylchloride /DCE/DIEA in step 5.

HPLC purity: 99%

Found mass (LC-MS): [M+H]⁺ = 717.5, calculated mass: M = 716.3

EXAMPLE 22

(1-Benzyloxycarbonylamino-2-phenyl-ethylHr(S)-1-((S)-2-biphenyl-4-yl-1-carbamoyl- ethylcarbamoyl)-2-(1 H-indol-3-yl)-ethylcarbamovπ-methyl)-phosphinic acid

The title compound can be prepared according to method A using 4-phenyl-L- phenylalanine in step 1 , L-tryptophane in step 2, no aldehyde in step 3 and benzyl- chloroformate /DCE/DIEA in step 5.

HPLC purity: 97% Found mass (LC-MS): [M+H]⁺ = 786.4, calculated mass: M = 785.3

EXAMPLE 23

(r(S)-1 -r(S)-1 -Carbamoyl-2-(1 H-indol-3-yl)-ethylcarbamoyll-2-(3H-imidazol-4-yl)- ethylcarbamoyll-methylH2-phenyl-1-r(thiophene-2-carbonyl)-amino1-ethyll-phosphinic acid

The title compound can be prepared according to method A using L-tryptophane in step 1 , L-histidine in step 2, no aldehyde in step 3 and 2-thiophenecarbonyl /DCE/DIEA in step 5.

HPLC purity: 90%

Found mass (LC-MS): [M+H]⁺ = 676.5, calculated mass: M = 675.2

EXAMPLE 24

{f(S)-1-((S)-1-Carbamoyl-but-3-enylcarbamoyl)-ethylcarbamovn-methyl)-ri-(2- naphthalen-2-yl-acetylamino)-2-phenyl-ethyll-phosphinic acid

The title compound can be prepared according to method A using L-allylglycine in step 1 , L-alanine in step 2, no aldehyde in step 3 and 2-(2-naphtyl)acetyl chloride /DCE/DIEA in step 5.

HPLC purity: 90% Found mass (LC-MS): [M+H]⁺ = 579.5, calculated mass: M = 578.2

EXAMPLE 25

({(S)-1 -r(S)-1 -Carbamoyl-2-(3-fluoro-phenyl)-ethylcarbamoyn-2-pyridin-4-yl- ^' ethylcarbamoyl)-methyl)-f1-(2-naphthalen-2-yl-acetylamino)-2-phenyl-ethvn-phosphinic acid

The title compound can be prepared according to method A using m-Fluoro-L- phenylalanine in step 1 , L-phenylalanine in step 2, no aldehyde in step 3 and 2-(2- naphtyl)acetyl chloride /DCE/DIEA in step 5.

HPLC purity: 99%

Found mass (LC-MS): [M+H]⁺ = 724.6, calculated mass: M = 723.3

EXAMPLE 26

(r(S)-1-((S)-1-Carbamoyl-3-phenyl-propylcarbamoyl)-3-phenyl-propylcarbamovn- methyl)-π-(4-methoxy-benzenesulfonylamino)-2-phenyl-ethvn-phosphinic acid

The title compound can be prepared according to method A using L- homophenylalanine in step 1 , L-homophenylalanine in step 2, no aldehyde in step 3 and 4-methoxybenzenesulfonyl chloride /DCE/DIEA in step 5.

HPLC purity: 99% Found mass (LC-MS): [M+H]⁺ = 735.5, calculated mass: M = 734.3

EXAMPLE 27

{^^-((S^-Benzorblthiophen-S-yl-l-carbamoyl-ethylcarbamovπ-Σ.Σ-diphenyl- ethylcarbamovn-methyl)-ri-(4-methoxy-benzenesulfonylamino)-2-phenyl-ethvπ- phosphinic acid

The title compound can be prepared according to method A using 3-(3-benzothiazine)- L-alanine in step 1 , L-diphenylalanine in step 2, no aldehyde in step 3 and 4- methoxybenzenesulfonyl chloride /DCE/DIEA in step 5.

HPLC purity: 90%

Found mass (LC-MS): [M+H]⁺ = 839.5, calculated mass: M = 838.2

EXAMPLE 28

{r(S)-1-r(S)-1-Carbamoyl-2-(3a,7a-dihvdro-benzorb1thiophen-3-vn-ethylcarbamoyll-2- (3H-imidazol-4-yl)-ethylcarbamoyll-methyl)-{1-r(naphthalene-2-carbonyl)-aminol-2- phenyl-ethyll-phosphinic acid

The title compound can be prepared according to method A using 3-(3-benzothiazine)- L-alanine in step 1 , L-histidine in step 2, no aldehyde in step 3 and 2-naphtoyl chloride chloride /DCE/DIEA in step 5.

HPLC purity: 97%

Found mass (LC-MS): [M+H]⁺ = 737.5, calculated mass: M = 736.2

EXAMPLE 29

(r(S)-1-((S)-1-Carbamoyl-2-naphthalen-2-yl-ethylcarbamoyl)-2-phenyl-ethylcarbamovn- methylH1-r2-(4-methoxy-phenyl)-acetylaminol-2-phenyl-ethyl)-phosphinic acid

The title compound can be prepared according to method A using 3-(2-naphthyl)-L- alanine in step 1 , L-phenylalanine in step 2, no aldehyde in step 3 and 4- methoxybenzenesulfonyl chloride /DCE/DIEA in step 5.

HPLC purity: 90%

Found mass (LC-MS): [M+H]⁺ = 735.5, calculated mass: M = 734.3

EXAMPLE 30

{r(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamovπ- methylH1-r(furan-2-carbonyl)-aminol-2-phenyl-ethyl}-phosphinic acid

The title compound can be prepared according to method A using L-styrylalanine in step 1 , L-leucine in step 2, no aldehyde in step 3 and 2-furoyl chloride /DCE/DIEA in step 5.

HPLC purity: 89% Found mass (LC-MS): [M+H]⁺ = 623.5, calculated mass: M = 622.3

EXAMPLE 31

{r(S)-1-((S)-1-Carbamoyl-3-phenyl-propylcarbamoyl)-propylcarbamoyll-methyl)-ri-(3- fluoro-benzoylamino)-2-phenyl-ethyll-phosphinic acid

The title compound can be prepared according to method A using L- homophenylalanine in step 1 , L-2-aminobutyric acid in step 2, no aldehyde in step 3 and 3-fluorobenzoyl chloride /DCE/DIEA in step 5.

HPLC purity: 99%

Found mass (LC-MS): [M+H]⁺ = 611.5, calculated mass: M = 610.2

EXAMPLE 32

{r(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-propylcarbamovn-methyl)- {1 -r(furan-2-carbonyl)-amino1-2-phenyl-ethyl)-phosphinic acid

The title compound can be prepared according to method A using L-styrylalanine in step 1 , L-2-aminobutyric acid in step 2, no aldehyde in step 3 and 2-furoyl chloride /DCE/DIEA in step 5.

HPLC purity: 99% Found mass (LC-MS): [M+H]⁺ = 595.5, calculated mass: M = 594.2

EXAMPLE 33

{r(S)-1-((S)-1-Carbamoyl-3-phenyl-propylcarbamoyl)-3-methyl-butylcarbamovn-methyl)- π -(3-fluoro-benzoylamino)-2-phenyl-ethvH-phosphinic acid

The title compound can be prepared according to method A using L- homophenylalanine in step 1 , L-leucine in step 2, no aldehyde in step 3 and 3- fluorobenzoyl chloride /DCE/DIEA in step 5.

HPLC purity: 99%

Found mass (LC-MS): [M+H]⁺ = 639.5, calculated mass: M = 638.3

EXAMPLE 34

{r(S)-1-((S)-1-Carbamoyl-3-phenyl-propylcarbamoyl)-3-methyl-butylcarbamovn-methyl)- {1-r(furan-2-carbonyl)-aminol-2-phenyl-ethyl)-phosphinic acid

The title compound can be prepared according to method A using L- homophenylalanine in step 1 , L-leucine in step 2, no aldehyde in step 3 and 2-furoyl chloride /DCE/DIEA in step 5.

HPLC purity: 99% Found mass (LC-MS): [M+H]⁺ = 611.5, calculated mass: M = 610.3

EXAMPLE 35

{r(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-propylcarbamovn-methyl)- f 1 -(3-fluoro-benzoylamino)-2-phenyl-ethyl1-phosphinic acid

The title compound can be prepared according to method A using L-styrylalanine in step 1 , L-2-aminobutyric acid in step 2, no aldehyde in step 3 and 3-fluorobenzoyl chloride /DCE/DIEA in step 5.

HPLC purity: 99%

Found mass (LC-MS): [M+H]⁺ = 623.5, calculated mass: M = 622.2

EXAMPLE 36

({r(S)-((S)-1-Carbamoyl-4-phenyl-butylcarbamoyl)-cvclohexyl-methyll-carbamoyl}- methylH1-(3-fluoro-benzoylamino)-2-phenyl-ethyll-phosphinic acid

The title compound can be prepared according to method A using L-2-amino-5-phenyl- pentanoic acid in step 1 , L-cyclohexylglycine in step 2, no aldehyde in step 3 and 3- fluorobenzoyl chloride /DCE/DIEA in step 5.

HPLC purity: 90%

Found mass (LC-MS): [M+H]⁺ = 679.5, calculated mass: M = 678.3

EXAMPLE 37

{[1-((S)-1-Carbamoyl-2-naphthalen-2-yl-ethylcarbamoyl)-cyclopropylcarbamovn- methyl)-ri-(3-methylsulfanyl-benzoylamino)-2-phenyl-ethyll-phosphinic acid

The title compound can be prepared according to method A using 3-(2-naphthyl)-L- alanine in step 1 , 1-Aminocyclopropane-1 -carboxylic acid in step 2, no aldehyde in step 3 and 3-(Methylthio)benzoic acid /TBTU/NEM in step 5.

HPLC purity: 90%

Found mass (LC-MS): [M+H]⁺ = 705.4, calculated mass: M = 672.2

EXAMPLE 38 ({r(S)-((R)-1-Carbamoyl-4-phenyl-butylcarbamoyl)-cvclohexyl-methvn-carbamoyl)- methylH1-r(2-chloro-pyridine-3-carbonyl)-amino1-2-phenyl-ethyl)-phosphinic acid

The title compound can be prepared according to method A using D-2-amino-5-phenyl- pentanoic acid in step 1 , L-cyclohexylglycine in step 2, no aldehyde in step 3 and 2- chloronicotinoyl chloride /DCE/DIEA in step 5.

HPLC purity: 90%

Found mass (LC-MS): [M+H]⁺ = 696.4, calculated mass: M = 695.3

EXAMPLE 39

([^"(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamovn- methylH2-phenyl-1-r(thiophene-2-carbonvπ-aminol-ethyl)-phosphinic acid

The title compound can be prepared according to method A using L-styrylalanine in step 1 , L-leucine in step 2, no aldehyde in step 3 and 2-thiophenecarbonyl /DCE/DIEA in step 5.

HPLC purity: 93%

Found mass (LC-MS): [M+H]⁺ = 639.4, calculated mass: M = 638.2

EXAMPLE 40 {f(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamovn- methylH1-r(5-methyl-thiophene-2-carbonyl)-amino1-2-phenyl-ethyl)-phosphinic acid

The title compound can be prepared according to method A using D-2-amino-5-phenyl- pentanoic acid in step 1 , L-cyclohexylglycine in step 2, no aldehyde in step 3 and 5- Methyl-2-thiophenecarboxylic acid /TBTU/NEM in step 5.

HPLC purity: 96%

Found mass (LC-MS): [M+H]⁺ = 653.4, calculated mass: M = 652.3

EXAMPLE 41

{1-r(5-Bromo-furan-2-carbonyl)-aminol-2-phenyl-ethylHr(S)-1-((E)-(S)-1-carbamoyl-4- phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamoyl1-methyl)-phosphinic acid

The title compound can be prepared according to method A using L-styrylalanine in step 1 , L-leucine in step 2, no aldehyde in step 3 and 5-Bromo-2-furoic acid /TBTU/NEM in step 5.

HPLC purity: 97%

Found mass (LC-MS): [M+H]⁺ = 701.3, calculated mass: M = 700.2

EXAMPLE 42 {r(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamovn- methyl}-ri-(3-chloro-benzoylamino)-2-phenyl-ethvn-phosphinic acid

The title compound can be prepared according to method A using L-styrylalanine in step 1 , L-leucine in step 2, no aldehyde in step 3 and 3-chlorobenzoyl chloride /DCE/DIEA in step 5.

HPLC purity: 97%

Found mass (LC-MS): [M+H]⁺ = 667.4, calculated mass: M = 666.2

EXAMPLE 43 π -(3-Bromo-benzoylamino)-2-phenyl-ethyll-(r(S)-1 -((E)-(S)-1 -carbamoyl-4-phenyl-but- 3-enylcarbamovD-3-methyl-butylcarbamoyll-methyl)-phosphinic acid

The title compound can be prepared according to method A using L-styrylalanine in step 1 , L-leucine in step 2, no aldehyde in step 3 and 3-bromobenzoyl chloride /DCE/DIEA in step 5.

HPLC purity: 94%

Found mass (LC-MS): [M+H]⁺ = 711.3, calculated mass: M = 710.2

EXAMPLE 44 {f(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamovπ- methyl)-r2-phenyl-1-(3-trifluoromethyl-benzoylamino)-ethyll-phosphinic acid

The title compound can be prepared according to method A using L-styrylalanine in step 1 , L-leucine in step 2, no aldehyde in step 3 and 3-trifluoromethylbenzoyl chloride /DCE/DIEA in step 5.

HPLC purity: 97%

Found mass (LC-MS): [M+H]⁺ = 701.4, calculated mass: M = 700.3

EXAMPLE 45

{r(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamoyll- methyl)-π-(3-methoxy-benzoylamino)-2-phenyl-ethvn-phosphinic acid

The title compound can be prepared according to method A using L-styrylalanine in step 1 , L-leucine in step 2, no aldehyde in step 3 and 3-methoxybenzoyl chloride /DCE/DIEA in step 5.

HPLC purity: 99%

Found mass (LC-MS): [M+H]⁺ = 663.4, calculated mass: M = 662.3

EXAMPLE 46 (r(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamoyll- methyl)-ri-(3-methyl-benzoylamino)-2-phenyl-ethyll-phosphinic acid

The title compound can be prepared according to method A using L-styrylalanine in step 1 , L-leucine in step 2, no aldehyde in step 3 and 3-methyl benzoyl chloride /DCE/DIEA in step 5.

HPLC purity: 97%

Found mass (LC-MS): [M+H]⁺ = 647.5, calculated mass: M = 646.3

EXAMPLE 47

{[(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamoyll- methyl)-ri-(2-fluoro-benzoylamino)-2-phenyl-ethvn-phosphinic acid

The title compound can be prepared according to method A using L-styrylalanine in step 1 , L-leucine in step 2, no aldehyde in step 3 and 2-fluorobenzoyl chloride /DCE/DIEA in step 5.

HPLC purity: 94%

Found mass (LC-MS): [M+H]⁺ = 651.5, calculated mass: M = 650.3

EXAMPLE 48 {r(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamoyll- methyl)-ri-(4-fluoro-benzoylamino)-2-phenyl-ethyll-phosphinic acid

The title compound can be prepared according to method A using L-styrylalanine in step 1 , L-leucine in step 2, no aldehyde in step 3 and 4-fluorobenzoyl chloride /DCE/DIEA in step 5.

HPLC purity: 97%

Found mass (LC-MS): [M+H]⁺ = 651.5, calculated mass: M = 650.3

EXAMPLE 49

(r(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamoyll- methyl)-π-(2-hvdroxy-3-methyl-benzoylamino)-2-phenyl-ethyll-phosphinic acid

The title compound can be prepared according to method A using L-styrylalanine in step 1 , L-leucine in step 2, no aldehyde in step 3 and 2-OH-3-Me-benzoic acid /TBTU/NEM in step 5.

HPLC purity: 86%

Found mass (LC-MS): [M+ f = 663.5, calculated mass: M = 662.3

EXAMPLE 50 {r(S)-1-((S)-1-Carbamoyl-4-phenyl-butylcarbamovπ-3-methyl-butylcarbamovn-methyl)- π -(3-fluoro-benzoylamino)-2-phenyl-ethyll-phosphinic acid

The title compound can be prepared according to method A using L-2-amino-5-phenyl- pentanoic acid in step 1 , L-leucine in step 2, no aldehyde in step 3 and 3-fluorobenzoyl chloride /DCE/DIEA in step 5.

HPLC purity: 96%

Found mass (LC-MS): [M+H]⁺ = 653.5, calculated mass: M = 652.3

EXAMPLE 51

((r((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-methyll-carbamoyl)-methyl)-H- (3-fluoro-benzoylamino)-2-phenyl-ethyll-phosphinic acid

The title compound can be prepared according to method A using L-styrylalanine in step 1 , glycine in step 2, no aldehyde in step 3 and 3-fluorobenzoyl chloride /DCE/DIEA in step 5.

HPLC purity: 77%

Found mass (LC-MS): [M+H]⁺ = 595.4, calculated mass: M = 594.2

EXAMPLE 52 (H -((E)-(S)-1 -Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-ethylcarbamoyll-methyl)-ri -(3- fluoro-benzoylamino)-2-phenyl-ethyri-phosphinic acid

The title compound can be prepared according to method A using L-styrylalanine in step 1 , L-alanine in step 2, no aldehyde in step 3 and 3-fluorobenzoyl chloride /DCE/DIEA in step 5.

HPLC purity: 88%

Found mass (LC-MS): [M+H]⁺ = 609.4, calculated mass: M = 608.2

EXAMPLE 53

([1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-2-methyl-propylcarbamoyll- methyl)-ri-(3-fluoro-benzoylamino)-2-phenyl-ethvn-phosphinic acid

The title compound can be prepared according to method A using L-styrylalanine in step 1 , L-valine in step 2, no aldehyde in step 3 and 3-fluorobenzoyl chloride /DCE/DIEA in step 5.

HPLC purity: 94%

Found mass (LC-MS): [M+H]⁺ = 637.4, calculated mass: M = 636.3

EXAMPLE 54 {ri-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-butylcarbamoyll-methyl)-ri-(3- fluoro-benzoylamino)-2-phenyl-ethvπ-phosphinic acid

The title compound can be prepared according to method A using L-styrylalanine in step 1 , L-norvaline in step 2, no aldehyde in step 3 and 3-fluorobenzoyl chloride /DCE/DIEA in step 5.

HPLC purity: 95%

Found mass (LC-MS): [M+H]⁺ = 637.4, calculated mass: M = 636.3

EXAMPLE 55

{ri-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-2-methyl-butylcarbamoyll- methylH1-(3-fluoro-benzoylamino)-2-phenyl-ethyll-phosphinic acid

The title compound can be prepared according to method A using L-styrylalanine in step 1 , L-isoleucine in step 2, no aldehyde in step 3 and 3-fluorobenzoyl chloride /DCE/DIEA in step 5.

HPLC purity: 97%

Found mass (LC-MS): [M+H]⁺ = 651.4, calculated mass: M = 650.3

EXAMPLE 56 {ri-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-2-cvclopropyl- ethylcarbamoyl1-methyl)-ri-(3-fluoro-benzoylamino)-2-phenyl-ethyll-phosphinic acid

The title compound can be prepared according to method A using L-styrylalanine in step 1 , L-cyclopropylalanine in step 2, no aldehyde in step 3 and 3-fluorobenzoyl chloride /DCE/DIEA in step 5.

HPLC purity: 96%

Found mass (LC-MS): [M+H]⁺ = 649.4, calculated mass: M = 648.3

EXAMPLE 57

{ri-((E -(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-2-cvclohexyl-ethylcarbamoyll- methylH1-(3-fluoro-benzoylamino)-2-phenyl-ethyll-phosphinic acid

The title compound can be prepared according to method A using L-styrylalanine in step 1 , L-cyclohexylalanine in step 2, no aldehyde in step 3 and 3-fluorobenzoyl chloride /DCE/DIEA in step 5.

HPLC purity: 95%

Found mass (LC-MS): [M+H]⁺ = 691.5, calculated mass: M = 690.3

EXAMPLE 58 in -((E)-(S)-1 -Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-4-methyl-pentylcarbamovπ- methylH1-(3-fluoro-benzoylamino)-2-phenyl-ethvπ-phosphinic acid

The title compound can be prepared according to method A using L-styrylalanine in step 1 , L-homoleucine in step 2, no aldehyde in step 3 and 3-fluorobenzoyl chloride /DCE/DIEA in step 5.

HPLC purity: 98%

Found mass (LC-MS): [M+H]⁺ = 665.5, calculated mass: M = 664.3

EXAMPLE 59

(\1 -((E)-(S)-1 -Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-pen-ylcarbamoyll-methylH1 ^■ (3-fluoro-benzoylamino)-2-phenyl-ethyll-phosphinic acid

The title compound can be prepared according to method A using L-styrylalanine in step 1, L-norleucine in step 2, no aldehyde in step 3 and 3-fluorobenzoyl chloride /DCE/DIEA in step 5.

HPLC purity: 98%

Found mass (LC-MS): [M+H]⁺ = 651.5, calculated mass: M = 650.3

EXAMPLE 60 (ri-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-cvclohexyl- propylcarbamoyl1-methyl)-π-(3-fluoro-benzoylamino)-2-phenyl-ethyll-phosphinic acid

The title compound can be prepared according to method A using L-styrylalanine in step 1 , L-homocyclohexylalanine in step 2, no aldehyde in step 3 and 3-fluorobenzoyl chloride /DCE/DIEA in step 5.

HPLC purity: 80%

Found mass (LC-MS): [M+H]⁺ = 705.5, calculated mass: M = 704.3

EXAMPLE 61

(((S)-1-l^"(S)-1-Carbamoyl-2-(4-hvdroxy-phenyl)-ethylcarbamovn-3-phenyl- propylcarbamoyl)-methyl)-ri-(3-fluoro-benzoylamino)-2-phenyl-ethyll-phosphinic acid

The title compound can be prepared according to Method A, using TENTA-GEL resin with a Rink amide linker, L-tyrosine in step 1 , homophenyl-L-alanine in step 2, no aldehyde in step 3 and 3-F-benzoyl chloride/DCE/DIEA in step 5.

EXAMPLE 62

{r(S)-1-((S)-1-Carbamoyl-but-3-enylcarbamoyl)-2-cvclopropyl-ethylcarbamovn-methyl)- n-(2-naphthalen-2-yl-acetylamino)-2-phenyl-ethyll-phosphinic acid

The title compound can be prepared according to Method A, using TENTA-GEL resin with a Rink amide linker, allyl-L-glycine in step 1 , cyclopropyl-L-alanine in step 2, no aldehyde in step 3 and 2-(2-naphtyl)-acetyl chloride/DCE/DIEA in step 5.

EXAMPLE 63 {r(S)-1-((S)-1-Carbamoyl-2-cyclopropyl-ethylcarbamoyl)-2-pyridin-4-yl-ethylcarbamovπ- methyl)-r2-phenyl-1-(2-thiophen-2-yl-acetylamino)-ethyll-phosphinic acid

The title compound can be prepared according to Method A, using TENTA-GEL resin with a Rink amide linker, cyclopropyl-L-alanine in step 1 , 3-(4-pyridyl)-L-alanine in step 2, no aldehyde in step 3 and 2-thiopheneacetyl chloride/DCE/DIEA in step 5. EXAMPLE 64

(r(S)-1-((S)-1-Carbamoyl-2-phenyl-ethylcarbamovπ-2.2-diphenyl-ethylcarbamovπ- methylH2-phenyl-1-r(thiophene-2-carbonyl)-aminol-ethyl)-phosphinic acid

The title compound can be prepared according to Method A, using TENTA-GEL resin with a Rink amide linker, phenyl-L-alanine in step 1 , diphenyl-L-alanine in step 2, no aldehyde in step 3 and 2-thiophenecarbonyl chloride/DCE/DIEA in step 5.

EXAMPLE 65 ({(S)-1-r(S)-1-Carbamoyl-2-(4-chloro-phenyl)-ethylcarbamovn-2-naphthalen-2-yl- ethylcarbamoyl)-methyl)-|^"1-(2-chloro-benzoylamino)-2-phenyl-ethvn-phosphinic acid

The title compound can be prepared according to Method A, using TENTA-GEL resin with a Rink amide linker, p-CI-phenyl-L-alanine in step 1 , 2-naphtyl-L-alanine in step 2, no aldehyde in step 3 and 2-CI-benzoyl chloride/DCE/DIEA in step 5.

EXAMPLE 66

(r(S)-1-((S)-1-Carbamoyl-2-phenyl-ethylcarbamoyl)-2-phenyl-ethylcarbamovn-methyl)- H -(3-fluoro-benzoylamino)-2-phenyl-ethvπ-phosphinic acid

The title compound can be prepared according to Method A, using TENTA-GEL resin with a Rink amide linker, L-phenylalanine in step 1 , 3-(4-pyridyl)-L-alanine in step 2, no aldehyde in step 3 and 3-F-benzoyl chloride/DCE/DIEA in step 5.

ASSAY METHODS

HIV protease inhibition assay

HIV-1 protease inhibitory activity may be assessed using an adaptation of the cell- based fluorescence assay method of Lindsten et al. (2001 ):

HIV-1 protease coding and flanking regions are amplified from a pK-HIV plasmid. The PCR product is cloned in frame with the GFP open reading frame from EGFP-N1 into the pcDNA3 vector, yielding the pcDNA3/GFP-PR construct. For the pcDNA3/PR construct, the protease is amplified and cloned in pcDNA3.

HeLa (human cervical carcinoma cell line) cells are infected e.g. with the recombinant virus vTF7-3 for 2 h before transfection. The transfected cells may be treated with protease inhibitor (the compounds of the invention) for 24 h before harvesting. For protease inhibitor treatment of cultured cells, the inhibitors are initially dissolved in dimethyl sulfoxide and diluted to appropriate concentrations in Iscove's modified Eagle's medium supplemented with 10% fetal calf serum.

Lysates of the HeLa cells are fractionated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and blotted onto nitrocellulose filters. The filters are probed with a rabbit polyclonal anti-GFP serum or anticapsid serum. The filters are developed by enhanced chemiluminescence. Quantification of Western blot bands is performed by densitometry.

Expression of GFP is detected 24 h after transfection using a FACS flow cytometer. Fluorimetric analyses are performed with an LS luminescence spectrometer with excitation wavelengths at 480 nm and emission at 510 nm.

Table 1. IC₅₀ values for selected examples and reference compounds (Amprenavir, Indinavir, Lopinavir, Nelfinavir, Ritonavir, and Saquinavir). ^a Mixture of diastereomers. ^b Pure diastereomer A. ^c Pure diastereomer B. NA = Not applicable.

The invention described and claimed herein is not to be limited in scope by the specific embodiments herein disclosed, since these embodiments are intended as illustrations of several aspects of the invention. Any equivalent embodiments are intended to be within the scope of this invention. Indeed, various modifications of the invention in addition to those shown and described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims.

Various references are cited herein, the disclosure of which are incorporated by reference in their entireties.

Other aspects of the invention

Specific embodiments of the invention are:

1. A compound of formula (I)

R 2. OH O Rs i J O " ,N ^f€ R₃ R₄ (|)

or a pharmaceutically acceptable salt or ester thereof, wherein one of Ri and R₂ is hydrogen and the other is R_y, -COR_y, -COOR_y, -CONR_y or -SO₂R_y, in which R_y is selected from the group consisting of Cι-₆alkyl, C₂-₆alkenyl, C₃- -_locycloalkyl, C₃.₇heterocycloalkyl, aryl, heteroaryl, biaryl, aryl-C^alkyl, heteroaryl-C^ ₅alkyl, Cι-₅alkylaryl, Ci-₅alkyl-heteroaryl,

and C₃- _T-heterocycloalkyl-Ci-_δalkyl, any of which may be mono- or disubstituted with halogen, hydroxy, C_halky!, C-ι-₃alkoxy, amino, cyano, trifluoromethyl, trifluoromethylthio or phenyl; R₃ is selected from hydrogen and a side chain of a natural or unnatural amino acid, where an aromatic ring of a side chain, if any, may be mono- or disubstituted with halogen, hydroxy, C^alkoxy, amino, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio; R₄ is hydrogen or C^-alkyl; R₅ is selected from hydrogen and a side chain of a natural or unnatural amino acid; R₆ is substituted aryl or a group

in which R₇ is selected from hydrogen and a side chain of a natural or unnatural amino acid; and R₈ is selected from hydroxy, methoxy, ethoxy, propoxy, amino, hydrazine, hydroxylamino, arylamino, heteroarylamino and C-i-e-alkylamino.

2. The compound according to item 1 , wherein R_yis a 5- or 6-membered alicyclic or heterocyclic ring, which may be mono- or disubstituted with one or more of fluoro, chloro, bromo, iodo, hydroxy, C-ι-₅alkyl, C-ι-₃alkoxy, amino, cyano, trifluoromethyl, trifluoromethylthio, phenyl.

3. The compound according to item 2, wherein R_yis selected from the group consisting of phenyl, biphenyl, thiophenyl, thiazinyl, furyl/furanyl, pyranyl, pyrrolyl, pyrazolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyridinyl, pyrazinyl, pyrimidinyl, oxazolyl, thiazolyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl and morpholinyl, which may be mono- or disubstituted with one or more of fluoro, chloro, bromo, iodo, hydroxy, methoxy, ethoxy, C^alkyl, amino, cyano, trifluoromethyl, trifluoromethylthio, phenyl.

4. The compound according to item 1 , wherein R_yis a fused 5- or 6-membered alicyclic or heterocyclic ring system, which may be mono- or disubstituted with one or more of fluoro, chloro, bromo, iodo, hydroxy, methoxy, ethoxy, C^alkyl, amino, cyano, trifluoromethyl, trifluoromethylthio, phenyl.

5. The compound according to item 4, wherein R_yis selected from the group consisting of ethoxy naphthyl, benzo[-6]furanyl, chromenyl, benzo[ό]thiophenyl, quinolinyl, benzimidazolyl, purinyl and indolyl which may be mono- or disubstituted with one or more of fluoro, chloro, bromo, iodo, hydroxy, methoxy, Cι-₅alkyl.

6. The compound according to item 1 , wherein one of R-i or R₂ is selected from C^- alkylcarbonyl, C-ι-₆-alkoxycarbonyl, Cι-₆-alkyl-carboxamidyl and C^e-alkylsulfonyl, which is optionally substituted with one or more halogen atoms (fluoro, chloro, bromo, iodo) and/or with a functional group selected among trifluoromethyl, trifluoromethylthio, amino, cyano, hydroxy, methoxy, ethoxy, phenyl, biphenyl, thiophenyl, thiazinyl, furanyl, pyranyl, pyrrolyl, pyrazolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyridinyl, pyrazinyl, pyrimidinyl, oxazolyl, thiazolyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl, ethoxy naphthyl, benzo[ϋ]furanyl, chromenyl, benzo[ό]thiophenyl, quinolinyl, benzimidazolyl, purinyl and indolyl, and where an aryl, a biaryl or heteroaryl substitutent, if any, may itself be substituted with one or more of fluoro, chloro, bromo, iodo, methoxy or ethoxy.

7. The compound according to item 1 , wherein one of R-i or R₂ is selected among cyclopropanoyl, benzoyl, fluorobenzoyl, o-chlorobenzoyl, 2-furoyl, 2-thiophenoyl, 2- naphtoyl, biphenyl-4-carbonyl, trimethylacetyl, methoxyacetyl, 2-thiopheneacetyl, 4- methoxyphenylacetyl, 2-naphthylacetyl, tetrahydrofuranyloxycarbonyl, 2- propanesulfonyl, benzenesulfonyl, frans-ό-styrenesulfonyl, 8-quinolinesulfonyl, 4- methoxybenzenesulfonyl and 4-f-butylbenzenesulfonyl.

8. The compound according to item 1 , wherein one of R^ or R₂ is selected among benzyloxycarbonyl, 3-fluorobenzoyl, o-chlorobenzoyl, 2-thiophenoyl, 2-thiopheneacetyl, 2-(2-naphthyl)-acetyl, 2-naphtoyl, 8-quinolinesulfonyl, tetrahydrofuranyloxycarbonyl and 4----butylbenzenesulfonyl.

9. The compound according to item 1 , wherein R₃ is selected from the group consisting of a side chain of any of the natural alpha amino acids alanine, valine, leucine, isoleucine, praline, phenylalanine, tryptophan, methionine, glycine (i.e. hydrogen), serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, and a side chain of any of the unnatural alpha amino acids diphenyl-L-alanine, 4-phenyl-L-phenylalanine, 3-(3-benzothiophene)-L-alanine, 2- naphthyl-L-alanine, p-chloro-phenyl-L-alanine, m-methoxy-phenyl-L-alanine, m-fluoro- phenyl-L-alanine, styryl-L-alanine, cyclopropyl-alanine, cyclohexyl-alanine, 3-(4- pyridyl)-L-alanine, homophenylalanine, L-allyl-glycine, 2-amino-butanoic acid, norvaline.

10. The compound according to item 1 , wherein R₃ is the side chain of a natural or unnatural amino acid comprising an aromatic ring, which ring may be mono- or disubstituted with any of halogen, hydroxy, C,-₃alkoxy, amino, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio.

11. The compound according to item 1 , wherein R₃ is the side chain of phenylalanine, i.e. benzyl, which is optionally mono- or disubstituted with any of halogen, hydroxy, Cι- ₃alkoxy, amino, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio. 12. The compound according to item 1 , wherein R₄ is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tetf-butyl, n-pentyl or n-hexyl.

13. The compound according to item 1 , wherein R₄ is hydrogen.

14. The compound according to item 1 , wherein R₅ is selected from the group consisting of a side chain of any of the natural alpha amino acids alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine (i.e. hydrogen), serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, and a side chain of any of the unnatural alpha amino acids diphenyl-L-alanine, 4-phenyl-L-phenylalanine, 3-(3-benzothiophene)-L- alanine, 2-naphthyl-L-alanine, p-chloro-phenyl-L-alanine, m-methoxy-phenyl-L-alanine, m-fluoro-phenyl-L-alanine, styryl-L-alanine, cyclopropyl-alanine, cyclohexyl-alanine, 3- (4-pyridyl)-L-alanine, homophenylalanine, L-allyl-glycine, 2-amino-butanoic acid, norvaline.

15. The compound according to item 1 , wherein R₅ is the side chain of an unnatural alpha amino acid.

16. The compound according to item 1 , wherein R₅ is the side chain of one of the unnatural alpha amino acids diphenyl-L-alanine, 4-phenyl-L-phenylalanine, 2-naphthyl- L-alanine, cyclopropyl-alanine, 3-(4-pyridyl)-L-alanine, homophenylalanine.

17. The compound according to item 1 , wherein R₆ is a group

^R8 (II)

18. The compound according to item 1 , wherein R₆ is a group of formula (II) and R₇ is selected from the group consisting of side chains of any of the natural alpha amino acids alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine (i.e. hydrogen), serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, and side chains of any of the unnatural alpha amino acids diphenyl-L-alanine, 4-phenyl-L-phenylalanine, 3-(3-benzothiophene)-L-alanine, 2-naphthyl-L-alanine, p-chloro-phenyl-L-alanine, m- methoxy-phenyl-L-alanine, m-fluoro-phenyl-L-alanine, styryl-L-alanine, cyclopropyl- alanine, cyclohexyl-alanine, 3-(4-pyridyl)-L-alanine, homophenylalanine, L-allyl-glycine, 2-amino-butanoic acid, norvaline.

19. The compound according to item 1 , wherein R₆ is a group of formula (II) and R₇ is the side chain of one of the unnatural alpha amino acids p-chloro-phenyl-L-alanine, cyclopropyl-alanine, L-allyl-glycine, or the side chain of one of the natural alpha amino acids tyrosine, phenylalanine.

20. The compound according to item 1 , wherein R₆ is a group of formula (II) and R₈ is any of hydroxy, methoxy, ethoxy and propoxy.

21. The compound according to item 1 , wherein R₆ is a group of formula (II) and R₈ is any of amino, hydroxylamino and hydrazino.

22. The compound according to item 1 , wherein R₆ is a group of formula (II) and R₈ is methoxy.

23. The compound according to item 1 selected from the group consisting of

2-(S)-[3-benzo[b]thiophen-3-yl-2-(S)-(2-{hydroxy-[2-phenyl-1-(quinoline-8- sulfonylamino)-ethyl]-phosphinoyl}-acetylamino)-propionylamino]-3-(3H-imidazol-4-yl)- propionic amide;

2-(S)-{2-[2-(hydroxy-{1-(S)-[(naphthalene-2-carbonyl)-amino]-2-phenyl-ethyl}- phosphinoyl)-acetylamino]-5-phenyl-pent-4-enoylamino}-3-(3H-imidazol-4-yl)-propionic amide; 2-(S)-{2-[2-(S)-({1-[(furan-2-carbonyl)-amino]-2-phenyl-ethyl}-hydroxy-phosphinoyl)- acetylamino]-butyrylamino}-4-phenyl-butyric amide;

2-(S)-[2-(2-(S)-{[1-(4-tert-butyl-benzenesulfonylamino)-2-phenyl-ethyl]-hydroxy- phosphinoyl}-acetylamino)-3-cyclohexyl-propionylamino]-3-(3-fluoro-phenyl)-propionic amide; 2-(S)-[2-(2-(S)-{[1-(3-fluoro-benzoylamino)-2-phenyl-ethyl]-hydroxy-phosphinoyl}- acetylamino)-4-methyl-pentanoylamino]-5-phenyl-pent-4-enoic amide;

2-(S)-[2-(2-(S)-{hydroxy-[1-(4-methoxy-benzenesulfonylamino)-2-phenyl-ethyl]- phosphinoyl}-acetylamino)-3-(3-methoxy-phenyl)-propionylamino]-3-naphthalen-2-yl- propionic amide; 2-(S)-{2-[2-(S)-(hydroxy-{1-[(naphthalene-2-carbonyl)-amino]-2-phenyl-ethyl}- phosphinoyl)-acetylamino]-4-methyl-pentanoylamino}-3-(4-hydroxy-phenyl)-propionic amide;

2-(S)-[2-(2-(S)-{hydroxy-[2-phenyl-1-(quinoline-8-sulfonylamino)-ethyl]-phosphinoyl}- acetylamino)-3-(3-methoxy-phenyl)-propionylamino]-4-phenyl-butyric amide;

2-(S)-[2-(2-(S)-{hydroxy-[2-phenyl-1-(quinoline-8-sulfonylamino)-ethyl]-phosphinoyl}- acetylamino)-3-(3H-imidazol-4-yl)-propionylamino]-3-(3H-imidazol-4-yl)-propionic amide;

2-(S)-[2-[2-(S)-(hydroxy-{1-[(naphthalene-2-carbonyl)-amino]-2-phenyl-ethyl}- phosphinoyl)-acetylamino]-3-(3H-imidazol-4-yl)-propionylamino]-3-(3H-imidazol-4-yl)- propionic amide;

2-(S)-{2-[2-(S)-(hydroxy-{2-phenyl-1-[(thiophene-2-carbonyl)-amino]-ethyl}- phosphinoyl)-acetylamino]-4-methyl-pentanoylamino}-3-(1 H-indol-3-yl)-propionic amide; 2-(S)-[3-benzo[b]thiophen-3-yl-2-(2-(S)-{hydroxy-[1 -(2-naphthalen-2-yl-acetylamino)-2- phenyl-ethyl]-phosphinoyl}-acetylamino)-propionylamino]-4-phenyl-butyric amide;

2-(S)-[2-(S)- (2-{[1-(3-fluoro-benzoylamino)-2-phenyl-ethyl]-hydroxy-phosphinoyl}- acetylamino)-4-phenyl-butyrylamino]-3-(4-hydroxy-phenyl)-propionic amide;

2-(S)-[3-cyclopropyl-(S)-2-(2-{hydroxy-[1-(2-naphthalen-2-yl-acetylamino)-2-phenyl- ethyl]-phosphinoyl}-acetylamino)-propionylamino]-pent-4-enoic amide;

3-cyclopropyl-2-(S)-[2-(S)-(2-{hydroxy-[2-phenyl-1-(2-thiophen-2-yl-acetylamino)-ethyl]- phosphinoyl}-acetylamino)-3-pyridin-4-yl-propionylamino]-propionic amide;

2-(S)-{2-(S)-[2-(hydroxy-{2-phenyl-1-[(thiophene-2-carbonyl)-amino]-ethyl}- phosphinoyl)-acetylamino]-3,3-diphenyl-propionylamino}-3-phenyl-propionic amide; 2-(S)-[2-(S)-(2-{[1-(2-chloro-benzoylamino)-2-phenyl-ethyl]-hydroxy-phosphinoyl}- acetylamino)-3-naphthalen-2-yl-propionylamino]-3-(4-chloro-phenyl)-propionic amide;

2-(S)-[2-(S)-(2-{[1-(3-fluoro-benzoylamino)-2-phenyl-ethyl]-hydroxy-phosphinoyl}- acetylamino)-3-pyridin-4-yl-propionylamino]-3-phenyl-propionic amide;

2-(S)-[3-biphenyl-4-yl-2-(S)-(2-{hydroxy-[2-phenyl-1-(tetrahydro-furan-3-(S)- yloxycarbonylamino)-ethyl]-phosphinoyl}-acetylamino)-propionylamino]-3-phenyl- propionic amide;

2-(S)-[3-biphenyl-4-yl-2-(S)-(2-{[1-(4-tert-butyl-benzenesulfonylamino)-2-phenyl-ethyl]- hydroxy-phosphinoyl}-acetylamino)-propionylamino]-3-(4-hydroxy-phenyl)-propionic amide; and stereoisomers thereof. 24. The compound according to item 1 , which exhibits an IC₅₀ value of less than 500 μM, preferably less than 100 //M, more preferably less than 50 μM, even more preferably less than 1 μM, especially less than 500 nM, particularly less than 100 nM.

25. Use of a compound according to item 1 or a pharmaceutically acceptable salt thereof for treatment of prevention of HIV mediated diseases, preferably diseases caused or mediated by HIV-1 proteases, especially diseases caused or mediated by multi-drug resistant mutant HIV-1 proteases.

26. A pharmaceutical composition comprising, as an active ingredient, a compound according to item 1 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent for use in the treatment or prevention of HIV mediated diseases, preferably diseases caused or mediated by HIV-1 proteases, especially diseases caused or mediated by multi-drug resistant mutant HIV-1 proteases.

27. The composition according to item 26 in unit dosage form, comprising from about 0.05 to about 500 mg, preferably from about 0.1 to about 100 mg, more preferably from about 0.1 to about 50 mg of the compound according to item 1 or a pharmaceutically acceptable salt or ester thereof.

28. The pharmaceutical composition according to item 26 for oral, nasal, transdermal, pulmonal or parenteral administration.

29. A method for the treatment of ailments, the method comprising administering to a subject in need thereof an effective amount of a compound according to item 1 or a pharmaceutically acceptable salt thereof, or of a composition according to item 25.

30. The method according to item 29, wherein the effective amount of the compound according to item 1 or a pharmaceutically acceptable salt or ester thereof is in the range of from about 0.05 to about 100 mg per day, preferably from about 0.1 to about 50 mg per day.

31. Use of a compound according to item 1 or a pharmaceutically acceptable salt thereof for the preparation of a medicament or a prodrug for treatment of HIV mediated diseases, preferably diseases caused or mediated by HIV-1 proteases, especially diseases caused or mediated by multi-drug resistant mutant HIV-1 proteases.

LITERATURE LIST

Renil, M et al.: POEPOP and POEPS: Inert polyethylene glycol crosslinked polymeric supports for solid synthesis. Tetrahedron Lett., 37, (1996), p. 6185-6188.

Lindsten, K. et al.: Cell-Based Flurescence Assay for Human Immunodeficiency Virus Type 1 Protease Activity, Antimicrobial Agents and Chemotherapy, Sept. 2001 , p. 2616-2622

Pauweis et al. J. Virol. Methods, 20, 1988, p. 309-321

Claims

1. A compound of formula (I)

or a pharmaceutically acceptable salt or ester thereof, wherein

one of R-i and R₂ is hydrogen and the other is R_y, -COR_y, -COOR_y, -CONR_y or -SO₂R_y, in which R_y is selected from the group consisting of Cι-₆alkyl, C₂-₆alkenyl, C₃- ₁₀cycloalkyl, C₃-₇heterocycloalkyl, aryl, heteroaryl, biaryl, C-ι-₅alkyl-aryl, C^alky!- heteroaryl, aryl-C|-₅alkyl, heteroaryl-C^alkyl, C-i-salkyl-Cs-_T-cycloalkyl, and,C-ι-₅alkyl-C₃- ₇heterocycloalkyl, optionally substituted with one or two substituents selected from the group consisting of halogen, hydroxy, C-ι-₅alkyl, C-,-₃alkoxy, amino, cyano, thioC^-alkyl, trifluoromethyl, trifluoromethylthio and phenyl;

R₃ is selected from Ci-salkyl-aryl, C^alkyl-heteroaryl, Cι-₅alkyl-biaryl, d-salkyl-Cs- ₇cycloalkyl and C^salkyl-C^heterocycloalkyl, optionally substituted with one or two substituents selected from the group consisting of halogen, hydroxy, C^alkyl, C-i- ₃alkoxy, amino, cyano, thioCι-₆-alkyl, trifluoromethyl, trifluoromethylthio and phenyl;

R₄ is hydrogen or C^-alkyl;

R₅ is selected from hydrogen, C^alkyl, C₂.₆alkenyl, C₃.₇cycloalkyl, C₃-₇heterocycloalkyl,

C-i-salkyl-biaryl, C₂.₆alkenyl-aryl, C₂.₆alkenyl-heteroaryl, and a side chain of a natural amino acid, optionally - if R₃ is different from hydrogen and a side chain of a natural amino acid - substituted with one or two substituents selected from the group consisting of halogen, hydroxy, C_halky!, C^alkoxy, amino, cyano, thioCi-e-alkyl, trifluoromethyl, trifluoromethylthio and phenyl;

R₇ is selected from hydrogen, C₂.₆alkenyl, C-^alkyl-aryl, C-i-salkyl-heteroaryl, C-,-₅alkyl- biaryl, Cι-₅alkyl-C₃.₇cycloalkyl, C₁.₅alkyl-C₃.₇heterocycloalkyl, C₂.₆alkenyl-aryl, C₂. ₆alkenyl-heteroaryl, C₂-₆alkenyl-biaryl, and a side chain of a natural amino acid, optionally - if R₃ is different from hydrogen and a side chain of a natural amino acid - substituted with one or two substituents selected from the group consisting of halogen, hydroxy, Cι-₅alkyl, C^alkoxy, amino, cyano, thioC.,-₆-alkyl, trifluoromethyl, trifluoromethylthio and phenyl;

R₈ is selected from hydroxy, methoxy, ethoxy, propoxy, amino, hydrazine, aminohydroxyl, aminoaryl, aminoheteroaryl, amino-Cι-₆-alkyl, Ci-salkyl-aryl, and C^ ₅alkyl-heteroaryl.

2. The compound according to claim 1 , wherein one of Ri or R is hydrogen and the other is R_y, -COR_y, -COOR_y, -CONR_y or -SO₂R_y, in which R_y is selected from the group consisting of C₃-ι₀cycloalkyl, C₃-₇heterocycloalkyl, aryl, heteroaryl, biaryl, C-i-salkyl-aryl, Ci-salkyl-heteroaryl,

and C-i- ₅alkyl-C₃. heterocycloalkyl, optionally substituted with one or two substituents selected from the group consisting of halogen, hydroxy, C^alkyl, C^alkoxy, amino, cyano, thioC^e-alkyl, trifluoromethyl, trifluoromethylthio, and phenyl.

3. The compound according to claim 1 or 2, wherein one of R^ or R₂ is hydrogen and the other is R_y, -COR_y, -COOR_y, -CONR_y or -SO₂R_y, in which R_y is selected from the group consisting of C₃-₇heterocycloalkyl, aryl, heteroaryl, Cι-₅alkyl-aryl, and Cι-₅alkyl- heteroaryl, optionally substituted with one or two substituents selected from the group consisting of halogen, hydroxy, C-i-salkyl, C-ι-₃alkoxy, thioC-i-e-alkyl, and trifluoromethyl.

4. The compound according to any of the preceding claims, wherein one of R₁ or R₂ is hydrogen and the other is R_y, -COR_y, -COOR_y, -CONR_y or -SO₂R_y, in which R_y is selected from the group consisting of phenyl, benzyl, thiophenyl, thiophenylmethyl, quinolinyl, naphthyl, naphthylmethyl, furanyl, pyridinyl and tetrahydrofuranyl, optionally substituted with one or two substituents selected from the group consisting of halogen, hydroxy, Cι-₅alkyl, Cι-₃alkoxy, thioCι-₆-alkyl, and trifluoromethyl.

5. The compound according to any of the preceding claims, wherein one of R-i or R₂ is hydrogen and the other is R_y, -COR_y, -COOR_y, -CONR_y or -SO₂R_y, in which R_y is selected from the group consisting of phenyl, benzyl, thiophenyl, thiophenylmethyl, quinolinyl, naphthyl, naphthylmethyl, furanyl, pyridinyl, and tetrahydrofuranyl, optionally substituted with one or two substituents selected from the group consisting of fluoro, chloro, bromo, hydroxy, methyl, tert-butyl, methoxy, methylthio, and trifluoromethyl.

6. The compound according to any of the preceding claims, wherein one of R^ or R₂ is hydrogen and the other is selected from the group consisting of 8-quinolinesulfonyl, 2- naphtoyl, 2-furoyl, 4-f-butylbenzenesulfonyl, 3-fluorobenzoyl, 4- methoxybenzenesulfonyl, 2-thiophenoyl, 2-naphthylacetyl, 2-chlorobenzoyl, 2- fluorobenzoyl, benzyloxycarbonyl, 4-methoxyphenylacetyl, 3-methylthio-phenylacetyl, 2-chloro-3-pyridinoyl, 5-methyl-2-thiophenoyl, 5-bromo-2-furoyl, 3-chlorobenzoyl, 3- bromobenzoyl, 3-trifluoromethylbenzoyl, 3-methoxybenzoyl, 3-methylbenzoyl, 4- fluorobenzoyl, 2-hydroxy-3-methylbenzoyl, 2-thiophenacetyl, and tetrahydro-2- furanyloxycarbonyl.

7. The compound according to any of claims 1-5, wherein one of Ri or R₂ is hydrogen and the other is benzoyl substituted with one or two substituents selected from the group consisting of fluoro, chloro, bromo, hydroxy, methyl, tert-butyl, methoxy, methylthio, and trifluoromethyl.

8. The compound according to any of the preceding claims, wherein R₃ is selected from the group consisting of Cι-₅alkyl-aryl and Cι-₅alkyl-heteroaryl, optionally substituted with one or two substituents selected from the group consisting of halogen, hydroxy, Ci- ₅alkyl, C^alkoxy, amino, cyano, thioC-ι-₆-alkyl, trifluoromethyl, trifluoromethylthio, and phenyl.

9. The compound according to any of the preceding claims, wherein R₃ is C^salkyl-aryl, optionally substituted with one or two substituents selected from the group consisting of halogen, hydroxy, C^alkyl, C^alkoxy, amino, cyano, thioC^-alkyl, trifluoromethyl, trifluoromethylthio, and phenyl.

10. The compound according to any of the preceding claims, wherein R₃ is benzyl, optionally substituted with one or two substituents selected from the group consisting of halogen, hydroxy, C^alkyl, C-ι-₃alkoxy, amino, cyano, thioCι-₆-alkyl, trifluoromethyl, trifluoromethylthio and phenyl.

11. The compound according to any of the preceding claims, wherein R₃ is benzyl.

12. The compound according to any of the preceding claims, wherein R₄ is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl.

13. The compound according to any of the preceding claims, wherein R₄ is hydrogen.

14. The compound according to any of the preceding claims, wherein R₅ is selected from the group consisting of Cι-₆alkyl, C₃-₇cycloalkyl, Cι-₅alkyl-C₃-₇cycloalkyl, Cι-₅alkyl- aryl, C-i-salkyl-heteroaryl, C^alkyl-biaryl, C₂.₆alkenyl-aryl, optionally substituted with one or two substituents selected from the group consisting of halogen, hydroxy, C^ ₅alkyl, C-ι-₃alkoxy, amino, cyano, thioC-ι-₆-alkyl, trifluoromethyl, trifluoromethylthio, and phenyl;

15. The compound according to any of the preceding claims, wherein R₅ is selected from the group consisting of hydrogen, C-ι-₆alkyl, C₃-₇cycloalkyl, C^salkyl-C^cycloalkyl, Cι-₅alkyl-aryl, Ci-salkyl-heteroaryl, C-ι-₅alkyl-biaryl, C₂.₆alkenyl-aryl, optionally substituted with one or two substituents selected from the group consisting of halogen, C-i-₃alkoxy, and phenyl;

16. The compound according to any of the preceding claims, wherein R₅ is selected from the group consisting of benzothiophenylmethyl, (E)-3-phenyl-2-propenyl, ethyl, cyclohexylmethyl, iso-butyl, benzyl, fluoro substituted benzyl, methoxy substituted benzyl, 3H-imidazolylmethyl, 1 H-indolylmethyl, methyl, pyridinylmethyl, phenylethyl, 1 ,1-diphenylmethyl, cyclopropyl, hydrogen, methyl, iso-propyl, propyl, sec-butyl, cyclopropylmethyl, isopentyl, butyl, cyclohexylethyl, napthylmethyl and biphenylmethyl.

17. The compound according to any of claims 1-15, wherein R₅ is C-ι-₆ alkyl.

18. The compound according to claim 17, wherein R₅ is selected from the group concisting of methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, iso-butyl and isopentyl.

19. The compound according to any of claim 1-15, wherein R₅ is C-_M alkyl.

20. The compound according to claim 19, wherein R₅ is selected from the group consisting of butyl, iso-butyl, sec-butyl and tert-butyl.

21. The compound according to any of the preceding claims, wherein R₅ is iso-butyl.

22. The compound according to any of the preceding claims, wherein R₇ is selected from the group consisting of C₂.₆alkenyl, Cι-₅alkyl-aryl, Ci-salkyl-heteroaryl, C^alky!- biaryl, C₂-₆alkenyl-aryl, C₂-₆alkenyl-heteroaryl, and C₂.₆alkenyl-biaryl, optionally substituted with one or two substituents selected from the group consisting of halogen, hydroxy, C_halky!, d-salkoxy, amino, cyano, thioC^e-alkyl, trifluoromethyl, trifluoromethylthio and phenyl.

23. The compound according to any of the preceding claims, wherein R₇ is selected from the group consisting of 3H-imidazolyl-methyl, phenylethyl, benzyl, (E)-3-phenyl-2- propenyl, naphthylmethyl, 1 H-indolylmethyl, biphenylmethyl, allyl, benzothiopenylmethyl, phenylpropyl, and cyclopropylmethyl, optionally substituted with one or two substituents selected from the group consisting of halogen, hydroxy, C-i- ₅alkyl, C^alkoxy, amino, cyano, thiod-β-alkyl, trifluoromethyl, trifluoromethylthio and phenyl.

24. The compound according to any of the preceding claims, wherein R₇ is selected from the group consisting of 3H-imidazolyl-methyl, phenylethyl, benzyl, fluoro substituted benzyl, chloro substituted benzyl, hydroxy substituted benzyl, (E)-3-phenyl- 2-propenyl, naphthylmethyl, 1 H-indolylmethyl, biphenylmethyl, allyl, benzothiopenylmethyl and phenylpropyl.

25. The compound according to any of the preceding claims, wherein R₇is selected from the group consisting of 3H-imidazol-4-yl-methyl, 2-phenylethyl, benzyl, 3-fluoro- benzyl, 4-chloro-benzyl, 4-hydroxy-benzyl, (E)-3-phenyl-2-propenyl, naphth-2-ylmethyl, 1 H-indol-3-ylmethyl, biphenylmethyl, allyl, benzothiopen-3-ylmethyl and 3-phenylpropyl.

26. The compound according to any of the preceding claims, wherein R₇ is (E)-3- phenyl-2-propenyl.

27. The compound according to any of the preceding claims, wherein R₈ is selected from the group consisting of hydroxy, methoxy, ethoxy, propoxy and amino.

28. The compound according to any of the preceding claims, wherein R₈ is selected from the group consisting of hydroxy, methoxy and amino.

29. The compound according to any of the preceding claims, wherein R₈ is amino.

30. The compound according to claim 1 selected from the group consisting of {[(S)-1-((S)-2-Benzo[b]thiophen-2-yl-1-carbamoyl-ethylcarbamoyl)-2-(3H-imidazol-4-yl)- ethylcarbamoyl]-methyl}-[2-phenyl-1 -(quinoline-8-sulfonylamino)-ethyl]-phosphinic acid; ({(S)-1-[(S)-1-Carbamoyl-2-(3H-imidazol-4-yl)-ethylcarbamoyl]-3-phenyl- propylcarbamoyl}-methyl)-{1-[(naphthalene-2-carbonyl)-amino]-2-phenyl-ethyl}- phosphinic acid; {[(S)-1 -((S)-1 -Carbamoyl-3-phenyl-propylcarbamoyl)-propylcarbamoyl]-methyl}-{1 - [(furan-2-carbonyl)-amino]-2-phenyl-ethyl}-phosphinic acid;

[1 -(4-tert-Butyl-benzenesulfonylamino)-2-phenyl-ethyl]-({(S)-1 -[(S)-1 -carbamoyl-2-(3- fluoro-phenyl)-ethylcarbamoyl]-2-cyclohexyl-ethylcarbamoyl}-methyl)-phosphinic acid; {[(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamoyl]- methyl}-[1-(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid; {[(S)-1 -((S)-1 -Carbamoyl-2-naphthalen-2-yl-ethylcarbamoyl)-2-(3-methoxy-phenyl)- ethylcarbamoyl]-methyl}-[1-(4-methoxy-benzenesulfonylamino)-2-phenyl-ethyl]- phosphinic acid;

({(S)-1-[(S)-1-Carbamoyl-2-(4-hydroxy-phenyl)-ethylcarbamoyl]-3-methyl- butylcarbamoyl}-methyl)-{1-[(naphthalene-2-carbonyl)-amino]-2-phenyl-ethyl}- phosphinic acid;

{[(S)-1-((S)-1-Carbamoyl-3-phenyl-propylcarbamoyl)-2-(3-methoxy-phenyl)- ethylcarbamoyl]-methyl}-[2-phenyl-1-(quinoline-8-sulfonylamino)-ethyl]-phosphinic acid; {[(S)-1-[(S)-1-Carbamoyl-2-(3H-imidazol-4-yl)-ethylcarbamoyl]-2-(3H-imidazol-4-yl)- ethylcarbamoyl]-methylH2-phenyl-1-(quinoline-8-sulfonylamino)-ethyl]-phosphinic acid; {[(S)-1 -[(S)-1 -Carbamoyl-2-(3H-imidazol-4-yl)-ethylcarbamoyl]-2-(3H-imidazol-4-yl)- ethylcarbamoyl]-methyl}-{1-[(naphthalene-2-carbonyl)-amino]-2-phenyl-ethyl}- phosphinic acid;

({(S)-1-[(S)-1-Carbamoyl-2-(3H-imidazol-4-yl)-ethylcarbamoyl]-2-cyclohexyl- ethylcarbamoyl}-methyl)-[1-(2-chloro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid; (1-Benzoylamino-2-phenyl-ethyl)-{[(S)-1-((S)-1-carbamoyl-3-phenyl-propylcarbamoyl)- 2-(3H-imidazol-4-yl)-ethylcarbamoyl]-methyl}-phosphinic acid; {[(S)-1-[(S)-1-Carbamoyl-2-(3H-imidazol-4-yl)-ethylcarbamoyl]-2-(3-fluoro-phenyl)- ethylcarbamoyl]-methyl}-{2-phenyl-1-[(thiophene-2-carbonyl)-amino]-ethyl}-phosphinic acid;

{[(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamoyl]- methyl}-[2-phenyl-1 -(quinoline-8-sulfonylamino)-ethyl]-phosphinic acid;

({(S)-1-[(S)-1-Carbamoyl-2-(3H-imidazol-4-yl)-ethylcarbamoyl]-3-methyl- butylcarbamoyl}-methyl)-{1-[(naphthalene-2-carbonyl)-amino]-2-phenyl-ethyl}- phosphinic acid;

({(S)-2-Biphenyl-4-yl-1-[(S)-1-carbamoyl-2-(4-chloro-phenyl)-ethylcarbamoyl]- ethylcarbamoyl}-methyl)-{2-phenyl-1 -[(S)-(tetrahydro-furan-3-yl)oxycarbonylamino]- ethyl}-phosphinic acid;

({(S)-2-Biphenyl-4-yl-1-[(S)-1-carbamoyl-2-(4-hydroxy-phenyl)-ethylcarbamoylj- ethylcarbamoyl}-methyl)-[1-(4-tert-butyl-benzenesulfonylamino)-2-phenyl-ethyl]- phosphinic acid; ({(S)-1 -[(S)-1 -Carbamoyl-2-(1 H-indol-3-yl)-ethylcarbamoyl]-2-cyclohexyl- ethylcarbamoyl}-methyl)-[1-(2-naphthalen-2-yl-acetylamino)-2-phenyl-ethyl]-phosphinic acid;

[1 -(4-tert-Butyl-benzenesulfonylamino)-2-phenyl-ethyl]-({(S)-1 -[(S)-1 -carbamoyl-2-(3- fluoro-phenyl)-ethylcarbamoyl]-3-methyl-butylcarbamoyl}-methyl)-phosphinic acid; (1 -Benzyloxycarbonylamino-2-phenyl-ethyl)-{[(S)-1 -((S)-2-biphenyl-4-yl-1 -carbamoyl- ethylcarbamoyl)-2-(1H-indol-3-yl)-ethylcarbamoyl]-methyl}-phosphinic acid;

{[(S)-1 -[(S)-1 -Carbamoyl-2-(1 H-indol-3-yl)-ethylcarbamoyl]-2-(3H-imidazol-4-yl)- ethylcarbamoyl]-methyl}-{2-phenyl-1-[(thiophene-2-carbonyl)-amino]-ethyl}-phosphinic acid; {[(S)-1 -((S)-1 -Carbamoyl-but-3-enylcarbamoyl)-ethylcarbamoyl]-methyl}-[1 -(2- naphthalen-2-yl-acetylamino)-2-phenyl-ethyl]-phosphinic acid;

({(S)-1-[(S)-1-Carbamoyl-2-(3-fluoro-phenyl)-ethylcarbamoyl]-2-pyridin-4-yl- ethylcarbamoyl}-methyl)-[1-(2-naphthalen-2-yl-acetylamino)-2-phenyl-ethyl]-phosphinic acid; {[(S)-1 -((S)-1 -Carbamoyl-3-phenyl-propylcarbamoyl)-3-phenyl-propylcarbamoyl]- methyl}-[1-(4-methoxy-benzenesulfonylamino)-2-phenyl-ethyl]-phosphinic acid;

{[(S)-1-((S)-2-Benzo[b]thiophen-3-yl-1-carbamoyl-ethylcarbamoyl)-2,2-diphenyl- ethylcarbamoyl]-methyl}-[1-(4-methoxy-benzenesulfonylamino)-2-phenyl-ethylj- phosphinic acid; {[(S)-1-[(S)-1-Carbamoyl-2-(3a,7a-dihydro-benzo[b]thiophen-3-yl)-ethylcarbamoyl]-2-

(3H-imidazol-4-yl)-ethylcarbamoyl]-methyl}-{1-[(naphthalene-2-carbonyl)-amino]-2- phenyl-ethylj-phosphinic acid;

{1 -[(furan-2-carbonyl)-amino]-2-phenyl-ethyl}-phosphinic acid;

[1-(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

{[(S)-1-((S)-1-Carbamoyl-3-phenyl-propylcarbamoyl)-3-methyl-butylcarbamoyl]-methyl}- {1 -[(furan-2-carbonyl)-amino]-2-phenyl-ethyl}-phosphinic acid;

[1-(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

({[(S)-((S)-1-Carbamoyl-4-phenyl-butylcarbamoyl)-cyclohexyl-methyl]-carbamoyl}- methyl)-[1-(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid; {[1 -((S)-1 -Carbamoyl-2-naphthalen-2-yl-ethylcarbamoyl)-cyclopropylcarbamoyl]- methyl}-[1-(3-methylsulfanyl-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

({[(S)-((R)-1-Carbamoyl-4-phenyl-butylcarbamoyl)-cyclohexyl-methyl]-carbamoyl}- methyl)-{1-[(2-chloro-pyridine-3-carbonyl)-amino]-2-phenyl-ethyl}-phosphinic acid;

{[(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamoyl]- methyl}-{2-phenyl-1 -[(thiophene-2-carbonyl)-amino]-ethyl}-phosphinic acid;

{[(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamoyl]- methyl}-{1-[(5-methyl-thiophene-2-carbonyl)-amino]-2-phenyl-ethyl}-phosphinic acid;

{1 -[(5-Bromo-furan-2-carbonyl)-amino]-2-phenyl-ethyl}-{[(S)-1 -((E)-(S)-1 -carbamoyl-4- phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamoyl]-methyl}-phosphinic acid; {[(S)-1 -((E)-(S)-1 -Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamoyl]- methyl}-[1-(3-chloro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

[1-(3-Bromo-benzoylamino)-2-phenyl-ethyl]-{[(S)-1-((E)-(S)-1-carbamoyl-4-phenyl-but-

3-enylcarbamoyl)-3-methyl-butylcarbamoyl]-methyl}-phosphinic acid;

{[(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamoyl]- methyl}-[2-phenyl-1 -(3-trifluoromethyl-benzoylamino)-ethyl]-phosphinic acid; {[(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamoyl]- methyl}-[1-(3-methoxy-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

{[(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamoyl]- methyl}-[1-(3-methyl-benzoylamino)-2-phenyl-ethyl]-phosphinic acid; {[(S)-1 -((E)-(S)-1 -Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamoyl]- methyl}-[1-(2-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

{[(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamoyl]- methyl}-[1 -(2-hydroxy-3-methyl-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

{[(S)-1-((S)-1-Carbamoyl-4-phenyl-butylcarbamoyl)-3-methyl-butylcarbamoyl]-methyl}-

[1 -(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid; {[1 -((E)-(S)-1 -Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-ethylcarbamoyl]-methyl}-[1 -(3- fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

{[1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-2-methyl-propylcarbamoyl]- methyl}-[1-(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

{[1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-butylcarbamoyl]-methyl}-[1-(3- fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

{[1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-2-methyl-butylcarbamoyl]- methyl}-[1-(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

{[1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-2-cyclopropyl- ethylcarbamoyl]-methyl}-[1-(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid; {[1 -((E)-(S)-1 -Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-2-cyclohexyl-ethylcarbamoyl]- methyl}-[1-(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

{[1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-4-methyl-pentylcarbamoyl]- methyl}-[1-(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

{[1 -((E)-(S)-1 -Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-pentylcarbamoyl]-methyl}-[1 - (3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

({(S)-1-[(S)-1-Carbamoyl-2-(4-hydroxy-phenyl)-ethylcarbamoyl]-3-phenyl- propylcarbamoyl}-methyl)-[1-(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid; {[(S)-1 -((S)-1 -Carbamoyl-but-3-enylcarbamoyl)-2-cyclopropyl-ethylcarbamoyl]-methyl}-

[1-(2-naphthalen-2-yl-acetylamino)-2-phenyl-ethyl]-phosphinic acid; {[(S)-1-((S)-1-Carbamoyl-2-cyclopropyl-ethylcarbamoyl)-2-pyridin-4-yl-ethylcarbamoyl]- methyl}-[2-phenyl-1-(2-thiophen-2-yl-acetylamino)-ethyl]-phosphinic acid;

({(S)-1-[(S)-1-Carbamoyl-2-(4-chloro-phenyl)-ethylcarbamoyl]-2-naphthalen-2-yl- ethylcarbamoyl}-methyl)-[1-(2-chloro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

31. The compound according to claim 1 selected from the group consisting of

{[(S)-1-((S)-1-Carbamoyl-3-phenyl-propylcarbamoyl)-propylcarbamoyl]-methyl}-[1-(3- fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

[1 -(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

{[(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamoylj- methyl}-[1-(3-chloro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid; [1-(3-Bromo-benzoylamino)-2-phenyl-ethyl]-{[(S)-1-((E)-(S)-1-carbamoyl-4-phenyl-but-

3-enylcarbamoyl)-3-methyl-butylcarbamoyl]-methyl}-phosphinic acid;

{[(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamoyl]- methyl}-[1-(2-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

{[(S)-1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-3-methyl-butylcarbamoyl]- methyl}-[1 -(4-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

{[1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-2-methyl-propylcarbamoyl]- methyl}-[1-(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid; {[1 -((E)-(S)-1 -Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-butylcarbamoyl]-methyl}-[1 -(3- fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid;

{[1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-2-cyclopropyl- ethylcarbamoyl]-methyl}-[1 -(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid; {[1 -((E)-(S)-1 -Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-pentylcarbamoyl]-methyl}-[1 -

32. The compound according to claim 1 selected from the group consisting of

{[1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-2-methyl-propylcarbamoyl]- methyl}-[1-(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid; {[1 -((E)-(S)-1 -Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-2-methyl-butylcarbamoyl]- methyl}-[1-(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid; {[1-((E)-(S)-1-Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-2-cyclopropyl- ethylcarbamoyl]-methyl}-[1-(3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid; {[1 -((E)-(S)-1 -Carbamoyl-4-phenyl-but-3-enylcarbamoyl)-pentylcarbamoyl]-methyl}-[1 - (3-fluoro-benzoylamino)-2-phenyl-ethyl]-phosphinic acid; and stereoisomers thereof.

33. The compound according to any of the preceding claims , which exhibits an IC₅₀ value in a HIV protease inhibition assay of less than 500 μM, preferably less than 100 μM, more preferably less than 50 μM, even more preferably less than 1 μM, especially less than 500 nM, particularly less than 100 nM, such as, e.g., 75 nM or less, 50 nM or less, or 25 nM or less.

34. The compound according to any of the preceding claims for use in medicine.

35. The compound according to any of the preceding claims for use as a protease inhibitor.

36. The compound according to any of the preceding claims for use as a HIV protease inhibitor, including a HIV-1 protease inhibitor.

37. Use of a compound as defined in any of claims 1-36 or a pharmaceutically acceptable salt thereof for treatment or prevention of HIV mediated diseases, preferably diseases caused or mediated by HIV-1 proteases, especially diseases caused or mediated by multi-drug resistant mutant HIV-1 proteases.

38. A pharmaceutical composition comprising, as an active ingredient, a compound as defined in any of claims 1-36 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent for use in the treatment or prevention of HIV mediated diseases, preferably diseases caused or mediated by HIV- 1 proteases, especially diseases caused or mediated by multi-drug resistant mutant HIV-1 proteases.

39. The pharmaceutical composition according to claim 38 in unit dosage form, comprising from about 1 μg to about 1000 mg, such as, e.g., from about 10 μg to about 500 mg, from about 50 μg to about 500 mg, from about 0.05 to about 100 mg, from about 0.1 to about 100 mg or from about 0.1 to about 50 mg of the compound as defined in any of claims 1-36 or a pharmaceutically acceptable salt or ester thereof.

40. The pharmaceutical composition according to claim 38 for oral, nasal, transdermal, pulmonal or parenteral administration.

41. A method for the treatment of ailments, the method comprising administering to a subject in need thereof an effective amount of a compound as defined in any of claims 1-36 or a pharmaceutically acceptable salt thereof, or a composition as defined in any of claims 38-40.

42. The method according to claim 41 for the treatment of diseases caused or mediated by HIV proteases, including HIV-1 proteases, the method comprising administering to a subject in need thereof an effective amount of a compound as defined in any of claims 1-36 or a pharmaceutically acceptable salt thereof, or a composition as defined in any of claims 38-40.

43. The method according to any of claims 41-42, wherein the effective amount of the compound as defined in any of claims 1-36 or a pharmaceutically acceptable salt or ester thereof is in the range of from about 1 μg to about 1000 mg, such as, e.g., from about 10 μg to about 500 mg, from about 50 μg to about 500 mg, from about 0.05 to about 100 mg, from about 0.1 to about 100 mg or from about 0.1 to about 50 mg per day.

44. Use of a compound as defined in any of claims 1-36 or a pharmaceutically acceptable salt thereof for the preparation of a medicament or a prodrug for treatment of HIV mediated diseases, preferably diseases caused or mediated by HIV-1 proteases, especially diseases caused or mediated by multi-drug resistant mutant HIV- 1 proteases.