MXPA00001498A - Hepatitis c inhibitor peptides - Google Patents

Abstract

Compound of formula (I) active against the Hepatitis C virus, wherein when Q is CH2, a is 0, b is 0 and B is an amide derivative;or when Q is N-Y wherein Y is H or C1-6 alkyl, then B is an acyl derivative;R6, when present, is C1-6 alkyl substituted with carboxyl;R5, when present, is C1-6 alkyl optionally substituted with carboxyl;when Q is either CH2 or N-Y, then Z is oxo or thioxo;R4 is C1-10alkyl, C3-7 cycloalkyl or C4-10 (alkylcycloalkyl);R3 is C1-10 alkyl optionally substituted with carboxyl, C3-7 cycloalkyl or C4-10 (alkylcycloalkyl);W is a proline derivative;R1'is hydrogen, and R1 is C1-6 alkyl optionnaly substituted with thiol;or R1 is C2-6 alkenyl;or R1'and R1 together form a 3- to 6-membered ring;and A is hydroxy or a pharmaceutically acceptable salt or ester thereof.

Description

PEPTIDOS HEPATITIS C INHIBITORS FIELD OF THE INVENTION The present invention relates to compounds, compositions and methods for the treatment of an infection with the hepatitis C virus (HCV). In particular, the present invention provides novel peptides and their analogs, pharmaceutical compositions containing said peptides, and methods for using said peptides in the treatment of an HCV infection.

BACKGROUND OF THE INVENTION Hepatitis C virus (HCV) is the main etiological agent of post-transfusion non-A hepatitis B hepatitis acquired in communities around the world. It is estimated that more than 100 million people around the world are infected by the virus. A high percentage of the carriers are chronically infected and many progress to a chronic liver disease, the so-called chronic hepatitis C. This group is also at high risk of contracting a serious liver disease such as liver cirrhosis, hepatocerebral carcinoma and liver disease.

REF .: 32692 terminal that leads to death. The mechanism by which HCV establishes viral persistence and causes a high rate of chronic liver diseases has not yet been fully explained. It is not known how HCV interacts with the immune system of a host organism and evades it. In addition, the roles of cellular and humoral immune responses in protection against infection and HCV disease have yet to be demonstrated. Immunoglobulins suitable for the prophylaxis of viral hepatitis associated with a transfusion have been reported. However, the Center for Disease Control does not currently recommend immunoglobulins for this purpose. The lack of an effective protective immune response is hampering the development of a vaccine or adequate measures of post-exposure prophylaxis, so that, in the short term, hopes are firmly placed on antiviral interventions. Several clinical studies have been conducted with the goal of identifying pharmaceutical agents that are capable of effectively treating an HCV infection in patients afflicted with chronic hepatitis C. These studies have involved the use of interferon-alpha, alone and in combination with other antiviral agents. These studies have shown that a substantial number of participants in them do not respond to these therapies, and among those who respond favorably, it was found that a large proportion of them relapse after the termination of treatment. Until recently, interferon (IFN) was the only available therapy with proven benefit that had been approved on a clinical scale for patients with chronic hepatitis C. However, the rate of prolonged responses is low, and a treatment with interferon also induces serious side effects (ie, retinopathy, thyroiditis, acute pancreatitis, depression) that decrease the quality of life of the treated patients. Recently, interferon in combination with ribavirin has been approved for patients who do not respond to IFN alone. However, the side effects caused by IFN are not alleviated with this combination therapy. Therefore, there is a need for the development of effective antiviral agents for the treatment of infections caused by HCV, which overcome the limitations of existing pharmaceutical therapies. HCV is an enveloped positive strand RNA virus of the Flaviviridae family. The single stranded HCV RNA genome has a length of appmately 9,500 nucleotides and has a single open reading frame (ORF) that encodes a single large protein of appmately 3,000 amino acids. In infected cells, this polyprotein is cut at multiple sites by cellular and viral proteases to produce the structural and non-structural proteins (NS, non-structural). In the case of HCV, the generation of mature non-structural proteins (NS2, NS3, NS4A, NS4B, NS5A and NS5B) is effected by two viral proteases. The first one, still poorly characterized, cuts at the junction between NS2 and NS3; the second one is a serine protease contained within the N-terminal region of NS3 (hereinafter referred to as NS3 protease) and mediates in all subsequent cuts made downstream of NS3, both in cis, in the NS3-NS4A cut site, as in trans, for remaining sites of NS4A-NS4B, NSAB-NS5A and NS5A-NS5B. The NS4A protein claims to serve multiple functions, acting as a cofactor for the NS3 protease and possibly assisting membrane localization of NS3 and other viral replicase components. The formation of an NS3 protein complex with NS4 appears to be necessary for treatment episodes, enhancing proteolytic efficiency at all sites. The NS3 protein also exhibits activities of nucleoside triphosphatases and RNA-helicases. NS5B is an RNA-dependent RNA polymerase, which is involved in the replication of HCV. A general strategy for the development of antiviral agents is to deactivate enzymes encoded by viruses that are essential for the replication of viruses. In this context, the patent application WO 97/06804 describes the (-) enantiomer of the nucleoside-like compound cytosine-1, 3-oxathiolane (also known as 3TC) as an active against HCV.

This compound, although it has been reported as safe in previous clinical trials against HIV and HBV, has yet to be tested on a clinical scale that it is active against HCV and its mechanism of action against the virus has yet to be reported. Intense efforts to discover compounds that inhibit the NS3 protease or the HCV RNA helicase have led to the following descriptions: U.S. Pat. 5,633,388 describes carboxamides substituted with heterocyclic radicals and compounds analogous thereto as being active against HCV. These compounds are directed against the helicase activity of the NS3 protein of the virus, but clinical trials have not yet been reported. It has been reported by Chu et al. (Tet. Lett., (1996), 7,229-7,232) about a phenanthrene-quinone as having activity against the NS3 protease of HCV in vi tro. No further development on this compound has been reported. An article presented at the Ninth International Conference on Anti-Viral Research, in Urabandai, Fu yshima, Japan (1996) (Antiviral Research, 3_0, 1, 1996, A23 (abstract 19)) reports that certain thiazolidine derivatives are protease inhibitors of the HCV.

Several studies have reported inhibitor compounds of other serine proteases, such as human leukocyte elastase. A family of these compounds is reported in PCT Patent Document WO 95/33764 (Hoechst Marion Roussel, 1995). The peptides described in that application are compounds analogous to morpholinylcarbonylbenzoyl peptides that are structurally different from the peptides of the present invention, WO 98/17679 of Vertex Pharmaceuticals Inc. describes inhibitors of a serine protease, particularly the NS3 protease of hepatitis C virus. These inhibitors are peptide analogues based on the natural substrate NS5A / 5B which contains a function carbonyl activated at the terminal end of C as an essential characteristic. It was also reported that these peptides are active against another serine protease and therefore are not specific for the HCV NS3 protease. Hoffman LaRoche has also reported on hexapeptides that are inhibitors of useful proteinases as antiviral agents for the treatment of an HCV infection. These peptides contain an aldehyde and a boronic acid at the terminal end of C. Steinkühler et al., And Ingallinella et al. Have published about the inhibition of the product NS4A-4B (Biochemistry (1998), 37, 8.899-8.905 and 8.906-8.914 ). These peptides and peptide analogs were published after the priority date of the present application. An advantage of the present invention is that it provides peptides that are inhibitors of the NS3 protease of hepatitis C virus.

A further advantage of one aspect of the present invention resides in the fact that these peptides specifically inhibit the NS3 protease and do not exhibit any significant inhibitory activity at concentrations up to 300 μM against other serine proteases such as human leukocyte elastase. (HLE, from human leukocyte elastase), porcine pancreatic elastase (PPE, from porcine pancreatic elastase), or bovine pancreatic chymotrypsin, or cysteine proteases such as cathepsin B (Cat B) from human liver.

BRIEF DESCRIPTION OF THE INVENTION The authors of the present invention have investigated peptides that are potentially inhibitors of the NS3 protease. The discovery that the N-terminal cleavage product (Ao-D-I-V-P-C-OH) of a compound analogous to a natural substrate of the NS3 protease was inhibitory led to the analogous compounds to peptides of the present invention. Included within the scope of the present invention are the compounds of the formula (I): Pß P5 P4 P3 P2 P1 (I) wherein Q is CH2 or N-Y wherein Y is H or Ci-β alkyl; a) when Q is CH2, a is 0, b is 0 and B is an amide derivative having the formula RnaN (Riib) -C (O) - wherein R a is H, Ci -io alkyl, aryl EC; C7-10 alkylaryl; C3-7 cycloalkyl optionally substituted with carboxyl; (C3-7 cycloalkyl) - (Ci-β alkyl); heterocyclyl-C1-6 alkyl such as I rent and Riib is C1-6 alkyl substituted with carboxyl, (Ci-e alkoxy) carbonyl or phenylmethoxycarbonyl; or C 1 -6 arylalkyl substituted on the aromatic portion with carboxyl; (Ci-e) alkoxycarbonyl or phenylmethoxycarbonyl; or Riia and Riit are joined to form a ring containing nitrogen of 3 to 7 elements, optionally substituted with carboxyl or (Ci-e alkoxy) -carbonyl; or b) when Q is N-Y, a is 0 or 1, b is 0 or 1, and B is an acyl derivative having the formula Rm > -C (O) - wherein Rii is (i) C? -? Alkyl or optionally substituted with carboxyl, Ci-β alkanoyloxy (eg AcOCH2) or C? -6 alkoxy (eg Boc); (ii) C3-7 cycloalkyl optionally substituted with carboxyl, (Ci-e) alkoxycarbonyl or phenylmethoxycarbonyl; (iii) C3-7 cycloalkyl substituted with carboxyl and one to three substituents of the Ci-β alkyl type; (iv) (C 4-10 alkylcycloalkyl) optionally substituted on the cycloalkyl portion with carboxy, (Ci-β) alkoxycarbonyl or phenylmethoxycarbonyl; (v) (v) aryl Ce or Cι or C 7-16 aralkyl optionally substituted with Ci-β alkyl; Re, when present, is C1-C alkyl substituted with carboxyl; R5, when present, is C1-6 alkyl optionally substituted with carboxyl; 0 when Q is either CH2 or N-Y; c) R4 is C1-10 alkyl, is C3-7 cycloalkyl or (alkylcycloalkyl) C4-10; x is oxo or thioxo; R3 is C1-10 alkyl optionally substituted with carboxyl; C3-7 cycloalkyl or C4-10 (alkylcycloalkyl); W is a group of formula II: Formula II wherein R2 is C1-10 alkyl or C3-? cycloalkyl or optionally substituted with carboxyl; Aryl or Cio or C7-16 aralkyl; or W is a group of formula II ': Formula II' wherein X is CH or N; and R2 'is divalent C3-4 alkylene which, together with X and the carbon atom to which X and R2 are attached, forms a ring of 5 or 6 elements, said ring being optionally substituted with OH; SH; NN2; carboxyl; R12; OR12; C (0) 0Ri2, SR12, NHR12 or NR12R12 'wherein 12 and R12' are independently: cyclic C3-I6 alkyl or acyclic Ci-iß alkyl or cyclic C3-16 alkenyl or C-? Acyclic alkenyl, said alkyl or alkenyl optionally substituted with NH 2, OH, 'SH, halo or carboxyl; said alkyl or alkenyl containing optionally at least one heteroatom independently selected from the group consisting of: O, S and N; or R 2 and R 2 'are independently Ce or C 1-6 aryl or C 7-16 aralkyl optionally substituted with C 1-6 alkyl, CF 3, NH 2, OH, SH, halo, carboxyl, Ci-β alkyl substituted with carboxyl or phenyl optionally substituted with C? _6 alkyl, C? -6 alkoxy, halo, acetylamido or nitro; said aryl or aralkyl optionally containing at least one hotero atom independently selected from the group consisting of: O, S and N; said cyclic alkyl, cyclic alkenyl, aryl or aralkyl being optionally condensed with a second ring of 5, 6 or 7 elements to form a cyclic system or a heterocyclic system, said second ring being optionally substituted with NH2, OH, SH, halo, carboxyl or carboxy-lower alkyl; said second ring optionally comprising at least one heteroatom independently selected from the group consisting of: O, S and N; or X is CH or N; and R2 'is a divalent C3-4 alkylene which together with X and the carbon atom to which X and R2' are attached, forms a ring of 5 or 6 elements, which in turn is condensed with a second ring of 5, 6 6 1 elements to form a cyclic system wherein the second ring is substituted with OR12"wherein R12" is aralkyl C7-16 '"Ri' is hydrogen, and Ri is Ci-e alkyl optionally substituted with thiol or halo; Ri is C2-6 alkenyl, or Ri 'and Ri together form a 3 to 6-membered ring optionally substituted with Ci-β alkyl and A is hydroxy or one of its pharmaceutically acceptable salts or esters.

Included within the scope of this invention is a pharmaceutical composition comprising an anti-hepatitis C virus effective amount of a compound of formula I, or one of its therapeutically acceptable salts or esters, in admixture with a support medium and auxiliary agent. pharmaceutically acceptable. An important aspect of the invention involves a method for treating an infection caused by the hepatitis C virus in a mammal, by administering to the mammal an amount effective against the hepatitis C virus of the compound of formula I, and one of its therapeutically acceptable salts or esters, or of a composition as described above. Another important aspect involves a method for inhibiting the replication of the hepatitis C virus, by exposing this virus to an inhibitory amount of the NS3 protease of the hepatitis C virus of the compound of formula I, or one of its salts or esters Therapeutically acceptable, or a composition as described above. Yet another aspect involves a method for treating an infection caused by the hepatitis C virus in a mammal, by administering to the latter an amount effective against the hepatitis C virus of a combination of the compound of formula I, or one of its therapeutically acceptable salts or esters, and an interferon. A pharmaceutical composition comprising the combination in admixture with a pharmaceutically acceptable support medium or auxiliary agent is also within the scope of this invention.

DETAILED DESCRIPTION OF THE INVENTION As used in the present context, the following definitions apply, unless otherwise stated: With reference to the cases in which it is used. { R) or (S) to designate the configuration of a radical, p. ex. R * of the compound of formula I, the designation is made in the context of the compound and not in the context of the radical alone. Natural amino acids, with the exception of glycine, contain a chiral carbon atom. Unless otherwise specifically indicated, compounds containing natural amino acids with the L configuration are preferred. However, applicants consider that, when specified, some amino acids of formula I may be of D or L configuration or may be mixtures of D and L isomers, including racemic mixtures. The designation "Pl, P2, P3, etc." as used in the present context, it refers to the position of the amino acid residues starting from the C terminal end of the analogous compounds to peptides and extending towards the N-terminus (i.e., Pl refers to position 1) from the terminal end of C; P2 is the second position from the terminal end of C, etc.) (see Berger A. &Schechter I., Transactions of the Royal Society London series B257, 249-264 (1970)). The abbreviations for the α-amino acids are set forth in Table A.

Table A As used in the present context, the term "aminobutyric acid" refers to a compound of the formula: As used in the present context, the term "allylglycine" refers to a compound of the formula: - As used in the present context, the term "1-amino-cyclopropylcarboxylic acid" (Acca) refers to a compound of the formula: As used in the present context, the term "tere-butylglycine" refers to a compound of the formula: The term "residue" referring to an amino acid or amino acid derivative means a radical derived from the corresponding α-amino acid by removing the hydroxyl from the carboxy group and a hydrogen from the α-amino group. For example, the terms Gln, Ala, Gly, Lie, Arg, Asp, Phe, Ser, Leu, Cys, Asn, Sar and Tyr represent the "residues" of L-glutamine, L-alanine, glycine, L-isoleucine , L-arginine, L-aspartic acid, L-phenylalanine, L-serine, L-leucine, L-cysteine, L-asparagine, sarcosine and L-tyrosine, respectively. The term "side chain" referring to an amino acid or amino acid residue means a group attached to the carbon atom of the α-amino acid. For example, the side chain R group for glycine is hydrogen, for alanine it is methyl, for valine it is isopropyl. For the R groups or specific side chains of the α-amino acids reference is made to the text of A.L. Lehninger on biochemistry (see chapter 4). The term "halo" as used in the present context means a halogen radical selected from bromine, chlorine, fluorine or iodine. The term "Ci-β alkyl" or "lower alkyl" as used in the present context, either alone or in combination with another radical, means straight or branched chain alkyl radicals containing up to six carbon atoms and include, for example, methyl, ethyl, propyl, butyl, hexyl, 1-methyl-ethyl, 1-methyl-propyl, 2-methyl-propyl, 1,1-dimethyl-ethyl. Similarly, the terms "C?-3 alkyl", C 1-4 alkyl "and" C alquilo-? Alkyl "or" are used to designate alkyl radicals containing up to three, four and ten carbon atoms, respectively. "The term" cycloalkyl " C3-7"as used in the present context, either alone or in combination with another radical, means a cycloalkyl radical containing from three to seven carbon atoms, and includes cyclopropyl, cyclobutyl, cyclohexyl and cycloheptyl. (alkylcycloalkyl) C4-? or "as used in the present context, means a cycloalkyl radical having from three to seven carbon atoms bonded to an alkyl radical, the linked radicals containing up to ten carbon atoms, for example cyclopropylmethyl, cyclopentylethyl , cyclohexylmethyl, cyclohexylethyl or cycloheptylethyl The term "C2- alkenyl" or "as used in the present context, either alone or in combination with another radical, means an alkyl radical as defined above. which contains from 2 to 10 carbon atoms, and also contains at least one double bond. For example, alkenyl includes allyl. The term "C3-C4 alkylene" as used in the present context, means a divalent alkyl radical obtained by the removal of two hydrogen atoms from a straight or branched chain aliphatic hydrocarbon, containing from three to four atoms and includes, for example, -CH2CH2CH-, -CH (CH3) CH2CH2-, -CH2C (CH3) 2- and -CH2CH2CH2CH2-. The term "Ci-β alkoxy" as used in the present context, either alone or in combination with another radical, means the radical -O-C 1-6 alkyl wherein the alkyl is as defined above, containing up to six carbon atoms. The alkoxy includes methoxy, ethoxy, propoxy, 1-methyl-ethoxy, butoxy and 1,1-dimethyl-ethoxy. This latter radical is commonly known as tert-butoxy. The term "Ce or Cyan aryl" as used in the present context, either alone or in combination with another radical, means either an aromatic monocyclic system containing 6 carbon atoms or an aromatic cyclic system containing 10 carbon atoms. carbon. For example, aryl includes phenyl or naphthyl. The term "C7-16 aralkyl" as used in the present context, either alone or in combination with another radical, means an aryl radical as defined above linked through an alkyl group, wherein the alkyl is like it has been previously defined that it contains from 1 to 6 carbon atoms. Aralkyl includes, for example, benzyl and butylphenyl. The term "carboxy-lower alkyl" as used in the present context, either alone or in combination with another radical, means a carboxyl group (COOH) linked through an alkyl group (lower) as above. defined and includes for example butyric acid or the groups: The term "cyclic" or "cyclic system" as used in the present context, either alone or in combination with another radical, means a monovalent radical obtained by removal of a hydrogen from a saturated or unsaturated cyclic hydrocarbon, which contains from three to seven carbon atoms, unless otherwise indicated, and which optionally contains one or more heteroatoms. The term cyclic or cyclic system includes, for example, cyclopropane, cyclopentane, cyclohexane, cyclohexene, decalin, tetralin, indene and naphthalene. The term "heterocycle" as used in the present context, either alone or in combination with another radical, means a monovalent radical obtained by elimination of a hydrogen from a saturated or unsaturated heterocycle of five, six or seven elements, containing one to four heteroatoms selected from nitrogen, oxygen and sulfur. Examples of suitable heterocycles include: pyrrolidine, titrahydrofuran, thiazolidine, pyrrole, thiophene, diazepine, iH-imidazole, 1-methyl-lH-imidazole, isoxazole, thiazole, 2-methyl-thiazole, 2-amino-thiazole, piperidine, 1,4-dioxane, 4-morpholine, pyridine, 2-methyl-pyridine, pyrimidine, 4-methyl-pyrimidine and 2,4-dimethyl-pyrimidine. The term "heterocyclic system" as used in the present context, either alone or in combination with another radical, means a heterocycle as defined above, condensed with one or more other cycles, whether it is a heterocycle or of any other type of cycle. Examples of suitable heterocyclic systems include: thiazolo [4,5-b] -pyridine, quinoline or indole. The term "pharmaceutically acceptable ester" as used in the present context, either alone or in combination with another radical, means esters of the compound of. Formula I in which any of the carboxyl functions of the molecule, but preferably the carboxy terminus, has been replaced by an alkoxycarboxy function: wherein the R moiety of the ester is selected from alkyl (e.g., methyl, ethyl, n-propyl, t-butyl, n-butyl); alkoxyalkyl (eg methoxymethyl); alkoxyacyl (eg acetoxymethyl); arylalkyl (eg benzyl); aryloxyalkyl (eg phenoxymethyl); aryl (eg phenyl), optionally substituted by halogen, C? -4 alquiloalkyl or C? -4 alcoalkoxy- Other appropriate prodrug esters can be found in the work of Design of produgs, Bundgaard, H., editing coordinator, Elsevier (1985) incorporated herein by reference. Such pharmaceutically acceptable esters are usually hydrolyzed in vivo when injected into a mammal and transformed into the acid form of the compound of formula I. The term "pharmaceutically acceptable salt" as used in the present context includes the salts that are derived of pharmaceutically acceptable bases. Examples of suitable bases include choline, ethanolamine and ethylenediamine. It is also considered that Na +, K + and Ca ++ salts are within the scope of the invention (see also Pharmaceutical salts, Birge, SM et al., J. Pharm. Sci. (1977) 6_6, 1-19 incorporated herein by reference) .

Preferred realizations A further preferred group of compounds are those represented by the formula la: P6 P5 P4 P3 P2 P1 < Ia) wherein Y is H or C? _6 alkyl; a is 0 or 1; b is 0 or 1; B is an acyl derivative of the formula Rn-C (O) - wherein Rn is (i) C? -? Alkyl or optionally substituted with carboxyl, Ci.sub.6 alkanoyloxy or Cx.sub.6 alkoxy; (ii) C3-7 cycloalkyl optionally substituted with carboxyl, (Ci-e) alkoxycarbonyl or phenylmethoxycarbonyl; (iii) C3-7 cycloalkyl substituted with carboxyl and one to three C sustitu-β! alkyl substituents; (iv) (alkylcycloalkyl) C -? or optionally substituted in the cycloalkyl portion with carboxy, (C? 6 -alkoxy) -carbonyl or phenylmethoxycarbonyl; (v) H (vi) aryl Ce or C 0 or arylalkyl C7_i6 optionally substituted with C? _ alquilo alkyl; R6, when present, is C6_6 alkyl substituted with carboxyl; RB when present, is C? _6 alkyl optionally substituted with carboxyl; and it is C1-10 alkyl, C3-7 cycloalkyl or (alkylcycloalkyl) C-? 0; R3, W, Rlf R 'and A are as defined above. Preferably, B is an acyl derivative of formula RuC (0) - wherein Ru is: C6_6 alkyl optionally substituted with carboxyl, C1_6 alkanoyloxy or C6_6alkoxy; C13-7 cycloalkyl optionally substituted with carboxyl, MeOC (O), EtOC (O) or BnOC (O); 3-carboxy-propionyl (DAD) or 4-carboxybutyl (DAE); or More preferably, B is acetyl, 3-carboxy-propionyl, 4-carboxybutyryl, AcOCH2C (0), Me3COC (0), p Still more preferably, B is acetyl, 3-carboxy-propionyl (DAD), 4-carboxy-butyryl (DAE), AcOCH2C (0), More preferably, B is acetyl. Preferably, Re, when present, is the side chain of Asp or Glu. Even more preferably, Re, when present, is the side chain of Asp. Alternatively, preferably, a is 0 and then Re is absent. Preferably, Rs, when present, is the side chain of an amino acid selected from the group consisting of: D-Asp, L-Asp, D-Glu, L-Glu, D-Val, L-Val, D- tert-butylglycine (Tbg) and L-Tbg. More preferably, R5, when present, is the side chain of D-Asp, D-Val or D-Glu. Even more preferably, R5, when present, is the side chain of D-Glu. Alternatively, preferably a is 0 and b is 0, and then both Re and R5 are absent. Alternatively, another preferred group of compounds is that represented by formula (Ib): P4 P3 P2 P1 wherein B is preferably an amide of the formula RiiaN (Riib) C (O) wherein Rn »is preferably C? -6 alkyl, C3-6 cycloalkyl, C3-7 (alkylcycloalkyl) optionally substituted with carboxy, C1-3 carboxyalkyl , aryl Ce, C7-10 arylalkyl 2-tetrahydrofuranylmethyl, or 2-thiazolidylmethyl; and Riib is preferably C?-alkyl substituted with carboxyl. More preferably, R 11 * cyclopropylmethyl, isopropyl, carboxyethyl, benzylmethyl, benzyl, or 2-tetrahydrofuranylmethyl. Even more preferably R? N > is C1-4 alkyl substituted with carboxyl. More preferably, Riib is ethyl carboxyl. The compounds of the invention include compounds of formula I wherein, preferably, R "is selected from the group consisting of: isopropyl, cyclohexyl, tere. -butyl, 1-methylpropyl and 2-methylpropyl. More preferably, it is cyclohexyl or 1-methylpropyl. Even more preferably, s is cyclohexyl. The compounds of the invention include compounds of the formula I wherein Z is preferably oxo. Compounds of the invention include compounds of formula I wherein preferably, R3 is the side chain of an amino acid selected from the group consisting of: Lie, Allo-Ile, Chg, Cha, Val, Tbg or Glu. More preferably, R3 is the side chain of Val, Tbg or Chg. Even more preferably, R3 is the side chain of Val. The compounds of the invention include compounds of formula I wherein preferably, W is a group of formula II: wherein R2 is Ci-β alkyl; C1-6 alkyl substituted with carboxyl, Ci-e alkoxycarbonyl, benzyloxycarbonyl or benzylaminocarbonyl; C3-7 cycloalkyl or benzyl. Preferably, R2 is the side chain of Abu, Leu, Phe, Cha, Val, Ala, Asp, Glu, Glu (OBn), or Glu (NHBn). Even more preferably, R2 is the side chain of Asp, aminobutyric acid (Abu) or Val. Still more preferably, the compounds of the invention include compounds of formula I wherein is a group of formula II ': wherein preferably, X is CH or N. More preferably R2 'is a C3 or C4 alkylene (shown in bold type) which binds X to form a ring of 5 or 6 elements of formula III: Formula III R2 'is optionally substituted at any of the positions with R13, wherein X is CH or N; n is 1 or 2; and R13 is as defined above. Even more preferably, X is N. For example, R2 'is preferably attached to propyl at X where X is nitrogen, to form a proline substituted with R13 at P2. Even more preferably R2 'is the chain 3 lateral of proline substituted in position 3-4, or -5 with R13, where R13 is as defined above. Also, even more preferably, R2 'is the proline side chain (as shown in bold type) substituted with R13 at position 4 with the stereochemistry shown in formula III': Formula III ' wherein R13 is preferably OH; SH; NH2; carboxyl; R12; OR12, SR12, NHR12 or NR12R12 'where R12 and R12 'are independently: cyclic C3-I6 alkyl or acyclic C1-16 alkyl or cyclic C3-16 alkenyl or acyclic C2-i6 alkenyl, said alkyl or alkenyl optionally substituted with NH2, OH, SH, halo or carboxyl; said alkyl or alkenyl containing optionally at least one heteroatom independently selected from the group consisting of: 0, S and N; or R12 and R12 'are independently C6-16 aryl or C7 O aralkyl optionally substituted with C1-6 alkyl, NH2, OH, SH, halo, carboxyl or carboxy-lower alkyl; said aryl or aralkyl containing said optionally at least one heteroatom selected independently from the group consisting of: O, S and N; said cyclic alkyl, cyclic alkenyl, aryl or aralkyl being optionally fused with a second ring of 5-, 6- or 7- elements to form a cyclic system or a heterocyclic system, said second ring being optionally substituted with NH2, OH, SH , halo, carboxyl or carboxy-lower alkyl; containing Said second ring optionally at least one heteroatom independently selected from the group consisting of: O, S and N.

Still more preferred, R13 is OR12 SR 12 wherein R12 is a Ce or C14 aryl or C7-16 aralkyl, said first aryl or aralkyl being optionally substituted with C1-6 alkyl, C3-7 cycloalkyl, NH2 , OH, SH, halo, C 1-6 alkoxy, carboxyl, carboxy-lower alkyl, or a second aryl or aralkyl; said first and second aryl or aralkyl optionally containing at least one heteroatom independently selected from the group consisting of: O, S and N. Still more preferably, R 13 is Bn; PhCH2CH2; PhCH2CH2CH2; O-Bn; o-1olylme toxi; m-tolylmethoxy; p-tolylmethoxy; 1-naphthyloxy; 2-naphthyloxy; 1-na f alenylme oxy; 2-naphthalenyl oxy; (4-tert-butyl) methoxy; (3I-Ph) CH20; (4Br-Ph) 0; (2Br-Ph) 0; (3Br-Ph) 0; (4I-Ph) 0; ' (3Br-Ph) CH20; (3,5-Br2-Ph) CH20; Still more preferably, R13 is PhCH2CH2CH2; O-Bn; 1-naphthyloxy; 2-naphthyloxy; 1-naphthalenylmethoxy; 2-naphthalenylmethoxy; Further included within the invention are compounds of formula I wherein Ri 'is preferably hydrogen and Ri is Ci-β alkyl optionally substituted with thiol. For example, Ri is preferably the side chain of the amino acid selected from the group consisting of: cysteine (Cys), aminobutyric acid (Abu), norvaline (Nva), or allylglycine (AlGly). More preferably, Ri 'is H and i is propyl. For example, Ri is more preferably the side chain of the amino acid Nva. Alternatively, preferably Ri 'and Ri together form a ring of 3-6-elements, said ring optionally being substituted with ethyl. For example Ri 'and Ri together preferably form a cyclopropyl ring, a cyclobutyl, a cyclopentyl or a cyclohexyl. Alternatively, more preferably, Ri 'and Ri together form a cyclopropyl ring, for example, Ri' and Ri together may be the side chain (shown in bold letters) of the following amino acid: cited as 1-amino-cyclopropylcarboxylic acid (Acca). Also included in the present invention are compounds of formula I wherein A is preferably hydroxy, a salt or an ester thereof. More preferably, A is hydroxy or an ester thereof. Even more preferably, A is hydroxy. More preferably, the ester is Ci-β alkoxy or (aryl-alkoxy Ci-β). Even more preferably, the ester is methoxy, ethoxy, phenoxy, or benzyloxy. Included within the scope of the invention are the compounds of formula I wherein Q is CH2, a is 0, b is 0, and then B is an amide of formula RnaN (Riib) -C (O) - wherein Rii »is C? -6 alkyl, C3-6 cycloalkyl, C3-7 (alkylcycloalkyl) optionally substituted with carboxy, C1-3 carboxyalkyl, phenyl, C7-10 arylalkyl, 2-tetrahydrofuranylmethyl, or 2-thiazolidylmethyl; and Riib is phenyl; or C 1-6 alkyl substituted with carboxyl or carboxyalkyl C? -; or Q is N-Y wherein Y is H or Ci-β alkyl; a is 0 or 1; b is 0 or 1; and B is an acyl derivative of formula Rn-C (O) - wherein Ru is (i) C6-6 alkyl, C6-6 alkyl substituted with carboxyl, MeC (0) 0-, MeO-, EtO- , MeCH2CH20- or Me3C-0-; (ii) cyclopentyl or cyclohexyl optionally substituted with carboxyl; (iv) (C4-10 alkylcycloalkyl) optionally substituted on the cycloalkyl portion with carboxyl; (v) (vi) phenyl, benzyl or phenylethyl; Re, when present, is CH2C00H or CH2CH2COOH, Rs, when present, is C1-6 alkyl or CH2C00H or CH2CH2C00H; and when Q is either CH2 or N-Y, R is C1-6 alkyl, C3-7 cycloalkyl or (alkylcycloalkyl) C4-? O; z is oxo or thio; R3 is Ci-β alkyl; C3-7 cycloalkyl or C4-? alkyl (alkylcycloalkyl); W is a group of formula II wherein R2 is C1-10 alkyl, C3-10 cycloalkyl, C7-11 aralkyl, CH2COOH or CH2CH2COOH; or W is a group of formula II 'wherein X is N or CH and R2' is the divalent radical -CH2CH2CH2- or -CH2CH2CH2CH2- which together with X and the carbon atom to which X and R2 'are attached form a ring of 5- or 6- elements, said ring optionally being substituted with OR12, C (0) ORi2, SR12, NHR12 or NR12R12 ', wherein R12 and R12' are, independently: cyclic C3-16 alkyl or C1-16 alkyl acyclic or cyclic C3-16 alkenyl or acyclic C2-i6 alkenyl, said alkyl or alkenyl being optionally substituted with NH2, OH, SH, halo or carboxyl; said alkyl or alkenyl containing optionally at least one heteroatom independently selected from the group consisting of: O, S and N; or R 12 and R 12 'are independently C 1 -C 6 aryl or C 7-16 aralkyl optionally substituted with C 1-6 alkyl, CF 3, NH 2, OH, SH, halo, carboxyl, C 1-6 alkyl substituted with carboxyl or phenyl optionally substituted with C 1-6 alkyl, C 1-6 alkoxy or halo; said aryl or aralkyl containing optionally at least one heteroatom independently selected from the group consisting of: O, S and N; said cyclic alkyl, cyclic alkenyl, aryl or aralkyl being optionally fused with a second ring of 5-, 6- or 7- elements to form a cyclic system or a heterocyclic system, said second ring being optionally substituted by NH2, OH, SH, halo, carboxyl or C6-alkyl substituted with carboxyl; said second ring optionally comprising at least one heteroatom independently selected from the group consisting of: O, S and N; or X is N; and R2 'is -CH2CH2CH2- or -CH2CH2CH2CH- which together with X and the carbon atom to which X and R2' are attached form a ring of 5- or 6 elements, which in turn is fused with a phenyl to form a cyclic system wherein the phenyl ring is substituted with OR12 wherein R12 is phenylmethyl or phenylethyl; Ri, is hydrogen and Ri is methyl, thiomethyl, 1-methyl-ethyl, propyl, 1-methylpropyl, 2- (methylthio) ethyl or 2-propylene; or Ri 'and Ri together with the carbon atom to which they are attached form a cyclopropyl which may optionally be substituted with ethyl; and A is hydroxy or a pharmaceutically acceptable salt thereof; Ci-β alkoxy, or (arylalkoxy Ci-β) • Compounds of Formula la are included in the scope of the invention, wherein B is an acyl derivative of the formula Rn-C (O) - wherein Rn is alkoxy C? -6, Ci-io alkyl optionally substituted with carboxyl; C3-7 cycloalkyl optionally substituted with carboxyl or benzylcarboxy; or HOOCCHjN r-CNCOOBn Re is absent; Rs is absent; i is C1-10 alkyl, C3-7 cycloalkyl or (alkylcycloalkyl) C4-10; R3 is C1-10 alkyl, C3-7 cycloalkyl or (alkylcycloalkyl) Co; W is a group of formula II: Formula II wherein R2 alkyl Ci-e, C3-6 cycloalkyl; Ci-e alkyl substituted with carboxyl; arilo Ce or Cío; or C7-11 aralkyl; or W is a group of formula II ': Formula II where X is N; and R2 'is as defined in claim 1, and A is hydroxy or one of its pharmaceutically acceptable salts; methoxy, ethoxy, phenoxy, or benzyloxy.

Included within the scope of the invention are compounds of formula la, wherein B is acetyl, 3-carboxypropionyl, 4-carboxybutyryl, AcOCH2C (O), Me3COC (0), And it is H or Me, a is 0 or 1, b is 0 or 1, Re, when present, is the side chain of Asp or Glu, Rs, when present, is the side chain of Asp, D-Asp, Glu, D-Glu, Val, D-Val or Tbg, Í is the side chain of Val, Chg, Tbg, lie, or Leu, Z is oxo or thioxo, R3 is hydrogen or the side chain of lie, Chg, Val, Glu; W is Abu, Leu, Phe, Val, Ala, Glu, Glu (OBn); or W is the group of formula III ': (III ') wherein R13 is Bn, PhCH2CH2, PhCH2CH2CH2, O-Bn, o-tolylmethoxy, m-tolylmethoxy, p-tolylmethoxy, 1-naphthalenylmethoxy, 2-naphthalenylmethoxy, (4-tert-butyl) benzyloxy, (3I- Ph) CH20, (4Br-Ph) 0, (2Br-Ph) 0, (lBr-Ph) 0, (4I-Ph) 0, (3Br-Ph) CH20, (3, 5-Br2-Ph) CH20, Ri 'is H and Ri is the side chain of Cys, Abu, Nva or allylglycine; or Ri 'and Ri together with the carbon atom to which they are attached form a cyclopropyl; and A is hydroxyl.

Also included within the scope of the invention are compounds of formula Ib, wherein B is an amide of formula Ri (R? U) -C (O) - wherein Rn »is C? -6 alkyl, C3 cycloalkyl -6, (C3-7 alkylcycloalkyl) optionally substituted with carboxy, C1-3 carboxyalkyl, phenyl, C7-10 arylalkyl, 2-tetrahydrofuranylmethyl, or 2-thiazolidylmethyl; and Riib is phenyl; or C 1-6 alkyl substituted with carboxyl or C 1-4 carboxyalkyl; R 4 is cyclohexyl; Z is oxo; R3 is hydrogen or the side chain of lie, Chg, Val, Glu; W is Abu, Leu, Phe, Val, Ala, Glu, Glu (OBn); or W is a group of formula III ': wherein R13 is Bn, PhCH2CH2, PhCH2CH2CH2, O-Bn, o-tolylmethoxy, m-tolylmethoxy, p-tolylmethoxy, 1-naphthalenylmethoxy, 2-naphthalenylmethoxy, (4-tert-butyl) methoxy, (3l-Ph) CH20, (4Br-Ph) 0, (2Br-Ph) 0, (3Br-Ph) 0, (4I-Ph) 0, (3Br-Ph) CH20, (3, 5-Br2-Ph) CH20, Ri 'is H and Ri is the side chain of Cys, Abu, Nva or allylglycine; or Ri 'and Ri together with the carbon atom to which they are attached form a cyclopropyl; and A is hydroxyl.

Also included within the scope of the present invention are compounds of formula I: wherein B is an acyl derivative of formula Rn-C (O) - wherein Ru is Ci-io alkyl optionally substituted with carboxyl; C3-7 cycloalkyl optionally substituted with carboxyl; or a C4-10 (alkylcycloalkyl) optionally substituted on the cycloalkyl portion with carboxyl; or R11 is C6 or C14 aryl or C7-C6 aralkyl optionally substituted with an alkyl Ci-e a is 0 or 1; Re, when present, is alkyl Ci-e optionally substituted with carboxyl; b is 0 or 1; Rs, when present, is Ci-Cß alkyl optionally substituted with carboxyl; Q is N-Y wherein Y is H or Ci-e alkyl; RI is C1-10 alkyl, C3-7 cycloalkyl or (alkylcycloalkyl) C4-10; Z is oxo; R3 is C1-10 alkyl, C3-7 cycloalkyl or (C4-alkyl) alkyl; W is a group of formula II: Formula II wherein R2 is alkyl Ci-e; C 1-6 alkyl optionally substituted with carboxyl; aryl Ce or Cio, or C7-16 aralkyl; W is a group of formula II ': Formula II1 where X is CH or N; and R2 'is C3-4 alkyl, which binds X to form a 5- or 6- element ring, said ring optionally substituted with OH; SH; NH2; carboxyl; R12; OR12, SR12, NHR12 or NR12R12 ', wherein R12 and R12' are independently: cyclic C3-16 alkyl or acyclic Ci-iß alkyl or cyclic C3-16 alkenyl or C2-? Acyclic alkenyl, said alkyl or alkenyl being optionally substituted with NH2, OH, SH, halo or carboxyl; said alkyl or alkenyl containing optionally at least one heteroatom independently selected from the group consisting of: O, S and N; or R12 and R12 'are independently Ce or C14 aryl or C7-16 aralkyl optionally substituted with C1-6 alkyl, NH2, OH, SH, halo, carboxyl, C1-6 alkyl substituted with carboxyl; Said aryl or aralkyl optionally containing at least one heteroatom independently selected from the group consisting of: O, S and N; said cyclic alkyl, alkenyl being Cyclic, aryl or aralkyl optionally fused with a second ring of 5-, 6- or 7- elements to form a cyclic system or a heterocyclic system, said second ring being optionally substituted with NH2, OH, SH, Halo, carboxyl or carbxy (lower) alkyl; said second ring optionally comprising at least one heteroatom independently selected from the group consisting of: O, S and N; Ri ', is hydrogen and Ri is C? -6 alkyl optionally substituted with thiol, or Ci-e alkenyl; or Ri 'and Ri together form a ring of 3- to 6- elements optionally substituted with Ci-β alkyl; and A is OH or one of its pharmaceutically acceptable salts or esters.

Finally, all the compounds of formula I presented in Tables 1 to 4 are included in the scope of the invention. According to an alternative embodiment, the pharmaceutical compositions of this invention may additionally comprise an antiviral agent. Examples of antiviral agents include ribavirin and amantadine. According to another alternative embodiment, the pharmaceutical compositions of this invention may additionally comprise other inhibitors of the HCV protease. According to yet another alternative embodiment, the pharmaceutical compositions of this invention may additionally comprise an inhibitor of other targets in the life cycle of HCV, such as helicase, polymerase or metalloprotease. The pharmaceutical compositions of this invention can be administered orally, parenterally or through an implanted reservoir. Oral administration or administration by injection is preferred. The pharmaceutical compositions of this invention may contain any of the pharmaceutically acceptable and non-toxic carriers, adjuvants or vehicles. In some cases, the pH of the formulation can be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. The term "parenteral" includes, as used herein, subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, and intralesional injection or infusion techniques. The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to techniques known in the art using appropriate dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The pharmaceutical compositions of this invention can be administered orally in any orally acceptable dosage form., including, but not limited to, capsules, tablets, as well as suspensions and aqueous solutions. In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubricating agents such as magnesium stearate are also typically added. For oral administration in the form of a capsule, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying agents and suspension formers. If desired, certain sweetening and / or flavoring and / or coloring agents may be added. Other vehicles or carriers suitable for the formulations and compositions noted above can be found in standard pharmaceutical texts, e.g. ex. in "Remington's Pharmaceutical Sciences," The Science and Practice of Pharmacy, 19 Mack Publishing Company, Easton, Penn., (1995). Dosage levels of between about 0.01 and about 100 mg / kg of body weight per day, preferably between about 0.5 and about 75 mg / kg of body weight per day of the protease inhibitor compounds described herein are useful in a monotherapy for the prevention and treatment of a disease mediated by HCV. Typically, the pharmaceutical compositions of this invention will be administered between about 1 and about 5 times per day, or alternatively, in the form of a continuous infusion. Said administration can be used as a chronic or acute therapy. The amount of the active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending on the host treated and the particular mode of administration. A typical preparation will contain between about 5% to about 95% of the active compound (weight / weight, w / w). Preferably, such preparations contain between about 20% to about 80% of the active compound. As will be appreciated by one skilled in the art, lower or higher doses than those mentioned above may be required. The specific dosing and treatment regimens for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration , the excretion regimen, the combination of drugs, the severity and course of the infection, the disposition of the patient for the infection and the criterion of the doctor who is performing the treatment. Generally, the treatment is initiated with small dosages substantially less than the optimal dose of the peptide. After that, the dosage is increased by small increments until the optimum effect is reached under the circumstances. In general, the compound is administered in a highly desirable manner at a level of concentrations that will generally provide antivirally effective results without causing any deleterious or deleterious side effects. When the compositions of this invention comprise a combination of a compound of formula I and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent should be present at dosage levels between about 10 to 100%, and more preferably between about 10 and 80% of the dosage normally administered in a monotherapy regimen. When these compounds or their pharmaceutically acceptable salts are formulated together with a pharmaceutically acceptable carrier, the resulting composition can be administered to mammals, such as humans, to inhibit the HCV NS3 protease or to treat or prevent an infection. caused by the HCV virus. Said treatment can also be achieved by using the compounds of this invention in combination with agents which include, but are not limited to: immunity modulating agents, such as interferons a-, β-, or; other antiviral agents such as ribavirin, amantadine; other inhibitors of the HCV NS3 protease; inhibitors of other targets in the HCV life cycle such as helicase, polymerase, metalloprotease, or the entry of internal ribosomes; or combinations of these. The additional agents can be combined with the compounds of this invention to create a single dosage form. Alternatively, these additional agents can be administered separately to a mammal as part of a multiple dosage form. Correspondingly, another embodiment of this invention provides methods for inhibiting the activity of the HCV NS3 protease in mammals by administration of a compound of the formula I, wherein the substituents are as defined above. In a preferred embodiment, these methods are useful for decreasing the activity of the HCV NS3 protease in a mammal. If the pharmaceutical composition undertakes only one compound of this invention as the active component, said methods may further comprise the step of administering to said mammal an agent selected from an immunity-modulating agent, an antiviral agent, an inhibitor of an HCV pretease. , or an inhibitor of other targets in the HCV life cycle such as helicase, polymerase, or metalloprotease. Such an additional agent may be administered to the mammal prior to, concurrent with, or following the administration of the compositions of this invention. In an alternative preferred embodiment, these methods are useful for inhibiting virus replication in a mammal. Such methods are useful for treating or preventing a disease caused by HCV. If the pharmaceutical composition comprises only one compound of this invention as the active component, said methods may further comprise the step of administering to said mammal an agent selected from an immunity modulating agent, an antiviral agent, an inhibitor of an HCV protease. , or an inhibitor of other targets in the HCV life cycle. Said additional agent may be administered to the mammal prior to, concurrent with, or following the administration of the composition according to this invention. The compounds described herein can also be used as laboratory reagents. The compounds of this invention can be used to treat or prevent virus contamination of materials and thereby reduce the risk of virus infection of laboratory or medical personnel or of patients who come in contact with such materials (e.g. eg blood, tissues, surgical instruments and surgical garments, instruments and clothing of laboratories and equipment and materials for blood collection).

PROCESS The compounds of the present invention were synthesized according to the procedure illustrated in scheme 1 (wherein PGI is a carboxyl protecting group and PG2 is an amino protecting group): P1-PG1 PG2-P2 PG2-P2-P1-PG1 P2-P1-PG1 + PG2-P3 PG2-P3-P2-P1-PG1 P3-P2-P1-PG1 + PG2-P4 PG2-P4-P3-P2-P1-PG1 P4-P3-P2-P1-PG1 + PG2-P5-OH PG2-P5-P4-P3-P2-P1-PG * G2-P6-P5-P4-P3-P2-P1-PG ' P6-P5.P4-P3-P2-P1-PG1 + BOH B-P6-P5-P4-P3-P2-P1-PG1 ß-Pß-P5-P4-P3-P2-P1OH (!) Briefly, Pl, P2, P3, P4, and optionally P5 and P6 can be linked by well known peptide coupling techniques. The groups Pl, P2, P3, P4, and P5 as well as P6 can be linked in any order as long as the final compound corresponds to peptides of formula I. For example, P6 can be linked to P5 to give P5- P6 which is linked to P4-P3-P2-P1; or P6 binds to P5-P4-P3-P2 and then binds to an appropriately protected Pl at the terminal end of C. Generally, the peptides are elongated by deprotection of the a-amino group from the N-terminal residue and coupling the carboxyl group deprotected from the following amino acid appropriately protected in N through a peptide bond using the methods described. This deprotection and coupling process is repeated until the desired sequence is obtained. This coupling can be performed with the constituent amino acids in a staggered manner, as described in Scheme I, or by fragment condensation. (of two or more amino acids), or a combination of both methods, or by a synthesis of solid phase peptides according to the method originally described in Merrifield, J. Am. Chem. Soc. (1963), 85, 2149- 2154, whose description is incorporated here by reference. The coupling between two amino acids, an amino acid and a peptide, or two peptide fragments can be carried out using standard coupling methods such as the azide method, the mixed anhydride method of carbonic acid and a carboxylic acid (isobutyl chloroformate) ), the method of a carbodiimide (dicyclohexylcarbodiimide, diisopropylcarbodiimide, or a water-soluble carbodiimide), the method of an active ester (p-nitrophenyl ester, N-hydroxysuccinic ester), the Woodward K reagent method, the carbonyldiimidazole method, phosphorus reagents or oxidation-reduction methods. Some of these methods (especially the carbodiimide method) can be improved by adding 1-hydroxybenzotriazole. These coupling reactions can be carried out either in the solution phase (liquid phase) or in the solid phase. More explicitly, the coupling step involves the dehydrogenating coupling of a free carboxyl of one reactant with the free amino group of the other reactant in the presence of a coupling agent to form a bonded amide bond. Descriptions of such coupling agents are found in general textbooks on the chemistry of peptides, for example, M. Bodanszky, "Peptide Chemistry", 2 revised edition, ed., Springer-Verlag, Berlin, Germany, (1993). ). Examples of suitable coupling agents are N, N'-dicyclohexylcarbodiimide, 1-hydroxybenzotriazole in the presence of N, N '-dicyclohexylcarbodiimide or N-ethyl-N' - [(3-dimethylamino) propyl] carbodiimide. A very practical and useful coupling agent is commercially available commercially available benzotriazol-1-yloxy) tris- (dimethylamino) phosphonium hexafluorophosphate, either alone or in the presence of 1-hydroxybenzotriazole. Another very useful and useful coupling agent is commercially available 2 (1H-benzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium tetrafluoroborate. Still another very practical and useful coupling agent is the commercially available O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate. The coupling reaction is carried out in an inert solvent, p. ex. dichloromethane, acetonitrile or dimethylformamide. An excess of a tertiary amine, p. ex. diisopropylethylamine, N-methylmorpholine or N-methylpyrrolidine, is added to maintain the reaction mixture at a pH of about 8. The reaction temperature usually fluctuates between 0 ° C and 50 ° C and the reaction time fluctuates between 15 min and 24 min. h. When a solid phase synthesis approach is employed, the terminal carboxylic acid of C is attached to an insoluble carrier (usually polystyrene). These insoluble carriers contain a group that will react with the carboxylic group to form a bond that is stable to the elongation conditions but that readily unfolds later. Examples of these are: a chloro- or bromo-methyl-resin, a hydroxy-methyl-resin and an amino-methyl-resin. Many of these resins are commercially available with the desired terminal amino acid of C already incorporated. Alternatively, the amino acid may be incorporated on the solid support by known methods, ang, S.-S., J. Am. Chem. Soc., (1973), 9_5, 1328; Atherton, E .; Shepard, R.C. "Solid-phase peptide synthesis; a practical approach" IRL Press: Oxford, (1989); 131-148. In addition to the foregoing, other methods of peptide synthesis are described in Stewart and Young, "Solid Phase Peptide Synthesis", 2nd. edition, Pierre Chemical Co., Rockford, IL (1984); Gross, Meienhofer, Udenfriend, Eds., "The Peptides: Analysis, Synthesis, Biology", Vol. 1, 2, 3, 5 and 9, Academic Press, New York, (1980-1987); Bodansky et al., "The Practice of Peptide Synthesis", Springer-Verlag, New York (1984), such descriptions are incorporated herein by reference. The functional groups of the constituent amino acids must generally be protected during the coupling reactions to avoid the formation of undesired bonds. Protective groups that can be used are listed in Greene, "Protective Groups in Organic Chemistry," John Wiley & Sons, New York (1981) and "The Peptides: Analysis, Synthesis, Biology", volume 3, Academic Press, New York (1981), such descriptions are incorporated herein by reference. The α-carboxyl group of the terminal residue of C is usually protected in the form of an ester (PGl) which can be split into the carboxylic acid. Protecting groups that can be used include: 1) alkyl esters such as methyl, trimethylsilylethyl and t-butyl, 2) arylalkyl esters such as benzyl and substituted benzyl, or 3) esters that can be split by treatment with a weak base or with weak reducing media such as the trichloroethyl and phenacyl esters. Yes a-amino group of each amino acid to be coupled to the growing peptide chain must be protected (PG2). Any protecting group known in the art can be used. Examples of such groups include: 1) acyl groups such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; 2) aromatic carbamates groups such as benzyloxycarbonyl (Cbz or Z) and substituted benzyloxycarbonyls, and 9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamates groups such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl and allyloxycarbonyl; 4) cyclic alkylcarbamate groups such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) alkyl groups such as triphenylmethyl and benzyl; 6) trialkylsilyl such as trimethylsilyl; and 7) thiol-containing groups such as phenylthiocarbonyl and dithiasuccinoyl. The preferred a-amino protecting group is either Boc or Fmoc. Many appropriately protected amino acid derivatives are commercially available for the synthesis of peptides. The a-amino protecting group of the amino acid residue that has just been added is separated before coupling the next amino acid. When the Boc group is used, the methods to be selected are those using trifluoroacetic acid, pure or dissolved in dichloromethane, or HCl in dioxane or in ethyl acetate. The resulting ammonium salt is neutralized either before coupling or in situ with alkaline solutions such as aqueous buffers, or tertiary amines in dichloromethane or acetonitrile or dimethylformamide. When the Fmoc group is used, the reagents to be selected are piperidine or a piperidine substituted in dimethylformamide, but any secondary amine can be used. The deprotection is carried out at a temperature between 0 ° C and room temperature (TA), usually 20-22 ° C. Any of the amino acids having side chain functionalities must be protected during the preparation of the peptide using any of the groups described above. Those skilled in the art will appreciate that the selection and use of appropriate protecting groups for these side chain functionalities depend on the amino acid and the presence of other protecting groups on the peptide. The selection of such protecting groups is important, since the group should not be removed during deprotection and coupling of the a-amino group. For example, when Boc is used as the a-amino protecting group, the following side chain protecting groups are suitable: p-toluenesulfonyl (tosyl) moieties can be used to protect the amino side chain of amino acids such as Lys and Arg; acetamidomethyl, benzyl (Bn), or t-butylsulfonyl moieties can be used to protect the sulfide-containing side chain of cysteine; benzyl ethers (Bn) can be used to protect the hydroxy-containing side chains of serine, threonine or hydroxyproline; and benzyl esters can be used to protect the carboxy-containing side chains of aspartic acid and glutamic acid. When Fmoc is chosen for a-amino protection, tere-butyl-based protecting groups are usually acceptable. For example, Boc can be used for lysine and arginine, tert-butyl ether for serine, threonine and hydroxyproline, and tert-butyl ester for aspartic acid and glutamic acid. The triphenylmethyl (Trityl) moiety can be used to protect the sulfide-containing side chain of cysteine.

Once the elongation of the peptide is complete, all of the protecting groups are removed. When a liquid phase synthesis is used, the protecting groups are removed in any manner that is dictated by the choice of protecting groups. These processes are well known to those skilled in the art. When a solid phase synthesis is used, the peptide is separated from the resin simultaneously with the removal of the protecting groups. When the Boc protection method is used in the synthesis, treatment with anhydrous HF containing additives such as dimethyl sulfide, anisole, thioanisole, or p-cresol at 0 ° C is the preferred method for separating the peptide from the resin . The separation of the peptide can be achieved by other acid reagents such as mixtures of trifluoromethanesulfonic acid and trifluoroacetic acid. If the Fmoc protection method is used, the Fmoc group located at the terminal end of N is separated with the reagents described above. The other protecting groups and the peptide are separated from the resin using a solution of trifluoroacetic acid and various additives such as anisole, etc. When Q is CH2, a is 0, b is 0 and B is RiiaN (Riib) C (O), the compounds were prepared according to a method analogous to the general method described for the peptides in Scheme I using an intermediate with readily available succinyl, t-BuO-C (O) CH2CH (R ») -C0-PG1 (eg PG1 = 2-oxo-oxazolidin-3-yl substituted in position 4). This succinyl intermediate can be easily prepared according to the method of Evans' et al (J. Am. Chem. Soc. (1982), 104, 1737) using the appropriate 3-acyl-2-oxazolidinone substituted in 4-position. , in the presence of a strong base such as lithium diisopropylamide or sodium bis (trimethylsilyl) amide and t-butyl bromoacetate. After the 2-oxazolidinone moiety was separated with LiOOH (Evans' et al., Tetrahedron Lett. (1987), 2_8, 6141J, ___ eJL_ resulting acid was coupled to the P3-P2-P1-PG1 segment to give t-Buo- C (O) -CH2CH (R4) -CO-P3-P2-P1-PG1. The latter was treated with hydrogen chloride to selectively convert the terminal t-butyl ester to the corresponding acid, which had finally been coupled to RiiaNH (Rm,) to give, after elimination of the protecting group (s), the desired peptide derivative.R a »NH (R? T) amines are commercially available or the syntheses are well known in the art A specific embodiment of this process is presented in Example 18. Alternatively, starting from the same succinyl intermediate (t-BuO-C (O) CH2CH (R4) -C0-PG1), the sequence of reactions can be reversed to first introduce RiiaNH (Rm >) and then P3-P2-P1-PG1 to give the desired peptide derivative.

Synthesis of the auction group B and of rest P6, P5, P4 and P3 Different buffer groups B are introduced to protect P6, P5, P4, the entire peptide or any segment of peptide with an appropriate acyl chloride, whether commercially available or for which the synthesis is well known in the art. .

Different residues of P6 to P3 are commercially available or their synthesis is well known in the art.

Synthesis of P2 residues. 1. Synthesis of precursors: A) Synthesis of haloarylmethane derivatives.

The preparation of halomethyl-8-quinoline id was carried out according to the method of K.N.

Campbell et al., J. Amer. Chem. Soc., (1946), 68, 1844.

Scheme II Briefly, the carboxylic acid of 8-quinoline was converted to the corresponding alcohol by reduction of the corresponding acyl halide Ilb with a reducing agent such as lithium aluminum hydride. The treatment of alcohol llb with the appropriate hydrohalic acid gives the desired halo derivative d. A specific embodiment of this procedure is presented in Example 1.

Synthesis of P2: A) The synthesis of substituted proline in position 4 (where R is linked to the ring through a carbon atom) (with the stereochemistry shown) is performed as shown in Scheme III according to the procedures described by J. Ezquerra et al. (Tetrahedron, (1993), 3JJ., 8665-8678) and C. Pedregal et al. (Tetrahedron Lett., (1994), 35, 2053-2056).

Scheme III lllb lile Briefly stated, Boc-pyroglutamic acid is protected as a benzyl ester. Treatment with a strong base such as lithium diisopropyl amide, followed by the addition of an alkylating agent (Br-R2 or I-R2) gives the desired lile compounds after reduction of the amide and deprotection of the ester.

B) The synthesis of 4- (i?) -hydroxy-proline alkylated in O: it can be carried out using the different procedures described below.

B.l) When R is aralkyl, the process can be carried out according to the procedure described by E.M. Smith et al. (J. Med. Chem. (1988), 3JL, 875-885). Briefly, the commercially available Boc-4 (R) -hydroxyproline is treated with a base such as sodium hydride and the resulting alkoxide is reacted with an alkylating agent (Br-R12 or I-R12) to give the desired compounds. Specific modalities of this procedure are presented in Examples 3 and 4.

B.2) When R12 is aryl, the compounds can be prepared by means of a reaction of Mitsunobu (Mitsunobu (1981), Synthesis, January, 1-28; Rano et al., (1995), Tet., Lett., 36 (22), 3779-3792; Krchnak et al., (1995), Tet., Lett. (5), 62193-6196, Richter et al., (1994), Tet. Lett. 35 (27), 4705-157070). Briefly, the commercially available Boc-4 (S) -hydroxyproline methyl ester is treated with the appropriate aryl alcohol or -thiol in the presence of triphenylphosphine and diethyl azodicarboxylate (DEAD) and The resulting ester is hydrolyzed to give the acid. Specific modalities of this procedure are presented in Examples 5 and 6.

Scheme IV Alternatively, the Mitsunobu reaction can be carried out in solid phase (as shown in Scheme IV). The 96-cavity block of the Model 396 (Advanced ChemTech) synthesizer is provided with aliquots of the compound (IVa) fixed to a resin and a variety of aryl alcohols or thiols and appropriate reagents are added. After incubation, each product (IVb) fixed to a resin is washed, dried and separated from the resin.

B.2.a) A Suzuki reaction (Miyaura et al., (1981), Synth Comm, 1: 1, 513; Sato et al., (1989), Chem. Lett., 1405; Watanabe et al., (1992), Synlett., 207; Takayuki et al., (1993), J. Org. Chem. 58, 2201; Frenette et al., (1994), Tet. Lett. 35 (49), 9177-9180; Guiles et al., (1996), J. Org. Chem. 61, 5169-5171) can also be used to further functionalize the aryl substituent.

Examples The present invention is illustrated in more detail by the following non-limiting Examples. Temperatures are given in degrees Celsius. The percentages of the solutions express a relation of weight to volume, and the relations of the solutions express a relation of volume to volume, unless otherwise indicated. The nuclear magnetic resonance (NMR) spectra were recorded on a Bruker 400 MHz spectrometer; chemical shifts (d) are reported in parts per million. Flash chromatography was carried out on silica gel (Si02) according to Still's rapid resolution chromatography technique (W.C. Still and collaborators, J. Org. Chem. (1978), 4_3, 2923). Abbreviations used in the Examples include Bn: benzyl; Boc: tert-butyloxycarbonyl. { Me3COC (0)}; BSA: bovine serum albumin; CHAPS: 3- [(3-colamidopropyl) -dimethylammonium] -1-propanesulfonate; DBU: 1,8-diazabicyclo [5.4.0] undec-7-ene; CH2C12 = DCM: methylene chloride; DIPEA: diisopropylethylamine; DMAP: dimethylaminopyridine; DCC: 1,3-dicyclohexylcarbodiimide; DME: 1,2-dimethyoxy-ethane; DMF: dimethylformamide; DMSO: dimethisulfoxide; DTT: dithiothreitol or threo-1,4-dimercapto-2,3-butanediol; EDTA: ethylenediaminetetraacetic acid; Et: ethyl; EtOH: ethanol; EtQAc: ethyl acetate; Et20: diethyl ether; HPLC: high performance liquid chromatography; MS: mass spectrometry (MALDI-TOF: Ionization-Desorption by Laser Assisted by Matrix-Time of Flight, FAB: Bombardment with Fast Atoms); LAH: lithium aluminum hydride; Me: methyl; MeOH: methanol; MES: (2- {N-morpholino} ethanesulfonic acid); NaHMDS: sodium bis (trimethylsilyl) amide; NMM: N-methylmorpholine; NMP: N-methylpyrrolidine; Pr: propyl; Succ: 4-hydroxy-l, 4-dioxobutyl; PNA: 4-nitrophenylamino or p-nitroanalide; TBAF: tetra-n-butylammonium fluoride; TCEP: tris (2-carboxyethyl) phosphine hydrochloride; TFA: trifluoroacetic acid; THF: tetrahydrofuran; TIS: triisopropylsilane; TLC: thin layer chromatography; TMSE: trimethylsilylethyl; Tris / HCl: tris (hydroxymethyl) -aminomethane hydrochloride.

Example 1 Synthesis of bromomethyl-8-quinoline (1) To a commercially available 8-quinoline carboxylic acid (2.5 g, 14.4 mmol) was added pure thionyl chloride (10 mL, 144 mmol). This mixture was heated at 80 ° C for 1 h before the excess thionyl chloride was distilled off under reduced pressure. To the resulting brownish solid was added absolute EtOH (15 ml), which was heated at 80 ° C for 1 h before being concentrated in vacuo. The residue was partitioned between EtOAc and saturated aqueous NaHCO3, and the organic phase was dried (MgSO4), filtered and concentrated to give a brownish oil (2.8 g). This material (approximately 14.4 mmol) was added dropwise during 35 min to a suspension of LAH (0.76 g, 20.2 mmol) / Et20 which was cooled to -60 ° C. The reaction mixture was slowly heated to -35 ° C for 1.5 h before the reaction was complete. The reaction mixture was quenched with MgSO4.10H2O slowly over the course of 30 min and then with wet THF. The mixture was partitioned between Et20 and 10% aqueous NaHCO3. The organic phase was dried (MgSO 4), filtered and concentrated to give a yellowish solid (2.31 g, 80% in the course of two steps) corresponding to the alcohol. The alcohol (2.3 g, 11.44 mmol) was dissolved in a mixture of AcOH / HBr (20 ml, 30% solution from Aldrich) and heated at 70 ° C for 2.5 h. The mixture was concentrated in vacuo to dryness, partitioned between EtOAc (100 mL) and saturated aqueous NaHCO3, before being dried (MgSO4), filtered and concentrated to give the desired compound (1) as a brownish solid (2.54 g, 100%).

Example 2 Synthesis of Boc-4 (R) - (3-phenylpropyl) roline (2d). 2c 2d a) Synthesis of compound 2b: To a solution of the benzyl ester of Boc-pyroglutamic acid (2a) (prepared as described by AL Johnson et al., J. Med. Chem. (1985), 2% _, 1596-1602) (500 mg, 1.57 mmol ) in THF (10 ml) at -78 ° C, slowly added lithium hexamethyldisilyl azide (1.72 ml, 1M solution in THF). After stirring for 1 h at -78 ° C, cinnamyl bromide (278 μL, 1.88 mmol) was added and stirring was continued for an additional 2 h. The reaction mixture was quenched with a saturated solution of ammonium chloride and extracted with diethyl ether (3 x 20 ml). The combined organic extracts were dried (MgS0), filtered and concentrated. The residue was purified by flash column chromatography (in a mixture of hexane: ethyl acetate 8: 2) to give compound 2b as an off-white solid (367 mg, yield 54%). 1H NMR (CDC13): d 7.35-7.19 (m, 10H), 6.43 (d, J = 15 Hz, 1H), 6.11 (ddd, J = 15, J '= J "= 8 Hz, 1 H), 5.26 (d, J = 16 Hz, 1H), 5.17 (d, J = 16 Hz, 1H), 4.59 (dd, J = 9.5, J '= 2 Hz, 1H), 2.83-2.70 (m, 2H), 2.41 -2.34 (m, 1H), 2.22-2.16 (m, 1H), 2.10-2.02 (m, 1H) 1.42 (s, 9 H). b) Synthesis of compound 2c: At -78 ° C, lithium triethylborohydride (1M solution in THF, 1.01 mL, 1.01 mmol) was added to a solution of compound 2b (367 mg, 0.843 mmol) in THF (5 mL) under a nitrogen atmosphere. After 30 min, the reaction mixture was quenched with saturated aqueous NaHC 3 (2 mL) and heated to 0 ° C. 30% H202 (5 drops) was added and the mixture was stirred at 0 ° C for 20 min. The organic volatiles were removed in vacuo, and the aqueous layer was extracted with CH2C12 (3 x 10 ml). The combined organic extracts were dried (MgS0), filtered and concentrated. To a cold solution (at -78 ° C) of the residue and triethylsilane (134 μl, 0.843 mmol) in CH2C12 (3 ml) was added dropwise boron trifluoride etherate (118 μl, 0.927 mmol) under an atmosphere of nitrogen. After 30 min, additional amounts of triethylsilane (134 μl) and boron trifluoride etherate (118 μl) were added. After stirring for 2 h at -78 ° C, the reaction mixture was quenched with saturated aqueous NaHC 3 (2 mL) and extracted with DCM (3 x 10 mL). The combined organic extracts were dried (over MgSO4), filtered and concentrated. The crude product was purified by flash column chromatography (a mixture of hexane and ethyl acetate 8: 2) to give compound 2c as a colorless oil (140 mg, 40% yield). 1 H NMR (CDCl 3) indicated the presence of two rotamers: d 7.34-7.22 (m, 10H), 6.38 (d, J = 15.5 Hz, 1H), 6.15-6.08 (m, 1H), 5.29-5.07 (m, 2H ), 4.44 (d, J = 7 Hz, 1 / 3H), 4.33 (d, J = 7 Hz, 2 / 3H), 3.76 (dd, J = 10.5, J '= 8.5 Hz, 2 / 3H) 3.69 ( dd, J = 10.5, J '= 8.5 Hz, 1 / 3H), 3.13 (dd, J = 9, J' = 8.5 Hz, 2 / 3H), 3.05 (dd, J = 9, J '= 8.5 Hz, 1 / 3H), 2.47-2.40 (m, 1H), 2.35-2.22 (m, 2H) 2.15-1.85 (m, 2H), 1.45 (s, (3/9) 9H), 1.33 (s, (6 / 9) 9H). c) Synthesis of compound 2d: To a solution of compound 20 (140 mg, 0.332 mmol) in ethanol (4 ml) was added 10% palladium on organic carbon (30 mg). The mixture was stirred under a hydrogen atmosphere for 2 h. The catalyst was removed by passing the mixture through a filter Millipore: Millex -HV of 0.45 μm. The clear solution was concentrated to give the desired compound 2d as a colorless oil (115 mg, quantitative yield). 1 H-NMR (DMSO-de) indicated the presence of two rotamers: d 7. 28-7.14 (m, 5H), 4.33 (broad s, 1H), 4.06-4.10, (m, 1H), 3. 56-3.42 (m, 3H), 2.89-2.79 (m, 1H),), 2.53-2.49 (m, 1H, under DMSO-de), 2.24-2.10 (m, 1H), 2.03-1.93 (m, 1H ), 1.87-1.75 (m, 1H), 1.62-1.45 (m, 2H), 1.38 (s, (3/9) 9H), 1.33 (s, (6/9) 9H).

Example 3 Synthesis of Boc-4 (R) - (naphthalen-1-ylmethoxy) proline (3): The commercially available Boc-4- (R) -hydroxyproline (5.00 g, 21.6 mmol) was dissolved in THF (100 ml) and cooled to 0 ° C. Sodium hydride (60% dispersion in oil, 1.85 g, 45.4 mmol) was added in portions over 10 minutes and the suspension was stirred at RT for 1 h. Then 1- (bromomethyl) naphthalene (8.00 g, 36.2 mmol) (prepared as described in EA Dixon et al., Can. J. Chem., (1981), 5_9, 2629-2641) was added and the mixture was heated refluxed for 18 h. The mixture was poured into water (300 ml) and washed with hexane. The aqueous layer was acidified with 10% aqueous HCl and extracted twice with ethyl acetate. The organic layers were combined and washed with brine, dried (MgS0), filtered and concentrated. The residue was purified by flash chromatography (a mixture of hexane, ethyl acetate and acetic acid 49: 49: 2), to give the title compound as a colorless oil (4.51 g, 56% yield). The H NMR (DMSO-de) indicated the presence of two rotamers: d 8.05 (m, 1H), 7.94 (m, 1H), 7.29 (d, J = 14 Hz, 1H), 7.55-7.45 (m, 4H) , 4.96 (m, 2H), 4.26 (broad s, 1H), 4.12 (dd, J = J = 8 Hz, 1H), 3.54-3.42 (m, 2H), 2.45-2.34 (m, 1H), 2.07- 1.98 (m, 1H) 1.36 (s, (3/9) 9H), 1.34 (s, (6/9) 9H).

Example 4 Synthesis of Boc-4 (R) - (8-quinoline-mehiloxy) proline (4): Boc-4 (R) -hydroxy-proline (1.96 g, 8.5 mmol) in anhydrous THF (20 ml) was added to a suspension of NaH (1.4 g, 60% in an oil, 34 mmol) in THF (100 ml). This mixture was stirred for 35 min before bromomethyl-8-quinoline from Example 1 (2.54, 11.44 mmol) in THF (30 ml) was added. The reaction mixture was heated to 70 ° C (5 h) before the excess NaH was carefully destroyed with wet THF. The reaction mixture was concentrated in vacuo and the resulting material was dissolved in EtOAc and H20. The alkaline aqueous phase was separated and acidified with 10% aqueous HCl to pH -5, before being extracted with EtOAc (150 mL). The organic phase was dried (MgSO 4), filtered and concentrated to give a brown oil. Purification by flash chromatography (eluent: mixture of 10% MeOH and CHCl3) gave the desired compound as a pale yellow solid (2.73 g, 86%). HPLC (97.5%); and the 1H-NÍ [R (DMSO-de) show populations of rotamers in a ratio of 6: 4, d 12-11.4 (bs, 1H), 8.92 (2 xd, J = 4.14 and 4.14 Hz, 1H), 8.38 (2 xd, J = 8.27 and 8.27 Hz, 1H), 7.91 (d, J = 7.94 Hz, 1H), 7.77 ( d, J = 7.0 Hz, 1H), 7.63-7.54 (m, 2H), 5.14 (2 xs, 2H), 4.32-4.29 (m, 1H), 4.14-4.07 (m, 1H), 3.52-3.44 (m , 2H), 2.43-2.27 (m, 1H), 2.13-2.04 (m, 1H), 1.36 and 1.34 (2 xs, 9H).

Example 5 Preparation of Bos-4 (R) - (7-chloroquinoline-4-oxo) proline (5): A commercially available Boc-4- (S) -hydroxyproline methyl ester (500 mg, 2.04 mmol) and 7-chloro-4-hydroxyquinoline (440 mg, 2.45 mmol) were placed in dry THF (10 mL) at 0 ° C. . Triphenylphosphine (641 mg, 2. 95 mmol), followed by a slow addition of DIAD (426 mg, 2. 45 mmol). The mixture was stirred at RT for 20 h. Then the reaction mixture was concentrated, taken up in ethyl acetate and extracted three times with IN HCl. The aqueous phase was basified with Na 2 C 3 and extracted twice with ethyl acetate. The organic layers were combined, dried over MgSO, filtered and concentrated to give a yellow oil. The oil was purified by flash chromatography to give the methyl ester of compound (5) as a white solid, 498 mg, 58% yield. This methyl ester (400 mg, 0.986 mmol) was hydrolyzed with 1 M aqueous sodium hydroxide (1.7 mL, 1.7 mmol) in methanol (4 mL), at 0 ° C, for 3 h. The solution was concentrated to remove methanol and neutralized with 1 M aqueous HCl. The suspension was concentrated to dryness and taken up in methanol (20 mL), the salts were separated by filtration and the filtrate was concentrated to give the compound ( 5) desired as a white solid, 387 mg, quantitative yield. "" "H-NMR (DMSO-dβ) (mixture about 1: 1 of rotamers) d 8.74 (d, J = 5 Hz, 1H), 8.13-8.09 (m, 1H), 7.99 and 7.98 (s, 1H ), 7.58 (d, J = 9 Hz, 1H), 7.02 (d, J = 5 Hz, 1H), 5.26-5.20 (m, 1H), 4.10-4.01 (m, 1H), 3.81-3.72 (m, 1H), 3.59 (dd, J = 12, 10Hz, 1H), 2.41-2.31 (m, 2H), 1.34 and 1.31 (s, 9H).

Example 6 General procedure for the Mitsunobu reaction in solid phase (Scheme IV) The peptide of general structure IVa fixed to a polymer (0.327 mmol of peptide per gram of Wang resin) was dried under high vacuum in a desiccator over P2Os. The 96-well block of the Advanced ChemTech Model 396 synthesizer was supplied with aliquots of peptide IVa (120 mg, 0.04 mmol of peptide per well) and each sample was washed for 5 min with anhydrous CH2C12 (5 x 1200 μl) and then with anhydrous THF (5 x 1500 μl). Anhydrous THF (200 μl) was added to each sample and the synthesizer was provisionally stopped to allow manual addition of the reagents. P? 13P (5 eq. In 400 μl of anhydrous THF) and diethylazodicarboxylate (DIAD, 5 eq. In 250 μl of anhydrous THF) were added before the addition of a phenol or thiophenol type reagent (5 eq. 0.2 mmol, dissolved in 500 μl of anhydrous THF); A collection of reagents was used to produce the collection of HCV protease inhibitors that are described in this patent application. After the edition of all the reagents the mixtures were shaken for a total of 4 h with a delay of 10 min after each hour. Each product bound to a resin was washed with THF (2 x 1500 μl), DMF (4 x 1500 μl), isopropanol (4 x 1500 μl), CH 2 C 12 (4 x 1,500 μl) and finally methanol (2 x 1,500 μl). The sample was dried under vacuum and then treated with 40% TFA in CH2C12 for 1 h in order to separate the peptide product (of general structure IVb) from the resin. All products were purified by preparative HPLC on a reverse phase C18 column using a linear gradient of solvents from 5% aqueous CH3CN to 100% CH3CN. The following description is an example of the further elaboration of the side chain R? 2 in P2 by the application of a biaryl synthesis by means of Suzuki coupling on a solid support (cf. R. Frenette and RW Friesen, Tetrehedron Lett. (1984) , 35, 9177). The precursor, the aromatic bromide compound 238 of Table 2, was first synthesized from the tetrapeptide bound to a polymer having a cis-hydroxyproline at the P2 position and 4-bromophenol, using the Mitsunobu protocol described above. .

Example 7 Suzuki Collection of Reactions in Solid Phase Synthesis All the reactions were carried out in test tubes with 16 x 100 mm high pressure threaded cap fitted with Teflon caps, equipped with small magnetic stirring bars. For each reaction, a degacized suspension of the peptide bound to a polymer (100 mg of a Wang resin with 0.033 mmol of the bound peptide) was first added to the test tube, followed by the addition of DME (2 mL), Pd (Ph3P ) 3 (~ 3 mg, 0.05 eq.), Na2C03 (70 μl of a 2M solution in H20, 2.5 eq.) And one of the phenyl-boronic acid reagents from our collection. The test tubes were quickly flushed with nitrogen gas, were hermetically sealed and placed in an oil bath at 80 ° C. All the reaction mixtures were gently shaken and allowed to progress for 15-18 h. Each peptide product bound to a resin was subsequently transferred to a plastic filtration tube, washed with a mixture of DME: H20 (1: 1, 5 x 2 mL), DME (5 2 L), methanol (5%), x2 mL), CH3CN (5 x 2 mL), CH2C12 (5 x 2 mL) and dried under high vacuum. Each product was packaged with respect to the resin by treating the sample with 45% TFA in CH2Cl2 (1 mL) for 1 hour. All products were purified by preparative HPLC on a reverse phase C18 column using a linear gradient of solvents from 5% aqueous CH3CN to 100% CH3CN. 8 Preparation of a collection of Ac-Chg-Val-Hyp (aryl) -Acca-OH This compound was synthesized according to the protocol of Example 6 where appropriate peptides were used.

Example 9 Synthesis of compound # 246 fixed to a polymer of Table 2.

The synthesis of compound 246 was carried out according to the procedure of Example 7.

Compound 246: ES ~ MS m / z 675.3 [(MH) "], pure at -95% by C18 reverse phase HPLC, mix of two rotamers in a ratio of -1: 3 by kissing at 1H NMR 1H NMR from the main rotamer (400 MHz, DMSO): d 8.44 (s, 1H), 7.84 (d, J = 8.6 Hz, 1H), 7.82 (d, J = -8.6 Hz, 1H), 7.54 (bd, J = 8.3 Hz, 4H), 6.99 (d, J = 8.9 Hz, 2H), 6.98 (d, J = 8.9 Hz, 2H), 5.11 (bs, 1H), 4.29-4.34 (m, 2H), 4.21 (bt, J = 7.8 Hz, 1H ), 3.94-4.02 (m, 2H), 3.78 (s, 3H), 2.29-2.33 (m, 2H), 2.15-2.21 (m, 1H), 1.95-1.99 (m, 1H), 1.83 (s, 3H) ), 1.45-1.70 (m, 8H), 1.33-1.40 (m, 1H), 1.20-1.28 (m, 1H), 1.02-1.18 (m, 2H), -0.9-1.02 (m, 2H), 0.90 ( d, J = 6.7 Hz, 3H), 0.84 (d, J = 6.7 Hz, 3H).

Example 10 General procedure for coupling reactions carried out in solution. { see also R. Knorr et al., Tetrahedron Letters, 30, 1927 (1989) ..}.

The reactants, ie a free amine (1 eq.) (Or its hydrochloride salt) and free carboxylic acid (1 eq.), Are dissolved in CH2C12, CH3CN or DMF. Under a nitrogen atmosphere, four equivalents of N-methylmorphine and 1.05 equivalents of the coupling agent were added to the stirred solution. After 20 min, one equivalent of the second reactant, ie a free carboxylic acid, was added. (Practical and efficient coupling reagents for this purpose are (benzotriazol-1-yloxy) tris- (dimethylamino) phosphonium hexafluorophosphate (HOBT) or preferably 2- (1H-benzotriazol-1-yl) -N, N tetrafluoroborate, N ',' -tetramethyluronium (TBTU) or O- (7-zabenzotriazol-1-yl) -N, N, ', N' -tetramethyluronium tetrafluoroborate (HATU) The reaction was observed by TLC. After the reaction, the solvent was evaporated under reduced pressure, the residue was dissolved in EtOAc, the solution was washed successively with 10% aqueous citric acid, saturated aqueous NaHC03 and brine, the organic phase was dried (MgSO4), filtered and concentrated under reduced pressure When the residue was purified, this was done by flash chromatography as defined above.

Example 11 Synthesis of the "tripóptide segment": Ac-Chg-Chg-Pro (4 (R) -naphthalen-1-ylmethoxy) -OH (llg) 11d 11e 11f 11g Compound lia (4.45 g, 11.98 mmol) was dissolved in anhydrous CH3CN (60 mL). DBU (2.2 mL, 14.38 mmol) and allyl bromide (1.1 mL, 13.18 mmol) were added consecutively, and the reaction mixture was stirred for 24 h at RT The mixture was concentrated, the resulting oil was diluted with EtOAc and with water and it was washed consecutively with water (2x) and with brine (lx) .The EtOAc layer was dried (over MgSO), filtered and evaporated to dryness.The yellow oil was purified by flash chromatography. (eluent: hexane / EtOAc mixture: 90:10 to 85:15) to give the product lb as a yellow oil. (2, 4.17 g, 85% yield). MS (FAB) 412 MH + H NMR (CDCl 3), rotamers mixture approx. 1: 2, d (d, J = 8 Hz, 1H), 7.87 (d, J = 8Hz, 1H), 7.82 (d, J = 8Hz, 1H), 7.55-7.41 (m, 4H), 5.95-5.85 (m, 1H), 5.34-5.21 (m, 2H), 5.03-4.88 (m, 2H), 4.70-4.56 (m, 2H), 4.48 and 4.39 (t, J = , 15 Hz, 1H), 4.28-4.23 (m, 1H), 3.81-3.55 (m, 2H), 2.46-2.36 (m, 1H), 2.13-2.05 (m, 1H), 1.44 and 1.41 (s, 9H ).

Compound IIb (2.08 g, 5.05 mmol) was treated for 30 min at RT with a mixture of 4N HCl and dioxane. Evaporation to dryness gave the corresponding amine-HCl compound in the form of an oil. Amine-HCl 11c was dissolved in anhydrous DCM (25 ml), NMM (2.2 ml, 20.22 mmol), Boc-Chg-OH • H20 (1.53 g, 5.56 mmol) and TBTU (1.95 g, 6.07 mmol) were consecutively added. . The reaction mixture was stirred at RT overnight, then diluted with EtOAc and washed consecutively with 10% aqueous citric acid (2x), saturated aqueous NaHC03 (2x), water (2x), and brine.

(Ix) The EtOAc layer was dried (over MgSO), filtered and evaporated to dryness to provide the crude product lid as a yellowish-white foam. (approximately 2.78 g, 100% yield). MS (FAB) 551.4 MH +. XH NMR (CDC13) d 8.03 (d, J = 8 Hz, 1H), 7.86 (bd, J = 8.5 Hz, 1H), 7.84 (d, J = 8 Hz, 1H), 7.56-7.40 (m, 4H) , 5.92-5.85 (m, 1H), 5.31 (dd, J = 1, 17 Hz, 1H), 5.22 (dd, J = 1, 10 Hz, 1H), 5.17 (d, J = 9 Hz, 1H), 5.05 (d, J = 12 Hz, 1H), 4.91 (d, J = 12 Hz, 1H), 4.67 -4.60 (m, 3H), 4.31-4.27 (m, 2H), 4.16 (bd, J = 11Hz, 1H), 3.71 (dd, J = 4, 11 Hz, 1H), 2.47-2.41 (, 1H), 2.08-1.99 (m, l'H), 1.85-1.63 (m, 5H), 1.44-1.40 (m, 1H), 1.36 (s, 9H), 1.28-1.00 (m, 5H).

The crude dipeptide lid (approximately 5.05 mmol) was treated with a mixture of 4N HCl and dioxane (25 ml) as described for compound 11c. The crude hydrochloride salt was coupled to Boc-Chg-OH "H20 (1.53 g, 5.55 mmol) with NMM (2.22 mL, 20.22 mmol) and TBTU (1.95 g, 6.07 mmol) in DCM (25 mL) as described for the compound lid in order to provide the crude tripeptide in the form of a yellow oily foam The crude material was purified by flash chromatography (eluent: mixtures of hexane and EtOAc: 80:20 to 75:25) to provide the tripeptide as a white foam (2.75 g, yield 79% over the course of 2 steps) MS (FAB) 690.5 MH +, H NMR (CDCI3), mainly a rotamer, d 8.06 (d, J = 8Hz , 1H), 7.87 (bd, J = 8.5Hz, 1H), 7.82 (d, J = 8Hz, 1H), 7.57-7.40 (m, 4H), 6.41 (d, J = 8.5Hz, 1H), 5.92- 5.84 (m, 1H), 5.31 (dd, J = 1, 17 Hz, 1H), 5.23 (dd, J = 1, 10.5 Hz, 1H), 5.04 (d, J = 12 Hz, 1H), 4.98 (bd) , J = 7 Hz, 1H), 4.93 (d, J = 12 Hz, 1H), 4.63-4.58 (m, 4H), 4.29-4.25 (m, 1H), 4.10-4.07 (m, 1H), 3.90- 3.84 (m, 1H), 3.72 (dd, J = 4, 11Hz, 1H) , 2.48-2.40 (m, 1H), 2.07-1.99 (m, 1H), 1.83-1.55 (m, 12H), 1.43 (s, 9H), 1.23-0.89 (m, 10H) The tripeptide lie (2.75 g, 3.99 'mmol) was treated with a mixture of 4N HCl and dioxane (20 ml) as described for compound 11c. The crude hydrochloride salt was dissolved in anhydrous DCM (20 ml). NMM (1.75 ml, 15.94 mmol) and acetic anhydride (752 μl, 7.97 mmol) were added consecutively. The reaction mixture was stirred overnight at RT, then diluted with EtOAc. The organic layer was washed consecutively with 10% aqueous citric acid (2x), with saturated aqueous NaHCO3 (2x), with water (2x) and with brine (lx), dried (MgSO4), filtered and evaporated to dryness to provide the crude tripeptide llf as a white foam 2.4 yield 98%). MS (FAB) 632.4 MH + 1. XH NMR (CDCI3), mainly a rotamer, d 8.06 (b d, J = 8 Hz, 1H), 7.87 (b d, J = 8 Hz, 1H), 7.83 (d, J = 8 Hz, 1H), 7.58-7.40 (m, 4H), 6.36 (d, J = 9Hz, 1H), 6.01 (d, J = 9Hz, 1H), 5.94-5.83 (m, 1H), 5.34-5.28 (m, 1H), 5.25-5.21 (m, 1H), 5.05 (d, J = 12 Hz, 1H), 4.94 (d, J = 12 Hz, 1H), 4.64-4.57 (m, 4H), 4.30-4.23 (m, 2H), 4.12-4.08 (m, 1H), 3.73 (dd, J = 4, 11Hz, 1H), 2.49-2.42 (m, 1H), 2.08-2.01 (m, 1H), 1.99 (s, 3H), 1.85-1.53 (m, 11H), 1.25-0.88 (m, 11H).

The crude tripeptide Ilf (2.48 g, 3.93 mmol) was dissolved in an anhydrous mixture of CH 3 CN and DCM (20 ml). Triphenylphosphine (53.5 mg, 0.200 mmol) and a tetrakis (trifeni Ifos fine) -palladium catalyst were added consecutively. (0) (117.9 mg, 0.102 mmol), followed by pyrrolidine (353.9 μl, 4.24 mmol). The reaction mixture was stirred at room temperature for 18 h. Subsequently, the solvent was evaporated. The residue was dissolved in EtOAc and 10% aqueous citric acid, then additional washings were carried out twice more with 10% aqueous citric acid, with water (2x), and with brine (Ix). The organic layer was dried (on MgSO), filtered and evaporated. The crude product was ground in a mixture of Et20 and DCM (85:15) to provide after filtration tripeptide llg as a white solid (2.09 g, 90% yield). MS (FAB) 592.4 MH + 614.3 (M + Na) +. 1 H NMR (CDCl 3), mainly one rotamer, d 8.08 (d, J = 8 Hz, 1 H), 7.93 (bd, J = 9 Hz, 1 H), 7.88 (bd, J = 8 Hz, 1 H), 7.82 (d , J = 8 Hz, 1H), 7.97-7.41 (m, 4H), 6.47 (d, J = 8.5 Hz, 1H), 5.05 (d, J = 12.5 Hz, 1H), 4.94 (d, J = 12.5 Hz, 1H), 4.73 (t, J = 9.5, 19 Hz, 1H), 4.44-4.35 (m, 2H), 4.26 (bs, 1H), 4.19 (d, J = 11.5 Hz, 1H), 3.75 (dd, J = 4, 11 Hz, 1H), 2.47 (bdd, J = 7.5, 13.5Hz, 1H), 2.20-2.11 (m, 1H), 2.04 (s, 3H), 1.88-1.41 (m, 11H), 1.30-0.80 (11H).

Example 12 Synthesis of the "tripeptide segment" -Ac-Chg-Val-Pro (4 (R) -naphthalen-1-ylmethoxy) -OH (12e) 12o Compound 12a (2.89 g, 7.02 mmol) was treated with a mixture of 4 N HCl and dioxane (30 mL) as described for compound 11c. The crude hydrochloride salt was coupled to Boc-Val-OH (1.53 g, 7.73 mmol) with NMM (3.1 mL, 28.09 mmol) and TBTU (2.71 g, 8.43 mmol) in DCM (35 mL) for 3.5 h as described for compound 3 in order to provide the crude dipeptide 12b as an oily foam of ivory color ( approximately 3.60 g, 100% yield). MS (FAB) 509.3 MH ~ 511.3 MH + 533.2 (M + Na) +. XH NMR (CDCl 3) d 8.04 (bd, J = 8 Hz, 1H), 7.87 (bd, J = 7 Hz, 1H), 7.82 (d, J = 8 Hz, 1H), 7.56-7.40 (m, 4H) , 5.93 5.85 (m, 1H), 5.34-5.28 (m, 1H), 5.24-5.19 (m, 2H), 5.04 (d, J = 12 Hz, 1H), 4.92 (d, J = 12 Hz, 1H) , 4.67-4.60 (m, 3H), 4.31-4.26 (m, 2H), 4.11-4.09 (m, 1H) 3. 72 (dd, J = 4, 11 Hz, 1H), 2.48-2.41 (m, 1H), 2.07-1.99 (m, 1H), 1.44-1.36 (m, 1H), 1.37 (s, 9H), 1.01 ( d, J = 7 Hz, 3H), 0.93 (d, J = 7 Hz, 3H). The crude dipeptide 12b (approximately 7.02 mmol) was treated with a mixture of 4 N HCl and dioxane (30 mL) as described for compound 11c. The crude hydrochloride salt was coupled to Boc-Chg-OH 'H20 (2.13 g, 7. 73 mmol) with NMM (3.1 mL, 28.09 mmol) and TBTU (2.71 g, 8.43 mmol) in CH2C12 (35 mL) as described for compound 3 in order to provide the crude tripeptide 12c as an ivory foam (approximately 4.6 g, 100% yield). MS (FAB) 648.5 MH "~ 672.4 (M + Na) +. ^? NMR (CDCl 3): d 8.06 (bd, J = 8Hz, 1H), 7.87 (bd, J = 7.5 Hz, 1H), 7.82 (bd , J = 8 Hz, 1H), 7.57-7.40 (m, 4H), 6.46 (bd, J = 8.5 Hz, 1H), 5.94-5.84 (m, 1H), 5.31 (dd, J = 1, 17 Hz, 1H), 5.23 (dd, J = 1, 10.5Hz, 1H), 5.03 ( d, J = 12 Hz, 1H), 5.00-4.97 (m, 1H), 4.93 (d, J =, 12Hz, 1H), 4.63-4.59 (m, 4H), 4.29-4.27 (m, 1H), 4.10 -4.07 (m, 1H), 3.92-3.86 (m, 1H), 3.72 (dd, J = 5, 11 Hz, 1H), 2.48-2.41 (m, 1H), 2.10-1.99 (m, 1H), 1.76-1.57 (m, 6H), 1.43 (s, 9H), 1.20-0.92 (m, 6H), 1.00 (d, J = 7 Hz, 3H ), 0.93 (d, J = 7Hz, 3H).

The crude tripeptide 12c (about 7.02 mmol) was treated with a mixture of 4N HCl and dioxane (30 ml) as described for compound 11c. The crude hydrochloride salt was further treated with acetic anhydride (1.33 ml, 14.05 mmol) and NMM (3.1 ml, 28.09 mmol) in CH2C12 (35 ml) as described for compound llf. The crude product was purified by flash resolution (eluent: hexane-EtOAc mixture: 30:70) to give the protected acetylated tripeptide 12d as a white foam (3.39 g, yield 81% over 3 steps). MS (FAB) 590.3 MH "592.4 MH + 614.4 (M + Na) +. 1 H NMR (CDCl 3), mainly one rotamer, d 8.06 (d, J = 8 Hz, 1 H), 7.88 (bd, J = 8 Hz, 1 H) , 7.83 (d, J = 8 Hz, 1H), 7.58-7.41 (m, 4H), 6.37 (d, J = 9 Hz, 1H), 5.97 (d, J = 8.5 Hz, 1H), 5.94-5.84 ( m, 1H) ', 5.31 (dd, J = 1, 17 Hz, 5.24 (dd, J = 1, 10.5 Hz, 1H), 5.05 (d, J = 12 Hz, 1H), 4.94 (d, J = 12 Hz, 1H), 4.66-4.57 (m, 4H), 4.31-4.22 (m, 2H), 4.11-4.05 (m, 1H), 3.73 (dd, J = 4.5, 11 Hz, 1H), 2.50-2.43 ( m, 1H), 2.09-2.01 (m, 2H), 2.00 (s, 3H), 1.68-1.55 (m, 5H), 1.15-0.89 (m, 6H), 0.99 (d, J = 7 Hz, 3H) , 0.91 (d, J = 7 Hz, 3H).

The tripeptide acetylated 12d (3.39 g, 5.73 mmol) was deprotected by the catalyst tetrakis (triphenylphosphine) -palladium (0) (172.1 mg, 0.149 mmol) with triphenylphosphine (78.1 mg, 0.298 mmol) and pyrrolidine (516 μl, 6.19 mmol) in a 1: 1 mixture of anhydrous CH3CN and DCM (30 ml) as described for compound llg. The crude product in the form of light yellow foam was triturated in a mixture of Et20 and DCM (85:15) to provide after filtration the tripeptide 12e as an off-white solid (3.0 g, 95% yield). MS (FAB) 550.3 XH NMR (CDCl 3): d 8.08 (d, J = 8Hz, 1H), 8.04 (bd, J = 9Hz, 1H), 7.88 (bd, J = 7.5 Hz, 1H), 7.82 (d, J = 8 Hz, 1H), 7.58-7.37 (m, 5H), 5.05 (d, J = 12 Hz, 1H), 4.94 (d, J = 12 Hz, 1H), 4.61 (t, J = 9.5, 19.5 Hz, 1H), 4.46-4.37 (m, 2H), 4.27 (bs, 1H), 4.17 (d, J = 11Hz, 1H ), 3.74 dd, J = 4, 11Hz, 1H), 2.49 (bdd, J = 7.5, 13Hz, 1H), 2.17-2.09 (m, 1H), 2.04 (s, 3H), 2.03-1.94 (m, 1H), 1.79 (bd, J = 12.5 Hz, 1H), 1.62-1.43 (m, 5H), 1.08-0.85 (m, 5H), 1.00 (d, J = 7 Hz, 3H), 0.90 (d, J = 7Hz, 3H ).

Example 13 General procedure for coupling reactions or carried out on a solid support The synthesis was performed on a parallel synthesizer of the ACT396 model from Advanced ChemTech® with the 96-well block. Typically, 24 peptides will be synthesized in parallel using classical solid phase techniques. The Fmoc-Nva-Wang resin starting and the 1- (Fmoc-amino) cyclopropane carboxylic acid-Wang resin were prepared by the coupling method with DCC and DMAP (Atherton, E; Scheppard, RC Solid Phase Peptide Synthesis, a Practical Approach IRL Press, Oxford (1989), pages 131-148). Other amino acid-Wang resins were obtained from commercial sources. Each well was loaded with 100 mg of the starting resin (approximately 0.05 mmol). The resins were washed consecutively with 1.5 ml portions of NMP (Ix) and DMF (3 X). The Fmoc protecting group was removed by treatment with 1.5 ml of a 25% v / v solution of piperidine in DMF for 20 min. The resins were lifted with 1.5 ml portions of DMF (4 X), MeOH (3 X) and DMF (3X) The coupling was performed in DMF (350 μl), using 400 μl (0.2 mmol) of a 0.5M solution of a mixture of Fmoc-amino acid and HOBt hydrate in DMF, 400 μl (0.4 mmol) of a 0.5 M solution of DIPEA in DMF and 400 μl (0.2 mmol) of a 0.5 M solution of TBTU in DMF. After stirring for 1 h, the wells were emptied, the resins were washed with 1.5 ml of DMF and the coupling was repeated once more under the same conditions. The resins were then washed as described above and the cycle was repeated with the next amino acid. The finishing groups were introduced in two ways: 1. In the form of a carboxylic acid using the protocol described above (eg acetic acid) or, 2. As an acylating agent such as an anhydride or an acid chloride. The following example illustrates the succinic anhydride cap: After deprotection of Fmoc and the subsequent washing protocol, DMF (350 μl) was added, followed by 400 μl of a solution of DMF of succinic anhydride (0.5 M, 0.2 mmol) and DIPEA (1.0 M, 0.4 mmol). The resins were stirred for 2 h and a re-coupling operation was performed. At the end of the synthesis the resin was washed with 1.5 ml portions of DCM (3 x), MeOH (3 x), DCM (3 x), and dried under vacuum for 2 h. The separation with respect to the resin and the concomitant deprotection of side chains were effected by the addition of 1.5 ml of a mixture of TFA, H20, DTT and TIS (92.5: 2.5: 2.5: 2.5). After stirring for 2.5 h, the resin was filtered and washed with 1.5 ml of DCM. The filtered materials were combined and concentrated by vacuum centrifugation.

Each compound was purified by preparative reverse phase HPLC using a C18 column (22 mm by 500 mm). Fractions containing products were identified by MALDI-TOF mass spectrometry, combined and lyophilized.

Example 14 Synthesis of compound 210 (Table 2) 210 Using the experimental protocol described in Example 11 and starting from a Fmoc-Cys (Trityl) -resin of Wang, the above compound was obtained as a white solid (15.7 mg). MS (FAB) 849.2 (MH +), 1H NMR (DMSO-de) d 12.8 (s wide, 1H), 12.1 (s wide, 2H), 8.27 (d, J = 8 Hz, 1H), 8.17 (d, J = 7.5 Hz, 1H), 8.07 (d, J = 8 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 7.75 (d , J = 8.9 Hz, 1H), 7.34-7.27 (m, 5H), 4.54-4.39 (m, 5H), 4.31-4.18 (m, 4H), 4.10 (d, J = 11 Hz, 1H), 3.68 ( dd, J = 3.9 Hz, J '= 10.8 Hz, 1H), 2.90-2.82 (m, 1H), 2.78-2.70 (m, 1H), 2.67-2.42 (m, 4H), 2.21-2.17 (m, 3H) ), 2.00-1.85 (m, 3H), 1.83 (s, 3H), 1.80-1.67 (m, 1H), 1.67-1.42 (m, 6H), 1.15-0.95 (m, 4H), 0.88 (dd) , J = 6.9 Hz, J '= 8.9 Hz, 6H).

Example 15 Synthesis of compound 215 (Table 2) 215 The synthesis was performed as shown below: 15e 15f 15 15h 25 a) Synthesis of compound 15b: __ 1 - (N-t-Boc-amino) cyclopropanecarboxylic acid (15a) (997 mg, 4.96 mmol) was dissolved in an anhydrous CH 2 Cl 2 mixture (25 ml) and THF (10 ml). The solution was cooled to 0 ° C, 2-trimethylsilylethanol (0.852 ml, . 95 mmol), DMAP (121.1 mg, 0.991 mmol) and a solution of DCC / CH2C12 (3.65 M, 1.63 mL, 5.95 mmol).

The reaction mixture was stirred at 0 ° C for about 4 h and then at RT overnight.

The white suspension was filtered through a pad of diatomaceous earth. The pad was washed and rinsed with CH2C12. The filtered and washed materials were evaporated to dryness. The residue was diluted with EtOAc and washed consecutively with 10% aqueous citric acid (2x), saturated NaHC03 (2x), water (2x) and brine (lx). The organic layer was dried (over MgSO), filtered and evaporated to give the ester 15b as an oil (approximately 1.5 g, 100%). XH NMR (CDCI3) d 5.08 (s 1H), 4.20-4.16 (m, 2H), 1.57-1.43 (m, 2H), 1.45 (s, 9H), 1.17-1.12 (m, 2H), 1.00-0.94 (m, 2H), 0.04 (s, 9H). b) Synthesis of compound 15c: Ester 15b (approximately 700 mg, 2.33 mmol) was treated for 40 min at RT with a mixture of 4N HCl and dioxane (11 mL). The solution was concentrated to dryness to afford the amine hydrochloride as a white solid, which was then subjected to the reaction conditions described in Example 6. The crude hydrochloride salt (950 mg, 2.55 mmol) and Boc-4 (R) -naphthalen-1-ylmethoxy) proline (3) were dissolved in anhydrous CH2C12. NMM (1.02 mL, 9.30 mmol) and HATU (1.06 g, 2.79 mmol) were added consecutively and the mixture was stirred at RT. After 1.75 h, the reaction mixture was diluted with EtOAc and washed consecutively with 10% aqueous citric acid (2x), saturated aqueous NaHCO3 (2x), water (2x), and brine (lx). The EtOAc layer was dried (MgS0), filtered and concentrated to dryness to provide the crude dipeptide 15c as a whitish foam (1.22 g). MS (FAB) 555.4 (MH +). 1 H NMR (CDCl 3); mixture of rotamers, d 8.06-8.04 (m, 1H), 7.87-7.80 (m, 2H), 7.55-7.41 (m, 5H), 4.99-4.93 (m, 2H), 4.45-4.21 (m, 2H), 4.16-4.11 (m, 2H), 3.97-3.45 (m, 2H), 2.70-1.80 (m, 2H), 1.73-1.40 (m, 2H), 1.53 (s, (6/9) 9H), 1.44 ( s, (3/9) 9H), 1.20-1.05 (m, 2H), 0.97-0.93 (m, 2H), 0.02 (s, 9H). c) Synthesis of compound 15d: The crude dipeptide 15d (approximately 2.20 mmol) was treated with a mixture of 4 N HCl and dioxane (11 mL) for 40 min at RT and the resulting hydrochloride salt was coupled to Boc-Val-OH (525 mg, 2.42 mmol). with NMM (968 mL, 8.80 mmol) and HATU (1.00 g, 2.64 mmol) as described for compound 15c (with the modification of a coupling time of 2.5 h). The crude tripeptide 15d was obtained as a whitish foam (1.5 g). MS (FAB) 654.4 (MH +). XH NMR (CDCl 3) d 8.05-8.02 (m, 1H), 7.87-7.80 (m, 2H), 7.55-7.40 (m, 5H), 7.30-7.28 (m, 1H), 5.19-4.62 (m, 4H) , 4.41-3.70 (m, 1H), 4.35-4.27 (m, 1H), 4.09-3.95 (m, 1H), 3.73-3.62 (m, 2H), 2.69-2.60 (m, 1H), 2.14-1.94 ( m, 2H), 1.55-1.38 (m, 2H), 1.39 (s, 9H), 1.22-1.18 (m, 1H), 1.11-1.07 (m, 1H), 0.98-0.90 (m, 8H) ', 0.02 (s, 9H). d) Synthesis of compound 15e: The 15d crude tripeptide (approximately 2.20 mmol) was treated with a mixture of 4 N HCl and dioxane (11 mL) for 40 min at RT and the resulting hydrochloride salt was coupled to Boc-Chg-OH (622 mg, 2.42 mmol) with NMM (968 mL, 8.80 mmol) and TBTU (847 mg, 2.64 mmol) as described for compound 15c (with the modifications of using TBTU as a coupling agent and stirring at RT for approximately 64 hrs. before carrying out the treatment). The residue as a foam was purified by flash chromatography (eluent: mixture of hexane and EtOAc; 6: 4) to provide the tetrapeptide 15e as a white foam (710.8 mg, 41% yield over the course of 3 steps). MS (FAB) 793.4 (MH +), XH NMR (CDC13) d 8.07-8.05 (m, 1H), 7.87-7.80 (m, 2H), 7.57-7.41 (m, 4H), 7.35 (s, 1H), 6.72-6.64 (m, 1H), 5.02-4.95 (m, 3H), 4.68 -4.62 (m, 2H), 4.43-4.40 (m, 1H), 4.15-4.00 (m, 2H), 3.96-3.93 (m, 2H), 3.68 (dd, J = 11, J '= 5 Hz, 1H ), 2.62-2.56 (m, 1H), 2.16-2.00 (m, 2H), 1.70-1.54 (m, 6H), 1.49-1.42 (m, 2H), 1.43 (s, 9H), 1.14-1.02 (m , 5H), 0.95-0.88 (m, 10H), 0.02 (s, 9H). e) Synthesis of compound 15: Tetrapeptide 15e (168.1 mg, 0.212 mmol) was treated with a solution of 4 N HCl and dioxane (2 mL) and the resulting hydrochloride salt was coupled to Boc- (D) Glu (OTMSE) -OH (81.0 mg, 0.233). mmol) with NMM (94 mL, 0. 848 mmol) and TBTU (81.7 mg, 0.254 mmol) as described for compound 15e (with the modification of a coupling time of 17 h). The crude pentapeptide 15f was obtained as a whitish foam (220 mg, 0.212 mmol). MS (FAB) 1022.8 (MH +) 1044.8 (MNa +). XH NMR (CDCl 3) d 8.07-8.05 (m, 1H), 7.88-7.81 (m, 2H), 7.57-7.41 (m, 4H), 7.29 (s, 1H), 6.70-6.55 (m, 2H), 5.45 -5.35 (m, 1H), 4.99-4.98 (m, 2H), 4.66-4.57 (m, 2H), 4.44-4.40 (m, 1H), 4.30-4.01 (m, 5H), 3.91 (dd, J = 11, J '= 4 Hz, 1H), 3.76-3.62 (m, 2H), 2.62-2.56 (m, 2H), 2.50-2.30 (m, 3H), 2.18-2.09 (m, 2H), 2.06-1.90 (m, 2H), 1.67-1.53 (m, 4H), 1.50-1.42 (m, 4H), 1.43 (s, 9H), 1.14-0.86 (m, 10H), 0.93 (d, J = 7 Hz, 3H ), 0.87 (d, J = 7 Hz, 3H), 0.04 (s, 9H), 0.02 (s, 9H). f) Synthesis of compound 15g: The crude pentapeptide 15f (approximately 0.212 mmol) was treated with a solution of 4 N HCl in dioxane (2.5 mL) for 40 min at RT and the resulting hydrochloride salt was coupled to Boc-Asp (OTMSE) -OH (77.8 mg , 0.233 mmol) with NMM (93 mL, 0.848 mmol) and TBTU (81.7 mg, 0.254 mmol) as described for compound 15e (with the modification of a coupling time of 2.5 h). The crude hexapeptide 15g was obtained as an ivory colored foam (278 mg, 0.212 mmol). MS (FAB) 1237.5 (MH +) 1259 (MNa +). g) Synthesis of compound 15h: The crude hexapeptide 15g (approximately 0.2 mmol) was treated for 40 min at RT with 2.5 mL of a solution of 4 N HCl in dioxane. The concentration to dryness afforded the amine hydrochloride as a white solid. The crude hydrochloride salt was dissolved in anhydrous DMF (2.5 mL) and treated consecutively with pyridine (377 μL, 4.66 mmol) and acetic anhydride (378 μL, 4.01 mmol). The reaction mixture was stirred overnight at RT, then poured into brine and extracted with EtOAc (3x). The combined organic layer was washed consecutively with 10% aqueous citric acid (2x), saturated NaHC03 (2x), water (2x), and brine (lx). The organic layer was dried (MgSO), filtered and evaporated to dryness. The foamy residue was purified by flash chromatography (eluent: mixture of hexane and EtOAc 3: 7) to give the acetylated hexapeptide 15h as a whitish foam (78.5 mg, 31% yield over the course of 3 steps). MS (FAB) 1179.6 (MH +) 1201.5 (Mna +). 1H NMR (CDC13) d 8.11-8.09 (m, 1H), 7.86-7.79 (m, 2H), 7.55-7.41 (m, 5H), 7.28 (s, 1H), 7.02-6.96 (m, 2H), 6.70 -6.68 (m, 1H), 5.13-5.10 (m, 1H), 4.96-4.91 (m, 2H), 4.58-4.41 (m, 4H), 4.22-4.08 (m, 8H), 3.77 (dd, J = 10.5, J '= 5 Hz, 1H), 3.09 (dd, J = 18, J' = 4 Hz, 1H), 2.76 (dd, J = 17.5, J '= 8 Hz, 1H), 2.51-2.20 (m , 3H), 2.12-2.08 (m, 2H), 2.09 (s, 3H), 1.73-1.53 (m, 8H), 1.27-1.09 (m, 7H), 1.01-0.85 (m, 8H), 0.98 (d , J = 6.5 Hz, 3H), 0.97 (d, J = 6 Hz, 3H), 0.04 (s, 9H), 0.03 (s, 9H), 0.01 (s, 9H). h) Synthesis of compound 215: The acetylated hexapeptide 15h (76.5 mg, 0.065 mmol) was dissolved in anhydrous THF (2 mL), a solution of TBAF (1M in THF, 389 μL, 0.389 mmol) was added and the mixture was stirred at RT for 16 h. The solution was concentrated in vacuo and the residue was dissolved in glacial acetic acid, filtered through a Millipore: Millex -HV 0.45 μm filtration unit and injected onto a C18 reversed phase column Whatman Partisil® 10-ODS-3 (2.2 x 50 cm). Purification program: Linear Gradient at 15 mL / min,? 230 nm, program at 5% A for 10 min, 5-30% A for 10 min, 30% A for 10 min, 30-60% A for 90 min. A: 0.06% of TFA in CH3CN; B: 0.06% of TFA in H20. The fractions were analyzed by an analytical HPLC. The collected product was lyophilized to give hexapeptide 215 as a white amorphous solid (26.9 mg, containing 41% by weight of tetrabutylammonium salts, yield 28%). MS (FAB) 879.4 (MH +) 901.3 (Mna +). In order to remove the tetrabutylammonium salt, the above product (approximately 18 mg) was dissolved in EtOAc and washed with 10% HCl (2x). The EtOAc layer was evaporated, then lyophilized with water to give the salt-free product as a white amorphous solid (3.8 mg, 36% yield). 1H NMR (DMSO-de) d 8.39 (s, 1H), 8.10-7.81 (m, 7H), 7.57-7.45 (m, 4H), 5.07-4.87 (m, 2H), 4.55-4.00 (m, 7H) , 3.76-3.71 (m, 1H), 2.67-2.62 (m, 1H), 2.33-2.10 (m, 3H), 2.05-1.42 (m, 8H), 1.79 (s, 3H), 1.38-0.71 (m, 1H), 0.89 (d, J = 6.68 Hz, 3H), 0.86 (d, J = 6.36 Hz, 3H).

Example 16 Synthesis of compound 214 (Table 2): For the synthesis of compound 214, the procedure described in example 15 was followed, using Boc-4 (R) - (naphthalen-2-ylmethoxy) proline for the introduction of the P2 fragment and with different protective groups in the carboxylic acid residues of the side chains. The synthesis is described below: 1ßh a) Synthesis of compound 16b: At 0 ° C, benzyl bromide (5.74 mL, 48.3 mmol) was added to a mixture of Boc-norvaline (16a) (10.0 g, 46.0 mmol) and DBU (7.57 L, 50.6 mmol) in acetonitrile (200 mL). After having stirred at RT for 20 h, the solution was concentrated and the residue was dissolved in ether. The organic solution was washed consecutively with 10% aqueous citric acid (2x), saturated aqueous NaHCO3 (2x) and brine (Ix), dried (MgSO4), filtered and concentrated to give the desired benzyl ester 16b as an oil colorless (13.7 g, yield 97%). 1 H NMR (CDCl 3) d 7.40-7.32 (m, 5H), 5.16 (dd, J = 26.7, J '= 12.4 Hz, 2H), 4.99 (d, J = 7.9 Hz, 1H), 4.35-4.32 (m, 1H), 1.82-1.73 (m, 1H), 1.66-1.57 (m, 1H), 1.43 (s, 9H), 1.41-1.32 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H). b, c, d, e, f, g) Synthesis of compound 16h: The above benzyl ester of Boc-Nva (121 mg, 0.48 mmol) was subjected to the same sequence of reactions as described in Example 7. However, for the introduction of P2 (step b) Boc-4- ( R) - (naphthalen-2-ylmethoxy) proline. Also for the introduction of P5 (stage e) and of P6 (stage f), the corresponding waste Boc-D-Glu-OH and Boc-Asp-OH were protected in the form of benzyl esters in the carboxylic acid side chain. h) Synthesis of compound 214: To a solution of hexapeptide 16h (approximately 0.210 mmol) in ethanol (3 mL) was added 10% palladium on organic carbon (01 mg) and ammonium acetate (10 mg). The mixture was stirred under a hydrogen atmosphere for 5 h, then filtered through a Millipore® filtration unit: Millex®-HV 0.45 μm and injected onto a C18 reverse phase column Whatman Partisil® 10-ODS- 3 (2.2 x 50 cm) balanced. Purification program: Linear Gradient at 15 mL / min,? 230 nm, at 5% up to 50% A in 60 min A: 0.06% TFA in CH3CN; B: 0.06% of TFA in H20. The fractions were analyzed by HPLC. The collected product was lyophilized to provide compound 214 as a white solid (20 mg, 0.02 mmol). MS (FAB) 895.5 (MH +). ? R NMR (CDC13) d 8.16 (d, J = 7.6 Hz, 1H), 8.11 (d, J = 8 Hz, 1H), 8.09 (d, J = 8 Hz, 1H), 7.98 (d, J = 9 Hz, 1H ), 7.91-7.88 (m, 3H), 7.85 (s, 1H), 7.77 (d, J = 9 Hz, 1H), 7.51-7.46 (m, 3H), 4.70 (d, J = 12 Hz, 1H) , 4.60 (d, J = 12 Hz, 1H), 4.53-4.45 (m, 2H), 4.33-4.10 (m, 6H), 3.69 (dd, J = 19, J '= 4.4 Hz, 1H), 2.66- 2.60 (m, 1H), 2.49-2.43 (m, 1H), 2.2T.-2.18 (m, 3H), 2.07-1.94 (m, 3H), 1.82 (s, 3H), 1.76-1.33 (m, 10H) ), 1.04-0.86 (m, 15H).

Example 17 Synthesis of compound 221 (Table 2) 221 The mono-benzyl succinic acid (prepared as described in: Bischoff, V. et al., Chem. Ber. (1902), 35, 4078) (27 mg, 0.134 mmol) was stirred in acetonitrile (2 mL) with TBTU (52 mg, 0.160 mmol) and NMM (47 mg, 0.469 mmol) for 5 min. To this mixture was added the appropriate tetrapeptide hydrochloride salt (prepared as described for compound 16e but using isoleucine instead of cyclohexylglycine and 4- (R) - (naphthalen-1-ylmethoxy) proline instead of 4 (R ) - (naphthalen-2-ylmethoxy) proline (97.0 mg, 0.134 mmol) The mixture was stirred at RT for 2.5 h, ethyl acetate was added and the mixture was washed with 10% citric or aqueous acid (2x) with NaHCO 3 saturated water (2x) and brine (lx), dried (MgSO), filtered and concentrated to give the protected tetrapeptide as a yellow oil.The above compound (approximately 0.134 mmol) was dissolved in ethanol ( 3 mL) and ammonium acetate (10 mg) and 20% palladium hydroxide on activated charcoal (30 mg) was added.The mixture was stirred under 1 atmosphere of hydrogen for 18 h, then filtered through a control unit. Millipore® filtration: Millex®-HV 0.45 μm and injected on a C18 Wh reverse phase column atman Partisil 10-ODS-3 balanced (2.2 x 50 cm). Purification program: Linear Gradient at 15 mL / min,? 230 nm, 5% A for 10 min, 5-60% A in 60 min (A: 0.06% TFA in CH3CN; B: 0.06% TFA in H20). The fractions were analyzed by HPLC. The collected product was lyophilized to provide compound 221 as a white solid (21 mg). MS (FAB) 683 (MH +). XH (DMSO-de) d 8.12 (d, J = 7.6 Hz, 1H), 8.07-8.03 (m, 1H), 7.96-7.81 (m, 4H), 7.59-7.51 (m, 3H), 7.55 (t, J = 8.0 Hz, 1H), 4.90 (d, J = 8 Hz, 1H), 4.82 (d, J = 8 Hz, 1H), 4.45 (t, J = 8.0 Hz, 1H), 4.36-4.31 (m, 2H), 4.24-4.12 (m, 3H), 3.74-3.68 (m, 1H), 2.43-2.31 (m, 4H), 2.24-2.18 (m, 1H), 2.01-1.92 (m, 2H), 1.67- 1.51 (m, 3H), 1.42-1.32 (m, 3H), 1.14-0.96 (m, 1H), 0.93-0.67 (m, 15H).

Example 18 The following description is an example of a compound of formula I wherein Q is CH2C (0). Preparation of compound 413 (Table 4) Compound 18b 1) To the cyclohexylacetic acid (18a) (8 g, 56.25 mmol) in DCM (160 mL) at room temperature was added oxalyl chloride (6.4 mL, 73.14 mmol) and 2 drops of DMF. The reaction mixture was stirred at room temperature for 1 h, then concentrated under reduced pressure to give the cyclohexylacetyl chloride. 2) The chiral auxiliary compound, (4S) - (-) - 4-isopropyl-2-oxazolidinone (7.63 g, 59.06 mmol) was dissolved in THF (200 mL) and cooled to -78 ° C. It was added slowly (for a period of 10 min) N-butyllithium (1.6 M) in hexane (36.9 mL, 59.06 mmol). The mixture was stirred at -78 ° C for 30 min (a gel formed). The aforementioned cyclohexylacetyl chloride was added to THF (50 L) at -78 ° C. The reaction mixture was stirred at -78 ° C for 30 min and then at 0 ° C for 1 h. The reaction mixture was quenched by adding an aqueous solution of NHC1 (16 mL). The reaction mixture was concentrated under reduced pressure. Et20 (300 mL) was added. The organic phase was separated and washed with a 10% aqueous solution of citric acid (2 x 200 mL), a saturated aqueous solution of NaHCO 3 (2 x 200 mL) and brine (200 mL), dried, filtered and concentrated under reduced pressure.The residue was purified by flash chromatography (silica gel, 40-60μ, 60 x 100 mm, hexane mixtures and EtOAc 9/1 - 8 / -> 2 to give compound 18b as a colorless oil (11.3 g, 79% yield)? E NMR (CDC13) d 4.40-4.36 (m, 1H), 4.20 (dd, J = 8.3 Hz, J = 9.1 Hz, 1H), 4.13 (dd, J = 2.9 Hz, 9.1 Hz, 1H), 2.86 (dd, J = 6.4 Hz, 15.7 Hz, 1H), 2.65 (dd, J = 7.1 Hz, J = 15.7 Hz, 1H), 2.35-2.27 (m, 1H), 1.8-1.76 (m, 1H), 1.70-.57 (m, 5H), 1.26-0.90 (m, 5H), 0.85 (d, J = 7.0 Hz, 3H), 0.81 (d, J = 6.7 Hz, 3H ).

Compound 18c To a solution of compound 18b (11.3 g, 44.68 mmol) in THF (125 mL) at -78 ° C was added a solution of NaHMDS (1 M in THF, 49.2 mL, 49.15 mmol). The reaction mixture was stirred at -78 ° C for 1.5 h. A solution of tere-butyl bromoacetate (8.67 mL, 53.62 mmol) in THF (25 mL) was added at -78 ° C. The mixture was stirred at that temperature for 3 h. A saturated aqueous solution of a solution of NH 4 Cl (33 mL) was slowly added. The cold bath was removed and the mixture was stirred at room temperature for 10 min. The THF was removed. EtOAc (200 mL) was added. The organic phase was separated, washed serially with a saturated aqueous solution of NaHCO3 (200 mL), H20 (200 mL), an aqueous solution of 1 N HCl (200 mL) and with brine (200 mL), dried ( on MgSO), filtered and concentrated under reduced pressure. The residue was purified by trituration with Et20 to give compound 18c as a white solid (12.655, 77% yield). XH NMR (DMSO-de) d 4.61-4.53 (m, 3H), 4.27-4.25 (m, 1H), 2.84-2.66 (m, 2H), 2.55-2.41 (m, 1H), 1.89-1.76 (m, 6H), 1.58 (s, 9H), 1.35-1.31 (m, 4H), 1.14-1.04 (m, 7H).

Compound 18d To an ice-cooled solution of compound 18c (12.2 g, 33.28 mmol) in a mixture of THF and H20 (mixture 3/1, 495 mL / 165 mL) was added H202 (30%, 15.1 mL, 133.1 mmol) , followed by a slow addition of LiOH-H20 (2.79 g, 66.56 mmol). The reaction mixture was stirred at 0 ° C for 1 h and then at RT overnight. The mixture was cooled to 0 ° C and a 1.5 N aqueous solution of Na 2 SO 3 was slowly added to decompose the excess peroxide. (guarded by a Kl paper). The mixture was concentrated under reduced pressure, the residual aqueous solution was washed with DCM (2 x 150 mL). The aqueous layer was made acidic with a 10% aqueous solution of citric acid. The mixture was extracted with EtOAc (3 x 200 mL). The combined organic phase was washed with brine (200 mL), dried (MgSO), filtered and concentrated under reduced pressure. Compound 18d was obtained as a colorless oil (8.38 g, 98% yield). XH NMR (CDC13) d 2.71-2.66 (m, 1H), 2.59 (dd,, J = 10.8 Hz, 16.0 Hz, 1H), 2.36 (dd, J = 3.8 Hz, 16.0 Hz, 1H), 1.78-1.57 ( m, 6H), 1.41 (s, 9H), 1.30-0.98 (m, 5H).

Compound 18f 1) The corresponding Boc derivative of compound 18e (1.63 g, 2.74 mmol) was treated with a mixture of 4 N HCl and dioxane (14 mL, 54.91 mmol) at RT for 1 h. The reaction mixture was concentrated under reduced pressure. A 5% aqueous solution of Na 2 CO 3 (25 mL) was added to the residue and the resulting solution was stirred vigorously for 5 min. EtOAc (25 mL) was added. The two resulting phases separated. The organic phase was washed with brine (50 mL) dried (over MgSO), filtered and concentrated under reduced pressure to give compound 18e which was used as it was for the next operation. 2) To the amino-tripeptide in DMF (5 mL) at RT was added compound 18d (739 mg, 288 mmol) in DMF (5 mL) followed by DIPEA (1.43 mL, 8.24 mmol) and TBTU (502 mg, 2.88 mmol). The reaction mixture was stirred at RT overnight. EtOAc (125 mL) was added. The organic phase was separated, washed with a saturated aqueous solution of NaHC 3 (100 mL), H 2 O (100 mL) and brine (100 mL), dried (MgSO 4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (on silica gel, 40-60 μ, 40 x 125 mm, hexane mixtures and EtOAc 6/4 -> 5/5) to give the tert-butyl ester compound 18f as a foam of white color (1.18 g, yield 59%). 1H NMR (CDC13) d 8.06 (d, J = 8.3 Hz, 1H), 7.86 (d, J = 7.6 Hz, 1H), 7.81 (d, J = 8.3 Hz, 1H), 7.55-7.40 (m, 4H) , 7.35 (s, 1H), 6.28 (d, J = 8.9 Hz, 1H), 5.86-5.79 (m, 1H), 5.24 (dd, J = 1.6 Hz, 17.2 Hz, 1H), 5.17 (dd, J = 1.3 Hz, J = 10.5 Hz, 1H), 4.98 (ABq,? V = 18.7 Hz, J = 12.1 Hz, 2H), 4.67-4.51 (m, 4H), 4.41-4.38 (m, 1H), 3.99 (dd) , J = 3.8 Hz, 10.8 Hz, 1H), 2.64-2.59 (m, 2H), 2.42-2.38 (m, 2H), 2.10-1.95 (m, 2H), 1.68-1.53 (m, 9H), 1.43- 1.41 (m, 1H), 1.42 (s, 9H), 1.15-1.04 (m, 4H), 0.97-0.91 (m, 8H).

Compound 18h To the commercially available 3- (benzyl-2-methoxycarbonyl-ethyl) amino] propionic acid methyl ester (18 g) (2 g, 7.16 mmol) in MeOH (24 mL) was added the palladium catalyst (10% Pd / C). %, 500 mg, 25% w / w). The reaction mixture was stirred under a nitrogen atmosphere (a balloon) for 18 h. The mixture was filtered through diatomaceous earth and the filter pad was washed with MeOH (20 mL). The MeOH (filtered material plus washed material) was evaporated to give 1.2 g (89% yield) of compound 18h as a pale yellow oil. This product was used as it was for the next stage.

Compound 18i 1) The t-butyl ester compound 18f, (1.18 g, 1.62 mmol) was treated with 4 N HCl in dioxane (8.5 mL, 32.4 mol) at RT for 6 h. The mixture was concentrated under reduced pressure and then evaporated together with a mixture of benzene and Et20 to give 1.04 g of the corresponding acid as a beige foam (95% yield). 2) To the last acid (200 mg, 0.29 mmol) in DMF (1 mL) at RT was added the amine (compound 18h, 59 mg, 0.31 mmol) in DMF (2 mL), followed by DIPEA (154 μL, 0.89 mmol) and TBTU (100 mg, 0.31 mmol). The reaction mixture was stirred at RT for 72 h. EtOAc (125 mL) was added. The organic phase was separated, washed with a saturated aqueous solution of NaHCO 3 (75 mL), H 2 O (75 mL) and with brine (75 mL), dried (MgSO 4), filtered and concentrated under reduced pressure. The product was purified by flash chromatography (silica gel, 40-60 μ, 20 x 100 mm, mixture of EtOAc and hexane 8/2 to give compound 18i as a yellow oil (82 mg, 33% yield). MS (ESI) 869.3 (M + Na +), 845.4 (MH) ~.

Compound 413 A 1 M aqueous solution of NaOH (774 μL, 0.774 mmol) was added to a solution of compound 18i (82 mg, 0.097 mmol) in a mixture of THF and MeOH (1/1, 1 mL each). The reaction mixture was stirred at RT for 18 h. H20 (15 mL) was added. The aqueous phase was separated and washed with DCM (3 x 15 mL). The aqueous phase was made acidic (at pH 3) by adding an aqueous solution of IN HCl. The mixture was extracted with EtOAc (3 x 15 mL). The organic phase was washed with brine (25 mL), dried (MgS0), filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (in 5% MeCN -> 53% in 60 min) to give compound 413 as a white lyophilized solid material (31 mg, 41% yield).

MS (ESI) 779.3 (M + H +), 801.3 (M + Na) +, 777.3 (MH) "? H NMR (DMSO-de) d 8.38 (S, 1H), 8.06 (d, J = 8.3 Hz, 1H ), 7.93 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 8.3 Hz, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.57-7.44 (m, 5H), 5.01 (d) , J = 12.1 Hz, 1H), 4.89 (d, J = 12.1 Hz, 1H), 4.35-4.31 (m, 2H), 4.25 (dd, J = 7.9 Hz, 8.3 Hz, 1H), 4.18 (d, J = 11.1 Hz, 1H), 3.80-3.49 (m, 3H), 3.37-3.34 (m, 2H), 2.63-2.61 (m, 2H), 2.56-2.52 (m, 1H), 2.39-2.35 (m, 2H) ), 2.25-2.20 (m, 2H), 2.05-1.91 (m, 2H), 1.62-1.59 (m, 1H), 1.41-1.22 (m, 5H), 0.96-0.73 (m, 16H).

Example 19 RADIOMETRIC ANALYSIS OF RECOMBINANT HCV NS3 PROTEASE a) Cloning, expression and purification of recombinant HCV type Ib NS3 protease The serum of a patient infected with HCV was obtained through an external collaboration (Bernard Willems MD, Hópital St-Luc, Montréal, Canada and Dr. Donald Murphy, laboratory of Santé Publique du Québec, Ste-Anne de Bellevue, Canada). A full-length cDNA template engineered from the HCV genome was constructed from DNA fragments obtained by a reverse transcription polymerase chain reaction (RT-PCR) of an RNA of serum and using specific primers selected on the basis of homology among other strains of genotype Ib. From the determination of the entire genomic sequence, a gonotype Ib was assigned to the HCV isolated material according to the classification of Simmonds et al. (J. Clin Microbiol. (1993), 3JL, 1493-1503.). It was shown that the amino acid sequence of the non-structural region, NS2-NS4B, was identical in more than 93% to the HCV genotype Ib (isolated materials BK, JK and 483) and 88% identical to the HCV genotype (material isolated from HCV-1). A DNA fragment encoding the polyprotein precursor (NS3 / NS4A / NS4B / NS5A / NS5B) was generated by PCR and introduced into eukaryotic expression vectors. After a transient transfection, the treatment of a polyprotein mediated by the HCV NS3 protease was demonstrated by the presence of the mature NS3 protein using a Western blot analysis. The mature NS3 protein was not observed with expression of a polyprotein precursor containing the S1165A mutation, which deactivates the NS3 protease confirming the functionality of the HCV NS3 protease. The DNA fragment encoding the recombinant HCV NS3 protease (amino acids 1027 to 1206) was cloned into the bacterial expression vector pETlld. Expression of the NS3 protease in E. coli BL21 (DE3) pLysS was induced by incubation with 1 mM IPTG for 3 h at 22 ° C. A typical fermentation (18 L) provided approximately 100 g of a wet cell paste. The cells were resuspended in a buffer for lysis (3.0 mL / g) consisting of 25 mM sodium phosphate, pH 7.5, 10% glycerol (v / v), 1 mM EDTA, and 0.01% NP-40. , and stored at -80 ° C. The cells were thawed and homogenized following the editing of 5 mM DTT. Magnesium chloride and DNase were then added to the homogenate at final concentrations of 20 mM and 20 μg / mL respectively. After incubation for 25 min at 4 ° C, the homogenate was sonicated and centrifuged at 15,000 x g for 30 min at 4 ° C. The pH of the supernatant was then adjusted to 6.5 using a 1 M solution of sodium phosphate.

An additional step of chromatography with gel filtration was added to the 2-step purification process which has been described in WO 95/22985 (incorporated here by your reference). Briefly, the supernatant from the bacterial extract was loaded onto a column with SP HiTrap® (Pharmacia) previously equilibrated at a flow rate of 2 mL / min in buffer A (50 mM sodium phosphate, pH 6.5, 10% glycerol) , 1 mM EDTA, 5 mM DTT, 0.01% NP-40). Then the column was washed with buffer A containing 0.15 M NaCl and the protease was eluted by applying 10 column volumes of a linear gradient of NaCl from 0.15 to 0.3 M. The fractions containing the NS3 protease were pooled and diluted to a final NaCl concentration of 0.1 M. The enzyme was further purified on a HiTrap® Heparin column (Pharmacia) equilibrated in buffer B (25 mM sodium phosphate, pH 7.5, 10% glycerol, 5 mM DTT, 0.01% NP-40). The sample was loaded at a flow rate of 3 mL / min. The column was then washed with buffer B containing 0.15 M NaCl at a flow rate of 1.5 mL / min. Two-step washes were performed in the presence of buffer B containing 0.3 or 1M NaCl. The protease was recovered in the wash with 0.3 M NaCl, diluted 3 times with buffer B, reapplied on the column with HiTrapO Heparin and eluted with buffer B containing 0.4 M NaCl. Finally, the fractions containing The NS3 protease was applied on a column with Superdex 75 HiLoad® 16/60 (Pharmacia) equilibrated in buffer B containing 0.3 M NaCl. The purity of the HCV NS3 protease, obtained from the fractions, was estimated to be grouped, was greater than 95% by SDS-PAGE followed by a densitometric analysis. The enzyme was stored at -80 ° C and thawed on ice, and diluted just before use. b) RADIOMETRIC ANALYSIS OF RECOMBINANT HCV NS3 PROTEASE The substrate used for the radiometric analysis of the HCV NS3 protease, DDIVPC-SMSYTW, is cut between the cysteine and cerin residues by the enzyme. The DDIVPC-SMSYTW sequence corresponds to the natural cut site of HS5A / NS5B where the system residue in P2 has been replaced by a proline. The DDIVPC-SMSYTW peptide substrate and the biotin-DDIVPCSMS [125I-Y] TW tracer were incubated with the recombinant NS3 protease in the absence or in the presence of inhibitors. Separation of the substrate from the products was performed by adding agarose beads coated with avidin to the analysis mixture, followed by filtration. The quantity of the SMS product [125 I-Y] TW found in the filtrate (with or without inhibitor) allowed the calculation of the substrate conversion percentage and the inhibition percentage.

A. Reagents Tris and Tris-HCl (UltraPure) were obtained from Life Technologies. Glycerol (UltraPure), MES and BSA were purchased from Sigma®. The TCEP was obtained from Pierce, the DMSO was obtained from Aldrich® and the NaOH was obtained from Anachemia ® Assay Buffer: 50 mM Tris-HCl, pH 7.5, 30% glycerol (w / v), "" 2% CHAPS (w / v), BSA "1 mg / mL, 1 mM TCEP (TCEP was added just before use from a 1 M reserve solution in water) Substrate: DDIVPC-SMSYTM, final concentration 25 μM (from a 2 mM stock solution in DMSO stored at -20 ° C to avoid oxidation).

Tracer: Reduced mono-iodinated substrate (biotin-DDIVPC-SMS [125I-Y] TW) (final concentration «1 nM).

Type Ib protease of HCV NS3, 25 nM final concentration (from a stock solution in 50 mM sodium phosphate, pH 7.5, 10% glycerol, 300 mM NaCl, 5 mM DTT, 0.01% NP-40 ).

B. Protocol The analysis was performed on a 96-well polypropylene plate. Each well contained: • 20 μl of a mixture of substrate and tracer in assay buffer; • 10 μl of inhibitor in a mixture of 20% DMSO and assay buffer; • 10 μl of protease Ib of NS3.

A sample was also prepared under vacuum (non-inhibitor and without enzyme) and a control sample (without inhibitor) on the same assay plate.

The enzymatic reaction was initiated by the addition of the enzyme solution, and the assay mixture was incubated for 60 min at 23 ° C under gentle agitation. Twenty (20) μL of 0.025 N NaOH was added to quench the enzymatic reaction. (20) μl of avidin-coated agarose beads (purchased from Pierce) were added to a Millipore® MADP N65 filtration plate. The smudged analysis mixture was transferred to the filter plate, and incubated for 60 min at 23 ° C under gentle agitation.

The plates were filtered using a Millipore® MultiScreen Vacuum Manifold Filtration vacuum manifold filtration apparatus and 40 μl of the filtrate was transferred to a 96-well opaque plate containing 60 μl of a scintillation fluid per well.

The filtered materials were counted in a Packard® TopCount instrument using a 125 μl-liquid protocol for 1 minute. The% inhibition was calculated with the following equation: 100- [(computation-computation-vault) / (computation-computation-computation-vault) x 100] A non-linear curve fitting was applied with the Hill model to the inhibition and concentration data and the effective concentration of 50% (IC50) was calculated by the use of a SAS software program (Statistical Software Systems, SAS Institute, Inc., Cary, NC).

Example 20 ETRIC RADIO ANALYSIS OF A RECOMBINANT HCV NS3 PROTEASE MIXTURE AND THE NS4A COFACTOR PITTY the enzyme was cloned, expressed and prepared according to the protocol described in Example 19. The enzyme was stored at -80 ° C, thawed on ice and diluted accurately before use in the assay buffer containing the peptide NS4A collector. The substrate used for the radiometric analysis of the NS3 protease mixture and the NS4A cofactor peptide, DDIVPC-SMSYTW (SEQ ID No. 2), is cut by the enzyme between the cysteine and serine residues. The DDIVPC-SMSYTW sequence corresponds to the natural cut site in NS5A / NS5B where the cysteine residue in P2 has been replaced by a proline. The peptide substrate DDIVPC-SMSYTW (SEQ ID No. 2) and the biotin-DDIVPC-SMS tracer [-1x2"5l-Y] TW (SEQ ID No. 3) are incubated with the recombinant NS3 protease and the cofactor peptide of NS4A KKGSVVIVGRIILSGRK (SEQ ID No. 1) (molar ratio of enzyme: cofactor 1: 100) in the absence or presence of inhibitors The separation of the substrate from the products is carried out by adding agarose beads coated with avidin to the mixture of analysis, followed by filtration The quantity of the product SMS [125I-Y] TW found in the filtered material allows the calculation of the substrate conversion percentage and the percentage of inhibition.

A. Reagents Tris and Tris-HCl (UltraPure) were obtained from Life Technologies. The glycerol (UltraPure), the MES and the BSAs were purchased from Sigma®. The TCÉP was obtained from Pierce, the DMSO was obtained from Aldrich® and the NaOH was obtained from Anachemia®.

Assay buffer: 50 mM Tris HCl, pH 7.5, 30% glycerol (w / v), 1 mg / mL BSA, 1 mM TCEP (TCEP was added just before use from a 1 M stock solution in Water) .

Substrate, DDIVPCSMSYTW: SEQ ID No. 2) 25 μM final concentration (from a 2 mM stock solution in DMSO stored at -20 ° C to avoid oxidation).

Tracer: Biotin reduced iodized mono substrate DDIVPC SMS [125I Y] TW (SEQ ID No. 3) (final concentration ~ 1 nM).

Type Ib protease of HCV NS3, 25 nM final concentration (from a stock solution in 50 mM sodium phosphate, pH 7.5, 10% glycerol, 300 mM NaCl, 5 mM DTT, 0.01% NP-40 ).

NS4A cofactor peptide: KKGSVVIVGRIILSGRK (SEQ ID No. 1), 2.5 μM final concentration (from a 2 mM stock solution in DMSO stored at -20 ° C).

B. Protocol The analysis was performed on a 96-well polypropylene plate. Each well contained: • 20 μL of a mixture of substrate and tracer in assay buffer; • 10 μL ± inhibitor in a mixture of 20% DMSO and assay buffer; • 10 μL of a mixture of protease Ib of NS3 and peptide of cofactor NS4 (molar ratio 1: 100).

A sample was also prepared under vacuum (non-inhibitor and without enzyme) and a control sample (without inhibitor) on the same assay plate.

The enzymatic reaction was initiated by the addition of the enzyme and peptide solution of NS4A, and the assay mixture was incubated for 40 min at 23 ° C under gentle agitation. Ten (10) μL of 0.5 N NaOH and 10 μL of 1 M MES, pH 5.8 were added to quench the enzymatic reaction.

Twenty (20) μL of avidin-coated agarose beads (purchased from Pierce®) were added to a Millipore® MADP N65 filtration plate. The smudged analysis mixture was transferred to the filter plate, covered for 60 min at 23 ° C under gentle agitation.

The plates were filtered using a filter apparatus with a Millipore® MultiScreen Vacuum Manifold Filtration vacuum manifold and 40 μL of the filtrate was transferred to a 96-well opaque plate containing 60 μL of a scintillation fluid per well. The filtered materials were counted in a Packard® TopoCount instrument using a 125 μl-liquid protocol for 1 minute.

The value of the IC50 was calculated in the same way as in example 19.

Example 21 ANALYSIS OF SPECIFICITY The specificity of the compounds was determined against a variety of serine proteases: human leukocyte elastase, porcine pancreatic elastase and bovine pancreatic a-chymotrypsin and a cysteine protease, human liver cathepsin B. In all cases a protocol with the 96-well plate format was used using a p-nitroaniline colorimetric substrate (pNA) specific for each enzyme. Each analysis included a pre-incubation of the enzyme and inhibitor mixture for 1 h at 30 ° C, followed by substrate addition and hydrolysis at a "30% conversion, as measured on a Thermomax® UV microplate reader. Substrate concentrations were kept as low as possible compared to KM to reduce substrate competition. The concentrations of the compound varied between 300 to 0.06 μM depending on its potency. The final conditions for each analysis were as follows: 50 mM Tris-HCl pH 8, Na2SO0. 5M, 50 mM NaCl, EDTA 0. 1 mM, 3% DMSO, 0.01% Tween-20 with: [100 μM Succ-AAPF-pNA (SEQ ID No. 4) and 250 pM a-chymotrypsin], [133 μM Succ-AAA-pNA and 8 nM porcine elastase] , [133 μM Succ-AAV-pNA and leukocyte elastase 8 nM]; or [NaHP04 100 mM pH 6, EDTA 01. MM, 3% DMSO, TCEP lmM, 0.01% Tween-20, 30 μM Z-FR-pNA and 5 nM cathepsin B (the reserve enzyme was activated in a buffer containing mM TCEP before use)].

A representative example for porcine pancreatic elastase is summarized below.

In a 96-well flat bottom polystyrene well, they were added using a Biomek® liquid handler (from Beckman): • 40 μL of the assay buffer (50 mM Tris-HCl, pH 8, 50 mM NaCl, 0.1 mM EDTA); • 20 μL of an enzyme solution (50 mM Tris / HCl, pH 8, 50 mM NaCl, 0.01 mM EDTA, 0.02% Tween-20, 40 nM porcine pancreatic elastase); and • 20 μL of an inhibitor solution (50 mM Tris-HCl, pH 8, 50 mM NaCl, 0.01 mM EDTA, 0.02% Tween-20, 1.5 mM-0.3 μM inhibitor, 15% v / v DMSO) .

After a pre-incubation for 60 min at 30 ° C, 20 μL of a substrate solution (55 mM Tris-HCl, pH 8, 0.5 M Na 2 SO 4, 50 mM NaCl, 0.1 mM EDTA, Succ) was added to each well. -AAA-pNA 665 μM) and the reaction mixture was further incubated at 30 ° C for 60 min, time after which the absorbance was read on the Thermomax® UV plate reader. Well rows were assigned for control samples (without inhibitor) and for samples in vacuum (without inhibitor and without enzyme). The 2-fold sequential dilutions of the inhibitor solution were performed on a plate disposed separately by the liquid handler, using 50 mM Tris-HCl pH 8, 50 mM NaCl, 0.1 mM EDTA, 0.02% Tween-20, DMSO at 15%. All other specificity analyzes were performed in a similar manner. The percent inhibition was calculated using the formula: [l- ((UVinh-UVvacio) / (UVctl-UVvacio))] X 100 A nonlinear curve fit with the Hill model was applied to the inhibition and concentration data, and the 50% effective concentration (IC50) was calculated by the use of a SAS software program (Statistical Software Systems, SAS Institute, Inc., Cary, NC).

Example 22 Compound tables The following tables list the IC 50 values of the representative compounds of the invention. The following abbreviations are used: IC50: The concentration required to obtain an inhibition of NS3 in the radiometric analysis of the NS3 protease mixture and NS4A cofactor peptide, according to Example 11; the results marked with * indicate an IC50 value obtained in the radiometric analysis of the recombinant HCV NS3 protease according to example 10; HLE: The concentration required to obtain a 50% inhibition in the elastase analysis of human leukocytes; PPE: The concentration required to obtain a 50% inhibition in porcine pancreatic elastase analysis; Other: Unlabelled data indicate the concentration required to obtain a 50% inhibition in the analysis of bovine pancreatic ochymotrypsin; the data marked with ** indicate the concentration required to obtain a 50% inhibition in the analysis of human liver cathepsin B; MS: Mass spectrometry data (MH + from FAB); AAA: Analysis data of amino acids expressed in% recovery of peptides; Acca: 1-amino-cyclopropylcarboxylic acid; Acpe: 1-amino-cyclopentylcarboxylic acid; Abu: 2-aminobutyric acid; Chg: cyclohexylglycine (2-amino-2-cyclohexyl-acetic acid); Hyp: 4 (R) -hydroxyproline; Hyp (4-Bn): 4 (R) -benzyloxyproline; Pip: pipecolic acid (ie, homoprolyl); Tbg: tert-butylglycine; Ac: acetyl; Bn: benzyl; O-Bn: benzyloxy; DAD: 3-carboxypropionyl; and DAE: 4-carboxybutyryl; AlGly: allylglycine (2-amino-4-pentanoic acid); Thioxole: L-thionisoisoleucine; Ph: phenyl; 31-Ph: 3-iodophenyl; 4I-Ph: 4-iodo-phenyl; 2Br-Ph: 2-bromophenyl; 3Br-Ph: 3-bromo-phenyl; 4 Br-h: 4-bromo-phenyl; l-NpCH20: naphthalen-1-ylmethoxy; 2-NpCH20: naphthalen-2-ylmethoxy; 3,5-Br2Ph: 3,5-dibromophenyl.

(Jl O ün TABLE 1 I heard or Ul O cp H OD K3 H1 OT O Ul O p < J0 m LO or m CN N K3 O p TABLE 3 t t (Jl or cp or Ül TABLE 4 to H (Jl O cp or Cp t t cp o (l or cp t to cp or Ül p to to I-1 H1 Cp or ül O Cp to to Ül o l O Cp to t I-1 cp O Ül l to t cp o l O Ül LIST OF SEQUENCES (1) GENERAL INFORMATION: (i) APPLICANT: (A) NAME: Boehringer Ingelheim (Canada) (B) STREET: 2100 Cunard (C) CITY: Laval (D) STATE: Quebec (E) COUNTRY: Canada (F) NUMBER ZIP ZIP CODE: HTS 2G5 (G) TELEPHONE: (450) 682-4640 (H) TELEFAX: (450) 682-8434 (ii) TITLE OF THE INVENTION: Peptides Inhibitors of Hepatitis C (üi) NUMBER OF SEQUENCES : 4 (iv) LEGIBLE FORMAT BY COMPUTER: (A) DATA SUPPORT: Floppy disk (B) COMPUTER: IBM PC compatible (C) OPERATING SYSTEM: PC-DOS / MS-DOS (D) LOGICAL SYSTEM - SOFTWARE: Patentln Reléase no . 1.0, version no. 1.25 (EPA) (v) CURRENT APPLICATION DATA: NUMBER OF APPLICATION: WO 98/00765 (vi) DATA FROM PREVIOUS APPLICATION: (A) NUMBER OF APPLICATION; US 60 / 055,186 (B) DATE OF SUBMISSION: AUGUST 11, 1997 (2) INFORMATION ABOUT SEQ ID NO: 1: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 17 amino acids (B) TYPE: amino acid (C) CHAIN FORM: single (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 1: Lys Lys Gly Val Val lie Val Gly Arg lie lie Leu Ser Gly Arg 1 5 10 15 Lys (2) INFORMATION ABOUT SEQ ID NO: 2: (i) CHARACTERISTICS OF THE SEQUENCE: (A) LENGTH: 12 amino acids (B) TYPE: amino acid (C) CHAIN FORM: single (D) TOPOLOGY: linear (ii) TYPE OF THE MOLECULE: peptide (xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 2 sp Asp lie Val Pro Cys Ser Met Ser Tyr Thr Trp 1 5 10 (2) INFORMATION ABOUT SEQ ID NO: 3: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 13 amino acids (E) TYPE: amino acid (F) ) CHAIN FORM: single (G) TOPOLOGY: linear (ii) TYPE OF MOLECULE: peptide (ix) FEATURE: (A) NAME / KEY: Modified site (B) SITUATION: 1 (D) OTHER INFORMATION: / product = "Asp BIOTINILADO" / marca = Xaa / nota = "Xaa in position 1 is biotinylated Asp (ix) FEATURE: (A) NAME / KEY: Modified site (B) SITUATION: 11 (D) OTHER INFORMATION .- / product =" [1251-Tyr] "/ mark = Xaa / note = w Xaa in position 1 is [125yodated]" (Xi) DESCRIPTION OF SEQUENCE: SEQ ID NO: 3: Xaa Asp Asp lie Val Pro Cys Ser Met Ser Xaa Thr Trp 1 5 20 (2) INFORMATION ABOUT SEQ ID NO: 4: (i) SEQUENCE CHARACTERISTICS: (A) LENGTH: 4 amino acids (B) TYPE: amino acid (C) CHAIN FORM: single (D) TOPOLOGY: linear (ii) TYPE OF MOLECULE : peptide (ix) CHARACTERISTICS: (A) NAME / KEY: Modified site (B) SITUATION: 1 (D) OTHER INFORMATION: / product = "Succ-Ala" / brand = Xaa / note = "Xaa in position 1 is Alanine Succinylated "(ix) CHARACTERISTICS: (A) NAME / KEY: Modified site (B) SITUATION: 4 (D) OTHER INFORMATION: / product =" F-pNA "/ brand = Xaa / note =" Xaa in position 4 is Phe -para-nitroaniline "(Xi) DESCRIPTION OF THE SEQUENCE: SEQ ID NO: 4: Xaa Ala Pro Xaa 1 It is noted that in relation to this date the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property

Claims (61)

1. A compound of formula (I) Pß P5 P4 P3 P2 P1 (D characterized in that Q is CH2 or N-Y wherein Y is H or Ci-β alkyl; a) when Q is CH2, a is 0, b is 0 and B is an amide derivative having the formula RiiaN (R? u) -C (O) - wherein ú is H, Ci-io alkyl optionally substituted with carboxyl or di amino (lower alkyl); C3-7 cycloalkyl; aryl Ce; C7-10 alkylaryl; (C3-7 cycloalkyl) - (Ci-β alkyl); heterocycloalkyl Ci-e; and iib is C1-6 alkyl substituted with carboxyl, (Ci-e alkoxy) carbonyl or phenylmethoxycarbonyl; or C7-16 aralkyl substituted on the aromatic portion with carboxyl; (Ci-e alkoxy) carbonyl, phenylmethoxycarbonyl, or Rn and Riib are bonded to form a nitrogen containing ring of 3 to 7 elements, optionally substituted with carboxyl or (C6-6 alkoxy) carbonyl; or b) when Q is N-Y, a is 0 or 1, b is 0 or 1, and B is an acyl derivative having the formula R? u > -C (0) - wherein Rii is (i) C? -? Alkyl or optionally substituted with carboxyl, C? -6 alkanoyloxy (eg AcOCH2) or C? -6 alkoxy (eg Boc); (ii) C3-7 cycloalkyl optionally substituted with carboxyl, (Ci-β) alkoxycarbonyl or phenylmethoxycarbonyl; (iii) C3-7 cycloalkyl substituted with carboxyl and one to three substituents of the Ci-β alkyl type; (iv) (alkylcycloalkyl) C-? or optionally substituted in the cycloalkyl portion with carboxy, (Ci-β) alkoxycarbonyl or phenylmethoxycarbonyl; (v) H, (vi) aryl e or Cι or C 7-16 aralkyl optionally substituted with Ci-β alkyl; Re, when present, is C1-β alkyl substituted with carboxyl; and Rs, when present, is Ci-e alkyl optionally substituted with carboxyl; or c) when Q is either CH2 or N-Y; Rs is C1-10 alkyl, C3-7 cycloalkyl or (alkylcycloalkyl) C4-10; Z is oxo or thioxo; R3 is C1-10 alkyl optionally substituted with carboxyl, C3-7 cycloalkyl or (C4-cycloalkyl) alkyl; W is a group of formula II: Formula II wherein R2 is C1-10 alkyl or C3-10 cycloalkyl optionally substituted with carboxyl; C6-16 aryl or C7-16 aralkyl; or is a group of formula II ': Formula II' where X is CH or N; and 2 'is divalent C3-4 alkylene which, together with X and the carbon atom to which X and R2 are attached, forms a ring of 5 or 6 elements, said ring optionally being substituted with OH; SH; NN2; carboxyl; R12; OR12; C (0) 0Ri2, SR12, NHR12 or NR12R12 'wherein Ri2 and R12' are independently: cyclic C3-cyclic alkyl or cyclic C1-6 alkyl or cyclic C3-16 alkenyl or C2- [beta] acyclic alkenyl, said alkyl or alkenyl optionally substituted with NH 2, OH, SH, halo or carboxyl; said alkyl or alkenyl containing optionally at least one heteroatom independently selected from the group consisting of: O, S and N; or R 2 and R 2 'are independently Ce or C 1-6 aryl or C 7-16 aralkyl optionally substituted with Ci-e alkyl, CF 3, NH 2, OH, SH, halo, carboxyl, C 1-6 alkyl substituted with carboxyl or phenyl optionally substituted with C1-6 alkyl, C1-6 alkoxy, halo, acetylamido or nitro; said aryl or aralkyl optionally containing at least one hotero atom independently selected from the group consisting of: O, S and N; said cyclic alkyl, cyclic alkenyl, aryl or aralkyl being optionally condensed with a second ring of 5, 6 or 7 elements to form a cyclic system or a heterocyclic system, said second ring being optionally substituted with NH 2, OH, SH, halo, carboxyl or carboxy-lower alkyl; said second ring optionally comprising at least one heteroatom independently selected from the group consisting of: O, S and N; or X is CH or N; and 2 'is a divalent C3-4 alkylene which together with X and the carbon atom to which X and R2' are attached, forms a ring of 5 or 6 elements, which in turn is condensed with a second ring of 5, 6 or 7 elements to form a cyclic system wherein the second ring is substituted with OR12"wherein R12" is C7-16 aralkyl; Ri 'is hydrogen, and Ri is Ci-e alkyl optionally substituted with thiol or halo; or Ri is C2-e alkenyl; Ri 'and Ri together form a 3 to 6-membered ring optionally substituted with C6-6 alkyl and A is hydroxy or one of its pharmaceutically acceptable salts or esters.

2. A compound of formula la: Pß P5 P4 P3 PZ P1 characterized in that Y is H or Ci-β alkyl; a is 0 or 1; b is 0 or 1; B is an acyl derivative of formula R n -C (O) - wherein R n is (i) C 1 - alquilo alkyl or optionally substituted with carboxyl, Ci-β alkanoyloxy or Ci-β alkoxy; (ii) C3-7 cycloalkyl optionally substituted with carboxyl, (Ci-e) alkoxycarbonyl or phenylmethoxycarbonyl; (iii) C3-7 cycloalkyl substituted with carboxyl and one to three Ci-β alkyl substituents; (iv) (C4-10 alkylcycloalkyl) optionally substituted on the cycloalkyl portion with carboxy, (Ci-e) alkoxycarbonyl or phenylmethoxycarbonyl; (v) H, (vi) C 1 -C 6 aryl or C 7-16 arylalkyl optionally substituted with Ci-β alkyl; Re, when present, is C 1-6 alkyl substituted with carboxyl; R5, when present, is C1-6 alkyl optionally substituted with carboxyl; and R4 is C1-10 alkyl, C3-7 cycloalkyl or (alkylcycloalkyl) Co; R3, W, Ri, Ri 'and A are as defined in claim 1.

3. A compound of the formula according to claim 2, characterized in that B is an acyl derivative of the formula RnC (O) - wherein Ru is: Ci-β alkyl optionally substituted by carboxyl, C 1-6 alkanoyloxy or Ci-alkoxy; C13-7 cycloalkyl optionally substituted with carboxyl, MeOC (O), EtOC (O) or BnOC (O); 3-carboxypropionyl (DAD) or 4-carboxybutyryl (DAE); or HOOCCH OOBn

4. A compound of the formula according to claim 3, characterized in that B is acetyl, 3-carboxy-propionyl, 4-carboxybutyryl, AcOCH2C (0), Me3COC (0), n "é -

5. A compound of the formula according to claim 4, characterized in that B is acetyl, 3-carboxypropionyl (DAD), 4-carboxybutyryl (DAE), AcOCH2C (O),

6. A compound of the formula according to claim 5, characterized in that B is acetyl.

7. A compound of the formula according to claim 2, characterized in that Re, when present, is the side chain of Asp or Glu.

8. A compound of formula according to claim 7, characterized in that, Re, when present, is the side chain of Asp.

9. A compound of the formula according to claim 2, characterized in that, R5, when present, is the side chain of an amino acid selected from the group consisting of: D-Asp, Asp, D-Glu, Glu, D -Val, Val, D-Tbg and Tbg.

10. A compound of the formula according to claim 9, characterized in that, R5, when present, is the side chain of D-Asp, D-Val or D-Glu.

11. A compound of the formula according to claim 10, characterized in that, R5, when present, is the side chain of D-Glu.

12. A compound of formula (Ib): P4 P3 P2 P1 (Ib) characterized in that B is an amide of formula RiiaN (Rut) C (O) wherein Ru is C? -6 alkyl, cycloalkyl C3-6, (C3-7 alkylcycloalkyl) optionally substituted with carboxy, C1-3 carboxyalkyl, aryl Ce, C7-10 arylalkyl 2-tetrahydrofuranylmethyl, or 2-thiazolidylmethyl; and Riib is preferably C.sub.4-4 alkyl substituted with carboxyl.

13. A compound of formula (Ib) according to claim 12, characterized in that, Rna is cyclopropylmethyl, isopropyl, carboxyethyl, benzylmethyl, benzyl, or 2-tetrahydrofuranylmethyl.

14. A compound of formula (Ib) according to claim 13, characterized in that, Rii ±, is C1-4 alkyl substituted with carboxyl.

15. A compound of formula (Ib) according to claim 1, characterized in that Rut is ethyl carboxyl.

16. A compound of formula I according to claim 1, characterized in that Ri is selected from the group consisting of: isopropyl, cyclopropyl, tere-butyl, 1-methylpropyl, or 2-methylpropyl.

17. A compound of formula I according to claim 16, characterized in that R is cyclopropyl or 1-methylpropyl.

18. A compound of the formula according to claim 17, characterized in that R 4 is cyclopropyl.

19. A compound of formula I according to claim 1, characterized in that, Z is oxo.

20. A compound of formula I according to claim 1, characterized in that, R3 is the side chain of lie, allo-Ile, Chg, Cha, Val, Tbg or Glu.

21. A compound of formula I according to claim 20, characterized in that, 3 is the side chain of Val, Tbg or Chg.

22. A compound of formula I according to claim 21, characterized in that, R3 is the side chain of Val.

23. A compound of formula I according to claim 1, characterized in that it is a group of formula II wherein R2 is C-e alkyl; C 1-6 alkyl substituted with carboxyl, Ci-β, benzyloxycarbonyl or benzylaminocarbonyl alkoxycarbonyl; or benzyl.

24. A compound of formula I according to claim 23, characterized in that it is a group of formula II wherein R2 is the side chain of Abu, Leu, Phe, Cha, Val, Ala, Asp, Glu, Glu (OBn), or Glu (NHBn).

25. A compound of formula I according to claim 24, characterized in that 2 is the side chain of Asp, aminobutyric acid (Abu) or Val.

26. A compound of claim I according to claim 1, characterized in that it is a group of formula III ': Formula III1 wherein R13 is OH; SH; NH2; carboxyl; R12; OR12, SR12, NHR12 or NR12R12 'wherein R12 and R12' are independently; cyclic C3-i6 alkyl or Ci-ie acyclic alkyl or cyclic C3-16 alkenyl or C2-16 acyclic alkenyl, said alkyl or alkenyl optionally substituted with NH2, OH, SH, halo or carboxyl; said alkyl or alkenyl optionally containing at least one heteroatom independently selected from the group consisting of: O, S and N; or R 12 and R 12 'are independently C 7 or C 0 O aralkyl C 7-16 alkyl optionally substituted with Ci-β, NH 2, OH, SH, halo, carboxyl or carboxy-alkyl alkyl (lower); said aryl or aralkyl containing optionally at least one heteroatom independently selected from the group consisting of: O, S and N; said cyclic alkyl, cyclic alkenyl, aryl or aralkyl being optionally fused with a second ring of 5-, 6- or 7- elements to form a cyclic system or a heterocyclic system, said second ring being optionally substituted with NH2, OH, SH, halo, carboxyl or carboxy-lower alkyl; said second ring optionally containing at least one heteroatom independently selected from the group consisting of: 0, S and N.

27. A compound of claim I according to claim 26, characterized in that, R13 is OR12 or SR12 wherein R12 is a C7-16 Ce or C 1 O aralkyl aryl, said first aryl or aralkyl being optionally substituted with C 1-6 alkyl, C3-7 cycloalkyl, NH2, OH, SH, halo, C1-6 alkoxy, carboxyl, carboxy-lower alkyl, or a second aryl or aralkyl; said first and second aryl or aralkyl optionally containing at least one heteroatom independently selected from the group consisting of: O, S and N.

28. A compound according to claim 27, characterized in that Ri3 is Bn; PhCH2CH2; PhCH2CH2CH2; O-Bn; o- 1-olylme toxy; m-tolylmethoxy; p-tolylmethoxy; 1-naphthyloxy; 2-naphthyloxy; 1-naphthalenylmethoxy; 2-naphthalenylmethoxy; (4-tert-butyl) ethoxy; (3l-Ph) CH20; (4Br-Ph) 0; (2Br-Ph) 0; (3Br-Ph) 0; (4I-Ph) 0; (3Br-Ph) CH20; (3,5-Br2-Ph) CH20;

29. A compound according to claim 28, characterized in that, R13 is O-Bn; PhCH2CH2CH2; 1-naphthyloxy; 2-naphthyloxy; 1-naphthalenylmethoxy; 2-naphthalenylmethoxy;

30. A compound of formula I according to claim 1, characterized in that Ri 'is hydrogen and Ri is C? -6 alkyl optionally substituted with thiol.

31. A compound of formula I according to claim 30, characterized in that, Ri is the side chain of the amino acid selected from the group consisting of: cysteine (Cys), aminobutyric acid (Abu), norvaline (Nva), or allyl glycine ( AlGly).

32. A compound of formula I according to claim 31, characterized in that Ri 'is H and Ri is propyl.

33. A compound of formula I according to claim 1, characterized in that, Ri 'and Ri together form a ring of 3- to 6- elements, said ring being optionally substituted with ethyl.

34. A compound of formula I according to claim 33, characterized in that, Ri 'and Ri together form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ring.

35. A compound of formula I according to claim 34, characterized in that Ri 'and Ri together form a cyclopropyl ring optionally substituted with Ci-β- alkyl

36. A compound of formula I according to claim 1, characterized in that a) Q is CH2, a is 0, b is 0, and then B is an amide of formula RiiaN (Riuo) -C (O) - wherein Riia is C? -6 alkyl, C3-6 cycloalkyl, C3-7 (alkylcycloalkyl) optionally substituted with carboxy, carbonyl (C1-3 alkoxy), phenyl, C7-10 arylalkyl, 2-tetrahydrofuranylmethyl, or 2-thienylmethyl; and Rut, is phenyl (C 0-2 alkyl) optionally substituted with carboxyl or carbonyl (C 1-4 alkoxy), C 1-4 alkyl substituted with carboxyl or carbonyl (C 1-4 alkoxy), - or Riia and Riib are joined to form a piperidine ring optionally substituted with carboxyl or carbonyl (alkoxy Ci-e); or b) Q is N-Y wherein Y is H or Ci-e alkyl; a is 0 or 1; b is 0 or 1; and B is an acyl derivative of formula Rn-C (O) -wherein Rn is (i) Ci-e alkyl, Ci-e alkyl substituted with carboxyl, MeC (0) 0-, MeO-, EtO-, MeCH2CH20 - or Me3C-0-; (ii) cyclopentyl or cyclohexyl optionally substituted with carboxyl; (iv) (C4-10 alkylcycloalkyl) optionally substituted on the cycloalkyl portion with carboxyl; (v) (vi) phenyl, benzyl or phenylethyl; Re, when present, is CH2COOH or CH2CH2COOH, Rs, when present, is C1-6 alkyl or CH2COOH or CH2CH2COOH; or c) when Q is either CH2 or N-Y, R4 is Ci-β alkyl, C3-7 cycloalkyl or (C4-6 alkylcycloalkyl); Z is oxo or thio; R3 is alkyl Ci-e; C3-7 cycloalkyl or C4-? alkyl (alkylcycloalkyl); W is a group of formula II wherein R2 is C1-10 alkyl, C3-10 cycloalkyl, C7-11 aralkyl, CH2COOH or CH2CH2COOH; or W is a group of formula II 'wherein X is N or CH and R2' is the divalent radical -CH2CH2CH2- or -CH2CH2CH2CH2- which together with X and the carbon atom to which X and R2 'are attached form a ring of 5- or 6- elements, said ring optionally being substituted with OR12, C (0) ORi2, SR12, NHR12 or NR12R12 ', wherein R12 and R12' are, independently: cyclic C3-16 alkyl or Ci-ie alkyl cyclic C3-16 acyclic or alkenyl or C2-C6 acyclic alkenyl, said alkyl or alkenyl being optionally substituted with NH2, OH, SH, halo or carboxyl; said alkyl or alkenyl containing optionally at least one heteroatom independently selected from the group consisting of: O, S and N; or R12 and R12 'are independently Ce or C14 aryl or C7-16 aralkyl optionally substituted with C1-6 alkyl, CF3, NH2, OH, SH, halo, carboxyl, C1-6 alkyl substituted with carboxyl or phenyl optionally substituted with C1 alkyl -6, C 1-6 alkoxy or halo; said aryl or aralkyl containing optionally at least one heteroatom selected independently from the 10 group consisting of: O, S and N; said cyclic alkyl, cyclic alkenyl, aryl or aralkyl being optionally fused with a second ring of 5-, 6- or 7- elements to form a cyclic system or a system Heterocyclic, said second ring being optionally substituted with NH 2, OH, SH, halo, carboxyl or C 1-6 alkyl substituted with carboxyl; said second ring containing optionally at least one heteroatom selected 20 independently from the group consisting of: O, S and N; or X is N; and R2 'is -CH2CH2CH2- or -CH2CH2CH2CH- which together with X and the carbon atom to which X and R2' are attached form a ring of 5- or 6 elements, which 25 in turn is fused with a phenyl to form a cyclic system wherein the phenyl ring is substituted with OR12"wherein R12" is phenylmethyl or phenylethyl; Ri, is hydrogen and Ri is methyl, thiomethyl, 1-methylethyl, propyl, 1-methylpropyl, 2- (methylthio) ethyl or 2-propylene; or Ri 'and Ri together with the carbon atom to which they are attached form a cyclopropyl which may optionally be substituted with ethyl; and A is hydroxy or a pharmaceutically acceptable salt thereof; C1-6 alkoxy, or (aryl-alkoxy Ci-β).

37. A compound of the formula according to claim 2, characterized in that, B is an acyl derivative of the formula Rn-C (O) - wherein R n is C 1-6 alkoxy, C 1-10 alkyl optionally substituted with carboxyl; C3-7 cycloalkyl optionally substituted with carboxyl or benzylcarboxy; or HOOCCH, NCOOBn Re is absent; R5 is absent; Ri is Ci-io alkyl, C3-7 cycloalkyl or C4-10 (alkylcycloalkyl); R3 is C1-10 alkyl, C3-7 cycloalkyl or (C4-10 alkylcycloalkyl); W is a group of formula II: Formula II wherein R2 C1-6 alkyl, C3-6 cycloalkyl; C 1-6 alkyl substituted with carboxyl; arilo Ce or Cío; or C7-11 aralkyl; or is a group of formula II ': Formula II where X is N; and R2 'is as defined in claim 1, and A is hydroxy or one of its pharmaceutically acceptable salts; methoxy, ethoxy, phenoxy, or benzyloxy.

38. A compound of the formula according to claim 2, characterized in that B is acetyl, 3-carboxypropionyl, 4-carboxylbutyryl, AcOCH2C (O), Me3COC (O), n Y is H or Me, a is 0 or 1, b is 0 or 1, Re, when present, is the side chain of Asp or Glu, R5, when present, is the side chain of Asp, D-Asp, Glu, D-Glu, Val, D-Val or Tbg, Ri is the side chain of Val, Chg, Tbg, lie, or Leu, R3 is hydrogen or the side chain of lie, Chg, Val, Glu; W is Abu, Leu, Phe, Val, Ala, Glu, or Glu (OBn); or W is the group of formula III ': wherein R13 is Bn, PhCH2CH2, PhCH2CH2CH2, O-Bn, o-tolylmethoxy, m-tolylmethoxy, p-tolylmethoxy, 1-naphthalenylmethoxy, 2-naphthalenylmethoxy, (4-tert-butyl) benzyloxy, (3I-Ph) CH20, (4Br-Ph) 0, (2Br-Ph) 0, (IBr-Ph) 0, (4I-Ph) 0, (3Br-Ph) CH20, (3, 5-Br2-Ph) CH2O, Ri 'is H and Ri is the side chain of Cys, Abu, Nva or allylglycine; or Ri 'and Ri together with the carbon atom to which they are attached form a cyclopropyl; and A is hydroxyl.

39. A compound of formula Ib according to claim 12, characterized in that, B is an amide of formula RnaN (Rut,) -C (O) - wherein Ri is C alquilo-C6 alkyl optionally substituted with carboxyl, C3-6 cycloalkyl (C 3-7 alkylcycloalkyl) optionally substituted with carboxy, carbonyl (C 1-3 alkoxy), phenyl, C 7-10 arylalkyl, 2-tetrahydrofuranylmethyl, or 2-thienylmethyl; and Riib is phenyl (C 0-2 alkyl) optionally substituted with carboxyl or carbonyl (C 1-4 alkoxy); Ci-β alkyl substituted with carboxyl or carbonyl (C 1-4 alkoxy); or Riia and Riib are joined to form a piperidine ring optionally substituted with carboxyl or carbonyl (C 1-6 alkoxy); Ri is cyclohexyl; Z is oxo; R3 is hydrogen or the side chain of lie, Chg, Val, Glu; W is Abu, Leu, Phe, Val, Ala, Glu, Glu (OBn); or W is a group of formula III ': wherein R13 is Bn, PhCH2CH2, PhCH2CH2CH2, O-Bn, o-tolylmethoxy, m-tolylmethoxy, p-tolylmethoxy, 1-naphthalenylmethoxy, 2-naphthalenylmethoxy, (4-tert-butyl) methoxy, (3l-Ph) CH20, (4Br-Ph) 0, (2Br-Ph) 0, (3Br-Ph) 0, (4I-Ph) 0, (3Br-Ph) CH20, (3, 5-Br2-Ph) CH20, Ri 'is H and Ri is the side chain of Cys, Abu, Nva or allylglycine; or Ri 'and Ri together with the carbon atom to which they are attached form a cyclopropyl; and A is hydroxyl.

40. A compound of formula I according to claim 1, characterized in that, B is an acyl derivative of formula R ?? -C (O) - wherein Ru is C? -? Alkyl or optionally substituted with carboxyl; C3-7 cycloalkyl optionally substituted with carboxyl; or a (C4-10 alkylcycloalkyl) optionally substituted on the cycloalkyl portion with carboxyl; or R 11 is C 1 -C 6 aryl or C 7-16 aralkyl optionally substituted with a C 1-6 alkyl a is 0 or 1; Re, when present, is Ci-e alkyl optionally substituted with carboxyl; b is 0 or 1; R5, when present, is Ci-Ce alkyl optionally substituted with carboxyl; Q is N-Y wherein Y is H or Ci-β alkyl; R 4 is C 1-10 alkyl, C 3-7 cycloalkyl or C 4-10 (alkylcycloalkyl); Z is oxo; R3 is C1-10 alkyl, C3-7 cycloalkyl or (C4-alkyl) alkyl; W is a group of formula II: Formula II wherein 2 is alkyl Ci-e; Ci-β alkyl optionally substituted with carboxyl; aryl Ce or Cio, or C7-16 aralkyl; W is a group of formula II ': Formula II where X is CH or N; and R2 'is C3-4 alkyl, which binds X to form a 5- or 6- element ring, said ring optionally substituted with OH; SH; NH2; carboxyl; R12; OR12, SR12, NHR12 or NR12R12 ', wherein R12 and R12' are independently: cyclic C3-16 alkyl or Ci-iß acyclic alkyl or cyclic C3-6 alkenyl or C2-? Acyclic alkenyl, said alkyl or alkenyl being optionally substituted with NH2, OH, SH, halo or carboxyl, said alkyl or alkenyl optionally containing at least one heteroatom independently selected from the group consisting of: 0, S and N; or R12 and R12 'are independently aryl Ce or Cio or C7-I6 aralkyl optionally substituted with C1-6 alkyl, NH2, OH, SH, halo, carboxyl, C 1-6 alkyl substituted with carboxyl; said aryl or aralkyl containing optionally at least one heteroatom independently selected from the group consisting of: O, S and N; Said cyclic alkyl, cyclic alkenyl, aryl or aryl alkyl being optionally fused with a second ring of 5-, 6- or 7- elements to form a cyclic system or a heterocyclic system, said second being Ring optionally substituted with NH 2, OH, SH, halo, carboxyl or carbxy (lower) alkyl; said second ring optionally containing at least one heteroatom independently selected from the group 25 consists of: O, S and N; Ri ', is hydrogen and Ri is C alquilo-alkyl and optionally substituted with thiol, or C 2-6 alkenyl; or Ri 'and Ri together form a ring of 3-6-elements optionally substituted with C1-6alkyl, and A is hydroxyl or one of its pharmaceutically acceptable salts or esters.

41. A pharmaceutical composition characterized in that it comprises an anti-hepatitis C virus effective amount of a compound of formula I according to claim 1, in admixture with a pharmaceutically acceptable carrier medium or auxiliary agent.

42. A method for treating a viral infection of hepatitis C in a mammal, characterized by administering to the mammal an effective amount against the hepatitis C virus of the compound of formula I according to claim 1, or a pharmaceutically acceptable salt or ester thereof .

43. A method for inhibiting the replication of the hepatitis C virus, characterized in that the virus is exposed to an inhibitory amount of the NS3 protease of the hepatitis C virus of the compound of formula I according to claim 1, or one of mss salts or therapeutically acceptable esters.

44. A method for treating an infection by the hepatitis C virus in a mammal, characterized in that an anti-hepatitis C virus effective amount of a combination of the compound of formula I of claim 1, or one of its salts or therapeutically acceptable esters, and an interferon.

45. The use of a compound of formula I according to claim 1, for the treatment of a hepatitis C infection in a mammal, comprising administering to the latter an amount effective against the hepatitis C virus of the compound of formula I.

46. The use of a compound of formula I according to claim 1 for the manufacture of a medicament for the treatment of a hepatitis C infection in a mammal.

47. A compound according to claim 1, characterized in that it is selected from the group consisting of: a compound of formula where B, P6, P5, P4, P3, P2, and Pl are co or are defined later:

48. A compound according to claim 1, characterized in that it is selected from the group consisting of: a compound of formula where B, P6, P5, P4, P3, R? 3, Ri and Ri 'are as defined below 13

49. A compound according to claim 1, characterized in that it is selected from the group consisting of: a compound of formula where B, P6, P5, P, P3, P2, W, and Pl are as defined below:

50. A compound according to claim 1, characterized in that it is selected from the group consisting of: a compound of formula where B, R, P3, R? 3, Pl are as defined below:

51. A process for the preparation of a peptide analog of formula (I) according to claim 1, characterized in that Ri and Ri 'form a ring of 3 to 6 elements, optionally substituted with Ci-e alkyl, comprising the step of : coupling a peptide selected from the group consisting of: PG2-P6-P5-P4-P3-P2; PG2-P5-P4-P3-P2; PG2-P4-P3-P2; PG2-P3-P2; and PG2-P2; - with an intermediate compound of the formula: wherein P6, P5, P4, P3, P2 'are defined in claim 1, PGI is a carboxyl protecting group and PG2 is an amino protecting group.

52. An intermediate compound of formula: O-PG, Rf Rr wherein Ri and Ri 'form a ring of 3 to 6 elements optionally substituted with C? -6 alkyl, for use in the synthesis of a peptide or a peptide analogue directed against the hepatitis virus C.

53. An intermediate compound of formula: wherein Ri and Ri form a 3-6-membered ring optionally substituted with C?-C alquilo alkyl for use in the synthesis of a peptide or a peptide analogue according to claim 1.

54. A process for the preparation of a peptide analog of formula (I), characterized in that, Pl is a residue of 1-aminocyclopropyl carboxylic acid (Acca), comprising the step of: coupling a peptide selected from the group consisting of from: PG2-P6-P5-P4-P3-P2; PG2-P5-P4-P3-P2; PG2-P4-P3-P2; PG2-P3-P2; and PG2-P2; - with an intermediate compound of the formula: wherein P6, P5, P4, P3, P2 are defined in claim 1, PGI is a carboxyl protecting group and PG2 is an amino protecting group.

55. An intermediate compound according to claim 52, characterized in that said intermediate compound is aminocyclopropyl carboxylic acid (Acca).

56. An intermediate compound according to claim 53, characterized in that said intermediate compound is aminocyclopropyl carboxylic acid (Acca).

57. A process for the preparation of a peptide analog of formula (I) characterized in that Pl is a residue of coronary acid, comprising the step of: coupling a peptide selected from the group consisting of: PG2-P6-P5- P4-P3-P2; PG2-P5-P4-P3-P2; PG2-P4-P3-P2; PG2-P3-P2; and PG2-P2; - with an intermediate compound of the formula: wherein PG1 is a carboxyl protecting group and PG2 is an amino protecting group.

58. An intermediate compound according to claim 52, characterized in that said intermediate compound is coronaric acid.

59. An intermediate compound according to claim 53, characterized in that said intermediate compound is coronaric acid.

60. The process according to claim 51, 54 or 57, characterized in that said carboxyl protecting group (PGI) is selected from the group consisting of: alkyl esters, aralkyl esters, and esters that are split by treatment with a weak base or weak reducing means.

61. The prs according to claim 51, 54 or 57, characterized in that said amino protecting group (PG2) is selected from the group consisting of: acyl groups, aromatic carbamate groups, aliphatic carbamate groups, cyclic alkyl carbamate groups, alkyl, trialkylsilyl groups, and thiol containing groups. SUMMARY OF THE INVENTION A compound of formula I active against the hepatitis C virus ß P5 P4 P3 P2 P1 (D wherein, when Q is CH2, a is 0, b is 0 and B is an amide derivative; or when Q is N-Y, where Y is H or C? -6 alkyl, then B is an acyl derivative; Re, when present, is C 1 -C 6 alkyl substituted with carboxyl; R5, when present, is C1-6 alkyl optionally substituted with carboxyl; when Q is either CH2 or N-Y, then Z is oxo or thioxo; R 4 is C 1-10 alkyl, C 3- cycloalkyl or (alkylcycloalkyl) Co; R3 is C1-10 alkyl optionally substituted with carboxyl, C3-7 cycloalkyl or (alkylcycloalkyl) C-? O; W is a proline derivative; Ri 'is hydrogen, and Ri is a C? -6 alkyl optionally substituted with thiol; or Ri is C2-6 alkenyl; or Ri 'and Ri together form a ring of 3 to 6 elements; and A is hydroxy or one of its pharmaceutically acceptable salts or esters.