Title of Invention	A COMPOUND OF FORMULA (I) FOR THE TREATMENT OF HEPATITIS C VIRUS (HCV) INFECTION
Abstract	Formula (I) wherein a is 0 or 1; b is 0 or 1; Y is H or C¿1-6? alkyl; B is H, an acyl derivative or a sulfonyl derivative; W is hydroxy or a N-substituted amino; or a pharmaceutically acceptable salt or ester thereof, for use in the treatment of hepatitis C virus (HCV) infection.

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FORM 2 THE PATENTS ACT 1970 [39 OF 1970] 8B The Patents Rule, 2003 COMPLETE SPECIFICATION [See Section 10 and Rule 13] "A COMPOUND OF FORMULA (I) FOR THE TREATMENT OF HEPATITIS C VIRUS (HCV) INFECTION"" BOEHRINGER INGELHEIM (CANADA) LTD., of 2100 Cunard Street, Laval, Quebec H7S 2G4, Canada, The following specification particularly describes the nature of the invention and the manner in which it is to be performed:- approved in the clinic lor patients with chronic hepatitis C. However the sustained response rate is low, and interferon treatment also induces severe side-effects (i.e. retinopathy, thyroiditis, acute pancreatitis, depression) that diminish the quality of life ol treated patients. Recently, interferon in combination with ribavirin has been 5 approved for patients non-responsive to I FN alone. However, the side effects caused by IFN are not alleviated with this combination therapy. Therefore, a need exists for the development of effective antiviral agents for treatment of HCV infection that overcomes the limitations of existing pharmaceutical therapies. 10 HCV is an enveloped positive strand RNA virus in the Flaviviridae family. The single strand HCV RNA genome is approximately 9500 nucleotides in length and has a single open reading frame (ORF) encoding a single large polyprotein of about 3000 amino acids. In infected cells, this polyprotein is cleaved at multiple sites by cellular and viral proteases to produce the structural and non-structural (NS) proteins. In the 15 case of HCV, the generation of mature nonstructural proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) is effected by two viral proteases. The first one, as yet poorly characterized, cleaves at the NS2-NS3 junction; the second one is a serine protease contained within the N-terminal region of NS3 (henceforth referred to as NS3 protease) and mediates all the subsequent cleavages downstream of NS3, both 20 in cis, at the NS3-NS4A cleavage site, and in trans, for the remaining NS4A-NS4B, NS4B-NS5A, NS5A-NS5B sites. The NS4A protein appears to serve multiple functions, acting as a cofactor for the NS3 protease and possibly assisting in the membrane localization of NS3 and other viral replicase components. The complex formation of the NS3 protein with NS4A seems necessary to the processing events, 25 enhancing the proteolytic efficiency at all of the sites The NS3 protein also exhibits nucleoside triphosphatase and RNA helicase activities. NS5B is a RNA-dependent RNA polymerase that is involved in the replication of HCV. A general strategy for the development of antiviral agents is to inactivate virally encoded enzymes that are essential for the replication of the virus. In this vein, 30 patent application WO 97/06804 describes the (-) enantiomer of the nucleoside analogue cytosine-1,3-oxathiolane (also known as 3TC) as active against HCV. This compound, although reported as safe in previous clinical trials against HIV and HBV, has yet to be clinically proven active against HCV and its mechanism of action aaamst the virus has yet to be reponed Intense efforts to discover compounds which inhibit the NS3 protease or RNA helicase of HCV have led to the following disclosures: US patent 5,633,388 describes heterocyclic-substituted carboxamides and analogues as being active against HCV. These compounds are directed against the 5 helicase activity of the NS3 protein of the virus but clinical tests have not yet been reported. A phenanthrenequinone has been reported by Chu el al (Tet. Lett., (1996), 7229-7232) to have activity against the HCV NS3 protease in vitro. No further development on this compound has been reported. 10 A paper presented at the Ninth International Conference on Antiviral Research, Urabandai, Fukyshima, Japan (1996) (Antiviral Research, 30, 1, 1996; A23 (abstract 19)) reports thiazolidine derivatives to be inhibitory to the HCV protease. Several studies have reported compounds inhibitory to other serine proteases, such as human leukocyte elastase. One family of these compounds is reported in WO 15 95/33764 (Hoechst Marion Roussel, 1995). The peptides disclosed in that application are morpholinyJcarbonyl-benzoyl-peptide analogues that are structurally different from the peptides of the present invention. WO 98/17679 from Vertex pharmaceuticals Inc. discloses inhibitors of serine protease, particularly, Hepatitis C virus NS3 protease. These inhibitors are peptide 20 analogues based on the NS5A/5B natural substrate. AH of these peptides contain C-terminal activated carboriyf function as an essential feature. These peptides-were also reported to be active against other serine protease and are therefore not specific for HCV NS3 protease. Hoffman LaRoche has also reported hexapeptides that are proteinase inhibitors 25 useful as antiviral agents for the treatment of HCV infection. These peptides contain an aldehyde or a boronic acid at the C-terminus. Steinkuhler et al. and Ingallinella et al. have published on N terminal cleavage product inhibition (Biochemistry (1998), 37, 8899-8905 and 8906-8914). However, the peptides and peptide analogues presented do not include nor do they lead to the 30 design o1 the peptides ol the present invention. WO 98/46597 from Emory University discloses serine protease inhibitors, particularly Hepatitis C virus protease. All of the compounds disclosed are structurally different from the peptides of the present invention. WO 98/46630 from Peptide Therapeutics Ltd. discloses hepatitis C NS3 protease inhibitors. However, none of the peptides disclosed are related to the peptides of the invention. 5 JP10298151 from Japan Energy Corp. discloses N-(2,3-dihydroxybenzoyI)- substituted serine derivatives as serine protease inhibitors, specifically as hepatitis C viral protease inhibitors. These compounds do not contain any structural similarity to the peptide analogs of the present invention. One advantage of the present invention is that it provides peptides that are inhibitory ) 0 to the NS3 protease of the 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 show significant inhibitory activity at concentrations up to 300µM against other serine proteases such as human leukocyte elastase (HLE), porcine pancreatic elastase (PPE), or bovine 15 pancreatic chymotrypsin, or cysteine proteases such as human liver cathepsin B (Cat B). SUMMARY OF THE INVENTION Included in the scope of the invention are racemates, diastereoisomers and optical isomers of a compound of formula (I): 20 25 B wherein a is 0 or 1; b is 0 or 1; Y is H or C1-6 alkyl; B is H, an acyl derivative of formula R7-C(0)- or a sulfonyl of formula R7-S02 wherein R7 is (i) C1-10alkyl optionally substituted with carboxyl, C1-6 alkanoyloxy or Ce alkoxy; (li) C3.7 cycloalkyl optionally substituted with carboxyl, (d-e alkoxy)carbonyl or phenyfmethoxycarbonyi; (iii) C6 or Cn0 aryl or C7.i6 aralkyl optionally substituted with d-e alkyl, hydroxy, or amino optionally substituted with d-6 alkyl; or (iv) Het optionally substituted with d-e alkyl, hydroxy, amino optionally substituted with C,-6 alkyl, or amido optionally substituted with d-6 alkyl; R6, when present, is d* alkyl substituted with carboxyl; Rs, when present, is d-e alkyl optionally substituted with carboxyl; R4 is d.10 alkyl, C3.7 cycloalkyl or C4-10 (alkylcycloalkyt); R3 is C,.,0 alkyl, C3.7 cycloalkyl or dio (alkylcycloalkyl); R2 is CHZ-RJO, NH-Rao, OR 20 or S-R20. wherein R20 is a saturated or unsaturated C3.7 cycloalkyl or C4-10 (alkyl cycloalkyl) being optionally mono-, di- or tri-substituted with R21J or RJO is a Ce or C10 aryl or die aralkyl optionally mono-, di- or tri-substituted with R2L or R20 is Het or (lower aikyl)-Het optionally mono-, di- or tri-substituted with R21, wherein each R21 is independently C1-6alkyi C1-6alkoxy; amino optionally mono- or di-substituted with d-e alkyl; sulfonyl; N02; OH; SH; halo; haloalkyl; amido optionally mono-substituted with d-e alkyl, C6 or do aryl,C7-16 aralkyl, Het or (lower alkyl)-Het; carboxyl; carboxy(lower alkyl); C6 or do aryl, C7-16 aralkyl or Het, said aryl, aralkyl or Het being optionally substituted with R22 wherein R22 C1-6 alkyl; d-ealkoxy; amino optionally mono- or di-substituted with d.6 alkyl; sulfonyl; N02; OH; SH; halo; haloalkyl; carboxyl; amide; or (lower alkyl)amide; R, is d-e alkyl or C2-6alkenyl optionally substituted with halogen; and W is hydroxy or a N-substituted amino; or a pharmaceutical^ acceptable salt or ester thereof. included within the scope oi this invention is a pharmaceutical composition comprising an anti-hepatitis C virally effective amount of a compound of formula I, or a therapeutically acceptable salt or ester thereof, in admixture with a pharmaceutically acceptable carrier meaium or auxiliary agent. An important aspect of the invention involves a method of treating a hepatitis C viral infection in a mammal by administering to the mammal an anti-hepatitis C virally effective amount of the compound of formula I, or a therapeutically acceptable salt or ester thereof or a composition as described above. 5 Another important aspect involves a method of inhibiting the replication of hepatitis C virus by exposing the virus to a hepatitis C viral NS3 protease inhibiting amount of the compound of formula I, or a therapeutically acceptable salt or ester thereof or a composition as described above-Still another aspect involves a method of treating a hepatitis C viral infection in a 10 mammal by administering thereto an anti-hepatitis C virally effective amount of a combination of the compound of formula I, or a therapeutically acceptable salt or ester thereof, and an interferon. A pharmaceutical composition comprising the combination in admixture with a pharmaceutically acceptable carrier medium or auxiliary agent is also within the scope of this invention. 15 DETAILED DESCRIPTION OF THE INVENTION Definitions As used herein, the following definitions apply unless otherwise noted: With reference to the instances where (R) or (S) is used to designate the configuration of a radical, e.g. R4 of the compound of formula I, the designation is 20 done in the context of the compound and not in the context of the radical atone. The natural amino acids, with exception of glycine, contain a chiral carbon atom. Unless otherwise specifically indicated, the compounds containing natural-amiho acids with the L-configuration are preferred. However, applicants contemplate that when specified, some amino acids of the formula 1 can be of either D- or L-25 configuration or can be mixtures of D- and L-isomers, including racemic mixtures. The designation "PI, P2, P3 etc" as used herein refer to the position of the amino acid residues starting from the C-terminus end of the peptide analogues and extending towards the N-terminus (i.e. P1 refers to position 1 from the C-terminus, P2: second position from the C-terminus, etc ) (see Berger A. & Schechter I., 30 Transactions of the Royal Society London series B257, 249-264 (1970)). The abbreviations for the a-amino acids are set forth in Table A. TABLE A AMINO ACID SYMBOL Alanine Ala Aspartic acid Asp Cysteine Cys , Cyclohexylglycine (also named: 2-ammo-2-cyclohexylacetic acid) Chg Glutamic acid Glu Isoieucine He Leucine Leu Phenylalanine Phe Proline Pro Valine Val te^Butylglycine Tbg As used herein the term "1-arninocyclopropyi-carboxylic acid" (Acca) refers to a compound of formula: As used herein the term "te/t-butylglycine" (Tbg) refers to a compound of formula: The term "residue" with reference Jo an amino acid or amino acid derivative means a radical derived from the corresponding o-amino acid by eliminating the hydroxy! of the carboxy group and one hydrogen of the a-amino group. For instance, the terms Gin, Ala, Gly, He. Arg, Asp, Phe, Ser. Leu. Cys. Asn. Sar and Tyr represent the "residues" of L-glutamine, L-alanine, glycine, L-isoleuane, L-argin»ne, L-aspartic acid, L-phenylalanine, L-serine, L-leucine, L-cysteine, L-asparagine, sarcosine and L-tyrosine, respectively. The term "side chain" with reference to an amino acid or amino acid residue means 5 a group attached to the a-carbon atom of the a-amino acid. For example, the R-group side chain for glycine is hydrogen, for alanine it is methyl, for valine it is isopropyi. For the specific R-groups or side chains of the a-amino acids reference is made to A.L. Lehninger"s text on Biochemistry (see chapter 4). The term "halo" as used herein means a halogen radical selected from bromo, JO chloro, fluoro or iodo. The term "C1-4 alky!" or "(lower)alkyT as used herein, either alone or in combination with another radical, means straight chain or branched alkyl radicals containing up to six carbon atoms and includes, for example, methyl, ethyl, propyl, butyl, hexyl, 1-methylethyl, 1 -methyipropyl, 2-methytpropyl, 1,1-dimethylethyl (e.g. terf-butyl). 15 The term "C3.7 cycloalkyl" as used herein, either alone or in combination with another radical, means a cycloalkyl radical containing from three to seven carbon atoms and includes cyclopropyl; cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyi. The term "unsaturated cycloalkyl" includes, for example, the cyclohexenyl: 20 The term "C4-10 (alkylcycloalkyl) as used herein means a cycloalkyl radical containing from three to seven carbon atoms linked to an alkyl radical, the linked radicals containing up to ten carbon atoms; for example, cyclopropylmethyl, cyclopentylethyi, cyclohexylmethyl, cyclohexylethyl or cycloheptylethyi. The term "C2.10 alkenyl" as used herein, either alone or in combination with another 25 radical, means an alkyl radical as defined above containing from 2 to 10 carbon atoms, and further containing at least one double bond. For example alkenyl includes allyl and vinyl. The term "C1-6alkanoyT as used herein, either alone or in combination with another radical, means straight or branched 1-oxoalkyl radicals containing one to six carbon 30 atoms and includes formyl, acetyl, 1 oxopropyl (propicnyl), 2-methyl-1-oxopropyl. 1- oxohexyl and the like. The term "C1-6 alkoxy" as used herein, either alone or in combination with another radical, means the radical -0(C1-6 alky!) wherein alkyl is as defined above containing up to six carbon atoms. Alkoxy includes methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy and 1,1-dimethylethoxy. The latter radical is known commonly as ferf-butoxy. The term "C:..7 cycloalkoxy" as used herein, either alone or in combination with another radical, means a C57 cycloalkyl group linked to an oxygen atom, such as, for example: 10 The term "C6 or C10 aryl" as used herein, either alone or in combination with another radical, means either an aromatic monocyclic group containing 6 carbon atoms or an aromatic bicyclic group containing 10 carbon atoms. For example, aryl includes phenyl, 1-naphthyl or 2-naphthyl. The term "C7-16aralkyt" as used herein, either alone or in combination with another 15 radical, means a C6 or Cr0 aryl as defined above linked to an alkyl group, wherein alkyl is as defined above containing from 1 to 6 carbon atoms. C7-16 Aralkyl includes for example benzyl, butylphenyl, and 1-naphthylmethyl. The term "amino aralkyl" as used herein, either alone or in combination with another radical, means an amino group substituted with a C7-16aralkyl group, such as, for 20 example, the amino aralkyl: The term "carboxy(lower)alkyl" as used herein, either alone or in combination with another radical, means a carboxyl group (COOH) linked through a (lower)alkyl group as defined above and includes for example butyric acid. 25 The term "heterocycle" or "Het" as used herein, either alone or in combination with another radical, means a monovalent radical derived by removal of a hydrogen from a five-, six-, or seven-membered saturated or unsaturated (including aromatic) heterocvcle containing from one to four heteroatoms selected from nitrogen, oxygen and sulfur Furthermore, "Het" as used herein, means a heterocycle as defined above fused to one or more other cycle be it a heterocycte or any other cycle. Examples of suitable heterocycles include: pyrrolidine, tetrahydrofuran, thiazolidine, pyrrole, thiophene, diazepine, 1H-imidazole, isoxazole, thiazole, tetrazoler piperidine, 1,4-dioxane, 4-morpholine, pyridine, pyrimidine, thiazolo[4,5-b]-pyridine, quinoline, or indole, or the following heterocycles: S i N The term "(lower alkyl)-Het" as used herein, means a heterocyclic radical as defined above linked through a chain or branched alkyl group, wherein alkyl is as defined above containing from 1 to 6 carbon atoms. Examples of (lower alkyl)-Het include: O The term "pharmaceutically acceptable ester" as used herein, 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, is replaced by an alkoxycarbonyl function: OR in which the R moiety of the ester is selected from alkyl (e.gl- methyl, ethyl, n-propyl, t-butyl, n-butyl); alkoxyalkyl (e.g. methoxymethyl); alkoxyacyl (e.g. acetoxymethyi); aralkyl (e.g. benzyl); aryloxyalkyl (e.g. phenoxymethyl); aryi (e.g. phenyl), optionally substituted with halogen, C1-4 alkyl or C1-4alkoxy. Other suitable prodrug esters can be found in Design of prodrugs, Bundgaard, H. Ed. Elsevier (1985) incorporated herewith by reference. Such pharmaceutically acceptable esters are usually hydrolyzed in vivo when injected in a mammal and transformed into the acid form of the compound of formula I. With regard to the esters described above, unless otherwise specified, any alkyl moiety present advantageously contains 1 to 16 carbon atoms, particularly 1 to 6 carbon atoms. Any aryi moiety present in such esters advantageously cornpnses a phenyl group. In particular the esters may be a C1-16 alkyl ester, an unsubstituted benzyl ester or a benzyl ester substituted with at least one halogen, C1-6 alkyl, C1-6 alkoxy, nitro or trifluoromethyl. The term "pharmaceutically acceptable salf as used herein includes those derived 5 from pharmaceutically acceptable bases. Examples of suitable bases include choline, ethanolamine and ethylenediamine. Na.,K\ and Ca~ salts are also contemplated to be within the scope o! the invention (also see Pharmaceutical salts: Birge, S.M. et al„ J. Pharm. Sci. (1977), 66, 1-19, incorporated herein by reference). Preferred embodiments 10 Included within the scope of this invention are compounds of formula I wherein B is preferably R7-S02 wherein R7 is preferably C6 or Cio aryl, a C7-16 aralkyl or Het all optionally substituted with C1-6alkyl. Alternatively, B is preferably H or an acyl derivative of formula R7C(0)- wherein R7 is preferably C,1-6alkyl; C1-6 alkoxy; C3-7 cycloalkyl optionally substituted with hydroxy; 15 amido optionally substituted with C1-6alkyl or Het; C6 or C10 aryl, C7-16 aralkyl or Het all optionally substituted with C,1-6 alkyl or hydroxy. More preferably, B is H or R7C{0)wherein R7 is more preferably C1-6alkyl or Heterocydes such as: Most preferably, B is H; acetyl; ° ; ° ; or ° 20 Even most preferably, B is acetyl. Included within the scope of the invention are compounds of formula I wherein R6 when present, is preferably the side chain of Asp or Glu. Most preferably, R6, when present, is the side chain ot Asp Alternatively, preterably, a is 0 and then R6 is absent. Included within the scope of the invention are compounds of formula I wherein, preferably, R5, 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 5 (Tbg), and L-Tbg. More preferably, R5, when present, is the side chain of D-Asp, D-Val, or D-Glu. Most preferably, R5, when present, is the side chain of D-Glu. Alternatively, preferably a is 0 and b is 0, and then both R6 and R5 are absent. Included within the scope of the invention are compounds of formula I wherein, preferably, R4 is the side chain of an amino acid selected from the group consisting 10 of: Val, cyclohexylglycine (Chg), Tbg, He or Leu. More preferably, R4 is the side chain of Chg or lie. Most preferably, R4 is the side chain of Chg. Included within the scope of the invention are compounds of formula I wherein, preferably, Y is H, or Me. Most preferably, Y is H. Included within the scope of the invention are compounds of formula I wherein, 15 preferably, R3 is the side chain of an amino acid selected from the group consisting of: He, Chg, Val or Tbg. More preferably, R3 is the side chain of Val, Chg or Tbg. Most preferably, R3 is the side chain of Val or Tbg. Included within the scope of the invention are compounds of formula I wherein, preferably, R2 is S-R20 or O-RM wherein R20 is preferably a C6 or Ci0 aryl, C7.16 20 aralkyl, Het or -CH2-Het, all optionally mono-, di- or tri-substituted with R^. Preferably, R21 is C1-6 alkyl; d-e alkoxy; amino; mono- or di-(lower a!kyI)amino; amido optionally mono-substituted with 1-6 alkyl, C6 or do aryl, C7.16 aralkyl, Het or (lower alkyl)-Het; N02; OH; halo; trilluoromethyi; carboxyl; C6 or C,o aryl, C7.16 aralkyl, or Het, said aryl, aralkyl or Het being optionally 25 substituted with R22- More preferably, R2i is d-e alkyl; d-e alkoxy; amino; di(lower alkyl)amino; (lower alkyl)amide; C6 or do aryl, or Het, said aryl or Het being optionally substituted with R^. Preferably, R22 is d6 alkyl; C1-6 alkoxy, amino; mono- ordi-(lower alkyl)amino; (lower alkyl)amide; N02; OH; halo; trifluoromethyl; or 30 carboxyl. More preferably, R22 is C1-6alkoxy; amino; di(lower aIkyi)amino; (lower alkyl)amide; halo; or trifluoromethyl. More prelerably, R2 is 1-napnthylmethoxy. 2-naphthylmethoxy: benzyioxy, 1- naphthytoxy; 2-naphthyloxy; of quinolinoxy unsubstituted , mono- or di-substituted with R21 as defined above. Most preferably, R2 is 1 -naphtylmethoxy, or quinolinoxy unsubstituted, mono- or di-substituted with R21 as defined above. Still, most preferably, R2 is : More preferably, R21A is amide optionally mono-substituted with C1-6 alkyl, C6 or C10 aryl, C7-i$ aralkyl or Het; or C6 or C10 aryl or Het optionally substituted with R22 Most preferably, R21A is C6 or C10 aryl or Het, all optionally substituted with R22. Most preferably, R22 is amino; di(lower alkyl)amino; or (lower alkyl)amide. Even most 10 preferably, R22 is amino; dimethylamino; or acetamido. Even most preferably, R^A is C6 or C10 aryl or Het, all unsubstituted. Preferably, R21B is Ci.6 alkyl; Cn^alkoxy;.amino; di(lower alkyl)amino; (lower alkyl)amide; N02; OH; halo; trifluoromethyl; or carboxyl. More preferably, R21B is C1-6 alkoxy; or di(lower alkyl)amino- Most preferably, R2IB is methoxy. 15 Included within the scope of the invention are compounds of formula I wherein, preferably, Rt is methyl, ethyl, propyl, vinyl all of which optionally substituted with halo. More preferably, R, is ethyl, vinyl or bromovinyl. Most preferably, R, is vinyl. Included within the scope of the invention are compounds of formula I wherein, preferably, W is hydroxy or a pharmaceutieally acceptable salt or ester thereof; or 20 (lower alkyi)amino, di(lower alkyl)amino or amino aralkyl. More preferably, W is hydroxy, or N(R13a)R13b wherein R13a and R13b are independently H, aryl or C^ alkyl optionally substituted with hydroxy or phenyl; or a pharmaceutieally acceptable salt thereof. Most preferably, W is -OH, -NH-benzyl or -NH-CH(Me)Ph. Still most preferably, W is -OH or -NH-(S)CH(Me)-phenyl. 25 When W is an ester, such ester is preferably selected from C1-6 alkoxy, phenoxy, or arly(C1-6 alkoxy)More preferable selected form C1-6 alkoxy phenoxy or cribed hereinabove the P1 seoment of the compounds of formula I is a cyclopropyl ring system of formula: o NH" 10 wherein C1 and C2 each represent an asymmetric carbon atom at positions 1 and 2 of the cyclopropyl ring. Notwithstanding other possible asymmetric centers at other segments of the compounds of formula I, the presence of these two asymmetnc centers means that the compound of formula I can exist as racemic mixtures of diastereoisomers. As illustrated in the examples hereinafter, the racemic mixtures can be prepared and thereafter separated into individual optical isomers, or these optical isomers can be prepared by chiral synthesis. Hence, the compound of formula I can exist as a racemic mixture of diastereoisomers wherein R, at position 2 is orientated syn to the carbonyl at position 1, represented by the radical: and or the compound of formula I can exist as a racemic mixture of diastereoisomers 15 wherein R-, at position 2 is orientated anti to the carbonyl at position 1, represented by the radical: In !urn: the racemic matures can be separated into individual optical isomers A most interesting finding of this invention pertains to the spatial orientation of the P1 segment. The finding concerns the configuration of the asymmetric carbon at position 1. A preferred embodiment is one wherein asymmetric carbon at position 1 has the R configuration. More explicitly, when carbon 1 has the R configuration, HCV NS3 protease inhibition is further enhanced by the position of the substituent R, (e.g. alkyl or alkylene) at carbon 2 of the cyclopropyl ring. A most preferred compound is an optical isomer having the Ri substituent and the carbonyt in a syn orientation in the following ]0 absolute configuration." In the case where R1, is ethyl, for example, the asymmetric carbon atoms at positions 1 and 2 have the R,R configuration. 15 By way of illustrating the role of the absolute configuration of the substituent on the level of potency of the compound, compound 112 (Table 1) having the absolute configuration as 1R,2R, has an IC50 of 1.6 u.M whereas the corresponding 1S.2S isomer (compound 113) has an IC50 of 27.5 u.M. Therefore, the 1R,2R isomer is 25 fold more potent than the corresponding 1S,2S isomer. 20 Further included in the scope of the invention are compounds of formula I. wherein B is H, lower alkyl-C(O)- or Het-C(O)-; R6, when present, is the side chain of Asp or Glu; Rs, when present, is the side chain of D- or L-: Asp, Glu, Val, or Tbg; Y is H or methyl. R4 is the side chain of Val, Chg, Tbg, lie or Leu; R3 is the side chain of He, Chg, Val or Tbg; R2 is 1 -naphthylmethoxy, 2-naphthylmethoxy, O-Bn, and R22is amino; di(lower alkyl)amino; (lower alkyl)amide; N02; OH; halo; CF3; or carboxy; P1 is a cyclopropyl ring system of formula wherein R, is ethyl, vinyl or bromovinyl; and W is hydroxy or N(R13a)Rl3b wherein R13a and R13t. are independently H aryl or C-,-6 alkyl optionally substituted with hydroxy or phenyl; or a pharmaceutical acceptable salt or ester thereof. A further preferred group of compounds is represented by formula I wherein B is H, acetyl or Het-C(O)-; R6, when present, is the side chain of Asp; R5, when present, is the side chain of D-Asp, D-Glu or D-Val; Y is H; R4 is the side chain of Chg or He; R3 is the side chain of Val, Chg or Tbg; R2 is 1-naphthylmethoxy, benzyloxy, 4-qumolinoxy, or W is hydroxy or -NH-(S)CH{Me)Ph, or a pharmaceutical acceptable salt or ester thereof. -IS - An even further preferred group of compounds is represented by formula I wherein B 15 is acetyl; R6, when present, is the side chain of Asp; Rs, when present, is the side chain of D-Glu; Y is H; R4 is the side chain of Chg; R3 is the side chain of Val or Tbg; R15: W is hydroxy, or a pharmaceuticallly acceptable salt or ester thereof. Finally, included in the scope ol the invention is each compound of tormula I presented in Tables 1 to 5. 5 According to an alternate embodiment, the pharmaceutical compositions of this invention may additionally comprise another anti-HCV agent. Examples of anti-HCV agents include a- or (β-interferon, ribavirin and amantadine. According to another alternate embodiment, the pharmaceutical compositions of this invention may additionally comprise other inhibitors of HCV protease. ] 0 According to yet another alternate embodiment, the pharmaceutical compositions of this invention may additionally comprise an inhibitor of other targets in the HCV life cycle, including but not limited to, such as helicase, polymerase, metalloprotease or internal ribosome entry site (IRES). The pharmaceutical compositions of this invention may be administered orally, 15 parenterally or via an implanted reservoir. Oral administration or administration by injection is preferred. The pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutical^ acceptable acids, bases or buffers to enhance the stability of the 20 formulated compound or its delivery form. The term parenteral as used herein includes 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 25 preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example Tween 80) and suspending agents. The pharmaceutical compositions of this invention may be orally aaministered in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspensions and solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a 5 capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added. Other suitable vehicles or carriers for the above noted formulations and 10 compositions can be found in standard pharmaceutical texts, e.g. in "Remington"s Pharmaceutical Sciences", The Science and Practice of Pharmacy, 19th Ed. Mack Publishing Company, Easton, Penn., (1995). Dosage levels of between about 0.01 and about 100 mg/kg body weight per day, preferably between about 0.5 and about 75 mg/kg body weight per day of the 15 protease inhibitor compounds described herein are useful in a monotherapy for the prevention and treatment of HCV mediated disease. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 5 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined 20 with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w/w). Preferably, such preparations contain from about 20% to about 80% active compound. As the skilled artisan will appreciate, lower or higher doses than those recited above 25 may be required. Specific dosage and treatment regimens for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, the severity and course of the infection, the patients disposition to the infection and the judgment of the treating 30 physician. Generally, treatment is initiated with small dosages substantially less than the optimum dose of the peptide. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. In general, the compound is most desirably administered at a concentration level that will generally allord antivirally effective results without caustng any harmful 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 agent, both the compound and the additional agent should be present at dosage levels of between 5 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 may be administered in vivo to mammals, such as man. to inhibit HCV NS3 protease or to ] 0 treat or prevent HCV virus infection. Such treatment may also be achieved using the compounds of this invention in combination with agents which include, but are not limited to: immunomodulatory agents, such as a-, p-, or -/-interferons; other antiviral agents such as ribavirin, amantadine; other inhibitors of HCV NS3 protease; inhibitors of other targets in the HCV life cycle, which include but not limited to, 15 helicase, polymerase, metalloprotease, or internal ribosome entry site (IRES); or combinations thereof. The additional agents may be combined with the compounds of this invention to create a single dosage form. Alternatively these additional agents may be separately administered to a mammal as part of a multiple dosage form. Accordingly, another embodiment of this invention provides methods of inhibiting 20 HVC NS3 protease activity in mammals by administering a compound of the formula I, wherein the substituents are as defined above. In a preferred embodiment, these methods are useful in decreasing HCV NS3 protease activity in a mammal. If the pharmaceutical composition comprises only a compound of this invention as the active component, such methods may additionally 25 comprise the step of administering to said mammal an agent selected from an immunomodulatory agent, an antiviral agent, a HCV protease inhibitor, or an inhibitor of other targets in the HCV life cycle such as helicase, polymerase, metalloprotease or IRES. Such additional agent may be administered to the mammal prior to, concurrently with, or following the administration of the compositions of this 30 invention. In an alternate preferred embodiment, these methods are useful for inhibiting viral replication in a mammal. Such methods are useful in treating or preventing HCV disease. 1) the pharmaceutics! composition corrpnses only a compound of this invention as the active component, such methods may additionally comprise the step of administering to said mammal an agent selected from an immunomodulatory agent, an antiviral agent, a HCV protease inhibitor, or an inhibitor of other targets in the HCV life cycle. Such additional agent may be administered to the mammal prior 5 to, concurrently with, or following the administration of the composition according to this invention. The compounds set forth herein may also be used as laboratory reagents. The compounds of this invention may also be used to treat or prevent viral contamination of materials and therefore reduce the risk of viral infection of laboratory or medical 10 personnel or patients who come in contact with such materials (e.g. blood, tissue, surgical instruments and garments, laboratory instruments and garments, and blood collection apparatuses and materials). The compounds set forth herein may also be used as research reagents. The compounds of this invention may also be used as positive control to validate 15 surrogate cell-based assays or in vitro or in vivo viral replication assays. PROCESS The compounds of the present invention were synthesized according to the process as illustrated in scheme I (wherein CPG is a carboxyl protecting group and APG is an amino protecting group): Briefly, the P1, P2, P3, P4, and optionally P5 and P6 can be linked by well known peptide coupling techniques. The P1, P2, P3, P4, and P5 and P6 groups maybe 5 linked together 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 that is linked to P4-P3-P2-P1 ; or P6 linked to P5-P4-P3-P2 then linked to an appropriately Oterminal protected P1. Generally, peptides are elongated by deprotecting the a-amino group of the N-10 terminal residue and coupling the unprotected carboxyl group of the next suitably N-protected amino acid through a peptide linkage using the methods described. This deprotection and coupling procedure is repeated until the desired sequence is obtained. This coupling can be performed with the constituent amino acids in stepwise fashion, as depicted in Scheme I, or by condensation of fragments (two or 15 several amino acids), or combination of both processes, or by solid phase peptide synthesis according to the method originally described in Memfield, J. Am. Chem. Soc. (1963), 85, 2149-2154, the disclosure of which is hereby incorporated by reference. Coupling between two amino acids, an amino acid and a peptide, or two peptide fragments can be carried out using standard coupling procedures such as the azide method, mixed carbonic-carboxylic acid anhydride (isobutyl chloroformate) method, carbodiimide (dicyclohexylcarbodiimide, diisopropylcarbodiimide, or water-soluble carbodiimide) method, active ester (p-nitrophenyl ester, N-hydroxysuccinic imido 5 ester) method, Woodward reagent K-method, carbonyldiimidazole method, phosphorus reagents or oxidation-reduction methods. Some of these methods (especially the carbodiimide method) can be enhanced by adding t-hydroxybenzotriazole. These coupling reactions can be performed in either solution (liquid phase) or solid phase. 10 More explicitly, the coupling step involves the dehydrative 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 linking amide bond. Descriptions of such coupling agents are found in general textbooks on peptide chemistry, for example, M. Bodanszky, "Peptide Chemistry", 2nd rev ed., Springer-Verlag, Berlin, Germany, (1993). )5 Examples of suitable coupling agents are N,/V-dicyclohexylcarbodiimide, 1- hydroxybenzotriazole in the presence of A/,A/"-dicyclohexylcarbodiimide or N-ethyl-AT-[(3-dimethylamino)propyf]carbodiimide. A very practical and useful coupling agent is the commercially available (benzotnazol-1-yloxy)tris-(dimethylaminp)phosRh6nium hexafluorophosphate, either by itself or in the presence of 1-hydroxybenzotriazole. 20 Another very practical and useful coupling agent is commercially, available 2-(1H-ben20triazol-1-yl)-A/, N, N\ /V"-tetramethyluronium tetrafluoroborate; Still another very practical and useful coupling agent is commercially available 0-(7-azabenzotriazol-1-yl)-A/,A/,A/",A/"-tetramethyluronium hexafluorophosphate. The coupling reaction is conducted in an inert solvent, e.g. dichloromethane« 25 acetonitrile or dimethyiformamide. An excess of a tertiary amine, e.g. diisopropylethylamine, AJ-methylmorpholine or A/-methylpyrrolidine, is added to maintain the reaction mixture at a pH of about 8 The reaction temperature usually ranges between 0°C and 50°C and the reaction time usually ranges between 15 min and 24 h. 30 When a solid phase synthetic approach is employed, the C-terminal carboxylic acid 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 readily cleaved later. Examples of which are: chloro- 0" bromomethyl resin, hydroxymethyl resin, and ammomethyl resin. Many of these resins are commercially available with the desired C-terminal amino acid already incorporated. Alternatively, the amino acid can be incorporated on the solid support by known methods Wang, S.-S., J. Am. Chem. Soc, (1973), 95, 1328; Atherton, E.; Shepard, R.C. "Solid-phase peptide synthesis; a practical approach" IRL Press: 5 Oxford, (1989); 131-148. In addition to the foregoing, other methods of peptide synthesis are described in Stewart and Young, "Solid Phase Peptide Synthesis", 2n0 ed.. Pierce Chemical Co., Rockford, IL (1984); Gross, Meienhofer, Udenfnend, 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" 10 Springer-Verlag, New-York (1984), the disclosures of which are hereby incorporated by reference. The functional groups of the constituent amino acids generally must be protected during the coupling reactions to avoid formation of undesired bonds. The protecting groups that can be used are listed in Greene, "Protective Groups in Organic 15 Chemistry", John Wiley & Sons, New York (1981) and The Peptides: Analysis, Synthesis, Biology", Vol. 3, Academic Press, New York (1981), the disclosures of which are hereby incorporated by reference. The ct-carboxyl group of the C-terminal residue is usually protected as an ester (CPG) that can be cleaved to give the carboxylic acid. Protecting groups that can be 20 used include: 1) alkyl esters such as methyl, trimethylsilylethyl and J-butyl, 2) aralkyi esters such as benzyl and substituted benzyl, or 3) esters that can be cleaved by mild base treatment or mild reductive means such as trichlorbethyl and phenacyl esters. The a-amino group of each amino acid to be coupled to the growing peptide chain 25 must be protected (APG). Any protecting group known in the art can be used. Examples of such groups include: 1) acyl groups such as tormyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; 2) aromatic carbamate groups such as benzyloxycarbonyl (Cbz or Z) and substituted benzyloxycarbonyls, and 9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate groups such as tert-30 butyloxycarbonyl (Boc), ethoxycarbonyt, diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4) cyclic alkyl carbamate 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 pheny!thiocarbonyl and dithiasuccinoyl. The preferred a-amino protecting group is either Boc or Fmoc. Many amino acid derivatives suitably protected for peptide synthesis are commercially available. The a-amino protecting group of the newly added amino acid residue is cleaved prior to the coupling of the next amino acid. When the Boc group is used, the methods of 5 choice are trifluoroacetic acid, neat or in dichioromethane, or HCI in dioxane or in ethyl acetate. The resulting ammonium salt is then neutralized either prior to the coupling or in situ with basic solutions such as aqueous buffers, or tertiary amines in dichioromethane or acetonitrile or dimethylformamide. When the Fmoc group is used, the reagents of choice are piperidine or substituted piperidine in 10 dimethylformamide, but any secondary amine can be used. The deprotection is carried out at a temperature between 0°C and room temperature (RT), 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 above-described groups. Those skilled in 15 the art will appreciate that the selection and use of appropriate protecting groups for these side chain functionalities depend upon the amino acid and presence of other protecting groups in the peptide. The selection of such protecting groups is important in that the group must not be removed during the deprotection and coupling of the a-amino group. 20 For example, when Boc is used as the a-amino protecting group, the following side chain protecting group 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 f-butylsulfonyl moieties can be used to protect the sulfide containing side chain of cysteine; benzyl (Bn) ethers can be used to protect the hydroxy 25 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 the a-amine protection, usually /ert-butyl based protecting groups are acceptable. For instance, Boc can be used for lysine and arginine, terl-30 butyl ether for serine, threonine and hydroxyproline. and fert-butyl ester for aspartic acid and glutamic acid. Triphenylmethyl (Trityl) moiety can be used to protect the sulfide containing side chain of cysteine. When W is an amide (w). P1 is coupled to an appropriate amine prior to the coupling to P2. Such amination will be readily recognized by persons skilled in the art. Once the elongation of the peptide is completed all of the protecting groups are removed. When a liquid phase synthesis is used, the protecting groups are removed in whatever manner is dictated by the choice of protecting groups. These 5 procedures are well known to those skilled in the art. When a solid phase synthesis is used, the peptide is cleaved 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, thioanisoie, or p-cresol at 0°C is the preferred 10 method for cleaving the peptide from the resin. The cleavage of the peptide can also be accomplished by other acid reagents such as trifluoromethanesulfonic acid/ trifluoroacetic acid mixtures. If the Fmoc protection method is used, the N-terminal Fmoc group is cleaved with reagents described earlier. The other protecting groups and the peptide are cleaved from the resin using solution of trifluoroacetic acid and 15 various additives such as anisole, etc. Synthesis of capping group B and P6, P5, P4, and P3 moieties Different capping groups B are introduced to protected P4, P5 or P6 or to any peptide segment with an appropriate acyl chloride or sulfonyl chloride that is either commercially available or for which the synthesis is well known in the art. 20 Different P6 to P3 moieties are available commercially or the synthesis is well known in the art. 1.Synthesis of P2 moieties. 1.1 Synthesis of precursors: A) Synthesis of haloarylmethane derivatives. 25 The preparation of halomethyl-8-quinoline lid was done according to the procedure of K.N. Campbell et al., J. Amer. Chem. Soc, (1946), 68,1844. 11a lib ||C nd Briefly, 8-quinoiine carboxyiic acid Ha was converted to the corresponding alcohol lie by reduction of the corresponding acyl haiide lib with a reducing agent such as lithium aluminium hydride. Treatment of alcohol lib with the appropnate hydrohaJoacid gives the desired halo derivative lid. A specific embodiment of this process is presented in Example 1 A. B) Synthesis of aryl alcohols derivatives: 2-phenyf-4-hydroxyquinoline derivatives lllc were prepared according to Giardina et al. (J. Med. Chem., (1997), 40,1794-1807). SCHEME III Benzoylacetamide (Ilia) was condensed with the appropriate aniline (Mb) and the imine obtained was cyclized with polyphosphoric acid to give the corresponding 2-phenyM-hydroxyquinoline (Hie). A specific embodiment of this process is presented in Example 1B and 1C. 1.2. Synthesis of P2: A) The synthesis of 4-substituted proline (wherein R2 is attached to the ring via a carbon atom) (with the stereochemistry as shown): is done as shown in Scheme IV according to the procedures described by J. Ezquerra et al. (Tetrahedron, (1993), 38, 8665-8678) and C. Pedregal et al. (Tetrahedron Lett., (1994), 35, 2053-2056). SCHEME IV Boc Boc COOBn JVc ]0 Briefly, Boc-pyroglutamic acid is protected as a benzyl ester. Treatment with a strong base such as lithium diisopropylamide followed by addition of an alkylating agent (Br-R20 or l-R20) gives the desired compounds IVe after reduction of the amide arid deprotection of the ester. B) The synthesis of Oaralkylated 4-f(R)hydroxyproline: 15 When R20 is aryl, Hel, aralkyl, or (lower alkyl)-Het, the process can be carried out according to the procedure described by E.M. Smith et al. (J. Med. Chem. (1988), 31, 875-885). Briefly, commercially available Boc-4(fty-hydroxyproline is treated with a base such as sodium hydride or K-fBuO and the resulting alkoxide reacted with an halo-R20 (Br-R20, l-R20, etc..) to give the desired compounds. Specific embodiments of this process ar. presented in Examples 2, 3 and 45 C) Alternatively, when R20 is aryl or Het, the compounds can also be prepared via a Mitsunobu reaction (Mitsunobu (1981), Synthesis, January. 1-28; Rano era/., (1995), Tet. Lett. 36(22), 3779-3792; Krchnak et a/., (1995), Tet. Lett. 36(5). 62193-6196; Richter et ai, (1994), Tet. Lett. 35(27). 4705-4706). Briefly, commercially available Boc-4 fSj-hydroxyproline methyl ester is treated with the appropriate aryl alcohol or thiol in the presence of triphenylphosphine and diethylazodicarboxylate (DEAD) and the resulting ester is hydrolyzed to the acid. Specific embodiment of this process is presented in Example 4A. SCHEME V 10 Va Vb Alternatively, the Mitsunobu reaction can be produced in solid phase (Scheme V). The 96-well block of the Model 396 synthesizer (advanced ChemTech) is provided with aliquots of resin-bound compound (Va) and a variety of aryl alcohols or thiols and appropriate reagents are added. After incubation, each resin-bound product 15 (Vb) is washed, dried, and cleaved from the resin. A Suzuki reaction (Miyaura et ai, (1981), Synth. Comm. 11_r 513; Sato et ai, (1989), Chem. Lett., 1405; Watanabe et ai, (1992), Synlett., 207;Takayuki et ai, (1993), J. Org. Chem. 58, 2201; Frenette etai, (1994), Tet. Lett. 35(49). 9177-9180; Guiles etai, (1996), J. Org. Chem. 61, 5169-5171) can also be 20 used to further functionalize the aryl substituent. 2. Synthesis of P1 moieties (2-substituted 1-aminocyclopropyI carboxylic acid) The synthesis was done according to scheme VI. 5 a) Briefly, di-protected malonate Via and 1,2-dihaloalkane Vlb or cyclic sulfate Vic (synthesized according to K. Burgess and Chun-Yen KE (Synthesis, (1996), 1463-1467) are reacted under basic conditions to give the diester Vld. b) A regioselective hydrolysis of the less hindered ester is performed to give the acid Vie. 10 c) This acid Vie is subjected to a Curtius rearrangement to give a racemic mixture of 1-aminocyclopropylcarboxyiic acid derivatives Vlf with R1 being syn to the carboxyl group. A specific embodiment for this synthesis is presented in Example 5. d, e) Alternatively, selective ester formation from the acid Vie with an appropriate halide (PXf) or alcohol (P*OH) forms diester Vlg in which the P* ester is compatible with the selective hydrolysis of the P ester. Hydrolysis of P ester provides acid Vlh. f) A Curtius rearrangement on Vlh gives a racemic mixture of 1-aminocyc/opropylcarboxyfic acid derivatives Vii with R1 group being antito the carboxyl group. A specific embodiment for this synthesis is presented in Example 10 An alternative synthesis for the preparation of derivatives Vlf (when R1 is vinyl, syn to the carboxyl group) is described below. SCHEME VII 10 15 20 Treatment of commercially available imtne Vila with 1,4-dihalobutene Vllb in presence of a base produces, after hydrolysis of the resulting imine Vile, Vlld having the atlyl substituent syn to the carboxyl group This process is presented in Example 11. Resolution of all of the above enantiomeric mixtures at carbon 1 (Vie and Vlld) can be carried out via: 1) eniymabc separation (Examples 9 and 13),; 2) crystallization with a chiral acid (Example 14); or 3) chemical derivatization (Example 6). Following resolution, determination of the absolute stereochemistry can be earned out as presented in Example 7. Resolution and stereochemistry determination can be carried out in the same manner tor the enantiomeric mixtures at carbon 1 wherein the substituent at C2 is anti to the carboxyl group (Vli). Accordingly, the invention further comprises a process for the preparation of a peptide analog ol formula (I) wherein P1 is a substituted aminocyclopropyl carboxylte acid residue, comprising the step of: coupling a peptide selected from the group consisting ot: APG-P6-P5-P4-P3-P2; APG-P5-P4-P3-P2; APG-P4-P3-P2; APG-P3-P2; and APG-P2; with a P1 intermediate of formula: wherein R., is d-e alkyl or C2-6 alkenyl optionally substituted with halogen. CPG is a carboxyl protecting group and APG is an amino protecting group, and P6 to P2 are as defined above. 10 Finally, the invention also comprises the use of an intermediate of formula: wherein R, is Ci-e alkyl or C2* alkenyl optionally substituted with halogen, for the preparation of a compound of formula I as defined above. EXAMPLES 15 The present invention is illustrated in further detail by the following non-limiting examples. Temperatures are given in degrees Celsius. Solution percentages express a weight to volume relationship, and solution ratios express a volume to volume relationship, unless stated otherwise. Nuclear magnetic resonance (NMR) spectra were recorded 20 on a Bruker 400 MHz spectrometer; the chemical shifts (6) are reported in parts per million. Flash chromatography was carried out on silica gel (Si02) according to Still"s flash chromatography technique (W.C Still et al., J. Org. Chem. (1978), 43, 2923). Abbreviation:: used in the examples include Bn benzyl; Boc: tert-butyioxycarbonyl (Me3COC(0)}; BSA: bovine serum albumin; CHAPS: 3-[(3-choiamidopropyi}-dimethylammonio]-1 -propanesulfonate; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; CH2CIZ= DCM; methylene chloride; DEAD: diethyiazodicarboxylate; DIAD; diisopropylazodicarboxylate; DIPEA: diisopropylethylamine; DMAP: 5 dimethylaminopyridine; DCC: 1,3-dicyclohexylcarbodiimide; DME: 1,2- dimethyoxyethane; DMF: dimethylformamide; DMSO: dimethylsulfoxide; DTT: dithiothreitol orthreo-1,4-dimercapto-2,3-butanediol; DPPA: diphenylphosphoryl azide; EDTA: ethylenediaminetetraacetlc acid; Et: ethyl; EtOH: ethanol; EtOAc: ethyl acetate; Et20: diethyl ether; HATU: [0-7-azabenzotriazol-1-yl)-1,1,3,3- 10 tetramethyluronium hexafluorophosphate]; HPLC: high performance liquid chromatography; MS: mass spectrometry (MALDI-TOF: Matrix Assisted Laser Disorption lonization-Time of Flight, FAB: Fast Atom Bombardment); LAH: lithium aluminum hydride; Me: methyl; MeOH: methanol; MES: (2-{N-morpholino}ethane-sulfonic acid); NaHMDS: sodium bis(trimethylsilyl)amide; NMM: N-methylmorpholine; 15 NMP: N-methylpyrrolidine; Pr: propyl; Succ: 3-carboxypropanoyt; PNA: 4- nitrophenylamino or p-nitroaniline; TBAF: tetra-n-butylammonium fluoride; TBTU: 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate; TCEP: tris(2-carboxyethyl) phosphine hydrochloride; TFA: trifluoroacetic acid; THF: tetrahydrofuran; TIS: triisopropylsilane; TLC: thin layer chromatography; TMSE: 20 trimethylsilylethyl; Tris/HCI: tris(hydroxymethyl)aminomethane hydrochloride. P2 BUILDINGBLOCKS EXAMPLE1A Synthesis of bromomethyl-8-quinoline (1 A): : (1A) 25 To commercially available 8-quinoline carboxylic acid (2.5 g, 14.4 mmol) was added neat 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 30 between EtOAc and saturated aqueous NaHC03, and the organic phase dried (MgS04), filtered and concentrated to give a brownish oil (2.8 g). This material (ca. 14.4 mmol) was added dropwise over 35 min to a LAH (0.76 g, 20.2 mmol)/Et20 suspension which was cooled to -60°C. The reaction mixture was slowly warmed to -35CC over 1.5 h before the reaction was complete. The reaction was quenched with 5 MgS04.10H2O slowly over 30 min and then wet THF. The mixture was partitioned between Et20 and 10% aqueous NaHC03.The organic phase was dried (MgS04), filtered and concentrated to give a yellowish solid (2.31 g, 80% over 2 steps) corresponding to the alcohol. The alcohol (2.3 g, 11.44 mmol) was dissolved in AcOH/HBr (20 mL, 30% solution from Aldrich) and heated at 70°C for 2.5 h. The 10 mixture was concentrated in vacuo to dryness, partitioned between EtOAc (100 mL) and saturated aqueous NaHC03 before being dried (MgSO*), filtered and concentrated to give the desired compound (1A) as a brownish solid (2.54 g, 100%). EXAMPLE1B Synthesis of 2-phenyl-4-hydroxyquinoiine (1B): 15 0H (TB) Commercially available ethyl benzoyiacetate (6.00 g, 31.2 mmol) was heated at 85°C (sealed tube) in 75 mL of 30% NH4OH for 2 hours. The solid formed upon cooling was filtered and refluxed in water tor 2 hours. The solution was extracted three times with CH2CI2. The organic layers were combined, dried over MgS04, filtered 20 and concentrated. The yellow residue was flash chromatographed^bn silica gel, eluting with EtOAc:hexane (3:7), to give the corresponding amide as a white solid, 1.60 g, 31% yield. This amide (250 mg, 1.53 mmol) was refluxed using a Dean-Stark apparatus with aniline (143 mg, 1.53 mmol) and aniline«HCI (10 mg, 0.08 mmol) in toluene (10 mL) 25 for 16 h. The solution was concentrated to afford a brown oil that was mixed with polyphosphoric acid (2 g) and heated at 135°C for 20 min. The reaction mixture was poured into water and adjusted to pH 8 with 5 M NaOH. The aqueous suspension was extracted twice with ethyl acetate. The organic layers were combined, washed with brine, dried over MgS04, filtered and concentrated. The residue was flash 30 chromatographed on silica gel, eluting with 3% MeOH in ethyl acetate, to give 2- 4-hydroxy-2-phenyl -7-methoxyquinoline (e): A solution of ethyl benzoylacetate (b) (100.0 g, 0.52 mol), m-anisidine (a) (128.1 g, 1.04 mol) and 4N HCI / dioxane (5.2 ml_) in toluene (1.0 L) was refluxed for 6.25 h in 10 a Dean-Stark apparatus. The cooled toluene solution was successively washed with aqueous 10% HCI (2 x 300 mL), IN NaOH (2 x 300 mL), H20 (300 mL) and brine (150 mL). The toluene phase was dried (MgS04), filtered and concentrated under reduced pressure to give a 1.2:1.0 mixture of ester c and amide d (144.6 g, 45% / 38% crude yield) as a dark brown oil. The crude oil was heated to 280 °C for 80 min 15 while distilling generated EtOH. The cooled dark solid obtained was triturated with CH2CI2 (200 mL). The suspension was filtered and the resulting solid washed with CH2CI2 to give e (22.6 g, 17% from a) as a beige solid: "H NMR (DMSO-d6) 6 8.00 (d, J = 9.0 Hz, 1H), 7.81-7.82 (m, 2H), 7.57-7.59 (m, 3H), 7.20 (d, J = 2.2 Hz, 1H), 6.94 (dd, J = 9.0, 2.2 Hz, 1H), 6.26 (s, 1H), 3.87 (s, 3H). 20 4-Chloro-2-phenyi-7-methoxyquinoline (1C): A suspension of e (8.31 g, 33.1 mmol) in POCI3 (90 mL) was heated to reflux for 2 h (clear solution obtained upon heating). The reaction mixture was concentrated under reduced pressure. The residue was partitioned between 1N NaOH (exothermic, 10N NaOH added to maintain high pH) and EtOAc (500 mL). The organic layer was washed with H20 (100 mL) and brine (100 mL) then was dried (MgS04), filtered and concentrated under reduced pressure to give 1C (8.60 g, 96%) 5 as a pale yellow solid: *H NMR (DMSO-d6) 8 8.28-8.30 (m, 2H), 8.20 (s, 1H), 8.10 (d, J = 9.1 Hz, 1H), 7.54-7.58 (m, 3H), 7.52 (d, J = 2.5 Hz, 1H), 7.38 (dd, J = 9.1, 2.5 Hz, 1H), 3.98 (s, 3H). This reaction was repeated three times and always gave 96-98% yield which is significantly higher that the 68% yield reported in J. Med. Chem. 1997, 40,1794. 10 EXAMPLE 2 Synthesis of Boc-4{R(naphthaIen-1-ylmethoxy) proline (2): COOH Commercially available Boc-4eF?>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, 15 45.4 mmol) was added portionwise over 10 minutes and the suspension was stirred at FIT for 1 h. Then, 1 -(bromomethyl)naphthalene (8.00 g, 36.2 mmol) (prepared as described in E.A. Dixon et al. Can. J. Chem., (1981), 59,2629-2641) was added and the mixture was heated at reflux for 18 h. The mixture was poured into water (300 mL) and washed with hexane. The aqueous layer was acidified with 10% aqueous 20 HCI and extracted twice with ethyl acetate. The organic layers were combined and washed with brine, dried (MgS04), filtered and concentrated. The residue was purified by flash chromatography (49:49:2 hexane: ethyl acetate: acetic acid) to give the title compound as a colorless oil (4.51 g, 56% yield). "H NMR (DMSO-d5) indicated the presence of two rotamers: 5 8.05 (m, 1H), 7.94 (m, 1H), 7.29 (d, J=14 25 Hz, 1H). 7.55-7.45 (m, 4H), 4.96 (m, 2H), 4.26 (br. 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 3 Synthesis of Boc-4(B>{8-quinoline-methoxy) proline (3): (3) Boc-4(fl)-hydroxyproline (1.96 g, 8.5 mmol) in anhydrous THF (20 mL) was added to 5 a suspension of NaH (1.4 g, 60% in oil, 34 mmol) in THF (100 mL). This mixture was stirred 30 min before bromornethyi-8-quinoline from Example 1A (2.54 g, 11.44 mmol) was added in THF (30 mL). The reaction mixture was heated at 70°C (5 h) before the excess NaH was destroyed carefully with wet THF. The reaction was concentrated in vacuo and the resulting material was dissolved in EtOAc and H20. 10 The basic aqueous phase was separated and acidified with 10% aqueous HCI to pH -5 before being extracted with EtOAc (150 mL). The organic phase was dried (MgSO„), filtered and concentrated to give a brown oil. Purification by flash chromatography (eluent: 10% MeOH/CHGI3) gave the desired compound as a pale yellow solid (2.73 g, 86%). HPLC (97.5%); 1H-NMR (DMSOd6) shows rotamer 15 populations in a 6:4 ratio, 612-11.4 (bs, 1H), 8.92 (2 x d, J - 4.14 and 4.14 Hz, 1H), 8.38 (2 x d, 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 x s, 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 x s, 9H). EXAMPLE 4A 20 Preparation of Boc-4(RH7-chloroquinoline-4-oxo)proline (4A): 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 dryTHF (10 mL) at 0°C. Triphenylphosphine (641 mg, 2.95 mmol) was added, followed by slow addition of DIAD (426 mg, 2.45 mmol). The mixture was stirred at RT for 20 h. The 5 reaction mixture was then concentrated, taken up in ethyl acetate and extracted three times with HC11N. The aqueous phase was basified with Na2C03 and extracted twice with ethyl acetate. The organic layers were combined, dried over MgS04) filtered and concentrated to give a yellow oil. The oil was purified by flash chromatography to give compound 4A methyl ester as a white solid, 498 mg, 58% 10 yield. This methyl ester (400 mg, 0.986 mmol) was hydrolyzed with 1M 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 the methanol and neutralized with 1M aqueous HCI. The suspension was concentrated to dryness and taken up in methanol (20 mL), the 15 salts were filtered off and the filtrate concentrated to give the desired compound 4A as a white solid, 387 mg, quant, yield. "H NMR (DMSO-d6) (ca. 1:1 mixture of rotamers) 6 8.74 (d, J = 5 Hz, 1 H), 8.13-8.09 (m, 1 H), 7.99 and 7.98 (s, 1 H), 7.58 (d, J = 9 Hz, 1 H), 7.02 (d, J = 5 Hz, 1 H), 5.26-5.20 (m, 1 H), 4.10- 4.01 (m, 1 H), 3.81-3.72 (m, 1 H), 3.59 (dd, J - T2,10 Hz, 1 H), 20 2.41 -2.31 (m, 2 H), 1.34 and 1.31 (s, 9H). EXAMPLE 4B Synthesis of Boc-4(R)-(2-|shenyl-7-methoxyquinoline-4-oxo) proline (4B): (4B) 1 -[(1,1 -Dimethylethoxy)carbonyl]-4(R)-[(7-methoxy-2-phenyl-4-quinolinyl)oxy]-L-proline (4B): 25 Potassium tert-butoxide (8.16 g, 72.7 mmol) was added in small portions, over 15 min, to a solution of commercially available 4-(S)-hydroxyproiine (6.73 g, 29.1 mmol) in DMSO (83 mL) maintained at 25°C. The mixture was stirred at 25°C for 1.5 h. Chloro-2-phenyl-7-methoxyquinoline 1C (8.61 g, 32.0 mmol) was added in 4 portions over 15 min to the reaction mixture. The reaction mixture was stirred at 25°C for 19 h. The resulting suspension was poured in H20 (650 mL) and the mixture was washed with Et20 (3 x 150 mL) to remove excess chloroquinoline (EtOAc was later found to be more efficient). The aqueous layer was acidified with aqueous 1N HCI (38 mL of calculated 1.5 equiv. required, 43.6 mL) to pH 4 - 5. The white solid that precipitated was recovered by filtration. The moist solid was dried under reduced pressure over P2Os to give the proline derivative 4B (12.6 g, 91%, contains 2.3% w/w of DMSO) as a beige solid: "H NMR (DMSO-d6) 8 (2:1 mixture of rotamers) 8.27 (d, J = 7.0 Hz, 2H), 8.00, 7.98 (2d, J = 9.2, -9.2 Hz, 1H), 7.48-7.56 (m, 3H), 7.45, 7.43 (2s, 1H), 7.39 (d, J = 2.5 Hz, 1H), 7.17 (dd, J = 9.2,2.5 Hz, 1H), 5.53-5.59 (m, 1H), 4.34-4.41 (m, 1H), 3.93 (s, 3H), 3.76 (broad s, 2H), 2.63-2.73 (m, IH)^ 2.32-2.43 (m, 1H), 1.36,1.33 (2s, 9H). P1 BUILDING BLOCKS EXAMPLE 5 Synthesis of mixture of (1H, 2R)t(1S, 2R) 1-ammo-2-ethylcycJopropyl carfooxylic acid a) To a suspension of benzyltriethylammonium chloride (21.0 g, 92.19 mmol) in a 50% aqueous NaOH solution (92.4 g in 185 mL H20) were successively added di-tert-butylmalonate (20.0 g, 92.47 mmol) and 1,2-dibromobutane (30.0 g, 138.93 mmol). The reaction mixture was vigorously stirred overnight at RT, a mixture of ice and water was then added. The crude product was extracted with CH2CI2 (3x) and sequentially washed with water (3x) and brine. The organic layer was dried (MgS04), filtered and concentrated. The residue was flash chromatographed (7 cm, 2 to 4 % Et20 in hexane) to afford the desired cyclopropane derivative 5c (19.1 g, 70.7 mmol, 76% yield). 1H NMR (CDCI3) 5 1.78-1.70 (m, 1H), 1.47 (s, 9H), 1.46 (s, 9H), 1.44-5 1.39 (m, 1H), 1.26-1.64 (m, 3H), 1.02 (t, 3H, J= 7.6 Hz). b) To a suspension of potassium te/t-butoxide (6.71 g, 59.79 mmol, 4.4 eq.) in dry ether (100 mL) at 0°C was added H20 (270 ^L, 15.00 mmol, 1.1 eq.). After 5 min diester 5c (3.675 g, 13.59 mmol) in ether (10 mL) was added to the suspension. The reaction mixture was stirred overnight at RT, then poured in a mixture of ice and 10 water and washed with ether (3x). The aqueous layer was acidified with a 10% aq. citric acid solution at 0°C and extracted with AcOEt (3x). The combined organic layer was successively washed with water (2x) and brine. After the usual treatment (Na2S04, filtration, concentration), the desired acid 5d was isolated as a pale yellow oil (1.86g, 8.68 mmol, 64% yield). "H NMR (CDCI3) 5 2.09-2.01 (m, 1H), 1.98 (dd, J= 15 3.8, 9.2 Hz, 1H), 1.81 -1.70 (m, 1H), 1.66 (dd, J= 3.0, J= 8.2 Hz, 1H), 1.63-1.56 (m, 1H), 1.51 (s, 9H), 1.0 (t, J= 7.3 Hz, 3H). c) To the acid 5d (2.017 g, 9.414 mmol) in dry benzene (32 mL) were successively added Et3N (1.50 mL, 10.76 mmol, 1.14 eq.) and DPPA (2.20 mL, 10.21 mmol, 1.08 eq.). The reaction mixture was refluxed for 3.5 h then 2-trimethylsilylethanol (2.70 20 mL, 18.84 mmol, 2.0 eq.) was added. The reflux was maintained overnight then the reaction mixture was diluted with EtzO and successively washed with a 10 % aqueous citric acid solution, water, saturated aqueous NaHC03, water (2x) and brine. After the usual treatment (MgS04l filtration, concentration) the residue was purified by flash chromatography (5 cm, 10% AcOEt- hexane) to afford the desired 25 carbamate 5e (2.60 g, 7.88 mmol, 84% yield) as a pale yellow oil. MS (FAB) 330 (MH+); "H NMR (CDCI3) 5 5.1 (bs, 1H), 4.18-4.13 (m, 2H), 1.68-1.38 (m, 4H), 1.45 (s, 9H), 1.24-1.18 (m, 1H), 1.00-0.96 (m, 5H), 0.03 (s, 9H). d) To carbamate 5e (258 mg, 0.783 mmol) was added a 1.0 M TBAF solution in THF (940 uL, 0.94 mmol, 1.2 eq.). After 4.5 h an additional amount of 1.0 M TBAF was 30 added (626 (J_, 0.63 mmol, 0.8 eq.). The reaction mixture was stirred overnight at RT, refluxed for 30 min and then diluted with AcOEt. The solution was successively washed with water (2x) and brine. After the usual treatment (MgS04, filtration and concentration) the desired amine 5f was isolated (84 mg, 0.453 mmol, 58 % yield) Starting from acid 5d described in Example 5: c) To 5d (1.023 g, 4.77 mmol) in CH3CN (25 m!_) were successively added DBU (860 \±, 5.75 mmol, 1.2 eq.) and allyl bromide (620 \il, 7.16 mmol, 1.5 eq.). The reaction mixture was stirred for 4 h at RT and then concentrated. The residue was 10 diluted with EtaO and successively washed with a 10 % aq. citric acid solution (2x), H20, saturated aqueous NaHC03, H20 (2x) and brine. After the usual treatment (MgSCXi, filtration and concentration) the desired ester 10a was isolated (1.106 g, 3.35 mmol, 91 % yield) as a colorless oil. MS (FAB) 255 (MH*); 1H NMR (CDCI3) 5 5.96-5.86 (m, 1H), 5.37-5.22 (m, 2H), 4.70-4.65 (m, 1H), 4.57-4.52 (m, 1H), 1.87- 15 1.79 (m, 1H), 1.47 (s, 9H), 1.45-1.40 (m, 1H), 1.33-1.24 (m, 3H), 1.03 (t, J=7.3 Hz, 3H). d) To ester 10a (1.106 g, 4.349 mmol) in dry CHZCI2 (5 mL) at RT was added TFA (5 ml_). The reaction mixture was stirred for 1.5 h and then concentrated to afford 10b (854 mg, 4.308 mmol, 99 % yield). MS (FAB) 199 (MhT); 1H NMR (CDCI3) 5 5.99- >0 5.79 (m, 1H), 5.40-5.30 (m, 2H), 4.71-4.62 (m, 2H), 2.22-2.00 (m, 2H), 1.95-1.88 (m, 1H), 1.84-1.57 (m, 2H), 0.98 (t, J=7.3 Hz, 3H). e) To acid 10b (853 mg, 4.30 mmol) in dry benzene (14.8 mL) were successively added Et3N (684 ^L, 4.91 mmol, 1.14 eq.) and DPPA (992 jiL, 4.60 mmol, 1.07 eq.). Compound 15b (2.08 g , 5.05 mmol) was treated tor 30 min at RT with 4N HCI / dioxane. Evaporation to dryness provided the corresponding amine-HC! as an oil. The amine-HCI 15c was dissolved in anhydrous DCM (25 mL) and 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) 5 were added successively. The reaction mixture was stirred at RT overnight, then, diluted with EtOAc and successively washed with 10% aqueous citric acid (2x), saturated aqueous NaHC03 (2x), water (2x), and brine (1x). The EtOAc layer was dried (MgSO,), filtered and evaporated to dryness to provide the crude product 15d as a yellowish-white foam (ca 2.78 g, 100% yield). MS (FAB) 551.4 MH*. 1H NMR 10 (CDCI3) 5 8.03(d, J= 8Hz, 1H), 7.86 (b d, J= 8.5Hz, 1H), 7.84 (d, J= 8Hz, 1H), 7.56- 7.40 (m, 4H), 5.92-5.85 (m, 1H), 5.31 (dd, J= 1,17Hz, 1H), 5.22 (dd, J= 1,10Hz, 1H), 5.17 (d, J= 9Hz, 1H), 5.05 (d, J= 12Hz, 1H), 4.91 (d, J= 12Hz, 1H), 4.67-4.60 (m, 3H), 4.31-4.27 (m, 2H), 4.16 (b d, J= 11 Hz, 1H), 3.71 (dd, J=4,11 Hz, 1H), 2.47- 2.41 (m, 1H), 2.08-1.99 (m,1H), 1.85-1.63 (m, 5H), 1.44-1.40 (m, 1H), 1.36 (s, 9H), 15 1.28-1.00 (m,5H). The crude dipeptide 15d (ca.5.05 mmol) was treated with 4N HCI/dioxane (25 mL) as described for the synthesis of compound 15c. 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 synthesis of 20 compound 15d to yield crude tripeptide 15e as a yellow-oil foam. The crude material was purified by flash chromatography (e!uent:hexane:EtOAc;80:20 to 75:25) to provide the tripeptide 15e as a white foam (2.75 g; 79% yield over 2 steps). MS (FAB) 690.5 MH*. "H NMR (CDCI3), mainly one rotamer, 6 8.06 (d, J= 8Hz, 1H), 7.87 (b d, J= 8.5Hz, 1H), 7.82 (d, J= 8Hz, 1H), 7.57-7.40 (m, 4H), 6.41 (d, J= 8.5Hz, 25 1H), 5.92-5.84 (m, 1H), 5.31 (dd, J= 1,17Hz, 1H), 5.23 (dd, J= 1,10.5Hz, 1H), 5.04 (d, J= 12Hz, 1H), 4.98 (b d, J= 7Hz, 1H), 4.93 (d, J=12Hz, 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). 30 The tripeptide 15e (2.75 g , 3.99 mmol) was treated with 4N HCI/dioxane (20 mL) as described for the synthesis of compound 15c. The crude hydrochloride salt was dissolved in anhydrous DCM (20 mL). NMM (1.75 mL, 15.94 mmol) and acetic anhydride (752 \i\, 7.97mmol) were added successively. The reaction mixture was stirred overnight at RT, then diluted with EtOAc. The organic layer was washed successively with 10% aqueous citric acid (2x), saturated aqueous NaHC03 (2x), water (2x) and brine (1x), dried (MgS04), filtered, and evaporated to dryness to provide the crude tripeptide 15f as a white foam (2.48g, 98% yield). MS (FAB) 632.4 MH+I. "H NMR (CDCI3), mainly one rotamer, 5 8.06(b d, J= 8Hz, 5 1H), 7.87 (b d, J= 8Hz, 1H), 7.83 (d, J= 8Hz, 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= 12Hz, 1H), 4.94 (d, J= 12Hz, 1H), 4.64-4.57 (m, 4H), 4.30-4.23 (m, 2H), 4.12-4.08 (m, 1H), 3.73 (dd, J=4,11 Hz, 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). 10 The crude tripeptide 15f (2.48 g, 3.93 mmol) was dissolved in an anhydrous mixture of CH3CN : DCM (20 mL). Triphenylphosphine (53.5 mg, 0.200 mmol) and tetrakis(triphenylphosphine)-palladium (0) catalyst (117.9 mg, 0.102 mmol) were added successively, followed by pyrrolidine (353.9 ul_, 4.24 mmol). The reaction mixture was stirred at RT for 18 h. Thereafter, the solvent was evaporated. The 15 residue was dissolved in EtOAc and 10% aqueous citric acid, and further washed twice more with 10% aqueous citric acid, water (2x), and brine (1x). The organic layer was dried (MgS04), filtered and evaporated. The crude product was triturated in Et20: DCM (85:15) to provide after filtration the tripeptide 15g as a white solid (2.09 g, 90% yield). MS (FAB) 592.4 MH* 614.3 (M+Na) \ 1H NMR (CDCfe), r- 20 mainly one rotamer, 6 8.08 (d, J= 8Hz, 1H), 7.93 (b d, J= 9Hz, 1H), 7.88 (b d, J= 8Hz, 1H), 7.82 (d, J= 8Hz, 1H), 7.57-7.41 (m, 4H), 6.47 (d, J= 8.5Hz, 1H), 5.05 (d, J= 12.5Hz, 1H), 4.94 (d, J= 12.5Hz, 1H), 4.73 (t, J= 9.5,19Hz, 1H), 4.44-4:35 (m, 2H), 4.26 (b s, 1H), 4.19 (d, J= 11.5Hz, 1H), 3.75 (dd, J=4,11 Hz, 1H), 2.47 (b dd, 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 16 Synthesis of segment Ac-Chg-Val-Pro(4(f?)-naphthaIen-1-ylmethoxy)-0H (16e) 10 Compound 16a (2.89 g, 7.02 mmol) was treated with 4N HCI/dioxane (30 mL) as described for the synthesis of compound 15c. 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 1/2 h as described for the synthesis of compound 15d to provide the crude dipeptide 16b as an ivory oil-foam (ca.3.60 g, 100% yield). MS (FAB) 509.3 MH" 511.3MH* 533.2 (M+Na)\ 1H NMR (CDCI3) 5 8.04 (b d, J= 8Hz, 1H), 7.87 (b d, J= 7Hz, 1H), 7.82 (d, J= 8Hz, 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= 12Hz, 1H), 4.92 (d, J= 12Hz. 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= 7Hz, 3H), 0.93 (d, J= 7Hz, 3H). The crude dipeptide 16b (ca.7.02 mmol) was treated with 4N HCI/dioxane (30mL) as described for the synthesis of compound 15c. 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) 5 and TBTU (2.71 g, 8.43 mmol) in CH2CI2 (35 mL) as described for the synthesis of compound 15d to provide the crude tripeptide 16c as an ivory foam (ca.4.6 g, 100% yield). MS (FAB) 648.5 MH" 672.4 (M+Na)+. 1H NMR (CDCI3) 5 8.06 (b d, J=8Hz, 1H), 7.87 (b d, J= 7.5 Hz, 1H), 7.82 (b d , J= 8Hz, 1H), 7.57-7.40 (m, 4H), 6.46 (b d, J= 8.5Hz, 1H>, 5.94-5.84 (m, 1H), 5.31 (dd, J= 1, 17Hz, 1H), 5.23 (dd, J= 1,10.5Hz, 10 1H), 5.03 (d, J= 12Hz, 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= 7Hz, 3H), 0.93 (d, J= 7Hz, 3H). The crude tripeptide 16c (ca.7.02 mmol) was treated with 4N HCI/dioxane (30 mL) 15 as described for the synthesis of compound 15c. 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 CH2CI2 (35 mL) as described for the synthesis of compound 15d. The crude product was flash purified (eluent:hexane:EtOAc;30:70) to provide the acetylated protected tripeptide 16d as a white foam (3.39 g, 81% yield over 3 steps). 20 MS (FAB) 590.3 MH" 592.4 MH+ 614.4 (M+Na)+ 1H NMR (CDCI3), mainly one rotamer, 5 8.06 (d, J= 8Hz, 1H), 7.88 (b d, J= 8Hz, 1H), 7.83 (d, J= 8Hz, 1H), 7.58^7.41 (m, 4H), 6.37 (d, J= 9Hz, 1H), 5.97 (d, J= 8.5 Hz, 1H), 5.94-5.84 (m, 1H), 5.31 (dd, J= 1,17Hz, 1H), 5.24 (dd, J= 1,10.5 Hz, 1H),5.05 (d, J= 12Hz, 1H), 4.94 (d, J= 12Hz, 1H), 4.66-4.57 (m, 4H), 4.31-4.22 (m, 2H), 4.11-25 4.05 (m, 1H), 3.73 (dd, J= 4.5, 11Hz, 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= 7Hz, 3H), 0.91 (d, J= 7Hz, 3H). The acetylated tripeptide 16d (3.39 g, 5.73 mmol) was deprotected by tetrakis(triphenylphosphine)- palladium (0) catalyst (172.1 mg, 0.149 mmol) with 30 triphenylphosphine (78.1 mg, 0.298 mmol) and pyrrolidine (516 nL, 6.19 mmol) in a 1:1 mixture of anhydrous CH3CN : DCM (30 mL) as described for the synthesis of compound 15g. The crude light yellow foam product was triturated in Et20: DCM (85:15) to provide after filtration the tripeptide 16e as an off-white solid (3.0g ; 95% yield). MS (FAB) 550.3 MH" 1H NMR (CDCb) 6 8.08 (d, J= 8Hz, 1H), 8.04 (b d, J= 9Hz, 1H), 7.88 (b d, J= 7.5Hz, 1H), 7.82 (d, J= 8Hz, 1H), 7.58-7.37 (m, 5H), 5.05 (d, J= 12Hz, 1H), 4.94 (d, J= 12Hz, 1H), 4.61 (t, J= 9.5,19.5Hz, 1H), 4.46-4.37 (m, 2H), 4.27 (b s, 1H), 4.17 (d, J= 5 11Hz, 1H),3.74 (dd, J=4,11Hz, 1H), 2.49 (b dd, J= 7.5,13Hz, 1H), 2.17-2.09 (m, 1H), 2.04 (s, 3H), 2.03-1.94 (m, 1H), 1.79 (b d, J= 12.5Hz, 1H), 1.62-1.43 (m, 5H), 1.08-0.85 (m, 5H), 1.00 (d, J= 7Hz, 3H), 0.90 (d, J= 7Hz, 3H). COMPOUNDS OF TABLES 1 TO 4 EXAMPLE 17 I0 Synthesis of compound 104 of Table 1 J7f compound 104 Compound 17a (4.27 g, 7.93 mmol, described as compound 6a in Example 6) was treated with 4N HCI/dioxane (40 mL) for 5 h as described for compound 15c. The crude hydrochloride salt was dissolved in THF (10 mL) and a solution of NaOH 5 (348.7 mg, 8.72 mmol) in H20 (5 mL) was added, followed by a dropwise addition of (Boc)20 (1.73 g, 7.93 mmol) dissolved in THF (13 mL). The pH was maintained at 8 by the addition of 10% aqueous NaOH as required. The reaction mixture was stirred vigorously, then diluted with Et20 and H20 and extracted one time more with Et20. The water layer was acidified to pH 3 with 10% aqueous citric acid. The mixture was 10 extracted with EtOAc (3x). The combined EtOAc extracts were washed with H20 (2x), brine(1x), dried (MgS04), filtered and evaporated to dryness to provide crude compound 17b as an ivory foam (ca.7.93mmoi). MS (FAB) 481.3 MH" 1H NMR (CDCI3), ca.1:1 mixture of rotamers. 5 8.04 (bd, J= "7.5Hz; 1H), 7.87 (b d, J= 7.5Hz, 1H), 7.82 (d, J= 7.5Hz, 1H), 7.56-7.40 (m, 5H), 4.96 (b s, 2H), 4.33 (t, J= 7.5, 15 14.5Hz, 1H), 4.21-4.09 (m, 0.5H), 3.99-3.84 (m, 0.5H), 3.78-3.75 (m, 0.5H), 3.68-3.62 (m, 0.5H), 3.61-3.42 (m, 1H), 2.55-2.41 (m, 1H), 2.22-2.11 (m, 1H), 1.61-1.52 (m, 3H), 1.43 (s, 9H), 1.40-1.31 (m, 1H), 1.25-1.19 (m, 1H), 0.99 (t, J= 7.5,14.5Hz, 3H)- Compound 17b (ca.7.93 mmol) was treated with DBU (1.18 mL, 93 mmol) and 20 allylbromide (4.12 mL, 47.61 mmol) in anhydrous CH3CN (40 mL) for 48 h as described for compound 15b to provide the allylated dipeptide 17c as an ivory foam (3.54 g; 86% yield over 2 steps). MS (FAB) 521.3 MH" 545.2 (M+Na)\ 1H NMR (CDCI3), ca.1:1 mixture of rotamers, 6 8.05 (b d, J= 8Hz, 1H), 7.86 (b d, J= 7.5Hz, 1H), 7.82 (d, J= 8Hz, 1H), 7.55-7.40 (m, 5H), 5.88-5.79 (m, 1H), 5.27 (b d, J= 25 17.5Hz, 1H), 5.18 (b d, J= 10Hz, 1H), 5.03-4.89 (m, 2H), 4.63-4.50 (m, 2H), 4.44-4.19 (m, 2H), 4.00-3.40 (m, 2H), 2.70-2.02 (m, 2H), 1.66-1.35 (m, 5H), 1.44 (s, 9H), 0.95 (t, J= 7.5, 14.5Hz, 3H). The crude dipeptide 17c (1.18 g, 2.26 mmol) was treated with 4N HCI/dioxane (35 mL) as described for compound 15c. The crude hydrochloride salt was coupled to Boc-Chg-OH • H20 (684 mg, 2.48 mmol) with NMM (993 nL 9.03 mmol) and TBTU (870 mg, 2.71 mmol) in DCM (11 mL) as described for compound 15d to provide the 5 crude tripeptide 17d as an ivory foam (1.41 g; 95%). MS (FAB) 660.4 MH" 662.3 MH*. 1H NMR (CDCI3), mainly one rotamer, 5 8.03 (b d, J= 8H2,1H), 7.85 (b d, J= 8H2, 1H), 7.81 (d, J= 8Hz, 1H), 7.56-7.39 (m, 5H), 5.88-5.77 (m, 1H), 5.26 (dd, J= 1.5, 17Hz, 1H),5.15 (dd, J= 1.5, 10.5Hz, 1H), 5.12 (s, 1H), 5.02-4.92 (m, 2H), 4.72-4.59 (m, 1H), 4.57-4.46 (m, 1H), 4.42-4.35 (m, 1H), 4.33-4.20 (m, 1H), 4.02-3.90 (m, 10 1H), 3.78-3.70 (m, 1H), 3.67-3.51 (m, 1H), 2.71-2.61 (m, 1H), 2.12-2.02 (m, 1H), 1.79-1.48 (m, 10H), 1.45-1.39 (m, 1H), 1.38 (s, 9H), 1.25-1.01 (m, 5H), 0.94 (t, J=7.5, 14Hz, 3H). The crude tripeptide 17d (265 mg, 0.400 mmol) was treated with 4N HCI/dioxane (3 mL) as described for compound 15c. The crude hydrochloride salt was coupled to 15 Boc-Chg-OH • HzO (143.3 mg, 0.521 mmol) with NMM (176 uL, 1.60 mmol) and TBTU (154.3 mg, 0.481 mmol) in DCM (3 mL) as described for compound 15d to provide crude tetrapeptide 17e as an ivory foam (ca.0.400 mmol; 100%). MS (FAB) 799.5 MH" 801.5 MH+ 823 (M+NaV\ "H NMR ( CDCI3), ca. 1 :1 mixture of rotamers, 5 8.05 (b d, J= 8.5Hz, 1H), 7.87 (b d, J= 7.5Hz, 1H), 7.81 (d, J=8.5Hz. 20 1H), 7.55-7.40 (m, 4H), 7.37 (s, 1H), 6.58-6.41 (m, 1H), 5.89-5.78 (m, 1H), 5.26 (b dd, J= 1.5,17Hz, 1H), 5.16 (b dd, J= 1.5, 10.5Hz, 1H), 5.20-4.92 (m, 3H), 4.68-4.58 (m, 2H), 4.57-4.47 (m, 1H), 4.43-4.26 (m, 1H), 3.99-3.81 (m, 2H), 3.78-3.60 (m, 2H), 2.67-2.60 (m, 1H), 2.11-2.02 (m, 1H), 1.78-1.42 (m, 14H), 1.44 &1.43 (s, 9H), 1.25-0.91 (m, 13H), 0.95 (t, J=7.5, 15Hz, 3H). 25 The crude tetrapeptide 17e (ca.0.400 mmol) was treated with 4N HCI/dioxane (3 mL) as described for compound 15c. The crude hydrochloride salt was further treated with acetic anhydride (83 pL, 0.884 mmol) and NMM (194 uL, 1.77 mmol) in DCM (3 mL) as described for compound 15f to provide the crude acetylated tetrapeptide 17f as an ivory foam (ca.0.400 mmol). 30 MS (FAB) 741.5 MH" 743.4 MH* 765.4 (M+NaV"H NMR (CDCI3) 6 8.05 (b d, J= 8.5Hz, 1H), 7.87 (b d, J= 7.5Hz, 1H), 7.82 (d, J= 8.5Hz, 1H), 7.55-7.41 (m, 4H), 7.39 (s, 1H), 6.63-6.48 (m, 1H), 6.01 (d, J= 8.5Hz, 1H), 5.90-5.79 (m, 1H), 5.27 (b dd, J= 1.5, 17Hz, 1H), 5.16 (b dd, J= 1.5, 10.5Hz, 1H), 5.01 (d, J= 12Hz, 1H), 4.96 (d, J= 12Hz, 1H), 4.69-4.48 5 The acetylated tetrapeptide 17f (ca.0.400 mmol) was deprotected by tetrakis(triphenylphosphine)- palladium (0) catalyst (11.3 mg, 0.010 mmol) with triphenylphosphine (5.12 mg , 0.020 mmol) and pyrrolidine (34 (iL, 0.406 mmol) in a 1:1 mixture of anhydrous CH3CN : DCM (2 mL) as described for compound 15g. The crude product was purified by flash chromatography (eluent - 1st EtOAc, then, 2nd 10 1.92% HOAc, 3.85% MeOH in DCM) to provide, after lyophilization, the tetrapeptide compound 104 of Table 1 as an off-white amorphous solid (193.1 mg; 73% yield over 5 steps). MS (FAB) 701.4 MH" 703.4 MH+ 725.4 (M+Na)+. "H NMR (DMSO), ca.1 : 5 mixture of rotamers, S 8.57 & 8.32 (s, 1H), 8.04 (d, J= 15 7.5Hz, 1H), 7.94 (b d, J= 7.5Hz, 1H), 7.88 (d, J= 8Hz, 1H), 7.83-7.78 (m, 2H), 7.58-7.30 (m, 4H), 4.99 (d, J= 12Hz, 1H), 4.90 (d, J= 12H2, 1H), 4.44-4.29 (m, 2H), 4.29-4.05 (m, 3H), 3.87-3.73 (m, 1H), 2.23-2.13 (m, 1H), 2.05-1.95 (m, 1H), 1.91 & 1.84 (s, 3H), 1.75-1.40 (m, 15H), 1.29-0.84 (m, 12H), 0.91 (t, J= 7.5,14.5Hz, 3H). EXAMPLE 18 20 Synthesis of compound 105 of Table 1 Compound 18b, i.e. corresponding to compound 5f of Example 5, was coupled to the preformed tripeptide 18a described previously in Example 15. More specifically, compound 18b (ca.0.521 mmol) was combined with compound 18a (323.6 mg, 0.547 mmol) in DCM (3 mL) and NMM (172 ^L, 1.562 mmol), followed by the addition of HATU (237.6 mg, 0.625 mmol). The reaction mixture was stirred at RT for 18 h, after which it was worked up as described for compound 15d to give the crude tetrapeptide as a racemic mixture at P1. Both isomers were partially 5 separated by flash chromatography (eluent- toluene : EtOAc ; 40:60). Combination of the first eluting fractions gave a 9:1 mixture in which analogous fert-butyl ester of 17f was the major component (58 mg). The middle fractions contain different ratios of the corresponding tert-butyl esters of 17f and compound 105 f-butyl ester (163 mg). The latter eluting fractions provided the corresponding tert-butyl ester of compound 10 105 as the major isomer (75.8 mg). The latter ester (74 mg, 0.0975 mmol) was dissolved in 4N HCI/dioxane (2 mL), stirred at RT for 5.5 h then evaporated to dryness to give an oil. Purification by flash chromatography (eluent- 1st EtOAc, then 2nd 1.92% HOAc, 3.85% MeOH, in DCM) yielded, after lyophilization, compound 105 as a white-amorphous solid (38.7 mg, 15 56% yield). HPLC analysis indicated a 3 :1 ratio of compound 105 and compound 104. MS and NMR data for compound 105: MS (FAB) 701.5 MH" 703.5 MH* 725.6 (M+Na)+. 1H NMR (DMSO), ca.1 : 2.5 mixture of rotamers, 5 8.76 & 8.34 (s, 1H), 8.05(b d, J= 7.5Hz, 1H), 7.94 (bd, J= 8Hz, 1H), 7.88 (d, J=8.5Hz, 1H), 7.85-7.78 (m, 2H), 7.59-7.43 (m, 4H), 4.99 (d, J= 12Hz, 1H), 4.89 (d, J= 12Hz, 1H), 4.41- 20 4.05 (m, 5H), 3.82-3.66 (m, 1H), 2.25-2.11 (m, 1H), 2.11-1.98 (m, 1H), 1.90 & 1.84 (s, 3H), 1.78-1.40 (m, 15H), 1.39-0.82 (m, 12H), 0.90 (t, J= 7,14Hz, 3H). EXAMPLE 19 Synthesis of compounds 103 of Table 1 Following the procedure described for the synthesis of compound 104 of Example 25 17, the mixtures of 1(fl), 2(R) and 1(f?),2(S) isomers of intermediate compound 10d, prepared in Example 10, were coupled with compound 2 to give a mixture of isomeric intermediate compounds 19a and 19b 10 Following the procedures of Example 18, isomeric compounds 19a and 19b were separated and transformed into their corresponding compound of formula 1; to isolate the corresponding compound 103 of Table 1. Spectral data: Compound 103: Rotamer population by NMR ca. (1:8.7): MS (FAB) m/z: 703 (MH+); 1H-NMR (DMSO-d6) 58.21-8.09 (bs, 1H), 8.05 (bd, J = 7.63 Hz, 1H), 7.94 (bd, J = 7.0 Hz, 1H), 7.91-7.83 (m, 2H), 7.83-7.76 (m, 1H), 7.59-7.5 (m, 3H), 7.5-7.43 (m, 1H), 4.99 (d, J = 11.8 Hz, 1H), 4.89 (d, J = 11.8 Hz, 1H), 4.43-4.30 (m, 3H), 4.23-4.16 (m, 1H), 4.13 (bd, J = 10.8 Hz, 1H), 3.71 (dd, J = 11.1, 4 Hz, 1H)7 2.2-2.02 (m, 2H), 1.87 and 1.84 (2 x s, 3H), 1.81-1.71 (m, 2H), 1.70-1.40 (m, 12H), 1.26-1.06 (m, 4H), 1.04-0.83 (m, 11H), 0.59 (m, 1H). EXAMPLE 20 Synthesis of compound 108 of Table 1 15 The crude tetrapeptide 17e from Example 17 (ca.0.963 mmol) was treated with 4N HCI /dioxane solution (5 mL) as described for compound 15c. The crude hydrochloride salt was coupled to Boc-(D)Glu(0-aIlyl)-OH (331.9 mg, 1.155 mmol) 5 with NMM (423 ul, 3.850 mmol) and TBTU (370.8 mg, 1.155 mmol) in DCM (5 mL) for 3 h at RT as described for compound 15d. The crude pentapeptide 20b was obtained as an ivory foam (ca.933.9 mg, 0.963 mmol). MS (FAB) 968.6 MH" 970.6 MH* 992.5 (M+Na). *H NMR (CDCI3), ca.1 :4 mixture of rotamers, 5 8.05 (d, J= 8.5Hz, 1H), 7.87 (b d, J= 10 7.5Hz, 1H), 7.81 (d, J= 8.5Hz, 1H), 7.58-7.34 (m, 5H), 6.77-6.25 (m, 2H), 5.98-5.77 (m, 2H), 5.38-5.21 (m, 4H), 5.16 (dd, J= 1.5,10.5Hz, 1H), 5.06-4.89 (m, 2H), 4.68-4.13 (m, 7H), 3.96-3.52 (m, 4H), 2.69-2.38 (m, 3H), 2£3-1.87 (m, 2H), 1.78-1.37 (m, 17H), 1.46 & 1.44 (s, 9H), 1.22-0.87 (m, 11H), 0.95 (t, J=7,14.5Hz, 3H). The crude pentapeptide 20b (ca.0.963 mmol) was treated with 4N HCI /dioxane 15 solutton (5 mL) as described for compound 15c. The crude hydrochloride salt was coupled to Boc-Asp(0-allyl)-OH (315.6 mg, 1.155 mmol) with NMM (423 ul, 3.85 mmol) and TBTU (370.8 mg, 1.155 mmol) in DGM (5 ml) as described for compound 15d. The crude hexapeptide 20c was obtained as an ivory foam (ca.1.083g, 0.963 mmol). MS (FAB) 1147.6 (M+Na)+. 1H NMR (CDCI3), ca.1:1 20 mixture of rotamers, 8 8.06 (b d, J= 8Hz, 1H), 7.86 (d, J= 8Hz, 1H), 7.81 (d, J= 8Hz, 1H), 7.59-7.39 (m. 5H), 7.39-6.34 (m, 4H), 5.98-5.76 (m, 3H), 5.38-5.10 (m, 6H), 5.10-4.89 (m, 2H), 4.66-4.05 (m, 10H), 3.87-3.58 (m, 4H), 3.30-2.65 (m, 2H), 2.65-1.89 (m 3H), 1.79-1.33 (m, 19H), 1.47 & 1.45 (s, 9H), 1.33-0.86 (m, 14H). The crude hexapeptide 20c (ca.0.963 mmol) was treated with 4N HCI /dioxane 25 solution (5 mL) as described for compound 15c. The crude hydrochloride was acetylated with acetic anhydride (182 ul, 1.193 mmol) and NMM (423.5 nL, 3.850 mmol) in DCM (5 mL) as described for compound 15f to provide the crude acetylated tetrapeptide. The foam residue was purified by flash chromatography (eluent: 1st hexane: EtOAc 20:80 to 10:90 and 2nd pure EtOAc) to provide the acetylated hexapeptide 20d as an ivory foam (528 mg, 51 % yield over 4 steps). MS (FAB) 5 1067.6 (MH+) 1089.6 (M+Na). The acetylated hexapeptide 20d (528 mg, 0.495 mmol) was dissolved in DCM (3 mL) and treated with a premixed, 15 min stirred solution of tetrakis(tiiphenylphosphine)-palladium (0) catalyst (90 mg, 0.078 mmol) and pyrrolidine (134 \iL, 1.603 mmol) in DCM (3 mL). The reaction mixture was stirred at 10 RT for 48 h after which the solvent was evaporated. The crude product was purified partially by trituration in Et20: DCM (85:15), then, purified in two batches by preparatory HPLC. Half of the partially purified material was dissolved in glacial HOAc (5 mL), filtered through a Millipore®: Millex®- HV 0.45}im filter and injected onto an equilibrated Whatman Partisil® 10-ODS-3 (2.2 x50cm) C18 reverse phase 15 column. Purification program : linear gradient at 15 mL/min, 230fim, injected at 5% A; once all HOAc had eluted the program was begun - at 5% A for 10 min, 5-58% A in 70 min; A: 0.06%TFA / CH3CN; B: 0.06%TFA / H20. Fractions were analyzed by analytical HPLC, appropriate fractions from both HPLC purifications were collected and lyophilized to provide the desired hexapeptide compound 108, as a white 20 amorphous solid (218.3 mg, 47% yield). MS (FAB) 945.5 MH- 947.4 MH+ 969.5 (M+Na)+ 985.4 (M+K)+. rH NMR (DMSO), ca.1:9 mixture of rotamers, 5 8.55 & 8.31 (s, 1H), 8.16 (d, J=7.5Hz, 1H), 8.11 (d, J= 8Hz, 1H), 8.05 (d, J= 8.5Hz, 1H), 7.97-7.85 (m, 2H), 7.88 (d, J= 8.5Hz, 1H), 7.75 (d, J= 9Hz, 1H), 7.59-7.39 (m, 4H), 4.99 (d, J= 12Hz, 1H), 4.89 (d, J= 25 12Hz, 1H), 4.53 (dd, J= 7,14Hz, 1H), 4.08-4.45 (m, 6H), 3.77 (b dd, J= 4,11 Hz, 1H), 2.64 (dd, J= 6.5,16.5Hz, 1H), 2.48-2.41 (m, 1H), 2.25-2.12 (m, 3H), 2.07 & 1.82 (s, 3H), 2.04-1.86 (m, 2H), 1.80-1.35 (m, 14H), 1.32-0.80 (m, 14H), 0.91 (t, J= 7.5, 14.5Hz, 3H). 5 A solution of lithium hydroxide monohydrate (23 mg, 0.56 mmol) in H20 (4mL) was added to a solution of the ester compound 21a (45 mg, 0.185 mmol, described previously as the (f?,fl) isomer 9c) in MeOH (3.5 mL) and THF (3.5 ml_). The resulting solution was stirred vigorously for 16 h and then partitioned between EtOAc (60 mL) and 10% aqueous HCI (20 mL). The organic phase was separated, dried 10 (MgSQ4), filtered and concentrated to give the corresponding acid in quantitative yield. This material (ca. 0.185 mmol) was combined with (S)-(-)-a-methylbenzylamine (27 mg, 0.22 mmol), HATU (77 mg, 0.20 mmol), and DIPEA (0.11 mL, 0.65 mmol) in DMF (5 mL). After 20 h, the reaction was concentrated. The residue dissolved in ] 5 EtOAc and the solution was washed sequentially with saturated aqueous NaHC03, 10% aqueous HCI, and brine before being dried (MgS04), filtered and concentrated in vacuo. Purification by flash chromatography (eluent: 35% EtOAc/hexane) gave 11 mg (28%) of the coupled product 21b. This material (11 mg, 0.033 mmol) was treated with 4N HCI/dioxane for 35 min. The reaction mixture thereafter was concentrated to dryness to give the hydrochloride salt of the corresponding amine. 5 The latter product was coupled with: (33 mg, 0.036 mmol, prepared by procedures analogous to those of Example 15 and 20), HATU (14 mg, 0.036 mmol) and DIPEA (0.116 mL, 0.02 mmol) in DMF (4 mL). After the reaction mixture has been stirred 16 h, the mixture was concentrated. The 10 residue was dissolved in EtOAc. The solution was washed sequentially with saturated aqueous NaHC03,10% aqueous HCI and brine, dried (MgS04), filtered and concentrated in vacuo to give a white solid. This material (ca. 0.033) was dissolved in EtOH (6 mL) and treated with ammonium acetate (7 mg, 0.09 mmol) and 10% Pd/C (10 mg) under an atmosphere of hydrogen gas. After 3 h, the reaction 15 mixture was filtered through diatomaceous earth. The filtrate was concentrated to dryness. The residue was then dissolved in DMSO and purified by preparative HPLC to give a white solid after lyophilization (17.6 mg, 57% yield over two steps). Spectral data: MS (FAB) ES" 932.6 (M-H)", 954.5 (M-Na)"; HRMS calcd for C48H67N7012 (MH+) 934.49261, found: 934.49010; 1H-NMR (DMSO,d6) 5 8.90 (s, 1H), 20 8.24 (d, J = 7.95 Hz, 1H), 8.14 (d, J = 7.63 Hz, 1H), 7.99 (d, J = 8.26 Hz, 1H), 7.79 (d, J = 8.9 Hz, 1H), 7.75 (d, J = 8.26 Hz, 1H), 7.42-7.17 (m, 10 H), 5.00 (quintet, J = 7.63 Hz, 1H), 4.7 (m, 1H), 4.52 (d, J = 11.76 Hz, 1H), 4.43 (d, J = 11.4 Hz, 1H), 4.33-4.2 (m, 6H), 3.70 (dd, J = 11.4 and 11.1 Hz, 2H), 2.63 (dd, J - 5.7 and 5.7 Hz, 1H), 2.45 (dd, J = 7.95 and 7.95 Hz, 1H), 2.21-2.11 (m, 3H), 2.07-1.97 (m, 1H), 1.93-1.83 25 (m, 2H), 1.81 (s, 3H), 1.78-1.63 (m, 2H), 1.54-1.41 (m, 2H), 1.39 (d, J = 7.0 Hz, 3H), 1.29 (dd, J = 7.94 and 7.63 Hz, 1H), 1.15 (quintet, J = 7.0 Hz, 1H), 1.05 (m, 1H), 0.90 (d, J = 6.36 Hz, 6H), 0.88-0.83 (m, 1H), 0.71 (m, 9H). EXAMPLE 22 Compound 107 of Table 1 was synthesized according to the protocol described in 30 Example 17. Rotamer population by NMR (1:7.6) MS (FAB) m/z: 675 (MH+); 1 H-NMR (DMSO-d6) 5 8.35-8.19 (bs, 1H), 8.04 (d, J = 7.63 Hz, 1H), 7.93 (bd, J = 7.31 Hz, 1H), 7.88 (d, J = 8.27 Hz, 1H), 7.86-7.79 (m, 2H), 7.59-7.49 (m, 3H), 7.46 (dd, J = 7.95, 7.95 Hz, 1H), 4.98 (d, J = 11.8 Hz, 1H), 5 4.89 (d, J = 11.8 Hz, 1H), 4.40-4.34 (m, 1H), 4.32 (bs, 1H), 4.29-4.24 (m, 1H), 4.22-4.15 (m, 1H), 4.09 (d, J = 11.8 Hz, 1H), 3.74 (dd, J = 11.1, 4 Hz, 1H), 2.20-2.12 (m, 1H), 2.05-1.94 (m, 2H), 1.84 (s, 3H), 1.72-1.42 (m, 7H), 1.20-1.13 (m, 1H), 1.08-0.87 (m, 13H), 0.85 (d, J = 6.68 Hz, 6H). EXAMPLE 23 10 Compound 114 of Table 1 was synthesized according to the protocol described in Example 17. Rotamer population by NMR (1:7.5): MS (FAB) m/z: 747 (M+Na*); 1H-NMR (DMSO-d6) 5 8.40-8.24 (bs, 1H), 8.07-8.01 (m, 1H), 7.96-7.91 (m, 1H), 7.87 (d J = 8.26 Hz, 1H), 7.85-7.78 (m, 2H), 7.58-7.49 15 (m, 3H), 7.46 (dd, J = 7.95, 7.95 Hz, 1H), 7.30-7.21 (m, 4H), 7.20-7.14 (m, 1H), 4.98 (d, J = 11.8 Hz, 1H), 4.89 (d, J = 11.8 Hz, 1H), 4.40-4.34 (m, 1H), 4.34-4.29 (m, 1H), 4.29-4.25 (m, 1H), 4.22-4.15 (m,1H), 4.09 (d, J = 11.8 Hz, 1H), 3.74 (dd, J = 11.1,4 Hz, 1H), 2.95-2.79 (m, 2H), 2.21 -2.11 (m, 1H), 2.05-1.94 (m, 2H), 1.89-1.83 (2 x s, 3H), 1.63-1.41 (m, 7H), 1.38-1.30 (m, 1H), 1.27-1.22 (m, 1H), 1.12-0.94 (m, 5H), 20 0.89 (d, J = 6.4 Hz, 3H), 0.84 (d, J = 6.4 Hz, 3H). EXAMPLE 24 Compound 118 of Table 1 was synthesized according to the protocol described in Example 17. Rotamer population by NMR ca. (1:6.3): 25 MS (FAB) m/z: 677.4 (MH+); 1 H-NMR (DMSO-d6) 6 8.58 and 8.38 (2 x bs, 1H), 8.04 (d, J = 7.63 Hz, 1H), 7.93 (d, J = 7.63 Hz, 1H), 7.91-7.81 (m, 3H), 7.59-7.49 (m, 3H), 7.49-7.43 (m, 1H), 4.98 (d, J = 12.1 Hz, 1H), 4.89 (d, J = 12.1 Hz, 1H), 4.41-4.29 (m, 2H), 4.29-4.14 (m, 2H), 4.1 (d, J = 10.8 Hz, 1H), 3.74 (bd, J = 7.63 Hz, 1H), 2.21-2.12 (m, 1H), 2.04-1.92 (m, 2H), 1.90 and 1.84 (2xs, 3H), 1.63-1.41 (m, 9H), 1.39- 30 1.26 (m, 3H), 1.21-1.15 (m, 1H), 1.06-0.92 (m, 5H), 0.92-0.80 (m, 9H). EXAMPLE 25 Compound 116 of Table 1 was synthesized according to the protocol described in Example 17. ^H NMR (DMSO-d6) 8 8.36 (s, 1 H), 8.14 (d, J = 8 Hz, 1 H), 8.04 (d, J = 8 Hz, 1 H), 5 7.99 (d, J = 9 Hz, 1 H), 7.79 (d, J = 9 Hz, 1 H), 7.33-7.26 (m, 5 H), 4.54-4.42 (m, 3 H), 4.30-4.21 (m, 5 H), 4.06 (d, J = 11 Hz, 1 H), 3.69 (dd, J = Hz, 1 H), 2.62 (dd, J = 16, 10 Hz, 1 H), 2.47-2.42 (m, 1 H), 2.18-2.14 (m, 3 H), 2.02-1.87 (m, 2 H), 1.82 (s, 3 H), 1.74-1.66 (m, 2 H), 1.54-1.47 (m, 2 H), 1.38-1.27 (m, 2 H), 1.21-1.18 (m, 1 H), 0.97-0.85 (m, 11 H), 0.80-0.70 (m, 7 H). 10 EXAMPLE 26 Compound 121 of Table 1 was synthesized according to the protocol described in Example 17. 1H NMR (DMSO-ds) 6 9.12 (d, J = 6 Hz, 1 H), 8.64 (s, 1 H), 8.30 (d, J = 8 Hz, 1 H), 8.12 (d, J = 9 Hz, 1 H), 8.05 (dd, J = 8, 7 Hz, 1 H), 7.97 (d, J = 8 Hz, 1 H), 7.80 (dd, J 15 = 8, 7 Hz, 1 H), 7.66 (d, J = 9 Hz, 1 H), 7.54 (d, J = 6 Hz, 1 H), 5.70-5.61 (m, 2 H), 5.26 (d, J = 17 Hz, 1 H), 5.07 (d, J = 12 Hz, 1 H), 4.52 (d, J = 12 Hz, 1 H), 4.39 (dd, J = 9, 8 Hz, 1 H), 4.23-4.12 (m, 2 H), 4.03-3.99 (m, 1 H), 2.66-2.54 (m, 1 H), 2.35-2.28 (m, 1 H), 2.08 (dd, J = 9,17 Hz, 1 H), 2.01-1.93 (m, 1 H), 1.83 (s, 3 H), 1.65-1.46 (m, 5 H), 1.41-1.38 (m, 1 H), 1.24-1.20 (dd, J = 9, 5 Hz. 1 H), 01.05-0.78 (m, 12 H). 20 EXAMPLE 27 Compound 205 of Table 2 was synthesized according to the protocol described in Example 17. "H NMR (DMSO-de) 5 9.14 (d, J = 6 Hz, 1 H), 8.60 (s, 1 H), 8.32 (d, J = 8 Hz, 1 H), 8.14-8.06 (m, 2 H), 7.98 (d, J = 8 Hz, 1 H), 7.82 (dd, J = 8, 7 Hz, 1 H), 7.66 (d, J = 9 25 Hz, 1 H), 7.55 (d, J = 8 Hz, 1 H), 5.75-5.66 (m, 2 H), 5.22 (d, J = 17 Hz, 1 H), 5.07 (d, J = 10 Hz, 1 H), 4.50 (d, J = 12 Hz, 1 H), 4.39 (dd, J = 9, 9 Hz, 1 H), 4.23-4.08 (m, 3 H), 2.56-2.50 (m, 1 H), 2.36-2.28 (m, 1 H), 2.04-1.97 (m, 1 H), 1.82 (s, 3 H), 1.62-1.41 (m, 7 H), 1.24 (dd, J = 5, 4 Hz, 1 H), 0.94-0.75 (m, 12 H). EXAMPLE 28 30 Compound 117 of Table 1 was synthesized according to the protocol described in Example 20. "H NMR (DMSO-d6) 5 8.36 (s, 1 H), 8.17 (d, J = 8 Hz, 1 H), 8.09 (d, J = 8 Hz, 1 H), 8.04 (d, J = 8 Hz, 1 H), 7.96-7.92 (m, 2 H), 7.87 (d, J = 8 Hz, 1 H), 7.77 (d, J = 9 Hz, 1 H), 7.56-7.45 (m, 4 H), 4.99 (d, J = 12 Hz, 1 H), 4.89 (d,J = 12 Hz, 1 H), 4.52 (dd, J = 14, 7 Hz, 1 H), 4.37-4.12 (m, 6 H), 3.78-3.73 (m, 1 H), 2.63 (dd, J = 17, 6 Hz, 1 5 H), 2.47-2.42 (m, 1 H), 2.22-2.16 (m, 3 H), 2.04-1.86 (m, 2 H), 1.82 (s, 3 H), 1.77-1.71 (m, 1 H), 1.69-1.42 (m, 8 H), 1.30 (quint., J = 8 Hz, 1 H), 1.20 (dd, J = 12, 8 Hz, 1 H), 1.10-0.85 (m, 15 H), 0.76-0.72 (m, 1 H). EXAMPLE 29 Compound 120 of Table 1 was synthesized according to the protocol described in 10 Example 20. "H NMR (DMSO-de) 6 8.34 (s, 1 H), 8.12 (d, J = 8 Hz, 1 H), 8.05 (d, J = 8 Hz, 1 H), 7.95-7.87 (m, 3 H), 7.81 (d, J = 9 Hz, 1 H), 7.64-7.52 (m, 4 H), 7.46 (dd, J = 8, 7 Hz, 1 H), 4.99 (d, J = 12 Hz, 1 H), 4.89 (d, J = 12 Hz, 1 H), 4.63 (dd, J = 14, 7 Hz, 1 H), 4.37-4.14 (m, 4 H), 3.74 (dd, J = 11, 4 Hz, 1 H), 3.41-3.35 (m, 2 H), 2.61 (dd, J = 16, 15 7 Hz, 1 H), 2.44 (dd, J = 16, 8 Hz, 1 H), 2.20-2.15 (m, 1 H), 2.04-1.96 (m, 3 H), 1.82 (s, 3 H), 1.70-1.64 (m, 1 H), 1.56-1.43 (m, 7 H), 1.30 (quint., J = 8 Hz, 1 H), 1.20 (dd, J = 8, 5 Hz, 1 H), 0.99-0.72 (m, 21 H). EXAMPLE 30 Cloning, expression and purification of the recombinant HCV NS3 protease 20 type 1b. Serum from an HCV-infected patient was obtained through an external collaboration (Bernard Willems MD, Hopital St-Luc, Montreal, Canada and Dr. Donald Murphy, Laboratoire de Sante Publique du Quebec, Ste-Anne de Bellevue, Canada). An engineered full-length cDNA template of the HCV genome was constructed from 25 DNA fragments obtained by reverse transcription-PCR (RT-PCR) of serum RNA and using specific primers selected on the basis of homology between other genotype 1b strains. From the determination of the entire genomic sequence, a genotype 1b was assigned to the HCV isolate according to the classification of Simmonds et al. (J. Clin. Microbiol., (1993), 31, p.1493-1503). The amino acid sequence of the non-30 structural region, NS2-NS4B, was shown to be greater than 93% identical to HCV genotype 1b (BK, JK and 483 isolates) and 88% identical to HCV genotype 1a (HCV-1 isolate). A DNA fragment encoding the polyprotein precursor (NS3/NS4A/NS4B/NS5A/NS5B) was generated by PCR and introduced into eukaryotic expression vectors. After transient transfection, the polyprotein processing mediated by the HCV NS3 protease was demonstrated by the presence of the mature NS3 protein using Western blot analysis. The mature NS3 protein was not observed with expression of a polyprotein precursor containing the mutation 5 S1165A, which inactivates the NS3 protease, confirming the functionality of the HCV NS3 protease. The DNA fragment encoding the recombinant HCV NS3 protease (amino acid 1027 to 1206) was cloned in the pET11d bacterial expression vector. The NS3 protease expression in E. coli BL21(DE3)pLysS was induced by incubation with 1 mM 1PTG ) 0 for 3 h at 22°C. A typical fermentation (18 L) yielded approximately 100 g of wet cell paste. The cells were resuspended in lysis buffer (3.0 mL/g) consisting of 25 mM sodium phosphate, pH 7.5,10% glycerol (WV), 1 mM EDTA, 0.01% NP-40 and stored at -80°C. Cells were thawed and homogenized following the addition of 5 mM DTT. Magnesium chloride and DNase were then added to the homogenate at final 15 concentrations of 20 mM and 20 u.g/ml_ respectively. After a 25 min incubation at 4°C, the homogenate was sonicated and centrifuged at 15000 x g for 30 min at 4°C. The pH of the supernatant was then adjusted to 6.5 using a 1M sodium phosphate solution. An additional gelftitration chromatography step was added to the 2 step punficafjbh 20 procedure described in WO 95/22985 (incorporated herein by reference); Briefly, the supernatant from the bacterial extract was loaded on a SP HIT rap columrY (Pharmacia) previously equilibrated at a flow rate of 2 mUmin in buffer A (50 mM sodium phosphate, pH 6.5,10% glycerol, 1 mM EDTA, 5 mM DTT, 0.01% NR-40), The column was then washed with buffer A containing 0.15 M NaCI and the protease 25 eluted by applying 10 column volumes of a linear 0.15 to 0.3 M NaCI gradient. NS3 protease-containing fractions were pooled and diluted to a final NaCI 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 30 then washed with buffer B containing 0.15 M NaCI at a flow rate of 1.5 mUmin. Two step washes were performed in the presence of buffer B containing 0.3 or 1M NaCI. The protease was recovered in the 0.3M NaCI wash, diluted 3-fold with buffer B, reapplied on the HiTrap Heparin column and eluted with buffer B containing 0.4 M NaCI. Finally, the NS3 protease-containing fractions were applied on a Superdex 75 HiLoad 16/60 column (Pharmacia) equilibrated in buffer B containing 0.3 M NaCI. The purity of the HCV NS3 protease obtained from the pooled fractions was judged to be greater than 95% by SDS-PAGE followed by densitometry analysis. The enzyme was stored at -80°C and was thawed on ice and diluted just prior to use. 5 EXAMPLE 31 Recombinant HCV NS3 protease/NS4A cofactor peptide radiometric assay. The enzyme was cloned, expressed and prepared according to the protocol described in Example 30. The enzyme was stored at -80°C, thawed on ice and diluted just prior to use in the assay buffer containing the NS4A cofactor peptide. 10 The substrate used for the NS3 protease/ NS4A cofactor peptide radiometric assay, DDIVPCSMSYTW, is cleaved between the cysteine and the serine residues by the enzyme. The sequence DDIVPC-SMSYTW corresponds to the NS5A/NS5B natural cleavage site in which the cysteine residue in P2 has been substituted for a proline. The peptide substrate DDIVPC-SMSYTW and the tracer biotin-DDIVPC-SMS[,25l- 15 YJTW are incubated with trie recombinant NS3 protease and the NS4A peptide cofactor KKGSWIVGRIILSGRK (molar ratio enzyme: cofactor 1:100) in the absence or presence of inhibitors. The separation of substrate from products is performed by adding avidirw:oated agarose J>eads to the assay mixture followed by filtration. The amount of SMS[125I-YJTW product found in the filtrate allows for the calculation of the 20 percentage of substrate conversion and of the percentage of inhibition. A. Reagents Tris and Tris-HCI (UltraPure)"were obtained from Gibco-BRL. Glycerol (UltraPure); MES and BSA were purchased from Sigma. TCEP was obtained from Pierce.DMSO from Aldrich and NaOH from Anachemia. 25 Assay buffer: 50 mM Tris HCI, pH 7.5, 30% (iv/v) glycerol, 1 mg/mL BSA, 1 mM TCEP (TCEP added just prior to use from a 1 M stock solution in water). Substrate: DDIVPCSMSYTW, 25 jiM final concentration (from a 2 mM stock solution in DMSO stored at -20°C to avoid oxidation). Tracer reduced mono lodinated substrate brcrtm DDIVPC SMSj125! YJTW (~1 nM 30 final concentration). HCV NS3 protease type lb, 25 nM final concentration (from a stock solution in 50 rnM sodium phosphate, pH 7.5, 10% glycerol, 300 mM NaCI, 5 mM DTT, 0.01% NP-40). NS4A Cofactor peptide: KKGSWIVGRDLSGRK, 2.5 nM final concentration (from a 2 mM stock solution in DMSO stored at -20°C). 5 B. Protocol The assay was performed in a 96-well polypropylene plate from Costar. Each well contained. • 20 JIL substrate/tracer in assay buffer; - 10 ^iL ± inhibitor in 20% DMSO/assay buffer; 10 " 10 nl_ NS3 protease 1 b/NS4 cofactor peptide (molar ratio 1.100). Blank (no inhibitor and no enzyme) and control (no inhibitor) were also prepared on the same assay plate. The enzymatic reaction was initiated by the addition of the enzyme/NS4A peptide solution and the assay mixture was incubated for 40 min at 23°C under gentle 15 agitation. Ten (10) yL of 0.5N NaOH were added and 10 jiL 1 M MES, pH 5.8 were added to quench the enzymatic reaction. Twenty (20) pL of avidin-coated agarose beads (purchased from Pierce) were added in a Millipore MADP N65 filtration plate. The quenched assay mixture was transferred to the filtration plate, and incubated for 60 min at 23°C under gentle 20 agitation. The plates were filtered using a Millipore Multiscreen Vacuum Manifold Filtration apparatus, and 40 ul. of the filtrate was transferred in an opaque 96-well plate containing 60 pL of scintillation fluid per well. The filtrates were counted on a Packard TopCount instrument using a 125l-liquid 25 protocol tor 1 minute. The % inhibition was calculated with the following equation: 100 - [(countSnh-countSbtanOAcountScB-countSwaniOx 100] A non-linear curve fit with the Hill model was applied to the inhibition-concentration data, and the 50% effective concentration (ICso) was calculated by the use of SAS 50 software (Statistical Software System: SAS Institute. Inc Cary, N.C ) EXAMPLE 32 Full-length NS3-NS4A heterodimer protein assay The NS2-NS5B-3" non coding region was cloned by RT-PCR into the pCR®3 vector (Invitrogen) using RNA extracted from the serum of an HCV genotype 1 b infected 5 individual (provided by Dr. Bernard Willems, Hopital St-Luc, Montreal, Quebec, Canada). The NS3-NS4A DNA region was then subcloned by PCR into the pFastBac7" HTa baculovirus expression vector (Gibco/BRL). The vector sequence includes a region encoding a 28-residue N-terminal sequence which contains a hexahistidme tag. The Bac-to-Bac™ baculovirus expression system (Gibco/BRL) 10 was used to produce the recombinant baculovirus. The full length mature NS3 and NS4A heterodimer protein (His-NS3-NS4AFL) was expressed by infecting 106 Sf21 cells/mL with the recombinant baculovirus at a multiplicity of infection of 0.1-0.2 at 27°C. The infected culture was harvested 48 to 64 h later by centrifugation at 4°C. The cell pellet was homogenized in 50mM NaP04l pH 7.5, 40% glycerol (wA/), 2mM 15 B-mercaptoethanol, in presence of a cocktail of protease inhibitors. His-NS3-NS4AFL was then extracted from the cell lysate with 1.5% NP-40,0.5% Triton X-100, 0.5M NaCI, and a DNase treatment. After ultracentrifugation, the soluble extract was diluted 4-fold and bound on a Pharmacia Hi-Trap Ni-chelating column. The His-NS3-NS4AFL was eluted in a >90% pure form (as judged by SDS-PAGE), using a 20 50 to 400 mM imidazole gradient. The His-NS3-NS4AFL was stored at -80°C in 50 mM sodium phosphate, pH 7.5,10% (w/v) glycerol, 0.5 M NaCI, 0.25 M imidazole, 0.1% NP-40. It was thawed on ice and diluted just prior to use. The protease activity of His-NS3-NS4AFL was assayed in 50 mM Tris-HCI, pH 8.0, 0.25 M sodium citrate, 0.01% (\NN) n-dodecyl-p-D-maltoside, 1 mM TCEP. Five (5) 25 pM of the internally quenched substrate anthranilyl-DDlVPAbu[C(0)-0]-AMY(3-N02)TW-OH in presence of various concentrations of inhibitor were incubated with 1.5 nM of His-NS3-NS4AFL for 45 min at 23°C. The final DMSO concentration did not exceed 5.25%. The reaction was terminated with the addition of 1M MES, pH 5.8. Fluorescence of the N-terminal product was monitored on a Perkin-Elmer LS- 30 50B fluorometer equipped with a 96-well plate reader (excitation wavelength: 325 nm; emission wavelength: 423 nm). A non-linear curve fit using the Hill model was then applied to the % inhibition-concentration data and 50% effective concentration (ICM) was calculated through the use of SAS (Statistical Software System. SAS Institute Inc., Cary, N.C.). EXAMPLE 33 NS3 Protease Cell-based assay This assay was done with Huh-7 cells, a human cell line derived from a hepatoma, 5 co-transfected with 2 DNA constructs: • one expressing a potyprotein comprising Yn& HCM noTi-slrutttneA proteins toseo to tTA in the following order: NS3-NS4A-NS4B-NS5A-ITA (called NS3); - the other expressing the reporter protein, secreted alkaline phosphatase, under the control of tTA (called SEAP). 10 The polyprotein must be cleaved by the NS3 protease for the mature proteins to be released. Upon release of the mature proteins, it is believed that the viral proteins will form a complex at the merribrane of the endoplasmic reticulum while tTA will migrate to the nucleus and transactivate the SEAP gene. Therefore, reduction of NS3 proteolytic activity should lead to reduction of mature tTA levels and 15 concomitant decrease in SEAP activity. To control for other effects of the compounds, a parallel transfectjon was done where a construct expressing tTA alone (called tTA) was co-trahsfected with the SEAP construct such that SEAP activity is independent of NS3 proteolytic activity. Protocol of the assay: Huh-7 cells, grown in CHO-SFMII + 10% FCS (fetal caff 20 serum), were co-transfected with either NS3 and SEAP or tTA and SEAP; using the FuGene protocol (Boehringer Mannheim). After 5 h at 37°, the cells were washed, trypsinized and plated (at 80 000 cells/well) in 96-well plates containirig?a^rahge of concentrations of the compounds to be tested. After a 24-h incubation period, an aliquot of the medium was drawn and the SEAP activity in this aliquot was measured 25 with the Phospha-Light kit (Tropix). Analysis of the percent inhibition of SEAP activity with respect to compound concentration was performed with the SAS software to obtain the ECSJ. The toxicity of the compound (TC50) was then assessed using the MTT assay as tattoos. 30 20jiL of a MTT solution (5mg/ml medium) was added per well and incubated at 37° for 4 hrs; the medium was removed and 50 l of 0.01 N HCI + 10% Triton X-100 was added; after shaking at RT for at least 1 hr, the OD of each well was read at 595 nm wavelength. The TC50 was calculated in the same way as the EC50. 5 EXAMPLE 34 Specificity assays 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 one cysteine protease: human liver cathepsin B. In 10 all cases a 96-well plate format protocol using a colorimetric p-nitroaniline (pNA) substrate specific for each enzyme was used. Each assay included a 1 h enzyme-inhibitor pre-incubation at 30°C followed by addition of substrate and hydrolysis to =30% conversion as measured on a UV Thermomax® microplate reader. Substrate concentrations were kept as low as possible compared to KM to reduce substrate 15 competition. Compound concentrations varied from 300 to 0.06 jiM depending on their potency. The final conditions for each assay were as follows: 50 mM Tris-HCI pH 8,0.5 M Na2S04> 50 mM NaCI, 0.1 mM EDTA, 3% DMSO, 0.01 % Tween-20 with; [100 |iM Succ-AAPF-pNA and 250 pM a-chymotrypsin], [133 uM Succ-AAA-pNA and 20 8 nM porcine elastase], [133 jiM Succ-AAV-pNA and 8 nM leukocyte elastase]; or [100 mM NaHPCv, pH 6, 0.1 mM EDTA, 3% DMSO, 1mM TCEP„0.01%irween-20, 30 pM Z-FR-pNA and 5 nM cathepsin B (the stock enzyme was activated in buffer containing 20 mM TCEP before use)]. A representative example is summarized below for porcine pancreatic elastase: 25 In a polystyrene flat-bottom 96-well plate were added using a Biomek liquid handler (Beckman): ■ 40 pL of assay buffer (50 mM Tris-HCI pH 8, 50 mM NaCI, 0.1 mM EDTA); ■ 20 pi of enzyme solution (50 mM Tns-HCI pH 8, 50 mM NaCI, 0.1 mM EDTA, 0.02% Tween-20, 40 nM porcine pancreatic elastase); and 30 ■ 20 ML ol inmbnor solution (50 mM Tns-HCI, pH 8. 50 mM NaCI, 0.1 mM EDTA, -If" TABLES OF COMPOUNDS Compounds of the invention were assayed either in one or both of the assays of Examples 31 and 32 and were found to be active with IC50 below 50pM (A); below 5 5nM (B) or below O.5µM (C). Activity in cells and specificity: Representative compounds of the invention were also tested in the surrogate cell-based assay of Example 33, and in one or several assays of Example 34. For 10 example, compound 233 from Table 2 was found to have an IC50 of 1 nM in the assay of Example 32. The EC5o as determined by the assay of Example 33 is 5.4 p.M whereas other effects (tTA) were not detectable at concentrations up to 120|iM. Compound 233 has also been tested in the MTT assay and its TC50 was determined to be greater than 120|iM, indicating that this compound is non toxic at its effective 15 concentration. In the specificity assays of Example 34, the same compound was found to have the following activity: HLE >75pM; PPE >75p.M; a-Chym. >75 uM; Cat. B >75nM. These results indicate that this family of compounds is highly specific for the NS3 protease. 20 The following tables list representative of the invention, he following abbreviations are used: MS: Mass spectrometric data; Ac: acetyl; Bn: benzyl; Chg: cydohexylglycine {2-amino-2-cyclohexyl-acetic acid); Dnl: Dansyl; O-Bn: benzyloxy; Pip: pipecolic acid; Tbg: fert-butylglycine. -17- ^77 -"7 8 - ^79- -81- WE CLAIM: 1. A compound of formula (I), including racemates, diastereoisomers and optical isomers. PG P5 P4 P3 P2 P1 B wherein a is 0 or 1; b is 0 or 1; Y is H or C,^ alkyi; B is H, an acyl derivative of formula FVC(O)- or a sulfonyi of formula R7-SO? wherein R2 is (i) C,.io alkyl optionally substituted with carboxyl, C1-5 alkanoyioxy or Ci.6 alkoxy; (ii) C3.7 cycloaikyl optionally substituted with carboxyl, (C1-5 alkoxy)carbonyf or phenylmethoxycarbony); (iii) C6 or C10 aryl or C7.,6 aralkyl optionally substituted with d_6 aikyl, hydroxy, or amino optionally substituted with C1-6aikyl; or (iv) Het optionally substituted with Chalky!, hydroxy, amino optionally substituted with C1-5alkyl, or amido optionally substituted with C,^ alkyi; R6, when present, is C1-6 alkyl substituted with carboxyl; Rs, when present, is C,1-6alkyl optionally substituted with carboxyl; R4 is C1-10 alkyl, C3.7 cycloaikyl or C4.10 (alkylcycloalkyl); R3 »s C10 alkyl, C3.7 cycloaikyl or C4.,0 (alkylcycloalkyl); R? is CH2-ROTt NH-RM, OR20 or S-R20, wherein Rzo is a saturated or unsaturated C3.7 cycloaikyl or Quo (alkyl cycloaikyl) being optionally mono-, di- or tri-substituted with "211 87 or Ra> is a C6 or C10 aryi or C7-16aralkyl optionally mono-, di- or tri-substituted with or B20 is Het or (lower alkyl)-Het optionally mono-, di- or tri-subsfituted with R^, wherein each R21 is independently C16 alkyl; C^alkoxy; amino optionally mono-or di-substituted with C1-5alkyl; sultonyl; NOa; OH; SH; halo; haloalkyl; amido optionally mono-substituted with C,1-5 alkyl, C6 or C10 aryl, C1-5aralkyl, Het or (lower a!kyl)-Het, carboxyl; carboxy(lower alky!); C6 or C!0 aryl. C7.16 aralkyl or Het, said aryl, aralkyl or Het being optionally substituted with R22; wherein Rja is C,.6alkyl; C1-6^alkoxy; amino optionally mono- or di-substituted with C1-6 alkyl; sultonyl; N02; OH; SH; halo; haloalkyl; carboxyi; amide or {lower a!kyi)amide; R, is CM. alkyl or C2^alkenyl optionally substituted with halogen; and W is hydroxy or a N-substituted amino; or a pharmaceutical^ acceptable salt or ester thereof. 2. The compound as claimed in claim 1, wherein, when B is H or an acyl derivative of formula R7C(0)-, wherein R7 is C1-6 alkyl; d-e alkoxy; C3.7 cycloalkyi optionally substituted with hydroxy; amido optionally substituted with C^alkyl or Het; C6 or C10 aryl, C7.16 aralkyl or Het all optionally substituted with C^ alkyl or hydroxy. 3. The compound as claimed in claim 2, wherein R7 is C^ alkyl or Het. The compound as claimed in claim 2, wherein B is selected from the group 88 4. The compound as claimed in claim 3, wherein said Het is selected from the group consisting of: consisting of: H. acetyl; ° ; ° ; or ° 6. The compound as claimed in claim 5, wherein B is acetyl. 7. The compound as claimed in claim 1, wherein B is R7-S02 and R7 is C6 or C10 aryl, a C7.16 aralkyl or Het, all optionally substituted with C^ alkyl. 8. The compound as claimed in claim 1, wherein R6 when present, is the side chain of AsporGlu. 9. The compound as claimed in claim 8, wherein R6l when present, is the side chain of Asp. 10. The compound as claimed in claim 1, wherein a is 0 and then R6 is absent. 11. The compound as claimed in claim 1, wherein R5, 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. 12. The compound as claimed in claim 11, wherein R5, when present, is the side chain of D-Asp, D-Val, or D-Glu. 13. The compound as claimed in claim 12, wherein R5, when present, is the side chain of D-Glu. 14. The compound as claimed in claim 1, wherein a is 0 and b is 0, and then both R6 and R5 are absent. 15. The compound as claimed in claim 1, wherein R4 is the side chain of an amino acid selected from the group consisting of: Val, cyclohexylglycine (Chg), Tbg, lie or Leu. 16. The compound as claimed in claim 15, wherein R4 is the side chain of Chg or lie. 17. The compound as claimed in claim 16, wherein R4 is the side chain of Chg. wherein R2IA is amido optionally substituted with C1-6 alkyl, C6 or C10 aryl, C7-16 aralkyi or Het; C6 or C10 aryl or Het optionally substituted with R22, and R22 is amino, di(lower alkyl)amino; or (lower alkyl)amide; and R2IB is C1-6 alkyl; C^alkoxy; amino; di(lower alkyl)amino; (lower alkyl)amide; N02; OH; halo; trifluoromethyl; or carboxyl. 28. The compound as claimed in claim 27, wherein R21Ais C6 or C10 aryl or Het, all optionally substituted with R22 and R22 is amino, dimethylamino, or acetamido. 29. The compound as claimed in claim 27, wherein R2IB is C^ alkoxy or di(lower alkyl)amino. 30. The compound as claimed in claim 29, wherein R2IB is methoxy. 31. The compound as claimed in claim 1, wherein the asymmetric carbon at position 1 has the R configuration, represented by the following absolute configurations: wherein R^ is as defined in claim 1. 32. The compound as claimed in claim 31, wherein the R1 substituent on P1 is oriented syn to the carbonyl group as represented by the following absolute configuration: wherein Ri is methyl, ethyl, propyl, vinyl, all of which optionally substituted with halo. 33. The compound as claimed in claim 32, wherein R1 is ethyl, vinyl or bromovinyl. 34. The compound as claimed in claim 33, wherein R1 is vinyl. 35. The compound as claimed in claim 1, wherein W is hydroxy or a pharmaceutical^ acceptable salt or ester thereof; or (lower alkyl)amino, di(lower alkyl)amino or amino aralkyl. 36. The compound as claimed in claim 33, wherein W is hydroxy, or N(R13a)R13b wherein R13a and R13b are independently H, aryl or 1-6 alkyl optionally substituted with hydroxy or phenyl; or a pharmaceutically acceptable salt thereof. 37. The compound as claimed in claim 36, wherein W is -OH, -NH-benzyl or -NH-CH(Me)Ph. 38. The compound as claimed in claim 37, wherein W is -OH or -NH-(S)CH(Me)-phenyl. 39. The compound as claimed in claim 38, wherein when W is an ester, said ester is selected from the group consisting of: C^ alkoxy, phenoxy, or aryl(Ci^ alkoxy). 40. The compound as claimed in claim 39, wherein said ester is methoxy, ethoxy, phenoxy, benzyloxy, or PhCH(Me)-0-. 41. The compound of formula I as claimed in claim 1, wherein B is H, lower alkyl-C(O)- or Het-C(O)-; 92 R8, when present, is the side chain of Asp or GIu; R5, when present, is the side chain of D- or L-: Asp, GIu, Val, Y is H or methyl; R4 is the side chain of Val, Chg, Tbg, He or Leu; R3 is hydrogen or the side chain of He, Chg, Val, or Tbg; R2 is 1-naphthylmethoxy, 2-naphthylmethoxy, O-Bn, or Tbg; NHCOCH3, halo, NHj. N02> alkoxy or Het wherein R, is ethyl, vinyl or bromovinyl; and W is hydroxy or N(R13a)R13„ wherein R13a and RI3D are independently H, aryl or C,^ alkyl optionally substituted with hydroxy or phenyl; or a pharmaceuticaHy acceptable salt or ester thereof. 93 42. The compound of formula I as claimed in claim 1, wherein B is H, acetyl or Het-C(O)-; R6, when present, is the side chain of Asp; R5, when present, is the side chain of D-Asp, D-Glu or D-Val; Y is H; R4 is the side chain of Chg or lie; R3 is the side chain of Val, Chg orTbg; R2 is 1-naphthylmethoxy, benzyloxy, 4-quinolinoxy, or OMe, halo, NH- or NO, P1 is a cyciopropyl ring system of formula wherein R, is Et or CH=CH2 or CH=CHBr, and W is hydroxy or NH-(S)-CHMePh, or a pharmaceutical^ acceptable salt thereof. 43. The compound of formula as claimed in claim 1, wherein B is acetyl; R6, when present, is the side chain of Asp; R5, when present, is the side chain of D-Glu; Y is H; R4 is the side chain of Chg; R3 is the side chain of Val or Tbg; R2 is: OMe P1is: ;and W is hydroxy, or a pharmaceutical^ acceptable salt or ester thereof. 95 44. The compound as claimed in claim 41, represented by formula: 96 99 49. A hexapeptide of formula I as claimed in claim 44, selected from the group consisting of compound*: 108; 116; 117; and 120. 50. A hexapeptide of formula I as claimed in claim 45, selected from the group consisting of compound #:212; 222; 236; and 238. 51. A hexapeptide of formula I as claimed in claim 46, selected from the group consisting of compound #:301 and 302. 52. A tetrapeptide of formula I as claimed in claim 44, selected from the group consisting of compound #:122; and 123. 53. A tetrapeptide of formula I as claimed in claim 45, selected from the group consisting of compound #: 202; 203; 205; 206; 207; 208; 209; 210; 211; 214; 215; 216; 218; 219; 220; 221; 223; 224; 225; 226; 228; 229; 230; 231; 232; 233; 234; 235. 54. A tetrapeptide of formula I as claimed in claim 47, selected from the group consisting of compound #:401. 55. A tetrapeptide of formula I as claimed in claim 48, selected from the group consisting of compound #:501; 502; 503; 504; 505; 506; 507; 508; 509; 510; and 511. 56. A pharmaceutical composition comprising between 5 and 95% of an anti-hepatitis C viraliy effective amount of a compound of formula I as claimed in claim 1, or a therapeutically acceptable salt or ester thereof, in admixture with a pharmaceutically acceptable carrier medium or auxiliary agent. 57. The pharmaceutical composition as claimed in claim 56, comprising a second antiviral agent. 58. The pharmaceutical composition as claimed in claim 57, wherein said second antiviral agent is ribavirin or amantadine. 59. The pharmaceutical composition as claimed in claim 56, comprising other inhibitors of HCV protease. 60. The pharmaceutical composition as claimed in claim 56, comprising an inhibitor of other targets in the HCV life cycle, selected from: helicase, polymerase, metalloprotease of IRES. 61. A process for the preparation of a peptide analog of formula (I) as claimed in claim 1, wherein P1 is a substituted aminocyclopropyl carboxylic acid residue, comprising the step of: • coupling ^ peptide selected from the group consisting of: APG-P6-P5-P4-P3-P2; AP6-P5-P4-P3-P2; APG-P4-P3-P2; APG-P3-P2; and APG-P2; • with a P1 intermediate of formula: wherein R1, is Cs alkyl or C2-6s alkenyi optionally substituted with halogen, CPG is a carboxyl protecting group and P6 to P2 are as defined in claim 1. 62. A process for the preparation of a peptide analog of formula (I) as claimed in claim 1, wherein P1 is a substituted aminocyclopropyl carboxylic acid residue, comprising the step of: » coupling a peptide selected from the group consisting of: APGLP6-P5-P4-P3-P2; APG-P5-P4-P3-P2; APG-P4-P3-P2; APG-P3-P2; and APG-P2; wherein R1 is ethyl, vinyl or bromovinyi, CPG is a carboxyl protecting and P6 to P2 are as defined in claim 1. 105 » with a P1 intermediate of formula: 63. A process for the preparation of a peptide analog of formula (I) as claimed in claim 1, wherein P1 is a substituted aminocyciopropyi carboxylic acid residue, comprising the step of: - coupling a peptide selected from the group consisting of: APG-P6-P5-P4-P3-P2; APG^5-P4-P3-P2; APG-P4-P3ip2; APG-P3-P2; and APG-I^; • with a P1 intermediate of formula: wherein R, is CPG is a carboxyl protecting group and PB to P2 are as defined in ctewnl. "■"■".. """* " 64. The process as claimed in claim 61, 62 or 63 wherein said carboxyl protecting group (CPG) is selected from the group consisting of: alkyl esters, aralkyl esters, and esters being cleavable by mild base treatement or mild reductive means. Dated this 7th day of February, 2001. OF REMFRY & SAGAR ATTORNEY FOR THE APPLICANTS

Documents:

IN-PCT-2001-00128-MUM-CANCELLED PAGES(17-8-2007).pdf

IN-PCT-2001-00128-MUM-CLAIMS(7-2-2001).pdf

in-pct-2001-00128-mum-claims(granted)-(26-11-2007).pdf

IN-PCT-2001-00128-MUM-CORRESPONDENCE(13-11-2007).pdf

IN-PCT-2001-00128-MUM-CORRESPONDENCE(IPO)-(21-1-2008).pdf

IN-PCT-2001-00128-MUM-DESCRIPTION(COMPLETE)-(7-2-2001).pdf

in-pct-2001-00128-mum-description(granted)-(26-11-2007).pdf

IN-PCT-2001-00128-MUM-FORM 1(17-8-2007).pdf

IN-PCT-2001-00128-MUM-FORM 1(3-4-2001).pdf

IN-PCT-2001-00128-MUM-FORM 1(7-2-2001).pdf

IN-PCT-2001-00128-MUM-FORM 13(17-8-2007).pdf

IN-PCT-2001-00128-MUM-FORM 18(28-12-2005).pdf

IN-PCT-2001-00128-MUM-FORM 2(COMPLETE)-(7-2-2001).pdf

in-pct-2001-00128-mum-form 2(granted)-(26-11-2007).pdf

IN-PCT-2001-00128-MUM-FORM 2(TITLE PAGE)-(7-2-2001).pdf

in-pct-2001-00128-mum-form 2(title page)-(granted)-(26-11-2007).pdf

IN-PCT-2001-00128-MUM-FORM 3(17-8-2007).pdf

IN-PCT-2001-00128-MUM-FORM 3(7-2-2001).pdf

IN-PCT-2001-00128-MUM-FORM 5(7-2-2001).pdf

IN-PCT-2001-00128-MUM-PETITION UNDER RULE 137(17-8-2007).pdf

IN-PCT-2001-00128-MUM-POWER OF AUTHORITY(17-8-2007).pdf

IN-PCT-2001-00128-MUM-POWER OF AUTHORITY(9-5-2001).pdf

IN-PCT-2001-00128-MUM-SPECIFICATION(AMENDED)-(17-8-2007).pdf

IN-PCT-2001-00128-MUM-WO INTERNATIONAL PUBLICATION REPORT(7-2-2001).pdf