MXPA06008527A - Hcv ns-3 serine protease inhibitors - Google Patents

Abstract

Compounds of the formula (F) where the variables are as defined in the specification inhibit the NS3 protease of flavivirus sych as hepatitis C virus (HCV). The compounds comprise a novel linkage between a heterocyclic P2 unit and those portions of the inhibitor more distal to the nominal cleavage site of the native substrate, which linkage reverses the orientation of peptidic bonds on the distal side relative to those proximal to the cleavage site.

Description

HCV SERINE PROTEASA NS-3 INHIBITORS TECHNICAL FIELD This invention relates to new inhibitors of the NS3 serine protease of the flavivirus HCV (or HVC), and to methods for use in the treatment or prophylaxis of HCV.

PREVIOUS TECHNIQUE The NS3 serine protease of HCV is a multifunctional protein that contains a serine protease domain and a RNA helicase domain. The protease cofactor NS4A, which is a relatively small protein, is absolutely necessary to enhance the activity of the serine protease. Serine protease NS3 is essential in the life cycle of the virus. From the analysis of the substrate binding site, as revealed by the crystal structure of X-rays, it has been shown that the NS3 protease binding site is remarkably shallow and is exposed to solvents, which makes the design of a small inhibitory molecule is a challenge. It is believed that there are two protease inhibitors HCV have entered the stage of clinical trials. These are BI LN-2061 from Boehringer Ingelheim, described in WO 0059929, and. VX-950 from Vértex, described in WO 0387092. A number of similar HCV protease inhibitor peptidomimetics have also been proposed in the academic and patent literature. The presence of a derivative of L- Proline in the P2 position of the inhibitor is common for the vast majority of the peptidomimetics of the prior art, allowing interaction with the S2 subsite the protease enzyme HCV. In the case of BILN-2061, L-proline is 4-substituted with a quinoline ether, while VX-950 has a carbocyclic ring fused to the L-proline ring. Most peptidomimetics additionally comprise peptide derivatives of L-amino acids joined at the P3 position, and many of the proposed inhibitors also include additional L-amino acid derivatives that extend within. P4, P5 and P6. It is evident that sustained administration of BI LN-2061 or VX-950 selects mutant HCVs that are resistant to the respective drug, termed drug escape mutants. These drug escape mutants have characteristic mutations in the HCV protease genome, notably D 168V, D 168Y and / or A165S. Therefore, treatment paradigms for HCV will be similar to treatments for HIV, where drug escape mutants also arise with ease. Therefore, additional drugs, with different resistance patterns, will be consistently needed to provide treatment options to patients whose treatment has failed, and combination therapies with multiple drugs are likely to be common in the future, even for treatments From first line. Experience with anti-HIV drugs, and HIV protease inhibitors in particular, has emphasized that suboptimal pharmacokinetics and complex dosage regimes quickly result in unavoidable treatment failures. This in turn means that the 24-hour concentration (minimum plasma concentration) for the respective drugs in an HIV treatment regimen often falls below the IC90 or ED90 threshold for most of the day. It is considered to be a level for at least 24 hours. to IC50, and, in realistic terms, equal to IC90 or ED90, is essential to reduce the rate of development of drug escape mutants and achieve the pharmacokinetics and drug metabolism necessary to provide the desired levels, which it is another challenge for drug design. The strongly peptidomimetic nature of the HCV protease inhibitors of the prior art, with several peptide bonds in native configurations, results in pharmacokinetic impediments to achieve effective dosage regimens.

BRIEF DESCRIPTION OF THE INVENTION According to a first aspect of the invention, compounds of the formula I are provided: R8 I w wherein A is C (= O) OR \ C (= O) NHSO2R2, C (= O) NHR3, or CR4R4 'where; R1 is hydrogen, C ^ Cealkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl; R2 is C? -Calkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl; R3 is C-t-C-alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl, -OC-t-C-alkyl, -OC0-C3alkylcarbocyclyl, -OC0-C3alkylheterocyclyl; R4 is halo, amino, or OH; or R4 and R4 'together are = O; R4 'is C ^ Cealkyl, C0-C3alkylcarbocyclyl, C0-C3alkyl heterocyclic; wherein R2, R3, and R4 'are each optionally substituted with 1 to 3 substituents selected independently from the group comprising halo, oxo, nitrile, azido, nitro, d-Cealkyl, C0-C3alkylcarbocyclyl, C0-C3alkheheterocyclyl , NH2CO-, Y-NRaRb, YO-Rb, YC (= O) Rb, Y- (C = O) NRaRb, Y-NRaC (= O) Rb, Y-NHSOpRb, YS (= O) pRb, YS ( = O) pNRaRb, YC (= O) Orb and Y-NRaC (= O) ORb; And it is independently a Ci-Csalkylene linkage; Ra is independently H or d-Csalkyl; Rb is independently H ', CT-Cealkyl, C0-C3alkylcarbocyclyl or C0-C3alkylheterocyclyl; p is independently 1 or 2; M is CR7R7 'or NRu; R7 is C ^ Cealkyl, C0-C3alkylC3-C7cycloalkyl, or C2-C6alkenyl, any of which is optionally substituted with 1 -3 halo atoms, or an amino group, -SH or C0-C3alkylcycloalkyl; or R7 is J; R7 'is H or taken together with R7 forms a C3-C6 cycloalkyl ring optionally substituted with R7 where; R7a is CT-Cealkyl, C3-C5cycloalkyl, C2-C6alkenyl any of which may be optionally substituted with halo; or R7 a can be J; q is between 0 and 3 and k is between 0 and 3; where q + k > 1; W is -CH2-, -O-, -OC (= O) H-, -OC (= O) -, -S-, -NH-, -NRa, -NHSO2-, -NHC (= O) N H - or -NHC (= O) -, -NHC (= S) NH- or a bond; R8 is a ring system containing 1 or 2 saturated, partially unsaturated or unsaturated rings each of which has between 4 and 7 ring atoms and each of which has between 0 and 4 heteroatoms independently selected from S, O and N, where the ring system is optionally separated from W by an Ci-Ca alkyl group; or R8 is C -? - C6 alkyl; any of said groups R8 can be mono, di or trisubstituted optionally with R9, where R9 is independently selected from the group comprising halo, oxo, nitrile, azido, nitro, C? -C6alkyl, C0- C3alkylcarbocyclyl, C0- C3alkylheterocyclyl, NH2C (= O) -, Y-NRaRb, YO-Rb, YC (= O) Rb, Y- (C = O) NRaRb, Y-NRaC (= O) Rb, Y-NHSOpRb, Y- S (= O) pRb, Y-S (= O) pNRaRb, Y-C (= O) ORb and Y-NRaC (= O) ORb; wherein said carbocyclyl or heterocyclyl portion is optionally substituted with R10; wherein R10 is C-C-alkyl, C3-C7-cycloalkyl, C-Cdalkoxy, amino, sulfonyl, (C ^ Cs alkyl) sulfonyl, NO2, OH, SH, halo, haloalkyl, carboxyl, amido; E is -C (= O) -, -C (= S) -, -S (= O) 2-, -S (= O) -, -C (= N-Rf) -; Rf is H, -CN, -C (= O) NRaRb; -C (= O) C1-C3alkyl; X is -NRx- where Rx is H, C? -C5aIlkyl or J; or in the case where E is -C (= O), X can also be -O- or -NRjNRj-; where one of Rj is H and the other is H, C ^ Cs alkyl or J; R1 1 is H, C? -C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl, any of which may be substituted with halo, oxo, nitrile, azido, nitro, CT-C-akyl, C0-C3alkylcarbocyclyl, C0-C3alkheheterocyclyl, NH2CO- , Y-NRaRb, YO-Rb, YC (= O) Rb, Y- (C = O) NRaRb, Y-NRaC (= O) Rb, Y-NHSOpRb, YS (= O) pRb, YS (= O) pNRaRb, YC (= O) ORb, Y-NRaC (= O) ORb; or R1 1 is J; J, if present, is a simple saturated or partially unsaturated alkylene chain of between 3 and 10 members extending from R7 / R7 'cycloalkyl or from the carbon atom to which R7 is attached to one of Rj, Rx, Ry or R11 to form a macrocycle, wherein the chain is optionally interrupted by between one and three heteroatoms independently selected from: -O-, -S- or -NR12-, and wherein from 0 to 3 carbon atoms in the chain is optionally substituted with R14; where; R12 is H, d-Cealkyl, C3-C6cycloalkyl, or C (= O) R13; R 13 is C 1 -C 6 alkyl, C 0 -C 3 alkylcarbocyclyl, C 0 -C 3 alkylheterocyclyl; R14 is independently selected from the group comprising H, d-C6alkyl, C? -C6haloalkyl, d-Cealkoxy, hydroxy, halo, amino, oxo, thio and d-Cetioalkyl; Ru is independently H or C? -C3alkyl; m is 0 or 1; n is 0 or 1; U is = O or is absent; R15 is H, Ci-Cealkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl, any of which may be substituted with halo, oxo, nitrile, azido, nitro, C- | -C6 alkyl, C0-C3alkheheterocyclyl, Co-C3alkyl; lcarbocyclic, NH2CO-, Y-NRaRb, YO-Rb, YC (= O) Rb, Y- (C = O) NRaRb, Y-NRaC (= O) Rb, Y-NHS (= O) pRb, YS (= O) pRb, YS (= O) pNRaRb, YC (= O) ORb, Y-NRaC (= O) ORb; G is -O-, -NRy-, -NRjNRj-: where one Rj is H and the other is H, d-C5 alkyl or J; Ry is H, dC3 alkyl; or Ry is J; R16 is H; or d-C6alkyl, C0-C3alkylcarbocyclic, C0-C3alkylheterocyclyl, any of which may be substituted with halo, oxo, nitrile, azido, nitro, C? -C6alkyl, C0- C3alkylcarbocyclyl, C0-C3alkylheterocyclyl, NH2CO-, Y-NRaRb, YO-Rb, YC (= O) Rb, Y- (C = O) NRaRb, Y-NRaC (= O) Rb, Y-NHSOpRb, Y- S (= O) pRb, Y-S (= O) pNRaRb, Y-C (= O) ORb, Y-NRaC (= O) ORb; with the proviso that when m = n = 0 and G is O then R16 is not tert-butyl or phenyl; or its salt or prodrug acceptable for pharmaceutical use. Without wishing to support a particular theory, the description of tentative binding modes for specific variables and the notions of the concepts of P1, P2, P3 and P4 are provided only for reasons of convenience, where the terms have substantially conventional meanings, as indicated in Schechter & Berger, (1976) Biochem Biophys Res Comm 27 157-162, and denote those portions of the inhibitor that are thought to complete the subsites S 1, S2, S3 and S4 of the enzyme, respectively, where S1 is adjacent to the site of cut and S4 is far from the cutting site. Regardless of the mode of attachment, the components defined by Formula I are within the scope of the invention. For example, it is expected that the coating group R16-G may interact with the subsites S3 and S4, especially when my / on are 0. Various embodiments of the present invention may be represented conceptually as R16-G-P4-P3-link -P2-P1, where P3 and / or P4 may be absent, and P1, P3 and P4 each represents a building block constituted by a derivative of a natural or unnatural amino acid, P2 is a heterocyclic residue and G -R16 is a protective group. The ensile is a carbonyl or other function as defined for E. The construction groups P1 and P2 and the Building blocks P3 and P4 are therefore typically joined together by amide bonds while the building blocks P2 and P3 are joined by means of the connection described above. The amide bonds in this manner are typically inverted with each other on each side of the link in the compounds of the invention. Other aspects of the invention include a pharmaceutical composition comprising a compound of the invention as defined, and a carrier or diluent thereof acceptable for pharmaceutical use. The compounds and compositions of the invention can be used in methods for the medical treatment or prophylaxis of HCV infections in humans. Therefore, another aspect of the invention is the use of a compound as previously described in a therapy, such as in the manufacture of a medicament for the prophylaxis or treatment of flavivirus infections in humans or animals. Examples of flaviviruses include BVDV, dengue and especially HCV. The compounds of the invention have a non-peptide bond at the junction between the building blocks P2 and P3, resulting in the reversal of the orientation of the P3 and P4 residues relative to their native substrate. This non-peptide linkage is also typically longer than the corresponding peptide would have been and means that the P3 and / or P4 groups (including the R16 protector insofar as it interacts with S3 or S4) move outward relative to the native peptide substrate. It would be expected that reversal and displacement in this way would favor unnatural D-stereochemistries for groups that complete the cavities (eg, side chains) of P3 and / or P4 and / or R6. Furthermore, these compounds typically exhibit high activity and they are within the scope of the invention. However, it has surprisingly been found that even the compounds of the invention containing side chains of L-amino acids such as P3 and / or P4 have good activity, regardless of whether the entity of the respective side chain is to approach cavity S3 or not. S4 from a different angle, relative to the native peptide substrate. Therefore, the L-stereochemistry in R1 1 and / or R15, and / or the corresponding configuration in R16 to mimic L-stereochemistry represents a favorable aspect of the invention. The different approach angle for accessing cavities S3 and / or S4 also has implications on the ability of the compounds of the invention to avoid the resistance patterns presented by prior art HCV protease inhibitors., which present a conventional peptide skeleton of natural or non-natural L-amino acid residues. Like the reverse transcriptase of VI H, which is remarkable for quickly generating mutants escaping drugs under the pressure of selection of an antiviral therapy, RNA RNA polymerase NS5A dependent on HCV RNA has a very limited reading correction ability . This in turn means that HCV polymerase is very susceptible to errors, and resistance patterns are likely to emerge characteristic when administering agents against the HCV virus for prolonged periods. Even before its appearance, it is evident that BILN 2061, with a substantially peptidic (ie macrocyclic) backbone and the Vertex NS3 protease inhibitor V3-950, with a linear peptide backbone P3 and P4, will give rise to resistance mutations. characteristics at positions 155, 156 or 168 of the NS3 protease (Lin et al J Biol Chem 2004 279 (17): 17808-17). A preferred group of compounds of the invention comprises those in which P1 represents a hydrazine derivative, ie M is NRu where Ru is typically H or d-C3alkyl. Compounds wherein M is CR7R7 constitute a further preferred aspect of the invention. Some preferred embodiments wherein M is CR7R7 'in the formulas I include the formulas IA: R8 I w Some preferred values for q and k in Formula l include 2: 1, 2: 2, 2: 3, 3: 2.3: 3, more preferably 1: 2 and 1: 0; and more preferably 1: 1, in which case the preferred compounds have the partial structure: where e is 1 or 2. It is currently preferred that E is -C (= O) - or -C = N-Rf, for example where Rf is -CN or -C (= O) NH2. The compounds of the invention may comprise a function P3 and P4, ie m and n are each 1. Preferred embodiments within Formula I incl.

Alternative modes include the structures corresponding to Ida, Idb, Idc and Idd where M is NRu. Alternative configurations of the compounds of the invention comprise a P3 function, but not a P4, that is, m is 1 and n is zero. Some preferred embodiments within Formula I include the read-read formulas below: R8 R8 i l w W read | eb R8 i W W R8 i W read Alternative modes include the structures corresponding to read, read, read, led and read where M is NRu. Still other alternative configurations of the compounds of the invention include those where m and n are zero and therefore groups R16-G is contiguous with P2, but as mentioned, the protecting group R16-G may interact favorably with S3 and / or S4.

Preferred embodiments within the Formula include the Ifa-Ife formulas below: R8 R8 R8 I I W W W Ifa Ifb Ifc R8 R8 I l W W Ifd Ife R1 6 in Figure Ifb and in general is typically H, d-C3alkyl, C5-C6alkyl, C0-C3alkylheterocyclyl, C-iC3alkylcarbocyclyl or C3-C7cycloalkyl, any of which may be optionally substituted, as described. For example, R16 can be substituted phenyl as described. Alternative modes include the structures corresponding to Ifa, Ifb, Ifc, Ife, and Ife where M is NRu. The compounds of the invention may comprise linear molecules, as described. Alternatively, in embodiments wherein R7 and R7 'together define a spiro cycloalkyl group, such as spiro-cyclopropyl, the compounds of the invention can be configured as macrocycles, wherein a binder group J extends between one of Rj, Rx, Ry or R11 of Formula l. Alternatively the macrocycle J may extend from the carbon adjacent to R7 to one of Rj, Rx, Ry or R1 1. Preferred embodiments of such macrocyclic structures within Formula I where m is 0 and n is 1 include those of the Iga-lgd formulas below: R8 R8 W W R8 R8 W W The corresponding structures in which the J chain joins the carbon adjacent to R7 are also preferred. Some additional preferred embodiments of such macrocyclic structures within Formula I where m is 0 and n is 1 include those of the Ige-lgf Formulas below: The corresponding structures in which the J chain joins the carbon adjacent to R7 are also preferred. The preferred macrocyclic structures within the Formula I, which comprises a function P3 and a P4, that is to say where m and n are each 1, include those of the formulas Iha-lhd below.

R8 R8 i W W The corresponding structures in which the J chain joins the carbon adjacent to R7 are also preferred. Preferred macrocyclic structures within Formula I, wherein both functions P3 and P4 are absent, ie, wherein m and n are each 0, include those of the formulas Ihe-lhh below, especially 1 he and 1 hf.

R8 R8 i i W W R8 R8 i i W W The corresponding structures wherein the J chain joins the carbon adjacent to R7 are also preferred, especially formula Ihe and 1 hf: In general, in optionally macrocyclic structures such as those illustrated, the binder J is a saturated alkylene chain of between 3 and 10 atoms, preferably between 5 and 8 atoms, such as 6 or 7 atoms, or a partially unsaturated alkylene chain, ie an alkylene chain with between 1 and 3 unsaturated bonds between adjacent carbons, typically unsaturation. The length of the chain will of course depend on whether J extends from Rd, Rj, Rx, Ry, R11 or the carbon adjacent to R7. Suitable chains are described in detail in WO 00/59929. Typically J will be dimensioned so as to provide a macrocycle of 13 to 16 atoms in the ring (including the atoms in the groups P1, P2 and if present, P3 that contribute to the ring). Conveniently J is sized to give a macrocycle of 14 or 1 5 atoms in the ring. Conveniently, the J chain contains one or two heteroatoms selected from: O, S, NH, NC? -C6 alkyl or N-C (= O) C1-C6alkyl. More preferably, the J chain optionally contains a heteroatom selected from: NH, or N-C (= O) d-C6alkyl, more preferably N (Ac). More preferably, the chain containing a nitrogen atom is saturated. In an alternative embodiment, J contains a heteroatom selected from O or S. The chain may be substituted with R 14, such as H or methyl. Typically, the structure of binder J is saturated.

Alternatively, J contains between 1 and 3, preferably 1 double bond, typically separated by a carbon of the cycloalkyl function R7, if present. The double ligature can be cis or trans. Representative examples of J therefore include pentylene, hexylene, heptylene, any of which is substituted with d-C6alkyl, d-C6haloalkyl, d-C6alkoxy, hydroxyl, halo, amino, oxo, thio or d-C6 thioalkyl; penten-3-yl, hexen-4-yl, hepten-5-yl, where 3, 4 or 5 refers to a double bond between carbon atoms 3 and 4, 4 and 5 etc. Suitable groups R7 and R7 'include those wherein R7 is H and R7 is n-ethyl, n-propyl, cyclopropylmethyl, cyclopropyl, cyclobutylmethyl, cyclobutyl, 2,2-difluoroethyl, or mercaptomethyl. Some preferred embodiments include those wherein R7 is n-propyl or 2,2-difluoroethyl. Preferred alternative configurations for R7 and R7 'include those wherein R7 is H and R7 is C3-C7 cycloalkyl or d-C3alkylC3-C7cycloalkyl. Still other preferred configurations for R7 and R7 'include those in which R7' is H and R7 is J. Alternatively, R7 and R7 'together define a spiro-cycloalkyl function, such as a spiro-cyclobutyl ring, and more preferably a ring spiro-cyclopropyl. "Spiro" in this context simply means that the cycloalkyl ring shares a single carbon atom with the peptide structure of the compound. The ring is substituted or unsubstituted. Preferred substituents include mono or di-substitutions with R7 a wherein R7'a is d-C6 alkyl, C3-C5 cycloalkyl, or C2-C6 alkenyl, any of which is optionally substituted with halo. Alternatively the substituent may be a binder J as described. The currently preferred sterochemicals for a spiro- cyclopropyl are defined below. Particularly preferred substituents include R7 a as ethyl, vinyl, cyclopropyl (ie, a spiro-cyclopropyl substituent of the cycloalkyl ring "Spiro" of R7 / R7 '), 1 - or 2-bromoethyl, 1 - or 2-fluoroethyl, 2-bromovinyl or 2-fluorethyl .. In one embodiment of the invention, A is -CR4R4 'as illustrated in detail in PCT / EP03 / 10595, whose contents they are incorporated as a reference. Suitable R4 'groups therefore include d-C6alkyl, such as methyl, ethyl, propyl, ethenyl and -CHCHCH3. Preferred alternative R4 groups include aryl or heteroaryl such as phenyl, pyridyl, thiazolyl or optionally substituted benzimidazolyl or d-C3alkylaryl or C, -C3alkylheteroaryl, where the alkyl portion is methyl, ethyl, propyl, ethenyl and -CH = CHCH3. Preferred aryl portions include: optionally substituted phenyl, benzothiazole and benzimidazole. Preferred R4 groups include -NH2, fluoro or chloro.

Other alternative preferred R4 groups include -OH and especially = O An alternative modality for A is C (= O) NHR3, where R3 is optionally substituted C0-C3alkylaryl, C0-C3alkylheteroaryl, OC0-C3alkylaryl or OC-C3alkylheteroaryl. Suitable substituents are presented in the definitions section below. A configuration currently favored for A is C (= O) OR \ especially where R1 is d-C6alkyl, such as methyl, ethyl, or tert-butyl and more preferably hydrogen. A particularly preferred configuration for A is C (= O) NHSO2R2, especially where R2 is optionally substituted C, -C6alkyl, preferably methyl, or optionally substituted C3-C7cycloalkyl, preferably cyclopropyl, or optionally substituted C0-C6alkylaryl, preferably optionally substituted phenyl. The appropriate substituents appear in the definitions section below. The substituent -W-R8 in the cyclic P2 group can employ any of the proline substituents which are profusely described in WO 00/59929, WO 00/09543, WO 00/09558, WO 99/07734, WO 99/07733, WO 02 / 60926, WO03 / 35060, WO 03/53349, WO03 / 064416, W = 03/661 03, WO03 / 064455, WO03 / 064456, WO03 / 62265, WO03 / 062228, WO03 / 87092, WO 03/99274, WO03 / 99316, WO03 / 99274, WO04 / 03670, WO04 / 032827, WO04 / 037855, WO04 / 43339, WO04 / 92161, WO04 / 72243, 5WO04 / 93798. WO04 / 93915, WO04 / 94452, WO04 / 101505, WO04 / 101602, WO04 / 103996, WO041 13365 and the like. Preferred functions W include W as -OC (= O) NH-, -OC (= O) -, -NH-, -NR8'-, -NHS (O) 2-or -NHC (= O) -, especially -OC (= O) NH- or -NH-. Preferred R8 groups for said W functions include optionally substituted C0-C3alkylcarbocyclyl or C0-C3alkyl-heterocyclyl, including those described in WO0009543, WO0009558 and WO 00/174768. For example ester substituents, -W-R8, in the cyclic P2 group, include those described in WO 01/74768 such as d-C6alkanoyloxy, C0-C3alkylaryloyloxy, particularly benzoyloxy (optionally substituted) or C0-C3alkheheterocycloyloxy, especially This publication also describes possibilities of alternative -W-R8 for example d-C6alkyl, such as ethyl, isopropyl, C0-C3alkylcarbocyclyl such as cyclohexyl, 2,2-difluoroethyl, -C (= O) NRc, where Rc is C? C6 alkyl, C0-C3 alkylcyclopropyl, C0-C3alkylaryl or C0-C3alkylheterocyclyl. The currently preferred functions W include -S- and especially -O-. Suitable values for R8 in such embodiments include C0-C3alkylaryl, or C0-C3alkylheteroaryl any of which is optionally mono, di, or tri substituted with R9, where; R9 is dC6 alkyl, dC6alkoxy, NO2, OH, halo, trifluoromethyl, amino or amido (for example amido or amino optionally mono- or di-substituted with d-C6alkyl), C0-C3alkylaryl, C0-C3alkylheteroaryl, or carboxyl, wherein the aryl or heteroaryl portion is optionally substituted with R 10; wherein R10 is d-C6alkyl, C3-C7cycloalkyl, d-C6alkoxy, amino, amido, sulfonyl-C3alkyl, NO2, OH, halo, trifluoromethyl, carboxyl, or heteroaryl. Typically, the C0-C3 alkyl component of R8 as C0- C3alkylaryl, or C0-C3alkylheteroaryl is methyl and is especially absent, ie C0. The aryl or heteroaryl component has the values that are broadly illustrated in the definitions section below. Preferred R9s include d-C6 alkyl, d-C6alkoxy, amino, (such as di-d-C3alkylamino), amido (such as -NHC (O) C -? - C6alkyl or C (= O) NHC1-C6alkyl), aryl or heteroaryl, the aryl or heteroaryl which is optionally substituted with R 10; wherein R10 is d-C6alkyl, C3-C7cycloaIlkyl, d-C6alkoxy, amino, (such as mono- or di-d-C3 alkylamino), amido (such as -NHC (O) C, -C3alkyl or C (= O) NHC1-C3alkyl), halo, trifluoromethyl, or heteroaryl. Preferred R 10 include d-C6alkyl, d-C6alkoxy, amino, amido (such as -NHC (O) C1-C6alkyl or C (= O) NHC1-C6alkyl), halo, or heteroaryl. Particularly preferred R10 include methyl, ethyl, isopropyl, tert-butyl, methoxy, chloro, amino, amido (such as -NHC (O) d-C6alkyl, for example -NC (= O) CHC (CH3) 3, or C (= O) NHd-C3alkyl) or d-C3alkyl thiazole. Preferred embodiments of R8 include 1-naphthylmethyl, 2-naphthylmethyl, benzyl, 1-naphthyl, 2-naphthyl, or quinolinyl, any of which is unsubstituted, mono, or disubstituted with R 9 as defined, in particular 1-naphthylmethyl, or unsubstituted, mono-, or disubstituted quinolinyl with R9 as defined. A currently preferred R9 is: Wherein R9a is d-C6alkyl; d-dalkoxy; thioC-i-C3alkyl; amino optionally substituted with d-C6alkyl; C0- C3aIcylaryl; or C0-C3alkylheteroaryl, C0-C3alkylheterocyclyl, said aryl, heteroaryl or heterocycle which is optionally substituted with R10 wherein R10 is d-C6alkyl, C3-C7cycOalkyl, d-C6alkoxy, amino, amido, heteroaryl or heterocyclyl; and R9b is C -? - C6alkyl, d-C6alkoxy, amino, amido, NO2, OH, halo, trifluoromethyl, carboxyl. Suitable R9a include aryl or heteroaryl, all optionally substituted with R10 as defined, especially where R9a is selected from the group consisting of: Wherein R10 is H, d-C6alkyl, or C0-C3alkyl-C3-C6cycloalkyl, amino optionally mono- or di-substituted with C-C6alkyl, amido (such as as -NHC (O) d-C6alkyl or C ( = O) NHC1-C6alkyl), heteroaryl or heterocyclyl. R9a is conveniently phenyl and therefore R8 is: Wherein R is H, d-C6alkyl; d-C6alkoxy; or halo; Y R 9b is d-C6 alkyl, d-C6-alkoxy, amino such as di (d-C3alkyl) amine, amido (such as -NHC (O) d-C3alkyl or C (= O) NHC1-C3alkyl), NO2, OH, halo, trifluoromethyl, carboxyl. An alternative preferred R8 is: Where R10a is H, d-C6alkyl, or C0-C3C3-C6alkylcycloalkyl, amine (such as amine mono- or di-substituted with d-C6alkyl), amido (such as as -NHC (O) d-C6alkyl or C (= O) NHd-C6alkyl), heteroaryl or heterocyclyl; and R9b is C? -C6 alkyl, dC6-alkoxy, amino (such as di (C? -C3 alkyl) amino), amido (such as -NHC (O) d-C3alkyl or C (= O) NHC1) -C3alkyl), NO2, OH, halo, trifluoromethyl, or carboxyl. In the embodiments described above R 9b is conveniently dC 6 -alkoxy, preferably methoxy. An additional convenient R8, for example when W is an ether, has the formula Where W 'is N or CH, r is 0 or 1, Ra' is H, d-C6 alkyl, C0-C3 alkylcycloalkyl, d-C6alkyloxy, hydroxy or amine and Rb 'is H, halo, d-C6alkyl, C0-C3alkylcycloalkyl , d-Cealkyloxy, d-C6thioacyl, C0-C3alkyloxycycloalkyl, d-Csalkyloxy-dalkyl, C0-C3aIkylaryl or C0-C3alkylheterocyclyl. A particularly preferred ether substituent is 7-methoxy-2-phenyl-quinolin-4-yl oxy. When W is a bond then R8 is preferably a substituted or unsubstituted heterocyclic ring system as described in WO2004 / 072243 or WO2004 / 1 13665. Representative examples of R8 when W is a bond include the following aromatics which may optionally be substituted : 1 H-pyrrole, 1 H-imidazole, 1 / -pyrazole, furan, thiophene, oxazole, thiazole, isoxazole, isothiazole, pyridine, pindazine, pyrimidine, pyrazine, phthalazine, quinoxaline, quinazoline, quinoline, cinnoline, 1 H- pyrrolo [2,3] -b] pyridine, 1 H-indole, I H-benzoimidazole, 1 H-indazole, 7 H-purine, benzothiazole, benzooxazole, 1 W-imidazo [4,5-c-pyridine, 1 H-imidazo [ 4,5-b] pyridine, 1,3-dihydro-benzoimidazol-2-one, 1,3-dihydro-benzoimidazole-2-thione, 2,3-dihydro-1-y-indole, 1, 3 -dihydro-indole-2-one, 1-indole-2,3-dione, 1,3-dihydro-benzoimidazol-2-one, 1 H, 1 H-pyrrolo [2,3-c] pyridine, benzofuran, benzo [b] thiophene, benzo [d] isoxazole, benzo [d] sothiazole, 1 H-quinotin-2-one, 1 H-q uinolin-4-one, 1 H-quinazolin-4-one, 9 H-carbazole, 1 H-quinazolin-2-one. Additional representative examples of R8 when W is a bond, include the following non-aromatic, which may be optionally substituted: aziridine, azetidine, pyrrolidine, 4,5-dihydro-I H-pyrazole, pyrazolidin, imidazolidin-2-one, imidazolidin- 2-thione, pyrroidin-2-one, pyrolidine-2,5-dione, piperidine-2,6-dione, piperidin-2-one, piperazine-2,6-dione, piperazin-2-one, piperazine, morpholine, thiomorpholin-1, 1-dioxide, pyraziudin-3-one, imidazolidin-2,4-dione, piperidine, tetrahydrofuran, tetrahydropyran, [1,4] dioxane, 1, 2,3,6-tetrahydropyridine. Some preferred values for R8 when W is a bond, include tetrazole and its derivatives. The tetrazole moiety is attached to the cyclic scaffold P2 and optionally substituted as shown below: Where Q * is selected from the group comprising absent, -CH2-, -O-, -NH-, -N (R1 *), -S-, -S (= O) 2- and - (C = 0 ) -; Q * is selected from the group consisting of: absent, -CH2- and -NH; Y * is selected from the group consisting of: H, d-C6alkyl, C0-C3aryl, C0-C3heterocyclyl; R1 * is selected from the group consisting of: H, d-C6alkyl, carbocyclyl, C0-C3aryl, C0-C3heterocyclyl, Representative examples of substituted tetrazoles are as described in Table 1 of WO2004 / 072243 and the structures listed immediately below, or WO2004 / 1 13665. Other preferred values for R8 when W is a bond, include triazole and its derivatives. The triazole moiety is attached to the cyclic scaffold P2 and optionally substituted as shown below: Where X * and Y * are independently selected from the group consisting of: H, halogen, d-C6alkyl, C0-C3carbocyclyl, -CH2-amino, -CH2-arylamino, -CH2-diarylamino, - (C = O) -amino, - (C = O) -arylamino, - (C = O) -aryl amino, C0-C3aryl, C0-C3heterocyclyl or alternatively, X * and Y * taken together with the carbon atoms to which they are attached form a cyclic portion selected from the group comprising aryl and heteroaryl. Representative examples of substituted triazoles are as described in Table 2 of WO2004 / 072243 and the structures listed immediately below, and in the tables of WO2004 / 1 13365. Other preferred values for R8 when W is a bond, include pyridazinone and its derivatives. The pyridazinone portion is attached to the cyclic scaffold P2 and optionally substituted as shows below: Where X *, Y * and Z * are independently selected from the group consisting of: H, N3, halogen, d-C6alkyl, carbocyclyl, amino, C0-C3aryl, -S-aryl, -O-aryl, - NH-aryl, diarylamino, diheteroarylamino, C0-C3heterocyclyl, -S-heteroaryl, -O-heteroaryl, NH-heteroaryl or, alternatively, X and Y or Y and Z taken together with the carbon atoms to which they are attached, they form a cyclic aryl or heteroaryl moiety. Representative examples of substituted pyridazinones are as described in Table 3 of WO2004 / 072243 and the structures listed immediately below, and in the tables of WO2004 / 1 1 3365. Preferred P3 groups, ie, when m is 1 , resemble natural or unnatural amino acids, especially aliphatic amino acids, such as L-valyl, L-leucyl, L-isoleucyl or L-t-leucyl. Other preferred P3 groups, as shown in WO 02/01898 include C0-C3alkylcycloalkylalanine, especially cyclohexylalanine, optionally substituted with CO2Rg, where Rg is H, is C? -C6alkyl, C0-C3alkylaryl, C0-C3alkheheterocyclyl, C0-C3alkylcycloalkyl or amine; or N-acetylpiperidine or tetrahydropyran. Preferred R11 groups therefore include d-C6alkyl, C0- C3alkylcarbocyclyl for example C0-C3alkylC3-C7cycloalkyl, C0-C3alkylaryl or C0-C3alkylheteroaryl, any of which is optionally substituted with hydroxy, halo, amino, d-C6alkoxy, d-C6thioalkyl, C (= O) OR14, carboxyl, (C1 -C6alkoxy) carbonyl, aryl, heteroaryl or heterocyclyl, especially where the substituent is hydroxy or C (= O) OR14. Particularly preferred R1 1 groups include tert-butyl, iso-butyl, cyclohexyl, phenylethyl, 2,2-dimethyl-propyl, cyclohexylmethyl, phenylmethyl, 2-pyridylmethyl, 4-hydroxy-phenylmethyl, or carboxylpropyl. Currently the most preferred values of R1 1 are tert-butyl, isobutyl, or cyclohexyl. One embodiment of the invention includes compounds wherein P4 is absent (ie, n is 0) and wherein the P3 function lacks a carbonyl, ie U is absent. Representative substructures include those of Formula l i below: li Where Rx and Ry are as defined, preferably H, R11 'is C? -C6 alkyl, preferably C3-C5 branched alkyl such as the side chains of L-valyl, L-leucyl, L-isoleucyl, Lt-leucyl; or C0-C2alkylC3-C7 cycloalkyl such as cyclohexyl or cyclohexylmethyl; R16a is -Rba, -S (= O) pRba, -C (= O) Rba; Rba is d-C6 alkyl, C0-C3alkylheterocyclic, C0-C3alkylcarbocyclic. Alternatively, the compounds of partial structure li can be macrocyclized between an appropriate value of R7 and one of Rx, Ry or R1 1 '. Representative embodiments of Groups P3 that lack a carboxy function (ie, the variable U is absent) include those of the Formula lia-lid below: lia lib Where Ar is carbocyclyl or heterocyclyl, especially aryl or heteroaryl, any of which is optionally substituted with R9. Although the partial structures of the Formulas lia - lid have been illustrated in the context of a compound within Formula I, it will be apparent that such configurations of Formula li also apply to other values of q and k. Similarly, although the partial structures of the lie and lid formulas show a group R1 1 corresponding to leucine, it will be evident that these configurations will be applicable to other R11 groups, especially those that resemble the side chains of natural or unnatural L-amino acids. , for example t-butyl alanine / t-leucine. R15 in those compounds of the invention wherein n is 1, is optionally optionally d-C6alkyl or C0-C3alkylcarbocyclyl substituted for example C -C3alkylC3-C7cycloalkyl, any of which may be optionally substituted. Preferred P4 groups are typically analogous to natural or unnatural amino acids, especially aliphatic amino acids such as L-valMo, L-leucyl, L-isoleucyl, Lt-leucyl or L-cyclohexyialanine and therefore preferred R15 groups include cyclohexyl, cyclohexylmethyl , tert-butyl, iso-propyl, or iso-butyl. Preferred G values include -NRy-, especially where Ry is methyl or preferably H, or hydrazine. Another preferred value of G is O thus defining an ester with the carbonyl of P4 (if present) or the carbonyl of P3 (if present) or an ether in the case of variants where group U is absent. Conventional pharmaceutically acceptable esters or ester protecting groups for R16 include d-C6alkyl (especially methyl or t-butyl), C0-C3alkylheterocyclyl (especially pyridyl, benzimidazolyl, piperidyl, morpholinyl, piperazinyl) or C0-C3alkylcarbocyclyl (especially phenyl, benzyl, indanyl) any of which is optionally substituted with hydroxy, halo, amino, or C? - C6alcoxy. It will be apparent that for compounds of Formula I, when m = n = 0, then R 6 G- is not a BOC or CBz protecting group, but this restriction does not apply to other permutations of m and n. The synthetic intermediates of Boc or CBz-protected 4-substituted proline described for example in WO 0059929 are therefore outside the scope of the invention. Preferred compounds of the invention may comprise a hydrazine functionality, for example where X is -NHNH- and m is 1; with n being zero or 1. Alternatively, especially where m is zero, G can be -NRjNRj- such as -NHNH-. The compounds in general do not comprise a hydrazine in both G and X. Typical hydrazines within Formula I, wherein m and n are zero include compounds of the partial structures Ija-Ijb below: R in the formulas Ija and Ijb can be considered as an alkyl (or d-C3-a-alkylheterocyclyl or d-C3alkyl carbocyclyl) wherein the first carbon of the alkyl is substituted with an oxo group to define the keto function and R16 'is the remainder of the alkyl, alkylheterocyclyl or alkylcarbocyclyl moiety. Formula Ijb represents a variant wherein R16 is a methylene group whose carbon is substituted with an oxo substituent and also -ORb, where Rb has the values that have been defined, typically, d-C6 alkyl, such as t-butyl, C0- C3alkylheterocyclyl such as pyridyl, or C0-C3alkylcarbocyclyl, such as benzyl or phenyl, any of which is optionally substituted as defined. The compounds of partial structures Ija and Ijb can be linear molecules as shown (both Rj are H), or preferably one of the Rj groups represented can be macrocyclized through J in an appropriate R7 group. Alternative hydrazines of Formula I where m is 1 include those of partial structures Ijc and Ijd below: Where R16, G, R1 1, R5, Rj and Ru have the values that have been defined for formula I above. The compounds of partial structures Ijc and Ijd can be linear molecules as shown (both Rj are H), or preferably one of the Rj groups shown, or the R1 1 group can be macrocyclized through J in an appropriate R7 group Although formulas Ija-ljd are described with a proline analog such as P2, it will be apparent that this aspect of the invention is equally suited to other configurations of q and k. Alternative configurations of the hydrazine type are found when G is amino, and m and n are 0, and R16 is an unsaturated heterocycle linked to N as defined below, for example pyridyl or pyrimidyl or a saturated heterocycle as defined below, such as piperazinyl. , piperidinyl and especially morpholinyl. Examples of such modalities include those of the Ije formulas: The compounds of partial structures Ije can be linear molecules as shown or preferably Rx can be macrocyclized through J in an appropriate R7 group. Although these partial structures are represented by a five-membered ring for P2, it will be clearly evident that this configuration extends to other values of q and k. In a similar way these configurations will be applicable to other heterocycles linked to N as R16. Turning now to the formulas I in general, the preferred R16 groups for the compounds of the invention include 2-indanol, indanyl, 2-hydroxy-1-phenyl-ethyl, 2-thiophenomethyl, cyclohexylmethyl, 2,3-methylenedioxybenzyl, cyclohexyl, phenyl, benzyl, 2-pyridylmethyl, cyclobutyl, iso-butyl, n-propyl, methyl, or 4-methoxyphenylethyl . Presently preferred R16 groups include 2-axanol, indan, 2-hydroxy-1-phenyl-ethyl, 2-thiophenomethyl, 2,3-methylenedioxybenzyl, or cyclohexylmethyl. The non-natural amino acids include L-amino acids where the side chain is not one of the 20 naturally occurring amino acids. Examples of unnatural amino acids include L-beta-methylsulfonylmethylalanine, L-cyclohexylalanine, L-leucine tertiary, L-norleucine, L-norvaline, L-ornithine, L-sarcosine, L-citurinine, L-homophenylalanine, L-homoserine , L-beta- (1-naphthyl) alanine, L-beta- (2-naphthyl) alanine etc. The non-natural amino acids also include the D-amino acids corresponding to the 20 natural amino acids and D-amino acids having other side chains, such as those listed above. 'd-Cealkyl' (also abbreviated as d-C6alq, or used in compound expressions such as d-C6alkyloxy, etc.) as applied herein is intended to include linear or branched aliphatic carbon chains such as methyl, ethyl, n-propyl , isopropyl, n-butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, heptyl and any of its simple isomers. The alkyl group may have an unsaturated bond. In addition, any C-C6alkyl atom may be optionally substituted by one, two-or where the valence allows three halogens and / or substituted or the alkyl chain interrupted by a heteroatom S, O, NH. If the heteroatom is located at a terminal position in the chain then it is appropriately substituted with one or 2 hydrogen atoms, d-dalkyl and d-C5alkyl have the corresponding value to adjust the C1-C6alkyl as necessary for the amount of carbon . 'd-C3alkyl' as applied herein includes methyl, ethyl, propyl, isopropyl, cyclopropyl, any of which may be optionally substituted or interrupted by heteroatom as described in the preceding paragraph or in the case of C2 0 C3, with an unsaturated bond such as CH2 = CH. "d-C3alkylene" as applied herein discloses a divalent C 1 -C 3 alkyldiyl portion, including propylene, ethylene and especially methylene. The typically longest alkylene chains of J may comprise between 1 and 3 unsaturations and / or heteroatom breaks as defined. ? mino 'includes NH2, NHd-C6alkyl or N (C1-C6-alkyl) 2, especially d-C3 alkyl variants 'Amido' includes C (= O) NH2, and alkylamido, such as C (= O) NHC, -C6alkyl, C ( = O) N (C1-C6alkyl) 2 especially C (= O) NHd-C3alkyl, C (= O) N (d-C3alkyl) 2 or -NH (C = O) C1-C6alkyl, for example -NHC (= O) CHC (CH3) 3, including -NH (C = O) C1-C3alkyl. 'Halo' or halogen as applied herein is meant to include F, Cl, Br, I, particularly chloro and preferably fluoro. 'C0-C3alkylaryl' as applied herein is meant to include an aryl moiety such as phenyl, naphthyl or phenyl fused to a C3-C7cycloalkyl (for example indanyl), the aryl being directly attached (i.e., C0) or through an intermediate methyl, ethyl, or propyl group as defined for d-C3alkylene above. Unless otherwise indicated the aryl and / or its fused cycloalkyl portion is optionally substituted with 1 to 3 substituents selected from halo, hydroxy, nitro, cyano, carboxy, d-Cealkyl, d-dalkoxy, d-Cealkoxid-Cealkyl, d -C-alkanoyl, amino, azido, oxo, mercapto, C0-C3alkylcarbocyclyl nitro, C0-C3alkylheterocyclyl. "Aryl" has the corresponding meaning, that is, where the C0-C3alkyl bond is absent. 'C0-C3alkylC3C7cycloalkyl' as applied herein is meant to include a C3-C7cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, and the cycloalkyl is attached directly (i.e., C0alkyl) or through a methyl intermediate group, ethyl, proyl or isopropyl as defined for C? -C3alkylene, above. The cycloalkyl group may contain an unsaturated bond. Unless otherwise indicated the cycloalkyl portion is optionally substituted with 1 to 3 substituents selected from halo, hydroxy, nitro, cyano, carboxy, d-Cealkyl, d-Cealkoxy, d-Cealkoxid-Cealkyl, d-C6alkanoyl, amino, azido , oxo, mercapto, C0-C3alkylcarbocyclyl nitro, C0-C3alkylheterocyclyl. 'C0-C3alkylcarbocyclyl' as applied herein is meant to include C0-C3alkylaryl and C0-C3alkylC3-C7cycloalkyl. Unless otherwise indicated, the aryl or cycloalkyl group is optionally substituted with 1 -3 substituents selected from halo, hydroxy, nitro, cyano, carboxy, d-C6alkyl, d-C6alkoxy, d-Cealkoxid-C-alkyl, d-C6alkanoyl, amino, azido, oxo, mercapto, nitro, C0-C3alkylcarbocyclyl and / or C0-C3alkylheterocyclyl. "Carbocyclyl" has the corresponding meaning, that is, where the C0-C3alkyl bond is absent. 'C0-C3alkylheterocyclyl' as applied herein is meant to include a monocyclic, saturated or unsaturated ring, containing a heteroatom such as piperidinyl, morpholinyl, piperazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazinolyl, isothiazinolyl, thiazolyl, oxadiazolyl, , 2,3-triazolyl, 1,4-triazolyl, tetrazolyl, furanyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, pyrazolyl, or any such group fused to a phenyl ring, such as quinolinyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazinolyl, benzisothiazinolyl, benzothiazolyl, benzoxadiazolyl, benzo-1, 2,3-triazolyl, benzo-1, 2,4-triazolyl, benzotetrazolyl, benzofuranyl, benzothienyl, benzopyridyl, benzopyrimidyl, benzopyridazinyl, benzopyrazolyl etc, and the ring is directly attached is say, (C0), or through a methyl, ethyl, propyl or isopropyl intermediate group as defined above for d-C3alkylene. Any such unsaturated rings with aromatic character can be mentioned as heteroaryl herein. Unless otherwise indicated the hetero ring and / or its fused phenyl portion is optionally substituted with 1 to 3 substituents selected from halo, hydroxy, nitro, cyano, carboxy, d-C6alkyl, C?-C6alkoxy, d-Cealkoxyd-Cealkyl, d-C6alkanoyl, amino, azido, oxo, mercapto, nitro, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl. "Heterocyclyl" and "Heteroaryl" have the corresponding meaning, that is, where the C0-C3alkyl bond is absent. Typically, the heterocycle and carbocyclyl moieties within the scope of the preceding definitions are therefore a monocyclic ring with 5 or especially 6 ring atoms, or a bicyclic ring structure comprising a six-membered ring fused to a ring of 4, 5 or 6 members. Typical groups of this type include C3-C8 cycloalkyl, phenyl, benzyl, tetrahydronaphthyl, indenyl, indanyl, heterocyclyl such as azepanyl, azocanyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiopyranyl, furanyl, tetrahydrofuranyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, tetrazolyl, pyrazolyl, indolyl , benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzisoxazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, tetrahydroquinazolinyl and quinoxalinyl, any of which may be optionally substituted as defined herein. The saturated heterocyclyl moiety therefore includes radicals such as pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, piperazinyl, indolinyl, azetidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, hexahydropyrimidinyl, hexahydropyridazinyl, 1,4,6,6-tetrahydropyrimidinylamine, dihydrooxazolyl, 1,2-thiazinanyl-1,1-dioxide, 1,2,6-thiadiazinanil -1,1-dioxide, isothiazolidinyl-1,1-dioxide and imidazolidinyl-2,4-dione, whereby the unsaturated heterocyclyl includes radicals with an aromatic character such as furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl , isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, indolyl, isoindolyl. In each case the heterocycle can be condensed with a phenyl ring to form a bicyclic ring system. The synthesis of the compounds of the present invention can be carried out using different chemical strategies, in solution or in solid phase, or a combination of both. First, the individual protected building blocks can be prepared in an appropriate way, and then they can be joined together, that is, P2 + P1 -? P2-P1. Alternatively, precursors of the building blocks can be prepared together, and can be modified at a later stage in the synthesis of the inhibitory sequence. Other building blocks, precursors of building blocks or larger prefabricated fragments of the desired structure can then be coupled to the growing chain, for example R16-G-P3 + E-P2-P1? R16-G-P3-P2-P1 or R16-G-P4-P3 + E-P2-P1? R16-G-P4-P3-E-P2-P1. The union between two amino acids, an amino acid and a peptide, or between peptide fragments, can be performed using conventional binding methods, such as the azide method, the mixed carbonic acid-carboxylic anhydride method (isobutyl chloroformate), the carbodiimide method (dicyclohexylcarbodiimide, diisopropylcarbodiimide or carbodiimide). soluble in water), the active ester method (p-nitrophenyl ester, N-hydroxysuccinic ester ester), the Woodward K reagent method, the carbonyldiimidazole method, the phosphorous or oxidation-reduction reagent methods. Some of these methods (especially the carbodiimide method) can be improved by adding 1-hydroxybenzotriazole or 4-DMAP. These binding reactions can be carried out in solution (liquid phase) or in solid phase. More explicitly, the binding step comprises the dehydration linkage of a free carboxyl group of one reagent with the free amino group of the other reagent, in the presence of a binding agent, to form an amide linkage linkage. Descriptions of these binding agents can be found in general textbooks on peptide chemistry, for example, M. Bodanszky, "Peptide Chemistry", 2nd revised edition, Springer-Verlag, Berlin, Germany, (1993) known herein. as Bodanszky, whose contents are incorporated in this documentation as a reference. Examples of suitable binding agents are N, N'-dicyclohexylcarbodiimide, 1-hydroxybenzotriazoI in the presence of N. N'-dicyclohexylcarbodiimide or N-ethyl-N '- [(3-dimethylamino) propyl] carbodiimide. A practical and useful union agent is commercially available hexafluorophosphate (benzotriazol-1-yloxy) tris- (dimethylamino) phosphonium, by itself or in the presence of 1-hydroxybenzotriazole or 4-DMAP. Another practical and useful binding agent is the commercially available 2- (1-benzotriazol-1-l) -N, N, N, N, -tetramethyluronium tetrafluoroborate. Yet another useful and useful binding agent is commercially available O- (7-azabenzotrizol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate. The binding reaction is carried out in an inert solvent, for example, dichloromethane, acetonitrile or dimethylformamide. An excess of a tertiary amine, for example, diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine or 4-DMAP, is added to maintain the reaction mixture at a pH of about 8. The reaction temperature usually varies between 0 ° C and 50 ° C, and the reaction period commonly varies between 15 minutes and 24 hours. In general, the functional groups of the constituent amino acids must be protected during the binding reactions to avoid the formation of unsuitable bonds. The protective groups that can be used are detailed Greene, "Protective Groups in Organic Chemistry", John Wiley & amp;; Sons, New York (1981) and "The Peptides: Analysis, Synthesis, Biology", Vol. 3, Academic Press, New York (1 981), hereinafter referred to as Greene, whose descriptions are incorporated in this documentation to reference mode. The α-carboxyl group of the C-terminal residue is commonly protected as an ester, which can be cut to give the acid carboxylic Protecting groups that can be used include 1) alkyl esters, such as methyl, trimethylsilyl and t-butyl, 2) aralkyl esters, such as benzyl and substituted benzyl, or 3) esters that can be cut with soft bases or using reductive media soft, such as esters of trichloroethyl and phenacyl. Typically, the a-amino group of each amino acid to be bound is protected. Any protecting group known in the art can be used. Examples of such groups include: 1) acyl groups, such as formyl, trifluoroacetyl, phthalyl and p-toluenesulfonyl; 2) aromatic carbamate groups, such as benzyloxycarbonyl (Cbz or Z) and substituted benzyloxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate groups, such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl and alkyloxycarbonyl; 4) cyclic alkyl carbamate groups, such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) alkyl groups, such as triphenylmethyl and benzyl; 6) trialkylsilyl groups, such as trimethylsilyl; and 7) thiol-containing groups, such as phenylthiocarbonyl and dithiasuccinyl. The preferred a-amino protecting group is Boc or Fmoc. There are many properly protected amino acid derivatives commercially available to synthesize peptides. The a-amino protecting group is cut before the next binding step. When the Boc group is used, the methods chosen are trifluoroacetic acid, pure or in dichloromethane, or HCl in dioxane or in ethyl acetate. Then the resulting ammonium salt is neutralized before making the bond, or in situ with basic solutions, such as aqueous regulators or tertiary amines in dichloromethane, acetonitrile or dimethylformamide. When the Fmoc group is used, the reagents chosen are piperidine or piperidine substituted with dimethylformamide, but any secondary amine can be used. The deprotection is carried out at a temperature between 0 ° C and room temperature, commonly at 20-22 ° C. Any of the natural or unnatural amino acids with side chain functionalities will typically be protected during the preparation of the peptide, using any of the groups previously described. Those skilled in the art will appreciate that the selection and use of appropriate protecting groups for these side chain functionalities depend on the amino acids and the presence of other protecting groups in the peptide. In the selection of these protecting groups, it is desirable that the group is not removed during deprotection and binding of the a-amino group. For example, when Boc is used as the a-amino protecting group, the following side chain protecting groups are appropriate: portions of p-toluenesulfonyl (tosyl) can be used to protect the side chain of amino acids such as Lys and Arg; acetamidomethyl, benzyl (Bn), or tert-butylsulfonyl portions can be used to protect the sulfide-containing side chains of cysteine; portions of benzyl ethers (Bn) can be used to protect the hydroxyl-containing side chains of serine, threonine or hydroxyproline; and esters can be used benzyl to protect the carboxyl-containing side chains of aspartic acid and glutamic acid. When Fmoc is selected to protect a-amine, tert-butyl-based protecting groups are commonly acceptable. For example, Boc can be used for lysine and arginine, terbutyl ether for serine, threonine and hydroxyproline, and tert-butyl ester for aspartic acid and glutamic acid. A portion of triphenylmethyl (trityl) can be used to protect the sulfide-containing side chain of cysteine. Once the inhibitory sequence is complete, all protecting groups are removed in any way appropriate for the selected protecting groups. These procedures are well known to those skilled in the art. In the compounds of Formula I, unit P2 comprises a ring with nitrogen content which is substituted with portions W and R8.

Synthesis of the Heterocyclic Building Blocks P2 The R8 group can be joined with the scaffolding P2 at any convenient stage of the synthesis of compounds according to the present invention. One approach is to first join the group R8 with the scaffolding P2, and subsequently add the other desired building blocks, ie, P1 and optionally P3 and P4. Another approach is to join the portions P1, and, if present, P3 and P4, using an unsubstituted P2 scaffolding, and add later the group R8. The compounds wherein W is O and R8 is alkyl, C0-C3 alkylcarbomyclyl, C0-C3alkylheterocyclylyl can be prepared according to the procedure described by E. M. Smith et al. (J. Med. Chem. (1988), 31, 875-885), as indicated in Scheme 1, which illustrates the technique in one portion, where q and k are 1. 1a 1b Scheme 1 Commercially available Boc-4- (R) -hydroxyproline, or any suitable proline analogue substituted with hydroxy, such as hydroxypiperidoic acid is treated with base such as sodium hydride or potassium t-butoxide in a solvent such as dimethylformamide and the resulting alkoxide is reacted with an alkylating agent, R8-X, wherein X is a suitable leaving group such as a halide, mesylate, triflate or tosylate or the like, to provide the desired substituted proline derivative . Alternatively, when W is O or S and R8 is carbocyclyl such as phenyl or heterocyclylyl such as heteroaryl, the building blocks P2 can also be prepared by means of a Mitsunobu reaction (Mitsunobu, 1981, Synthesis, January, 1-28).; Rano et al. , Tetrahedron Lett. , 1995, 36, 22.3779-3792; Krchnak et al., Tetrahedron Lett., 1995, 36, 5, 6193-6196; Richter et al., Tetrahedron Lett. , 1994, 35, 27, 4705-4706) as shown in Scheme 2, which illustrates the technique in a portion where q and k are 1. 2a 2b 2c Scheme 2 The treatment of the appropriate hydroxy substituted proline analog, such as a hydroxypiperidoic acid, shown here as commercially available methyl ester of Boc-4-hydroxyproline, with the desired alcohol or thiol (R8-WH) in the presence of triphenylphosphine and an activating agent such as diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD) or the like, provides the ester compound (2b). The hydrolyzation of the ester in acid by standard procedures provides the building block P2 (2c). Alternatively, the alcohol (2a) can be treated with phosgene, thus obtaining the corresponding chloroformate which, when reacted with an amine, R8NH2, in the presence of a base such as sodium acid carbonate or triethylamine, provides carbamates, i.e. is -OC (= O) NH-, while the reaction of alcohol (2a) with an acylating agent, R8-CO-X, as an anhydride acid or acid halide for example acid chloride, to give esters, that is, W is -OC (= O) -. Various alcohols R8-OH, and alkylating agents R8-X are described in WO 00/09543 and WO00 / 59929. An example of the synthesis wherein R8 is a substituted quinoline derivative is shown in Scheme 3.

Scheme 3 Friedel-Craft acylation of an appropriate substituted aniline (3a), commercially available or as indicated in the literature, is performed using an acylating agent, such as acetyl chloride or the like, in the presence of boron trichloride and trichloride Aluminum, in a solvent such as dichloromethane, provides (3b). The binding of (3b) with a heterocyclic carboxylic acid (3c) under basic conditions, such as in pyridine, - in the presence of an activating agent for the carboxylate group, for example, POCI3, followed by ring closure and low dehydration Basic conditions, such as in potassium tert-butoxide in tert-butanol, provide the quinoline derivative (3e). The quinoline derivative (3e) can be linked in a reaction of Mitsunobu with an alcohol as described, or the hydroxyl group can be displaced with an appropriate leaving group, such as a halide, for example, chloride, bromide or iodide, employing a treatment with quinoline (3e) with an appropriate halogenating agent, for example, phosphoryl chloride or the like. A variety of carboxylic acids with the general structure (3c) can be used in Scheme 3. These acids are commercially available or as indicated in the literature. An example of the preparation of 2- (substituted) -amino-carboxy-aminothiazole derivatives, according to the procedure of Berdikhina et al. Chem. Heterocicl. Compd. (translated into English) (1991), 427-433, below.

O H X ^ N_R 'S S HO ^^ Br N = H2N-R '? TR '- HJ? N'R' ^ -? - H0 S 'H H 2 H II O 4a 4b 4c 4 Scheme 4 Thiourea (4c) can be formed with various alkyl substituents R 'using a reaction of the appropriate amine (4a) with tert-butyl isothiocyanate, in the presence of a base, such as diisopropylethylamine, in a solvent, such as dichloromethane , followed by the elimination of the tert-butyl group under acidic conditions. Subsequent condensation of the thiourea derivative (4c) with 3-bromopyruvic acid provides the acid (4d). The construction blocks P2, where the Substituent R8 through an amine, an amide, a urea or a sulfonamide, can be prepared from aminoproline analogues, which can be achieved, either from a commercially available suitable aminoproline, or by transforming the hydroxyl group of the corresponding hydroxyl derivative in an azide group, for example, by transforming the hydroxyl group into an appropriate leaving group, such as a mesylate or a halogen, for example, chloride, followed by substituting the leaving group with azide, or using a azide transfer agent, such as diphenylphosphoryl azide (DPPA). Reduction of azide by catalytic hydrogenation or employing any other appropriate reduction method provides the amine. The amino derivative can be reacted in a displacement reaction with an alkylating agent of general formula R8-X, where R8 and X are as described for scheme 1, to form building blocks P2 for use in the preparation of compounds of general formula I, where W is -NH-. The reaction of the aminoproline analogue with an acid of the general formula R8-COOH under conventional conditions for amide bonding provides compounds where the R8 substituent is linked through an amide bond, while the reaction of the aminoproline analogue with a derivative of Suitable sulfonic acid R8-S (O) 2-X, where X is a leaving group, for example, chloride, in the presence of a base, provides sulfonamides. Compounds where the bond between the cyclic scaffold and the substituent R8 is composed of a urea group can be obtained, for example, by employing the treatment a analog of aminoproline with phosgene, to obtain the corresponding chlorocarbamate, followed by reaction with the desired amine. Alternatively, the amino proline analogue can be reacted with the carbamyl chloride or isocyanate of the appropriate R8 substituent to form the urea linkage. It will be evident that the corresponding reactions will be available for groups P2 with other ring sizes and substitution patterns. 4-Substituted heterocyclyl derivatives, such as 4-substituted proline to be used as building blocks P2 where W is -CH2- can be prepared as shown in Scheme 5, which illustrates the technique in a portion in which q and k is 1, 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 5 The treatment of pyrrolidone or piperidinone protected in a suitable form such as commercially available Boc-pyroglutamic acid (5a) with a strong base such as lithium diisopropylamide in a solvent such as tetrahydrofuran followed by the addition of an alkylating agent R8-CH2 -X where X is a suitable leaving group such such as a halide such as chloride or bromide, followed by reduction of the amide and ester despretection gives the desired compound (5d). The compounds of the present invention where a heterocyclic group R8 is attached directly to the cyclic scaffold P2, ie W is a bond in the general formula I, can be prepared, for example, using a replacement reaction, where a leaving group is replaced. appropriate, on scaffolding P2, by the appropriate R8 group, such as a heterocyclic group. Alternatively, the R8 group can be introduced using a Mitsunobu reaction, where the hydroxyl group of the scaffold P2 is reacted with a nitrogen atom in the heterocyclic group R8.

Compounds where there is a tetrazole derivative bonded to one of the heterocyclic ring carbons are conveniently prepared by preparing the tetrazole portion directly on the precursor P2. This can be achieved, for example, by transforming the hydroxyl group of the precursor P2 into a cyano group, followed by a reaction with an azide reagent, such as sodium azide. Triazole derivatives can also be prepared directly on the precursor P2, for example, by transforming the hydroxyl group of the precursor P2 in an azide group, followed by a 3 + 2 cycloaddition reaction to obtain the azide and an appropriate alkyne derivative. Tetrazoles with various structures for use in the substitution or Mitsunobu reactions previously described can be prepared by reacting commercially available nitrile compounds with sodium azide. The triazole derivatives can be prepared using a reaction of an alkyne compound and a trimethylsilyl azide. Useful alkyne compounds are commercially available or can be prepared, for example, according to the Sonogashira reaction, that is, the reaction of a primary alkyne, an aryl halide and triethylamine in the presence of PdCl2 (PPh) 3 and Cul, as described, for example, in A. Elangovan, Y.-H. Wang, T.-l. Ho, Org. Lett. , 2003, 5, 1841 -1844. The heterocyclic substituent can also be modified when it is attached to the building block P2, before or after joining the building block P2 with the other building blocks. These methods, and other alternatives for preparing compounds where W is a bond and R8 is an optionally substituted heterocycle, are described in detail in WO2004 / 072243. Compounds with a ring size and a position of the alternative substituent W-R8 in the proline derivatives of Schemes 1, 2 and 5 can also be used in the preparation of the compounds according to the present invention. For example, the alkylation of 3- Commercially available hydroxyproline provides compounds of the general formula (I) wherein k is 0 and q is 2. Accordingly, the alkylation of 5-hydroxyproline, prepared for example as described in Hallberg et al., J. Med. Chem. (1999), 4524-4537, provides compounds of the general formula (I) wherein k is 2 and q is 0. Various methods are described in the literature for the preparation of hydroxylated 2-piperidinecarboxylic acids, for example Celestini et al. . , Org. Lett., (2002), 1367-1370, Hoarau et al. , Tetrahedron: Asymmetry, (1996), 2585-2594, Zhu et al. , Tetrahedron Lett. , 41, (2000), 7033-7036. For example, the corresponding pyridine carboxylic acids can be reduced to give hydroxylated 2-piperidine carboxylic acids. Enzymatic methods can also be used for the preparation of hydroxylated proline analogues. For example, a 3-hydroxy substituent may be introduced into commercially available 4, 5 or 6-membered heterocyclic acids by the use of proline 3-hydroxylase as described in Ozaki et al. , Tet. Letters, 40, (1 999), 5227-5230.

Synthesis and Introduction of P1 Building Blocks The amino acids used in the preparation of P1 fragments are commercially available or as indicated in the literature; see, for example, WO 00/09543 and WO00 / 59929 of Boehringer-lngelheim, or US2004 / 0048802 of BMS. In Scheme 6 an example of the preparation of a sulfonamide derivative which can be used as fragment P1, and the subsequent binding with a building block P2 protected with Boc.

Scheme 6 The sulfonamide group can be introduced into the protected amino acid suitably (6a) by treating the amino acid with a binding agent, for example, N, N'-carbonyldiimidazole (CDl) or the like, in a solvent, such as THF, followed by the reaction with the desired sulfonamide (6b) in the presence of a strong base, such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU). Alternatively, the amino acid can be treated with the desired sulfonamide (6b), in the presence of a base, such as diisopropylethylamine, followed by treatment with a binding agent, such as PyBOP®, to effect the introduction of the sulfonamide group. Removal of the amino protecting group using appropriate methods, and subsequent bonding with a P2 building block, prepared as described above, using conventional methods to form an amide bond, such as by the use of a binding agent, such as O- (7-azabenzotriazol-1-yl) -N, N, N ', N' hexafluorophosphate. -tetramethyluronium (HATU), in the presence of a base, such as diisopropylamine, in a solvent, such as dimethylformamide, gives a protected P2-P1 compound with Boc (6e) Alternatively, the sulfonamide group can be introduced at a later stage of the synthesis, for example, as the last step. In this case, an amino acid is linked to the inverted protection pattern, ie, with an unprotected amino function and a protected acid function, with the function of the P2 building block, using conventional conditions for the binding of peptides, for example, as described previously. Removal of the acid protecting group, using the conditions appropriate for the protecting group used, followed by the sulfonamide binding as described, allows compound 6e to be obtained. The building blocks P1 for the preparation of compounds according to the general formula I, wherein A is an ester or an amide, can be prepared by reacting the amino acid (6a) with the appropriate amine or alcohol, respectively, under conventional conditions for the formation of amides or esters. The compounds according to the general formula I, wherein A is CR4R4 ', can be prepared by joining the appropriate building block P1 with the building block P2, as described in Oscarsson et al Bioorg Med Chem 2003 1 1 (13) 2955- 2963 and PCT / EP03 / 10595, filed on September 23, 2003, the contents of which are incorporated by reference. Compounds comprising a P1 azapeptide residue, ie, Q is NRu in general formula I, can be prepared using an appropriate aza-amino acyl portion P1 at the junction with the P2 fragment. The preparation of aza-amino acyl moieties is described in M. D. Bailey et al. in J. Med. Chem., 47, (2004), 3788-3799, and an example is presented in scheme 6A.

Rl 'is with »is defined for Rl but is not H 6Ac 6Ad Scheme 6A The incorporation of the appropriate N-linked side chain Ru into the commercially available tert-butylhydrazine can be performed, for example, by employing a reductive amination reaction with the appropriate aldehyde or ketone, as described in scheme 1 9 below, which allows to produce the N-alkylated carbazate (6Aa). The condensation of 6Aa with a desired chloroformate, in the presence of a base, such as triethylamine or diisopropylethylamine, in a solvent, such as THF, provides 6Ab. The portion R1 'can then be optionally removed using the appropriate conditions, depending on the specific portion R1', such as by carrying out a catalytic hydrogenation of R1 ', which is benzyl, which allows the corresponding acids to be obtained. Subsequent reaction of the acid obtained with a desired sulfonamide derivative, as described in scheme 6, provides the building blocks coated with sulfonamide. Alternatively, the reaction of carbazate 6Aa with an isocyanate R3-N = C = O provides building blocks for the preparation of compounds according to general formula V, where M is N Ru and A is CON HR3. The portions P2 and P3 can be joined together before or after the introduction of the building block P1.

Synthesis of Protected Building Blocks P3 and P3-P4 The building blocks R16-G-P3 and R16-G-P4-P3 can be prepared as generally illustrated in Scheme 7. 7a 7b OR R1 1 'has the same definition as R1 1 but it is not part of a 7c macrocycle ^ 7d 7e Scheme 7 An appropriate N-protected amino acid (7a) can be linked with an amino-coating group (R16-NHRy) using conventional conditions for binding peptides, such as with binding agents such as HATU, DCC, HOBt or the like, in presence of a base, such as DI EA or DMAP, in a solvent, such as dichloromethane, chloroform or dimethylformamide, or a mixture thereof, and conditions of ester formation, such as those that allow to prepare amides, ie G is NHRy (7b). Alternatively, the reaction of amino acid (7a) with a compound of general formula R16-X, wherein R16 is as previously defined and X is a leaving group, such as a halide, in the presence of a base, such as carbonate of cesium or silver oxide (I), provides esters, that is, G is O (7b). On the other hand, the amino acid (7a) can be linked to a second amino acid protected with O in a suitable form (7d), using conventional conditions for the production of peptides, as previously described, to obtain (7e). The displacement of the ester group with an appropriate coating group (7b) provides the fragment (7f), useful for the preparation of the compounds according to the present invention where m and n are 1. When G is N-Ry, the building block P2 or P2 covered in a solid support can also be prepared, as illustrated in Scheme 8.

O Ry R16 R16. dc ^ Pg Ry R15 8d Scheme 8 An appropriate N-protected amino acid, for example, protected with Boc (8a), can be immobilized on a solid support, as exemplified in this case with the Agronaut PS-TFP resin, by reacting the amino acid with the appropriate solid support, in the presence of a binding reagent, such as N, N'-diisopropylcarbodiimide, and a base, such as DMAP, in a solvent, such as dichloromethane and dimethylformamide. The immobilized amino acid can then be separated from the support with an appropriate protecting group (8c), in order to obtain the fragments, useful for preparing the compounds according to the present invention, where m or n is 1. Optionally, the amino protecting group can be removed after binding the appropriate amino acid, using conventional methods, in order to obtain the fragments useful for the preparation of the compounds according to the present invention where m and n are 1.

Union Of A Protection Group Or A Building Block Suitable For Construction P2-P1 Building Block R16-G, R16-G-P3 Or R16-G-P4-P3 Linked Through A Urea Function To Construction P2-P1 construct, can be introduced as described in scheme 9, which illustrates the technique with a variant in which the scaffolding P2 is a 5-membered ring. ? a 9b Rx 'and R1 1' have the same definition as Rx and R1 1 respectively but are not part of a macrocycle. A 'is a protected carboxylic acid, an amide or substituted sulfonamide or CR4R4'.

Scheme 9 A chlorocarbamate group can be formed on the amine ring of the P1 -P2 construct (9a) by removing the amine protection group by standard procedures as an acid treatment with for example TFA in dichloromethane or the like when the Boc group is used, followed by the reaction of the free amine with phosgene in toluene in the presence of a base such as sodium acid carbonate or triethylamine in a solvent such as tetrahydrofuran. The subsequent reaction of the electrophilic center formed with the amino group of a building block R16-NH2) R16-NH-NH2, R16-G-P3 or R16-G-P4-P3 (9c) in a solvent such as dichloromethane in the presence from a base such as sodium acid carbonate provides (9d). The compounds of general formula (I) wherein E is C = S, S (= O) or S (= O) 2 can be prepared according to the preceding procedure but with the use of reagents such as thiocarbonyldiimidazole, thionyl chloride or sulfurylchloride respectively instead of phosgene. 10d Scheme 1 0 The reaction of tert-butyl carbazate (10a), optionally alkyl-substituted on one or both nitrogens, with p-nitrophenylchloroformate in the presence of a base such as sodium hydrogen carbonate followed by the addition of the building block P2 ( 10b) provides the urea derivative 10c. The phosgene method described in Scheme 9 as an alternative can be used to effect the binding of the fragments 10a and 10b. The optional removal of the boc group by standard procedures as acid treatment with for example TFA in a suitable solvent such as dichloromethane, provides the hydrazine containing the derivative (10d). Alternatively, any suitable hydrazine derivative, such as morpholin-1-ylamine, piperidin-1-ylamine or the like may be attached to 9Ab in place of the tert-butyl carbazate derivative. The compound obtained can be further extended by attaching a building block P3 or P4'P3 to the primary amine of compound 9Ad for example as shown in Scheme 1.

Prepared as described in the schemes 7 or 8 1 1 a R1 1 * has the same definition as R1 1 but is not part of an A 'is a protected carboxylic acid, an amide or substituted sulfonamide or CR4R4'.

Scheme 1 1 The treatment of the a-amino compound (1 1 a) with sodium nitrite, potassium bromide and sulfuric acid (Yang et al., J. Org.

Chem. (2001), 66, 7303-7312) provides the corresponding a-bromo compound (1 1 b), which, by reacting with the previously described derivative (10d), provides the hydrazine-containing derivative (1 1 c) . The junction between the building blocks P2 and P3 can also be constituted by a carbamate group and a route In general, such compounds are represented in Scheme 12, which illustrates the technique with a variant in which P2 is a proline derivative. 4' 12e Scheme 12 The desired, optionally protected amino protecting group (12a) is attached to a hydroxy acid (10b) using standard coupling techniques followed by the reaction with the electrophilic building block P2 (12d) described above and the deprotection. { on optional construction (12e). Compounds lacking a carboxy group in unit P3 can be prepared as illustrated in Scheme 13, which represents the technique applied to a compound of Formula I 13a 13c 13d 13e R1 1 'has the same definition as R1 1 but is not part of a macrocycle. A 'is a protected carboxylic acid, an amide or substituted sulfonamide or CR4R4'.

Scheme 13 The chlorocarbamoyl derivative (1 3a) can be reacted in a displacement reaction with an azide derivative (13b), prepared by methods known in the literature, in the presence of a base such as sodium hydrogen carbonate to give ( 13c). X is as described for the general formula (I). The reduction of the azide function for example by triphenylphosphine bound to polymer in a solvent such as methanol or any other suitable reduction method provides the intermediate (1 3d) which can then be reacted with an acid under coupling conditions peptide or with an amine in a reductive amination reaction that provides amides and secondary amines respectively. Scheme 14 shows an alternative route towards compounds lacking a carboxy group in unit P3. 14a 14b 14c 14d 14e R1 1 'has the same definition as R1 1 but is not part of a macrocycle. A1 is a protected carboxylic acid, a substituted amide or sulfonamide or CR4R4 ' Scheme 14 Instead of using the azide derivative (13b) in scheme 13, the corresponding hydroxyl derivative (14b), optionally protected, can be used in the displacement reaction with the chlorocarbamate (14a), which results in the introduction of a primary alcohol. The alcohol (14c) can then be oxidized, after optional deprotection, with an appropriate oxidizing agent, such as, for example, Dess-Martin periodinnan, to form the corresponding aldehyde. The reaction of the aldehyde with an amine desired in a reductive amination reaction, using a reagent such as, for example, cyanoborohydride attached to polysetirene, in a solvent, such as THF, provides the amine derivatives (14e). Alternatively, the alcohol (14c) can be reacted with an appropriate acylating or alkylating agent, under the appropriate conditions, to provide ester and ether compounds respectively, ie G is O in the general formula (I). Subsequent reaction of the alcohol formed with an appropriate acylating or alkylating agent, using the appropriate conditions, provides the ester and ether compounds respectively, ie G is O in the general formula (I) 1. Alternatively the link between the building blocks P2 and P3 can be through a guanidine group and a general route to such compounds is described in Scheme 1 5. 15a 15b 15d 15e R1 1 'has the same definition as R 1 1 but is not part of a macrocycle. A 'is a protected carboxylic acid, an amide or substituted sulfonamide or CR4R4'.

Scheme 15 Treatment of the building block P2 (15a) with thiocarbonyl diimidazole or the like in a solvent such as dimethylformamide followed by condensation with sodium cyanamide in a solvent such as ethanol yields the thiolate intermediate (15b). The reaction of the intermediate (15b) with the desired building block, here shown as a protected building block P3 (12c) provides the cyanoguanidine derivative (15d). Other building blocks, R16-G or R16-G-P4-P3, can be coupled as an alternative to the intermediate (15b). Hydrolysis of the cyano group by treatment of (15d) with dilute hydrochloric acid gives the guanylurea derivative (15e). When R7, R7 'and A' contain functional groups, these they are optionally protected in a suitable manner employing methods known to those skilled in the art; see, for example, Bodanzky or Greene, previously cited.

Formation of macrocyclic compounds The compounds according to the present invention, which contain an alkylene chain extending from R7 / R7 'cycloalkyl to Rx or R1 to form a macrocycle, can be prepared as described below. Suitable building blocks P1, P2 and P3, or precursors thereof, are joined using the strategies previously described, followed by a ring closure reaction (macrocyclization). The substituent W-R8 of the building block P2 can be incorporated through a Mitsunobu reaction, as previously described, before or after forming the macrocycle, or the desired building blocks can be joined using the appropriately substituted building block P2. . . For the macrocyclic structures extending from R7 / R7 'cycloalkyl to R1 1, amino acids containing the appropriate P3 side chain can be prepared as described in WO00 / 59929. A typical route for the macrocylic compounds is shown in Scheme 18, which illustrates the technique applied to a compound having a 5-member P2 scaffold and a spirocyclopropyl group in the P1 portion, where the macrocycle is extruded from the P3 side chain. 16d Scheme 16 The binding of the acid derivative (1 6a) with the amino acid protected with appropriate acid (16b), using for example the phosgene conditions, as described above, provides (16c). Accordingly, macrocycle formation can be performed through an olefin metathesis reaction, using a Ru-based catalyst, such as that described by Miller, S.J. , Blackwell, H. E .; Grubbs, R.H. J. Am. Chem. Soc. 1 18, (1996), 9606-9614, Kingsbury, JS, Harrity, JPA, Bonitatebus, PJ, Hoveyda, AH, J. Am. Chem. Soc. 121, (1999), 791 -799 and Huang et al. , J. Am. Chem. Soc. 121, (1999), 2674-2678. It will also be recognized that catalysts containing other transition metals, such as Mo, can be used in this reaction. Optionally, the double bond is reduced and / or the ethyl ester is hydrolyzed using conventional hydrogenation and / or hydrolyzing methods well known in the art, respectively. Alternatively, the methyl ester can be selectively hydrolysed, followed by the binding of a building block R16-G-P4, under conventional conditions appropriate for the binding of peptides. The macrocycling step described in Scheme 16 can also be applied over the appropriate carbocyclic analogs described previously. When the connector contains a nitrogen atom, ring closure could be performed by reductive amination, as described in WO00 / 59929. Macrocyclic compounds without the cyclopropyl moiety can be prepared in the P1 part, ie, compounds where the macrocyclic ring extends directly from the peptide backbone to the adjacent carbon R7, using the methods described herein. An example is presented, where a proline derivative is used as the cyclic scaffolding P2, in scheme 17. , 17f Scheme 1 7 The binding of an appropriate allylglycine derivative (17a) with the acid function of the building block. { on P2 (17b), using conventional conditions appropriate for the binding of peptides, provides the amide derivative (17c). The removal of the Boc protecting group by acid treatment, followed by the formation of a chlorocarbamate by treatment in phosgene in the presence of sodium acid carbonate by treatment with phosgene in the presence of sodium hydrogen carbonate and the subsequent reaction with the amino acid substituted olefin (17d) provides the urea compound (17e) Then a ring closure metathesis reaction is performed using, for example, the Hoveyda-Grubbs catalyst, which provides the macrocyclic compound (17f). Although scheme 17 shows the synthesis sequence using a building block P2 where the substituent R8 is attached to the scaffolding, it will be apparent that an unsubstituted P2 scaffold could be used and the R8 group introduced at any suitable stage of the synthesis, using either the methods that have been described. The building blocks that will be used in the preparation of compounds wherein the macrocycle is extruded from the nitrogen at the junction between the P2 and P3 fragments ie X is N Rx in the general formula I, or in the preparation of compounds in the where the fragments P3 and P4 are absent, ie m and n are 0 and G has the general formula NRj in the general formula I, they can be prepared in the manner described in scheme 1 8b.

Scheme 18 The carbamate of 18a, which is commercially available or can be easily prepared through the reaction of the desired alkyl amine with di-tert-butyl dicarbonate, can be reacted with an appropriate α-unsaturated alcohol under from Mitsunobu, in order to obtain the alkylated carbamate (18b). Placement of 18Bb under acidic conditions, such as, for example, treatment with trifluoroacetic acid in a solvent, such as dichloromethane, provides the free amine (18c), which can be linked to a P2 fragment using any of the strategies previously described. Macrocyclic structures containing a hydrazine group, ie, X is NRjNRj or m and n are 0, and G is NRjNRj in general formula I, can be prepared by linking the N-alkylated carbazate derivative suitably with the P2 fragment. Alkylated carbazate derivatives can be prepared, for example, as described in Scheme 1 9.

Scheme 1 9 Oxidation of the appropriate alcohol (19a), effected with an appropriate oxidation method, such as, for example, with N-methyl morpholine oxide and tetrapropylammonium perruthenate, in a solvent, such as dichloromethane, provides the aldehyde ( 19b). The reductive alkylation of tert-butyl carbazate with the obtained aldehyde gives the desired N-alkylated building block (19c). Alternatively, any suitable hydrazine derivative, such as morpholin-1-ylamine, piperidin-1-alamine or similar, in place of the tert-butyl carbazate in the reaction with the aldehyde 19b. In Scheme 20 for synthesizing sequences illustrated construction blocks suitable for preparing those compounds wherein the "outer" nitrogen of the hydrazine group is alkylated, either with an alkyl chain? Unsaturated, appropriate for subsequent macrocycle formation or with any other suitable alkyl group. 20e 20d Scheme 20 The reaction of a suitably protected hydrazine derivative, for example, (1,3-dioxo-1,3-dihydro-isonidol-2-yl) -carbamic acid tert-butylester (20a), which may be easily prepared by those trained in the art, with a desired alcohol, R-OH, under Mitsunobu conditions, provides the compound of N-alkylated hydrazine (20b). The elimination of the phthalimido group, effected by a treatment with a hydrazine or a derivative thereof, such as hydrazine hydrate or hydrazine acetate, provides the carbazate (20c). The obtained primary amine can then be attached to any desired P2 fragment, using any of the methods previously described to give the urea derivative (20d), or, alternatively, it can be further alkylated using, for example, the reductive amination method described in Scheme 19, followed by the joining of a P2 fragment, as previously described, to give 20e. In Scheme 21, the union of a P3 building block containing hydrazine with a cyclopentane scaffold is exemplified, followed by a macrocyclization. 21a 21b n = 1, 2, 3, 4, 5 21c 21 d Scheme 21 The binding of the carbazate derivative (21 b) with the block of construction P2-P1 (21 a), using conventional conditions appropriate for the binding of peptides, provides the intermediate (21 c). The ring closure of (21 c) using an olefin metathesis reaction, as described in scheme 18, allows to obtain the macrocyclic compound (21 d). The term "N-protecting group" or "N-protected", as used herein, refers to those groups used to protect the N-terminus of an amino acid or a peptide, or to protect an amino group against reactions. undesirable during synthetic procedures. N-protecting groups commonly used in Greene, "Protective Groups in in Organic Synthesis" (John Wiley &Sons, New York, 1981) are described, which is incorporated herein by reference. The N-protecting groups include acyl groups, such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4- chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl and the like; sulfonyl groups, such as benzenesulfonyl, p-toluenesulfonyl and the like, carbamate-forming groups, such as benzyloxycarbonyl, p-chlorobenzyl-oxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4- dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1- (p-biphenylyl) -1-methylethoxycarbonyl,. -dimethyl-S.d.-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butoxycarbonyl, diisopropyl methoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, alkyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups, such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups, such as trimethylsilyl and the like. Suitable N-protecting groups include, formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butoxycarbonyl (BOC) and benzyloxycarbonyl (Cbz). A hydroxyl protecting group, as used herein, refers to a substituent that protects hydroxyl groups against undesirable reactions during synthetic processes, such as those O-protecting groups described in Greene, "Protective Groups in Organic Synthesis. , "(John Wiley &Sons, New York (1 981)). The hydroxyl protecting groups comprise substituted methyl ethers, for example, methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, t-butyl and other lower alkyl ethers, such as isopropyl, ethyl and especially methyl, benzyl and triphenylmethyl; tetrahydropyranyl ethers; ethers of substituted ethyl, for example, 2,2,2-trichloroethyl; silyl ethers, for example, trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; and esters prepared by reacting the hydroxyl group with a carboxylic acid, for example, acetate, propionate, benzoate and the like.

To treat conditions caused by flaviviruses, such as HCV, the compounds of formula I are typically administered in an amount that allows obtaining a plasma level of between about 100 and 5000 nM, such as between 300 and 2000 nM. This corresponds to a dosage rate, depending on the bioavailability of the formulation, in the order of between 0.01 and 10 mg / kg / day, preferably between 0.1 and 2 mg / kg / day. A typical dosage rate for a normal adult will be between about 0.05 and 5 g per day, preferably between 0.1 and 2 g, such as 500-750 mg, in one to four dosage units per day. As with all pharmaceutical substances, dosage rates will vary with the size and metabolic condition of the patient, as well as with the severity of the infection, and may need to be adjusted for concomitant medications. As indicated by good prescription practice with antiviral therapies, the compounds of formula I are typically co-administered with other therapies for HCV to avoid the generation of drug escape mutants. Examples of these therapies for HCV include ribavirin, interferons, including pegylated interferons. Additionally, there is a number of nucleoside analogues and protease inhibitors in clinical or preclinical development, and it will be possible to co-administer them with the compounds of the invention. Therefore, another aspect of the invention provides a composition comprising a compound of formula I and at least another antiviral substance against HCV in a common dosage unit, ta! as any of the dosage forms described below, but especially an orally administered tablet, or a capsule, a liquid suspension or a solution for oral or injection use. Another aspect of the invention provides a method for the treatment or prophylaxis of a flavivirus infection, such as HCV, comprising the consecutive or simultaneous administration of a compound of formula I and at least one other antiviral substance against HCV. A related aspect of the invention provides a set of elements for the patient, comprising a first pharmaceutical composition, preferably in the form of individual dosages, of the compound of formula I, and a second pharmaceutical composition of a second antiviral substance against HCV, typically also in the form of individual dosages, and generally in a separate container in the set of elements for the patient. Conveniently, the set of items for the patient will also contain instructions printed on the package or container, or on an insert in the package, for simultaneous or consecutive administration of the respective pharmaceutical compositions. Many patients with HCV are co-infected, or are susceptible to suffering from superinfection, with other infectious diseases. Therefore, another aspect of the invention provides combination therapies, which comprise the compound of the invention co-formulated in the same dosage unit, or co-packaged with the less another anti-infective pharmaceutical substance. The compound of the invention and the at least one other anti-infective drug substance are administered simultaneously or consecutively, typically at doses corresponding to the monotherapeutic dose of the agent in question. However, certain anti-infectious substances can induce a synergistic response, which will allow the administration of one or both active ingredients at a lower dose than the corresponding monotherapy. For example, in drugs susceptible to being rapidly metabolized by Cyp3A4, co-dosing with the HIV protease inhibitor will allow administration of lower dosing regimens. Typical co-infections or superinfections with HCV include the hepatitis B virus or the LV virus H. Therefore, the compound of the invention is advantageously co-administered (co-packaged in the same dosage unit or in a unit of dosage prescribed separately) with at least one antiviral substance against HIV and / or at least one antiviral substance against HBV. Representative antiviral substances against HIV include NRTI, such as alovudine (FLT), zudovudine (AZT, ZDV), stavudine (d4T, Zerit), zalcitabine (ddC), didanosine (ddl, Videx), abacavir, (ABC, Ziagen) , lamivudine (3TC, Epivir), emtricitabine (FTC, Emtriva), racevir (racemic FTC), adefovir (ADV), entacavir (BMS 200475), alovudine (FLT), tenofovir disoproxil fumarate (TNF, Viread), amdoxavir (DAPD) ), D-d4FC (DPC-817), -dOTC (Shire) SPD754), elvucitabine (Achillion ACH-126443), BCH 10681 (Shire) SPD-756, racivir, D-FDOC, GS7340, INK-20 (phospholipid thioether AZT, Kucera), 2'3'-d-deoxy-3 '-fluoroguanosine (FLG) and its prodrugs, such as MIV-210, reverset (RVT, D-D4FC, Pharmasset DPC-817). Representative NNRTIs include delavirdine (Rescriptor), efavirenz (DMP-266, Sustiva), nevirapine (BIRG-587, Viramune), (+) calanolide A and B (Advanced Life Sciences), capravirin (AG1549I S-1 1 53, Pfizer ), GW-695634 (GW-8248; GSK), MIV-150 (Medivir), MV026048 (R-1495; Medivir AB / Roche), NV-05 2 2 (Idenix Pharm.), R-278474 (Johnson & Johnson), RS-1588 (Idenix Pharm.), TMC-120/125 (Johnson &Johnson), TMC-125 (R-165335; Johnson &Johnson), UC-781 (Biosyn I nc.) And YM215389 ( Yamanoushi). Representative HIV protease inhibitors include PA-457 (Panacos), KPC-2 (Kucera Pharm.), 5 HGTV-43 (Enzo Biochem), amprenavir (VX-478, Agenerase), atazanavir (Reyataz), indinavir sulfate (MK-639, Crixivan), Lexiva (fosamprenavir calcium, GW -433908 or 908, VX-175), ritonavir (Norvir), lopinavir + ritonavir (ABT-378, Kaletra), tipranavir, nelfinavir mesylate (Viracept), saquinavir (Invirase, Fortovase), AG 1776 (JE-2147, KNI-764; Nippon Mining Holdings), AG-1859 (Pfizer), DPC-681/684 (BMS), GS224338; Gilead Sciences), KN I-272 (Nippon Mining Holdings), Nar-DG-35 (Narhex), P (PL) -1 00 (P-1946, Procyon Biopharma), P-1 946 (Procyon Biopharma), R- 944 (Hoffmann-LaRoche), RO-0334649 (Hoffmann-LaRoche), TMC-1 14 (Johnson & Johnson), VX-385 (GW640385; GSK / Vertex), VX-478 (Vertex / GSK). Other antiviral substances against HIV include inhibitors of entry, including fusion inhibitors, CD4 receptor inhibitors, CCR5 co-receptor inhibitors and CXCR4 co-receptor inhibitors, or pharmaceutically acceptable salts or prodrugs thereof. Examples of input inhibitors include AMD-070 (AMD1 1070; AnorMed), BlockAide / CR (ADVENTRX Pharm.), BMS 806 (BMS-378806; BMS), Enfurvirtide (T-20, R698, Fuzeon), KRH 1636 ( Kureha Pharmaceuticals), ONO-4128 (GW-873140, AK-602, E-91 3; ONO Pharmaceuticals), Pro-140 (Progenies Pharm), PRO542 (Progenies Pharm.), SCH-D (SCH-41 7690; Schering -Plough), T-1249 (R724, Roche / Trimeris), TAK-220 (Takeda Chem. Ind.), TNX-355 (Tanox) and UK-427.857 (Pfizer). Examples of integrase inhibitors include L-87081 0 (Merck &Co.), c-2507 (Merck &Co.) and S (RSC) -1 838 (shionogi / GSK). Examples of antiviral substances against HBV include adefovir dipivoxil (Hepsera), and especially lamivudine and 2'3'-dideoxy-3'-fluoroguanosine (FLG), and their prodrugs, such as MIV-21 0, 5'-O-vaIyl-L-lactyl prodrug of FLG. These latter antiviral substances against HBV are particularly convenient, since they also have activity against HIV. While it is possible to administer the active agent alone, it is preferable that it be present as part of a pharmaceutical formulation. This formulation will comprise the active agent previously defined together with one or more acceptable vehicles or excipients, and optionally with other therapeutic ingredients. The vehicle (s) must be acceptable in the sense of being compatible with the other ingredients of the formulation, and must not be harmful to the recipient. The formulations include those suitable for rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral administration (including subcutaneous, intramuscular, intravenous and intradermal), but preferably the formulation is an oral administration formulation. The formulations can conveniently be presented in the form of individual dosages, for example, sustained release tablets and capsules, and can be prepared using any method well known in the pharmaceutical field. These methods include the step of associating the active agent previously defined with the vehicle. In general, the formulations are prepared by uniformly and intimately associating the active agent with liquid carriers, finely divided solid carriers or both, and then shaping the product, if necessary. The invention encompasses methods for preparing a pharmaceutical composition comprising combining or associating a compound of Formula I, a salt thereof acceptable for pharmaceutical use, with a vehicle or transport acceptable for pharmaceutical use. If the manufacture of the pharmaceutical formulations comprises the intimate mixture of the pharmaceutical excipients and the active ingredient in the form of a salt, then it is commonly preferable to use excipients of non-basic nature, that is, acids or neutrals. Formulations for oral administration of the present invention may be presented as discrete units, such as capsules, pills or tablets, each of which contains a predetermined amount of the active agent; as powder or granules; as a solution or suspension of the active agent in an aqueous or non-aqueous liquid; or as a liquid emulsion of oil in water or a liquid emulsion of water in oil, and as a bolus, and so on. With regard to compositions for oral administration (e.g., tablets and capsules), the term "suitable vehicle" includes carriers, such as common excipients, for example, binding agents, e.g., syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone. (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers, for example, corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants, such as magnesium stearate, sodium stearate and other metal stearates, stearic acid, glycerol stearate, silicone fluid, talc, waxes, oils and colloidal silica. Flavoring agents may also be used, such as wild mint, Canadian tea oil, cherry flavor or the like. It may be desirable to add a coloring agent to facilitate identification of the dosage form. The tablets can also be coated using methods well known in the art.

A tablet may be prepared by compression or molding, optionally with one or more accessory ingredients.

Compressed tablets can be prepared by compressing the active agent, in a free-flowing form, such as powder or granules, in an appropriate machine, performing an optional mixture with a binder, a lubricant, an inert diluent, a preservative, an active agent on surface or a dispersant. Molded tablets can be prepared by molding a mixture of the powdered compound, moistened with an inert liquid diluent, in an appropriate machine. The tablets can optionally be coated or labeled, and formulated to provide slow or controlled release of the active agent. Other formulations suitable for oral administration include pills comprising the active agent in a flavored base, usually sucrose and acacia or tragacanth; pills comprising the active agent in an inert base, such as gelatin and glycerin, or sucrose and acacia; and buccal washes comprising the active agent in an appropriate liquid vehicle. The compounds of formula VI can form salts, which constitutes a further aspect of the invention. Salts acceptable for the pharmaceutical use of suitable compounds of formula I include organic acid jumps, especially carboxylic acids, including, without limitation, salts of acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, isethionate. , adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, palmoate, pectinate, 3-phenylpropionate, picrate, pivalate, proprionate, tartrate, lactobionate, pivolate, camphorate, undecanoate and succinate, organic sulfonic acids, such as methanesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, camphorsulfonate, 2-naphthalenesulfonate, benzenesulfonate, p-chlorobenzenesulfonate and p-toluenesulfonate; and inorganic acids, such as hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, hemisulfate, thiocyanate, persulfate, phosphoric and sulphonic acid. In addition, the invention encompasses the salts of the compounds of formula I which may or may not be acceptable for pharmaceutical use, but which are useful as synthetic intermediates, where the salt portion may be displaced or replaced as needed. The invention includes prodrugs of the compounds of formula I. Prodrugs of the compounds of formula I are those compounds which, after being administered to the patient, release a compound of formula VI in vivo, generally after undergoing hydrolysis in the intestine, liver or plasma. Typical prodrugs are ethers acceptable for pharmaceutical use, and especially esters (including phosphate esters) of hydroxyl functions, amides or carbamates of amine functions acceptable for pharmaceutical use, or esters of carboxyl functions acceptable for pharmaceutical use. Preferred pharmaceutically acceptable esters include alkyl esters, including acetyl esters, ethanoyl, butyryl, t-butyryl, stearyl and pivaloyl, phosphate esters and sulfonic esters (ie, those derived from RSO2OH, where R is lower alkyl or aryl). Acceptable esters for pharmaceutical use include lower alkyl ethers and the ethers described in WO00 / 47561, especially methoxyaminoacyl and ethoxyaminoacyl. The compounds of the invention have several steric centers, and the invention comprises the racemates and the enantiomers in each of these steric centers. Typically, the stereochemistry of those corresponding to the side chains P3 and P4 (ie, R15 and / or R1) will correspond to the configuration of an L-amino acid, although the invention also comprises the D-isomers in one or both of these centers . It is worth noting that the configuration L is active regardless of the nature of the portion E, which means that P3 and P4 are typically translated into an atom relative to a conventional polypeptide, and the fact that the inversion of a peptide residue, as contemplated for P3 and P4, tilts the side chain of the amino acid to the side opposite, compared to the conventional peptide substrate. The stereochemistry of the skeletal component of the cyclic P2 group (ie, encompassing the carbonyl of the P1 amide bond and the carbonyl extending to P3) will typically correspond to L-proline. The stereochemistry of the ring atom P2 to which W is attached is typically as illustrated below: .R8 W (CH2) q (CH2) k In the compounds of the invention where R7 and R7 together define a spiroalkyl group, this spiroalkyl will typically comprise an R7a substituent on the spiro-cyclopropyl ring, which will have an orientation syn with respect to A: or anti regarding A: Conveniently, the spiro carbon of this spiro-cyclopropyl ring has the configuration R: Conveniently, the R substituent on the ring of Spiro-cyclopropyl adjacent to A has an orientation syn in the following absolute configuration: Particularly preferred variants have R7 a include ethyl, therefore the asymmetric carbon atoms in position 1 and 2 have the R, R configuration. Particularly preferred variants have R7 to include vinyl, hence the asymmetric carbon atoms in position 1 and 2 have the configuration R, S. When the compound of the invention is a macrocycle comprising a group J, J is preferably a diastereomer represented by the partial structures (i) or (ii): J syn respect j syn reSpect of the amide (i) of A (ü) especially when J is syn with respect to A.

DETAILED DESCRIPTION OF THE MODALITIES The following illustrate various embodiments of the invention by way of illustration only, with reference to the following non-limiting examples.

Example 1 7-Methoxy-2-phenyl-quinolin-4-ol (1). To a round base vessel under stirring with toluene (100 mL) was added ethylbenzoyl acetate (18.7 g, 97 mmol) and m-anisidine (12 g, 97 mmol). 4 M HCl in dioxane (0.5 mL) was added and the reaction mixture was refluxed for 6 h (140 ° C). The mixture was co-evaporated with toluene. To the crude mixture was added diphenyl ether (50 mL) and the mixture was heated at 280 ° C for 2 h. When the theoretical amount of ethanol (6 mL) had been collected in a Dean Stark trap the heating was stopped and the mixture was cooled to room temperature. The crude mixture was dissolved in CH2Cl2 (100 mL) and stirred for 30 min. The formed precipitate was removed by filtration and dried to give 1 (4.12 g, 16.4 mmol, 17%): pale yellow powder. 1H (300 MHz, DMSO-D6): d 3.8 (s, 3H), 6.24 (s, 1H), 6.38-6.96 (dd, 1H, J = 9.07 Hz, J = 2.47 Hz), 7.19 (d, 1H, J = 2.19 Hz), 7.56 (t, 3H, J = 2.19 Hz), 7.8 (dd, 2H, J = 7, 14 Hz, J = 2.19 Hz), 8.0 (d, 1H, J = 9.06 Hz); 3C (75.5 MHz, DMSO-D6): d 55.3, 99.6, 106.9, 113.1, 119.1, 126.4, 127.5, 128.8, 130.2, 134 , 1, 142.2, 149.4, 161.8, 176.4. Example 2 Boc-L-ferr-leucine-OH (2). Triethylamine (890 DL, 6.40 mmol) was added dropwise to a stirred solution of L-ferr-leucine (300 mg, 2.29 mmol) and di-rer-butyl dicarbonate (599 mg, 2.74 mmol). ) in dioxane / water 1: 1 (8 mL) and the solution was stirred overnight. The mixture was extracted with petroleum ether (2?) And the aqueous phase was cooled to 0 ° C and carefully acidified to pH 3 by slow addition of 4M NaHSO4-H2O. The acidified aqueous phase was extracted with EtOAc (3?) And the combined organic phases were washed with brine (2?) And then dried, filtered and concentrated to give the title compound (522 mg, 99%) as a colorless powder. No further purification was necessary. 1 H-NMR (300 MHz, CD3OD) d 0.99 (s, 9H), 1.44 (s, 9H), 3.96 (s, 1 H); 13 C-NMR (75.5 MHz, CD3OD) d 27, 1, 28.7, 34.9, 68.0, 80.5, 157.8, 174.7. Example 3 tert-butylester ((S) -Cyclohexyl-methylcarbamoyl-methyl) -carbamic acid (3).

Boc-Chg-OH (387 mg, 1.50 mmol) was coupled with methylamine hydrochloride (111 mg, 1.65 mmol) using the same HATU coupling conditions as in the synthesis of compound 7. The crude product was extracted with EtOAc, washed with brine and concentrated. Purification by flash column chromatography (EtOAc) gave the title compound (307 mg, 76%) as a colorless solid. 1 H-NMR (300 MHz, CDCl 3) d 0.91-1.13 (m, 2H), 1.14-1.31 (m, 3H), 1.44 (s, 9H), 1.61-1.80 (m, 6H), 2.80 (d, J = 4.7 Hz, 3H), 3.91 (dd, J = 7.1, 9.1 Hz, 1H), 5.23 (b, 1H), 6.52 (bs, 1H); 13 C-NMR (75.5 MHz, CDCl 3) d 25.9, 26.0, 26.1, 28.3, 28.5, 29.6, 40.5, 59.5, 79.7, 155.9, 172.4. Example 4 acid tert-butyl ester. { (S) -1 - [((S) -Cyclohexyl-methylcarbamoi (-methi () -carbamoyl] -2,2-dimethyl-propyl} -carbamic acid (4) To a solution of compound 3 (98 mg 0.362 mmol) in methylene chloride (3 mL) were added triethylsilane (115 mL, 0.742 mmol) and TFA (3 mL) The mixture was stirred for 2 h at room temperature and then evaporated and coevaporated with toluene. Deprotected was dissolved in DMF (5 mL) and coupled with compound 2 (84 mg, 0.363 mmol) using the same HATU coupling conditions as in the synthesis of 7. The crude product was extracted with EtOAc, washed with brine, dried, filtered and concentrated. Purification by flash column chromatography (toluene / EtOAc 1: 1) gave the title compound (128 mg, 92%) as a colorless solid. 1 H-NMR (300 MHz, CDCl 3) d 0.99 (s, 9H), 1.02-1.30 (m, 5H), 1.44 (s, 9H), 1.58-1.77 (m, 4H), 1.78-1.89 (m, 2H), 2.79 (d, J = 4.7 Hz , 3H), 4.11 (d, J = 9.3 Hz, 1H), 4.33 (app.t, J = 8.5 Hz, 1H), 5.65 (b, 1H), 7.25 (b, 1H), 7.39 (b, 1H); 13 C-NMR (75.5 MHz, CDCl 3) d 25.9, 25.9, 26.0, 26.2, 26.8, 28.4, 29.0, 29.7, 34.5, 39, 7, 58.4, 62.4, 79.4, 156.0, 171.4, 171.8. Example 5 Hept-6-enal (5) To a solution of hept-6-en-1-ol (1 mL, 7.44 mmol) and N-methylmorpholine N-oxide (1.308 g, 11.17 mmol) in DCM ( 17 mL) powdered molecular sieves (3.5 g, 4 A) were added. The mixture was stirred for 10 min at room temperature under a nitrogen atmosphere before adding tetrapropylammonium perruthenate (TPAP) (131 mg, 0.37 mmol). After stirring for another 2.5 h the solution was filtered through celite. The solvent was then carefully evaporated and the remaining liquid was purified by flash column chromatography (DCM) to give the volatile aldehyde 5 (620 mg, 74%) as an oil. Example 6 acid tert-butylester? '-Hept-6-en- (E) -iidene-hydrazinecarboxylic acid (6) To a solution of 5 (68 mg, 0.610 mmol) and ferf-butyl carbazate (81 mg, 0.613 mmol) in MeOH (5 mL) was they added powdered molecular sieves (15 mg, 3Á). The mixture was stirred for 3 h after which it was filtered through celite and evaporated. The residue was dissolved in dry THF (3 mL) and AcOH (3 mL). NaBH3CN (95 mg, 1.51 mmol) was added and the solution was stirred overnight. The reaction mixture was diluted with saturated NaHCO3 solution (6 mL) and EtOAc (6 mL). The organic phase was washed with brine, saturated NaHC03, brine, dried over MgSO4 and evaporated. The cyanoborane adduct was hydrolyzed by treatment with MeOH (3 mL) and 2 M NaOH (1.9 mL). The mixture was stirred for 2 h and the MeOH was evaporated. H2O (5 mL) and DCM (5 mL) were added and the aqueous phase was extracted three times with DCM. The combined organic phases were dried and evaporated. Purification by flash column chromatography (toluene / ethyl acetate 9: 1 with 1% triethylamine and toluene / ethyl acetate 6: 1 with 1% triethylamine) gave the title compound (85 mg, 61%) as an oil. Example 7 tert-butylester of ((S) -1-cyclopentylcarbamoyl-2,2-dimethyl-propyl) - carbamic (7). To a cold solution of 2 (133 mg, 0.575 mmol), cyclopentylamine (64 μL, 0.648 mmol) and DIEA (301 μL, 1.73 mmol) in DMF (3 mL) was added the coupling agent HATU (240 mg, 0.631 mmol). The mixture was stirred for half an hour and for another two hours at room temperature. The solvent was removed by heating the reaction vessel in a water bath under reduced pressure and the residue was dissolved in ethyl acetate, after which the organic phase was washed three times with brine, dried, filtered and evaporated. Purification by flash column chromatography (toluene / ethyl acetate 4: 1) gave the title compound (140 mg, 82%) as colorless crystals. 1 H-NMR (300 MHz, CDCl 3): d 0.95 (s, 9H), 1, 28-1, 48 (m, superimposed, 2H), 1.40 (s, 9H), 1, 49-1, 71 (m, 4H), 1, 86-2.01 (m, 2H), 3.76 (b, 1 H), 4.09-4.23 (m, 1 H), 5.32 (b, 1 H), 5.91 (b, 1 H); 13 C-NMR (75.5 MHz, CDCl 3): d 23.6, 23.7, 26.5, 28.3, 32.6, 33, 1, 34.5, 51, 0, 62.2, 79 , 4, 155.9, 170.3. Example 8 (S) -reryl-Butoxycarbonylamino-cyclohexyl-acetic acid methyl ester (8) To a solution of Boc-Chg-OH (53 mg, 0.206 mmol) in acetone (3 mL) were added methyl iodide (195 μL, 3.1 mmol) and silver oxide (I) (53 mg, 0.229 mmol). . The mixture was left stirring overnight in a reaction vessel that was covered with aluminum foil. The solution was then filtered through celite and evaporated. Purification by flash column chromatography (toluene / ethyl acetate 15: 1) gave methyl ester 8 (56 mg, 100%) as a colorless oil. 1 H-NMR (300 MHz, CDCl 3): d 1.00-1.34 (m, 5H), 1.44 (s, 9H), 1.54-1.82 (m, 6H), 3.73 ( s, 3H), 4.20 (dd, J = 2.8, 5.0 Hz, 1H), 5.05 (bs, 1H); 13 C-NMR (75.5 MHz, CDCl 3): d 26.0, 28.2, 28.3, 29.5, 41.1, 52.0, 58.3, 79.7, 155.6, 172 , 9. Example 9 (S) - ((S) -2-Benzyloxycarbonylamino-3-methyl-butyrylamino) -cyclohexyl-acetic acid methyl ester (9) Compound 8 (93 mg, 0.4343 mmol) was deprotected and coupled with Z-Val-OH (95 mg, 0.378 mmol) according to the method for the preparation of 39. Flash column chromatography (toluene / ethyl acetate 4: 1) gave the title compound (131 mg, 94%) as a colorless solid. 1 H-NMR (300 MHz, CDCl 3): d 0.92-1.30 (m, 11H), 1.54-1.88 (m, 6H), 2.02-2.18 (m, 1H), 3.72 (s, 3H), 4.05-4.18 (m, 1H), 4.52 (dd, J = 3.0, 5.5 Hz, 1H), 5.12 (s, 2H) , 5.49 (bs, 1H), 6.52 (bs, 1H), 7.34 (s, 5H); 13 C-NMR (75.5 MHz, CDCl 3): d 17.8, 19.0, 25.8, 28.2, 29.3, 31.2, 40.5, 51.9, 56.8, 60 , 0, 66.8, 127.7, 127.9, 128.1, 128.3, 136.2, 156.3, 171, 3, 172.2. Example 10 N-Boc-4R- (2-phenyl-7-methoxyquinolinyl-4-oxo) proline (10). To an agitated solution of N-Boc-trans-4-hydroxy-L-proline (3.9 g, 16.9 mmol) in DMSO (90 mL) was added potassium tert-butoxide (4.5 g, 40%). 1 mmol). After 1 hr, 4-chloro-2-phenyl-7-methoxyquinoline (4.5g, 16.7 mmol) was added and the mixture was stirred at room temperature for 12 hrs. The mixture was diluted with water (180 mL), washed with ethyl acetate (1 x 30 mL) and neutralized with 1 N HCl. The solid was filtered, washed with water and dried to give (4.65 g, 10 mmol) of product. > 95% purity by HPLC. M + H + 464.2. Example 1 1 2- (1-Ethoxycarbonyl-2-vinyl- tert -butylester cyclopropylcarbamoyl) -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidin-1-carboxylic acid (11). To a solution of 1-amino-2-vinyl-cyclopropanecarboxylic acid ethyl ester (41 mg, 0.26 mmol), 1.0 (1.1 mg, 0.22 mmol), HATU (204 mg, 0.54 mmol) in DMF (4 mL) was added diisopropylethylamine (187 DL, 1.08 mmol). After stirring at room temperature for 1 hr, dichloromethane (4 mL) was added. The solution was washed with aqueous NaHCO3 (sat) and with two portions of water. The organic layer was dried and concentrated. The product was sufficiently pure (> 95% by HPLC) to be used in the next step. M + H + 602.2. Example 12 ethylester of 1 - acid. { [4- (7-Methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic (12). Compound 11 was maintained in 1: 2 TFA-DCM (3 mL) at room temperature for 60 min. Toluene (3 mL) was added. The sample was co-evaporated to dryness. Purity by HPLC > 95% M + H + 502.4. Example 13 ethylester of 1 - acid. { [1 - [1 - (2-Hydroxy-indan-1-ylcarbamoyl) -2,2-dimethyl-propylcarbamoyl] -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl ]-Not me} -2-vinyl-cyclopropanecarboxylic (13). To a solution of compound 12 (0.13 mmol) in THF (2 mL), a large excess of NaHCO3 (s) and a solution of phosgene in toluene (1.6 M, 600 D L) were added. After 10 min of stirring the suspension was removed by filtration and concentrated to dryness. The solid was redissolved in dichloromethane and a large excess of NaHCO3 (s) and 2-Amino-? '- (2-hydroxy-indan-1 -yl) -3,3-dimethyl-butyramide (0.65 mmol) was added. . The suspension was stirred for 24-40 hrs at room temperature. The suspension was filtered, concentrated and subjected to column silica chromatography (gradient elution from 100% DCM to MeOH / DCM 2:98) to give the title compound (89.6 mg, 0.1 mmol). . Purity by HPLC > 95% M + H + 790.3. Example 14 1 - [1 - [1 - (2-HHiiddrroo 22, -2-dimethyl-propyl] -4- (6- methoxy-3-phenyl-naphthalen-1-yoloxy) -pyrrolidin-2-yl] -2-vinyl-cyclopropanecarboxylic acid (14). To a solution of 1 3 (76.7mg, 0.097mmol) in THF-MeOH 2: 3 (2mL) was added 5 equiv. of 1 M LiOH. The solution was maintained at 60 ° C for 60 min. After cooling to room temperature, 15-30 eq. of HOAc followed by toluene (2 mL) and then concentrated to dryness. The residue was taken up in DCM and washed with water. The organic layer was dried and concentrated to give the title compound (72 mg, 0.094 mmol). Purity > 95% by HPLC M + H + 762.2. Example 15 ? - (2-Hydroxy-indan-1 -yl) -2- [4- (6-methoxy-3-phenyl-naphthalen-1-yloxy) -2- (1-phenylmethanesulfonylaminocarbonyl-2-vinyl-cyclopropyl) -pyrrolidin- 1 -yl] -3,3-dimethyl-butyramide (15). To a solution of 14 (25 mg, 0.033 mmol) in chloroform (1 mL) was added benzenesulfonamide (1 0.5 mg, 0.066 mmol) followed by diisopropylethylamine (34 D L, 0.197 mmol). The solution was stirred at room temperature for 10 min and then at -20 ° C for 30 min. Then PyBOP (76 mg, 0.13 mmol) was added as a solid. The solution was maintained at -20 ° C for 48 hours. The solution is then The mixture was poured onto aqueous NaHCO3 (sat.) and washed with water. The organic layer was dried, concentrated and subjected to purification by HPLC, giving the title compound as a white solid. Example 16 2-tert-butoxycarbonylamino-3,3-dimethylbutyric acid bound to resin (16). Argonaut PS-TFP resin (1.38 mmol / g, 10 g) and 2-rerr-butoxycarbonylamino-3,3-dimethyl-butyric acid (4.5 g, .7mmol) dichloromethane (40 mL) and DMF (10 mL). To this mixture was added DMAP (1 g, 8.28 mmol) and then DI C (9.5 mL, 60.7 mmol). After 3 hrs of stirring at room temperature the resin was removed by filtration and washed consecutively with DMF, THF, DCM, THF, DCM and ether and then dried under vacuum. Example 17 [1- (2-Hydroxy-indan-1-carbamoyl) -2,2-dimethyl-propyl-carbamic acid tert -butylester (17). To a portion of 16 (200 mg) in DCM was added aminoindanol (0.14 mmol). The mixture was stirred for 2 hrs. He The liquid was removed by filtration and the resin was washed with 2xDCM. The combined liquids were combined and concentrated to dryness to give the title compound (20.5 mg, 0.055 mmol) Purity > 95% by HPLC. M + H + 363, 15. 13 C NMR D (100 MHz; CDCl 3; Me 4 Si) 27.0, 28.5, 34.2.39. 8, 50.8, 57.9, 68.2, 73.7, 124.8, 125.6, 127.4, 128.5, 140.4, 171, 6. 1H NMR DH (400 MHz; CDCl 3; Me 4 Si) 1, 07 (9H, s, CCH 3), 1.44 (9H, s, OCCH 3), 2.93 (1 H, dd, Jgem 16.4 Hz, J3.2 2.3 Hz, CH2), 3.15 (1 H, dd, Jgem16.4 Hz, J3.2 5.2 Hz, CH2), Example 18 2-Aniino-butyramide? - (2-hydroxy-indan-1 -yl) -3,3-dimethyl (18). Compound 17 was maintained in DCM-TFA 2: 1 (2 mL) for 60 min at room temperature. The solution was co-evaporated with toluene to dryness. Example 19 (2-iyer-Butoxycarbonylamino-3,3-dimethyl-butyrylamino) -cyclohexyl-acetic acid methyl ester (1 9). To a solution of 2-tert-butoxycarbonylamino-3,3- acid dimethylbutyric acid (500 mg, 2.16 mmol), amino-cyclohexyl-acetic acid methylester (444 mg, 2.59 mmol) and HATU (2 g, 5.40 mmol) in DMF (20 mL) was added diisopropylethylamine (1 ml). 88 mL, 10.8 mmol). The solution was stirred for 1 hr at room temperature and diluted with dichloromethane (40 mL). This solution was washed with aqueous NaHCO3 (sat.) And water (x2), dried and concentrated. The product resulted > 95% purity. M + H + 385.4. Example 20 acid tert-butyl ester. { 1 - [(Cyclohexyl-methylcarbamoyl-methyl) -carbamoyl] -2,2-dimethyl-propyl} -carbámico (20). To compound 19 in EtOH-THF 1: 2 a large excess of methylamine (30% in water) was added and left at room temperature for 2 weeks. The solution was concentrated to dryness and the residue was subjected to a short column of silica gel eluted with 2% MeOH in dichloromethane to give a pure product (> 95%) M + H + 384.5. Example 21 2-Amino -? / - (cyclohexyl-methylcarbamoyl-methyl) -3,3-dimethyl-butyramide (7.1). Compound 20 was maintained in dichloromethane-trifuoroacetic acid 2: 1 for 1 h at room temperature and concentrated to dryness. The residue was dried under vacuum for 16 hrs. Analysis by C18 HPLC in reversed phase showed > 95% purity M + H + 283, 1. Example 22 acid (1 R, 2S) -1 -. { [(2S, 4R) -1 - ((1 S, 2R) -2-Hydroxy-indan-1-ylcarbamoyl) -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine- 2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic (22). Compound 12 was treated as described for the preparation of 13 but with the use of (1 S, 2R) -cis-1-amino-2-indanol in place of 2-amino-N- (2-hydroxyindan-) butyramide. 1-yl) -3,3-dimethyl followed by ester hydrolysis as described for the preparation of compound 14 gave the title compound. Purity by HPLC > 95% M + H + 649, 1. Example 23 r ^ X acid (1 R, 2S) -1 -. { [(2S, 4R) -1 - [(1 S) -1 - (Cyclohexylmethyl-carbamoyl) -2-methyl-propylcarbamoyl] -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidin- 2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic (23). N- (Tert-butoxycarbonyl) -L-valine was attached to the resin as described for the preparation of compound 16 and then reacted with cyclohexylamine as described for the preparation of 17 and the Boc group was removed as described for The resulting compound was then reacted with the chlorocarbamate obtained from 12 as described for the preparation of 13 which gave the title compound. Purity by HPLC > 95% M + H + 712.3. Example 24 acid (1 R, 2S) -1 -. { [(2S, 4R) -1 - ((1 R) -2-Hydroxy-1-phenyl-ethylcarbamoyl) -4- (7- methoxy-2-phenyl-quinoIin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic (24). Compound 12 was treated as described for the preparation of 13 but with the use of (R) -2-phenylglycinol in place of 2-amino-N- (2-hydroxyindan-1-yl) -3,3-butyramide dimethyl followed by ester hydrolysis as described for the preparation of compound 14 gave the title compound. Purity by HPLC > 95% M + H + 637.1. Example 25 Acid (1 R, 2S) -1 -. { [(2S, 4R) -1 -. { [(1 S) -Cyclohexyl- (cyclohexylmethyl-carbamoyl) -methyl] -carbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyridinidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic (25). N- (tert-butoxycarbonyl) -L-cyclohexylglycine was attached to the resin as described for the preparation of compound 16 and then reacted with cyclohexanmethylamine as described for the preparation of 17 and the Boc group was removed as described for The resulting compound was then reacted with the chlorocarbamate obtained from 12 as described for the preparation of 13 which gave the title compound. Purity by HPLC > 95% M + H + 752.4. Example 26 acid (1 R, 2S) -1 -. { [(2S, 4R) -1 - [(1 S) -2-Cyclohexyl-1 - (cyclohexylmethyl-carbamoyl) -ethylcarbamoyl] -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrole id n-2-carbonyl] -amino} -2-vinyl-cyclopropane carboxylic acid (26). N- (Tert-butoxycarbonyl) -L-cyclohexylalanine was bound to the resin as described for the preparation of compound 16 and then reacted with cyclohexanmethylamine as described for the preparation of 17 and the Boc group was removed as described for 18. The resulting compound was then reacted with the chlorocarbamate obtained from 12 as described for the preparation of 13 which gave the title compound. Purity by HPLC > 95% M + H + 766.4. Example 27 acid (1 R, 2S) -1 -. { [(2S, 4R) -1 - [(1 S) -1 - (Cyclohexylmethylcarbamoyl) -2.2- dimethyl-propylcarbamoyl] -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic (27). N- (tert-butoxycarbonyl) -L-tert-butylglycine was attached to the resin as described for the preparation of compound 16 and then reacted with cyclohexanmethylamine as described for the preparation of 17 and the Boc group was removed as described. described for 18. The resulting compound was then reacted with the chlorocarbamate obtained from 12 as described for the preparation of 13 which gave the title compound. Purity by HPLC > 95% M + H + 726.3. Example 28 acid (1 R, 2S) -1 -. { [(2S, 4R) -1 - [(1 S) -1 - (Cyclohexylmethylcarbamoyl) -2-phenyI-ethylcarbamoyl] -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrole Din-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic (28). N- (Tert-butoxycarbonyl) -L-phenylalanine was attached to the resin as described for the preparation of compound 16 and then reacted with cyclohexanmethylamine as described for the preparation of 17 and the Boc group was removed as described for 18. The resulting compound was then reacted with the chlorocarbamate obtained from 12 as described for the preparation of 13 which gave the title compound. Purity by HPLC > 95% M + H + 760.4. Example 29 acid (1 R, 2S) -1 -. { [(2S, 4R) -1 - [(1 S) -1 - ((1 S, 2R) -2-Hydroxy-indan-1-carbamoyl) -3-phenyl-propylcarbamoyl] -4- (7-methoxy) 2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic (29). N- (tert-butoxycarbonyl) -L-phenethylglycine was attached to the resin as described for the preparation of compound 16 and then reacted with (1 S, 2R) -cis-1-amino-2-indanol as described for the preparation of 17 and the Boc group was removed as described for 18. The resulting compound was then reacted with the chlorocarbamate obtained from 12 as described for the preparation of 13 which gave the title compound. Purity by HPLC > 95% M + H + 810.4. Example 30 acid (1 R, 2S) -1 -. { [(2S, 4R) -1 - ((1 S) -1-Benzylcarbamoyl-2-methyl-propylcarbamoyl) -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyridinidine-2-carbon I] -amino} -2-vinyl-cyclopropanecarboxylic (30). N- (tert-butoxycarbonyl) -L-valine was bound to the resin as described for the preparation of compound 16 and then reacted with benzylamine as described for the preparation of 17 and the Boc group was removed as described for The resulting compound was then reacted with the chlorocarbamate obtained from 12 as described for the preparation of 13 which gave the title compound. Purity by HPLC > 95% M + H + 706.2. Example 31 acid (1 R, 2S) -1 -. { [(2S, 4R) -1 - [(1 S) -1 - ((1 R) -2-Hydroxy-1-phenyl- ethylcarbamoyl) -2,2-dimethyl-propylcarbamoyl] -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-v1niI-cyclopropanecarboxylic acid (31) N- (tert-butoxycarbonyl) -L-tert-butylglycine was bound to the resin as described for the preparation of compound 16 and then reacted with (R) -2-phenylglycinol as described for the preparation of 17 and the Boc group was removed as described for 18. The resulting compound was then reacted with the chlorocarbamate obtained from 12 as described for the preparation of 1 3 which gave the title compound. Purity by HPLC > 95% M + H + 750.3. Example 32 acid (1 R, 2S) -1 -. { [(2S, 4R) -1 - [(1 S) -1 - ((1 R) -lndan-1 -Icarbamoyl) -2-methyl-propiIcarbamoyl] -4- (7-methoxy-2-phenol -quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic (32). (2S) -ferf-butoxycarbonylamino-3-methylbutyric acid was attached to the resin as described for the preparation of compound 16 and then reacted with (1 R) -1-amino dinin as described for the preparation of 17 and eliminated the Boc group as described for 18. The resulting compound was then reacted with the chlorocarbamate obtained from 12 as described for the preparation of 13 which, after purification by HPLC, gave the title compound (12.5 mg, 28% yield), Purity by HPLC > 90% M + H + 732.2. Example 33 acid (1 R, 2S) -1 -. { [(2S, 4R) -1 - [(1 S) -1 - ((1 S) -lndan-1 -ylcarbamoyl) -2-methyl-propylcarbamoyl] -4- (7-methoxy-2-phenyl-quinoline- 4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic (33). (2S) -ferf-butoxycarbonylamino-3-methylbutyric acid was attached to the resin as described for the preparation of compound 1 6 and then reacted with (1 S) -1-amino dinin as described for the preparation of 17 and the Boc group was removed as described for 18. The resulting compound was then reacted with the chlorocarbamate obtained from 12 as described for the preparation of 13 which, after purification by HPLC, gave the title compound (22 mg, 49% yield), Purity by HPLC > 90% M + H + 732.2. Example 34 acid (1 R, 2S) -1 -. { [(2S, 4R) -1 - [(1 S) -1- (2-hydroxyethylcarbamoyl) -2-methyl-propylcarbamoyl] -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidin- 2-carboniI] -amino} -2-vinyl-cyclopropanecarboxylic (34). (2S) -ery-butoxycarbonylamino-3-methylbutyric acid was attached to the resin as described for the preparation of compound 16 and then reacted with 2-aminoethanol as described for the preparation of 17 and the Boc group was removed as it is described for 18. The resulting compound was then reacted with the chlorocarbamate obtained from 12 as described for the preparation of 13 which, after purification by HPLC, gave the title compound (3 mg, 8% yield), Purity by HPLC > 90% M + H + 660.2. Example 35 acid (1 R, 2S) -1 -. { [(2S, 4R) -1 - [(1 S) -1 - ((1 S, 2R) -2-Hydroxy-indan-1 - ilcarbamoyl) -2-methyl-propylcarbamoyl] -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic (35). (2S) -ferf-butoxycarbonylamino-3-methylbutyric acid was attached to the resin as described for the preparation of compound 16 and then reacted with (1 S, 2R) -1-amino-2-indanol as described for the preparation of 17 and the Boc group was removed as described for 18. The resulting compound was then reacted with the chlorocarbamate obtained from 12 as described for the preparation of 13 which, after purification by HPLC, gave the title (10 mg, 22% yield), Purity by HPLC > 90% M + H + 748.2. Example 36 acid (1 R, 2S) -1-. { [(2S, 4R) -1 - [(1 S) -1 - ((1 R, 2S) -2-Hydroxy-indan-1-carbamoyl) -2-methyl-propylcarbamoyl] -4- (7- methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic (36). (2S) -ferf-butoxycarbonylamino-3-methylbutyric acid was attached to the resin as described for the preparation of compound 16 and then reacted with (1R, 2S) -I-amino-2-indanol as described for the preparation of 17 and it The Boc group was removed as described for 18. The resulting compound was then reacted with the chlorocarbamate obtained from 12 as described for the preparation of 13 which, after purification by HPLC, gave the title compound (1.1 mg, 24% yield), Purity by HPLC > 75% M + H + 748. Example 37 acid (1 R, 2S) -1 -. { [(2S, 4R) -1 -. { [CyclohexyI- (S) - ((1 S, 2R) -2-hydroxy-indan-1-carbamoyl) -methyl] -carbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic (37). (2S) -tert-butoxycarbonylamino-cyclohexylacetic acid was attached to the resin as described for the preparation of compound 16 and then reacted with (1 S, 2R) -1-amino-2-indanol as described for the preparation of 17 and the Boc group was removed as described for 18. The resulting compound was then reacted with the chlorocarbamate obtained from 12 as described for the preparation of 13 which, after purification by HPLC, gave the title compound ( 7.5 mg, 16% yield), Purity by HPLC > 95% M + H + 788.3. Example 38 AOH OR acid (1 R, 2S) -1 -. { [(2S, 4R) -1 - [(1 S) -1 - ((1 S, 2R) -2-Hydroxy-indan-1-ylcarbamoyl) -2,2-dimethyl-propiIcarbamoyl] -4- (7- methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic (38). (2S) -ferf-butoxycarbonylamino-3,3-dimethylbutyric acid was attached to the resin as described for the preparation of compound 16 and then reacted with (1 S, 2R) -1-amino-2-indanol as described for the preparation of 17 and the Boc group was eliminated as described for 18. The resulting compound was then reacted with the chlorocarbamate obtained from 12 as described for the preparation of 1 3 which, after purification by HPLC, gave the title compound (12 mg, 26% yield), Purity by HPLC > 95% M + H + 762.3. Example 39 acid (1 R, 2S) -1 -. { [(2S, 4R) -1 - [(1 S) -1 - ((1 S, 2R) -2-Hydroxy-indan-1 - ilcarbamoyl) -3,3-dimethyl-butylcarbamoyl-4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic (39). (2S) -reryl-butoxycarbonylamino-4,4-dimethylpentanoic acid was attached to the resin as described for the preparation of compound 16 and then reacted with (1 S, 2R) -1-amino-2-indanol as described for the preparation of 17 and the Boc group was eliminated as described for 1 8. The resulting compound was then reacted with the chlorocarbamate obtained from 12 as described for the preparation of 13 which, after purification by HPLC, gave the title compound (14.2 mg, 30% yield), Purity by HPLC > 95% M + H + 776.3. Example 40 acid (1 R, 2S) -1 -. { [(2S, 4R) -1 - [(1 S) -1 - ((1 S, 2R) -2-Hydroxy-indan-1 -Icarbamoyl) -2-phenyl-ethylcarbamoyl] -4- (7 -methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic (40). (2S) -erf-butoxycarbonylamino-3-phenylpropanoic acid was attached to the resin as described for the preparation of compound 16 and then reacted with (1 S, 2R) -1-amino-2-indanol as described for the preparation of 17 and it The Boc group was removed as described for 18. The resulting compound was then reacted with the chlorocarbamate obtained from 12 as described for the preparation of 13 which, after purification by HPLC, gave the title compound (2.4 mg , 5% yield), Purity by HPLC > 95% M + H + 796.2. Example 41 acid (1 R, 2S) -1 -. { [(2S, 4R) -1 - [(1 S) -2-Cyclohexyl-1 - ((1 S, 2R) -2-hydroxy-indan-1-carbamoyl) -ethylcarbamoyl] -4- (7-methoxy) 2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic (41). (2S) -reryl-Butoxycarbonyl-amino-3-cyclohexylpropanoic acid was attached to the resin as described for the preparation of compound 16 and then reacted with (1 S, 2R) -1-amino-2-indanol as described for the preparation of 17 and the Boc group was removed as described for 18. The resulting compound was then reacted with the chlorocarbamate obtained from 12 as described for the preparation of 13 which, after purification by HPLC, gave the title (12.3 mg, 25% yield), Purity by HPLC > 95% M + H + 802.3. Example 42 n acid (1 R, 2S) -1 -. { [(2S, 4R) -1 -. { (1 S) -1 - [(S) - (Cyclohexyl-methylcarbamoyl-methyl) -carbamoyl] -2,2-dimethyl-propylcarbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic (42). Compound 12 was treated as described for the preparation of 13 but with the use of 21 in place of 2-amino-? / - (2-hydroxy-indan-1 -yl) -3,3-dimethyl-butyramide followed by ester hydrolysis as described for the preparation of compound 14 which, after purification by HPLC, gave the title compound (8.6 mg, 18% yield). Purity by HPLC > 95% M + H + 783.3. Example 43 1 - . 1- (2-Amino-4-methoxyphenyl) ethanone (43) m-Anisidine (10.0 g, 82 mmol) was dissolved in CH2Cl2 (50 mL), and the solution was cooled to -50 ° C. BCI3 (1 M in CH2Cl2, 82 mL, 82 mmol) was added slowly over 20 min, after which the mixture was stirred at -50 ° C for 30 min, and then added consecutively AcCl (6.0 mL, 84 mmol) and ACI3 (1 1 g, 82 mmol). The mixture was stirred at -50 ° C for 1 h and then allowed to reach room temperature. After stirring at room temperature overnight, the solution was heated at 40 ° C for 4 h, after which the mixture was poured onto ice. The aqueous mixture was basified with 10% NaOH (w / v) and extracted with EtOAc (4 x 200 mL). The combined organic phases were washed with brine, dried (MgSO 4), and evaporated to give a black solid, which was purified by flash column chromatography (ether / CH 2 Cl 2 20:80). The resulting solid was recrystallized from ether / hexane to give compound 93 as bright toasted flakes (5.6 g, 42%). Example 44? / - (rerí-Butii) -? '-isopropylthiourea (44) To a solution of rt-butyl isothiocyanate (5), 0 mL, 39 mmol) in CH2Cl2 (200 mL) were added isopropylamine (4.0 mL, 47 mmol) and diisopropylethylamine (DIEA) (6.8 mL, 39 mmol), and the mixture was stirred at room temperature for 2 h . The reaction mixture was diluted with EtOAc, washed with 1 0% citric acid (2x), saturated NaHCO3 (2x), H2O (2x), and brine (1x). The organic layer was dried (MgSO4) and evaporated to give compound 94 (3.3 g, 52%) as a white solid which was used without further purification. Example 45: Msopropylthiourea (45) Compound 44 (3.3 g, 20 mmol) was dissolved in conc. HCl. (45 mL) and the solution was refluxed for 40 min. Mix it was allowed to cool to room temperature and then cooled in an ice bath and basified to pH 9.5 with solid and saturated NaHCO3, after which the product was extracted with EtOAc (3x). The combined organic phases were washed with H2O (2x) and brine (1x), dried (MgSO4), and evaporated to give crude compound 95 (2.1 g, 90%) which was used without further purification. Example 46 2- (lsopropylamino) -1,3-thiazole-4-carboxylic acid hydrobromide (46) A suspension of compound 45 (2.1 g, 1 8 mmol) and 3-bromopyruvic acid (3.0 g, 18 mmol) in dioxane (180 mL) was heated to 80 ° C. Upon reaching 80 ° C the mixture became transparent, and then the product began to precipitate as a white solid.

After 2 h of heating, the reaction mixture was cooled to room temperature and the precipitate was removed by filtration and collected. This gave pure compound 46 (4.4 g, 94%). Example 47 ? / - (2-Acetyl-5-methoxyphenyl) -2- (isopropylamino) -1,3-thiazole-4-carboxamide (47) A mixture of compound 46 (4.4 g, 16.5 mmol) and the aniline derivative 93 (2.75 g, 16.5 mmol) in pyridine (140 mL) was cooled to -30 ° C (upon cooling, the clear solution partially turned into a suspension). POCI3 (3.3 mL, 35 mmol) was added slowly over a period of 5 min. The mixture was stirred at -30 ° C for 1 h, and then allowed to reach room temperature. After stirring at room temperature for 1.5 h the reaction mixture was poured onto ice, the pH was adjusted to about 9-1 0 using solid and saturated NaHCO3. The crude product was extracted with CH2Cl2 (3x) and the combined organic phases were dried (MgSO4) and evaporated. The crude dark beige solid was purified by flash column chromatography (hexane / EtOAc 55:45) to give compound 47 (5.6 g, 76%) as a pale yellow solid. Example 48 2- [2- (lsopropylamino) -1,3-thiazol-4-yl] -7-methoxyquinolin-4-ol (48) A solution of t. BuOK (2.42 g, 21 mmol) in t. Anhydrous BuOH (40 mL) was heated to reflux. Compound 47 (1.8 g, 5.4 mmol) was added in portions over a period of 5 min, and the dark red colored solution was stirred at reflux for another 20 min. The mixture was cooled to room temperature, and HCl (4) was added.

M in dioxane, 8.0 mL, 32 mmol), after which the reaction mixture was concentrated under vacuum, to ensure that all HCl and dioxane had been removed, the crude product was redissolved in CH2Cl2 twice and evaporated completely to obtain the slightly impure HCl salt of compound 98 (1.62 g) as a brown solid. The product was dissolved in CH 2 Cl 2 and washed with saturated NaHCO 3, after which the aqueous phase was extracted several times with CH 2 Cl 2. The combined organic phases were dried (MgSO4) and evaporated to give the title compound (1.38 g, 81%) as a light brown solid (> 95% purity according to HPLC assays). H-NMR (MeO -d4, 400 MHz): d 1.30 (d, J = 6.0 Hz, 6H), 3.93 (s, 3H), 3.95-4.07 (m, 1 H ), 6.73 (s, 1 H), 6.99 (dd, J = 2.4, 9.2 Hz, 1 H), 7.26 (d, J = 2.4 Hz, 1 H), 7.37 (s, 1 H), 8, 10 (d, J = 9.2 Hz, 1 H). Example 49 tert-butylester of (1S) -1 - acid. { [(2S, 4R) -2- (1-methoxycarbonyl-butylcarbamoyl) -4- (7-methoxy-2-phenyl-quinolin-4-yloxy]] - pyrrolidine} -carboxylic (49) The reaction of 10 with Nva-OMe hydrochloride according with the method described in Example 1 1 gave the title compound.

Purity > 95% by HPLC, M + H + 578.24. Example 50 acid methyl ester (1 S) -1 -. { [(2S, 4R) -2- [4- (7-Methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} pentanoic (50) Compound 49 was maintained in TFA-DCM 1: 2 (3 mL) at room temperature for 60 min. Toluene (3 L) was added. The sample was co-evaporated to dryness. Purity by HPLC > 95% M + H + 478.21. Example 51 acid methyl ester (1 S) -2-. { [(2S, 4R) -1 - [(1 S) -1 - (Cyclohexylmethyl-carbamoyl) -2-methyl-propylcarbamoyl] -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidin- 2-carbonyl] -amino} -pentanoco (51) To a solution of 50 (0.1 mmol) in THF (4 mL), cooled to 0 ° C, a large excess of NaHCO3 (s) and a solution of phosgene in toluene (0.2 mmol, 21 DL) were added. . After 10 min of stirring the suspension was removed by filtration and concentrated to dryness. The solid was redissolved in dichloromethane and a large excess of NaHCO3 (s) and 2-amino-N-cyclohexylmethyl-3-methyl-butyramide, described in Example 23, (0.15 mmol) was added. The suspension was stirred 30 hrs at room temperature. The suspension was filtered, concentrated and subjected to column silica chromatography (gradient elution from 100% DCM to MeOH / DCM 2:98) to give the title compound (30 mg, 0.042 mmol). Purity by H PLC > 95% M + H + 716.40. Example 52 acid (1 S) -2-. { [(2S, 4R) -1 - [(1 S) -1 - (Cyclohexylmethyl-carbamoyl) -2-methyl-propylcarbamoyl] -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrididin- 2-carbonyl] -amino} pentanoic acid (52) To a solution of 51 (26 mg, 0.036 mmol) in THF-MeOH 2: 3 (2 mL) was added 1.5 equiv. of 1 M LiOH. The solution was maintained at 60 ° C for 60 min. After cooling to room temperature, added HOAc followed by toluene (2 mL) and then concentrated to dryness to give the title compound (25 mg, 0.035 mmol). Purity > 95% by HPLC M + H + 702.34. Example 53 Ethyl ester of acid (1 R, 2S) -1 -. { [(2S, 4R) -1 - [2- (2-Methoxy-phenoxy) -ethylcarbamoyl] -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic acid (53) To a solution of 12 (0.06 mmol) in THF (2 mL), a large excess of NaHCO3 (s) and a solution of phosgene in toluene (0.078 mmol) were added. After 10 min of stirring the suspension was removed by filtration and concentrated to dryness. The solid was redissolved in dichloromethane and a large excess of NaHCO3 (s) and 2- (2-methoxy-phenoxy) -ethylamine (15 mg, 0.09 mmol) was added. The suspension was stirred for 30 hrs at room temperature. The suspension was filtered, concentrated to dryness, redissolved in MeOH and subjected to purification by HPLC to give the title compound (10.6 mg, 0.01 mmol). Purity by HPLC > 95% M + H + 695, 17. Example 54 acid (1 R, 2S) -1 -. { [(2S, 4R) -1 - [2- (2-Methoxy-phenoxy) -ethylcarbamoyl] -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic (54) To a solution of 53 (0.6 mg, 0.0153 mmol) in THF-MeOH 2: 3 (2 mL) was added 10 equiv. of 1 M LiOH. The solution was maintained at 50 ° C for 60 min. After cooling to room temperature, 25 equiv. of HOAc followed by toluene (2 mL) and then concentrated to dryness. The residue was taken up in ethyl acetate, filtered and concentrated to dryness to give the title compound (9.4 mg, 0.014 mmol). Purity > 95% by HPLC M + H + 667, 14. Example 55 acid (1 R, 2S) -1 -. { [(2S, 4R) -1 - ((1 S, 2R) -5-Hydroxy-4,5,6,7-tetrahydro- benzo [b] thiophen-4-yl-carbamoyl)) - 4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic acid (55) The procedure described in example 53 was followed but with the use of 2-amino-4,5,6,7-tetrahydro-benzo [b] thiophen-5-ol instead of 2 - (2-methoxy-phenoxy) -ethylamine, and then the ethyl ester was hydrolysed as described in Example 54 which gave the title compound (7.5 mg, 0.01 mmol). Purity > 95% by HPLC M + H + 669. Example 56 acid (1 R, 2S) -1 -. { [(2S, 4R) -1 - [(3R) -3-Hydroxy-pyrrolidin-1 -carbonyl)] - 4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -Not me} -2-vinyl-cyclopropanecarboxylic acid (56) The procedure described in Example 53 was followed but with the use of (R) -3-pyrrolidinol in place of 2- (2-methoxy-phenoxy) -ethylamine, and then the hydrolyzed ethyl ester as described in example 54 gave the title compound (4 mg, 0.007 mmol). Purity > 95% by HPLC M + H + 587, 1.

Example 57 acid (1 R, 2S) -1 -. { [(2S, 4R) -4- (7-Methoxy-2-phenyl-quinolin-4-yloxy) -1 - [(thiophen-2-yl-methyl) -carbamoyl] -pyrrolidin-2-carbonyl} -amino) -2-vinyl-cyclopropanecarboxylic acid (57) The procedure described in example 53 was followed but with the use of thiophen-2-methylamine instead of 2- (2-methoxy-phenoxy) -ethylamine, and then hydrolyzed Ethyl ester as described in Example 54 gave the title compound (8 mg, 0.013 mmol). Purity > 95% by HPLC M + H + 613.08. Example 58 acid (1 R, 2S) -1 -. { [(2S, 4R) -1 [(1,1-Dioxo-tetrahydro-1-D6-thiophen-3-ylcarbamoyl) -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyridinidine -2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic (58) The procedure described in example 53 was followed but with the use of 3-aminotetrahydro-1 H-1 D6-thiophen-1, 1-dione in place of 2- (2-methoxy-phenoxy) -ethylamine, and then the ethyl ester was hydrolyzed as described in example 54 which gave the title compound (13 mg, 0.02 mmol). Purity > 95% by HPLC M + H + 635.05. Example 59 2-Amino-3,3-dimethyl-N-thiophen-2-yl-methyl-butyramide (59) The title compound was prepared as described in example 17 but with the use of thiophen-2-methylamine instead of aminoindanol and eliminating the Boc group as described in example 18. Example 60 2-Amino-N- (6-hydroxy-4I5,6,7-tetrahydro-benzo [b] thiophen-5-yl) -3,3-dimethyl-butyramide (60) The title compound was prepared as described in Example 17 but with the use of 2-amino-4,5,6,7-tetrahydro- benzo [b] thiophen-5-ol in place of aminoindanol and eliminating the Boc group as described in example 18. Example 61 2-Amino-N- (2-diethylamino-etiI) -3,3-dimethyl-butyramide (61) The title compound was prepared as described in example 17 but with the use of N, N-diethylethylenediamine instead of aminoindanol and eliminating the Boc group as described in Example 1 8. Example 62 2-Amino-N- [2- (2-methoxy-phenoxy) -ethyl] -3,3-dimethyl-butyramide (62) The title compound was prepared as described in example 17 but with the use of 2-methoxyphenoxyethyl amine instead of aminoindanol and eliminating the Boc group as described in example 18. Example 63 2-Amino-1- (3-hydroxy-pyrrolidin-1-yl) -3,3-dimethyl-butan-1-one (63) The title compound was prepared as described in example 17 but with the use of (R) -3-pyrrolidinone in place of aminoindanol and eliminating the Boc group as described in example 18. Example 64 2-Amino-N- (1,1-dioxo-tetrahydro-1-? 6-thiophen-3-yl) -3,3-dimethyl-butyramide (64) The title compound was prepared as described in example 17 but with the use of 2-methoxyphenoxyethylamine in place of aminoindanol and eliminating the Boc group as described in example 18. Example 65 acid ethyl ester (1 l-1 - [(thiophen 2-yl-methyl) -carbamoyl] -propylcarbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic acid (65) To a solution of 12 (0.06 mmol) in THF (2 mL), a large excess of NaHCO3 (s) and a solution of phosgene in toluene (0.078 mmol) were added. After 10 min of stirring the suspension was removed by filtration and concentrated to dryness. The solid was redissolved in dichloromethane and a large excess of NaHCO3 (s) and 59 (0.09 mmol) was added. The suspension was stirred for 30 hrs at room temperature. The suspension was filtered, concentrated to dryness, redissolved in MeOH and subjected to purification by HPLC to give the title compound (15.5 mg, 0.02 mmol). Purity by HPLC > 95% M + H + 754.2. Example 66 acid (1 R, 2S) -1 -. { [(2S, 4R) -1 - [(1 S) -1 - (2,2-Dimethyl-1 - [(thiophen-2-ylmethyl) -carbamoyl] -propylcarbamoyl.} -4- (7-methoxy) 2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino.} -2-vinyl-cyclopropanecarboxylic acid (66) To a solution of 65 (14 mg, 0.017 mmol) in THF-MeOH 2: 3 (2 mL) 10 equiv. Of 1 M LiOH was added The solution was kept at 50 ° C for 60 min. environment, 20 equiv. of HOAc followed by toluene (2 mL) and then concentrated to dryness. The residue was taken up in ethyl acetate, filtered and concentrated to dryness to give the title compound (13 mg, 0.017 mmol). Purity > 95% by HPLC M + H + 748, 1 3. Example 67 acid (1 R, 2S) -1 -. { [(2S, 4R) - (1 S) -1 - [(1 S, 2R) -1 - [1 - (5-Hydroxy-4,5,6,7-tetrahydro-benzo [b] thiophen-4- il-carbamoyl) -2,2-dimethyl-propylcarbamoyl] -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic acid (67) The procedure described in Example 65 was followed but with the use of 60 instead of 59, and then the ethyl ester was hydrolyzed as described in Example 66 which gave the title compound ( 4 mg, 0.005 mmol). Purity > 95% by HPLC M + H + 782, 16. Example 68 acid (1 R, 2S) -1 -. { [(2S, 4R) -1 - [(1 S) -1 - (2-Diethylamino-ethylcarbamoyl) -2,2-dimethyl-propylcarbamoyl] -4- (7-methoxy-2-phenyl-quinolin-4-yloxy ) -pyrrolidin-2-carboniI] -amino} -2-vinyl-cyclopropanecarboxylic acid (68) The procedure described in Example 65 was followed but with the use of 61 instead of 59, and then the ethyl ester was hydrolysed as described in Example 66 which gave the title compound ( 6 mg, 0.008 mmol). Purity > 95% by HPLC M + H + 729.24. Example 69 acid (1 R, 2S) -1 -. { [(2S, 4R) -1 - [(1 S) -1 - [2- (2-Methoxy-phenoxy) -ethylcarbamoyl] -2,2-dimethyl-propylcarbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic (69) The procedure described in Example 65 was followed but with the use of 62 instead of 59, and then the ethyl ester as described in example 66 gave the title compound (3 mg, 0.004 mmol). Purity > 95% by HPLC M + H + 780.19. Example 70 acid (1R, 2S) -1-. { [(2S, 4R) - (1S) -1 - [(3R) -1- (3-Hydroxy-pyrrolidine-1-carbonyl) -2,2-dimethyl-propylcarbamoyl] -4- (7-methoxy-2- phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic acid (70) The procedure described in Example 65 was followed but with the use of 63 instead of 59, and then the ethyl ester was hydrolysed as described in Example 66 which gave the title compound ( 12.4 mg, 0.02 mmol). Purity > 95% by HPLC M + H + 700.16. Example 71 acid (1R, 2S) -1-. { [(2S, 4R) -1 - [(1S) -1- (1,1-Dioxo-tetrahydro-1-? 6-thiophene 3-yl-carbamoyl) -2,2-dimethyl-propylcarbamoyl] -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic acid (71) The procedure described in Example 65 was followed but with the use of 64 instead of 59, and then the ethyl ester was hydrolyzed as described in Example 66 which gave the title compound ( 13 mg, 0.014 mmol). Purity > 95% by HPLC M + H + 748, 13. Example 72 (4R) -1 - (ferf-butoxycarbonyl) -4 - [(7-methoxy-2-phenylimin-4-yl) oxy] -L-prolyl-? / 1- (phenylsulfonyl) -L-norvalineamide (72) To a solution of 10 (60 mg, 0.13 mmol) in DMF, HATU (124 mg, 0.325 mmol), diisopropylethylamine (1 14 DL, 0.65 mmol) was added and stirred for 30 min at room temperature. ambient. A solution of 75 (0.157 mmol) in DMF was added. The suspension was stirred for 16 hrs at room temperature and then concentrated to dryness. The residue was taken up in DCM and washed with NaHCO3 (sat.), And water. The organic layer was dried, concentrated and subjected to silica column chromatography (elution gradient). from 100% DCM to 2% MeOH / DCM) to give the title compound (61 mg, 0.087 mmol). Purity > 90% by HPLC. M + H + 703.23. Example 73 (4f?) - 4 - [(7-methoxy-2-phenylq uinolin-4-yl) oxy] -L-prolyl-A / 1- (phenylsulfonyl) -L-norvalinemide (73) Compound 72 was maintained in DCM -TFA 2: 1 (2 mL) for 2.5 hr at room temperature. The solution was co-evaporated with toluene to dryness. Performance 1 00%. M + H 603, 12 Example 74 [(1 S) -1 - [[(phenylsulfonyl) amino] carbonyl] butyl] -carbamic acid phenylmethyl ester (74) To a stirred solution of Z-Nva-OH (150 mg, 0.59 mmol) in THF (6 mL), CDI (400 mg, 2.4 mmol) was added. The The suspension was stirred for 30 min at room temperature and then DBU (200 D L, 1.3 mmol) and a solution of benzenesulfonamide (250 mg, 1.59 mmol) in THF (2 mL) were added. The mixture was stirred at 60 ° C for 48 hrs and then concentrated to dryness. The residue was dissolved in MeOH and subjected to purification by HPLC to give the title compound (1 18.5 mg, 0.304 mmol). Purity > 95% by HPLC. M-H + 389.0, + Na 412.96. Example 75 (2S) -2-Amino-N- (phenylsulfonyl) pentanamide (75) Compound 74 was dissolved in MeOH (5 mL) and then Pd / C was added and subjected to hydrogenation for 2 hrs. The suspension was filtered through celite, washed with MeOH and concentrated to dryness to give the title compound. 100% performance M + H + 257.3. Example 76 1 - . 1 - . 1 - ( { 1 - [(cyclohexyl-methylcarbamoyl-methyl) -carbamoyl] -2,2-dimethyl-propiI.} - amide) -2- [(1-phenylmethanesulfonylaminocarbonyl-2-vinyl-cyclopropyl) -amide] 4- (7-Methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidin-1,2-dicarboxylic acid (76) To a solution of 42 (8.7 mg, 0.01 mmol) in chloroform (1 ml) was added D-toluenesulfonamide (7 mg, 0.04 mmol) followed by diisopropylethylamine (21 DL, 0.12 mmol). The solution was stirred at room temperature for 10 min and then at -20 ° C for 30 min. Then PyBOP (46.5 mg, 0.08 mmol) was added as a solid. The solution was maintained at -20 ° C for 48 hours. The solution was then poured over aqueous NaHCO3 (sat.) And washed with water. The organic layer was dried, concentrated and subjected to purification by HPLC, to give the title compound as a white solid (2.8 mg, 0.0049 mmol), Purity by H PLC > 95%, M + H + 936.26. Example 77 ? / - (2-Hydroxy-indan-1 -yl) -2- [4- (6-methoxy-3-phenyl-naphthalen-1-yloxy) -2- (1-methanesulfonylaminocarbonyl-2-vinyl-cyclopropyl) -pyrrolidin-1 -yl] -3,3-dimethyl-butyramide (77) The title compound was prepared as described in Example 76, using 14 as the starting material carboxylic acid and methanesulfonamide in place of D-toluenesulfonamide. Yield 13%, Purity by HPLC > 95%, M + H + 839.16. Example 78 4- (7-Methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidin-1,2-dicarboxylic acid 1 -. { [1- (Cyclohexylmethylcarbamoyl) -2-methyl-propyl] -amide} 2 - [(1-phenylmethanesulfonylaminocarbonyl-2-vinyl-cyclopropyl) -amide] (78) The title compound was prepared as described in Example 76, using 23 as the carboxylic acid starting material. 2% yield. Purity > 95% by HPLC. M + H + 865.28. Example 79 1 -. { [1 - (cyclohexylmethyl-carbamoyl) -2-methyl-propyl] -amide} 2 - [(1 - Phenylmethanesulfonylaminocarbonyl-butyl) -amide] 4- (7-Methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidin-1,2-dicarboxylic acid (79) The title compound was prepared as described in example 76 , using 52 as carboxylic acid starting material. 8% yield. Purity > 95% by HPLC. M + H + 855.28. Example 80 2 - [(1-benzenesulfonylaminocarbonyl-butyl) -amide] 1 -. { [1 - (cyclohexylmethyl-carbamoyl) -2-methyl-propyl] -amide} 4- (7-Methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidin-1,2-dicarboxylic acid (80) The title compound was prepared as described in example 76, using 52 as starting material carboxylic acid and benzenesulfonamide in place of D-toluenesulfonamide. Yield 21, 5%. Purity > 95% by HPLC. M + H + 841, 28 Example 81 r ^ 2 - [(1-benzenesulfonylaminocarbonyl-2-vinyl-cyclopropyl) -amide] 1 - (. {1 - [(cyclohexyl-methylcarbamoyl-methyl) -carbamoyl] -2,2-dimethyl-propyl} -amide) 4- (7-Methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidin-1,2-dicarboxylic acid (81) The title compound was prepared as described in example 76, using benzenesulfonamide instead of D -toluenesulfonamide. Performance 26%. Purity by HPLC > 95%, M + H + 922.23. Example 82 2 - [(1-benzenesulfonylaminocarbonyl-butyl) -amide] 1 -. { [1 - (2-hydroxy-indan-1-carbamoyl) -2-methyl-propyl] -amide} 4- (7-Methoxy-2-phenyliminol-4-yloxy) -pyrrolidin-1,2-dicarboxylic acid (82) To a solution of 73 (24.1 mg, 0.04 mmol) in DCM (2) ml), a large excess of NaHCO3 (s) and a solution of phosgene in toluene (50 D L, 0.096 mmol) were added. After 10 min of stirring the suspension was removed by filtration and concentrated to dryness. The solid was redissolved in DCM and a large excess of NaHCO3 (s) and 2-amino-γ / - (2-hydroxy-indan-1-yl) -3-methyl-butyramide, described in Example 35, was added ( 0.1 mmol). The suspension was stirred for 40 hrs at room temperature. The suspension was filtered, concentrated and subjected to purification by HPLC, to give the title compound (1.6 mg, 0.0018 mmol). Purity > 95% by HPLC. M + H + 877.21. Example 83 2 - [(1-Benzenesulfonylaminocarbonyl-butyl) -amide] 1 - ( { 1 - [(cyclohexyl-methylcarbamoylmethyl) -carbamoyl] -2,2-dimethyl-propyl} -amide) 4- (7-Methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidin-1,2-dicarboxylic acid (83) The title compound was prepared as described in example 82 but using 21 instead of 2-amino-? / - (2-hydroxy-indan-1 -yl) -3-methyl-butyramide. 2% yield. Purity > 95% by HPLC.

M + H + 912.25. Example 84 Ethyl ester of acid (1 R, 2S) -1 -. { [(4R, 2S) 1 - (1 - (1 S) -Hydroxymethyl-2,2-dimethyl-propiIcarbamoyl) -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbon il] -amino} -2-vi or I-pro-pancarboxylic cycle (84) The treatment of compound 12 as described for preparation 13 but with the use of (S) -tert-leucinol in place of 2-amino-N- (2-hidoxy) -indan-1 -yl) 3,3-dimethyl-butyramide gave the title product. M + H + 645.2. Example 85 Ethyl ester of acid (1 R, 2S) -1 -. { [(4R, 2S) 1 - (1 - (1 S) -Forml-2,2-dimethyl- propylcarbamoyl) -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyridinidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic acid (85) To a stirred solution of compound 84 (64 mg) in dichloromethane was added Dess-Martin periodinone (80 mg) at room temperature. After 4 hrs the suspension was filtered through basic alumina and concentrated to dryness. M + H + 643.2. Example 86 Ethyl ester of acid (1 R, 2S) -1 -. { [(4R, 2S) 1 -. { 1 - [((1 S, 2R) -2-Hydroxy-indan-1-ylamino) -methyl] -2,2-dimethyl-propylcarbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic acid (86) To a solution of compound 85 in THF (2 ml) and HOAc (0.5 ml) was added cyanoborohydride bound to polystyrene (2.36 mmol / g, 100 mg) and (1 S). , 2R) -1-aminoindan-2-ol (18 mg) and stirred for 4 hrs. The mixture was filtered, concentrated and purified on preparative HPLC. Purity by HPLC > 90% M + H + 776.5 Example 87 acid (1 R, 2S) -1 -. { [(4R, 2S) 1 -. { 1 - [((1 S, 2R) -2-Hydroxy-indan-1-ylamino) -methyl] -2,2-dimethyl-propylcarbamoyl} -4- (7-methoxy-2-phenyl-quinoIin-4-yloxy) -pyrol I id i n-2-carbonyl] -amino} -2-vin i I-propan carboxylic cycle (87) To a solution of compound 86 in THF (2 mL) and MeOH (1 mL) was added 1 N LiOH (0.2 mL) and the solution was maintained at 60 ° C. C for 1, 5 hrs. The suspension was neutralized with 1 N HCl to pH 7, concentrated and purified on preparative HPLC to give pure product by HPLC > 95% M + H + 748.4. Example 88 acid (1 R, 2S) -1 -. { [(4R, 2S) 1 - (1 -. {[[(1 S) - (Cyclohexyl-methylcarbamoyl-methyl) -amino] -methyl] -2,2-dimethyl-propylcarbamoyl) -4- (7- methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic (88) The treatment of compound 85 as described for preparation of 86 but with the use of 2-amino-2-cyclohexyl-N-methyl-acetamide (17 mg) instead of (1 S, 2R) -1-aminoindan-2-ol and then hydrolysis of the ethyl ester as described described in Example 87 gave the product of the title. Purity by HPLC > 95% M + H + 769.5 Example 89 (1S, 2R) -1 - ((2S) -2-amino-3,3-dimethyl-butyrylamino) -indan-2-yl ester of acetic acid (89) A solution of compound 17 (4g) was maintained in anhydride pyridine-acetic 2: 1 for 30 min. DCM was added and the solution was washed with citric acid (aq) and NaHCO3 (aq). The organic layer was concentrated to dryness which gave the acetylated product > 90% purity by HPLC. The resulting compound was then kept in a solution of 30% TFA in DCM for 1.5 hrs and then concentrated to dryness. Co-evaporation twice from toluene gave the title product > 90% purity by HPLC. Example 90 (2S, 4R) -2 - ((1 S, 2R) 1-Ethoxycarbonyl-2-vinyl- tert -butylester cyclopropylcarbamoyl) -4-hydroxy-pyrrolidin-1-carboxylic acid (90) A solution of HATU (6 g), diisopropylethylamine (6.8 mL), ethyl ester of (1R, 2S) -1-amino-2-vinyl-cyclopropanecarboxylic acid (1.5 g) and BOC-L-hydroxyproline (1.6 g) in dichloromethane was stirred for 1 hrs. The mixture was extracted with DCM-NaHCO3 (aq), dried and concentrated. HPLC, purity approximately 90% M + H + 369.1. Example 91 (1S, 2R) -1 - [(2S, 4R) - (4-Hydroxy-pyrrolidin-2-carbonyl) -amino] -2-vinyl-cyclopropanecarboxylic acid ethyl ester (91). Compound 90 was maintained in 30% trifluoroacetic acid in dichloromethane and 1% MeOH for 2 hrs before concentrating to dryness. The residue was redissolved in dichloromethane and with stirring 1N NaOH was added until pH 10-11. The organic layer was separated and concentrated giving 1.6 g of the title product. HPLC, purity approximately 90% M + H + 269.1. Example 92 Ethyl ester of (1R, 2S) -1- ( { (2S, 4R) -1 - [(1S) -1 - ((1S, 2R) -2-Acetoxy- indan-1-carbamoyl) -2,2-dimethyl-propylcarbamoyl] -4-hydroxy-pyrrolidine-2-carbonyl} -amino) -2-vinyl-cyclopropanecarboxylic acid (92). To a stirred solution of compound 89 (1.81 g) in acetonitrile at 0 ° C was added solid NaHCO3 (800 mg) and p-nitrophenylchlorocarbonate (1.2 g). The suspension was collected at room temperature and stirred for another 30 min. To this suspension was added a solution of compound 91 (1.6 g) in acetonitrile (5 mL) and diisopropylethylamine (1 mL). After 10 min the resulting mixture was concentrated, redissolved in ethyl acetate and washed with K2CO3 (aq) and then with 0.5 N HCl. Dried and concentrated giving a product > 80% purity by HPLC M + H + 599.6 Example 93 acid ester (1 R, 2S) -1 - ( { (2S, 4R) -1 - [(1) -1 - ((1 S, 2R) -2-Acetoxy-indan-1-carbamoyl) -2,2-dimethyl-propylcarbamoyl] -4-phenyIcarbamoyloxy-pyrrolidine-2-carbonyl} -amino) -2-vinyl-cyclopropanecarboxylic acid (93) To a stirred solution of compound 92 (20mg) in DCM and solid K2CO3 (200 mg) was added phosgene in toluene 20% (1 mL). After 6 hrs the suspension was removed by filtration and concentrated to dryness. To this residue was added a mixture of aniline (30 mg) DCM (3 mL) and solid NaHCO3 (50 mg) and stirred for 10 hrs. The mixture was filtered, concentrated and purified by preparative HPLC which gave the title product, > 95% purity M + H + 718.6. Example 94 acid (1 R, 2S) -1 - ( { (2S, 4R) -1 - [1 - ((1 S, 2R) -2-Hydroxy-indan-1-carbamoyl) -2,2-dimethyl- propylcarbamoyl] -4-phenylcarbamoyloxy-pyrrolidine-2-carbonyl} -amino) -2-vinyl-cyclopropanecarboxylic acid (94) To a solution of compound 93 in THF-MeOH 2: 1 (3 mL) was added 1 N LiOH (0.2 mL). The solution was heated at 60 ° C for 2 hrs. After cooling to room temperature acetic acid (0.5 mL) was added and the solution was concentrated to dryness. The remaining residue was purified by preparative HPLC which gave the title product > 95% purity M + H + 648.5. - ((1 S, 2R) -2 hydroxy-indan-1-ylcarbamoyl) -2,2-dimethyl-propylcarbamoyl] -pyrrolidin-3-yl ester of (5S, 3R) -3,4-Dihydro-1 H-isoquinoline-2-carboxylic acid (95) Treatment of compound 92 as described for the preparation of 93 but with the use of 1, 2,3,4-tetrahydro-isoquinoline in place of aniline and then hydrolysis of the ethyl ester as described in Example 94 gave the compound of Title. Purity > 90% M + H + 688.6. Example 96 (5S, 3R) -3,4-Dihydro-2H-quinoline-1-carboxylic acid 5 - ((1 R, 2S) -1-carboxy-2-vinyl-cyclopropylcarbamoyl) -1 - [1 - ((1 S , 2R) -2-hydroxy-indan-1-ylcarbamoyl) -2,2-dimethyl-propylcarbamoyl] -pyrrolidin-3-yl ester (96) The treatment of compound 92 as described for the preparation of 93 but with the use of 1, 2,3,4-tetrahydro-quinoline in place of aniline and then hydrolysis of the ethyl ester as described in Example 94 gave the title compound. Purity > 90% M + H + 688.6. Example 97 acid (1 R, 2S) -1 -. { [(2S, 4R) -1 - [(1 S) -1 - ((1 S, 2R) -2-Hydroxy-indan-1-carbamoyl) -2,2-dimethyl-propylcarbamoyl] -4- (pyridine- 3-ylmethylcarbamoyloxy) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic acid (97) The treatment of compound 92 as described for the preparation of 93 but with the use of 2-pyridin-3-yl-ethylamine instead of aniline and then the hydrolysis of the ethyl ester as described in Example 94 gave the title compound. Purity > 90% M + H + 663.5. Example 98 acid (1 R, 2S) -1 -. { [(2S, 4R) -1 - [(1 S) -1 - ((1 S, 2R) -2-Hydroxy-indan-1-carbamoyl) -2,2-dimethyl-propylcarbamoyl] -4- (methyl- phenethyl-carbamoyloxy) -pyrrole id i n-2-carbonyl] -amino} -2-vin i I-propan carboxylic cycle (98) The treatment of compound 92 as described for the Preparation of 93 but with the use of N-methylphenethylamine instead of aniline and then hydrolysis of the ethyl ester as described in example 94 gave the title compound. Purity > 90% M + H + 690.6. Example 99 acid (1 R, 2S) -1 - ( { (2S, 4R) -4-Benzylcarbamoyloxy-1 - [(1 S) -1 - ((1 S, 2R) -2-hydroxy-indan-1 - ilcarbamoyl) -2,2-dimethyl-propylcarbamoyl] -pyrrolidine-2-carbonyl.] -amino) -2-vinyl-cyclopropanecarboxylic acid (99) The treatment of compound 92 as described for the preparation of 93 but with the use of benzylamine instead of aniline and then hydrolysis of the ethylester as described in example 94 gave the title compound. Purity > 90% M + H + 662.4.

Example 100 acid (1 R, 2S) -1 - ( { (2S, 4R) -1 - [(1 S) -1 - ((1 S, 2R) -2-Hydroxy-indan-1-carbamoyl) -2 , 2-dimethyl-propylcarbamoyl] -4-phenethylcarbamoyloxy-pyrrolidine-2-carbonyl} -amino) -2-vinyl-cyclopropanecarboxylic acid (100) Treatment of compound 92 as described for the preparation of 93 but with the use of phenethylamine instead of aniline and then hydrolysis of the ethyl ester as described in example 94 gave the title compound. Purity > 90% M + H + 676.5. Example 101 Ethyl ester of (1 R, 2S) -1 - ( { (4R) -1 - { [2- (fert-butoxycarbonyl) hydrazino] carbonyl} -4- [(7-methoxy-2- phenylisoquinolin-4-yl) oxy] -L-prolyl.} amino) -2-vinylcyclopropanecarboxylic acid (101) To a solution of urea-butyl carbazate (0.3 mmol) and p-nitrophenyl chloroformate (0.3 mmol ) in acetonitrile (6 ml) was added sodium acid carbonate (0.48 mmol) as a solid. The solution was stirred at room temperature for 5 hrs and then cooled to 0 ° C. Compound 62 (0.3 mmol) dissolved in acetonitrile (10 mL) was mixed together with diisopropylethylamine (0.75 mmol) at 0 ° C, and then added to the above solution. The mixture was stirred at room temperature overnight and then concentrated to dryness. The residue was dissolved in DCM and then washed with citric acid pH 4, followed by NaHCO3 (aq) and water, dried over anhydrous sodium sulfate, filtered and concentrated to dryness. The crude product was dissolved in DCM and purified by column chromatography eluting with 0.1 to 0.2% MeOH / DCM to give the title compound (101 mg). Purity > 95% by H PLC, M + H + 660, 1. Example 102 Acid (1 R, 2S) -1 - ( { (4f?) - 1 - { [2- (Iyer-butoxycarbonyl) hydrazino] carbonyl} -4- [(7-methoxy-2-phenylquinoline -4-yl) oxy] -L-prolyl.} Amino) -2-vinylcyclopropanecarboxylic acid (159) Method A: To a solution of compound 01 (0.01 mmol) in THF-MeOH 2: 3 (2). ml) was added 1 M LiOH (10 equiv) The solution was maintained at 50 ° C for 60 min. After cooling to room temperature, HOAc (20 equiv) was added followed by toluene (2 ml) and then concentrated to dryness. The residue was taken up in MeOH and then purified by preparative LCMS which gave the title compound (0.7 mg). Purity > 95% by HPLC M + H + 732.2. Method B: To a solution of feri-butyl carbazate (0.07 mmol) and p-nitrophenyl chloroformate (0.07 mmol) in acetonitrile (3 mL) was added sodium acid carbonate (0.112 mmol) as a solid. The solution was stirred at room temperature for 2.5 hrs and then cooled to 0 ° C. Compound 1 03 (described below) (0.07 mmol) dissolved in acetonitrile (10 ml) was mixed together with diisopropylethylamine (0.175 mmol) at 0 ° C, and then added to the previous solution. The mixture was stirred at room temperature overnight and then concentrated to dryness. The crude material was dissolved in MeOH and purified by preparative LCMS which gave the title compound (4.8 mg). Purity > 95% by HPLC M + H + 632.2 Example 103 acid (1 R, 2S) -1 -. { [(2S, 4R) -4- (7-Methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic acid (1 03) To a solution of compound 12 (0.067mmol) in THF-MeOH 2: 3 (2 ml) was added 10 equiv. of 1 M LiOH. The solution was maintained at 50 ° C for 2.5 hrs. After cooling to room temperature, 20 equiv. of HOAc followed by toluene (2 ml) and then concentrated to dryness. The residue was taken up in DCM and the salts were filtered giving the title compound (0.07 mmol). Purity > 95% by HPLC M + H + 474. Example 104 acid (1 R, 2S) -1 - ( { (4R) -1 - (hydrazin'ocarbonyl) -4 - [(7-methoxy-2- phenylquinolin-4-yl) oxy] -L-prolyl} amino) -2-vinylcyclopropanecarboxylic acid (104) Compound (102) was maintained in TFA-DCM 1: 2 (3 ml) at room temperature for 60 min. Toluene (1 ml) was added. The sample was co-evaporated to dryness which gave the title compound (10.5 mg) as the trifluoroacetic acid salt. Purity by HPLC > 95% M + H + 532. Example 1 05 Ethylester of acid (1 R, 2S) -1 - ( { (4R) -1 - (hydrazinocarbonyl) -4 - [(7-methoxy-2-phenylquinolin-4-yl) oxy] -L-prolyl. amino) -2-vinylcyclopropanecarboxylic acid (105) Compound 101 (50 mg) was maintained in TFA-DCM 1: 2 (3 ml) at room temperature for 60 min. Toluene (1 ml) was added. The sample was co-evaporated to dryness and then taken up in DCM and washed with K2CO3, dried over anhydrous sodium sulfate and concentrated to dryness to give the title compound (41.8 mg).

Purity by HPLC > 95% M + H + 560. Example 106 Ethyl ester of (1 R, 2S) -1 - ( { (4R) -1 - [(2-Benzylhydrazino) carbonyl] -4 - [(7-methoxy-2-phenylquinolin-4-yl) oxy] - L-prolyl.} Amino) -2-vinylcyclopropanecarboxylic acid (1 06) To a solution of compound 105 (0.037 mmol) in MeOH: THF (4: 1) was added benzaldehyde (0.0448 mmol). The solution was stirred at room temperature for 18 hrs. Borane-pyridine complex (0.37 mmol) was added followed by HCl (37%, 400 pl). The solution was stirred for 1.5 hrs and then filtered and concentrated to dryness. The crude material was dissolved in MeOH and purified by preparative LCMS which gave the title compound (0.01 mmol). Purity by HPLC > 95% M + H + 650. Example 107 acid (1 R, 2S) -1 - ( { (4R) -1 - [(2-benzylhydrazino) carbonyl] -4 - [(7-methoxy-2-phenylquinolin-4-yl) oxy] -L- prolyl.}. amino) -2-vinylcyclopropanecarboxylic (164107 To a solution of compound 1 06 (0.0101 mmol) in THF-MeOH 2: 3 (3 mL) was added 10 equiv. of 1 M LiOH. The solution was maintained at 50 ° C for 18 hrs. After cooling to room temperature the sample was neutralized with HCl and concentrated to dryness. The crude material was dissolved in DCM (2 ml) and a solution of TFA: TES 1: 1 (1 ml) was added. The mixture was stirred for 3 hrs at room temperature and then concentrated to dryness. The crude material was dissolved in MeOH and purified by preparative LCMS which gave the title compound (0.6 mg). Purity by HPLC > 95% M + H + 622. Example 108 Ethyl ester of acid (1 R, 2S) -1 -. { [(2S, 4R) -1 - ((1 S) -1-Azidomethyl-3-methyl butylcarbamoyl) -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] - Not me} -2-vinyl-cyclopropanecarboxylic (108) i) 2-tert-butoxycarbonylamino-4-methyl-pentylester of (2S) -metanesulfonic acid To a solution of tert-butylester of ((1S) -1 - hydroxymethyl-3-methyl-butyl) -carbamic acid (25 g, 15 mmol) in dichloromethane (500 ml) cooled with an ice-water bath was added consecutively diisopropylethylamine (35.7 g, 276 mmol) and methanesulfonyl chloride (1 g. 5.81 g, 138 mmol). The resulting solution was stirred overnight, during this time the mixture was allowed to warm gradually to room temperature. The mixture was washed consecutively with water, 10% citric acid (aq), water and saturated NaHCO3 (aq), then dried with Na2SO4 and concentrated to give a brown solid (32.6 g, 96%) which was used in the next reaction without further purification. ii) tert-butylester ((1 S) -1-Azidomethyl-3-methyl-butyl) -carbamic acid The mesylate from step i (32.6 g, 11.0 mmol) was treated with sodium azide (21, 45 g, 330 mmol) in DMF at 80 ° C for 24 hrs. The solvent was evaporated, the residue was taken up in DCM, filtered and washed with saturated NaHCO3 (aq). The solution was dried with Na2SO and concentrated to give a brown oil which was purified by flash chromatography using a gradient of ethyl acetate and hexane to give the title compound as a white solid (19.55 g, 73%). iii) (1 S) -1-Azidomethyl-3-methyl-butylamine The ((1 S) -1-Azidomethyl-3-methyl-butyl) -carbamic acid tert-butylester (9) was treated., 64 g, 39.78 mmol) with TFA (30 ml) in DCM (150 ml) for 3 hrs, the mixture was evaporated under reduced pressure and the residue was dissolved in ethyl acetate and washed with 1 M aqueous K2CO3, dried with Na2SO4 and concentrated to give a yellow liquid (4.55 g, 80%). Compound 12 was treated with phosgene as described in Example 13 which gave the corresponding chlorocarbamate compound. The obtained chlorocarbamate (568 mg, 1.1 mmol) was dissolved in a solution of DCM-THF (1: 1, 10 ml) and (1 S) -1-azidomethyl-3-methyl-butylamine (401 mg) was added. , 2.82 mmol) and a large excess of NaHCO3 (s). The resulting mixture was stirred for 18 hrs, filtered and washed with dilute citric acid (aq, pH 5). The organic layer was dried with Na2SO4 and evaporated to give the desired product as a light yellow oil (837 mg, 99%) sufficiently pure to be used in the next step. M + H + 670, 1. Example 109 Ethyl ester of acid (1 R, 2S) -1 -. { [(2S, 4R) -1 - ((1 S) -1-Aminomethyl-3-methyl- butylcarbamoyl) -4- (7-methoxy-2-phenyl-quinoIin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic acid (109) A solution of 108 (717 mg, 1.07 mmol) in THF (25 ml) was stirred together with PS-triphenylphosphine (diphenylphosphino polystyrene) resin (3.24 g, 1.65 mmol) PPh3 / g) and methanol (2.5 ml) for 78 hrs. The mixture was removed by filtration and the polymer was washed repeatedly with DCM and methanol. The combined filtrates were evaporated to give the title compound as a light beige foamy solid (685 mg, 99%) with more than 95% purity as determined by reverse phase HPLC. M + H + 644, 1. General Procedure 1 a For the Preparation of Compounds 1 10-1 1 6 To a solution of the acyl chloride (0.075 mmol) in DCM (0.5 mL) was added NaHCO3 (s) (60 mg, 07 mmol) and a Solution of amine 109 (25 mg, 0.037 mmol) in THF (1 mL). The resulting mixture was stirred at room temperature overnight, filtered and then stirred in the presence of PS-trisamine resin (tris- (2-aminoethyl) aminomethyl polystyrene) (3.91 mmol / g, 50 mg, 0.2 mmol) for 5 hrs. The mixture was removed by filtration and evaporated. The resulting solid residue was dissolved in MeOH-THF (2: 1, 1.5 ml) and treated with 1 M LiOH (aq) (170 μl) at 50 ° C between 2 and 1 6 hrs. The reaction was followed by HPLC-MS. The mixture was acidified with acetic acid and evaporated to dryness. The residue was dissolved in methanol and purified by reverse phase HPLC. General Procedure 1 b For Preparation of Compounds 1 10-1 16 To the acid (0.039 mmol) was added consecutively a solution of HATU (14.7 mg, 0.039 mmol) in DMF (0.5 ml), a solution of the amine 109 (20 mg, 0.031 mmol) in DMF (0.5 ml) and diisopropylethylamine (30 μl, 0.155 mmol). The resulting mixture was stirred for 16 hrs then the solvent was evaporated and the residue was dissolved in DCM and washed with water and saturated aqueous NaHCO3. The solvent was evaporated and the residue was dissolved in methanol-THF (2: 1, 1.5 ml). To this was added 1 M LiOH (aq) (155 μl) and the mixture was stirred at 60 ° C for 3-5 hrs. Glacial acetic acid (50 μl) was added and the mixture was concentrated, dissolved in methanol and purified by reverse phase HPLC. Example 1 10 acid (1 R, 2S) -1 -. { [(2S, 4R) -1 -. { (1 S) -1 - [(3-Fluoro-benzoylamino) -methyl] -3-methylbutylcarbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic acid (1 10) The general procedure 1A was followed by using 3-fluorobenzoyl chloride (12 mg) as acyl chloride which gave the title compound as a solid (13.6 mg, 50%). M + H + 738.1.

Example 111 acid (1R, 2S) -1-. { [(2S, 4R) -4- (7-Methoxy-2-phenyl-quinolin-4-yloxy) -1 - ((1S) -3-methyl-1-. {[[(Pyridine-3-carbonyl) - amino] -methyl.} - butilcarbamoyl) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic acid (111) The general procedure 1A was continued using nicotinoyl chloride (10.5 mg) as acyl chloride which gave the title compound as a solid (10 mg, 37%). M + H + 721.1. Example 112 acid (1R, 2S) -1-. { [(2S, 4R) -4- (7-Methoxy-2-phenyl-quinolin-4-yloxy) -1 - ((1S) -3-methyl-1- { [(Pyrazine-2-carbonyl) - amino] -methyl.} - buty-carbamoyl) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic acid (112) The general procedure 1B was continued using pyrazine-2-carboxylic acid (5 mg) as acid which gave the title compound as a solid (5.7 mg, 25%). M + H + 722.1. Example 113 Acid (1 R, 2S) -1 -. { [(2S, 4R) -4- (7-Methoxy-2-phenyl-quinolin-4-yloxy) -1 - ((1 S) -3-methi 1-1 -. {[[(Tiof en-3- carbonyl) -amino] -methyl.} - butilcarbamoyl) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic acid (13) The general procedure 1 A was followed by using thiophene-3-carbonyl chloride (11 mg) which gave the title compound as a solid (4.3 mg, 16%). M + H + 726, 1. Example 1 14 acid (1 R, 2S) -1 -. { [(2S, 4R) -4- (7-Methoxy-2-phene-quinolin-4-yloxy) -1 - ((1 S) -3-methyl-1 -. {[[(Tetrahydro-furan-2- carbonyl) -amino-3-methyl.}. -butylcarbamoyl) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic (14) The general procedure 1B was continued using tetrahydrofuran-2-carboxylic acid (4.5 mg) as acid which gave the compound of the title as a solid (7.9 mg, 36%). M + H + 714, 1. Example 1 15 acid (1 R, 2S) -1 -. { [(2S, 4R) -4- (7-Methoxy-2-phenyl-quinolin-4-yloxy) -1 - ((1 S) -3-methyl-1 - { [(5-phenyl-oxazole- 4-ca'rbonyl) -amino] -metii.} - butylcarbamoyl) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic (1 15) The general procedure 1B was followed by using 5-phenyl-oxazole-4-carboxylic acid (7.5 mg) as acid which gave the title compound as a solid (7.5 mg, 31%). M + H + 787.1. Example 1 16 acid (1 R, 2S) -1 -. { [(2S, 4R) -1 - ((1S) -1 - { [(Benzofuran-2-carbonyl) -amino] -methyl} -3-methyl-butylcarbamoyl) -4- (7-methoxy -2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic (1 16) The general procedure 1B was continued using acid benzofuran-2-carboxylic acid (6.5 mg) as the acid gave the title compound as a solid (5.4 mg, 23%). M + H + 760, 1.

General Procedure 2 For the Preparation of Compounds 1 17-1 19 To a solution of the sulfonyl chloride (0.075 mmol) in DCM (0.5 mL) was added NaHCO3 (s) (60 mg) and a solution of the amine 109 (25 mg, 0.037 mmol) in THF (1 ml). The resulting mixture was stirred at room temperature for 18 hrs, filtered and then stirred with PS-trisamine (tris- (2-aminoethyl) aminomethyl polystyrene, 3.91 mmol / g, -50 mg) for 5 hrs. The mixture was removed by filtration and the polymer was washed consecutively with DCM, THF and methanol. The solid residue resulting from the evaporation of the combined filtrates was dissolved in MeOH-THF (2: 1, 1.5 ml) and treated with 1 M LiOH (aq) (170 μl) at 50 ° C for reaction times from 1 8 hrs up to a week depending on the actual structure. The reaction was followed by HPLC-MS. The mixture was acidified with acetic acid and evaporated to dryness. The residue was dissolved in methanol and purified by reverse phase HPLC. Example 1 17 acid (1 R, 2S) -1 - ( { (2S, 4R) -4- (7-Methoxy-2-phenyl-quinolin-4-yloxy) -1 - [(1 S) -3-methyl-1 - (phenyl-methanesulfonylamino-methyl) -butylcarbamoyl] -pyrrolidine-2-carbonyl} amino) -2-vinyl-cyclopropanecarboxylic acid (17) General procedure 2 was continued using a-toluenesulfonyl chloride (14 mg) as sulfonyl chloride which gave the title compound as a white solid (4.9 mg, 17%). M + H + 770, 1.

Example 1 18 acid (1 R, 2S) -1 - [((2S, 4R) -4- (7-Methoxy-2-phenyl-quinolin-4-yloxy) -1 -. {(1 S) -3-methyl- 1 - [(5-Methyl-isoxazole-4-sulfonylamino) -methyl] -butylcarbamoyl.] - pyrrolidine-2-carbonyl) -amino] -2-vinyl-cyclopropanecarboxylic acid (18) General procedure 2 was followed using 5-methyl-isoxazole-4-sulfonyl chloride (14 mg) as sulfonyl chloride which gave the title compound as a white solid (1.6 mg, 6%).

M + H + 761, 0 Example 1 19 o o acid (1 R, 2S) -1 -. { [(2S, 4R) -1 -. { (1 S) -1 - [(5-lsoxazol-3-yl-thiophen-2-sulfonylamino) -methyl] -3-methyl-butylcarbamoyl} -4- (7-methoxy-2-phenyl-quinoIin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic acid (1 19) General procedure 2 was continued using 5-isoxazol-3-yl-thiophene-2-sulfonyl chloride (19 mg) as sulfonyl chloride which gave the title compound as a solid white (3.0 mg, 10%). M + H + 828.98. Example 120 ethylester of 1 - acid. { [1 - (N'-tert-butoxycarbonyl-N-hept-6-enyl-hydrazinocarbonyl) -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic acid (120) Compound 12 (200 mg, 0.4 mmol) was dissolved in tetrahydrofuran (10 ml). One tablespoon of sodium acid carbonate was added, followed by phosgene (1.8 μl, 1.9 M in toluene). The reaction mixture was stirred for 30 min and filtered. The solvent was evaporated and the crude chloride was redissolved in dichloromethane (10 ml). Sodium carbonate (1 tablespoon) and tert-butylester of? / '- hept-6-enyl-hydrazinecarboxylic acid (182 mg, 0.8 mmol). The reaction mixture was stirred at room temperature for 40 h. and then filtered and purified by chromatography on silica (1% methanol in ether? 2% methanol in ether) to give pure title product (240 mg, 79%).

Example 121 Ethyl ester of 14-tert-butoxycarbonylamino-18- (7-methoxy-2-phenyl-quinolin-4-yloxy) -2, 15-dioxo-3, 14, 16-friaza-tricicio [14,3,0,0 * 4.6 *] nonadec-7-en-4-carboxylic acid (121) Compound 120 (200 mg, 0.26 mmol) was dissolved in degassed dichloromethane (30 ml). Second generation Hoveyda-Grubbs catalyst (16 mg, 0.026 mmol) was then added and the mixture was refluxed under argon atmosphere overnight. The solvent was then evaporated and the crude product was purified by chromatography on silica (1% methanol in ether) which gave 39 mg (20%) of the title product. MS (M + H +) 728.2 Example 122 14-tert-butoxycarbonylamino-1 8- (7-methoxy-2-phenyl-quinolin-4-yloxy) -2, 15-dioxo-3, 14, 16-triaza-tricyclo [14.3,0,0 *] 4.6 *] nonadec-7-en-4-carboxylic acid (122) Compound 121 (39 mg, 0.054 mmol) was dissolved in tetrahydrofuran (3.5 ml), water (1.75 ml) and methanol (1, 75 ml). Then lithium hydroxide (430 μl, 1 M in water) was added and the reaction was stirred at room temperature for 24 h. The volume was reduced by half and water (10 ml) was added. Acidification (pH = 5) followed by extraction with chloroform gave 34 mg (90%) of pure acid 179. MS (M + H +) 700.2 Example 123 acid ethyl ester hydrazinocarbonyl) -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cycloprpanecarboxylic acid (123) The title compound was prepared from compound 12 (800 mg, 1.6 mmol) and tert-butylester of? T-hex-5-enyl-hydrazinecarboxylic acid (620 mg, 2%). , 9 mmol) according to the procedure described in example 120 which gave 1 g (85%). MS (M + H +) 742.37 Example 124 Ethyl ester of 1-3-tert-butoxycarbonylamino-17- (7-methoxy-2-phenyl-q u-noli n-4-yloxy) -2, 14-dioxo-3, 13, 15-triaza-tricyclo [13, 3.0.0 * 4.6 *] octadec-7-en-4-carboxylic acid (124) The treatment of compound 123 (400 mg, 0.54 mmol) according to the procedure described in example 121 gave a product raw. Purification by chromatography on silica gel (1% methanol in ether) gave the title product (67 mg, 17%). MS (M + H +) 714.29 Example 125 13-tert-butoxycarbonylamino-17- (7-methoxy-2-phenyl-quinolin-4-loxi) -2, 14-d-oxo-3, 13, 15-tpaza-tricyclo [1 3.3.0] acid , 0 * 4.6 *] octadec-7-en-4-carboxylic acid (125) The title compound was prepared from compound 124 (67 mg, 0.09 mmol) by the same procedure as described for 122 what gave 46 mg (71%) of the pure acid. Chloroform was replaced by 1,2-dichloroethane in the extraction step for the preparation of this compound. MS (M + H +) 686.33 Example 126 13-tert.Amino-17- (7-methoxy-2-phenyl-quinolin-4-yloxy) -2, 14-dioxo-3, 1, 3, 15-triaza-tricyclic acid [13,3,0,0 * 4,6 *] octadec-7-en-4-carboxylic acid (126) Compound 125 (10 mg) was dissolved in dichloromethane (4 ml). Trifluoromethanesulfonic acid (4 ml) was added and the mixture was left at 50 ° C for 6 hours. The solvent was removed and the residue was washed with acetonitrile which gave 3 mg of the pure title product (35%). MS (M + H +) 586.25 Example 127 ethylester of 1 - acid. { [1- (1-Methoxycarbonyl-oct-7-enylcarbamoyl) -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-v1n-1-cyclopropanecarboxylic acid (127) The title compound was prepared from compound 12 (380 mg, 0.758 mmol) and 2-aminononan-8-enylcarboxylic acid methester (250 mg, 1%). 89 mmol) using the conditions described in Example 120 gave the pure product (405 mg, 75%). Example 128 4-Ethyl ester 14 methyl ester of 19- (7-Methoxy-2-phenyl-quinolin-4-yloxy) - 2, 16-dioxo-3, 15) 17-triaza-tricyclo [15.3,0,0 * 4,6 *] icos-7-en-4,14-dicarboxylic (128) Compound 127 (170mg, 0 , 2385 mmol) was dissolved in dichloromethane (40 ml) and degassed by bubbling nitrogen for 20 min. Then second generation Hoveyda-Grubbs catalyst (10 mg, 0.016 mmol, 6.7 mol%) was added and the mixture was refluxed under a nitrogen atmosphere overnight. The solvent was then evaporated, the catalyst and salts were removed by flash chromatography (5% methanol in chloroform) and the crude product (120 mg, 73% yield, 85-90% purity) was used in the next step MS (M + H +) 685 Example 129 3-Ethyl ester of 1-9- (7-Methoxy-2-phenyl-quinolin-4-yloxy) -2,16-dioxo-3,15,17-triaza-tricyclo [15.3,0,0 * 4, 6 *] icos-7-en-3, 14-dicarboxylic (129) Compound 128 (120 mg, 0.175 mmol) was dissolved in dioxane (9 ml) and water (6 ml). Lithium hydroxide (12 mg, 0.526 mmol) and the reaction was stirred at room temperature during 3.5 h. The mixture was acidified with acetic acid until pH = 5, and co-evaporated with toluene. The crude product was used in the next step.

MS (M + H +) 671 Example 130 OR- 3-Ethyl ester of 14 - [(Cyclohexyl-methylcarbamoyl-methyl) -19- (7-methoxy-2-phenyl-quinolin-4-yloxy) -2, 16-dioxo-3, 1, 5, 7-triaza- tricyclo [15.3,0,0 * 4,6 *] icos-7-en-4-carboxylic (130) Compound 129 (crude, 1 00 mg), indanelamine (33 mg, 0.209 mmol) and Hunig's base (DI EA) (0.2 ml) were dissolved in DMF (14 ml). After stirring at 0 ° C for 10 min, HATU was added. The reaction was followed by LC-MS. After 5h the conversion was 100%. DMF and DI EA were removed under vacuum. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried and concentrated in vacuo. The crude yield was 120 mg, the purification by HPLC prep. gave 21 mg (25%) of the title product. MS (M + H +) 802 Example 1 31 14 - [(Cyclohexyl-methylcarbamoyl-methyl) -19- (7-methoxy-2-phenyl- quinolin-4-yloxy) -2,1 6-dioxo-3,15,17-triaza-tpcyclo [15.3,0,0 * 4,6 *] icos-7-en-4-carboxylic acid (131 ) To a solution of ester 130 (19 mg, 0.024 mmol) in the mixture of THF (0.2 ml) and methanol (0.3 ml) was added LiOH solution (6 mg, 0.237 mmol) in 0.15 ml of water. The resulting mixture was stirred at 60 ° C for 3.5 h. After cooling to room temperature, acetic acid (30 eq) was added. The mixture was co-evaporated with toluene. The residue was distributed between chloroform and water phases, the aqueous phase was extracted with chloroform and ethyl acetate, the organic phases were combined, dried over sodium sulfate, evaporated to give 15 mg of pure product. MS (M + H +) 774 Example 132 [14-Cyclopropanesulfonylaminocarbonyl-1-7- (7-methoxy-2-phenyl-quinolin-4-yloxy) -2, 14-dioxo-3, 13, 15-triaza-tricyclo [13,3,0] tert-butylester , 0 * 4,6 *] octadec-7-en-13-yl] -carbamic acid (132) To the acid 125 (19 mg, 0.028 mmol) in 0.5 ml of DMF was added 5.5 mg (0.044 mmol) of DMAP and 10.7 mg (0.056 mmol) of EDC. After 6.5 h of stirring, 20 mg of cyclopropylsulfonamide and 0.04 ml of DBU. The mixture was stirred overnight, acidified with 5% citric acid (in water) and extracted with ethyl acetate. It was dried, evaporated and purified with 5% to 10% methanol in chloroform (or LC-MS prep) which gave 8 mg of the title compound (37%) MS (M + H +) 783 Example 133 1 - . 1 - 4- [2- (2-lsopropylamino-thiazol-4-yl) -7-methoxy-quinolin-4-yloxy] -pyrrolidin-1,2-dicarboxylic acid-butylester (133) To a stirring solution of N-Boc-trans-4-hydroxy-L-proline (221 mg, 0.96 mmol) in DMSO was added potassium tert-butoxide (320 mg, 2.9 mmol). After 1 h, 2- [2-isoprpylamino) -1,3-thiazol-4-yl] -7-methoxyquinolin-4-ol (319 mg, 0.96 mmol) was added and the mixture was stirred at 70 ° C. for 72 hours. The mixture was diluted with water and extracted with ethyl acetate. The product was used without further purification. Yield 429 mg, 85%. Example 134 2- (1-Ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -4- [2- (2-isopropylamino-thiazol-4-yl) -7-methoxy-quinoxy-4-yloxy] -pyrrolidin-1-tert-butylester carboxylic acid (134) Compound 133 (300 mg, 0.56 mmol) was reacted with 1-amino-2-vinyl-cyclopropanecarboxylic acid ethyl ester (1 30 mg, 0.84 mmol) as described in Example 1 1 gave the title compound (302 mg, 80%). Example 135 1 - (. {4- [2- (2-lsopropylamino-thiazol-4-yl) -7-methoxy-quinolin-4-yloxy] -pyrrolidine-2-carbonyl} -amino) -2-ethyl ester -vinyl-cyclopropanecarboxylic acid (135) Compound 134 (302 mg, 0.45 mmol) was treated as described in Example 12 to give the title compound (195 mg, 76%).

Example 136 1 - (. {1 - [1 - (2-Hydroxy-indan-1-ylcarbamoyl) -2,2-dimethyl-propylcarbamoyl] -4- [2- (2-isopropylamino-thiazol-4-yl) ethyl ester ) -7-methoxy-quinolin-4-yloxy] -pyrrolidine-2-carbonyl] -amino-2-vinyl-cyclopropanecarboxylic acid (136) Compound 135 (80 mg, 0.14 mmol) was treated as described in Example 1 3 what gave the title product (87 mg, 72%) Example 137 1 - ( { 1 - [1 - (2-Hydroxy-indan-1-ylcarbamoyl) -2,2-dimethyl-propylcarbamoyl] -4- [2- (2-isopropylamino-thiazol-4-yl) - 7-methoxy-quinolin-4-yloxy] -pyrrolidine-2-carbonyl} -amino-2-vinyl-cyclopropanecarboxylic acid (137) The ethyl ester of compound 1 36 (80 mg, 0.09 mmol) was hydrolysed following the The procedure described in Example 14 gave the title product Performance after preparative LC-MS (7.5 mg, 10%). Example 138 ethylester of 1 - acid. { [1-Ethylcarbamoyl-4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidin-2-carbonyl] amino} -2-vinyl-cyclopropanecarboxylic acid (138) The reaction of compound 12 (330 mg, 0.66 mmol), phosgene (1.6 ml, 1.9 M in toluene, 3 mmol) and hex-5-enylamine hydrochloride ( 500 mg, 3.68 mmol) following the procedure described in Example 1 gave the pure title product (328 mg, 80%), MS (M + H +) 627. Example 139 17- (7-Methoxy-2-phenyl-quinolin-4-yloxy) -2,14-dioxo-3, 13, 15-triaza-tricyclic acid ethyl ester [13.3,0,0 * 4,6 *] octadec-7-en-4-carboxylic acid (139) Compound 138 (200 mg, mol) was dissolved in dry degassed dichloromethane (200 ml), bubbled with nitrogen. Then Hoveyda-Grubbs catalyst (second generation) (5 mg, 2 mol%) was added and the reaction mixture was refluxed for 20 h under nitrogen. The resulting mixture was cooled to room temperature and concentrated by rotary evaporation. The resulting oil was purified by column chromatography on YMC silica (ethyl acetate-toluene 1: 1 to 9: 1) to give 55 mg of the title compound as a beige solid. Performance 29%. MS (M + H +) 599. Example 140 7-7- (7-Methoxy-2-phenyl-qu-nolin-4-yloxy) -2, 14-d-dioxo-3, 13, 1-triaza-tricyclic acid [13.3,0,0 * 4, 6 *] octadec-7-en-4-carboxylic acid (140) Compound 139 (55 mg, mol) was dissolved in 2 ml of methanol and mixed with 3 eq. of aqueous NaOH and heated for 2 h at 60 ° C in a closed vial. The reaction mixture was then extracted with ethyl acetate. The aqueous solution was collected and acidified with 1N HCl solution until pH 2. The resulting solution was concentrated by rotary evaporation, dissolved in methanol and purified by preparative HPLC (acetonitrile-water) to give 34 mg of the product of the product.

Title. Performance 65%. MS (M + H +) 571. Example 141 acid 1 -. { [1 -. { 1 - [(Cyclohexyl-methoxycarbonyl-methyl) -carbamoyl] -2,2-dimethyl-propylcarbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic acid (141). Compound 1 03 was dissolved in dichloromethane (3 ml) and solid sodium bicarbonate (1000 mg) and phosgene in toluene 20% (0.1 ml) was added. After 30 min at room temperature the mixture was concentrated to dryness. Methyl ester of (S) - (2S-2-Amino-3,3-dimethyl-butyrylamino) -cyclohexyl-acetic acid (12 mg in dichloromethane 2 ml) was added. After 3 days of stirring at room temperature, the reaction mixture was filtered, concentrated to dryness and purified by preparative HPLC-MS to give the title product (4.4 mg). M + H + 784.7. Example 142 ethylester of 1 - acid. { [1 - (1 -Aminometii-2,2-dimethyl-propylcarbamoyl-4- (7- methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic acid (142) The title compound was prepared from compound 12 (1.22 g, 2.43 mmol) following the procedure described for the preparation of compound 1 08 but using 2-tert-butoxycarbonyl amine- 3,3-dimethyl-buty-ester of methanesulfonic acid in place of 2-tert-butoxycarbonylamino-4-methyl-pentylester of methanesulfonic acid, in example 165 step i). Reduction of the azide as described in Example 109 gave the title compound (1.49 g, 95%). Purity according to HPLC > 95%, M + H + 644.2. Example 143 acid 1 -. { [1 - (2,2-Dimethyl-1 - { [Thiophene-3-carbonyl) -amino] -methyl} -propylcarbamoyl) -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cycloprocarcarboxylic acid (143) Compound 142 (100 mg, 0.155 mmol) was reacted according to general procedure 1 A for the preparation of compounds 1 10-1 16, using thiophene-3-chloride carbonyl (28.5 mg, 0.194 mmol) as acyl chloride gave the title compound as a white solid (45 mg, 40%). Purity according to HPLC > 95%, M + H + 726.

Example 144 acid 1 -. { [1 -. { 1 - [(5-lsoxazol-3-yl-thiophen-2-sulfonylamino) -methyl] -2,2-dimethyl-propylcarbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidine-2-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic acid (144) Compound 142 (25 mg, 0.039 mmol) was reacted according to general procedure 1A for the preparation of compounds 1 10-1 16, using 5-isoxazol-3-yl chloride -thiophen-2-sulfonyl (14.5 mg, 0.058 mmol) as acyl chloride which gave the title compound as a white solid (1.8 mg, 6%). Purity according to HPLC resulted > 94%, M + H + 829. Example 145 acid 1 -. { [1 - (3-Fluoro-benzoylamino) -methyl] -propylcarbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidin-2-carbonyl] -amino} -2-vinyI-cyclopropanecarboxylic acid (145) Compound 142 (25 mg, 0.039 mmol) was reacted according to general procedure 1A for the preparation of compounds 1 10-1 16, using 3-fluorobenzoyl chloride (12.3 mg, 0.078 mmol) as acyl chloride which gave the title compound as a white solid (4). , 1 mg, 14%). Purity according to HPLC resulted > 94%, M + H + 738. Example 146 acid 1 -. { [1 - (1 { [(-Furan-3-carbbonyl) -amino] -methyl] -2,2-dimethyl-propylcarbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidin-2-carbonyl] -amino.) -2-vinyl-cyclopropanecarboxylic acid (146) Compound 142 (25 mg, 0.039 mmol) was reacted according to general procedure 1B for the preparation of compounds 1 10-16, using 3-furanoic acid (5.5 mg, 0.049 mmol) as acyl chloride which gave the title compound as a white solid (4.1 mg, 14%). Purity according to HPLC resulted> 99%, M + H + 710. Example 147 or 2 - [(1-cyclopropanesulfonicaminocarbonyl-2-vinyl-cyclopropyl) -amide] 1 - [(2,2-dimethyl-1 -. {[[(Thiophene-3-carbonyl) amino] -methyl]. propyl) -amide of 4- (7-Methoxy-2-phenyl-quinolin-4-yloxy) -pyrrolidin-1,2-dicarboxylic acid (147) To the solution of compound 143 (42.2 mg, 0.058 mmol) in chloroform (3 mL) was added cyclopropylsulfonamide (14 mg, 0.116 mmol) followed by diisopropylethylamine (60.5 μL, 0.17 mmol). The solution was stirred at room temperature for 10 min and then at -20 ° C for 30 min. Then PyBOP (121 mg, 0.116 mmol) was added as a solid. The solution was maintained at -20 ° C for 10 days. The solution was then poured over aqueous NaHCO3 (sat.) And washed with water. The organic layer was dried, concentrated and subjected to purification by HPLC to give the title compound as a white solid (2.3 mg, 0.0028 mmol), HPLC Purity > 95%, M + H + 830. Example 148 Fmoc-4-amino-2- (1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -pyrrolidin-1-carbocyclic acid tert-butylester (148) (2S, 4R) Fmoc-4-amino-1-Boc acid was dissolved -pyrrolidin- 2-carboxylic acid (5.3 g, 11.1 mmol) in DCM (100 ml), HATU (4.94 g, 12.99 mmol), DIEA (4.63 ml, 26.57 mmol) were added and vinylcyclopropylglycine ethyl ester (2.26 g, 1 1.81 mmol) consecutively. The mixture was stirred for 16 h at room temperature, and then diluted with DCM (50 ml), washed with citric acid (10% aq), water, NaHCO3 (sat.aq) and water. The organic phase was dried over Na2SO4 and concentrated to give a beige foamy solid (8.1 1 g) which was subjected to silica gel column chromatography to give the title compound (7.14 g, 12.1 l). mmol). Example 149 1 - [(Fmoc-4-amino-pyrrolidine-2-carbonyl) -amino] -2-vinyl-cyclopropanecarboxylic acid ethyl ester (149) Compound 148 (3.65 g, 6.04 mmol) was treated with a solution of TFA / DCM (10ml TFA, 50ml DCM) for 2.5h and then concentrated to give the title compound (2.99g, 6.12 mmol). Example 150 1 - (. {Fmoc-4-amino-1 - [1 - (2-hydroxy-indan-1 - ilcarbamoyl-2,2-dimethyl-propylcarbamoyl] -pyrrolidin-2-carbonyl} amino) -2-vinyl-cyclopropanecarboxylic acid (150) The aminoproline derivative 149 (2.96 g, 6.04 mmol) was stirred together with phosgene (1.93 M in toluene, 4 ml, 7.55 mmol) during 10 minutes. Solvents and excess phosgene were evaporated. The residue was dissolved in DCM (30 ml) and t-Bug-aminoindanol (1.9 g, 7.24 mmol) was added as a solution in DCM (30 ml), followed by NaHCO3 (2 g). The mixture was stirred for 48 h, then diluted with DCM, washed with water, 1.0% citric acid and NaHCO3 (sat, aq), dried over Na2SO4, and evaporated to dryness. The residue was subjected to purification by column chromatography, 0-30% EtOAc-hexane to give the title compound (1 g, 1.3 mmol). Example 151 Ethyl ester of 1 - (. {4-Amino-1 - [1- (2-hydroxy-indan-1 -ylcarbamoyl) -2,2-dimethyl-propylcarbamoyl] -pyrrolidine-2-carbonyl} -amino) -2-vinylcyclopropanecarboxylic acid (151) Compound 150 (595 mg, 0.765 mmol) was dissolved in DMF (20 ml) and treated with Si-piperazine (0.08 mmol / g, 4.78 g, 3%). , 82 mmol) for 48 h. The silica was removed by filtration and washed once with DMF and then with several portions of DCM. The solvents were evaporated and the residue was subjected to column chromatography for give the title compound (170 mg, 0.3 mmol). Example 152 1 - ( { 1 - [1 - (2-Hydroxy-indan-1-carcarbamoyl) -2,2-dimethyl-propylcarbamoyl] -4 - [(pyridine-3-carbonyl) -amino] -pyrrolidin -2-carbonyl.} -amino) -2-vinyl-cyclopropanecarboxylic acid (152) To a stirred solution of compound 151 (35 mg, 0.064 mmol) in DCM (1 ml), DIEA (0.12 mmol, 19 μl) and nicotinoyl chloride hydrochloride (0.12 mmol, 17 mg). The solution was stirred at room temperature for 18 h, PS-trisamine was added and then it was stirred at room temperature for 4 h. After filtration, the solution was washed with citric acid (10% aq) and NaHCO3 (sat, aq), the organic phase was dried over Na2SO4 and concentrated. The residue was dissolved in THF: MeOH (2: 1, 1.5 ml). LiOH (1 N aq, 3.2 mmol, 320 μl) was added. The solution was stirred at 60 ° C for 24 h. Acetic acid was added and then concentrated. The residue was dissolved in MeOH and subjected to purification by HPLC to give the title compound (19.5 mg, 0.03 mmol). Purity by HPLC > 98%, M + H + 633, 1. Example 1 53 1 - ( { 1 - [1 - (2-Hydroxy-indan-1 -ylcarbamoyl) -2,2-dimethyl-propylcarbamoyl] -4-phenylacetamino-pyrrolidine-2-carbonyl} -amino) -2 -vinyl-cyclopropanecarboxylic acid (153) The procedure described in example 152 was followed but using phenylacetyl chloride instead of nicotinoyl chloride hydrochloride, which gave the title compound (12.7 mg, 0.01 9 mmol). Purity by HPLC > 90%, M + H + 646, 1. Example 154 1 - ( { 1 - [1 - (2-Hydroxy-indan-1 -ylcarbamoyl) -2,2-dimethyl-propylcarbamoyl] -4 - [(5-methyl-3-phenyl-isoxazole-4-carbonyl) ) -amino] -pyrrolidine-2-carbonyl.] -amino) -2-vinyl-cyclopropane carboxylic acid (1 54) The procedure described in example 152 was followed but using 5-methyl-3-phenylisoxazoyl chloride. 4-carbonyl instead of nicotinoyl chloride hydrochloride, which gave the title compound (3.6 mg, 00055 mmol). Purity by HPLC > 98%, M + H + 713, 1.

Example 155 acid 1 -. { [1 - [1 - (2-Hydroxy-indan-1 -ylcarbamoyl) -2,2-dimethyl-propylcarbamoyl] -4- (3-phenyl-ureido) -pyrrolidine-2-carbonyl] -amino} -2-vinyI-cyclopropanecarboxylic acid (155) To a stirred solution of compound 1 51 (30 mg, 0.054 mmol) in acetonitrile: dichloromethane (2: 1, 3 ml), triethylamine (0.0648 mmol, 9 μl) was added. and phenylisocyanate (0.0648 mmol, 7 μl). The solution was stirred at room temperature for 3 h, methanol was added (1 ml) and then concentrated. The residue was dissolved in methanol and subjected to purification by HPLC to give the compound ester as a white solid (32.7mg, 0.047 mmol), HPLC purity > 95%, M + H + 675.31. LiOH 1 N aq. (0.47mmol, 475μl) was added to the ester dissolved in THF: MeOH (2: 1). The reaction was stirred at 50 ° C for 15 min and then at 8 ° C for 12 h and then acetic acid (0.98 mmol, 53 μl) was added before concentrating. The residue was dissolved in MeOH and subjected to purification by HPLC to give the title compound as a white solid (3.8 mg, 0.006 mmol), HPLC Purity > 98%, M + H + 675.31. Example 156 1 - ( {4-Bencensulfoni lamino-1 - [1 - (2-hydroxy-indan-1-ylcarbamoyl) -2,2-dimethyl-propylcarbamoyl] -pyridinidine-2-carbonyl} -amino) -2-vinyl-cyclopropanecarboxylic (156) To a stirred solution of compound 151 (30 mg, 0.054 mmol) in DCM (2 ml), DIEA (0.0648 mmol, 11.5 μl) and phenylsulfonylchloride (0.0648 mmol, 11.5 μl) were added consecutively. The solution was stirred at room temperature for 3 h , and then concentrated. The residue was dissolved in MeOH and subjected to purification by HPLC to give the ester compound as a white solid (17.9 mg, 0.0257 mmol), HPLC Purity > 95%, M + H + 696.24. LiOH 1 N aq, (0.25 mmol, 257 μl) was added to the ester dissolved in THF: MeOH (2: 1). The reaction was stirred at 50 ° C for 1.5 h before adding acetic acid (0.98 mmol, 53 μl). The solution was concentrated. The residue was dissolved in DCM and washed with water; The aqueous phase was acidified to pH 5 and then extracted with dichloromethane and ethyl acetate. The combined organic phases were dried over Na2SO4 and concentrated to give the title compound as a white solid (7.1 mg, 0.01 mmol), HPLC purity > 98%, M + H + 668, 19. Example 157 ^ OH s U "Jl o A acid 1 -. { [1 - [1 - (2-Hydroxy-indan-1 -ylcarbamoyl) -2,2-dimethyl-propylcarbamoyl] -4- (3-phenyl-thioureido) -pyrrolidine-2-carbonyl} amino) -2-vinyl-cyclopropanecarboxylic (1 57) To a stirred solution of compound 1 51 (30 mg, 0.054 mmol) in acetonitrile (3 ml), TEA (0.0648 mmol, 9 μl) and phenylthioisocyanate (0.0648 mmol, 7.8 μl) were added consecutively. The solution was stirred at room temperature for 1 6 h, and then concentrated. The residue was dissolved in MeOH and subjected to purification by HPLC, giving the ester compound as a white solid (22.7mg, 0.0328mmol), Purity by HPLC > 95%, M + H + 691, 2. LiOH 1 N aq, (0.33 mmol, 328 μl) was added to the ester dissolved in THF: MeOH (2: 1). The reaction was stirred at 50 ° C for 2.5 h before adding acetic acid (0.98 mmol, 53 μl). The solution was concentrated. The residue was dissolved in dichloromethane and washed with water, the aqueous phase was extracted with EtOAc. The combined organic phases were dried over Na2SO and concentrated to give the title compound as a white solid (7.2 mg, 0.01 mmol), HPLC purity > 98%, M + H + 663.26. Assays In the compounds of the invention, an evaluation is made suitably the activity against the NS3 protease of flavlvirus, such as HCV, using conventional in vivo (enzymatic) assays or cell culture assays. A useful assay is the Bartenshlager replicon assay described in EP 1043399. An alternative replicon assay is described in WO 03064416. A convenient enzymatic assay comprising the inhibition of hepatitis C complete NS3 is essentially as described in Polyakov, 2002 Prot Expression & Purification 25 363 371. Briefly, the hydrolysis of a depsipeptide substrate, Ac-DED (Edans) EEAbu [COO] ASK (Dabcil) -NH2 (AnaSpec, San Jose, USA), by spectrofluorometry, in the presence of a peptide cofactor, KKGSVVIVGRIVLSGK, is measured is described in Landro, 1 997 Biochem 36 9340-9348. Enzyme (1 nM) is incubated in a regulator, such as 50 mM HEPES, pH 7.5, 10 mM DTT, 40% glycerol, 0.1% n-octyl-β-D-glucoside, with cofactor. μM and inhibitor at about 30 ° C for 10 minutes, after which the reaction is started by adding the substrate, typically 0.5 μM substrate. The inhibitors typically dissolve in DMSO, and are sonicated for 30 s and vortexed. The solutions are usually stored at -20 ° C between the measurements. An alternative enzymatic assay is described in WO 0399316, which employs a FRET peptide assay with a VHC NS3 / 4A protein complex. The purpose of this in vitro assay is to measure the inhibition of HCV NS3 protease complexes, derived from strains BMS, H77C or J416S, as described below, by the compounds of the present invention. This assay provides an indication of how effective the compounds of the present invention can be in inhibiting the proteolytic activity of HCV. Serum was taken from a patient infected with HCV. A modified complete cDNA template of the HCV genome (BMS strain) was constructed from DNA fragments obtained by reverse transcription PCR (RT-PCR) of serum RNA, using primers selected on the basis of homology between strains of other genotypes. From the determination of the complete genome sequence, a genotype was assigned to the isolated HCV according to the classification of Simmonds et al. (see P Simmonds, KA Rose, S Graham, SW Chan, F McOmish, BC Dow, EA Follett, PL Yap and H Marsden, J. Chin Microbiol., 31 (6), 1493-1503 (1 993)). It was shown that the amino acid sequence of the non-structural region, NS2-5B, was >97% identical to HCV (H77C) genotype and 87% identical to genotype Ib (J4L6S). Infectious clones H77C (genotype la) and J4L6S (genotype Ib) can be obtained from R. Purcell (NIH), and their sequences are published in Genbank (AAB67036, see Yanagi, M., Purcell, RH, Emerson, SU and Bukh. Proc. Nati, Acad. Sci. USA 94 (16) 8738-8743 (1997); AF054247, see Yanagi, M., St Claire, M., Shapiro, M., Emerson, SU, Purcell, RH and Bukhj, Virology 244 (1), 161 (1998)). Strains BMS, H77C and J4L6S are conventional strains to produce complexes of recombinant NS3 / 4A proteases. HE manipulated the DNA encoding the recombinant HCV NS3 / 4A protease complex (amino acids 1027 to 171 1) for these strains as described in P. Gallinari et al. (see Gallinari P, Paolini C, Brennan D, Nardi C, Steinkuhler C, De Francesco R. Biochemistry 38 (17): Briefly, a solubilizing tail of three mills was added at the 3 'end of the coding region of NS4A. The cysteine at the P1 position of the NS4A-NS4B cut-off site (amino acid 171 1) was changed for glycine, in order to avoid proteolytic cleavage of the lysine label, and a cysteine-to-serine mutation can be introduced by PCR in the amino acid at position 1454, to prevent autolytic cleavage of the NS3 helicase domain.The DNA fragment of the variant can be cloned into the bacterial expression vector pET21b (Novagen), and the NS3 / 4A complex can be expressed in the strain of Escherichia coli BL21 (DE3) (Invitrogen) according to the protocol described by P. Gallinari et al. (see Gallinari P, Brennan D, Nardi C, Brunetti M, Tomei L, Steinkuhler C, De Francesco R., J Virol 6758-69 (1998)) with modifications Briefly, it can be induced the expression of NS3 with 0.5 mM isopropyl beta-D thiogalactopyranoside (IPTG) for 22 hours at 20 ° C. A typical fermentation (10 I) allows to obtain approximately 80 g of wet cell paste. The cells are resuspended in a lysis buffer (10 ml / g) consisting of N- (2-hydroxyethyl) piperazine-N '- (2-ethanesulfonic acid) (HEPES) 25 mM, pH 7.5, 20% of glycerol, 500 mM sodium chloride (NaCl), 0.5% Triton-X100, 1 μg / ml lysozyme, 5 mM magnesium chloride (MgCl2), 1 μg / ml DNase, beta-mercaptoethanol (BME) 5 mM, inhibitor of free protease of ethylenediaminetetraacetic acid (EDTA) (Roche), homogenized and incubated for 20 minutes at VC. The homogenate is sonicated and clarified by ultracentrifugation at 235000 G for 1 hour at 4 ° C. Imidazole is added to the supernatant at a final concentration of 15 mM and the pH is adjusted to 8. The crude protein extract is loaded on a nickel and nitrilotriacetic acid (Ni-NTA) column, previously equilibrated with buffer B (25 mM HEPES). , pH 8, 20% glycerol, 500 mM NaCl, 0.5% Triton-X1 00, 15 mM imidazole, 5 mM BME). The sample is loaded at a flow rate of 1 ml / minute. The column is washed with 15 column volumes of regulator C (same as regulator B, except with 0.2% Triton-X100). The protein is eluted with 5 column volumes of regulator D (same as regulator C, except with 200 mM imidazole). The fractions containing the NS3 / 4A protease complex are pooled and loaded onto a Superdex-S200 desalting column, previously equilibrated with regulator D (25 mM HEPES, pH 7.5, 20% glycerol, 300 mM NaCl, 0.2% Triton-X100, 10 mM BME). The sample is loaded at a flow rate of 1 ml / minute. Fractions containing the NS3 / 4A protease complex are pooled and concentrated to approximately 0.5 mg / ml. Typically, the purity determined for the NS3 / 4A protease complexes, derived from strains BMS, H77C and J4L6S, is greater than 90%, according to SDS-PAGE analysis and mass spectrometry. The enzyme is usually stored at -80 ° C, thaws on ice and diluted before use in the test regulator. The substrate used for the NS3 / 4A protease assay is conveniently RETS1 (depsipeptide substrate for resonance energy transfer; AnaSpec, Inc. cat # 22991) (FRET peptide), described by Taliani et al. in Anal. Biochem. 240 (2): The sequence of this peptide is loosely based on the natural cut site of NS4A / NS4B, except that there is an ester linkage instead of an amide bond at the cut site. The peptide substrate is incubated with one of the three recombinant NS3 / 4A complexes, in the absence or presence of a compound of the present invention, and the formation of the fluorescent reaction product is followed in real time, using a Cytofluor Series 4000 device. The following are useful reagents: HEPES and glycerol (ultrapure) are obtained in GIBCO-BRL. Dirnethylsulphoxide (DMSO) is obtained in Sigma. Beta-Mercaptoethanol is obtained in Bio Rad. Test regulator: 50 mM HEPES, pH 7.5; NaCl 0.15 M; 0, 1% > of Triton; 15% Glycerol; BME 10 mM. Substrate: Substrate: final concentration of 2 μM (from a 2 mM stock solution in DMSO stored at -20 ° C). HCV NS3 / 4A type la (Ib), final concentration 2-3 nM (from a 5 μM stock solution in 25 mM HEPES, pH 7.5, 20% glycerol, 300 mM NaCl, 0.2% Triton-X100 , BME 10 mM). For compounds with potencies close to the assay limit, the assay may be more sensitive by adding 50 μg / ml of BSA to the assay regulator and / or reducing the final protease concentration to 300 pM.

The test is conveniently carried out on a 96-well Falcon polystyrene plate. Each cavity contains 25 μl of NS3 / 4A protease complex in assay buffer, 50 μl of a compound of the present invention in 10% DMSO / assay buffer and 25 μl of substrate in assay buffer. A control (without compound) is also prepared on the same test plate. The enzyme complex is mixed with compound or control solution, typically for 1 minute, before starting the enzymatic reaction by adding substrate. The assay plate is usually read immediately using a spectrophotometer, such as a Cytofluor Series 4000 (Perspective Biosysterns). The instrument is conveniently prepared to read an emission 340 nm and an excitation of 490 nm at 25 ° C. In general, the reactions are followed for approximately 15 minutes. The percent inhibition can be calculated with the following equation. 100 - [(dFinh / d Fcon) x 100], where dF is the change in fluorescence in the linear range of the curve. A non-linear curve is applied to the inhibition-concentration data, and the 50% effective concentration is calculated.

(IC50) using software such as Excel XI software, which uses the equation: y = A + ((B - A) / (1 + ((C / x)? D))). Enzymatic assays conveniently use a fluorescence resonance energy transfer principle (FRET) to generate a spectroscopy response to a NS4A / 4B cut event catalyzed by an NS3 serine protease of HCV. Typically the activity is measured in a continuous fluorometric assay, using an excitation wavelength of 355 nm and an emission wavelength of 500 nm. The initial velocity can be determined from 10 minutes of continuous reading of the fluorescence intensity, as a result of the cut event catalyzed by the NS3 protease. An alternative enzymatic assay can be performed as follows: Materials The recombinant enzyme of HCV whole length NS3 can be prepared as shown in Polyakov et al Protein Expression & purification 25 (2002) 363-371. The cofactor NS4A conveniently has an amino acid sequence of KKGSVVIVGRIVLSGK (commercially available), generally prepared as a 10 mM mother solution in DMSO The substrate FRET (Ac-Asp-Glu-Asp (EDANS) -Glu-Glu-Abu -? - [COO] Ala-Ser-Lys (DABCYL) -NH2, MW 1548.60, can be purchased from AnaSpec RET S 1, CA. USA), and is typically prepared as a 1.61 mM stock solution in DMSO. Aliquots (50 μl / tube) should be wrapped with aluminum foil to protect them from direct light, and should be stored at -20 ° C. Compound re reference 1, N-1725, with a sequence of AcAsp-D-Gla-Leu-lle-Cha-Cys, MW 830.95, can be purchased from BACHEM, Switzerland, and is generally prepared as a 2 mM stock solution in DMSO, and stored in aliquots at -20 ° C . The HEPES 1 M regulator can be purchased from Invitrogen Corporation, and stored at 20 ° C. Sigma glycerol can be purchased with 99% purity. CHAPS, 3 - [(3-Colamidopropyl) dimethylammonium] -1 -propanesulfonate: available from Research Organics, Cleveland, OH44125, USA. MW 614.90 DTT, DL-Dithiothreitol (Cleland Reagent: DL-DTT) 99% pure, MW 154.2, stored at + 4 ° C DMSO can be purchased from SDS, 13124 Peypin, France, with a 99.5% purity Ultrapure TRIS (TRIS- (hydroxymethylaminomethane)) can be purchased from ICN Biomedicals Inc. Sodium chloride can be obtained from KEBOlab AB. The N-dodecyl-β-D-maltoside, with a minimum of 98%, can be purchased in Sigma, and stored at -20 ° C. Equipment Microtiter plates (white cliniplaca, ThermoLab Systems cat no. 9502890) Eppendorf pipettes Biohit pipette, for multiple dosages Upstream fluorometer, excitation filter pair at 355 nm and emission at 500 nm Method Experimental procedure: 10 mM stock solution of the compounds is prepared in DMSO. The stock solutions are stored at room temperature during the evaluations, and placed at -20 ° C for long-term storage. Test Regulator A: 50 mM HEPES buffer, pH = 7.5 40% Glycerol 0.1% CHAPS Storage: at room temperature. 1 μM DTT (stored in aliquots at -20 ° C and added fresh to each experiment). Test Regulator B: 25 mM TRIS pH7.5 0.15 M NaCI 10% glycerol 0.05% n-dodecyl-β-D-maltoside DTT 5 mM (stored in aliquots at -20 ° C and added fresh for each experiment). Sequence of the experiment: Preparation of the Reaction Regulator (For a Plate, 1 00 Reactions) (Regulator A) 1. 9500 μl of assay regulator is prepared (HEPES, pH = 7.5, 40% glycerol and 0.1% CHAPS in deionized water). DTT is added until a final concentration of 10 mM is obtained (it is prepared fresh for each experiment). 2. The NS3 protease is rapidly frozen. 3. 13.6 μl of NS3 protease and 13.6 μl of NS4A peptide are added and mixed correctly. The mixture is left at room temperature for 15 minutes. 4. Place the enzyme stock again in liquid nitrogen at -80 ° C as soon as possible. Preparation of the Reaction Regulator (For One Plate 100 Reactions) (Regulator B) 5. Prepare 9500 μl of assay buffer (TRIS, pH = 7.5, 0.1 M NaCl, 0.5 mM EDTA, 1.0% glycerol and 0 , 05% of n-dodecyl β-D-maltoside in deionized water). DTT is added until a final concentration of 5 mM is obtained (it is prepared fresh for each experiment). 6. The NS3 protease is rapidly frozen. 7. Add 27.2 μl of NS3 protease and 13.6 μl of NS4A peptide, and mix correctly. The mixture is left at room temperature for 15 minutes. 8. Place the enzyme stock again in liquid nitrogen at -80 ° C as soon as possible. Preparation of the Inhibitor / Reference Compound A series of dilution of the inhibitors in DMSO is prepared up to 100x the final concentrations 10, 1, 0, 1, 0.01 and 0.001 μM. The final concentration of DMSO in a total reaction volume of 100 μl is 1%. A dilution series of the reference compound N-1725 in DMSO is prepared up to 100x the final concentrations 120, 60, 30, 15, 7.5 and 3.75 nM. Eight control enzyme cavities are needed for each experiment. The white cavities contain 95 μl of regulator (without NS3 PR), 1 μl of DMSO and 5 μl of substrate. Preparation of Fret Substrate Dilute the substrate solution (1.61 mM) with assay buffer until a working solution of 40 μM is obtained. Exposure to light is avoided. Test Sequence A 96 cavity cliniplate is used, the total assay volume per cavity is 1 00 μl. 1 . Add 95 μl of assay regulator to each well. 2. Add 1 μl of inhibitor / reference compound. 3. Pre-incubate for 30 minutes at room temperature. 4. Start the reaction by adding 5 μl of 40 μM substrate solution (final concentration: 2 μM) 5. Read continuously for 20 minutes with an excitation of 355 nm and an emission of 500 nm, the increase in fluorescence per minute is monitored. 6. Represent the progression curve (within the linear range, 8-10 time points) and determine the slope as an initial velocity for each individual inhibitor concentration. 7. Calculate the% inhibition with respect to the control enzyme. Treatment of Results The result is expressed as% inhibition at a certain concentration (analysis) or as a Ki value in nM or μM. Calculation of the% inhibition: The initial velocity is determined from 10 minutes of continuous reading of increases in fluorescence intensity as a result of the cut event catalyzed by the NS3 protease. The change in the slope of the inhibitor compared to the control enzyme provides the% inhibition at a given concentration. Calculation of Ki: I know all inhibitors are treated as if they followed the rules of competitive inhibition. The IC50 value is calculated from the inhibition values of a series of inhibitor concentrations. The calculated value is used in the following equation: K¡ = IC50 / (1 + S / Km) The graphic representation is made with the help of two calculation programs: Grafit and Graphpad Several detailed compounds of the invention previously they presented values of IC50 in the range of between 1 nM and 6.9 micromolar, and values of ED50 in the range between sub-micromolar and micromolar. Pattern and rate of development of resistance to drug escape Replicon cultures in microtitre plates can be used to determine rates of resistance development and select drug escape mutants. The compounds to be evaluated are added at concentrations close to their ED50, using, for example, 8 duplicates per concentration. After an appropriate incubation period for the replicon has elapsed, the activity of the protease in the supernatant or the cells used is measured. The following procedure is carried out after subjecting the crops to subsequent passages. Viruses produced are subjected to the concentration of test compound, with >50% protease activity compared to untreated infected cells (SIC, initial inhibition concentration), to fresh replicon cultures. An aliquot, for example, of 15 μl of supernatant from each of the eight duplicates, is transferred to replicon cells without test compound (control) and to cells with test compound at the same concentration, and in addition to two concentrations five times older, respectively (see table below). (See table below) When the propagation of the viral component of the replicon can be obtained (for example, measured through the activity of the HCV protease) at the highest non-toxic concentration (5-40 μM), 2-4 parallel cavities are collected and expanded, in order to obtain material for sequence analysis and cross-resistance. Key: Permitted Viral Growth Production of inhibited virus 125 x SIC 125 x SIC 25 x SIC? 25 x SIC 5 x SIC 25 x SIC 5 x SIC? Without compound 25 x SIC 5 x SIC? Without compound 5 x SIC SIC SIC? Without compound SIC? Without compound Step 1 Step 2 Step 3 Step 4 Step 5 Alternative methods for evaluating activity on drug escape mutants include the preparation of mutant enzymes that exhibit the distinctive mutation for use in conventional Ki determinations, as previously indicated.

For example, WO 04/039970 discloses constructs that allow HCV proteases containing the drug escape mutants 155, 156 and / or 168 to arise as a consequence of the selective pressure of BILN-2061 and VX-950. These constructs can then be introduced into replicon vectors, instead of the wild-type protease, which allows a simple evaluation of the activity of a given compound on a drug escape mutant in a cell assay.

Metabolism of P450 The metabolism of the compounds of the invention through the major isoform of the human cytochrome P450 system is conveniently determined in cells of Baculovirus infected insects, transfected with cytochrome P450 cDNA (supersomes) Gentest Corp. Woburnm USA. The test compounds are incubated at concentrations of 0.5, 5 and 50 μM in duplicate, in the presence of supersomes that overexpress several isoforms of cytochrome P450, including CYP1 A2 + P450 reductase, CYP2A6 + P450 reductase, CYP2C9-Arg 144 + P450 reductase, CYP2C1 9 + P450 reductase, CYP2D6-Val, 374 + P450 reductase and CYP3A4 + P 450 reductase. Incubations are carried out with a fixed concentration of cytochrome P450 (for example, 50 pmol) that are extended for 1 hour. The participation of a given isoform in the metabolism of the test compound is determined by UV HPLC chromatography, measuring the disappearance of the original compound.

Claims (56)

1. CLAIMS A compound of formula I: wherein A is C (= OO) R \ C (= O) NHSO2R2, C (= O) NHR3, or CR4R4 'where; R1 is hydrogen, Ci-Cealkyl, C0-C3alkylcarbocyclyl, C0-C3alkyl heterocyclyl; R2 is CT-Ceal uilo, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl; R3 is CT-Ceal uilo, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl, -OC ^ Cealkyl, -OC0-C3alkylcarbocyclyl, -OC0-C3alkyl heterocyclyl; R4 is = O, halo, amino, or OH; or R4 and R4 'together are = O; R4 'is d-C-alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl; wherein R2, R3, and R4 'are each optionally substituted with from 1 to 3 substituents selected independently from the group comprising halo, oxo, nitrile, azido, nitro, Ci-Cealkyl, C0-C3alkylcarbocyclyl, C0-C3alkheheterocyclyl, NH2CO-, Y-NRaRb, Y- O-Rb, YC (= O) Rb, Y- (C = O) NRaRb, Y-NRaC (= O) Rb, Y-NHSOpRb, YS (= O) pRb and YS (= O) pNRaRb, YC (= O) ORb, Y-NRaC (= O) ORb; And it is independently a bond or CT-Cjsalquileno; Ra is independently H or C? -C3alkyl; Rb is independently H, C ^ Cealkyl, C0-C3alkylcarbocyclyl or C0-C3alkylheterocyclyl; p is independently 1 or 2; M is CR7R7 'or NRu; R7 is C ^ Cealkyl, C0-C3alkylC3-C7cycloalkyl, or C2-C6alkenyl, any of which is optionally substituted with 1 -3 halo atoms, or an amino group, -SH, or C0-C3alkylcycloalkyl; or R7 is J; R7 'is H or taken together with R7 forms a C3-C6 cycloalkyl ring optionally substituted with R7 where; R7 a is C ^ Cealkyl, C3-C5cycloalkyl, C2-C6alkenyl any of which may be optionally substituted with halo; or R7 a can be J; q is between 0 and 3 and k is between 0 and 3; where q + k = 1; W is -CH2-, -O-, -OC (= O) H-, -OC (= O) -, -S-, -NH-, -NRa, -NHSO2-, -NHC (= O) NH- or -NHC (= O) -, -NHC (= S) NH- or a bond; R8 is a ring system containing 1 or 2 saturated, partially saturated or unsaturated rings each of which has between 4 and 7 ring atoms and each of which has between 0 and 4 heteroatoms independently selected from S, O and N, where the ring system is separated optionally from W by a C1-C3 alkylene group; or R8 is I rent; any of said groups R8 may optionally be mono-, di-, or tri-substituted with R9, where R9 is independently selected from the group comprising halo, oxo, nitrile, azido, nitro, Ci-Cealkyl, C0-C3alkylcarbo-cyclyl , C0-C3alkylheterocyclyl, NH2C (= O) -, Y-NRaRb, YO-Rb, YC (= O) Rb, Y- (C = O) NRaRb, Y-NRaC (= O) Rb, Y-NHSOpRb, YS (= O) pRb, YS (= O) pNRaRb, YC (= O) ORb, Y-NRaC (= O) ORb; wherein said carbocyclyl or heterocyclyl is optionally substituted with R 0; wherein R10 is C ^ Cealkyl, C3-C7cycloalkyl, CT-Cealkoxy, amino, amido, sulfonyl, (C? -C3 alkyl) sulfonyl, NO2, OH, SH, halo, haloalkyl, carboxyl; E is -C (= O) -, -C (= S) -, -S (= O) 2-, -S (= O) -, -C (= N-Rf) -; Rf is H, -CN, -C (= O) NRaRb; -C (= O) C1-C3alkyl; X is -NRx- where Rx is H, C ^ Csalkyl or J; or in the case where E is -C (= O), X can also be -O- or -NRjNRj-; where one of Rj is H and the other is H, C ^ Cs alkyl or J; R1 1 is H, C? -C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl, any of which may be substituted with halo, oxo, nitrile, azido, nitro, C ^ Cealkyl, C0-C3alkylcarbocyclyl, C0-C3alkheheterocyclyl, NH2C (= O) -, Y-NRaRb, YO-Rb, YC (= O) Rb, Y- (C = O) NRaRb, Y-NRaC (= O) Rb, Y-NHSOpRb, YS (= O) pRb , YS (= O) pNRaRb, YC (= O) ORb, Y-NRaC (= O) ORb; or R11 is J; J, if present, is a simple saturated or partially unsaturated alkylene chain of between 3 and 10 members extending from the R7 / R7 cycloalkyl or from the carbon atom to which R7 is attached to one of Rj, Rx, Ry or R1 1 to form a macrocycle, wherein the chain is optionally interrupted by between one and three heteroatoms independently selected from: -O-, -S- or -NR12-, and wherein from 0 to 3 carbon atoms in the chain they are optionally substituted with R 4; where; R12 is H, Cn-Cealkyl, C3-C6cycloalkyl, or C (= O) R13; R 13 is Ci-Cealkyl, C0-C3alkylcarbocyclic, C0-C3alkyl heterocyclyl; R14 is independently selected from the group comprising H, C-C6alkyl, C ^ Cehaloalkyl, C ^ Cealkoxy, hydroxy, halo, amino, oxo, thio and CT-Cetioalkyl; Ru is independently H or CT-Csalkyl; m is 0 or 1; n is 0 or 1; U is = O or is absent; R15 is H, C? -Calkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl, any of which may be substituted with halo, oxo, nitrile, azido, nitro, alkyl, C0-C3alkylheterocyclyl, C0-C3alkylcarbocyclyl, NH2CO-, Y-NRaRb, YO-Rb, YC (= O) Rb, Y- (C = O) NRaRb, Y-NRaC (= O) Rb, Y-NHSOpRb, YS (= O) pRb, YS (= O) pNRaRb, YC (= O) ORb, Y-NRaC (= O) ORb; G is -O-, -NRy-, -NRjNRj-: where one Rj is H and the other Rj is H, CT -CS alkyl or J; Ry is H, C ^ Cs alkyl; or Ry is J; R16 is H; or C ^ Cealkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl, any of which may be substituted with halo, oxo, nitrile, azido, nitro, C ^ Cealkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl, NH2CO-, Y-NRaRb, YO-Rb, YC (= O) Rb, Y- (C = O) NRaRb, Y-NRaC (= O) Rb, Y-NHSOpRb, YS (= O) pRb, YS (= O) pNRaRb, YC (= O) ORb, Y-NRaC (= O) ORb; with the proviso that when m = n = 0 and G is O then R16 is not tert-butyl or phenyl; or its salt or prodrug acceptable for pharmaceutical use.
2. 2. A compound according to claim 1, wherein M is CR7R7 '.
3. 3. A compound according to claim 1, with partial structure la, Ib or laa: where e is 1 or 2.
4. 4. A compound of claim 1, wherein E is -C (= O) -.
5. 5. A compound according to claim 1, wherein m is 0 and n is 0.
6. 6. A compound according to claim 5, wherein G is -NRy- or -NRjNRj-.
7. 7. A compound according to claim 6, wherein Ry or one of the groups Rj is J, thereby defining a macrocyclic compound.
8. 8. A compound according to claim 7, wherein R16 is H, Ci-Cs alkyl or C3-C6 cycloalkyl.
9. 9. A compound according to claim 1, wherein m is 1.
10. 10. A compound according to claim 9, wherein X is -NRx-. eleven .
11. A compound according to claim 9, wherein U is O.
12. 12. A compound according to claim 9, wherein R1 1 is C? -C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylaryl or C0-C3alkylheteroaryl, of which is optionally substituted with halo, amino, C? -C6alkoxy, C ^ Cetioalkyl, carboxyl, aryl, heteroaryl or heterocyclyl, and especially wherein the substituent is hydroxy or C (= O) OR14.
13. 13. A compound according to claim 12, wherein R1 1 is phenylethyl, 2,2-dimethyl-propyl, cyclohexylmethyl, phenylmethyl, 2-pyridylmethyl, 4-hydroxy-phenylmethyl, or carboxylpropyl; or especially tert-butyl, iso-butyl, or cyclohexyl.
14. 14. A compound according to claim 9, wherein one of Rx or R is J, thereby defining a compound macrocyclic.
15. 15. A compound according to claim 9, wherein n is 1.
16. 16. A compound according to claim 15, wherein R15 is or C0-C3alkylcarbocyclyl, any of which is optionally substituted.
17. 17. A compound according to claim 16, wherein R15 is cyclohexyl, cyclohexylmethyl, tert-butyl, iso-propyl, or iso-butyl.
18. 18. A compound according to claim 9, wherein G is NRy or -NRjNRj-, where Ry or a Rj is H or methyl, and the other Rj is H.
19. 19. A compound according to claim 1 8, wherein R16 is H, C ^ Cealkyl, or a 5- or 6-membered heterocycle, especially morpholine, piperidine or piperazine.
20. 20. A compound according to claim 9, wherein R16 is C? -C6alkyl, C0-C3alkylheterocyclyl, C0-C3alkylcarbocyclyl, any of which is optionally substituted with hydroxy, halo, amino, or CTC? Alkoxy. twenty-one .
21. A compound according to claim 20, wherein R 6 is 2-indanol, indanyl, 2-hydroxy-1-phenyl-ethyl, 2-thiophenomethyl, cyclohexylmethyl, 2,3-methylenedioxybenzyl, cyclohexyl, benzyl, 2-pyridylmethyl, cyclobutyl, iso-butyl, n-propyl, or 4-methoxyphenylethyl.
22. 22. A compound according to claim 1, wherein W is -OC (= O) -, -NRa-, -NHS (O) 2-or -NHC (= O) -; or especially -OC (= O) NH- or -NH.
23. 23. A compound according to claim 1, wherein W is -S-, a bond or especially -O-.
24. 24. A compound according to claim 22 or 23 wherein R8 is optionally substituted C0-C3alkylcarbocyclyl or optionally substituted Co-C3-alkenylhecyccyclyl.
25. 25. A compound according to claim 24, wherein the C0-C3 alkyl moiety is methylene or preferably a bond.
26. 26. A compound according to claim 25 wherein R8 is C0-C3alkylaryl, or C0-C3alkylheteroaryl, any of which is optionally mono, di, or tri substituted with R9, where; R9 is C, -C6 alkyl, C ^ Cealkoxy, NO2, OH, halo, trifluoromethyl, amino amido optionally mono- or di-substituted with C-C6alkyl, C0-C3alkylaryl, C0-C3alkylheteroaryl, carboxyl, aryl or heteroaryl which is optionally replaced with R10; wherein R 10 is Ci-Cealkyl, C 3 -C 7 cycloalkyl, C-α-C6alkoxy, amino optionally mono- or di-substituted with Ci-Cßalkyl, amido, sulfonylCT-Csalkyl, NO 2, OH, halo, trifluoromethyl, carboxyl, or heteroaryl.
27. 27. A compound according to claim 26 wherein R9 is C? -C6 alkyl, C -? - C? Alkoxy, amino, d-Cs alkyl) amino, C? -C3alkylamide, aryl or heteroaryl, the aryl or heteroaryl which is optionally substituted with R10; wherein R10 is d-Cealkyl, C3-C7cycloalkyl, d-C6alkoxy, amino, mono- or di-d-C3 alkylamino, amido, halo, trifluoromethyl, or heteroaryl.
28. 28. A compound according to claim 27, wherein, R10 is d-C6alkyl, d-C6alkoxy, amino optionally mono- or di substituted with d-C3 alkyl, amido, d-C3-alkylamide, halo, or heteroaryl.
29. 29. A compound according to claim 28 wherein R10 is methyl, ethyl, isopropyl, tert-butyl, methoxy, chloro, amino optionally mono- or di substituted with d-C3 alkyl, amido, or d-C3alkyl thiazolyl.
30. 30. A compound according to claim 29, wherein R8 is 1-naphthylmethyl, 2-naphthylmethyl, benzyl, 1-naphthyl, 2-naphthyl, or quinolinyl any of which is unsubstituted, mono, or disubstituted with R9 as Has defined.
31. 31 A compound according to claim 30 wherein R8 is 1-naphthylmethyl, or quinolinyl any of which is unsubstituted, mono, or disubstituted with R9 as defined.
32. 32. A compound according to claim 31 wherein R8 is: wherein R9a is dC6 alkyl; d-C6alkoxy; thiod- C3alkyl; amino optionally substituted with d-C6alkyl; C0- C3alkylaryl; or C0-C3alkylheteroaryl, C0-C3alkylheterocyclyl, wherein said aryl, heteroaryl or heterocycle which is optionally substituted with R10 wherein R10 is C? -C6alkyl, C0-C3C3-C7alkylcycloalkyl, dC6alkoxy, amino optionally mono- or di-substituted with d-C6alkyl, amido, d-C3alkyl amide; and R9b is d-C6 alkyl, d-C6-alkoxy, amine, di (d-C3a! qil) amino, (d-C3alkyl) amide, NO2, OH, halo, trifluoromethyl, carboxyl.
33. 33. A compound according to claim 32, wherein R9a is aryl or heteroaryl, any of which is optionally substituted with R10 as defined.
34. 34. A compound according to 33, wherein R9a is selected from the group consisting of: wherein R10 is H, C? -C6alkyl, or C0-C3alkylcycloalkyl, amino optionally mono- or di-substituted with d-C6alkyl, amido, (d-C3alkyl) amide.
35. 35. A compound according to claim 33, wherein. R9a is optionally substituted phenyl, preferably phenyl substituted with d-C6alkyl; d-C6alcox¡; or halo.
36. 36. A compound according to claim 32, wherein R is: wherein R10a is H, d-C6alkyl, or C0-C3alkylcarbocyclyl, amino optionally mono- or di-substituted with d-C6alkyl, amido, heteroaryl or heterocyclyl; and R9b is d-C6 alkyl, d-C6-alkoxy, amino, di (C? -C3 alkyl) amino, amido, NO2, OH, halo, trifluoromethyl, or carboxyl.
37. 37. A compound according to claim 32, wherein R9b is d-C6-alkoxy, preferably methoxy.
38. 38. A compound according to claim 1, wherein A is C (= O) NHSO2R2.
39. 39. A compound according to claim 38, wherein R2 is optionally substituted d-C6 alkyl, preferably methyl.
40. 40. A compound according to claim 38, wherein R2 is optionally substituted C3-C7cycloalkyl, preferably cyclopropyl.
41. 41 A compound according to claim 38, wherein R2 is optionally substituted C0-C6alkylaryl, preferably optionally substituted phenyl.
42. 42. A compound according to claim 1, wherein A is C (= O) OR1.
43. 43. A compound according to claim 42, wherein R1 is H or C? -C6 alkyl, preferably hydrogen, methyl, ethyl, or tert-butyl.
44. 44. A compound according to claim 2, wherein R7 'is H and R7 is n-ethyl, cyclopropylmethyl, cyclopropyl, cyclobutylmethyl cyclobutyl or mercaptomethyl, preferably n-propyl or 2,2-difluoroethyl.
45. 45. A compound according to claim 2, wherein R7 and R7 together define a spiro-cyclopropyl or spiro-cyclobutyl ring, both optionally mono- or di-substituted with R7'a wherein; R7 a is C, -C6 alkyl, C3-C5cycloalkyl, or C2-C6 alkenyl, any of which is optionally substituted with halo; or R7a is J.
46. 46. A compound according to claim 45 wherein the ring is a spiro-cyclopropyl ring substituted with R7'a wherein; R7a is ethyl, vinyl, cyclopropyl, 1- or 2-bromoethyl, 1-or 2-fluoroethyl, 2-bromovinyl or 2-fluoroethyl.
47. 47. A compound according to claim 2, wherein R7 is J and R7 'is H.
48. 48. A compound according to claim 1, wherein J is a saturated or unsaturated alkylene chain of between 3 and 8 members which optionally contains one to two heteroatoms independently selected from: -O-, -S- or -NR12-, wherein R12 is H, d-C6 alkyl, such as methyl, or -C (= O) C1-C6 alkyl, such as acetyl.
49. 49. A compound according to claim 48, wherein J is a saturated or unsaturated alkylene carbonate chain of between 4 and 7 members.
50. 50. A compound according to claim 48, wherein J is saturated or mono-unsaturated.
51. 51 A compound according to claim 48, wherein J is sized to give a macrocycle of 14 or 15 atoms in the ring.
52. 52. A pharmaceutical composition comprising a compound as defined in claim 1, and a vehicle acceptable for pharmaceutical use therefor.
53. 53. A pharmaceutical composition according to claim 52, further comprising an additional HCV antiviral, selected from nucleoside analogue polymerase inhibitors, polymerase inhibitors, protease inhibitors, ribavirin and interferon.
54. 54. Use of a compound as defined in claim 1 in therapy.
55. 55. Use of a compound as defined in claim 1 in the manufacture of a medicament for the prophylaxis or treatment of flavlvirus infections, including HCV.
56. 56. A method for the treatment or prophylaxis of a flavivirus infection such as HCV comprising the administration of an effective amount of a compound as defined in claim 1 to an individual affected by said infection or at risk of acquiring it.