MXPA06008530A - Hcv ns-3 serine protease inhibitors - Google Patents

Abstract

Peptidomimetic compounds are described which inhibit the NS3 protease of the hepatitis C virus (HCV). The compounds have the formula where the variable definitions are as provided in the specification. The compounds comprise a carbocyclic P2 unit in conjunction with a novel linkage to 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 PROSTHETIC INHIBITORS NS-3 TECHNICAL FIELD This invention relates to new inhibitors of the NS3 serine protease of the flavivirus HCV (or HCV), and to methods for use in the treatment or prophylaxis of HCV.

TECHNICAL BACKGROUND HCV serine protease NS3 is a multifunctional protein containing a serine protease domain and a helicase RNA 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 BILN-2061 from Boehringer Ingelheim, described in WO 0059929, and VX-950 from Vertex, described in WO 0387092. A number of similar VHC protease inhibitor peptidomimetics have also been proposed in the academic and patent literature. The presence of an L-proline derivative at the P2 position of the inhibitor is common for the vast majority of the peptidomimetics of the prior art, which allows the interaction with the S2 subsite the HCV protease enzyme. 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 into P4, P5 and P6. It is evident that sustained administration of BILN-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 D168V, D168Y 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 dosing regimes quickly result in unavoidable treatment failures. This in turn means that the concentration for 24 hours (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 that a level for 24 hours at least equal to the IC50, and, in realistic terms, equal to the IC90 or ED90, is essential to reduce the speed of development of drug escape mutants and achieve pharmacokinetics and metabolism of drugs needed to provide the desired levels, which constitutes 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 VI are provided: where A is C (= O) OR \ C (= O) NHSO2R2, C (= O) NHR3, or CR4R4 'where; R1 is hydrogen, CT-Cealkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl; R2 is d-C-alkyl, C0-C3 alkylcarbocyclyl, C0-C3alkyl heterocyclyl; R3 is C6C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl, -OC, -C6alkyl, -OC0-C3alkylcarbocyclyl, -OC0-C3alkylheterocyclyl; R4 is halo, amino, or OH; or R4 and R4 'are = O; R4 'is C6C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl; where R2, R3, and R4 'are each optionally substituted with 1 to 3 substituents selected independently from the group comprising one or more halo, oxo, nitrile, azido, nitro, C? -alkyl, C0 -C3alkylcarbocyclyl, 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 and Y-NRaC (= O) ORb; And it is independently a Ci-Csalkylene linkage; Ra is independently H or d-Csalkyl; Rb is independently H, C? -C6alkyl, C0-C3alkylcarbocyclyl or C0-C3alkylheterocyclyl; p is independently 1 or 2; M is CR7R7 'or NRu; Ru is H or C? -C3alkyl; 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 is J; q 'is 0 or 1 and k is between 0 and 3; Rz is H, or together with the carbon with asterisk forms an olefinic bond; Rq is H or C? -C6alkyl; 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 selected from S, O and N , wherein the ring system is optionally separated from W by a C? -C3alkyl group; or R8 is d-Cealkyl; any of said R8 groups may be mono, di or trisubstituted optionally with R9, where R9 is independently selected from the group comprising halo, oxo, nitrile, azido, nitro, d-C6alkyl, 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; wherein said carbocyclyl or heterocyclyl portion is optionally substituted with R10; wherein R10 is d-C-alkyl, C3-C7-cycloalkyl, d-C6-alkoxy, amino, sulfonyl, (d-C3 alky1) sulfonyl, NO2, OH, SH, halo, haloalkyl, carboxyl, amido, Rx is H or d-C5 alkyl; or Rx is J; T is -CHR1 1- or -NRd-, where Rd is H, d-C3alkyl; or Rd is J; R1 is H, d-C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl, any of which may be substituted with halo, oxo, nitrile, azido, nitro, d-C6alkyl, 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 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 Rd, Rj , Rx, Ry or R1 1 to form a macrocycle, where the chain is optionally interrupted by between one and three heteroatoms selected independently between: -O-, -S- or -N R12-, and where between 0 and 3 carbon atoms in the chain are optionally substituted with R14; where; R 12 is H, dC 6 alkyl, C 3 -C 6 cycloalkyl, or C (= O) R 13; 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, C ^ Cealkyl, d-C6haloalkyl, Ci-Cealkoxy, hydroxy, halo, amino, oxo, thio and d-C6 thioalkyl; m is 0 or 1; n is 0 or 1; U is = O or is absent; R15 is H, d-C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl, any of which may be substituted with halo, oxo, nitrile, azido, nitro, d-C6alkyl, C0-C3alkylheterocyclyl, C0-C3alkylcarbocyclyl, 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-; Ry is H, dC3 alkyl; or Ry is J; one Rj is H and the other Rj is H or J; R16 is H; or R16 is d-C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl, any of which may be substituted with halo, oxo, nitrile, azido, nitro, d-C6alkyl, 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; or a salt or prodrug acceptable for pharmaceutical use thereof. Without wishing to support a particular theory, the description of the 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 which are believed to complete subsites S1, S2, S3 and S4 of the enzyme, respectively, where S1 is adjacent to the cut site and S4 is far from the cutting site. Regardless of the mode of attachment, the components defined by Formula VI and others are within the scope of the invention. For example, it is expected that the protecting group R16-G may interact with the subsites S3 and S4, especially when my / on is 0. The notions of the various embodiments of the present invention may be represented as R16-G-P4-P3- P2-P1, where P3 and / or P4 may be absent. P1, P3 and P4 each represent a building block, constituted by a derivative of a natural or unnatural amino acid, P2 is a substituted carbocyclic residue, and G-R6 is a protecting group. The building blocks are typically linked together by an amide bond, which is reversed on either side of the building block P2 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. In the compounds of the invention, the amide bond linking P2 and P3 is inverted with respect to the amide bond linking P1 and P2, ie, the amino acid derivatives, P1 and P3, on each side of the scaffold P2, both are aids through its amino functions with the acid groups on each side of the scaffold P2. This means that the side chains of P3 and P4 (including the R16 shield, which interacts with S3 or S4) point in opposite directions, as compared to the native peptide substrate. Another consequence of the inverted P3 and P4 amino acids is that the side chains of these amino acids are displaced one atom outward, as compared to the native peptide substrate. It is expected that the change of direction of the side chains P3 and P4 in this way favor unnatural D-stereochemistries for the groups that complete the cavities (for example, side chains) of P3 and / or P4 and / or R16. Moreover, these compounds typically exhibit high activity and are within the scope of the invention. However, it has surprisingly been found that even compounds of the invention containing L-amino acid side chains such as P3 and / or P4 exhibit good activity, regardless of whether the respective entity should approach cavity S3 or S4 from an angle. different, with respect to the native peptide substrate. Therefore, the L-stereochemistry in R1 1 and / or R 5, and / or the corresponding configuration in R16 to mimic L-stereochemistry represents a favorable aspect of the invention. The different approach angle to access the 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 peptide backbone. conventional residues of natural or non-natural L-amino acids. Like the reverse transcriptase of VI H, which is remarkable for rapidly generating drug escaping mutants under the pressure of selecting 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 characteristic resistance patterns are likely to emerge when HCV agents are administered 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. The compounds wherein M is CR7R7 'constitute a further preferred aspect of the invention. Some preferred embodiments wherein M is CR7R7 'in the formulas VI include the VIA formulas below: Some preferred values for q 'and k in formula VI include 1: 1, 1: 2, 1: 3, 2: 2, 2: 3, more preferably 0: 2 and 0: 0; and more preferably 0: 1, in which case the preferred compounds have one of the partial structures: especially where Rz is H or Rq is H or methyl. The compounds of the invention may comprise a function P3 and P4, ie m and n are each 1. Preferred embodiments within Formula VI comprising both functions P3 and P4 include the formula Vlda-Vldb below: Alternative modes include the structures corresponding to Life, and Vldb where M is NRu. Alternative configurations of the compounds of the invention comprise a function P3, but not a P4, ie m is 1 and n is zero. Preferred embodiments within Formula VI comprising a P3 but not P4 include the Vlea-Vleb formula below: Alternative modes include the structures corresponding to Vlea and Vleb 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 abut P2, but as mentioned, the protecting group R16-G may interact favorably with S3 and / or S4. Preferred embodiments within Formula VI where m and n are zero include those of Formula Vlfa below: Alternative modes include the structures corresponding to Vlfa, 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 linking group J extends between one of Rj, Rx, Ry , Rd or R1 1 of Formula VI. Alternatively, the macrocycle J may extend from the carbon adjacent to R7 to one of Rj, Rx, Ry, Rd or Ru. Preferred embodiments of such macrocyclic structures within Formula VI where m is 0 and n is 1 include those of the formula Viga-Vlgc below: The corresponding structures in which the J chain joins the carbon adjacent to R7 are also preferred. Preferred embodiments of macrocyclic structures within Formula VI comprising both functions P3 and P4, ie, wherein both m and n are 1, include those of the formula Vlha-Vlhc below: The corresponding structures in which the J chain joins the carbon adjacent to R7 are also preferred. Preferred macrocyclic structures within Formula VI, wherein both functions P3 and P4 are absent, that is, where m and n are each 0, include those of the following formulas Vlhe-Vlhf.

Vlhe Vlhf The corresponding structures in which the J chain joins the carbon adjacent to R7 are also preferred. In general, in optionally macrocyclic structures such as those illustrated, the binder J is a saturated or partially unsaturated alkylene chain of 3 to 10 atoms, preferably 4 to 7 atoms, such as 5 or 6 atoms, i.e. an alkylene chain with between 1 and 3 unsaturated bonds between adjacent carbons, typically an unsaturation. The length of the chain will of course depend on whether J extends from Rd, Rj, Rx, Ry, R1 1 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 15 atoms in the ring. Conveniently, the J chain contains one or two heteroatoms selected from: O, S, NH, NCrC6 alkyl or N-C (= O) d-C6alkyl. More preferably, the J chain optionally contains a heteroatom selected from: NH, or N-C (= O) C1-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 can be substituted with R14, such as H or methyl. Typically the structure of binder J is saturated. Alternatively, J contains between 1 and 3, preferably a double bond, typically separated by a carbon from 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 C? -C6alkyl, dC6haloalkyl, dC6alkoxy, hydroxyl, halo, amino, oxo, thio or d-? C6thioalkyl; penten-3-yl, hexen-4-yl, hepten-5-yl, where 3, 4 or 5 refers to a double bond between the 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, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, 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 wherein 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 spiro-cycloalkyl ring. 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 ring are defined below. Particularly preferred substituents include R7 a as ethyl, vinyl, cyclopropyl (i.e., a spiro-cyclopropyl substituent of the cycloalkyl ring "Spiro" of R7 / R7 '), 1- or 2-bromoethyl, 1- or 2-fluoroethyl, -bromovinyl or 2-fluorethyl. In one embodiment of the invention A is -CR4R4 'as illustrated in detail in PCT / EP03 / 10595, the contents of which are incorporated by 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-C3alkyl aryl or d-C3alkylheteroaryl, where the alkyl portion is methyl, ethyl, propyl, ethenyl and -CHCHCH3. 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 embodiment for A is C (= O) NHR3, where R3 is optionally substituted by C0-C3alkylaryl, C0-C3alkylheteroaryl, OC0-C3alkylaryl or OC0-C3alkylheteroaryl. Suitable substituents are presented in the definitions section below. Another alternative preferred configuration for A is C (= O) OR 1, especially where R 1 is d-Cealkyl, 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 d-C6alkyl, preferably methyl, or optionally substituted C3-C7cycloalkyl, preferably cyclopropyl, or optionally substituted C0-C6alkylaryl, preferably optionally substituted phenyl. Suitable substituents are presented in the definitions section below. The substituent -W-R8 in the cyclic P2 group can employ any of the proline substituents that 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 = 03/66103, 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 W functions 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 C0-C3alkylcarbocyclyl or optionally substituted C0-C3alkylheterocyclyl, including those described in WO0009543, WO0009558 and WO 00/174768. For example, ester substituents, -W-R8, in the cyclic group P2, 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 d-Cealkyl , C0-C3alkylcyclopropyl, 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 (such as amino or amido optionally mono- or di-substituted with d-C6alkyl), C0-C3alkylaryl, C0-C3alkylheteroaryl, carboxyl, aryl or heteroaryl which is optionally substituted with R 10; where R10 is d-C6alkyl, C3-C7cycloalkyl, d-C6alkoxy, amino (such as amino mono- or di-substituted with d-C6alkyl), amido (such as d-C3 alkyl amide), 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 especially absent, ie C0. The aryl or heteroaryl component has the values that are broadly illustrated in the definitions section below. Preferred R 9s include d-Cβ alkyl, d-C6alkoxy, amino (such as di- (d-C3 alkyl) amino), amide (such as -NHC (O) d-C6alkyl or C (= O) NHd- C3alkyl), aryl or heteroaryl, the aryl or heteroaryl portion which is optionally substituted with R10; wherein R10 is d-C6alkyl, C3-C cycloalkyl, C? -C6aIkoxy, amino (such as mono-di-C3-alkylamino), amido (such as -NHC (O) C? -C3alkyl or C (= O) NHC1-C6alkyl), halo, trifluoromethyl, or heteroaryl. Preferred R 10 include d-C6alkyl, d-C6alkoxy, amino, amido (such as -NHC (O) d-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-C3alkyl or C (= O) NHC1-C6alkyl), 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, or mono- or disubstituted with R9 as defined, in particular 1 -naphthylmethyl, or unsubstituted quinolinyl, mono, or disubstituted with R9 as defined. A currently preferred R is: wherein R9a is d-C6alkyl; d-C6alkoxy; thio-C3alkyl; amino optionally substituted with C 1 -C 6 alkyl; C0-C3alkylaryl; or C0-C3alkylheteroaryl, C0-C3alkylheterocyclyl, said aryl, heteroaryl or heterocycle which is optionally substituted with R10 wherein R 0 is d-C6alkyl, C3-C7cycloalkyl, d-C6alkoxy, amino, amido, heteroaryl or heterocyclyl; and R9b is d-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-C6a-alkyl, or C0-C3-C3-C6-cycloalkyl-alkyl, amino (such as amino mono- or di-substituted with d-C6alkyl), amido (such as -NHC (O) C? C6alkyl or C (= O) NHd-C6alkyl) heteroaryl or heterocyclyl. R9a is conveniently phenyl and therefore R8 is: wherein R is H, d-C6alkyl; d-C6alkoxy; or halo; Y R is CT -CS alkyl, Ci-d-alkoxy, amino (such as C?-C3alkylamino), amido (such as -NHC (O) d-C6alkyl or C (= O) NHC1-C3alkyl), NO2, OH, halo, trifluoromethyl or carboxyl. An alternative preferred R8 is: wherein R 0a is H, d-C6alkyl, or C0-C3-C3-C6alkylcycloalkyl, amino (such as amino optionally mono- or disubstituted with d-C6alkyl), amido (such as -NHC (O) d-) C6alkyl or C (= O) NHC1-C3alkyl or C (= O) N (C1-C3alkyl) 2), heteroaryl or heterocyclyl; and R9b is d-Cβ alkyl, d-C6-alkoxy, amino optionally mono- or di-substituted with d-C6alkyl, amido (such as -NHC (O) C, -C6alkyl or C (= O) NHC1) -C3alkyl or C (= O) N (C1-C3alkyl) 2), NO2, OH, halo, trifluoromethyl, or carboxyl. In the embodiments described above R 9b is conveniently C?-C 6 -alkoxy, preferably methoxy. An additional R8 group, 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, C? -C6alkyl, C0 -C3alkylcycloalkyl, d-C6alkyloxy, d-C6thioalkyl, C0-C3alkyloxycycloalkyl, d-Csalkyloxyd-Csalkyl, C0-C3alkylaryl or C0-C3alkylheterocyclyl. A particularly preferred ether substituent is 7-methoxy-2-phenyl-quinolin-4-yloxy. 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, I H-imidazole, 1 H-pyrazole, furan, thiophene, oxazole, thiazole, isoxazole, isothiazole, pyridine, pindazine , pyrimidine, pyrazine, phthalazine, quinoxaline, quinazoline, quinoline, cinnoline, 1 H-pyrrolo [2,3] - £ »] pyridine, 1 H-indole, 1-benzoimidazole, 1 H-indazoI, 7H-purine, benzothiazole , benzooxazole, 1 H-imidazo [4, 5-c] pyridine, 1 H-imidazo [4,5-jb] pyridine, 1,3-dihydro-benzoimidazol-2-one, 1,3-dihydro-benzoimidazole-2 -thione, 2, 3-dihydro-1 H-indole, 1,3-dihydro-indol-2-one, 1 -indole-2,3-dione, 1,3-dihydro-benzoimidazol-2-one, 1 H, 1 H-pyrrolo [2,3-cyridine, benzofuran, benzo [o] thiophene, benzo [] isoxazole, benzo [d] isothiazole, 1 Hq uinotin-2-one, I W-quinolin-4-one , Mi-quinazolin-4-one, 9H-carbazole, 1 H-quinazolin-2-one. Further 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-1 H-pyrazole, pyrazolidin, imidazolidin-2-one, imidazolidine- 2-thione, pyrrolidin-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, pyrrazolidin-3-one, imidazolidine-2,4-dione, piperidine, tetrahydrofuran, tetrahydroadiraine, [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: wherein Q * is selected from the group comprising absent, -CH2-, -O-, -NH-, -N (R1 *) -, -S-, -S (= O) 2- and - (C = OR)-; 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, CoC3heterocyclyl and 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 1 3665. 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: wherein 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, or WO2004 / 1 13665. Other preferred values for R8 when W is a bond, include pyridazinone and its derivatives. The pyridazinone moiety is attached to the cyclic scaffold P2 and optionally substituted as shown below: wherein 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 or Preferred P3 groups, ie, when m is 1 they 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 d-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-C3alkyl3-C7cycloalkyl, C0-C3alkylaryl or C0-C3alkylheteroaryl, any of which is optionally substituted with hydroxy, halo, amino, d -C6alkoxy, Ci-C6thioalkyl, C (= O) OR14, carboxyl, (d-C6alkoxy) carbonyl, aryl, heteroaryl or heterocyclyl, especially where the substituent is hydroxy or C (= O) OR14. Particularly preferred R 1 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 I as follows: wherein R x and R y are as defined, preferably H, R 11 'is d-C 6 alkyl, preferably C 3 -C 5 branched alkyl such as the side chains of L-valyl, L-leucyl, L-isoleucyl, L-t-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-C3alkylheterocyclyl, C0-C3alkylcarbocyclium. 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 Vlia-Vlid below: Vlia Vlib where Ar is carbocyclyl or heterocyclyl, especially aryl or heteroaryl, any of which is optionally substituted with R9. Although the partial structures of the Vlia-Vlid Formulas have been illustrated in the context of a compound where k is 1 and q 'is 0, it will be apparent that such configurations of the Formula Vli are also applied to other values of q' and k. In a similar way, although the partial structures of the Vlic and Vlid formulas show a group R1 1 corresponding to leucine, it will be evident that these configurations will be applicable to other R1 1 groups, especially those that resemble the side chains of natural or unnatural L-amino acids, by example t-butilalan i na / t. Leucine R15 in those compounds of the invention wherein n is 1, is optionally optionally d-C6alkyl or C0-C3alkylcarbocyclic substituted for example C0-C3alkylC3-C7cycloalkyl, any of which may be optionally substituted. Preferred P4 groups are typically analogs of natural or non-natural amino acids, especially aliphatic amino acids such as L-valyl, L-leucyl, L-isoleucyl, Lt-leucyl or L-cyclohexylalanine 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 Ci-Cealkyl (especially methyl or t-butyl), C0-C3alkheheterocyclyl (especially pyridyl, benzimidazolyl, piperidyl, morpholinyl, piperazinyl) or C0-C3alkylcarbocyclyl (especially phenyl, benzyl, indanyl) any of which is optionally substituted by hydroxy, halo, amino, or C6alkoxy. The preferred compounds of the invention may comprise a hydrazine functionality, for example where T is -NRd- and m is 1; with n being zero or 1. Alternatively, especially when m is zero, G can be -NRjNRj- such as -NHNH-. The compounds in general do not comprise a hydrazine in both G and T. Preferred hydrazines within Formula VI, where m and n are zero, include compounds of the partial structures VIja-VIjb below: VIja Vljb R in the formulas VIja and VIjb can be considered as an alkyl (or C? -alkylheterocyclyl or d-dalkylcarbocyclyl) wherein the first alkyl carbon is substituted with an oxo group to define the keto function and R1B is the remainder of the alkyl, alkylheterocyclyl or alkylcarbocyclyl moiety. Formula VIjb represents a variant wherein R16 is a methylene group whose carbon is substituted with an oxo substituent and also with -ORb, where Rb has the values that have been defined, typically, d-C6alkyl, 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 VIja and VIjb 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 VI where m is 1 include those of partial structures Vljc and Vljd below: where G, R15, R16, Rx, Rd, Rq, Rz, and Ru have the values that have been defined for the preceding formula VI . The compounds of partial structures Vljc and Vljd can be linear molecules as shown (both Rx and Rd are H), or preferably one of the Rx or Rd groups represented can be macrocyclized through J in an appropriate R7 group. Although formulas Vlja-Vljd are represented by a five-membered carbocyclic ring as scaffold P2, it will be apparent that this aspect of the invention is equally suited to other configurations of q 'and k. Preferred embodiments within Formula Vlja-Vljd include those in which Rq and Rz are H, or those in which Rz is an olefinic bond and Rq is C? -C3alkyl. 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 formulas Vljc and Vljd: The compounds of partial structures Vljc and Vljd 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 with a ring of five members as the scaffolding 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 VI in general, the preferred R 1 d groups for the compounds of the invention include 2-indanol, Ndanyl, 2-hydroxM-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 non-natural amino acids include L-beta-methylsulfonylmethylalanine, L-cyclohexylalanine, L-tertiary-leucine, L-norleucine, L-norvaline, L-ornithine, L-sarcosine, L-citurinine, L-homophenylalanine, L-homoserin , L-beta- (1-napthyl) alanine, L-beta- (2-napthyl) 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-C-alkyl' (also abbreviated as d-C6alk, 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-atom in d-C6alkyl may be optionally substituted by one, two or where the valence allows three halogens and / or substituted or the alkylene 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 two hydrogen atoms, d-dalkyl and d-C5alkyl have the corresponding value for C1-C6alkyl to be adjusted as necessary for the amount of carbons. 'd-Csalkyl' as applied herein includes methyl, ethyl, propyl, isopropyl, cyclopropyl, any of which may be optionally substituted or interrupted heteroatom as described in the preceding paragraph or in the case of C2 0 C3, with an unsaturated bond such as CH2 = CH. "d-C3 alkylene" as applied herein discloses a divalent C1-C3alkyldiyl portion, which includes propylene, ethylene and especially methylene. The alkylene chains typically longer than J may comprise between 1 and 3 unsaturations and / or interruptions with heteroatoms as defined. 'Arrimo' includes NH2, NHd-C6alkyl or N (d-C6-aIquilo) 2. , especially C1-C3-alkyl variants. 'Amido' includes C (= O) NH2 and alkylamido such as C (= O) NHd-C6alkyl, C (= O) N (C1-C6alkyl) 2 especially C (= O) NHd-C3alkyl, C (= O) N (C1-C3alkyl) 2 0 -NH (C = O) C1-C6alkyl, for example -NHC (= O) CHC (CH3) 3, which includes - NH (C = O) d-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 intended to include an aryl moiety such as phenyl, naphthyl or phenyl fused to a C3-C7cycloalkyl for example indanyl, the aryl being directly attached (ie, C0) either through a methyl, ethyl, propyl or isopropyl intermediate group as defined above for d-C3alkylene. 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-C6alkyl, dC6alkoxy, dC6alkoxydC6alkyl, d -C6alkanoyl, amino, azido, oxo, mercapto, nitro Co-C3alkylcarbocyclyl, Co-C3alkylheterocyclyl. "Arílo" 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 an intermediate group methyl, ethyl or propyl as defined above for d-C3alkylene. 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, dC6alkyl, dC6alkoxy, dCealkoxyddalkyl, C6Calkanoyl, amino, azido, oxo, mercapto, nitro C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl. 'C0-C3alkylcarbocyclyl' as applied herein is meant to include C0-C3alkylaryl and C0-C3alkyl3-C7c-cycloalkyl. Unless otherwise indicated the aryl or cycloalkyl group is optionally substituted with 1 to 3 substituents selected from halo, hydroxy, nitro, cyano, carboxy, d-C-alkyl, 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 intended to include a monocyclic, saturated or unsaturated ring, containing a heteroatomotal such as piperidinyl, morpholinyl, piperazinyl , pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazinolyl, isothiazinolyl, thiazolyl, oxadiazolyl, 1,2,3-triazolyl, 1,4-triazolyl, tetrazolyl, furanyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, pyrazolyl, or any of such groups 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 attached directly ie (C0), or through a methyl, ethyl, propyl or isopropyl intermediate 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 portion is optionally substituted with 1 to 3 substituents selected from halo, hydroxy, nitro, cyano, carboxy, d-C6alkyl, d-C6alkoxy, d-Cealkoxid-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 member ring fused to a 4, 5 or 6 member ring. Typical groups of this type include C3-C8cycloalkyl, 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, hexah id ropyrimidyl, hexahydropyridazinyl, 1, 4,5,6-tetrahydropyrimidinylamine, dihydro-oxazolyl, 1,2-thiazinanyl-1,1-dioxide, 1,2,6-thiadiazinnyl-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.

Synthesis 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, ie, 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. Then, more building blocks, precursors of building blocks or larger prefabricated fragments of the desired structure can be joined to the developing chain, for example R16-G-P3 + C (= O) -P2-P1? R16-G-P3-C (= O) -P2-P1 or R16-G-P4-P3 + C (= O) -P2-P1? R16-G-P4-P3-C (= O) -P2-P1. The binding 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 water soluble carbodiimide), the active ester method (p-nitrophenyl ester, - N-hydroxysuccinic acid ester), the Woodward K reagent method, the carbonyldiimidazole method, the methods with phosphorous reagents or oxidation-reduction. 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, (1 993) known herein documentation such as Bodanszky, whose contents are incorporated in this documentation as a reference. Examples of suitable binding agents are N.N'-dicyclohexylcarbodiimide, 1-hydroxybenzotriazole in the presence of N, N'-dicyclohexylcarbodiimide or N-ethyl-N '- [(3-dimethylamino) propyl] carbodiimide. A practical and useful binding agent is commercially available hexafluorophosphate (benzotriazol-1-yloxy) tris- (dimethylamino) phosphonium, either alone or in the presence of 1-hydroxybenzotriazole or 4-DMAP. Another practical and useful binding agent is commercially available 2- (1-benzotriazol-1-yl) -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 undesired bonds. The protecting groups that can be used are detailed Greene, "Protective Groups in Organic Chemistry", John Wiley & Sons, New York (1981) and "The Peptides: Analysis, Synthesis, Biology", Vol. 3, Academic Press, New York (1981), 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 carboxylic acid. 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 employing mild reductive means, such as trichloroethyl and phenacyl esters. 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 tertbutyloxycarbonyl (Boc), ethoxycarbonyl, düsopropylmethoxycarbonyl 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. The resulting ammonium salt is then neutralized before bonding, 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 may be used to protect the sulphide-containing side chains of the cistern; portions of benzyl ethers (Bn) can be used to protect the hydroxyl-containing side chains of the. serine, threonine or hydroxyproline; and benzyl esters can be used 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, tert-butyl 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. Introduction of the substituent P2 The group R8 can be linked with the scaffold 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 consists of joining the portions P1 and P2, and, if present, P3 and P4, using an unsubstituted P2 scaffolding, and subsequently adding the R8 group. The compounds wherein W is O and R 8 is alkyl, C 0 -C 3 alkylcarbomyclyl, C 0 -C 3 alkylheterocyclyl 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 procedure employing a saturated P2 scaffold, where q 'is 0 and k is 1. 1a 1b Scheme 1 The treatment of a compound containing an unsubstituted P2 scaffold (1 a), which can be prepared as described below in the present documentation, with a base, such as sodium hydride or potassium t-butoxide, in a solvent, such as dimethylformamide, followed by the reaction of the resulting alkoxide with an alkylating agent R8-X, where X is an appropriate leaving group, such as halide, mesylate, triflate or tosylate, provides the appropriate substituted derivative (1). b) Alternatively, if X is OH or SH, substituent P2 can be introduced through a Mitsunobu reaction, by reacting the hydroxyl group of compound 1 a with the desired alcohol or thiol, in the presence of triphenylphosphine and an activating agent, such such as diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD) or the like. (Mitsunobu, 1 981, 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). Alternatively, the alcohol (1 a) can be treated with phosgene to obtain the corresponding chloroformate, which, by reacting with an amine R8NH2 in the presence of a base, such as sodium hydrogen carbonate or triethylamine, provides the carbamate of s, i.e. , W is -OC (= O) NH-, while the reaction of the alcohol (1 a) with an acylating agent R8-CO-X, such as an acid anhydride or acid halide, for example, an acid chloride , provides the esters, that is, W is -OC (= O) -. Various alcohols R8-OH and R8-X alkylating agents are described in WO 00/09543 and WO00 / 59929. An example of synthesis is presented, where R8 is a substituted quinoline derivative, in Scheme 2.

Scheme 2 Friedel-Craft acylation of an appropriate substituted aniline (2a), 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 of aluminum, in a solvent such as dichloromethane, provides (2b). The binding of (2b) with a heterocyclic carboxylic acid (2c) 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 dehydration under conditions basic, such as in potassium tert-butoxide in tert-butanol, provides the quinoline derivative (2e). The quinoline derivative (2e) can be linked in a Mitsunobu reaction 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, using a treatment with quinoline (2e) with an appropriate halogenating agent, for example, phosphoryl chloride or the like. A variety of carboxylic acids with the general structure (2c) can be used in Scheme 2. 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, in scheme 3 below.

H2 Scheme 3 Thiourea (3c) can be formed with various alkyl substituents R 'employing a reaction of the appropriate amine (3a) 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 (3c) with 3-bromopyruvic acid provides the acid (3d). The building blocks P2, where the R8 substituent is attached through an amine, an amide, a urea or a sulfonamide, can be prepared from amino substituted carbocycles, which can be achieved, for example, by transforming the hydroxyl group of the corresponding hydroxyl derivative in an azide group, for example, by converting the hydroxyl group to an appropriate leaving group, such as a mesylate or a halogen, for example, chloride, followed by substituting the leaving group with azide, or using an 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 VI, where W is -NH-. The reaction of the amino-substituted carbocycle with an acid of the general formula R8-COOH under conventional conditions for the amide bonding provides compounds where the R8 substituent is attached through an amide bond, while the reaction of the amino-substituted carbocycle with a Suitable sulfonic acid derivative R8-S (O) 2-X, wherein X is a leaving group, eg, 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 of a carbocycle substituted with amino with phosgene, to obtain the corresponding chlorocarbamate, followed by the reaction with the desired amine. Alternatively, the amino-substituted carbocycle 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. Compounds where a heterocyclic group R8 is attached directly to the cyclic scaffold P2, ie W is a bond in the general formula VI, can be prepared, for example, using a replacement reaction, where an appropriate leaving group is replaced, such as a halide, a mesylate or the like, 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 precursor P2 is reacted with a nitrogen atom in the heterocyclic group R8.

Rq, F? 2 and * are as previously described by Wes a bond "Compounds where there is a tetrazole group attached to one of the ring carbons are conveniently prepared by preparing the tetrazole portion directly on the precursor P2. 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, or triazole derivatives can be prepared directly on the precursor P2, for example, by transforming the group hydroxyl 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 having a ring size and a position of the alternative substituent W-R8 in the carbocyclic derivative of scheme 1 can also be used in the preparation of the compounds according to the present invention. Synthesis and introduction of building blocks P1 The amino acids used in the preparation of the P1 fragments are commercially available or as indicated in the literature; see, for example, WO 00/09543 and WO00 / 59929 from Boehringer-lngelheim, or US2004 / 0048802 from BMS. In Scheme 4 an example of the preparation of a sulfonamide derivative which can be used as a building block P1, and the subsequent connection with a building block P2 is presented. 4a 4b 4c Scheme 6 The sulfonamide group can be introduced into the protected amino acid suitably (4a) 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 (4b), in the presence of a base, such as diisopropylethylamine, followed by treatment with a binding agent, such as PyBOP®, to effect introduction of the sulfonamide group. The removal of the amino protecting group using appropriate methods, and the subsequent binding with a building block P2, prepared as described below, 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'-tetramethyluronium hexafluorophosphate (HATU), in the presence of a base, such as diisopropylamine, in a solvent, such as dimethylformamide, gives as result 4e. 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, that is, 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 present protecting group, followed by the sulfonamide binding as described, allows compound 4e to be obtained. The building blocks P1 for the preparation of compounds according to the general formula VI, wherein A is an ester or an amide, can be prepared by reacting the amino acid (4a) 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 residue of azapeptide P1, ie, M is NRu in the general formula VI, 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 5. 5a Sb Rí e s as defined by row R1, but it is not H Xo 5d Scheme 5 Incorporation of the appropriate N-linked side chain Ru in the commercially available tert-butylhydrazine can be carried out, for example, using a reductive amination reaction with the appropriate aldehyde or ketone, as described in scheme 19 below , which allows to produce the N-alkylated carbazate (5a). Condensation of 5a with a desired chloroformate, in the presence of a base, such as triethylamine or diisopropylethylamine, in a solvent, such as THF, provides 5b. 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 makes it possible to obtain the corresponding acids. Subsequent reaction of the acid obtained with a desired sulfonamide derivative, as described in scheme 4, provides the building blocks coated with sulfonamide. Alternatively, the reaction of carbazate 5a with an isocyanate R3-N = C = O provides building blocks for the preparation of compounds according to general formula VI, where M is NRu and A is CONHR3. Synthesis of covered building blocks P3 and P4-P3 The building blocks R16-G-P3 and R6-G-P4-P3 can be prepared as generally illustrated in Scheme 6. 7a 7b .NH, "" OR 'R 11' has the same definition as R11 R15 but is not part of a macrocycle 7c 7d 7e Scheme 6 An appropriate N-protected (6a) amino acid can be linked to an amino protecting group (R16-NHRy) using standard conditions for binding peptides, such as with binding agents such as HATU, DCC, HOBt or the like, in the presence of a base, such as DIEA or DMAP, in a solvent, such as dichloromethane, chloroform or dimethylformamide, or a mixture of these, and ester-forming conditions, such as those that allow to prepare amides, ie G is NHRy (6b) Alternatively, the reaction of amino acid (6a) with a compound of general formula R 6 -X, where R 16 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 (6b). On the other hand, the amino acid (6a) can be linked to a second amino acid protected with O in a suitable form (6d), using conventional conditions for the production of peptides, as previously described, to obtain (6e). The displacement of the ester group with an appropriate protecting group (6b) provides the fragment (6f), 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 7.

O H Ry '7c - * - Ry R15 7d Scheme 7 An appropriate N-protected amino acid, for example, protected with Boc (7a), can be immobilized on a solid support, as exemplified in this case with 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 (7b) can then be separated from the support with an appropriate protecting group (7c), in order to obtain the fragments (7d), 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: Preparation and incorporation of blocks Construction P2 A typical route is provided to obtain compounds containing a 5-member saturated P2 scaffold in Scheme 8.

Rx 'and T' have the same definitions as Rx and T, respectively, but they are not part of a macrocíclo. A 'is a protected carboxylic acid, an amide or a substituted sulfone amide, or Cr4R4' Scheme 8 The cyclic scaffolding (8b) can be prepared, for example, from 3,4-bis (methoxycarbonyl) cyclopentanone (8a), as it is described in Rosenquist et al. in Acta Chem. Scand. 46 (1992) 1 127-1 129, reducing the keto group with a reducing agent, such as sodium borohydride, in a solvent, such as methanol, followed by hydrolysis of the esters and, finally, ring closure in acetic anhydride, in the presence of pyridine. The bicyclic acid (8b) provided with the amine function of the desired P3 fragment (8c), the P3-P4 fragment or the R16-NHRy protecting group can then be bound using conventional conditions for the binding of peptides, such as with HATU and diisopropyl. amine, in a solvent, such as dimethyl formamide, to provide (8d). The opening of the lactone of (8d), for example, with lithium hydroxide, provides the acid, which may subsequently be linked to the group of a building block P1 or a precursor of a desired P1 (8e) fragment, using conventional conditions for the binding of peptides. The substituent R8 of the carbocycle can be introduced, for example, by using a Mitsunobu reaction with the appropriate alcohol, as described, or by employing any other suitable method previously described. When R7, R7 'and A' contain functional groups, they are optionally protected in a suitable manner using methods known to those skilled in the art; see, for example, Bodanzky or Greene, previously cited. In Scheme 9 an alternative route to obtain the compounds of formula VI containing a saturated P2 scaffold is presented, where the building blocks are introduced in reverse order, that is, the P1 fragment is introduced before the protective group or the blocks of construction P3 or P3-P4. 9e Rx 'and T' have the same definitions as Rx and T, respectively, but are not part of a macrocycle. A 'is a protected carboxylic acid, an amide or a substituted sulfone amide, or Cr4R4' Esq uema 9 The protection of the acid group of (9a), for example, as the tert-butyl ester, using a di-carbonate di-carbonate treatment -ter-butyl in the presence of a base, such as dimethylaminopyridine and triethylamine, in a solvent, such as dichloromethane, provides the ester (9b). The opening of the lactone and the binding of a building block P1 (9c), as described in scheme 13, or the direct use of the amino group of the fragment P1, provides (9d). The introduction of the substituent R8 as described, followed by the removal of the acid protecting group, by subjecting the ester to acidic conditions, such as trifluoroacetic acid and triethylsilane, in a solvent, such as methylene chloride, and finally the binding of the building block P3 (9e), the building block P3-P4 or protecting group R16-NHRy, as described, provides (9f). When R7, R7 'and A' contain functional groups, they are optionally protected in a suitable manner using methods known to those skilled in the art; see, for example, Bodanzky or Greene, previously cited. An unsaturated P2 scaffold, which can be used in the preparation of compounds of formula VI, can be prepared with cyclopentene, as illustrated below. The cyclopentene scaffold is typically prepared as described in scheme 10. 15a 15b 15c Scheme 10 A bromination-elimination reaction of 3,4-bis (methoxycarbonyl) cyclopentanone (10a), as described by Dolby et al. in J. Org. Chem. 36 (1971) 1277-1285, followed by reduction of the keto functionality with a reducing agent, such as sodium borohydride, provides the unsaturated hydroxyl compound (10b). Selective hydrolysis of the ester using, for example, lithium hydroxide, in a solvent, such as a mixture of dioxane and water, provides the substituted mono-ester derivative (10c). An unsaturated binding scaffold P2 can be prepared, where Rq is other than hydrogen, such as a methylated cyclopentene scaffold, as indicated in scheme 1 1. 16g 16h 16¡ Scheme 1 1 Oxidation of commercially available 3-methyl-3-buten-1-ol (11) a) using an oxidation agent, such as pyridinium chlorochromate, followed by treatment with acetyl chloride, bromine and methanol, provides the bromine ester (1 1 c). The ester (1 1 c) obtained with the enolate (1 1 e) can then be reacted, which can be achieved, for example, by carrying out the treatment of the corresponding tert-butylester with a base, such as lithium diisopropyl amide, in a solvent, such as tetrahydrofuran, to give the alkylated compound (1 1f). The tert-butylester (1 1 e) can be prepared by treating the corresponding commercially available acid (1 1 d), wherein k 'is between 1 and 3, with di-tert-butyl dicarbonate, in the presence of a base, such as dimethylaminopyridine. . Cyclization of (1 1 f) by an olefin metathesis reaction, performed as described, provides the cyclopentene derivative (1 1 g). The stereoselective epoxidation of (1 1 g) can be carried out using the asymmetric epoxidation method of Jacobsen, in order to obtain the epoxide (1 1 h). Finally, the addition of a base, such as DBN (1,5-diazabicyclo- [4.3.0] non-5-ene), provides the alcohol (11). Optionally, the double bond of the compound (1 1 i) can be reduced, for example, by catalytic hydrogenation, using a catalyst, such as palladium on carbon, which provides the corresponding saturated compound. Cyclic scaffolds can then be used, as described, to complete the inhibitory sequence. An example is presented in scheme 12.

Rx 'and T' have the same definitions as Rx and T, respectively, but are not part of a macrocycle. A 'is a protected carboxylic acid, an amide or a substituted sulfone amide, or Cr4R4' Scheme 12 The amino group of a building block P 1, or an appropriate precursor thereof (12b), can be attached to the acid of the derivative of cyclopentene (12a), using conventional conditions for the binding of amines, such as through the use of HATU in the presence of a base, such as diisopropyl phenylamine or the like, followed by the introduction of substituent R8, for example, under of Mitsunobu, as described, to obtain (12d). Hydrolysis of the remaining ester and subsequent binding of the amide of a desired P3 or P3-P4 building block (12e), optionally followed by manipulations of the P1 part, provides the compounds containing cyclopentene (12f) according to the formula general VI. When R7, R7 'and A' contain functional groups, they are optionally protected in a suitable manner using methods known to those skilled in the art; see, for example, Bodanzky or Greene, previously cited. Compounds containing a hydrazine, comprising a protecting group directly attached to the P2 portion, ie, P3 and P4 are absent and G is NRjNRj, can be prepared as illustrated in Scheme 13. 13d A 'is a protected carboxylic acid, an amide or a substituted sulfone amide, or Cr4R4' Scheme 13 The reaction of tert-butyl carbazate (13a), optionally with an alkyl substituent on one or both nitrogens, with the acid (13b) ), under conditions appropriate for the binding of peptides, such as with HATU and DIEA, in a solvent, such as DMF, provides 9Ac. Optional elimination of the boc group by conventional methods, such as through a. Acid treatment, such as, for example, with TFA, in a suitable solvent, such as dichloromethane, provides the hydrazine-containing derivative (1 -3d).

Alternatively, any hydrazine derivative, such as morpholin-1-ylamine, piperidin-1-ylamine or the like, can be linked with the (1-3b) acid in place of the tert-butyl carbazate derivative. The compound obtained can then be extended by attaching a building block P3 or P4-P3 with the primary amine compound 1 3d, for example, as indicated in Scheme 14.

R1 1 'has the same definition as R1 1, but it is part of a macrocycle. A 'is a protected carboxylic acid, an amide or a substituted sulfone amide, or Cr4R4' Scheme 14 The treatment of the a-amino compound (14a) with sodium nitrite, potassium bromide and sulfuric acid (Yang et al. Org. Chem. (2001), 66, 7303-7312) provides the corresponding a-bromine compound (14b), which, by reacting with the previously described derivative (13d), provides the hydrazine derivative containing (14c). Compounds lacking a carboxyl group in unit P3 can be prepared as illustrated in Scheme 15, for example, with a cyclopentane derivative as scaffold P2. (1 15 e 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 a substituted amide sulfone, or Cr4R4' Scheme 15 The acid (15a) can be linked with the amino azide derivative (15b), prepared using methods known in the literature, using appropriate conventional conditions for the binding of peptides, to give the amide derivative (15c). The reduction of the azide function, for example, using polymer-bound triphenyl phosphine, in a solvent, such as methanol, or using any other suitable reduction method, provides the intermediate (15d), which can be subsequently reacted with an acid, under conditions appropriate for the binding of peptides, or with an amine, in a reductive amination reaction, to obtain secondary amides and amines, respectively. In Scheme 16 an alternative route to obtain compounds lacking a carboxyl group in unit P3 is presented. oxidation 16a 16c ? and R7 R7 '16d 16 e 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 a substituted sulfone amide, or Cr4R4' Scheme 16 Instead of using the azide derivative (15b) in scheme 15, the corresponding hydroxyl derivative (16b), optionally protected, can be used , in the union with the acid (16a), which results in the introduction of a primary alcohol. The alcohol (16c) 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 a desired amine in a reductive amination reaction, using a reagent such as, for example, cyanoborohydride attached to polysetirene, in a solvent, such as TH F, provides the amine derivatives (16e). Alternatively, the alcohol (16c) 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 VI. 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 VI. Although Schemes 1 5 and 1 6 have been described with reference to a cyclopentane derivative, ie q 'is 0 and k is 1 in Formula VI, it will be apparent that the corresponding methodology can be applied to other compounds of formula VI. When R7, R7 'and A' contain functional groups, they are optionally protected in an appropriate manner employing methods known to those skilled in the art; see, for example, Bodanzky or Greene, previously cited. Formation of macrocyclic compounds Compounds according to the present invention, containing an alkylene chain extending from R7 / R7 'cycloalkyl to Rx, Rd or R1 1 to form a macrocycle, can be prepared as described below. Appropriate building blocks P 1, P 2 and P 3, 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 assembly with the substituted proline analog or the required carbocycle can be performed. For the macrocyclic structures extending from R7 / R7 'cycloalkyl to R11, amino acids containing the appropriate P3 side chain can be prepared as described in WO00 / 59929. A typical route to prepare macrocyclic compounds is presented in Scheme 17, which illustrates the procedure applied to a spiro-cyclopropyl P1-containing compound, where the macrocycle incorporates the P3 side chain. 17d Scheme 17 The binding of the acid derivative (17a) with the appropriate amino acid protected (17b), using conventional conditions suitable for the binding of peptides, as described above, provides (17c). 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 macrocyclic step described in Scheme 17 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 5-membered cycloalkyl derivative is used as scaffolding P2, in scheme 18. ester hydrolysis 18f A 'is a protected carboxylic acid, a substituted amide or a sulfonamide. n is 1, 2, 3, 4 or 5 Scheme 18 The binding of an appropriate allylglycine derivative (1 8a) with the acid function of the scaffold P2 (18b), using conventional conditions appropriate for the binding of peptides, provides the derivative of amide (18c). Hydrolysis of the ester group, followed by a peptide-binding reaction with the olefin-substituted amino acid (18Ad), provides the amide compound (18e). Then a ring closure metathesis reaction is performed using, for example, the Hoveyda-Grubbs catalyst, which provides the macrocyclic compound (18f). Although in Scheme 18 the synthesis sequence is indicated using a P2 scaffold with an unsubstituted hydroxyl group, it will be apparent that the R8 substituent can be introduced at any convenient stage of the synthesis, for example, as described in Schemes 9 and 10, or it can be introduced after the metathesis reaction, ie, in compound 18f, using any of the methods described herein. The building blocks that are used in the preparation of those compounds where the macrocium extends from the amide nitrogen in the P3 fragment, ie, Rx is J in the general formula VI, or in the preparation of those compounds where the fragments P3 and P4 are absent, ie, m and n are 0, and G is NRj in general formula VI, typically they can be prepared as detailed in scheme 1 8B.

Scheme 18B The 18Ba carbamate, 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 Mitsunobu conditions, with in order to obtain the alkylated carbamate (1 8Bb). Placement of 1 8Bb under acidic conditions, such as, for example, treatment with trifluoroacetic acid in a solvent, such as dichloromethane, provides the free amine (18Bc), which can be linked to a P2 fragment using any of the strategies previously described . Macrocyclic structures containing a hydrazine group, ie, T is NRd or m and n are 0, and G is NRjNRj in general formula VI, 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.

I ° / > NH OV ^ N ^^ ,, "l: OH O> O O N H n = 1,2,3,4,5 19a 19b 19c Scheme 19 The oxidation of the alcohol (19a) proper, made with a method appropriate oxidation, such as, for example, oxide N-methyl morpholine and tetrapropylammonium perruthenate in a solvent like dichloromethane provides 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-ylamine or the like, may be used 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.

R is Ci-Cs alkyl or a chain of Cs-Cn alkyl D-unsaturated Scheme 20 The reaction of a hydrazine derivative suitably protected, for example, tert-butylester of acid (1,3-dioxo-1, 3- dihydro-isonidol-2-yl) -carbamic acid (20a), which can be easily prepared by those trained in the art, with a desired alcohol, R-OH, under Mitsunobu conditions, provides the N-alkylated hydrazine compound (20b) ). The elimination of the phthalimide 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 bound with any desired P2 fragment, using any of the methods previously described to give 20d, or, alternatively, it can be further alkylated using, for example, the reductive amination method described in scheme 19, followed by the binding 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. 21c 21 d Scheme 21 The binding of the carbazate derivative (21 b) with the building block 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 Organic Synthesis" (John Wiley &Sons, New York, 1981), which is incorporated herein by reference, are described. The N-protecting groups include acyl such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl groups , 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-nitrobenzyl oxycarbonyl-, p-bromobenzyloxycarbonyl, 3,4- groups dimethoxy benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1 - (p-biphenylyl) -1 -metiletoxicarbonilo, a, a-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butoxycarbonyl, dlisopropilmetoxicarbonílo, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 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 Fmoc, 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 (1981)). The hydroxyl protecting groups comprise substituted methyl ethers, for example, methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2- (tpmethylsilyl) 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 VI 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 patient's size and metabolic condition, as well as 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 one other antiviral substance against HCV in a common dosage unit, such as any of the dosage forms described below, but especially an oral administration 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 patient kit will also contain instructions printed on the container or container, or in an insert in the container, for the 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 at least one other 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 the 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 (co-packaged in the same dosage unit or in a prescribed dosage unit) is advantageously co-administered. separately) with at least one antiviral substance against VI H and / or at least one antiviral substance against HBV. Representative antiviral agents against the VI H 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, I NK-20 (thioether) of phospholipid AZT, Kucera), 2'3'-dideoxy-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 Inc.), 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, KN I-764, Nippon Mining Holdings), AG-1859 (Pfizer), DPC-681/684 (BMS), GS224338; Gilead Sciences), KNI-272 (Nippon Mining Holdings), Nar-DG-35 (Narhex), P (PL) -1 00 (P-1946, Procyon Biopharma), P-1946 (Procyon Bíopharma), 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 entry inhibitors, 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-913, ONO Pharmaceuticals), Pro-140 (Progenies Pharm), PRO542 (Progenies Pharm.), SCH-D (SCH-417690; Schering-Plow ), T-1249 (R724, Roche / Trimeris), TAK-220 (Takeda Chem. Ind.), TNX-355 (Tanox) and UK-427.857 (Pfizer). Examples of integ rase inhibitors include L-870810 (Merck &Co.), c-2507 (Merck &Co.) and S (RSC) -1838 (shionogi / GSK). Examples of antiviral substances against HBV include adefovir dipivoxil (Hepsera), and especially lamivudine and 2'3'-d, deoxy-3'-fluoroguanosine (FLG), and its prodrugs, such as MIV-21 0, the prodrug of 5'-O-valyl-L-lactyl from 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 carriers 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 VI, 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, ie, 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. As regards compositions for oral administration (eg, tablets and capsules), the term "vehicle", suitable, includes vehicles, such as common excipients, for example, binding agents, for example, 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, kaoiin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants, such as magnesium stearate, sodium stearate and other metal stearates, stearic acid, glycerol stearate, silipone 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, hydrochloride, 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. The prodrugs of the compounds of formula VI 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, ethanoyl, butyryl, t-butyryl, stearyl, and pivaloyl esters, phosphate esters, and sulfonic esters (ie, those derived from RSO2OH, where R is lower alkyl or aril). Acceptable esters for pharmaceutical use include lower alkyl ethers and the ethers described in WO00 / 47561, especially methoxylamino acyl and ethoxy amino acyl. 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, R 5 and / or R 11) 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 L configuration is active regardless of the nature of the E-portion, 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, such as it is contemplated for P3 and P4, it tilts the side chain of the amino acid to the opposite side, in comparison with the conventional peptide substrate. The stereochemistry of the skeletal component of the cyclic P2 group (ie, encompassing the carbonyl of the amide bond P1 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: In the compounds of the invention where R7 and R7 'together define a spiroalkyl group, this spiroalkyl will typically comprise a 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 R7a substituent on the spiro-cyclopropyl ring adjacent to A exhibits a syn orientation in the following absolute configuration: R7'a 1H tí ^ A Particularly preferred variants comprising R include ethyl, whereby the asymmetric carbon atoms in positions 1 and 2 have the R, R configuration. Preferred alternative R7a include vinyl, whereby the asymmetric carbon atoms in positions 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 with respect to the amide (i) J syn with respect to A (ii) especially when J is syn with respect to A.

DETAILED DESCRIPTION OF THE MODALITIES Various embodiments of the invention will now be described by way of illustration only through 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 amount of theoretical 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), 6.88-6.96 (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); 13 C (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 (Rac) -4-oxocyclopent-2-en-1,2-dicarboxylic acid dimethyl ester (2) (1, 2S) -4-oxo-cyclopentan-1,2-dicarboxylic acid dimethyl ester (4.8 g) , 23.8 mmol) and CuBr2 (11.9 g, 53.2 mmol) in dry THF (70 mL) and the mixture was refluxed for two hours at 90 ° C. The formed CuBr was removed by filtration and the organic phase was concentrated. CaCO3 (2.7 g, 27.2 mmol) and DMF (70 mL) were added and the mixture was maintained at 100 ° C for one hour. The dark brown mixture was poured onto ice (35 g) and the precipitate formed was removed by filtration. The aqueous phase was extracted with ethyl acetate (1 x 300mL + 3 x 150 mL). The organic phases were dried, filtered and concentrated. Purification by flash chromatography (toluene / EtOAc 9: 1) gave 2 (2, 1 g, 45%) as yellow crystals. Example 3 dimethyl ester ((1 S, 4f?) & (1 f?, 4S)) - 4-hydroxy-cyclopent-2-en-1,2-dicarboxylic acid (3) To a cold solution (-30 ° C) of 2 (3.18 g, 16.1 mmol) dissolved in MeOH (23 mL), NaBH4 (0.66 g, 17.5 mmol) was added.

After nine minutes the excess NaBH was destroyed by adding brine (80 mL). The mixture was concentrated and extracted with ethyl acetate (4 x 80 mL). The organic phases were dried, filtered and concentrated and gave 3 (3.0 g, 92%) as a yellow oil.

Example 4 2-methyl ester of acid (1S, 4R) & (1R, 4S) -4-hydroxy-cyclopent-2-en-1,2-dicarboxylic acid (4) To a freezing solution of 3 (3.4 g, 22 mmol) dissolved in dioxane and water (1: 1, 110mL ), LiOH (0.52 g, 22 mmol) was added. After two and a half hours the mixture was co-evaporated with toluene and methanol. Purification by flash chromatography (toluene / ethyl acetate 3: 1 + 1% HOAc) gave the title compound (1.0 g, 27%) as yellow-white crystals. 1 H-NMR (300 MHz, CD 3 OD): d 1.78-1.89 (m, 1H), 2.70-2.84 (m, 1H), 3.56-3.71 (m, 1H), 3.76 (s, 3H), 4.81-4.90 (m, 1H), 6.76-6.81 (m, 1H); 13 C-NMR (75.5 MHz, CDCl 3): d 38.0, 48.0, 52.4, 75.7, 137.0, 146.2, 165.0178.4. Example 5 acid ((3S.5R) &(3R, 5S)) - 5 - ((S) -1-tert-Butoxycarbonyl-butylcarbamoyl) -3-hydroxy-cyclopent-1-enecarboxylic acid (5) To a solution? frost of 4 (0.20 g, 1.1 mmol) and tert-butylester of 2-amino-pentanoic acid (0.24 g, 1.4 mmol) in DMF (7 mL), DIPEA (0.18 g.) was added. g, 1.4 mmol) and HATU (0.53 g, 1.4 mmol). After two hours the solution was concentrated and purified using column chromatography (toluene / ethyl acetate 3: 1). This gave the title compound as a yellow oil (0.22 g, 63%). 1 H-NMR (300 MHz, CDCl 3): d 0.84-0.96 (m, 3H), 1.14-1.39 (m, 2H), [(1.44 & 1,49) s, 9H ], 1.50-1.60 (m, 1H), 1.61-1.85 (m, 1H), 1.97-2.10 (m, 1H), 2.11-2.28 (m , 1H), 3.57-3.68 (m, 1H), [(3.73 &3.76) s, 3H], 4.30-4.50 (m, 1H), 4.63- 4.73 (m, 1H), 6.80-6.95 (m, 1H), 6.95-7.00 (m, 1H). Example 6 ((3S, 5R) &(3R, 5S)) - 5 - ((S) -1-rerr-Butoxycarbonyl-propylcarbamoyl) -3-hydroxy-cyclopent-1-enecarboxylic acid methyl ester (6) The reaction of (141 mg, 76 mmol) according to the method described for the preparation of 5 using L-2-amino-N-butyric acid tert-butylester in place of 2-amino-pentanoic acid tert-butylester gave the compound of title as a slightly yellow oil (171 mg, 69%). 1 H-NMR (300 MHz, CDCl 3): d 0.89-0.98 (m, 3H), [(1.42 & 1.44) s, 9H], 1.60-1.78 (m, 1H), 1.79-1.95 (m, 1H), 1.99-2.11 (m, 1H), 2, 18-2.30 (m, 1H), 3.58-3.65 (m, 1H), [3.75 & 3.78) s, 3 H], 4.22-4.39 (m, 1H), 4.61-4.66 (m, 1H), é, 77-6.90 (m, 1H), 6 91-6.92 (m, 1H). Example 7 ((3S.5R) &(3R, 5S)) - 5 - ((1R, 2S) -1-ferf-Butoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -3-hydroxy-cyclopent-1 acid methyl ester incarboxylic (7) The reaction of 4 (50 mg, 37 mmol) according to the method described for the preparation of 5 using (1R, 2S) -1-amino-2-vinyl-cyclopropanecarboxylic acid tert-butylester instead of 2-amino-pentanoic acid tert-butylester gave the title compound as a slightly yellow oil (50 mg, 38%). 1 H-NMR (300 MHz, CDCl 3): d [(1.38 & 1,42) s, 9H], 1.75-1.83 (m, 1H), 2.00-2.21 (m, 3H), 3.55-3.63 (m, 1H), [(3.77 &3.82) s, 3H], 4.20-4.38 (m, 1H), 4.65-4 , 80 (m, 1H), 5.13-5.20 (m, 1H), 5.22-5.38 (m, 1H), 5.60-5.82 (m, 1H), 6.95 -6.96 (m, 2H). Example 8 ((3R, 5R) &(3S, 5S)) - 5 - ((S) -1-tert-Butoxycarbonyl-butylcarbamoyl) -3- (7-methoxy-2-phenyl-quinolin-4-yloxy) methyl ester ) -cic | opent-1-enecarboxylic (8) To an ice solution of 5 (0.23 g, 0.67 mmol) in dry THF, 7-methoxy-2-phenyl-quinolin-4-ol ( , 22 g, 0.88 mmol) and triphenylphosphine (0.23 g, 0.88 mmol). Then DIAD (0.19 g, 0.92 mmol) was dissolved in THF (2 mL) and added dropwise to the solution. After one hour the mixture was concentrated and purified using flash chromatography (toluene / ethyl acetate 3: 1). This gave the title compound as a white powder (0.30 g, 77%). 1 H-NMR (300 MHz, CDCl 3): d 0.88-1.00 (m, 3H), 1.18-1.43 (m, 2H), [(1.45 &1.50) s, 9H], 1.53-1.65 (m, 1H), 1.66-1.85 (m, 1H), 2, 29-2.43 (m, 1H), 3.10-3.25 (m, 1H), [(3.79 &3.83) s, 3H], 3.97 (s, 3H), 4 , 05-4.20 (m, 1H), 4.38-4.50 (m, 1H), 6.03-6.13 (m, 1H), 6.65-6.90 (m, 1H) , 7.04-7.18 (m, 3H), 7.40-7.56 (m, 4H), 8.00-8.12 (m, 3H). Example 9 ((3R, 5R) &(3S, 5S)) - 5 - ((S) -1-Rebu-Butoxycarbonyl-propylcarbamoyl) -3- (7-methoxy-2-phenyl-quinolin-4-yloxy) methyl ester ) -cyclopent-1-enecarboxylic (9) The reaction of 6 (132 mg, 40 mmol) according to the method described for the preparation of 8 gave the title compound as a yellow oil (137 mg, 61%). 1 H-NMR (300 MHz, CDCl 3): d 0.83-0.98 (m, 3H), [(1.42 & amp;; 1.44) s, 9H], 1.65-1.78 (m, 1H), 1.80-1.97 (m, 1H), 2.30-2.40 (m, 1H), 3, 05-3.20 (m, 1H), [(3.78 &3.80) s, 3H], 3.94 (s, 3H), 3.95-4.01 (m, 1H), 4 , 38-4.44 (s, 1H), 6.05-6.15 (m, 1H), 6.80-6.94 (m, 1H), 7.02-7.15 (m, 3H) , 7.38-7.55 (m, 4H), 7.97-8.18 (m, 3H). Example 10 acid methyl ((3R.5R) &(3S, 5S)) - 5 - ((1R, 2S) -1-ferf-Butoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -3- (7-methoxy-2-phenyl) -quinolin-4-yloxy) -cyclopent-1-encarboxylic acid (10) The reaction of 7 (41 mg, 116 mmol) according to the method described for the preparation of 8 gave the title compound as a yellow oil. 1 H-NMR (300 MHz, CDCl 3): d 1.52-1.57 (m, 1H), 1.58 (m, 9H), 1.80-1.83 (m, 1H), 2.00- 2.17 (m, 1H), 2.20-2.38 (m, 1H), 3.20-3.37 (m, 1H), 3.80 (s, 3H), 3.81-3- 3.98 (m, 1H), 3.99 (s, 3H), 5.12-5.20 (m, 1H), 5.22-5.40 (m, 1H), 5.63-5, 80 (m, 1H), 6.05-6-20 (m, 1H), 7.00-7.21 (m, 4H), 7.40-7.58 (m, 4H), 8.02- 8.18 (m, 3H). Example 11 ((3R, 5R) &(3S, 5S)) - 5 - ((S) -1-tert-Butoxycarbonyl-butylcarbamoyl) -3- (7-methoxy-2-phenyl-quinolin-4-yloxy) - acid Cyclopent-1-incarboxylic acid (11) Methyl ester 8 (0.35 g, 0.61 mmol) was dissolved in dioxane / water (1: 1, 7 mL) and LiOH (0.031 g, 1.3 mmol) was added. The reaction was stirred overnight and then co-concentrated. This gave the lithium salt of 11 (0.32 g, 90%) as a brown powder. Example 12 ((3R.5R) &(3S, 5S)) - 5 - ((S) -1-Fert-Butoxycarbonyl-propylcarbamoyl) -3- (7-methoxy-2-phenyl-quinolin-4-yloxy) - acid Cyclopent-1-incarboxylic acid (12) The reaction of 9 (225 mg, 40 mmol) according to the method described for the preparation of 1 1 gave the title compound as a yellow salt (157 mg, 72%). Example 13 ((3R.5R) &(3S, 5S)) - 5 - ((1 R, 2S) -1-Fe / -f-Butoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -3- (7-methoxy-2) acid phenyl-quinolin-4-yloxy) -cyclopent-1-incarboxylic acid (13) The reaction of 10 (35 mg, 59 mmol) according to the method described for the preparation of 11 (33 mg, 97%) gave the title compound as a yellow salt. Example 14 tert-butylester of (S) -2- acid. { [((1S, 4S) &(1R, 4R)) - 2-. { (S) -1 - [((S) -Cyclohexyl-methoxycarbonyl-metll) -carbamoyl] -2-methyl-propylcarbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -cyclopent-2-encarbonyl] -amino} -butyric acid (14) Acid 12 (38.4 mg, 0.070 mmol) and (2-amino-3-methyl-butyrylamino) -cyclohexylacetic acid methyl ester (26.6 mg, 0.098 mmol) were dissolved in DMF (1, 5 mL) and cooled in an ice bath. DIPEA (17.1 μL, 0.098 mmol) and HATU (37.4 mg, 0.098 mmol) were added. After ninety minutes the mixture was co-concentrated with toluene and methanol and then purified by flash column chromatography (toluene / ethyl acetate 6: 1). Additional purification was performed by HPLC (90% MeOH + 0.2% TEA). The diastereomer mixture 14 was concentrated and gave a slightly yellow oil (20.6 mg, 37%). After lyophilization, 14 was collected as a white powder. 1 H-NMR (300 MHz, CDCl 3): dO, 93-1, 02 (m, 9H), 1.03-1.25 (m, 4H), 1.44 (s, 9H), 1.65-1 , 86 (m, 9H), 2.05-2.10 (m, 1H), 2.22-2.40 (m, 1H), 3.05-3.20 (m, 1H), 3.77. (s, 3H), 3.98 (s, 3H), 4.18-4.22 (m, 1H), 4.38-4.60 (m, 3H), 6.01-6.10 (m , 1H), 6.61-6.70 (m, 2H), 6.80-6.85 (m, 1H), 7.05-7.18 (m, 2H), 7.40-7.58 (m, 5H), 8.00-8.13 (m, 3H). 13 C-NMR (75.5 MHz, CDCl 3): d 9.7, 18.4, 19.2, [25.9 & 26.1], [28.2 & 28.5], 29.6, 32.0, 37.3, 41.0, 46.2, 50.7, 52.4, 54.4, 55.8, 57.2, 58.5, 82 , 0.82.8, 98.4, 110.2, 118.4, 120.1, 123.2, 127.9, 128.2, 128.9, 129.5, 131.2, 135.1 , 135.2, 142.7, 144.2, 161.6, 164.3, 164.7, 170.9, 171.4, 172.4. MALDI-TOF m / z 821.56 [(M + Na) + calculated for C45H58N4Na? 9+ 821.41]. Example 15 tert-butylester of (S) -2- acid. { [((1, 4R) &(1S, 4S)) - 2-. { (R) -1 - [((R) -Cyclohexyl-methoxycarbonyl-methyl) -carbamoyl] -2-methyl-propylcarbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -cyclopent-2-encarbonyl] -amino} -butyric (15) The reaction of 12 (20 mg, 37 mmol) according to the method described for the preparation of 14 using (2-amino-3-methyl-butyrylamino) - (R) -cyclohexylacetic acid methyl ester in place of (2-amino-3-methyl-butyplamino) - (S) -cyclohexylacetic acid methyl ester gave the title compound (19 mg, 66%) as a white powder. 1 H-NMR (300 MHz, CDCl 3): d 0.91-0.98 (m, 3H), 0.99-1.10 (m, 6H), 1.11-1.38 (m, 4H), [(1,43 &; 1.45) s, 9H], 1-45-1.94 (m, 9H), 2.05-2.18 (m, 1H), 2.22-2.40 (m, 1H), 3, 16-3.24 (m, 1H), 3.77 (s, 3H), 3.98 (s, 3H), 4.04-4.18 (m, 1H), 4.36-4.57 ( m, 3H), 6.00-6.08 (m, 1H), 6.13-6.21 (m, 1H), 6.62-6.70 (m, 1H), 6.81-6, 85 (m, 1H), 7.05-7.18 (m, 3H), 7.41-7.57 (m, 4H), 8.02-8.13 (m, 3H). 13 C-NMR (75.5 MHz, CDCl 3): d 9.3, 18.2, 19.0, [25.5 & 25.9], [28.0 & 28.3], 29.4, 31.4, 32.1, 35.7, 40.7, 50.4, 52.2, 54.2, 55.5, 57.0, 58.2, 81 , 8, 82.4, 98.2, 107.5, 115.0, 118.1, 122.9, 127.6, 128.7, 128.8, 128.9, 129.2, 135.1 , 140.4, 142.2, 151.4, 161.3, 163.9, 170.4, 170.9, 171.2, 172.0. MALDITO F m / z 821, 60 [(M + Na) + calculated for C45H58N4NaO9 + 821.41]. Example 16 methyl ester of (S) -2- acid. { [((3R, 5R) &(3S, 5S)) - 5 - ((S) -1-rerf-Butoxycarbonyl-propylcarbamoyl) -3- (7-methoxy-2-phenyl-quinolin-4-yloxy) - cyclopent-1-encarboníí] -amíno} -3-methyl-butyl (16) The reaction of 12 (24 mg, 44 mmol) according to the method described for the preparation of 14 using D-valine methyl ester in place of (2-amino-3) methyl ester -met.I.-butyrylamino) cyclohexylacetic, gave the title compound (27 mg, 97 %) as a white powder. 1 H-NMR (300 MHz, CDCl 3): d 0.82-0.99 (m, 9H), [(1.42 & 1.44) s, 9H] 1.65-1.95 (m, 2H), 2.18-2.25 (m, 1H), 2.26-2.40 (m, 1H), 3.20-3.25 (m, 1H), 3.75 (s, 3H), 3.97 (s, 3H), 4.15-4.19 (m, 1H), 4.36-4, 43 (m, 1H), 4.64-4.75 (m, 1H), 6.03-6.15 (m, 1H), 6.80-6.85 (m, 2H), 7.10- 7.20 (m, 3H), 7.42-7.58 (m, 4H), 8.0-8.10 (m, 3H). 13C-NMR (75.5 MHz, CDCl 3): d 9, 7, [18.2 & 19.1], 25.7, [28.1 & 28.2], 32.0, 35.6, 50.4, 52.4, 54.5, 55.7, 57.6, 81.7, 82.7, 98.4, 107.7, 115 , 2, 118.4, 123.2, 127.8, 129.0, 129.2, 129.5, 134.8, 135.0, 140.4, 142.5, 151.6, 159.6 , [161.1 & 161.5], 164.6, 171.1, 172.2. MALDI-TOF m / z 682.51 [(M + Na) + calculated for C37H45N3NaO8 + 682.31]. Example 17 tert-butylester of (S) -2- acid. { [((1R, 4R) &(1S, 4S)) - 2-. { (S) -1 - [(2,5-Dimethoxy-phenyl) -ethyl-carbamoyl] -2-methyl-propylcarbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -cyclopent-2-encarbonyl] -amino} -butyric (17) Compound 17 (28.6 mg, 59%) was prepared from 12 (33 mg, 60 mmol) according to the method for the preparation of 14 using 2-amino-N- butyramide ( 2,5-dimethoxy-phenyl) -N-ethyl-3-methyl in place of (2-amino-3-methyl-butyrylamino) -cyclohexylacetic acid methyl ester. This gave the title compound as a white powder. 1 H-NMR (300 MHz, CDCl 3): d 0.75-0.95 (m, 9H) 1.05-1.18 (m, 3H), [(1.42 & 1,44) s, 9H ], 1.60-1, 95 (m, 3H), 2.20-2.40 (m, 1H), 3.20-3.34 (m, 1H), 3.60-3.80 (m) , 2H), [3,62-3,65 (m, 3H)], [3,79-3,82 (m, 3H)], 3,98 (s, 3H), 4,02-4-18 (m, 1H), 4.30-4.44 (m, 2H), 6.05-6.18 (m, 1H), 6.60-6.63 (m, 1H), 6.77-6 , 80 (m, 2H), 6.85-6.93 (m, 2H), 7.12-7.20 (m, 2H), 7.35-7.60 (m, 5H), 8.02 -8.20 (m, 3H). 13 C-NMR (75.5 MHz, CDCl 3): d [9.6 & 9.7], [12.5 & 12.8], [17.1 & 17.5], [19.4 & 19.5], 25.6, [28.0 & 28.1], 32.4, 35.8, 43.0, 44.3, [50.2 & 50.3], 54.3, [54.8 & 55.0 & 55.2 & 55.5], [55.6 & 55.7 & 55.9 & 56.0], 81.7, 82.8, 98.4, 106.9, [112.4 & 112.5], 113.7, 115.0, 115.2, 115.9, 116.3, 118.4, [123.0 & 123.1], [127.7 & 127.8], 128.8, 128.9, 129.5, 130.1, [134.1 & ? 34.2], 142.6, 149.1, 149.4, 153.4, 158, 9, [161, 4 & 161.6], [163.2 & 163.5], 170.9, [171.3 & 171.5], 172.3. MALDI-TOF m / z 831.62 [(M + Na) + calculated for C46H56N4NaO9 + 831.39]. Example 18 tert-butylester of (S) -2- acid. { [((1, 4R) &(1S, 4S)) - 2-. { (S) -1 - [((S) -Cyclohexyl-methoxycarbonyl-methyl) -carbamoyl] -2,2-dimethyl-propylcarbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -cyclopent-2-encarbonyl] -amino} -butyric (18) Compound 18 (16.1 mg, 26%) was prepared from 12 (43.2 mg, 0.077 mmol) according to the method for the preparation of 14 using acid methyl ester (2-amino) -3,3-dimethyl-butyriamino) -cyclohexyl-acetic acid in place of (2-amino-3-methyl-butyrylamino) -cyclohexylacetic acid methyl ester. Flash column chromatography was performed in toluene / ethyl acetate 3: 1 instead of 6: 1: This gave the title compound as a white powder. 1 H-NMR (300 MHz, CDCl 3): dO, 77-0, 83 (m, 3H), [(0.92 &0.93) s, 9H] 0.94-1.20 (m, 4 H ), [(1.36 &1.38) s, 9H], 1.42-1.76 (m, 8H), 2.20-2.38 (m, 1H), 2.81-2, 96 (m, 1H), 3.20-3.22 (m, 1H), 2.78 (s, 3H), [(3.83 &3.85) s, 3H], 3.97-4 , 02 (m, 1H), 4.17-4.21 (m, 1H), 4.22-4.37 (m, 2H), 5.85-5.97 (m, 1H), [6, 76-6.78 (m, 0.5H)], [6.80-6.82 (m, 0.5H)], 6.98-7.05 (m, 3H), 7.23-7.41 ( m, 6H), 7.82-7.99 (m, 3H). 13 C-NMR (75.5 MHz, CDCl 3): d [9.4 & 9.5], [25.4 & 25.5], 25.8, [26.5 & 26.6], [27.9 & 28.0], [28.4 & 28.5], 29.3, [35.4 & 35.7], [36.0 & 36.4], [40.5 & 40.7], [50.2 & 50.5], [52.1 & 52.2], [54.1 & 54.3], 55.5, [57.0 & 57.3], [60.4 & 60.7], [81.8 & 82.0], [82.4 & 82.5] 98.1, 107.5, 115.0, 118.1, 123.0, 127.5, 128.7, 128.8, 129.2, 134.9, 135.8, 141, 9, 142.5, 151.3, 159.4, [160.9 & 161.3], [163.7 & 163.9], [169.9 & 170.0] [170.0 & 171.3], [172.5 & 172.4]. MALDI-TOF m / z 835.68 [(M + Na) + calculated for C46H60N4NaO9 + 835.43]. Example 19 7 tert-butylester of (S) -2- acid. { [(1, 4R) -2-. { (S) -1 - [((S) -Cyclohexyl-methoxycarbonyl-methyl) -carbamoyl] -2-methyl-propylcarbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -cyclopent-2-encarbonyl] -amino} pentanoic (19a) and tert-butylester of (S) -2- acid. { [(1S, 4S) -2-. { (S) -1 - [((S) -Cyclohexyl-methoxycarbonyl-methyl) -carbamoyl] -2-methyl-propylcarbamoyl} -4- (7-methoxy-2-phene-quinolin-4-yloxy) -cyclopent-2-encarbonyl] -amino} pentanoic acid (1 9b) The acid 1 1 (0.051 g, 0.087 mmol) and (2-amino-3-methyl-butyrylamino) -cyclohexyl-acetic acid methyl ester (0.054 g, 0.21 mmol) were dissolved in DMF (1.5 mL) and cooled in an ice bath. DIPEA (16 mg, 0.12 mmol) and HATU (47 mg, 0.13 mmol) were added. After two and a half hours the mixture was co-concentrated with toluene and methanol and then purified by flash column chromatography (toluene / ethyl acetate 3: 1). Additional purification was performed by HPLC (90% MeOH + 0.2% TEA). This gave after co-concentration the two diastereomers 1 9a (9.4 mg, 13%) and 19b (5.3 mg, 7%) as slightly yellow syrups. After lyophilization, 19a and 19b were collected as white powders: 1 H-NMR (300 MHz, CDCl 3): dO, 86-0, 93 (m, 3H), 0.94-1.00 (m, 6H), 1 , 00-1.41 (m, 7H), 1.46 (s, 9H), 1.50-1.88 (m, 8H), 2.05-2.20 (m, 1H), 2.20 -2.37 (m, 1H), 3.12-3.25 (m, 1H), 3.73 (s, 3H), 3.97 (s, 3H), 4.05-4.20 (m , 1H), 4.40-4.55 (m, 3H), 6.02-6.18 (m, 1H), 6.30 (d, J = 8.52 Hz, 1H), 6.63 ( s, 1H), 6.76 (d, J = 8.51 Hz, 1H), 7.06-7.16 (m, 2H), 7.42-7.56 (m, 5H), 8.00 -8.12 (m, 3H); 3C-NMR (75.5 MHz, CD3OD): d 14.0, 18.4, 19.3, 26.1, 28.3, 28.5, 29.7, 31.9, 34.9, 36 , 0.41.0, 50.7, 52.4, 53.3, 55.7, 57.2, 58.6, 82.0, 82.7, 98.4, 105.7, 107.7 , 115.2, 118.4, 123.2, 125.3, 127.9, 129.0, 129.1, 135.1, 138.0, 142.4, 151.6, 159.4, 161 , 6, 164.3, 170.7, 171.2, 172.3. 19b: 1H-NMR (300 MHz, CDCl 3): dO, 90-1, 04 (m, 9H), 1.04-1.43 (m, 7H), 1.47 (s, 9H), 1.50 -1.87 (m, 8H), 2.10-2.27 (m, 1H), 2.33-2.45 (m, 1H), 3.10-3.20 (m, 1H), 3 , 73 (s, 3H), 3.96 (s, 3H), 4.02-4.10 (m, 1H), 4.36-4.53 (m, 3H), 6.00-6.16 (m, 1H), 6.30 (d, J = 8.52 Hz, 1H), 6.73 (s, 1H), 6.86 (d, J = 7.96 Hz, 1H), 7.08 -7.16 (m, 2H), 7.36-7.56 (m, 5H), 8.03-8.11 (m, 3H). 13 C-NMR (75.5 MHz, CD3OD): d 14.0, 18.6, 19.2, 26.1, 28.2, 28.7, 29.7, 34.5, 36.1, 36 , 6, 40.8, 50.5, 52.4, 53.4, 55.7, 57.3, 59.1, 64.8, 82.3, 98.4, 105.8, 107.8 , 115.3, 118.4, 123.2, 127.8, 129.0, 129.4, 135.2, 142.2, 144.9, '"151.0, 151.6, 159.2 , 164.3, 164.3, 170.2, 171.6, 171.9 Example 20 tert-butylester of (S) -2- acid. { [(1, 4R) -2-. { (R) -1 - [((S) -Cyclohexyl-methoxycarbonyl-methyl) -carbamoyl] -2,2-dimethyl-propylcarbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -cyclopent-2-encarbonyl] -amino} pentanoic (20a) and tert-butylester of (S) -2- acid. { [(1S, 4S) -2-. { (R) -1 - [((S) -Cyclohexyl-methoxycarbonyl-methyl) -carbamoyl] -2,2-dimethyl-propylcarbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -cyclopent-2-encarbonyl] -amino} pentanoic (20b) Method A: The carboxylic acid 1 1 (57 mg, 0.10 mmol) was dissolved in warm (50 ° C) THF (2 mL) warm. Methyl ester (2-amino-3,3-dimethyl-butyrylamino) -cyclohexyl-acetic acid (50 mg, 0.12 mmol), DIPEA (30 mg, 0.23 mmol) were added. DCC (25 mg, 0.12 mmol) and HOBt (17 mg, 13 mmol). After two hours the mixture was concentrated and added to a short column (toluene / ethyl acetate 1: 3 + 3% AcOH). Then it was further purified by HPLC using 90% MeOH + 0.2% TEA. The diastereomeric products did not separate. After HPLC the solution was co-concentrated with toluene and methanol to give 20 (28 mg, 34%).

Method B: To an ice-cold solution of 11 (60 mg, 0.10 mmol) and (2-amino-3,3-dimethyl-butyrylamino) -cyclohexyl-acetic acid methyl ester (42 mg, 0.15 mmol) were added. DIPEA (19 mg, 0.15 mmol) and HATU (62 mg, 0.16 mmol). After two and a half hours the mixture was concentrated and purified using column chromatography, (toluene / ethyl acetate 3: 1). The diastereomeric mixture was separated using HPLC (90% MeOH + 0.2% TEA). This gave 20a (6 mg, 6%) and 20b (9 mg, 10%). 20a: 1 H-NMR (300 MHz, CDCl 3): d 0.82-0.90 (m, 3H), 1.01 (s, 9H), 1.05-1.40 (m, 7H), 1, 46 (s, 9H), 1.50-1.80 (m, 8H), 2.20-2.35 (m, 1H), 3.07-3.25 (m, 1H), 3.73 ( s, 3H), 3.97 (s, 3H), 4.11 (d, J = 7.96 Hz, 1H), 4.38-4.52 (m, 3H), 6.03-6.12 (m, 1H), 6.24 (d, J = 8.79 Hz, 1H), 6.63 (s, 1H), 6.82 (d, J = 9.06 Hz, 1H), 7.07 -7.27 (m, 2H), 7.36 (d, J = 7.96 Hz, 1H), 7.41-7.55 (m, 4H), 8.01-8.10 (m, 3H) ); 13 C-NMR (75.5 MHz, CD3OD): d14.0, 18.8, 26.1, 26.8, 28.2, 28.6, 29.6, 34.9, 35.6, 36, 2, 40.9, 50.7, 52.4, 53.3, 55.7, 57.3, 60.8, 82.0, 82.7, 98.4, 105.2, 107.7, 115.2, 118.4, 123.2, 127.9, 129.0, 129.4, 131.1, 135.1, 138.4, 142.4, 153.3, 159.6, 161, 6, 164.2, 170.1, 171.3, 172.2. 20b: 1H-NMR (300 MHz, CDCl 3): d 0.90-0.98 (m, 3H), 1.04 (s, 9H), 1.08-1.40 (m, 7H), 1, 44 (s, 9H), 1.55-1.90 (m, 8H), 2.20-2.38 (m, 1H), 3.10-3.22 (m, 1H), 3.73 ( s, 3H), 3.97 (s, 3H), 4.02-4.15 (m, 1H), 4.35-4.48 (m, 3H), 6.00-6.08 (m, 1H), 6.72 (s, 1H), 6.90 (d, J = 9.06 Hz, 1H), 7.09-7.20 (m, 3H), 7.44-7.55 (m , 5H), 8.03-8.11 (m, 3H). Example 21 tert-butylester of (1R, 2S) -1- acid. { [((1R, 4R) &(1S, 4S)) - 2-. { (S) -1 - [((S) -Cyclohexyl-methoxycarbonyl-methyl) -carbamoyl] -2,2-dimethyl-propylcarbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -cyclopent-2-in carbon i] -amino} -2-vinyl-cyclo or propan carboxylic acid (21) Acid 13 (35 mg, 0.060 mmol) and methyl ester of (2-amino-3,3-dimethyl-butyrylamino) -cyclohexyl-acetic acid (22 mg, 0.080 mmol) they were dissolved in dry THF (1.5 mL) and heated to 50 ° C. HOBt (11 mg, 0.080 mmol) and DCC (31 mg, 0.15 mmol) were added. After one hour the mixture was co-concentrated with toluene and methanol and then purified by flash column chromatography (toluene / ethyl acetate 1: 1). Further purification was carried out by HPLC (80% MeOH + 0.2% TEA) The diastereomer mixture 21 was concentrated and gave a slightly yellow oil (26.4 mg, 53%) After lyophilization 21 it was collected as a white powder 1 H-NMR (300 MHz, CDCl 3): d [(0.98 &1.00), s, 9H], 1.01-1.38 (m, 5H), [(1.39 & , 40) s, 9H], 1.52-1.63 (m, 4H), 1.65-1.80 (m, 4H), 1.90-2.05 (m, 1H), 2.20 -2.40 (m, 1H), 3.02-3.20 (m, 1H), [(3.66 &3.67) s, 3H), 3.98 (s, 3H), 3, 99-4.02 (m, 1H), 4.30-4.45 (m, 2H), 5.05- 5.11 (m, 1H), 5.20-5.30 (m, 1H), 5.60-5.81 (m, 1H), 6.03-6.17 (m, 1H), 6.77-6.82 (m, 1H), 6.95-7.22 (m, 5H) ), 7.40-7.50 (m, 4H), 8.01-8.10 (m, 3H). 13C-NMR (75.5 MHz, CDCl3): d 22.3, [25.7 & amp;; 25.8], [26.4 & 26.5], [28.0 & 28.4] 29.2, 32.7, 33.3, [35.3 & 35.4], 36.0, [40.2 & 40.3], 40.7, 52.0, 55.4, [57.2 & 57.4] [60.4 & 60.5], [87.6 & 87.7], [82.3 & 82.5], 98.4, 107.0, 114.9, [117.4 & 117.5], 118.1, 122.9, 127.6, 128.6, 128.9, 129.2, [133.6 & 133.8], 135.9, 136.9, 140.1, [141.4 & 141.6], 151.1, 159.6, [160.9 & 161.3], [164.2 & 164.6], 168.9, 170.3, [172.1 & 172.6]. MALDI-TOF m / z 859.77 [(M + Na) + calculated for C48H6oN4NaO9 + 859.43]. Example 22 acid (S) -2-. { [(1R, 4R) -2-. { (R) -1 - [((S) -Cyclohexyl-methoxycarbonyl-methyl) -carbamoyl] -2,2-dimethyl-propylcarbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -cyclopent-2-encarbonyl] -amino} -pentanoic (22a) and acid (S) -2 ~. { [(1S, 4S) -2-. { (R) -1 - [((S) -Cyclohexyl-methoxycarbonyl-methyl] -carbamoyl] -2,2-dimethyl-propylcarbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -cyclopent-2-encarbonyl] -amino} pentanoic (22b) Tert-butylester 20 (28 mg, 0.034 mmol), TES (8.7 mg, 0.075 mmol), DCM (1 mL) and TFA (1 mL) were mixed in a round-bottom container. Two hours later the mixture was concentrated and the diastereomers were separated by HPLC using 65% MeOH + 0.2% TEA as the mobile phase. This gave 22a (15 mg, 55%) and 22b (12 mg, 45%) as slightly yellow syrups. After lyophilization the title compounds were collected as white powders. 22a: [a] 22D + 155.8; 1 H-NMR (300 MHz, CD 3 OD): d 0.90-0.97 (m, 3H), 1.03 (s, 9H), 1.05-1.50 (m, 7H), 1.50- 1.80 (m, 8H), 2.43-2.55 (m, 1H), 2.77-2.90 (m, 1H), 3.68 (s, 3H), 3.96 (s, 3H), 4.20-4.30 (m, 2H), 4.31-4.40 (m, 1H), 4.45-4.50 (m, 1H), 6.03-6.11 ( m, 1H), 6.98 (s, 1H), 7.12-7.19 (m, 1H), 7.36 (s, 1H), 7.41 (d, J = 2.2 Hz, 1H ), 7.50-7.60 (m, 3H), 8.03-8.10 (m, 3H): 13 C-NMR (75.5 MHz, CD3OD): d 13.1, 19.1, 26 , 1, 28.7, 28.9, 29.5, 34.3, 34.8, 35.9, 40.1, 50.8, 51.2, 54.8, 55.0, 57.9 , 60.7, 83.5, 99.1, 106.0, 115.2, 118.2, 123.3, 127.8, 128.0, 128.7, 128.8, 129.7, 135 , 2, 139.8, 143.7, 150.6, 160.1, 162.2, 165.2, 171.7, 172.2, 173.4. 22b: [a] 22D -72.3; 1 H-NMR (300 MHz, CD 3 OD): d 0.90-0.97 (m, 3H), 1.02 (s, 9H), 1.07-1.35 (m, 7H), 1.53- 1.90 (m, 8H), 2.46-2.61 (m, 1H), 2.76-2.88 (m, 1H), 3.69 (s, 3H), 3.96 (s, 3H), 4.15-4.35 (m, 2H), 4.37-4.41 (m, 1H), 4.42-4.47 (m, 1H), 6.02-6.12 ( m, 1H), 7.02 (s, 1H), 7.16 (dd, J = 2.47, 9.34 Hz, 1H), 7.32 (s, 1H), 7.40 (d, J = 2.47 Hz, 1H), 7.48-7.58 (m, 3H), 8.03-8.12 (m, 3H); 13 C-NMR (75.5 MHz, CD3OD): d 13.0, 18.8, 25.9, 26.0, 28.8, 29.4, 34.2, 34.8, 36.3, 39 , 9, 48.8, 50.5, 51.1, 54.8, 57.9, 60.5, 82.8, 99.0, 106.0, 115.1, 118.2, 123.1 , 127.8, 127.9, 128.7, 129.0, 129.5, 136.7, 139.8, 142.8, 150.6, 160.1, 162.0, 162.2, 164 , 7, 172.1, 173.5. Example 23 acid (S) -2-. { [(1R, 4R) -2-. { (R) -1 - [((R) -Cyclohexyl-methoxycarbonyl-methyl) -carbamoyl] -2-methyl-propylcarbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -cyclopent-2-encarbonyl] -amino} -butyric (23a) and (S) -2-. { [(1S, 4S) -2-. { (R) -1 - [((R) -Cyclohexyl- methoxycarbonylmethyl) -carbamoyl] -2-methyl-propylcarbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -cyclopent-2-encarbonyl] -amino} -butyric (23b) Compound 23a (6.6 mg, 50%) and compound 23b (1.3 mg, 10%) were prepared from 15 (14 mg, 0.018 mmol) according to the method for the preparation of 22a and 22b. This gave the title compounds as white powders. 23a: 1H-NMR (300 MHz, CD3OD): 0.88-1.02 (m, 9H), 1.02-1.40 (m, 7H), 1.55-1.97 (m, 6H) , 2.01-2.10 (m, 1H), 2.38-2.52 (m, 1H), 2.88-3.00 (m, 1H), 3.77 (s, 3H), 3 , 98 (s, 3H), 4.08-4.20 (m, 1H), 4.22-4.40 (m, 3H), 6.03-6.18 (m, 1H), 6.86. -6.99 (m, 1H), 7.08-7.20 (m, 1H), 7.23 (s, 1H), 7.40-7.43 (m, 1H), 7.45-7 , 70 (m, 3H), 8.02-8.20 (m, 3H). 13 C NMR (75.5 MHz, CD3OD): d 9.0, 17.6, 18.2, 24.5, 25.3, 28.1, 28.8, 30.9, 35.4, 39 , 4, 49.6, 51.1, 54.7, 57.2, 58.0, 82.4, 98.5, 105.5, 114.5, 117.7, 122.7, 127.2 , 127.3, 128.2, 129.0, 135.6, 136.4, 141.7, 149.9, 159.5, 161.2, 161.4, 164.0, 171.0, 171 , 7, 172.4. 23b: 1H-NMR (300 MHz, CD3OD): d 0.9-1.20 (m, 9H), 1.21-1.53 (m, 7H), 1.55-1.93 (m, 6H) ), 2.05-2.20 (m, 1H), 2.41-2.50 (m, 1H), 2.96-3-05 (m, 1H), 3.77 (s, 3H), 4.00 (s, 3H), 4.05-4.40 (m, 4H), 6.05-6.18 (m, 1H), 6.90-6.95 (m, 1H), 7, 05-7.22 (m, 2H), 7.50-7.65 (m, 4H), 8.01-8.16 (m, 3H). Example 24 acid (S) -2-. { [((1R, 4R) &(1S, 4S)) - 2-. { (S) -1 - [((S) -Carboxy-cyclohexyl-methyl) -carbamoyl] -2-methyl-propylcarbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -cyclopent-2-encarbonyl] -amino} -butyric (24) Tert-butyl ester 14 (13.4 mg, 0.017 mmol), TES (4.83 mg, 0.042 mmol), DCM (2 mL) and TFA (2 mL) were mixed in a round base vessel. One hour later the mixture was concentrated and purified by HPLC using 65% MeOH + 0.2% TEA as the mobile phase. This gave 24 (4.3 mg, 34%) as a slightly yellow syrup. After lyophilization 24 was collected as a white powder. 1 H-NMR (300 MHz, CD 3 OD): d 0.91-0.99 (m, 9H), 1.00-1.28 (m, 4H), 1.55-1.78 (m, 9H), 1.92-1.95 (m, 1H), 2.00-2.05 (m, 1H), 2.93-3.01 (m, 1H), 3.75 (s, 3H), 3, 97 (s, 3H), 4.10-4.40 (m, 4H), 6.05-6.15 (m, 1H), 6.88-6.94 (m, 1H), 7.05- 7.10 (m, 2H), 7.41-7.43 (m, 1H), 7.44-7.55 (m, 2H), 8.62-8.68 (m, 1H), 8, 69-8.79 (m, 1H), 7.97-8.05 (m, 2H). 13 C-NMR (75.5 MHz, CD3OD): d 9.2, 18.5, 25.5, [29.0 & 29.2], [30.0 & 30.5], 35.3, 37.7, 39.7, 46.2, 50.0, [51.4 & 51.5], 53.6, 55.1, 57.1, 58.4, 83.1, 98.9, 104.9, 114.6, 118.3, 123.0, 123.4, 127 , 5, 128.4, 128.5, 129.7, 135.0, 142.1, 145.7, 146.2, 159.2, 161.9, 164.3, 171.5, 171.9 172.2. MALDI-TOF m / z 791.27 [(M + K) + calculated for C42H48KN4O9 + 791.31]. Example 25 methyl ester of (S) -2- acid. { [((3R, 5R) &(3S, 5S)) - 5 - ((S) -1-Carboxy-propylcarbamoyl) -3- (7-methoxy-2-phenyl-quinolin-4-yloxy) -c Clopent-1-encarbonil] -amino} -3-methyl-butyric (25) Compound 25 (8.0 mg, 60%) was prepared from 16 (13.8 mg, 0.022 mmol) according to the method for the preparation of 24 which gave the Composed of the title as a white powder. 1 H-NMR (300 MHz, CD 3 OD): d 0.83-1.02 (m, 9H), 1.68-1.80 (m, 1H), 1.82-2.02 (m, 1H), 2.10-2.22 (m, 1H), 2.40-2.60 (m, 1H), 2.81-2.95 (m, 1H), 3.75 (s, 3H), 4, 00 (s, 3H), 4.18-4.22 (m, 1H), 4.27-4.40 (m, 2H), 6.05-6.12 (m, 1H), 6.99- 7.02 (m, 1H), 7.16-7.21 (m, 1H), 7.38 (s, 1H), 7.40-7.43 (m, 1H), 7.48-7, 61 (m, 3H), 7.98-8.12 (m, 3H). Example 26 acid (S) -2-. { [((1R, 4R) &(1S, 4S)) - 2-. { (S) -1 - [(2,5-Dimethoxy-phenyl) -ethyl-carbamoyl] -2-methyl-propylcarbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -cyclopent-2-encarbonyl] -amino} -butyric (26) Compound 26 (5.7 mg, 36%) was prepared from 17 (16.7 mg, 0.021 mmol) according to the method for the preparation of 24 which gave the title compound as a white powder. 1 H-NMR (300 MHz, CD 3 OD): d 0.75-0.81 (m, 6H), 0.82-0.98 (m, 3H), 1.00-1.10 (m, 3H), 1.60-2.00 (m, 3H), 2.40-2.56 (m, 1H), 2.80-2.88 (m, 1H), 3.18-3.24 (m, 1H) ), 3.40-3.46 (m, 1H), [3.67-3.80 (m, 6H)], 3.97 (s, 3H), 4.10-4.20 (m, 1H) ), 4.21-4.40 (m, 2H), 6.02-6.17 (m, 1H), 6.75-6.82 (m, 1H), 6.84-7.01 (m , 3H), 7.10-7.20 (m, 1H), 7.30-7.37 (m, 1H), 7.40-7.43 (m, 1H), 7.50-7.60 (m, 3H), 8.00-8.17 (m, 3H). 13C-NMR (75.5 MHz, CD3OD): d 9.6, [11.8 & amp;; 12.0], [17.2 & 17.4], 18.9, 25.0, 32.3, 35.7, 43.3, 44.2, [50.3 & 50.5], [54.5 & 54.8 & 54.9 & 55.0], [55.1 & 55.2 & 55.3 & 56.0], 58.7, 83.6, 99.3, 105.5, [112.5 & 112.7], 114.3, [15.1 & 115.2], 115.7, 116.1, 118.4, [123.3 & 123.4], 125.2, [128.0 & 128.1, 128.8, 129.1, 129.8, [135.1 & 135.3], 139.2, [143.3 & 144.4], 149.2, [149.6 & 149.9], 153.8, 159.9, 162.4, [163.9 & 164.5], 172.1, 172.8, [173.6 & 173.7]. MALDI-TOF m / z 775.30 [(M + Na) + calculated for C42H48N4NaO9 + 775.33]. Example 27 acid (S) -2-. { [((1R, 4R) &(1S, 4S)) - 2-. { (S) -1 - [((S) -Cyclohexyl-methoxycarbonyl-methyl) -carbamoyl] -2,2-dimethyl-propylcarbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -cyclopent-2-encarbonyl] -amino} -butyric (27) Compound 27 (6.0 mg, 72%) was prepared from 18 (8.6 mg, 0.011 mmol) according to the method for the preparation of 24. Purification by HPLC (60% methanol + 0.2% TEA) gave the title compound as a white powder. 1 H-NMR (300 MHz, CD 3 OD): d 0.88-0.95 (m, 3H), 0.96 (s, 9H), 0.97-1.24 (m, 4H), 1.57- 1.62 (m, 3H), 1.58-1.78 (m, 4H), 1.79-1.99 (m, 1H), 2.35-2.44 (m, 2H), 2, 85-2.98 (m, 1H), [(3.67 &3.69) s, 3H], 3.94 (s, 3H), 4.10-4.20 (m, 1H), 4 , 30-4.40 (m, 3H), 6.00-6.09 (m, 1H), [6.80-6.82 (m, 0.5H)] [6.85-6.87 (m , 0.5H)], 7.05-7.19 (m, 2H), 7.38-7.55 (m, 4H), 7.95-8.07 (m, 3H). 13 C-NMR (75.5 MHz, CD3OD): d [9.1 & 9.2], [24.7 & 24.9], [25.4 & 25.5], [25.9 & 26.0], [28.3 & 28.4], 28.9, [34.8 & 34.9], [35.6 & 35.9], [39.6 & 39.7], [49.9 & 50.1], [51.4 & 51.2], [53.9 & 54.0] 55.0, [57.2 & 57.4], 60.0, [82.1 & 82.5], 98.6, 106. 2, 114.7, 117.8, 122.7, 127.5, 127.7, [128.4 & 128.5], 129.1, 135. 3, 136.3, 141.6, 142.0, 150.5, 159.8, [161.0 & 161.3] [164.0 & 164.1], [171.6 & 171.9], [172.2 & 172.3], [173.0 & 173.2]. ALDI-TOF m / z 779.43 [(M + Na) + calculated for C42H52N4NaO9 + 779.36]. Example 28 tert-butylester of (S) -2- acid. { [(1R, 4R) -2-. { (S) -1 - [((S) -Cyclohexyl-methoxycarbonyl-methyl) -carbamoyl] -2-methyl-propylcarbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -cyclopent-2-encarbonyl] -amino} pentanoic (28) Tert-butylester 19a (7.6 mg, 0.0094 mmol) and TES (2.4 mg, 0.021 mmol) were dissolved in DCM (1 mL) and the mixture was cooled in an ice bath. . TFA (1 mL) was added. After two hours the mixture was concentrated and purified by HPLC using 60% MeOH + 0.2% TEA as the mobile phase. This gave 28 (6.1 mg, 86%) as a slightly yellow syrup. After lyophilization the title compound was collected as a white powder. 1 H-NMR (300 MHz, CD 3 OD + CDCl 3 (1: 1)): d 0.90-1.00 (m, 9H), 1.00-1.30 (m, 7H), 1.50-1.90 (m, 8H), 2.00-2.10 (m, 1H), 2.40-2 , 50 (m, 1H), 2.85-2.98 (m, 1H), 3.65-3.72 (s, 3H), 3.99 (s, 3H), 4.15-4.22 (m, 1H), 4.24-4.35 (m, 2H), 4.38-4.44 (m, 1H), 6.10-6.20 (m, 1H), 6.95-6 , 96 (m, 1H), 7.16-7.23 (m, 1H), 7.31 (s, 1H), 7.42 (d, J = 2.47 Hz, 1H), 7.53- 7.72 (m, 3H), 7.97-8.16 (m, 3H); 13 C-NMR (75.5 MHz, CD3OD + CDCl 3 1: 1): d 13.5, 18.3, 19.0, 26.0, 29.0, 29.7, 31.0, 34.1, 35.8, 40.2, 51.9, 55.9, 57.7, 58.9, 63.5, 68.4, 84.0, 99.6, 104.8, 105.7, 115, 1, 119.0, 123.7, 128.1, 128.9, 129.1, 130.4, 131.3, 135.3, 138.0, 142.9, 159.5, 162.8, 164.8, 172.2, 172.2, 172.4 Example 29 tert-butylester of (S) -2- acid. { [(1S, 4S) -2-. { (S) -1 - [((S) -Cyclohexyl-methoxycarbonyl-methyl) -carbamoyl] -2-methyl-propylcarbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -cyclopent-2-encarbonyl] -amino} pentanoic (29) Compound 29 (1.3 mg, 26%) was prepared from 19b (5.3 mg, 0.065 mmol) according to the method for the preparation of 28. This gave the title compound as a white powder. 1 H-NMR (300 MHz, CD 3 OD): d 0.85-1.00 (m, 9H), 1.00-1.23 (m, 7H), 1.50-1.78 (m, 8H), 2.05-2.23 (m, 1H), 2.50-2.66 (m, 1H), 2.70-2.85 (m, 1H), 3.69 (s, 3H), 3, 92 (s, 3H), 4.02-4.16 (m, 1H), 4.20-4.25 (m, 1H), 4.35-4.40 (m, 2H), 6.09 ( m, 1H), 7.00 (s, 1H), 7.12-7.18 (dd, J = 2.47, 2.19 Hz, 1H), 7.30 (s, 1H), 7.40 (d, J = 2.42 Hz, 1H), 7.48-7.74 (m, 3H), 8.03-8.10 (m, 3H); 13 C-NMR (75.5 MHz, CDCl 3): d 11.7, 16.5, 17.0, 24.4, 27.2, 27.9, 29.0, 29.1 37.5, 41, 8, 49.7, 50.5, 53.3, 56.3, 63.5, 66.5, 81.0, 100.3, 101.0, 105.7, 113.6, 121.6, 126.3, 127.1, 127.9, 130.1, 131.4, 135.6, 138.7, 141.1, 150.4, 160.2, 160.5, 165.3, 173, 0.173.6, 173.7 Example 30 acid (1R, 2S) -1-. { [(1R, 4R) -2-. { (S) -1 - [((S) -Cyclohexyl-methoxycarbonyl-methyl) -carbamoyl] -2,2-dimethyl-propylcarbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -cyclopent-2-enecarbonyl] -amino} -2-vinyl-cyclopropanecarboxylic (30a) and acid 1 R, 2S) -1 -. { [(1S, 4S) -2-. { (S) -1 - [((S) -Cyclohexyl-methoxycarbonyl-methyl) -carbamoyl] -2,2-dimethyl-propylcarbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -cyclopent-2-encarbonyl] -amino} -2-vinyl-cyclopropane-carboxylic acid (30b) Compound 30a (6.3 mg, 49%) and compound 30b (5.6 mg, 43%) were synthesized from 21 (13.8 mg, 0, 0016 mmol) according to the method of the preparation of 22a and 22b. 30a and 30b: White powder. 30a: 1H-NMR (300 MHz, CD3OD): d 1.02 (s, 9H), 1.03-1.43 (m, 5H), 1.61-1.95 (m, 8H), 2, 11-2.21 (m, 1H), 2.43-2.58 (m, 1H), 2.97-3.04 (m, 1H), 3.78 (s, 3H), 4.01 ( s, 3H), 4.02-4.17 (m, 1H), 4.25-4.40 (m, 2H), 5.10-5-20 (m, 1H), 5.27-5, 40 (m, 1H), 6.77-6.94 (m, 1H), 6.10-6.20 (m, 1H), 6.97 (s, 1H), 7.18 (dd, J = 2.5, 9.2 Hz, 1H), 7.22 (s, 1H), 7.46 (d, J = 2.5 Hz, 1H), 7.52-7.65 (m, 3H), 8.00-8.18 (m, 3H). 13 C-NMR (75.5 MHz, CD3OD): d 13.5, 25.3, 25.7, 28.3, 28.7, 29.0, 32.8, 34.6, 35.3, 39 , 3, 49.7, 51.1, 54.6, 57.2, 59.8, 82.1, 98.4, 105.8, 114.5, 116.3, 117.6, 122.6 , 127.2, 128.1, 128.2, 128.8, 130.2, 133.7, 136.0, 139.5, 141.5, 150.3, 159.7, 161.0, 161 , 2, 163.4, 171.6, 172.5. MALDI-TOF m / z 803.56 [(M + Na) + calculated for C44H52N4NaO9 + 803.36]. 30b: 1H-NMR (300 MHz, CD3OD): d 1.03 (s, 9H), 1.04-1.42 (m, 5H), 2.60-2.90 (m, 8H), 2, 17-2.22 (m, 1H), 2.40-2.55 (m, 1H), 2.96-3.10 (m, 1H), 3.77 (s, 3H), 4.01 ( s, 3H), 4.05-4.16 (m, 1H), 4.30-4.40 (m, 2H), 5.15-5.20 (m, 1H), 5.25-5, 40 (m, 1H), 5.78-5.95 (m, 1H), 6.10-6.20 (m, 1H), 6.98 (S.-1H), 7.17 (dd, J = 2.5, 9.1 Hz, 1H), 7.26 (s, 1H), 7.46 (d, J = 2.5 Hz, 1H), 7.50-7.65 (m, 3H) , 8.03-8.28 (m, 3H). 13 C-NMR (75.5 MHz, CD3OD): d 13.7, 26.0, 26.3, 28.8, 29.4, 29.6, 34.0, 35.2, 35.8, 40 , 1, 50.6, 51.7, 55.3, 57.8, 60.6, 83.0, 99.1, 106.3, 115.2, 117.0, 118.3, 123.2 , 127.9, 128.0, 128.8, 129.6, 130.6, 134.4, 136.1, 140.0, 142.5, 150.8, 160.3, 161.8, 162 , 0. 165.7, 172.3, 173.0 Example 31 rrans- (3R, 4R) -Bis (methoxycarbonyl) cyclopentanol (31) Sodium borohydride (1.11 g, 0.029 mol) was added to a stirring solution of (1R, 2S) -4-oxo-cyclopentan dimethyl ester. -1,2-dicarboxylic acid (4.88 g, 0.0244 mol) in methanol (300 mL) at 0 ° C. After 1 h the reaction was set with 90 mL brine, concentrated and extracted with ethyl acetate. The organic phases were combined, dried, filtered and concentrated. The crude product was purified by flash column chromatography (toluene / ethyl acetate 1: 1) to give 31 (3.73 g, 76%) as a yellow oil. Example 32 3-Oxo-2-oxa-bicyclo [2.2.1] heptan-5-carboxylic acid (32) Sodium hydroxide (1M, 74 mL, 0.074 mol) was added to a stirring solution of 31 (3, 73 g, 0.018 mol) in methanol (105 mL) at room temperature. After 4 h, the reaction mixture was neutralized with 3M HCl, evaporated and co-evaporated with toluene several times. Pyridine (75 mL) and Ac2O (53 mL) were added and the reaction mixture was allowed to stir overnight at room temperature. The mixture was then co-evaporated with toluene and purified by flash column chromatography (ethyl acetate + 1% acetic acid) to give 32 (2.51 g, 88%) as a yellow oil. Example 33 3-Oxo-2-oxa-bicyclo [2.2.1] heptan-5-carboxylic acid tert-butylester (33) DMAP (14 mg, 0.1-15 mmol) and Boc2O (252 mg, 1, 44 mmol) was added to a stirring solution of 32 (180 mg, 1.15 mmol) in 2 mL CH2Cl2 under an inert atmosphere of argon at 0 ° C. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated and the crude product was purified by flash column chromatography (gradient of toluene / ethyl acetate 15: 1, 9: 1, 6: 1, 4: 1, 2: 1) to give 33 (124 mg, 51%) as white crystals. 1 H-NMR (300 MHz, CD 3 OD) d 1.45 (s, 9 H), 1.90 (d, J = 11.0 Hz, 1 H), 2.10-2.19 (m, 3 H), 2, 76-2.83 (m, 1H), 3.10 (s, 1H), 4.99 (s, 1H); 13 C-NMR (75.5 MHz, CD3OD) d 27.1, 33.0, 37.7, 40.8, 46.1, 81.1, 81.6, 172.0, 177.7. Example 34 (1R, 2R, 4S) -2 - ((1R, 2S) -1-Ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -4-hydroxy-cyclopentanecarboxylic acid tert -butylester (34) Compound 33 (56 mg, 0.264 mmol ) was dissolved in dioxane / water 1: 1 (5 mL) and the mixture was cooled to 0 ° C. 1 M Lithium hydroxide (0.52 mL, 0.520 mmol) was added and the mixture was stirred at 0 ° C for 45 minutes, after which the mixture was neutralized with 1M hydrochloric acid and evaporated and coevaporated with toluene. The residue was dissolved in DMF (5 mL) and (1R, 2S) -1-amino-2-vinylcyclopropanecarboxylic acid (60 mg, 0.313 mmol) and dlisopropylethylamine (DIEA) ethylester hydrochloride (138 DL, 0.792) were added. mmol) and the solution was cooled to 0 ° C. HATU (120 mg, 0.316 mmol) was added and the mixture was stirred for 0.5 h at 0 ° C and for another 2 h at room temperature. The mixture was then evaporated and extracted with EtOAc, washed with brine, dried, filtered and concentrated. Purification by flash column chromatography (toluene / EtOAc 1: 1) gave compound 34 (86 mg, 89%) as a colorless oil. Example 35 acid tert-butyl ester (1R, 2R, 4R) -2 - ((1R, 2S) -1-Ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -4- (7-methoxy-2-phenyl-quinoline- 4-yloxy) -cyclopentanecarboxylic acid (35) Compound 34 (73 mg, 0.199 mmol) was dissolved in dry THF (4 mL) and 2-phenyl-7-methoxy-4-quinolinol (86 mg, 0.342 mmol) was added. ) and triphenylphosphine (141 mg, 0.538 mmol). The mixture was cooled to 0 ° C and DIAD (0.567 mmol) dissolved in 1 mL THF was added dropwise. The mixture was stirred for 48 h at room temperature. The solvent was evaporated and the crude product was purified by flash column chromatography with an elution gradient (toluene / EtOAc 9: 1, 6: 1, 4: 1) to give compound 35 (81 mg, 68%). Example 36 Boc-L-feri-leucine-OH (36) Triethylamine (890 uL, 6.40 mmol) was added dropwise to a stirred solution of L-ferf-leucine (300 mg, 2.29 mmol) and di-dicarbonate. -err-butyl (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 compound 36 (522 mg, 99%) as a powder colorless. 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 37 ((S) -Cyclohexyl-methylcarbamoyl-methyl) -carbaric acid tert-butylester (37) Boc-Chg-OH (387 mg, 1.50 mmol) was coupled with methylamine hydrochloride (11.1 mg, 1.65) mmol) using the same HATU coupling conditions as in the synthesis of compound 34. The crude product was extracted with EtOAc, washed with brine and concentrated. Purification by flash column chromatography (EtOAc) gave compound 37 (307 mg, 76%) as a colorless solid. 1 H-NMR (300 MHz, CDCl 3) d 0.91 -1, 13 (m, 2 H), 1, 14-1, 31 (m, 3 H), 1.44 (s, 9 H), 1.61 -1 , 80 (m, 6H), 2.80 (d, J = 4.7 Hz, 3H), 3.91 (dd, J = 7, 1, 9, 1 Hz, 1 H), 5.23 (b , 1 H), 6.52 (bs, 1 H); 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 38 acid tert-butyl ester. { (S) -1 - [((S) -Cyclohexyl-methylcarbamoyl-methyl) -carbamoyl] -2,2-dimethyl-propyl} -carbamic (38) To a solution of compound 37 (98 mg, 0.362 mmol) in methylene chloride (3 mL) were added triethylsilane (1 15 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. The deprotected amine was dissolved in DMF (5 mL) and coupled with compound 36 (84 mg, 0.363 mmol) using the same HATU coupling conditions as in the synthesis of 34. The crude product was extracted with EtOAc, washed with brine, dried, filtered and concentrated. Purification by flash column chromatography (toluene / EtOAc 1: 1) gave compound 38 (128 mg, 92%) as a colorless solid. 1 H-NMR (300 MHz, CDCl 3) d 0.99 (s, 9 H), 1, 02-1, 30 (m, 5 H), 1.44 (s, 9 H), 1.58-1, 77 (m , 4H), 1, 78-1, 89 (m, 2H), 2.79 (d, J = 4.7 Hz, 3H), 4, 1 1 (d, J = 9.3 Hz, 1 H) , 4.33 (app.t, J = 8.5 Hz, 1 H), 5.65 (b, 1 H), 7.25 (b, 1 H), 7.39 (b, 1 H); 13C-.NMR (75.5 MHz, CDCI3) 8 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 39 Ethyl ester of acid (1 R, 2S) -1 -. { [(1 R, 2R, 4S) -2-. { (S) -1 - [((S) -Cyclohexyl-methylcarbamoyl-methyl) -carbamoyl] -2,2-dimethyl-propylcarbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -cyclopentanecarbonyl] -amino} -2-vinyl-cyclopropanecarboxylic acid (39) To a solution of compound 35 (30 mg, 0.050 mmol) in methylene chloride (1.5 mL) were added triethylsilane (21 DL, 0. 132 mmol) and TFA (1.5 mL). The mixture was stirred for 2 h at room temperature and then evaporated and coevaporated with toluene. Amine 38 (1, 3 eq) was deprotected in the same manner as compound 35 and then coupled with the deprotected compound using the same HATU coupling conditions as in the synthesis of 34. The crude product was extracted with EtOAc, it was washed with brine, dried, filtered and concentrated. Purification using HPLC (MeOH / water 9: 1 + 0.2% or triethylamine) gave compound 39 (30 mg, 74%) as a colorless solid. 1 H-NMR (300 MHz, CD 3 OD) d 0.81-1.14 (m, 4H), 0.99 (s, superimposed, 9H), 1.21 (t, J = 7.1 Hz, 3H), 1.35-1.51 (m, 4H), 1.52-1.65 (m, 3H), 1.66-1.72 (m, 2H), 2.03-2.20 (m, 2H) ), 2.24-2.39 (m, 1H), 2.46-2.56 (m, 1H), 2.66 (s, 3H), 2.72-2.85 (m, 1H), 3.39-3.48 (m, 2H), 3.90 (s, 3H), 4.03-4.15 (m, 3H), 4.44 (s, 1H), 5.09 (dd, J = 1.9, 10.3 Hz, 1H), 5.19-5.27 (m, 1H), 5.25 (dd, superimposed, 1H), 5.79 (ddd, J = 8.8, 10.3, 17.2 Hz, 1H), 6.99 (s, 1H), 7.07 (dd, J = 2.5, 9.1, Hz, 1H), 7.29 (d, J = 2.5 Hz, 1H), 7.43-7.52 (m, 3H), 7.86-7.98 (m, 2H), 8.05 (d, J = 9.3 Hz, 1H); 13 C-NMR (75.5 MHz, CD3OD) d 14.7, 23.4, 26.0, 26.9, 27.1, 27.3, 30.1, 30.7, 35.0, 35, 4, 38.3, 38.8, 40.9, 41.0, 47.9, 55.9, 59.6, 62.0, 62.4, 79.8, 99.9, 107.3, 116.4, 118.0, 119.1, 124.4, 128.9, 129.8, 130.5, 135.3, 141.3, 152.1, 161.1, 162.4, 163, 0, 171.6, 172.5, 173.7, 175.2, 176.8. Maldi-TOF- spectrum: (M + H) + calculated: 810.4, found: 810.5; (M + Na) + calculated: 832.4, found: 832.4; (M + K) + calculated: 848.5, found: 848.4. Example 40 acid (1R, 2S) -1-. { [(1R, 2R, 4S) -2-. { (S) -1 - [((S) -Cyclohexyl-methylcarbamoyl-methyl) -carbamoll] -2,2-dimethyl-propylcarbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -cyclopentanecarbonyl] -amino} -2-vinyl-cyclopropanecarboxylic acid (40) To a solution of compound 39 (20 mg, 0.025 mmol) in THF / MeOH / water 2: 1: 1 (2 mL) at 0 ° C was added 1M LiOH (175 uL, 0.175 mmol) and the solution was allowed to reach room temperature and stirred for 48 h. The solution was acidified to pH 3 with 1M HCl and then evaporated and coevaporated with toluene. The crude product was purified by HPLC (MeOH / water 6: 4 + 0.5% TFA followed by MeOH / water 4: 1 + 0.2% TFA) to give compound 40 (13 mg, 67%) as a solid colorless. 1 H-NMR (300 MHz, CD 3 OD) d 0.82-0.98 (m, 1H), 1.01 (s, 9H), 1.05-1.26 (m, 3H), 1.34-1 , 43 (m, 1H), 1.49-1.77 (m, 8H), 2.10-2.21 (m, 1H), 2.28-2.42 (m, 2H), 2.50 -2.61 (m, 1H), 2.64 (s, 3H), 2.68-2.81 (m, 1H), 3.36-3.45 (m, 2H), 4.04-4 , 11 (m, 1H), 4.06 (s, superimposed, 3H), 4.27 (d, J = 8.8 Hz, 1H), 5.10 (dd, J = 1.8, 10.3 Hz, 1H), 5.28 (dd, J = 1.8, 17.2 Hz, 1H), 5.59-5.68 (m, 1H), 5.82 (ddd, J = 9.1, 10.3, 17.2 Hz, 1H), 7.44 (dd, J = 2.5, 11.8 Hz, 1H), 7.50 (s, 1H), 7.53 (d, J = 2 , 5 Hz, 1H), 7.69-7.78 (m, 3H), 8.02-8.07 (m, 2H), 8.39 (d, J = 9.3 Hz, 1H); 13 C-NMR (75.5 MHz, CD3OD) d 23.5, 26.0, 26.9, 27.2, 27.3, 30.0, 30.7, 34.7, 35.3, 37, 0, 38.7, 41.0, 41.3, 47.4, 56.9, 59.4, 62.7, 83.9, 100.4, 102.2, 116.2, 117.7, 1'21 ', 7, 126.7, 129.8, 130.8, 133.4, 133.9, 135.6, 143.5, 158.0, 166.6, 168.6, 172.5 , 173.4, 173.6, 175.4, 176.4. Maldi-TOF-spectrum: (M + H) + calculated: 782.4, found: 782.2; (M + Na) + calculated: 804.4, found: 804.2; (M + K) + calculated: 820.5, found: 820.2. Example 41 3-Oxo-2-oxa-bicyclo [2.2.1] heptan-5-carboxylic acid methyl ester (41) Compound 32 (1.014 g, 6.50 mmol) was dissolved in acetone (35 mL) before adding Methyl iodide (13.68 g, 96.4 mmol) and silver oxide (I) (1.61 g, 6.95 mmol). After stirring for 3 h the mixture was filtered through celite and the filtrate was evaporated before purification by flash column chromatography (toluene / ethyl acetate 4: 1) to give methyl ester 41 (702 mg, 64%) as white crystals. . 1 H-NMR (300 MHz, CDCl 3): d 1.96 (d, J = 10.7 Hz, 1H), 2.21-2.25 (m, 3H), 2.91-2.95 (m, 1H), 3.16 (s, 1H), 3.75 (s, 3H), 4.98 (app.s, 1H). Example 42 acid methyl ester (1 R, 2R, 4S) -2 - ((S) -1 -ferf-Butoxycarbomyl-butylcarbamoll) -4-hydroxy-cyclopentanecarboxylic acid (42) Compound 41 (263 mg, 1.55 mmol) and H -Nva-OfBu (420 mg, 2.42 mmol) was dissolved in dry THF (20 mL). DIEA (530 uL, 3.04 mmol) and 2-hydroxypyridine (260 mg, 2.73 mmol) were added and the mixture was refluxed for five days. The solvent was evaporated and the crude product was purified by flash column chromatography (toluene / EtOAc 1: 2) to give 42 (510 mg, 96%). Example 43 acid methyl ester (1 R, 2R, 4R) -2 - ((S) -1-ferf-Butoxycarbonyl-butylcarbamoyl) -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -cyclopentanecarboxylic acid (43) Compound 42 (249 mg, 0.725 mmol), 2-phenyl-7-methoxy-4-quinolinol (310 mg, 1.23 mmol) and PPh3 (580 mg, 2.21 mmol) were dissolved in dry THF and the temperature it was brought to 0 ° C. DIAD (435 uL 2.21 mmol) dissolved in 2 mL dry THF was added to the mixture for five minutes. After two hours the temperature was raised to room temperature and the solution was stirred overnight. Evaporation and purification by flash column chromatography (toluene / EtOAc gradient from 6: 1 to 4: 1) gave 43 (324 mg, 78%). Example 44 tert-butylester of (S) -2- acid. { [(1 R, 2R, 4S) -2-. { (S) -1 - [((S) -Cyclohexyl-methylcarbamoylmethyl) -carbamoyl] -2,2-dimethyl-propylcarbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -cyclopentanecarbonyl] -amino} pentanoic (44) Compound 43 (38 mg, 0.066 mmol) was dissolved in dioxane / water 1: 1 (4 mL) and the solution was cooled to 0 ° C and 1 M LiOH (132 ul, 0.132 g) was added. mmol). The temperature was raised to room temperature and the solution was stirred for 2 hours after which it was neutralized by the addition of 1 M HCl and evaporated and coevaporated with toluene. The residue and the deprotected amine 38 (1.1 eq) were dissolved in DMF and coupled using the standard HATU coupling conditions of the synthesis of compound 34. The crude product was extracted with EtOAc, washed with brine, dried, filtered and concentrated. Purification with HPLC (MeOH / water 9: 1 + 0.2% TEA) gave compound 44 (44 mg, 81%) as a colorless solid. 1 H-NMR (CDCl 3, 300 MHz) rotamers (5: 1) d 0.79 (t, J = 7.3 Hz, 3 H), 0.85-1.19 (m, 3 H), 0.93 (s) , superimposed, 9H), 1.20-1.35 (m, 2H), 1.39 (s, 1.5 H), 1.43 (s, 7.5 H), 1.54-1.79 (m, 6H), 2.06-2.28 (m, 3H), 2.39-2.51 (m, 2H), 2.66-2.78 (m, 1H), 2.74 (d. , superimposed, J = 4.7 Hz, 3H), 3.42-3.68 (m, 2H), 3.84 (s, 2.5 H), 3.88 (s, 0.5 H), 4.19 (t, J = 8.9 Hz, 1H), 4.39-4.59 (m, 1H), 4.68 (d, J = 9.6 Hz, 1H), 5.04-5 , 14 (m, 1H), 6.77 (s, 1H), 6.88-7.06 (m, 2H), 7.26-7.47 (m, 6H), 7.53 (b, 1H) ), 7.85-7.97 (m, 3H); 13 C-NMR (75.5 MHz, CDCl 3) d 13.7, 18.7, 25.6, 25.7, 26.0, 26.7, 28.0, 28.9, 29.7, 34, 5, 34.7, 37.7, 38.0, 39.2, 46.6, 47.7, 52.7, 55.3, 58.5, 60.3, 77.9, 81.7, 98.0, 107.4, 115.0, 117.9, 122.8, 127.4, 128.6, 129.0, 140.2, 151.2, 158.9, 160.6, 161, 1, 170.9, 171.6, 171.8, 172.7, 173.3. Maldi-TOF-spectrum: (M + H) + calculated: 828.5, found: 828.6; (M + Na) + calculated: 850.5, found: 850.6; (M + K) + calculated: 866.6, found: 866.6. Example 45 acid (S) -2-. { [(1R, 2R, 4S) -2-. { (S) -1 - [((S) -Cyclohexyl-methylcarbamoii-methyl) -carbamoyl] -2,2-dimethyl-propylcarbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -cyclopentanecarbonyl] -amino} pentanoic (45) Compound 44 (21 mg, 0.025 mmol) was dissolved in CH2Cl2 (1.5 mL) and triethylsilane (10 uL, 0.063 mmol) and TFA (1.5 mL) were added. The solution was stirred for 2 hours at room temperature after which the solvents were evaporated and co-evaporated with toluene to give compound 45 (20 mg, 100%) as a colorless solid. 1 H-NMR (300 MHz, CD 3 OD) d 0.93 (t, superimposed, 3 H), 0.98 (s, 9 H), 0.99-1.25 (m, 4 H), 1.30-1.49 (m, 3H), 1.50-1.90 (m, 8H), 2.25-2.39 (m, 2H), 2.54-2.62 (m, 1H), 2.64 (s) , 3H), 2.72-2.87 (m, 1H), 3.34-3.57 (m, 3H), 4.02-4.13 (m, 1H), 4.06 (s, superimposed , 3H), 4.27-4.36 (m, 1H), 4.37-4.47 (m, 1H), 5.57-5.66 (m, 1H), 7.45 (dd, J = 2.3, 9.2 Hz, 1H), 7.48 (s, 1H), 7.54 (d, J = 2.2 Hz, 1H), 7.69-7.79 (m, 3H) , 8.01-8.07 (m, 2H), 8.42 (d, J = 9.3 Hz, 1H); 3C-NMR (75.5 MHz, CD3OD) d 14.0, 20.2, 26.0, 26.9, 27.2, 30.1, 30.7, 34.6, 35.3, 37, 2, 39.1, 41.2, 47.7, 53.7, 56.9, 59.4, 59.5, 62.5, 83.7, 100.4, 101.3, 102.2, 116.2, 121.7, 126.7, 129.8, 130.8, 133.3, 133.9, 143.5, 157.9, 166.6, 168.5, 172.5, 173, 6, 175.3, 175.4, 175.5. Maldi-TOF-spectrum: (M + H) + calculated: 772.4, found: 772.6; (M + Na) + calculated: 794.4, found: 794.6; (M + K) + calculated: 810.5, found: 810.6. Example 46 Hept-6-enal (46) To a solution of hept-6-en-1 -ol (1 mL, 7.44 mmol) and N-oxido of N-methylmorpholine (1, 308 g, 1 1, 17 mmol) DCM (17 mL) was added powdered molecular sieves (3.5 g, 4 Á). 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 46 (620 mg, 74%) as an oil. Example 47 acid / tert-butylester-Hept-6-en- (£) -ylidene-hydrazinecarboxylic acid (47) To a solution of 46 (68 mg, 0.610 mmol) and rer-butyl carbazate (81 mg, 0.613 mmol) in MeOH (5 mL) were added powdered molecular sieves (15 mg, 3 A). 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 NaHCO3, brine, dried over MgSO 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 47 (85 mg, 61%) as an oil. Example 48 Ethyl ester of acid (1 R, 2S) -1 -. { [(1R, 2R, 4R) -2 - (/ V'-ferf-Butoxycarbonyl- / v-hept-6-enyl-hydrazinocarbonyl) -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -cyclopentanecarbonyl] -amino} -2-vinyl-cyclopropanecarboxylic (48) The scaffold molecule 35 (135 mg, 0.225 mmol) and triethylsilane (71 μL, 0.447 mmol) was dissolved in DCM (2 mL) after which trifluoroacetic acid (TFA) was added. ) (2 mL). The mixture was stirred for 2 h and then co-evaporated with toluene to remove the TFA. The residue was dissolved in DMF (3 mL) and 47 (60 mg, 0.263 mmol) and DIEA (1-1.8 μL, 0.677 mmol) were added. The temperature was brought to 0 ° C and the coupling agent of O- (7-azabenzotriazol-1-yl) -? /,? /,? / ',? /' - tetramethyluronium (HATU) (94 mg, 0.247 mmol). The cold solution was left stirring for half an hour and then for another 16 h at room temperature. The solvent was removed by heating the reaction vessel in a water bath under reduced pressure. The residue was then dissolved in ethyl acetate and the organic phase was washed three times with brine, dried, filtered and evaporated. Purification by HPLC (90:10 MeOH / H2O with 0.2% triethylamine) gave 48 (140 mg, 82%) as an oil. H-NMR (300 MHz, CDCl 3, 40 ° C): d 1.22 (t, J = 7.1 Hz, 3H), 1.28-1.42 (m, 6H), 1.46 (s, 9H), 1.52-1.62 (m, 2H), 1.82-1.91 (m, 1H) , 1.96-2.16 (m, 3H), 2.18-2.34 (tn, 2H), 2.42-2.56 (m, 1H), 2.58-2.72 (m, 1H), 3.42 (app.bs, 3H), 3.66-3.84 (m, 1H), 3.92 (s, 3H), 4.15 (q, J = 7.1 Hz, 2H ), 4.88-5.02 (m, 2H), 5.07-5.18 (m, 2H), 5.20-5.32 (m, 1H), 5.63-5.84 (m , 2H), 6.62 (bs, 1H), 6.94 (s, 1H), 7.09 (dd, J = 2.6, 9.2 Hz, 1H), 7.36-7.51 ( m, 4H), 7.99-8.10 (m, 3H); 13 C-NMR (75.5 MHz, CDCl 3): d 14.3, 23.0, 26.4, 26.6, 28.3, 28.6, 33.2, 33.5, 35.6, 37 , 6, 40.6, 44.7, 47.1, 48.6, 55.5, 61.5, 81.9, 98.4, 107.9, 114.5, 115.6, 118.1 , 123.2, 127.6, 128.3, 128.7, 129.1, 133.5, 138.7, 140.7, 151.5, 154.5, 159.2, 160.9, 161 , 5, 170.5, 174.2, 176.3.

Example 49 Ethyl ester of (Z) - (1R, 4R, 6S, 16R, 18R) -14-feri-Butoxycarbonyl-lamino-18- (7-methoxy-2-f-enyl-quinol-4-yloxy) -2 , 15-dioxo-3,14-diaza-tricyclo [14.3,0,0 ^] nonadec-7-en-4-carboxylic acid (49) A solution of 48 (158 mg, 0.209 mmol) in dry DCM (25 mL) was bubbled with argon for 5 min. To the stirred solution under argon atmosphere was then added a second generation Hoveyda-Grubbs catalyst solution (11 mg, 0.018 mmol) in dry DCM (5 mL). The mixture was stirred at reflux under an argon atmosphere for 16 h. The solvent was evaporated and purification by HPLC (90:10 MeOH / H2O with 0.2% triethylamine) gave 49 (107 mg, 70%) as a colorless solid. 1 H-NMR (300 MHz, CD 3 OD): d 1.03-1.22 (m, 1H), 1.28 (t, J = 7.1 Hz, 3H), 1.32-1.44 (m, 4H), 1.49 (s, 9H), 1.55-1.73 (m, 2H), 1.81-1.91 (m, 1H), 2.04-2.28 (m, 3H) , 2.30-2.52 (m, 3H), 2.53-2.70 (m, 1H), 2.86-3.00 (m, 1H), 3.34-3.44 (m, 1H), 3.46-3.62 (m, 1H), 3.95 (s, 3H), 4.19 (q, J = 7.1 Hz, 2H), 4.32-4.48 (m , 1H), 5.20-5.33 (m, 1H), 5.34 (bs, 1H), 5.58-5.70 (m, 1H), 7.10 (s, 1H), 7, 14 (dd, J = 2.5, 9.1 Hz, 1H), 7.39 (d, J = 2.5 Hz, 1H), 7.45-7.55 (m, 3H), 8.00 (d, J = 8.0 Hz, 2H), 8.17 (d, J = 9.3 Hz, 1H); 13 C-NMR (75.5 MHz, CD3OD): d 14.6, 23.4, 27.5, 27.7, 28.0, 28.5, 30.7, 36.1, 38.1, 42.5 , 45.6, 56.0, 62. 7, 79.9, 82.8, 100.2, 107.4, 116.6, 119.1, 124.5, 126.5, 128.9, 129.8, 130.5, 135.8, 141.5, 152.2, 156.4, 161.3, 162.5, 163.1, 171.9, 175.8, 179.0. MALDI-TOF-spectrum: (M + H) + calculated: 727.4, found: 727.5. Example 50 (Z) - (1, 4R, 6S, 16R, 18R) -14-ferf-Butoxycarbonyllamine-18- (7-methoxy-2-phenyl-quinolin-4-yloxy) -2,15-dioxo acid -3,14-diaza-tricyclo [14.3,0,04 '] nonadec-7-en-4-carboxylic acid (50) To a solution of 49 (27 mg, 0.037 mmol) in THF / MeOH / H2O 2 : 1: 1 (5 mL) was added 1 M LiOH (300 μL, 0.300 mmol). The solution was stirred for 24 h at room temperature and finally for one hour at reflux. After acidification to pH 3-4 with 1 M HCl and evaporation the residue was purified by HPLC (80:20 MeOH / H2O and 90:10 MeOH / H2O) giving 50 (12 mg, 46%) as a colorless solid. . 1 H-NMR (300 MHz, CD 3 OD): d 1.06-1.24 (m, 1H), 1.26-1.42 (m, 3H), 1.48 (s, 9H), 1.52- 1.73 (m, 3H), 1.80-1.90 (m, 1H), 2.02- 2.15 (m, 1H), 2.15-2.40 (m, 4H), 2, 43-2.54 (m, 1H), 2.54-2.68 (m, 1H), 2.88-3.00 (m, 1H), 3.35-3.48 (m, 1H), 3.49-3.66 (m, 1H), 3.96 (s, 3H), 4.32-4.48 (m, 1H), 5.25-5.42 (m, 2H), 5, 56-5.68 (m, 1H), 7.14 (s, 1H), 7.17 (dd, J = 2.5, 9.1 Hz, 1H), 7.40 (d, J = 2, 2 Hz, 1H), 7.46-7.58 (m, 3H), 8.00 (d, J = 8.0 Hz, 2H), 8.19 (d, J = 9.1 Hz, 1H); 13 C-NMR (75.5 MHz, CD3OD): d 23.6, 26.8, 27.8, 28.3, 28.5, 30.5, 35.8, 38.1, 43.0, 45 , 5, 56.0, 80.2, 82.7, 100.4, 106.9, 116.6, 119.2, 124.7, 127.4, 129.0, 129.8, 130.7 , 134.8, 140.9, 151.6, 156.5, 161.1, 163.0, 163.4, 173.8, 175.7, 179.3. Example 51 ((S) -1-Cyclopentylcarbamoyl-2,2-dimethyl-propyl) -carbamic acid tert-butylester (51) To a cold solution of 36 (133 mg, 0.575 mmol), cyclopentylamine (64 μL, 0.648 mmol ) and DIEA (301 μL, 1.73 mmol) in DMF (3 mL) was added 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 51 (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 (, 4H), 1.86-2.01 (m, 2H), 3.76 (b, 1H), 4.09-4.23 (m, 1H), 5.32 (b, 1H), 5.91 (b, 1H); 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 52 Ethyl ester of (1R, 2S) -1- acid. { [(1R, 2R, 4S) -2 - ((S) -1- Cyclopentylcarbamoyl-2,2-dimethyl-propylcarbamoyl) -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -cyclopentanecarbonyl] - amino} -2-v1n-1-cyclopropanecarboxylic acid (52) Compound 51 (298 mg, 0.048 mmol) and 35 (16 mg, 0.054 mmol) was deprotected and coupled according to the method for the preparation of 39. Purification HPLC (90:10 MeOH / H2O with 0.2% triethylamine) gave 52 (22 mg, 63%) as a colorless solid. 1 H-NMR (CDCl 3, 300 MHz): d 0.97 (s, 9H), 1.21 (t, J = 7.1 Hz, 3H), 1.26-1.37 (m, 1H), 1 , 38-1.46 (m, 2H), 1.48-1.58 (m, 4H), 1.78-1.85 (m, 1H), 1.86-2.02 (m, 3H) , 2.03-2.19 (m, 1H), 2.28-2.40 (m, 2H), 2.41-2.54 (m, 1H), 2.64-2.78 (m, 1H), 3.10-3.24 (m, 1H), 3.30-3.44 (m, 1H), 3.95 (s, 3H), 4.04-4.21 (m, 3H) , 5.12 (dd, J = 1.7, 10.3 Hz, 1H), 5.14-5.22 (m, 1H), 5.28 (dd, J = 1.7, 17.0 Hz , 1H), 5.59 (b, 1H), 5.75 (ddd, J = 8.8, 10.3, 17.0 Hz, 1H), 6.66-6.82 (m, 2H), 6.99 (s, 1H), 7.09 (dd, J = 2.5, 9.1 Hz, 1H), 7.41-7.55 (m, 4H), 7.99-8.09 ( m, 3H); 13 C-NMR (75.5 MHz, CDCl 3): d 14.3, 22.9, 23.6, 23.6, 26.7, 32.7, 33.2, 33.7, 34.8, 35 , 9, 36.6, 40.2, 46.4, 47.5, 51.3, 55.5, 61.1, 61.4, 78.0, 98.4, 107.1, 115.2 , 117.9, 118.2, 123.1, 127.6, 128.8, 129.3, 133.5, 159.1, 161.4, 169.4, 169.9, 173.1, 174 , 0. MALDI-TOF-spectrum: (M + H) + calculated: 725.4, found: 725.6; (M + Na) + calculated: 747.4, found: 747.6; (M + K) + calculated: 763.3, found: 763.5. Example 53 acid (1R, 2S) -1-. { [(1R, 2R, 4S) -2 - ((S) -1-Cyclopentylcarbamoyl-2,2-dimethyl-propylcarbamoyl) -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -cyclopentanecarbonyl ]-Not me} -2-vinyl-cyclopropanecarboxylic acid (53) To a solution of 52 (14 mg, 0.019 mmol) in dioxane / H 2 O 1: 1: (4 mL) was added 1 M LiOH (115 μL, 0.115 mmol). The solution was stirred for 24 h at room temperature. Then an additional portion of LiOH (75 μL, 0.075 mmol) was added and the solution was stirred for another 24 h. After acidification to about pH 3 with 1M HCl and coevaporation with toluene the residue was purified by HPLC (MeOH / H20 70:30 with 0.2% TFA) to give 53 (8 mg, 60%) as a colorless solid . 1 H-NMR (300 MHz, CD 3 OD): d 0.98 (s, 9H), 1.28-1.48 (m, 3H), 1.49-1.76 (m, 5H), 1.78- 1.94 (m, 2H), 2.10-2.24 (m, 1H), 2.26-2.45 (m, 2H), 2.50-2.62 (m, 1H), 2, 66-2.79 (m, 1H), 3.35-3.48 (m, 2H), 3.94-4.03 (m, 1H), 4.06 (s, 3H), 4.16- 4.24 (m, 1H), 5.10 (dd, J = 1.8, 10.3 Hz, 1H), 5.29 (dd, J = 1.8, 17.2 Hz, 1H), , 62 (b, 1H), 5.82 (ddd, J = 9.1, 10.3, 17.2 Hz, 1H), 7.43 (dd, J = 2.5, 9.3 Hz, 1H ), 7.50 (s, 1H), 7.50-7.69 (dd, superimposed, 1H), 7.67-7.80 (m, 3H), 8.01-8.11 (m, 2H) ), 8.39 (d, J = 9.3 Hz, 1H); 13 C-NMR (75.5 MHz, CD3OD): d 24.7, 24.7, 27.3, 33.1, 33.6, 34.7, 35.4, 36.9, 38.7, 41 , 0.47.4, 52.3, 56.9, 62.3, 83.9, 100.4, 102.3, 116.2, 117.7, 121.6, 126.7, 129.8 , 130.8, 133.4, 133.8, 135.6, 143.5, 158.0, 166.5, 168.6, 171.9, 173.4, 175.2, 176.4. MALDI-TOF-spectrum: (M + H) + calculated: 697.4, found: 697.3; (M + Na) + calculated: 718.7, found: 719.3; (M + K) + calculated: 735.3, found: 735.3. Example 54 (S) -ferf-Butoxycarbonylamino-cyclohexyl-acetic acid methyl ester (54) 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 allowed to stir 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 54 (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, 1 H), 5.05 (bs, 1 H); 3C-N MR (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 55 (S) - ((S) -2-Benzyloxycarbonylamino-3-methyl-butyrylamino) -cyclohexyl-acetic acid methyl ester (55) Compound 54 (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 55 (131 mg, 94%) as a colorless solid. 1 H-NMR (300 MHz, CDCl 3): d 0.92-1, 30 (m, 1 1 H), 1.54-1.88 (m, 6H), 2.02-2, 18 (m, 1 H), 3.72 (s, 3 H), 4.05-4, 18 (m, 1 H), 4.52 (dd, J = 3.0, 5.5 Hz, 1 H), 5, 12 (s, 2H), 5.49 (bs, 1 H), 6.52 (bs, 1 H), 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 56 tert-butylester of (S) -2- acid. { [(1 R, 2R, 4S) -2-. { (S) -1 - [((S) -Cyclohexyl-methoxycarbonyl-methyl) -carbamoyl] -2-methyl-propylcarbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -cyclopentanecarbonyl] -amino} pentanoic (56) To a solution of 55 (40 mg, 0.099 mmol) in ethanol (95%) (7.5 mL) was added palladium on activated carbon (1.0%, 40 mg) and the mixture was hydrogenated under pressure at room temperature, for 2 h. The mixture was filtered through celite and evaporated. Compound 43 (38 mg, 0.083 mmol) was dissolved in dioxane / H 2 O 1: 1 (3 mL) and the mixture was cooled to 0 ° C before adding 1 M LiOH (140 μL, 0. 140 mmol) to the stirred solution . After 1 h the mixture was neutralized with 1 M hydrochloric acid and the solvent was evaporated and co-evaporated with toluene. The residue was coupled to deprotected using the same HATU coupling conditions as in the synthesis of compound 48. Purification by HPLC (90:10 MeOH / H2O with 0.2% triethylamine) gave 56 (56 mg, 88%) as a colorless solid. 1 H-NMR (300 MHz, CDCl 3): d 0.82-0.96 (m, 9H), 0.82-1.22 (m, superimposed, 6H), 1.23-1.40 (m, 2H ), 1.44 (s, 9H), 1.50-1.69 (m, 4H), 1.71-1.87 (m, 2H), 1.95-2.06 (m, 1H), 2.07-2.22 (m, 1H), 2.28-2.54 (m, 3H), 2.60-2.75 (m, 1H), 3.08-3.28 (m, 1H) ), 3.30-3.49 (m, 1H), 3.70 (s, 3H), 3.94 (s, 3H), 4.28-4.38 (m, 1H), 4.41- 4.57 (m, 2H), 5.17 (b, 1H), 6.54-6.70 (m, 2H), 6.74 (b, 1H), 6.95 (s, 1H), 7 , 09 (dd, J = 2.5, 9.1 Hz, 1H), 7.39-7.55 (m, 5H), 7.98-8.10 (m, 3H); 13 C-NMR (75.5 MHz, CDCl 3): d 13.7, 18.1, 18.6, 19.2, 25.9, 28.0, 28.2, 29.6, 30.7, 34 , 6, 36.5, 37.6, 40.8, 47.4, 47.5, 52.1, 52.8, 55.5, 56.8, 58.9, 77.8, 82.0 , 98.3, 107.5, 115.3, 118.1, 123.1, 127.5, 128.7, 129.1, 140.5, 151.4, 159.2, 160.7, 161 , 3, 171.0, 171.5, 172.3, 172.8, 173.0. MALDI-TOF-spectrum: (M + H) + calculated: 815.5, found: 815.7; (M + Na) + calculated: 837.4, found: 837.6; (M + K) + calculated: 853.4, found: 853.6. Example 57 acid (S) -2-. { [(1R, 2R, 4S) -2-. { (S) -1 - [((S) -Cyclohexyl-methoxycarbonyl-methyl) -carbamoyl] -2-methyl-propylcarbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -cyclopentanecarbonyl] -amino} pentanoic (57) Tert-butyl ester 56 (28 mg, 0.034 mmol) and triethylsilane (14 μL, 0.088 mmol) were dissolved in DCM (2 mL) after which trifluoroacetic acid (2 mL) was added and the mixture was added. stirred for 2 h.

Co-evaporation with toluene gave 57 (26 mg, 100%) as a colorless solid. 1H-NMR (300 MHz, CD3OD): d 0.86-1.00 (m, 9H), 1, Ol1.24 (m, 4H), 1.36-1.46 (m, 2H), 1, 48-1.75 (m, 8H), 1.70-1.89 (m, superimposed, 1H), 1.96-2.12 (m, 1H), 2.22-2.40 (m, superimposed , 2H), 2.49-2.64 (m, 1H), 2.72-2.91 (m, 1H), 3.26-3.40 (m, superimposed, 1H), 3.50-3 , 68 (m, superimposed, 1H), 3.62 (s, 3H), 4.05 (s, 3H), 4.09-4.17 (m, 1H), 4.17-4.25 (m , 1H), 4.35-4.45 (m, 1H), 5.62 (b, 1H), 7.44 (dd, J = 2.2, 9.3 Hz, 1H), 7.49 ( s, 1H), 7.53 (d, J = 2.2 Hz, 1H), 7.65-7.78 (m, 3H), 7.98-8.06 (m, 2H), 8.41 (dd, J = 2.8, 9.3 Hz, 1H); 13 C-NMR (CD3OD, 75.5 MHz): d 13.9, 18.8, 19.7, 20.2, 27.0, 29.7, 30.5, 31.8, 34.6, 37 , 7, 38.9, 41.1, 47.8, 52.3, 53.6, 56.9, 58.8, 58.9, 60.3, 83.8, 100.4, 102.2 , 116.2, 121.6, 126.7, 129.8, 130.8, 133.3, 133.8, 143.5, 157.9, 166.5, 168.5, 173.3, 173 , 9, 175.5, 175.5, 175.6. MALDI-TOF-spectrum: (M + H) + calculated: 759.4, found: 759.7; (M + Na) + calculated: 781.4, found: 781.7; (M + K) + calculated: 797.4, found: 797.7. Example 58 acid (S) -2-. { [(1R, 2R, 4S) -2-. { (S) -1 - [((S) -Cyclohexyl-methoxycarbonyl-methyl) -carbamoyl] -2-methyl-propylcarbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -cyclopentanecarbonyl] -amino} -butyric (58) The procedure described in example 42 was followed but with the use of tert-butylester of L-2-amino-N-butyric acid instead of H-Nva-OfBu. The resulting compound was then reacted as described in Example 43 which gave (1R, 2R, 4R) -2 - ((S) -1-ferf-butoxycarbonyl-propylcarbamoyl) -4- (7-methoxy) acid methyl ester. -2-phenyl-quinolin-4-yloxy) -cyclopentanecarboxylic acid. Coupling this compound with 55 as described in Example 56 followed by sterhydrolysis as described in Example 57 gave 58 as a colorless solid. 1 H-NMR (300 MHz, CD3OD): d 0.82-0.99 (m, 9H), 0.82-1.40 (m, superimposed, 6H), 1.48-1.78 (m, 6H), 1.80- 1.95 (m, 1H), 1.97-2.12 (m, 1H), 2.22-2.40 (m, superimposed, 2H), 2.51-2.64 (m, 1H), 2.71-2.90 (m, 1H), 3.16-3.39 (m, superimposed, 1H), 3.49-3.59 (m, 1H), 3.63 (s, 3H), 3.95 (s, 3H), 4.12-4.23 (m, 2H), 4.28-4.38 (m, 1H), 5.31 (b, 1H), 7.43 (dd, J = 2.2, 9.3 Hz, 1H), 7.47 (s, 1H), 7.51 (s, 1H), 7.66-7.89 (m, 3H), 7.99-8 , 07 (m, 2H), 8.42 (d, J = 9, 1 Hz, 1 H); 13 C-NMR (75.5 MHz, CD3OD): d 10.7, 18.8, 19.7, 25.8, 27.0, 27.0, 29.7, 30.5, 31, 8, 37 , 7, 38.9, 41, 2, 47.9, 52.3, 55.3, 56.9, 58.8, 60.6, 83.6, 100.7, 102.2, 16, 3, 121, 5, 126.7, 129.8, 130.8, 133.7, 133.8, 143.9, 158.2, 166.4, 168.3, 173.3, 173.8, 175.2, 175.5, 175.6. MALDI-TOF-spectrum: (M + H) + calculated: 745.4, found: 744.9; (M + Na) + calculated: 767.4, found: 766.9; (M + K) + calculated: 783.5, found: 782.9. Example 59 acid (S) -2-. { [(1 R, 2R, 4S) -2-. { (R) -1 - [((R) -Cyclohexyl-methoxycarbonyl-methyl) -carbamoyl] -2-methyl-propylcarbamoyl} -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -cyclopentanecarbonyl] -amino} -butyric (59) The procedure described in Example 54 was followed but with the use of Boc-D-cyclohexylglycine instead of Boc-L-cyclohexylglycine. The resulting compound was then reacted as described in example 55 followed by coupling with (1R, 2R, 4R) -2 - ((S) -1-ferr-Butoxycarbonyl-pentylcarbamoyl) -4- methyl ester ( 7-methoxy-2-phenyl-quinolin-4-yloxy) -cyclopentanecarboxylic acid as described in Example 56. Removal of the ester group as described in Example 57 gave compound 59 as a colorless solid. 1 H-NMR (CD 3 OD, 300 MHz): d 0.82-1.02 (m, 9H), 1.04-1.42 (m, 6H), 1.52-1.80 (m, 6H), 1.80-1.96 (m, superimposed, 1H), 2.00-2.14 (m, 1H), 2.29-2.46 (m, 2H), 2.51-2.65 (m , 1H), 2.68-2.84 (m, 1H), 3.24-3.39 (m, superimposed, 1H), 3.47-3.60 (m, 1H), 3.67 (s) , 3H), 4.07 (s, 3H), 4.18-4.27 (m, 2H), 4.28-4.38 (m, 1H), 5.64 (app.bs, 1H), 7.44 (d, J = 2.3, 6.9 Hz, 1H), 7.42 (s, 2H), 7.67-7.81 (m, 3H), 8.04 (d, J = 7.8 Hz, 2H), 8.41 (d, J = 9.1 Hz, 1H); 13 C-NMR (CD 3 OD, 75.5 MHz): d 10.8, 18.5, 19.6, 25.7, 27.1, 27.1, 30.1, 30.6, 31.9, 37 , 3, 38.2, 41.1, 47.8, 52.3, 55.4, 56.9, 59.0, 59.1, 60.2, 83.8, 100.5, 102.2 , 116.3, 121.6, 126.8, 129.8, 130.8, 133.6, 133.8, 143.7, 158.1, 166.5, 168.5, 173.4, 173 , 8, 175.4, 175.7, 175.7. MALDI-TOF-spectrum: (M + H) + calculated: 745.4, found: 745.4; (M + Na) + calculated: 767.4, found: 767.4; (M + K) + calculated: 783.5, found: 783.3. Example 60 2-tert-butoxycarbonylamino-3,3-dimethylbutyric acid bound to resin (60) To a resin Argonaut PS-TFP (1.38 mmol / g, 10 g) and 2-ferf-butoxycarbonylamino-3,3-dimethyl acid butyric (4.5 g, 20.7 mmol) dichloromethane (40 mL) and DMF (10 mL) were added. To this mixture was added DMAP (1 g, 8.28 mmol) and then DIC (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 61 [1- (2-Hydroxy-indan-1-ylcarbamoyl) -2,2-dimethyl-propyl-carbamic acid tert -butylester (61) To a portion of 60 (200 mg) in DCM was added aminoindanol (0.14). mmol). The mixture was stirred for 2 hrs. The liquid was removed by filtration and the resin was washed with 2xDCM. The 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 dc (100 MHz; CDCl 3; Me 4 S) 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. 1 HOUR NMR dH (400 MHz; CDCl 3; Me 4 Si) 1, 07 (9H, s, CCH 3), 1.44 (9H, s, OCCH3), 2.93 (1 H, dd, Jgem16.4 Hz, J3.2 2.3 Hz, CH2), 3.15 (1 H, dd, Jgep? 16.4 Hz, J3.2 5.2 Hz, CH2), Example 62 2-Amino -? / - (2-hydroxy-indan-1-yl) -3,3-dimethylbutyramide (62) Compound 61 was maintained in DCM-TFA 2: 1 (2 mL) for 60 min at room temperature ambient. The solution was co-evaporated with toluene to dryness. Example 63 (2-Ferf-Butoxycarbonylamino-3,3-dimethyl-butyrylamino) -cyclohexy-1-acetic acid methyl ester (63) To a solution of 2-tert-butoxycarbonylamino-3,3-dimethylbutyric acid (500 mg, 2.16 mmol) ), amino-cyclohexyl-acetic acid methyl ester (444 mg, 2.59 mmol) and HATU (2 g, 5.40 mmol) in DMF (20 mL) was added diisopropylethylamine (1.88 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 64 acid tert-butyl ester. { 1 - [(Cyclohexyl-methylcarbamoll-methyl) -carbamoyl] -2,2-dimethyl-propyl} -carbamic (64) To compound 63 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 65 2-Amino-? - (cyclohexylmethylcarbamoylmethyl) -3,3-dimethyl-butyramide (65) Compound 64 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 66 1 - . 1- (2-Amino-4-methoxyphenyl) ethanone (66). 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 AcCl (6.0 mL, 84 mL) was added consecutively. mmol) and ACI3 (11 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 L). 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 67? / - (ε-Butyl) - '-isopropylthiourea (67) To a solution of ferf-butyl isothiocyanate (5.0 mL, 39 mmol) in CH2Cl2 (200 mL) was added isopropylamine (4.0 mL, 4.7 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 the title compound (3.3 g, 52%) as a white solid which was used without further purification. Example 68: Msopropylthiourea (68) Compound 67 (3.3 g, 20 mmol) was dissolved in conc. HCl. (45 mL) and the solution was refluxed for 40 min. The mixture 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 (1 x), dried (MgSO), and evaporated to give the crude title compound (2.1 g, 90%) which was used without further purification. Example 69 2- (lsopropylamino) -1,3-thiazole-4-carboxylic acid hydrobromide (69) A suspension of compound 68 (2.1 g, 18 mmol) and 3-bromopyruvic acid (3.0 g, 18 mmol) in Dioxane (1 80 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 title product (4.4 g, 94%). Example 70 ? / - (2-Acetyl-5-methoxyphenyl) -2- (isopropylamino) -1,3-thiazole-4-carboxamide (70) A mixture of compound 69 (4.4 g, 16.5 mmol) and the derivative of aniline 66 (2.75 g, 16.5 mmol) in pyridine (140 mL) was cooled to -30 ° C (when cooled, 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 70 (5.6 g, 76%) as a pale yellow solid. Example 71 2- [2- (lsopropylamino) -1, 3-thiazol-4-yl] -7-methoxyquinolin-4-ol (71) A solution of t.BuOK (2.42 g, 21 mmol) in anhydrous t-BuOH (40 mL) was heated to reflux. Compound 70 (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 M in dioxane, 8.0 mL, 32 mmol) was added, 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 completely evaporated to obtain the slightly impure HCl salt of compound 71 (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 compound 71 (1.38 g, 81%) as a light brown solid (>; 95% purity according to HPLC assays). 1 HN MR (MeOH-a, 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 72 (1 R, 4R, 5R) -? / - [(1 S) -1 - [[[(1 S) -1-Cyclohexyl-2- (methylamino) -2-oxoethyl] amino] carbonyl] -2.2 -dimethylpropyl] -3-oxo-2-oxabicyclo [2.2.1] heptan-5-carboxamide (72) To a solution of compound 32 (53 mg, 0.34 mmol) in DMF (9 mL) was added to compound 65 (80 mg, 0.28 mmol) and DIEA (290 D L, 1.66 mmol). The solution was cooled to 0 ° C and HATU (127 mg, 0.33 mmol) was added. After stirring at 0 ° C for 1 h and at room temperature for 1 h the solvent was evaporated, and the crude product was purified by flash column chromatography (EtOAc / toluene 2: 1) to give compound 72 (1 mg, 92 mg). %) as a white solid. Example 73 acid ethyl ester (1 R) -1 - [[[(1 R, 2R, 4R) -2 - [[[(1 S) -1 - [[[1 S) -1-Cyclohexyl-2- (methylamino ) -2-oxoethyl] amino] carbonii] -2,2-dimethylpropyl] amino] carbonyl] -4-hydroxycyclopentyl] carbonyl] amino] -2-ethenyl-cyclopropanecarboxylic acid (73) Compound 72 (60 mg, 0.14 mmol ) was dissolved in dioxane (3.5 mL) and H2O (2.5 mL) and the solution was cooled to 0 ° C. LiOH (1 M, 280 μL, 0.28 mmol) was added per drop for 5 min, after which the reaction mixture was stirred at 0 ° C for 40 min. The pH was adjusted to 7 using 1 M HCl, and the solvents were evaporated. The residue was suspended in DMF (5 mL) and 1-amino-2-vinyl-cyclopropanecarboxylic acid ethyl ester (32 mg, 0.17 mmol), and DIEA (146 LD, 0.84 mmol) were added. After cooling to 0 ° C, HATU (64 mg, 0.17 mmol) was added and the mixture was stirred at 0 ° C for 1 h and at room temperature for 1 h. The solvent was evaporated and the product was purified using flash column chromatography (EtOAc / MeOH 9: 1) to give compound 73 (67 mg, 82%) as a white solid. Example 74 (1 R, 2R, 4R) -2 - [[[(1 R) -1 - (ethoxycarbonyl) -2-vinylcyclopropyl] amino] carbonyl] -4 - [[2- [2- (isopropylamino) -1] 3-thiazol-4-yl] -7-methoxyquinolin-4-yl] oxy] cyclopentanecarboxylate of ferf-Butyl (74) The title compound was prepared according to the procedure described in example 76 method A but with the use of the compound 34 in place of compound 73. (Note: 4 equivalents of Ph3P and DIAD were used.) Chromatography eluent: Toluene / EtOAc 1: 1. Example 75 acid (1 R, 2R, 4R) -2 - [[[(1 R) -1 - (Ethoxycarbonyl) -2-vinylcyclopropyl] amino] carbonyl] -4 - [[2- [2- (isopropylamino) -1,3-thiazol-4-yl] -7-methoxyquinolin-4-yl] oxy] cyclopentanecarboxylic acid (75) To a solution of compound 74 (20 mg, 30 mmol) in CH 2 Cl 2 (2 mL) was added TFA (2 mL) and Et3SiH (10 uL, 63 umol). After 2 h the volatile materials were evaporated and the product was used without any purification step. Compound 75: 18 mg, quant. as a white solid. Example 76 Ethyl ester of acid (1 R) -1 - [[[(1 R, 2R, 4S) -2 - [[[(1 S) -1 - [[[(1 S) -1-Cyclohexyl- 2- (methylamino ) -2-oxoethyl] amino] carbonyl] -2,2-d-methylpropyl] amino] carbonyl] -4 - [[7-methoxy-2- [2 - [(1-methylethyl) amino] -4-thiazolyl ] -4-quinolinyl] oxy] cyclopentyl] carbonyl] amino] -2-ethenyl-cyclopropanecarboxylic acid (76) Method A: To a solution of compound 73 (59 mg, 0.10 mmol) in dry THF (4 mL) was added quinoline 71 (49 mg, 0.16 mmol) and Ph3P (65 mg, 0.25 mmol). After cooling to 0 ° C DIAD (50 uL, 0.25 mmol) was added dropwise for 5 min. The solution was stirred at 0 ° C for 1 h and at room temperature for 48 h. The solvent was evaporated and the remainder was purified using flash column chromatography (CHCl3 / 2 M NH3 in MeOH 95: 5) to give compound 76 (9 mg, 10%) as a white solid. Method B: Compound 75 was coupled with compound 65 according to the procedure of Example 72 which gave the title compound (82%). Example 77 acid (1 R) -1 - [[[(1 R, 2R, 4S) -2 - [[[(1 S) -1 - [[[(1 S) -1-Cyclohexyl-2- (methylamino) - 2-oxoethyl] amino] carbonyl] -2,2-dimethylpropyl] amino] carbonyl] -4 - [[7-methoxy-2- [2 - [(1-methylethyl) amino] -4-thiazolyl] -4-quinolinyl ] oxy] cyclopentyl] carbonyl] amino] -2-ethenyl-cyclopropanecarboxylic acid (77) Compound 76 (8 mg, 9 μmol) was dissolved in a mixture of MeOH (150 μL) and THF (100 uL). A solution of LiOH (1 mg, 42 μmol) in H 2 O (25 D L) was added and the mixture was stirred at 50 ° C overnight. The solution was neutralized with HOAc and evaporated. The residue was suspended in CH2Cl2 and washed with H2O. The organic phase was evaporated to give the title compound (8 mg, quant.) as a white solid. 1 H-NMR (MeOH-4, 400 MHz) (mixture of rotamers): d 0.60-1.33 (m, 21H), 1.35-1.73 (m, 12H), 1.90-2, 42 (m, 2H), 2.51-2.75 (m, 6H), 3.20-3.38 (m, 1H), 3.85 (s, 3H), 3.95-4.28 ( m, 1H), 4.91-5.02 (m, 1H), 5.12-5.23 (m, 1H), 5.64-5.83 (m, 1H), 7.01-7, 11 (m, 1H), 7.25-7.40 (m, 1H), 7.42-7.57 (m, 1H), 7.85-8.08 (m, 1H). Example 78 2-Amino-3,3-dimethyl-N-thiophen-2-yl-methyl-butyramide (78) The title compound was prepared as described in Example 61 but with the use of thiophen-2-methylamine instead of aminoindanol and eliminating the Boc group as described in example 62. Example 79 2-Amino-N- (6-hydroxy-4,5,6,7-tetrahydro-benzo [b] thiophen-5-yl) -3,3-dimethyl-butyramide (79) The title compound was prepared as described in Example 61 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 62. Example 80 2-Amino-N- (2-diethylamino-ethyl) -3,3-dimethyl-butyramide (80) The title compound was prepared as described in Example 61 but with the use of N, N-diethylethylenediamine instead of aminoindanol and eliminating the Boc group as described in example 62. Example 81 2-Amino-N- [2- (2-methoxy-phenoxy) -ethyl] -3,3-dimethyl-butyramide (81) The title compound was prepared as described in Example 61 but with the use of 2- methoxyphenoxyethylamine in place of aminoindanol and eliminating the Boc group as described in example 62.

Example 82 2-Amino-1- (3-hydroxy-pyrrolidin-1-yl) -3,3-dimethyl-butan-1 -one (82) The title compound was prepared as described in Example 61 but with the use of (R) -3-pyrrolidinone in place of aminoindanol and eliminating the Boc group as described in example 62. Example 83 2-Amino-N- (1,1-dioxo-tetrah id ro-1 -thiophen-3-yl) -3,3-di methyl-butyramide (83) The title compound was prepared as described in Example 61 but with the use of 2-methoxyphenoxyethylamine in place of aminoindanol and eliminating the Boc group as described in Example 62. Example 84 [(1 S) -1 - [[(phenylsulfonyl) amino] carbonyl] butyl] -carbamic acid phenylmethyl ester (84) 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 suspension was stirred for 30 min at room temperature and then DBU (200 uL, 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 H PLC. M-H + 389.0, + Na 412.96. Example 85 (2S) -2-Amino-N- (phenylsulfonyl) pentanamide (85) Compound 84 was dissolved in MeOH (5 mL) and then Pd / C was added and hydrogenated 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 86 1 - . 1 -. { [1 - (cyclohexylmethyl-carbamoyl) -2-methyl-propyl] -amide} 2 - [(1-Phenylmethanesulfonylaminocarbonyl-2-vinyl-cyclopropyl) -amide] 4- (7-Methoxy-2-phenyl-quinolin-4-yloxy) -cyclopentan-1,2-dicarboxylic acid (86) N - (tert-Butoxycarbonyl) -L-valine bound to Argonaut resin PS-TFP as described in example 60 and then reacted with cyclohexanmethylamine as described in example 61 and the Boc group was removed as described in example 62. The obtained amine was used in a coupling reaction with the compound 35 as described in Example 39 and then the ethyl ester was hydrolysed as described in Example 40 which gave acid 1 -. { [2- [1 - (cyclohexylmethylcarbamoyl) -2-methyl-propylcarbamoyl] -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -cyclopentanecarbonyl] -amino} -2-vinyl-cyclopropanecarboxylic acid. The acid obtained was then treated as described in Example 94 but using toluenesulfonamide in place of cyclopropylsulfonamide which gave the title compound. Performance 6%. Purity > 95% by HPLC. M + H + 864.32. Example 87 (1S, 2R) -1 - ((2S) -2-amino-3,3-dimethyl-butyrylamino) -indan-2-yl ester of acetic acid (87) A solution of compound 61 (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 88 2-tert-butoxycarbonylamino-4-methyl-pentylester of (2S) -Metanesulfonic acid (88) To a solution of ((1S) -1-hydroxymethyl-3-methyl-butyl) -carbamic acid tert-butylester (25) g, 15 mmol) in dichloromethane (500 mL) cooled by an ice water bath was added consecutively diisopropylethylamine (35.7 g, 276 mmol) and methanesulfonyl chloride (15.81 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, citric acid 10% (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. Example 89 ii) ((1 S) -1-Zidomethyl-3-methyl-butyl) -carbamic acid tert-butylester (89) The mesylate of Example 88 (32.6 g, 10 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%). Example 90 (1 S) -1-Azidomethyl-3-methyl-butylamine (90) ((1 S) -1-Azidomethyl-3-methyl-butyl) -carbamic acid tert-butylester (9.64 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%). Example 91 ethylester of 1 - acid. { [2-Hex-5-enylcarbamoyl-4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -cyclopentanecarbonyl] -amino} -2-vinylcyclopropanecarboxylic acid (91) The tert-butyl ester of compound 35 was removed by treatment with triethylsilane as described in example 39. The acid obtained (724 mg, 1.33 mmol), hex-5-enylamine hydrochloride (271 mg, 2 mmol) and diisopropylethylamine (1.85 ml, 10.65 mmol) was dissolved in DMF (20 ml) and cooled to 0 ° C. After 30 min. HATU (608 mg, 1.6 mmol) was added and the vessel removed from the ice bath. The reaction was followed with LC-MS. After 3 h the reaction mixture was extracted between EtOAc (100 ml) and aqueous sodium hydrogen carbonate (15 ml). The EtOAc phase was dried over magnesium sulfate, evaporated and purified by chromatography on silica gel (25% EtOAc in hexane → 50% EtOAc in hexane) to give the pure title product (726 mg, 87%). MS (M + H +): 525.8 Example 92 17- (7-Methoxy-2-phenyl-quinolin-4-yloxy) -2, 14-dioxo-3, 13-diaza-tricyclo [13.3,0,0 * 4,6 *] octadec acid ethyl ester 7-en-4-carboxylic acid (92) Compound 91 (363 mg, 0.58 mmol) was dissolved in degassed dichloromethane (100 ml). Second generation Hoveyda-Grubbs catalyst (26 mg, 0.041 mmol) was added and the mixture was refluxed under argon atmosphere overnight. The reaction mixture was evaporated on silica and purified by chromatography on silica gel (50% EtOAc in hexane → 70% EtOAc in hexane) to give the pure title product (11.1 mg, 32%). MS (M + H +): 597.7 Example 93 17- (7-Methoxy-2-phenyl-quinolin-4-yloxy) -2, 14-dioxo-3, 13-diaza-tricyclo [13.3,0,0 * 4,6 *] octadec-7 acid en-4-carboxylic acid (93) Compound 92 (95 mg, 0.159 mmol) was dissolved in tetrahydrofuran (10 ml), methanol (5 ml) and water (4 ml). Lithium hydroxide (40 mg, 1 g) was dissolved. , 67 mmol) in water (1 ml) and added. The reaction mixture was heated to 65 ° C. After 3 h the reaction mixture was cooled, acidified with aqueous HCl (pH = 5), evaporated on silica and purified by chromatography on silica gel (10% MeOH in dichloromethane? 15% MeOH in dichloromethane) to give the pure title product (65 mg, 72%). MS (M + H +): 569.8 Example 94 [17- (7-methoxy-2-phenyl-quinolin-4-yloxy) -2, 14-dioxo-3, 13-diaza-t-cyclo [13.3,0,0 * 4,6 * octadec-7-en-4-carbonyl] -amide of cyclopropanesulfonic acid (94) Compound 93 (65 mg, 0, 12 mmol), DMAP (21 mg, 0.17 mmol) and EDAC (44 mg, 0.23 mmol) were dissolved in DMF (0.2 mL). The reaction mixture was stirred for 5 h at room temperature after which cyclopropylsulfonamide (69 mg, 0.57 mmol) and DBU (80 μL, 0.57 mmol) were added. After stirring at room temperature overnight the reaction mixture was extracted between EtOAc (80 ml) and aqueous citric acid (1.0%, 2 x 1.5 ml). The organic phase was dried over MgSO, evaporated on silica and purified twice by chromatography on silica gel (5% MeOH in dichloromethane 1 1.5% MeOH in dichloromethane) which gave a syrup. This syrup was dissolved in a small volume of acetonitrile and precipitated with ethyl ether to give the pure title product (19 mg, 23%). MS (M + H +): 673.2 Example 95 ethylester of 1 - acid. { [2-Hex-5-enyl-methyl-carbamoyl) -4- (7-methoxy-2-phenyl-quinolin-4-yloxy) -cyclopentanecarbonyl] -amino-2-vinyl-cyclopropanecarboxylic acid (95) The tert-butyl ester of the Compound 35 was removed according to the procedure described in Example 39. The obtained acid (850 mg, 1.56 mmol), N -methylhex-5-enylamine hydrochloride (380 mg, 2.5 mmol) and diisopropylethylamine (2 mg). , 3 mL, 1.4 mmol) were dissolved in DMF (60 mL) and cooled to 0 ° C. After 30 min. HATU (0.76 mg, 2.0 mmol) was added and the vessel removed from the ice bath. The reaction was followed with TLC. After 2 h the reaction mixture was added to 5% citric acid and extracted three times with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel to give the title product (820 mg, 82% Example 96 17- (7-Methoxy-2-phenyl-quinolin-4-yloxy) -13-methyl-2, 14-dioxo-3, 13-diaza-tricyclic acid ethyl ester [13.3,0,0 * 4.6 *] octadec-7-en-4-carboxylic acid (96) Compound 95 (648 mg, 1.01 mmol) was dissolved in degassed dichloroethane (500 mL). Second generation Hoveyda-Grubbs catalyst (35 mg, 0.055 mmol) was added and the mixture was refluxed under argon atmosphere overnight. The reaction mixture was evaporated on silica and purified by chromatography on silica gel (30% EtOAc in toluene? 50% EtOAc in toluene) to give the pure title product (230 mg mg, 37%). MS (M + H +): 612.8 Example 97 17- (7-Methoxy-2-phenyl-quinolin-4-yloxy) -13-methylene-2, 14-dioxo-3, 13-diaza-tricyclic acid ethyl ester [13,3,0,0 * 4,6 *] octadec-7-en-4-carboxylic acid (97) Compound 96 (260 mg, 0.42 mmol) was dissolved in 1,4-dioxane (20 mL), added with 1.0 M lithium hydroxide (6.0 mL) and the mixture was stirred at room temperature during the night and then for six hours at 60 ° C. The mixture was added to 5% citric acid and extracted 3 times with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel with DCM and 5% MeOH which gave the title product (130 mg, 53%). MS (M + H): 584.7 Example 98 [17- (7-methoxy-2-phenyl-quinolin-4-yloxy) -13-methyl-2, 14-dioxo-3,13-diaza-tricyclo [1 3.3.0.0 * 4.6 * octadec-7-en-4-carbonyl] -amide of cyclopropanesulfonic acid (98) Compound 97 (58.3 mg, 0.1 mmol), DMAP (18.3 mg, 0.15 mmol) and EDAC (38, 7 mg, 0.2 mmol) were dissolved in DMF (1.0 mL). The reaction mixture was stirred overnight at room temperature after which cyclopropylsulfonamide (60.5 mg, 0.5 mmol) and DBU (76 μg, 0.5 mmol) were added. After stirring at room temperature overnight the reaction mixture was added to 5% citric acid and extracted three times with ethyl acetate. The organic phase was dried over sodium sulfate and evaporated. The resulting residue was purified twice by chromatography on silica gel to give the title product (20 mg). MS (M + H) 687.8. Example 99 [4-Cyclopropanesulfonylaminocarbonyl-17- (7-methoxy-phenyl-quinolin-4-yloxy) -2, 14-dioxo-3, 13-diaza-tricyclo [13.3,0,0 *] tert-butylester 4,6 *] octadec-7-en-13-yl] -carbamic acid (99) N'-Hex-5-en- (E) -ylidene-hydrazinecarboxylic acid tert-butylester was prepared according to the procedure described in Example 46 and 47 but starting with hex-5-en-ol instead of hept-6-en-ol. Compound 35 was treated as described in Example 48 but using the tert-butylester of N'-Hex-5-en- (E) -ylidene-hydrazinecarboxylic acid described in place of the corresponding hept-6-en derivative and then macrocycled as described in Example 49 and the ethyl ester was hydrolyzed as described in Example 50 to give the acid. The acid obtained (58 mg, 0.0846 mmol) was dissolved in dry DMF (7 mL) and DI EA was added dropwise for one minute. The solution was stirred at room temperature for 1 h before adding a solution containing cyclopropylsulfonamide (41 mg, 0.338 mmol), DMAP (41.3 mg, 0.338 mmol) and DBU (50 μL, 0.338 mmol) in dry DMF (1, 5 mL). The solution was stirred at room temperature for 5 days. The solution was diluted with EtOAc (50 mL) and washed with sat. NaHCO3. The aqueous phase was extracted with DCM. The combined organic phases were dried, concentrated and subjected to purification by HPLC, which gave the title compound as a white solid (14.3 mg, 0.018 mmol), purity by HPLC >; 95%, M + H + 788.3. Example 100 Trifluoroacetic acid salt of [13-amino-17- (7-methoxy-2-phenyl-quinolin-4-yloxy) -2,14-dioxo-3,13-diaza-tricyclo [1 3,3,0,0 * 4,6 *] octadec-7-en-4-carbonyl] -amide of cyclopropanesulfonic acid (100) Compound 99 (2.4 mg, 0.00304 mmol) was maintained in TFA-DCM 1: 2 (3mL) at room temperature for 60 min. Toluene (3 mL) was added. The sample was co-evaporated to dryness to give the title compound (2.1 mg, 0.0026 mmol) HPLC Purity > 95% M + H + 688.3. Example 101 3-Oxo-2-oxa-bicyclo [2,2, 1] heptan-5-carboxylic acid hex-5-enyl-methylamide (101) A HATU (2.17 g, 5.7 mmol) and N- hydrochloride methylhex-5-enylamine (6.47 mmol) in 5 mL DMF, under argon in an ice bath, were added IR, 4R, 5R-3-oxo-2-oxa-bicyclo [2.2.1] heptan -5-carboxylic acid (835.6 mg, 5.35 mmol) in 1 mL mL DMF followed by DIEA (2.80 mL, 16 mmol). After stirring for 40 min, the mixture was stirred at room temperature for 5 h. The solvent was evaporated, the residue was dissolved in EtOAc (70 mL) and washed with saturated NaHCO3 (10 mL). The aqueous phase was extracted with EtOAc (2 x 25 mL). The organic phases were combined, washed with saturated NaCl (20 mL), dried over Na2SO4, and evaporated. Flash column chromatography (150 g silica gel, 2/1 EtOAc-petroleum ether (PE), detection by TLC with aqueous KmnO 4, Rf 0.55 in 4/1 EtOAc-PE) gave the compound as an oil yellow color (1, 01 g, 75%). Example 1 02 1 - . 1 - [(1-Cyclopropanesulfonylaminocarbonyl-2-vinylcyclopropyl) -amide] 2- (hex-5-enyl-methylamide 4-hydroxyclopentan-1,2-dicarboxylic acid (102) LiOH solution (0.15M, 53) mL, 8 mmol) was added to the iactonamide 101 (996 mg, 3.96 mmol) in an ice bath and stirred for 1 h.The mixture was acidified to pH 2-3 with 1 N HCl and evaporated, mixed. It was evaporated with toluene several times and dried under vacuum overnight, ((1R, 2S) -cyclopropanesulfonic acid (1-amino-2-vinyl-cyclopropancarbonyl) amide hydrochloride (4.21 mmol) and HATU ( 1.78 g, 4.68 mmol) The mixture was cooled in an ice bath under argon, DMF (25 mL) and then DIEA (2.0 mL, 11.5 mmol) were added. 30 min, the mixture was stirred at room temperature for 3 h After evaporation of the solvent, the residue was dissolved in EtOAc (120 mL), washed consecutively with 0.5 N HCl (20 mL) and saturated NaCl (2 mL). x 20 mL), and dried over Na2SO4. Flash column atography (200g YMC silica gel, 2-4% MeOH in CH 2 Cl 2 gave white solids (1.25 g, 66%). Example 103 (17-hydroxy-13-methyl-2, 14-dioxo-3, 13-diazatricyclo [13.3,0,0 * 4,6 *] octadec-7-en-4-carbonyl) -amide of cyclopropanesulfonic acid ( 103) Cyclopentanol 102 (52.0 mg, 0.108 mmol) was dissolved in 1 mL of 1,2-dichloroethane (bubbled with argon before use). The second generation Hoveyda-Grubbs catalyst (6.62 mg, 10 mole%) was dissolved in DCE (2 x 0.5 mL) and added. The green solution was bubbled with Ar for 1 min. Aliquots (4 mL each) were transferred to five microwave tubes between 2 and 5-mL. To the last tube was added 0.8 mL of rinse with solvent. Each tube was heated by microwaves (room temperature up to 160 ° C in 5 min). All aliquots were combined and the solvent was evaporated. Flash column chromatography (silica gel, 3-7% MeOH in CH 2 Cl 2) gave 24.39 mg solids (Rf 0.28 in 10% MeOH-CH 2 Cl 2 with two spots). The solids were combined with a 9.66-mg sample and subjected to a second chromatography (2-8% MeOH in EtOAc) to give creamy solids (23 mg) with 80% of the desired compound (26% yield). Example 1 04 . { 17- [2- (4-isopropylthiazol-2-yl) -7-methoxyquinolin-4-yloxy] -13-methyl-2,14-dioxo-3,13-diazatricyclo [13.3,0,0 * 4, 6 *] octadec-7-en-4-carbonyl) -amide of cyclopropanesulfonic acid (104) DIAD (22 uL, 0.11 mmol) was added to a mixture of the metathesis product 103 (23 mg), 2- (4). -sopropyl-1,3-thiazol-2-yl) -7-methoxyquinolin-4-ol (24 mg, 0.08 mmol), and PPh3 (30 mg, 0.11 mmol) in 1 mL dry THF, in an ice bath. The mixture was stirred at room temperature overnight and then evaporated. The residue (1.2 mL of a 1.5-mL MeCN solution) was purified by preparative HPLC (Hypercarb 7 uL100 x 21.2 mm, 40% up to 99% aqueous MeCN in 10 min) to give 3.18 mg of MV062308 as solid cream (13% yield). 1H NMR (DMSO-d6) D ppm: main rotamer 0.99 (m, 2H), 1.11 (m, 2H), 1.20-1.30 (, 2H), 1.37 and 1.38 ( 2d, J = 7.0 Hz, 6H), 1.46-1.58 (m, 2H), 1.70 (m, 1H), 1.85 (m, 1H), 1.90 (dd, J = 8.5, 6.0 Hz, 1H), 2.06 (br, 1H), 2.26 (m, 1H), 2.38 (m, 1H), 2.52-2.62 (m, 3H), 2.90-2.97 (m, 2H), 3.06 (s, 3H), 3.21 (m, 1H), 3.40- 3.56 (m, 2H) 3.97 ( s, 3H), 4.60 (m, 1H), 5.04 (m, 1H), 5.41 (br, 1H), 5.66 (m, 1H), 7.16 (m), 7, 58 (br), 8.02 (m), 10.92 (s, 1H) Example 105 N-. { 4- [4- (4-Cyclopropanesulfonylaminocarbonyl-1 3-methyl-2, 14-dioxo-3, 13-diaza-tricyclo [13.3,0,0 * 4,6] octadec-7-en-17-yloxy ) -7-methoxy-quinoli-2-yl] -thiazole-2-yl} -3,3-dimethylbutyramide (105) The treatment of compound 103 with 4-hydroxy-7-methoxy-2- [2- (2,2-dimethylbutanoyl) aminothiazol-4-yl] quinoline as described in Example 1 04 gave the title compound. LCMS: retention time 2.30 min gradient of 30% - 80% B in 3 min (flow: 0.8 mL / min, UV 220 nm, ACE C8 3 x 50 mm, mobile phase A 1 0 mM NH4Ac in 90 % H2O, B 10 mM NH Ac in 90% ACN), (M + 1) + = 807. Example 1 06 ethylester of 1 - acid. { [2- (Hex-5-enyl-metii-carbamoyl) -4-hydroxy-cyclopentanecarbonyl] -amino} -2-vinyl-cyclopropanecarboxylic acid (106) The reaction of compound 101 as described in Example 102 but using 1-amino-2-vinylcyclopropanecarboxylic acid ethyl ester in place of (1-amino-2-vinyl-cyclopropanecarbonyl) amide hydrochloride of (1 R, 2 S) -cyclopropanesulfonic acid gave the title compound. Example 107 ethylester of 1 - acid. { [4- (4-Bromo-benzensulfonyloxy-2- (hex-5-enyl-methyl-carbamoyl) -cyclopentanecarbonyl] -amino} 2-vinyl-cyclopropanecarboxylic acid (107) Compound 1 06 (1 15 mg, 0.286 mmol ) was dissolved in 5 ml of toluene and 1 ml of dichloromethane DABCO (2,2,2-diazobicyclooctane) (96 mg, 0.857 mmol, 3 eq.) was added to the solution, and then BsCI (109 mg, 0.428 mmol, 1.5 eq.) The reaction was stirred at room temperature overnight, diluted with toluene (+ 10% ethyl acetate), washed with saturated sodium bicarbonate, brine, dried over sodium sulfate and evaporated The desired product was obtained by column chromatography (eluent EtOAc) Rf 0.25). Conversion 80%. Yield 1 06 mg. Example 108 17- (4-Bromo-benzensulfonyloxy) -13-methyl-2, 14-dioxo-3, 13-diaza-tricyclic acid [13,3,0,0 * 4,6 *] octadec-7-en- 4-carboxylic acid (108) Compound 107 (106 mg, 0.169 mmol) was dissolved in dichloromethane (40 ml) and degassed by bubbling nitrogen through the solution for 20 min. Next, first generation Hoveyda-Grubbs catalyst (10 mg, 0.01 7 mmol, 10 mol%) was added and the mixture was refluxed under a nitrogen atmosphere overnight. The reaction mixture was then cooled to room temperature and a palladium MP-TMT scavenger (approx. 100 mg) was added and stirred for 2.5 h. The scrubber was removed by filtration and washed with 50 ml of dichloromethane. The obtained solution was concentrated by rotary evaporation. The crude product was purified by column chromatography (EtOAc) to give 61 mg of product. Yield 60%. Example 1 09 17- [2- (2-lsopropylamino-thiazol-4-yl) -7-methoxy-quionlin-4-yloxy] -1-3-methyl-2, 14-dioxo-3, 13-diaza-tricyclic acid ethyl ester [ 13.3.0.0 * 4.6 *] octadec-7-en-4-carboxylic acid (109) 2- (lsopropylamino-thiazol-4-yl) -7-methoxy-quinolin-4-ol (220) was dissolved mg, 0.7 mmol) (prepared as described in WO 00/59929) in 7 ml of NMP (N-methylpyrrolidinone), one tablespoon of Cs2CO3 was added, it was stirred at 60 ° C for 1.5 h. Then compound 108 (150 mg, 0.24 mmol) was added. The reaction mixture was stirred at 80 ° C overnight. It was diluted with chloroform and washed with sodium bicarbonate, brine. The aqueous phases were extracted again with chloroform. The combined organic phases were dried over sodium sulfate and evaporated. The crude product was purified by preparative HPLC (Gilson) (MeOH-H2O, 65%) to give 21 mg of product (13% yield) as well as 12 mg of isomer. Example 1 1 0 17- [2- (2-lsopropylamino-thiazol-4-yl) -7-methoxy-quionyl-4-yloxy] -13-methyl-2, 14-dioxo-3, 13-diaza-tricyclo [13] , 3.0.0 * 4.6 *] octadec-7-en-4-carboxylic acid (1 10) To the solution of ester 09 (21 mg, 0.031 mmol) in a THF mixture (0.2 ml) and methanol (0.3 ml) was added LiOH solution (4 mg, 0.17 mmol) in 0.15 ml 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, the aqueous phase was extracted with chloroform 3 times, the organic phases were combined, dried over sodium sulfate and evaporated giving 20 mg of pure product (yield 99%). Example 1 1 1 . { 17- [2- (2-isopropylamino-thiazol-4-yl) -7-methoxy-quionlin-4-yloxy] -13-methyl-2,14-dioxo-3,1-diaza-tricyclo [13.3 , 0.0 * 4.6 *] octadec-7-en-4-carbonyl} cyclopropanesulfonic acid amide (11) 1 1 0 acid (20 mg, 0.15 mmol), DMAP (28 mg, 0.225 mmol) and EDAC (58 mg, 0.3 mmol) were dissolved in DMF (1, 5 mL). The reaction mixture was stirred overnight at room temperature after which cyclopropylsulfonamide (91 mg, 1.125 mmol) and DBU (14 μL, 0.75 mmol) were added. After stirring at room temperature overnight the reaction mixture was added to 5% citric acid and extracted three times with chloroform. The organic phase was dried over sodium sulfate and evaporated. The resulting residue was purified by preparative HPLC to give the title product (5.6 mg) (24% yield). Tests In the compounds of the invention, activity against the NS3 protease of flaviviruses, such as HCV, is conveniently evaluated. 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, 1997 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.

Typically the inhibitors are dissolved in DMSO, sonicated for 30 seconds and shaken. 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 professed VHC NS3 / 4A complex. The purpose of this in vitro assay is to measure the inhibition of NS3 HCV 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 the 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, JCIin Microbiol., 31 (6), 1493-1503 (1993)). It was shown that the amino acid sequence of the non-structural region, NS2-5B, was > 97% identical to HCV genotype la (H77C) 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. The DNA encoding the recombinant HCV NS3 / 4A protease complex (amino acids 1 027 to 171 1) was manipulated 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): 5620-32, (1 999)). 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. In addition, a mutation of cysteine into serine can be introduced by PCR at the amino acid at position 1454, to prevent autolytic cleavage of the NS3 helicase domain. The variant DNA fragment can be cloned into the bacterial expression vector pET21b (Novagen), and the NS3 / 4A complex can be expressed in the Escherichia coli strain 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 72 (8): 6758-69 (1,998)) with modifications. Briefly, the expression of NS3 can be induced with 0.5 mM isopropyl beta-D thiogalactopyranoside (I PTG) for 22 hours at 20 ° C. A typical fermentation (10 I) allows to obtain approximately 80 g of wet cell paste. Cells are resuspended in a lysis buffer (10 ml / g) consisting of 25 mM N- (2-hydroxyethyl) piperazine-N '- (2-ethanesulfonic acid) (HEPES), 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, free protease inhibitor 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 extract of crude proteins 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-X100, 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% Tpton-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% Tpton-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, thawed on ice and diluted before use in the assay regulator. The substrate used for the NS3 / 4A protease assay is conveniently RETS1 (depsipeptide substrate resonance energy transfer; AnaSpec, Inc. cat # 22991) (FRET peptide), described by Taliani et al. in Anal. Biochem. 240 (2): 6067 (1996). 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% Triton; 15% Glycerol; BME 10 mM. 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 well 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 / dFcon) 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 (IC50) is calculated using software such as Excel XI software, which uses the equation: y = A + ((B - A) / (1 + ((C / x)? D))). Enzyme assays conveniently utilize a fluorescence resonance energy transfer (FRET) principle to generate a spectroscopic 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 1 0 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 Recombinant HCV whole enzymes can be prepared as indicated in Polyakov et al Protein Expression & purification 25 (2002) 363-371. The cofactor NS4A conveniently has an amino acid sequence of KKGSVVIVGRIVLSGK (commercially available) and is generally prepared as a 10 mM stock 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 S1, 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. The 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 Store 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] -propanesulfonate can be purchased from Research Organics, Cleveland, OH44125, USA. MW 614.90 DTT, DL-Dithiothreitol (Cleland Reagent: DL-DTT) 99% purity, MW 154.2, is stored at + 4 ° C. DMSO can be purchased from SDS, 13124 Peypin, France, with 99.5% purity. Ultrapure TRIS (TRIS- (hydroxymethylaminomethane)) can be purchased from ICN Biomedicals Inc. Sodium chloride can be obtained from KEBOlab AB. N-dodecyl-β-D-maltoside, with a minimum of 98%, can be purchased from Sigma, and stored at -20 ° C. Equipment Microtitre plates (white cliniplaca, ThermoLab Systems cat no. 9502890) Eppendorf pipettes Biohit pipette, for multiple dosing Ascending fluorometer, excitation filter pair at 355 nm and emission at 500 nm Method Experimental procedure: 10 mM stock solution is prepared the compounds in DMSO. The stock solutions are stored at room temperature during the evaluations, and placed at -20 ° C for long-term storage. Assay regulator A: 50 mM HEPES regulator, pH = 7.5, 40% glycerol, 0.1% CHAPS Storage: at room temperature. 10 mM DTT (stored in aliquots at -20 ° C and added fresh to each experiment). Test Regulator B: 25 mM TRIS, pH 7.5, 0.15 M NaCl, 10% glycerol, 0.05% n-dodecyl-β-D-maltoside. 5 mM DTT (stored in aliquots at -20 ° C and added fresh for each experiment). Test sequence: Preparation of the reaction regulator (for a plate, 100 reactions) (regulator A) 1. Prepare 9500 μl of assay buffer (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 a plate, 1 00 reactions) (regulator A) 5. Prepare 9500 μl of assay buffer (TRIS, pH = 7.5, 0.15 M NaCl, 0.5 mM EDTA, 10 % glycerol and 0.05% 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 of 1, 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. FRET substrate preparation The substrate stock solution (1.61 mM) is diluted 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 100 μl. 1. Add 95 μl of assay buffer to each well. 2. Add 1 μl of inhibitor / reference compound. 3. 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 excitement. 355 nm and an emission of 500 nm, the increase in fluorescence per minute is monitored. 6. The progression curve is represented (within the linear range, 8-10 time points) and the slope is determined as an initial velocity with respect to each individual inhibitor concentration. 7. The% inhibition is calculated with respect to the control enzyme.

Treatment of the results The result is expressed as% inhibition at a determined 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: All inhibitors are treated as if they followed the rules of competitive inhibition. The value of IC50 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: Graphite and Graphpad Several compounds of the invention previously presented presented IC50 values in the range of between 1 nM and 6.9 micromolar, and ED50 values in the range between sub-micromolar and micromolar in the previous trials.

Pattern and rate of development of resistance to drug escape Replicon cultures can be used in microtiter plates to determine the 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. Virus produced is subjected to the concentration of test compound, with > 50% protease activity in comparison with 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). When the propagation of the viral component of the replicon (for example, measured through the activity of the HCV protease) can be obtained at the highest non-toxic concentration (5-40 μM), 2-4 parallel cavities are collected and expanded, in order to obtain material to perform sequence analysis and cross-resistance.

Key: Allowed 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 1 55, 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, allowing 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 main 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 CYP 1 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 (57)

1. REIVI NDICATIONS 1. A compound of formula VI: SAW where A is C (= O) OR \ C (= O) NHSO2R2, C (= O) NHR3, or CR4R4 'where; R1 is hydrogen, C? -C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl; R2 is Ci-C-alkyl, C0-C3 alkylcarbocyclyl, C0-C3alkyl heterocyclyl; R3 is C? -Calkyl, Co-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl, -OC? .- C6alkyl, -OC0-C3alkylcarbocyclyl, -OC0-C3alkullheterocyclyl; R4 is halo, amino, or OH; or R4 and R4 'together are = O; R4 'is Ci-Cealkyl, C0-C3alkylcarbocyclyl, C0-C3alkyl heterocyclyl; 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-C-alkyl, C0-C3 alkylcarbocyclyl, C0-C3 alkylheterocyclyl , 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 and Y-NRaC (= O) ORb; And it is independently a bond or C? -C3alkylene; Ra is independently H or CT-Csalkyl; Rb is independently H, C ^ Cealkyl, C0-C3alkylcarbocyclyl or C0-C3alkylheterocyclyl; p is independently 1 or 2; M is CR7R7 'or NRu; Ru is H or C ^ Csalquiio; 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 is J; q 'is O or 1 and k is between 0 and 3; Rz is H, or together with the carbon with asterisk forms an olefinic bond; Rq is H or Ci-Cealkyl; 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 selected from S, O and N, wherein the ring system is optionally separated from W by a d-Csalkyl group; or R8 is d-C-alkyl; any of said groups R8 may be mono, di or trisubstituted optionally with R9, where R9 is independently selected from the group comprising halo, oxo, nitrile, azido, nitro, d-Cealkyl, C0- C3alkylcarbocyclyl, C0-C3alkylheterocycline Cl, NH2C (= O) -, Y-NRaRb, Y- O-Rb, YC (= O) Rb, Y- (C = O) NRaRb, Y-NRaC (= O) Rb, Y-NHSOpRb , Y- S (= O) pRb, YS (= O) pN RaRb, YC (= O) ORb and Y-NRaC (= O) ORb; wherein said carbocyclyl or heterocyclyl portion is optionally substituted with R10; wherein R10 is Ci-Cealkyl, C3-C7cycloalkyl, d-Cealkoxy, amino, sulfonyl, (CIS-alkyl) sulfonyl, NO2, OH, SH, halo, haloalkyl, carboxyl, amido; Rx is H or Ci-Cs alkyl; or Rx is J; T is -CHR1 1- or -NRd-, where Rd is H, d-Csalkyl or Rd is J; R1 1 is H or R1 1 is C -? - C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl, any of which may be substituted with 1 to 3 substituents selected independently from the group comprising halo, oxo, nitrile, azido, nitro, d-C6alkyl, 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; 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 the R7 / R7 cycloalkyl, or from the carbon atom to which R7 is attached to one of Rd, Rj, Rx , Ry or R 1 to form a macrocycle, where the chain is optionally interrupted by between one and three heteroatoms selected independently between: -O-, -S- or -NR12-, and wherein between 0 and 3 carbon atoms in the chain they are optionally substituted with R14; where; R12 is H, d-C6 alkyl, C3-C6 cycloalkyo, or COR13; R13 is d-C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkyneheterocyclyl; R14 is independently selected from H, Ci-C6alkyl, C, -C6haloalkyl, dC6alkoxy, hydroxy, halo, amino, oxo, thio, or dC6 thioalkyl; m is 0 or 1; n is 0 or 1; U is O or is absent; R15 is H, C? -C6alkyl, C0-C3alkylcarbocyl, C0-C3alkheheterocyclyl, any of which may be substituted with 1 to 3 substituents selected independently from the group consisting of halo, oxo, nitrile , azido, nitro, d-C6 alkyl, C0-C3alkylheterocyclyl, C0-C3alkylcarbocyclyl, 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 and Y- NRaC (= O) ORb; G is -O-, -NRy-, -NRjNRj-; Ry is H, dC3 alkyl; or Ry is J; one Rj is H and the other Rj is H or J; R16 is H; or R16 is d-C6alkyl, C0-C3alkylcarbocyclyl, C0-C3alkylheterocyclyl, any of which may be substituted with halo, oxo, nitrile, azido, nitro, d-C6alkyl, 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; 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 the partial structure:
4. 4. A compound according to claim 1, with the partial structure
5. 5. A compound according to claim 4, wherein Rq is C1-C3 alkyl, preferably methyl.
6. 6. A compound according to claim 1, wherein m is 0 and n is 0.
7. 7. A compound according to claim 6, wherein G is -NRy- or -NRjNRj-.
8. 8. A compound according to claim 7, wherein Ry or one of the groups Rj is J, thereby defining a macrocyclic compound.
9. 9. A compound according to claim 7, wherein R16 is H, d-C6alkyl or C3-C6 cycloalkyl. 1 0.
10. A compound according to claim 1, wherein m is 1. 1 .
11. A compound according to claim 10, wherein U is O.
12. 12. A compound according to claim 10, wherein T is CR11.
13. 13. A compound according to claim 12, wherein R1 1 is d-Cealkyl, C0-C3alkylcarbocyclyl, C0-C3alkylaryl or C0-C3alkylheteroaryl, any of which is optionally substituted with halo, amino, d-C6alkoxy, d- C6thioalkyl, COOR14, carboxyl, (d-C6alkoxy) carbonyl, aryl, heteroaryl or heterocyclyl; or especially substituted with hydroxyl or COOR14.
14. 14. A compound according to claim 13, wherein R1 1 is tert-butyl, iso-butyl, cyclohexyl, phenylethyl, 2,2-dimethyl-propyl, cyclohexylmethyl, phenylmethyl, 2-pyridylmethyl, 4-hydroxy-phenylmethyl, or carboxylpropyl, especially tert-butyl, iso-butyl, or cyclohexyl. 5.
15. A compound according to claim 10, wherein one of Rd, Rx or R1 is J, thereby defining a macrocyclic compound.
16. 16. A compound according to claim 10, wherein n is 1.
17. 17. A compound according to claim 16, wherein R 5 is d-C6alkyl or C0-C3alkylcarbocyclyl, any of which is optionally substituted.
18. 18. A compound according to claim 17, wherein R15 is cyclohexyl, cyclohexylmethyl, tert-butyl, iso-propyl, or iso-butyl.
19. 19. A compound according to claim 10, wherein G is NRy or NRjNRj, where Ry or a Rj is H or methyl and the other is H.
20. 20. A compound according to claim 19, wherein R16 is H , d-C6alkyl or a 5- or 6-membered heterocycle, especially morpholine, piperidine or piperazine. twenty-one .
21. A compound according to claim 10, wherein R16 is d-C6alkyl, C0-C3alkylheterocyclyl, C0-C3alkylcarbocyclyl, any of which is optionally substituted with hydroxy, halo, amino, or dC6alkoxy.
22. 22. A compound according to claim 21, wherein R16 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.
23. 23. 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.
24. 24. A compound according to claim 1, wherein W is -S-, a bond or especially -O-.
25. 25. A compound according to claim 23 or 24 wherein R8 is optionally substituted C0-C3alkylcarbocyclyl or optionally substituted C0-C3-alkylheterocyclyl.
26. 26. A compound according to claim 25, wherein the C0-C3 alkyl moiety is methylene or preferably a bond.
27. 27. A compound according to claim 26 wherein R8 is C0-C3alkylaryl, or C0-C3alkylheteroaryl, any of which is optionally mono, di, or tri substituted with R9, wherein; R9 is dC6 alkyl, C, -C6alkoxy, NO2, OH, halo, trifluoromethyl, amino or amido optionally mono- or di-substituted with d-Cealkyl, Co-dalkylaryl, C0-C3alkylheteroaryl, carboxyl, aryl or heteroaryl which is optionally substituted with R10; where R 0 is C? -C6alkyl, C3-C7cycloalkyl, d-C6alkoxy, amino optionally mono- or di-substituted with d-C6alkyl, d-C3alkylamide, sulfonyl-C3alkyl, NO2, OH, halo, trifluoromethyl, carboxyl, or heteroaryl.
28. 28. A compound according to claim 27 wherein R9 is d-C6 alkyl, d-C6alkoxy, amino, di- (d-C3 alkyl) amino, d-C3alkylamide, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with R10; wherein R10 is d-C6alkyl, C3-C7cycloalkyl, d-C6alkoxy, amino, mono- or di-d-C3 alkylamino, amido, C1-C3 alkylamide, halo, trifluoromethyl, or heteroaryl.
29. 29. A compound according to claim 28, wherein, R10 is d-C6alkyl, d-C6alkoxy, amino optionally mono- or di substituted with d-C3 alkyl, amido, d-Cs-alkylamide, halo, or heteroaryl.
30. 30. A compound according to claim 29 wherein R10 is methyl, ethyl, isopropyl, tert-butyl, methoxy, chloro, amino optionally mono- or di substituted with d-C3 alkyl, amido, d-C3alkylamide, or C? -C3alkylthiazolyl.
31. A compound according to claim 26, 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 definite.
32. 32. A compound according to claim 31 wherein R8 is 1-naphthylmethyl, or quinolinyl any of which is unsubstituted, mono, or disubstituted with R9 as defined.
33. 33. A compound according to claim 32 wherein R8 is: wherein R9a is dC6 alkyl; d-C6alcox¡; tiod-C3alkyl; amino optionally substituted with d-C6alkyl; C0-C3alkylaryl; or C0-C3alkylheteroaryl, C0-C3alkylheterocyclyl, wherein said aryl, heteroaryl or heterocycle is optionally substituted with R10 wherein R10 is d-C6alkyl, C0-C3alkylC3-C7cycloalkyl, d-C6alkoxy, amino optionally mono- or di-substituted with d- C6alkyl, amido, d-C3alkyl amide; and R9b is d-C6 alkyl, d-C6-alkoxy, amino, di (d-C3alkyl) amino, (d-C3alkyl) amide, NO2, OH, halo, trifluoromethyl, carboxyl.
34. 34. A compound according to claim 33, wherein R9a is aryl or heteroaryl, any of which is optionally substituted with R10 as defined.
35. 35. A compound according to 34, 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-Cealkyl, amido, (d-C3alkyl) amide.
36. 36. A compound according to claim 34, wherein R9a is optionally substituted phenyl, preferably phenyl substituted with d-C6alkyl; d-C6alkoxy; or halo.
37. 37. A compound according to claim 33, wherein R8 is: wherein R 0a is H, d-C6alkyl, or C0-C3alkylcarbocyclyl, amino optionally mono- or di-substituted with d-C6alkyl, amido, (d-C3alkyl) amide, heteroaryl or heterocyclyl; and R9b is d-C6 alkyl, d-C6-alkoxy, amino, di (d-C3 alkyl) amino, (d-C3 alkyl) amide, NO2, OH, halo, trifluoromethyl, or carboxyl.
38. 38. A compound according to claim 33, wherein R9b is d-C6-alkoxy, preferably methoxy.
39. 39. A compound according to claim 1, wherein A is C (= O) NHSO2R2.
40. 40. A compound according to claim 39, wherein R2 is optionally substituted d-C6 alkyl, preferably methyl.
41. 41 A compound according to claim 39, wherein R2 is optionally substituted C3-C7cycloalkyl, preferably cyclopropyl.
42. 42. A compound according to claim 39, wherein R2 is optionally substituted C0-C6alkylaryl, preferably optionally substituted phenyl.
43. 43. A compound according to claim 1, wherein A is C (= O) OR1
44. 44. A compound according to claim 43, wherein R1 is H or d-C6 alkyl, preferably hydrogen, methyl, ethyl, or tert-butyl.
45. 45. A compound according to claim 2, wherein R7 'is H and R7 is n-ethyl, cyclopropylmethyl, cyclobutylmethyl or mercaptomethyl, preferably n-propyl or 2,2-difluoroethyl.
46. 46. 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, wherein; R7 a is d-C6 alkyl, C3-C5 cycloalkyl, or C2-C6 alkenyl, any of which is optionally substituted with halo; or R7a is J.
47. 47. A compound according to claim 47 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-fluoroetyl, 2-bromovinyl or 2-fluorethyl.
48. 48. A compound according to claim 2, wherein R7 is J and R7 'is H.
49. 49. 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) d-C6 alkyl , such as acetyl.
50. 50. A compound according to claim 49, wherein J is a saturated or unsaturated alkylene carbonate chain of between 4 and 7 members.
51. 51 A compound according to claim 49, wherein J is saturated or mono-unsaturated.
52. 52. A compound according to claim 49, wherein J is sized to give a macrocycle of 14 or 15 atoms in the ring.
53. 53. A pharmaceutical composition comprising a compound as defined in claim 1 and a vehicle acceptable for pharmaceutical use therefor.
54. 54. A pharmaceutical composition according to claim 53, which further comprises an additional HCV antiviral, selected from among nucleoside analogue polymerase inhibitors, protease inhibitors, protease inhibitors, ribavirin and interferon.
55. 55. Use of a compound as defined in claim 1 in therapy.
56. 56. Use of a compound as defined in claim 1 in the manufacture of a medicament for the prophylaxis or treatment of flavivirus infections, including HCV.
57. 57. A method for the treatment or prophylaxis of a flavivirus infection such as HCV comprising the administration of an effective amount of the compound as defined in claim 1 to an individual affected by said infection or at risk of acquiring it.