MX2008001404A - Macrocyclic inhibitors of hepatitis c virus - Google Patents

Abstract

Inhibitors of HCV replication of formula (I) and theN-oxides, salts, and stereoisomers, wherein each dashed line represents an optional double bond;X is N, CH and where X bears a double bond it is C;R1is -OR7, -NH-SO2R8;R2is hydrogen, and where X is C or CH, R2may also be C1-6alkyl;R3is hydrogen, C1-6alkyl, C1-6alkoxyC1-6alkyl, C3-7cycloalkyl;R4is aryl or Het;n is 3, 4, 5, or 6;R5is halo, C1-6alkyl, hydroxy, C1-6alkoxy, phenyl, or Het;R6is C1-6alkoxy, or dimethylamino;R7is hydrogen;aryl;Het;C3-7cycloalkyl optionally substituted with C1-6alkyl;or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or with Het;R8is aryl;Het;C3-7cycloalkyl optionally substituted with C1-6alkyl;or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or with Het;aryl is phenyl optionally substituted with one, two or three substituents;Het is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, and being optionally substituted with one, two or three substituents;pharmaceutical compositions containing compounds (I) and processes for preparing compounds (I). Bioavailable combinations of the inhibitors of HCV of formula (I) with ritonavir are also provided.

Description

MACROCYCLIC INHIBITORS OF HEPATITIS C VIRUSES DESCRIPTIVE MEMORY The present invention relates to macrocyclic compounds having inhibitory activity on the replication of hepatitis C virus (HCV). In addition, it relates to compositions comprising these compounds as active ingredients, as well as processes for preparing these compounds and compositions. The hepatitis C virus is the leading cause of chronic liver disease worldwide and has become a focus of considerable medical research. HCV is a member of the Flaviviridae family of viruses of the hepacivirus genus, and is closely related to the genus flavivirus, which includes a number of viruses involved in human diseases, such as dengue virus and yellow fever virus and the pestivirus family of animals, which includes the bovine virus of viral diarrhea (VBDV). HCV is a positive-sense, single-stranded RNA virus with a genome of about 9600 bases. The genome comprises the two 5 'and 3' untranslated regions that adopt secondary RNA structures and a central open reading frame encoding a unique polyprotein of about 3.010-3.030 amino acids. Polyprotein encodes ten gene products that are generated from the precursor polyprotein by an organized series of endoproteolytic cleavages co- and post- translationals mediated by host and viral proteases. Viral structural proteins include the core nucleocapsid protein and two envelope glycoproteins E1 and E2. The non-structural proteins (NS) encode some essential viral enzymatic functions (helicase, polymerase, protease), as well as proteins of unknown function. Replication of the viral genome is mediated by an RNA-dependent RNA polymerase, encoded by the non-structural protein 5b (NS5B). In addition to the polymerase functions, it was shown that the functions of viral helicase and protease, both encoded in the bifunctional NS3 protein, are essential for the replication of HCV RNA. In addition to the serine protease NS3, HCV also encodes a metalloproteinase in the NS2 region. After the initial acute infection, a majority of infected individuals developed chronic hepatitis because HCV replicates preferentially in hepatocytes, but is not directly cytopathic. In particular, the lack of a vigorous response of T lymphocytes and the high tendency of the virus to mutate appear to promote a high degree of chronic infection. Chronic hepatitis can progress to liver fibrosis producing cirrhosis, terminal liver disease and HCC (hepatocellular carcinoma), making it the main cause of liver transplants. There are 6 major genotypes of HCV and more than 50 subtypes, which are distributed geographically differently. Type 1 HCV is the predominant genotype in Europe and the United States. The extensive genetic heterogeneity of HCV has an important diagnosis and implications clinics, possibly explaining the difficulties for the development of vaccines and the lack of response to therapy. HCV transmission can occur through contact with contaminated blood or blood products, for example following the transfusion of blood or use of intravenous drugs. The introduction of diagnostic tests used in the evaluation of blood produced a downward trend in the incidence of HCV in post-transfusion. However, given the slow progress to terminal liver disease, existing infections will continue to present a medical and economic burden for decades. Current therapies against HCV are based on interferon-alpha (IFN-a) (pegylated) in combination with ribavirin. This combination therapy produces a sustained virological response in more than 40% of patients infected by genotype 1 virus and around 80% of those infected with genotypes 2 and 3. In addition to limited efficacy on type 1 HCV, this combination therapy has side effects and is poorly tolerated in many patients. Most side effects include influenza-like symptoms, hematologic abnormalities, and neuropsychiatric symptoms. Therefore, there is a need for more effective, convenient and better tolerated treatments. Recently, two peptide mimetic HCV protease inhibitors gained attention as clinical candidates, namely, BILN-2061 described in WO00 / 59929 and VX-950 described in WO03 / 87092. A The amount of similar HCV protease inhibitors has also been revealed in the academic and patent literature. It is already evident that prolonged administration of BILN-2061 or VX-950 selects HCV mutants 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, D168A and / or A156S. Therefore, additional drugs with different resistance patterns are required to provide patients who do not improve treatment options and it is likely that multi-drug combination therapy is the norm in the future, even for first-line treatment. Experience with anti-HIV drugs and HIV protease inhibitors in particular has emphasized that sub-optimal pharmacokinetics and complex dosage regimes quickly result in unintended compliance failures. This in turn means that the minimum concentration of 24 hours (minimum plasma concentration) for the respective drugs in a regimen for HIV often decreases below the threshold of IC90 or DE90 for much of the day. It is considered that a minimum level of 24 hours of at least the IC5o, and more realistically, Cl9u or DE90, is essential to decrease the development of drug escape mutants. Achieving the pharmacokinetics and metabolism of the drug necessary to allow such minimal levels provides a challenge rigorous for the design of drugs. The strong peptide mimetic nature of the HCV protease inhibitors of the prior art, with multiple peptide bonds, represents pharmacokinetic barriers for effective dosage regimens. There is a need for HCV inhibitors that can overcome the disadvantages of current HCV therapy, such as side effects, limited efficacy, the emergence of resistance and compliance failures. The present invention relates to HCV inhibitors which are superior in one or more of the following related pharmacological properties, ie potency, reduced cytotoxicity, improved pharmacokinetics, improved resistance profile, acceptable dosage and pellet loading. In addition, the compounds of the present invention have relatively low molecular weight and are easy to synthesize, from starting materials that are commercially available or that are readily available through synthetic methods known in the art. WO05 / 010029 describes macrocyclic azapeptide inhibitors of hepatitis C serine protease, pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection and methods for the treatment of HCV infection in a patient by administering a pharmaceutical composition comprising the mentioned compounds. The present invention relates to inhibitors of HCV replication, which can be represented by Formula (I): and the n-oxides, salts and stereoisomers thereof, wherein each dotted line (represented by) represents an optional double bond; X is N, CH and where X has a double bond is C; R1 is -OR7, -NH-SO2R8; R 2 is hydrogen and wherein X is C or CH, R 2 may also be C 6 alkyl; R3 is hydrogen, C-? 6 alkyl, C? -6 alkoxy, C? -6 alkyl, C3-7 cycloalkyl, R4 is aryl or Het; n is 3, 4, 5, 0 6; R 5 represents halogen, C 1-6 alkyl, hydroxy, C? -6 alkoxy, polyhalo-C? -6 alkyl, phenyl or Het; R6 represents C?-6 alkoxy, d- or β-monoalkylamino; R7 is hydrogen; aril; Het; C3-7 cycloalkyl optionally substituted with alkyl of or C-? -6 alkyl optionally substituted with C3-7 cycloalkyl, aryl or with Het; R8 is aryl; Het; C3-7 cycloalkyl optionally substituted with C1-6 alkyl; or C-? 6 alkyl optionally substituted with C3.7 cycloalkyl, aryl or with Het; aryl as a group or part of a group is phenyl optionally substituted with one, two or three substituents selected from halogen, hydroxy, nitro, cyano, carboxyl, C-? 6 alkyl, C1-6 alkoxy, C1- alkoxy 6-C de6 alkyl, C1.6 alkylcarbonyl, amino, mono- or dialkylamino of C ?6, azido, mercapto, polyhalogen-C alquilo-6alkyl, polyhalo-C alco6alkoxy, cycloalkyl C3-7, pyrrolidinyl, piperidinyl, piperazinyl, 4-C6-piperazinyl-4-alkyl, C-6-piperazinyl-4-alkylcarbonyl and morpholinyl; wherein the morpholinyl and piperidinyl groups may be optionally substituted with one or two alkyl radicals of C-? - 6; Het as a group or part of a group is a saturated, partially unsaturated or completely unsaturated, 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, said heterocyclic ring being optionally condensed with a benzene ring; and Het as a complete ring optionally substituted with one, two or three substituents each independently selected from the group consisting of halogen, hydroxy, nitro, cyano, carboxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy C? -6 alkyl, C-6 alkylcarbonyl, amino, C? -6 mono- or di-alkylamino, azido, mercapto, C? -6 polyhaloalkyl, C-? 6 polyhaloalkoxy, C3 cycloalkyl. 7, pyrrolidinyl, piperidinyl, piperazinyl, 4-C 1-6 alkyl-piperazinyl, 4-alkylcarbonyl of C-? -6-piperazinyl and morpholinyl; wherein the morpholinyl and piperidinyl groups may be optionally substituted with one or two alkyl radicals of The invention furthermore relates to methods for the preparation of the compounds of formula (I), the? / - oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms thereof, their intermediates and the use of intermediates in the preparation of the compounds of formula (I). The invention relates to the compounds of formula (I) per se, the? / - oxides, addition salts, quaternary amines, metal complexes and isomeric forms esterochemically thereof, for use as a medicament. The invention further relates to pharmaceutical compositions comprising a carrier and an effective antiviral agent loading of a compound of formula (I), as specified herein. The pharmaceutical compositions may comprise combinations of the aforementioned compounds with other anti-HCV agents. The invention also relates to the aforementioned pharmaceutical compositions previously for administration to a subject suffering from HCV infection. The invention also relates to the use of a compound of formula (I), or an N-oxide, addition salt, quaternary amine, metal complex, or stereochemically isomeric forms thereof, for the manufacture of a medicament for inhibiting replication of the HCV or the invention relates to a method for inhibiting the replication of HCV in a warm-blooded animal, said method comprising administering an effective amount of a compound of formula (I), or a pro-drug,? / - oxide, addition salt, quaternary amine, metal complex, or stereochemically isomeric forms thereof. As used above and hereinafter, the following definitions apply unless otherwise specified. The term halogen is generic for fluoro, chloro, bromo and iodo. The term "polyhalogenoalkyl of C-? - 6" as a group or part of a group, for example in polyhalo-C-6-alkoxy, is defined as substituted mono- or polyhalo-alkylC 1-6 alkyl, especially d-6 substituted by up to one, two, three, four, five, six or more halogen atoms, such as methyl or ethyl by one or more fluoro atoms, for example, difluoromethyl, trifluoromethyl, trifluoroethyl. Trifluoromethyl is preferred. Also included are perfluoro-alkyl groups of C-β6, which are C?-6 alkyl groups in which all hydrogen atoms are replaced by fluoro atoms, for example pentafluoroethyl. In the case where more than one halogen atom is attached to an alkyl group in the definition of polyhalogenyl of C? -6, the halogen atoms may be the same or different. As used herein, "C- \ X 'alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms, such as for example methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-1-propyl; "C-? 6 alkyl" comprises C? -4 alquilo alkyl radicals and the higher homologs thereof having 5 or 6 carbon atoms such as, for example, 1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl, 2-methyl-1-butyl, 2-methyl-1-pentyl, 2- ethyl-1-butyl, 3-methyl-2-pentyl and the like C 1-6 alkyl is of interest, the term "C 2-6 alkenyl", as a group or part of a group, defines straight and branched chain hydrocarbon radicals having saturated carbon-carbon bonds and at least one double bond and having from 2 to 6 carbon atoms, such as, for example, ethenyl (or vinyl), 1 -propenyl, 2-propenyl (or allyl), 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 2-hexenyl, -hexenyl, 4-hexenyl, 2-methyl-2-butenyl, 2-methyl-2-pentenyl and the like. Of interest among the C2-6 alkenyls is the C2-4 alkenyl group. The term "C2-6 alkynyl", as a group or part of a group, defines straight and branched chain hydrocarbon radicals having saturated carbon-carbon bonds and at least one triple bond and having from 2 to 6 carbon atoms, such as, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl and the like . Of interest among C2-6 alkynyl is the C2-4 alkynyl. The C3-7 cycloalkyl is generic for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. C.sub.6 alkanediyl defines straight and branched bivalent chain hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methylene, ethylene, 1,3-propanediyl, 1,4-butanediyl, 1,2-propanediyl, 2,3-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the like. The alkanediyl of C, ^ is of interest among the C1-C6-alkanediyl. C -? - 6 alkoxy means C? -6 alkyloxy wherein C? -6 alkyl is as defined above. As used herein, above, the term (= 0) or oxo forms a carbonyl moiety when attached to a carbon atom, a sulfoxide moiety when it is attached to a sulfur atom and a sulfonyl moiety when two such terms they join a sulfur atom. Whenever a ring or an annular system is replaced by an oxo group, the carbon atom to which the oxo is attached is a saturated carbon. The radical Het is a heterocycle, as specified herein and claims. Preferred among the Het radicals are those which are monocyclic. Examples of Het include, for example, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazinolyl, isothiazinolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl (including 1,2,3-triazolyl, 1,4-triazolyl), tetrazolyl, furanyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, triazinyl and the like. Of interest among Het radicals are those that are unsaturated, especially those that have an aromatic character. Of additional interest are those Het radicals that have one or two nitrogens. Each of the Het radicals mentioned in this and the following paragraphs can be optionally substituted with the amount and type of substituents mentioned in the definitions of the compounds of formula (I) or any of the subgroups of compounds of formula (I). Some of the Het radicals mentioned in this paragraph and in the following may be substituted by one, two or three hydroxy substituents. Such hydroxy-substituted rings can be produced as their tautomeric forms having keto groups. For example, a 3-hydroxypyridazine moiety may be presented in its tautomeric form, 2 / - / - pyridazin-3-one. When Het is piperazinyl, it is preferably substituted in the 4-position by a substituent attached to the nitrogen 4 with a carbon atom, for example 4-C- [alpha] -6-, 4-polyhalogen-C-6 alkyl, alkoxy C -? - 6-C-6-alkyl, C-? -6-alkylcarbonyl, C3-7-cycloalkyl. The interest Het radicals comprise, for example pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl (nclud 1, 2,3-triazolyl, 1, 2,4-triazolyl), tetrazolyl, furanyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, pyrazolyl, triazinyl, or any such heterocycles condensed with a benzene ring, such as indolyl, indazolyl (in particular 1 H-indazolyl), indolinyl, quinolinyl, tetrahydroquinolinyl (in particular 1, 2,3,4-tetrahydroquinolinyl), isoquinolinyl, tetrahydroisoquinolinyl (including 1, 2,3,4-tetrahydroisoquinolinyl), quinazolinyl, phthalazinyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzofuranyl, benzothienyl. The Het pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperazinyl substituted at the 4-position are preferably attached via their nitrogen atom (i.e., 1-pyrrolidinyl, 1-piperidinyl, 4-thiomorpholinyl, 4-morpholinyl, 1-piperazinyl, piperazinyl substituted at the 4-position). It should be noted that the locations of the radicals in any molecular portion used in the definitions can be found anywhere on said portion, provided it is chemically stable. The radicals used in the definitions of the variables include all possible isomers, unless indicated otherwise. For example, pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl; Pentyl includes 1-pentyl, 2-pentyl and 3-pentyl. When any variable occurs more than once in any constituent, each definition is independent. Whenever used hereinafter, the term "compounds of formula (I)", or "the present compounds" or terms similar, it is intended to include the compounds of formula (I), their prodrugs,? / - oxides, addition salts, quaternary amines, metal complexes and stereochemical isomeric forms. One embodiment comprises the compounds of formula (I) or any subgroup of compounds of formula (I) as specified herein, as well as the α / - oxides, salts, as the possible stereoisomeric forms thereof. Another embodiment comprises the compounds of formula (I) or any subgroup of compounds of formula (I) that is specified herein, as well as salts as their possible stereoisomeric forms. The compounds of formula (I) have several centers of chirality and exist as stereochemical isomeric forms. The term "stereochemical isomeric forms" as used herein, defines all possible compounds prepared from the same atoms attached by the same sequence of bonds, but having different three-dimensional structures that are not interchangeable, which may have the compounds of formula (I) Referring to the instances in which (R) or (S) is used to designate the absolute configuration of a chiral atom in a substituent, the designation is carried out considering the entire compound and not the isolated substituent. Unless otherwise mentioned or indicated, the chemical designation of a compound comprises the mixture of all possible stereochemical isomeric forms, which said compound may have.

Said mixture may contain all the diastereomers and / or enantiomers of the basic molecular structure of said compound. It is intended that all isomeric stereochemical forms of the compounds of the present invention that require both, the pure form or in combination with each other, are within the scope of the present invention. The pure stereoisomeric forms of the compounds and intermediates as mentioned herein are defined as isomers essentially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates. In particular, the term "stereoisomerically pure" refers to compounds or intermediates having a stereoisomeric excess of at least 80% (ie 90% minimum of one isomer and a maximum of 10% of other possible isomers) to a stereoisomeric excess 100% (ie 100% of an isomer and none of the others), more in particular, the compounds and intermediates having a stereoisomeric excess of 90% up to 100%, even more especially having a stereoisomeric excess of 94% up to 100% and even more especially that have a stereoisomeric excess of 97% up to 100%. The terms "enantiomerically pure" and "diastereomerically pure" should be understood in a similar manner, but considering the enantiomeric excess and the diastereomeric excess, respectively, of the mixture in question. The pure stereoisomeric forms of the compounds and intermediates of the present invention can be obtained by application of procedures known in the art. For example, the enantiomers can be separated from each other by selective crystallization of their diastereomeric salts with optimally active acids or bases. Examples thereof are tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphor sulfonic acid. Alternatively, the enantiomers can be separated by chromatographic techniques using chiral stationary phases. Said pure stereochemical isomeric forms can also be derived from the corresponding stereochemical pure isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, if a specific stereoisomer is desired, said compound will be synthesized by specific methods of preparation. These methods will advantageously use the enantiomerically pure starting materials. The diastereomeric racemates of the compounds of formula (I) can be obtained separately by conventional methods. The appropriate physical separation methods that can be used advantageously are, for example, selective crystallization and chromatography, for example, column chromatography. For some of the compounds of formula (I), their prodrugs,? / - oxides, salts, solvates, quaternary amines, or metal complexes and the intermediates used in the preparation thereof, the absolute stereochemical configuration was not determined from experimental way. A person skilled in the art is capable of determining the absolute configuration of such compounds using methods known in the art, such as, for example, X-ray diffraction. It is also intended that the present invention include all isotopes of atoms that are produced in the present compounds. Isotopes include those atoms that have the same atomic quantity but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Carbon isotopes include C-13 and C-14. The term "pro-drug", as used throughout this text, means acceptable derivatives for pharmaceutical use such as esters, amides and phosphates, so that the product resulting from biotransformation in vivo of the derivative is the active drug, as defined in the compounds of formula (I). The reference by Goodman and Gillman (The Pharmacological Basis of Therapeutics, 8, ed., McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", p. 13-15) which generally describes prodrugs is incorporated herein by reference. . The pro-drugs preferably have excellent aqueous solubility, increased bioavailability and are easily metabolized to active inhibitors in vivo. Pro-drugs of a compound of the present invention can be prepared by modifying functional groups present in the compound, so that the modifications are cleaved, either by routine manipulation or in vivo, for the parent compound. Acceptable ester pro-drugs are preferred for use pharmaceutical which are hydrolysable in vivo and which are derived from those compounds of formula (I) having a hydroxy or a carboxyl group. A hydrolysable ester in vivo is an ester, which is hydrolyzed in the human or animal body to produce the original acid or alcohol. Suitable esters acceptable for pharmaceutical use for carboxy include alkoxymethyl esters of d-β, for example methoxymethyl esters, C?-6 alkanoyloxymethyl esters for example pivaloyloxymethyl, phtalidyl esters, esters of C 3-8 cycloalkoxycarbonyloxy-C 1-6 alkyl for example 1-cyclohexylcarbonyloxyethyl; 1, 3-dioxolen-2-onylmethyl esters, for example 5-methyl-1,3-dioxolen-2-onylmethyl; and C?-6 alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl, which can be formed at any carboxy group in the compounds of this invention. A in vivo hydrolysable ester of a compound of the formula (I) containing a hydroxy group includes organic esters such as phosphate esters and α-acyloxyalkyl esters and related compounds which as a result of the in vivo hydrolysis of the ester break are broken to give the parent hydroxy group. Examples of α-acyloxyalkyl esters include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy includes alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N- (dyalkylaminoethyl) -N-alkylcarbamoyl (to give carbamates) , dialkylaminoacetyl and carboxyacetyl. Examples of substituents in the benzoyl include morpholino and piperazino linked from an annular nitrogen atom by a methylene group to the 3 or 4 position of the benzoyl ring. For therapeutic use, the salts of the compounds of formula (I) are those in which the counterion is acceptable for pharmaceutical use. However, salts of acids and bases that are not acceptable for pharmaceutical use can also be used, for example, in the preparation or purification of a compound acceptable for pharmaceutical use. All salts, whether acceptable for pharmaceutical use or not included in the scope of the present invention. The addition salts with acids and bases are acceptable for pharmaceutical use as mentioned above herein are intended to comprise the forms of addition salts with non-toxic therapeutically active acids and bases which the compounds of formula (I) are capable of forming. Acid addition salts acceptable for pharmaceutical use can be conveniently obtained by treating the base form with said appropriate acid. Suitable acids comprise, for example, inorganic acids such as hydrazides, for example hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyrubic, oxalic (ie ethanedioic), malonic, succinic (ie butanedioic acid), maleic, fumaric, malic (ie hydroxybutanedioic acid), tartaric acids. , citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and similar acids. On the contrary, such salt forms can be transformed by treatment with an appropriate base in the free base form. The compounds of formula (I) which contain an acidic proton can also be transformed into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. The salt forms with bases comprise, for example, the ammonium salts, the alkali metal and alkaline earth metal salts, for example, lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, for example benzathine. ,? / - methyl-D-glucamine, hydrabamine salts and salts with amino acids such as, for example, arginine, lysine and the like. The term "addition salt", as used hereinabove, also comprises the solvates which the compounds of the formula (I) are capable of forming, as well as the salts thereof. Such solvates are, for example, hydrates, alcoholates and the like. The term "quaternary amine" as used hereinbefore, defines the quaternary ammonium salts that the compounds of formula (I) are capable of forming by reaction between a basic nitrogen of a compound of formula (I) and an agent suitable quaternization, such as, for example, an alkyl halogenide of aryl halide or optionally substituted arylalkyl halide, for example, methyl iodide or benzyl iodide. Other reagents with good leaving groups, such as alkyl trifluoromethanesulfonates, can also be used. alkyl methanesulfonates and alkyl p-toluenesulfonates. A quaternary amine has a positively charged nitrogen. Acceptable counterions for pharmaceutical use include chlorine, bromine, iodine, trifluoroacetate and acetate. The counterion of choice can be introduced using ion exchange resins. The? / -oxide forms of the present compounds are intended to comprise the compounds of formula (I) wherein one or several nitrogen atoms are oxidized for the so-called? / -oxide. It will be appreciated that the compounds of formula (I) can have metal binding, chelating, complexing properties and, therefore, can exist as metal complexes or metal chelates. It is intended that such metal derivatives of the compounds of formula (I) be included within the scope of the present invention. Some of the compounds of formula (I) may also exist in their tautomeric form. It is intended that such forms, although not explicitly indicated in the above formula, be included within the scope of the present invention. As mentioned above, the compounds of formula (I) have several asymmetric centers. To refer more efficiently to each of these asymmetric centers, the numbering system will be used, as indicated in the following structural formula.

The asymmetric centers are present in the positions 1, 4 and 6 of the macrocycle, as well as in the carbon atom 3 'in the 5-membered ring, carbon atom in the 2' position where the substituent R2 is C1-alkyl -6 and in the 1 'position of the carbon atoms, where X is CH Each of these asymmetric centers can be presented in their R or S configuration The stereochemistry at position 1, preferably, corresponds to that of an amino acid configuration L, ie, that of the L-prohna When X is CH, the 2 carbonyl groups substituted at the 1 'and 5' positions of the cyclopentane ring are preferably in a trans configuration The carbonyl substituent at the 5 'position, preferably is in that configuration that corresponds to a configuration of L-prolma Carbonyl groups substituted in positions V and 5 ', preferably, are as described below in the structure of the following formula.

The compounds of formula (I) include a cyclopropyl group, as represented in the structural fragment below: where C7 represents the carbon at position 7 and the carbons at position 4 and 6 are asymmetric carbon atoms of the cyclopropane ring. Regardless of other possible asymmetric centers in other segments of the compounds of formula (I), the presence of these two asymmetric centers means that the compounds can exist as mixtures of diastereomers, such as the diastereomers of the compounds of formula (I) wherein the carbon at position 7 is configured either syn for the carbonyl or syn for the amide, as shown below.

C7 syn for carbonyl C7 syn for amide C7 syn for carbonyl C7 syn for amide One embodiment refers to compounds of formula (I) wherein the carbon at the 7-position is syn for the carbonyl. Another embodiment refers to compounds of formula (I) wherein the configuration at the carbon in the 4-position is R. A specific subgroup of compounds of formula (I) are those in which the carbon in the 7-position is configured syn for the carbonyl and wherein the configuration at the carbon in the 4-position is R. The compounds of formula (I) may also include a proline residue (when X is N) or a cyclopentyl or cyclopentenyl residue (when X is CH or C ). Preferred are compounds of formula (I) wherein the substituent at the position (or 5 ') and the substituent at the 3' position are in a trans configuration. Of particular interest are compounds of formula (I) wherein position 1 has the configuration corresponding to L-proline and the substituent at the 3 'position is found in a trans configuration with respect to position 1. Preferably, the compounds of formula (I) have the stereochemistry as indicated in the structures of formulas (1-a) and (1-b) below: (Ia) (lb) An embodiment of the present invention relates to compounds of formula (I) or formula (la) or any subgroup of compounds of formula (I), wherein one or more of the following conditions apply : (a) R2 is hydrogen; (b) X is nitrogen; (c) a double bond is present between carbon atoms 7 and 8. One embodiment of the present invention relates to compounds of formula (I) or formulas (la), (lb), or any subset of compounds of formula (I), where one or more of the following apply conditions: (a) R2 is hydrogen; (b) X is CH; (c) a double bond is present between carbon atoms 7 and 8. The special subgroups of compounds of formula (I) are those represented by the following structural formulas: (l-c) (l-d) Among the compounds of formula (1-c) and (1-d), those having the stereochemical configuration of the compounds of formulas (1-a) and (1-b), respectively, are of particular interest. The double bond between carbon atoms 7 and 8 in the compounds of formula (I), or in any subgroup of compounds of formula (I), can be found in a cis or a trans configuration.

Preferably, the double bond between the carbon atoms 7 and 8 is in a cis configuration, as described in the formulas (1-c) and (1-d). A double bond between the 1 'and 2' carbon atoms may be present in the compounds of formula (I), or in any subgroup of compounds of formula (I), as described in formula (I-e) below.

Still another particular subgroup of compounds of formula (I) are those represented by the following structural formulas: (l-f) d-g) (l-h) Among the compounds of formulas (1-f), (l-g) or (l-h), those having the stereochemical configuration of the compounds of formulas (1-a) and (1-b) are of particular interest.

In (la), (lb), (lc), (ld), (le), (1-f), (lg) and (lh), where applicable, X, n, R1, R2, R3, R4, R5 and R6 are as specified in the definitions of the compounds of formula (I) or in any of the subgroups of compounds of formula (I) as specified herein. It should be understood that the above defined subgroups of compounds of formulas (l-a) are intended to be, (lb), (lc), (ld), (le), (lf), (lg) or (lh), like any other subgroup defined herein, also encompass any? / - oxide, salts of addition, quaternary amines, metal complexes and stereochemical isomeric forms of such compounds. When n is 2, the -CH2- portion grouped by "n" corresponds to ethanediyl in the compounds of formula (I) or in any subgroup of compounds of formula (I). When n is 3, the -CH2- portion grouped by "n" corresponds to propanediyl in the compounds of formula (I) or in any subgroup of compounds of formula (I). When n is 4, the -CH2-group grouped by "n" corresponds to butanediyl in the compounds of formula (I) or in any subgroup of compounds of formula (I). When n is 5, the -CH2- portion grouped by "n" corresponds to pentanediyl in the compounds of formula (I) or in any subgroup of compounds of formula (I). When n is 6, the -CH2- portion grouped by "n" corresponds to hexanediyl in the compounds of formula (I) or in any subgroup of compounds of formula (I). Particular subgroups of the compounds of formula (I) are those compounds where n is 4 or 5.

The embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I), in which R1 is -OR7, in particular where R7 is C? -6 alkyl, such as methyl, ethyl , or tert-butyl (or t.butyl) and more preferably wherein R7 is hydrogen; R1 is -NHS (= O) 2R8, particularly where R8 is C1-6 alkyl, C3-C7 cycloalkyl, or aryl, for example where R8 is methyl, cyclopropyl, or phenyl; or R1 is -NHS (= O) 2R8, particularly where R8 is C3 cycloalkyl. 7 substituted with C1-6alkyl, preferably wherein R8 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, any of which is substituted by C- [alpha] alkyl, ie by methyl, ethyl, propyl, isopropyl, butyl, ter -butyl, or isobutyl. In addition, the embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein R1 is -NHS (= O) 2R8, particularly where R8 is cyclopropyl substituted by C1- alkyl 4, ie by methyl, ethyl, propyl, or isopropyl. In addition, the embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein R 1 is -NHS (= 0) 2 R 8, particularly where R 8 is 1-methylcyclopropyl. In addition, the embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein (a) R2 is hydrogen; (b) R2 is C-? 6 alkyl, preferably methyl. The embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein (a) X is N, C (X being bound by a double bond) or CH (X being bound by a simple bond) and R2 is hydrogen; (b) X is C (X being linked by a double bond) and R2 is C-? 6 alkyl, preferably methyl. Other embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein (a) R3 is hydrogen; (b) R3 is C1-6 alkyl; (c) R3 is C6-6alkyl-C6-6alkyl or C3-7cycloalkyl. Preferred embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein R3 is hydrogen, or C-? 6 alkyl, more preferably hydrogen or methyl. The embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein R 4 is aryl or Het, each independently, optionally substituted with any of the substituents of Het or aryl mentioned in definitions of the compounds of formula (I) or of any of the subgroups of compounds of formula (I); or specifically, said ary or Het being each one independently substituted optionally with C 1-6 alkyl, halogen, amino, mono- or dialkylamino of C? .6, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 4-C 1-6 alkyl-piperazinyl; and wherein the morpholinyl and piperidinyl groups can be optionally substituted by one or two C-? --6 alkyl radicals. The embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein R 4 is a radical or, in particular, where R4 is selected from the group consisting of: (q-1) (q-2) (q-3) (-4) wherein, when possible a nitrogen may have a R4a substituent or a linkage to the rest of the molecule; each R a in any of the substituents R 4 can be selected from those mentioned as possible substituents on Het, as specified in the definitions of the compounds of formula (I) or of any of the subgroups of compounds of formula (I); more specifically each R4a can be hydrogen, halogen, C-? -6 alkyl, amino, or mono- or di-alkylamino of C? -6, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 4-alkyl C-? 6- piperazinyl; and wherein the morpholinyl and piperidinyl groups can be optionally substituted by one or two Cis alkyl radicals more specifically each R4a is, each independently, hydrogen, halogen, C-? 6 alkyl, amino, or mono- or di- C1-6 alkylamino; and wherein R 4a is substituted on a nitrogen atom, preferably it is a carbon containing the substituent which is connected to the nitrogen by a carbon atom or one of its carbon atoms; and wherein in this instance R4a is preferably alkyl of C-i-6. The embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein R 4 is phenyl or pyridyl (in particular 4-pyridyl) which can each be substituted by 1, 2 or 3 substituents selected from those mentioned for aryl in the definitions of the compounds of formula (I) or any of their subgroups. In particular, said phenyl or pyridyl is substituted by 1-3 (or by 1-2, or by one) substituent or substituents selected from halogen, C? -6 alkyl or C? -6 alkoxy. The embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein R5 is halogen, or C-? -6 alkyl, preferably methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, or bromo. They include polyhalogen-C1-6alkyl. The embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein R6 is C6.6 alkoxy or C6.6 alkylamino; preferably R6 is methoxy or dimethylamino; more preferably R6 is methoxy. The compounds of formula (I) consist of three building blocks P1, P2, P3. The building block P1 also contains a tail P1 '. The carbonyl group marked with an asterisk in the compound (I-c) below can be part of either the building block P2 or the building block P3. Due to chemical reasons, the building block P2 of the compounds of formula (I) wherein X is C incorporates the carbonyl group attached to the 1 'position. The joining of the building blocks P1 with P2, P2 with P3 and P1 with P1 '(when R1 is -NH-S02R8 or -OR7) comprises forming an amide bond. The union of the blocks P1 and P3 comprises the formation of the double bond. The joining of the building blocks P1, P2 and P3 to prepare the compounds (l-i) or (l-j) can be carried out in any given sequence. One of the steps involves the cyclization by which the macrocycle is formed. The compounds (I-i) which are compounds of the formula (I) in which the carbon atoms C7 and C8 are linked by a double bond and the compounds (l-j) which are compounds of formula (I) wherein C7 and C8 carbon atoms are linked by a single bond. The compounds of formula (1-j) can be prepared from the corresponding compounds of formula (I-I) by reducing the double bond in the macrocycle.

It should be noted that in compounds of formula (I-c), the formation of the amide bond between blocks P2 and P3 can be achieved in two different positions of the urea fragment. A first amide bond comprises the nitrogen of the pyrrolidine ring and the adjacent carbonyl (marked with an asterisk). A second alternative amide bond formation comprises the reaction of a carbonyl marked with an asterisk with a -NHR3 group. The two amide bond formations between the building blocks P2 and P3 are feasible. The synthesis procedures described below in the present are also intended to be applicable to racemates, stereochemically pure intermediates or final products, or any stereochemical mixture. The racemates or stereochemical mixtures can be separated into stereoisomeric forms at any stage of the synthesis procedures. In one embodiment, the intermediates and final products have the stereochemistry that was specified above in the compounds of formula (1-a) and (1-b). To simplify the structural representation of the compounds of formula (I) or the intermediates, the group it is represented by R9 and the dashed line represents the bond joining said group represented by R9 for the portion of the molecule. In one embodiment, the compounds (I-i) are first prepared by forming the amide bonds and subsequently form the binding of the double bond between P3 and P1 with the cyclization concomitant with the macrocycle. In a preferred embodiment, the compounds (I) in which the bond between C7 and C8 is a double bond, which are compounds of formula (li), as defined above, can be prepared as indicated in the following reaction scheme : The formation of the macrocycle can be carried out by an olefin metathesis reaction in the presence of a suitable metal catalyst, such as for example the Ru-based catalyst reported by Miller, S.J., Blackwell, H.E., Grubbs, R.H. J. Am. Chem. Soc. 118, (1996), 9606-9614; Kinsbury, J. S., Harrity, J.P.A., Bonitatebus, P.J., Hoveyda, A.H., J. Am. Chem. Soc. 121, (1999), 791-799; and Huang et al., J. Am. Chem. Soc. 121, (1999), 2674-2678; for example a Hoveyda-Grubbs catalyst. Air-stable ruthenium catalysts such as bis (tricyclohexylphosphine) -3-phenyl-1 H -inden-1-ylidene ruthenium chloride (Neolyst M1®) or bis (tricyclohexylphosphine) - [(phenylthio ) methylene] ruthenium (IV). Other catalysts that can be used are the first and second generation Grubbs catalysts, ie, benzylidene-bis (tricyclohexylphosphine) dichlororuthenium and (1,3-bis- (2,4,6-trimethylphenyl) -2-imidazolidinylidene ) dichloro (phenylmethylene) - (tricyclohexylphosphine) ruthenium, respectively. Of particular interest are the first and second generation catalysts from Hoveyda-Grubbs, which are dichloro (o- isopropoxyphenylmethylene) (tricyclohexylphosphine) -ruthium (II) and 1,3-bis- (2,4,6-trimethylphenyl) -2-imidazolidinylidene) dichloro (o-iopropoxyphenylmethylene) ruthenium respectively. Likewise, other catalysts containing other transition metals, such as Mo, can be used for this reaction. The metathesis reactions can be carried out in a suitable solvent such as, for example, ethers, for example THF, dioxane; halogenated hydrocarbons, for example dichloromethane, CHCl3, 1,2-dichloroethane and the like, hydrocarbons, for example toluene. In a preferred embodiment, the metathesis reaction is carried out in toluene. These reactions are carried out at increased temperatures under a nitrogen atmosphere. The compounds of formula (I) wherein the bond between C7 and C8 in the macrocycle is a single bond, ie compounds of formula (Ij), can be prepared from the compounds of formula (Ii) by reducing the double C7-C8 bond in the compounds of formula (l-¡). this reduction can be carried out by catalytic hydrogenation with hydrogen in the presence of a noble metal catalyst, such as, for example, Pt, Pd, Rh, Ru or Raney nickel. It is of Rh interest in alumina. The hydrogenation reaction is preferably carried out in a solvent, such as, for example, an alcohol such as methanol, ethanol, or an ether such as THF, or mixtures thereof. Water can also be added to these solvents and solvent mixtures. The group R1 can be connected to the block of P1 construction at any stage of the synthesis, that is, before or after the cyclization or before or after the cyclization and reduction, as described hereinabove. The compounds of formula (I), in which R represents -NHSO2R8, said compounds being represented by the formula (l-k-1), can be prepared by linking the group R1 to P1 by forming an amide bond between the two moieties. Similarly, the compounds of formula (I), in which R1 represents -OR7, ie the compounds (l-k-2), can be prepared by linking the group R1 to P1 by the formation of an ester linkage. In one embodiment, the -OR5 groups are introduced in the last step of the synthesis of the compounds the compounds (I) as indicated in the following reaction schemes in which G represents a group: O G-COOH + H2N-S02R8 HN- -S02Re (2a) (2b) (l-k-1) (| -k-2) The intermediate (2a) can be coupled to the amine (2b) by an amine-forming reaction such as any of the methods for the formation of an amide bond described hereinafter. In particular, (2a) can be treated with the coupling agent, for example? /,? / '- carbonyldiimidazole (CDI), EEDQ, IIDQ, EDCI or benzotriazol-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (available commercially as PyBOP®), in a solvent such as ether, for example THF, or a halogenated hydrocarbon, for example dichloromethane, chloroform, dichloroethane and can be reacted with the desired sulfonamide (2b), preferably after the reaction (2a) with the coupling agent . The reactions of (2a) with (2b) are preferably carried out in the presence of the base, for example to tricalkylamine such as triethylamine or diisopropylethylamine, or 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU). The Intermediary (2a) can also be transformed into an active form, for example an active form of the general formula G-CO-Z, wherein Z represents halogen, or the remaining part of an active ester, for example Z is a group aryloxy such as phenoxy, p.nitrophenoxy, pentafluorophenoxy, trichlorophenoxy, pentachlorophenoxy and the like; or Z may be the portion of a combined anhydride. In one embodiment, G-CO-Z is an acid chloride (G-CO-CI) or a mixed acid anhydride (G-CO-O-CO-R or G-CO-O-CO-OR, R in the latter being, for example, C 1-4 alkyl, such as methyl, ethyl, propyl, i-propyl, butyl, t-butyl, i-butyl or benzyl). The active form G-CO-Z is reacted with the sulfonamide (2b).

The activation of the carboxylic acid in (2a) as described in the above reactions can lead to an internal cyclization reaction to an intermediate azalactone of formula where X, R2, R3, R9, n are as specified above and wherein the stereogenic centers may have the stereochemical configuration as specified above, for example as in (l-a) or (l-b). The intermediates (2a-1) can be isolated from the reaction mixture, using the conventional methodology and the isolated intermediate (2a-1) is then reacted with (2b), or the reaction mixture containing (2a-1) it can be further reacted with (2b) without the isolation of (2a-1). In one embodiment, where the reaction with the coupling agent is carried out in a water-immiscible solvent, the reaction mixture containing (2a-1) can be washed with water or with slightly basic water to remove all the products secondary soluble in water. The washed solution obtained in this way can then be reacted with (2b), without additional purification steps. The isolation of intermediates (2a-1), on the other hand, can provide certain advantages in that the isolated product, after optional additional purification, it can be reacted with (2b), resulting in fewer side products and easier processing of the reaction. The intermediate (2a) can be coupled with the alcohol (2c) by an ester formation reaction. For example, (2a) and (2c) are reacted together with the removal of water, either physically, for example, by azeotropic removal of water, or chemically, by the use of a dehydrating agent. The intermediate (2a) can also be converted into an active form of G-CO-Z, such as the active forms mentioned above and which are subsequently reacted with the alcohol (2c). The ester formation reactions, preferably, are carried out in the presence of a base such as an alkali metal carbonate or hydrogen carbonate, for example sodium or potassium hydrogen carbonate, or a tertiary amine, such as the amines mentioned herein in relation to the amide formation reactions, in particular, a trialkylamine, for example triethylamine. Solvents that can be used in the ester forming reactions comprise ethers such as THF; halogenated hydrocarbons, such as dichloromethane, CH 2 Cl 2; hydrocarbons such as toluene; polar aprotic solvents such as DMF, DMSO, DMA; and similar solvents. The compounds of formula (I) wherein R3 is hydrogen, said compounds being represented by (I-I), can also be prepared by removing a PG protecting group from a corresponding intermediate protected by nitrogen (3a), as in the following reaction scheme. The PG protecting group in particular is any of the nitrogen protecting groups mentioned hereinafter and can be removed using methods that are also mentioned hereinafter: (3a) (I-I) The starting materials (3a) in the above reaction can be prepared following the procedures for the preparation of compounds of formula (I), but using intermediates where the group R3 is PG. The compounds of formula (I) can also be prepared by reacting an intermediate (4a) with the intermediate (4b) as indicated in the following reaction scheme where the various radicals have the meanings specified above: (4a) And in (4b) represents hydroxy or a leaving group LG such as halide, for example bromide or chloride, or an arylsulfonyl group, for example mesylate, triflate or tosylate and the like. In one embodiment, the reaction of (4a) with (4b) is an O-arylation reaction and Y represents a leaving group. This reaction can be carried out following the procedures described by E. M. Smith et al. (J. Med. Chem. (1988), 31, 875-885). In particular, this reaction is carried out in the presence of a base, preferably a strong base, in an inert solvent of the reaction, for example one of the solvents mentioned for the formation of an amide bond. In a particular embodiment, the starting material (4a) is reacted with (4b) in the presence of a base that is strong enough to reduce a hydroxygen of the hydroxy group, for example, an alkali metal hydride alkali such as LH or sodium hydride, or alkali metal alkoxide, such as sodium or potassium methoxide or ethoxide, potassium tert-butoxide, in an inert solvent of the reaction as a dipolar aprotic solvent, for example DMA, DMF and the like. The resulting alcoholate is reacted with an arylating agent (4b), wherein Y is a suitable leaving group, mentioned above. The conversion of (4a) to (I) using this type of O-arylation reaction does not change the stereochemical configuration in the carbon having the hydroxy group. Alternatively, the reaction of (4a) with (4b) can also be carried out by a Mitsunobu reaction (Mitsunobu, 1981, Synthesis, January, 1-28; Rano et al., Tetrahedron Lett., 1995, 36, 22, 3779-3792; Krchnak et al., Tetrahedron Lett., 1995, 36, 5, 6193-6196; Richter et al., Tetrahedron Lett., 1994, 35, 27, 4705-4706). This reaction comprises the treatment of intermediate (4a) with (4b) wherein Y is hydroxyl, in the presence of triphenylphosphine and an activating agent such as a dialkyl azocarboxylate, for example, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD) or similar. The Mitsunobu reaction changes the stereochemical configuration in the carbon that the hydroxy group has. Alternatively, to prepare the compounds of formula (I), an amide bond is first formed between the building blocks P2 and P1, followed by the coupling of the building block P3 to the residue P1 at P1-P2 and the subsequent formation of the carbamate or ester link between P3 and the portion P2 in P2-P1-P3 with simultaneous ring closure. Yet another alternative synthetic methodology is the formation of an amide bond between the building blocks P2 and P3, followed by the coupling of the building block P1 to the P3 moiety in P3-P2 and a final amide bond formation between P1 and P2 in P1-P3-P2 with simultaneous ring closure. The building blocks P1 and P3 can be joined to a sequence P1-P3. If desired, the binding of the double bond P1 and P3 can be reduced. The sequence P1-P3 formed in this manner, whether reduced or not, can be coupled to the building block P2 and thus form the sequence P1-P3-P2, subsequently cyclized, by the formation of an amide bond. The building blocks P1 and P3 in any of the above approaches can be joined by the formation of double bonds, for example, by the olefin metathesis reaction which is described hereinafter or a Wittig type reaction. If desired, the double bond formed in this way can be reduced, in a manner similar to that described above for the conversion of (I-i) to (l-j). The double bond can also be reduced at a later stage, ie after the addition of a third building block or after the formation of the macrocycle. The building blocks P2 and P1 are joined by the formation of amide bond and P3 and P2 are linked by the formation of carbamate or ester. The tail P1 'can be found bound by binding to the building block P1 at any stage of the synthesis of the compounds of formula (I), for example before or after the coupling of the building blocks P2 and P1; before or after the coupling of the building block P3 to P1; or before or after the ring closes. The individual building blocks can be prepared first and subsequently coupled together or in an alternative way, the precursors of the building blocks can be coupled together and modified in a step subsequent to the desired molecular composition. The functional groups in each of the blocks of Construction can be protected to avoid side reactions. The formation of amide linkages can be carried out using standard procedures, such as those used for linkage coupling in peptide synthesis. The latter comprises the dehydrating coupling of a carboxyl group of one reactant with an amino group of the other reagent to form a binding amide bond. The formation of the amide bond can be carried out by reacting the starting materials in the presence of a coupling agent by converting the carboxyl functional group to an active form, such as an active ester, combined anhydride or a carboxyl chloride or bromide . General descriptions of such coupling reactions and the reagents used therein can be found in general textbooks on peptide chemistry, for example, M. Bodanszky, "Peptide Chemistry", 2nd rev. ed., Springer-Verlag, Berlin, Germany, (1993). Examples of coupling reactions with amide bond formation include the azide method, the mixed anhydride method of carbonic acid carboxylic acid (isobutyl chloroformate), the carbodiimide method (dicyclohexylcarbodiimide, diisopropylcarbodiimide or a water soluble carbodiimide) such as? / - ethyl -? / '- [(3-dimethylamino) propyl] carbodiimide), the active ester method (for example esters of p-nitrophenyl, p-chlorophenyl, trichlorophenyl, pentachlorophenyl, pentafluorophenyl,? / - hydroxysuccinic Mido and similar), the K method of the Woodward reagent, the 1-carbonyldiimidazole method (CDI or N, N'- carbonyldiimidazole), the methods of phosphorous reagents or oxidation-reduction. Some of these methods can be refined by adding suitable catalysts, for example in the carbodiimide method by the addition of 1-hydroxybenzotriazole, DBU (1,8-diazabicyclo [5.4.0] undec-7-ene), or 4- DMAP. Other coupling agents are (benzotriazol-1-yloxy) tris- (dimethylamino) phosphonium hexafluorophosphate, either by itself or in the presence of 1-hydroxybenzotriazole or 4-DMAP; or 2- (IH-benzotriazol-1-yl) -? /,? /,? / ',? / - tetra-methyluronium tetrafluoroborate, or O- (7-azabenzotriazol-1-yl) -? / hexafluorophosphate, ? /,? / ';? /' - tetramethyluronium. These coupling reactions can be carried out in any solution (liquid phase) or solid phase. A preferred amide bond formation is carried out using N-ethyloxycarbonyl-2-ethyloxy-1,2-dihydroquinoline (EEDQ) or N-isobutyloxycarbonyl-2-isobutyloxy-1,2-dihydroquinoline (IIDQ). Unlike the classical anhydride procedure, EEDQ and IIDQ do not require base or low reaction temperatures. Typically, the process comprises reacting equimolar amounts of the carboxyl and amine components in an organic solvent (a wide variety of solvents can be used). Then, EEDQ or IIDQ is added in excess and the mixture is allowed to stir at room temperature. The coupling reactions are preferably carried out in an inert solvent, such as halogenated hydrocarbons, for example dichloromethane, chloroform, dipolar aprotic solvents such as acetonitrile, dimethylformamide, dimethylacetamide, DMSO, HMPT, ethers such as tetrahydrofuran (THF). In many instances, the coupling reactions are carried out in the presence of a suitable base such as a tertiary amine, for example triethylamine, diisopropylethylamine (DIPEA),? / - methyl-morpholino, N-methylpyrrolidine, 4-DMAP or 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU). The reaction temperature can range from 0 ° C to 50 ° C and the reaction time can vary between 15 min and 24 hr. The functional groups in the building blocks that are attached can be unprotected to avoid the formation of unwanted bonds. Suitable protecting groups that can be used are listed for example in Greene, "Protective Groups in Organic Chemistry," John Wiley & Sons, New York (1999) and "The Peptides: Analysis, Synthesis, Biology", Vol. 3, Academic Press, New York (1987). The carboxyl groups can be protected as an ester that can be cleaved to carboxylic acid. Protecting groups that may be used include 1) alkyl esters such as methyl, trimethylsilyl and tertbutyl; 2) arylalkyl esters such as benzyl and substituted benzyl; or 3) esters that can be cleaved by a moderate base or mild reducing media, such as trichloroethyl and phenacyl esters. Amino groups can be protected by a variety of protecting groups, such as: 1) acyl groups, such as formyl, trifluoroacetyl, phthalyl and p- toluenesulfonyl; 2) aromatic carbamate groups, such as benzyloxycarbonyl (Cbz or Z) and substituted benzyloxycarbonyls and 9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate groups such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl and allyloxycarbonyl; 4) cyclic alkyl carbamate groups, such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) alkyl groups, such as triphenylmethyl, benzyl or substituted benzyl such as 4-methoxybenzyl; 6) trialkylsilyl, such as trimethylsilyl or t.Bu dimethylsilyl; and 7) thiol-containing groups, such as phenyltiocarbonyl and dithiacuccinoyl. The amino protecting groups of interest are Boc and Fmoc. Preferably, the protective amino group is cleaved before the next coupling step. The removal of the N-protecting groups can be carried out following procedures known in the art. When a Boc group is used, the methods of choice are trifluoroacetic acid, pure or in dichloromethane, or HCl in dioxane or in ethyl acetate. The resulting ammonium salt is then neutralized, either before coupling or in situ with basic solutions such as aqueous pH regulators, or tertiary amines in dichloromethane or acetonitrile or dimethylformamide. When the Fmoc group is used, the reagents of choice are piperidine or piperidine substituted in dimethylformamide, but can be used any secondary amine The deprotection is carried out at a temperature between 0 ° C and room temperature, commonly around 15-25 ° C or 20-22 ° C. Other functional groups that can interfere in the coupling reactions of the building blocks can also be protected. For example, the hydroxyl groups can be protected as benzyl or substituted benzyl ethers, for example 4-methoxybenzyl ether, benzoyl or substituted benzoyl esters, for example 4-nitrobenzoyl ester, or with trialkylsilyl groups (for example trimethylsilyl or ter- butyldimethylsilyl). Other amino groups can be protected by means of protective groups that can be selectively cleaved. For example, when Boc is used as the a-amino protecting group, the following side chain protecting groups are suitable: p-toluenesulfonyl (tosyl) moieties can be used to protect other amino groups; benzylic ethers (Bn) can be used to protect hydroxy groups; and benzylic ethers can be used to protect other carboxyl groups. Or when Fmoc is chosen for a-amino protection, tertiary butyl protecting groups are generally acceptable. For example, Boc can be used for other amino groups; tert-butyl esters for hydroxyl groups; and tert-butyl esters for other carboxyl groups. Any of the protecting groups can be removed at any stage of the synthesis process, but preferably, the protecting groups of any of the functional groups involved in the reaction steps are eliminated after completing the preparation of the macrocycle. The removal of the protecting groups can be carried out in any way determined by the choice of protecting groups, whose manners are known to those persons skilled in the art. The intermediates of the formula (1a) wherein X is N, said intermediates being represented by the formula (1a-1), can be prepared from the intermediates (5a) which are reacted with an alkene amine (5b) in the presence of a carbonyl introducing agent as indicated in the following reaction scheme. (5a) (1a-1) Carbonyl (CO) introduction agents include phosgene or phosgene derivatives, such as carbonyl diimidazole (CDI) and the like. In one embodiment (5a), it is reacted with the CO introduction agent in the presence of a suitable base and a solvent, which may be the bases and solvents used in the amide formation reactions, as described above. In a particular modality, the base is a bicarbonate, for example NaHCO3, or a tertiary amine, such as triethylamine and the like, and the solvent is an ether or halogenated hydrocarbon, for example THF, CH2Cl2, CHCl3 and the like. Then, the amine (5b) is added obtaining in that way intermediaries (1 a-1) as in the previous scheme. A route alternative that uses similar reaction conditions comprises, first, reacting the CO introduction agent with the alkene amine (5b) and Then, react the intermediary formed in this way with (5a).

Intermediaries (1 a-1), alternatively, can be Prepare as follows: deprotection (1a-1) PG1 is a protecting group of O, which may be any of the groups mentioned herein and, in particular, is a benzoyl or substituted benzoyl group, such as 4-nitrobenzoyl. In this last instance, this group can be eliminated by reaction with an alkali metal hydroxide (LiOH, NaOH, KOH), in particular where PG1 is 4-nitrobenzoyl, with LiOH, in an aqueous medium comprising water and an organic solvent soluble in water, such as alkanol (methanol, ethanol) and THF. The intermediates (6a) are reacted with (5b) in the presence of a carbonyl introducing agent, similar as described above and this reaction produces the intermediates (6c). These are unprotected, in particular, using the reaction conditions mentioned above. The resulting alcohol (6d) is reacted with intermediates (4b), as described above for the reaction of (4a) with (4b) and this reaction produces the intermediates (1a-1). The intermediates of the formula (1a) wherein X is C, said intermediates being represented by the formula (1a-2), can be prepared by means of an amine formation reaction starting from the intermediates (7a) which are reacted with a amine (5b), as shown in the following reaction scheme, using the reaction conditions to prepare amides, such as those described above.

Intermediaries (1 a-1) can be prepared alternatively, as follows: d PG1 is an O-protecting group, as described above. The same reaction conditions can be used, depending on described earlier; the amide formation, as described above, the removal of PG1 as in the description of the protecting groups and the introduction of R9, as in the reactions of (4a) with the reactants (4b). The intermediates of the formula (2a) can be prepared by first cyclizing the open amide (9a) to a macrocyclic ester (9b), which in turn is transformed into (2a), as follows: PG2 is a carboxyl protecting group, for example one of the carboxyl-protecting groups mentioned above, in particular a C- or benzyl-alkyl group, for example a methyl, ethyl or t-butyl ester. The reaction of (9a) to (9b) is a metathesis reaction and is carried out as described above. The group PG2 is removed following the procedures that were also described above. When PG1 is an alkyl ester of C-, it is removed by alkaline hydrolysis, for example with NaOH or preferably LiOH, in an aqueous solvent, for example a mixture of C- / alkanol / water. A benzyl group can be removed by catalytic hydrogenation.

In an alternative synthesis, the intermediates (2a) can be prepared in the following manner: (10c) The group PG1 is selected so that it can be excised from selectively with respect to PG2. PG2 can be for example, esters methyl or ethyl, which can be eliminated by treatment with a alkali metal hydroxide in an aqueous medium, in which case PG1, by example, it is t-butyl or benzyl. PG2 can be t-butyl esters that can be stir in weakly acidic conditions or PG1 can be benzyl esters which can be removed with strong acid or by catalytic hydrogenation, in the last two cases, PG1 for example is a benzoic ester such as a 4-nitrobenzoic ester. First, intermediaries (10a) are cycled to esters macrocyclic (10b), the latter are deprotected by removing the group PG1 a (10c), which are reacted with intermediaries (4b), followed by removal of the carboxyl protecting group PG2. Cyclization, deprotection of PG1 and PG2 and the coupling with (4b) are as described earlier.

Groups R1 groups can be introduced at any stage of the synthesis, either as the last step, as described above, or before, before the formation of the macrocíclo. In the next scheme, the R1 groups are introduced being -NH-SO2R8 or -OR7 (which are as specified above): In the previous scheme, PG2 is as defined above and L1 is a P3 group or? ^^ - R3 (b), where n and R3 are as defined above and where X is N, L can also be a nitrogen protecting group (PG, as defined above) and where X is C, L1 can also be a -COOPG2a group, wherein the PG2a group is a carboxyl-protective group similar to PG2, but where PG2a can be selectively cleaved with respect to PG2. In one embodiment, PG2a is t-butyl and PG2 is methyl or ethyl. The intermediaries (11c) and (11d) wherein L1 represents a group (b) correspond to the intermediates (1a) and can be further processed as specified above.

Coupling of the building blocks P1 and P2 The building blocks P1 and P2 are joined using an amide-forming reaction following the procedures described above. The building block P1 may have a carboxyl protecting group PG2 (as in (12b)) or it may already be attached to the group P1 '(as in (12c)). L2 is a protecting group N (PG), or a group (b), as specified above. L3 is hydroxy, -OPG1 or a group -O-R9 as specified above. When in any of the following reaction schemes, L3 is hydroxy, before each reaction step, it can be protected as a -OPG1 group and, if desired, then it can be deprotected again for a free hydroxy function. Similarly, as described above, the hydroxy function can be converted to a -O-R9 group.

In the procedure of the above scheme, a cyclopropyl amino acid (12b) or (12c) is coupled to the acid function of the building block P2 (12a) with the formation of an amide bond, following the procedures described above. Intermediates (12d) or (12e) were obtained. where in the latter, L2 is a group (b), the resulting products are sequences of P3-P2-P1 comprising some of the intermediates (11c) or (11 d) in the above reaction scheme. Removal of the acid protecting group at (12d), using the appropriate conditions for the protecting group used, followed by coupling with an amine H2N-SO2R8 (2b) or with HOR7 (2c), as described above, again gives the intermediates (12e), wherein -COR1 are amide or ester groups. When L2 is an N-protecting group, it can be removed by giving the intermediates (5a) or (6a). In one modality, PG in this reaction it is a BOC group and PG2 is methyl or ethyl. When, in addition, L3 is hydroxy, the starting material (12a) is Boc-L-hydroxyproline. In a particular embodiment, PG is BOC, PG2 is methyl or ethyl and L3 is -O-R9. In one embodiment, L2 is a group (b) and these reactions comprise the coupling of P1 to P2-P3, which produces the intermediates (1 a-1) or (1 a) mentioned above. In another embodiment, L2 is a protective group N PG, which is as specified above and the coupling reaction produces intermediates (12d-1) or (12e-1), from which the PG group can be eliminated, using the conditions of reaction mentioned above, obtaining the intermediates (12-f) or respectively (12g), which comprises the intermediates (5a) and (6a), as specified above: In one embodiment, the group L3 in the above schemes represents a group -O-PG1 which can be introduced into a starting material (12a) wherein L3 is hydroxy. In this instance, PG1 is selected so which can be selectively cleaved with respect to the group L2 which is PG. Similarly, the building blocks P2 where X is C, which are cyclopentane or cyclopentene derivatives, can be attached to the building blocks P1, as indicated in the following scheme where R1, R2, L3 are as previously specified and PG2 and PG2a are carboxyl protecting groups. PG2a is typically selected so that it can be cleaved selectively with respect to the PG2 group. The removal of the PG group a in (13c) gives the intermediates (7a) or (8a), which can be reacted with (5b), as described above.

In a particular embodiment, where X is C, R2 is H and where X and R2 having carbon are linked by a single bond (P2 being a cyclopentane residue), PG2a and L3 taken together form a link and the building block P2 is represented by the formula: The bicyclic acid (14a) is reacted with (12b) or (12c) similar, as described above for (14b) and (14c) respectively, wherein the lactone is opened giving the intermediates (14c) and (14e). The lactones can be opened using ester hydrolysis methods, for example using the reaction conditions described above for the alkaline removal of a PG1 group in (9b), in particular using basic conditions, such as an alkali metal hydroxide, for example, NaOH, KOH, in particular LiOH.

The intermediaries (14c) and (14e) can be further processed, as described hereinafter.

Coupling of building blocks P3 and P2 For building blocks P2 having a pyrrolidine moiety, building blocks P3 and P2 or P3 and P2-P1 are joined using a carbamate forming reaction following the procedures described previously for the coupling of (5a) with (5b). A general procedure for coupling the P2 blocks having a pyrrolidine residue is represented in the following reaction scheme where L3 is as specified above and L4 is a group -O-PG2, a group In one embodiment, L4 in (15a) is a group -OPG2, the group PG2 can be eliminated and the resulting acid coupled with the cyclopropyl amino acids (12a) or (12b), giving the intermediates (12d) or (12e) wherein L2 is a radical (d) or (e). A general procedure for the coupling of blocks P3 with a block P2 or with a block P2-P1 where P2 is a cyclopentane or Cyclopentene is shown in the following scheme. L3 and L4 are as specified above.

In a particular embodiment, L3 and L4 taken together can form a lactone bridge as in (14a) and the coupling of a block P3 with a block P2 is as follows: The bicyclic lactone (14a) is reacted with (5b) in an amide to amide formation reaction (16c) in which the lactone bridge is opened at (16d). The reaction conditions for the amide formation and lactone opening reactions are as described above or hereinafter. The intermediary (16d) in turn can be coupled to a group P1, as described above. The reactions in the above schemes are carried out using the same procedures as described above for the reactions of (5a), (7a) or (8a) with (5b) and, in particular, the above reactions where L4 is a group (d) or (e) correspond to the reactions of (5a), (7a) or (8a) with (5b), as described above. The building blocks P1, P1 ', P2 and P3 used in the preparation of the compounds of formula (I) can be prepared from intermediates known in the art. A number of such syntheses are described below in greater detail. The individual building blocks can be prepared first and then coupled together or alternatively, the precursors of the building blocks can be coupled together and modified at a later stage for the desired molecular composition. The functional groups in each of the building blocks can be protected to avoid side reactions.

Synthesis of the building blocks P2 The building blocks P2 contain any of a pyrrolidine residue, a cyclopentane or cyclopentene substituted by a -O-R4 group. The building blocks P2 containing a pyrrolidine moiety can be commercially available hydroxy proline derivatives. The preparation of the building blocks P2 containing a cyclopentane ring can be carried out as shown in the following scheme.

The bicyclic acid (17b) can be prepared, for example, from 3,4-bis (methoxycarbonyl) cyclopentanone (17a), as described by Rosenquist et al. in Acta Chem. Scand. 46 (1992) 1127-1129. A first step in this process comprises the reduction of a keto group with a reducing agent such as sodium borohydride in a solvent such as methanol, followed by the hydrolysis of the esters and finally the ring closure for the bicyclic lactone (17b) using lactone formation, in particular by the use of acetic anhydride in the presence of a weak base, such as pyridine. The carboxylic acid functional group at (17b) can then be protected by the introduction of a suitable carboxyl protecting group, such as a PG2 group, which is as specified above, thereby providing bicyclic ester (17c). The PG2 group in particular is unstable acid, such as a t group. butyl and is introduced for example by treatment with isobutene in the presence of a Lewis acid or with di-re-butyl dicarbonate in the presence of a base such as a tertiary amine, such as dimethylaminopyridine or triethylamine in a solvent such as dichloromethane. The lactone opening (17c) using the reaction conditions described above, in particular with lithium hydroxide, gives the acid (17d), which can also be used in coupling reactions with the building blocks P1. The free acid in (17d) can also be protected, preferably with an acid protecting group PG2a which can be selectively cleaved with respect to PG2 and the hydroxy function can be converted into a -OPG1 group or a -O-R9 group. The products obtained by removing the PG2 group are the intermediaries (17g) and (17i) that correspond to the intermediaries (13a) or (16a) specified above. Intermediates with specific stereochemistry can be prepared by resolving the intermediates in the above reaction sequence. For example, (17b) can be resolved following the be resolved following procedures known in the art, for example by the action of the salt form with an optically active base or by chiral chromatography and the resulting stereoisomers can also be processed as described previously. The OH and COOH groups in (17d) are in this cis position. The trans analogs can be prepared by reversing the stereochemistry at the carbon having the OH function by using specific reagents in the reactions introducing OPG1 or O-R9 which reverse the stereochemistry, such as, for example, by the application of a Mitsunobu reaction. In one embodiment, the intermediaries (17d) are coupled to the blocks P1 (12b) or (12c), whose coupling reactions correspond to the coupling of (13a) or (16a) with the same blocks P1, using the same conditions. The subsequent introduction of a substituent -O-R9, as described above, followed by the removal of the acid protecting group PG2 gives the intermediates (8a-1), which are a subclass of the intermediates (7a), or a part of the intermediaries (16a). The reaction products of the removal of PG2 can also be coupled to the building block P3. In a PG2 mode in (17d) it is t-butyl which can be removed under acidic conditions, for example with trifluoroacetic acid.

An unsaturated building block P2, ie a cyclopentene ring can be prepared as illustrated in the scheme below.

A 3,4-bromination elimination reaction bis (methoxycarbonyl) cyclopentanone (17a) as described by Dolby et al. in J. Org. Chem. 36 (1971) 1277-1285 followed by reduction of the keto functional group with a reducing agent such as sodium borohydride provides the cyclopentenol (19a). Selective ester hydrolysis using, for example, lithium hydroxide in a solvent such as a mixture of dioxane and water, yields cyclopentenol monoester substituted by hydroxy (19b). An unsaturated building block P2 where R2 can also be different from hydrogen, can be prepared as illustrated in the scheme below. (20g) (20h) (20i) Oxidation of commercially available 3-methyl-3-buten-1-ol (20a), in particular by means of an oxidation agent such as pyridinium chlorochromate, gives (20b), which becomes the corresponding methyl ester, for example, by treatment with acetyl chloride in methanol, followed by the bromination reaction with bromine to give the bromine a-bromo ester (20c). The latter can be condensed with the alkenyl ester (20e), obtained from (20d) by an ester formation reaction. The ester in (20e) is preferably a t-butyl ester which can be prepared from the corresponding commercially available acid (20d), for example, by treatment with di-re-butyl dicarbonate in the presence of a base such as dimethylaminopyridine. The intermediate (20e) is treated with a base, such as lithium diisopropylamide in a solvent such as tetrahydrofuran and reacted with (20c) to give the alkenyl ester (20f). Cyclization of (20f) by an olefin metathesis reaction, which is carried out as described above, provides cyclopentene derivative (20g). The stereoselective epoxidation of (20g) can be carried out using the Jacobsen asymmetric epoxylation method to obtain the epoxide (20h). Finally, an epoxide opening reaction under basic conditions, for example, by the addition of a base, in particular DBN (1.5-diazabicyclo- [4,3,0] non-5-ene), gives the alcohol (20). ). Optionally, the double bond in the intermediate (20i) can be reduced, for example by catalytic hydrogenation using a catalyst such as palladium on carbon, giving the corresponding cyclopentane compound. The t-butyl ester can be removed to the corresponding acid, which is subsequently coupled to a building block P1. The -R9 group can be introduced into the pyrrolidine, cyclopentane or cyclopentene rings at any convenient stage of the synthesis of the compounds according to the present invention. One approach is first introduce the group -R9 to the mentioned rings and then add the other desired building blocks, ie P1 (optionally with the tail P1 ') and P3, followed by the formation of the macrocyclic. Another approach is to couple the building blocks P2, which has no substituent -O-R9, with each P1 and P3 and to add the group -R9 either before or after the formation of the macrocycle. In this last procedure, the P2 residues have a hydroxy group, which can be protected by a PG1 protecting group. The R9 groups can be introduced into the building blocks P2 by reacting the intermediates substituted by hydroxy (21a) or (21b) with the similar intermediates (4b), as described above for the synthesis of (1) from of (4a). These reactions are represented in the following schemes, wherein L2 is as previously specified and L5 and L5a independently of each other, represent hydroxy, a carboxyl protecting group -OPG2 or -OPG2a, or L5 may also represent a group P1 such as a group (d) or (e), as specified above, or L5a may also represent a group P3 such as a group (b) as specified above. The PG2 and PG2a groups are as specified above. When groups L5 and L5a are PG2 or PG2a, they are selected so that each group can be selectively cleaved with respect to the other. For example, one of L5 and L5a can be a methyl or ethyl group and the other a benzyl or t-butyl group. In a mode in (21a), L2 is PG and L5 is -OPG2 or in (21d), L 5a is -OPG ^. and,, L5 is -OPG and the PG groups are removed as described above. (21 b-1) (21c) Alternatively, when cyclopentane analogues substituted by hydroxy are manipulated, the quinoline substituent may be introduced by a similar Mitsunobu reaction by reacting the hydroxy group of a compound (2a ') with the desired alcohol (3b) in the presence of triphenylphosphine and of an activating agent such as diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD) or similar. In another embodiment, the group L2 is BOC, L5 is hydroxy and the starting material (21 a) is commercially available BOC-hydroxyproline, or any other stereoisomeric form thereof, for example BOC-L-hydroxyproline, in particular, the trans isomer of the latter. When L5 in (21 b) is a carboxyl protecting group, it can be removed by following the procedures described above for (21c). In yet another embodiment, PG in (21 b-1) is Boc and PG 2 is a lower alkyl ester, in particular a methyl or ethyl ester. The hydrolysis of this latter ester to the acid can be carried out by standard procedures, for example, acid hydrolysis with hydrochloric acid in methanol or with an alkali metal hydroxide such as NaOH, in particular with LiOH. In another embodiment, the cyclopentane or cyclopentene analogs substituted by hydroxy (21d) are converted to (21e), which, when L5 and L5a are -OPG2 or -OPG2a, can be converted into the corresponding acids (21f) by removing the PG2 group. the removal of PG2a in (21e-1) leads to similar intermediates. The intermediates Y-R9 (4b) can be prepared following methods known in the art using known starting materials. A number of synthesis routes for such intermediaries will be described in more detail below. For example, the preparation of the quinolines of intermediary mentioned above, is shown below in the following scheme.

Friedel-Craft acylation of a suitable substituted aniline (22a), available either commercially or by methods known in the art, using an acylating agent such as acetyl chloride or the like in the presence of one or more Lewis acids, such as boron trichloride and aluminum trichloride in a solvent as dichloromethane provides (22b). The coupling of (22b) with a carboxylic acid (22c), preferably 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 basic conditions such as potassium fer-butoxide in tert-butanol gives quinoline derivative (22e). The latter can be converted to (22f) where LG is a leaving group, for example by reacting (22e) with a halogenating agent, for example phosphoryl chloride or the like, or with an arylsulfonyl chloride, for example with tosyl chloride. The quinoline derivative (22e) it can be coupled in a Mytosunobu reaction to an alcohol, as described above, or the quinoline (22f) can be reacted co (1a) in an O-arylation reaction, as described above. A variety of carboxylic acids with the general structure (22c) can be used in the above synthesis. These acids are available, either commercially or can be prepared by methods known in the art. An example of the preparation derived from 2- (substituted) aminocarboxiaminothiazole (23a-1) is shown, following the procedure described by Berdikhina et al. in Chem. Heterocycl. Compd. (Engl Transí.) (1991), 427-433, in the following reaction scheme illustrating the preparation of 2-carboxy-4-isopropyl-thiazole (22c-1): Ethyl thiooxamate (23a) is reacted with the β-bromoketone (23b) to form the thiazolyl ester of the carboxylic acid (23c), which is hydrolyzed to the corresponding acid (25c-1). The ethyl ester in these intermediates can be replaced by the carboxyl protecting groups PG2, as defined above. In the above scheme, R4a is as defined above and in particular is C- alkyl, more in particular, i-propyl. The bromoketone (23b) can be prepared from 3-methyl- butan-2-one (MIK) with a silylating agent (such as TMSCI) in the presence of a suitable base (in particular LiHMDS) and bromine. The synthesis of other carboxylic acids (22c), in particular, of amino substituted thiazole carboxylic acids (25a-2) is illustrated in the following: Thiourea (24c) with several substituents R 4a, which, in particular, are C 1-6 alkyl, can be formed by reaction of the appropriate amine (24a) with fer-butyl isothiocyanate in the presence of a base such as diisopropylethylamine in a solvent as dichloromethane followed by the removal of the tert-butyl group under acidic conditions. The subsequent condensation of the thiourea derivative (24c) with 3-bromopyruvic acid provides the thiazole carboxylic acid (22c-2).

Synthesis of the P1 building blocks The cyclopropanamino acid used in the preparation of the P1 fragment is commercially available or can be prepared using procedures known in the art. In particular, the amino-vinyl-cyclopropylethyl ester (12b) can be obtained in accordance with the process described in WO00 / 09543 or as illustrated in the following scheme, wherein PG is a carboxyl protecting group as specified above: (12b-1) (12b) The imine treatment (25a) commercially available or easily obtainable with 1,4-dihalogenobutene in the presence of a base produces (25b), which after hydrolysis gives cyclopropyl amino acid (12b), which has the alyl substituent syn for the carboxyl group. The resolution of the enantiomeric mixture (12b) produces (12b-1). The resolution is carried out using procedures known in the art such as enzymatic separation; crystallization with a chiral acid; or chemical derivation; or by chiral column chromatography. Intermediates (12b) or (12b-1) may be coupled to the appropriate P2 derivatives as described above. The building blocks P1 for the preparation of compounds according to the general formula (I) wherein R1 is -OR7 or -NH-S02R8 can be prepared by reacting the amino acids (23a) with the appropriate alcohol or amine, respectively, in standard conditions for the formation of ester or amide. The cyclopropyl amino acids (23a) are prepared by introducing a protecting group N PG and removing PG2 and the amino acids (a) are converted into the amides (12c-1) or esters (12c-2), which are subgroups of the intermediates (12c) , as indicated in the following reaction scheme, where PG is as specified above.

The reaction of (26a) with amine (2b) is an amine-forming process. The similar reaction with (2c) is an ester formation reaction. Both can be carried out following the procedures described above. This reaction gives the intermediates (26b) or (26c) from which the protective amino group is removed by standard methods such as those described above. This, in turn, produces the desired intermediary (12c-1). The starting materials (26a) can be prepared from the aforementioned intermediates (12b) by first introducing a protecting group N PG and subsequently, removing the PG2 group. In one embodiment, the reaction of (26a) with (2b) is carried out by treating the amino acid with the coupling agent, for example N, N'-carbonyl-diimidazole (CDI) or the like, in a solvent such as THF, followed by the reaction with (2b) in the presence of a base such as , 8-diazabicyclo [5.4.0] undec-7-ene (DBU). Alternatively, the amino acid can be treated with (2b) in the presence of a base such as diisopropylethylamine, followed by treatment with a coupling agent, such as benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (available on the market as PyBOP®) to effect the introduction of the sulfonamide group. The Intermediates (12c-1) or (12c-2) in turn, can be coupled to the appropriate proline, cyclopentane or cyclopentene derivatives as described above.

Synthesis of the building blocks P3 The building blocks P3 are available on the market or can be prepared in accordance with known methodologies for those with experience in the art. One of these methodologies is shown in the scheme that follows and uses monoacylated amines, such as trifluoroacetamide or a Boc-protected amine.

In the above scheme, R together with the group CO forms a protecting group N, in particular R is / -butoxy, trifluoromethyl; R3 and n are as previously defined and LG is a leaving group, in particular halogen, eg. chlorine or bromine. The monoacylated amines (27a) are treated with a strong base such as sodium hydride and subsequently reacted with a C5-8 LG-alkenyl reagent (27b), in particular C5-8 haloalkenyl, to form the corresponding protected amines (27c). ). The deprotection of (27c) produces (5b), which are building blocks P3. The deprotection will depend on the functional group R, so if R is f-butoxy, the deprotection of the corresponding amine protected with Boc can be achieved with treatment with an acid, e.g. trifluoroacetic acid. Alternatively, when R is for example trifluoromethyl, the elimination of the R group is achieved with a base, e.g. sodium hydroxide. The following scheme illustrates even another method for preparing a building block P3, ie a Gabriel synthesis of primary C5-B alkenylamines, which can be carried out by treating a phthalimide (28a) with a base, such as NaOH or KOH, and with (27b), which is as previously specified, followed by hydrolysis of the intermediate N-alkenylimide to generate a primary C5.8 alkenylamine (5b-1).

In the previous scheme, n is as previously defined. The compounds of formula (I) can be converted to one another following reactions of transformation of functional groups known in the art. For example, the amino groups can be N-alkylated, the nitro groups can be reduced to amino groups, a halogen atom can be changed to another halogen atom. The compounds of formula (I) can be converted to the corresponding? / -oxide form following art-known procedures for converting a trivalent nitrogen into its? / -oxide form. Said? / -oxidation reaction can be carried out in general by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide. Suitable inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal peroxides or alkaline earth metals, e.g. sodium peroxide, potassium peroxide; suitable organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or benzenecarboperoxoic acid substituted with halogen, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, eg. fer-butyl hydroperoxide. Suitable solvents are, for example, water, lower alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, eg. 2-butanone, halogenated hydrocarbons, eg. dichloromethane, and mixtures of said solvents. The stereochemically pure form of the compounds of formula (I) can be obtained by the application of methods known in the art. The diastereomers can be separated by physical methods such as chromatographic techniques and selective crystallization, eg, countercurrent distribution, liquid chromatography and the like. The compounds of formula (I) can be obtained as racemic mixtures of enantiomers which can be separated from others following art-known resolution procedures. The racemic compounds of formula (I), which are sufficiently alkaline or acidic, can be converted into the corresponding diastereomeric salt form by reaction with an appropriate chiral acid, respectively chiral base. Said diasteromer salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated from them by alkali or acid. An alternative way of separating the enantiomeric form of the compounds of formula (I) involves liquid chromatography, in particular liquid chromatography using a chiral fixed phase. Said stereochemically pure isomeric form can also be derived from the corresponding stereochemically pure form of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound can be synthesized by stereospecific preparation methods. These methods can advantageously employ enantiomerically pure starting materials. In a further aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as specified herein, or a compound of any of the sub-groups of the compounds of formula (I) ) as specified here, and a pharmaceutically acceptable vehicle. A therapeutically effective amount in this context is an amount sufficient to act prophylactically, to stabilize or reduce viral infection, and in particular viral HCV infection, in infected subjects or subjects at risk of infection. Even in a further aspect, this invention relates to a process for preparing a pharmaceutical composition as specified herein, comprising thoroughly mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of a compound of formula (I), as specified herein, or of a compound of any of the sub-groups of the compounds of formula (I) as specified herein. Therefore, the compounds of the present invention or any subgroup thereof may be formulated in various dosage forms for administration purposes. Suitable compositions include all the compositions normally used for the systemic administration of drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in the form of addition salt or metal complex, as a component active is combined in intimate admixture with a pharmaceutically acceptable vehicle, which vehicle can take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desired in a unit dosage form suitable, in particular, for administration orally, rectally, percutaneously or by parenteral injection. For example, in the preparation of the compositions in oral dosage form, any of the usual pharmaceutical means such as, for example, water, glycols, oils, alcohols and the like can be employed in the case of oral liquid preparations such as suspensions, syrups. , elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the vehicle will usually comprise sterile water, at least in large part, although other components may be included, for example, to aid in solubility. Injectable solutions can be prepared, for example, in which the vehicle comprises saline solution, glucose solution or a mixture of saline solution and glucose solution. Injectable suspensions may also be prepared in which case suitable liquid carriers, suspending agents and the like may be employed. Form preparations are also included solid that they intend to become, immediately before use, in liquid form preparations. In the compositions suitable for percutaneous administration, the vehicle optionally comprises a penetration enhancing agent and / or an appropriate wetting agent, optionally combined with appropriate additives of any nature in minor proportions, whose additives do not introduce an effect significant detrimental effect on the skin. The compounds of the present invention can also be administered by inhalation or oral insufflation by means of methods and formulations employed in the art for administration by this route. In this way, in general the compounds of the present invention can be administered to the lungs in the form of a solution, a suspension or a dry powder, with a solution being preferred. Any system developed for the administration of solutions, suspensions or dry powders by inhalation or oral insufflation are suitable for the administration of the present compounds. Thus, the present invention provides, additionally, a pharmaceutical composition adapted for administration by inhalation or insufflation through the mouth comprising a compound of formula (I) and a pharmaceutically acceptable carrier. Preferably, the compounds of the present invention are administered by inhalation of a solution in nebulized doses or in aerosols. It is especially advantageous to formulate the compositions Pharmaceuticals mentioned above in individual dosage form for ease of administration and uniformity of dosage. Individual dosage form as used herein refers to physically individual units appropriate as unit dosages, each unit containing a predetermined quantity of active component calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Some examples of such unit dosage forms are tablets (including slit or coated tablets), capsules, pills, suppositories, powder packets, wafers, injectable solutions or suspensions and the like, and their additional multiples. The compounds of formula (I) show antiviral properties.

Viral infections and their associated diseases that can be treated using the compounds and methods of the present invention include those infections generated by HCV and other pathogenic flaviviruses such as yellow fever, dengue fever (types 1-4), St. Louis encephalitis. , Japanese encephalitis, Murray Valley encephalitis, West Nile virus and Kunjin virus. Diseases associated with HCV include progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, terminal liver disease, and HCC; and for the other pathogenic flaviviruses the diseases include yellow fever, dengue fever, hemorrhagic fever and encephalitis. An amount of the compounds of this invention are even active against mutated strains of HCV. Additionally, many of the compounds of this invention show a favorable pharmacokinetic profile and have attractive properties with respect to bioavailability, including a half-life, ABC (area under the curve) and acceptable peak values and lack of unfavorable phenomena such as insufficient rapid onset and tissue retention. The in vitro antiviral activity against the HCV of the compounds of formula (I) was evaluated in a cellular HCV replicon system based on Lohmann et al. (1999) Science 285: 110-113, with the additional modifications described by Krieger et al. (2001) Journal of Virology 75: 4614-4624, which is further exemplified in the examples section. This model, while not a complete infection model for HCV, is widely accepted as the most robust and efficient model of autonomous HCV RNA replication currently available. Compounds that exhibit anti-HCV activity in this cellular model are considered candidates for further development in the treatment of infections caused by HCV in mammals. It will be appreciated that it is important to distinguish between compounds that specifically interfere with the functions of HCV from those that exert cytotoxic or cytostatic effects in the HCV replicon model, and as a consequence cause a reduction in the HCV RNA or concentration of related informant enzymes. Tests for the evaluation of cellular cytotoxicity based, for example, on the activity of mitochondrial enzymes using fluorogenic redox dyes such as resazurin are known in the art. Additionally, there are cell counter-screens for the evaluation of non-selective inhibition of cell activity. related informant genes, such as luciferase from the fire fly. Appropriate cell types can be equipped by stable transfection with a luciferase reporter gene whose expression depends on a constitutively active promoter, and said cells can be used as counter-screens to eliminate non-selective inhibitors. Due to their antiviral properties, in particular their anti-HCV properties, the compounds of formula (I) or any subgroup thereof, their prodrugs,? / - oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms , are useful in the treatment of individuals who experience a viral infection, in particular an HCV infection, and for the prophylaxis of these infections. In general, the compounds of the present invention can be useful in the treatment of warm-blooded animals infected with viruses, in particular flaviviruses such as HCV. The compounds of the present invention or any subgroup thereof may therefore be used as medicaments. Said use as a medicament or method of treatment comprises the systemic administration to subjects infected with the virus or subjects susceptible to contracting viral infections of an amount effective to combat the conditions associated with viral infection, in particular HCV infection. The present invention further relates to the use of the present compounds or any subgroup thereof in the manufacture of a medicament for the treatment or prevention of viral infections, in particularly HCV infection. The present invention additionally relates to a method of treating a warm-blooded animal infected with a virus, or presenting a risk of infection by a virus, in particular by HCV, said method comprising administering an effective amount from the antiviral viewpoint of a compound of formula (I), as specified herein, or of a compound of any of the sub-groups of the compounds of formula (I), as specified herein. Additionally, the combination of the anti-HCV compound known above, such as, for example, interferon-a (IFN-a), pegylated interferon-a and / or ribavirin, and a compound of formula (I) can be used as a medication in a combination treatment. The term "combined treatment" refers to a product that mandatorily contains (a) a compound of formula (I), and (b) in optionally another anti-HCV compound, as a combined preparation for simultaneous, separate or sequential use in the treatment of infections caused by HCV, in particular, in the treatment of infections with HCV. The anti-HCV compounds encompass agents selected from a HCV polymerase inhibitor, a HCV protease inhibitor, an inhibitor of another target in the life cycle of HCV, and an immunomodulatory agent, an antiviral agent and combinations thereof. HCV polymerase inhibitors include, but are not limited to, NM283 (valopicytabine), R803, JTK-109, JTK-003, HCV-371, HCV- 086, VHC-796 and R-1479. Inhibitors of HCV proteases (NS2-NS3 inhibitors and NS3-NS4A inhibitors) include, but are not limited to, the compounds of WO02 / 18369 (see, eg, page 273, lines 9-22 and page 274, line 4 to page 276, line 11); BILN-2061, VX-950, GS-9132 (ACH-806), SCH-503034, and SCH-6. Other additional agents that may be used are those described in WO-98/17679, WO-00/056331 (Vertex); WO 98/22496 (Roche); WO 99/07734, (Boehringer Ingelheim), WO 2005/073216, WO2005073195 (Medivir) and agents with similar structures. Inhibitors of other targets in the life cycle of HCV, including NS3 helicase; metalloprotease inhibitors; inhibitors of antisense oligonucleotides, such as ISIS-14803, AVI-4065 and the like; siRNA such as SIRPLEX-140-N and the like; RNA of short hair bulbs encoded by vectors (shRNA); DNAzymes; HCV specific ribozymes such as heptazyme, RPI, 13919 and the like; entry inhibitors such as HepeX-C, HuMax-HepC and the like; alpha glucosidase inhibitors such as celgosivir, UT-231 B and the like; KPE-02003002; and BIVN 401. Immunomodulatory agents include, without limitation; compounds with isoform of natural and recombinant interferon, including a-interferon, β-interferon, β-interferon, β-interferon and the like, such as Intron A®, Roferon-A®, Canferon-A300®, Advaferon®, Infergen®, Humoferon®, Sumiferon MP®, Alfaferone®, IFN-beta®, Feron® and the like; compounds with structure of interferon derivative (pegylated) of polyethylene glycol, such as interferon-a-2a PEG (Pegasys®), interferon-a-2b PEG (PEG-Intron®), pegylated IFN-a-conl and the like; long-acting formulations and derivations of compounds with interferon structure such as interferon fused with albumin albufferone and the like; compounds that stimulate the synthesis of interferon in cells, such as resiquimod and the like; interleukins; compounds that enhance the development of the response of helper T cells of type 1, such as SCV-07 and the like; TOLL like receptor agonists such as CpG-10101 (actilon), isatoribine and the like; thymosin a-1; ANA-245; ANA-246; histamine dihydrochloride; propagermanium; tetrachlorodecaoxide; amplify; IMP-321; KRN-7000; antibodies, such as civacir, XTL-6865 and the like; and prophylactic and therapeutic vaccines such as InnoVac C, HCV E1 E2 / MF59 and the like. Other antiviral agents include, without limitation, ribavirin, amantadine, viramidine, nitazoxanide; Telbivudine; NOV-205; Taribavirin; inhibitors of internal rhoshome entry; broad-spectrum viral inhibitors, such as IMPDH inhibitors (e.g., compounds of US5,807,876, US6,498,178, US6,344,465, US6,054,472, WO97 / 40028, WO98 / 40381, WO00 / 56331, and microphenolic acid and its derivatives, and including, without limitation, VX-950, merimepodib (VX-497), VX-148, and / or VX-944); or combinations of any of the above. Thus, to combat or treat HCV infections, the compounds of formula (I) can be administered concomitantly in combination with, for example, interferon-a (IFN-a), pegylated interferon-a and / or ribavirin, as well as therapeutic products based on antibodies directed against HCV epitopes, small interfering RNA (Si RNA), ribozymes, DNAzymes, Antisense RNA, small molecule antagonists of eg NS3 protease, NS3 helicase and NS5B polymerase. Accordingly, the present invention relates to the use of a compound of formula (I) or any subgroup thereof as defined above for the manufacture of a medicament useful for inhibiting the activity of HCV in a mammal infected with human HCV, wherein said medicament is used in a combination treatment, said combined treatment preferably comprises a compound of formula (I) and another HCV inhibitor compound, e.g. IFN-a (pegylated) and / or ribavirin. In yet another aspect, combinations of a compound of formula (I) as specified herein and an anti-HIV compound are provided. The latter are preferably those HIV inhibitors that have a positive effect on the metabolism of the drugs and / or on their pharmacokinetics that improve bioavailability. An example of said HIV inhibitor is ritonavir. As such, the present invention additionally provides a combination comprising (a) an HCV NS3 / 4a protease inhibitor of formula (I) or one of its pharmaceutically acceptable salts; and (b) ritonavir or one of its pharmaceutically acceptable salts.

The ritonavir compound, and its pharmaceutically acceptable salts, and methods for its preparation are described in WO94 / 14436. To obtain a preferred dosage form of ritonavir, see US6,037,157, and the documents cited therein: US 5,484,801, US 08 / 402,690, and WO95 / 07696 and WO95 / 09614. Rítonavir has the following formula: In a further embodiment, the combination comprises (a) an HCV NS3 / 4a protease inhibitor of formula (I) or a pharmaceutically acceptable salt thereof; and (b) ritonavir or one of its pharmaceutically acceptable salts; additionally it comprises an additional anti-HCV compound selected from the compounds as described herein. In one embodiment of the present invention there is provided a process for preparing a combination as described herein, comprising the step of combining an NS3 / 4a protease inhibitor of the HCV of formula (I) or one of its acceptable salts from the point of pharmaceutical view, and ritonavir or one of its salts acceptable from the point of view pharmacist. An alternative embodiment of this invention provides a process in which the combination comprises one or more additional agents as described herein. The combinations of the present invention can be used as medicaments. Said use as a medicament or method of treatment comprises the systemic administration to subjects infected with HCV of an amount effective to combat the conditions associated with HCV and other pathogenic flavi- and pesti-viruses. Accordingly, the combinations of the present invention can be used in the manufacture of a medicament useful for treating, preventing or combating the infection or disease associated with HCV infection in a mammal, in particular for treating conditions associated with HCV and other flavones. and pathogenic pestiviruses. In one embodiment of the present invention there is provided a pharmaceutical composition comprising a combination in accordance with any of the embodiments described herein and a pharmaceutically acceptable excipient. In particular, the present invention provides a pharmaceutical composition comprising (a) a therapeutically effective amount of an HCV NS3 / 4a protease inhibitor of the formula (I) or a pharmaceutically acceptable salt thereof, (b) ) a therapeutically effective amount of ritonavir or one of its pharmaceutically acceptable salts, and (c) a pharmaceutically acceptable excipient. Optionally, the pharmaceutical composition additionally comprises an agent additional selected one of a HCV polymerase inhibitor, a HCV protease inhibitor, an inhibitor of another target in the life cycle of HCV, and an immunomodulatory agent, an antiviral agent and combinations thereof. The compositions can be formulated in appropriate pharmaceutical dosage forms such as the dosage form described above. Each of the active components can be formulated separately and the formulations can be administered concomitantly or a formulation containing both and if desired additional active components can be provided. As used herein, the term "composition" is intended to encompass a product comprising the specified components, as well as any product that is obtained, directly or indirectly, from the combination of the specified components. In one embodiment the combinations provided herein may also be formulated as a combined preparation for simultaneous, separate or sequential use in HIV therapy. In such a case, the compound of general formula (I) or any subgroup thereof, is formulated into a pharmaceutical composition containing other pharmaceutically acceptable excipients, and ritonavir is formulated separately in a pharmaceutical composition containing other excipients acceptable from the pharmaceutical point of view. Conveniently, these two separate pharmaceutical compositions may be part of a device for simultaneous, separate or sequential use.

Thus, the individual components of the combination of the present invention can be administered separately at different times during the course of treatment or concurrently in the form of an individual or divided combination. It should be understood that the present invention, therefore, encompasses all such alternative or simultaneous treatment regimens and the term "administer" should be interpreted accordingly. In a preferred embodiment, the separate dosage forms are administered approximately simultaneously. In one embodiment, the combination of the present invention contains an amount of ritonavir, or one of its pharmaceutically acceptable salts, which is sufficient to clinically improve the bioavailability of the NS3 / 4a protease inhibitor of the formula VHC (I) in relation to bioavailability when said HCV NS3 / 4a protease inhibitor of formula (I) is administered alone. In another embodiment, the combination of the present invention contains an amount of ritonavir, or one of its pharmaceutically acceptable salts, which is sufficient to increase at least one of the pharmacokinetic variables of the NS3 / 4a protease inhibitor. of HCV of formula (I) selected from t1 / 2, Cmn, Cmax, Css, ABC at 12 o'clock, or AUC at 24 hours, in relation to said at least one variable of pharmacokinetics when the protease inhibitor NS3 / 4a of the HCV of formula (I) is administered alone. An additional modality refers to a method to improve the bioavailability of an HCV NS3 / 4a protease inhibitor comprising administering to a subject in need of such improvement a combination as defined herein, comprising a therapeutically effective amount of each component of said combination. In a further embodiment, the invention relates to the use of ritonavir or one of its pharmaceutically acceptable salts, as an enhancer of at least one of the pharmacokinetic variables of an NS3 / 4a protease inhibitor of the formula VHC (I) selected from t-? 2, Cm, Cmax, Css, ABC at 12 o'clock, or ABC at 24 o'clock; with the exception that said use is not practiced in the human body or an animal. The term "individual" as used herein refers to an animal, preferably a mammal, most preferably a human, which has been the subject of treatment, observation or experimentation. Bioavailability is defined as the fraction of administered dose that reaches the systemic circulation. t? / 2 represents the half-life or elapsed time for the plasma concentration to return to half its original value. Css is the steady state concentration, that is, the concentration at which the rate of drug entry is equal to the elimination rate. Cmn is defined as the lowest (minimum) concentration measured during the dosing interval. Cma, represents the highest (maximum) concentration during the dosing interval. ABC is defined as the area under the plasma concentration-time curve for a defined period of time.

The combinations of this invention can be administered to humans in specific dosage ranges for each component included in said combinations. The components comprised in said combinations can be administered together or separately. The NS3 / 4a protease inhibitors of formula (I) or any subgroup thereof, and ritonavir or one of its pharmaceutically acceptable salts or esters, may have dosage levels in the order of 0.02 to 5, 0 grams per day. When the HCV NS3 / 4a protease inhibitor of formula (I) and ritonavir are administered in combination, the weight ratio of the HCV NS3 / 4a protease inhibitor of formula (I) to ritonavir is suitably in the range from about 40: 1 to about 1: 15, or from about 30: 1 to about 1: 15, or from about 15: 1 to about 1: 15, usually from about 10: 1 to about 1: 10, and more normally from about 8: 1 to about 1: 8. Also useful are the weight ratios of the HCV NS3 / 4a protease inhibitors of formula (I) to ritonavir ranging from about 6: 1 to about 1: 6, or from about 4: 1 to about 1: 4, or from about 3: 1 to about 1: 3, or from about 2: 1 to about 1: 2, or from about 1.5: 1 to about 1: 1.5. In one aspect, the amount by weight of the HCV NS3 / 4a protease inhibitors of formula (I) is equal to or greater than that of ritonavir, wherein the weight ratio of the HCV NS3 / 4a protease inhibitor of formula (I) to ritavir is suitably in the range of from about 1: 1 to about 15: 1, usually from about 1: 1 to about 10: 1, and more usually from about 1: 1 to about 8: 1. The weight ratios of the HCV NS3 / 4a protease inhibitor of formula (I) to ritonavir ranging from about 1: 1 are also useful. to about 6: 1, or from about 1: 1 to about 5: 1, or from about 1: 1 to about 4: 1, or from about 3: 2 to about 3: 1, or from about 1: 1 to about 2: 1 or from about 1: 1 to about 1.5: 1. The term "therapeutically effective amount" as used herein refers to that amount of active compound or component or pharmaceutical agent that produces the biological or medicinal response that is sought in a tissue, system, animal or human, in view of the present invention. , by a researcher, veterinarian, doctor or other clinician, which includes relief of the symptoms of the treated disease. Since the present invention relates to combinations comprising two or more agents, the "therapeutically effective amount" is that amount of agents taken together such that the combined effect produces the desired biological or medicinal response. For example, the therapeutically effective amount of a composition comprising (a) the compound of formula (I) and (b) ritonavir, it would be the amount of the compound of formula (I) and the amount of ritonavir that when taken together have a combined effect that is therapeutically effective. It is generally contemplated that an effective antiviral daily amount would be from 0.01 mg / kg to 500 mg / kg of body weight, more preferably from 0.1 mg / kg to 50 mg / kg of body weight. It may be appropriate to administer the required dose as two, three, four, or more sub-doses at appropriate intervals during the day. Said sub-doses may be formulated as a unit dosage form, for example, containing 1 to 1000 mg, and in particular 5 to 200 mg of active component per unit dosage form. The exact dose and frequency of administration depends on the particular compound of formula (I) used, the condition treated in particular, the severity of the condition treated, the age, weight, sex, degree of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is known to those with experience in art. Additionally, it is evident that said effective daily amount can be reduced or increased depending on the response of the treated subject and / or depending on the evaluation of the prescribing physician of the compounds of the present invention. The effective daily quantity ranges mentioned above are, therefore, only guides. According to one modality, the protease inhibitor NS3 / 4a of the HCV of formula (I) and ritonavir can be administered concomitantly once or twice a day, preferably orally, wherein the amount of the compounds of formula (I) per dose is from about 1 to about 2500 mg, and the amount of ritonavir per dose is from 1 to about 2500 mg. In another embodiment, the amounts per dose for concomitant administration once or twice per day are from about 50 to about 1500 mg of the compound of formula (I) and from about 50 to about 1500 mg of ritonavir. Even in another embodiment, the amounts per dose for concomitant administration once or twice per day are from about 100 to about 1000 mg of the compound of formula (I) and from about 100 to about 800 mg of ritavir. Even in another embodiment, the amounts per dose for concomitant administration once or twice per day are from about 150 to about 800 mg of the compound of formula (I) and from about 100 to about 600 mg of ritonavir. Even in another embodiment, the amounts per dose for concomitant administration once or twice per day are from about 200 to about 600 mg of the compound of formula (I) and from about 100 to about 400 mg of ritonavir. Even in another embodiment, the amounts per dose for concomitant administration once or twice per day are from about 200 to about 600 mg of the compound of formula (I) and from about 20 to about 300 mg of ritonavir. Even in another embodiment, the amounts per dose for concomitant administration once or twice per day are from about 100 to about 400 mg of the compound of formula (I) and from about 40 to about 100 mg of ritonavir. Exemplary combinations of the compound of formula (I) (mg) / ritonavir (mg) for one or twice daily dosing 50/100, 100/100, 150/100, 200/100, 250/100, 300 / 100, 350/100, 400/100, 450/100, 50/133, 100/133, 150/133, 200/133, 250/133, 300/133, 50/150, 100/150, 150/150 , 200/150, 250/150, 50/200, 100/200, 150/200, 200/200, 250/200, 300/200, 50/300, 80/300, 150/300, 200/300, 250 / 300, 300/300, 200/600, 400/600, 600/600, 800/600, 1000/600, 200/666, 400/666, 600/666, 800/666, 1000/666, 1200/666 , 200/800, 400/800, 600/800, 800/800, 1000/800, 1200/800, 200/1200, 400/1200, 600/1200, 800/1200, 1000/1200, and 1200/1200. Other example combinations of the compound of formula (I) (mg) / ritonavir (mg) for a dosage once or twice a day 1200/400, 800/400, 600/400, 400/200, 600/200, 600 / 100, 500/100, 400/50, 300/50, and 200/50. In one embodiment of the present invention there is provided an article of manufacture comprising a composition effective to treat an HCV infection or inhibit the NS3 protease of HCV; and packaging material comprising a label indicating that the composition can be used to treat the infection caused by the hepatitis C virus; where the The composition comprises a compound of formula (I) or any subgroup thereof, or the combination as described herein. Another embodiment of the present invention relates to a device or container comprising a compound of formula (I) or any subgroup thereof, or a combination according to the invention combining a protease inhibitor NS3 / 4a of the HCV of formula (I) or one of its pharmaceutically acceptable salts, and ritonavir or one of its pharmaceutically acceptable salts, in an amount effective to be used as a standard or reagent in a test or assay to determine the ability of potential pharmaceutical products to inhibit HCV NS3 / 4a protease, HCV growth, or both. This aspect of the invention can find its use in pharmaceutical research programs. The compounds and combinations of the present invention can be used in analyzes of high resolution white analytes such as those to measure the efficacy of said combination in the treatment of HCV. EXAMPLES The following examples are intended to illustrate the present invention and not to limit it.

EXAMPLE 1 Preparation of representative intermediaries.

Synthesis of 4-hydroxy-7-methoxy-8-methyl-2- (thiazol-2-yl) quinoline (4) Step A A solution of BCI3 (1.0 M in CH2Cl2, 194 ml) was added dropwise through a cannula for 20 min, under argon pressure, at 0 ° C, to a solution of 3-methoxy-2-methylaniline (25.4 g, 185 mmol) in xylene (300 ml).

The temperature was maintained between 0 ° C and 10 ° C, until the addition was completed. After an additional 30 min at 0 ° C, acetonitrile (12.6 ml, 241 mmol) was added dropwise under argon at 0 ° C. After 30 min at 0 ° C, the resulting suspension was transferred into a dropping funnel and diluted with CH2Cl2 (40 ml). This mixture was added at 0 ° C under argon for 20 min to a suspension of AICI3 (25.9 g, 194 mmol) in CH2Cl2 (40 mL). The resulting orange solution was heated in an oil bath at 70 ° C under a stream of nitrogen for 12 hr. Then, the reaction mixture was cooled to room temperature and frozen water and CH2Cl2 were added. This mixture was refluxed for 6 hr and then cooled to room temperature. After 12 hr, the pH was adjusted to 0 ° C to 3 with 6N NaOH. The solution was extracted with CH2Cl2, subsequently washed with water, 1 N NaOH and brine. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was triturated at room temperature in diisopropyl ether (50 ml) for 0.5 hr. Then, the suspension was cooled to 0 ° C, filtered and washed with a small amount of diisopropyl and dried under high vacuum to give 15.4 g (46%) of the desired product 2: m / z = 180 (M + H ) X Step B EDCI (257 mg, 1.34 mmol) and HOAt (152 mg, 1.12 mmol) were added to a stirred solution of 2 (200 mg, 1.12 mmol) in CH2Cl2 (10 mL) and dry DMF (1 mL). The resulting solution was stirred at room temperature for 3 days. Then, the reaction mixture was divided between CH2Cl2 and NaHCO3 1. The organic layer was washed successively with 1 N NH 4 Cl and water, dried (Na 2 SO 4) and evaporated. Purification by flash chromatography (gradient AcOEt / heptane, 10:90 to 50:50) gave 62 mg (19%) of the desired product: m / z = 291 (M + H) X Step C FBuOK (50 mg, 0.448 mmol) was added to a suspension of acetophenone 3 (62 mg, 0.213 mmol) in rBuOH (5 mL). The resulting mixture was stirred at 80 ° C until the next day, then cooled to room temperature. The reaction mixture was diluted with AcOEt, acidified with KHS04 and subsequently washed with water and brine. The organic layer was dried (Na2SO4) and evaporated to give 43 mg (74%) of the desired product as a white powder: m / z = 273 (M + H) X Synthesis of (hex-5-enyl) (methyl) amine (21) Step A Sodium hydride (1.05 eq) was added slowly at 0 ° C to a solution of? / -methyltrifluoroacetamide (25 g) in DMF (140 ml). The mixture was stirred for 1 hr at room temperature under nitrogen. Then, a solution of bromohexene (32.1 g) in DMF (25 ml) was added dropwise and the mixture was heated at 70 ° C for 12 hours. The reaction mixture was emptied in water (200 ml) and extracted with ether (4 x 50 ml), dried (MgSO 4), filtered and evaporated to give 35 g of the desired product 20 as a yellow oil which was used without further purification in the next step.

Step B A solution of potassium hydroxide (187.7 g) in water (130 ml) was added dropwise to a solution of 20 (35 g) in methanol (200 ml). The mixture was stirred at room temperature for 12 hours. Then, the reaction mixture was poured into water (100 ml) and extracted with ether (4 x 50 ml), dried (MgSO 4), filtered and the ether was distilled at atmospheric pressure. The resulting oil was purified by vacuum distillation (13 mm Hg pressure, 50 ° C) to give 7.4 g (34%) of the title 21 product as a colorless oil: H-NMR (CDCl 3): d 5.8 (m, 1 H), 5 (ddd, J = 17.2 Hz, 3.5 Hz, 1.8 Hz, 1H), 4.95 (m, 1 H), 2.5 (t, J = 7.0 Hz, 2H), 2.43 (s, 3H), 2.08 (q, J = 7.0 Hz, 2H), 1.4 (m, 4H), 1.3 (br s, 1 H).

EXAMPLE 2 Preparation of 17-7-methoxy-8-methyl-2- (thiazol-2-yl) quinolin-4-yloxyl-13-methyl-2,14-dioxo-3,13-diazatricic acid 13.3.0.0 61octacid 7-en ^ 4- carboxylic (29) Step A 3-Oxo-2-oxa-bicyclo [2.2.1] heptane-5-carboxylic acid was added 22 (500 mg, 3.2 mmol) in 4 ml of DMF at 0 ° C to HATU (1.34 g, 3.52 mmol) and? / - methylhex-5-enylamine (435 mg, 3.84 mmol) in DMF (3 ml), followed by DIPEA. After stirring for 40 min at 0 ° C, the mixture was stirred at room temperature for 5 hr. Then, the solvent was evaporated, the residue was dissolved in EtOAc (70 ml) and washed with saturated NaHCO 3 (10 ml). The aqueous layer was extracted with EtOAc (2 x 25 ml). The organic layers were combined, washed with saturated NaCl (20 ml), dried (Na2SO4) and evaporated. Purification by flash chromatography (EtOAc / petroleum ether, 2: 1) gave 550 mg (68%) of the desired product 23 as a colorless oil: m / z = 252 (M + H) X Step B A solution of LiOH (105 mg in 4 ml of water) was added at 0 ° C to the amide lactone 23. After 1 hr, the conversion was complete (HPLC). The mixture was acidified to pH 2-3 with 1N HCl, extracted with AcOEt, dried (MgSO4), evaporated, co-evaporated with toluene several times and dried in high vacuum until the next day to give 520 mg (88%) of the desired product 24: m / z = 270 (M + H) X Step C The 1- (amino) -2- (vinyl) cyclopropanecarboxylic acid ethyl ester hydrochloride (4.92 g, 31.7 mmole) and HATU (12.6 g, 33.2 mmole) were added to 24 (8.14 g, 30.2 mmole). The mixture was cooled in an ice bath under argon and then DMF (100 ml) and DIPEA (12.5 ml, 11.5 mmol) were added subsequently. After 30 min at 0 ° C, the solution was stirred at room temperature for an additional 3 hr. Then, the reaction mixture was partitioned between EtOAc and water, subsequently washed with 0.5 N HCl (20 ml) and saturated NaCl (2 x 20 ml) and dried (Na2SO). Purification by flash chromatography (AcOEt / CH2Cl2 / petroleum ether, 1: 1: 1) gave 7.41 g (60%) of the desired product 26 as a colorless oil: m / z = 407 (M + H) X Step D DIAD (218 μl, 1.11 mmol) was added at -20 ° C under nitrogen to a solution of 26 (300 mg, 0.738 mmol), quinoline 4 (420 mg, 1.03 mmol) and triphenylphosphine (271 mg, 1.03 mmol) in dry THF (15 ml). Then, the reaction was warmed to room temperature. After 1.5 h, the solvent was evaporated and the crude product was purified by flash column chromatography (petroleum ether / CH2Cl2 / ether gradient, 3: 1.5: 0.5 to 1: 1: 1) to give the desired product 27: m / z = 661 (M + H) X A solution of 27 (200 mg, 0 30 mmol) and 1 st generation catalyst from Hoveyda-Grubbs (18 mg, 0 030 mmol) 1, 2-d? Chloroethane dried and dephosulated (300 ml) at 70 ° C was heated. under nitrogen for 12 hr. Then, the solvent was evaporated and the residue purified by silica gel chromatography (petroleum ether / CH2Cl2 / Et20, 3 1 1) to give the desired product 28 m / z = 633 (M + H) + Step F A solution of LiOH (327 mg) in water (3 ml) was added to a stirred solution of 28 (150 mg, 0.237 mmol) in THF (15 ml) and MeOH (10 ml) After 48 hr, the solvent evaporated and the residue was divided between water and ether. The aqueous layer was acidified (pH = 3) and extracted with AcOEt, dried (MgSO 4) and evaporated. The residue was crystallized from ether to give objective compound 29: m / z = 605 (M + H) X EXAMPLE 3 Preparation of M-RI7-R7-methoxy-8-methyl-2- (thiazol-2-yl) quinolin-4-yloxy] -13-methyl-2,14-dioxo-3,13-diazatricyclo [13.3.0.0, 6] octadec-7-en-4-carbonn- (cyclopropyl) sulfonamide (30) A mixture of 29 (85 mg, 0.14 mmol) and CDI (47 mg, 0.29 mmol) in dry THF (7 mL) was heated at reflux for 2 hr under nitrogen. The LC-MS analysis showed a peak of the intermediate (ta = 5.37). The reaction mixture was cooled to room temperature and cyclopropylsulfonamide (52 mg, 0.43 mmol) was added. Then, DBU (50 μl, 0.33 mmol) was added and the reaction mixture was stirred at room temperature for 1 hr and then heated at 55 ° C for 24 hr. The solvent was evaporated and the residue was partitioned between AcOEt and acid water (pH = 3). The crude material was purified by column chromatography (AcOEt CH2Cl2 / petroleum ether, 1: 1: 1). The residue was crystallized from Et20, filtered to give the objective compound contaminated with the cyclopropyl sulfonamide. This material was triturated in 3 ml of water, filtered, washed with water and dried until the next day in the high vacuum pump to give the objective compound 30 as a white powder: m / z = 708 (M + H) X EXAMPLE 4 Preparation of 17-r2- (4-isopropylthiazol-2-yl) -7-methoxy-8-methyl-quinolin-4-yloxyl-13-methyl-2.14-dioxo-3.13-diazatric-chloro3.3.0.04.61octactac acid 7-en-4-carboxylic acid (46) Synthesis of 4-hydroxy-2- (4-isopropylthiazol-2-yl) -7-methoxy-8-methylquinoline (36) Step 1: Synthesis of? / - (fer-butyloxycarbonyl) -3-methoxy-2-methylaniline (32) 31 32 Triethylamine (42.4 ml, 302 mmol) was added to a suspension of 3-methoxy-2-methylbenzoic acid (45.6 g, 274 mmol) in dry toluene (800 ml). A clear solution was obtained. Then, dppa (65.4 mL, 302 mmol) in toluene (100 mL) was slowly added. After 1 hr at temperature At room temperature, the reaction mixture was subsequently heated at 50 ° C for 0.5 hr, at 70 ° C for 0.5 hr then at 100 ° C for 1 hr. To this solution, f-BuOH (30.5 g, 411 mmol) in toluene (40 ml) was added at 100 ° C and the resulting mixture was refluxed for 7 hr. The solution was cooled to room temperature then it was subsequently washed with water, 0.5 N HCl, 0.5 N NaOH and brine, dried (Na 2 SO 4) and evaporated to give 67 g of the desired product: m / z = 237 (M) X Step 2: Synthesis of 3-methoxy-2-methylaniline (33) 32 33 TFA (40.7 mL, 548 mmol) was added to a solution of N- (tert-butyloxycarbonyl) -3-methoxy-2-methylaniline, in dichloromethane (500 mL). After 2 hr at room temperature, TFA (40.7 ml, 548 mmol) was added and the resulting mixture was stirred at room temperature until the next day. Then, the volatiles evaporated. The residue was triturated with toluene (100 ml) and diisopropyl ether (250 ml), filtered and washed with diisopropyl ether (100 ml) to give 56.3 g of the title product as a TFA salt: m / z = 138 ( M + H) X The TFA salt was transformed into the free aniline by treatment with NaHCO3.

Step 3: Synthesis of (2-amino-4-methoxy-3-methylphenyl) (methyl) ketone A solution of BCI3 (1.0 M, 200 mL, 200 mmol) in CH2Cl2 in nitrogen was slowly added to a solution of 3-methoxy-2-methylaniline (26.0 g, 190 mmol) in xylene (400 mL). The temperature was monitored during the addition and kept below 10 ° C. The reaction mixture was stirred at 5 ° C for 0.5 hr. Then, dry acetonitrile (13 ml, 246 mmol) was added at 5 ° C. After 0.5 hr at 5 ° C, the solution was transferred into a dropping funnel and slowly added at 5 ° C to a suspension of AICI3 (26.7 g, 200 mmol) in CH2Cl2 (150 mL). After 45 min at 5 ° C, the reaction mixture was heated to 70 ° C under a stream of nitrogen. After evaporation of CH 2 Cl 2, the temperature of the reaction mixture reached 65 ° C. After 12 hr at 65 ° C, the reaction mixture was cooled to 0 ° C, emptied on ice (300 g) and heated slowly to reflux for 7 hr. After 2 days at room temperature, 6 N NaOH (50 ml) was added. The pH of the resulting solution was 2-3. The xylene layer was decanted. The organic layer was extracted with CH2Cl2. The xylene and the CH2Cl2 layers were combined, then washed with water, 1 N NaOH and brine, dried (Na2SO4) and evaporated. The residue was triturated in diisopropyl ether at 0 ° C, filtered and washed with diisopropyl ether to give 13.6 g (40%) of the title product as a yellowish solid: m / z = 180 (M + H) X Step 4: Synthesis of 2 '- [[(4-isopropylthiazol-2-yl) (oxo) methyl-amino-1-4'-methoxy-3'-methylacetophenone (35) A solution of (2-amino-4-methoxy-3-methylphenyl) (methyl) ketone (18.6 g, 104 mmol) in dioxane (50 ml) in nitrogen was added to a suspension of 4-isopropylthiazole-2-carbonyl chloride. in dioxane (250 ml). After 2 hr at room temperature, the reaction mixture was concentrated until dried. Then, the residue was partitioned between an aqueous solution of NaHCO 3 and AcOEt, the organic layer was washed with brine, dried (Na 2 SO 4) and evaporated. The residue was triturated in diisopropyl ether, filtered and washed with diisopropyl ether to give 30.8 g (90%) of the title product 35.

Step 5: Synthesis of 4-hydroxy-2- (4-isopropylthiazol-2-yl) -7-methoxy-8-methylquinoline (36) Potassium fer-butoxide (21.8 g, 195 mmol) was added to a suspension of 2 '- [[(4-isopropylthiazol-2-yl) (oxo) methyl] amino] -4'-methoxy-3'-methylacetophenone (35, 30.8 g, 92.7 mmol) in fer-butanol. The mixtures of The resulting reaction was heated at 100 ° C until the next day. Then, the reaction mixture was cooled to room temperature and diluted with ether (100 ml). The precipitate was filtered and washed with Et20 to give a powder (fraction A). The mother liquor was concentrated under vacuum, triturated in ether, filtered and washed with ether to give a powder (fraction 2). Fractions 1 and 2 were mixed and poured into water (250 ml). The pH of the resulting solution was adjusted to 6-7 (control with pH paper) with 1 N HCl. The precipitate was filtered, washed with water and dried. Then, the solid was triturated in diisopropyl ether, filtered and dried to give 26 g (88%) of the title product 36 as a brownish solid: #n z = 315 (M + H) +.

Synthesis of (hex-5-enyl) (methyl) amine (38) Step A: Sodium hydride (1.05 eq) was slowly added at 0 ° C to a solution of N-methyltrifluoroacetamide (25 g) in DMF (140 ml). The mixture was stirred for 1hr at room temperature under nitrogen. Then, a solution of bromohexene (32.1 g) in DMF (25 ml) was added dropwise and the mixture was heated at 70 ° C for 12 hours. The reaction mixture was poured into water (200 ml) and extracted with ether (4 x 50 ml), dried (MgSO), filtered and evaporated to give 35 g of the desired product 37 as a yellow oil which was used without further purification in the next step.

Step B: A solution of potassium hydroxide (187.7 g) in water (130 ml) was added dropwise to a solution of 37 (35 g) in methanol (200 ml). The mixture was stirred at room temperature for 12 hours. Then, the reaction mixture was poured into water (100 ml) and extracted with ether (4 x 50 ml), dried (MgSO), filtered and the ether was distilled at atmospheric pressure. The resulting oil was purified by vacuum distillation (13 mm Hg pressure, 50 ° C) to give 7.4 g (34%) of the title product 38 as a colorless oil: 1 H-NMR (CDCl 3): d 5.8 (m, 1 H), 5 (ddd, J = 17.2 Hz, 3.5 Hz, 1.8 Hz, 1 H), 4.95 (m, 1 H), 2.5 (t, J = 7.0 Hz, 2 H), 2.43 (s, 3 H), 2.08 (q, J = 7.0 Hz, 2H), 1.4 (m, 4H), 1.3 (br s, 1 H).

Preparation of 17- [2- (4-isopropylthiazol-2-yl) -7-methoxy-8-methyl-quinolin-4-yloxy-13-methyl-2,14-dioxo-3,13-diazatricyclo [13.3. 0.04 6-octadec-7-en-4-carboxylic (46) Step A 3-Oxo-2-oxa-bicyclo [2.2.1] heptan-5-carboxylic acid 39 (500 mg, 3.2 mmol) in 4 ml of DMF at 0 ° C was added to HATU (1.34 g, 3.52 mmol) and? / -methylhex-5-enylamine (435 mg, 3.84 mmol) in DMF (3 ml), followed by DIPEA. After stirring for 40 min at 0 ° C, the mixture was stirred at room temperature for 5 hr. Then, the solvent was evaporated, the residue was dissolved in EtOAc (70 ml) and washed with saturated NaHCO 3 (10 ml). The aqueous layer was extracted with EtOAc (2 x 25 ml). The organic phases were combined, washed with saturated NaCl (20 ml), dried (Na2SO4) and evaporated. Purification by flash chromatography (EtOAc / petroleum ether, 2: 1) gave 550 mg (68%) of the desired product 40 as a colorless oil: m / z = 252 (M + H) X Step B A solution of LiOH (105 mg in 4 ml of water) was added at 0 ° C to lactone amide 40. After 1 hr, the conversion was complete (HPLC). The mixture was acidified to pH 2-3 with 1N HCl, extracted with AcOEt, dried (MgSO), evaporated, co-evaporated with toluene several times and dried in high vacuum until the next day to give 520 mg (88%) of the desired product 41: m / z = 270 (M + H) X Step C COOEl The hydrochloride of 1- (amino) -2- (vinyl) cyclopropane-carboxylic acid ethyl ester 42 (4.92 g, 31.7 mmoles) and HATU (12.6 g, 33.2 mmoles) were added to 41 (8.14 g, 30.2 mmoles) ). The mixture was cooled in an ice bath under argon and then DMF (100 ml) and DIPEA (12.5 ml) were added., 1.5 mmol) later. After 30 min at 0 ° C, the solution was stirred at room temperature for an additional 3 hr. Then, the reaction mixture was partitioned between EtOAc and water, subsequently washed with 0.5 N HCl (20 ml) and saturated NaCl (2 x 20 ml) and dried (Na 2 SO). Purification by flash chromatography (AcOEt / CH2Cl2 / petroleum ether, 1: 1: 1) gave 7.41 g (60%) of the desired product 43 as a colorless oil: m / z = 407 (M + H) X DIAD (1.02 ml, 5.17 mmol) was added at -15 ° C under a nitrogen atmosphere to a solution of 43 (1.5 g, 3.69 mmol), quinoline 36 (1.39 g, 4. 43 mmol) and triphenylphosphine (1.26 g, 4.80 mmol) in dry THF (40 ml). After 4.5 hr, at -15 ° C, the reaction mixture was partitioned between ice water and AcOEt, dried (Na2SO4) and evaporated. The crude material was purified by flash column chromatography (AcOEt / CH2Cl2 petroleum gradient, 1: 9 to 2: 8) to give 1.45 g (56%) of the desired product 44: m / z = 703 (M + H) X A solution of 44 (1.07 g, 1524 mmol) and 1 st generation Hoveyda-Grubbs catalyst (33 mg, 0.03 eq) in dry and degassed 1,2-dichloroethane (900 ml) was heated at 75 ° C under nitrogen for 12 hr. Then, the solvent was evaporated and the residue purified by silica gel chromatography (25% EtOAc in CH 2 Cl 2). 620 mg (60%) of pure macrocycle 45 were obtained. M / z = 674 (M + H) X H NMR (CDCl 3): 1.18-1.39 (m, 12H), 1.59 (m, 1 H), 1.70-2.08 ( m, 5H), 2.28 (m, 1H), 2.38 (m, 1 H), 2.62 (m, 2H), 2.68 (s, 3H), 2.83 (m, 1H), 3.06 (s, 3H), 3.19 (sept, J = 6.7 Hz, 1 H), 3.36 (m, 1 H), 3.83 (m, 1 H), 3.97 (s, 3H), 4.09 (m, 2H), 4.65 (td, J = 4 Hz, 14 Hz , 1H), 5.19 (dd, J = 4 Hz, 10 Hz, 1H), 5.31 (m, 1 H), 5.65 (td, = 4 Hz, 8 Hz, 1 H), 7.00 (s, 1 H), 7.18 (s, 1 H), 7.46 (d, J = 9 Hz, 1 H), 7.48 (s, 1 H), 8.03 (d, J = 9 Hz, 1 H).

A solution of lithium hydroxide (1.65 g, 38.53 mmol) in water (15 ml) was added to a stirred solution of ester 45 (620 mg, 0.920 mmol) in THF (30 ml) and MeOH (20 ml). After 16 hr at room temperature, the reaction mixture was quenched with sat. NH 4 Cl, concentrated under reduced pressure, acidified to pH 3 with 1N HCl and extracted with CH 2 Cl 2, dried (MgSO 4) and evaporated to give 560 mg (88%) of carboxylic acid 46, m / z = 647 (M + H) X 1 H NMR (CDCl 3): 1.11-1.40 (m, 8H), 1.42-1.57 (m, 2H), 1.74 (m, 2H), 1.88-2.00 (m, 2H), 2.13 (m, 1 H), 2.28 (m, 1H), 2.40 (m, 1H), 2.59 (m, 2H), 2.67 (s, 3H), 2.81 ( m, 1H), 2.97 (s, 3H), 3.19 (m, 1 H), 3.31 (m, 1 H), 3.71 (m, 1 H), 3.96 (s, 3 H), 4.56 (dt, J = 4 Hz, 12 Hz, 1 H), 5.23 (m, 2 H), 5.66 (m, 1 H), 7.01 (s, 1 H), 7.10 (s, 1H), 7.22 (d, J = 10 Hz, 1 H), 7.45 (s, 1 H), 8.00 (d, J = 10 Hz, 1H).

Step G A solution of 17- [2- (4-isopropylthiazol-2-yl) -7-methoxy-8-methylinquinolin-4-yloxy] -13-methyl-2, 14-dioxo-3, 13-diazatricyclo acid was stirred. 13.3.0.04.6] octadec-7-en-4-carboxylic acid 46 (138.3 mg, 0.214 mmol) prepared according to the procedure described above and carbonyldiimidazole (96.9 mg, 0.598 mmol) in dry THF (5 ml) a reflux in nitrogen for 2 hr. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between EtOAc and 1 N HCl, the organic layer was washed with brine, dried (Na2SO4) and evaporated. Then, the solid was triturated in i-Pr ether to obtain 46 'as a white powder: m / z = 629 (M + H) X 1 H NMR (CDCl 3): 0.99-1.00 (m, 1 H), 1.20-1.35 (m, 2H), 1.39 (d, J = 6.9 Hz, 6H), 1.55-1.7 (m, 1 H), 1.9-2 (m, 2H), 2.15-2.25 (m, 2H), 2.3-2.60 (m, 4H), 2.68 (s, 3H), 2.71-2.82 (m, 1 H), 2.82-2.9 (m, 1 H), 3.08 (s, 3H), 3.1-3.2 (m, 1 H), 3.4-3.5 (m, 1 H), 3.65-3.71 (m, 1 H), 3.91 (s, 3H), 4.28-4.4 (m, 1 H), 5.32-5.46 (m, 2H), 5.85-5.95 (m, 1 H), 7.00 (s, 1 H), 7.22 (d, J = 9.2 Hz, 1 H), 7.45 (s) , 1H), 8.09 (d, J = 9.2 Hz, 1 H).

EXAMPLE 5 Preparation of N-RI7- [2- (4-isopropylthiazol-2-yl) -7-methoxy-8-methylquinolin-4-yloxy-13-methylene-2,14-dioxo-3,13-diazatr Ciclori3.3.0.04 61octadec-7-en-4-carbonyl1- (cyclopropyl) sulfonamide (47) A solution of 17- [2- (4-isopropylthiazol-2-yl) -7-methoxy-8-methylquinolin-4-yloxy] -13-methyl-2,14-dioxo-3,13-diazatricyclo acid was stirred. [13.3.0.04.6] octadec-7-en-4-carboxylic acid 46 (560 mg, 0.867 mmol) prepared according to example 4 and carbonyldiimidazole (308 mg, 1.90 mmol) in dry THF (10 ml) at reflux in nitrogen for 2 hr. The The reaction mixture was cooled to room temperature and cyclopropylsulfonamide (400 mg) was added., 3,301 mmoles) and DBU (286 mg, 1881 mmoles). This solution was heated at 50 ° C for 15 hr. Then, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between CH2Cl2 and 1 N HCl, the organic layer was washed with brine, dried (MgSO4) and evaporated. Purification by flash chromatography (gradient of EtOAc (0 to 25%) in CH2Cl2) gave 314 mg of an off-white solid which was further washed with water, then isopropyl ether and dried in the vacuum oven to give 282 mg ( 40%) of the pure title 47 product as a white powder: m / z = 750 (M + H) X 1 H NMR (CDCl 3): 0.99-1.52 (m, 14H), 1.64-2.05 (m, 4H), 2.77 (m, 1 H), 2.41 (m, 2H), 2.59 (m, 2H), 2.69 (s, 3H), 2.92 (m, 2H), 3.04 (s, 3H), 3.19 (m, 1 H), 3.40 (m, 2H), 3.98 (s, 3H), 4.60 (t, J = 13 Hz, 1 H), 5.04 (t, J = 1 1 Hz, 1 H), 5.37 (m, 1 H), 5.66 (m, 1 H), 6.21 (s, 1 H), 7.02 (s, 1 H), 7.22 (d, J = 10 Hz, 1 H), 7.45 (s, 1 H), 7.99 (d, J = 10 Hz, 1 H), 10.82 (broadband, 1 H).

EXAMPLE 6 Preparation of V- [17- [2- (4-isopropylthiazol-2-yl) -7-methoxy-8-methylquinolin-4-yloxyl-13-methyl-2,14-dioxo-3,13- diazatricicloI13.3.0.04 61octadec-7-en- - carbonin (1-methylcyclopropyl) sulfonamide (48) A solution of carboxylic acid 46 (240 mg, 0.38 mmol) and carbonyldiimidazole (2 eq) in dry THF (5 ml) was stirred at reflux under nitrogen for 2 hr. The reaction mixture was cooled to room temperature and 1-methylcyclopropylsulfonamide (2 eq) and DBU (2 eq) were added. This solution was heated at 50 ° C for 15 hr. Then, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between CH2Cl2 and 1N HCl, the organic layer was washed with brine, dried (MgSO4) and evaporated. Purification by flash chromatography (gradient of EtOAc (0 to 25%) in CH 2 Cl 2) gave 170 mg (58%) of the title compound 48 as an off white solid which was further washed with water, then isopropyl ether and dried in water. The vacuum oven: m / z = 764 (M + H) X 1 H NMR (acetone-d 6): 0.86 (m, 2H), 1.15-1.78 (m, 19H), 1.87 (m, 2H), 2.13-2.54 (m, 3H), 2.57-2.71 (m, 4H), 2.96-3.25 (m, 4H), 3.54 (m, 2H), 4. 02 (s, 3H), 4.58 (t, J = 13 Hz, 1 H), 5.04 (m, 1 H), 5.46 (m, 1 H), 5.62 (m, 1 H), 7. 31 (s, 1 H), 7.43 (d, J = 9 Hz, 1 H), 7.58 (s, 1 H), 8.07 (d, J = 13 Hz, 1 H), 8.19 (s broadband, 1 H), 11.44 (broadband, 1 H).

EXAMPLE 7 Preparation of acid 17- [8-chloro-2- (4-isopropylthiazol-2-yl) -7-methoxyquinolin-4-yloxn-13-methyl-2.14-dioxo-3.13-diazatricycloM 3.3.0.04 ß1octadec-7- en-4-carboxylic (25) Step A: Synthesis of (2-amino-3-chloro-4-methoxyphenyl) (methyl) ketone (50) Cl - °? ? NH2 50 ° C A solution of BCI3 (1.0 M, 138 mL, 138 mmol) in CH2Cl2 was slowly added under nitrogen to a solution of 2-chloro-3-methoxyaniline 49 (20.6 g, 131 mmol) in xylene (225 mL). The temperature was monitored during the addition and kept below 10 ° C. The reaction mixture was stirred at 5 ° C for 0.5 hr. Then, dry acetonitrile (9.0 ml, 170 mmol) was added at 5 ° C. After 0.5 hr at 5 ° C, the solution was transferred in a dropping funnel and slowly added at 5 ° C to a suspension of AICI3 (18.4 g, 138 mmoles) in CH2CI2 (80 ml). After 45 min at 5 ° C, the reaction mixture was heated to 70 ° C under a stream of nitrogen. After evaporation of CH 2 Cl 2, the temperature of the reaction mixture reached 65 ° C. After 12 hr at 65 ° C, the reaction mixture was cooled to 0 ° C, emptied on ice (200 g) and slowly heated to reflux for 7 hr. After 2 days at room temperature, 6N NaOH (25 ml) and CH2Cl2 (100 ml) were added. The mixture was filtered, the filtrate was washed with CH2Cl2. The organic layer was decanted and subsequently washed with water, 1 N NaOH and brine, dried (Na2SO4) and evaporated. The residue was triturated in diisopropyl ether at 0 ° C, filtered and washed with diisopropyl ether to give 19.0 g (73%) of the title product 50 as a white solid: m / z = 200 (M + H) X Step B: Synthesis of 2'-f [(4-isopropylthiazol-2-yl) (oxo) methyl-1-aminol-3'-chloro-4'-methoxyacetophenone (51) The title 51 product (79%) was prepared from (2-amino-3-chloro-4-methoxyphenyl) - (methyl) ketone (50) following the reported procedure for 2 '- [[(4-isopropylthiazole- 2-yl) (oxo) methyl] amino] -4'-methoxy-3'-methylacetophenone (35): m / z = 353 (M + H) X Step C: Synthesis of 8-chloro-4-hydroxy-2- (4-isopropylthiazol-2-yl) -7-methoxy-quinoline (52) The title product 52 was prepared (58%) of 2 '- [[(4-isopropylthiazol-2-yl) (oxo) -methyl] amino] -3'-chloro-4'-methoxyacetophenone (51) following the procedure reported for 4-hydroxy-2- (4-isopropylthiazol-2-yl) -7-methoxy-8-methylquinoline (36): m / z = 335 (M + H) X Step D: Preparation of compound 53 Compound 53 was prepared from alcohol 43 and 8-chloro-4-hydroxy-2- (4-isopropylthiazol-2-yl) -7-methoxy-quinoline (52) following the procedure described for 44: m / z = 723 (M + H) X Step E: Preparation of compound 54 Compound 54 was prepared from 53 following the procedure described for 45: m / z = 695 (M + H) X Step F: Preparation of compound 55 54 55 A solution of lithium hydroxide (3.85 g, 90.1 mmol) in water (30 ml) was added to a stirred solution of ester 54 (1.64 g, 2.36 g. mmoles) in THF (55 ml) and MeOH (40 ml) After 16 hr at room temperature, more LiOH (1.0 g) was added. After 20 hr at room temperature, the reaction mixture was quenched with a saturated solution of NH4CI, concentrated under reduced pressure, acidified to pH 5 with 1N HCl, extracted with EtOAc, dried (MgSO4) and evaporated to give 1 37 g (87%) of the carboxylic acid 55 m / z = 667 ( M + H) + EXAMPLE 8 Preparation of W- [17- [8-Chloro-2- (4-isopropylthiazol-2-yl) -7-methoxy-quinolin-4-yloxy-M3-methylene-2.14-dioxo-3.13-diazatricichlori3.3.0.0 61octadec -7-en-4-carbonylK-cyclopropi-sulphonamide (56) A solution of carboxylic acid 55 (1 37 g, 2.52 mmol) and carbonildnmidazole (2 eq) in dry THF (75 ml) was stirred at reflux under nitrogen for 2 hr. The reaction mixture was cooled to room temperature and they added cyclopropylsulfonamide (2 eq) and DBU (2 eq). This solution was heated at 50 ° C for 36 hr. Then, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between EtOAc and 1 N HCl, the organic layer was washed with brine, dried (MgSO 4) and evaporated. Purification by flash chromatography (gradient of EtOAc (0 to 25%) in CH2Cl2) gave 880 mg (55%) of the title compound 56 as an off-white solid: m / z = 770 (M + H) X 1 H NMR (CDCl 3 , main rotamer): 0.93-1.52 (m, 13H), 1.60-2.07 (m, 5H), 2.21-2.64 (m, 5H), 2.92 (m, 2H), 3.04 (s, 3H), 3.19 (m, 1 H), 3.41 (m, 2H), 4.07 (s, 3H), 4.60 (t, J = 13 Hz, 1H), 5.04 (t, J = 11 Hz, 1H), 5.37 (m, 1 H), 5.66 (m, 1 H), 6.33 (s, 1 H), 7.07 (s, 1 H), 7.24 (d, J = 9 Hz, 1 H), 7.52 (s, 1 H), 8.05 (d, J = 9 Hz, 1 H), 10.81 (broad band, 1 H).

EXAMPLE 9 Preparation of WH 7-r8-chloro-2- (4-isopropylthiazol-2-yl) -7-methoxyquinolin-4-yloxy-13-methyl-2,14-dioxo-3,13-diazatricichlori3.3.0.04 61octadec-7-en-4- carbonilld -methylcyclopropylsulfonamide (57) A solution of carboxylic acid 55 (49 mg, 0.073 mmol) and carbonyldiimidazole (2 eq) in dry THF (5 ml) was stirred at reflux under nitrogen for 2 hr. The reaction mixture was cooled to room temperature and 1-methylcyclopropyl sulfonamide (2 eq) and DBU (2 eq) were added. This solution was heated at 50 ° C for 15 hr. Then, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between EtOAc and 1 N HCl, the organic layer was washed with brine, dried (MgSO 4) and evaporated. Purification by flash chromatography (gradient of EtOAc (0 to 25%) in DCM) gave 10 mg (20%) of the title compound 57: m / z = 784 (M + H) X EXAMPLE 10 Preparation of 17- [2- (3-isopropylpyrazol-1-yl) -7-methoxy-8-methylquinolin-4-yloxy-13-methyl-2.14-dioxo-3.13-diazatricicof 13.3.0.04.6] octadec acid -7-en-4-carboxylic (65) Step 1: Synthesis of ethyl 4-hydroxy-7-methoxy-8-methylquinoline-3-carboxylate (58) Diethyl ethoxymethylene malonate (17.2 g, 79.6 mmol) was added to 2-methyl-m-anisidine (8.4 g, 61.2 mmol) (exothermic reaction). Then, diethyl ether (100 ml) was added and the mixture was stirred overnight at room temperature. The solvent was evaporated and the residue redissolved in ether (50 ml), filtered, washed with heptane and dried to give 12 g of an intermediate. This intermediate was added in portions to diphenyl ether (50 ml) it was pre-heated at 230 ° C. The reaction mixture was subsequently heated at 250 ° C for 1.5 hr, cooled to room temperature and diluted with heptane (200 ml). The precipitate was filtered and subsequently washed with heptane and ether to give 9.2 g (57.5%) of the desired product 58 as a yellow powder: m / z = 262 (M + H) X Step 2: Synthesis of 4-Hydroxy-7-methoxy-8-methylquinoline (59) A suspension of ethyl 4-hydroxy-7-methoxy-8-methylquinoline-3-carboxylate (58.2.2 g, 35.2 mmol) in 5N NaOH (150 mL) was refluxed for 1.5 hr (until a solution was obtained clear). Then, the solution was cooled to 0 ° C and the pH was adjusted to 2-3 with concentrated HCl. The solid was filtered and subsequently washed with water, acetone and ether. This powder was added in small portions to diphenyl ether (40 ml), pre-heated to 250 ° C. The resulting suspension became a solution after 20 min (CO 2 formation was observed). After 1 hr at 250 ° C, the brown solution was cooled to room temperature and diluted with heptanes (200 ml). The precipitate was filtered and washed with heptanes and ether to give 6.4 g (96%) of the desired product 59 as a yellow powder: m / z = 190 (M + H) X Step 3: Synthesis of 4-Chloro-7-methoxy-8-methylquinoline (60) A solution of 4-hydroxy-7-methoxy-8-methylquinoline (59.6.4 g, 33.8 mmol) in POCI3 (17.2 g, 111.6 mmol) was heated at reflux for 1 hr. hr in nitrogen. Then, the resulting solution was cooled to room temperature and the excess of POCI3 was evaporated under reduced pressure. The residue was partitioned between cold 1N NaOH and AcOEt. The organic layer was dried (Na2SO4) and evaporated. The product was purified by filtration through silica gel (AcOEt / CH2Cl2 / Heptane, 4: 4: 2) to give 6.5 g (92.5%) of the desired product 60 as yellow needles: m / z = 208 (M + H) X Step 4: Synthesis of? / - 4-chloro-7-methoxy-8-methylquinoline oxide I61) Methachloroperbenzoic acid (90.2 g, 366.0 mmol) was added in portions over 3 hr to a solution of 4-chloro-7-methoxy-8-methylquinoline (60.15.2 g, 73.2 mmol) in CHCl3 (1 L). Then, the solution was divided between cold 1N NaOH and CH2CI2 (8 successive extractions). The organic layers were combined, dried (Na2SO4) and evaporated. The product was purified by column chromatography (gradient AcOEt / CH2Cl2, 1: 2 to 1: 0) to give 3.0 g (18.3%) of the title product 61 as a pale yellow powder: m / z = 224 (M + H) X Step 5: Synthesis of? / - 4-benzyloxy-7-methoxy-8-methylquinoline oxide (62) NaH (973 mg, 60% in mineral oil, 24.3 mmol) was added at 0 ° C, under an inert atmosphere, to benzyl alcohol (2.96 ml, 28.6 mmol) in DMF (10 ml). After 5 min at 0 ° C, the solution was warmed to room temperature. After 10 min at room temperature,? / - 4-chloro-7-methoxy-8-methylquinoline oxide (61.2.3 g, 14.3 mmol) was added in one portion. The resulting black solution was stirred at room temperature under inert atmosphere for another 30 min, then it was drained in cold water and extracted 4 times with AcOEt. The combined organic layers were dried (Na2SO) and evaporated. The product was purified by column chromatography (gradient AcOEt / CH2CI2, 1: 1 to 1: 0, then AcOEt / MeOH 9: 1) to give 2.5 g (59%) of the desired product 62 as a yellow powder: m / z = 296 (M + H) X Step 6: Synthesis of 4-benzyloxy-2-chloro-7-methoxy-8-methylquinoline (63.} POCI 3 was added under inert atmosphere at -78 ° C to α / 4-benzyloxy-7-methoxy-8-methylquinoline oxide (62, 2.5 g, 8.47 mmol). Then, the reaction mixture was allowed to warm to room temperature, then heated to reflux. After 35 min, the solution was cooled to room temperature and the excess of POCI3 was evaporated under reduced pressure. The residue was partitioned between cold water and AcOEt, dried (Na2SO) and evaporated. The residue was triturated in ether, then filtered and then washed with small portions of methanol and ether to give 2.4 g (90.4%) of the desired product 63 as a white powder: m / z = 314 (M + H) X Step 7: Synthesis of 4-hydroxy-2- (3-isopropylpyrazol-1-yl) -7-methoxy-8-methylquinoline (64) A mixture of 4-benzyloxy-2-chloro-7-methoxy-8-methylquinoline (63, 1.00 g, 3.19 mmol) and 3-isopropylpyrazole was heated at 155 ° C for 12 hr. Then, the reaction mixture was partitioned between AcOEt and water, dried (Na2SO4) and evaporated. The product was purified by column chromatography (AcOEt CH2Cl2, 1: 1) to give 900 mg (95%) of the desired product 64 as a yellowish powder: m / z = 298 (M + H) X Step 8: Synthesis of 17- [2- (3-? - sopropylpyrazol-1-yl) -7-methoxy-8-methyl-quinolin-4-yloxy-13-methylene-2,14-dioxo-3 acid , 13-diazatriciclof13.3.0.04 61 octadec-7-en-4-carboxylic acid (65) The title compound was prepared from 4-hydroxy-2- (3-isopropylpyrazol-1-yl) -7-methoxy-8-methylquinoline (64) and intermediate 26 following the procedure (Step DF) reported for the preparation of 17- [7-methoxy-8-methyl-2- (thiazol-2-yl) quinolin-4-yloxy] -13-methyl-2,14-dioxo-3,13-diazatricyclo [13.3.0.04'6] octadec-7-en-4-carboxylic acid (29): m / z = 630 (M + H) X EXAMPLE 11 Preparation of V-RI7-R2- (3-isopropylpyrazol-1-yl) -7-methoxy-8-methylquinolin-4-yloxyM3-methyl-2.14-dioxo-3.13-diazatricichlori3.3.0.04.61octadec-7- en-4- carbonyl] (cyclopropyl) sulfonamide (66) The title compound was prepared from 17- [2- (3-isopropylpyrazol-1-yl) -7-methoxy-8-methylquinolin-4-yloxy] -13-methyl-2,14-dl acid. oxo-3,13-diazatricyclo- [13.3.0.04,6] octadec-7-en-4-carboxylic acid (65) and cyclopropylsulfonamide following the reported procedure for the preparation of? / - [17- [8-chloro-2- (4-Isopropyl thiazol-2-yl) -7-methoxyquinolin-4-yloxy] -13-methyl-2,14-dioxo-3,13-diazatricyclo [13.3.0 04'6] -octadec- 7-en-4-carbonyl] (cyclopropyl) sulfonamide (56): m / z = 733 (M + H) +. 1 H NMR (CDCl 3): 0.80-1.50 (m, 12H), 1.65-1.78 (m, 1 H), 1.79-2.05 (m, 4H), 2.15-2.31 (m, 1 H), 2.32-2.48 (m, 2H), 2.49-2.63 (m, 5H), 2.84-2.96 (m, 2H), 3.03 (s, 3H), 3.05-3.14 (m, 1 H), 3.33-3.42 (m, 2H), 3.61-3.70 (m, 1 H), 3.96 (s, 3H), 4.60 (t, J = 12.3 Hz, 1 H), 5.04 (t, J = 10.6 Hz, 1 H), 5.26-5.46 (m, 1H), 5.61-5.69 (m, 1H), 6.32 (d, J = 2.5 Hz, 1 H), 6.37 (br s, 1H), 7.13 (d, J) = 9.0 Hz, 1 H), 7.30 (s, 1 H), 7.95 (d, J = 9.0 Hz, 1 H), 8.68 (d, J = 2.5 Hz, 1 H), 10.88 (br s, 1 H) .

EXAMPLE 12 Preparation of 17-f8-ethyl-2- (4-isopropylthiazol-2-yl) -7-methoxyquinolin-4-yloxy-13-methyl-2,14-dioxo-3,13-diazatricicof 13.3.0 acid. 0 ß1octadec-7-en-4-carboxylic (70) Step 1: Synthesis of? / - f2- (1-hydroxyethyl) -3-methoxyphenylpyivaloylamide (66) A solution of? / -butyllithium (2.5 M in hexanes, 4.4 ml, 11.1 mmol) was added dropwise at 0 ° C under nitrogen to a stirred solution of? / - (3-methoxyphenyl) pivaloylamide. After 1 hr at room temperature, the reaction mixture was cooled to -78 ° C. Then, a solution of acetaldehyde (544 μl, 9.64 mmol) in THF (1 ml) was added. After 10 min, the reaction mixture was allowed to warm to room temperature for 30 min. Then, the reaction mixture was partitioned between AcOEt and water, dried (Na2SO) and evaporated to give 500 mg (45%) of the desired product 66 as a yellow solid: m / z = 252 (M + H) X Step 2: Synthesis of? / - [2-ethyl-3-methoxyphenyl-1-pivaloylamide (67) 66 67 A mixture of? / - [2- (1-hydroxyethyl) -3-methoxy-phenyljpivaloylamide (66.42 g, 167 mmol), Pd / C (10%, 2.00 g) and H2SO (10 mL) in acetic acid was stirred ( 400 ml) at room temperature for 30 minutes. Then, the resulting reaction mixture was hydrogenated for 4 days, after which the catalyst was removed by filtration over kieselguhr. The filtrate was concentrated to 300 ml, then it was emptied into 1.0 l of water. The solid formed was filtered, washed with water to give the desired product 67 as a yellow solid: m / z = 236 (M + H) X Step 3: Synthesis of 2-ethyl-m-anisidine (68) 67 68 A solution of / V- [2-ethyl-3-methoxyphenyl] pivaloylamide (67.167 mmol) and 37% HCl (700 mL) in EtOH (700 mL) was refluxed for 48 hr. Then, the reaction mixture was cooled to room temperature environment and concentrated under reduced pressure (1/3 volume). This solution was maintained at 5 ° C for 6 hr. The solid that appeared was filtered and washed with diisopropyl ether to give 22.35 g of the desired product as its HCl salt. The free base was generated by treatment with K2C03 to give 20.85 g (83%) of the desired product 68: m / z = 152 (M + H) X Step 4: Synthesis of 8-ethyl-4-hydroxy-2- (4-isopropylthiazol-2-yl) -7-methoxyquinoline (69) The title compound was prepared from 2-ethyl-m-anisidine (68) following the procedure (steps 3-5) reported for the preparation of 4-hydroxy-2- (4-isopropylthiazol-2-yl) -7-methoxy-8-methylquinoline (36): m / z = 329 ( M + H) X Step 5: Synthesis of 17-f8-ethyl-2- (4-isopropylthiazol-2-yl) -7-methoxyquinolin-4-yloxy-13-methyl-2,14-dioxo-3,13- acid diazatriciclo [13.3.0.04'61 octadec-7-en-4-carboxilico (70) The title compound was prepared from 8-ethyl-4-hydroxy-2- (4-isopropylthiazol-2-yl) -7-methoxyquinoline (69) and intermediate 43 following the procedure (steps DF) reported for the preparation of 17- [2- (4-isopropylthiazol-2-yl) -7-methoxy-8-methylquinolin-4-yloxy] -13-methyl-2,14-dioxo-3, 13-diazatricyclo [13.3.0.0, 6] octadec-7-en-4-carboxylic acid (46): m / z = 661 (M + H) X EXAMPLE 13 W- [17- [8-Ethyl-2- (4-isopropylthiazol-2-yl) -7-methoxyquinolin-4-yloxyl-13-methyl-2.14-dioxo-3.13-diazatricichlori3.3.0.04, 61octadec-7-en-4- carbonylKciclopropiD-sulfonamide (71) The title compound was prepared from 17- [8-ethyl-2- (4-isopropylthiazol-2-yl) -7-methoxyquinolin-4-yloxy] -13-methyl-2,14-dioxo-3 acid, 13-diazatri-cyclo [13.3.0.04.6] -octadec-7-en-4-carboxylic acid (70) and cyclopropylsulfonamide following the reported procedure for the preparation of? / - [17- [8-chloro-2- (4 -isopropylthiazol-2-yl) -7-methoxyquinolin-4-yloxy] -13-methyl-2,14-dioxo-3,13-diazatricyclo- [13.3.0.0 6] -octadec-7-en-4-carbonyl] (cyclopropyl) sulfonamide (56): m / z = 764 (M + H) X EXAMPLE 14 Preparation of 17-r8-f1uoro-2- (4-isopropylthiazol-2-yl) -7-methoxyquinoline-l-xyl-13-methyl-2.14-dioxo-3.13-diazatricichlori3.3.0.0 61- octadec-7 acid -en-4-carboxylic (73) Step 1j 8-fluoro-4-hydroxy-2- (4-isopropylthiazol-2-yl) -7-methoxyquinoline (72) The title compound was prepared from 2-fluoro-3-methoxybenzoic acid following the procedure (steps 1-5) reported for the preparation of 4-hydroxy-2- (4-isopropylthiazol-2-yl) -7-methoxy -8-methylquinoline (36): m / z = 319 (M + H) X Step 2: Synthesis of 17-f8-fluoro-2- (4-isopropylthiazol-2-yl) -7-methoxyquinolin-4-yloxy-13-methyl-2,14-dioxo-3,13-diazatricyclo [13.3. 0.0 61 octadec-7-en-4-carboxylic (73) The title compound was prepared from 8-fluoro-4-hydroxy-2- (4-isopropylthiazol-2-yl) -7-methoxyquinoline (72) and alcohol 43 following the procedure (steps DF) reported for the preparation of 17- [2- (4-Isopropylthiazol-2-yl) -7-methoxy-8-methylquinolin-4-yloxy] -13-methyl-2,14-dioxo-3,13-diazatricyclo [13.3.0.04, 6] octadec-7-en-4-carboxylic acid (46): m / z = 651 (M + H) +.

EXAMPLE 15 < V-RI7- [8-fluoro-2- (4-isopropylthiazol-2-yl) -7-methoxyquinolin-yloxy] -13-methyl-2.14-dioxo-3.13-diazatricichlori3.3.0.04 61octadec-7-en- 4- carbonyl Kcyclopropylsulfonamide (74) The title compound was prepared from 17- [8-fluoro-2- (4-isopropylthiazol-2-yl) -7-methoxy-quinolin-4-yloxy] -13-methyl-2,14- dioxo-3,13-diazatricyclo [13.3.0.04,6] -octadec-7-en-4-carboxylic acid (73) and cyclopropylsulfonamide following the procedure reported for the preparation of? / - [17- [8-chloro- 2- (4-isopropylthiazol-2-yl) -7-methoxyquinolin-4-yloxy] -13-methyl-2, 14-dioxo-3, 13-diazatricyclo [13.3.0.04 6] -octadec-7-en-4 -carbonyl] (cyclopropyl) sulfonamide (56): m / z = 754 (M + H) X 1 H NMR (CDCl 3): 1 H NMR (CDCl 3): 0.75-1.52 (m, 15H), 1.64-2.05 (m, 4H ), 2.77 (m, 1 H), 2.41 (m, 2H), 2.59 (m, 2H), 2.92 (m, 2H), 3.04 (s, 3H), 3. 19 (m, 1 H), 3.40 (m, 2H), 4.07 (s, 3H), 4.60 (m, 1 H), 5.05 (t, J = 10.5 Hz, 1 H), 5.37 (m, 1 H), 5.66 (m, 1 H), 6.17 (s, 1 H), 7.07 (s, 1 H), 7.54 (s, 1 H), 7.86 (m, 1 H), 10.77 (broadband, 1 H).

EXAMPLE 16 Acid 18-f2- (4-isopropylthiazol-2-yl) -7-methoxy-8-methylquinolin-4-yloxp-2.15-dioxo-3.14-diazatricyclo [14.3.0.04.61nonadec-7-en-4-carboxylic acid (80) Step 1. Synthesis of? / - (hept-6-enyl) phthalimide (75) A solution of potassium phthalamide (627 mg, 3.38 mmol) and 7-bromohept-1-ene in dry DMF (10 ml) was stirred at 100 ° C under nitrogen for 1 hr. Then, the reaction mixture was subsequently cooled to room temperature, filtered, diluted with ether and filtered again. The filtrate was concentrated under reduced pressure to give the desired product 75 as an oil, which was used without further purification in the next step: m / z = 244 (M + H) X Step 2. Synthesis of 6-heptenylamine (76) A solution of? / - (hept-6-enyl) phthalimide (75.66.2 g, 272 mmol) and hydrazine hydrate (19.8 mL, 408 mmol) in MeOH (1.0 I) was stirred Room temperature until the next day. Then, the reaction mixture was cooled to room temperature and the solid was removed by filtration. The filtrate was diluted with ether and the solid formed was removed by filtration. The ether was evaporated under reduced pressure. Then, 5N HCl (50 ml) was added and the resulting mixture was stirred at reflux. After 45 min., The reaction mixture was cooled to room temperature and the solid formed was filtered. The pH of the filtrate was adjusted to 3 to 0 ° C with NaOH. Then, the reaction mixture was extracted with ether and dried (Na2SO4) and evaporated. The crude product was purified by distillation to give 34.57 g of the desired product 76 as an oil: m / z = 14 (M + H) X Step 3. Synthesis of the intermediary 77 The title compound was prepared from 6-heptenylamine (76) and 3-Oxo-2-oxa-bicyclo [2.2.1] heptane-5-carboxylic acid (22) following the reported procedure for the preparation of intermediate 23: m / z = 252 (M + H) X The title compound was also prepared (82 in isolated yield) using other coupling conons (EDCI.HCI (1.1 eq.), HOAT (1.1 eq.) and diisopropylethylamine in dry DMF. ).

Step 4. Intermediary synthesis 78 The title compound was prepared (65%) from intermediate 77 and LiOH following the reported procedure for the preparation of intermediate 24: m / z = 270 (M + H) X Step 5. Intermediary synthesis 79 The title compound was prepared (65%) from intermediate 78 and 1- (amino) -2- (vinyl) cyclopropanecarboxylic acid ethyl ester hydrochloride following the reported procedure for the preparation of intermediate 26: m / z = 407 (M + H) X Step 6. Synthesis of 18-f2- (4-isopropylthiazol-2-yl) -7-methoxy-8-methylquinolyl-4-yloxy1-2,15-dioxo-3,14-diazatriciclof14.3.0.04 acid, 61nonadec-7-en-4-carboxyl (80) The title compound was prepared from intermediate 79 and quinoline 36 following the procedure (steps DF) reported for the preparation of 17- [2- (4-isopropylthiazol-2-yl) -7-methoxy-8-methylquinoline- 4-yloxy] -13-methyl-2,14-dioxo-3,13-diazatricyclo [13.3.0.04'6] octadec-7-en-4-carboxylic acid (46): m / z = 647 (M + H) X EXAMPLE 17 / V-f18- [2- (4-isopropyl-thiazol-2-yl) -7-methoxy-8-methylalquinolin--yloxy-2.15-d -oxo-3,14-diazatrichlof14. 3.0.04.61nonadec-7-en-4-carbonin (cyclopropyl) -sulfonamide (81) 81 The title compound was prepared from 18- [2- (4-isopropyl-thiazol-2-yl) -7-methoxy-8-methyl-quinolin-4-yloxy] -2,15-dioxo-3,14- acid. diazatricyclo [14.3.0.0, 6] -nonadec-7-en-4-carboxylic acid (80) and cyclopropylsulfonamide following the reported procedure for the preparation of? / - [17- [2- (4-isopropylthiazol-2-yl) - 7-methoxy-8-methylquinolin-4-yloxy] -13-methyl-2,14-dioxo-3,13-diazatricyclo [13.3.0.04'6] -octadec-7-en-4-carbonyl] (cyclopropyl) sulfonamide (47): m / z = 750 (M + H) X 1 H NMR (CDCl 3): 0.90-0.96 (m, 1H), 1.1-1.2 (m, 4H), 1.39 (d, J = 6. 9 Hz, 6H), 1.4-1.55 (m, 5H), 1.80-1.92 (m, 5H), 2.15-2.25 (m, 1 H), 2.30-2.40 (m, 1H), 2.45-2.55 (m, 2H) ), 2.68 (s, 3H), 2.85-2.92 (m, 1 H), 3.15-3.30 (m, 2H), 3.45-3.55 (m, 2H), 3.96 (s, 3H), 4.09 (dd, J = 11.5 Hz, J = 3.8 Hz, 1 H), 4.61 (t, J = 7.9 Hz, 1H), 4.99 (t, J = 9.0 Hz, 1H), 5.51-5.53 (m, 1H), 5.71 (dd, J = 18.6 Hz, J = 8.2 Hz, 1H), 6.86 (s, 1H), 7.03 (s, 1H), 7.20 (d, J = 9.2 Hz, 1H), 7.50 (s, 1H), 7.88 (d, J = 9.2 Hz, 1H), 9.40 (br s, 1H).

EXAMPLE 18 / -rri8- r2-f4- (isopropyl) thiazol-2-in-7-methoxy-8-methyl-quinolin-4-yloxy-2-14-dioxo-14- (4-methoxy-benzyl) -3.14.16-triazatriciclof14 .3.0.0,61nonadec-7-en-4- pcarbonyl] (cyclopropyl) sulfonamide (90) Step A: Synthesis of the intermediary 82 Ethyl ester of Boc-c / s-hydroxy-L-proline (500 mg, 2.04 mmol), 4-hydroxy-2- [4- (sopropyl) thiazol-2-yl] -7-methoxy-8- was dried. methylquinoline (36, 769 mg, 2.04 mmol) and 2-diphenylphosphanylpyridine (751 mg, 2.86 mmol) in high vacuum for 1 hr. Dry THF was then added under nitrogen and the resulting reaction mixture was cooled to -15 ° C. Then, DIAD was added drop by drop. After 1 hr at -5 ° C the solution was allowed to warm to room temperature. After 16 hr, the reaction mixture was partitioned between cold water and AcOEt. The organic layer was then vigorously washed with 1 M HCl and brine, dried (MgSO), filtered and evaporated. Purification by column chromatography on silica gel (gradient AcOEt / CH2Cl2, 0:10 to 5:95) gave 940 mg (85%) of the desired product 82 as a colorless oil: m / z = 542 (M + H) +.

Step B: Synthesis of the intermediary 83 A solution of LiOH (592 mg, 13.8 mmol) in water was added to a solution of intermediate 82 (1.5 g, 2.77 mmol) in MeOH / THF 1: 1. After 16 hr at room temperature, the reaction mixture was acidified to pH 3-4 with dilute HCl, extracted with AcOEt, washed with brine, dried (MgSO4) and evaporated. The product was purified by flash chromatography (gradient AcOEt / CH2CI2, 1: 9 to 4: 6) to give 1.26 g (86%) of the title 83 product as an orange oil: m / z = 528 (M + H ) X Step C: Synthesis of the broker 84 To a stirred solution of carboxylic acid 83 (1.26 g, 2.39 mmol) in dry DMF (20 ml) was added (7f?, 2S) -1-amino-2-vinylcyclopropanecarboxylic acid ethyl ester tosylate (860 mg, 2.63 mmol). ) and diisopropylethylamine (1.04 ml, 5.98 mmol). Then, HATU (999 mg, 2.63 mmol) was added at 0 ° C under nitrogen. The resulting solution was stirred at 0 ° C for 30 minutes, then at room temperature. After 4 hr, the reaction mixture was diluted with water and extracted with AcOEt. The organic layers were combined and then washed with a saturated solution of NaHCO 3, water and brine, dried (MgSO 4) and evaporated. Purification by column chromatography (gradient AcOEt CH2Cl2, O 1 to 2 8) gave 1 44 g (90%) of the title product 84 as a white solid m / z = 665 (M + H) + Step D Synthesis of the broker 85 To a stirred solution of proline derivative protected by Boc 84 (1 44 g, 2 16 mmol) in CH 2 Cl 2 (20 ml) was added trifluoroacetic acid (5 ml) After 2 hr at room temperature, the reaction mixture was concentrated and the residue was partitioned between a saturated solution of NaHCO 3 and CH 2 Cl 2 The organic layer was dried (MgSO 4) filtered and concentrated to give 10 g (81%) of the title product 85 as a colorless oil m / z = 565 (M + H) + Step E: Synthesis of? / - (hept-6-enyl) -? / - (4-methoxybenzyl) amine 86 A solution of hept-6-enylamine (2.0 g, 13.4 mmol) and anisaldehyde (1.79 mL, 14.7 mmol) in EtOH (50 mL) was stirred at room temperature for 1 hr. Then, NaBH (556 mg, 14.7 mmol) was added at 0 ° C under nitrogen. The resulting solution was allowed to warm to room temperature for 4 hr. Then, the reaction mixture was partitioned between freezing water and CH 2 Cl 2, washed with brine, dried (Na 2 SO 4) and evaporated. The product was purified by chromatography (gradient AcOEt / CH2CI2 0: 1 to 2: 8, then CH2Cl2 / MeOH 9: 1) to give 1.8 g (34%) of the title product 86 as a colorless oil: m / z = 234 (M + H) X Step F: Synthesis of the intermediary 87 To a solution of proline derivative 85 in THF (50 ml) was added NaHCO3 (1.0 g). Then, phosgene was added (4.7 ml, 20% solution in toluene) at 0 ° C under nitrogen. After 1.5 hr, the white solid was filtered and washed with THF and CH2Cl2. Then, the filtrate was concentrated under reduced pressure and the residue was redissolved in dry dichloromethane (50 ml). To this solution, NaHCO3 (1.0 g) and subsequently protected amine 86 were added. After 16 hr at room temperature, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure the resulting residue was purified by silica chromatography (gradient AcOEt / CH2CI2, 0: 1 to 2: 8) to give 1.36 g (90%) of the title product 87: m / z = 824 ( M + H) X Step G: Synthesis of the intermediary 88 88 1st generation Hoveyda-Grubbs catalyst (50 mg, 0.082 mmol) was added to a degassed solution of diene 87 (1.36 g, 1.65 mmol) in toluene (170 ml). The resulting solution was heated at 80 ° C under nitrogen for 4 hr. Then, the reaction mixture was concentrated and purified by flash chromatography (gradient AcOEt / CH2Cl2, 0: 1 to 2: 8) to give 900 mg (65%) of the title 88 product as a brownish foam: m / z = 796 (M + H) X Step H: Synthesis of the intermediary 89 A solution of LiOH (242 mg, 5.65 mmol) in water (20 ml) was added to a solution of ester 88 (900 mg, 1.13 mmol) in MeOH / THF 1: 1. The reaction mixture was stirred at 50 ° C for 2 hr, then cooled to room temperature, acidified to pH 3-4 with dilute HCl and extracted with AcOEt. The organic layers were subsequently combined, washed with brine, dried (MgSO 4), filtered and evaporated to give 840 mg (97%) of the title product 89 as a slightly yellow solid: m / z = 768 (M + H) X Step I: Synthesis of? / - [[18-f2-f4- (isopropyl) thiazol-2-yl-1-7-methoxy-8-methylquinolin-4-yloxy-2, 15-dioxo-14- (4-methoxybenzyl) -3, 14, 16-triazatriciclo [14.3.0.04,61nonadec-7-en-4-incarbonil1 (cyclopropyl) sulfonamide (90) A solution of carboxylic acid 65 (830 mg, 1.03 mmol) and carbonyldiimidazole (333 mg, 2.06 mmol) in dry THF (20 ml) was stirred under reflux under nitrogen for 2 hr. Then, the reaction mixture was cooled to room temperature and cyclopropylsulfonamide (249 mg, 2.06 mmoles) and DBU (313 mg, 2.06 mmoles) were added. The resulting solution was stirred at 50 ° C for 12 hr, then cooled to room temperature. The reaction mixture was quenched with water and extracted with CH 2 Cl 2, washed with dilute HCl, dried (MgSO 4), filtered and evaporated. The crude material was purified by column chromatography (CH2Cl2 / EtOAc, 80:20) and re-crystallized from CH2Cl2 / ether to give 450 mg (50%) of the title 90 product as a white powder: m / z = 871 (M + H) +; 1 H-NMR (CDC): 1.05-1.61 (m, 18H), 2.00 (m, 1 H), 2.12-2.22 (m, 2H), 2.59-2.70 (m, 5H), 2.96 (m, 1 H), 3.15-3.20 (m, 3H), 3.63 (s, 3H), 3.71-3.78 (m, 2H), 3.88-3.94 (m, 4H), 4.54 (d, J = 15 Hz, 1H), 5.08 (t, J = 8.5 Hz, 1 H), 5.16 (t, J = 9.4 Hz, 1H), 5.38 (m, 1 H), 5.75 (m, 1 H), 6.45 (d, J = 8.4 Hz, 2H), 6.65 (d, J = 8.4 Hz, 2H), 7.03 (s, 1 H), 7.10 (d, J = 9.1 Hz, 1 H), 7.41 (s, 1 H), 7.73 (d, J = 9.1 Hz, 1 H), 7.76 (br s, 1 H), 10.15 (br s, 1 H).

EXAMPLE 19 / V- rri8-f2-r4- (isopropyl) thiazole-2-n-7-methoxy-8-methylquinoline-4-yloxp-2-dioxo-3.14.16-triazatriciclof14.3.0.04 61nonadec-7 en-4- M1carboniH (cyclopropyl) -sulfonamide (91) TFA (10 ml) was added to a solution of? / - [[18- [2- [4- (isopropyl) thiazol-2-yl] -7-methoxy-8-methyl-quinolin-4-yloxy] -2 , 15-d¡oxo-14- (4-methoxybenzyl) -3,1,16-triazatricyclo [14.3.0.04,6] nonadec-7-en-4-yl] carbonyl] (cyclopropyl) sulfonamide (90) in DCM (20 ml). After 30 min to Room temperature, water (20 ml) was added to the reaction mixture and the pH was adjusted to 3-4 with NaHCO3. The organic layer was washed with brine, dried (Na 2 SO 4), filtered and evaporated. The product was purified by column chromatography (gradient MeOH / CH CI2, 0: 1 to 1:99, then AcOEt / CH2CI21: 1) to give 313 mg (73%) of the desired title product 91 as a yellowish solid : m / z = 751 (M + H) X 1 H-NMR (CDCl 3): 0.88-1.64 (m, 16H), 1.96 (m, 2H), 2.52 (m, 1H), 2.68 (ms, 5H), 2.79 -2.92 (m, 3H), 3.18 (m, 1H), 3.63-3.69 (m, 2H), 3.86 (m, 1H), 3.97 (s, 3H), 4.34 (m, 1H), 4.59 (m, 1H) ), 5.08 (m, 1H), 5.40 (m, 1H), 5.80 (m, 1H), 6.73 (s, 1H), 7.03 (s, 1H), 7.21 (d, J = 8.9 Hz, 1H), 7.26 (br s, 1H), 7.47 (s, 1H), 7.92 (d, J = 8.9 Hz, 1H), 10.20 (brs, 1H).

EXAMPLE 20 ^ -pp8-r8-chloro-2- [4- (isopropyl) thiazol-2-yl] -7-methoxyquinolin-4-yloxy-2.15-dioxo-3,14,16-triazatric-clof14.3.0 .04 61nonadec-7-en-4- ncarbonyl] (cyclopropyl) sulfonamide (94) Step A: Synthesis of 4,8-dichloro-2- (4-isopropylthiazol-2-yl) -7-methoxyquinoline (92) A solution of 8-chloro-4-hydroxy-2- (4-isopropyl-thiazol-2-yl) -7-methoxy-quinoline (2.0 g, 5.97 mmol) in POCI3 (10 mL) was heated at 85 ° C for 30 min. . Then, the reaction mixture was concentrated under reduced pressure. The residue was poured into cold water (20 ml), the pH was adjusted to 10 with 50% NaOH and extracted with CH2Cl2. The organic layer was washed with brine, dried (MgSO 4), filtered and evaporated to give 2.05 g (97%) of the title compound 92 as a yellow solid: m / z = 353 (M + H) +.

Step B: Synthesis of the intermediary 93 NaH (60% in mineral oil, 679 mg, 17.0 mmol) in nitrogen was added to a solution of Boc-fra / is-hydroxy-L-proline-OH (2.0 g, 5.661 mmol) in dry DMF (50 mL). After 30 min at room temperature, a solution of 4,8-dichloro-2- (4-isopropylthiazol-2-yl) -7-methoxyquinoline (92, 1.38 g, 5.94 mmol) in dry DMF and the resulting solution was added. it was stirred until the next day at room temperature. Then, the reaction mixture was quenched with dilute HCl to pH 2, extracted twice with AcOEt and the combined organic layers were washed with brine, dried (MgSO4) and evaporated. The product was purified by column chromatography (gradient AcOEt CH2Cl2, 0: 1 to 1: 1) to give 2.35 g (75%) of the title 93: m / z = 548 (M + H) X Step C: Synthesis of? / - f [18-f8-chloro-2- [4- (isopropyl) thiazol-2-ill-7-methoxyquinolin-4-yloxy-2,15-dioxo-3, 14,16-triazatriciclo [14.3.0.04,61nona7-en-4-incarbon¡p- (cyclopropyl) sulfonamide (94) The title compound was synthesized from intermediate 93 following the procedure (steps C-1) reported for? / - [[18- [2- [4- (isopropyl) thiazol-2-yl] -7-methoxy- 8-Methyl-quinolin-4-yloxy] -2,15-dioxo-14- (4-methoxybenzyl) -3,14,16-triazatricyclo- [14.3.0.04.6] nona7-en-4 -il] carbon] (cyclopropyl) sulfonamide (90) and para? / - [[18- [2- [4- (isopropyl) thiazol-2-yl] -7-methoxy-8-methylquinolin-4-yloxy] -2,15-dioxo -3, 14,16-triazatricyclo [14.3.0.04.6] nona7-en-4-yl] carbonyl] (cyclopropyl) -sulfonamide (91): m / z = 771 (M) + 1 H-NMR ( CDCI3): 0.93 (m, 1H), 1.06-1.63 (m, 15H), 1.92 (m, 3H), 2. 50 (m, 1 H), 2.64 (m, 2 H), 2.76 (m, 1 H), 2.87 (m, 2 H), 3.20 (m, J = 6.9 Hz, 1 H), 3.70 (m, 1 H) , 3.77-3.87 (m, 1 H), 4.00 (dd, J = 4.0 Hz, 10.1 Hz, 1 H), 4.04 (s, 3H), 4.42 (m, 1 H), 4.59 (t, J = 7.3 Hz , 1 H), 5.05 (dd, J = 8.3 Hz, 9.9 Hz, 1 H), 5.51 (m, 1 H), 5.79 (m, 1 H), 7.03 (m, 1 H), 7.08 (s, 1 H), 7.22 (d, J = 9.3 Hz, 1 H), 7.54 ( s, 1 H), 7.95 (d, J = 9.3 Hz, 1 H).

EXAMPLE 21 A / -rri8-r8-chloro-2-r4- (isopropyl) thiazol-2-yn-7-methoxyquinolin-4-yloxy-2.15-dioxo-3.14.16-triazatricichlori4.3.0.04 61nona7-en -4-incarbonin (1- methylcyclopropylsulfonamide (95) The title compound was synthesized from intermediate 93 and 1-methyl-cyclopropylsulfonamide following the procedure (steps Cl) reported for? / - [[18- [2- [4- (isopropyl) thiazol-2-yl] -7] -methoxy-8-methylquinolin-4-yloxy] -2,15-dioxo-14- (4-methoxybenzyl) -3,14,16-triazatrichyl [14.3.0.04,6] nona7-en-4- il] carbonyl] - (cyclopropyl) sulfonamide (90) and for? / - [[18- [2- [4- (isopropyl) thiazol-2-yl] -7-methoxy-8-methylquinolin-4-yloxy] - 2,15-dioxo-3,14,16-triazatricyclo [14.3.0.04,6] -nona7-en-4-yl] carbonyl] (cyclopropyl) sulfonamide (91): m / z = 785 (M) X 1 H-NMR (CDCl 3): 0.90 (m, 1H), 1.12-1.60 (m, 16H), 1.74 (m, 1H), 1.90-1.99 (m, 4H), 2.51 ( m, 1H), 2.65-2.78 (m, 3H), 2.88 (m, 1H), 3.20 (m, J = 6.7 Hz, 1H), 3.69 (m, 1H), 3.84 (m, 1H), 3.96-4.00 (m, 1H), 4.01 (s, 3H), 4.46 (m, 1H), 4.63 (t, J = 7.4 Hz, 1H), 5.09 (t, J = 9.1 Hz, 1H), 5.50 (m, 1H) , 5.79 (m, 1H), 7.08 (m, 2H), 7.22 (d, J = 9.2 Hz, 1H), 7.52 (s, 1H), 7.95 (d, J = 9.2 Hz, 1H), 10.08 (brs, 1 HOUR).

EXAMPLE 22 (17-r2- (6-Methyl-2-pyridyl) -7-methoxy-8-methyl-quinolin-4-yloxyl-13-methyl-2.14-dioxo-3,13-diaza-tricyclo [13.3 .0.046locta7-in-4-carbonyl> -cyclopropanesulfonic acid amide (103) 103 Step A: Synthesis of 6-methyl-pyridine-2-carboxylic acid (6-acetyl-3-methoxy-2-methylphenyl) -amide (96) 6-Methylpicolinic acid (1.12 g, 8,167 mmol) was dissolved in dry DCM (100 ml) and kept in an ice bath. Then, 6-acetyl-3-methoxy-2-methylaniline (1.48 g, 8.17 mmol) and pyridine (6.6 ml, 0.082 mol) were added followed by the dropwise addition of POCI3 (1.53 ml, 0.016 mol) for 15 minutes. . The resulting solution was stirred at -5 ° C for 1 hr. Then, water (100 ml) was carefully added and after 5 min of stirring, NaOH (40%, 20 ml) was added dropwise consecutively, followed by separation of the organic layer. The water layer was extracted three times with CH2Cl2 and the combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated. The product was purified by column chromatography (Heptane / AcOEt, 3: 1) to give the title compound (2.1 g, 86%): m / z = 299 (M + H) X Step B: Synthesis of 4-hydroxy-2- (6-methyl-2-pyridyl) -7-methoxy-8-methylquinoline (97) To a solution of 6-methylpyridine-2-carboxylic acid (6-acetyl-3-methoxy-2-methylphenyl) -amide (96) in pyridine (15 ml) was added 2.5 equivalents of freshly ground KOH together with water (200 μl). The mixture was heated by microwave irradiation at 150 ° C for 30 min, then 80-85% of the pyridine was evaporated under reduced pressure. The residue was emptied on ice and neutralized with acetic acid. The precipitate was filtered, then dried to give the title compound (1.8 g, 95%): m / z = 299 (M + H) X Step C: Synthesis of 2- (1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -4- [2- (6-methyl-2-pyridyl) -7-methoxy-8-methylquinoline- tert -butyl ester. 4-yloxyl-cyclopentanecarboxylic acid (98) A solution of 2- (1-ethoxycarbonyl-2-vinylcyclopropylcarbamoyl) -4-hydroxycyclopentanecarboxylic acid tert-butyl ester (500 mg, 1.5 mmol), prepared as described in WO2005 / 073195, 4-hydroxy-2- (6-methyl-2-pyridyl) -7-methoxy-8-methylquinoline (97, 504 mg, 1.8 mmol) and triphenylphosphine ( 990 mg, 3.75 mmol) in dry THF (40 ml) at 0 ° C for 10 min. Then, DIAD (0.74 ml, 3.75 mmol) was added drop by drop. The resulting reaction mixture was stirred at a temperature of 0 ° C to 22 ° C until the next day. Then, the volatiles were evaporated and the product was purified by column chromatography on silica gel (gradient CH2Cl2 / AcOEt, 1: 0 to 95: 5) to give 1.1 g (88%) of the title compound 98: m / z = 630 (M + H) X Step D: Synthesis of 2- (1-ethoxycarbonyl-2-vinylcyclopropylcarbamoyl) -4- [2- (6-methyl-2-pyridyl) -7-methoxy-8-methylquinolin-4-yloxylcyclopentanecarboxylic acid (99) TFA (24 ml) was added at room temperature to a solution of 2- (1-ethoxycarbonyl-2-vinylcyclopropylcarbamoyl) -4- [2- (6-methyl-2-pyridyl) -7-methoxy-tert-butyl ester. -8-methylquinolin-4-yloxy] cyclopentanecarboxylic acid (98.1.1 g, 1.75 mmol) and triethylsilane (510 mg, 2.5 eq) in CH2Cl2 (24 ml). After After 2 hr, the reaction mixture was concentrated under reduced pressure and then coevaporated with toluene. The residue was re-dissolved in AcOEt and subsequently washed with a solution of NaHCO3 and brine. The organic layer was dried (MgSO 4), filtered and evaporated, to give 800 mg (80%) of the title compound 99 (800 mg, 80%): m / z = 574 (M + H) +.

Step E: Synthesis of ethyl ester of acid 1-. { 2- (hex-5-enylmethylcarbamoyl) -4- [2- (6-methyl-2-pyridyl) -7-methoxy-8-methylquinolin-4-yloxylcyclopentanecarbonyl) amino-2-vinylcyclopropanecarboxylic acid (100) A solution of 2- (1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -4- [2- (6-methyl-2-pyridyl) -7-methoxy-8-methylquinolin-4-yloxy acid was stirred. ] -cyclopentanecarboxylic acid (99, 0.77 g, 1344 mmol),? / - methylhex-5-enylamine hydrochloride (221 mg, 1.95 mmol) and diisopropylethylamine (1.17 mL, 6.72 mmol) in DMF (25 mL) at 0 ° C under inert atmosphere. After 30 min, HATU (741 mg, 1.95 mmol) was added and the reaction mixture was allowed to warm to room temperature until the next day. Then, the DMF was evaporated and the residue was partitioned between AcOEt and a solution of NaHCO3. The The organic layer was washed successively with water and brine, dried (MgSO 4), filtered and evaporated. The crude product was purified by silica gel chromatography (gradient Heptane / AcOEt 80:20 to 50:50) to give 735 mg (82%) of the title compound: m / z = 669 (M + H) X Step F: Synthesis of 17- [2- (6-Methylpyridin-2-yl) -7-methoxy-8-methylene-quinolin-4-loxi-13-methylene-2,14 ethyl ester. -dioxo-3,13-diaza-tricyclo [13.3.0.04 6-octadec-7-en-4-carboxylic acid (101) 101 1-ethyl ester was dissolved. { 2- (Hex-5-enylmethylcarbamoyl) -4- [2- (6-methyl-2-pyridyl) -7-methoxy-8-methylquinolin-4-yloxy] cyclopentanecarbonyl} amino-2-vinyl-cyclopropanecarboxylic acid (100.250 mg, 0.37 mmol) in dry 1,2-dichloroethane (250 ml). Then, nitrogen gas was bubbled through the solution for 30 min before adding 2nd generation Hoveyda-Grubbs (25 mg). The resulting solution was refluxed overnight, then cooled to room temperature and evaporated. The product was purified by column chromatography on silica gel (gradient AcOEt / Heptane, 3: 7 to 5: 5) to give 139 mg (58%) of the title compound 101.

Step G: Synthesis of 17- [2- (6-methyl-2-pyridyl!) - 7-methoxy-8-methylquinolin-4-yloxy-13-methyl-2,14-dioxo-3,13- acid diazatricyclo [13.3.0.04 61octadec-7-en-4-carboxylic acid (102) LiOH (0.42 mL, 1 M) was added to a solution of 17- [2- (6-methylpyridin-2-yl) -7-methoxy-8-methyl-quinoline-4-yloxy acid ethyl ester! ] -13-methyl-2,14-dioxo-3,13-diaza-tricyclo [13.3.0.04'6] octadec-7-en-4-carboxylic acid (101.27 mg, 0. 042 mmol) in a mixture of THF: MeOH: H 2 O, 2: 1: 1 (6 ml). The resulting solution was stirred at room temperature until the next day, then the pH was adjusted to 6 with acetic acid. The reaction mixture was subsequently diluted with water, extracted with CH2Cl2, dried (MgSO4), filtered and evaporated to give 17 mg (65%) of the title compound: m / z = 613 (M + H) X Step H: Synthesis of (17- [2- (6-methyl-2-pyridyl) -7-methoxy-8-methyl-quinolin-4-yloxy-13-methyl-2,14-dioxo-3,13-diaza -triciclof13.3.0.0 6loctadec-7-in-4-carbonyl) -cyclopropanesulfonic acid amide (103) 103 A mixture of 17- [2- (6-methyl-2-pyridyl) -7-methoxy-8-methylquinolin-4-yloxy] -13-methyl-2,14-dioxo-3,13-d acid was heated. [13.3.0.04'6] octadec-7-en-4-carboxylic acid (102.28 mg, 0.046 mmol) and CDI (15 mg, 0.092 mmol) in dry THF (3 mL) at reflux for 2 hr in nitrogen. Activation was monitored by LC-MS. The reaction mixture was cooled to room temperature and cyclopropylsulfonamide (17 mg, 0.137 mmol) was added. Then, DBU (16 μL, 0.105 mmol) was added and the reaction was heated to 55 ° C. After 24 hr, the pH of the reaction mixture was adjusted to 3 with citric acid (5%). Then, the solvent was evaporated and the residue was partitioned between AcOEt and water. The crude material was purified by preparative HPLC to give 17 mg (52%) of the objective compound 103: m / z = 716 (M + H) X EXAMPLE 23 (17-r2- (6-isopropyl-2-pyridyl) -7-methoxy-8-methyl-quinolin-4-yloxyl-13-methyl-2.14-dioxo-3.13-diaza-tricyclo [13.3.0.04.61octac -7-en-4-carbonyl) -cyclopropanesulfonic acid amide (114) 114 Step A: Synthesis of 2-isopropy pyridine N-oxide (104) A mixture of isopropilpyridine (2.1 g, 17.75 mmol) and m-CPBA (5.0 g, 1.3 eq.) In CH2Cl2 was stirred until the next day at room temperature. Then, the reaction mixture was diluted with CH 2 Cl 2 (twice the volume) and subsequently washed with aqueous sodium carbonate (twice) and brine, dried (Na 2 SO) and evaporated to give 2.0 g (85%) of the compound of title 104.

Step B: Synthesis of 2-cyano-6-isopropylpyridine (105) A mixture of 2-isopropylpyridine N-oxide (104, 1.33 g, 9.7 mmol), cyanotrimethylsilane (TMS-CN) (1.42 mL, 1.06 g, 11.0 mmol) in 1,2-dichloroethane (40 mL) was stirred at room temperature during 5 min Then, diethylcarbamoyl chloride (Et2NCOCI, 1.23 ml, 9.7 mmol) was added and the mixture was stirred at room temperature under inert atmosphere. After 2 days, an aqueous solution of potassium carbonate (10%) was added and stirring was continued for 10 min. The organic layer was separated and the water layer was extracted twice with 1,2-dichloroethane. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated. The product was purified by column chromatography on silica gel (Hexanes / AcOEt, 3: 1) to give 1.06 (74%) of the title compound: m / z = 147 (M + H) X Step C: Synthesis of 6-isopropylpyridine-2-carboxylic acid (106) A solution of 2-cyano-6-εorpopilpyridine (105, 1.06 g, 7.3 mmol) in 37% aqueous HCl-MeOH (1: 2) was heated to reflux until the day following. Then, the solvent was evaporated and the residue was emptied into a saturated solution of KOH. The resulting solution was refluxed until the next day. Then, the solution was subsequently cooled to room temperature and the pH of was adjusted to 5 by the addition of aqueous HCl. The resulting reaction mixture was then extracted with chloroform, washed with brine, dried (Na 2 SO 4) and evaporated to give 0.97 g (81%) of the title compound 106: m / z = 166 (M + H) X Step D: Synthesis of 6-isopropylpyridine-2-carboxylic acid (6-acetyl-3-methoxy-2-methylphenol!) (107) POCI3 (0.88 mL, 9.53 mmol) was added at -25 ° C dropwise for 5 min under nitrogen, to a stirred solution of 6-isopropylpyridine-2-carboxylic acid (106, 1.43 g, 8.66 mmol) and 6-acetyl. 3-methoxy-2-methylaniline (1.55 g, 8.66 mmol) in dry pyridine (70 ml). The resulting solution was stirred at -10 ° C for 2.5 hr. Then, the reaction mixture was emptied on ice, neutralized with aqueous sodium carbonate and extracted 3 times with AcOEt. The organic layers were combined, washed with brine, dried (Na2SO) and evaporated. The product was purified by chromatography on column (hexanes / AcOEt, 3: 1) to give 3.54 g (72%) of the title compound 107: m / z = 327 (M + H) X Step E: Synthesis of 4-hydroxy-2- (6-isopropyl-2-pyridyl) -7-methoxy-8-methylquinoline (108) To a solution of 6-isopropylpyridine-2-carboxylic acid (6-acetyl-3-methoxy-2-methylphenyl) -amide (107, 0.70 g, 2.14 mmol) in pyridine (5 ml) was added 2.5 equivalents of freshly ground KOH. together with water (50 μl). The mixture was heated by microwave irradiation at 133 ° C for 55 min, then 80-85% of the pyridine was evaporated under reduced pressure. The residue was emptied on ice and neutralized with acetic acid. The precipitate was filtered, then dried to give 0.62 g (95%) of the title compound 108 (1.8 g, 95%): m / z = 309 (M + H) X Step F: Synthesis of 2- (1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -4-f2- (6-isopropyl-pyridin-2-yl) -7-methoxy-8-tert-butyl ester. -methyl-quinoline-4-yloxp-cyclopentanecarboxylic acid (109) The title compound was prepared in 62% isolated yield of 2- (1-ethoxycarbonyl-2-vinylcyclopropylcarbamoyl) -4-hydroxy-cyclopentanecarboxylic acid tert-butyl ester and 4-hydroxy-2- (6-isopropyl-2-) pyridyl) -7-methoxy-8-methylquinoline (108) following the reported procedure for the preparation of 2- (1-ethoxycarbonyl-2-vinylcyclopropylcarbamoyl) -4- [2- (6-methyl-2-tert.-butyl ester. -pyridyl) -7-methoxy-8-methylquinolin-4-yloxy] cyclopentanecarboxylic acid (98): m / z = 658 (M + H) X Step G: Synthesis of 2- (1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -4-f2- (6-isopropyl-2-pyridyl) -7-methoxy-8-methylquinolin-4-yloxyfluoropentanecarboxylic acid (110) TFA (5 ml) was added at room temperature to a solution of 2- (1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -4- [2- (6-isopropyl-pyridin-2-yl) tert-butyl ester) 7-methoxy-8-methyl-quinolin-4-yloxy] -cyclopentanecarboxylic acid (109.590 mg, 0.90 mmol) and triethylsilane (280 mg, 2.5 eq) in CH2Cl2 (5 mL). After 2 hr, the reaction mixture was concentrated under reduced pressure to give the desired product 110, which was used in the next step without further purifications.

Step H: Synthesis of ethyl ester of acid 1-. { 2- (hex-5-enylmetlcarbamoyl) -4- [2- (6-isopropyl-2-pyridyl) -7-methoxy-8-methylquinolin-4-yloxy-1-cyclopentanecarbonyl) amino-2-vinyl-cyclopropanecarboxylic acid (11) The title compound 111 was prepared in 70% isolated yield of 2- (1-ethoxycarbonyl-2-vinylcyclopropylcarbamoyl) -4- [2- (6-isopropyl-2-pyridyl) -7-methoxy-8- methylquinolin-4-yloxy] cyclopentanecarboxylic acid (110) following the procedure reported for the preparation of ethyl ester of acid 1-. { 2- (hex-5-enylmetlcarbamoyl) -4- [2- (6-methyl-2-pyridyl) -7-methoxy-8-methylquinolin-4-yloxy] -cyclopentanecarbonyl} amino-2-vinylcyclopropanecarboxylic acid (100): m / z = 697 (M + H) X Step I: Synthesis of 17- [2- (6-isopropyl-2-pyridyl) -7-methoxy-8-methylquinolin-4-yloxy] -13-methyl-2,14-dioxo-3-ethyl ester , 13-diazatriciclo f13.3.0.04 61octadec-7-en-4-carboxylic (112) 112 1- ethyl ester was dissolved. { 2- (hex-5-enylmethylcarbamoyl) -4- [2- (6-isopropyl-2-pyridyl) -7-methoxy-8-methylquinolin-4-yloxy] cyclopentanecarbonyl} amino-2-vinyl-cyclopropanecarboxylic acid (111, 438 mg, 0.50 mmol) in dry 1,2-dichloroethane. Then, nitrogen gas was bubbled through the solution for 30 min before adding 1st generation Hoveyda-Grubbs (15 mg). The resulting solution was refluxed for 3 hr, then more catalyst (20 mg) was added. After 2 hr at reflux, another 10 mg of the catalyst was added. After 12 hr at reflux, the reaction mixture was cooled to room temperature. Then, sweeping agent MP-TMT (Agronaut Technologies Inc.) (-300 mg) was added and the mixture was stirred at room temperature for 45 min. The catalyst was removed by filtration on silica gel (gradient of CHCl3 / MeOH, 1: 0 to 98: 2) to give 220 mg (66%) of the title compound 112: m / z = 669 (M + H) X Step J: Synthesis of 17-22- (6-isopropyl-2-pyridyl) -7-methoxy-8-methylquinolyl-4-yloxp-13-methyl-2,14-dioxo-3,13-diazatricyclo acid 13.3.0.04,61octadec-7-en-4-carboxylic acid (113) 113 A solution of LiOH (40 mg) in water (1.5 ml) was added to a solution of 17- [2- (6-isopropyl-2-pyridyl) -7-methoxy-8-methylquinoline-4-ethyl ester. iloxy] -13-methyl-2,14-dioxo-3,13-diazatricyclo [13.3.0.0, 6] octadec-7-en-4-carboxylic acid (112, 220 mg, 0.33 mmol) in a mixture of MeOH (3 ml) and THF (1 ml). The resulting solution was subsequently heated to 55 ° C for 3 hr, then stirred at room temperature for 5 hr. Then, the pH of the reaction mixture was adjusted to pH 6 with acetic acid and water (3 ml) was added. The resulting solution was extracted with CHCl3. Then, the organic layer was dried (Na2SO4), filtered and evaporated to give 200 mg (95%) of the title compound 113 as a white powder: m / z = 641 (M + H) X Step K: Synthesis of (17-22- (6-isopropyl-2-pyridyl) -7-methoxy-8-methyl-quinolin-4-yloxyl-13-methyl-2,14-dioxo-3.13-diaza-tricyclo [ 13.3.0.04 6loctadec-7-en-4-carboni!) Cyclopropanesulfonic acid amide (114) 114 A solution of 17- [2- (6-isopropyl-2-pyridyl) -7-methoxy-8-methylquinolin-4-yloxy] -13-methyl-2,14-dioxo-3,13-diazatr acid was stirred. Cyclo [13.3.0.04 6] octadec-7-en-4-carboxylic acid (113.200 mg, 0.31 mmol), DMAP (76.5 mg, 0.62 mmol) and EDC (151 mg, 0.78 mmol) in DMF (5 ml) at room temperature until the next day (activation of the acid was monitored by LC-MS). Then, cyclopropylsulfonamide (191 mg, 1.56 mmole) was added, followed by DBU (228 μL, 1.56 mmole). The resulting solution was stirred overnight at room temperature, then neutralized with acetic acid and evaporated. The residue was redissolved in MeOH and purified by preparative HPLC to give 90 mg (39%) of the title compound 114: m / z = 744 (M + H) X EXAMPLE 24 (17-r2- (2-Cyclohexyl-thiazol-4-yl) -7-methoxy-8-methylquinolin-4-yloxy] -13-methyl-2.14-dioxo-3.13-diaza-trichlori3.3.0.04 61octadec -7-en-4-carbonyl) (6S) -cyclopropanesulfonic acid (123) and (17-r2- (2-cyclohexylthiazol-4-yl) -7-methoxy-8-methylquinolin-4-yloxy] - 13-methyl-2,14-dioxo-3,13-diazatricyclo [13.3.0.04, ßloctadec-7-en-4-carbonyl) (6R) -cyclopropanesulfonic acid amide (124) Step A: Synthesis of cyclohexanecarbothioic acid amide (115) To a suspension of cyclohexanecarboxamide (10 g, 78.6 mmol) in diethyl ether (300 ml) was added phosphorus pentasulfide (9.0 g, 200 mmol) in three portions over 5 hr. After stirring until the next day the reaction mixture was filtered. The mother liquor evaporated to give . 5 g (49%) of the title compound 115.

Step B: Synthesis of 2-cyclohexylthiazole-4-carboxylic acid ethyl ester (116) A solution of cyclohexanecarbothioic acid amide (115.5.5 g, 38.3 mmol) and ethyl 3-bromopyruvate (90%, 8.3 g, 38.3 mmol) in THF (200 mL) was heated to reflux. After 2 hr, the reaction mixture was cooled to room temperature for 12 hr. Then, the solvent was evaporated and the product was purified by column chromatography (gradient of heptane / AcOEt, 90:10 to 75:25) to give 6.8 g (74%) of the title compound 116 as a clear liquid.

Step C: Synthesis of 2-cyclohexylthiazole-4-carboxylic acid (117) To a solution of 2-cyclohexylthiazole-4-carboxylic acid ethyl ester (116.6.8 g, 28.5 mmol) in water was added 1 M LiOH (50 mL). The solution was maintained at room temperature and monitored by LC-MS. When the hydrolysis was complete, the reaction mixture was neutralized with myric acid and extracted with ethyl acetate and diethyl ether. The organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure to give 5.0 g (83%) of the title compound 117: m / z = 212 (M + H) X Step D: Synthesis of 2-cyclohexylthiazole-4-carboxylic acid (6-acetyl-3-methoxy-2-methylphenyl) amide (118) POCI3 (1.4 mL, 14.9 mmol) was added dropwise at -35 ° C for 5 min to a stirred solution of 2-cyclohexylthiazole-4-carboxylic acid (117.1.5 g, 7.1 mmol) and 2-acetyl-5 -methoxy-6-methylaniline (1.27 g, 7.1 mmol) in dry pyridine (40 ml). After 1 hr, the reaction mixture was subsequently heated to room temperature for 2.5 hr, evaporated and neutralized with an aqueous solution of sodium bicarbonate. The precipitate was filtered, washed with water and dried to give 2.6 g (95%) of the title compound 118: m / z = 373 (M + H) X Step E: Synthesis of 2- (2-cyclohexylthiazol-4-yl) -4-hydroxy-7-methoxy-8-methylquinoline (119) Freshly ground KOH (2 mmole, 112 mg) was added to a solution of 2-cyclohexylthiazole-4-carboxylic acid (6-acetyl-3-methoxy-2-methylphenyl) amide (118, 373 mg, 2 mmol) in pyridine (20 ml). The mixture was divided into several batches and each batch was individually heated by microwave irradiation at 150 ° C for 30 min. Then, the different batches were combined and the pyridine was evaporated. The residue was treated with aqueous citric acid to give a suspension, which was subsequently diluted with a small volume of EtOH, then partitioned between water and CH2Cl2. The organic layer was dried (Na2SO4) and evaporated. The product was purified by column chromatography (gradient of CH2Cl2: MeOH, 1: 0 to 93: 7) to give 1.8 g (72.5%) of the title compound 119 as a white powder: m / z = 355 (M + H ) X Step F: Synthesis of ethyl ester of acid 1-. { [4- [2- (2-cyclohexylthiazol-4-yl) -7-methoxy-8-methyl-quinolin-4-yloxy-2- (hex-5-enylmethyl-carbamoyl) cyclopentanecarbonyl-amino) -2-vinylcyclopropanecarboxylic (120) The title compound 120 was prepared in 42% yield from the ethyl ester of acid 1-. { [4- [2- (2-cyclohexylthiazol-4-yl) -7-methoxy-8-methyl-quinolin-4-yloxy] -2- (hex-5-enylmethylcarbamoyl) -cyclopentanecarbonyl] amino} -2-vinylcyclopropane-carboxylic acid (120) following the procedure reported for the preparation of ethyl ester of acid 1-. { 2- (hex-5-enylmethylcarbamoyl) -4- [2- (6-isopropyl-2-pyridyl) -7-methoxy-8-methyl-quinolin-4-yloxy] -cyclopentanecarbonyl} amino-2-vinyl-cyclopropanecarboxylic acid (111): m / z = 743 (M + H) X Step G: Synthesis of 17- [2- (2-cyclohexylthiazol-4-yl) -7-methoxy-8-methyl-quinolin-4-yloxy-13-methyl-2,14-dioxo- acid ethyl ester 3.13-diazatricicof 13.3.0.04 6-octadec-7-en-4-carboxylic acid (121) 121 The title compound 121 was prepared in 50% yield from 2- (2-cyclohexyl thiazol-4-yl) -4-hydroxy-7-methoxy-8-methylenequinoline (19) and ternary ester. butyl 2- (1-ethoxycarbonyl-2-vinylcyclopropylcarbamoyl) -4-hydroxycyclopentanecarboxylic acid following the reported procedure for the preparation of ethyl ester of 17- [2- (6-methylpyridin-2-yl) -7 -methoxy-8-methyl-quinolin-4-yloxy] -13-methyl-2,14-dioxo-3,13-diaza-tricyclo [13.3.0.04'6] octadec-7-en-4-carboxylic acid ( 101): m / z = 715 (M + H) X Step H: Synthesis of 17- [2- (2-cyclohexylthiazol-4-yl) -7-methoxy-8-methylquinolin-4-yloxy-13-methyl-2,14-dioxo-3,13-diazatricyclo [13.3] .0.04 6l octadec-7-en-4-carboxylic (122) 122 An aqueous solution of LiOH (1 M, 5 mL) was added to a solution of 17- [2- (2-cyclohexylthiazol-4-yl) -7-methoxy-8-methyl-quinolin-4-yloxy acid ethyl ester. ] -13-methyl-2,14-dioxo-3,13-diazatricyclo [13.3.0.04.6) octadec-7-en-4-carboxylic acid (121) in MeOH (10 ml), THF (20 ml) and water (5 ml). The resulting solution was stirred at 50 ° C for 19 hr. Then, the pH of the reaction mixture was adjusted to 6 with myristic acid (3M, 1.7 ml). The resulting solution was evaporated on silica gel and purified by column chromatography (AcOEt / MeOH / AcOH, 74: 25: 1) to give 273 mg (95%) of the title compound 122 as a white powder: m / z = 687 (M + H) +.

Step I: Synthesis of. { 17- [2- (2-cyclohexylthiazol-4-yl) -7-methoxy-8-methylquinolin-4-yloxy-1, 13-methyl-2,14-dioxo-3,13-diaza-tri-cyclic 13.3.0.0 | octodec -7-en-4-carbonyl) (6S) -cyclopropanesulfonic acid amide (123) and (17- [2- (2-cyclohexylthiazol-4-yl) -7-methoxy-8-methylquinolin-4-yloxyl) L-13-methyl-2,14-dioxo-3, 13-diaza-tricyclo [13.3.0.0, 6-octadec-7-en-4-carbonyl) (6R) -cyclopropanesulfonic acid amide (124) (6R) 124 A solution of 17- [2- (2-cyclohexylthiazol-4-yl) -7-methoxy-8-methylquinolin-4-yloxy] -13-methyl-2,14-d -oxo-3,13- acid was heated. diazatricyclo [13.3.0.04'6] octadec-7-en-4-carboxylic acid (122, 173 mg, 0.25 mmol) and CDI (81 mg, 0.5 mmol) in THF (7.5 ml) at reflux for 2 hr (activation of the acid was monitored by LC-MS). Then, the reaction mixture was cooled to room temperature and cyclopropylsulfonamide (91 mg, 0.75 mmol) and DBU (8 μl, 0.575 mmol) were added subsequently. After 12 hr, the reaction mixture was neutralized with acetic acid, evaporated. The residue was re-dissolved in water and acetonitrile, then purified by preparative HPLC to give 21 mg (11%) of the title compound (123, first isomer): m / z = 790 (M + H) + and 35 mg (18%) of the second isomer 124: m / z = 790 (M + H) \ EXAMPLE 25 Preparation of ^ - [^ - [SO-isopropylpyrazol-l-iD ^ -methoxy-S-methylquinolin-4-yloxyl-13-methyl-2,14-dioxo-3,13-diazatricicloI13.3.0.04 61octac 7- € n-4-carbonylip- (methyl) cyclopropylsulfonamide (125) The title compound was prepared from 17- [2- (3-isopropyrazol-1-yl) -7-methoxy-8-methylquinolin-4-yloxy] -13-methyl-2,14-dioxo-3 acid. , 13-diazatricyclo- [13.3.0.04.6] octadec-7-en-4-carboxylic acid (65) and 1-methylcyclopropyl-sulfonamide following the reported procedure for the preparation of N- [17- [8-chloro-2- (4-isopropylthiazol-2-yl) -7-methoxyquinolin-4-yloxy] -13-methyl-2,14-dioxo-3,13-diazatricyclo [13.3.0.0, 6] octadec-7-en-4-carbonyl ] (cyclopropyl) sulfonamide (56): m / z = 747 (M + H) X 1 H NMR (CDCl 3): 0.79-0.92 (m, 2H), 1.20-2.03 (m, 19H), 2.20-2.32 (m, 1 H), 2.35-2.48 (m, 2H), 2.52-2.64 (m, 5H), 2.85-2.93 (m, 1 H), 3.04 (s, 3H), 3.05-3.14 (m, 1 H), 3.35 -3.46 (m, 2H), 3.97 (s, 3H), 4.60 (td, J = 13.2 Hz, J = 2.2 Hz, 1 H), 5.04 (t, J = 10.5 Hz, 1 H), 5.30-5.47 (m, 1 H), 5.61-5.69 (m, 1 H), 6.30 (s, 1 H), 6.32 (d, J = 2.4 Hz, 1 H), 7.12 (d, J = 9.2 Hz, 1 H), 7.30 (s, 1 H), 7.95 (d, J = 9.0 Hz, 1 H), 8.61 (d, J = 2.5 Hz, 1 H), 10.9 (br s, 1 H).

EXAMPLE 26 Preparation of 17- [2- (3-tert-Butylpyrazol-1-yl) -7-methoxy-8-methylquinolin-4-yloxy] -13-methyl-2,14-dioxo-3,13-diazatricycloH3 acid .3.0.04 61octadec-7-in-4 -carboxylic (127) Step 1: Synthesis of 4-hydroxy-2- (3-rer-butylprazrazol-1-yl) -7-methoxy-8-methylquinoline (126) The title compound was prepared from 4-benzyloxy-2-chloro-7-methoxy-8-methylquinoline (63) and 3-tert-butylpyrazol following the reported procedure for the preparation of 4-hydroxy-2- (3- isopropylpyrazol-1-yl) -7-methoxy-8-methylquinoline (64): m / z = 312 (M + H) X Step 2: Synthesis of acid 17- [2- (3- / er-butylpyrazol-1-yl) -7-methoxy-8-methylquinolin-4-yloxy1-13-methyl-2.14-dioxo-3,13-diazatricyclo [ 13.3.Q.04 6l octadec-7-en-4-carboxylic (127) The title compound was prepared from 4-hydroxy-2- (3-fer-butylpyrazol-1-yl) -7-methoxy-8-methylquinoline (126) and intermediate 26 following the procedure (step DF) reported for the preparation of 17- [7-methoxy-8-methyl-2- (thiazol-2-yl) quinolin-4-yloxy] -13-methyl-2,14-dioxo-3,13-diazatricylic acid [13.3 .0.04'6] octadec-7-en-4-carboxylic acid (29): m / z = 644 (M + H) +.

EXAMPLE 27 Preparation of JV-f 17- [2- (3-tert-butylpyrazol-1-yl) -7-methoxy-8-methylquinolin-4-yloxy-1, 13-methyl-2,14-dioxo-3,13- diazatriciclof13.3.0.04 61octadec-7- ^ n-4-carbonyl] (cyclopropyl) sulfonamide (128) The title compound was prepared from 17- [2- (3-fer-butylpyrazol-1-yl) -7-methoxy-8-methylquinolin-4-yloxy] -13-methyl-2,14-dioxo- 3,13-diazatricyclo- [13.3.0.04,6] octadec-7-en-4-carboxylic acid (127) and cyclopropylsulfonamide following the reported procedure for the preparation of N- [17- [8-chloro-2- ( 4-isopropylthiazol-2-yl) -7-methoxyquinolin-4-yloxy] -13-methyl-2,14-dioxo-3,13-diazatricyclo [13.3.0.04,6] -octadec-7-en-4-carbonyl ] (cyclopropyl) sulfonamide (56): m / z = 747 (M + H) +. 1 H NMR (CDCl 3): 0.95-1.12 (m, 2H), 1.13-1.30 (m, 2H), 1.31-1.55 (m, 11 H), 1.63-2.05 (m, 4H), 2.20-2.55 (m, 9H ), 2.80-2.98 (m, 1 H), 3.03 (s, 3H), 3.36-3.47 (m, 2H), 3.61-3.70 (m, 1 H), 3.97 (s, 3H), 4.60 (t, J = 12.2 Hz, 1 H), 5.04 (t, J = 10.3 Hz, 1 H), 5.26-5.46 (m, 1 H), 5.61-5.69 (m, 1 H), 6.35 (d, J = 2.5 Hz, 1 H), 6.42 (br s, 1 H), 7.13 (d, J = 9.1 Hz, 1 H), 7.32 (s, 1 H), 7.95 (d, J = 9.1 Hz, 1 H), 8.67 (d, J = 2.5 Hz, 1 H), 10.9 (br s, 1 H).

EXAMPLE 28 Preparation of acid 17-f2- (3,5-dimethylpyrazol-1-yl) -7-methoxy-8-methylquinolin-4-yloxyl-13-methyl-2.14-dioxo-3.13-diazatricichlori3.3.0.04.61octadec-7 -4-carboxylic acid (130) Step 1: Synthesis of 4-hydroxy-2- (3,5-dimethylpyrazol-1-yl) -7-methoxy-8-methylquinoline (129) The title compound was prepared from 4-benzyloxy-2-chloro-7-methoxy-8-methylquinoline (63) and 3,5-dimethylpyrazol following the procedure reported for the preparation of 4-hydroxy-2- (3- isopropylpyrazol-1-yl) -7-methoxy-8-methylquinoline (64): m / z = 284 (M + H) X Step 2: Synthesis of 17- [2- (3,5-dimethyl-pyridol-1-yl) -7-methoxy-8-methyl-quinolin-4-yloxy-1-1,3-methyl-2,14-dioxo-3,13-diazatricyclo [13.3] .0.04 6l octadec-7-en-4-carboxylic (130) The title compound was prepared from 4-hydroxy-2- (3,5-dimethylpyrazolol-1-yl) -7-methoxy-8-methylquinoline (129) and intermediate 26 following the procedure (step DF) reported for the Preparation of 17- [7-methoxy-8-methyl-2- (thiazol-2-yl) quinolin-4-yloxy] -13-methyl-2,14-dioxo-3,13-diazatricyclo [13.3.0.04 '6] octadec-7-en-4-carboxylic acid (29): m / z = 616 (M + H) X EXAMPLE 29 Preparation of / V-f17-[2-(3.5- dimethylpyrazol-1-yl) -7-methoxy-8-methylquinolin-4-yloxy-M3-methyl-2.14-dioxo-3.13-diazatricichlori3.3.0.0 61octadec-7 -in-4-carboniH (cyclopropyl) sulfonamide (131) The title compound was prepared from 17- [2- (3,5-dimethylpyrazol-1-yl) -7-methoxy-8-methylquinolyl-4-yloxy] -13-methyl-2 acid, 14-dioxo-3,13-diazatriciclo- [13.3.0.04,6) octadec-7-en-4-carboxylic acid (130) and cyclopropyl-sulfonamide following the reported procedure for the preparation of? / - [17- [8-] chloro-2- (4-isopropylthiazol-2-yl) -7-methoxyquinolin-4-yloxy) -13-methyl-2,14-dioxo-3,13-diazatricyclo [13.3.0.04.6) -octadec- 7-en-4-carbonyl] (cyclopropyl) sulfonamide (56): m / z = 719 (M + H) X 1 H NMR (CDCl 3): 0.70-0.96 (m, 1 H), 1.1-1.2 (m, 5H ), 1.4-1.55 (m, 2H), 1.80-1.93 (m, 4H), 2.15-2.25 (m, 1 H), 2.30-2.40 (m, 2H), 3.30 (s, 3H), 2.45-2.55 (m, 2H), 2.52 (s) , 3H), 2.80 (s, 3H), 2.82-2.91 (m, 2H), 3.00 (s, 3H), 3.45-3.55 (m, 2H), 3.95 (s, 3H), 4.51-4.60 (m, 1 H), 4.99-5.1 (m, 1 H), 5.21 -5.33 (m, 1 H), 5.51 (m, 1 H), 6.00 (s, 1 H), 7.03 (s, 1 H), 7.10 (d, J = 9.1 Hz, 1 H), 7.20 (s, 1 H) , 7.98 (d, J = 9.1 Hz, 1 H), 10.80 (br s, 1 H).

EXAMPLE 30 2- (1-Ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (132) Boc protected proline (4 g, 17.3 mmol), HATU (6.9 g) were dissolved. , 18.2 mmoles) and 1-amino-2-vinyl-cyclopropanecarboxylic acid ethyl ester, prepared as described in WO03 / 099274, (3.5 g, 18.3 mmoles) in DMF (60 ml) and cooled to 0 ° C in a water bath. ice. Diisopropylethylamine (DIPEA) (6 ml) was added. The ice bath was stirred and the mixture was allowed to stand at room temperature until the next day. Then dichloromethane (~ 80 ml) was added and the organic phase was washed with aqueous sodium hydrogen carbonate, citric acid, water, brine and dried over sodium sulfate. Purification by flash chromatography (ether? 7% methanol in ether) gave pure title compound (6.13 g, 96%) EXAMPLE 31 2- (1-Ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -4- (4-nitro-benzoyloxy) -pyrrolidin-1-carboxylic acid tert-butyl ester (133) Compound 132 (6.13 g, 16.6 mmol) was dissolved , 4-nitrobenzoic acid (4.17 g, 25 mmol) and PPh3 (6.55 g, 25 mmol) in THF (130 ml). The solution was cooled to -0 ° and diisopropyl azidocarboxylate (5.1 g, 25 mmol) was slowly added. Then, the cooling was removed and the mixture was left until the next day at ambient conditions. Aqueous sodium hydrogen carbonate (60 ml) was added and the mixture was extracted with dichloromethane. Purification by flash chromatography (pentane-ether, 2: 1 → pentane-ether, 1: 2 → 2% methanol in ether) gave pure title compound (6.2 g, 72%).

EXAMPLE 32 Ester 5- (1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -pyrrolidin-3-yl of 4-nitro-benzoic acid (134) Compound 133 (6.2 g, 12 mmol) was dissolved in a cold mixture of trifluoromethanesulfonic acid, 33% in dichloromethane. The ice bath was then stirred and the mixture was left at room temperature for -1.5 hr. The solvent was evaporated and 0.25 M sodium carbonate was added and the mixture was extracted with dichloromethane. Evaporation gave the title compound (4.8 g, 95%) as a yellowish powder.

EXAMPLE 33 Ester 5- (1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -1-rhept-6-enyl- (4-methoxy-benzyl) -carbamoyl-pyrrolidin-3-yl of 4-nitro-benzoic acid ( 135) To a solution of compound 134 (4.5 g, 10.8 mmoles) in THF (160 ml) were added NaHCO3 (1 tablespoon) and phosgene in toluene (1.93 M, 11.5 ml, 22 mmoles). The mixture was stirred vigorously for 1 hr at room temperature and then filtered and evaporated. The residue was dissolved in CH2Cl2 (160 mL) and NaHCO3 (1 tablespoon) and hept-5-enyl- (p-methoxybenzyl) -amine (4.3 g, 18.5 mmol) were added. After stirring overnight at room temperature, the reaction mixture was filtered and evaporated until dried. Flash column chromatography on silica gel (EtOAc.toluene 25:75 → 40:60) gave the title compound (6.59 g, 90%) as a light brown jelly.

EXAMPLE 34 Ethyl ester of 18-hydroxy-14- (4-methoxy-benzyl) -2,15-dioxo-3,14,16-triaza-tricichlori4.3.0.0 * 4,61nonadec-7-en-4-carboxylic acid ( 136) Compound 135 (1 g, 1.48 mmol) was dissolved in 1,2-dichloroethane (2 I). The mixture was degassed for 15 min using a stream of argon. Hoveyda-Grubbs (II) catalyst (50 mg, 5 mol%) was added and the mixture was refluxed for 4 hr. The solvent was evaporated and the crude ester was dissolved in tetrahydrofuran (100 ml), methanol (50 ml) and water (50 ml). The mixture was cooled 0 ° C in an ice bath. Aqueous lithium hydroxide (20 ml, 1M) was added and the mixture was stirred at 0 ° C for 4 hr. The volume was then doubled with water and the mixture was acidified with acetic acid. Extraction (dichloromethane) followed by flash chromatography (1~5% methanol in ether) gave pure title compound (450 mg, 61%). MS (M + H) + 500.

EXAMPLE 35 Ethyl ester of 18- [2- (4-isopropyl-thiazol-2-yl) -7-methoxy-8-methyl-quinolin-4-yloxy-1- (4-methoxy-benzyl) -2.15 -dioxo-3,14,16-triaza-trichloride4.3.0.0 * 4,6 * lnonadec-7-en-4-carboxylic acid (137) Alcohol 136 (230 mg, 0.460 mmol), quinolinol 36 ( 218 mg, 0.690 mmol) and triphenylfine (182 mg, 0.690 mmol) in dry THF and the mixture was cooled to 0 ° C. DIAD (130 μL, 0.690 mmol) was added dropwise to the stirred solution at 0 ° C for 30 minutes after which the solution was allowed to reach room temperature and then stirred until the next day. The solvent was evaporated and the crude material was purified by flash column chromatography (toluene / ethyl acetate 1: 1) to give the title compound (366 mg) (M + H) + calculated: 796.4; found: 796.7 EXAMPLE 36 Acid 18-f2- (4-lsopropyl-thiazol-2-yl) -7-methoxy-8-methyl-quinolin-4-yloxy-1- (4-methoxy-benzyl) -2,15-dioxo-3 , 14, 16-triaza-tricyclo [14.3.0.0 * 4,6 * 1 nonadec-7-en-4-carboxylic acid (138). Ethyl ester 137 (366 mg, 0.460 mmol) was dissolved in THF / MeOH / H20 2: 1: 1 (30 ml) and 1 M LiOH (4.6 ml, 4.40 mmol) was added dropwise at room temperature for 5 minutes after which the solution was stirred until the next day. The mixture was acidified to pH 3-4 by the addition of solid citric acid and the organic solvents were evaporated. The water phase was diluted with brine (50 ml) and then extracted twice with DCM. The combined organic phase was washed twice with brine and then dried, filtered and concentrated. The crude product was then purified by flash column chromatography (ethyl acetate / methanol 7: 1) to give the title compound (212 mg, 60%). (M + H) + calculated: 768.3; found: 768.7.

EXAMPLE 37 [18- [2- (4-lsopropyl-thiazol-2-yl) -7-methoxy-8-methyl-quinolin-4-yloxp-14- (4-methoxy-benzyl) -2,15-dioxo- 3,14,16-triaza-tricichlori4.3.0.0 * 4,6 * 1nonadec-7-en-4-carbonyl-amide of 1-methyl-cyclopropanesulfonic acid (139) To the acid 138 (212 mg, 0.276 mmol) discharged in dichloromethane (7 ml) EDC (69 mg, 0.359 mmol) was added and the reaction mixture was stirred at room temperature. After 7 hours CCD and LCMS indicated the complete conversion of the starting material into the corresponding oxazolipinone. The reaction mixture was diluted with dichloromethane (20 ml) and the organic phase was washed twice with water after which the organic phase was dried, filtered and concentrated. The residue was dissolved in dichloromethane (5 ml) and cyclopropylmethylsulfonamide (53 mg, 0.394 mmol) and DBU (78 μl, 0.525 mmol) were added and the reaction mixture was stirred at room temperature for 20 hours. The mixture was diluted with dichloromethane (30 ml) and the organic phase was washed twice with 10% citric acid and once with brine. The organic phase was dried, filtered and concentrated and the crude product was purified by column chromatography.

Instantaneous (toluene / ethyl acetate 1: 1, 1: 2, ethyl acetate, ethyl acetate / methanol 9: 1) to give the title compound (108 mg, 44%) as a colorless solid. LC-MS purity: > 95% (M + H) + calculated: 885.4; found: 885.7.

EXAMPLE 38 . { 18- [2- (4-lsopropyl-thiazol-2-yl) -7-methoxy-8-methyl-quinolin-4-yloxy-2,15-dioxo-3,14,16-triaza-tricyclo [ 14.3.0.0 * 4.6 * 1nonadec-7-en-4-carbonl} 1-methyl-cyclopropanesulfonic acid amide (140) To the compound 139 (106 mg, 0.120 mmol) dissolved in dichloromethane (18 ml) were added triplylsilane (38 μl, 0.240 mmole) and TFA (9 ml) and the reaction mixture it was stirred at room temperature for 1 hour. The solvents were evaporated and co-evaporated rapidly with toluene. The residue was dissolved in dichloromethane and the organic phase was washed twice with saturated NaHCO 3 solution. The organic phase was dried, filtered and concentrated and the crude product was purified by flash column chromatography (toluene / ethyl acetate 1: 1) to give the title compound (73 mg, 80%) as a slightly yellow solid. Purity of LC-MS: > 95% (M + H) + calculated: 765.3; found: 765.7.

EXAMPLE 39 Alternative route for the preparation of compound 34 Step A: Synthesis of 4-amino-5-cyano-2-hydroxy-3-methylbenzoic acid ethyl ester (141) To a solution of sodium ethoxide (1.3 I) (freshly prepared by the addition of sodium metal (7.9 g, 0.35 mol) to ethanol (1.3 I)) at 0 ° C was added ethylpropionyl acetate (25 g, 0.17 mol). ) and the solution was stirred at for 1 hr. To the above solution was added ethoxymethylene malononitrile (21 g, 0.17 mol) at t.a. and the reaction mixture was refluxed at 80 ° C for 2 hr. The reaction mixture was cooled, neutralized to pH = 7 by the addition of 1.5 N HCl and concentrated in vacuo. The obtained residue was diluted with water (100 ml) and filtered. The solid was washed with water and dried under vacuum at 50 ° C to give the crude product (27 g). The crude solid was washed with 5% ethyl acetate in pet ether. which gave pure title compound (22.5 g, 59%). CCD: EtOAc / Pet. Ether, 3: 7, Rf = 0.4 Step B: Synthesis of 4-amino-5-cyano-2-hydroxy-3-methylbenzoic acid (142) To a solution of L¡OH x H 20 (8.4 g, 0.2 mol) in ethanol / water (1: 1, 300 ml) was added compound 74 (22 g, 0.1 mol) at t.a. and the reaction mixture was refluxed at 80 ° C for 4 hr. The reaction mixture was concentrated under vacuum, the residue obtained was diluted with water (100 ml), washed with pet.ethyl ether / ethyl acetate (1: 1, 2 × 200 ml). The aqueous layer was separated, acidified to pH = 5 using 1.5N HCl and the obtained solid product was filtered. The aqueous layer was further extracted with ethyl acetate (2x300 ml), dried and concentrated to give more product. The combined products were washed with 5% ethyl acetate in pet ether. to give the pure title compound (19 g, > 95%). CCD: MeOH / chloroform, 1: 4, Rf = 0.2 Step C: Synthesis of 2-Amino-4-hydroxy-3-methylbenzonitrile (143) A mixture of compound 75 (19 g, 0.1 mol) in quinoline (50 ml) was heated at 170 ° C for 2 hr (until the effervescence stopped).

The reaction mixture was cooled to T.A. and aqueous NaOH solution (1 M, 500 ml) was added followed by pet ether. (500 ml). The reaction mixture was stirred for 15 min and the aqueous layer was separated. The aqueous layer was further washed with pet ether. (2x300 ml) to completely eliminate the quinoline. The aqueous layer was acidified with 1.5 N HCl to pH = 5, the solid was filtered and dried in vacuo. The solid obtained was further washed with 5% ethyl acetate in pet ether. to give pure title compound (12 g, 82%). CCD: EtOAc / pet ether, 3: 7, Rf = 0.35 Step D: Synthesis of 2-Amino-4-methoxy-3-methylbenzonitrile (144) A mixture of compound 76 (12 g, 0.08 mol), K2C03 (11 g, 0.08 mol) in dry DMF (200 ml) was stirred for 15 min at T.A. To this, Mel (13.6 g, 0.096 moles) was added and the mixture was stirred for 4 hr at T.A. The reaction mixture was diluted with water (800 ml), extracted with 30% ethyl acetate in pet ether. (3x300 ml). The combined organic layers were washed with water and brine, dried and concentrated to give a crude product. The crude product was washed with pet ether. to give pure title compound (12 g, 93%). CCD: Pet ether / EtOAc, 7: 3, Rf = 0.4 Step E: Synthesis of 1- (2-Amino-4-methoxy-3-methyl-phenyl) -ethanone (3. 4) To a solution of compound 77 (12 g, 0.074 moles) in THF (150 mL) was added MeMgBr in diethyl ether (3M, 100 mL, 0.296 moles) at 0 ° C dropwise. The reaction mixture was stirred at t.a. for 1 hr and then at 55 ° C for 3 hr. The reaction mixture was cooled to 0 ° C, quenched with cold 1.5N HCl until effervescence stopped (pH = 6). The reaction mixture was diluted with water (100 ml), extracted with ethyl acetate (2x300 ml). The combined organic layers were washed with brine, dried and concentrated to give a brown solid. The crude solid was dissolved in ethyl acetate (150 ml), pet ether was added. (150 ml) and was passed through a pad of silica gel to remove the color impurities and concentrated. The solid obtained was washed with 5% ethyl acetate in pet ether. which gave pure title compound (9 g, 68%) as a yellow solid. CCD: Pet ether / EtOAc, 7: 3, Rf = 0.4 EXAMPLE 40 Synthesis of 3-oxo-2-oxa-biciclof2.2.nheptan-5-carboxylic acid tert-butyl ester (146) DMAP (14 mg, 0.115 mmol) and Boc20 (252 mg, 1.44 mmol) were added to a stirred solution of 145 (180 mg, 1.15 mmol) in 2 mL of CH2Cl2 under an atmosphere of inert argon at 0 ° C. The reaction was allowed to warm to room temperature and stirred until the next day. The reaction mixture was concentrated and the crude product was purified by flash column chromatography (toluene / ethyl acetate, gradient 15: 1, 9: 1, 6: 1, 4: 1, 2: 1) which gave the compound of title (124 mg, 51%) as white crystals. 1 H-NMR (300 MHz, CD 3 OD) d 1.45 (s, 9H), 1.90 (d, J = 11.0 Hz, 1 H), 2.10-2.19 (m, 3H), 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.

Alternative method for the preparation of compound 146 Compound 145 (13.9 g, 89 mmol) was dissolved in dichloromethane (200 ml) and then cooled to about -10 ° C, under nitrogen. Then, isobutylene was bubbled into the solution until the total volume increased to about 250 ml that gave a cloudy solution.

BF3 Et20 (5.6 ml, 44.5 mmol, 0.5 eq.) Was added and the reaction mixture was maintained at about -10 ° C under nitrogen. After 10 min, a clear solution was obtained. The reaction was monitored by CCD (EtOAc-toluene 3: 2 was acidified with a few drops of acetic acid and hexane-EtOAc 4: 1, immunoblotting with basic permanganate solution). At 70 min, only traces of compound 145 were removed and saturated aqueous NaHCO3 (200 ml) was added to the reaction mixture, which was then stirred vigorously for 10 min. The organic layer was washed with saturated NaHCO 3 (3 x 200 ml) and brine (1 x 150 ml), then dried, sodium sulphite, filtered and the residue was evaporated to give an oily residue. When hexane was added to the residue, the product was precipitated. The addition of more hexane and heating to reflux gave a clear solution from which the product crystallized. The crystals were collected by filtration and washed with hexane (t.a.), then dried with air for 72 hr to give colorless needles (12.45 g, 58.7 mmol, 66%).

Synthesis of (1 f?, 2 4S) -2 - ((1 f?. 2 S) -1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -4-hydroxy-cyclopentanecarboxylic acid tert-butyl ester (147) Compound 146 (56 mg, 0.264 mmol) was dissolved in dioxane / water 1: 1 (5 mL) and the mixture was cooled to 0 ° C. 1M 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 1 M hydrochloride acid and evaporated and co-evaporated with toluene. . The crystalline residue was dissolved in DMF (5 ml) and (1, 2S) -1-amino-2-vinylcyclopropanecarboxylic acid ethyl ester hydrochloride (60 mg, 0.313 mmol) and diisopropylethylamine (DIEA) (138 μl) were added., 0.792 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 hr at 0 ° C and for an additional 2 hr 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 the title compound (86 mg, 89%) as a colorless oil. The oil was crystallized from ethyl acetate-hexane.

EXAMPLE 41 Activity of the compounds of formula (I) Replicon assay The compounds of formula (I) were examined for activity in the inhibition of HCV RNA replication in a cellular assay. The test showed that the compounds of formula (I) exhibited activity against the functional HCV replicons in a cell culture. The cellular assay was based on a bicistronic expression construct, as described in the text written by Lohmann et al. (1999) Science vol. 285 pp. 110-113 with the modifications described by Krieger et al. (2001) Journal of Virology 75: 4614-4624, in a strategy of multiple target selection. In essence, the method was the following. The assay used the stably transfected cell line Huh-7 luc / neo (hereinafter referred to as Huh-Luc). This cell line hosts a bicetronic expression construct encoding an RNA comprising the wild-type NS3-NS5B regions of the transfected HCV type 1 b from an Internal Ribosome Entry Site (IRES) of the encephalomyocarditis (EMCV), preceded by a reporter portion (FfL-luciferase), and a selectable marker portion (neoR, neomycin phosphotransferase). The construction is bordered by 5 'and 3' NTRs (untranslated regions) of HCV type 1 b. The continuous culture of the replicon cells in the presence of G418 (neoR) depends on the replication of the HCV RNA. Stably transfected replicon cells expressing HCV RNA, which replicates autonomously and up to high levels, which encode luciferase, among others, are used for evaluation of the antiviral compounds. Replicon cells were plated in 384 well plates in the presence of the test and control compounds that are added in various concentrations. After a three-day incubation, HCV replication was measured by assay of luciferase activity (using substrates for standard luciferase assays and reagents and an imaging device with Perkin Elmer ViewLuxT ultraHTS mycoplasma). The replicon cells in the control cultures have high luciferase expression in the absence of an inhibitor. The inhibitory activity of the compound on luciferase activity was monitored on Huh-Luc cells, allowing the modality of a dose-response curve for each test compound. The EC50 values were then calculated, value representing the amount of compound required to reduce by 50% the level of luciferase activity detected, or more specifically, the replication capacity of the genetically linked HCV replicon RNA.

Inhibition assay The objective of this in vitro assay was to measure the inhibition of HCV NS3 / 4A protease complexes by the compounds of the present invention. This assay provides an indication of the effectiveness of the compounds of the present invention in the inhibition of the proteolytic activity of HCV NS3 / 4A. Inhibition of full length hepatitis C protease NS3 enzyme was measured in essence as described in Polyakov, 2002 Prot Expression & Purification 25 363 371. In synthesis, the synthesis of a dipsipyptide substrate, Ac-DED (Edans) EEAbu [COO] ASK (Dabcyl) -NH2 (AnaSpec, San José, E.U.A.), was measured by spectrofluorometry in the presence of a peptide co-factor, KKGSWIVGRIVLSGK (Ake Engstrom, Department of Medical Biochemistry and Microbiology, Uppsala University, Sweden).

[Landro, 1997 #Biochem 36 9340-9348]. The enzyme (1 nM) was incubated in 50 mM HEPES, pH 7.5, 10 mM DTT, 40% glycerol, 0.1% n-octyl-D-glucoside, with 25 μM of NS4A cofactor and inhibitor at 30 ° C for 10 min, after which the reaction was initiated with the 0.5 μM substrate aggregate. The inhibitors were dissolved in DMSO, sonicated for 30 sec. and they were shaken with swirling action. The solutions were stored at -20 ° C between measurements. The final concentration of DMSO in the test sample was adjusted to 3.3%. The hydrolysis rate was corrected for the internal filter effects in accordance with published procedures. [Liu, 1999 Analytical Biochemistry 267 331-335]. Ki values were estimated by non-linear regression analysis (GraFit, Eríthacus Software, Staines, MX, UK), using a model for competitive inhibition and a fixed value for Km (0.15 μM). A minimum of two replications was performed for all measurements. The following table 1 lists compounds that were prepared according to any of the above examples. The activities of the compounds analyzed are also shown in table 1.

TABLE 1 EXAMPLE 42 In Vivo Effects of Ritonavir on the Pharmacokinetics of Compound No. 47 in Rats The oral pharmacokinetics of compound No. 47 were investigated in male and female Sprague-Dawley rats after a single dose of 10 mg / kg, using a formulation in 50% PEG400 in water and the influence of "booster" with 10 mg / kg. kg of ritonavir. Four male and female Sprague-Dawley (SD) rats were randomly divided (body weight approx 200-250 g) into 2 groups of 2 males and females each (reinforced and non-reinforced) based on body weight. The weight of the individual animals did not differ too much from the group's average. The animals were fasted briefly before the test. Water intake remained available ad libitum. Rats from the unreinforced group received a single oral dose of 10 mg / kg of compound No. 47, formulated as 3 mg / ml in PEG400 / 50% water at pH 8. The reinforced group rats received a single oral dose of ritonavir, about 30 minutes before receiving the single oral dosage of 10 mg / kg of compound No. 47. The formulations of the drug were administered by oral priming. A blood sample of 0.5 ml was collected from each rat at 0.5 hr, 1 hr, 2 hr, 4 hr and 8 hr after dosing. Plasma concentrations were determined by the use of CLAR-MS. The results are shown in Table 2 below, expressed as a factor of change in the pharmacokinetic parameter of the reinforced group, compared to the non-reinforced group.

TABLE 2 These results show that ritonavir essentially improves the pharmacokinetics of compound No. 47 in rats, increasing global exposures expressed as ABC by more than 2 times.

Claims (24)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound that has the formula

an N-oxide, salt or stereoisomer thereof, wherein each dotted line (represented by) represents an optl double bond; X is N, CH and where X has a double bond is C; R1 is -OR7, -NH-S02R8; R 2 is hydrogen and wherein X is C or CH, R 2 may also be C 1 -β alkyl; R3 is hydrogen, C1-6 alkyl, C6-6 alkoxy of C? -6 alkyl, C3-7 cycloalkyl; R4 is aryl or Het; n is 3, 4, 5 or 6; R5 represents halogen, C-? 6 alkyl, hydroxy, C?. 6 alkoxy, polyhaloalkyl of C-? -6, phenyl or Het; R6 represents C1-6 alkoxy or dimethylamino; R7 is hydrogen; aril; Het; C3-7 cycloalkyl optlly substituted with C 1-6 alkyl; or C? -6 alkyl optlly substituted with C3- cycloalkyl, aryl or with Het; R8 is aryl; Het;

C3-7 cycloalkyl optlly substituted with C-? -6 alkyl; or C? -6 alkyl optlly substituted with C3-7 cycloalkyl, aryl or with Het; aryl as a group or part of a group is phenyl optlly substituted with one, two or three substituents selected from halogen, hydroxy, nitro, cyano, carboxyl, C? -6 alkyl, C? -6 alkoxy > C6-C6-alkyl-C6-alkoxy, C6-C6-alkylcarbonyl > amino, C1-6 mono- or di-alkylamino, azido, mercapto, polyhaloalkyl of d-6, polyhalogenoalkoxy of C6-6 cycloalkyl of C3-7, pyrrolidinyl, piperidinyl, piperazinyl, 4-alkyl of C1-6-piperazinyl , 4-alkylcarbonyl of C? -6-piperazinyl and morpholinyl; wherein the morpholinyl and piperidinyl groups may be optlly substituted with one or two C? -6 alkyl radicals; Het as a group or part of a group is a saturated, partially unsaturated or completely unsaturated 5 or 6 membered heterocyclic ring containing 1 to 4 heteroatoms, each independently selected from nitrogen, oxygen and sulfur, said heterocyclic ring optlly being condensed with a benzene ring; and wherein said het as a whole is optlly substituted with one, two or three substituents, each independently selected from the group consisting of halogen, hydroxy, nitro, cyano, carboxyl, C? -6 alkyl, C- alkoxy? .6, C6-C6 alkoxy, C6 alkyl, C1-6 alkylcarbonyl, amino, C1-6 mono- or di-alkylamine, azido, mercapto, C6-6 polyhaloalkyl, C6 polyhaloalkoxy; -6, C3-7 cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-alkyl-6-piperazinyl, 4-alkylcarbonyl of C? -6-piperazinyl and morpholinyl; where the morpholinyl and piperidinyl groups can be

optlly substituted with one or two alkyl radicals of C-? -6.

2. The compound according to claim 1, further characterized in that the compound has the formula (l-c), (l-d) or (l-e):

3. - The compound according to any of claims 1-2, further characterized in that R4 is selected from the group consisting of phenyl, pyridin-4-yl,

wherein R4a is, each independently, hydrogen, halogen, C6-6alkyl, amino, or mono- or di-alkylamino of C-? -6.

4. The compound according to any of claims 1-3, further characterized in that R5 is methyl, ethyl, isopropyl, tert-butyl, fluoro, chloro, or bromo; and R6 is methoxy.

5. The compound according to any of claims 1-4, further characterized in that (a) R1 is -OR7, wherein R7 is d6 alkyl or hydrogen; (b) R1 is -NHS (= 0) 2R8, wherein R8 is methyl, cyclopropyl or phenyl; or R1 is -NHS (= 0) 2R8, wherein R8 is cyclopropyl substituted with methyl.

6. The compound according to any of claims 1-5, further characterized in that n is 4 or 5.

7. The compound according to any of claims 1-6, further characterized in that R3 is hydrogen or alkyl of C1-6, in particular R3 is hydrogen or methyl.

8. The compound according to any of claims 1-7, further characterized in that R4 is a radical

wherein, when possible a nitrogen may have a R4a substituent or a linkage to the rest of the molecule; each R4a in any of the substituents

R4 can be selected from those mentioned as possible substituents in Het, as specified in claim 1.

9. The compound according to any of claims 1-7, further characterized in that R is selected from the group consisting of:

(q-1) (q-2) (q-3) (q-4)

wherein each R4a is hydrogen, halogen, C-? -6 alkyl, amino, or mono- or di-alkylamino of C-? -6, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 4-alkyl of C? -6- piperazinyl; and wherein the morpholinyl and piperidinyl groups may be optionally substituted with one or two alkyl radicals of

10. - The compound according to any of claims 1-9, further characterized in that R6 is methoxy.

11. The compound according to claim 1, further characterized in that the compound is:

12. The compound according to claim 11, further characterized in that the compound is in amorphous form. 13. A form of the compound of claim 11 obtainable by: a) stirring at reflux in nitrogen for 2 hr of a solution of 560 mg (0.867 mmol) of compound no. 46 and 308 mg (1.90 mmol) of carbonyldiimidazole in 10 ml of dry tetrahydrofuran;

b) then the reaction mixture obtained in step a) is allowed to reach room temperature and 400 mg (3.301 mmol) of cyclopropylsulfonamide and 286 mg of DBU (1881 mmol) are added; c) the

solution obtained in step b) at 50 ° C for 15 hours; d) the reaction mixture obtained in step c) is cooled to room temperature and concentrated under reduced pressure; e) divide the residue obtained in step d) between CH2Cl2 and 1 N HCl, wash the organic layer with brine, dry said organic layer with MgSO4 and evaporate; f) the organic layer obtained in step e) is purified by flash chromatography (gradient of EtOAc (0 to 25%) in CH 2 Cl 2), after which 314 mg of an off-white solid are obtained, and g) said off-white solid is washed in step f) with water, and then with isopropyl ether and drying it in the vacuum oven. with claim 1,

15. - The compound according to claim 1, further characterized in that the compound is:

16. - The compound according to claim 1, further characterized in that the compound is:

17. - The compound according to any of claims 1-16, further characterized in that it is not an N-oxide or salt.

18. A combination comprising (a) a compound according to any of claims 1 to 17 or a pharmaceutically acceptable salt thereof; and (b) ritonavir, or an acceptable salt from the pharmaceutical point of view thereof.

19. A combination comprising (a) a compound of

according to any of claims 1 to 17 or a pharmaceutically acceptable salt thereof; and (b) interferon-alpha (pegylated), or an acceptable salt from the pharmaceutical point of view thereof.

20. A pharmaceutical composition comprising a vehicle and as an active component, an anti-viral agent effective amount of a compound according to any of claims 1-17 or a combination according to any of claims 18-19.

21. The compound according to any of claims 1-17 or a combination according to any of claims 18-19, for use as a medicament.

22. The use of a compound as claimed in any of claims 1-17 or a combination according to any of claims 18-19, for the manufacture of a medicament for inhibiting the replication of HCV.

23.- A method to inhibit the replication of HCV in a warm-blooded animal, said method comprises administering an effective amount of a compound according to claims 1-17 or an effective amount of each component of the combination of any of claims 18-19.

24. A method for preparing a compound according to any of claims 1-17, wherein said method comprises: (a) preparing a compound of formula (I) wherein

the bond between C and C8 is a double bond, which is a compound of formula (Ii), by the formation of a double bond between C7 and C8, in particular by an olefinic metathesis reaction, with the concomitant cyclization to the macrocycle as Indicate in the following reaction scheme:

where in the previous and in the following reaction schemes R9 represents a radical

(b) converting a compound of formula (1-i) into a compound of formula (I) wherein the bond between C7 and C8 in the macrocycle is a single bond, ie a compound of formula (I-j):

(l-j) by a reduction of the C7-C8 double bond in the compounds of formula (I-j); (c) preparing a compound of formula (I) wherein R1 represents -NHS02R8, said compounds represented by the formula (lk-1), forming an amide bond between an intermediate (2a) and a sulfonylamin (2b), or a compound of formula (I) wherein R1 represents -OR7, ie a compound (lk-2), by the formation of an ester bond between an intermediate (2a) and an alcohol (2c) as indicated in the following scheme , where G represents a group:

(l-k-1)

(d) preparing a compound of formula (I) wherein R3 is hydrogen, said compound represented by (I-I), from a corresponding intermediate with protected nitrogen (3a), wherein PG represents a nitrogen protecting group:

(e) reacting an intermediate (4a) with the intermediate (4b) as indicated in the following reaction scheme:

wherein Y in (4b) represents hydroxy or a leaving group; and when Y represents hydroxy, the reaction of (4a) with (4b) is a Mitsunobu reaction; and when Y represents a leaving group the reaction of (4a) with (4b) is a substitution reaction; (f) converting the compounds of formula (I) to each other by a reaction of transformation of functional groups; or (g) preparing a salt form by reacting the free form of a compound of formula (I) with an acid or a base.

SUMMARY OF THE INVENTION

Inhibitors of HCV replication of formula (I)

and the n-oxides, salts and stereoisomers thereof, wherein each dotted line represents an optional double bond; X is N, CH and where X has a double bond is C; R1 is -OR7, -NH-S02R8; R2 is hydrogen and wherein X is C or CH, R2 may also be d-β alkyl; R3 is hydrogen, C-? 6 alkyl, C? -6 alkoxy, C? -6 alkyl, C3-7 cycloalkyl; R4 is aryl or Het; n is 3, 4, 5, or 6; R5 is halogen, C6-6 alkyl, hydroxy, C-? 6 alkoxy, phenyl or Het; R6 is C6-C6 alkoxy, or dimethylamino; R7 is hydrogen; aril; Het; C3.7 cycloalkyl optionally substituted with C-? 6 alkyl; or C 1 alkyl optionally substituted with C 3-7 cycloalkyl, aryl or with Het; R8 is aryl; Het; C3- cycloalkyl optionally substituted with C? -6 alkyl; or C-? -6 alkyl optionally substituted with C3-7 cycloalkyl, aryl or with Het; aryl is phenyl optionally substituted with one, two or three substituents; Het is a

saturated, partially unsaturated or completely unsaturated, 5 or 6 membered heterocyclic ring containing 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur, optionally being condensed with one, two or three substituents; Also provided are pharmaceutical compositions containing compounds (I) and processes for preparing compounds (I); bioavailable combinations of the HCV inhibitors of the formula (I) with ritonavir.

9B P07 / 2302F