MX2008001399A - Macrocyclic inhibitors of hepatitis c virus - Google Patents

Abstract

Inhibitors of HCV replication of formula (I) and theN-oxides, salts, and stereoisomers thereof, wherein X is N, CH and where X bears a double bond it is C;R1is -OR5, -NH-SO2R6;R2is hydrogen, and where X is C or CH, R2may also be C1-6alkyl;R3is hydrogen, C1-6alkyl, C1-6alkoxyC1-6alkyl, or C3-7cycloalkyl;R4is isoquinolinyl optionally substituted with one, two or three substituents each independently selected from C1-6alkyl, C1-6alkoxy, hydroxy, halo, polyhalo- C1-6alkyl, polyhaloC1-6alkoxy, amino, mono- or diC1-6alkylamino, mono- or DiC1-6alkylaminocarbonyl, C1-6alkylcarbonyl-amino, aryl, and Het;n is 3, 4, 5, or 6;each dashed line (represented by ) represents an optional double bond;R5is hydrogen;aryl;Het;C3-7cycloalkyl optionally substituted with C1-6alkyl;or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or with Het;R6is aryl;Het;C3-7cycloalkyl optionally substituted with C1-6alkyl;or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or with Het;each aryl is phenyl optionally substituted with one, two or three substituents;and each Het is a 5 or 6 membered saturated, partially unsaturated or completely unsaturated heterocyclic ring containing 1 to 4 heteroatoms each independently 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 VIRUS DESCRIPTIVE MEMORY The present invention relates to macrocyclic compounds that possess inhibitory activity on the replication of the hepatitis C virus (HCV). It also refers to compositions comprising these compounds as active components, 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 genus hepacivirus, 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 family of animal pestevirus, which includes the viral bovine virus of diarrhea (BVDV-for its acronym in English). HCV is a positive-sense, single-stranded RNA virus with a genome of about 9,600 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. The polyprotein encodes ten gene products that are generated from the precursor polyprotein by an organized series of co-and post-translational endoproteolytic cleavages 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 NS3 serine protease, 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 hepatic fibrosis producing cirrhosis, terminal liver disease and HCC (hepatocellular carcinoma), making it the main cause of liver transplantation. There are 6 major genotypes of HCV and more than 50 subtypes, which are distributed geographically differently. HCV type 1 is the predominant genotype in Europe and the United States. The extensive genetic heterogeneity of HCV has an important diagnosis and clinical implications, possibly explaining the difficulties for the development of vaccines and the lack of response to therapy. The transmission of HCV 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 progression to terminal liver disease, existing infections will continue to pose a serious 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 HCVThis 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 number of similar HCV protease inhibitors have also been described 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 possess 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 an HIV regimen often decreases below the IC90 or ED90 threshold for much of the day. It is considered that a minimum level of 24 hours of at least the IC50, and more realistically, the ICgo or ED90, 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 rigorous challenge 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 hurdles 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. WO04 / 094452 refers to macrocyclic peptide inhibitors of isoquinoline of HCV. Also described are compositions comprising the compounds and methods for the use of the compounds to inhibit HCV. WO05 / 010029 describes inhibitors of serine protease aza-peptides macrocyclic hepatitis C; 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 subject by administration of a pharmaceutical composition comprising the compounds of the present invention. The present invention relates to inhibitors of HCV 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 possess relatively low molecular weight and are easy to synthesize, from starting materials that are commercially available or that are readily available through synthesis methods known in the art. The present invention relates to inhibitors of HCV replication, which can be represented by Formula (I): and the? / - oxides, salts and stereoisomers thereof, where X is N, CH and when X has a double bond is C; R1 is -OR5, -NH-SO2R6; R 2 is hydrogen, and when X is C or CH, R 2 may also be C 1 -β alkyl; R3 is hydrogen, C? -6 alkyl, C-? -6-alkoxy of C-? -6, or C3-7 cycloalkyl; R 4 is isoquinolinyl optionally substituted by one, two or three substituents each independently selected from C-α-6 alkyl > C? -6 alkoxy, hydroxy, halo, polyhaloC? -6 alkyl, polyhaloC-i alkoxy. 6) amino, mono- or di-alkylamino of C? -6, mono- or di-alkylaminocarbonyl of C? .6, alkylcarbonyl of C? -6-amino, aryl, and Het; n is 3, 4, 5, or 6; where each dotted line (represented by) represents an optional double bond; R5 is hydrogen; aril; Het; C3-7 cycloalkyl optionally substituted by C? -6 alkyl; or C? -6 alkyl optionally substituted by C3- cycloalkyl, aryl or Het; R6 is aryl; Het; C3-7 cycloalkyl optionally substituted by C-i ^ alkyl; or C? -6 alkyl optionally substituted by C3-7 cycloalkyl, aryl or with Het; each aryl is a group or part of a group is phenyl optionally substituted by one, two or three substituents selected from halo, hydroxy, nitro, cyano, carboxyl, C? -6 alkyl, C-? 6 alkoxy, alkoxy C -? - 6-C? -6 alkyl, C? -6 alkylcarbonyl, amino, C 1-6 mono- or di-alkylamino, azido, mercapto, polyhaloalkyl of C -? - 6, polyhalo-alkoxy of C1 -6, C3_7 cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-alkylpiperazinyl of C -? - 6, 4-alkylcarbonyl-C? -6-piperazinyl, and morpholinyl; and wherein the morpholinyl and piperidyl groups may be optionally substituted by one or two C1-6 alkyl radicals; and each 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 substituted by one, two or three substituents each independently selected from the group consisting of halo, hydroxy, nitro, cyano, carboxyl, C? -6 alkyl, C1-6 alkoxy, C? alkoxy? -6-C?-C6 alkyl, C?-6 alkyl, amino, mono- or dialkylamino of azido, mercapto, polyhaloalkyl of C ?.6, polyhalo-C alco-6alkoxy, C3-7 cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C6-piperazinyl-alkyl, 4- alkylcarbonyl-piperazinyl, and morpholinyl and wherein the morpholinyl and piperidyl groups may be optionally substituted by one or two C---6 alkyl radicals. 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 stereochemically isomeric forms thereof, for use as a medicament. The invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. The pharmaceutical compositions may comprise combinations of the aforementioned compounds with other anti-HCV agents. 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 the replication of HCV. Or the invention relates to a method for inhibiting the replication of HCV in a warm-blooded animal said method comprises administering an effective amount of a compound of formula (I), or a? / -oxide, addition salt, amine quaternary, metallic complex, or stereochemically isomeric forms thereof. As used hereinafter and hereinbefore, the following definitions apply unless otherwise specified. The term halo is generic for fluoro, chloro, bromo and iodo. The term "polyhaloC1-6 alkyl" as a group or part of a group, for example, in polyhaloC1-6alkoxy, is defined as mono- or polyhalo substituted C- [alpha] -C6 alkyl, special C- [alpha] -6 alkyl substituted by up to one, two, three, four, five, six or more halo atoms, such as methyl or ethyl by one or more fluoro atoms, for example, difluoromethyl, trifluoromethyl, trifluoromethyl. Trifluoromethyl is preferred. Also included are perfluoroalkyl groups of C? -6, which are alkyl groups of C-? -6 where 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 polyhaloalkyl definition of C 6, the halogen atoms may be the same or different. As used herein, "C1_alkyl" as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals possessing 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- 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. Of interest among the C6 alkyl is C6 alkyl. The term "C2-6 alkenyl" as a group or part of a group defines straight and branched chain hydrocarbon radicals possessing saturated carbon-carbon bonds and at least one double bond and possessing 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, 3-hexenyl, 4-hexenyl, 2-methyl-2-butenyl, 2-methyl-2-pentenyl and the like. Of interest among C2-6 alkenyls is C2-4 alkenyl, The term "C2-6 alkynyl" as a group or part of a group defines straight and branched chain hydrocarbon radicals possessing saturated carbon-carbon bonds and at least one triple bond and possessing from 2 to 6 carbon atoms, such as, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 2-pentynyl, -pentinyl, 2-hexynyl, 3-hexynyl and the like. Of interest among the C2-6 alkynyls is the C2- alkynyl. The C3.7 cycloalkyl is generic for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. C 6-6 alkanediyl defines straight and branched bivalent chain hydrocarbon radicals possessing 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. It is of interest among the alkanediyl of C, _6 the alkanediyl of C, ^. C 6 -alkoxy means C 1-6 alkyloxy wherein C 1-6 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 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. 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 possess one or two nitrogens. Each of the Het radicals mentioned in this and in the following paragraphs can be optionally substituted by 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 subsitiated hydroxy rings can be produced as their tautomeric forms which possess 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?-6 alkyl, 4-polyhalo-C?-6 alkyl, alkoxy C? -6, C 1-6 alkylcarbonyl, C 3-7 cycloalkyl. Het radicals of interest, comprise, for example, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl (including 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 (especially 1 H-indazolyl), indolinyl, quinolinyl, tetrahydroquinolinyl (especially 1, 2,3,4-tetrahydroquinolinyl), isoquinolinyl, tetrahydroisoquinolinyl (especially 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 linked by their nitrogen atom (ie 1-pyrrolidinyl, 1-piperidinyl, 4-thiomorpholinyl, 4-morpholinyl, 1-piperazinyl, piperazinyl substituted in the 4-position). It should be noted that the locations of the radicals in any molecular moiety used in the definitions can be found anywhere on said moiety, 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 the term "compounds of formula (I)" or "the present compounds" or similar terms is used hereinafter, it is intended to include the compounds of formula (I), each and any of the subgroups of the same, their pro-drugs,? / - 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) possess 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 bound by the same sequence of bonds, but having different three-dimensional structures that are not interchangeable, which the compounds of formula may possess (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 possess. 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 essentially free isomers 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 that possess 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 especially, the compounds and intermediates that possess a stereoisomeric excess of 90% to 100%, even more especially having a stereoisomeric excess of 94% up to 100% and even more especially that they possess 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 the application of procedures known in the art. For example, the enantiomers can be separated from each other by the 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. Suitable physical separation methods which can be used advantageously are, for example, selective crystallization and chromatography, for example column chromatography. For some of the compounds of formula (I), their α / - oxides, salts, solvates, quaternary amines, or metal complexes and the intermediates used in the preparation thereof, the absolute stereochemical configuration was not determined experimentally. A person skilled in the art is able to determine 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 in vivo biotransformation of the derivative is the active drug, as defined in the compounds of formula (I). The reference by Goodman and Gilman (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. The pro-drugs of a compound of the present invention can be prepared by modifying functional groups present in the compound, such that the modifications are cleaved, either by routine manipulation or in vivo, for the parent compound. The pharmaceutically acceptable ester pro-drugs which are hydrolysable in vivo and which are derived from those compounds of formula (I) which possess a hydroxy or a carboxyl group are preferred. 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 C.sub.6-alkoxymethyl esters, for example methoxymethyl, C.sub.6 -alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C.sub.3 -β-cycloalkoxycarbonyloxy esters of C.sub.1- alkyl 6 for example 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters, for example 5-methyl-1,3-dioxolen-2-onylmethyl; and alkoxycarbonyloxyethyl esters of d-β for example 1-methoxycarbonyloxyethyl, which can be formed in any carboxy group in the compounds of this invention. An 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 ethers 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 ethers 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- (dialkylaminoethyl) -N-alkylcarbamoyl (to give carbamates) , dialkylaminoacetyl and carboxyacetyl. Examples of substituents on the benzoyl include morpholino and piperazino attached 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 counter-ion 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 hydrocides, for example hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, 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. Conversely, 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 aryl alkyl halide or optionally substituted arylalkyl halide, for example, methyl iodide or benzyl iodide. Other reagents with good leaving groups can also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates and alkyl p-toluenesulfonates. A quaternary amine possesses 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 more nitrogen atoms are oxidized to the so-called? / -oxide. It will be appreciated that the compounds of formula (I) may possess metal bonding, chelating, complexing properties and, therefore, may 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) possess 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 C-alkyl. -? - 6 and at 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 in position 1, preferably, corresponds to that of an amino acid configuration L, that is, that of L-proline. 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 is preferably in that configuration corresponding to an L-proline configuration. The substituted carbonyl groups 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 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 at position 4 is R. The compounds of formula (I) may 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 -O-R4 (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 -O-R 4 is in a configuration trans with respect to position 1. Preferably, the compounds of formula ( I) possess the stereochemistry as indicated in the structures of the formulas (Ia) and (lb) below: (Ia) db) An embodiment of the present invention relates to compounds of formula (I) or formula (Ia) or any subgroup of compounds of formula (I), where 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 (Ia), (lb), or any subset of compounds of formula (I), where one or more of the following conditions apply: (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 (I-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 (l-c) and (l-d).

A double bond between the carbon atoms 1 'and 2' can be find present in the compounds of formula (I), or in any subgroup of compounds of formula (I), as described in formula (1-e) then.

(I-e) Yet another particular subgroup of compounds of formula (I) are those represented by the following structural formulas: (1-f) d-g) (l-h) Among the compounds of formulas (l-f), (l-g) or (l-h), those having the stereochemical configuration of the compounds of formulas (I-a) and (lb) are of particular interest: In (the), (lb), (lc), (ld), (Ie), (lf), (lg) and (lh), where applicable, X, n, R1 , R2, R3 and R4 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 (1-a), (lb), (lc), (ld), (le), (1-f), (lg) or (lh) are intended to be intended. , like any other subgroup defined herein, also encompass any prodrug,? / - oxide, addition salts, quaternary amines, metal complexes and stereochemical isomeric forms of such compounds. When n is 2, the residue -CH2- 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 residue -CH2- 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 residue -CH2-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 residue -CH2- 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 residue -CH2- 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 the compounds of formula (I) or any of the subgroups of the compounds of formula (I) wherein (a) R1 is -OR5, particularly where R5 is C6-alkyl, such as methyl, ethyl, or tert-butyl and higher preference where R5 is hydrogen; or (b) R is -NHS (= O) 2R6, particularly where R6 is C? -6 alkyl, C3-cycloalkyl optionally substituted by C? -6 alkyl) or aryl, for example where R6 is methyl, cyclopropyl, methylcyclopropyl, or phenyl. 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 C6-6 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 linked by a double bond) or CH (X being bound by a simple bond) and R2 is hydrogen; (b) X is C (X being joined by a double bond) and R2 is C 1 -β 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 C? -6 alkyl; (c) R3 is C-ε-C alco-C6 alkyl alkoxy or C3.7 cycloalkyl.

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 the compounds of formula (I) wherein R 4 is isoquinolin-1-yl optionally mono, di, or tri substituted by C alkyl, C alco alkoxy -? - 6, hydroxy, halo, trifluoromethyl, mono- or di-alkylamino of d-β, mono- or di-alkylaminocarbonyl of C 1-6, aryl, Het; where aryl or Het are each, independently, optionally substituted by halo, C-? -6 alkyl, polyhalo-C6-6 alkoxy, amino, mono- or di-alkylamino of C -? - 6 , C3-7 cycloalkyl (especially cyclopropyl), pyrrolidinyl, piperidinyl, piperazinyl, 4-alkylpiperazinyl of (especially 4-methyl-piperazinyl) or morpholinyl. The embodiments of the invention are compounds of formula (I) or any of the subgroups of the compounds of formula (I) wherein R4 is isoquinolin-1-yl optionally mono, di, or tri substituted by methyl, ethyl, isopropyl, ter- butyl, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, fluoro, chloro, bromo, mono- or di-alkylamino of C? -6, mono- or di-alkylaminocarbonyl of Ci. 6, phenyl, methoxyphenyl, cyanophenyl, halophenyl, pyridyl, C? - alkylpyridyl, pyrimidinyl, morpholinyl, piperazinyl, Cr4-piperazinyl alkyl, pyrrolidinyl, pyrazolyl, Cr4-pyrazolyl alkyl, thiazolyl, d-4 alkylthiazolyl, cyclopropyl- thiazolyl, or mono- or di-alkyl of Ci ^ -aminothiazolyl.

The embodiments of the invention are compounds of formula (I) or any of the subgroups of the compounds of formula (I) wherein R 4 is: wherein in this and in the following formulas structures representing radical moieties R4, each R a, R 4b, R 4b are independently any of the substituents selected from those mentioned as possible substituents in the monocyclic or bicyclic ring systems of R 1, according to it was specified in the definitions of the compounds of formula (I) or of any of the subgroups of the compounds of formula (I). Specifically, R 4a may be hydrogen, halo, C 1 -6 alkyl, C 6 -alkoxy, mono- or C 1-6 alkylamino, amino, aryl, or Het; said aryl or Het each being, independently, optionally substituted by any of the substituents of Het or aryl mentioned in the definitions of the compounds of formula (I) or of any of the subgroups of the compounds of formula (I); or specifically said aryl or Het each being, independently, optionally substituted by C-? -6alkyl, C? -6alkoxy, polyhalo-C6-6alkoxy, amino, mono- or di-alkylamino of C -? - 6, halo, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, 4-alkylpiperazinyl of C? -6 (such as 4-methylpiperazinyl); and each R4b and Rb are, independently, hydrogen, C? -6 alkyl, C? -6 alkoxy, C? -6 mono- or di-alkylamino, C1-6 mono- or di-alkylaminocarbonyl. , hydroxy, halo, trifluoromethyl, aryl, or Het; said aryl or Het each being, independently, optionally substituted by any of the substituents of Het or aryl mentioned in the definitions of the compounds of formula (I) or of any of the subgroups of the compounds of formula (I); or specifically said aryl or Het each being, independently, optionally substituted by C-? -6 alkyl, C? -6alkoxy, polyhalo-C-?, alkylamino, mono- or di-alkylamino of C ? -6; morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, 4-alkylpiperazinyl of C-? -6 (such as 4-methylpiperazinyl). The embodiments of the invention are compounds of formula (I) or any of the subgroups of the compounds of formula (I) wherein R 4a is a radical or, in particular, where R1a is selected from the group consisting where, when possible a nitrogen may possess a substituent R4c or a linkage to the rest of the molecule; wherein each R4c is, each independently, any of the Het substituents mentioned in the definitions of the compounds of formula (I) or any of the subgroups of the compounds of formula (I); or specifically each R4c is, each independently, hydrogen, halo, C-? -6 alkyl, amino, or mono- or dialkylamino of C? -6, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, 4-alkylpiperazinyl of C -? - 6 (such as 4-methylpiperazinyl); and wherein the morpholinyl and piperidyl groups can be optionally substituted by one or two C-i-β alkyl radicals; more specifically, each R 4c is, independently, hydrogen, halo, C-α-6 alkyl, amino, or mono- or di-alkylamino of C e; and when R 4c is substituted on a nitrogen atom, preferably it is a carbon containing substituent which is connected to the nitrogen by a carbon atom or one of its carbon atoms; and wherein in the instance R c is preferably C-? 6 alkyl. The embodiments of the invention are compounds of formula (I) or any of the subgroups of the compounds of formula (I) wherein R 4 is: where each R b and R 4b, independently, are as specified above; or specifically each R4b and Rb, independently, are hydrogen, C? -6 alkyl, C-? 6 alkoxy, C-? 6 mono- or dialkylamino, mono- or di-alkylaminocarbonyl C? -6, hydroxy, halo, trifluoromethyl, aryl, or Het; and R4d and R4d, independently are any of the aryl substituents mentioned in the definitions of the compounds of formula (I) or of any of the subgroups of the compounds of formula (I); or specifically R4d or R4d, independently are hydrogen, C? -6 alkyl, C? -6 alkoxy, or halo. Other embodiments of the invention are compounds of formula (I) or any of the subgroups of the compounds of formula (I) wherein R 4 is: wherein each R b and R 4b are, independently, as specified above; or specifically each R 4b and R 4b, independently, are hydrogen, C 1-6 alkyl, C? -6 alkoxy, C? -6 mono- or dialkylamino, C? -6 mono- or di-alkylaminocarbonyl. , hydroxy, halo, trifluoromethyl, aryl or Het; and R4e is any of the aryl substituents mentioned in the definitions of the compounds of formula (I) or of any of the subgroups of the compounds of formula (I); or specifically R 4e is hydrogen, C 1-6 alkyl > C -? - 6 alkoxy, or halo. The embodiments of the invention are compounds of formula (I) or any of the subgroups of the compounds of formula (I) wherein R 4 is: wherein each R4b and Rb are as previously specified; or specifically each R4b and R4b are, independently, hydrogen, C-? 6 alkyl, C? -6 alkoxy, C 1-6 mono- or di-alkylamino, mono- or di-alkylaminocarbonyl C -? - 6, hydroxy, halo, trifluoromethyl; preferably R4b is C6 -6 alkoxy, more preferably methoxy; and R4f is any of the aryl substituents mentioned in the definitions of the compounds of formula (I) or of any of the subgroups of the compounds of formula (I); or specifically R4f hydrogen, C? -6 alkyl, amino, mono- or dialkylamino of C? -6, pyrrolidinyl, piperidinyl, piperazinyl, 4-alkylpiperazinyl of C? -6 (especially 4-methyl-piperazinyl), or morpholinyl. The embodiments of the invention are compounds of formula (I) or any of the subgroups of the compounds of formula (I) wherein R 4 is: wherein each R4b and R4 are as previously specified; or specifically each R by R b are, independently, hydrogen, C? -6 alkyl, C?? 6 alkoxy, C1-6 mono- or di-alkylamino, mono- or di-alkylaminocarbonyl C? -6, hydroxy, halo, trifluoromethyl; Preferably R4 is C-? 6 alkoxy, more preferably methoxy, halo, or C? -3 alkyl; and R4g is any of the aryl substituents mentioned in the definitions of the compounds of formula (I) or of any of the subgroups of the compounds of formula (I); or specifically R g is hydrogen, C-? 6 alkyl, amino, mono- or di-C1-6 alkylamino, pyrrolidinyl, piperidinyl, piperazinyl, 4-alkylpiperazinyl of C6 (especially 4-methyl-piperazinyl), or morpholinyl. The embodiments of the invention are compounds of formula (I) or any of the subgroups of the compounds of formula (I) wherein R 4 is: wherein each R4b and Rb are as previously specified; or specifically each R by R4b are, independently, hydrogen, C? -6 alkyl, C?? 6 alkoxy, C-? - 6 mono- or di-alkylamino, mono- or di-alkylaminocarbonyl of C1-6, hydroxy, halo, trifluoromethyl; preferably R 4b is C 1-6 alkoxy, more preferably methoxy, halo, or C? -3 alkyl; and R 4h is any of the aryl substituents mentioned in the definitions of the compounds of formula (I) or of any of the subgroups of the compounds of formula (I); or specifically R4h is hydrogen, C6-6alkyl, amino, mono- or di-alkylamino of C-? -6, pyrrolidinyl, piperidinyl, piperazinyl, 4-alkylpiperazinyl of C1-6 (especially 4-methyl-piperazinyl) , or morpholinyl; and wherein R4h can also be substituted on one of the nitrogen atoms of the pyrazole ring in which case, it is preferably C-? -6 alkyl. The embodiments of the invention are compounds of formula (I) or any of the subgroups of the compounds of formula (I) wherein R 4 is: wherein each R4 and R4b are as previously specified; or specifically each R4b and Rb are, independently, hydrogen, C- | 6 alkyl, C-uß alkoxy, C-? 6 mono- or di-alkylamino, mono- or di-alkylaminocarbonyl of C? -6, hydroxy, halo, trifluoromethyl; preferably R 4b is C 1-6 alkoxy, more preferably methoxy, halo, or C 1-3 alkyl; and R4 'is any of the aryl substituents mentioned in the definitions of the compounds of formula (I) or of any of the subgroups of the compounds of formula (I); or specifically R4 'is hydrogen, C6-6 alkyl, amino, mono- or di-alkylamino of C-? 6, pyrrolidinyl, piperidinyl, piperazinyl, 4- alkylpiperazinyl of d-6 (especially 4-methyl-piperazinyl) ), or morpholinyl.

Preferred embodiments of the invention are compounds of formula (I) or any of the subgroups of the compounds of formula (I) wherein R 4 is: wherein R 4a is as defined in any of the groups or sub-groups of compounds of formula (I); and R4b is hydrogen, halo, or trifluoromethyl. Other preferred embodiments of the invention are compounds of formula (I) or any of the subgroups of the compounds of formula (I) wherein R 4 is: where R a is methoxy, ethoxy or propoxy; and R 4b is hydrogen, fluoro, bromo, chloro, iodo, methyl, ethyl, propyl, or trifluoromethyl. Other embodiments of the invention are compounds of formula (I) or any of the subgroups of the compounds of formula (I) wherein R 4 is: wherein R 4b is hydrogen, halo, or trifluoromethyl. 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 union of the building blocks P1 with P2, P2 with P3 and P1 with P1 '(when R1 is -NH-S02R6) 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 (I-i) or (l-j) can be carried out in any given sequence. One of the stages comprises the cyclization by which the macrocycle is formed. Hereinafter, the compounds (Ii) which are compounds of the formula (I) where the carbon atoms C7 and C8 are linked by a double bond and the compounds (Ij) which are compounds of the formula (I) are represented the 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. (l-i) (l-j) The synthetic processes described hereinafter are intended to be applicable also 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 possess the stereochemistry that was specified above in the compounds of formula (1-a) and (1-b). In one embodiment, the compounds (l-¡) are prepared by first forming the amide bonds and subsequently forming the binding of the double bond between P3 and P1 with the cyclization following the macrocycle.

In a preferred embodiment, the compounds (I) wherein the bond between C7 and C8 is a double bond, which are compounds of formula (Ii), as defined above, can be prepared as indicated in the following reaction scheme: (1a) The macrocycle formation can be carried out by an olefin metathesis reaction in the presence of a suitable metal catalyst, such as for example the Ru-b catalyst reported by Miller, SJ, Blackwell, HE, Grubbs , RH J. Am. Chem. Soc. 118, (1996), 9606-9614; Kingsbury, 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. The air-stable ruthenium catalysts such as bis (tricyclohexylphosphine) -3-phenyl-1H-inden-1-ylidene ruthenium chloride can be used (Neolyst M1®) or bis (triciciohexylphosphine) - [(phenylthio) methylene] ruthenium bichloride (IV). Other catalysts that can be used are Grubbs' first and second generation catalysts, i.e., benzylidene-bis (tricyclohexylphosphine) dichloro-ruthenium 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 of Hoveyda-Grubbs, which are dichloro (o-isopropoxyphenylmethylene) (tricyclohexylphosphine) -ruthium (ll) and 1,3-bis- (2,4,6-trimethylphenyl) -2 -imidazolidinylidene) dichloro (o-isopropoxyphenylmethylene) 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 (Li) by reducing the double bond C7-C8 in the compounds of formula (li). 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 building block P1 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 R1 represents -NHSO2R6, 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 both moieties. Similarly, compounds of formula (I), in which R represents -OR5, ie the compounds (l-k-2), can be prepared by linking the group R to P1 by the formation of an ester linkage. In one embodiment, the -OR5 groups are introduced in the last stage of the synthesis of the compounds the compounds (I) as indicated in the following reaction schemes in which G represents a group: (l-k-1) 0 '/ G-COOH + HOR5 - < OR5 (2a) (2c) "(i-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 trialkylamine 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, where Z represents halo, or the remaining part of an active ester, for example Z is an aryloxy group such as phenoxy, p.nitrophenoxy, pentafluorophenoxy, trichlorophenoxy, pentachlorophenoxy and the like; or Z may be the remainder 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? -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 the formula: where X, R2, R3, R4, n are as specified above and where the stereogenic centers may possess 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 secondary products soluble in water. The washed solution obtained in this way can then be reacted with (2b), without further purification steps. The isolation of the intermediates (2a-1), on the other hand, can provide certain advantages in that the isolated product, after optional additional purification, can be reacted with (2b), resulting in fewer byproducts and processing Easiest 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 mentioned amines in the present in relation to the amide formation reactions, in particular, a trialkylamine, for example triethylamine. Solvents that can be used in 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 (II), can also be prepared by removing a PG protecting group, from a corresponding intermediate protected by nitrogen (3a), as in the following scheme of reaction. The PG protecting group in particular is any of the nitrogen protecting groups mentioned hereinafter and can be removed using methods also mentioned below herein: 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: 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 LiH 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), where 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 possessed by 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) where 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 possesses. 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 remainder P1 at P1-P2 and the subsequent formation of the carbamate or ester bond between P3 and the residue 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 thus formed, 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 (1-i) to (1-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 building blocks 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 the like), the K method of the Woodward reagent, the 1-carbonyldiimidazole method (CDI or N, N'-carbonyldiimidazole), the phosphorus or oxidation-reduction reagent methods. 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 0- (7-azabenzotriazole-1-yl) hexafluorophosphate - / V,? /, / V,? / - 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-isobutyloxy-carbonyl-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 range between 15 min and 24 h. 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 can be used include 1) alkyl esters such as methyl, trimethylsilyl and tert-butyl; 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 phenylthiocarbonyl and dithiasuccinoyl. 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 any secondary amine can be used. 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; Benzyl (Bn) ethers can be used to protect hydroxy groups; and benzyl esters can be used to protect other carboxyl groups. Or when Fmoc is chosen for the protection of a-amino, tert-butyl-based protecting groups are generally acceptable. For example, Boc can be used for other amino groups; tert-butyl ethers 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 removed after completing the macrocycle preparation. The removal of the protecting groups can be carried out in any way determined by the choice of the protecting groups, whose manners are known to those 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 introduction agent as indicated in the following reaction scheme. (5a) (l a- 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 embodiment, the base is a hydrogen carbonate, 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 this way intermediaries (1a-1) as in the previous scheme. An alternative route using similar reaction conditions comprises, first, reacting the CO introduction agent with the alkene amine (5b) and then reacting the intermediate formed in that manner with (5a). Intermediaries (1a-1), alternatively, can be prepared as follows: 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 the latter instance, this group can be removed by reaction with an alkali metal hydroxide (LiOH, NaOH, KOH), especially 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 deprotected, 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 an amine formation reaction starting from the intermediates (7a) which are reacted with an amine (5b), as shown in the following reaction scheme, using the reaction conditions to prepare amides, such as those described above.

The intermediaries (1a-1) can be prepared alternatively as follows: despr choice PG1 is an O-protecting group, as described above. The same reaction conditions can be used, as described above; the amide formation, as described above, the removal of PG1 as in the description of the protecting groups and the introduction of R4, 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 above-mentioned carboxyl protecting groups, especially C 1-4 alkyl or benzyl ester, for example to 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? -4 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.

The group PG1 is selected so that it can be selectively cleaved with respect to PG2. PG2 can be, for example, methyl or ethyl esters, which can be removed by treatment with an alkali metal hydroxide in an aqueous medium, in which case PG1, for example, is t.butyl or benzyl. PG2 can be t-butyl esters that can be removed under weakly acidic conditions or PG1 can be benzyl esters that 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, the intermediaries (10a) are cyclized to the macrocyclic esters (10b), the latter are deprotected by removing the group PG1 a (10c), which are reacted with intermediates (4b), followed by the removal of the protecting group from carboxyl PG2. Cyclization, deprotection of PG1 and PG2 and coupling with (4b) are as described above. The R1 groups may be introduced at any stage of the synthesis, either as the last stage, as previously described, or before, before the formation of the macrocycle. In the following scheme, the R1 groups are introduced being -NH-SO2R6 or -OR5 (which are as specified above): In the previous scheme, PG2 is as defined above and L1 is a P3 group where n and R3 are as defined above and where X is N, L1 can also be a nitrogen protecting group (PG, as defined above) and where X is C, L1 can also be a -COOPG2a group, where the PG2a group is a carboxyl-protective group similar to PG2, but where PG2a it can be selectively cleaved with respect to PG2. In one embodiment, PG2a is t-butyl and PG2 is methyl or ethyl. Intermediates (11c) and (11d) where 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 PV group (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-R4 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-R4 group.

In the procedure of the above scheme, a cyclopropyl amino acid amino (12b) or (12c) is coupled to the acid function of the building block P2 (12a) with the formation of an amide linkage, 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 (11d) 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-SO2R6 (2b) or with HOR5 (2c), as described above, again gives the intermediates (12e), where -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 embodiment, PG in this reaction 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-R4. In one embodiment, L2 is a group (b) and these reactions comprise the coupling of P1 to P2-P3, which produces the intermediates (1a-1) or (1a) mentioned above. In another embodiment, L2 is a protecting 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) where L3 is hydroxy. In this instance, PG1 is selected so that it can be selectively cleaved with respect to the group L2 which is PG. In a similar way, 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 bond and the block of Construction 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, where the lactone is opened giving the intermediates (14c) and (14e). The lactones can be opened using ester hydrolysis procedures, for example using the reaction conditions described above for the alkaline removal of a PG1 group in (9b), especially using basic conditions, such as an alkali metal hydroxide, for example NaOH, KOH, especially LiOH.

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

Coupling of building blocks P3 and P2 For building blocks P2 that possess 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 the coupling of the P2 blocks possessing 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 (e) In one embodiment, L4 in (15a) is a group -OPG2, the PG 2 group can be eliminated and the resulting acid coupled with the cyclopropyl amino acids (12a) or (12b), giving the intermediates (12d) or (12e) where L2 is a radical (d) or (e). A general procedure for the coupling of the 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, especially, 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, especially by the use of acetic anhydride in the presence of a weak base, such as pyridine. The carboxylic acid functional group in (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.butyl group and is introduced, for example, by treatment with isobutene in the presence of a Lewis acid or with di-tert-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, especially 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 that can be selectively cleaved with respect to PG2 and the hydroxy function can be converted into a -OPG1 group or a -O-R4 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 that OH function possesses by using specific reagents in the reactions introducing OPG1 or O-R4 that reverse the stereochemistry, such as, for example, by applying a reaction of Mitsunobu. 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-R4, 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 collected in 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 bromination elimination reaction of 3,4-bis (methoxycarbonyl) cyclopentanone (17a) as described by Dolby et al. in J. Org. Chem. 36 (1971) 1277-1285 followed by the 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.

Oxidation of commercially available 3-methyl-3-buten-1-ol (20a), especially by an oxidation agent such as pyridinium chlorochromate, gives (20b), which is converted to the corresponding methyl ester, for example, by treatment with acetyl chloride in methanol, followed by the bromination reaction with bromine giving 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-tert-butyl dicarbonate in the presence of a base such as dimethylaminopyridine. The intermediate (20e) is treated with a base, such as lithium diisopropyl amide 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 Jacobsen's asymmetric epoxidation method to obtain the epoxide (20h). Finally, an epoxide opening reaction under basic conditions, for example, by the addition of a base, especially DBN (1,5-diazabicyclo- [4,3,0] non-5-ene), gives the alcohol (20i) 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 group -O-R4 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 to first introduce the group -O-R4 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 macrocycle. Another approach is to couple the building blocks P2, which does not possess a substituent -O-R4, with each P1 and P3 and add the group -O-R4 either before or after the formation of the macrocycle. In the latter process, the P2 moieties possess a hydroxy group, which can be protected by a protecting group PG1. The R4 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, where L2 is as previously specified and L5 and L5a independently from 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 one embodiment in (21a), L2 is PG and L5 is -OPG2 or in (21d), L5a is -OPG2 and L5 is -OPG2 and groups PG2 are removed as described above.

In another embodiment, the group L is BOC, L5 is hydroxy and the starting material (21a) 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 (21b-1) is Boc and PG2 is a lower alkyl ester, especially 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, especially with LiOH. In another embodiment, the cyclopentane or cyclopentene analogs substituted by hydroxy (21 d) are converted into (21 e), which, when L5 and L5a are -OPG2 or -OPG2a, can be converted into the corresponding acids (21f) by the Removal of the PG2 group. The removal of PG2a in (21e-1) leads to similar intermediates. Intermediates (4b), which are isoquinoline derivatives, can be prepared using procedures known in the art. For example, US 2005/0143316 provides various methods for the synthesis of isoquinolines such as R4-OH or intermediates R -LG. The methodology for the synthesis of such isoquinolines has been described by N. Briet et al., Tetrahedron, 2002, 5761 and is shown below, where R4a, R4b and R4b 'are substituents on the isoquinoline residue having the meanings that are they define in lapse for the substituents of the group R4.

The cinnamic acid derivatives (22b) are transformed into 1-chloroisoquinolines in a three-step process. The resulting chloroisoquinolines (22e) can be subsequently coupled to hydroxypyrrolidine, hydroxycyclopentane or hydroxycyclopentenoderivatives derivatives as described herein. In a first step, the carboxyl group is activated in the cinnamic acids (22b), for example by treatment with a C?-6 alkyl chloroformate (especially methyl or ethyl) in the presence of a base. The resulting combined anhydrides are then treated in sodium acid to give the acyl azides (22c). Various other methods are available for the formation of acylazides from carboxylic acids, eg the carboxylic acid can be treated with diphenylphosphoryl azide (DPPA) in an aprotic solvent, such as methylene chloride, in the presence of a base. In a next step, the acylazides (22c) are transformed into the corresponding isoquinolones (22d), in particular, by heating the acylazides in a high boiling solvent, such as diphenylether. The starting cinnamic acids (22d) are commercially available or can be obtained from the corresponding benzaldehydes (22a) by direct condensation with masonic acids or derivatives thereof, or by using a Wittig reaction. The isoquinolones of the intermediate (22d) can be transformed into the corresponding 1-chloro-isoquinolines by treatment with a halogenating agent such as phosphorus oxychloride. The R4 groups which are isoquinolines can also be prepared by following the following procedures, as described in K. Hirao, R. Tsuchiya, Y. Yano, H. Tsue, Heterocycles 42 (1) 1996, 415-422.

An alternative method for the synthesis of the isoquinoline ring system is the Pomeranz-fritsh process. This method begins with the conversion of a benzaldehyde derivative (23a) into a functionalized imine (23b), which is then transformed into an isoquinoline ring system by treatment with an acid at elevated temperature. This method is especially useful for the preparation of isoquinoline intermediates which are substituted at the C8 position indicated by the asterisk. The isoquinolines of the intermediate (23c) can be transformed into the corresponding 1-chloroquinolines (23e) in a two-step process. The first step comprises the formation of an isoquinoline N-oxide (23d) by treatment of isoquinoline (23c) with a peroxide such as meta-chloroperbenzoic acid in a suitable solvent such as dichloromethane. The intermediate (23d) is transformed into the corresponding 1-chloroisoquinoline by treatment with a halogenating agent, such as phosphorus oxychloride. Another method for the synthesis of the isoquinoline ring system is shown in the scheme below.

In this process, the anionic form of the ortho-alkylbenzamide derivative (24a) is obtained by treatment with a strong base such as tert-butyl lithium in a solvent such as THF and subsequently condensed with a nitrile derivative, giving isoquinoline ( 24b). The latter can be transformed into the corresponding 1-chloroisoquinoline by the methods described above. R 'and R "in (24a) are alkyl groups, especially C1-4 alkyl groups, for example methyl or ethyl The following scheme shows a further method for the synthesis of isoquinolines.

The intermediate (24a) is deprotonated using a strong base such as those described above. R 'and R "are as specified above The anion of the resulting intermediate is condensed with an ester (25a), obtaining ketone intermediate (25b). In a subsequent reaction, the last intermediate (25b) is reacted with an ammonia or ammonium salt, for example, ammonium acetate, at elevated temperature, giving the formation of isoquinolone (24b). A variety of carboxylic acids with the general structure (25a) 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-aminocarboxy- (substituted) -aminothiazole (25a-1), 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 (25a-1): Ethyl thiooxamate (26a) is reacted with the β-bromoketone (26b) to form the thiazolyl ester of the carboxylic acid (26c), which is hydrolyzed to the corresponding acid (25a-1). The ethyl ester in these intermediates can be replaced by the carboxyl protecting groups PG2, as defined above. In the above scheme, R4c is as defined above and in particular is C1- alkyl, more especially i-propyl. The bromoketone (26b) can be prepared from 3-methyl-butan-2-one (MIK) with a silylating agent (such as TMSCI) in the presence of a suitable base (especially LiHMDS) and bromine.

The synthesis of other carboxylic acids (25a), in particular, of substituted amino-thiazole carboxylic acids (25a-2) is illustrated in the following: Thiourea (33c) with several R a substituents, which, in particular, are C 1 -C 6 alkyl, can be formed by reaction of the appropriate amine (33a) with tert-butylisothiocyanate in the presence of a base such as diisopropylethylamine in a solvent such as dichloromethane followed by removal of the tert-butyl group under acidic conditions. The subsequent condensation of the thiourea derivative (33c) with 3-bromopyruvic acid yields the thiazole carboxylic acid (25a-2). In addition, an additional method for the preparation of isoquinolines is illustrated in the following reaction scheme.

In the first step of this process an ortho-alkylarylimine derivative (28a) is subjected to deprotonation conditions (for example sec-butyl lithium, THF) and the resulting anion is condensed with an active carboxylic acid derivative, such as an amide of Weinreb (28b). The resulting keto imine (28c) is converted to isoquinoline (28d) by condensation with ammonium acetate at elevated temperatures. The isoquinilines obtained in this manner can be converted to the corresponding 1-chloroisoquinolines by the methods described herein. The isoquinolines described herein, acting either as such or incorporated into the hydroxypyrrolidine, hydroxycyclopentane or hydroxycyclopentane moieties in the compounds of formula (I) or in any of the intermediates mentioned herein, may also be functionalized. An example of such functionalization is illustrated below in the present.

The above scheme shows the conversion of a 1-chloro-6-fluoro-isoquinoline to the corresponding residue of 1-chloro-6-alkoxy C-? -6-isoquinoline (29b), by treating (29a) with an alkoxide of sodium or potassium in an alcohol solvent from which the alkoxide is derived. L6 in the previous scheme represents halo or a group R in the above scheme represents C1-6 alkyl and LG is an exit group. In an LG mode it is fluoro. L7 and L8 represent vario substituents that can be attached at these positions of the P2 moiety, in particular groups such as OL5, or L8 can be a group P1 and L7 a group P3, or L7 and L8 taken together can form the remainder of the macrocyclic ring system of the compounds of formula (I). The following scheme provides an example for the modification of isoquinolines by Suzuki reactions. These couplings can be used to functionalize an isoquinoline at each position of the annular system provided that said ring is activated or is functionally adequate, such as with chlorine. (30e) (30f) This sequence begins with 1-chloroisoquinoline (30a) which when treated with a peroxide such as metachloroperbenzoic acid is transformed into the corresponding N-oxide (30b). The last intermediate is transformed into the corresponding 1,3-dichloroisoquinoline (30c) by treatment with a halogenating agent, for example oxyphosphorus chloride. The intermediate (30c) can be coupled with an intermediate (30d), where L6 is a PG group when X is N, or L6 is a -COOPG2 group when X is C, using methods described herein to introduce -O- groups R4-, to provide the intermediary (30e). The intermediate (30e) is derived using a Suzuki coupling with an aryl boronic acid, in the presence of a palladium catalyst and a base, in a solvent such as THF, toluene or an aprotic dipolar solvent such as DMF, to give the C3-aryl isoquinoline intermediate (30f). Heteroarylboronic acids can also be used in this coupling process to provide C3-heteroaryl isoquinolines. Suzuki couplings of isoquinoline systems with aryl or heteroaryl groups can also be employed in a subsequent synthesis step in the preparation of compounds of formula (I). Annular isoquinoline systems can also be converted to functional groups by the use of other palladium catalyst reactions, such as Heck, Sonogashira or Stille couplings, as illustrated for example in US 2005/1043316.

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-cyclopropyl ethyl ester (12b) can be obtained according to the process described in WO 00/09543 or as illustrated in the following scheme, where PG2 is a carboxyl protecting group as specified above: -1) (12b) The imine treatment (31a) commercially available or obtainable easily with 1,4-dihalobutene in the presence of a base produces (31b), which after hydrolysis gives cyclopropyl amino acid (12b), which possesses the allyl 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. The 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 -OR5 or -NH-SO2R6 can be prepared by reacting the amino acids (32a) with the appropriate alcohol or amine, respectively, under conditions standard for the formation of ester or amide. The cyclopropyl amino acids (32a) are prepared by introducing a protecting group N PG and removing PG2 and the amino acids (32a) are converted to 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 (32a) with amine (2b) is a process of amine formation. 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 (32b) or (32c) 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 (32a) 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 (32a) with (2b) is carried out by treating the amino acid with the coupling agent, for example N.N'-carbonyl-dmidazole (CDI) or the like, in a solvent such as THF, followed by the reaction with (2b) in the presence of a base such as 1,8-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. 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 P3 building blocks The P3 building blocks are available in the market or can be prepared according to 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 1-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 (33a) are treated with a strong base such as sodium hydride and subsequently reacted with an LG-alkenyl reagent of C5-β (33b), in particular haloalkenyl of Cs-β, to form the corresponding protected amines (33c). The deprotection of (33c) produces (5b), which are building blocks P3. Deprotection will depend on the functional group R, so if R is f-butoxy, deprotection of the corresponding Boc-protected amine can be achieved with treatment with an acid, e.g. trifluoroacetic acid. Alternatively, when R is, for example, trifluoromethyl, removal of the R group is achieved with a base, e.g. sodium hydroxide. The following scheme illustrates even another method for preparing a P3 building block, ie a Gabriel synthesis of the primary C5-8 alkenylamines, which can be carried out by treating a phthalimide (34a) with a base, such as NaOH or KOH, and with (33b), 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 halo atom can be changed to another halo. 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 peroxyacids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, eg. tert-butyl hydroperoxide. Suitable solvents are, for example, water, lower alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, for example 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 one another 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 diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom 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 infection by HCV, in infected subjects or subjects at risk of infection. Even in a further aspect, this invention relates to a method 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 the addition salt or metal complex, as the active component is combined in intimate admixture with a pharmaceutically acceptable carrier, whose vehicle It 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 media 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. Also included are solid form preparations which are intended to be converted, immediately before use, into 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. Thus, 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 pharmaceutical compositions 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, AUC (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. Assays 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 counter-cellular screens for the evaluation of the non-selective inhibition of the activity of related reporter genes, such as firefly luciferase. 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 the viral infection, in particular the 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 particular 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 view 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 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 consecutive 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 an HCV polymerase inhibitor, a protease inhibitor of HCV, 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, without limitation, NM283 (valopicitabine), R803, JTK-109, JTK-003, HCV-371, HCV-086, HCV-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 can 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 HCV life cycle, 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 a polyethylene glycol derivative (pegylated) interferon structure, 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 ribosome entry; broad-spectrum viral inhibitors, such as inhibitors of IMPDH (e.g., compounds of US5,807,876, US6,498,178, US6,344,465, US6,054,472, WO97 / 40028, WO98 / 40381, WO00 / 56331, and mycophenolic 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 also therapeutic products based on antibodies directed against HCV epitopes, small interference 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 of these 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. Even in 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 a pharmaceutically acceptable salt thereof; 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 W094 / 14436. To obtain a preferred dosage form of ritonavir, see US6,037,157, and the documents cited there: US 5,484,801, US 08 / 402,690, and WO95 / 07696 and WO95 / 09614. Ritonavir 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 method for preparing a combination as described herein, comprising the step of combining an HCV NS3 / 4a protease inhibitor of formula (I) or one of its acceptable salts from the point of pharmaceutical view, and ritonavir or one of its pharmaceutically acceptable salts. An alternative embodiment of this invention provides a method 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 pestiviruses. 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 according to 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 additional agent selected from a polymerase inhibitor of HCV, an inhibitor of protease of HCV, an inhibitor of another target in the life cycle of HCV, and an immunomodulatory agent, an agent antiviral and its combinations. 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, it covers all such alternative or simultaneous treatment regimens and the term "administer" must 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 ccally improve the bioavailability of the HCV NS3 / 4a protease inhibitor of formula (I) in relation to bioavailability when said HC3 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 the HCV of formula (I) selected from t-? 2, Cm, Cma, Css, AUC at 12 o'clock, or AUC at 24 hours, with respect to said at least one pharmacokinetic variable when the HCV NS3 / 4a protease inhibitor of formula (I) is administer alone A further embodiment relates to a method for improving the bioavailability of an HCV NS3 / 4a protease inhibitor which comprises 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 HCV NS3 / 4a protease inhibitor of formula (I) selected from t-? 2, Cm, Cmax, Css, AUC at 12 o'clock, or AUC 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. t1 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 equals the rate of elimination. Cmn is defined as the lowest (minimum) concentration measured during the dosing interval. Cmax, represents the highest (maximum) concentration during the dosing interval. AUC 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 at specific dosage scales 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 found appropriately on the scale 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, where the weight ratio of the HCV NS3 / 4a protease inhibitor of formula (I) ) to ritonavir 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 are useful ranging from about 1: 1 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, would be the amount of the compound of formula (I) and the amount of ritonavir that when taken together have a combined effect which 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 one, 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, age, weight, sex, degree of disorder and general physical condition. of the particular patient as well as other medication that the individual may be taking, as is known to those with experience in the 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 physician prescribing the compounds of the present invention. The scales of effective daily amount mentioned above are, therefore, only guides. According to one embodiment, the HCV NS3 / 4a protease inhibitor of formula (I) and ritonavir can be administered concomitantly once or twice a day, preferably orally, where 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 ritonavir. 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) / r¡tonavir (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 an effective composition for treating an HCV infection or inhibiting 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; wherein 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 formula HCV (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 capacity of potential pharmaceutical products to inhibit the NS3 / 4a protease of HCV, the growth of HCV, 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 It is intended that the following examples illustrate the present invention and not limit it.

EXAMPLE 1 Preparation of representative intermediaries Synthesis of 1-hydroxy-3- (4-isopropylthiazol-2-yl) -6-methoxyisoquinoline Í6) Stage A To a stirred solution of 3-methyl-2-butanone (27.0 g, 313 mmol) in methanol (150 ml) was added bromine (50 g, 313 mmol). The reaction was allowed to continue (discoloration) below 10 ° C. Then, stirring was continued at room temperature for 30 min before adding water (100 ml). After 15 min, the mixture was diluted with water (300 ml) and extracted four times with diethyl ether Et20. The ether extracts were subsequently washed with 10% Na2CO3 solution, water, brine, and dried (Na2SO4) to give 42 g (81%) of the objective product as a liquid.

Stage B To a boiling solution of ethyl thiooxamate (13.3 g, 100 g, 100 mmol) in ethanol (100 ml) was added 1-bromo-3-methylbutan-2-one (17.6 g, g, 106 mmol) dropwise over 15 minutes. minutes The solution was refluxed for one hour. The solution was added to 250 ml of frozen water and made basic with concentrated ammonia solution. This mixture was extracted twice with ethyl acetate AcOEt. The organic phase was washed with brine, dried (Na 2 SO 4) and evaporated under reduced pressure. The crude product was purified by column chromatography with dichloromethane to dichloromethane with 2% methanol MeOH to give 13.1 g (65%) of the objective product: 1 H-NMR-CDCl 3: 7.20 (s, 1 H), 4.49 (m, 2H), 3.25 (m, 1 H), 1.42 (t, 3H), 1.35 (d, 6H).

Stage C To a solution of? /,? / - diethyl-4-methoxy-2-methylbenzamide 4 (2.4 g, 11 mmol) in THF anhydride (30 ml) s -78 ° C under nitrogen was added dropwise n-buLi ( 8.9 ml, 2.5 M solution in hexanes). The solution was maintained at -78 ° C for 30 min. additional Then, a solution of thiazole 3 in THF (5 ml) was added dropwise. After 2 h, the reaction was partitioned between ice water and AcOEt-ethyl acetate. Purification by column chromatography (ethyl acetate AcOEt / Petroleum ether / CH2Cl2, 1: 2: 1) gave 1.8 g (43%) of the objective product 4 as a yellow oil: > 95% pure by LCMS.

Stage D A mixture of 5 (1.98 g, 5.29 mmol) and ammonium acetate (12.2 g, 159 mmol) was heated at 140 ° C in a sealed tube for 1 h, then cooled to room temperature. The reaction mixture was partitioned between freezing water and CH2Cl2, dried (Na2SO4) and filtered over silica gel to give 1.59 g (78%) of the objective product 6 as a white powder m / z = 301 (M + H ) + Synthesis of 1-hydroxy-3- (4-cyclopropylthiazol-2-yl) -6-methoxyisoquinoline (7) The title product was obtained from methylcyclopropyl ketone following the reported procedures for 1-hydroxy-3- (4-isopropylthiazol-2-yl) -6-methoxyisoquinoline 6.

Synthesis of 1,3-dichloro-6-methoxyisoquinoline (12) Stage A Triethylamine (80.5 ml, 578 mmol) was added at 0 ° C under nitrogen to a suspension of 3-methoxycinnamic acid (49.90 g, 280 mmol) in acetone (225 ml). After 10 min at 0 ° C, ethyl chloroformate (46.50 g, 429 mmol) was added dropwise while the temperature was maintained at 0 ° C. After 1 h at 0 ° C, a solution of sodium azide (27.56 g, 424 mmol) in water (200 ml) was added slowly, then the reaction mixture was allowed to warm to RT, room temperature. After 16 h, the reaction mixture was poured into water (500 ml) and the acetone was evaporated. The residue was extracted with toluene to give a solution of 8, which was used as such in the next step.

Stage B The toluene solution of 8 from the previous step was added dropwise to a hot solution of diphenylmethane (340 ml) and tributylamine (150 ml) at 190 ° C. The toluene was distilled immediately using a Dean-Srark device. After the addition was complete, the reaction temperature was raised to 210 ° C for 2 h. After cooling, the precipitated product was collected by filtration, washed with heptane to give 49.1 g (29%) of the objective product 9 as a white powder: m / z = 176 (M + H) +; 1 H-NMR (CDCl 3): 8.33 (d, J = 8.9 Hz, 1 H), 7.13 (d, J = 7.2 Hz, 1 H), 7.07 (dd, J = 8.9 Hz, 2.5 Hz, 1H), 6.90 ( d, J = 2.5 Hz, 1H), 6.48 (d, J = 7.2 Hz, 1H), 3.98 (s, 3H).

Phosphorus oxychloride (25 ml) was added slowly to 9 (1 0.0 g, 57 mmol) and this mixture was heated to gentle reflux for 3 h. After completing the reaction, phosphorus oxychloride was evaporated. The residue was poured into frozen water (40 ml) and the pH was adjusted to 10 with a solution of NaOH in water (50%). The mixture was extracted with CHCl3, washed with brine, dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (CH2Cl2), to give 8.42 g of the objective product 10 as a yellow solid: m / z = 194 (M + H) +; H-NMR (CDCl 3): 8.21 (d, J = 9.3 Hz, 1 H), 8.18 (d, J = 5.7 Hz, 1 H), 7.47 (d, J = 5.6 Hz, 1 H), 7.28 (dd, J = 9.3 Hz, 2.5 Hz, 1 H), 7.06 (d, J = 2.5 Hz, 1 H), 3.98 (s, 3H).

Stage D Methachloroperbenzoic acid (6.41 g, 28.6 mmol) was added in small portions at 0 ° C to a solution of 10 (2.70 g, 13.9 mmol) in CH2Cl2 (10 mL). After 30 min at 0 ° C, the reaction mixture was warmed to room temperature for 12 h. Then, the reaction mixture was partitioned between 1 N NaOH and CH 2 Cl 2 and subsequently washed with 1 N NaOH and brine. The organic layer was dried (Na2SO4), filtered and evaporated to give 1.89 g (64%) of the objective product 11 as an orange solid: m / z = 209.9 (M + H) + Stage E A solution of 11 (1.86 g, 8.86 mmol) in phosphorus oxychloride (18 ml) was heated at reflux for 3 h. Then, the phosphorus oxychloride was evaporated in vacuo. The residue was poured into frozen water (50 ml) and the pH was adjusted to 10 with 50% NaOH in water. The mixture was extracted with CHCl3, the organic layer was washed with brine, dried (Na2SO4), filtered and evaporated. The crude material was purified by column chromatography (CH2Cl2), to give 350 mg (17%) of the objective product 12 as a yellow solid: m / z = 227.9 (M + H) +; 1 H-NMR (CDCl 3): 8.16 (d, J = 9.3 Hz, 1 H), 7.50 (s, 1 H), 7.25 (dd, J = 9.3 Hz, 2.5 Hz, 1 H), 6.98 (d, J = 2.5 Hz, 1 H), 3.98 (s, 3H).

Synthesis of 4-bromo-1-hydroxy-6-methoxyquinoline (13) Add? / -bromosuccinimide (2.33 g, 143 mmol) to a solution of 9 (2.06 g, 11.8 mmol) in DMF (40 mL). The resulting mixture was stirred at room temperature until the next day. Then, the DMF was evaporated and CH2Cl2 was added to the residue. This suspension was heated at 45 ° C for 15 min. The white solid was filtered and washed with isopropyl ether, to give 2.07 g (69%) of the objective product 13: m / z = 253.7 (M + H) +; 1 H NMR (DMSO 6): 8.14 (d, J = 8.8 Hz, 1 H); 7.52 (s, 1 H), 7.17 (dd, J = 8.8 Hz, 2.5 Hz, 1 H), 7.11 (d, J = 2.4 Hz, 1 H), 3.83 (s, 3H).

Synthesis of 5-bromo-1-chloro-6-methoxyisoquinoline (19) Stage A An equimolesar solution of p-methoxybenzaldehyde (10 g, 73.5 mmol) and aminoacetaldehyde dimethylacetal (7.93 g, 75.4 mmol) in toluene (50 mL) was refluxed overnight in a Dean-Stark apparatus. Then, the solution was evaporated in vacuo to give the objective product 14 which was used in the next step without further purification: m / z = 224 (M + H) 0 Stage B Ethyl chloroformate (8.02 g, 73.9 mmol) was added at -10 ° C, with vigorous stirring, to a solution of 14 (73.5 mmol) in dry THF (50 mL). After 30 min, the reaction mixture was allowed to warm to room temperature and trimethylphosphite (10.6 g, 85.2 mmol) was added. After 15 h, the volatiles were evaporated in vacuo. The resulting oil was co-evaporated 3 times with toluene to give the objective product 15 as an oil: m / z = 406 (M + H) 0 Stage C The material obtained from Step B (15) was dissolved in CH 2 Cl 2 (200 ml) and cooled to 0 ° C. Then, titanium tetrachloride (86.0 g, 453 mmol) was added and the solution was refluxed until the next day. The reaction mixture was allowed to cool to room temperature. Then, a solution of NaOH (73 g) in water (500 ml) was added and the mixture was stirred for 10 min. The precipitate of Ti02 was filtered, and the filtrate was extracted with 3N HCl. The pH of the aqueous layer was adjusted to 10 with NaOH. The product was extracted with CH2Cl2, dried (Na2SO4) and evaporated to give 5.32 g (45%) of the objective product 16, which was used without further purification in the next step: m / z = 16O (M + H) 0 Stage D 6-Methoxyisoquinoline 16 (5.32 g, 33.4 mmol) was slowly added at 0 ° C to H2SO4 conc. (33.5 ml). The mixture was cooled to -25 ° C and NBS (7.68 g, 43.2 mmol) was added to an extent such that the reaction temperature was maintained between -25 ° C and -22 ° C. The mixture was stirred at -22 ° C for 2 h and at -18 ° C for 3 h, then poured onto crushed ice. The pH was adjusted to 9 using concentrated aqueous NH3 and then, the alkaline suspension was extracted with diethyl ether. The combined organic fractions were washed with 1 N NaOH and water, dried (Na 2 SO 4), filtered and evaporated until dried to give 5.65 g (71%) of the objective product 17: m / z = 237.8 (M + H) 0 17 18 Methachloroperbenzoic acid (6.73 g, 30 mmol) was added at 0 ° C to a solution of 17 (5.65 g, 24 mmol) in CH2Cl2 (50 mL). After 30 min at 0 ° C to allow the reaction mixture to warm to room temperature for 3.5 h. Then, additional CH2Cl2 (300 ml) was added and this mixture was washed successively with 1N NaOH and with brine. The organic layer was dried (MgSO4), filtered and evaporated to give 6.03 g (100%) of the objective product 18 which was used as such in the next step: m / z = 253.9 (M + H) 0 Phosphorus oxychloride (60 ml) was added slowly to a cold 18 (6.03 g, 23.7 mmol) and then this mixture was heated to gentle reflux for 30 min. After the reaction was complete, the phosphorus oxychloride was evaporated. The residue was poured into frozen water (50 ml) and the pH was adjusted to 10 with NaOH. The mixture was extracted with CHCl3, the organic layer was washed with brine, dried (Na2SO4), filtered and evaporated. The crude material was purified by column chromatography (CH2Cl2) to give 1.15 g (18%) of the title product as a white powder: m / z = 271.7 (M + H) +; 1 H-NMR (CDCl 3): 8.17 (d, J = 9.3 Hz, 1 H), 8.28 (d, J = 6.0 Hz, 1 H), 7.94 (d, J = 6.0 Hz, 1 H), 7.41 (d, J = 9.3 Hz, 1 H).

Synthesis of (hex-5-enyl) (methyl) amine (21) 0 CF, 1 ^ ^ ^ L 3 F3C ^ N ^ Br ^^^ > ~ ^^^ N ^ 0 - ^^^^ NH H 20 I 21 I 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 h 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 diethyl ether (4 x 50 ml), dried (MgSO 4), filtered and evaporated to give 35 g of the objective product 20 as a yellow oil which was used without further purification in the next stage.

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 diethyl ether (4 x 50 ml), dried (MgSO 4), filtered and the diethyl 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 21 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), 495 (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).

EXAMPLE 2 Preparation of 17- [3- (4-cyclopropylthiazol-2-yl) -6-methoxy-isoquinolin-1-yloxy-M3-methyl-2.14-dioxo-3.13-diazatriciciori3.3.0.046loctadec-7-ene ^ 4- acid carboxylic (29) Stage A 3-Oxo-2-oxa-bicyclo [2.2.1] heptane-5-carboxylic acid 22 (500 mg, 3.2 mmol) in 4 ml DMF was added at 0 ° C to 2- (7-Azafluorophosphate) 1H-benzotriazol-1-yl) -1, 1, 3,3-tetramethyluronium (HATU) (1.34 g, 3.52 mmol) and? / - methylhex-5-enylamine (435 mg, 3.84 mmol) in DMF (3 ml) , followed by N, N-diisopropylethylamine (DIPEA). After stirring for 40 min at 0 ° C, the mixture was stirred at room temperature for 5 h. Then, the solvent was evaporated, the residue was dissolved in EtOAc ethyl acetate (70 ml) and washed with saturated NaHC 3 (10 ml). The aqueous layer was extracted with ethyl acetate EtOAc (2 x 25 ml). The organic phases were combined, washed with saturated NaCl (20 ml), dried (Na2SO4) and evaporated. Purification by flash chromatography (ethyl acetate EtOAc / petroleum ether, 2: 1) gave 550 mg (68%) of the objective product 23 as a colorless oil: m / z = 252 (M + H) 0 Stage B A solution of LiOH (105 mg in 4 ml of water) was added at 0 ° C to lactone amide 23, after 1 h, the conversion was complete (HPLC). The mixture was acidified to pH 2-3 with 1N HCl, extracted with ethyl acetate 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 objective product 24: m / z = 270 (M + H) 0 Stage C The 1- (amino) -2- (vinyl) cyclopropanecarboxylic acid ethyl ester hydrochloride (4.92 g, 31.7 mmol) and HATU (12.6 g, 33.2 mmol) were added at 24 (8.14 g, 30.2 mmol). 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 consecutively. After 30 min at 0 ° C, the solution was stirred at room temperature for an additional 3 h. Then, the reaction mixture was partitioned between EtOAc ethyl acetate and water, subsequently washed with 0.5 N HCl (20 ml) and saturated NaCl (2 x 20 ml), and dried (Na 2 SO 4). Purification by flash chromatography (ethyl acetate AcOEt / CH 2 Cl 2 / petroleum pter, 1: 1: 1) gave 7.41 g (60%) of the objective product 26 as a colorless oil: m / z = 407 (M + H) 4 .

Stage D DIAD (218 μl, 1.11 mmol) was added at -20 ° C under nitrogen atmosphere to a solution of 26 (300 mg, 0.738 mmol), isoquinoline 7 (308 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 / CH 2 Cl 2 / ether, 3: 1.5: 0.5 to 1: 1: 1) to give 290 mg of the product of target contaminated with secondary products (90% pure). Second, purification (same eluent) gave 228 mg (43%) of the objective product 27: m / z = 687 (M + H) +, 1 H-NMR (CDCl 3): 8.11-7.98 (m, 1 H), 7.98 (s, 1 H), 7.13-7.10 (m, 2H), 6.89 (s, 1 H), 5.78-5.69 (m, 2H), 5.30-5.25 (m, 1 H), 5.11-5.09 (m, 1H), 499-487 (m, 2H), 415-408 (m, 2H), 3.92 (s, 3H), 3.71-3.58 (m, 1 H), 3.48-3.15 (m, 4H), 3.03 (s, 3H), 2.90-2.85 (m, 2H), 2.60-2.25 (m, 2H), 2.11-1.82 (m, 6H), 1.55-1.10 (m, 7H), 0.98-0.96 (m, 4H) ).

Stage E A solution of 27 (220 mg, 0.32 mmol) and 1 st generation Hoveyda-Grubbs catalyst (19 mg, 0.032 mmol) in degassed dry 1,2-dichloroethane (400 ml) at 70 ° C under nitrogen for 12 h was heated. . Then, the solvent was evaporated and the residue purified by silica gel chromatography (Petroleum ether / CH 2 Cl 2 / Et 2 Odiethyl ether: 3: 1: 1) to give 180 mg (85%) of the objective product 28: m / z = 659 (M + H) \ 1 H-NMR (CDCl 3): 8.11-8.08 (m, 1 H), 7.98 (s, 1 H), 7.10-7.19 (m, 2 H), 7.09 (s, 1 H), 6.88 ( s, 1 H), 5.70-5.78 (m, 1 H), 5.61-5.69 (m, 1H), 5.18-5.29 (m, 1 H), 463-469 (m, 1H), 405-415 (m, 3H), 3.92 (s, 3H), 401-408 (m, 1 H), 3.28-3.36 (m, 1 H), 3.06 (s, 3H), 2.88-3.05 (m, 2H), 2.61-2.69 ( m, 2H), 2.10-2.41 (m, 3H), 1.90-2.02 (m, 4H), 1.71-1.90 (m, 3H), 0.87-1.62 (m, 9H).

Stage F A solution of LiOH (327 mg) in water (3 ml) was added to a stirred solution of 28 in THF (15 ml) and MeOH methanol (10 ml). After 48h, the solvent was evaporated and the residue was partitioned between water and diethyl ether. The aqueous layer was acidified (pH = 3) and extracted with AcOEt ethyl acetate, dried (MgSO 4) and evaporated. The residue was crystallized from diethylether to give 128 mg (74%) of objective compound 29: m / z = 631 (M + H) +, 1 H-NMR (CDCl 3): 8.00-8.03 (d, J = 9.0 Hz, 1 H), 7.86 (s, 1 H), 7.12 (s, 1 H), 7.10 (dd, J = 9.0 Hz, 2.4 Hz, 1 H), 7.06 (d, J = 2.4 Hz, 1 H) , 6.87 (s, 1 H), 5.64-5.71 (m, 1 H), 5.57-5.61 (m, 1 H), 5.16 (t, J = 9.5 Hz, 1 H), 457-464 (m, 1 H) ), 3.92 (s, 3H), 3.52-3.60 (m, 1 H), 3.25-3.37 (m, 1 H), 2.42-2.68 (m, 4H), 2.17-2.33 (m, 3H), 2.08-2.17 (m, 2H), 1.71-2.00 (m, 5H), 1.33-1.62 (m, 5H), 0.96-0.99 (m, 4H).

EXAMPLE 3 Preparation of ^ -f17-f3- (4-cyclopropylthiazol-2-yl) -6-methoxy-isoquinolin-1-yloxy-1, 13-methyl-2,14-dioxo-3,13-diazatricichlori3.3.0.04 61octac 7-ene-4-carbonylK-cyclopropiDsulfonamide (30) A mixture of 29 (91 mg, 0.14 mmol) and 1,1'-carbonyldiimidazole (CDI) (47 mg, 0.29 mmol) in dry THF (7 mL) was heated to reflux for 2 h under nitrogen. The LCMS analysis showed a peak of the intermediate (TA = 5.37). Optionally, if desired, the azalactone derivative can be isolated. 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 h, and then heated at 55 ° C for 24 h. The solvent was evaporated, and the residue was partitioned between AcOEt ethyl acetate and acid water (pH = 3). The crude material was purified by column chromatography (ethyl acetate AcOEt / CH 2 Cl 2 / Petroleum ether, 1: 1: 1). The residue was crystallized from diethyl ether, filtered to give the objective compound contaminated with cyclopropylsulfonamide. This material was triturated in 3 ml of water, filtered, washed with water and dried until the next day with the high vacuum pump to give 60 mg (57%) of the objective compound 30 as a powder of slightly yellow color. : m / z = IZA (M + H) +, 1 H-NMR (CDCl 3): 10.94 (s, 1 H), 8.08 (d, J = 8.6 Hz, 1 H), 8.00 (s, 1 H), 7.12 -7.15 (m, 2H), 6.91 (s, 1 H), 6.35 (s, 1 H), 5.74-5.77 (m, 1H), 5.63-5.69 (m, 1 H), 5.06 (t, J = 10.4) Hz, 1H), 460 (t, J = 12.3 Hz, 1H), 3.93 (s, 3H), 3.35-3.42 (m, 2H), 3.04 (s, 3H), 2.89-2.96 (m, 2H), 2.52 -2.52 (m, 2H), 2.37-2.45 (m, 2H), 2.10-2.32 (m, 2H), 1.61-1.93 (m, 4H), 1.3-1.51 (m, 4H), 0.90-1.30 (m, 8H).

EXAMPLE 4 Preparation of 17- [3- (4-isopropylthiazol-2-yl) -6-methoxyisoquinolin-1-yloxy-13-methyl-2,14-dioxo-3,13-diazatricicof 13.3.0.04 61octadec-7 acid -eno-4-carboxylic acid (31) The title product was obtained from 1-hydroxy-3- (4-isopropylthiazol-2-yl) -6-methoxyisoquinoline 6, following the reported procedures for 17- [3- (4-cyclopropylthiazol-2-yl) acid 6-methoxyisoquinolin-1-yloxy] -13-methyl-2,14-dioxo-3,13-diazatricyclo [13.3.0.0'6] octadec-7-ene-4-carboxylic acid 29 (Example 2): m / z = 633 (M + H) +, 1 H-NMR (CDCl 3): 8.03 (d, J = 8.9 Hz, 1 H), 7.91 (s, 1 H), 7.20 (s, 1 H), 7.08-7.13 (m , 2H), 6.93 (s, 1 H), 5.61-5.69 (m, 2H), 5.17 (t, J = 9.5 Hz, 1 H), 457-464 (m, 1 H), 3.92 (s, 3H) , 3.55-3.63 (m, 1 H), 3.25-3.36 (m, 1 H), 3.11-3.20 (m, 1 H), 3.05 (s, 3H), 2.72-2.83 (m, 1 H), 2.53- 2.66 (m, 2H), 2.40-2.51 (m, 1 H), 2.17-2.32 (m, 2H), 1.89-1.93 (m, 2H), 1.71-1.83 (m, 2H), 1.43-1.60 (m, 2H), 1.37 (dd, J = 6.9 Hz, 2.5 Hz, 6H), 1.18-1.36 (m, 2H).

EXAMPLE 5 Preparation of ^ - [17-f3- (4-isopropylthiazol-2-yl) -6-methoxyisoquinolin-1-yloxyl-13-methyl-2,14-dioxo-3,13-diazatricichlori3.3.0.04 61octac 7-ene-4-carbonin (cyclopropyl) sulfonamide (32) The title product was obtained from 17- [3- (4-isopropylthiazol-2-yl) -6-methoxyisoquinolin-1-yloxy] -13-methyl-2,14-dioxo-3,13-diazatricyclo [] 13.3.0.0-, 4, '6-] octadec-7-ene-4-carboxylic acid 31, following the procedures reported for? / - [17- [3- (4-cyclopropylthiazol-2-yl) -6-methoxyisoquinol) n-1-yloxy] -13-methyl-2,14-dioxo-3,13-diazatricyclo- [13.3.0.04.6) octadec-7-ene-4-carbonyl] (cyclopropyl) sulfonamide (Example 3): m / z = 736 (M + H) +, 1 H-NMR (CDCl 3): 10.90 (s, 1 H), 8.02-8.09 (m, 2H), 7.11- 7.14 (m, 2H), 6.96 (s, 1 H), 6.29 (s, 1 H), 5.78-5.83 (m, 1 H), 5.62-5.69 (m, 1 H), 5.06 (t, J = 10.5 Hz, 1 H), 456-464 (m, 1 H), 3.93 (s, 3H), 3.37-3.42 (m, 2H), 3.15-3.21 (m, 1 H), 3.04 (s, 3H), 2.89-2.98 (m, 2H), 2.52-2.61 ( m, 2H), 2.23-2.43 (m, 3H), 1.64-1.93 (m, 4H), 1.31-1.50 (m, 10H), 1.18-1.30 (m, 2H), 0.96-1.15 (m, 2H).

EXAMPLE 6 Preparation of 17- [3- (2-isopropylaminothiazol-4-yl) -6-methoxy-isoquinolin-1-yloxy-M3-methyl-2,14-dioxo-3,13-diazatricichlori3.3.0.04 61- octadec acid -7-ene-4-carboxylic acid (33) The title product was obtained from 1-hydroxy-3- (2-isopropylaminothiazol-4-yl) -6-methoxyisoquinoline, following the procedures reported for 17- [3- (4-cyclopropylthiazol-2-yl) - 6-methoxyisoquinolin-1-yloxy] -13-methyl-2,14-dioxo-3,13-diazatricyclo [13.3.0.04 6] octadec-7-ene-4-carboxylic acid 29 (Example 2): m / z = 648 (M + H) +, 1 H-NMR (CDCl 3): 8.03 (d, J = 9.0 Hz, 1 H), 7.69 (s, 1 H), 7.19 (s, 1 H), 7.04-7.11 (m, 3H ), 5.60-5.68 (m, 2H), 5.20 (t, J = 9.2 Hz, 1 H), 454-461 (m, 1H), 3.93 (s, 3H), 3.54-3.70 (m, 2H), 3.12 -3.20 (m, 1 H), 2.83 (s, 3H), 2.35-2.60 (m, 4H), 2.11-2.30 (m, 2H), 1.80-1.93 (m, 2H), 1.69-1.79 (m, 2H) ), 1.40-1.51 (m, 2H), 1.30 (d, = 13.1 Hz, 6H), 1.10-1.21 (m, 2H).

EXAMPLE 7 Preparation of V-f17- [3- (2-isopropylaminothiazol-4-yl) -6-methoxyisoquinolin-1-yloxy1-13-methyl-2,14-dioxo-3,13-diazatricichlori3.3.0.0 61octac 7-ene ^ -carbonylK-cyclopropiDsulfonamide (34) The title product was obtained from 17- [3- (2-isopropylaminothiazol-4-yl) -6-methoxyisoquinolin-1-yloxy] -13-methyl-2, 14-dioxo-3, 13-diazatricyclo [ 13.3.0.04,6] octadec-7-ene-4-carboxylic acid 33, following the procedures reported for? / - [17- [3- (4-cyclopropylthiazol-2-yl) -6-methoxyisoquinolin-1-yloxy] - 13-methyl-2,14-dioxo-3,13-diazatricyclo [13.3.0.04,6] octadec-7-ene-4-carbonyl] (cyclopropyl) sulfonamide 30 (Example 3): m / z = 751 (M + H) +, 1 H-NMR (CDCl 3): 10.90 (s, 1 H), 8.04 (d, J = 9.3 Hz, 1 H), 7.75 (s, 1 H), 7.04-7.07 (m, 3 H), 6.32 (s, 1 H), 5.80-5.84 (m, 1 H), 5.62-5.69 (m, 1 H), 5.06 (t, J = 10.3 Hz, 2H), 458-465 (m, 1 H), 3.91 (s, 3H), 3.71-3.79 (m, 1 H), 3.24-3.41 (m, 2H), 3.03 (s, 3H), 2.71-2.97 (m, 2H), 2.57-2.60 (m, 2H), 2.30-2.41 (m, 2H), 2.15-2.30 (m, 1 H), 1.78-2.02 (m, 4H), 0.87-1.58 (m, 14 H).

EXAMPLE 8 Preparation of acid 17- [3- (pyrazol-1-yl) -6-methoxy * soqt? Inolin-1-? Lox1-13-methyl-2,14-dioxo-3,13-diazatricichlori3.3.0 .04,61octadec-7-ene- -carboxylic] 22] The title product was obtained from 1-hydroxy-3- (pyrazol-1-yl) -6-methoxyisoquinoline, following the reported procedures for 17- [3- (4-cyclopropylthiazol-2-yl) -6- acid. methoxyisoquinolin-1-yloxy] -13-methyl-2,14-dioxo-3,13-diazatricyclo [13.3.0.04.6] octadec-7-ene-4-carboxylic acid 29 (Example 2): m / z = 574 ( M + H) +, 1 H-NMR (CDCl 3): 8.45 (d, J = 2.3 Hz, 1 H), 8.03 (d, J = 8.9 Hz, 1 H), 7.71 (d, J = 1.0 Hz, 1 H ), 7.64 (s, 1 H), 7.22 (s, 1 H), 7.01-7.05 (m, 2H), 6.43-6.45 (m, 1 H), 5.63-5.70 (m, 2H), 5.18 (dd, J = 10.3 Hz, 2.0 Hz, 1 H), 453-442 (m, 1 H), 3.90 (s, 3 H), 3.58-3.67 (m, 1 H), 3.26-3.35 (m, 1 H), 3.02 (s, 3H), 2.65-2.77 (m, 1 H), 2.59-2.68 (m, 1 H), 2.35-2.58 (m, 2H), 2.15-2.30 (m, 2H), 1.89-2.05 (m, 2H), 1.70-1.75 (m, 2H), 1.18-1.61 (m, 4H).

EXAMPLE 9 Preparation of yV-f17-r3- (p -razol-1-yl) -6-methoxyisoquinolin-1-yloxy-13-methyl-2,14-dioxo-3,13-diazatricycloM 3.3.0.04, 61octactac 7-ene-4-carbonyl] (cyclopropyl) sulfonamide (36) The title product was obtained from 17- [3- (pyrazol-1-yl) -6-methoxyisoquinolin-1-yloxy] -13-methyl-2,14-dioxo-3,13-diazatricyclo [13.3. 0.04,6] octadec-7-ene-4-carboxylic acid 22, following the procedures reported for / - [17- [3- (4-cyclopropylthiazol-2-yl) -6-methoxyisoquinolin-1-yloxy] -13-methyl -2,14-dioxo-3,13-diazatricyclo [13.3.0.04.6] -octadec-7-ene-4-carbonyl] (cyclopropyl) sulfonamide 30 (Example 3): m / z = 677 (M + H) +, 1 H-NMR (CDCl 3): 8.49 (d, J = 2.4 Hz, 1 H), 8.06 (d, J = 9.7 Hz, 1 H), 7.74 (d, J = 6.4 Hz, 2 H), 7.04-7.08 ( m, 2H), 6.46-6.48 (m, 1 H), 6.37 (br s, 1 H), 5.71-5.82 (m, 1 H), 5.63-5.69 (m, 1 H), 5.06 (t, J = 10.5 Hz, 1 H), 458-465 (m, 2H), 3.93 (s, 3H), 3.36-3.44 (m, 2H), 3.04 (s, 3H), 2.80-2.95 (m, 2H), 2.50- 2.62 (m, 2H), 2.33-2.45 (m, 2H), 2.20-2.31 (m, 1H), 1.80-2.00 (m, 4H), 1.32-1.70 (m, 2H), 1.17-1.30 (m, 2H) ), 0.90-1.15 (m, 4H).

EXAMPLE 10 Synthesis of the acid 17- (3-chloro-6-methoxyisoquinolin-1-yloxy) -13-methyl-2,14-dioxo-3.1315-triaza-tricyclo | 3.3.0.0 '61octadec-7-ene-4-carboxylic (42) Stage A To a solution of Boc-hydroxyproline (760 mg, 3.29 mmol) in DMSO (50 mL) was added potassium tert-butoxide (1.11 g, 9.87 mmol). The resulting solution was stirred at room temperature for 1 h before adding 1,3-dichloro-6-methoxyisoquinoline 12 (750 mg, 3.29 mmol). After 12 h at room temperature under nitrogen the reaction mixture was quenched with cold water, acidified to pH 4 with HCl, and extracted with AcOEt ethyl acetate, washed with brine, dried (MgSO), filtered, evaporated to give 1.39 g (90%) of 37 as a white solid: m / z = 423 (M + H) +; 1 H-NMR (CDCl 3): 8.10 (d, J = 9.3 Hz, 1 H), 7.15 (d, J = 2.4 Hz, 1 H), 7.10 (dd, J = 9.3 Hz, 2.5 Hz, 1 H), 6.9 (s, 1 H), 5.80-5.67 (br s, 1 H), 445 (t, J = 7.9, 1 H), 3.95 (s, 3H), 3.80-3.90 (br s, 1 H), 3.70- 3.80 (m, 1 H), 2.75-2.6 (m, 1 H), 2.35-2.45 (m, 1H), 1.50 (s, 9H).

Stage B A solution of compound 37 (1.25 g, 2.96 mmol), ethyl ester hydrochloride of 1-amino-2-vinylcyclopropane carboxylic acid 25 (526 mg, 2.96 mmol), HATU (1.12 g, 2.96 mmol) and DIPEA (1.29 g. ml, 7.39 mmol) in DMF (50 ml) at room temperature under nitrogen atmosphere. After 12 h, dichloromethane was added and the solution was washed consecutively with aqueous NaHCO 3 and water. The organic layer was dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel (CH2Cl2 / MeOH, 95: 5) to give 1.5 g (90%) of the desired product 38 as a yellow foam: m / z = 561 (M + H) +; 1 H-NMR (CDCl 3): 8.10 (d, J = 9.3 Hz 1 H), 7.50 (s, 1 H), 7.25 (dd, J = 9.3 Hz, 2.5 Hz, 1 H), 6.98 (d, J = 2.4 Hz, 1 H), 5.80-5.67 (m, 1 H), 5.29 (d, J = 17.1 Hz, 1 H), 5.12 (d, J = 10.3 Hz, 1 H), 445-45 (br s, 1 H), 41-418 (m, 2H), 3.95 (s, 3H), 3.8-3.9 (br s, 1 H), 3.7-3.8 (m, 1 H), 3.25-3.35 (m, 2H), 2.35 -2.45 (m, 1 H), 2.1-2.2 (m, 1 H), 1.5-2 (m, 6H), 1.5 (s, 9H).

A solution of 38 (3.0 g, 5.36 mmol) in 1: 2 TFA-dCM (3 mL) was stirred at RT at room temperature for 60 min. Then, toluene (3 ml) was added and the resulting mixture was evaporated until dried to give the objective product 39 (purity by HPLC> 95%) which was used in the next step without further purification: m / z = 460 (M + H) 0 Stage D mmoles) to a solution of 39 (1.0 g, 2.17 mnnole ^ s) in tetrahydrofuran (25 ml). Then, phosgene (1.6 ml, 1.9 M in toluene 45 eq) was added. The reaction mixture was stirred at room temperature for 1 h then filtered. The solvent was evaporated and the residue was dissolved in dichloromethane (25 ml). Then, hydrogenated sodium carbonate (1.83 g, 21.7 mmol) was added followed by (hex-5-enyl) (methyl) amine 21 (1.2 g, 8.04 mmol). After 12h at room temperature, the reaction mixture was filtered. The filtrate was divided between water and dichloromethane. The organic layer was dried (MgSO 4), filtered, and evaporated. The residue was purified by column chromatography on silica gel (CH2Cl2 / EtOAc, 95: 5) to give 0.80 g (69.3%) of the objective product 40: m / z = 600 (M + H) +; 1 H-NMR (CDCl 3): 8.10 (d, J = 9.3 Hz, 1 H), 7.50 (s, 1 H), 7.39 (s, 1 H), 7.25 (dd, J = 9.3 Hz, 2.4 Hz, 1 H ), 6.98 (d, J = 2.4 Hz, 1 H), 5.81-5.62 (m, 2H), 5.56 (t, J = 3.8 Hz 1 H), 5.29 (dd, J = 1.3 Hz, 17.2 Hz, 1 H ), 5.12 (dd, J = 1.5 Hz, 10.4 Hz, 1 H), 5.00-486 (m, 3H), 435 (t, J = 7.5 Hz, 2H), 3.98 (s, 3H), 3.48-3.37 ( m, 1 H), 3.10-3.00 (m, 1 H), 2.87 (s, 3H), 2.77-2.67 (m, 2H), 2.41-2.32 (m, 1 H), 2.10 (dd, J = 8.6 Hz , 17.4 Hz, 1 H), 1.98 (dd, J = 144 Hz, 7.1 Hz, 2H), 1.88 (dd, J = 5.6 Hz, 8.1 Hz, 1 H), 1.57-1.46 (m, 3H), 1.35- 1.18 (m, 5H).

Stage E 1st generation Hoveyda-Grubbs catalyst (261 mg, 20 mole%) was added to a solution of 40 (1.3 g, 2.17 mmol) in degassed dry dichloroethane (1 L). Then, the reaction mixture was heated at 70 ° C for 20 h under nitrogen. The resulting mixture was cooled to room temperature and concentrated by rotary evaporation. The resulting oil was purified by column chromatography on silica gel (CH 2 Cl 2 / EtOAc 90/10) to give 720 mg (58%) of the title product 41 as a beige solid: m / z = 572 (M + H ) +; H-NMR (CDCl 3): 7.95 (d, J = 9.1 Hz, 1H), 7.55 (s, 1H), 7.15 (s, 1 H), 7.10 (dd, J = 9.1 Hz, 2.4 Hz, 1 H), 6.91 (d, J = 2.4 Hz, 1 H), 5.85 (br s, 1 H), 5.65 (dd, J = 18.2 Hz, 8.0 Hz, 1 H), 5.15 (t, J = 10.0 Hz, 1 H), 480 (t, J = 7.2 Hz, 1 H), 419-428 (m, 2H), 405 (dd, J = 3.7 Hz, J = 11.3 Hz, 1H), 3.90 ( s, 3H), 3.69 (d, J = 11.5 Hz, 1 H), 3.49-3.58 (m, 1 H), 3. 00-3.10 (m, 1 H), 2.90 (s, 3H), 2.45-2.55 (m, 2H), 2.30-2.45 (m, 1 H), 2.10-2.20 (m, 1 H), 1.90-1.95 ( m, 3H), 1.50-1.70 (m, 2H), 1.20-1.45 (m, 5H).

Stage F Lithium hydroxide (150 mg, 3.6 mmol) in water (3 ml) was added to a solution of 41 (100 mg, 0.18 mmol) in tetrahydrofuran (5 ml) and methanol (2 ml). After 48 h at room temperature, water was added and the pH of the resulting solution was adjusted to 3 with 1N HCl. Then, the reaction mixture was extracted with ethyl acetate, dried (Na2SO4), and evaporated. The residue was triturated with diethyl ether and filtered to give 85 mg (89%) of the title product 42 as a white powder: m / z = 544 (M + H) +; 1 H-NMR (CDCl 3): 7.95 (d, J = 9.1 Hz, 1 H), 7.55 (s, 1 H), 7.15 (s, 1 H), 7.10 (dd, J = 9.1 Hz, 2.4 Hz, 1 H ), 6.90 (d, J = 2.4 Hz, 1H), 5.85 (br s, 1H), 5.65 (dd, J = 18.2 Hz, 8.0 Hz, 1 H), 5.15 (t, J = 10.0 Hz, 1 H) , 480 (t, J = 7.2 Hz, 1 H), 405 (dd, J = 11.3 Hz, 3.7 Hz, 1H), 3.90 (s, 3H), 3.70-3.80 (m, 1 H), 3.60 (d, J = 11.3 Hz, 1 H), 2.85 (s, 3H), 2.80-2.85 (m, 1 H), 2.25-2.50 (m, 4H), 1.95-2.00 (m, 1 H), 2.90 (dd, J = 8.6 Hz, 5.9 Hz, 1 H), 1.55-1.60 (m, 3H), 1.30-1.50 (m, 3H).

EXAMPLE 11 Synthesis of V- [17- (3-chloro-6-methoxy-isoquinolin-1-yloxy) -13-methyl-2,14-dioxo-3.13.15-triaza-trichlori3.3.0.04.61octadec- 7-ene-4-carbonylK-cyclopropyl) sulfonamide (43) A solution of 17- (3-chloro-6-methoxyisoquinolin-1-yloxy) -13-methyl-2, 14-dioxo-3, 13,15-triaza-tricyclo [13.3.0.04 6] octadec-7 was stirred. -eno-4-carboxylic acid (42), (80 mg, 0.147 mmol) and carbonyldiimidazole (48 mg, 0.295 mmol) in dry THF (25 ml) under reflux under nitrogen for 3 h. Then, the reaction mixture was cooled to room temperature and cyclopropylsulfonamide (54 mg, 0.442 mmole) and DBU (52 mg, 0.34 mmole) were added. The resulting solution was stirred at 50 ° C for 48 h. Then, the reaction mixture was partitioned between AcOEt ethyl acetate and water. The organic layer was dried (MgSO), filtered and evaporated. The residue was purified by column chromatography on silica gel (CH2Cl2 / EtOAc, 95: 5) to give the title product contaminated with cyclopropylsulfonamide. This solid was triturated 10 min in water and filtered, washed with water, dried under high vacuum, triturated again in diethyl ether and filtered to give 37 mg (39%) of the title product 43 as a white powder: m / z = 647 (M + H) +; H-NMR (CDCl 3): 10.40 (br s, 1 H), 7.95 (d, J = 9.1 Hz, 1 H), 7.55 (s, 1 H), 7.15 (s, 1 H), 7.10 (dd, J = 9.12 Hz, 2.4 Hz, 1H), 6.90 (d, J = 2.4 Hz, 1H), 5.85 (br s, 1H), 5.65 (dd, J = 18.2 Hz, 8.0 Hz, 1H), 5.15 (t, J = 10.0 Hz, 1H), 48 (t, J = 7.2 Hz, 1H), 410 (dd, J = 11.3 Hz, 3.8 Hz, 1H), 3.9 (s, 3H), 3.60-3.70 (m, 1 H), 3.6 (d, J = 11.3 Hz, 1H), 3.10-3.20 (m, 1H), 2.90-3.00 (m, 1 H), 2.85 (s, 3H), 2.4-2.6 (m, 3H), 1.90 -2.20 (m, 3H), 1.25-1.60 (m, 7H), 0.90-1.10 (m, 2H).

EXAMPLE 12 Synthesis of 17- (5-bromo-6-methoxyisoquinolin-1-yloxy) -13-methyl-2,14-dioxo-3,15,15-triazatricichloride3.3.0.04.61octadec-7-ene-4-carboxylic acid (fifty) Diisopropylethylamine (1.9 ml, 10.9 mmol) was added to a solution of Boc-hydroxyproline (1.0 g, 44 mmol), cyclopropylamino acid 25 (825 mg, 43 mmol), HATU (1.7 g, 448 mmol) in DMF (10 ml). After 2 h at room temperature, dichloromethane (200 ml) was added. The solution was washed consecutively with saturated NaHC 3 3 and water. The organic layer was dried and concentrated. The residue was purified by column chromatography (CH2Cl2 / EtOAc, 50:50) to give 1.2 g (76%) of the objective product 44: m / z = 369 (M + H) +; 1 H-NMR (CDCl 3): 5.80-5.67 (m, 1 H), 5.32-5.24 (d, J = 17.1 Hz, 1H), 5.16-5.08 (d, J = 10.3 Hz, 1H), 461-445 (m , 1H), 445-429 (bs, 1 H), 423-403 (m, 2H), 3.78-3.39 (m, 2H), 2.14-1.97 (m, 1 H), 1.97-1.81 (br s, 1 H), 1.81-1.32 (m, 12 H), 1.22 (t, J = 7.1 Hz, 3H).

Triethylamine (3.2 ml, 22 mmol) was added at 0 ° C to a solution of 44 (5.42 g, 7.4 mmol) in CH2Cl2 (100 ml). After 5 min, a solution of para-nitrobenzoyl chloride (3.26 g, 18 mmol) in CH2Cl2 (50 mL) was added dropwise at 0 ° C. Then, the reaction mixture was allowed to warm to room temperature. After 20 h, the solution was poured into cold water, washed with brine, dried (Na 2 SO 4), filtered, and evaporated. The crude residue was purified by column chromatography (CH2Cl2 / EtOAc, 90:10) to give 2.15 g (56%) of the objective product 45: m / z = 518 (M + H) +; 1 H-NMR (CDCl 3): 8.30 (d, J = 8.8 Hz, 2 H), 8.16 (d, J = 8.8 Hz, 2 H), 5.82-5.70 (m, 1 H), 5.59-5.54 (m, 1 H) , 5.31 (dd, J =? L 2 Hz, 1.5 Hz, 1 H), 5.14 (d, J = 10.1 Hz, 1 H), 456-440 (br s, 1 H), 426-415 (m, 2H ), 3.80-3.67 (m, 2H), 2.16-2.06 (m, 1 H), 1.98-1.84 (bs, 1 H), 1.59-1.48 (bs, 1H), 1.48-1.38 (bs, 12H), 1.28 -1.21 (m, 3H).

Stage C A solution of 45 (2.15 g, 415 mmol) in TFA-dCM 1: 2 (80 ml) was maintained at room temperature for 4 h. Then, toluene (10 ml) was added and the solution was evaporated until dried to give the objective compound 46 (Purity by HPLC> 95%): m / z = 418 (M + H) 0 Phosgene (1.6 ml, 1.9 M in toluene 9.28 g, 45 eq) was added to a mixture of 46 (1.73 g, 414 mmol) and hydrogenated sodium carbonate (3.53 g, 42 mmol) in THF (35 ml). After 1.5 h at room temperature, the reaction mixture was filtered, the resulting filtrate was evaporated and the crude product was redissolved in dichloromethane (35 ml). Then, hydrogenated sodium carbonate (3.35 g, 42 mmol) was added followed by (hex-5-enyl) (methyl) amine 21 (1.1 g, 9.67 mmol). After 12 h at room temperature, the reaction mixture was filtered. Then, water was added and the mixture was extracted with dichloromethane. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica gel (CH2Cl2 / EtOAc, 95: 5) to give 2.31 g (79%) of the objective product 47: m / z = 557 (M + H) +; 1 H-NMR (CDCl 3): 8.28 (d, J = 8.9 Hz, 2H), 8.13 (d, J = 8.9 Hz, 2H), 7.39 (s, 1 H), 5.81-5.62 (m, 2H), 5.56 ( t, J = 3.8 Hz, 1 H), 5.29 (dd, J =? l .2 Hz, 1.3 Hz, 1 H), 5.12 (dd, J = 10.4 Hz, 1.52 Hz, 1H), 5.00-486 (m , 3H), 420-406 (m, 2H), 3.79 (dd, J = 12.1 Hz, 3.5 Hz, 1 H), 3.57 (dd, J = 12.1 Hz, 1.8 Hz, 1 H), 3.48-3.37 (m , 1 H), 3.10-3.00 (m, 1 H), 2.87 (s, 3H), 2.77-2.67 (m, 1H), 2.41-2.32 (m, 1 H), 2.10 (dd, J = 8.6, 17.4 Hz, 1 H), 1.98 (dd, J = 144 Hz, 7.1 Hz, 2H), 1.88 (dd, J = 8.1 Hz, 5.6 Hz, 1H), 1.57-1.46 (m, 3H), 1.35-1.18 (m , 5H).

Stage E A mixture of 47 (1.8 g, 3.28 mmoles) 1st generation Hoveyda-Grubbs catalyst (400 mg, 20 mol%) in degassed dry dichloroethane (2.0 L) was heated at 70 ° C under nitrogen for 20 h. The reaction mixture was cooled to room temperature and concentrated by rotary evaporation. The residue was purified by column chromatography (CH2Cl2 / EtOAc, 90:10) to give 888 mg (51%) of the desired compound as a beige solid 48: m / z = 529 (M + H) +; 1 H-NMR (CDCl 3): 8.28 (d, J = 8.8 Hz, 2 H), 8.16 (d, J = 8.8 Hz, 2 H), 7.47 (s, 1 H), 5.76-5.67 (m, 1 H), 5.62 -5.57 (t, J = 3.5 Hz, 1 H), 5.29 (dd, J = 10.5 Hz, 7.8 Hz, 1 H), 482 (dd, J = 9.8 Hz, 7.1 Hz, 1 H), 418-407 ( m, 2H), 400-3.88 (m, 2H), 3.55 (d, J = 11.6 Hz, 1H), 3.07-2.97 (m, 1 H), 2.91 (s, 3H), 2.64-2.54 (m, 1 H), 2.48-2.29 (m, 2H), 2.16 (dd, 1 H, J = 17.4 Hz, 8.6 Hz, 1 H), 1.96-1.83 (m, 3H), 1.80-1.61 (m, 2H), 1.45 -1.25 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H).

Stage F 0 A solution of lithium hydroxide (71 mg, 1.66 mmol) in water (5 ml) at 0 ° C was added to a solution of 48 (451 mg, 853 mmol) in THF (25 ml). After 3 h at 0 ° C, the reaction mixture was diluted with water (25 ml), then acidified to pH 3 with 1 N HCl. The resulting solution was extracted with AcOEt ethyl acetate, dried (MgSO4), it filtered and evaporated. The residue was purified by column chromatography (CH2Cl2 / MeOH, 90:10) to give 234 mg (72%) of 49: 8.18 (s, 1 H), 7.66 (s, 1H), 5.69 (dd, J = 18.0 Hz, 7.6 Hz, 1 H), 5.37 (\, J = 9.6 Hz, 1H), 468 (dd, J = 9.6 Hz, 7.6 Hz, 1 H), 478-411 (bs, 1H), 418-3.91 ( m, 2H), 3.79-3.61 (m, 2H), 3.34 (d, J = 11.1 Hz, 1 H), 3.19-3.06 (m, 1 H), 2.85 (s, 3H), 2.34-2.09 (m, 4H), 2.00-1.89 (m, 2H), 1.73 (dd, J = 8.8 Hz, 5.6 Hz, 1 H), 1.69-1.52 (m, 2H), 1.40-1.27 (m, 2H), 1.20 (t, J = 7.1 Hz, 3H).

Stage G Sodium hydride (68.25 mg, 1.7 mmol) was added in small portions at 0 ° C to a solution of 49 (260 mg, 0.683 mmol) in DMF (8 ml). The mixture was stirred at room temperature for 2 h. Then, isoquinoline 19 (241 mg, 0.887 mmol) was added under nitrogen in one portion. The mixture was allowed to warm to room temperature. After 20 hrs., The reaction mixture was poured into cold water (20 ml) and extracted with CH2Cl2, dried (Na2SO4), filtered and evaporated. Purification by column chromatography (CH 2 Cl 2 / MeOH 96/4), followed by hydrolysis of the ester as described above, gave 159 mg (40%) of the title product 50 as a white powder: m / z = 588 (M + H) +; 1 H-NMR (CDCl 3): 8.13 (d, J = 9.1 Hz, 1 H), 7.97 (d, J = 6.2 Hz, 1 H), 7.54 (d, J = 6.2 Hz, 1 H), 7.39-7.30 ( bs, 1 H), 7.22 (d, J = 9.2 Hz, 1 H), 5.90-5.83 (bs, 1 H), 5.71 (dd, J = 17.9 Hz, 8.1 Hz, 1 H), 5.18 (t, J = 10.1 Hz, 1 H), 479 (dd, J = 9.1 Hz, 7.3 Hz, 1 H), 410-3.97 (m, 4H), 3.81-3.66 (m, 1 H), 3.62 (d, 1 H, J = 11.6 Hz, 1 H), 3.19- 3.05 (m, 1 H), 2.85 (s, 3H), 2.59-2.22 (m, 4H), 2.01-1.90 (m, 1 H), 1.89 (dd, J = 8. 6 Hz, 5.8 Hz, 1 H), 1.70 (dd, J = 9.8 Hz, 6.1 Hz, 1 H), 1.67-1.58 (m, 2H), 1.43-1.28 (m, 2H).

EXAMPLE 13 Synthesis of iV-f17- (5-bromo-6-methoxyisoquinolin-1-yloxy) -13-methyl-2,14-dioxo-3,13,15-triaza-triciclof13.3.0.04,61octadec-7-ene- 4-carbonin (cyclopropyl) sulfonamide (51) A solution of 50 (151 mg, 0.257 mmol) and carbonyldiimidazole (162 mg, 0.437 mmol) in dry THF (10 mL) was stirred under reflux under nitrogen for 2 h. Optionally, the azalactone derivative, if desired, can be isolated. Then, the reaction mixture was cooled to room temperature and cyclopropylsulfonamide (58 mg, 0.482 mmole) and DBU (76 mg, 0.502 mmole) were added. The resulting solution was stirred at 50 ° C for 12 h, then cooled to room temperature. The reaction mixture was quenched with water and extracted with AcOEt ethyl acetate, dried (MgSO4), filtered and evaporated. The crude material was purified by column chromatography (CH2Cl2 / EtOAc, 95: 5). The solid obtained was triturated in water, filtered, dried under high vacuum, triturated in diethylether and dried again under high vacuum to give 138 mg (77%) of the title product 51 as a white powder: m / z = 691 (M + H) +; 1 H-NMR (CDCl 3): 10.70 (br s, 1 H), 8.12 (d, J = 9.1 Hz, 1 H), 7.97 (d, J = 6.3 Hz, 1 H), 7.54 (d, J = 6.3 Hz , 1 H), 7.21 (d, J = 9.1 Hz, 1 H), 6.70 (bs, 1 H), 5.88 (bs, 1 H), 5.74 (dd, J = 17.3 Hz, 8.3 Hz, 1 H), 5.16 (t, J = 10.4 Hz, 1 H), 474 (dd, J = 9.4 Hz, 7.3 Hz, 1 H), 411-3.98 (m, 4H), 3.69-3.55 (m, 2H), 3.27-3.10 (m, 1 H), 3.02-2.89 (m, 1 H), 2.83 (s, 3H), 2.58-2.35 (m, 3H), 2.29-2.13 (m, 1 H), 2.11-1.92 (m, 2H) ), 1.75-0.76 (m, 9H).

EXAMPLE 14 Synthesis of N - \ "\ 7-f5- (4-methyl-3-pyridyl) -6-methoxyisoquinolin-1-yloxyl-13-methyl-2,14-dioxo-3,13,15-triaza-trichlori3 .3.0.04 ß1octadec-7-ene-4- carbonill (cyclopropyl) sulfonamide (52) A solution of 51 (17.3 mg, 0.025 mmol), 6-methylpyridine-3-boronic acid (5.9 mg, 0.028 mmol), tetrahydrofosphine palladium (8.2 mg, 0.005 mmol) and sodium carbonate (5.8 mg, 0.055 mmole) in DMF (2 ml) at 90 ° C for 20 h. Then, the reaction mixture was cooled to room temperature and the solvent was evaporated. The residue was purified by HPLC to give 3.7 mg (21%) of the title product 52 as a white powder, m / z = 703 (M + H) +; 1 H-NMR (CDCl 3): 10.6 (bs, 1H), 8.8 (s, 1H), 8.12 (d, J = 9.1 Hz, 1H), 7.97 (d, J = 6.3 Hz, 1H), 7.9 (d, J = 9.0 Hz, 1H), 7.54 (d, J = 6.3 Hz, 1H), 7.3 (d, J = 9.0 Hz, 1H), 7.21 (d, J = 9.1 Hz, 1H), 6.68 (brs, 1H), 5.87 (br s, 1H), 5.74 (dd, J = 17.3 Hz, 8.3 Hz, 1H), 5.16 (t, J = 10.4 Hz, 1H), 474 (dd, J = 9.4 Hz, 7.3 Hz, 1H), 411-3.98 (m, 4H), 3.69-3.55 (m, 2H), 3.27-3.10 (m, 1H), 3.02-2.89 (m, 1H), 2.83 (s, 3H), 2.58-2.35 (m, 3H) ), 2.50 (s, 3H), 2.29-2.13 (m, 1H), 2.11-1.92 (m, 2H), 0.75-1.76 (m, 9H).

EXAMPLE 15 Synthesis of N- \ 17-r5- (4-methoxy-phenyl) -6-methoxyisoquinolin-1-yloxy] -13-methyl-2,14-dioxo-3,13,15-triaza-tricichlori3.3.0.0461octadec -7-ene-4-carbonin (cyclopropyl) sulfonamide (53) The title product was prepared from? / - [17- (5-bromo-6-methoxyisoquinolin-1-yloxy) -13-methyl-2, 14-dioxo-3, 13,15-triaza-tricyclo [13.3 .0.04.6] octadec-7-ene-4-carbonyl] (cyclopropyl) sulfonamide (51, example 13) and 4-methoxybenzeneboronic acid following the procedure described for? / - [17- [5- (4-methyl-3 -pyridyl) -6-methoxyisoquinolin-1-yloxy] -13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo [13.3.0.0 '6] octadec-7-ene-4-carbonyl] ( cyclopropyl) sulfonamide (52, Example? A): m / z = 718 (M + H) +.

EXAMPLE 16 Synthesis of JV-rI7-f5-phenyl-6-methoxy-5-quinolin-1-yloxp-13-methyl-2,14-d-oxo-3,13,15-triaza-tricyclo [13.3.0.04,61octadec-7-ene- 4-carbonin (cyclopropyl) sulfonamide (54) The title product was prepared from? / - [17- (5-bromo-6-methoxyisoquinolin-1-yloxy) -13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo [13.3 .0.04.6] octadec-7-ene-4-carbonyl] (cyclopropyl) sulfonamide (51, example 13) and benzeneboronic acid following the procedure described for? / - [17- [5- (4-methyl-3-pyridyl ) -6-methoxyisoquinolin-1-yloxy] -13-methyl-2,14-dioxo-3, 13,15-triaza-tricyclo [13.3.0.04 6] octadec-7-ene-4-carbonyl] (cyclopropyl) sulfonamide (52, Example 14): m / z = 688 (M + H) 0 EXAMPLE 17 Synthesis of 17- (6-methoxyisoquinolin-1-yloxy) -13-methyl-2,14-dioxo-3,13,15 acid -triaza-triciclof 13.3.0.04 ß1octadec-7-ene-4-carboxylic acid (55) The title product 55 was prepared from 1-chloro-6-methoxyisoquinolinone 10 following the same procedures described for the preparation of 17- (3-chloro-6-methoxyisoquinolin-1-yloxy) -13-methyl-2 acid, 14-d.oxo-3,13,15-triaza-tricyclo [13.3.0.04.6] octadec-7-ene-4-carboxylic acid (42, Example 10): m / z = 509 (M + H) +; 1 H-NMR (CDCl 3): 7.98 (d, J = 9.2 Hz, 1 H), 7.9 (d, J = 6.1 Hz, 1 H), 7.2 (s, 1 H), 7.1 (dd, J = 9.2 Hz, 2.4 Hz, 1 H), 7.10 (d, J = 6.1 Hz, 1 H), 6.90 (d, J = 2.4 Hz, 1 H), 5.85 (br s, 1 H), 5.65 (dd, J = 18.2 Hz , 8.0 Hz, 1H), 5.15 (t, J = 10.0 Hz, 1 H), 480 (t, J = 7.2 Hz, 1 H), 405 (dd, J = 11.3 Hz, 3.7 Hz, 1 H), 3.90 (s, 3H), 3.70-3.80 (m, 1H), 3.60 (d, J = 11.3 Hz, 1H), 2.85 (s, 3H), 2.80-2.85 (m, 1 H), 2.25-2.50 (m, 4H), 1.95-2.00 (m, 1 H), 2.90 (dd, J = 8.6 Hz, 5.9 Hz, 1H), 1.55-1.60 (m, 3H), 1.30-1.50 (m, 3H).

EXAMPLE 18 Synthesis of V-RI7- (3-phenyl-6-methoxyisoquinolin-1-yloxy) -13-methyl-2,14-dioxo-3.13,15-triaza-trichloro 3.3.0.04.61octadec-7-ene-4 -carbonin (cyclopropyl) sulfonamide (56) The title product 56 was prepared from 17- (6-methoxyisoquinolin-1-yloxy) -13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo [13.3.0.0, 6] octadec -7-ene-4-carboxylic acid (55) following the same procedures described for the preparation of? / - [17- (3-chloro-6-methoxyisoquinolin-1-yloxy) -13-methyl-2,14-dioxo- 3,13,15-triaza-tricyclo- [13.3.0.04.6] octadec-7-ene-4-carbonyl] (cyclopropyl) sulfonamide (43, Example 11): m / z-688.

EXAMPLE 19 Synthesis of 17- (3- (4-trifluoromethoxyphenyl) -6-methoxyisoquinolin-1-yloxy) -13-methyl-2.14-dioxo-3.13.15-triaza-triciclof13.3.0.04 61octadec-7-ene- acid 4-carboxylic (57) The title product 57 was prepared from 1-chloro-3- [4- (trifluoromethyl) phenyl] -6-methoxyisoquinolinone following the same procedures described for the preparation of 17- (3-chloro-6-methoxyisoquinolin-1) acid. -iloxy) -13-methyl-2,14-dioxo-3,13,15-triazatricyclo- [13.3.0.04'6] octadec-7-ene-4-carboxylic acid (42, Example 10): m / z = 669 (M + H) +; H-NMR (CDCl 3): 8.08 (d, J = 8.4 Hz, 2H), 8.02 (d, J = 9.1 Hz, 1 H), 7.55 (s, 1 H), 7.30 (d, J = 8.4 Hz, 2H ), 7.11 (dd, J = 9.1 Hz, 1.5, 1 H), 7.05 (d, J = 1.5 Hz, 1 H), 6.07-5.95 (bs, 1H), 5.71 (dd, J = 8.8 Hz, J = 17.4 Hz, 1 H), 5.24-5.09 (m, 1 H), 484-479 (m, 1 H), 414-403 (m, 1 H), 3.92 (s, 3 H), 3.77-3.58 (m, 3H), 3.20-3.07 (m, 1 H), 2.86 (s, 3H), 2.63-2.38 (m, 3H), 2.38-2.22 (m, 1 H), 2.01-1.84 (m, 2H), 1.74- 1.38 (m, 5H).

EXAMPLE 20 Synthesis of V- [17- (3- (4-trifluoromethoxyphenyl) -6-methoxyisoquinolin-1-yloxy) -13-methyl-2.14-dioxo-3.13.15-triaza-trichlori3.3.0.04 61octac 7-ene-4-carbonyl] (cyclopropyl) sulfonamide (58) The title product 58 was prepared from 17- (3- (4-trifluoromethoxyphenyl) -6-methoxyisoquinolin-1-yloxy) -13-methyl-2,14-dioxo-3,13,15-triaza-tricyclic acid [13.3.0.04,6] octadec-7-ene-4-carboxylic (57) following the same procedures described for the preparation of? / - [17- (3-chloro-6-methoxyisoquinolin-1-yloxy) - 13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo [13.3.0.04,6] octadec-7-ene-4-carbonyl] (cyclopropyl) sulfonamide (43, Example 11): m / z = 772 (M + H) +; 1 H-NMR (CDCl 3): 10.63-10.57 (br s, 1 H), 8.00 (d, J = 8.5 Hz, 2 H), 7.94 (d, J = 9.0 Hz, 1 H), 7.49 (s, 1 H) , 7.26 (d, J = 8.5 Hz, 2H), 7.01 (dd, J = 9.0 Hz, 2.4, 1H), 6.98 (d, J = 2.4 Hz, 1 H), 6.79-6.72 (bs, 1 H), 5.98-5.92 (m, 1 H), 5.67 (dd, J = 7.8 Hz, J = 18.9 Hz, 1 H), 5.09 (t, J = 10.4 Hz, 1 H), 471 (t, J = 8.1 Hz, 1 H), 403 (dd, J = 11.0 Hz, 40, 1 H), 3.85 (s, 3H), 3.64 (d, J = 11.0 Hz, 1 H), 3.61-3.53 (m, 1 H), 3.15 -3.03 (m, 1 H), 2.93-2.82 (m, 1 H), 2.77 (s, 3H), 2.54-2.38 (m, 3H), 2.25-2.08 (m, 1 H), 2.04-1.87 (m , 2H), 1.66-0.86 (m, 9H).

EXAMPLE 21 Synthesis of 17- (4-bromo-6-methoxyisoquinolin-1-yloxy) -13-methyl-2.14-dioxo-3.13,15-triaza-tricyclo [13.3.0.0 61octadec-7-ene-4-carboxylic acid ( 65) Stage A DIAD (8.2 g, 41 mmol) was added at 0 ° C under nitrogen atmosphere to a solution of 44 (10 g, 27 mmol), 4-nitrobenzoic acid (6.8 g, 41 mmol) and triphenylphosphine (11 g, 41 mmol) ) in dry THF (200 ml). Then, the reaction was warmed to room temperature. After 12 h, the solvent was evaporated and the crude product was purified by flash column chromatography (gradient EtOAc / CH2Cl2, 95/5 to 75/25) to give 8.1 g (58%) of the target product, m / z = 518 (M + H) +, 1 H-NMR (CDCl 3): 8.20 (s, 4H), 5.65-5.80 (m, 1 H), 5.55 (br s, 1 H), 5.2 (dd, J = 17.0 Hz, 10.2 Hz, 1 H), 44-45 (m, 1 H), 3.9-41 (m, 2 H), 3.75-3.85 (m, 1 H), 3.6-3.7 (m, 1 H), 2.0- 2.1 (m, 1 H), 1.80-1.90 (m, 1 H), 1.50-1.70 (m, 5), 1.50 (s, 9H), 1.10 (t, J = 7.1 Hz, 3H).

Stage B A solution of 59 (6.89 g, 13.3 mmol) in 1: 4 TFA-dCM (250 ml) was kept at room temperature for 4 h. Then, toluene (30 ml) was added and the solution was evaporated until dried to give the objective compound 60 (Purity by HPLC> 97%): m / z = 418 (M + H) 0 Stage C Phosgene (1.6 ml, 1.9 M in toluene, 45 eq) was added to a mixture of 60 (5.56 g, 13.3 mmol) and hydrogenated sodium carbonate (11.5 g, 137 mmol) in THF (120 ml). After 1.5 h at room temperature, the reaction mixture was filtered, the resulting filtrate was evaporated and the crude product was redissolved in dichloromethane (35 ml). Then, hydrogenated sodium carbonate (11.55 g, 137 mmol) was added followed by (hex-5-enyl) (methyl) amine 21 (2.65 g, 23.4 mmol). After 12 h at room temperature, the reaction mixture was filtered. Then, water was added and the mixture was extracted with dichloromethane. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica gel (CH2Cl2 / EtOAc, 95: 5) to give 7.41 g (58%) of the objective product 61: m / z = 557 (M + H) +; 1 H-NMR (CDCl 3): 8.28 (d, J = 8.9 Hz, 2H), 8.13 (d, J = 8.9 Hz, 2H), 7.39 (s, 1 H), 5.81-5.62 (m, 2H), 5.56 (t, J = 3.8 Hz, 1 H), 5.29 (dd, J = 17.2 Hz, 1.3 Hz, 1 H), 5.12 (dd, J = 10.4 Hz, 1.52 Hz, 1 H), 5.00-486 (m, 3H), 420-406 (m, 2H), 3.79 (dd, J = 12.1 Hz, 3.5 Hz, 1 H), 3.57 (dd, J = 12.1 Hz, 1.8 Hz, 1 H), 3.48-3.37 (m, 1 H), 3.10-3.00 (m, 1 H), 2.87 (s, 3H), 2.77-2.67 (m, 1 H), 2.41-2.32 (m, 1 H), 2.10 (dd, J = 8.6, 17.4 Hz, 1 H), 1.98 (dd, J = 144 Hz, 7.1 Hz, 2H), 1.88 (dd, J = 8.1 Hz, 5.6 Hz, 1H), 1.57-1.46 (m, 3H), 1.35-1.18 (m , 5H).

Stage D A solution of lithium hydroxide (632 mg, 148 mmol) in water (40 ml) at 0 ° C was added to a solution of 61 (434 g, 6.39 mmol) in THF (180 ml). After 2 h, at 0 ° C, the reaction mixture was diluted with water (25 ml), then acidified to pH 6 with 1 N HCl. The resulting solution was extracted with AcOEt ethyl acetate, dried (Na 2 SO 4) , it was filtered and evaporated. The residue was purified by column chromatography (CH2Cl2 / MeOH, 96:04) to give 2.1 g (80%) of 62: m / z = 408 (M + H) +; 1 H-NMR (CDCl 3): 5.84-5.68 (m, 2H), 5.29 (dd, J =? L Hz, 1.3 Hz, 1 H), 5.12 (dd, J = 10.4 Hz, 1.52, 1 H), 5.05- 493 (m, 2H), 478 (dd, J = 9.1 Hz, 1.77, 1 H), 460 (d, J = 9.1, 1 H), 446-437 (m, 1 H), 424-405 ( m, 2H), 3.66 (d, J = 10.4 Hz, 1 H), 3.43 (dd, J = 10.4 Hz, 455, 1 H), 3.37-3.26 (m, 1 H), 3.17-3.07 (m, 1 H), 2.88 (s, 3H), 2.29-2.02 (m, 5H), 1.87 (dd, J = 8.3 Hz, 5.6, 1 H), 1.67-1.52 (m, 3H), 1.49 (dd, J = 9.8 Hz, 5.31, 1 H), 1.44-1.38 (m, 2H), 1.22 (t, J = 7.1 Hz, 3H).

Stage E DIAD (669 mg, 3.31 mmol) was added at -25 ° C under nitrogen atmosphere to a solution of 62 (900 mg, 2,208 mmol), isoquinoline 13 (673 mg, 2.65 mmol) and triphenylphosphine (810 mg, 3.1 mmol) in dry THF (50 ml). Then, the reaction was maintained at -10 to -15 ° C for 3 h. The mixture was poured into a cold water solution and extracted with ethyl acetate. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by flash column chromatography (gradient EtOAc / CH 2 Cl 2, 90/10) to give 1 g of the objective product 63: m / z = 644 (M + H) 0 Stage F A mixture of 63 (1 g, 1.55 mmoles) and 1ra catalyst was heated. Generation of Hoveyda-Grubbs (186 mg, 310 mmol) in degassed dry dichloroethane (1.0 L), at 70 ° C under nitrogen for 20 h. The reaction mixture was cooled to room temperature and concentrated by rotary evaporation. The residue was purified by column chromatography (CH2Cl2 / EtOAc, 90:10) to give 360 mg (38%) of the desired compound 64 as a beige solid: m / z = 616 (M + H) 0 Stage G Lithium hydroxide (375 mg, 8.77 mmol) in water (3 ml) was added to a solution of 64 (360 mg, 0.585 mmol) in tetrahydrofuran (15 ml) and methanol (5 ml). After 48 h at room temperature, water was added and the pH of the resulting solution was adjusted to 3 with 1N HCl. Then, the reaction mixture was extracted with EtOAc ethyl acetate, dried (Na2SO4), and evaporated. The residue was triturated with diethyl ether and filtered to give 300 mg (87%) of the title product 65 as a white powder: m / z = 588 (M + H) +; 1 H-NMR (CDCl 3): 8.5 (s, 1 H), 8.2 (d, J = 9.1 Hz, 1 H), 7.35 (br s, 1 H), 7.3 (d, J = 2.5 Hz, 1 H), 7.17 (dd, = 9.1 Hz, 2.5 Hz, 1 H), 5.8-5.85 (br s, 1 H), 5.7 (dd, J = 18.3 Hz, 7.8 Hz, 1 H), 5.15 (t, J = 10.0 Hz , 1 H), 480 (dd, J = 9.2 Hz, 7, 1 H), 405 (dd, J = 11.2 Hz, 4 Hz, 1 H), 3.95 (s, 3H), 3.70-3.80 (m, 1 H), 3.60 (d, J = 11.2 Hz, 1H), 3-3.1 (m, 1 H), 2.85 (s, 3H), 2.40-2.50 (m, 3H), 2.25-2.40 (m, 1 H) , 1.85-1.95 (m, 3H), 1.6-1.7 (m, 4H).

EXAMPLE 22 Synthesis of N-H7- (4-bromo-6-methoxyisoquinolin-1-yloxy) -13-methylene-2.14-dioxo-3.13.15-triaza-tricycof 13.3.0.04.6] octadec-7-ene -4- carbonylKcyclopropyl) sulfonamide (66) The title product 66 was prepared from 17- (4-bromo-6-methoxyisoquinolin-1-yloxy) -13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo [13.3.0.04 , 6] octadec-7-ene-4-carboxylic acid (65) following the same procedures described for the preparation of? / - [17- (3-chloro-6-methoxyisoquinolin-1-yloxy) -13-methyl-2, 14-dioxo-3, 13,15-triaza-tricyclo- [13.3.0.0, 6] octadec-7-ene-4-carbonyl] (cyclopropyl) sulfonamide (43, Example 11): m / z = 691 (M + H) +; 1 H-NMR (CDCl 3): 10.7 (br s, 1 H), 8.09 (d, J = 9.1 Hz, 1 H), 7.3 (d, J = 2.4 Hz, 1 H), 7.25 (s, 1 H), 7.15 (dd, J = 9.1 Hz, 2.4, 1 H), 7 (br s, 1 H), 5.8 (br s, 1 H), 5.74 (dd, J = 18.2 Hz, 8, 1 H), 5.16 ( t, J = 10.3 Hz, 1 H), 474 (dd, J = 9.3 Hz, 7, 1 H), 405 (dd, J = 11.1 Hz, 4, 1 H), 3.95 (s, 3H), 3.6 ( d, J = 11.1 Hz, 1H), 3.1-3.2 (m, 1 H), 2.9-3 (m, 1 H), 2.83 (s, 3H), 2.4-2.5 (m, 3H), 2.19- 2 (m, 2H), 2.5-2.7 (m, 4H), 1.4-1 (m, 3H), 1.2-1.35 (m, 2H), 1.05-1.15 (m, 1 H), 0.95-1 (m, 1 HOUR).

EXAMPLE 23 Synthesis of acid 17- (3-pyrazol-1-yl-6-methoxyisoquinolin-1-yloxy) -13-methyl-2.14-dioxo-3.13.15-triaza-tricichlori3.3.0.04 &loctadec-7- eno-4-carboxylic acid (67) The title product 67 was prepared from 1-hydroxy-6-methoxy-3- (pyrazol-1-yl) isoquinoline following the same procedures described for the preparation of 17- (3-chloro-6-methoxyisoquinoline-1) acid. -iloxy) -13-methyl-2,14-dioxo-3,13,15-triazatricyclo [13.3.0.04,6] octadec-7-ene-4-carboxylic acid (42, Example 10): m / z = 575 (M + H) 0 EXAMPLE 24 Synthesis of < V-Ri7- (3-pyrazol-1-yl-6-methoxyisoquinolin-1-yloxy) -13-methyl-2.14-dioxo-3.13.15-triaza-triciclof13.3.0.04.6] octadec-7-eno- 4-carbonin (cyclopropyl) sulfonamide (68) The title product 68 was prepared from 17- (3-pyrazol-1-yl-6-methoxyisoquinolin-1-yloxy) -13-methyl-2,14-dioxo-3,13,15-triaza-tricyclic acid [13.3.0.04.6] octadec-7-ene-4-carboxylic acid (67) following the same procedures described for the preparation of? / - [17- (3-chloro-6-methoxyisoquinolin-1-yloxy) -13- methyl-2,14-dioxo-3,13,15-triaza-tricyclo [13.3.0.04,6] octadec-7-ene-4-carbonyl] (cyclopropyl) sulfonamide (43, Example 11): m / z = 678 (M + H) +; 1 H-NMR (CDCl 3): 10.5 (br s, 1 H), 8.4 (dd, J = 2.5 Hz, 0.5, 1 H), 8 (d, J = 9.8 Hz, 1 H), 7.75 (s, 2 H) , 7.00-7.10 (m, 2H), 6.55 (s, 1 H), 6.45 (dd, J = 2.5 Hz, 0.5, 1 H), 5.95 (br s, 1 H), 5.75 (dd, J = 18.1 Hz , 8 Hz, 1 H), 5.1 (t, J = 10.3 Hz, 1 H), 475 (t, J = 7.0 Hz, 1 H), 41 (dd, J = 11.0 Hz, 43, 1 H), 3.90 (s, 3H), 3.70 (d, J = 11.0 Hz, 1 H), 3.10-3.20 (m, 1 H), 2.90-3.01 (m, 1 H), 2.85 (s, 3H), 2.50-2.62 ( m, 3H), 2.20-2.30 (m, 1 H), 1.90-2.00 (m, 2H), 1.55-1.60 (m, 4H), 1.30-1.50 (m, 6H).

EXAMPLE 25 Synthesis of acid 17-f3- (4-isopropylthiazol-2-yl) -6-methoxyisoquinolin-1-yloxp-13-methyl-2.14-dioxo-3.13.15-triaza-trichlori3.3.0.0461octadec-7-ene 4-carboxylic acid (69) Title product 69 was prepared from 1-hydroxy-3- (4-isopropylthiazol-2-yl) -6-methoxyisoquinoline (6) following the same procedures described for the preparation of 17- (3-chloro-6 acid -methoxyisoquinolin-1-yloxy) -13-methyl-2,14-dioxo-3,13,15-triazatricyclo [13.3.0.04,6] octadec-7-ene-4-carboxylic acid (42, Example 10): m / z = 634 (M + H) 0 EXAMPLE 26 Synthesis of W-RI7- [3- (4-isopropylthiazol-2-yl) -β-methoxyisoquinolin-1-yloxy-13-methyl-2.14-dioxo-3.13.15-triaza-tricyclo3.3.0. 04 61octadec-7-ene-4- carbonill (cyclopropyl) sulfonamide (70) The title product 70 was prepared from 17- [3- (4-isopropylthiazol-2-yl) -6-methoxyisoquinolin-1-yloxy] -13-methyl-2,14-dioxo-3,13,15 acid. -triaza-tricyclo [13.3.0.04,6] octadec-7-ene-4-carboxylic acid (69) following the same procedures described for the preparation of? / - [17- (3-chloro-6-methoxyisoquinolin-1-yloxy] ) -13-methyl-2, 14-dioxo-3, 13,15-triaza-tricyclo [13.3.0.04,6] octadec-7-ene-4-carbonyl] (cyclopropyl) sulfonamide (43, Example 11): m / z = 737 (M + H) 0 EXAMPLE 27 Synthesis of acid 17-r3- (2-isopropylaminothiazol-4-yl) -6-methoxyisoquinolin-1-yloxyM3-methyl-2.14-dioxo-3.13.15-triaza-tricichlori3.3.0.04 61octadec-7- eno-4-carboxylic acid (71) The title product 71 was prepared from 1-hydroxy-3- (2-isopropylaminothiazol-4-yl) -6-methoxyisoquinoline following the same procedures described for the preparation of 17- (3-chloro-6-methoxyisoquinoline- 1-yloxy) -13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo [13.3.0.04,6] octadec-7-ene-4-carboxylic acid (42, Example 10): m / z = 649 (M + H) 0 EXAMPLE 28 Synthesis of W-ri7- [3- (2-isopropylaminothiazo-yl) -6-methoxyisoquinolin-1-yloxn-13-methyl-2,14-dioxo-3,13.15-triaza-triciclof13.3.0.04 61octac 7-ene-4-carbonin (cyclopropyl) sulfonamide (72) The title product 72 was prepared from 17- [3- (2-isopropylaminothiazol-4-yl) -6-methoxyisoquinolin-1-yloxy] -13-methyl-2,14-dioxo-3,13,15 acid. -triaza-tricyclo [13.3.0.04,6] octadec-7-ene-4-carboxylic acid (71) following the same procedures described for the preparation of? / - [17- (3-chloro-6-methoxyisoquinolin-1-yloxy] ) -13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo [13.3.0.04,6] octadec-7-ene-4-carbonyl] (cyclopropyl) sulfonamide (43, Example 11): m / z = 752 (M + H) 0 1 H NMR (CDCl 3): 0.93-1.03 (m, 1 H), 1.05-1.15 (m, 1H), 1.18-1.28 (m, 3H), 1.32 (d, J = 6.6 Hz, 3H), 1.34 (d, J = 6.6 Hz, 3H), 1.36-1.67 (m, 4H), 1.93-2.07 (m, 2H), 2.22-2.36 (m, 1H), 2.45-2.65 (m, 3H), 2.85 (s, 3H), 2.91-3.00 (m, 1 H), 3.05-3.17 (m, 1 H), 3.64-3.80 (m, 3H), 3.89 (s, 3H) ), 408 (dd, J = 3.8 Hz, J = 10.9 Hz, 1 H), 478 (t, J = 8.1 Hz, 1 H), 5.15 (t, J = 10.4 Hz, 1 H), 5.21-5.36 ( broad s, 1 H), 5.73 (dd, J = 8.1 Hz, J = 18.4 Hz, 1 H), 5.94-6.02 (m, 1 H), 6.92-6.99 (broad s, 1 H), 7.00- 7.07 (m, 2H), 7.22 (s, 1 H), 7.74 (s, 1 H), 7.95 (d, J = 8.6 Hz, 1 H), 10.54-10.99 (broad s, 1 H).

EXAMPLE 29 Synthesis of 18- [5-bromo-6-methoxyisoquinolin-1-yloxy] -2,15-dioxo-3.14.16-triazatricichlori43.0.04,61nonadec-7-ene-4-carboxylic acid (74) Stage A To a solution of Boc-hydroxyproline (1.15 g, 499 mmol) in THF (50 mL) was added NaH (60% in mineral oil, 500 mg, 12.5 mmol). The resulting solution was stirred at room temperature for 1 h before adding 5-bromo-6-methoxyisoquinoline (1.36 g, 499 mmol). After 48 h at room temperature under nitrogen, the reaction mixture was quenched with cold water, acidified to pH 4 with HCl and extracted with ethyl acetate, washed with brine, dried (MgSO 4), filtered, and evaporated The residue was purified by column chromatography (gradient EtOAc / CH2Cl2, 5:95 to 50:50) to give 751 mg (32.2%) of 73 as a white solid: m / z = 468 (M + H) 0 Synthesis of 18- [5-bromo-6-methoxyisoquinolin-1-yloxfl-2.15-dioxo-3,14,16-triazatricyclo [143,0,04'61nonadec-7-ene-4-carboxylic acid (74)] Stage B The title compound was prepared from intermediate 73 and hept-8-enamine following the procedure (Steps Bf) reported for 17- (3-chloro-6-methoxyisoquinolin-1-yloxy) -13-methyl-2,14 acid -dioxo-3,13,15-triaza-tricyclo [13.3.0.04'6] octadec-7-ene-4-carboxylic acid (42): m / z = 588 (M + H) 0 EXAMPLE 30 Synthesis of V-f18- [5-bromo-6-methoxyisoquinolin-1-yloxyl-2.15-dioxo-3.14.16-triazatricichlori43,0.04.6lnonadec-7-ene-4- carbonill (cyclopropyl) sulfonamide (75) The title compound was prepared from 18- [5-bromo-6-methoxyisoquinolin-1-yloxy] -2,15-dioxo-3, 14,16-triazatricyclo [143,0,04,6] nonadec- acid. 7-ene-4-carboxylic acid (74) following the reported procedure for synthesis of? / - [17- [3- (4-cyclopropylthiazol-2-yl) -6-methoxyisoquinolin-1-yloxy] -13-methyl-2 , 14-dioxo-3,13-diazatricyclo [13.3.0.04.6] -octadec-7-ene-4-carbonyl] (cyclopropyl) sulfonamide (30): m / z = 691 (M + H) 0 EXAMPLE 31 Synthesis of crystalline cyclopentane Synthesis of tert-butyl ester of 3-oxo-2-oxa-biciclof2,2.nheptan-5-carboxylic acid (77) DMAP (14 mg, 0.115 mmol) and Boc20 (252 mg, 1.44 mmol) were added to a stirred solution of 76 (180 mg, 1.15 mmol) in 2 mL CH2Cl2 under an inert argon atmosphere 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 title (124 mg, 51%) as white crystals. 1 H-NMR (300 MHz, CD 3 OD) d 1.45 (s, 9 H), 1.90 (d, J = 11.0 Hz, 1 H), 2.10-2.19 (m, 3 H), 2.76-2.83 (m, 1 H), 3.10 (s, 1 H), 499 (s, 1 H); 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 77 Compound 76 (13.9 g, 89 mmol) was dissolved in dichloromethane (200 ml) and then cooled to about -10 ° C in nitrogen. Then, isobutylene was bubbled into the solution until the total volume increased to about 250 ml which gave a cloudy solution. BF3 Et20 (5.6 mL, 445 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 TLC (ethyl acetate-toluene 3: 2 was acidified with a few drops of acetic acid and hexane-etOAc ethyl acetate 4: 1, transfer with basic permanganate solution). At 70 min, only traces of compound 76 were removed and saturated aqueous NaHC 3 (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 sulfite, filtered and the residue was evaporated to 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 (room temperature), then dried with air for 72 h giving colorless needles (12.45 g, 58.7 mmol, 66%).

EXAMPLE 32 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 cell 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 bicistronic expression construct encoding an RNA comprising the wild-type NS3-NS5B regions of HCV type 1b transfected from an Internal Ribosome Entry Site (IRES) of the encephalomyocarditis virus. (EMCV), preceded by an informant 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 1b. The continuous culture of the replicon cells in the presence of G418 (neoR) depends on the replication of HCV RNA. Stably transfected replicon cells expressing HCV RNA, which replicates autonomously and up to high levels, encoding inter alia luciferase, 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 luciferase activity assay (using substrates for standard luciferase assays and reagents and a Perkin Elmer ViewLux ™ ultraHTS mycoplasma imaging device). 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 ECso values were then calculated, the value of which represents 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 the full-length hepatitis C protease NS3 enzyme was measured in essence as described in Polyakov, 2002 Prot Expression & The purification 25 363 371. In synthesis, the synthesis of a dipsipeptide substrate, Ac-DED (Edans) EEAbu [COO] ASK (Dabcyl) -NH2 (AnaSpec, San Jose, USA), 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 days. min, after which the reaction was initiated with the addition of 0.5 μM of substrate. The inhibitors were dissolved in DMSO, sonicated for 30 sec. and they waved with vortex. 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 according to published procedures. [Liu, 1999 Analytical Biochemistry 267 331-335]. Ki values were estimated by non-linear regression analysis (GraFit, Erithacus 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.

TABLE 1

Claims (14)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound that has the formula a? / - oxide, salt or stereoisomer thereof, where X is N, CH and when X has a double bond is C; R1 is -OR5, -NH-S02R6; R2 is hydrogen, and when X is C or CH, R2 may also be C-? -6 alkyl; R3 is hydrogen, C? -6 alkyl, C? -6-alkoxy of d-6, or C3-7 cycloalkyl; R 4 is isoquinolinyl optionally substituted with one, two or three substituents each independently selected from C 1-6 alkyl, C 1-6 alkoxy, hydroxy, halo, C 1-6 polyhaloalkyl, C 1-6 polyhaloalkoxy, amino, mono - or di-alkylamino of C -? - 6, mono- or di-alkylaminocarbonyl of C 1-6, alkylcarbonyl of C? -6-amino, aryl and Het; n is 3, 4, 5 or 6; where each dotted line (represented by) represents an optional double bond; R5 is hydrogen; aril; Het; C3-7 cycloalkyl optionally substituted with C6-6 alkyl or optionally substituted with C3.7 cycloalkyl, aryl or with Het; R6 is aryl; Het; C3-7 cycloalkyl optionally substituted with C? -6 alkyl; or C-? 6 alkyl optionally substituted with C3-7 cycloalkyl, aryl or with Het; each aryl as a group or part of a group is phenyl optionally substituted with one, two or three substituents selected from halo, hydroxy, nitro, cyano, carboxyl, C-? 6 alkyl, C-? 6 alkoxy, alkoxy, C-? 6-C-? -6 alkyl, C-6 alkylcarbonyl, amino, C 1-6 mono- or dialkylamino, azido, mercapto, C? -6 polyhaloalkyl, C? -6 polyhaloalkoxy, cyclopropyl , pyrrolidinyl, piperidinyl, piperazinyl, 4-alkylpiperazinyl of C -? - 6, 4-alkylcarbonyl C? -6-piperazinyl and morpholinyl; and wherein the morpholinyl and piperidyl groups may be optionally substituted by one or two C1-6 alkyl radicals; and each Het as a group or part of a group is a saturated, partially unsaturated or fully unsaturated 5 or 6 membered heterocyclic ring containing 1 to 4 heteroatoms, each independently selected from nitrogen, oxygen and sulfur, and optionally substituted with one, two or three substituents, each independently selected from the group consisting of halo, hydroxy, nitro, cyano, carboxyl, C? -6 alkyl, C1-6 alkoxy, C-? - alkoxy 6-C de-C6 alkyl, C?-6 alkylcarbonyl, amino, C mono-6 mono- or di-alkylamino, azido, mercapto, C poli-6 polyhaloalkyl, C-α-6 polyhaloalkoxy, C3-7 cycloalkyl, pyrrolidinyl, piperidinyl, piperazinyl, C? -6-piperazinyl 4-alkyl, C? -6-piperazinyl-4-alkylcarbonyl and morpholinyl, and wherein the morpholinyl and piperidyl groups may be optionally 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 (I-e): 3 - .

3 - The compound according to any of claims 1-2, further characterized in that R4 is wherein each R4b and R4b are independently hydrogen, C ^ e alkyl, C? -6 alkoxy, C-? 6 mono- or di-alkylamino, C? -6 mono- or di-alkylaminocarbonyl. , hydroxy, halo, trifluoromethyl, aryl or Het; and R4d or R4d independently are hydrogen, d-β alkyl, C- | 6 alkoxy or halo.

4. The compound according to any of claims 1-2, further characterized in that R4 is where R is selected from the following remains where R c is each independently hydrogen, halo, C? -6 alkyl, amino, or mono- or di-alkylamino of C?, morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, 4-alkylpiperazinyl of C6; and R 4 is hydrogen, halo or trifluoromethyl.

5. - The compound according to any of claims 1-4, further characterized in that (a) R1 is -OR5, where R5 is C6-6 alkyl or hydrogen; or (b) R1 is -NHS (= 0) 2R6, where R6 is methyl, cyclopropyl, methylcyclopropyl or phenyl.

6. The compound according to any of claims 1-5 further characterized in that R3 is hydrogen or C? _6 alkyl.

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

8. The compound according to any of claims 1-7, further characterized in that it is not an N-oxide or a salt.

9. A combination comprising: (a) a compound defined in any of claims 1 to 7 or a pharmaceutically acceptable salt thereof; and (b) ritonavir, or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a vehicle and as an active component, an anti-viral agent effective amount of a compound claimed in any of claims 1-7 or a combination according to claim 9.

11.- The compound of any of claims 1-7 or a combination of claim 9, for use as a medicament.

12. - Use of a compound as claimed in any of claims 1-7 or a combination of claim 9, for the manufacture of a medicament useful for inhibiting the replication of HCV.

13. The use of a compound as claimed in claims 1-7 or an effective amount of each component of the combination of claim 9, for the manufacture of a medicament useful for inhibiting the replication of HCV in a blood animal. hot.

14. A process for preparing a compound claimed in any of claims 1-8, 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 (li), by forming a double bond between C7 and C8, especially by an olefinic metathesis reaction, with the concomitant deletion to the macrocycle as indicated in the following reaction scheme: (b) converting a compound of formula (Ii) to 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): (-i) 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 -NHS02R6, said compounds represented by the formula (lk-1), by forming an amide bond between an intermediate (2a) and a sulfonylamine (2b), or preparing a compound of formula (I) wherein R1 represents -OR5 , ie a compound (lk-2), by forming an ester bond between an intermediate (2a) and an alcohol (2c) as indicated in the following scheme, where G represents a group: O G-COOH + H2N-S02R6 HN-S02R6 (2a) (2b) (l-k-1) (d) preparing a compound of formula (I) wherein R3 is hydrogen, said compound being represented by (1-l), from a corresponding intermediate with protected nitrogen (3a), where PG represents a group Nitrogen protector: (3a) (1-11) (e) reacting an intermediate (4a) with an intermediate (4b) as indicated in the following reaction scheme: (4a) m where Y in (4a) represents hydroxy or a leaving group; which reaction is in particular an O-arylation reaction where Y represents a leaving group, or a Mitsunobu reaction, where Y represents hydroxy; (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 the replication of HCV of formula (I) and the? / - oxides, salts and stereoisomers thereof, where X is N, CH and when X has a double bond is C; R1 is -OR5, -NH-S02R6; R2 is hydrogen, and when X is C or CH, R2 may also be C ^ alkyl; R3 is hydrogen, C6-6alkyl, C6-6alkoxy-C6-6alkyl, or C3- cycloalkyl; R4 is isoquinolinyl optionally substituted with one, two or three substituents each independently selected from C? .6alkyl, C? -6alkoxy, hydroxy, halo, polyhaloalkyl C ^, polyhaloalkoxy of C? _6, amino, mono - or C1-6 di-alkylamino, mono- or di-alkylaminocarbonyl of Ci. 6, C6-arnino alkylcarbonyl, aryl and Het; n is 3, 4, 5, or 6; each dotted line (represented by) represents an optional double bond; R5 is hydrogen; aril; Het; C3.7 cycloalkyl optionally substituted with C? -6 alkyl; or C? -6 alkyl optionally substituted with C3-7 cycloalkyl, aryl or with Het; R6 is aryl; Het; C3-7 cycloalkyl optionally substituted with C? -6 alkyl; or C -6 alkyl optionally substituted with C3- cycloalkyl, aryl or with Het; each aryl is phenyl optionally substituted with one, two or three substituents; and each Het is a 5 or 6 membered heterocyclic ring saturated, partially unsaturated or completely unsaturated containing 1 to 4 heteroatoms, each independently selected from nitrogen, oxygen and sulfur and optionally being substituted with one, two or three substituents; pharmaceutical compositions containing the compounds (I) and processes for preparing the compounds (I); bioavailable combinations of the HCV inhibitors of formula (I) with ritonavir are also provided.41 B P08 / 31 F