ES2369284T3 - MACROCYCLIC INHIBITORS OF HEPATITIS VIRUS C. - Google Patents

Abstract

A compound having the formula an N-oxide, addition salt, quaternary amine, metal complex, and stereochemically isomeric form thereof, wherein the dashed line represents an optional double bond between the C7 and C8 atoms; R1 is aryl or a saturated 5- or 6-membered monocyclic, saturated or partially unsaturated heterocyclic ring system, or 9 to 12-membered bicyclic ring wherein said ring system contains a nitrogen atom, and optionally 1 to 3 additional heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, and wherein the remaining members of the ring are carbon atoms; wherein said ring system may optionally be substituted on any carbon or nitrogen atom of the ring with one, two, three, or four substituents each independently selected from C3-7cycloalkyl, aryl, Het, -C (= O) NR5aR5b, -C (= O) R7, -C (= O) OR6a, and C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl, Het, -C (= O) NR5aR5b, -NR5aR5b, -C (= O) R7, -NR5aC (= O) R7, -NR5aSOpR8, -SOpR8, - SOpNR5aR5b, -C (= O) OR6, or -NR5aC (= O) OR6a; and wherein the substituents on any carbon atom of the heterocyclic ring can also be selected from -OR8, -SR8, halo, polyhalo-C1-6alkyl, oxo, thio, cyano ,, nitro, azido, -NR5aR5b, -NR5aC (= O ) R7, -NR5aSOpR8, -SOpR8, -SOpNR5aR5b, -C (= O) OH, and -NR5aC (= O) OR6a; L is a direct bond, -O-, -O-C1-4alkanediyl-, -O-CO-, -O-C (= O) -NR5a- or -O-C (= O) -NR5a-C1-4alcanediyl-; R2 represents hydrogen, -OR6, -C (= O) OR6, -C (= O) R7, -C (= O) NR5aR5b, -C (= O) NHR5c, - NR5aR5b, -NHR5c, - NHSOpNR5aR5b, -NR5aSOpR8 , or -B (OR6) 2; R3 and R4 are hydrogen or C1-6alkyl; or R3 and R4 considered together, can form a C3-7cycloalkyl ring; n is 3, 4, 5, or 6; p is 1 or 2; each of R5a and R5b are, independently, hydrogen, C3-7cycloalkyl, aryl, Het, C1-6alkyl optionally substituted with halo, C1-6alkoxy, cyano, polyhaloC1-6alkoxy, C3-7cycloalkyl, aryl, or with Het ; or R5a and R5b considered together with the nitrogen atom to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl, 4- C1-6alkylpiperazinyl, 4-C1-6alkylcarbonyl-piperazinyl, and morpholinyl; wherein the morpholinyl and piperidinyl groups may be optionally substituted with one or two C1-6alkyl radicals; R5c is C3-7cycloalkyl, aryl, Het, -O-C3-7cycloalkyl, -O-aryl, -O-Het, C1-6alkyl, or C1-6alkoxy, wherein said C1-6alkyl or C1-6alkoxy can be substituted every one optionally with -C (= O) OR6, C3-7cycloalkyl, aryl or Het; R6 is hydrogen; C2-6alkenyl; Het; C3-7cycloalkyl optionally substituted with C1-6alkyl; or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or Het; R6a is C2-6alkenyl, C3-7cycloalkyl, Het, or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or Het; R7 is hydrogen, C1-6alkyl, C3-7cycloalkyl, or aryl; R8 is hydrogen, polyhaloC1-6alkyl, aryl, Het, C3-7cycloalkyl optionally substituted with C1-6alkyl, or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or Het; aryl as a group or part of a group is phenyl, naphthyl, indanyl, or 1,2,3,4-tetrahydronaphthyl, each of which may be optionally substituted with one, two or three substituents selected from halo, C1-6alkyl, polyhaloC1-6alkyl, hydroxy, C1-6alkoxy, polyhaloC1-6alkoxy, C1-6alkoxyC1-6alkyl, carboxyl, C1-6alkylcarbonyl, C1-6alkoxycarbonyl, cyano, nitro, amino, mono- or diC1-6alkylamino, aminocarbonyl, mono- or di-carbonyl C1-6alkylaminocarbonyl, azido, mercapto, C3-7cycloalkyl, phenyl, pyridyl, thiazolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C1-6alkylpiperazinyl, 4-C1-6alkylcarbonyl-piperazinyl, and morpholinyl; wherein the morpholinyl and piperidinyl groups may be optionally substituted with one or two C1-6alkyl radicals; and the phenyl, pyridinyl, thiazolyl, pyrazolyl groups may optionally be substituted with one, two or three substituents each independently selected from C1-6alkyl, C1-6alkoxy, halo, amino, mono- or diC1-6alkylamino; Het as a group or part of a group is a saturated, partially unsaturated or completely unsaturated 5 or 6-membered heterocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, said heterocyclic ring being optionally condensed with a benzene ring, and wherein the Het group as a whole may optionally be substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo, C1-6alkyl, polyhaloC1-6alkyl, hydroxy, C1- 6alkoxy, polyhaloC1-6alkoxy, C1-6alkoxyC1-6alkyl, carboxyl, C1-6alkylcarbonyl, C1-6alkoxycarbonyl, cyano, nitro, amino, mono- or diC1-6alkylamino, aminocarbonyl, mono- or di- C1-6alkylaminocarbonyl, C3-7alkyl phenyl, pyridyl, thiazolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C1-6alkylpiperazinyl, 4-C1-6alkylcarbonyl-piperazinyl, and morpholinyl; wherein the morpholinyl and piperidinyl groups may be optionally substituted with one or two C1-6alkyl radicals; and the phenyl, pyridyl, thiazolyl, pyrazolyl groups may optionally be substituted with 1, 2 or 3 substituents each independently selected from C1-6alkyl, C1-6alkoxy, halo, amino, mono- or diC1-6alkylamino.

Description

Hepatitis C virus macrocyclic inhibitors

The present invention relates to macrocyclic compounds that have inhibitory activity on hepatitis C virus (HCV) replication. It further concerns compositions comprising these compounds as active ingredients and processes for the preparation of 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 comprised in 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 with the animal pestivirus family, which includes the bovine viral diarrhea virus (BVDV). HCV is a positive sense single-stranded RNA virus, with a genome of around 9,600 bases. The genome comprises 5 'and 3' untranslated regions that adopt secondary RNA structures, and an open central reading frame encoding a single polyprotein of about 3010-3030 amino acids. Polyprotein encodes 10 gene products, which are generated from precursor polyprotein by an orchestrated series of co-and post-translational endoproteolytic cleavages mediated by both host and viral proteases. Viral structural proteins include the nucleocapsid protein of the nucleus, and two envelope glycoproteins E1 and E2. Non-structural proteins (NS) encode certain 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 a non-structural 5b protein (NS5B). In addition to polymerase, it has been shown that viral helicase and protease functions, both encoded in the bifunctional NS3 protein, are essential for HCV RNA replication. 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 develop chronic hepatitis since HCV preferentially replicates in hepatocytes but is not directly cytopathic. In particular, the lack of an energetic response of T lymphocytes and the high propensity of the virus to mutate appear to promote a high rate of chronic infection. Chronic hepatitis can progress to liver fibrosis, which in turn leads to cirrhosis, end-stage liver disease, and HCC (hepatocellular carcinoma), making it the leading cause of liver transplants.

There are 6 main HCV genotypes and more than 50 subtypes, which are distributed geographically differently. Type 1 HCV is the predominant genotype in Europe and the United States. The extensive genetic heterogeneity of HCV has important diagnostic and clinical implications, perhaps explaining the difficulties in developing vaccines and the lack of response to therapy.

Transmission of HCV can occur through contact with contaminated blood or blood products, for example after blood transfusions or intravenous drug use. The introduction of diagnostic tests used in blood selection has led to a decreasing trend in the incidence of posttransfusion HCV. However, given the slow progression to end-stage liver disease, existing infections will continue to present a significant medical and economic burden for decades.

Current HCV therapies are based on interferon alfa (IFN-α) (pegylated) in combination with ribavirin. This combination therapy provides a sustained virological response in more than 40% of patients infected by genotype 1 viruses and approximately 80% of those infected by genotypes 2 and 3. In addition to the limited efficacy on HCV type 1, this Combination therapy has important side effects and is poorly tolerated in many patients. The main side effects include flu-like symptoms, hematological abnormalities, and neuropsychiatric symptoms. Therefore there is a need for more effective, comfortable and better tolerated treatments.

Recently, two peptidomimetic HCV protease inhibitors have been the subject of 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 has been revealed that the sustained administration of BILN-2061 or VX-950 selects HCV mutants that are resistant to the respective drug, called drug escape mutants. These drug escape mutants have characteristic mutations in the HCV protease genome, particularly D168V. D168A and / or A156S. Accordingly, additional drugs with different resistance patterns are required to provide treatment options to patients who fail, and combination therapy with multiple drugs is likely to be the norm in the future, even for first-line treatment.

Experience with HIV drugs, and in particular with HIV protease inhibitors, has further revealed that suboptimal pharmacokinetics and complex dosing regimens quickly result in involuntary compliance failures. This in turn means that the 24 hour valley concentration (minimum plasma concentration) for the respective drugs in an HIV regimen frequently fails below the

CI90 or DE90 threshold during large parts of the day. A 24-hour valley level of at least IC50, and more realistically, IC90 or DE90, is considered to be essential to slow the development of drug escape mutants.

The achievement of the necessary pharmacokinetics and the metabolism of drugs to reach such valley levels constitute a difficult challenge for drug design. The strong peptidomimetic nature of the HCV protease inhibitors of the prior art, with multiple peptide bonds, poses pharmacokinetic difficulties for effective dosage regimens.

There is a need for HCV inhibitors that can counteract the disadvantages of current HCV therapy such as side effects, limited efficacy, resistance development, and compliance failures.

The present invention concerns inhibitors of HCV replication that are attractive not only in terms of their activity as HCV inhibitors, but also for their satisfactory cellular permeability and concomitant bioavailability.

The present invention concerns inhibitors of HCV replication, which can be represented by formula (I):

the N-oxides, salts, and stereochemically isomeric forms thereof, wherein the dashed line represents an optional double bond between the C7 and C8 atoms;

R1 is aryl or a saturated 5- or 6-membered monocyclic, saturated or partially unsaturated heterocyclic ring system, or 9 to 12-membered bicyclic ring wherein said ring system contains a nitrogen atom, and optionally 1 to 3 additional heteroatoms selected from the group consisting of oxygen, sulfur and nitrogen, and wherein the remaining members of the ring are carbon atoms; wherein said ring system may optionally be substituted on any carbon or nitrogen atom of the ring with one, two, three,

or four substituents each independently selected from C3-7cycloalkyl, aryl, Het, -C (= O) NR5aR5b, -C (= O) R7, -C (= O) OR6a, and C1-6alkyl optionally substituted with C3 -7cycloalkyl, aryl, Het, -C (= O) NR5aR5b, -NR5aR5b, -C (= O) R7, -NR5aC (= O) R7, -NR5aSOpR8, -SOpR8, -SOpNR5aR5b, -C (= O) OR6 , or -NR5aC (= O) OR6a; and wherein the substituents on any carbon atom of the heterocyclic ring can also be selected from -OR8, -SR8, halo, polyhalo-C1-6alkyl, oxo, thio, cyano ,, nitro, azido, -NR5aR5b, -NR5aC (= O ) R7, -NR5aSOpR8, -SOpR8, -SOpNR5aR5b, -C (= O) OH, and -NR5aC (= O) OR6a;

L is a direct bond, -O-, -O-C1-4alkanediyl-, -O-CO-, -O-C (= O) -NR5a-u -O-C (= O) -NR5a-C1-4alcanediyl-;

R2 represents hydrogen, -OR6, -C (= O) OR6, -C (= O) R7, -C (= O) NR5aR5b, -C (= O) NHR5c, -NR5aR5b, -NHR5c, -NHSOpNR5aR5b, -NR5aSOpR8 , or -B (OR6) 2;

R3 and R4 are hydrogen or C1-6alkyl; or R3 and R4 considered together, can form a C3-7cycloalkyl ring;

n is 3, 4, 5, or 6;

p is 1 or 2;

each of R5a and R5b are, independently, hydrogen, C3-7cycloalkyl, aryl, Het, C1-6alkyl optionally substituted with halo, C1-6alkoxy, cyano, polyhaloC1-6alkoxy, C3-7cycloalkyl, aryl, or with Het; or R5a and R5b considered together with the nitrogen atom to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl, 4C1-6alkylpiperazinyl, 4-C1-6alkylcarbonyl-piperazinyl, and morpholinyl; wherein the morpholinyl and piperidinyl groups may be optionally substituted with one or two C1-6alkyl radicals;

R5c

it is C3-7cycloalkyl, aryl, Het, -O-C3-7cycloalkyl, -O-aryl, -O-Het, C1-6alkyl, or C1-6alkoxy, wherein said C1-6alkyl or C1-6alkoxy can each be substituted optionally with -C (= O) OR6, C3-7cycloalkyl, aryl or Het; R6 is hydrogen; C2-6alkenyl; Het; C3-7cycloalkyl optionally substituted with C1-6alkyl; or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or Het;

R6a

it is C2-6alkenyl, C3-7cycloalkyl, Het, or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or Het;

R7 is hydrogen, C1-6alkyl, C3-7cycloalkyl, or aryl;

R8 is hydrogen, polyhaloC1-6alkyl, aryl, Het, C3-7cycloalkyl optionally substituted with C1-6alkyl, or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or Het;

aryl as a group or part of a group is phenyl, naphthyl, indanyl, or 1,2,3,4-tetrahydronaphthyl, each of which may be optionally substituted with one, two or three substituents selected from halo, C1-6alkyl, polyhaloC1-6alkyl, hydroxy, C1-6alkoxy, polyhaloC1-6alkoxy, C1-6alkoxyC1-6alkyl, carboxyl, C1-6alkylcarbonyl, C1-6alkoxycarbonyl, cyano, nitro, amino, mono- or diC1-6alkylamino, aminocarbonyl- mono-oCyl 6-alkylaminocarbonyl, azido, mercapto, C3-7cycloalkyl, phenyl, pyridyl, thiazolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C1-6alkylpiperazinyl, 4-C1-6alkylcarbonyl-piperazinyl, and morpholinyl; wherein the morpholinyl and piperidinyl groups may be optionally substituted with one or two C1-6alkyl radicals; and the phenyl, pyridinyl, thiazolyl, pyrazolyl groups may optionally be substituted with one, two or three substituents each independently selected from C1-6alkyl, C1-6alkoxy, halo, amino, mono- or diC1-6alkylamino;

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 fused with a benzene ring, and wherein the Het group as a whole may optionally be substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo, C1-6alkyl, polyhaloC1-6alkyl, hydroxy, C1-6alkoxy , polyhaloC1-6alkoxy, C1-6alkoxyC1-6alkyl, carboxyl, C1-6alkylcarbonyl, C1-6alkoxycarbonyl, cyano, nitro, amino, mono- or diC1-6alkylamino, aminocarbonyl, mono- or diC1-6alkylaminocarbonyl, C3-7cycloalkyl-pyridyl , thiazolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C1-6alkylpiperazinyl, 4-C1-6alkylcarbonyl-piperazinyl, and morpholinyl; wherein the morpholinyl and piperidinyl groups may be optionally substituted with one or two C1-6alkyl radicals; and the phenyl, pyridyl, thiazolyl, pyrazolyl groups may optionally be substituted with 1, 2 or 3 substituents each independently selected from C1-6alkyl, C1-6alkoxy, halo, amino, mono- or diC1-6alkylamino.

The compounds of the present invention are surprising because, despite their decreasing structural flexibility, they are active drugs against HCV. This is contrary to the prevailing opinion that expects less active drugs with less flexible macrocyclic rings.

Additionally, the compounds of the present invention having relatively low molecular weight are easy to synthesize, from raw materials that are commercially available or readily available by synthetic methods known in the art.

The invention further relates to methods for the preparation of the compounds of formula (I), the Noxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms thereof, their intermediate compounds, and the use of the compounds intermediates in the preparation of the compounds of formula (I).

The invention relates to the compounds of formula (I) per se, the N-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 a vehicle and an anti-virally effective amount of a compound of formula (I) as specified herein. The pharmaceutical compositions may comprise combinations of the aforementioned compounds with other anti-HCV agents. The invention further relates to the pharmaceutical compositions mentioned above for administration to an individual suffering from an HC infection.

The invention also relates to the use of a compound of formula (I), or an N-oxide, addition salt, quaternary amine, metal complex, or stereochemically isomeric forms thereof, for the manufacture of a medicament to inhibit the replication of the HCV Or, the invention relates to a method for inhibiting HCV replication in a warm-blooded animal, said method comprising administering an effective amount of a compound of formula (I), or an N-oxide, addition salt. , quaternary amine, metal complex, or stereochemically isomeric forms thereof.

As used above and thereafter, the following definitions apply unless otherwise indicated.

The term halo is generic for fluoro, chloro, bromo and iodo.

The term " polyhaloC1-6alkyl " as a group or part of a group, e.g. in C1-6alkoxy polyhalo, it is defined as C1-6 mono- or polyhalo-substituted alkyl, in particular C1-6alkyl substituted with up to one, two, three, four, five, six or more halogen atoms, such as methyl or ethyl with one or more fluorine atoms, for example, difluoromethyl, trifluoromethyl, trifluoroethyl. Trifluoromethyl is preferred. Also included are perfluoro C1-6 alkyl groups, which are C1-6 alkyl groups in which all hydrogen atoms are replaced by fluorine atoms, e.g. pentafluoroethyl. In the event that more than one halogen atom is attached to an alkyl group within the definition of C 1-6 alkylhalo, the halogen atoms may be the same or different.

As used herein "C1-6alkyl" as group or part of a group it defines saturated straight or branched chain hydrocarbon radicals having 1 to 4 carbon atoms such as for example methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2 -methyl-1-propyl; "C1-6alkyl" it encompasses C1-4alkyl radicals and the higher homologs thereof having 5 or 6 carbon atoms such as, for example, 1-pentyl, 2-pentyl, 3-pentyl, 1hexyl, 2-hexyl, 2-methyl-1-butyl , 2-methyl-1-pentyl, 2-ethyl-1-butyl, 3-methyl-2-pentyl, and the like. Of interest between C1-6alkyl is C1-4alkyl.

The term "C2-6alkenyl" as a group or part of a group it defines straight and branched chain hydrocarbon radicals that have saturated carbon-carbon bonds and at least one double bond, and that have 2 to 6 carbon atoms, such as, for example, ethenyl (or vinyl ), 1-propenyl, 2-propenyl (or allyl), 1-butenyl, 2-butenyl, 3butenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl, 2-hexenyl, 3-hexenyl, 4- hexenyl, 2-methyl-2-butenyl, 2-methyl2-pentenyl and the like. Of interest between C2-6alkenyl is C2-4alkenyl.

The term " C2-6alkynyl " as a group or part of a group it defines straight and branched chain hydrocarbon radicals that have saturated carbon-carbon bonds and at least one triple bond, and that have 2 to 6 carbon atoms, such as, for example, ethynyl, 1- propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 2-pentinyl, 3pentinyl, 2-hexinyl, 3-hexinyl, and the like. Of interest between C2-6alkynyl is C2-4alkynyl.

C3-7cycloalkyl is generic for cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. C3-7cycloalkyl when substituted in aryl or Het in particular is cyclopropyl.

C1-6alkanediyl defines straight and branched straight chain bivalent saturated hydrocarbon radicals having 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. Of interest between C1-6alkanediyl is C1-4alcanediyl.

C1-6alkoxy means C1-6alkyloxy wherein C1-6alkyl is as defined above.

As used hereinbefore, the term (= O) or oxo forms a carbonyl moiety when attached to a carbon atom, a sulfoxide moiety when attached to a sulfur atom and a sulphonyl moiety when two of these terms are attached to a sulfur atom. Whenever a ring or ring system is substituted with an oxo group, the carbon atom to which the oxo is bound is a saturated carbon.

The bivalent radical L can be -O-C1-4alkanediyl-, -O-CO-, -O-C (= O) -NR5a-u -O-C (= O) -NR5a-C1-4alcanediyl-; These bivalent radicals in particular are linked to the pyrrolidine moiety by their oxygen atom.

The Het radical is a heterocycle as specified in this specification and in the claims. Examples of Het include, for example, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazinolyl, isothiazinolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl inclusion (1,2-triazolyl-triazolyl) , 1,2,4-triazolyl), tetrazolyl, furanyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, triazinyl, or any such heterocycle condensed with a benzene ring, such as indolyl, indazolyl (in particular 1H-indazolyl), indolinyl , quinolinyl, tetrahydroquinolinyl (in particular 1,2,3,4-tetrahydroquinolinyl), isoquinolinyl, tetrahydroisoquinolinyl (in particular 1,2,3,4-tetrahydroisoquinolinyl), quinazolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, benzimidazolyl, benzoxazolyl, benzyloxazolin , bencisothiazinolyl, benzothiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzo-1,2,3-triazolyl, benzo-1,2,4-triazolyl, benzotetrazolyl, benzofuranyl, benzothienyl, benzo pyrazolyl, and the like. Of interest among Het radicals are those that are unsaturated, particularly those that have an aromatic character. Of additional interest are those Het radicals that are monocyclic.

Each of the Het or R1 radicals mentioned in the preceding paragraph and the following may be optionally substituted with the number and class 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 or R1 radicals mentioned in this paragraph and the following may be substituted with one, two or three hydroxy substituents. Such hydroxysubstituted rings may exist as their tautomeric forms bearing keto groups. For example, a 3-hydroxypyridazine moiety may exist in its 2H-pyridazine-3-one tautomeric form. Some examples of keto-substituted Het or R1 radicals are 1,3-dihydro-benzimidazol-2-one, 1,3-dihydro-indole-2-one, 1H-indole-2,3-dione, 1Hbenzo [d] isoxazole , 1H-benzo [d] isothiazole, 1H-quinolin-2-one, 1H-quinolin-4-one, 1H-quinazolin-4-one, 9H-carbazole, and 1H-quinazolin-2-one. Where Het is piperazinyl, it is preferably substituted in its 4-position by a nitrogen-linked substituent of the 4-position with a carbon atom, e.g. 4-C1-6alkyl, 4-polyhaloC1-6alkyl, C1-6alkoxyC1-6alkyl, C1-6alkylcarbonyl, C3-7cycloalkyl.

R1 may be a saturated, partially unsaturated or fully unsaturated 5 or 6 membered monocyclic or bicyclic 9 to 12 membered heterocyclic ring system, as specified herein and in the claims. Examples of said monocyclic or bicyclic ring system comprise any of the rings mentioned in the preceding paragraph as examples of the Het radical and additionally any of the monocyclic heterocycles mentioned in the preceding paragraph that are fused with pyridyl or pyrimidinyl such as, for example, pyrrolopyridine (in particular 1H-pyrrolo [2,3] -b] pyridine, 1H-pyrrolo [2,3] -c] pyridine), naphthyridine (in particular 1,8naphthyridine), imidazopyridine (in particular 1H-imidazo [4,5 -c] pyridine, 1H-imidazo [4,5-b] pyridine), pyridopyrimidine, purine (in particular 7H-purine) and the like.

Interesting Het or R1 radicals comprise, for example, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl (including 1,2,3-triazolyl, , 2,4-triazolyl), tetrazolyl, furanyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, pyrazolyl, triazinyl, or any such heterocycle condensed with a benzene ring, such as indolyl, indazolyl (in particular 1 Hindazolyl), indolinyl, quinolinyl , tetrahydroquinolinyl (in particular 1,2,3,4-tetrahydroquinolinyl), isoquinolinyl, tetrahydroisoquinolinyl (in particular 1,2,3,4-tetrahydroisoquinolinyl), quinazolinyl, phthalazinyl, benzimidazolyl, benzoxazolyl, bencisoxazolyl, benzothiazolyl, benzoxadiazolyl, benzoxadiazolyl, benzoxadiazolyl benzothienyl.

The radicals Het pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, piperazinyl substituted in position 4 are preferably linked by their nitrogen atom (i.e. 1-pyrrolidinyl, 1-piperidinyl, 4-morpholidinyl, 1-piperazinyl, 1piperazinyl substituted in position 4).

Every "arilo" it is as specified above, and preferably it is phenyl substituted with the substituents specified above. This applies equally to arylC1-6alkyl, which in particular can be arylmethyl, e.g. benzyl

It should be noted that the positions of the radicals in any molecular moiety used in the definitions can be anywhere in said moiety as long as it is chemically stable.

The radicals used in the definitions of the variables include all possible isomers unless otherwise indicated. For example, pyridyl includes 2-pyridyl, 3-pyridyl and 4-pyridyl; pentyl includes 1-pentyl, 2-pentyl and 3pentyl.

When any variable exists more than once in any constituent, each definition is independent.

Whenever used hereinafter, the expression "compounds of formula (I)" or "the present compounds" or similar expressions, it should be understood that it includes the compounds of formula (I), each and every one of the subgroups thereof, their N-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms, An embodiment comprises the compounds of formula (I) or any subgroup of compounds of formula (I) specified herein, both the N-oxides and the salts and the possible stereoisomeric forms thereof, Another embodiment comprises the compounds of formula (I) or any subgroup of compounds of formula (I) specified herein, both salts and possible stereoisomeric forms thereof.

The compounds of formula (I) have several chirality centers and exist with stereochemically isomeric forms. The expression "stereochemically isomeric forms" As used herein, it defines all possible compounds consisting of the same atoms linked by the same sequence of bonds but having different three-dimensional structures that are not interchangeable, which the compounds of formula (I) may possess.

With reference to the cases in which (R) or (S) is used to designate the absolute configuration of a chiral atom within a substituent, the designation is made taking into consideration the total compound and not the substituent considered alone.

Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms, which said compound may possess. Said mixture may contain all diastereomers and / or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of the present invention, both in pure form and in admixture with each other, should be understood to be encompassed within the scope of the present invention.

The pure stereoisomeric forms of the compounds and intermediates mentioned herein are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates. In particular, the expression "stereoisomerically pure" refers to compounds or intermediates having an excess of stereoisomer of at least 80% (i.e. at least 90% of an isomer and at most 10% of the other possible isomers) to an excess of 100% stereoisomer (i.e. 100% of one isomer and none of the other); more particularly, compounds or intermediates having an excess of 90% to 100% stereoisomer, even more particularly having an excess of 94% to 100% stereoisomer and very particularly having an excess of stereoisomer from 97% to 100%. The expressions "enantiomerically pure" and "diastereomerically pure" they should be understood in a similar way, but referring then to the enantiomeric excess, and the diastereomeric excess, respectively, of the mixture in question.

The pure stereoisomeric forms of the compounds and intermediates of this invention can be obtained by the application of methods known in the art. For example, enantiomers can be separated from each other by selective crystallization of their diastereomeric salts with optically active acids or bases. Examples thereof are tartaric acid, dibenzoyltartaric acid, ditholuoyltartaric acid and canphosulfonic acid. Alternatively, the enantiomers can be separated by chromatographic techniques using chiral stationary phases. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction proceeds stereospecifically. Preferably, if a specific stereoisomer is desired, said compound is synthesized by stereospecific methods of preparation. These methods will advantageously use enantiomerically pure starting materials.

The diastereomeric racemates of the compounds of formula (I) can be obtained separately by conventional methods. Appropriate physical separation methods that can be advantageously employed are, for example, selective crystallization and chromatography, e.g., column chromatography.

For some of the compounds of formula (I), their N-oxides, salts, solvates, quaternary amines, or metal complexes, and intermediate compounds used in the preparation thereof, the absolute stereochemical configuration was not determined experimentally, One person One skilled in the art can determine the absolute configuration of such compounds using methods known in the art such as, for example, X-ray diffraction.

The present invention also aims to include all isotopes of the atoms that exist in the present compounds. Isotopes include those atoms that have the same atomic number but different mass numbers. By way of general example and without limitation, hydrogen isotopes include tritium and deuterium. Carbon isotopes include C-13 and C-14.

For therapeutic use, salts of the compounds of formula (I) are those in which the counterion is pharmaceutically acceptable. However, salts of acids and bases that are not pharmaceutically acceptable may also find utility, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not, are included within the scope of the present invention.

It should be understood that the pharmaceutically acceptable acid and base addition salts mentioned hereinbefore comprise the therapeutically active and non-toxic forms of acid and base addition salts that are capable of forming the compounds of formula (I). Pharmaceutically acceptable acid addition salts may conveniently be obtained by treating the base form with an appropriate acid of this type. Suitable acids comprise, for example, inorganic acids such as halogenated hydrogens, eg hydrochloric or hydrobromic acid, and acids sulfuric, nitric, phosphoric and the like; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic acid (i.e. hydroxybutanedioic acid), tartaric acids , citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like.

Conversely, said salt forms can be converted by treatment with an appropriate base in the free base form.

Compounds of formula (I) containing an acidic proton can also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Suitable forms of salts with bases comprise, for example, ammonium salts, alkali metal and alkaline earth metal salts,

e.g. salts of lithium, sodium, potassium, magnesium, calcium and the like, salts with organic bases, e.g. salts of benzathine, N-methyl-D-glucamine, hydrabamine, and salts with amino acids such as, for example, arginine, lysine and the like.

The term "addition salt" as used hereinbefore also includes the solvates that the compounds of formula (I) may form, as well as the salts thereof. Such solvates are for example hydrates, alcoholates and the like.

The expression "quaternary amine" as used hereinbefore it defines the quaternary ammonium salts that the compounds of formula (I) can form by reaction between a basic nitrogen of a compound of formula (I) and an appropriate quaternization agent, such as, for example, an optionally substituted alkyl halide, aryl halide or arylalkyl halide, eg Methyl iodide or benzyl iodide, Other reactants with suitable labile groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl p-toluenesulfonates. A quaternary amine has a positively charged nitrogen. Pharmaceutically acceptable counterions include chlorine, bromine, iodine, trifluoroacetate and acetate. The counterion of choice can be introduced using ion exchange resins.

It should be understood that the N-oxide forms of the present compounds comprise the compounds of the formula (I) in which one or more nitrogen atoms are oxidized to form the so-called N-oxide.

It will be appreciated that the compounds of formula (I) may have metal fixation properties, chelate formation properties or complexes and, therefore, may exist as metal complexes or metal chelates. Such metallated derivatives of the compounds of formula (I) should be considered included within the scope of the present invention.

Some of the compounds of formula (I) may also exist in their tautomeric form. Such forms, although not explicitly stated in the above formula, should be understood to be included within the scope of the present invention.

As mentioned above, the compounds of formula (I) have several asymmetric centers. In order to refer more efficiently to each of these asymmetric centers, the numbering system indicated in the following structural form will be used:

Asymmetric centers are present in positions 1, 4 and 6 of the macrocycle as well as in the 3'15 carbon atom of the pyrrolidine residue, or proline residue, which bears the group -L-R1. Each of these asymmetric centers can exist in its R or S configuration.

The stereochemistry at position 1 preferably corresponds to that of an L-amino acid configuration, ie that of L-proline.

The compounds of formula (I) include a cyclopropyl group as depicted in the following structural fragment:

wherein C7 represents the carbon of position 7 and the carbons of positions 4 and 6 are asymmetric carbon atoms of the cyclopropane ring.

Despite other possible asymmetric centers in other segments of the compounds of the invention, the presence

25 of these two asymmetric centers means that the compounds may exist as mixtures of diastereomers, such as the diastereomers of the compounds of formula (I) in which the carbon of position 7 has a syn configuration with respect to carbonyl or syn with respect to the amide as it's shown in the following.

One embodiment concerns compounds of formula (I) wherein the carbon of position 7 has a syn configuration with respect to carbonyl, Another embodiment concerns compounds of formula (I) where the carbon configuration of position 4 is R. A specific subgroup of compounds of formula (I) are those in which the carbo

5 no of position 7 has syn configuration with respect to carbonyl and where the carbon configuration of position 4 is R.

The compounds of formula (I) also include a proline residue. Compounds of formula (I) in which the substituent of the 1 (or 5 ') position and the substituent -L-R1 (in the 3' position) are in a trans configuration are preferred. Of particular interest are the compounds of formula (I) where position 1 has the current configuration

10 relative to L-proline and the substituent -L-R1 is in trans configuration with respect to position 1. Preferably the compounds of formula (I) have the stereochemistry indicated in the structure of formula (Ia) as represented then:

An embodiment of the present invention concerns compounds of formula (I) or of formula (I-a), or of any subgroup of compounds of formula (I), wherein one or more of the following conditions apply:

(to)

 R3 and R4 are both hydrogen;

(b)

 L is -O-;

(C)

a double bond between carbon atoms 7 and 8 is present. A particular subgroup of compounds of formula (I) are those represented by the following structural formula:

Among the compounds of formula (I-b), those having the stereochemical configuration of the compounds of formula (I-a) are particularly interesting.

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 in cis or trans configuration. Preferably, the double bond between carbon atoms 7 and 8 is in cis configuration, as depicted in formula (I-b).

Still another particular subgroup of compounds of formula (I) are those represented by the following structural formula:

Among the compounds of formula (I-c), those having the stereochemical configuration of the compounds of formula (I-a) are particularly interesting.

In (Ia), (Ib) and (Ic), whenever applicable, L, 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) specified herein.

It should be understood that the above defined subgroups of compounds of formulas (Ia), (Ib) or (Ic) as well as any other subgroup defined herein, are also intended to comprise any N-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms of such compounds.

When n is 2, the remainder -CH2-delimited 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 remainder -CH2-delimited by " n " corresponds to 20 propanediyl in the compounds of formula (I) or in any subgroup of compounds of formula (I). When n is 4, the remainder -CH2-delimited 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 remainder -CH2-delimited 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 remainder -CH2 delimited by " n " corresponds to hexanediyl in the compounds of formula (I) or in any subset of compounds

25 cough of formula (I). Particular subgroups of the compounds of formula (I) are those compounds in which n is 4 or 5.

Additional groups of the compounds of formula (I) are those compounds of formula (I), or any subgroup of compounds of formula (I) specified herein, in which R 1 is phenyl, naphthyl, pyridyl, pyridazinyl, triazolyl, tetrazolyl , quinolinyl, isoquinolinyl, quinazolinyl, pyrimidinyl, [1,8] naphthyrinyl, indolinyl, 1,2,3,430 tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl; all optionally substituted with one, two or three substituents selected from those mentioned in relation to R1 in the definitions of the compounds of formula (I)

or any of the subgroups of compounds of formula (I).

Other subgroups of the compounds of formula (I) are those compounds of formula (I), or any subgroup of compounds of formula (I) specified herein, wherein

(to)

R1 is phenyl, naphthyl (such as naft-1-yl or naphth-2-yl), quinolinyl (in particular quinolin-4-yl), isoquinolinyl (in particular isoquinolin-1-yl), quinazolinyl (in particular quinazolin-4 -yl), pyridyl (in particular 3-pyridyl), pyrimidinyl (in particular pyrimidin-4-yl), pyridazinyl (in particular pyridazin-3-yl and pyridazin-2-yl), [1,8] naphthyridinyl (in particular [1,8] naphthyridin-4-yl);

(b)

R1 is triazolyl (in particular triazol-1-yl, triazol-2-yl), tetrazolyl (in particular tetrazol-1-yl, tetrazol-2-yl), 6oxo-pyridazin-1-yl, pyrazolyl (in particular pyrazol- 1-yl), or imidazolyl (in particular imidazol-1-yl, imidazol-2-yl);

(C)

R1 is a heterocycle selected from

Y

and wherein each of the above-mentioned R1 radicals may be optionally substituted with one, two or three substituents selected from those mentioned in relation to R1 in the definitions of the compounds of formula (I) or any of the subgroups of compounds of formula (I).

Embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein L is a direct bond, -O-, -OC (= O) -, or -OC (= O) NR5a-, or in particular where L is OC (= O) NH-u -O-, or more particularly where L is -O-.

Preferably L is -O-, and R1 is as specified above in (a). Preferably, L is a direct link, and R1 is as specified above in (b). Preferably L is a bivalent radical -OC (= O) -, and R1 is as specified above in (c).

Embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein L is -O-, and R1 is quinolinyl (in particular quinolin-4-yl), isoquinolinyl (in particular isoquinolin1 -yl), quinazolinyl (in particular quinazolin-4-yl), or pyrimidinyl (in particular pyridimidin-4-yl), any of which is, independently, optionally mono-, di-, or tri-substituted with C1 -6alkyl, C1-6alkoxy, nitro, hydroxy, halo, trifluoromethyl, -NR5aR5b, -C (= O) NR5aR5b, C3-7cycloalkyl, aryl, Het, -C (= O) OH, or -C (= O) OR6a ; wherein aryl or Het are each, independently, optionally substituted with halo, C1-6alkyl, C1-6alkoxy, amino, mono- or diC1-6alkylamino, pyrrolidinyl, piperidinyl, piperazinyl, 4-C1-6alkylpiperazinyl (eg 4-methylpiperazinyl) , thiomorpholinyl or morpholinyl; and wherein the morpholinyl, thiomorpholinyl and piperidinyl groups may optionally be substituted with one or two C1-6alkyl radicals.

Embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein L is -O and R 1 is quinolinyl (in particular quinolin-4-yl), isoquinolinyl (in particular isoquinolin-1-yl) , quinazolinyl (in particular quinazolin-4-yl), or pyrimidinyl (in particular pyrimidin-4-yl), any of which is, independently, optionally mono-, di-, or tri-substituted with methyl, ethyl, isopropyl, tert-butyl, methoxy, trifluoromethyl, trifluoromethoxy, fluoro, chloro, bromo, -NR5aR5b, -C (= O) NR5aR5b, phenyl, methoxyphenyl, cyanophenyl, halophenyl, pyridyl, C1-6alquilpiridilo, pyrimidinyl, piperidinyl, morpholinyl, piperazinyl , C1-4alkylpiperazinyl, pyrrolidinyl, pyrazolyl, C1-4alkyl-pyrazinyl, thiazolyl, C1-4alkylthiazolyl, cyclopropylthiazolyl, or mono- or diC1-4alkyl-aminothiazolyl; and wherein the morpholinyl, thiomorpholinyl and piperidinyl groups may optionally be substituted with one or two C1-6 alkyl radicals (in particular one or two methyl radicals).

Embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein R 1 is quinolinyl, optionally substituted with 1, 2, 3 or 4 (or with 1, 2 or 3) substituents selected of those mentioned as possible substituents in the monocyclic or bicyclic ring systems of R1, as specified in the definitions of the compounds of formula (I) or of any of the subgroups of compounds of formula (I).

Specific embodiments of the invention are those compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein R1 is

(d-1) a radical of formula

(d-2) a radical of formula

(d-3) a radical of formula

(d-4) a radical of formula

or in particular, (d-4-a) a radical of formula

10 (d-5) a radical of formula or in particular, (d-5-a) a radical of formula

where, in the radicals (d-1) - (d-5), as well as in (d-4a) and (d-5-a):

Each of R1a, R1b, R1b ', R1d, R1d', R1e, R1f are independently any of the substituents selected from those mentioned as possible substituents in the R1 monocyclic or bicyclic ring systems, as specified in the definitions of the compounds of formula (I) or of any of the subgroups of compounds of formula (I);

or, in particular, where in the radicals (d-1) - (d-5), as well as in (d-4-a) and (d-5-a):

R1b, R1b 'can, independently, be hydrogen, C1-6alkyl, C1-6alkoxy, -NR5aR5b (in particular amino or mono- or diC1-6alkylamino), -C (= O) -NR5aR5b (in particular aminocarbonyl or mono- or diC1-6alkylaminocarbonyl), nitro, hydroxy, halo, trifluoromethyl, -C (= O) OH, or -C (= O) OR6a (in particular where R6a is C1-6alkyl);

wherein each of R5a, R5b, R6a mentioned above or hereafter is independently as defined in the definitions of the compounds of formula (I) or any of the subgroups of compounds of

Formula (I);

or, in particular, where in the radicals (d-1) - (d-5), as well as in (d-4-a) and (d-5-a):

R1a is hydrogen, C1-6alkyl, C1-6alkoxy, C1-6alkylthio, mono-C1-6alkylamino, amino, C3-7cycloalkyl, aryl or Het;

more specifically R1a is C1-6alkoxy, aryl, or Het; Of interest are embodiments in which R 1a is methoxy, ethoxy, propoxy, phenyl, pyridyl, thiazolyl, pyrazolyl, each substituted as specified in the definitions of the compounds of formula (I) or any of the subgroups of the compounds of formula (I); in specific embodiments, said aryl or Het may be independently substituted each optionally with C1-6alkyl, C1-6alkoxy, amino, mono- or diC1-6alkylamino, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 4-C1-6alkylpiperazinyl ; and wherein the morpholinyl and piperidinyl groups may be optionally substituted with one or two C1-6alkyl radicals; and in particular R1a can be a Het radical; wherein Het may include pyrrolidinyl, piperidinyl, morpholini

25 lo, piperazinyl, 4-C1-6 alkylpiperazinyl; and wherein the morpholinyl, thiomorpholinyl and piperidinyl groups may optionally be substituted with one or two C1-6alkyl radicals.

Embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein R1a is a radical

30 or, in particular, where R1a is selected from the group consisting of:

or

where, whenever possible, a nitrogen may carry an R1c substituent or a link with the rest of the molecule; each R1c is any of the R1 substituents, and those selected as possible substituents in the monocyclic or bicyclic ring systems of R1 may be selected, as specified in the definitions of the compounds of formula (I) or any of the subgroups of compounds of formula (I);

specifically, each R1c can be hydrogen, halo, C1-6alkyl, C1-6alkoxy, polyhaloC1-6alkyl (in particular trifluoromethyl), -NR5aR5b (in particular amino or mono- or diC1-6alkylamino), -C (= O) NR5aR5b ( in particular aminocarbonyl or mono- or diC1-6alkylaminocarbonyl), nitro, hydroxy, -C (= O) OH, or -C (= O) OR6a (in particular where R6a is C1-6alkyl), phenyl, pyridyl, thiazolyl, pyrazolyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 4-C1-6alkylpiperazinyl (in particular 4-methylpiperazinyl); and wherein the morpholinyl and piperidinyl groups may be optionally substituted with one or two C1-6alkyl radicals;

more specifically, each R1c may be hydrogen, halo, C1-6alkyl, amino, or mono- or di-C1-6alkylamino, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 4-C1-6alkylpiperazinyl; and wherein the morpholinyl and piperidinyl groups may be optionally substituted with one or two C1-6alkyl radicals; and the phenyl, pyridyl, thiazolyl, pyrazolyl groups may be optionally substituted with one, two or three (in particular with one or two) substituents each independently selected from C1-6alkyl, C1-6alkoxy, halo, amino, mono- or diC1-6alkylamino;

more specifically, each R1c may be hydrogen, halo, C1-6alkyl, amino, or mono- or di-C1-6alkylamino, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 4-C1-6alkylpiperazinyl; and wherein the morpholinyl and piperidinyl groups may be optionally substituted with one or two C1-6alkyl radicals;

and where R1c is substituted on a nitrogen atom, it is preferably a carbon-containing substituent that is connected to the nitrogen by a carbon atom or one of its carbon atoms;

specifically, each R1d and R1d 'can independently be hydrogen, C1-6alkyl, C1-6alkoxy, or halo;

or more specifically, each R1d in (d-3) can be hydrogen, C1-6alkyl, C1-6alkoxy or halo;

specifically, R1e may be hydrogen, C1-6alkyl, amino, mono- or diC1-6alkylamino, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 4-C1-6alkylpiperazinyl (in particular 4-methylpiperazinyl); and wherein the morpholinyl and piperidinyl groups may be optionally substituted with one or two C1-6alkyl radicals;

preferably each R1b is C1-6alkoxy, more preferably methoxy;

specifically R1f can be hydrogen, C1-6alkyl, amino, mono- or diC1-6alkylamino, pyrrolidinyl, piperidinyl, piperazinyl, 4-C1-6alkylpiperazinyl (in particular 4-methylpiperazinyl), or morpholinyl.

Specific embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein R1 is 7-methoxy-2-phenyl-quinolin-4-yl and L is -O-.

Embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein R1 is

(e) isoquinolinyl (in particular 1-isoquinolinyl), optionally substituted with 1, 2, 3 or 4 (or with 1, 2 or 3) substituents selected from those mentioned as possible substituents in R1 monocyclic or bicyclic ring systems, as specified in the definitions of the compounds of formula (I) or of any of the subgroups of compounds of formula (I).

Specific embodiments of this class are those in which R1 is

(e-1) a radical of formula:

or in particular (e-1-a) a radical of formula:

wherein R9a, R9b, R9c, independently of one another, are any of the substituents selected from those mentioned as possible substituents in the monocyclic or bicyclic ring systems of R1, as specified in the definitions of the compounds of formula (I) or of any of the subgroups of compounds of formula (I); in particular

R9a can have the same meanings as R1a as specified above; in particular, it may be aryl or Het, any of which is optionally substituted with any of the radicals mentioned as substituents of aryl or Het as specific definitions of the compounds of formula (I) or any of the subgroups of compounds of formula (I) (including the number of substituents); specifically, said aryl or Het may be substituted with 1, 2 or 3 radical (s) R10 (in particular with one); where said

R10 is any of the radicals mentioned as substituents of aryl or Het as specific definitions of the compounds of formula (I) or of any of the subgroups of compounds of formula (I) as defined above; or in particular R10 is hydrogen, C1-6alkyl, C3-7cycloalkyl, phenyl, pyridyl, thiazolyl, pyrazolyl, amino mono- or optionally substituted with C1-6alkyl, or aminocarbonyl or mono- or diC1-6alkylaminocarbonyl; wherein Het also includes pyrrolidinyl, piperidinyl, piperazinyl, 4-C1-6alkylpiperazinyl (e.g. 4-methylpiperazinyl) or morpholinyl; and wherein the morpholinyl or piperidinyl groups may be optionally substituted with one or two C1-6 alkyl radicals; and the phenyl, pyridyl, thiazolyl, pyrazolyl groups may optionally be substituted with 1, 2 or 3 (in particular with 1 or 2) substituents each independently selected from C1-6alkyl, C1-6alkoxy, halo, amino, mono- or diC1 -6alkylamino;

R9b can have the same meanings as R1b as specified above; in particular, it can be hydrogen, C1-6alkyl, C3-7cycloalkyl, aryl, Het, halo (e.g. bromine, chlorine or fluoro); R9c can have the same meanings as R1c as specified above; in particular it can be hydrogen or C1-6alkoxy.

In particular, R9a in the isoquinolinyl radical specified under (e-1) or (e-1-a) includes phenyl, pyridyl, thiazolyl, oxazolyl

or pyrazolyl, any of which is optionally substituted with R10 as defined above, in particular optionally substituted with an R10 which may be hydrogen, C1-6alkyl (eg methyl, ethyl, isopropyl, tertbutyl), amino, pyrrolidinyl, piperidinyl, piperazinyl, 4-C1-6alkylpiperazinyl (eg 4-methylpiperazinyl), or morpholinyl, C1-6alkylamino, (C1-6alkyl) 2amino, aminocarbonyl, or mono- or diC1-6alkylaminocarbonyl; and wherein the morpholinyl and piperidinyl groups may be optionally substituted with one or two C1-6 alkyl radicals.

Preferably, R9a in the isoquinolinyl radical specified under (e-1) or (e-1-a) includes any of the radicals (q), (q '), (q'-1), (q-1), ( q-2), (q-3), (q-4) specified above as well as:

wherein each R10 is any of the radicals mentioned as substituents of Het as specified in the definitions of the compounds of formula (I) or of any of the subgroups of compounds of formula (I); or in particular R10 is as defined above; especially R10 is hydrogen, C1-6alkyl (eg methyl, ethyl, isopropyl, tert-butyl), amino, pyrrolidinyl, piperidinyl, piperazinyl, 4-C1-6alkylpiperazinyl (eg 4-methylpiperazinyl), morpholinyl, C1-6alkylamino, (C1- 6alkyl) 2amino, aminocarbonyl, or mono- or diC1-6alkylaminocarbonyl; and wherein the morpholino and piperidino may be optionally substituted with one or two C1-6alkyl radicals.

Also, preferably R9a in the isoquinolinyl radical specified under (e-1) or (e-1-a) includes:

wherein each R10 is as defined above, and especially is hydrogen, halo, C1-6alkyl (e.g., methyl, ethyl, iso

10 propyl, tert-butyl), amino, pyrrolidinyl, piperidinyl, piperazinyl, 4-C1-6alkylpiperazinyl (eg 4-methylpiperazinyl), morpholinyl, C1-6alkylamino, (C1-6alkyl) 2amino, aminocarbonyl, or mono- or diC1-6alkylaminocarbonylcarbonyl ; and wherein the morpholinyl and piperidinyl groups may be optionally substituted with one or two C1-6 alkyl radicals.

R9b in the isoquinolinyl radical specified under (e-2) may be hydrogen, C1-6alkyl, halo (e.g. bromine, chlorine or fluoro), especially hydrogen or bromine.

R9b in the isoquinolinyl radical specified under (e-2) may be hydrogen or C1-6alkoxy (e.g. methoxy).

Embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein R1 is

wherein R9b is hydrogen or halo (e.g. bromine) and R9c is hydrogen or C1-6alkoxy (e.g., methoxy).

Embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein R1 is

wherein R9a is as defined in any of the groups or subgroups of compounds of formula (I); and R9b is hydrogen, halo, or trifluoromethyl. Additional preferred embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein R1 is:

wherein R9a is methoxy, ethoxy or propoxy; and R9b is hydrogen, fluoro, bromine, chlorine, iodine, methyl, ethyl, propyl, or trifluoromethyl. Additional embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds

cough of formula (I) where R1 is:

wherein R9b is hydrogen, halo, or trifluoromethyl.

Embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein R1 is:

10 (f) quinazolinyl (in particular quinazolin-4-yl), optionally substituted with 1, 2, 3 or 4 (or with 1, 2 or 3) substituents selected from those mentioned as possible substituents in monocyclic or bicyclic ring systems of R1, as specified in the definitions of the compounds of formula (I) or of any of the subgroups of compounds of formula (I).

Quinazoline embodiments of R1 include

15 (f-1) a radical:

or in particular (f-1-a) a radical:

wherein R9a, R9b and R9c have the meanings indicated above in relation to R1 which is isoquinolinyl (such as in the radicals (e-1), (e-1-a), etc);

wherein specifically R9a is C3-7cycloalkyl, aryl or Het, any of which is optionally substituted with 1, 2 or 3 R10 (in particular with one); where

R10 is hydrogen, C1-6alkyl, C3-7cycloalkyl, phenyl, pyridyl, thiazolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-methylpiperazinyl, thiomorpholinyl or morpholinyl, aminocarbonyl, mono- or diC1-6alkylaminocarbonyl; where the pipe

Rothinyl or morpholinyl may be optionally substituted with one or two C1-6 alkyl radicals; and the phenyl, pyridyl, thiazolyl, pyrazolyl groups may be optionally substituted with 1, 2 or 3 (or with 1 or 2) substituents each independently selected from C1-6alkyl, C1-6alkoxy, halo, amino, mono- or diC1- 6alkylaminocarbonyl (selected in particular from C1-6alkyl);

R9b is hydrogen, halogen, C1-6alkyl (in particular methyl), C3-7cycloalkyl, aryl, Het, halo (in particular bromine, chlorine, or fluoro);

R9c is hydrogen or C1-6alkoxy.

Preferred embodiments of R9a for quinazolines include aryl or Het, especially where R9a is phenyl, pyridyl, thiazolyl, oxazolyl or pyrazolyl any of which is optionally substituted with 1, 2 or 3 R10 (in particular with one) as defined.

R10 embodiments for quinazoline include hydrogen, methyl, ethyl, isopropyl, tert-butyl, halo (including dihalo, such as difluoro), pyrrolidinyl, piperidinyl, piperazinyl, 4-C1-6alkylpiperazinyl (eg 4-methylpiperazinyl) or morpholinyl , C1-6alkylamino, (C1-6alkyl) 2amino, aminocarbonyl, or mono- or diC1-6alkylaminocarbonyl or C3-7cycloalkyl (in particular cyclopropyl).

Preferably, R9a in the quinazolyl radical specified under (f-1) or (f-1-a) includes any of the radicals (q), 20 (q '), (q'-1), (q-1), (q-2), (q-3), (q-4), (q-5), (q-6), (q-7), (q-8) specified above;

wherein in these radicals R10 is as defined above or in particular is hydrogen, C1-6alkyl (such as methyl, ethyl, isopropyl, tert-butyl), pyrrolidinyl, piperidinyl, piperazinyl, 4-C1-6alkylpiperazinyl, N-methylpiperazinyl or morpholinyl, C1-6alkylamino, (C1-6alkyl) 2amino or aminocarbonyl, mono- or diC1-6alkylaminocarbonyl.

R9a for quinazolines may include

wherein R10 is hydrogen, halogen, C1-6alkyl (such as methyl, ethyl, isopropyl, tert-butyl), C1-6alkylamino, (C1-6alkyl) 2amino, C1-6alkylamido, morpholinyl or piperidin-1-yl, the Morpholinyl and piperidinyl optionally substituted with one or two C1-6alkyl groups.

Additional embodiments of R9a for quinazolines include phenyl substituted with one or two R10 groups such as

Hydrogen, methyl, ethyl, isopropyl, tert-butyl, methoxy, saturated monocyclic amino, C1-6alkylamino, (C1-6alkyl) 2amino or aminocarbonyl, mono- and diC1-6alkylaminocarbonyl or halo (in particular fluoro).

Embodiments of R9b for quinazolines include hydrogen, C1-6alkyl (in particular methyl), halo (e.g. bromine, chlorine

or fluoro) especially where R9 is hydrogen or bromine. Embodiments of R9c for quinazolines include hydrogen or C1-6alkoxy (in particular methoxy).

Specific embodiments of the compounds of formula (I) or any of the subgroups of compounds of formula (I) are those in which R1 is: wherein R9b is hydrogen or methyl; and each of R10 and R9c are as specified above and in particular R9c is hydrogen or C1-6alkoxy (e.g. methoxy).

Embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein R1 is:

wherein R9a is as defined in any of the groups or subgroups of compounds of formula (I), preferably R9a is p-methoxyphenyl or p-fluoromethyl; Y

R9b is hydrogen, halo, methyl, or trifluoromethyl.

Additional preferred embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein R1 is:

wherein R9a is methoxy, ethoxy or propoxy; and R9b is hydrogen, fluoro, bromine, chlorine, iodine, methyl, ethyl, propyl, or trifluoromethyl. Additional embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein R1 is:

wherein R9b is hydrogen, halo, or trifluoromethyl.

Preferred among the subgroups of compounds of embodiments in which R1 is a radical (d-1) - (d-5), (e-1) - (e-3), (f1) - (f-3), ( g-1) - (g-2) as specified above, are those compounds within these subgroups in which L is -O-.

Embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein L is a direct bond and R1 is selected from the group consisting of 1H-pyrrole, 1H-imidazole, 1Hpyrazole, furan, Thiophene, oxazol, thiazole, isoxazole, isothiazole, pyridine, pyridazine, pyrimidine, pyrazine, phthalazine, quinoxaline, quinazoline, quinoline, cinnoline, 1H-pyrrolo [2,3] -b] pyridine, 1H-indole, 1H-benzoimidazole, 1H -indazol, 7H-purine, 10 benzothiazole, benzoxazole, 1H-imidazo [4,5-c] pyridine, 1H-imidazo [4,5-b] pyridine, 1,3-dihydro-benzimidazol-2-one, 1, 3dihydro-benzimidazol-2-thione, 2,3-dihydro-1H-indole, 1,3-dihydro-indole-2-one, 1H-indole-2,3-dione, 1H-pyrrolo [2,3c] pyridine, benzofuran, benzo [b] thiophene, benzo [d] isoxazole, benzo [d] isothiazole, 1H-quinolin-2-one, 1H-quinolin-4-one, 1H-quinazolin-4-one, 9H-carbazole, and 1H -quinazolin-2-one, each optionally substituted with the R1 substituents specified in the definitions of the compounds of formula (I) or any of the subgroups of compounds

15 of formula (I).

Additional embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein L is a direct bond and R1 is selected from the group consisting of pyrrolidine, 4,5-dihydro-1H-pyrazole, pyrazolidine , imidazolidin-2-one, pyrrolidin-2-one, pyrrolidine-2,5-dione, piperidine-2,6-dione, piperidin-2-one, piperazine-2,6-dione, piperazin-2-one, piperazine , morpholine, pyrazolidin-3-one, imidazolidine-2,4-dione,

Piperidine, tetrahydrofuran, tetrahydropyran, 1,4-dioxane, and 1,2,3,6-tetrahydropyridine, each optionally substituted with the R1 substituents specified in the definitions of the compounds of formula (I) or any of the subgroups of compounds of formula (I).

Embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) in which L is a direct bond and R1 is optionally substituted tetrazolyl as represented by

25 continued:

wherein R1g is hydrogen, C1-6alkoxy, hydroxy, -NR5aR5b, -C (= O) R7, -SOpR8, C3-7cycloalkyl, aryl, Het, or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl, or Het;

R1h is hydrogen, -NR5aR5b, C3-7cycloalkyl, aryl, Het, or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl, or Het; Y

R5a, R5b, R7 and R8 are as defined above.

Embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein L is a direct bond and R1 is optionally substituted triazolyl as shown below:

wherein R1i and R1j are each independently selected from the group consisting of hydrogen, halo, C (= O) NR5aR5b, -C (= O) R7, C3-7cycloalkyl, aryl, Het, and C1-6alkyl optionally substituted with -NR5aR5b, or aryl; or alternatively, R1i and R1j considered together with the carbon atoms to which they are attached, can form a cyclic moiety selected from the group consisting of aryl and Het.

Additional preferred substituents for R1 when L is a direct bond, include pyridazinone and derivatives thereof as shown below:

R1l

wherein R1k, and R1m are independently selected from the group consisting of hydrogen, azido, halo,

C1-6alkyl, -NR5aR5b, C3-7cycloalkyl, aryl, and Het; or alternatively, R1k and R1l or R1l and R1m, considered together with the carbon atoms to which they are attached, can form a phenyl moiety, which can be substituted in turn with azido, halo, C1-6alkyl, -NR5aR5b, C3 -7cycloalkyl, aryl or Het.

Embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein L is -O- (C = O) -NR5a-or in particular where L is -O- (C = O) -NH- and R1 is aryl as defined

15 above; or R1 is phenyl optionally substituted with 1, 2 or 3 substituents selected from those mentioned as possible substituents of the aryl radical as in the definitions of the compounds of formula (I) or of any of the subgroups of compounds of formula (I); specifically, R1 is a radical of formula:

wherein R9c is hydrogen, C1-6alkyl, polyhaloC1-6alkyl or halo;

R9f is -COOH, -C (= O) OR6a, halo, Het or aryl; where Het and aryl are as defined herein and

R6a is C1-6alkyl, preferably R6a is methyl or ethyl.

In particular, R9e can be hydrogen, fluoro or trifluoromethyl.

In particular, R9f can be -COOC1-6alkyl (e.g. -C (= O) OEt), phenyl, thiazolyl, 1-piperidinyl or 1-pyrazolyl, the

Phenyl, piperidinyl and pyrazolyl groups optionally substituted with C1-6alkyl, in particular with methyl. Other embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein L is -O- (C = O) -NR5a-o, in particular, where L is -O - (C = O) -NH- and R1 is a radical of formula: 21

wherein R10 and R11, independently of one another, are hydrogen, halo, hydroxy, nitro, cyano, carboxyl, C1-6alkyl, C1-6alkoxy, C1-6alkoxyC1-6alkyl, C1-6alkylcarbonyl, C1-6alkoxycarbonyl, amino, azido, mercapto, C1-6alkylthio, polyhaloC1-6alkyl, aryl or Het; especially R10 and R11, independently of each other, are hydrogen, halo, nitro, car

5 boxilo, methyl, ethyl, isopropyl, t-butyl, methoxy, ethoxy, isopropoxy, t-butoxy, methylcarbonyl, ethylcarbonyl, isopropylcarbonyl, t-butyl-carbonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl, methylthio, ethylthio, isopropylthio , t-butylthio, trifluoromethyl, or cyano;

W is aryl or Het, or W is -COOH or -COOR6a, wherein R6a is C1-6alkyl, preferably methyl or ethyl.

Other subgroups of the compounds of formula (I) are those compounds of formula (I), or any subgroup of

10 compounds of formula (I) specified herein, wherein W is phenyl, naphthyl (in particular naphth-1-yl, or naphth-2-yl), pyrrolyl (in particular pyrrol-1-yl), pyridyl (in in particular 3-pyridyl), pyrimidinyl (in particular pyrimidin-4-yl), pyridazinyl (in particular pyridazin-3-yl and pyridazin-2-yl), 6-oxo-pyridazin-1-yl, triazolyl (in particular 1, 2,3-triazolyl, 1,2,4-triazolyl, more particularly 1,2,3-triazol-2-yl, 1,2,4-triazol-3-yl), tetrazolyl (in particular tetrazol-1 -yl, tetrazol-2-yl), pyrazolyl (in particular pyrazol-1-yl, pyrazol-3-yl), imidazolyl (in particular imidazol-1-yl, imidazol-2

15-yl), thiazolyl (in particular thiazol-2-yl), pyrrolidinyl (in particular pyrrolidin-1-yl), piperidinyl (in particular piperidin-1yl), piperazinyl (in particular 1-piperazinyl), 4-C1-6alkylpiperazinyl ( in particular 4-C1-6alkylpiperazin-1-yl, more particularly 4-methyl-piperazin-1-yl), furanyl (in particular furan-2-yl), thienyl (in particular thien-3-yl), morpholinyl (in particular morpholin-4-yl), all optionally substituted with one or two substituents selected from C1-6alkyl, polyhaloC1-6alkyl, or C1-6alkoxycarbonyl.

In particular W can be phenyl, naft-1-yl, naft-2-yl, pyrrol-1-yl, 3-pyridyl, pyrimidin-4-yl, pyridazin-3-yl, pyridazin-2-yl, 6-oxo- pyridazin-1-yl, 1,2,3-triazol-2-yl, 1,2,4-triazol-3-yl, tetrazol-1-yl, tetrazol-2-yl, pyrazol-1-yl, pyrazole- 3-yl, imidazol-1-yl, imidazol-2-yl, thiazol-2-yl, pyrrolidin-1-yl, piperidin-1-yl, furan-2-yl, thien-3-yl, morpholin-4- ilo; all optionally substituted with one or two substituents selected from C1-6alkyl, polyhaloC1-6alkyl (such as trifluoromethyl) and C1-6alkoxycarbonyl.

Additional subgroups of the compounds of formula (I) are those compounds of formula (I), or any subgroup of compounds of formula (I) specified herein, wherein W is thiazol-2-yl substituted with one or two C1 -6alkyl, such as methyl, ethyl, isopropyl or tert-butyl. Preferred subgroups of the compounds of formula

(I) are those compounds of formula (I), or any subgroup of compounds of formula (I) specified herein, wherein W is selected from the following structures:

Embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein R10 and R11, independently of each other are hydrogen, halo, nitro, carboxyl, C1-6alkyl, C1-6alkoxy, C1-6alkylcarbonyl, C1-6alkoxycarbonyl, C1-6alkylthio, polyhaloC1-6alkyl, cyano, aryl or Het.

Embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of

Formula (I) wherein R10 and R11, independently of one another, are hydrogen, halo, nitro, carboxyl, methyl, ethyl, isopropyl, tert-butyl, methoxy, ethoxy, isopropoxy, tert-butoxy, methylcarbonyl, ethylcarbonyl, isopropylcarbonyl , tert-butylcarbonyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, methylthio, ethylthio, isopropylthio, tert-butylthio, trifluoromethyl or cyano.

Preferred embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein one of R10 and R11 is hydrogen.

Preferred embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein one of R10 and R11 is halo (in particular fluoro), trifluoromethyl or C1-6alkyl (in particular methyl), Other preferred embodiments are those in which one of R10 and R11 is halo (in particular fluoro), trifluoromethyl or methyl, and the other of R10 and R11 is hydrogen.

Preferred embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein one of R10 and R11 is in position for with respect to group W. Additional preferred embodiments are compounds of formula ( I) or any of the subgroups of compounds of formula (I) wherein one of R10 and R11 is halo (in particular fluoro), trifluoromethyl or methyl, and is in position for

5 with respect to group W; the other of R10 and R11 may be as defined above or may be hydrogen.

Embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein

(a) R2 is -NHR5c, in particular where R5c is C1-6alkyl, aryl, Het, C1-6alkoxy, -O-aryl, or -O-Het;

(b) R2 is -OR6, in particular where R6 is C1-6alkyl, such as methyl, ethyl, or tert-butyl and preferably where R6 is hydrogen;

(C)

R2 is -NHS (= O) 2R8, in particular where R8 is C1-6alkyl, C3-C7cycloalkyl optionally substituted with C1-6alkyl, or aryl, e.g. wherein R8 is methyl, cyclopropyl, methylcyclopropyl, or phenyl;

(d)

R2 is -C (= O) OR6, -C (= O) R7, -C (= O) NR5aR5b, or -C (= O) NHR5c, where R5a, R5b, R5c, R6, or R7 are as defined above, and R2 is preferably -C (= O) NHR5c, wherein R5c is cyclopropyl;

15 (e) R2 is -NHS (= O) 2NR5aR5b, in particular where R5a and R5b are each independently hydrogen, C3-7cycloalkyl or C1-6alkyl, e.g. -NHS (= O) N (C1-3alkyl) 2.

Additional embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein R2 is -NHR5c, and R5c is a Het group selected from

Additional embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein R2 is -NHR5c, and R5c is a C1-6 alkyl substituted with -C (= O) OR6.

Additional embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein

25 (a) R3 and R4 are both hydrogen;

(b)

 R3 and R4 are both C1-6alkyl;

(C)

R3 and R4, considered together with the carbon atom to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group.

Compounds of formula (I) that have a double or single bond in the macrocycle (ie between carbon atoms 7 and 8), represented by formula (Id) or (Ie) hereinafter, are constituted by three building blocks P1, P2, P3. The building block P1 additionally contains a tail P1 '.

The bonding of the building blocks P1 with P2, P3 with P2, and optionally P1 with P1 ', implies formation of an amide bond. The linking of the building blocks P1, P1 ', P2 and P3 to prepare compounds (I-d) or (I-c) can be performed in any given sequence. One of the steps involves a cyclization by which the macro is formed

35 cycle Compounds of formula (I-e) can be prepared from compounds of formula (I-b) by double bond reduction:

It should be understood that the synthesis procedures described hereinbelow are applicable to both racemates, stereochemically pure intermediates or final compounds, as well as to any mixtures of stereoisomers. Racemates or stereochemical mixtures can be separated into this form.

5 reoisomers at any stage of the synthesis procedures. In one embodiment, the intermediate compounds and final products have the stereochemistry specified above in the compounds of formula (I-a).

In one embodiment, the compounds (I-d) are prepared by first forming the amide bonds and subsequently forming the double bond link P3 and P1 with concomitant cyclization to form the macrocycle.

In a preferred embodiment, the compounds (I) wherein the bond between C7 and C8 is a double bond, which are composed of formula (Ia), as defined above, can be prepared as outlined in the following reaction scheme :

The formation of the macrocycle can be carried out by a reaction of olefin metathesis in the presence of a suitable metal catalyst such as e.g. the Ru-based catalyst consigned by Miller. S.J. Blackwell, H.E.,

15 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.

Air-stable ruthenium catalysts such bis (tricyclohexylphosphine) -3-phenyl-1H-inden1-ylidene-ruthenium (Neolyst M1®) chloride or bis (tricyclohexylphosphine) [(phenylthio) methylene] ruthenium (IV) dichloride can be used. Other catalysts that can be used are first and second generation Grubbs catalysts, that is benzylidenobis (tricyclohexylphosphine) dichlororrutenium and (1,3-bis- (2,4,6-trimethylphenyl) -2-imidazolidinylidene) -dichloro (phenylmethylene ) (tricyclohexylphosphine) ruthenium, respectively. Of particular interest are the first and second generation Hoveyda-Grubbs catalysts, which are dichloro (o-isopropoxyphenylmethylene) (tricyclohexylphosphine) -ruthenium (II) and 1,3-bis- (2,4,6-trimethylphenyl) -2-imid- azolidinylidene) dichloro (o-isopropoxyphenylmethylene) ruthenium, respectively. They can also

Other catalysts containing other transition metals such as Mo. be used for this reaction.

Metathesis reactions can be conducted in a suitable solvent such as for example ethers, e.g. THF, dioxane; halogenated hydrocarbons, e.g. dichloromethane, CHCl3, 1,2-dichloroethane and the like. In a preferred embodiment, the metathesis reaction is conducted in toluene. These reactions are carried out at elevated temperatures under nitrogen atmosphere.

Compounds of formula (I) wherein the link between C7 and C8 in the macrocycle is a single bond, that is compounds of formula (Ie), can be prepared from compounds of formula (Id) by a double bond reduction C7-C8 in the compounds of formula (Ia). This reduction can be effected by catalytic hydrogenation with hydrogen in the presence of a noble metal catalyst, such as, for example, Pt, Pd, Rh, Ru or nickel Ra

5 ney. Presents Rh interest on alumina. The hydrogenation reaction is preferably carried out in a solvent such as, e.g., an alcohol such as methanol, ethanol, or an ether such as THF, or mixtures thereof. Water can also be added to these solvents or solvent mixtures.

The group R2 can be connected to the block P1 was constructed at any stage of the synthesis, ie before or after the cyclization, or before or after the cyclization and reduction as described earlier in this memoir. The compounds of formula (I) wherein R2 represents -NR5aR5b, -NHR5c, -NHSOpNR5aR5b, -NR5aSOpR8, these groups being collectively represented by -NR2-aR2-b, compounds represented by the formula (Id-1), can be represented Prepare by linking the group R2 to P1 by forming an amide bond between both moieties. Similarly, the compounds of formula (I) wherein R2 represents -OR6, that is to say the compounds (I-d-2), can be prepared by joining the group R2 to P1 by forming an ester bond. In one embodiment, the groups -NR2-aR2-b u

OR6 are introduced in the last step of the synthesis of the compounds (I) as outlined in the following reaction schemes where G represents a group:

The intermediate compound (III) can be coupled to the amine (IV-a) by an amide formation reaction such as any of the methods for forming an amide bond described later herein. In particular, (III) can be treated with a coupling agent, for example, N, N'-carbonyl diimidazole (CDI). EEDQ, IIDQ. EDCI, or benzotriazol-1-yl-oxy-3-pyrrolidine-phosphonium hexafluorophosphate (commercially available as Py-BOP®), in a solvent such as an ether, e.g. THF, a halogenated hydrocarbon, e.g. dichloromethane, chloroform,

Dichloroethane, followed by reaction with the desired (IV-a), preferably after the reaction of (III) with the coupling agent. The reactions of (III) with (IV-a) are preferably carried out in the presence of a base, for example a trialkylamine such as triethylamine or diisopropylethylamine, or 1,8-diazabicyclo [5,4,0] undec-7- eno (DBU). The intermediate compound (III) can also be converted into an activated form, e.g. an activated form of the general formula G-CO-Z, wherein Z represents halo, or the remainder of an active ester, e.g. Z is an aryloxy group such co

30 m or phenoxy, p-nitrophenoxy, pentafluorophenoxy, trichlorophenoxy, pentachlorophenoxy and the like; or Z can be the rest of a mixed anhydride. In one embodiment, G-CO-Z is an acid chloride (G-CO-Cl) or a mixed acid anhydride (G-CO-O-CO-R or G-CO-O-CO-OR, where R in the last eg C1-4alkyl, such as methyl, ethyl, propyl, i.propyl, butyl, t.butyl, i.butyl, or benzyl). The activated form G-CO-Z is reacted with the desired (IV-a).

Activation of the carboxylic acid in (III) as described in the above reactions can lead to an internal cyclization reaction to give an intermediate azalactone of formula

wherein L, R1, R3, R4, n are as specified above and where the stereogenic centers may have the stereochemical configuration specified above, for example as in (I-a) or (I-b). The intermediate compounds (III-a) can be isolated from the reaction mixture, using conventional methodology, and the isolated intermediate (III-a) is then reacted with (IV-a), or the reaction mixture containing ( III-a) can be reacted further with (IV-a) without isolation from (III-a). In one embodiment, where the reaction with the coupling agent is conducted in a solvent immiscible with water, the reaction mixture containing (IIIa) can be washed with water or with slightly basic water in order to remove all soluble by-products. in water The washed solution thus obtained can then be reacted with (IV-a) without purification steps adi

10 regionals. On the other hand, the isolation of the intermediate compounds (III-a) can provide certain advantages in that the isolated product, after further optional purification, can be reacted with (IV-a), resulting in fewer secondary products and an easier reaction finish.

The intermediate compound (III) can be coupled with the alcohol (IV-b) by an ester formation reaction. For example, (III) and (IV-b) are reacted with water removal either physically, e.g. by azeotropic removal of water, or chemically using a dehydrating agent. The intermediate compound (III) can also be converted into an activated form G-CO-Z, such as the activated forms mentioned above, and then reacted with the alcohol (IV-b). Ester formation reactions are preferably conducted in the presence of a base such as an alkali metal carbonate or hydrogen carbonate, e.g. sodium or potassium hydrogen carbonate, or a tertiary amine such as the amines mentioned herein in relation to the formation reactions of

20 amide, in particular a trialkylamine, e.g. triethylamine Solvents that can be used in ester formation reactions comprise ethers such as THF; halogenated hydrocarbons such as dichloromethane, CHCl3; hydrocarbons such as toluene; polar aprotic solvents such as DMF. DMSO DMA; and analogous solvents.

Compounds of formula (I) wherein R2 represents hydrogen, that is, compounds (I-d-4), can be pre

Stopping from the esters (Id-2-a), which are intermediate compounds of formula (Id-2) wherein R6 is C1-4alkyl, can be obtained by a reduction reaction to give the corresponding alcohols (Id- 3), eg with a complex metal hydride such as LiAlH4 or NaBH4, followed by an oxidation reaction with a mild oxidant, e.g. with MnO2, thus obtaining the intermediate compounds (I-d-4):

The compounds of formula (I) can also be prepared by reacting an intermediate compound (V) with intermediate compounds (VI-a) - (VI-e) as described in the following reaction scheme where the various radicals have the meanings specified above and C1-4Alk represents C1-4alkanediyl:

In (VI-a), X represents hydroxy or a labile group such as a halide, e.g. bromide or chloride, or an arylsulfonyl group,

e.g. mesylate, triflate or tosylate and the like.

In one embodiment, the reaction of (V) with (VI-a) is an arylation reaction in O and X represents a labile group. This reaction can be conducted following the procedures described by E.M. Smith et al, (J. Med. Chem, (1988), 31, 875-885). In particular, this reaction is conducted in the presence of a base, preferably a strong base, in an inert solvent in the reaction, e.g. one of the solvents mentioned for the formation of an amide bond.

In a particular embodiment, the starting material (V) is reacted with (VI-a) in the presence of a base that is strong enough to subtract a hydrogen from the hydroxy group, for example an alkali metal hydride alkali such as LiH or sodium hydride, or an alkali metal alkoxide such as sodium or potassium methoxide or ethoxide, potassium tert-butoxide, in an inert solvent in the reaction such as an aprotic dipolar solvent, eg DMA DMF and the like. The resulting alcoholate is reacted with the arylating agent (VII), wherein X is a suitable labile group as mentioned above. The conversion of (V) into (I) using this type of O-arylation reaction does not change the stereochemical configuration in the carbon carried by the hydroxy group or -L-R1.

Alternatively, the reaction of (V) with (VI-a) can also be conducted by a reaction of Mitsunobu (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 treatment of intermediate (V) with (VI-a) wherein X is hydroxyl, in the presence of triphenylphosphine and an activating agent such as a dialkyl azocarboxylate, e.g. diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD) or the like. The Mitsunobu reaction changes the stereochemical configuration in the carbon carried by the hydroxy group or -L-R1.

Compounds of formula (I) wherein L is a urethane group (L is -OC (= O) -NR5a-) can be prepared by reacting (V) with (VI-b) or (VI-c) in the presence of a carbonyl introducing agent. The latter comprise reagents such as phosgene or phosgene derivatives such as carbonyl diimidazole (CDI). In one embodiment, (V) is reacted with phosgene thus providing the corresponding chloroformate which, by reaction with an amine, R1-NH2, or H-NR1R5a, provides carbamates, that is, L is -OC (= O) NH- or -OC (= O) NR5a-. The reactions of the chloroformate with the amine are preferably conducted using the same solvents and bases as those mentioned for an amide bond formation, mentioned hereinafter, in particular those mentioned in relation to the reaction of (III) with (IV- to). Particular bases are alkali metal carbonates or hydrogen carbonates, e.g. sodium or potassium hydrogen carbonate, or tertiary amines, such as a trialkylamine, e.g. triethylamine

The reaction of alcohol (V) with an acid (VI-d) produces esters, that is, L is -O-C (= O) -. This ester formation reaction can be conducted using procedures similar to those described for the reaction of (III) and (IV-b). In particular, the acid (VI-d) becomes a corresponding acylating agent, e.g. an acid anhydride or acid halide, e.g. an acid chloride (R1-C (= O) Cl).

Compounds of formula (I) wherein L is -O-C1-4alkanediyl-, can be prepared by an ether formation reaction with (VI-e). The formation of ethers can be by azeotropic removal of water, or chemically, e.g. by a reaction from Williamson.

Alternatively, in order to prepare the compounds of formula (I), an amide bond is first formed between the building blocks P2 and P1, followed by coupling of the building block P3 to the remainder P1 in P1-P2, and a subsequent formation of amide bond between P3 and the remainder P2 in P2-P1-P3 with concomitant ring closure, Again, the tail P1 'can be attached 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 coupling of the building blocks P3 and P2 and the concomitant ring closure.

Another alternative synthesis 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 P3, and final formation of the amide bond between P1 and P2 with concomitant ring closure, A again, the tail P1 'can be attached to the building block P1 at any stage of the synthesis of the compounds of formula (I), that is to say in the present case, before or after the coupling of the building blocks P2 and P3; before or after the coupling of the building blocks P1 and P3; before or after the coupling of P1 and P2 with concomitant ring closure.

The building blocks P1 and P3 can be joined by double bond formation on carbons 7 and 8, if desired, followed by a reduction of the double bond C7-C8. The block P1-P3 thus formed can be coupled to the building block P2 and subsequently cycled, by formation of amide bonds. In a preferred embodiment, the building block P1-P3 is not reduced and is coupled as such with P2 and cycled, providing compounds (I1).

The building blocks P1 and P3 in any of the previous approaches can be joined by double bond formation, e.g. by the olefin metathesis reaction described hereinafter, or by a Wittig type reaction.

The individual building blocks can be prepared first and then coupled to each other or, alternatively, the precursors of the building blocks can be coupled to each other and modified at a later stage to give the desired molecular composition.

The functionalities in each of the building blocks can be protected in order to avoid side reactions.

The formation of amide bonds can be carried out using standard procedures such as those used for amino acid coupling in peptide synthesis. The latter involves the dehydrating coupling of a carboxyl group of a reactant with an amino group of the other reactant to form an amide bond bond. The amide bond formation can be performed by reacting the starting materials in the presence of a coupling agent or by converting the carboxyl functionality into an active form such as an ester, mixed anhydride or active carboxylic acid chloride or bromide. General descriptions of such coupling reactions and the reagents used therein can be found in general textbooks about 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 carbonic-carboxylic acid anhydride (isobutyl chloroformate) method, the carbodiimide (dicyclohexylcarbodiimide, diisopropylcarbodiimide, or water soluble carbodiimide method such as N-ethyl-N '- [(3dimethylamino) propyl] carbodiimide), the active ester method (p-nitrophenyl ester, N-hydroxysuccinic imido-ester), the Woodward K reagent method, the 1,1- method carbonyldiimidazole (CDI or N, N'-carbonyldiimidazole), phosphorus reagents, or oxidation-reduction methods. Some of these methods can be improved by the addition of suitable catalysts, e.g. in the carbodiimide method by adding 1-hydroxybenzotriazole. DBU (1,8diazabicyclo [5,4,0] undec-7-ene), or 4-DMAP. Additional 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- (1H-benzotriazol-1-yl) -N, N, N ', N'-tetra-methyluronium tetrafluoroborate, or O- (7-azabiciclotriazol-1-yl) N, N, N', N'-tetramethyluronium. These coupling reactions can be carried out in solution (liquid phase) or in solid phase.

A preferred amide bond formation is carried out using N-ethyloxycarbonyl-2-ethyloxy-1,2-dihydroquinoline (EEDQ) or N-isobutyl-carbonyl-2-isobutyl-1,2-dihydroquinoline (IIDQ). Unlike the classic anhydride procedure. EEDQ and IIDQ do not require base or low reaction temperatures. Typically, the process involves 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 left under stirring at room temperature.

Coupling reactions are preferably conducted in an inert solvent, such as halogenated hydrocarbons, e.g. dichloromethane, chloroform, aprotic dipole solvents such as acetonitrile, dimethylformamide, dimethylacetamide. DMSO, HMPT. ethers such as tetrahydrofuran (THF).

In many cases, the coupling reactions are carried out in the presence of a suitable base such as a tertiary amine, e.g. triethylamine, diisopropylethylamine (DIPEA), N-methyl-morpholine, N-methylpyrrolidine, 4-DMAP or 1,8-diazabicyclo [5,4,0] undec-7-ene, (DBU). The reaction temperature can reach between 0 ° C and 50 ° C and the reaction time can be between 15 minutes and 24 h.

Functional groups in the building blocks that are attached to each other can be protected to prevent the formation of undesirable bonds. Appropriate protective 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, 9. Academic Press, New York (1987).

Carboxyl groups can be protected as an ester that can be cleaved to give the carboxylic acid. Protective groups that may be used include 1) alkyl esters such as methyl, trimethylsilyl and tert-butyl; 2) alkylaryl esters such as benzyl and substituted benzyl; or 3) esters that can be cleaved by a weak base or moderate reducing means such as trichlorethyl and phenacyl esters.

The amino groups can be protected by a variety of N-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, as well as 9-fluorenylmethyloxycarbonyl (Fmoc);

3) aliphatic carbamate groups such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and aryloxycarbonyl;

4)

cyclic alkylcarbamate 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; Y

7)

thiol-containing groups such as phenylthiocarbonyl and dithiasuccinoyl,

Interesting amino protecting groups are Boc and Fmoc.

Preferably, the amino protecting group is cleaved before the next coupling step. The removal of the N protecting groups can be performed following procedures known in the art. When the Boc group is used, the methods of choice are trifluoroacetic acid, pure or dichloromethane, or HCl in dioxane or ethyl acetate. The resulting ammonium salt is then neutralized either before coupling or in situ with basic solutions such as aqueous buffers, 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, usually around 15-25 ° C, or 20-22 ° C,

Other functional groups that can interfere with the coupling reactions of the building blocks can also be protected. For example, hydroxyl groups can be protected as benzyl ethers or substituted benzyl ethers, e.g. 4-methoxybenzyl ether, benzoyl esters or substituted benzoyl esters, e.g. 4-nitrobenzoyl ester, or with trialkylsilyl groups (e.g. trimethylsilyl or tert-butyldimethylsilyl).

Additionally, amino groups can be protected by protective groups that can be selectively cleaved. For example, when Boc is used as the α-amino protecting group, the following side chain protecting groups are suitable: p-toluenesulfonyl (tosyl) moieties can be used to protect additional amino groups; Benzyl (Bn) ethers can be used to protect hydroxy groups; and benzyl esters can be used to protect additional carboxyl groups, or, when Fmoc is selected for α-amino protection, tert-butyl based protecting groups are usually acceptable. For example, Boc can be used for additional amino groups; tert-butyl ethers for hydroxyl groups; and tert-butyl esters for additional carboxyl groups.

Any of the protecting groups can be removed at any stage of the synthesis procedure, but preferably the protecting groups of any of the functionalities not involved in the reaction steps are removed after the macrocycle formation is complete. The removal of the protective groups can be carried out in any manner dictated by the choice of the protective groups, ways that are well known to those skilled in the art.

The intermediate compounds of formula (II) can be prepared by reacting an intermediate compound (VII) with an alkene carboxylic acid or a derivative thereof (VIII) as described in the following reaction scheme:

The intermediate compound (VII) is reacted with the alkenyl acid (VIII) by applying the reaction procedures for amide bond formation described above.

Intermediates (II) may alternatively be prepared as follows:

PG1 is an O-protecting group, which can be any of the groups mentioned herein and in particular it is a benzoyl or substituted benzoyl group such as 4-nitrobenzoyl.

The reaction of (VIII) with (IX) produces the intermediate compounds (X), these are deprotected using particular

10 the reaction conditions mentioned above. For example, where PG1 is benzoyl or substituted benzoyl, this group is removed by reaction with an alkali metal hydroxide (LiOH, NaOH, KOH), in particular where PG1 is 4-nitrobenzoyl, with LiOH, in an aqueous medium comprising water and a water soluble organic solvent such as an alkanol (methanol, ethanol) and THF. The resulting alcohol (XI) is reacted with the intermediate compounds (VI-a) - (VI-e) as described above for the reaction of (V) with (VI-a) - (VI-e) and this reaction results

Tado intermediate compounds (II).

The intermediate compounds of formula (III) can be prepared by first cyclizing the open ester (XII) to give a macrocyclic ester (XIII), which in turn is converted into the corresponding macrocyclic carboxylic acid (III) as follows:

L is as specified above, and PG2 is a carboxyl protecting group, e.g. one of the above-mentioned carboxyl protecting groups, in particular a C1-4alkyl- or benzyl ester, e.g. a methyl, ethyl or t.butyl ester. The reaction of (X) to give (XI) is a metathesis reaction and is conducted as described above. The PG2 group is removed following procedures also described above. Where PG1 is a C1-4-alkyl ester, it is separated by alkaline hydrolysis, e.g. with NaOH or preferably LiOH, in an aqueous solvent, e.g. a C1-4alcanol / water mixture, A benzyl group can be removed by catalytic hydrogenation.

In an alternative synthesis, intermediate compounds (III) can be prepared as follows:

10 The PG1 group can be removed using methodologies known in the art, e.g. methyl-or ethyl esters by treatment with an alkali metal hydroxide in an aqueous medium, t-butyl esters with weak acids and benzyl esters with strong acids or by catalytic hydrogenation. Where L is a radical (a) this sequence of reactions produces the intermediate compounds (III), These can also be prepared by elimination of L which is a protective group of O and etherification of the alcohol thus formed with an intermediate compound (VI-a) as It has been described above.

First, the intermediate compounds (XIV) are cycled to give the macrocyclic ester (XV), deprotected (XV) by removal of the PG1 group to give (XVI), after which it is reacted with the intermediate compounds ( VI-a) - (VI-e) to give intermediate compounds (XIII), followed by removal of the carboxyl protecting group PG2, obtaining the intermediate compounds (III). Cyclization, deprotection of PG1 and PG2 and coupling with (VI-a) - (VI-e) can be performed as described above.

R2 groups can occur at any stage of the synthesis, either as the last step as described above, or before, before the formation of the macrocycle. In the following scheme, the group -NR2-aR2-b is as specified above:

5 L and PG2 are as defined above and L2 is a nitrogen protecting group (PG, as defined above), or L2 is a group

where R3, R4 and n are as defined above. The intermediate compounds (XIX-a) and (XIX-b) where L1 represents a group (b) correspond to the intermediate compounds (II) and can be further processed as specified above,

10 Coupling of building blocks P1 and P2

Building blocks P1 and P2 are linked using an amide formation reaction following the procedures described above. The building block P1 may have a carboxyl protecting group PG2 (as in (XVI-a)) or it may already be linked to the group P1 '(as in (XVI-b)), L3 is hydroxy, -OPG1 or a group -L-R1 as specified above. Where in any of the following reaction schemes L3 is hydroxy, it can protect

15 be generated before each step to give an OPG1 group and, if desired, subsequently deprotected again to give a free hydroxy function. Similarly, a hydroxy function can be converted into an L-R1 group.

In the procedure of the above scheme, a cyclopropyl-amino acid (XXI-a) or (XXI-b) is coupled to the acid function of building block P2 using an amide formation reaction such as the standard peptide coupling conditions above. described. Intermediate compounds (XVII) or (XXII) are obtained. Some of the last

5 mos correspond to intermediate compounds (XIX-a) or (XIX-b) in the previous reaction scheme. The removal of the acid protection group in (XVII), using the appropriate conditions for the protective group used, followed by coupling with an amine HNR2-aR2-b (IV-a) or with HOR6 (IV-b) as has been described above, it produces again the intermediate compounds (XXII), wherein -COR2 are amide or ester groups.

In one embodiment, L2 is a group (b) and these reactions involve coupling of P1 to P2-P3, which gives as

10 the intermediate compounds (X) or (II) mentioned above result. In another embodiment, L2 is a PG protective group of N, which is as specified above, and the coupling reaction results in an intermediate compound (XXII-a), from which the PG group can be removed by obtaining the intermediate compounds ( XVII-a), which are intermediate compounds (XVII) as specified above in which L2 is hydrogen, using reaction conditions also mentioned above:

In one embodiment, PG in this reaction is a BOC group. In cases where L3 is additionally hydroxy, the starting material is Boc-L-hydroxyproline.

In the above schemes, the group L3 may be a group -O-PG1 that is introduced into a starting material (XX), wherein L3 is hydroxy. In this case, PG1 is selected such that it can be selectively cleaved.

20 to give the PG group.

Coupling of building blocks P3 and P2

The building blocks P3 and P2 are linked using an amide formation reaction following the procedures described above for the coupling of (VII) with (VIII), A general procedure is depicted in the following reaction scheme in which L3 is as specified above and L4 is a group -O-PG2, or a group

In cases where L4 in (XXIII) is a -OPG2 group, the PG2 group can be removed and the resulting acid coupled with cyclopropyl amino acids (XXI-a) or (XXI-b), obtaining intermediate compounds (XVII) or (XXII) in which 5 L2 is a radical (b).

The building blocks P1, P1 ', P2 and P3 used in the preparation of the compounds of formula (I) can be prepared from intermediate compounds known in the art. A number of such syntheses are described in more detail below.

Synthesis of P2 building blocks

10 The P2 building blocks contain a pyrrolidine moiety substituted with a group -L-R1. The group R1 can be coupled to the pyrrolidine ring at any convenient stage of the synthesis of the compounds according to the present invention. One approach is to first couple the group R1 to the pyrrolidine ring and subsequently add the other desired building blocks, it is say 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 do not carry

15 any substituent R1, with each of P1 and P3, and add the group R1 before or after the formation of the macrocycle.

The P2 building blocks can be prepared by reacting a hydroxyproline derivative (XXV) with the intermediate compounds (VI-a) - (VI-e) as described above for the synthesis of (I) from (V) . This reaction is represented in the following scheme, in which L5 is hydroxy or a group -OPG2, or L5 can represent a group

P1 such as groups (b) and (c) as specified above, and where additionally groups L2 and PG2 are as mentioned above. In one embodiment, L2 is PG, that is to say a protective group of N:

In one embodiment, the L2 group is PG, in which the latter is t.butoxycarbonyl (Boc), L5 is hydroxy and the starting material (XXV) is the commercially available Boc-hydroxyproline, or any other stereoisomeric form thereof.

25 ma, e.g. Boc-L-hydroxyproline, in particular the trans isomer of the latter.

Where L5 in (XXVI) is -OPG2, the carboxyl protecting group can be removed following procedures described above for hydroxyproline derivatives (XXVII). In one embodiment L2 is Boc and L5 is -OPG2, wherein PG2 is a lower alkyl ester, in particular a methyl or ethyl ester. Hydrolysis of the last ester to give the acid can be carried out by standard procedures, e.g. acid hydrolysis with hydrochloric acid in methanol or ethanol with a

30 alkali metal hydroxide such as NaOH, in particular with LiOH.

Intermediates (VI-a), (VI-b), (VI-c), (VI-d) and (VI-e) are the compounds known in the art or can be prepared following methods known in the art with use of known starting materials.

Intermediate compounds (VI-a) that are quinoline derivatives, such as those in which L1 is a radical (d-1), (d-2), (d-3), (d-4), (d -4a), (d-5), or (d-5a) as specified above, can be prepared as shown below:

The Friedel-Crafts acylation of a 3-methoxyaniline (XXVIII), commercially available or by methods known in the art, using an acylating agent such as acetyl chloride or the like in the presence of one or more Lewis acids such as trichloride. Boron and aluminum trichloride in a solvent such as dichloromethane, provides (XXIX). The coupling of (XXIX) with 4-isopropyl-thiazol-2-carboxylic acid (XXX), preferably under basic conditions, for example in pyridine, in the presence of an activating agent for the carboxylate group, by

POCl3 example, followed by ring closure and dehydration under basic conditions such as potassium tert-butoxide in tert-butanol provides the quinoline derivative (VI-a-1). The latter can become (VI-a-2) where LG is a labile group, e.g. by reacting (VI-a-1) with a halogenating agent, for example phosphoryl chloride or the like, or with an aryl sulfonyl chloride, e.g. with tosyl chloride.

Substituted anilines (XXVIII) are commercially available or can be prepared from a benzoi acid

Suitable substituted co (XXXII), which is reacted with diphenylphosphoryl azide at elevated temperature and subsequently treated with a C1-4 alkanol, in particular t-butanol, providing C1-4alkoxycarbonylamines such as the compound (XXXIII). Deprotection of the compound (XXXIII) provides the substituted anilines (XXVIII).

Alternatively, substituted anilines (XXVIII) can be prepared from the corresponding substituted nitrobenzenes by reduction of the latter with elemental zinc, tin or iron in the presence of an acid.

In the above synthesis a variety of carboxylic acids with the general structure (XXX) can be used. These acids are commercially available or can be prepared by methods known in the art, An example of the preparation of aminocarboxyaminethiazole derivatives substituted in position 2, following the procedure described by Berdikhina et al, in Chem. Heterocycl. Compd, (English translation) (1991), 427-433, shown

25 in the following reaction scheme illustrating the preparation of 2-carboxy-4-isopropyl-thiazole (XXX-a): Ethyl thiooxamate (XXXIV) is reacted with β-bromoketone (XXXV) to form the acid ester thiazolylcarboxylic acid (XXXVI) which is hydrolyzed to give the corresponding acid (XXX-a). The ethyl ester in these intermediates can be replaced by other PG2 carboxyl protecting groups, as defined above.

Bromoketone (XXXV) can be prepared from 3-methyl-butan-2-one (MIK) with a silylating agent (such as TMSCl) in the presence of a suitable base (in particular LiHMDS) and bromine.

Intermediates (XXVIII) having a methoxy substituent, intermediates represented by the formula (XXVIII-a), can be prepared as described by Brown et al ,, J. Med. Chem, 1989, 32, 807 -826, or as outlined in the following scheme:

The starting materials ethylacetyl acetate and ethoxymethylene malononitrile, which are commercially available, are reacted in the presence of a suitable base, such as sodium ethoxide, and a solvent, such as ethanol and the like. This reaction provides the intermediate compound (XXXVI). The latter is hydrolyzed, e.g. with a base such as an alkali metal hydroxide, e.g. NaOH or LiOH, in a suitable solvent such as ethanol / water to produce (XXXVII). Decarboxylation of the intermediate compound (XXXVII) to give the intermediate compound (XXXVIII) is carried out at elevated temperature until effervescence ceases, preferably in the presence of a basic solvent such as quinoline. Methylation of the intermediate compound (XXXVIII), in particular with a methylating agent such as MeI in the presence of a suitable base (e.g. K2CO3) in a suitable solvent (such as DMF and the like) provides (XXXIX). The latter is reacted with a Grignard reagent such as MeMgBr in pre

Sequence of a suitable solvent (e.g. THF), followed by hydrolysis, for example with aqueous HCl, providing the intermediate compound (XXVIII-a).

The Synthesis of the additional carboxylic acids (XXX), in particular of substituted aminothiazole carboxylic acids (XXX-b) is illustrated below:

Thioureas (XLII) can be formed with various R 'alkyl substituents by reaction of the appropriate amine (XL) with tert-butyl isothiocyanate in the presence of a base such as diisopropylethylamine in a solvent such as dichloromethane, followed by removal of the tert-butyl group in acid conditions. Subsequent condensation of the thiourea derivative (XLII) with 3-bromopyruvic acid provides thiazole carboxylic acid (XXX-b).

The compounds of the present invention or building blocks P2 in which a heterocyclic group R1 is linked by a nitrogen atom directly to the pyrrolidine ring, that is L is a direct bond in the general formula (I), can be prepared by example by use of a substitution reaction in which a suitable labile group in the pyrrolidine ring is replaced by a cyclic group containing nitrogen. This can be done at the stage of the building block or after assembly and / or cycling of the building blocks. In one process, the pyrrolidine derivative (V), (XI), (XVI), (XXV) or any intermediate compound having an L3 group that is hydroxy is reacted with a reagent that introduces a labile group, for example with a halogenating agent, such as phosphoryl chloride or the like, or with an arylsulfonyl chloride, eg with tosyl chloride. The intermediate thus formed is then reacted with a heterocycle having a substituted nitrogen.

10 with hydrogen in the ring (ie N-H).

The compounds of formula (I) wherein L is a direct bond and R1 is a ring system connected to the pyrrolidine moiety by a carbon atom can be prepared by constructing the ring from the hydroxylated compounds. This can be done at the stage of the building blocks or after assembly and / or cycling of the building blocks. For example, the hydroxy function can be converted into a labile group that is substituted in turn by a cyano group. This cyano group can subsequently become the desired heterocycles. For example, compounds in which a tetrazole derivative is linked through a carbon atom of the tetrazole ring are conveniently prepared by constructing the tetrazole moiety directly on the pyrrolidine ring precursor. This can be achieved, for example, by condensation of the cyano group thus introduced followed by reaction with an azide reagent such as sodium azide. Triazole direc derivatives can also be constructed

20 on the nitrogen ring precursor, for example, by transformation of the hydroxy group of the nitrogen ring precursor into an azide group followed by a 3 + 2 cycloaddition reaction of the azide obtained with a suitable alkyne derivative.

Structurally diverse derivatives for use in the above reactions in order to introduce an R1 group can be prepared by reacting commercially available nitrile compounds with sodium azide. The triazole derivatives can be prepared by reacting an alkyne compound and trimethylsilyl azide. Useful alkyne compounds are commercially available or can be prepared for example by the Sonogashira reaction, ie the reaction of a primary alkyne, an aryl halide and triethylamine in the presence of PdCl2 (PPh) 3 and CuI as described for example in A Elangovan, Y.-H. Wang, T.-I. Ho, Org. Lett ,, 2003, 5, 1841-1844. The heterocyclic substituent can also be modified when it is attached to the building block P2 before or after the coupling of the block.

30 that of construction P2 to the other building blocks.

Additional alternatives for the preparation of compounds in which L is a bond and R1 is an optionally substituted heterocycle can be found for example in WO2004 / 072243.

Synthesis of building blocks P1

The cyclopropane-amino acid used in the preparation of the P1 fragment is commercially available or can be prepared using methods known in the art,

The amino-vinyl cyclopropyl-ethyl ester (XXI-a) can be obtained according to the procedure described in WO00 / 09543 or as illustrated in the following scheme, in which PG2 is a carboxyl protecting group as specified above. :

The treatment of commercially available or readily obtainable imine (XLIII) with 1,4-dihalobutene in the presence of a base produces (XLIV) which, after hydrolysis, provides the cyclopropyl amino acid (XXI-a), which has the substituent allyl in syn position with respect to the carboxyl group. The resolution of the mixture of enantiomers (XXI-a) results in (XXI-a-1). Resolution is performed using methods known in the art such as enzymatic separation; crystallization with a chiral acid; or chemical derivatization; or by chiral column chromatography. The intermediate compounds (XXI-a) or (XXI-a-1) can be coupled to the appropriate proline derivatives as described above.

The introduction of a PG protective group of N and elimination of PG2 results in cyclopropyl-amino acids (XXI-c) which become the amides (XXI-b-1) or esters (XXI-b-2) as described in the following reaction scheme, in which R2-a, R2-b and PG are as specified above.

The reaction of (XXI-c) with the amine (IV-a) is an amide formation process. The similar reaction with (IVb) is an ester formation reaction. Both can be done following the procedures described above. This reaction provides the intermediate compounds (XXI-d-1) or (XXI-d-2) from which the pro group is removed

10 amino tector by standard methods as described above. This in turn results in the desired intermediate compound (XXI-b-1). The starting materials (XXI-c) can be prepared from the intermediate compounds (XXI-a) by first introducing an N protective PG group and subsequent elimination of the PG2 group.

In particular, the reaction of (XXI-c) with (IV-a) is carried out by treating the amino acid with a coupling reagent

15, for example N, N'-carbonyl diimidazole (CDI) or the like in a solvent such as THF followed by reaction with (IV-a) in the presence of a base such as 1,8-diazabicyclo [5,4,0 ] undec-7-eno (DBU). Alternatively, the amino acid can be treated with (IV-a) in the presence of a base such as diisopropylethylamine followed by treatment with a coupling agent such as benzotriazol-1-yl-oxy-tris-pyrrolidine-phosphonium hexafluorophosphate (commercially available as PyBOP® ) to effect the introduction of the sulfonamide group.

The intermediate compounds (XXI-b-1) or (XXI-b-2) can in turn be coupled to the appropriate proline derivatives as described above.

Synthesis of P3 building blocks

P3 building blocks are commercially available or can be generated according to methodologies known to those skilled in the art. The following scheme illustrates the preparation of building blocks

25 P3.

The ester (XLV) can be transformed into the corresponding acid (IX) by hydrolysis in the presence of an acid or a base, R3, R4 and n are as defined above.

The coupling of the appropriate building block P3 to the remainder P2-P1 or to the remainder P2 can only be carried out by forming an amide bond as explained above (reaction of (XXIII) with (IX)).

The coupling of a building block P3 to a residue P1 alone (with or without the tail P1 ') can be achieved by an olefin metathesis reaction as described hereinbefore,

The compounds of formula (I) can be converted into one another following functional group transformation reactions known in the art,

The compounds of formula (I) can be converted into the corresponding N-oxide forms following procedures known in the art to convert a trivalent nitrogen into its N-oxide form. Said oxidation reaction in N can generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or alkaline earth metal peroxides, e.g. sodium peroxide, potassium peroxide; Appropriate organic peroxides may comprise peroxyacids such as, for example, benzenecarboperoxoic acid or halosubstituted benzenecarboperoxoic acid, e.g. 3-Chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkyl hydroperoxides, e.g. tert-butyl hydroperoxide. Suitable solvents are, for example, water, lower alcohols e.g. ethanol and the like, hydrocarbons e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons e.g. dichloromethane, and mixtures of such solvents.

Pure stereochemically isomeric forms 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 selective crystallization and chromatographic techniques, e.g. countercurrent distribution, liquid chromatography and the like.

The compounds of formula (I) can be obtained as racemic mixtures of enantiomers that can be separated from one another following resolution procedures known in the art. The racemic compounds of formula (I) that are sufficiently basic or acidic can be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid, especially a chiral base. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization, and the enantiomers are released therefrom by means of alkali or acid. An alternative way of separating the enantiomeric forms of the compounds of formula (I) implies liquid chromatography, in particular liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction proceeds stereospecifically. Preferably, if a specific stereoisomer is desired, said compound can be synthesized by stereospecific methods of preparation. These methods can advantageously use enantiomerically pure starting materials.

In a further aspect, the present invention concerns a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as specified herein, or a compound of any of the subgroups of compounds of formula (I) as are specified herein, and a pharmaceutically acceptable carrier, A therapeutically effective amount in this context is an amount sufficient to act prophylactically against, stabilize or reduce viral infection, and in particular HCV viral infection, in infected individuals or individuals who They are at risk of being infected. In a further aspect, this invention relates to a process of preparing a pharmaceutical composition as specified herein, comprising intimately 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 subgroups of compounds of formula (I) as specified herein.

Accordingly, the compounds of the present invention or any subgroup thereof can be formulated in various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemic administration of drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in the form of an addition salt or metal complex, as the active ingredient, is combined in intimate admixture with a pharmaceutically acceptable carrier, which vehicle can take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unit dosage form suitable, particularly, for oral, rectal, percutaneous or parenteral injection administration. For example, in the preparation of the compositions in oral dosage form, any of the usual pharmaceutical means such as, for example, water, glycols, oils, alcohols and the like can be used in the case of liquid oral preparations such as suspensions, syrups , elixirs, emulsions and solutions; or solid vehicles such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Due to their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical vehicles are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, although other ingredients may be included, for example, to favor solubility. For example, injectable solutions in which the vehicle comprises saline solution, glucose solution or a mixture of saline solution and glucose solution can be prepared. Injectable suspensions may also be prepared, in which case suitable liquid vehicles, suspending agents and the like can be used. Preparations are also included in solid form which are intended to become, shortly before use, preparations in liquid form. In the compositions suitable for percutaneous administration, the vehicle optionally comprises a penetration enhancing agent and / or a suitable moisturizing agent, optionally combined with suitable additives of any nature in smaller proportions, additives that do not introduce a significant deleterious effect on the skin.

The compounds of the present invention can also be administered by oral inhalation or insufflation by 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, a solution being preferred. Any systems developed for the delivery of solutions, suspensions or dry powders by oral inhalation or insufflation are suitable for the administration of the present compounds,

Thus, the present invention also provides a pharmaceutical composition adapted for administration by inhalation or insufflation through the mouth comprising a compound of formula (I) and a pharmaceutically acceptable carrier. The compounds of the present invention can be administered by inhalation of a solution in nebulized or aerosolized doses.

It is especially advantageous to formulate the pharmaceutical compositions mentioned above in unit dosage form for ease of administration and uniformity of dosage. The term "unit dose form", as used herein, refers to physically discrete units suitable as unit dose, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical vehicle. Examples of such unit dose forms are tablets (including grooved or coated tablets), capsules, pills, suppositories, powder packs, pills, injectable and analogous solutions or suspensions, and segregated multiples thereof.

The compounds of formula (I) exhibit antiviral properties. Viral infections and their associated diseases that can be treated using the compounds and methods of the present invention include those infections caused by HCV and other pathogenic flaviviruses such as Yellow Fever, Dengue Fever (types 1-4), San Encephalitis Luis, 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, end-stage liver disease, and HCC, and for the other pathogenic flaviviruses the diseases include yellow fever, dengue fever, hemorrhagic fever and encephalitis. A number of the compounds of this invention are also active against mutated strains of HCV. Additionally, many of the compounds of this invention exhibit a favorable pharmacokinetic profile and have attractive properties in terms of bioavailability, including an acceptable half-life. AUC (area under the curve) and peak values, and absence of unfavorable phenomena such as insufficiently rapid onset and tissue retention.

In vitro antiviral activity against HCV of the compounds of formula (I) was tested in an HCV cell replicon system based on Lohmann et al, (1999) Science 285: 110-113, with the subsequent modifications described by Krieger et al. , (2001) Journal of Virology 75: 4614-4624 which is illustrated in greater detail in the examples section. This model, while not a complete HCV infection model, 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 as candidates for further development in the treatment of HCV infections in mammals. It will be appreciated that it is important to distinguish between compounds that specifically interfere with the functions of HCV and those that exert cytotoxic or cytostatic effects in the HCV replicon model, and as a consequence cause a decrease in HCV RNA or concentration of associated forming enzymes. . Field trials are known for the evaluation of cellular cytotoxicity based, for example, on the activity of mitochondrial enzymes using redox fluorogenic dyes such as resazurin. Additionally, there are cellular contrafilters for the evaluation of the non-selective inhibition of the activity of associated 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 gene promoter, and such cells can be used as a counter filter to eliminate non-selective inhibitors.

Due to their antiviral properties, particularly their anti-HCV properties, the compounds of formula (I) or any subgroup thereof, their N-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms are useful in the treatment. of individuals suffering from a viral infection, particularly an HCV infection, and for the prophylaxis of these infections. In general, the compounds of the present invention may 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 can therefore be used as medicaments. Said use as a medicine comprises the systemic administration to individuals infected with viruses or to individuals prone to viral infections of an amount effective to combat the conditions associated with viral infection, in particular HCV infection,

The present invention also 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, particularly HCV infection.

Also, the combination of previously known anti-HCV compounds, such as, for example, interferon-α (IFN-α), pegylated interferon-α and / or ribavirin, and a compound of formula (I) can be used as a medicament in a combination therapy The expression "combination therapy" refers to a product that necessarily contains (a) a compound of formula (I), and (b) optionally another anti-HCV compound, as a combined preparation for simultaneous, separate or sequential use in the treatment of HCV infections, in particular in the treatment of infections with HCV.

The anti-HCV compounds comprise agents selected from an HCV polymerase inhibitor, an HCV protease inhibitor, an inhibitor of another target in the HCV life cycle, and an immunomodulating agent, an antiviral agent, and combinations of the same.

HCV polymerase inhibitors include, but are not limited to, M283 (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 973, 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. Additional agents that can be used are those described in WO98 / 17679, WO00 / 056331 (Vertex); WO98 / 22496 (Roche); WO99 / 07734, (Boehringer Ingelheim), WO2005 / 073216, WO2005 / 073195 (Medivir) and structurally similar agents.

Inhibitors of other targets in the HCV life cycle, including Helicasa NS3; metalloprotease inhibitors; antisense oligonucleotide inhibitors, such as ISIS-14803. AVI-4065 and the like; siRNA's such as SIRPLEX-140-N and the like; Short-hair vector-encoded RNA (shRNA); DNAzymes; HCV specific ribozymes such as heptazyme, RPI, 13919 and the like; input inhibitors such as HepeX-C, HuMax-HepC and the like; alpha-glucosidase inhibitors such as celgosivir, UT-231B and the like; KPE-02003002; and BIVN 401.

Immunomodulatory agents include, but are not limited to: natural and recombinant interferon isoforms compounds, including α-interferon, β-interferon, γ-interferon, ω-interferon and the like, such as Intron A®, Roferon-A®, Canferon-A300®. Advaferon®, Infergen®, Humoferon®, Sumiferon MP®. Alfaferone®, IFN-beta®, Feron® and the like; derivatized (pegylated) interferon compounds with polyethylene glycol, such as PEG interferon-α-2a (Pegasys®), interferon PEG-α-2b (PG-Intron®), pegylated IFN-α-con1 and the like; long-acting formations and derivatizations of interferon compounds such as interferon-albuferone α fused with albumin and the like; compounds that stimulate the synthesis of interferon in cells, such as resiquimod and the like; interleukins; compounds that enhance the response development of type 1 adjuvant T cells, such as SCV-07 and the like; agonists of the TOLL type receptors such as CpG-10101 (Actilon), isatoribine and the like; thymosin α-1; ANA-245; ANA-246; histamine dihydrochloride; propagermanium; tetrachlorodecaoxide; ampligen; IMP-321; KRN-7000; antibodies, such as civacir, XTL-6865 and the like; and prophylactic and therapeutic vaccines such as InnoVac C, HCV E1E2 / MF59 and the like.

Other antiviral agents include, but are not limited to, ribavirin, amantadine, viramidine, nitazoxanide; telbivudine; NOV-205; taribavirin; inhibitors of internal ribosome entry; broad spectrum viral inhibitors, such as IMPDH inhibitors (eg, 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 which include, but are not limited to, 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 co-administered in combination with, for example, interferon-α (IFN-α), pegylated interferon-α and / or ribavirin, as well as treatments therapeutic based on antibodies directed against HCV epitopes, small interference RNA (Si RNA), ribozymes. DNAzymes, antisense RNA, small molecule antagonists of, for example, NS3 protease, NS3 helicase and NS5B polymerase.

In accordance with the foregoing, the present invention relates to the use of a compound of formula (I) or any subgroup thereof as defined above for the manufacture of a medicament useful for inhibiting HCV activity in a virus-infected mammal. HCV, wherein said medicament is used in a combination therapy, said combination therapy preferably comprising a compound of formula (I) and another HCV inhibitor compound, eg IFN-α (pegylated) and / or ribavirin.

In a further 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 drug metabolism and / or pharmacokinetics that improve availability. An example of such an HIV inhibitor is ritonavir.

As such, the present invention further provides a combination comprising (a) an HCV NS3 / 4a protease inhibitor of formula (I) or a pharmaceutically acceptable salt thereof; and (b) ritonavir or a pharmaceutically acceptable salt thereof.

The compound ritonavir, and its pharmaceutically acceptable salts, and methods for its preparation are described in WO94 / 14436. For preferred dosage forms of ritonavir, see US6,037,157, and the documents cited therein: US5,464,801, US08 / 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 a pharmaceutically acceptable salt thereof; and further comprises an additional anti-HCV compound selected from the compounds described herein.

In one embodiment of the present invention there is provided a process for preparing a combination as described herein, comprising the step of combining an HCV NS3 / 4a protease inhibitor of formula (I) or a pharmaceutically acceptable salt thereof. , and ritonavir or a pharmaceutically acceptable salt thereof, An alternative embodiment of the present invention provides a process in which the combination comprises one or more additional agents as described herein.

The combinations of the present invention can be used as medicaments. Said use as a medicine comprises the systemic administration to individuals infected with HCV in 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 infections or diseases associated with HCV infection in a mammal, in particular for treating conditions associated with HCV and other flavi-and pestivirus. pathogens

In one embodiment of the present invention there is provided a pharmaceutical composition comprising a combination according to any one 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 a pharmaceutically acceptable salt thereof, and (c) a pharmaceutically acceptable excipient. Optionally, the pharmaceutical composition further comprises an additional agent selected from an HCV polymerase inhibitor, an HCV protease inhibitor, an inhibitor of another target in the HCV life cycle, an agent. immunomodulator, an antiviral agent, and combinations thereof.

The compositions may be formulated in suitable pharmaceutical dosage forms, such as the dosage forms described above. Each of the active ingredients can be formulated separately and the formulations can be co-administered, or a formulation containing both active ingredients can be provided and other additional active ingredients are desired.

As used herein, the term "composition" It is intended to cover a product that comprises the specified ingredients, as well as any product that results, directly or indirectly, from the combination of the specified ingredients.

In one embodiment, the combinations provided herein can 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 in a pharmaceutical composition containing other pharmaceutically acceptable excipients, and ritonavir is separately formulated in a pharmaceutical composition containing other pharmaceutically acceptable excipients. Conveniently, these two separate pharmaceutical compositions may be part of a kit 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 therapy or simultaneously in divided combination forms.

or individual It should therefore be understood that the present invention encompasses all such simultaneous or alternating treatment regimens and the term "administer" It must be interpreted analogously. 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 a pharmaceutically acceptable salt thereof, that is sufficient to clinically improve the bioavailability of the HCV NS3 / 4a protease inhibitor of formula (I) relative to the bioavailability when said HCV NS3 / 4a protease inhibitor of formula (I) is administered alone.

In another embodiment, the combination of the present invention contains an amount of ritonavir, or a pharmaceutically acceptable salt thereof, that is sufficient to increase at least one of the pharmacokinetic variables of the HCV NS3 / 4a protease inhibitor of formula (I ) selected from t1 / 2, Cmin, Cmax, Css, AUC at 12 hours, or AUC at 24 hours, relative to said at least one pharmacokinetic variable when the NSV / NS3 protease inhibitor HCV (I) is manage alone

A further embodiment relates to a method for improving the bioavailability of an HCV NS3 / 4a protease inhibitor which comprises administering to an individual who is in need of such improvement a combination as defined herein, which comprises an amount therapeutically effective of each component of said combination.

In a further embodiment, the invention relates to the use of ritonavir or a pharmaceutically acceptable salt thereof, as an enhancer of at least one of the pharmacokinetic variables of an NSV / NS3 / 4a protease inhibitor of formula (I) selected from t1 / 2, Cmin, Cmax, Css, AUC at 12 hours, or AUC at 24 hours; with the proviso that such use is not practiced in the human or animal body.

The term "individual" As used herein, it refers to an animal, preferably a mammal, most preferably a human, that has been the object of treatment, observation or experiment.

Bioavailability is defined as the fraction of the administered dose that reaches the systemic circulation, t1 / 2 represents the half-life or time required for the plasma concentration to drop to half of its original value, Css is the steady state concentration , that is, the concentration at which the drug introduction rate is equal to the elimination rate, Cmin is defined as the lowest (minimum) concentration measured during the dosing interval, Cmax, represents the highest (maximum) concentration measured during the dosing interval. AUC is defined as the area under the plasma-time concentration curve for a defined period of time.

The combinations of this invention can be administered to humans at specific dosage ranges for each component comprised in said formulations. The components included in said combinations can be administered together or separately. The NS3 / 4a protease inhibitors of formula (I) or any subgroup thereof, and ritonavir or a pharmaceutically acceptable salt or ester thereof, may have dosage levels of 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 conveniently in the range ranging 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, as a rule from about 10: 1 to about 1:10 , and more typically from about 8: 1 to about 1: 8. Also useful are weight ratios of the HCV NS3 / 4a protease inhibitors of formula (I) to ritonavir ranging from about 6: 1 to about 1: 6, or from about 4: 1 to about 1: 4, or from about 3: 1 to about 1: 3, or from about 2: 1 to about 1: 2,

or from about 1.5: 1 to about 1: 1.5. In one aspect, the amount by weight of the HCV NS3 / 4a protease inhibitors of formula (I) is equal to or greater than that of ritonavir, wherein the weight ratio of the HCV NS3 / 4a protease inhibitor of formula (I) to ritonavir is conveniently in the range from about 1: 1 to about 15: 1, as a typical value from about 1: 1 to about 10: 1, and more typically from about 1: 1 to about 8 :one. Also useful are weight ratios of the HCV NS3 / 4a protease inhibitor of formula (I) at ritonavir between approximately

1: 1 and 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 expression "therapeutically effective amount", as used herein, means that amount of active compound or component or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is intended, in light of the present invention, by a researcher, veterinarian, medical doctor or other clinic doctor, which includes the relief of the symptoms of the disease being treated. Since the present invention relates to combinations comprising two or more agents, the "therapeutically effective amount" it is that quantity of the agents considered together such that the combined effect provokes 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 administered together, they provide a combined effect that is therapeutically effective,

In general it is contemplated that an effective daily amount as an antiviral could be from 0.01 mg / kg to 500 mg / kg body weight, more preferably from 0.1 mg / kg to 50 mg / kg body weight. It may be appropriate to administer the required dose as one, two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 1 to 1000 mg, and in particular 5 to 200 mg of active ingredient per unit dosage form,

The exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, age, weight, sex, the degree of the disorder and the general physical condition of the particular patient, as well as other medication that the individual may be taking, as is well known to those skilled in the art. Additionally, it is evident that said effective daily amount can be reduced or increased depending on the response of the treated individual and / or depending on the evaluation of the physician prescribing the compounds of the present invention. The effective daily amount ranges mentioned hereinbefore are therefore only guidelines.

According to one embodiment, the HCV NS3 / 4a protease inhibitor of formula (I) and ritonavir can be co-administered once or twice daily, preferably orally, wherein the amount of the compounds of formula (I) per dose is from about 1 to about 2500 mg, and the amount of ritonavir per dose is from 1 to about 2500 mg. In another embodiment, the amounts per dose for co-administration once or twice a 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. In another additional embodiment, the amounts per dose for co-administration once or twice a 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. In another additional embodiment, the amounts per dose for co-administration once or twice daily are from about 150 to about 800 mg of the compound of formula (I) and from about 100 to about 600 mg of ritonavir. In another additional embodiment, the amounts per dose for co-administration once or twice a 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. In another additional embodiment, the amounts per dose for co-administration once or twice a 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. In another additional embodiment, the amounts per dose for co-administration once or twice a 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.

Illustrative combinations of the compound of formula (I) (mg) / ritonavir (mg) for dosing once or twice daily include 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 illustrative combinations of the compound of formula (I) (mg) / ritonavir (mg) for dosing once or twice daily include 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, an article of manufacture is provided comprising a composition effective to treat an HCV infection or to inhibit NSV HCV protease; and packaging material comprising a label indicating that the composition can be used to treat a hepatitis C virus infection; wherein the composition comprises a compound of the formula (I) or any subgroup thereof, or the combination described herein.

Another embodiment of the present invention concerns a kit or package comprising a compound of the formula (I)

or any subgroup thereof, or a combination according to the invention comprising an inhibitor of the HCV NS3 / 4a protease of formula (I) or a pharmaceutically acceptable salt thereof, and ritonavir or a pharmaceutically acceptable salt thereof, in an amount effective for use as a standard or reagent in a test or assay for the determination of the ability of potential pharmaceutical compounds to inhibit the NS3 / 4a protease of HCV, the growth of HCV, or both. This aspect of the invention may find its usefulness in pharmaceutical research programs,

The compounds and combinations of the present invention can be used in high capacity target analyte assays such as those used to measure the efficacy of said combination in the treatment of HCV.

Examples

The following examples are intended to illustrate the present invention and not limit it.

Example 1: Synthesis of 18- [2- [4- (isopropyl) thiazol-2-yl] -7-methoxyquinolin-4-yloxy] -2,15-dioxo-3,16 diazatricyclo [14,3,0.04] , 6] nonadec-7-eno-4-carboxylic 10.

To a stirred solution of Boc-hydroxyproline 1 (5 g, 22 mmol) in dry DMF (200 ml) was added tosylate of the

5 1-amino-2-vinylcyclopropanecarboxylic acid ethyl ester 2 (8 g, 24 mmol) and diisopropylethylamine (7 g, 54 mmol). This solution was cooled to 0 ° C and then HATU (9 g, 24 mmol) was added. The reaction mixture was stirred at 0 ° C for 30 minutes under nitrogen and then at RT (room temperature) for 4 hours, the reaction mixture was diluted with water (250 ml) and extracted with EtOAc (3 x 150 ml). The organic layers were combined and washed with a saturated solution of NaHCO3, water and brine, dried over MgSO4, filtered and concentrated. The

Purification by column chromatography (gradient from DCM to EtOAc) provided 7.7 g (97%) of the desired product 3: m / z = 369 (M + H) +.

Step B

To a solution of alcohol 3 (7.7 g, 20.9 mmol), para-nitrobenzoic acid (5.23 g, 31.3 mmol) and triphenylphosphine

15 (8.22 g, 31.3 mmol) in dry THF (200 ml) was added dropwise at -20 ° C under DIAD nitrogen (6.34 g, 31.35 mmol). After 1 hour at -20 ° C, the reaction mixture was allowed to warm to RT. After 3 days, the reaction mixture was filtered off and the precipitate was washed with EtOAc. The filtrate was diluted with EtOAc and washed with water, dried (MgSO4), filtered and evaporated. Purification by column chromatography (gradient of EtOAc (0 to 10%) in CH2Cl2) provided 8.45 g (78%) of the desired product 4 as a colorless oil: m / z = 518 (M + H) +.

20 Step C

To a stirred solution of proline derivative 4 (1.25 g, 2.17 mmol) protected with Boc in CH2Cl2 (20 ml) was added trifluoroacetic acid (2.48 g, 21.7 mmol). After 30 min at RT, the reaction mixture was concentrated and the residue was partitioned between a saturated solution of NaHCO3 and EtOAc. The organic layer was dried (MgSO4), filtered and concentrated to give 0.9 g of the desired product 5 as a colorless oil: m / z = 418 (M + H) +.

Step d

To a stirred solution of proline derivative 5 (734 mg, 1.76 mmol) in dry DMF (20 ml) acid was added

10 nonenoic acid (330 mg, 2.11 mmol) and diisopropylethylamine (455 mg, 3.52 mmol). Next, HATU (802 mg, 2.11 mmol) was added at 0 ° C under nitrogen. The reaction mixture was stirred at 0 ° C for 30 minutes and then at RT for 4 hours, then diluted with water (25 ml) and extracted with EtOAc (3 x 15 ml). The organic layers were combined and washed successively with a saturated solution of NaHCO3, water and brine, dried over MgSO4, filtered and concentrated. Purification by column chromatography (gradient of EtOAc (0 to 20%)

15 in DCM) provided 950 mg (97%) of the desired product 6: m / z = 556 (M + H) +.

Step E

A solution of lithium hydroxide (300 mg, 7.02 mmol) in water (10 ml) was added at 0 ° C to a stirred solution of 6 (1.95 g, 3.51 mmol) in THF (30 ml). After 2 hours at 0 ° C, the reaction mixture was acidified with 1N HCl 20 (pH = 6) and extracted with AcOEt, the organic layer was washed with saturated NaHCO3 solution, dried (MgSO4), filtered and concentrated. to give 1.3 g (91%) of the desired product 7 as a colorless oil: m / z = 407 (M + H) +.

Step FA a solution of alcohol 7 (0.5 g, 1.23 mmol), 2- [4- (isopropyl) thiazol-2-yl] -7-methoxyquinolin-4-ol (0.48 g, 1.6 mmol) and triphenylphosphine (0.45 g, 1.72 mmol) in dry THF (15 ml) DIAD (0.37 g, 1.85 mmol, 1.5 eq) was added dropwise at -20 ° C, under nitrogen . After 1 h at -20 ° C, the reaction mixture was allowed to warm to RT. After

5-20 h, the mixture was poured into ice / water and extracted with EtOAc. The organic layers were combined, washed with brine, dried (MgSO4) and concentrated under reduced pressure. Purification by column chromatography (CH2Cl2 / EtOAc, 80/20) provided 535 mg (63%) of the desired product 8 as a yellow foam: m / z = 689 (M + H) +.

Step G

A solution of 8 (540 mg, 0.78 mmol) and first-generation Hoveyda-Grubbs catalyst (45 mg, 0.07 mmol) in CH2Cl2 (540 ml) was stirred under nitrogen at 70 ° C for 19 h. The reaction mixture was evaporated and purified by flash chromatography (gradient of AcOEt (0 to 20%) in CH2Cl2) to provide 390 mg (76%) of the desired macrocycle 9: m / z = 661 (M + H) +.

15 Step H

A solution of lithium hydroxide (1 g, 23.6 mmol) in water (15 ml) was added to a stirred solution of ester 9 (390 mg, 0.59 mmol) in THF (30 ml) and MeOH (20 ml ). After 16 h at room temperature, the reaction mixture was quenched with sat. NH4Cl, concentrated under reduced pressure, acidified to pH 3 with 1N HCl and extracted with

CH2Cl2, dried (MgSO4) and evaporated to give 325 mg (84%) of 18- [2- [4- (isopropyl) -thiazol-2-yl] -7methoxyquinoline-4-yloxy] -2.15 -dioxo-3,16-diazatricyclo [14,3,0,04,6] -nonadec-7-eno-4-carboxylic 10 as an oil that slowly crystallized. The product was recrystallized from ether: m / z = 633 (M + H) +.

Example 2: Synthesis of N - [[18- [2- [4- (isopropyl) thiazol-2-yl] -7-methoxyquinolin-4-yloxy] -2,15-dioxo-3,16 diazatricyclo [14,3, 0.04.6] nonadec-7-en-4-yl] carbonyl] (cyclopropyl) sulfonamide 11.

A solution of carboxylic acid 10 (100 mg, 0.158 mmol) and carbonyldiimidazole (38 mg, 0.237 mmol) in THF

Dry (8 ml) was stirred under reflux under nitrogen for 2 h. Optionally, the azalactone derivative can be isolated, if desired. The reaction mixture was cooled to room temperature and cyclopropylsulfonamide (29 mg, 0.237 mmol) and DBU (36 mg, 0.237 mmol) were added. This solution was heated at 50 ° C for 5 h. Then, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between CH2Cl2 and 1N HCl, the organic layer was washed with brine, dried (MgSO4) and evaporated to give 180 mg of a

10 colorless oil. Purification by flash chromatography (EtOAc gradient (0 to 20%) in DCM) provided 90 mg (74%) of the title product 11 as a white powder: m / z = 736 (M + H) +, 1H NMR ( CDCl3): 0.9-1.6 (m, 18H), 1,801.96 (m, 3H), 2.20-2.28 (m, 1H), 2.37 (t, 1H, J = 12 Hz ), 2.45-2.72 (m, 4H), 2.88-2.95 (m, 1H), 3.20 (q, 1H, J = 6 Hz), 3.96 (s, 3H) , 4.0 (d, 1H, J = 11 Hz), 4.11 (dd, 1H, J = 3.8 Hz, 11 Hz), 4.6 (t, 1H, J = 8Hz), 5.0 (t, 1H, J = 10 Hz), 5.52 (s wide, 1H), 5.73 (dd, 1H, J = 8 Hz, 18 Hz), 6.68 (s, 1H), 7.05 (s, 1H), 7.12 (dd, 1H, J = 2.5 Hz, 9 Hz), 7.38 (d, 1H,

15 J = 2.5 Hz), 7.57 (s, 1H), 7.94 (d, 1H, J = 9 Hz), 10.23 (s, 1H).

Example 3: Synthesis of 18- [2- [2- (isopropylamino) thiazol-4-yl] -7-methoxyquinolin-4-yloxy] -2,15-dioxo-3,16 diazatricyclo [14,3,0.04] , 6] nonadec-7-eno-4-carboxylic 12

The title compound was prepared from 4-hydroxy-2- [2- (isopropylamino) thiazol-4-yl] -7-methoxyquinoline and compounds

20 to intermediate 7 following the procedure (Steps FH) consigned for the acid 18- [2- [4- (isopropyl) thiazol-2-yl] -7methoxyquinolin-4-yloxy] -2,15-dioxo-3,16- diazatricyclo [14,3,0,04,6] nonadec-7-ene-4-carboxylic 10: m / z = 648 (M + H) +, 1H NMR (CDCl3): 1.01-1.41 (m , 12H), 1.81-1.95 (m, 3H), 2.11-2.30 (m, 3H), 2.43 (m, 1H), 2.55 (m, 1H), 2, 91 (m, 1H), 3.47 (m, 2H), 3.60 (m, 1H), 3.94 (s, 3H), 4.27 (M, 1H) 4.78 (d, J = 8.0 Hz, 1H), 5.52-5.70 (m, 3H), 7.10 (d, 1H, J = 8.6 Hz), 7.32 (s, 1H), 7.45- 7.52 (m, 2H), 7.96 (d, 1H, J = 8.6 Hz), 9.5 (s, 1H).

Example 4: Synthesis of N - [[18- [2- [2- (isopropylamino) thiazol-4-yl] -7-methoxyquinolin-4-yloxy] -2,15-dioxo-3,16 diazatricyclo [14.3] , 0,04,6] nonadec-7-en-4-yl] carbonyl] (cyclopropyl) sulfonamide 13

A solution of 18- [2- [2- (isopropylamino) thiazol-4-yl] -7-methoxyquinolin-4-yloxy] -2,15-dioxo-3,16 diazatricyclo [14,3,0,04,6 ] nonadec-7-ene-4-carboxylic acid (12.54 mg, 0.083 mmol) and carbonyldiimidazole (20 mg, 0.125 mmol, 1.5 eq) in dry THF (4 ml) was stirred under reflux under nitrogen for 2 h, Optionally, the azalactone derivative can be isolated if desired. The reaction mixture was cooled to room temperature and cyclopropylsulfonamide (15 mg, 0.125 mmol) and DBU (19 mg, 0.125 mmol) were added. This solution was heated at 50 ° C for 16 h. Then, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between CH2Cl2 and 1N HCl, the organic layer was washed with brine, dried (MgSO4) and concentrated. Purification by flash chromatography (EtOAc gradient (0 to 50%) in DCM) provided 45 mg (72%) of the

10 title product that was recrystallized from water to give 12 mg of the desired product as a slightly yellow powder, m / z = 751 (M + H) +, 1H NMR (CDCl3): 0.8-1.9 (m, 21 H), 2.17 (m, 1H), 2.28-2.56 (m, 4H), 2.65 (m, 1H), 2.86, (m, 1H), 3.55 (m , 1H), 3.87 (m, 4H), 4.10 (m, 1H), 4.57 (m, 1H), 4.94 (t, J = 9.5 Hz, 1H), 5.43 (m, 2H), 5.64 (m, 1H), 6.92 (broad s, 1H), 6.98 (dd, J = 9.0 Hz, 3.0 Hz, 1H), 7.28 ( m, 2H), 7.37 (s, 1H), 7.80 (d, J = 9.0 Hz, 1H).

Example 5: Synthesis of 18- [1,3-dihydroisoindole-2-ylcarbonyloxy] -2,15-dioxo-3,16-diazatricyclo [14,3,0,04,6] nonadec15 7-ene-4-carboxylic acid 18.

To a solution of alcohol 7 (300 mg, 0.738 mmol), para-nitrobenzoic acid (123 mg, 1 eq) and triphenylphosphine (194 mg, 1 eq) in dry THF (10 ml) was added dropwise at -20 ° C under DIAD nitrogen (149 mg, 1 eq). After 1 h at -20 ° C the reaction mixture was allowed to warm to RT. After 16 h, the reaction mixture was diluted with EtO

20 Ac and washed with water, dried (MgSO4), filtered and evaporated. Purification by column chromatography (0 to 10% EtOAc gradient in CH2Cl2) provided 200 mg (50%) of the desired product as a colorless oil, m / z = 556 (M + H) +.

To the para-nitrobenzoic ester 14 (200 mg, 0.23 mmol) dissolved in THF (3 ml) and cooled to 0 ° C was added LiOH monohydrate (30 mg, 2 eq) dissolved in water (1 ml). The mixture was stirred at 0 ° C for 2 h, then acidified with a dilute HCl solution (pH 6) and extracted with AcOEt. The organic layer was extracted with a saturated solution of NaHCO3, washed with brine, dried (MgSO4) and evaporated. The colorless oil obtained was dried under high vacuum to

5 give 140 mg (98%) of the desired product as a white solid, m / z = 407 (M + H) +.

Alcohol 15 (140 mg, 0.344 mmol) and CDI (56 mg, 1 eq) were mixed in DCM (3 ml) and stirred at RT. After 16 h, the amine (45 mg, 2.5 eq) was added and the reaction mixture was stirred at RT until complete reaction as indicated by LC-MS. The RM (reaction mixture) was then extracted with 1N HCl in water, washed with brine, dried,

10 was filtered and concentrated. Purification by flash chromatography on silica gel (EtOAc in DCM 0 to 20%) provided 50 mg of the desired product, m / z = 552 (M + H) +.

At diene 16 (50 mg, 0.091 mmol) dissolved in dichloroethane (9 ml -0.01M) and under N2, second generation Hoveyda-Grubbs catalyst (2.8 mg, 0.05 eq) was added. The reaction mixture was heated at 80 ° C with a septum under N2

15 overnight. After 15 h, the RM was concentrated and purified by flash chromatography on silica gel (0-20% EtOAc in DCM) to give 30 mg (63%) of the desired product 17 as a colorless oil, m / z = 524 (M + H) +.

A solution of LiOH monohydrate 17 (98 mg, 2,292 mmol) in water (1 ml) was added to an ester solution

Ethyl (30 mg, 0.057 mmol) in MeOH / THF (1/1). The MRI was stirred at RT for 20 h. It was then acidified with dilute HCl to pH 4-5 and extracted with EtOAc (3X). The organic layers were combined, washed with brine, dried over MgSO4, filtered and concentrated to give 30 mg of the desired product 18 as a colorless solid, m / z = 496 (M + H) +.

Example 6: Synthesis of N- [18- [1,3-dihydroisoindole-2-ylcarbonyloxy] -2,15-dioxo-3,16-diazatricyclo [14,3,0,04,6] nonadec-725 eno-4 -carbonyl] (cyclopropyl) sulfonamide 19.

The mixture of carboxylic acid 18 (30 mg, 0.06 mmol) and CDI (20 mg, 2 eq) in dry THF (3 ml) was refluxed for 2h30m under nitrogen. Optionally, the azalactone derivative can be isolated if want. Then, the reaction mixture was cooled to room temperature and cyclopropylsulfonamide (15 mg, 2 eq) was added

5 and DBU (18 mg, 2 eq). The reaction mixture was stirred at 50 ° C until the reaction was terminated as indicated by LC-MS. The RM was then concentrated, redissolved in DCM and extracted with 1N HCl and then with brine, dried and concentrated. Purification by flash chromatography on silica gel gave the desired product 19, m / z = 599 (M + H) +.

Example 7: Synthesis of 18- [2- (thiazol-2-yl) -7-methoxy-8-methylquinolin-4-yloxy] -2,15-dioxo-3,1610 diazatricyclo [14,3,0.04 , 6] nonadec-7-eno-4-carboxylic 25.

Step A:

Triethylamine (42.4 ml, 302 mmol) was added to a suspension of 3-methoxy-2-methylbenzoic acid (45.6 g, 274 mmol) in dry toluene (800 ml). A clear solution was obtained. Then, diphenylphosphorylazide 15 (dppa) (65.4 ml, 302 mmol) in toluene (100 ml) was added slowly. After 1 hour at room temperature, the reaction mixture was successively heated at 50 ° C for 0.5 hours, at 70 ° C for 0.5 hours and finally at 100 ° C for 1 hour. To this solution t-BuOH (30.5 g, 411 mmol) in toluene (40 ml) was added at 100 ° C and the resulting mixture was refluxed for 7 hours. The solution was cooled to room temperature and then washed successively with water, 0.5N HCl, 0.5N NaOH and brine, dried (Na2SO4), and evaporated to give 67 g of target product 20:

20 m / z = 237 (M +).

Step B

TFA (40.7 ml, 548 mmol) was added to a solution of N-tert-butyloxycarbonyl) -3-methoxy-2-methylaniline (33), in dichloromethane (500 ml). After 2 hours at room temperature, TFA (40.7 ml, 548 mmol) was added and the

The resulting mixture was stirred at room temperature overnight. The volatiles were then evaporated. The residue was triturated with toluene (100 ml) and diisopropylether (250 ml), filtered off and washed with diisopropylether (100 ml) to give 56.3 g of the title product 21 as a TFA salt: m / z = 138 (M + H) +. The TFA salt was transformed into free aniline by treatment with NaHCO3.

Step c

A solution of BCl3 (1.0 M in CH2Cl2, 194 ml) was added dropwise by a cannula for 20 min, under argon pressure, at 0 ° C to a solution of 3-methoxy-2-methylaniline (21, 2, 54 g, 185 mmol) in xylene (300 ml). The temperature was maintained between 0 ° C and 10 ° C until the addition was complete. After an additional 30 minutes at 0 ° C, acetonitrile (12.6 ml, 241 mmol) was added dropwise under argon at 0 ° C. After 30 min at 0 ° C, the sus

The resulting pension was transferred to a drip funnel, and diluted with CH2Cl2 (40 ml). This mixture was added at 0 ° C

under argon for 20 min at a suspension of AlCl3 (25.9 g, 194 mmol) in CH2Cl2 (40 ml). The orange solution

The resulting heat was heated in an oil bath at 70 ° C under a nitrogen current for 12 h. The mixture then cooled

5 reaction temperature at room temperature, and ice-cold water and CH2Cl2 were added. This mixture is

heated to reflux for 6 h, and then cooled to room temperature. After 12 h, the pH was adjusted to 0 ° C

up to 3 with 6N NaOH. The solution was extracted with Ch2Cl2, washed successively with water, 1M NaOH, and brine.

The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The residue was triturated at room temperature

in diisopropyl ether (50 ml) for 0.5 h. The suspension was then cooled to 0 ° C, filtered, washed with a small portion of diisopropyl ether and dried under high vacuum to give 15.4 g (46%) of the desired product 22: m / z =

180 (M + H) +.

Step d

EDCI (257 mg, 1.34 mmol) and HOAt (152 mg, 1.12 mmol) were added to a stirred solution of 22 (200 mg,

15 1.12 mmol) in CH2Cl2 (10 ml) and dry DMF (1 ml). The resulting solution was stirred at room temperature for 3 days. The reaction mixture was then partitioned between CH2Cl2 and 1M NaHCO3. The organic layer was washed successively with 1M NH4Cl and with water, dried (Na2SO4), and evaporated. Purification by flash chromatography (AcOEt / heptane gradient, 10:90 to 50:50) provided 62 mg (19%) of the target product 23: m / z = 291 (M + H) +.

Step E. Synthesis of 4-hydroxy-7-methoxy-8-methyl-2- (thiazol-2-yl) quinoline (24)

TBuOK (50 mg, 0.448 mmol) was added to a suspension of acetophenone 23 (62 mg, 0.213 mmol) in tBuOH (5 ml). The resulting mixture was stirred at 80 ° C overnight, and then cooled to room temperature. The reaction mixture was diluted with AcOEt, acidified with KHSO4, and washed successively with water and brine. The organic layer was dried (Na2SO4) and evaporated to give 43 mg (74%) of target product 24 as a white powder: m / z =

25 273 (M + H) +.

Step F. Synthesis of 18- [2- (thiazol-2-yl) -7-methoxy-8-methylquinolin-4-yloxy] -2,15-dioxo-3,16 diazatricyclo [14,3,0.04, 6] nonadec-7-eno-4-carboxylic 25.

The title compound was prepared from quinoline 24 and intermediate 7 following procedure 30 (Steps FH) consigned for 18- [2- [4- (isopropyl) thiazol-2-yl] -7-methoxyquinoline-4 acid -yloxy] -2,15-dioxo-3,16 diazatricyclo [14,3,0,04,6] nonadec-7-eno-4-carboxylic 10: m / z = 605 (M + H) +.

Example 8: Synthesis of N- [18- [2- (thiazol-2-yl) -7-methoxy-8-methylquinolin-4-yloxy] -2,15-dioxo-3,16 diazatricyclo [14,3,0, 04.6] nonadec-7-eno-4-carbonyl] (cyclopropyl) sulfonamide (26)

The title compound was prepared from 18- [2- (thiazol-2-yl) -7-methoxy-8-methylquinolin-4-yloxy] -2,15-dioxo3,16-diazatricyclo [14,3, 0,04,6] nonadec-7-eno-4-carboxylic 25 following the procedure set for the synthesis of N - [[18- [2- [4- (isopropyl) thiazol-2-yl] -7-methoxyquinolin- 4-yloxy] -2,15-dioxo-3,16-diazatricyclo- [14,3,0,04,6] nonadec-7-en-4yl] carbonyl] (cyclopropyl) sulfonamide 11: m / z = 708 ( M + H) +.

Example 9: Synthesis of 18- [2- (4-isopropylthiazol-2-yl) -7-methoxy-8-methylquinolin-4-yloxy] -2,15-dioxo-3,16 diazatricyclo [14,3,0, 04.6] nonadec-7-eno-4-carboxylic (29)

Step a

A solution of (2-amino-4-methoxy-3-methylphenyl) (methyl) ketone (22, 18.6 g, 104 mmol) in dioxane (50 ml) was added under nitrogen to a chloride suspension of 4- isopropylthiazol-2-carbonyl in dioxane (250 ml). After 2 h at room temperature, the reaction mixture was concentrated to dryness. Then, the residue was partitioned between an aqueous solution of NaHCO3 and AcOEt, the organic layer was washed with brine, dried (Na2SO4), and evaporated. The residue was triturated in diisopropylether, filtered and washed with diisopropyl ether to give 30.8 g (90%) of the product of the

15 title 27: m / z = 333 (M + H) +.

Step B

Potassium tert-butoxide (21.8 g, 195 mmol) was added to a suspension of 2 '- [[(4-isopropylthiazol-2-yl) (oxo) methyl] amino] -4'-methoxy-3'-methylacetophenone ( 27, 30.8 g, 92.7 mmol) in tert-butanol. The resulting reaction mixture 20 was heated at 100 overnight. Then, the reaction mixture was cooled to room temperature and diluted with ether (100 ml). The precipitate was filtered off and washed with Et2O to give a powder (fraction A). The mother liquors were concentrated in vacuo, triturated in ether, filtered, and washed with ether to give a powder (fraction 2). Fractions 1 and 2 were mixed and poured into water (250 ml). The pH of the resulting solution was adjusted to 6-7 (control with pH paper) with 1N HCl. The precipitate was filtered off, washed with

25 water and dried. The solid was then triturated in diisopropylether, filtered off and dried to give 26 g (88%) of the title product 28 as a brownish solid: m / z = 315 (M + H) +.

Step C. Synthesis of 18- [2- (4-isopropylthiazol-2-yl) -7-methoxy-8-methylquinolin-4-yloxy] -2,15-dioxo-3,16 diazatricyclo [14,3,0, 04.6] nonadec-7-eno-4-carboxylic (29)

The title compound was prepared from quinoline 28 and intermediate 7 following the procedure (Steps FH) consigned for 18- [2- [4- (isopropyl) thiazol-2-yl] -7-methoxyquinoline-4 acid -yloxy] -2,15-dioxo-3,16 diazatricyclo [14,3,0,04,6] nonadec-7-eno-4-carboxylic 10: m / z = 647 (M + H) +.

5 Example 10: Synthesis of N- [18- [2- (4-isopropylthiazol-2-yl) -7-methoxy-8-methylquinolin-4-yloxy] -2,15-dioxo-3,16 diazatricyclo [14.3] , 0,04,6] nonadec-7-eno-4-carbonyl] (cyclopropyl) sulfonamide (30)

The title compound was prepared from 18- [2- (4-isopropylthiazol-2-yl) -7-methoxy-8-methylquinolin-4-yloxy] -2,15 dioxo-3,16-diazatricyclo [14, 3,0.04.6] nonadec-7-eno-4-carboxylic acid (29) following the procedure set forth for the synthesis of N - [[18- [2- [4- (isopropyl) thiazol-2-yl]] -7-methoxyquinolin-4-yloxy) -2,15-dioxo-3,16 diazatricyclo [14,3,0,04,6] nonadec-7-en-4-yl] carbonyl] (cyclopropyl) sulfonamide 11: m / z = 750 (M + H) +, 1H NMR (CDCl3): 0.90-1.00 (m, 1H), 1.1-1.2 (m, 4H), 1.4 (d, J = 6.9 Hz, 6H), 1.4-1.6 (m, 4H), 2.15-2.25 (m, 1H), 2.3-2.4 (m, 1H), 2,452.55 (m, 2H), 2.65 (s, 3H), 2.6-2.7 (m, 2H), 2.85-2.95 (m, 1H), 3.15-3.5 (m , 7H), 3.95 (d, J = 10.8 Hz, 1H), 3.95 (s, 3H), 4.1 (dd, J = 11.5 Hz, J = 3.8 Hz, 1H ), 4.6 (t, J = 8 Hz, 1H), 5.0 (t, J = 9 Hz, 1H), 5.5 (t, J = 3.14 Hz, 1H), 5.7- 5.8

15 (dd, J = 18.2 and J = 8.2 Hz, 1H), 6.85 (s, 1H), 7.02 (s, 1H), 7.2 (d, J = 9.5 Hz , 1H), 7.5 (s, 1H), 7.85 (d, J = 9.5 Hz, 1H), 10.5 (br s, 1H).

Example 11: Synthesis of 18- [7-methoxy-2- (thiazol-2-yl) quinolin-4-yloxy] -2,15-dioxo-3,16 diazatricyclo [14,3,0,04,6] nonadec -7-eno-4-carboxylic (31)

The title compound was prepared from 4-hydroxy-7-methoxy-2- (thiazol-2-yl) quinoline and intermediate 7 following the procedure (Steps FH) consigned for acid 18- [2- [ 4- (isopropyl) thiazol-2-yl] -7-methoxyquinolin-4-yloxy] -2,15-dioxo-3,16-diazatricyclo [14,3,0,04,6] nonadec-7-eno-4-carboxylic 10: m / z = 591 (M + H) +.

Example 12: Synthesis of N- [18- [7-methoxy-2- (thiazol-2-yl) quinolin-4-yloxy] -2,15-dioxo-3,16-diazatricyclo [14,3,0.04 , 6] nonadec-7-eno-4-carbonyl] (cyclopropyl) -sulfonamide (32)

The title compound was prepared from 18- [7-methoxy-2- (thiazol-2-yl) quinolin-4-yloxy] -2,15-dioxo-3,16 diazatricyclo [14,3,0.04, 6] nonadec-7-eno-4-carboxylic acid (31) following the procedure set for the synthesis of N - [[18- [2- [4- (isopropyl) thiazol-2-yl] -7-methoxyquinolin-4- yloxy] -2,15-dioxo-3,16-diazatricyclo [14,3,0,04,6] nonadec-7-en-4

5 il] carbonyl] (cyclopropyl) sulfonamide 11: m / z = 694 (M + H) +, 1 H NMR (CDCl 3): 0.90-1.5 (m, 9H), 1.6-1.8 ( m, 8H), 2.1-2.4 (m, 2H), 2.45-2.55 (m, 2H), 2.6-2.7 (m, 1H), 2.9-3 ( m, 1H), 3.9 (s, 3H), 4.12 (dd, J = 11.6 Hz, J = 3.7 Hz, 1H), 5.1 (t, J = 7.9 Hz, 1H), 5.00 (t, J = 9 Hz, 1H), 5.48 (t, J = 2.9 Hz, 1H), 5.7 (dd, J = 18.2 Hz, J = 8, 8 Hz, 1H), 7 (br s, 1H), 7.15 (dd, J = 9.1 Hz, J = 2.4 Hz, 1H), 7.4 (d, J = 2.4 Hz, 1H), 7.5 (d, J = 3.2 Hz, 1H), 7.59 (s, 1H), 7.9 (d, J = 3.2 Hz, 1H), 7.9 (d, J = 9.1 Hz, 1H), 10.3 (br s, 1H).

Example 13: Synthesis of 18- [6-methoxy-3- (pyrazol-1-yl) isoquinolin-1-yloxy] -2,15-dioxo-3,16 diazatricyclo [14,3,0,04,6] nonadec-7-eno-4-carboxylic (33).

The title compound was prepared from 1-hydroxy-6-methoxy-3- (pyrazol-1-yl) -isoquinoline and intermediate 7 following the procedure (Steps FH) consigned for acid 18- [2- [4 - (isopropyl) thiazol-2-yl] -7-methoxyquinolin-415-yloxy] -2,15-dioxo-3,16-diazatricyclo [14,3,0,04,6] nonadec-7-eno-4-carboxylic 10: m / z = 574 (M + H) +.

Example 14: Synthesis of N- [18- [6-methoxy-3- (pyrazol-1-yl) isoquinolin-1-yloxy] -2,15-dioxo-3,16 diazatricyclo [14,3,0,04,6 ] nonadec-7-eno-4-carbonyl] (cyclopropyl) -sulfonamide (34).

The title compound was prepared from 18- [6-methoxy-3- (pyrazol-1-yl) isoquinolin-1-yloxy] -2,15-dioxo-3.16 acid

20 diazatricyclo [14,3,0,04,6] nonadec-7-ene-4-carboxylic acid (33) following the procedure set for the synthesis of N - [[18- [2- [4- (isopropyl) thiazole-] 2-yl] -7-methoxyquinolin-4-yloxy] -2,15-dioxo-3,16-diazatricyclo [14,3,0,04,6] nonadec-7-en-4-yl] carbonyl] (cyclopropyl) sulfonamide 11: m / z = 677 (M + H) +.

Example 15: Synthesis of 18- [7-methoxy-2- (thiazol-4-yl) quinolin-4-yloxy] -2,15-dioxo-3,16-diazatricyclo [14,3,0,0,4, 6] nonadec7-eno-4-carboxylic (35).

The title compound was prepared from 4-hydroxy-7-methoxy-2- (thiazol-4-yl) quinoline and intermediate 7 following the procedure (Steps FH) consigned for acid 18- [2- [4- (isopropyl) thiazol-2-yl] -7-methoxyquinolin-4-yloxy] -2,15-dioxo-3,16-diazatricyclo [14,3,0,04,6] nonadec-7-eno-4-carboxylic 10: m / z = 591 (M + H) +.

5 Example 16: Synthesis of N- [18- [7-methoxy-2- (thiazol-4-yl) quinolin-4-yloxy] -2,15-dioxo-3,16 diazatricyclo [14,3,0.04, 6] nonadec-7-eno-4-carbonyl] (cyclopropyl) -sulfonamide (36).

The title compound was prepared from 18- [7-methoxy-2- (thiazol-4-yl) quinolin-4-yloxy] -2,15-dioxo-3.16 acid

diazatricyclo [14,3,0,04,6] nonadec-7-eno-4-carboxylic (35) following the procedure set forth for the synthesis of

10 N - [[18- [2- [4- (isopropyl) thiazol-2-yl] -7-methoxyquinolin-4-yloxy] -2,15-dioxo-3,16-diazatricyclo [14,3,0, 04.6] nonadec-7-en-4-yl] carbonyl] (cyclopropyl) sulfonamide 11: m / z = 694 (M + H) +, 1H NMR (CDCl3): 0.80-1.55 (m, 13H) , 1.80-1.98 (m, 3H), 2.19-2.28 (m, 1H), 2.30-2.40 (m, 1H), 2.47-2.62 (m, 2H), 2.63-2.75 (m, 2H), 2.88-2.96 (m, 1H), 3.97 (9s, 3H), 4.02 (d, J = 11.5 Hz , 1H), 4.11 (dd, J = 11.4 Hz, J = 3.8 Hz, 1H), 4.60 (t, J = 7.9 Hz, 1H), 5.00 (t, J = 9.5 Hz, 1H), 5.49 (br s, 1H), 5.70-5.77 (m, 1H), 6.68 (s, 1H), 7.12 (dd, J = 2 , 5 Hz, J = 9.1 Hz, 1H), 7.40 (d, J = 2.4 Hz, 1H), 7.59 (s, 1H), 7.96

15 (d, J = 9.1 Hz, 1H), 8.35 (d, J = 2.1 Hz, 1H), 8.94 (d, J = 2.1 Hz, 1H), 9.2 ( br s, 1H).

Example 17: Synthesis of 18- [8-bromo-7-methoxy-2- (thiazol-2-yl) quinolin-4-yloxy] -2,15-dioxo-3,16 diazatricyclo [14,3,0.04 , 6] nonadec-7-eno-4-carboxylic (41)

Step a

A solution of 2-bromo-1-methoxy-3-nitrobenzene (500 mg, 2.16 mmol) in CH3OH (5 ml) and THF (5 ml) was added to a solution of NH4Cl (572 mg, 10.7 mmol ) in water (5 ml). Then, iron (325 mesh, 601 mg, 10.7 mmol) was added and the resulting mixture was heated at 70 ° C under nitrogen. After 2.5 h, the reaction mixture was cooled to room temperature, filtered on diatomite, diluted with AcOEt, and washed successively with a saturated solution of NaHCO3 in water and brine. The organic layer was dried (Na2SO4) and evaporated. The residue was triturated in CH2Cl2, and then filtered to give 390 mg (89%) of target product 37 as a beige solid.

Step B

Intermediate 38 was prepared from 2-bromo-m-anisidine (37) following the procedure set forth for the synthesis of intermediate 22.

Step c

10 Intermediate 38 (11.2 g, 45.9 mmol) was added under nitrogen to a suspension of thiazole-2-carboxylic chloride, HCl (1.5 eq, 68.8 mmol) in dry dioxane (500 ml). After 12 h at room temperature, the reaction mixture was concentrated under reduced pressure. Then, ether (200 ml) was added and the resulting mixture was cooled to 0 ° C. The precipitate was filtered off and washed with ether to give a solid fraction A. The filtrate was concentrated under reduced pressure. The residue was partitioned between AcOEt and 1 N NaHCO3, dried (Na2SO4), and evaporated. The

Purification by column chromatography (heptane / AcOEt, 1: 1) provided 9.8 g (60%) of target product 39 as a yellow powder: m / z = 355, 357.

Step D. Synthesis of 8-bromo-4-hydroxy-7-methoxy- (2-thiazol-2-yl) quinoline (40)

The title compound was prepared from intermediate 39 following the procedure set forth for the synthesis of 4-hydroxy-7-methoxy-8-methyl-2- (thiazol-2-yl) quinoline (24): m / z = 337, 339.

Step E. Synthesis of 18- [8-bromo-7-methoxy-2- (thiazol-2-yl) quinolin-4-yloxy] -2,15-dioxo-3,16 diazatricyclo [14,3,0.04 , 6] nonadec-7-eno-4-carboxylic (41)

The title compound was prepared from 8-bromo-4-hydroxy-7-methoxy-2- (thiazol-2-yl) quinoline (40) and intermediate compound 7 following the procedure (Steps FH) reported for acid 18 - [2- [4- (isopropyl) thiazol-2-yl] -7methoxyquinolin-4-yloxy] -2,15-dioxo-3,16-diazatricyclo [14,3,0,04,6] nonadec-7- eno-4-carboxylic 10: m / z = 670 (M + H) +.

Example 18: Synthesis of N- [18- [8-bromo-2- (thiazol-2-yl) -7-methoxyquinolin-4-yloxy] -2,15-dioxo-3,16 diazatricyclo [14,3,0, 04.6] nonadec-7-eno-4-carbonyl] (cyclopropyl) sulfonamide (42)

The title compound was prepared from 18- [8-bromo-7-methoxy-2- (thiazol-2-yl) -quinolin-4-yloxy] -2,15-dioxo acid

5 3,16-diazatricyclo [14,3,0,04,6] nonadec-7-eno-4-carboxylic (41) following the procedure set for the synthesis of N - [[18- [2- [4- ( isopropyl) thiazol-2-yl] -7-methoxyquinolin-4-yloxy] -2,15-dioxo-3,16-diazatricyclo [14,3,0,04,6] nonadec-7-en-4yl] carbonyl] (cyclopropyl) sulfonamide 11: m / z = 773 (M + H) +, 1H NMR (CDCl3): 0.90-0.98 (m, 1H), 1.05-2.0 (m, 2H), 1,271.58 (m, 9H), 1.80-1.97 (m, 3H), 2.18-2.24 (m, 1H), 2.29-2.38 (m, 1H), 2, 48-2.62 (m, 2H), 2.69-2.73 (m, 2H), 2,882.94 (m, 1H), 4.01 (d, J = 11.8 Hz, 1H), 4 , 08 (s, 3H), 4.12 (dd, J = 11.5 Hz, J = 3.6 Hz, 1H), 4.61 (t, J = 7.9 Hz, 1H),

10 5.00 (t, J = 9.5 Hz, 1H), 5.47-5.60 (m, 1H), 5.70-5.77 (m, 1H), 6.69 (br s, 1H), 7.24 (d, J = 9.2Hz, 1H), 7.55 (d, J = 3.2Hz, 1H), 7.59 (s, 1H), 7.98 (d, J = 3.2 Hz, 1H), 8.05 (d, J = 9.2 Hz, 1H), 8.20 (br s, 1H).

Example 19: Synthesis of 18- [8-Chloro-2- (4-isopropylthiazol-2-yl) -7-methoxyquinolin-4-yloxy] -14,14-dimethyl-2,15-dioxo3,16-diazatricyclo [ 14,3,0,04,6] nonadec-7-eno-4-carboxylic (49).

Step A: Synthesis of (2-amino-3-chloro-4-methoxyphenyl) (methyl) ketone (44):

A solution of BCl3 (1.0 M, 138 ml, 138 mmol) in CH2Cl2 was slowly added under nitrogen to a solution of 2-chloro-3-methoxyaniline 43 (20.6 g, 131 mmol) in xylene (225 ml) . The temperature was monitored during the addition and maintained below 10 ° C. The reaction mixture was stirred at 5 ° C for 0.5 h. Then, dry acetonitrile (9.0 ml, 170 mmol) was added at 5 ° C. After 0.5 h at 5 ° C, the solution was transferred to a dropping funnel 20 and slowly added at 5 ° C to a suspension of AlCl3 (18.4 g, 138 mmol) in CH2Cl2 (80 ml). After 45 min at 5 ° C, the reaction mixture was heated to 70 ° C under a stream of nitrogen. After evaporation of CH2Cl2, the temperature of the reaction mixture reached 65 ° C. After 12 h at 65 ° C, the reaction mixture was cooled to 0 ° C, poured on ice (200 g), and slowly heated to reflux for 7 h. After 2 days at room temperature, 6 N NaOH (25 ml) and CH2Cl2 (100 ml) were added. The mixture was filtered, and the filter was washed with CH2Cl2. The

The organic layer was decanted, and washed successively with water, 1M NaOH, and brine, dried (Na2SO4) and evaporated. The residue was triturated in diisopropylether at 0 ° C, filtered and washed with diisopropylether to give 19.0 g (73%) of the title product 44 as a white solid: m / z = 200 (M + H) +.

Step B. Synthesis of 2 '- [[(4-isopropylthiazol-2-yl) (oxo) methyl] amino] -3'-chloro-4'-methoxyacetophenone (45)

The title product 45 was prepared (79%) from (2-amino-3-chloro-4-methoxyphenyl) - (methyl) ketone (44) following the procedure set for intermediate 39: m / z = 353 (M + H) +.

Step C. Synthesis of 8-chloro-4-hydroxy-2- (4-isopropylthiazol-2-yl) -7-methoxyquinoline (46).

The title product 46 was prepared (58%) from 2 '- [[(4-isopropylthiazol-2-yl) (oxo) -methyl] amino] -3'-chloro-4'methoxyacetophenone (45) following the consigned procedure for 4-hydroxy-7-methoxy-8-methyl-2- (thiazol-2-yl) quinoline (24): m / z = 335 (M + H) +.

Step D. Synthesis of 4,8-dichloro-2- (4-isopropylthiazol-2-yl) -7-methoxyquinoline (47)

A solution of 8-chloro-4-hydroxy-2- (4-isopropylthiazol-2-yl) -7-methoxyquinoline (46, 2.0 g, 5.973 mmol) in POCl3 (100 ml) was heated at 85 ° C for 30 min. . Then, the reaction mixture was concentrated under reduced pressure. The residue was poured into ice-cold water (20 ml), the pH was adjusted to 10 with 50% NaOH, and extracted with CH2Cl2.

The organic layer was washed with brine, dried (MgSO4), filtered, and evaporated to give 2.05 g (97%) of the title compound 47 as a yellow solid: m / z = 353 (M + H ) +.

Step E. Synthesis of 4- [8-Chloro-2- (4-isopropylthiazol-2-yl) -7-methoxyquinolin-4-yloxy] pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (48)

15 NaH (60% in mineral oil, 679 mg, 17.0 mmol) under nitrogen was added to a solution of Boc-trans-hydroxy-Lproline (2.0 g, 5.66 mmol) in dry DMF (50 ml) . After 30 min at room temperature, a solution of 4,8-dichloro-2- (4-isopropylthiazol-2-yl) -7-methoxyquinoline (47, 1.38 g, 5.94 mmol) in DMF was added dry (5 ml). After 12 h at room temperature, the reaction mixture was quenched with dilute HCl to pH 2, extracted twice with EtOAc, washed with brine, dried (MgSO4), filtered and concentrated under reduced pressure to

20 give 3.2 g of crude product. Purification by flash chromatography (EtOAc / DCM gradient, 0: 100 to 50:50) provided 2.35 g (75%) of the title product 48: m / z = 549 (M + H) +.

Step F. Synthesis of 4- [8-Chloro-2- (4-isopropylthiazol-2-yl) -7-methoxyquinolin-4-yloxy] -2- (1-ethoxycarbonyl-3-vinylcyclopropylcarbamoyl) pyrrolidine- tert-butyl ester 1-carboxylic (49)

To a stirred solution of 4- [8-chloro-2- (4-isopropylthiazol-2-yl) -7-methoxyquinolin-4-yloxy] pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (48, 3.4 g, 6.20 mmol) in dry DMF (50 ml) tosylate of the ethyl acid ester (1R, 2S) -1-amino-2-vinylcyclopropanecarboxylic acid (2.23 g, 6.82 mmol) was added and diisopropylethylamine (2.70 ml, 17.1 5 mmol). Next, HATU (2.59 g, 6.82 mmol) was added at 0 ° C under nitrogen. After 30 min at 0 ° C, the reaction mixture was allowed to warm successively to room temperature for 4 h, then diluted with water (150 ml) and extracted with EtOAc (3 x 150 ml). The organic layers were combined and washed with a saturated solution of NaHCO3, water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. Purification by column chromatography (gradient EtOAc / CH2Cl2, 0: 1 to 2: 8) provided 3.0 g (70%) of the pro

10 pipeline of title 49: m / z = 685 (M + H) +.

Step G. Synthesis of 1 - [[4- [8-Chloro-2- (4-isopropylthiazol-2-yl) -7-methoxyquinolin-4-yloxy] pyrrolidine-2-carbonyl] amino] -2-vinylcyclopropanecarboxylic acid ethyl ester (fifty).

To a stirred solution of 4- [8-Chloro-2- (4-isopropylthiazol-2-yl) -7-methoxyquinolin-4-yloxy] -2 tert-butyl ester

15 (1-Ethoxycarbonyl-2-vinylcyclopropylcarbamoyl) pyrrolidine-1-carboxylic acid (49, 0.7 g, 1.02 mmol) in CH2Cl2 (8 ml) was added trifluoroacetic acid (2.0 ml). After 2 h at room temperature, the reaction mixture was concentrated and the residue was partitioned between a saturated solution of NaHCO3 and DCM. The organic layer was dried (MgSO4), filtered and concentrated to give 580 mg (97%) of the title product (50) as a colorless oil: m / z = 585 (M + H) +.

Step H. Synthesis of 2,2-dimethylnon-8-enoic acid ethyl ester (51).

A solution of 2.5 M n-BuLi in hexanes (3.79 ml, 9.48 mmol) was added at -78 ° C under nitrogen to a solution of diisopropylamine (1.33 ml, 9.46 mmol) in dry THF ( 10 ml) After 15 min, a solution of ethyl isobutyrate (1.0 g, 8.61 mmol) in dry THF (5.0 ml) was added slowly. After 30 min at -78 ° C, a solution of 7-bromohept-1-ene (1.68 g, 9.47 mmol) in HMPA (2.0 ml) was added dropwise and the reaction mixture was

25 allowed to warm to room temperature. After 16 h, the reaction mixture was quenched with dilute HCl, extracted with AcOEt, washed with brine, dried (MgSO4), filtered and concentrated. Purification by flash chromatography (DCM / heptane, 2: 8) provided 800 mg (44%) of the title product (51) as a colorless oil, TLC (DCM / hexanes 1/1): Rf = 0.7.

A solution of 2,2-dimethylnon-8-enoic acid ethyl ester (51, 800 mg, 3.77 mmol) and LiOH (806 mg, 18.9 mmol) in THF / MeOH / water, 1: 1: 0 , 5, was heated at 50 ° C for 2.5 h. Then, additional LiOH (1.60 g, 10 eq) was added. After 15 h, the reaction mixture was concentrated under reduced pressure. The pH of the residue was adjusted to 3 with 1N HCl, extracted with CH2Cl2, washed with brine, dried (MgSO4), filtered and concentrated to give 650 mg (94%) of the title product (52) as a colorless oil

Step J. Synthesis of 1 - [[4- [8-Chloro-2- (4-isopropylthiazol-2-yl) -7-methoxyquinolin-4-yloxy] -1- (2,2-dimethylnon-8-) ethyl ester enoyl) pyrrolidine-2-carbonyl] amino] -2-vinylcyclopropanecarboxylic acid (53).

To a solution of 2,2-dimethylnon-8-enoic acid (52, 239 mg, 1.3 mmol) in dry CH2Cl2 (10 mL) were added oxalyl chloride (165 mg, 2.6 mmol) and 2 drops of DMF After 3 h at room temperature, the reaction mixture was concentrated and coevaporated with toluene. This crude acid chloride was successively redissolved in CH2Cl2 and added to a stirred solution of 1 - [[4- [8-chloro-2- (4-isopropylthiazol-2-yl) -7-ethyl acid ester]

Methoxyquinolin-4-yloxy] pyrrolidine-2-carbonyl] amino] -2-vinylcyclopropanecarboxylic acid (50, 380 mg, 0.65 mmol) and triethylamine (264 µl, 1.95 mmol) in CH2Cl2 (30 ml). After 1.5 h, the resulting solution was washed successively with a saturated NaHCO3 solution and brine, dried (MgSO4), filtered and concentrated under reduced pressure. Purification by flash chromatography (gradient EtOAc / CH2Cl2 0: 1 to 2: 8) provided the title product (53) as a colorless oil (490 mg, 100%): m / z = 751 (M + H) +.

Step K. Synthesis of 18- [8-Chloro-2- (4-isopropylthiazol-2-yl) -7-methoxyquinolin-4-yloxy] -14,14-dimethyl-2,15-dioxo-3,16 diazatricyclo acid [14,3,0,04,6] nonadec-7-eno-4-carboxylic (54).

The title compound was prepared from 1 - [[4- [8-Chloro-2- (4-isopropylthiazol-2-yl) -7-methoxyquinoline-4-yloxy] -1- (2,2- dimethylnon-8-enoyl) pyrrolidine-2-carbonyl] amino] -2-vinylcyclopropanecarboxylic acid (53) following the procedure (Steps G and H) reported for 18- [2- [4- (isopropyl) thiazole-2- acid il] -7-methoxyquinolin-4-yloxy] -2,15-dioxo-3,16-diazatricyclo [14,3,0,04,6] nonadec-7-eno-4-carboxylic 10: m / z = 695 (M + H) +.

Example 20: Synthesis of N- [18- [8-chloro-2- (4-isopropylthiazol-2-yl) -7-methoxyquinolin-4-yloxy] -14,14-dimethyl-2,15-dioxo-3, 16 diazatricyclo [14,3,0.04,6] nonadec-7-ene-4-carbonyl] (cyclopropyl) sulfonamide (55).

The title compound was prepared from 18- [8-chloro-2- (4-isopropylthiazol-2-yl) -7-methoxyquinolin-4-yloxy]

5 14,14-dimethyl-2,15-dioxo-3,16-diazatricyclo [14,3,0,04,6] nonadec-7-eno-4-carboxylic (54) following the procedure set for the synthesis of N - [[18- [2- [4- (isopropyl) thiazol-2-yl] -7-methoxyquinolin-4-yloxy] -2,15-dioxo-3,16 diazatricyclo [14,3,0,04,6] nonadec-7-en-4-yl] carbonyl] (cyclopropyl) sulfonamide 11: m / z = 798 (M + H) +, 1H NMR (CDCl3): 0.96 (m, 1H), 1.05-1 , 15 (m, 2H), 1.17 (s, 3H), 1.32 (s, 3H), 1.23-1.36 (m, 7H), 1.38 (d, J = 6.8 Hz, 6H), 1.43-1.53 (m, 2H), 1.75-1.94 (m, 3H), 2.39 (m, 1H), 2.56 (m, 3H), 2 , 85-2.95 (m, 1H), 3.20 (m, 1H), 4.02 (s, 3H), 4.15 (dd, J = 3.7

10 Hz, J = 11.6 Hz, 1H), 4.23 (d, J = 11.6 Hz, 1H), 4.73 (t, J = 7.5 Hz, 1H), 4.99 (t , J = 9.4 Hz, 1H), 5.52 (m, 1H), 5.80 (q, J = 8.8 Hz, 1H), 7.08 (s, 1H), 7.17 (m , 2H), 7.54 (s, 1H), 7.84 (d, J = 9.2 Hz, 1H), 10.3 (s, 1H).

Example 21: Synthesis of 17- [8-Chloro-2- (4-isopropylthiazol-2-yl) -7-methoxyquinolin-4-yloxy] -2,14-dioxo-3,15 diazatricyclo [13,3,0, 04.6] octadec-7-eno-4-carboxylic (56):

The title compound was prepared from 8-chloro-4-hydroxy-2- (4-isopropylthiazol-2-yl) -7-methoxyquinoline acid (46), oct-7-enoic acid and intermediate 5 following the Procedure (DH Steps) consigned for 18 [2- [4- (isopropyl) thiazol-2-yl] -7-methoxyquinolin-4-yloxy] -2,15-dioxo-3,16-diazatricyclo [14,3 , 0,04,6] nonadec-7-ene-4-carboxylic 10: m / z = 653 (M + H) +.

Example 22: Synthesis of N- [17- [8-chloro-2- (4-isopropylthiazol-2-yl) -7-methoxyquinolin-4-yloxy] -2,14-dioxo-3,1520 diazabicyclo [13.3 , 0,04,6] octadec-7-eno-4-carbonyl] (cyclopropyl) sulfonamide (57).

The title compound was prepared from 17- [8-chloro-2- (4-isopropylthiazol-2-yl) -7-methoxyquinolin-4-yloxy] -2,14-dioxo-3,15-diazatricyclo [13, 3,0,04,6] octadec-7-eno-4-carboxylic acid (56) following the procedure set for the synthesis of N - [[18- [2- [4- (isopropyl) thiazol-2-yl] - 7-methoxyquinolin-4-yloxy] -2,15-dioxo-3,165 diazatricyclo [14,3,0,04,6] nonadec-7-en-4-yl] carbonyl] (cyclopropyl) sulfonamide 11: m / z = 756 (M + H) +, 1H NMR (CDCl3): 0.90-0.98 (m, 1H), 1.05-2.0 (m, 2H), 1.3-1.4 (m, 9H), 1.5-1.6 (m, 2H), 1.6-1.65 (m, 1H), 1.75-1.9 (m, 5H), 2.2-2.3 ( m, 1H), 2.3-2.4 (m, 1H), 2.45-2.55 (m, 2H), 2.6-2.7 (m, 1H), 2.75-2, 85 (m, 1H), 3.15-3.25 (m, 1H), 3.8 (d, J = 11.2 Hz, 1H), 4.15 (s, 3H), 3.25 (dd , J = 11.15 Hz, J = 4.5 Hz, 1H), 4.7 (t, J = 7.1 Hz, 1H), 5.2 (t, J = 10.4 Hz, 1H), 5.5 (br s, 1H), 5.6-5.7 (m, 1H), 6.9 (br s, 1H), 7.1 (s, 1H), 7.21 (d, J = 9.5 Hz, 1H), 7.6 (s, 1H), 8 (d, J = 9.5 Hz, 1H), 10.8 (br s,

10 1H).

Example 23: Synthesis of 17- [2- (4-isopropylthiazol-2-yl) -7-methoxy-8-methylquinolin-4-yloxy] -2,14-dioxo-3,15 diazatricyclo [13,3,0, 04.6] octadec-7-eno-4-carboxylic (58).

The title compound was prepared from 4-hydroxy-2- (4-isopropylthiazol-2-yl) -7-methoxy-8-methylquinoline acid (28),

Oct-7-enoic acid and intermediate 5 following the procedure (Steps DH) reported for 18 [2- [4- (isopropyl) thiazol-2-yl] -7-methoxyquinolin-4-yloxy] -2, 15-dioxo-3,16-diazatricyclo [14,3,0,04,6] nonadec-7-ene-4-carboxylic 10: m / z = 633 (M + H) +.

Example 24: Synthesis of N- [17- [2- (4-isopropylthiazol-2-yl) -7-methoxy-8-methylquinolin-4-yloxy] -2,14-dioxo-3,15 diazatricyclo [13.3, 0.04.6] octadec-7-eno-4-carbonyl] (cyclopropyl) sulfonamide (59).

The title compound was prepared from 17- [2- (4-isopropylthiazol-2-yl) -7-methoxy-8-methylquinolin-4-yloxy] -2,14 dioxo-3,15-diazatricyclo acid [13, 3,0.04.6] octadec-7-eno-4-carboxylic acid (58) following the procedure set for the synthesis of N - [[18- [2- [4- (isopropyl) thiazol-2-yl] - 7-methoxyquinolin-4-yloxy] -2,15-dioxo-3,16 diazatricyclo [14,3,0,04,6] nonadec-7-en-4-yl] carbonyl] (cyclopropyl) sulfonamide 11: m / z = 736 (M + H) +, 1H NMR (CDCl3):

5 0.90-1.01 (m, 1H), 1.05-1.15 (m, 1H), 1.15-1.45 (m, 5H), 1.45 (d, J = 6, 9 Hz, 6H), 1.4-1.55 (m, 3H), 1.6-1.8 (m, 2H), 2.85-2.95 (m, 1H), 2.15-2 , 25 (m, 2H), 2.3-2.4 (m, 1H), 2.45-2.55 (m, 1H), 2.6-2.7 (m, 1H), 2.65 (s, 3H), 2.9-3 (m, 1H), 3-3.1 (m, 1H), 3.15-3.25 (m, 1H), 3.85 (d, J = 10 , 8 Hz, 1H), 3.95 (s, 3H), 4.1 (dd, J = 11.3 Hz, J = 3.6 Hz, 1H), 4.6 (t, J = 8.0 Hz, 1H), 5.0 (t, J = 10.6 Hz, 1H), 5.5 (t, J = 3.2 Hz, 1H), 5.60-5.70 (m, 1H), 6.75 (s, 1H), 7.02 (s, 1H), 7.2 (d, J = 9.2 Hz, 1H), 7.5 (s, 1H), 7.9 (d, J = 9.2 Hz, 1H), 11 (br s, 1H).

Example 25: Synthesis of N- [17- [2- (4-isopropylthiazol-2-yl) -7-methoxy-8-methylquinolin-4-yloxy] -2,14-dioxo-3,15 diazatricyclo [13.3 , 0,04,6] octadec-7-eno-4-carbonyl] (1-methylcyclopropyl) sulfonamide (60).

The title compound was prepared from 17- [2- (4-isopropylthiazol-2-yl) -7-methoxy-8-methylquinolin-4-yloxy] -2,14 dioxo-3,15-diazatricyclo acid [13, 3,0,04,6] octadec-7-ene-4-carboxylic (58) and 1-methylcyclopropylsulfonamide following the procedure set forth for the synthesis of N - [[18- [2- [4- (isopropyl) thiazole-] 2-yl] -7-methoxyquinolin-4-yloxy] -2,15-dioxo-3,16 diazatricyclo [14,3,0,04,6] nonadec-7-en-4-yl] carbonyl] (cyclopropyl) sulfonamide 11: m / z = 750 (M + H) +, 1H NMR (CDCl3): 0.90-1.01 (m, 1H), 1.05-1.15 (m, 1H), 1.15- 1.45 (m, 4H), 1.45 (d, J = 6.9 Hz, 6H), 1.4-1.5 (m, 3H), 1.55 (s, 3H), 1.61 , 8 (m, 2H), 2.85-2.95 (m, 1H), 2.15-2.25 (m, 2H), 2.3-2.4 (m, 1H), 2.45 -2.55 (m, 1H), 2.6-2.7 (m, 1H), 2.65 (s, 3H), 2.9-3.0 (m, 1H), 3-3.1 (m, 1H), 3.15-3.25 (m, 1H), 3.85 (d, J = 10.8 Hz, 1H), 3.95 (s, 3H), 4.1 (dd, J = 11.3 Hz, J = 3.6

20 Hz, 1H), 4.6 (t, J = 8.0 Hz, 1H), 5.0 (t, J = 10.6 Hz, 1H), 5.5 (t, J = 3.3 Hz , 1H), 5.60-5.70 (m, 1H), 6.75 (s, 1H), 7.02 (s, 1H), 7.2 (d, J = 9.2 Hz, 1H) , 7.5 (s, 1H), 7.9 (d, J = 9.2 Hz, 1H), 11 (br s, 1H).

Example 26: Synthesis of N- [17- [8-chloro-2- (4-isopropylthiazol-2-yl) -7-methoxyquinolin-4-yloxy] -2,14-dioxo-3,15 diazatricyclo [13,3, 0.04.6] octadec-7-eno-4-carbonyl] (1-methylcyclopropyl) sulfonamide (61).

The title compound was prepared from 17- [8-chloro-2- (4-isopropylthiazol-2-yl) -7-methoxyquinolin-4-yloxy] -2,14 dioxo-3,15-diazatricyclo [13 , 3,0,04,6] octadec-7-ene-4-carboxylic (56) and 1-methylcyclopropylsulfonamide following the procedure set forth for the synthesis of N - [[18- [2- [4- (isopropyl) thiazole-] 2-yl] -7-methoxyquinolin-4-yloxy] -2,15-dioxo-3,16 diazatricyclo [14,3,0,04,6] nonadec-7-en-4-yl] carbonyl] (cyclopropyl) sulfonamide 11: m / z = 770 (M + H) +, 1H NMR (CDCl3): 0.90-0.98 (m, 1H), 1.05-2.0 (m, 2H), 1.3- 1.4 (d, J = 6.9 Hz, 6H), 1.45-1.55 (m, 2H), 1.5 (s, 3H), 1.55-1.7 (m, 2H) ,

30 1.75-1.9 (m, 2H), 1.9-2.1 (m, 2H), 2.1-2.4 (m, 2H), 2.4-2.5 (m, 2H), 2.6-2.7 (m, 2H), 3-3.1 (m, 1H), 3.15-3.25 (m, 1H), 3.3-3.4 (m, 1H), 3.6-3.7 (m, 1H), 3.9 (d, J = 11.6 Hz, 1H), 4.05 (s, 3H), 4.6 (t, J = 8 , 0 Hz, 1H), 5.2 (t, J = 10.6 Hz, 1H), 5.5 (br s, 1H), 5.6-5.7 (m, 1H), 6.9 ( br s, 1H), 7.1 (s, 1H), 7.2 (d, J = 9.3 Hz, 1H), 7.53 (s, 1H), 7.95 (d, J = 9, 3 Hz, 1H), 10.8 (br s, 1H).

Example 27: Synthesis of 17- [2- (4-isopropylthiazol-2-yl) -7-methoxy-8-methylquinolin-4-yloxy] -2,14-dioxo-3,15 diazatricyclo [13,3,0, 04.6] octadec-7-eno-4-carboxylic (62).

The title compound was prepared from 4-hydroxy-2- (4-isopropylthiazol-2-yl) -7-methoxyquinoline, oct-7-enoic acid

5 and intermediate 5 following the procedure (Steps DH) consigned for the acid 18- [2- [4- (isopropyl) thiazol2-yl] -7-methoxyquinolin-4-yloxy] -2,15-dioxo-3.16 -diazatricyclo [14,3,0,04,6] nonadec-7-ene-4-carboxylic 10: m / z = 619 (M + H) +.

Example 28: Synthesis of N- [17- [2- (4-isopropylthiazol-2-yl) -7-methoxyquinolin-4-yloxy] -2,14-dioxo-3,15

diazatricyclo [13,3,0,04,6] octadec-7-eno-4-carbonyl] (cyclopropyl) sulfonamide (63):

10 The title compound was prepared from 17- [2- (4-isopropylthiazol-2-yl) -7-methoxy-8-methylquinolin-4-yloxy] -2,14-dioxo-3,15-diazatricyclo [13 , 3,0,04,6] octadec-7-eno-4-carboxylic (62) following the procedure set for the synthesis of N - [[18- [2- [4- (isopropyl) thiazol-2-yl]] -7-methoxyquinolin-4-yloxy] -2,15-dioxo-3,16

15 diazatricyclo [14,3,0.04,6] nonadec-7-en-4-yl] carbonyl] (cyclopropyl) sulfonamide 11: m / z = 722 (M + H) +, 1H NMR (CDCl3): 0 , 99-1.77 (m, 17H), 1.94 (dd, J = 6.0 Hz, J = 9.7 Hz, 1H), 2.12-2.26 (m, 2H), 2, 37 (dd, J = 7.3 Hz, 16.4 Hz, 1H), 2,572.71 (m, 3H), 2.96 (m, 1H), 3.04 (m, 1H), 3.22 ( m, 1H), 3.92 (m, 1H), 3.96 (s, 3H), 4.14 (dd, J = 3.7 Hz, 11.3 Hz, 1H), 4.58 (t, J = 7.9 Hz, 1H), 5.05 (t, J = 10.6 Hz, 1H), 5.53 (m, 1H), 5.66 (m, 1H), 6.58 (s, 1H), 7.06 (s, 1H), 7.12 (dd, J = 2.5 Hz, J = 9.1 Hz, 1H), 7.37 (d, J = 2.5 Hz, 1H) , 7.56 (s, 1H), 7.93 (d, J = 9.1 Hz, 1H), 10.8 (br s, 1H).

Example 29: Synthesis of N- [17- [2- (4-isopropylthiazol-2-yl) -7-methoxyquinolin-4-yloxy] -2,14-dioxo-3,15 diazatricyclo [13,3,0,04 , 6] octadecane-4-carbonyl] (cyclopropyl) sulfonamide (64):

To a solution of the olefin N- [17- [2- (4-isopropylthiazol-2-yl) -7-methoxyquinolin-4-yloxy] -2,14-dioxo-3,15 diazatricyclo [13,3,0,04 , 6] octadec-7-ene-4-carbonyl] (cyclopropyl) sulfonamide (63, 100 mg, 0.139 mmol) in MeOH (3.0 ml) heated to 80 ° C, 2,4,6-triisopropylbenzene sulfonohydrazide ( Tris-NHNH2) and triethylamine little by little for 5 hours. The reaction mixture was then concentrated under reduced pressure. The residue was partitioned between CH2Cl2 and a saturated NaHCO3 solution, washed successively with 1N HCl and brine, dried (MgSO4), filtered and evaporated. Purification by flash chromatography (gradient of AcOEt / CH2Cl2, 0: 1 to 1: 9) followed by recrystallization from isopropyl ether / petroleum ether, and then preparative HPLC provided 6 mg (6%) of the title product (59) as a white powder: m / z = 724 (M + H) +. 1H NMR (CDCl3): 0.90-1.70 (m, 21H), 1.95-2.03 (m, 2H),

10 2.25-2.35 (m, 2H), 2.63-2.68 (m, 2H), 2.99 (m, 1H), 3.22 (m, 1H), 3.41 (m , 1H), 3.96 (m, 5H), 4.15 (d, J = 15 Hz, 1H), 4.60 (t, J = 7.9 Hz, 1H), 5.53 (m, 1H ), 6.57 (s, 1H), 7.05 (s, 1H), 7.12 (dd, J = 2.5 Hz, 9.1 Hz, 1H), 7.38 (d, J = 2 , 5 Hz, 1H), 7.56 (s, 1H), 7.93 (d, J = 9.1 Hz, 1H), 10.8 (br s, 1H).

Example 30: Synthesis of a quinazoline as a P2 building block

2- (4-Fluoro-benzoylamino) -4-methoxy-3-methyl-benzoic acid methyl ester (65)

4-Fluoro-benzoic acid (700 mg, 5 mmol) was dissolved in dichloromethane (20 ml) and pyridine (2 ml). 2-Amino-4-methoxy-3-methyl-benzoic acid methyl ester (878 mg, 4.5 mmol) was added and the mixture was refluxed for 5 hours. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried, filtered and evaporated and the residue obtained was purified by column chromatography on silica gel and eluted with 1: 1 ether-pentane.

20 which gave the pure title compound (870 mg, 61%). MS (M + H +) 1318.

2- (4-Fluoro-benzoylamino) -4-methoxy-3-methyl-benzoic acid (66)

LiOH (1M, 4 ml) was added to a solution of 2- (4-fluoro-benzoylamino) -4-methoxy-3-methylbenzoic acid (65) (870 mg, 2.7 mmol) in tetrahydrofuran (15 ml), water (7.5 ml) and methanol (7.5 ml). The mixture was heated at 50 ° C for 4 h. Water (30 ml) was then added and the volume was reduced by half. Acidification with acetic acid followed by filtration gave the pure title compound (830 mg, 100%). MS (M + H +) 304.

2- (4-Fluoro-phenyl) -7-methoxy-8-methylquinazolin-4-ol (67) 2- (4-fluoro-benzoylamino) -4-methoxy-3-methyl-benzoic acid (66) ( 830 mg, 2.7 mmol) at 150 ° C in formamide (20 ml) for 4 h. Excess formamide was removed by distillation. Water was added and the precipitated product was filtered to give the pure title compound (462 mg, 83%). MS (M + H +) 285.

Example 31: General procedure for the preparation of substituted quinazolin-4-oles

To a suspension of a substituted 2-amino-benzamide [A] (1 eq) in dry THF (60 ml) was added pyridine (2 eq) and the mixture was cooled to 5 ° C. The acid chloride [B] (1.25 eq) was added slowly and the mixture was stirred at room temperature overnight. The mixture was evaporated under reduced pressure and then suspended in water. The compound

10 was left in the water for several hours, filtered and washed with cold water and diethyl ether. The product [C] was dried under vacuum. Yield: 90-100%.

When the acid chloride [B] used was a nicotinyl chloride hydrochloride, then 2.5 eq of pyridine was used and the mixture was stirred for 2-3 days at room temperature instead of overnight.

The amide formed [C] (1 eq) was added to a suspension of sodium carbonate (2.5 eq) in a 1: 1 mixture of water

15 and EtOH, and the mixture was refluxed for 2 hours. EtOH was removed under reduced pressure, a 5% citric acid solution was added and the mixture was allowed to stand overnight. The product [D] was isolated by filtration, then washed with water and diethyl ether and dried in vacuo.

Example 32: 7-Methoxy-8-methyl-2-pyridin-3-quinazolin-4-ol (68)

The general procedure described in Example 31 was followed using 2-amino-4-methoxy-3-methyl-benzamide as a benzamide derivative and nicotinyl chloride hydrochloride as an acid chloride, which gave the title compound (2, 5 g, 92%), [M + H] = 268.

Example 33: 7-Methoxy-8-methyl-2-pyridin-4-quinazolin-4-ol (69)

The general procedure described in Example 31 was followed using 2-amino-4-methoxy-3-methyl-benzamide as a benzamide derivative and isonicotinoyl chloride hydrochloride as acid chloride, which gave the title compound (1, 6 g, 60%), [M + H] = 268.

The general procedure described in Example 31 was followed using 2-amino-4-methoxy-3-methyl-benzamide as a benzamide derivative [A] and acetic acid chloride as acid chloride [B], which gave the compound of title (2.2 g, 100%). 1H-NMR DMSO-D6 δ 1.2 (m, 3H), 2.38 (s, 3H), 2.6 (m, 2H), 3.90 (s, 3H), 7.18 (d, 2H ), 7.96 (d, 2H), 11.88 (s, 1H).

Example 35: 7-Methoxy-8-methyl-2- (4-methoxyphenyl) -quinazolin-4-ol (71)

The general procedure described in Example 31 was followed using 2-amino-4-methoxy-3-methyl-benzamide as

10 derived from benzamide [A] and 4-methoxybenzoic acid chloride as acid chloride [B], which gave the title compound (5.5 g, 92%). 1H-NMR DMSO-D6 δ 2.38 (s, 3H), 3.82 (s, 3H), 3.92 (s, 3H), 7.04 (d, 2H), 7.20 (d, 1H ), 8.00 (d, 1H), 8.20 (d, 2H), 12.18 (s, 1H).

Example 36: 8-Methoxy-2-phenyl-quinazolin-4-ol (72)

The general procedure described in Example 31 was followed using 2-amino-4-methoxy-3-methyl-benzamide as a benzamide derivative [A] and benzoyl chloride as acid chloride [B], which gave the compound of titer (2.0 g, 80%), [M + H] = 253. 1H-NMR DMSO-D6 δ 3.97 (s, 3H), 7.39-7.72 (m, 6H), 8, 19 (m, 2H), 12.48 (s, 1H) .Example 37: 2 (3-Fluoro-phenyl) -7-methoxy-8-methylquinazolin-4-ol (73)

The general procedure described in Example 31 was followed using 2-amino-4-methoxy-3-methyl-benzamide as a benzamide derivative [A] and 3-fluorobenzoyl chloride as acid chloride [B], which gave the title compound (2.1 g, 73%), [M + H] = 271.

Example 38: 2- (3,5-Difluoro-phenyl) -7-methoxy-8-methylquinazolin-4-ol (74) The general procedure described in Example 31 was followed using 2-amino-4-methoxy-3- methyl-benzamide as a benzamide derivative [A] and 3,5-difluoro-benzoyl chloride as acid chloride [B], which gave the title compound (2.1 g, 85%), [M + H] = 303.

Example 39: 7-Methoxy-8-methylquinazolin-4-ol (75)

The title compound was formed as a byproduct when the ring closure reaction, step [B] to [C], in the general procedure was carried out in DMF instead of in EtOH.

Example 40: Activity of the compounds of formula [1]

Replicon Assay

The compounds of formula (I) were examined for activity in inhibiting HCV RNA replication in a cell assay. The assay demonstrated that the compounds of formula (I) exhibited activity against functional HCV replicons in a cell culture. The cell assay was based on a bicistronic expression construct, as described 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 screening strategy

15 multi-target In essence, the method was as follows:

The assay used the stably transfected Huh-7 luc / neo cell line (referred to hereafter as Huh-Luc). This cell line harbors an RNA that encodes a bicistronic expression construct comprising the NS3-NS5B wild type regions of HCV type 1b translated from an Internal Ribosome Entry Site (IRES) of the encephalomyocarditis virus (EMCV), preceded for an infor portion

20 madora (FfL-luciferase), and a selectable marker portion (neo®, neomycin phosphotransferase). The construct is limited by 5 'and 3' NTRs (untranslated regions) of HCV type 1b. Continued culture of the replicon cells in the presence of G418 (neo®) depends on the replication of HCV RNA. Stably transfected replicon cells expressing HCV RNA, which replicates autonomously and at high levels, encoding inter alia luciferase, are used to screen antiviral compounds.

The replicon cells were spread in 384 well plates in the presence of test and control compounds that were added in various concentrations. After a 3 day incubation, HCV replication was measured by luciferase activity assay (using standard luciferase assay substrates and reagents, and a Perkin Elmer ViewLuxTM ultraHTS microplate imaging processor). Replicon cells in control cultures have high luciferase expression in the absence of any inhibitor. The inhibitory activity of com

The position on luciferase activity was monitored in Huh-Luc cells, making possible a dose response curve for each compound tested. The EC50 values were then calculated, which represents the amount of the compound required to reduce the level of luciferase activity detected by 50%, or more specifically, the ability of the genetically bound HCV replicon RNA to replicate.

Table 1 below lists compounds that were prepared according to any one of the examples before

35 riores. The compounds are numbered with the same numbers provided in Examples 1-29. The activities of the tested compounds are also represented.

Table 1

Compound No.

Structural formula EC50 (µM)

57

0.012

12

1,978

eleven

0.017

10

5,045

Compound No.

Structural formula EC50 (µM)

13

0.020

31

4,941

32

0.017

26

0.004

63

0.024

Compound No.

Structural formula EC50 (µM)

33

6,103

3. 4

0.040

29

1,956

30

0.006

41

0.280

Compound No.

Structural formula EC50 (µM)

42

0.002

64

0.067

35

1,631

36

0.004

59

0.003

Compound No.

Structural formula EC50 (µM)

58

1,595

56

0.318

61

0.001

60

0.014

54

10

Compound No.

Structural formula EC50 (µM)

55

0.198

Example 31: In vitro metabolic blockade of HCV NS3 / 4a protease inhibitors by ritonavir.

Compound No. 11 of Table 1 was tested in a metabolic blocking experiment using 3 μM test compound together with 10 μM ritonavir that acted as a enhancer.

5 The test compound and ritonavir were added to human liver microsomes (protein concentration 1 mg / ml) suspended in potassium phosphate buffer (pH = 7.4), until final concentrations were obtained in the reaction mixture of compound of 3 μM test and 10 μM ritonavir. In parallel non-reinforced reactions, ritonavir was not added. Boiled human liver microsomes were used for blank experiments. After the addition (in a 1: 3 ratio) of a cofactor mixture consisting of β-nicotinamide-adenine-dinucleotide-phosphate (β-NADP,

10 0.5 mg / ml, 653.2 μM). D-glucose-6-phosphate (2 mg / ml, 7.1 mM), glucose-6-phosphate dehydrogenase (1.5 U / ml) in 2% NaH-CO3, the reaction mixture was incubated at 37 ° C for 30 or 120 minutes, after which the reaction was stopped by increasing the temperature to 95 ° C. The concentrations of the test compound were determined using HPLC-MS.

The results are summarized below in Table 2. Values are percentages of the test compound detected.

15 tados after the indicated incubation times compared to the initial concentration of test compound. Each value is the average value of the results of two independent experiments.

Table 2

Compound no.

30 ' 120 '

% Compound Detected

% Compound Detected

Without booster

Ritonavir  Without booster Ritonavir

eleven

28 79 0 91

The experiment demonstrates a practically complete blockade of the compound of metabolization of the test compound (3 μM) by the addition of 10 μM ritonavir.

Claims (13)

1. A compound that has the formula an N-oxide, addition salt, quaternary amine, metal complex, and stereochemically isomeric form thereof, wherein the dashed line represents an optional double bond between the C7 and C8 atoms; R1 is aryl or a saturated 5-or 6-membered monocyclic, partially unsaturated or completely unsaturated heterocyclic ring system, or 9 to 12 bicyclic ring wherein said ring system contains a nitrogen atom, and optionally 1 to 3 additional heteroatoms selected of the group constituted by 10 oxygen, sulfur and nitrogen, and wherein the remaining members of the ring are carbon atoms; wherein said ring system may optionally be substituted on any carbon or nitrogen atom of the ring with one, two, three, or four substituents each independently selected from C3-7cycloalkyl, aryl, Het, -C (= O) NR5aR5b, -C (= O) R7, -C (= O) OR6a, and C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl, Het, -C (= O) NR5aR5b, -NR5aR5b, -C (= O) R7, -NR5aC (= O) R7, -NR5aSOpR8, -SOpR8, SOpNR5aR5b, -C (= O) OR6, or -NR5aC (= O) OR6a; and wherein the substituents on any carbon atom of the heterocyclic ring can also be selected from -OR8, -SR8, halo, polyhalo-C1-6alkyl, oxo, thio, cyano ,, nitro, azido, -NR5aR5b, -NR5aC (= O ) R7, -NR5aSOpR8, -SOpR8, -SOpNR5aR5b, -C (= O) OH, and -NR5aC (= O) OR6a; L is a direct bond, -O-, -O-C1-4alkanediyl-, -O-CO-, -O-C (= O) -NR5a-u -O-C (= O) -NR5a-C1-4alcanediyl-; R2 represents hydrogen, -OR6, -C (= O) OR6, -C (= O) R7, -C (= O) NR5aR5b, -C (= O) NHR5c, -NR5aR5b, -NHR5c, 20 NHSOpNR5aR5b, -NR5aSOpR8 , or -B (OR6) 2; R3 and R4 are hydrogen or C1-6alkyl; or R3 and R4 considered together, can form a C3-7cycloalkyl ring; n is 3, 4, 5, or 6; p is 1 or 2; each of R5a and R5b are, independently, hydrogen, C3-7cycloalkyl, aryl, Het, C1-6alkyl substituted op Tionally with halo, C1-6alkoxy, cyano, polyhaloC1-6alkoxy, C3-7cycloalkyl, aryl, or with Het; or R5a and R5b considered together with the nitrogen atom to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl, 4C1-6alkylpiperazinyl, 4-C1-6alkylcarbonyl-piperazinyl, and morpholinyl; wherein the morpholinyl and piperidinyl groups may be optionally substituted with one or two C1-6alkyl radicals; R5c it is C3-7cycloalkyl, aryl, Het, -O-C3-7cycloalkyl, -O-aryl, -O-Het, C1-6alkyl, or C1-6alkoxy, wherein said C1-6alkyl or C1-6alkoxy can each be optionally substituted with -C (= O) OR6, C3-7cycloalkyl, aryl or Het; R6 is hydrogen; C2-6alkenyl; Het; C3-7cycloalkyl optionally substituted with C1-6alkyl; or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or Het; R6a it is C2-6alkenyl, C3-7cycloalkyl, Het, or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or Het; R7 is hydrogen, C1-6alkyl, C3-7cycloalkyl, or aryl; R8 is hydrogen, polyhaloC1-6alkyl, aryl, Het, C3-7cycloalkyl optionally substituted with C1-6alkyl, or C1-6alkyl optionally substituted with C3-7cycloalkyl, aryl or Het; aryl as a group or part of a group is phenyl, naphthyl, indanyl, or 1,2,3,4-tetrahydronaphthyl, each of which may be optionally substituted with one, two or three substituents selected from halo, C1-6alkyl, po5 lihaloC1-6alkyl, hydroxy, C1-6alkoxy, polyhaloC1-6alkoxy, C1-6alkoxyC1-6alkyl, carboxyl, C1-6alkylcarbonyl, C1-6alkoxycarbonyl, cyano, nitro, amino, mono- or diC1-6alkylamino, aminocarbonyl, monocarbonyl, monocarbonyl, monocarbonyl -6alkylaminocarbonyl, azido, mercapto, C3-7cycloalkyl, phenyl, pyridyl, thiazolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C1-6alkylpiperazinyl, 4-C1-6alkylcarbonyl-piperazinyl, and morpholinyl; wherein the morpholinyl and piperidinyl groups may be optionally substituted with one or two radicals C1-6alkyl; and the phenyl, pyridinyl, thiazolyl, pyrazolyl groups may optionally be substituted with one, two or three substituents each independently selected from C1-6alkyl, C1-6alkoxy, halo, amino, mono- or diC1-6alkylamino; Het as a group or part of a group is a saturated, partially unsaturated or completely unsaturated 5- or 6-membered heterocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, said heterocyclic ring being optionally condensed with a benzene ring, and wherein the Het group as a whole may optionally be substituted with 1, 2 or 3 substituents each independently selected from the group consisting of halo, C1-6alkyl, polyhaloC1-6alkyl, hydroxy, C1- 6alkoxy, polyhaloC1-6alkoxy, C1-6alkoxyC1-6alkyl, carboxyl, C1-6alkylcarbonyl, C1-6alkoxycarbonyl, cyano, nitro, amino, mono- or diC1-6alkylamino, aminocarbonyl, mono- or di C1-6alkylaminocarbonyl, C3-7cycloalkyl, phenyl, pyridyl, thiazolyl, pyrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-C1-6alkylpiperazinyl, 4-C1-6alkylcarbonyl-piperazinyl, and morpholinyl; wherein the morpholinyl and piperidinyl groups may be optionally substituted with one or two C1-6alkyl radicals; and the phenyl, pyridyl, thiazolyl, pyrazolyl groups may optionally be substituted with 1, 2 or 3 substituents each independently selected from C1-6alkyl, C1-6alkoxy, halo, amino, mono- or diC1-6alkylamino. 2. A compound according to claim 1 wherein the compound has the formula (I-a):

3.

A compound according to any one of claims 1-2, wherein L is -O-, -O-CO- or a direct bond.

Four.

A compound according to any one of claims 1-2, wherein L is -O- and R1 is quinoli

Nile (in particular quinolin-4-yl, isoquinolinyl (in particular isoquinolin-1-yl), quinazolinyl (in particular quinazolin-4yl), or pyrimidinyl (in particular pyrimidin-4-yl), any of which is, with independence, mono-di-or trisubstituted optionally with C1-6alkyl, C1-6alkoxy, nitro, hydroxy, halo, trifluoromethyl, -NR5aR5b, -C (= O) NR5aR5b, C3-7cycloalkyl, aryl, Het, -C (= O ) OH, or -C (= O) OR6a; wherein aryl or Het are each, independently, optionally substituted with halo, C1-6alkyl, C1-6alkoxy, amino, mono- or diC1-6alkylamino, pyrrolidinyl, piperidinyl , Piperazinyl, 4-C1-6alkylpiperazinyl (e.g. 4-methylpiperazinyl), or morpholinyl; and wherein the morpholinyl and piperidinyl groups may be optionally substituted with one or two C1-6 alkyl radicals. 5. A compound according to claim 4, wherein L is -O- and R1 is (d-1) a radical of formula (d-2) a radical of formula (d-3) a radical of formula (d-4) a radical of formula or in particular, (d-4-a) a radical of formula (d-5) a radical of formula where in the radicals (d-1) - (d-5), as well as in (d-4a) and (d-5a): each of R1a, R1b, R1b ', R1d, R1d', R1e, R1f are independently any of the substituents selected from those mentioned as possible substituents in the R1 monocyclic or bicyclic ring systems, as specified in claim 1. 6. A compound according to claim 4, wherein L is -O- and R1 is a radical of formula Wherein R1f is hydrogen, C1-6alkyl, amino, mono- or diC1-6alkylamino, pyrrolidinyl, piperidinyl, piperazinyl, 4C1-6alkylpiperazinyl (in particular 4-methylpiperazinyl), or morpholinyl. 7. A compound according to any one of claims 1-6, wherein (f) R2 is -NHR5c, where R5c is C1-6alkyl, aryl, Het, C1-6alkoxy, -O-aryl, or -O-Het; or

(g)

R2 is -OR6, where R6 is hydrogen, methyl, ethyl, or tert-butyl; or 15 (h) R2 is -NHS (= O) 2R8, where R8 is methyl, cyclopropyl, methylcyclopropyl, or phenyl; or

(i)

R2 is -C (= O) OR6, -C (= O) R7, -C (= O) NR5aR5b, or -C (= O) NHR5c, where R5a, R5b, R5c, R6 or R7 are as defined in claim 1, and wherein R5c is cyclopropyl; or

(j)

R2 is -NHS (= O) 2NR5aR5b where R5a and R5b are each independently hydrogen, C3-7cycloalkyl or C1-6alkyl.

8.

A compound according to any one of claims 1-7, wherein R3 and R4 are both hydrogen.

9.

A compound according to any one of claims 1-8, wherein n is 4 or 5.

10.

A compound according to any one of claims 1-9 other than an N-oxide, or salt.

5 11. A combination comprising

(to)

a compound as defined in any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof; Y

(b)

ritonavir, or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising a vehicle, and as an active ingredient an effective amount 10 as an antiviral of a compound according to any one of claims 1-10 or a combination according to claim 11. 13. A compound according to any of claims 1-10 or a combination according to claim 11, for use as a medicament. 14. Use of a compound according to any of claims 1-10 or a combination according to claim 11, for the manufacture of a medicament for inhibition of HCV replication. 15. A process for preparing a compound according to any of claims 1-10, wherein said process comprises: (a) preparing a compound of formula (I) wherein the bond between C7 and C8 is a double bond, which is a compound of formula (Id), by forming a double bond between C7 and C8, in particular by a reaction from 20 olefin metathesis, with concomitant cyclization to give the macrocycle as outlined in the following reaction scheme: (b) converting a compound of formula (I-d) into a compound of formula (I) wherein the bond between C7 and C8 in the macrocycle is a simple bond, that is compound of formula (I-e): by a reduction of the double bond C7 and C8 in the compounds of formula (I-d);

(C)

preparing a compound of formula (I) wherein R2 represents -NR5aR5b, -NHR5c, -NHSOpNR5aR5b, -NR5aSOpR8, these groups being collectively represented by -NR2-aR2-b, which is represented by the formula (Id-1), by formation of an amide bond between an intermediate compound (III) and an H-NR2-aR2-b (IVa), or to prepare a compound of formula (I) wherein R2 represents -OR6, ie a compound (Id-2) , by formation of an ester bond between an intermediate compound (III) and an alcohol (IV-b) as outlined in the following scheme where G represents a group:

(d)

preparing a compound of formula (I) wherein R2 represents hydrogen, that is to say a compound (Id-4), from an ester (Id-2-a), which is an intermediate compound of formula (Id-2) in where R6 is C1-4alkyl, by a reduction reaction to give the corresponding alcohol (Id-3), followed by an oxidation reaction with a mild oxidant:

(and)

reacting an intermediate compound (V) with the intermediate compounds (VI-a), (VI-b), (VI-c), (VI-d)

or (VI-e) as outlined in the following reaction scheme where the various radicals have the meanings specified above and C1-4 Alk represents C1-4alkanediyl:

and wherein X in (VI-a) represents hydroxy or a labile group; reaction which is in particular an O-arylation reaction wherein X represents a labile group, or a Mitsunobu reaction, wherein X is hydroxy; (f) prepare a compound of formula (I) wherein L is a urethane group (L is -O-C (= O) -NR5a-) by reaction 5 of an intermediate compound (V) with an amine (VI-b) or (VI-C) in the presence of a carbonyl introducing agent, the latter comprising in particular phosgene or a phosgene derivative; (g) preparing a compound of formula (I) wherein L is -OC (= O) - by reaction of an alcohol (V) with an acid (VI-d) or active derivative thereof, such as an acylating agent corresponding, in particular an acid anhydride or acid chloride; 10 (h) preparing a compound of formula (I) wherein L is -O-C1-4alkanediyl-by an ether formation reaction between (V) and (VI-e); (i) convert compounds of formula (I) into one another by a functional group transformation reaction; or (j) preparing a salt form by reacting the free form of a compound of formula (I) with an acid or a base.