MX2008001393A - Macrocyclic inhibitors of hepatitis c virus - Google Patents

Abstract

Compounds of the formula (I), and N-oxides, salts, and stereoisomers thereof wherein A is OR1, NHS(=O)PR2;wherein;R1is hydrogen, C1-C6alkyl, C0-C3alkylenecarbocyclyl, C0-C3alkylene-heterocyclyl;R2is C1-C6alkyl, C0-C3alkylenecarbocyclyl, C0-C3alkyleneheterocyclyl;p is independently 1 or 2;n is 3, 4, 5 or 6;---- deonotes an optional double bond;L is N or CRz;Rz is H or forms a double bond with the asterisked carbon;Rq is H or when L is CRz, Rq can also be C1-C6alkyl;Rr is quinazolinyl, optionally substituted with one two or three substituents each independently selected from C1-C6alkyl, C1-C6alkoxy, hydroxyl, halo, haloC1-C6alkyl, amino, mono- or dialkylamino, mono- or dialkylaminocarbonyl, C1-C6alkyl- carbonylamino, C0-C3alkylenecarbocyclyl and C0-C3alkyleneheterocyclyl;R5is hydrogen, C1-C6alkyl, C1-C6alkoxyC1-C6alkyl or C3-C7cycloalkyl;R6is hydrogen, C1-C6alkyl, C1-C6alkoxy, C0-C3alkylenecarbocyclyl, C0-C3alkyleneheterocyclyl, hydroxy, bromo, chloro or fluoro have utility in the treatment or prophylaxis of flaviviral infections such as HCV.

Description

MACROCYCLIC INHIBITORS OF HEPATITIS C VIRUS DESCRIPTIVE MEMORY The present invention relates to macrocyclic compounds that possess inhibitory activity on the replication of the hepatitis C virus (HCV). It also refers to compositions comprising these compounds as active ingredients, as well as processes for preparing these compounds and compositions. The hepatitis C virus is the leading cause of chronic liver disease worldwide and has become a focus of considerable medical research. HCV is a member of the Flaviviridae family of viruses in the hepacivirus gene, 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 family of animal pestiviruses, which includes the bovine virus of viral diarrhea (VBDV). HCV is a positive-sense, single-stranded RNA virus with a genome of about 9600 bases. The genome comprises the two 5 'and 3' untranslated regions that adopt secondary RNA structures and a central open reading frame encoding a unique polyprotein of about 3010-3.030 amino acids. The polyprotein encodes ten gene products that are generated from the precursor polyprotein by an organized series of co-and post-translational endoproteolytic cleavages. mediated by host and viral proteases. Viral structural proteins include the core nucleocapsid protein and two envelope glycoproteins E1 and E2. The non-structural proteins (NS) encode some essential viral enzymatic functions (helicase, polymerase, protease), as well as proteins of unknown function. Replication of the viral genome is mediated by an RNA-dependent RNA polymerase, encoded by the non-structural protein 5b (NS5B). In addition to the polymerase functions, it was shown that the functions of viral helicase and protease, both encoded in the bifunctional NS3 protein, are essential for the replication of HCV RNA. In addition to the serine protease NS3, HCV also encodes a metalloproteinase in the NS2 region. After the initial acute infection, a majority of infected individuals developed chronic hepatitis because HCV replicates preferentially in hepatocytes, but is not directly cytopathic. In particular, the lack of a vigorous response of T lymphocytes and the high tendency of the virus to mutate appear to promote a high degree of chronic infection. Chronic hepatitis can progress to hepatic fibrosis producing cirrhosis, terminal liver disease and HCC (hepatocellular carcinoma), making it the main cause of liver transplantation. There are 6 major genotypes of HCV and more than 50 subtypes, which are distributed geographically differently. Type 1 HCV is the predominant genotype in Europe and the United States. The extensive genetic heterogeneity of HCV has an important diagnosis and implications clinics, possibly explaining the difficulties for the development of vaccines and the lack of response to therapy. HCV transmission can occur through contact with contaminated blood or blood products, for example following the transfusion of blood or use of intravenous drugs. The introduction of diagnostic tests used in the evaluation of blood produced a downward trend in the incidence of HCV in post-transfusion. However, given the slow progression to terminal liver disease, existing infections will continue to pose a serious medical and economic burden for decades. Current therapies against HCV are based on interferon-alpha (IFN-a) (pegylated) in combination with ribavirin. This combination therapy produces a sustained virological response in more than 40% of patients infected by genotype 1 virus and around 80% of those infected with genotypes 2 and 3. In addition to limited efficacy on type 1 HCVThis combination therapy has important side effects and is poorly tolerated in many patients. Most side effects include influenza-like symptoms, hematologic abnormalities, and neuropsychiatric symptoms. Therefore, there is a need for more effective, convenient and better tolerated treatments. Recently, two peptidomimetic HCV protease inhibitors gained attention as clinical candidates, namely, BILN-2061 disclosed in WO00 / 59929 and VX-950 disclosed in WO03 / 87092. A The amount of similar HCV protease inhibitors has also been revealed in the academic and patent literature. It is already evident that prolonged administration of BILN-2061 or VX-950 selects HCV mutants that are resistant to the respective drug, termed drug escape mutants. These drug escape mutants possess characteristic mutations in the HCV protease genome, notably D168V, D168A and / or A156S. Therefore, additional drugs with different resistance patterns are required to provide patients who do not improve treatment options and it is likely that multi-drug combination therapy is the norm in the future, even for first-line treatment. Experience with anti-HIV drugs and HIV protease inhibitors in particular has emphasized that sub-optimal pharmacokinetics and complex dosage regimes quickly result in unintended compliance failures. This in turn means that the minimum concentration of 24 hours (minimum plasma concentration) for the respective drugs in an HIV regimen often decreases below the IC90 or ED90 threshold for much of the day. It is considered that a minimum level of 24 hours of at least the IC50, and more realistically, the IC90 or ED90, is essential to decrease the development of drug escape mutants. Achieving the pharmacokinetics and metabolism of the drug necessary to allow such minimal levels provides a rigorous challenge for the design of drugs. The strong The peptidomimetic nature of the HCV protease inhibitors of the prior art, with multiple peptide bonds, represents pharmacokinetic hurdles for effective dosing regimes. There is a need for HCV inhibitors that can overcome the disadvantages of current HCV therapy, such as side effects, limited efficacy, the emergence of resistance and compliance failures. The present invention relates to inhibitors of HCV replication which exhibit at least one improved property in view of the compounds of the prior art compounds. In particular, the inhibitors of the present invention are superior in one or more of the following related pharmacological properties, ie potency, decreased cytotoxicity, improved pharmacokinetics, improved resistance profile, acceptable dosage and pill load. In addition, the compounds of the present invention have a relatively low molecular weight and are typically easy to synthesize, starting from starting materials that are commercially available or readily available through the synthesis methods known in the art. The present invention relates to inhibitors of HCV replication, which may be represented by the formula (I): and their N-oxides, salts, and stereoisomers where A is OR1, NHS (= O) pR 2; wherein R1 is hydrogen, C6 alkyl, alkylene Co-C3-carbocyclyl, C0-C3 alkylene-heterocyclyl; R 2 is C 1 -C 6 alkyl, C 0 -C 3 alkylenecarbocyclyl, C 0 -C 3 alkylene heterocyclyl; p is independently 1 or 2; n is 3, 4, 5 or 6; - denotes an optional double link; L is N or CRz; Rz is H or forms a double bond with carbon with an asterisk; Rq is H or when L is CRz, Rq can also be alkyl Rr is quinazolinyl, optionally substituted with one or two substituents each independently selected from Ci-Cß alkyl, CrC6 alkoxy, hydroxyl, halo, haloalkyl of CrC6l amino, mono- or dialkylamino, mono- or dialkylaminocarbonyl, C 1 -C 6 alkylcarbonylamino, Co-C 3 alkylenecarboxy and C 0 -C 3 alkyleneheterocyclyl; R 5 is hydrogen, C 1 -C 7 alkyl, C 1 -C 6 alkoxy C 1 -C 6 alkyl or C 3 -C 7 cycloalkyl; and wherein each CrC6 alkyl, C0-C3 alkylenecarbocyclyl or C0-C3 alkylene heterocyclyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, oxo, nitrile, azido, nitro, Ci-Cß alkyl, alkylene Co-C3-carbocyclyl, C0-C3 alkylene-heterocyclyl, NH2C (= O) -, Y-NRaRb, YO-Rb, YC (= O) Rb, Y- (C = O) NRaRb, Y-NRaC (= O) Rb, Y-NHSOpRb, YS (= O) pRb and YS (= O) pNRaRb, YC (= O) ORb, Y-NRaC (= O) ORb; And independently it is a C3 bond or alkylene; Ra is independently H, CrC6 alkoxy, C ^ Cs alkyl or; Rb is independently H, CrC6 alkyl, C-pCβ alkoxy, C0-C3 alkylenecarbocyclyl or C0-C3 alkylene heterocyclyl; or Ra and Rb together with the nitrogen to which they are attached are joined to form a heterocyclyl group. The invention furthermore relates to methods for the preparation of the compounds of formula (I), their prodrugs, N-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms, their intermediates, and the use of the intermediates in the preparation of the compounds of formula (I). The invention relates to the compounds of formula (I) per se, prodrugs, N-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms, for use as a medicament. The invention furthermore relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. The pharmaceutical compositions may comprise combinations of the aforementioned compounds with other anti-HCV agents. The invention further relates to the use of a compound of formula (I), or its prodrug, N-oxide, addition salt, quaternary amine, metal complex, or stereochemically isomeric form, for the manufacture of a medicament for inhibiting the replication of the VHC. Or the invention relates to a method for inhibiting the replication of HCV in a warm-blooded animal, said method comprising administering an effective amount of a compound of formula (I), or its prodrug, N-oxide, addition salt , quaternary amine, metal complex, or stereochemically isomeric form. The invention further encompasses compounds of formula I repreed by the formula (It): (It) and its N-oxides, salts, and stereoisomers, where Xt is N, CH and where Xt carries a double bond it is C; Rt1 is -ORt5, -NH-SO2Rt6; Rt2 is hydrogen, and where Xt is C or CH, Rt2 can also be C? -6 alkyl; Rt3 is hydrogen, C? -6 alkyl, C1-6 alkoxy-C-? 6 alkyl, or C3-7 cycloalkyl; Rt 4 is quinazolinyl optionally substituted with one, two or three substituents, each independently selected from C-α-6 alkyl, C β alkoxy. hydroxy, halo, polyhaloalkyl of C -? - 6, polyhaloalkoxy of C 1-6, amino, mono- or dialkylamino of C -? - 6, mono- or dialkylamino C? -6-carbonyl, alkyl Cr6-carbonylamino, aryl and Het; n is 3, 4, 5, or 6; where each dotted line (repreed by) repres an optional double bond; Rt5 is hydrogen; aril; Het; C3-7 cycloalkyl optionally substituted with C-? -6 alkyl; or C? -6 alkyl optionally substituted with C3-7 cycloalkyl, aryl or with Het; Rt6 is aryl; Het; C3-cycloalkyl optionally substituted with C? -6 alkyl; or d-6 alkyl optionally substituted with C 3-7 cycloalkyl, aryl or Het; each aryl as a group or part of a group is phenyl optionally substituted by one, two or three substituents selected from halo, hydroxy, nitro, cyano, carboxyl, C? -6 alkyl, C? -6 alkoxy, C-? alkoxy? -6-C C-alkyl (6-alkyl-6-carbonyl, amino, mono- or dialkylamino of C?-6, azido, mercapto, polyhaloalkyl of C-α-6, polyhaloalkoxy of C - ?. 6, cyclopropyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-alkyl C6- piperazinyl, 4-alkylC6-6-carbonylpiperazinyl, and morpholinyl, and each Het as a group or part of a group is a saturated 5- or 6-membered heterocyclic ring, partially unsaturated or completely unsaturated containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, and optionally being substituted with one, two or three substituents each independently selected from the group consisting of halo, hydroxy, nitro, cyano, carboxyl, C -? - 6alkyl, C-? -6alkoxy, C? -6alkyl-C? -6alkyl, Ci-b-alkyl bonyl, amino, mono- or dialkylamino of C -? - 6, azido, mercapto, polyhaloalkyl of C 1-6, polyhaloalkoxy of C? -6, cyclopropyl, pyrrolidinyl, piperidinyl, piperazinyl, 4-alkyl d-β-piperazinyl, 4-alkyl C? -6-carbonyl-piperazinyl and morpholinyl. It will be apparent that in the alternative embodiment of the invention in the immediately preceding paragraph, Rt1 broadly corresponds to A, Rt2 broadly corresponds to Rq, Rt3 broadly corresponds to R5, X broadly corresponds to L, aryl is broadly encompassed by C0-C3 alkylene " carbocyclyl where C 0 -C 3 alkylene is zero (ie a bond) and Het is broadly encompassed by C 0 -C 3 alkyl heterocyclyl, where C 0 -C 3 alkylene is zero (ie a bond). The preferences expressed below for formula (I) apply even to the corresponding values in formula It and references to formula (I) should be considered as including the corresponding compounds of formula (It). As used above and will be used hereafter, the following definitions apply unless otherwise specified. The term halo is generic for fluorine, chlorine, bromine and iodine. The term "haloalkyl of C -? - 6" as a group or part of a group, e.g. in C?-6 haloalkoxy, is defined as C ?_6 mono- or substituted polyhalo alkyl, in particular d.6 alkyl substituted with up to one, two, three, four, five, six, or more halo atoms , such as methyl or ethyl with one or more fluorine atoms, for example, difluoromethyl, trifluoromethyl, trifluoroethyl. HE prefers trifluoromethyl. Also included are perfluoro-alkyl groups of d-6, which are C1-6 alkyl groups where all hydrogen atoms are replaced by fluorine atoms, e.g. pentafluoroethyl. In case more than one halogen atom is attached to an alkyl group within the polyhaloalkyl definition of d-6, the halogen atoms may be the same or different. As used herein "C 1-4 alkyl" as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as for example methyl, ethyl, 1-propyl , 2-propyl, 1-butyl, 2-butyl, 2-methyl-1-propyl; "d-6 alkyl" embraces d-4 alkyl radicals and their higher homologs having 5 or 6 carbon atoms such as, for example, 1-pentyl, 2-pentyl, 3-pentyl, 1 -hexyl, 2- hexyl, 2-methyl-1-butyl, 2-methyl-1-pentyl, 2-ethyl-1-butyl, 3-methyl-2-pentyl, and the like. Of interest among alkyl of C? -6 is alkyl of d-4. The term "C2-6 alkenyl" as a group or part of a group defines straight and branched chain hydrocarbon radicals having saturated carbon-carbon bonds and at least one double bond, and having from 2 to 6 carbon atoms, such as, for example, ethenyl (or vinyl), 1-propenyl, 2-propenyl (or allyl), 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 2-pentenyl, 3-pentenyl , 2-hexenyl, 3-hexenyl, 4-hexenyl, 2-methyl-2-butenyl, 2-methyl-2-pentenyl and the like. Of interest among C2-6 alkenyl is alkenyl of C2-4- The term "C2-6 alkynyl" as a group or part of a group defines straight and branched chain hydrocarbon radicals having saturated carbon-carbon bonds and at least one triple bond, and having from 2 to 6 carbon atoms, such as, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 2-pentynyl, 3-pentynyl, 2-hexynyl, 3-hexynyl and the like. Of interest between C2-6 alkynyl is C2-4 alkynyl. Cycloalkyl of C3.7 is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. C0_3 alkylene defines a (C0) bond or straight-chain or branched bivalent saturated hydrocarbon radicals having from 1 to 3 carbon atoms such as, for example, methylene, ethylene, 1,3-propandiyl, 1,2-propandiyl, and similar, especially methylene. "Alkoxy" of d-6 means C-6-alkyloxy where C? -6 alkyl is as defined above. As used herein, 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 sulfonyl moiety when two such terms are they bind to a sulfur atom. Whenever a ring or ring system is substituted with an oxo group, the carbon atom to which the oxo is attached is a saturated carbon. 'Amino' unless the context suggests otherwise, includes NH2, NHalkyl of C? .C6 or N (C? -C6-) alkyl 2, where in the amino definitions each alkyl of d.Ce is especially an alkyl variant of d-C3, or amines saturated cyclics such as pyrrolidinyl, piperidinyl, piperazinyl, 4-C6-C6-piperazinyl alkyl, such as 4-methylpiperazinyl, 4-C6-alkylcarbonylpiperazinyl and morpholinyl. 'Amido' includes C (= O) NH2, and alkylamido, such as C (= O) NHCalkyl C6, C (= O) N (C6alkyl) 2 especially C (= O) NHalkyl d-C3, C ( = O) N (C3 alkyl) 2 or -NH (C = O) C6 alkyl, for example -NHC (= O) CHC (CH3) 3, including -NH (C = O) C3 alkyl. 'C0-C3 alkylenearyl' as applied herein includes an aryl moiety such as a phenyl, naphthyl or phenyl fused to C3-C7 cycloalkyl (for example indanyl), said aryl being directly linked (ie Co) or through of a methyl, ethyl, or propyl intermediate group as defined for C 1 -C 3 alkylene above. Unless otherwise indicated the aryl and / or its fused cycloalkyl moiety is optionally substituted with 1-3 substituents selected from halo, hydroxy, nitro, cyano, carboxy, d-C6 alkyl, d-C6 alkoxy, C6 alkoxy CrC6 alkyl, d-C6 alkanoyl, amino, azido, oxo, mercapto, nitro Co-C3alkylenecarbocyclyl, alkylene Co-C3-heterocyclyl, it should be understood that the heterocyclic and carbocyclic portions in the substituent C0-C3 alkylene-carbocyclyl or alkylene Co-C3-heterocyclyl may be substituted as provided herein but typically not with another C0-C3 alkylenecarbocyclyl or C0-C3 alkylene-heterocyclyl. "Aryl" has the following meaning, that is, where the alkyl bond of C0-C3 is absent. 'Co-C3 alkylene C3C7 cycloalkyl' as applied herein includes a C3-C7 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, said cycloalkyl is directly linked (ie Co alkyl) or through an intermediate methyl, ethyl, propyl or isopropyl group as defined for C C3 alkylene above. The cycloalkyl group may contain a unsaturated bond. Unless otherwise indicated the cycloalkyl portion is optionally substituted with 1-3 substituents selected from halo, hydroxy, nitro, cyano, carboxy, d-C6 alkyl, d-C6 alkoxy, C6-C6 alkoxy-alkyl d -C6, C? -C6 alkanoyl, amino, azido, oxo, mercapto, nitro C0-C3-carbocyclyl alkyl, Co-C3-heterocyclyl alkyl, it being understood that the heterocyclic and carbocyclic portions in the C0-C3-carbocyclyl alkylene substituent or C0-C3-alkylene heterocyclic may be substituted as provided herein but typically not with another alkylene Co-C3-carbocyclyl or alkylene Co-C3-heterocyclyl. 'C0-C3-carbocyclyl alkyl' as applied herein includes C0-C3 alkylaryl and C0-C3 alkyl-C3-C7 cycloalkyl. Unless otherwise indicated the aryl or cycloalkyl group is optionally substituted with 1-3 substituents selected from halo, hydroxy, nitro, cyano, carboxy, d-C6 alkyl, d-C6 alkoxy, d6-C6 alkoxy C? -C6, d-C? Alkanoyl, amino, azido, oxo, mercapto, nitro, Co-C3-carbocyclyl alkyl and / or Co-C3-heterocyclyl alkyl, it being understood that the heterocyclic and carbocyclic portions in the substituent C0-C3-carbocyclyl alkylene or C0-C3-alkylene heterocyclyl alkylene may be substituted as provided herein but typically not with another C0-C3 alkylene-carbocyclyl or C0-C3 alkylene-heterocyclyl. "Carbocyclyl" has the corresponding meaning, that is, where the alkyl bond of Co-C3 he is absent. 'C0-C3heterocyclyl alkylene' as applied herein includes a ring containing a monocyclic, saturated or unsaturated heteroatom such as piperidinyl, morpholinyl, piperazinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazinolyl, isothiazinolyl, thiazolyl, oxadiazolyl, , 2,3-triazolyl, 1,4-triazolyl, tetrazolyl, furanyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, or any such group fused to a phenyl ring, such as quinolinyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazinolyl, benzisothiazinolyl, benzothiazolyl, benzoxadiazolyl, benzo-1, 2,3-triazolyl, benzo-1, 2,4-triazolyl, benzotetrazolyl, benzofuranyl, benzothienyl, benzopyridyl, benzopyrimidyl, benzopyridazinyl, benzopyrazolyl, etc., said ring is attached directly, ie (C0), or through an intermediate group methyl, ethyl, propyl, or isopropyl as defined for C 1 -C 3 alkylene above. Any unsaturated ring having an aromatic character can be recognized as heteroaryl herein. Unless otherwise indicated the hetero ring and / or its fused phenyl moiety is optionally substituted with 1-3 substituents selected from halo, hydroxy, nitro, cyano, carboxy, d-Cß alkyl, C -? - C6 alkoxy , d-Cß alkoxy-d-C6 alkyl, C?-C6 alkanoyl, amino, azido, oxo, mercapto, nitro, C 0 -C 3 alkylcarbocyclyl, C 0 -C 3 alkyl-heterocyclyl. "Heterocyclyl" and "Heteroaryl" have the corresponding meaning, that is, where the C0-C3 alkyl bond is absent. Typically the heterocyclyl and carbocyclyl moieties within the The scope of the above definitions is thus a monocyclic ring with 5 or especially 6 ring atoms, or a bicyclic ring structure comprising a 6-membered ring fused to a 4, 5 or 6 membered ring. Typically such groups include C3-C8 cycloalkyl, phenyl, benzyl, tetrahydronaphthyl, indenyl, indanyl, heterocyclyl such as azepanyl, azocanyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, thiopyranyl, furanyl. , tetrahydrofuranyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, tetrazolyl, pyrazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzisoxazolyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, tetrahydroquinazolinyl and quinoxalinyl, any of which may be optionally substituted as defined herein. Thus, the saturated heterocycle moiety includes radicals such as pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, piperazinyl, idolinyl, azetidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, hexahydropyrimidinyl, hexahydropyridazinyl, 1,4. , 5,6-tetrahydropyrimidinylamine, dihydrooxazolyl, 1,2-thiazinanyl-1,1-dioxide, 1, 2,6-tiadiazinnyl-1,1-dioxide, isothiazolidinyl-1,1-dioxide and imidazolidinyl-2 , 4-dione, whereby the unsaturated heterocycle includes radicals with an aromatic character such as furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, indolyl, isoindolyl. In each case the heterocycle may be fused with a phenyl ring to form a bicyclic ring system. The radical Het is a heterocycle as specified in the present specification and claims. Examples of Het comprise, for example, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazinolyl, isothiazinolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl (including 1, 2,3- triazolyl, 1,4-triazolyl), tetrazolyl, furanyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, pyrazolyl, triazinyl, and the like. Of interest among Het radicals are those that are non-saturated, particularly those that have an aromatic character. Of greater interest are those Het radicals that have one or two nitrogens. Each of the Het radicals mentioned above may be optionally substituted with the amount and class of substituents mentioned in the definitions of the compounds of formula (I), (It) or any of the subgroups of the compounds of formula (I). Some of the Het radicals mentioned in this and in the following paragraph may be substituted with one, two or three hydroxy substituents. Such substituted hydroxy rings can occur as their tautomeric forms bearing keto groups. For example a 3-hydroxypyridazine portion can occur in its tautomeric form 2H-pyridazin-3-one.

It should be noted that the positions of the radical on any molecular portion used in the definitions can be anywhere on such a portion 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 3-pentyl. When a variable occurs more than once in any constituent, each definition is independent. Whenever used from now on, the term "compounds of formula (I)", or "the present compounds" or similar terms, include the compounds of formula (I), their prodrugs, N-oxides, addition salts, quaternary amines, metal complexes, and stereochemically isomeric forms. One embodiment comprises the compounds of formula (I) or any subgroup of compounds of formula (I) specified herein, as well as the N-oxides, salts, as well as their possible stereoisomeric forms. Another embodiment comprises the compounds of formula (I) or any subgroup of compounds of formula (I) specified herein, as well as the salts and their possible stereoisomeric forms. The compounds of formula (I) have several chiral centers and exist as stereochemically isomeric forms. The term "stereochemically isomeric forms" as used herein defines all possible compounds made from the same atoms linked by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds of formula (I) can have. With reference to cases where (R) or (S) are used to designate the absolute configuration of a chiral atom within a substituent, the designation is made taking into consideration the complete compound and the substituent in isolation. Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms that said compound may have. Said mixture can contain all the diastereomers and / or enatomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of the present invention both in the pure form and mixed together are 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 term "stereoisomerically pure" refers to compounds or intermediates having a stereoisomeric excess of at least 80% (ie at least 90% of an isomer and maximum 10% of the others possible isomers) up to a stereoisomeric excess of 100% (ie 100% of one isomer and none of the other), more in particular, compounds or intermediates having a stereoisomeric excess of 90% up to 100%, even more in particular having a stereoisomeric excess of 94% up to 100% and more in particular having a stereoisomeric excess of 97% up to 100%. The terms "enantiomerically pure" and "diastereomerically pure" should be understood in a similar manner, but then taking into consideration 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 procedures known in the art. For example, the enantiomers can be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids or bases. Examples of these include tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphor sulfonic acid. Alternatively, the enantiomers can be separated by chromatographic techniques using chiral stationary phases. Said pure stereochemically isomeric forms can also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction originates stereospecifically. Preferably, if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will employ advantageous the enantiomerically pure starting materials. Diastereomeric racemates of the compounds of formula (I) can be obtained separately by conventional methods.

Suitable physical separation methods that can be used advantageously are, for example, selective crystallization and chromatography, for example column chromatography. For some of the compounds of formula (I), their prodrugs, N-oxides, salts, solvates, quaternary amines, or metal complexes, and the intermediates used in their preparation, the absolute stereochemical configuration was not determined experimentally. One skilled in the art can determine the absolute configuration of said compounds using methods known in the art such as, for example, X-ray diffraction. It is furthermore the intention of the present invention to include all isotopes of atoms that are produced in the present compounds Isotopes include those atoms that have the same atomic number but different mass numbers. By way of example and without limitation, hydrogen isotopes include tritium and deuterium. The carbon isotopes include C-13 and C-14. The term "prodrug" as used throughout this text means acceptable derivatives for pharmacological use such as esters, amides and phosphates, so that the in vivo biotransformation product resulting from the derivative is the active drug as defined in the compounds of formula (I). The reference of Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8th ed, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", p. 13-15) which describes prodrugs in general are incorporated herein. Preferably, the prodrugs have excellent aqueous solubility, increased bioavailability and are readily metabolized within the active inhibitors in vivo. Prodrugs of a compound of the present invention can be prepared by modifying the functional groups present in the compound such that the modifications are split, either by routine manipulation or in vivo, to the parent compound. Preferred are ester prodrugs acceptable for pharmaceutical use which are hydrolysable in vivo and are derived from those compounds of formula (I) having a hydroxy group or a carboxyl group. A hydrolysable ester in vivo is an ester that is hydrolyzed in the animal or human body to produce the parent acid or alcohol. Esters suitable for pharmaceutical use for carboxy include Ci-β alkoxymethyl esters for example methoxymethyl, d-6 alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, esters of C3-8 cycloalkoxycarbonyloxy-d-6 alkyl for example 1- cyclohexylcarbonyloxyethyl; 1, 3-dioxolen-2-onylmethyl esters for example 5-methyl-1,3-dioxolen-2-onylmethyl; and C6-C6 alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl which can be formed in any carboxy group in the compounds of this invention. An in vivo hydrolysable ester of a compound of formula (I) which contains a hydroxy group includes inorganic esters such as phosphate esters and α-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester are cleaved to give the parent hydroxy group. Examples of α-acyloxyalkyl ethers include those of acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give esters of alkyl carbonate), dialkylcarbamoyl and N- (dialkylaminoethyl) -N-alkylcarbamoyl (to give carbamates ), dialkylaminoacetyl and carboxyacetyl. Examples of substituents on benzoyl include morpholino and piperazino attached from a nitrogen atom in the ring by a methylene group in the 3 or 4 position of the benzoyl ring. For therapeutic use, salts of the compounds of formula (I) are those where the counterion is acceptable for pharmaceutical use. However, salts of acids and bases that are not acceptable for pharmaceutical use can also find their use, for example, in the preparation or purification of a compound acceptable for pharmaceutical use. All salts, whether or not acceptable for pharmaceutical use, are included in the scope of the present invention. Acceptable base and acid addition salts for pharmaceutical use as mentioned hereinbefore comprise the therapeutically active non-toxic base and acid addition salt forms from which the formula (I) compounds can be formed. The salts of acid addition acceptable for pharmaceutical use can conveniently be obtained by treating the base form with said appropriate acid. Suitable acids comprise, for example, inorganic acids such as hydrohalic acids, eg, hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and similar acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (ie ethanedioic), malonic, succinic (ie butanedioic acid), maleic, fumaric, malic (ie, hydroxybutanedioic acid), tartaric acid , citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and similar acids. On the contrary said salt forms can be converted by the treatment with an appropriate base into the free base form. The compounds of formula (I) which contain an acidic proton can also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic or inorganic bases. Suitable base salt forms include, for example, ammonium salts, alkali metal and alkaline earth salts, eg, lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, for example, the 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 salts" as used hereinabove comprises the solvates that the compounds of formula (I) as well as their salts, can form. Such solvates are for example hydrates, alcoholates and the like. The term "quaternary amine" as used herein defines the quaternary ammonium salts that the compounds of formula (I) can form by the reaction between a basic nitrogen of a compound of formula (I) and an appropriate quaternizing agent, such as, for example, alkyl halide, aryl halide or optionally substituted arylalkyl halide, e.g. Methyl iodide or benzyl iodide. Other reagents with good leaving groups can also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates and alkyl p-toluenesulfonates. A quaternary amine has a positively charged nitrogen. Acceptable counterions for pharmaceutical use include chlorine, bromine, iodine, trifluoroacetate and acetate. The counterion of choice can be introduced using ion exchange resins. The? / -oxide forms of the present compounds comprise the compounds of formula (I) wherein one or more nitrogen atoms are oxidized to the so-called N-oxide. It will be appreciated that the compounds of formula (I) may have metal-binding, chelating, complexing properties and therefore may exist as metal complexes or metal chelates. Such metal derivatives of the compounds of formula (I) are included within the scope of the present invention. Some of the compounds of formula (I) may also exist in their tautomeric forms. Such forms, although not indicated explicitly in the above formula are 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 will be used as indicated in the following structural formula.

The asymmetric centers are present in positions 1, 4 and 6 of the macrocycle as well as in the carbon atom 3 'in the five-membered ring, in the carbon atom 2' when the substituent Rq is C1-6 alkyl, and on the carbon atom Y when L is CH. Each of these asymmetric centers can occur in their R or S configuration. The stereochemistry at position 1 preferably corresponds to that of an L-amino acid configuration, ie that of L-proline. When L is CH, the two carbonyls carried by the cyclopentane ring are preferably trans as described below.

The structure of formula (I) includes a cyclopropyl group as represented in the P1 fragment below: where C7 represents the carbon at position 7 and the carbons at position 4 and 6 are asymmetric carbon atoms of the cyclopropane ring. Notwithstanding other possible asymmetric centers in other segments of the compounds of the invention, the presence of these two asymmetric centers means that the compounds can exist as mixtures of diastereomers, such as the diastereomers of compounds of formula (I) wherein the carbon in position 7 is configured syn to carbonyl or syn to amide as shown below.

C7 syn to amide The structure of formula (I) may also include a proline residue (when L is N). Preferred are compounds of formula (I) wherein the substituent at the 1 (or 5 ') position and the -O-Rr substituent (at the 3' position) are in the trans configuration. Of particular interest are the compounds of formula (I) wherein position 1 has the configuration corresponding to L-proline and the substituent -O-Rr is in a configuration trans with respect to position 1. Preferably the compounds of formula (I) ) have the stereochemistry as indicated in the structures of formulas (Ia) and (lb) below: .Rr O ' , Rr O ' (Ia) (lb) An embodiment of the present invention relates to compounds of formula (I) or formula (Ia) or any subgroup of compounds of formula (I), where one or more of the following conditions apply: (a) Rq is hydrogen; (b) L is nitrogen; (c) a double bond is present between carbon atoms 7 and 8. One embodiment of the present invention relates to compounds of formula (I) or formulas (Ia), (lb), or any subset of compounds of formula (I), where one or more of the following conditions apply: (a) Rq is hydrogen; (b) X is CH; (c) a double bond is present between the carbon atoms 7 and 8. One embodiment of the present invention comprises compounds comprising the partial structure: Particular subgroups of compounds of formula (I) are those represented by the following structural formulas: (l-c) (l-d) Among the compounds of formula (1-c) and (1-d), those having the stereochemical configuration of the compounds of formulas (I-a), and (1-b), respectively, are of particular interest. The double bond between carbon atoms 7 and 8 in the compounds of formula (I), or in any subgroup of compounds of formula (I), can be in a cis configuration or in a trans configuration. Preferably the double bonds between the carbon atoms 7 and 8 are in a cis configuration as described in formulas (1-c) and (1-d). The double bond between carbon atoms 7 and 8 in the compounds of formula (I), or in any subgroup of compounds of formula (I), may be in a cis configuration or in a trans configuration. Preferably, the double bond between the carbon atoms 7 and 8 is in a cis configuration, as described in the formulas (l-c) and (l-d). In (Ia), (lb), (lc) and (ld), as applicable, A, L, n, Rr, Rq, R5 are as specified in the definitions of the compounds of formula (I) or of 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), (lb), (lc) or (ld), as well as any other subgroup defined herein, also include all prodrugs, N-oxides, salts of addition, quaternary amines, metal complexes and stereochemically isomeric forms of such compounds. When n is 2, the -CH2- portion in parentheses with "n" corresponds to an ethanediyl in the compounds of formula (I) or in any subgroup of compounds of formula (I). When n is 3, the -CH2- portion in parentheses with "n" corresponds to a propandiyl in the compounds of formula (I) or in any subgroup of compounds of formula (I). When n is 4, the -CH2- portion in parentheses with "n" corresponds to a butandiyl in the compounds of formula (I) or in any subgroup of compounds of formula (I). When n is 5, the -CH2- portion in parentheses with "n" corresponds to a pentandiyl in the compounds of formula (I) or in any subgroup of compounds of formula (I). When n is 6, the -CH2- portion in parentheses with "n" corresponds to a hexandyloyl in the compounds of formula (I) or in any subgroup of compounds of formula (I). Particular subgroups of the compounds of formula (I) are those compounds where n is 4 or 5. Modalities of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein (a) A is - OR1, in particular where R1 is C6-6 alkyl, such as methyl, ethyl, or tert-butyl and more preferably where R1 is hydrogen; or (b) A is -NHS (= O) 2R2, particularly where R2 is C6-C6 alkyl optionally substituted with C3-C7 cycloalkyl, C3-C7 cycloalkyl optionally substituted with d-C6 or aryl alkyl, e.g. where R2 is methyl, cyclopropyl or phenyl. For example R2 can be 1-methylcyclopropyl. Other embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein (a) Rq is hydrogen; L is CH or N; (b) Rq is methyl, L is C and the dotted line represents a double bond. Other embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein (a) R5 is hydrogen; (c) R5 is C6 alkyl; (d) R5 is CrCß-C6-C6 alkoxy or C3-C7 cycloalkyl. Preferred embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein R5 is hydrogen, or C6-6 alkyl) more preferably hydrogen or methyl. Modalities of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein Rr is quinazolin-4-yl. Typically, quarzolin-4-yl Rr is optionally mono, di, or tri substituted, for example with d-C6 alkyl, d-C6 alkoxy, hydroxy, halo, trifluoromethyl, mono- or dialkylamino of C? -C6) mono- or dialkylaminocarbonyl of d-Cβ, aryl, heteroaryl or heterocyclyl, wherein aryl heteroaryl or heterocyclyl are each independently, optionally substituted with halo, d-Cd alkyl, C6 alkoxy, polyhalo-C6 alkoxy , amino, mono- or dialkylamino of CrC6, cyclopropyl, pyrrolidinyl, piperidinyl, piperazinyl, N-methyl-piperazinyl or morpholinyl. Quinazoline moieties of Rr include a radical (f-1): or in particular a radical (f-1 -a): where R9, R6 and R1 have the meanings stated for the substituents of Rr or Rt4 where specifically R9 is C3-C7 cycloalkyl, aryl or Het, any of which is optionally substituted with one, two or three (in particular with one ) R 10.; d Jo? "ndJe? or R 10 is hydrogen, C 1 -C 6 alkyl) C 3 -C 7 cycloalkyl, aryl, Het (preferably mono- or di-substituted with d-C 6 alkyl), pyrrolidinyl, piperidinyl, piperazinyl, 4-methyl-piperazinyl, thiomorpholinyl or morpholinyl, aminocarbonyl, mono or dialkylamino C? -C6carbonyl; wherein the piperidinyl, morpholinyl or thiomorpholinyl may be optionally substituted with one or two d-C6 alkyl radicals; or R 9 is C C β alkoxy; R6 is hydrogen, halogen, d-C6 alkyl, especially methyl, C3-C cycloalkyl, aryl, Het, halo, in particular bromine, chlorine or fluorine; R11 is hydrogen or C6-C6 alkoxy; Favorable embodiments of R9 for quinazolines include aryl or Het, especially where R9 is phenyl, pyridyl, thiazolyl, oxazolyl or pyrrazolyl any of which is optionally substituted with one, two or three (in particular with one) R10 as defined. Another alternative embodiment of R9 is alkoxy, especially ethoxy and isopropoxy. Modalities of R 10 for quinazolines include hydrogen, methyl, ethyl, isopropyl, tert-butyl, alkoxy such as methoxy, halo (including dihalo), such as difluoro), pyrrolidinyl, piperidinyl, piperazinyl, 4-alkyl d-Cβ-piperazinyl (eg 4-methylpiperazinyl), thiomorpholinyl or morpholinyl, C 1-6 alkylamino, (C 6 alkyl) 2 amino, aminocarbonyl , mono or dialkylaminoC? -6-carbonyl, or C3-C7 cycloalkyl (in particular cyclopropyl). Preferred moieties of R9 for quinazolines include phenyl substituted with one or two R10 groups such as hydrogen, methyl, ethyl, isopropyl, tert-butyl, alkoxy such as methoxy, saturated monocyclic amino, alkylamino of d-6) (alkyl d-6) 2 amino or alkylamido of d-6 or halo (in particular fluorine) especially when R6 is hydrogen, methyl or bromine. Preferably the phenyl substituent is in the para position. Especially favorable structures for R9 according to this embodiment are phenyl, p-methoxyphenyl and p-fluorophenyl. Other configurations for R9 at the quinazolyl radical specified in (f-1) or (f-1 -a) include any of the radicals: where R10 is as defined above or in particular hydrogen, d-C6 alkyl (such as methyl, ethyl, isopropyl, tert-butyl), pyrrolidinyl, piperidinyl, piperazinyl, 4-alkyl d-C6-piperazinyl, N-methylpiperazinyl, thiomorpholinyl or morpholinyl, CrC 6 alkylamino, (C 1 -C 6 alkyl) 2amino or aminocarbonyl, mono or dialkylamino CrCβ-carbonyl. R9 for quinazolines may include wherein R10 is hydrogen, d-6 alkyl (such as methyl, ethyl, isopropyl, tert-butyl), d-C6 alkylamino, (CrC6 alkyl) 2amino, C? -C6 alkylamido, morpholinyl, thiomorpholinyl or piperidin-1 -yl, the morpholine or pipieridine is optionally substituted with one or two C6 alkyl groups. Moieties of R6 for quinazolines include alkyl of d-6, in particular methyl, halo (eg bromine, chlorine fluorine) especially bromine. Modalities of R 11 for quinazolines include hydrogen, d-6 alkyloxy (in particular methoxy). Specific moieties of the compounds of formula (I) or any other subgroup of formula (I) are those where Rr is: (f-2) (f-3) where R10, R10, and R11 are as specified above, and in particular R11 is hydrogen or d-β alkoxy (eg methoxy) and R10 and R10, are particularly hydrogen, methoxy or halo such as fluorine or difluor. Conveniently, when R10 or R10 is not hydrogen, it is in the para position of the phenyl ring. Other favorable structures are the compounds of formula (I) or any other subgroup of formula (I) wherein Rr is: (f-2-Me) (f-3- e) where R 10, R 0, and R 11 are as specified above and in particular R 11 is hydrogen or d-6 alkoxy (eg methoxy) and R 10 and R 10, are particularly hydrogen, methoxy or halo such as fluorine or difluor. Conveniently, R10 or R10 is in the para position of the phenyl ring. Particularly favorable compounds of this modality are those where Rr is in agreement with the formulas (f-4), (f-5) or (f-6) The compounds of the invention are prepared as generally described below and in detail in the experimental part. A convenient intermediate to the compounds of formula (I) wherein Rr which is an 8-methyl substituted quinazolinyl derivative is the tri-substituted aniline of formula (II): said aniline derivative constitutes another aspect of the present invention. Other intermediates useful for the preparation of compounds of formulas (I) are quinazolinyl derivatives having the general formula (III) and in particular the formula (III-a), wherein X is OH or a leaving group such as a chloride, bromide or iodide type halide, or a sulfonic acid derivative such as a tosylate, triflate, mesylate or the like. Preferably X is OH. R6, R9 and R11 are according to previously defined for the compounds of formulas (f-1) and (f-1-a). Compounds (III) and (Illa) are novel compounds and constitute another aspect of the present invention. The various embodiments described above for the quinazolinyl portion is further applied to the compounds of formulas (III) and (Illa). Preferred moieties of R9 for the compounds of formula (III) and (Illa) include pyridyl and phenyl optionally substituted with one or two R10 groups such as hydrogen, methyl, ethyl, isopropyl, tert-butyl, saturated monocyclic amino, CrC6 alkylamino, (I rent or d-C6 alkylamido or halo (in particular fluorine) especially when R6 is hydrogen, methyl or bromine. Preferably the substituent is in the para position of the phenyl ring. A favorable structure for R9 is parafluorophenyl. Specific modalities of the compounds of formula (III) are those having the structure indicated in formulas (III-2) and (III-3): where X, R10, R10, and R11 are as specified above and in particular R11 is hydrogen or d-6alkoxy (eg methoxy) and R10 or R10 are particularly hydrogen, methoxy or halo such as fluorine or difluor. Fit convenient, R10 or R 0 is in the para position of the phenyl ring. Other favorable structures for the compounds of formula (III) are those according to the formulas (III-2-Me) and (III-3-Me): where X, R10, R10, and R11 are as specified above and in particular R11 is hydrogen or d-6alkoxy (eg methoxy) and R10 or R10 is particularly hydrogen, methoxy or halo such as fluorine or difluor. Conveniently, R10 or R10 is in the para position of the phenyl ring. Particularly favorable compounds of formula (III) are those having the formulas (III-4) or (III-5): (HI-4) (III-5) (III-6) where X is as described above. Modes of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein Rr is quinazolin-4-yl optionally mono, di, or tri substituted with methyl, ethyl, isopropyl, tert-butyl ( or t-butyl), methoxy, trifluoromethyl, trifluoromethoxy, fluorine, chlorine, bromine, mono- or dialkylamino of d-Cβ, mono- or dialkylamino carbonyl of Ci-Cß-, phenyl, methoxyphenyl, cyanophenyl, halophenyl, pyridyl, C 1 -C 4 alkyl-pyridyl, pyrimidinyl, morpholinyl, piperazinyl, alkyl dd- piperazinyl, pyrrolidinyl, pyrazolyl, alkyl dd-pyrazolyl, thiazolyl, alkyl dd.thiazolyl, cyclopropylthiazolyl, or mono- or dialkylamino d-4-tiazolyl. Modalities of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein Rr is: where R9 is hydrogen, halo, d-C6 alkyl > d-C6 alkoxy, d-C6 mono- or alkylamino, amino, aryl, heteroaryl or heterocyclyl, said aryl or heteroaryl or heterocyclyl is each independently and optionally substituted with one or two d-6alkyl alkoxy C? -C6, polyhalo-d-C6 alkoxy, halo, amino, mono- or dialkylamino of Ci.Ce; and each R6 and R11 are, independently, hydrogen, d-6 alkyl. C? -6 alkoxy, C? -6 mono- or dialkylamino, C 1-6 mono- or dialkylaminocarbonyl, hydroxy, halo, trifluoromethyl, aryl, heteroaryl or heterocyclyl; said aryl, heteroaryl or heterocyclyl is each, independently, optionally substituted with C-C-alkyl, d-C6-alkoxy, polyhalo-d-C-alkoxy, amino, saturated cyclic amino, mono- or dialkylamino of CrC6. Modalities of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein R9 is selected from the group consisting of: where R10 is, each independently, hydrogen, halo, d-C6 alkyl, amino, saturated cyclic amino, or mono- or di-alkylamino of d-C6. Modalities of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein Rr is: where R6 and R11 are, independently, hydrogen, d-Cß alkyl, C?-C6 alkoxy, d- C6 mono- or di-alkylamino, C6-mono- or di-alkylaminocarbonyl, hydroxy, halo, trifluoromethyl , aryl, heteroaryl or heterocyclyl; and R10 is independently hydrogen, d-C6 alkyl, d-Cß alkoxy, or halo. Other embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein Rr is: where R6 and R11 are, independently, hydrogen, d-Cß alkyl, d-Cβ alkoxy, d- C6 mono- or di-alkylamino, C?-6-carbonyl mono- or di-alkylamino, hydroxy, halo , trifluoromethyl, aryl or Het; and R10 is hydrogen, C6-6alkyl, CrC6alkoxy, or halo. Modalities of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein Rr is: where R6 and R11 are, independently, hydrogen, C6-C6alkyl, d-C6alkoxy, mono- or di-alkylamino of CrC6, mono- or di-alkylamino of CrC6-carbonyl, hydroxy, halo, trifluoromethyl; preferably R 4b is C-C alkoxy, more preferably methoxy; and R 0 is hydrogen, CrC 6 alkyl) amino, mono- or dialkylamino of C C 6, pyrrolidinyl, piperidinyl, piperazinyl, N-methyl-piperazinyl, or morpholinyl. Modalities of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein R4 is: where R6 and R11 are, independently, hydrogen, d-C6 alkyl, d-C6 alkoxy, d- C6 mono- or di-alkylamino) C- or C-carbonyl mono- or di-alkylamino, hydroxy, halo, trifluoromethyl; preferably R4b is d-6 alkoxy, more preferably methoxy, halo, or C? -3 alkyl; and R 10 is hydrogen, C 1 -C 6 alkyl, amino, mono- or di-alkylamino of d-Cß, pyrrolidinyl, piperidinyl, piperazinyl, N-methyl-piperazinyl, or morpholinyl. Modalities of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein Rr is: where R6 and R11 are, independently, hydrogen, d-C6 alkyl, d-Cß alkoxy, d- or C-, mono- or di-alkylamino, C- or C6-carbonyl mono- or di-alkylamino, hydroxy, halo , trifluoromethyl; preferably R 4b is C 1 -C 6 alkoxy, more preferably methoxy, halo, or C 1 -C 3 alkyl; and R 10 is hydrogen, CrC 6 alkyl, amino, mono- or di-alkylamino of CrC 6, pyrrolidinyl, piperidinyl, piperazinyl, N-methyl-piperazinyl, or morpholinyl.

Modalities of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein Rr is: where R6 and R11 are, independently, hydrogen, d-C6 alkyl, d-6 alkoxy, C- or C6 mono- or di-alkylamino, C- or C6-carbonyl mono- or di-alkylamino, hydroxy, halo, trifluoromethyl; preferably R 4b is C 1 -C 6 alkoxy, more preferably methoxy, halo, or d-C 3 alkyl; and R 4 'is hydrogen, C 1 -C 6 alkyl, amino, mono- or di-alkylamino of d-6, pyrrolidinyl, piperidinyl, piperazinyl, N-methyl-piperazinyl, or morpholinyl. Preferred embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein Rr is: wherein R9 is as defined in any of the groups or subgroups of compounds of formula (I); and R6 is hydrogen, halo, or trifluoromethyl. Other embodiments of the invention are compounds of formula (I) or any of the subgroups of compounds of formula (I) wherein R4 is: where R6 is hydrogen, halo, or trifluoromethyl. Other embodiments of the invention include those where R9 is wherein R10 is hydrogen, methyl, ethyl, isopropyl, tert-butyl, C3-C3 alkylamino, (C3-alkyl) 2-amino, (CrC6 alkyl) amido morpholin-4-yl, piperidin-1-yl, morpholine and piperidine optionally substituted with C1-C3 alkyl. Other embodiments of the invention include those where Rr is where R > 11 is H or methoxy. The compounds of formula (lc) and (ld) having a double bond in the macrocycle (ie between carbon atoms 7 and 8, represented by the formula (ld), (Ie), and (lf) hereinafter ), consist of three building blocks P1, P2, P3. For chemical purposes, the P2 building block of the compounds of formula (1-d) and (I-e) incorporates the carbonyl group attached to the 1 'position. The union of the building blocks P1 with P2 and P2 with P3 involves the formation of an amide bond. The union of blocks P1 and P3 involves the formation of the double bond. The joining of the building blocks P1, P2 and P3 to prepare the compounds (l-c) or (l-d) can be carried out in any given sequence. The last steps obviously involve a cyclization by which the macrocycle is formed.

In a preferred embodiment, the compounds (l-c) are prepared, first forming the amide bonds and the subsequent formation of the double bond bond between P3 and P1 with concomitant cycling to the macrocycle. Alternatively, in the compound of formula (I-c), a first amide bond is formed between the building blocks P2 and P1, followed by of the coupling of the building block P3, and the formation of a subsequent amide bond between P3 and P2 with concomitant ring closure. Still another methodology of alternative synthesis 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 the formation of a last amide bond between P1 and P2 with concomitant ring closure. It should be noted that in the compounds of formula (I-c), the formation of the amide bond between the blocks P2 and P3 can be obtained in two different positions of the urea motif. A first amide bond encompasses the nitrogen of the pyrrolidine ring and the adjacent carbonyl (marked with an asterisk). The formation of a second amide bond involves the reaction of the carbonyl with asterisk with a -NHR3 group. Both amide bond formations between the building blocks P2 and P3 are feasible. Compounds of formulas (l-d) can be prepared by linking P1 to P2 or vice versa, followed by the formation of the second amide bond between the building blocks P3 and P2 with cyclization concomitant with the macrocycle. Alternatively, in the compound of the formulas (1-d), the building block P1-P3 can also be synthesized before it is coupled to the building block P2. This building block P1-P3 can be made by a metathesis reaction, Wittig reaction, or the like, which is followed by the formation of two amide bonds with the building block P2, and the concomitant ring closure.

The individual building blocks can be prepared first and then coupled together or alternatively, the precursors of the building blocks can be coupled together and modified in a step subsequent to the desired molecular composition. The functionalities in each of the building blocks can be protected to avoid collateral reactions. The formation of the amide linkages can be carried out using standard procedures such as those used for the coupling of amino acids in the synthesis of peptides. The latter involves the dehydrated coupling of one carboxyl group of one reagent with one amino group of the other reagent to form a binding amide linkage. The formation of the amide bond can be carried out by reacting the starting materials in the presence of a coupling agent or by converting the carboxyl functionality to an active form such as an active ester or an acyl chloride. General descriptions of such coupling reactions and the reagents used therein can be found in the general texts on peptide chemistry, for example, M. Bodanszky, "Peptide Chemistry", 2nd ed., Springer-Verlag, Berlin, Germany, (1993), hereinafter simply referred to as Bodanszky, the contents of which are incorporated herein by reference. Examples of coupling reactions with amide bond formation include the azide method, the carbonic acid-carboxylic acid anhydride mixing method (isobutyl chloroformate), the carbodiimide (dicyclohexylcarbodiimide, diisopropylcarbodiimide, or water-soluble carbodiimide such as N-ethyl-N '- [(3-dimethylamino) propyl] carbodiimide), the active ester method (p-nitrophenyl ester, N-hydroxysuccinic ester), the K method of Woodward reagent, the carbonyldiimidazole method, the reduction-oxidation methods or phosphorous reagents. Some of these methods can be improved by adding suitable catalysts, eg, in the carbodiimide method by adding 1-hydroxybenzotriazole or 4-DMAP. Other coupling agents are (benzotriazol-1-yloxy) tris- (dimethylamino) phosphonium hexafluorophosphate, either by itself or in the presence of 1-hydroxybenzotriazole or 4-DMAP; or 2- (1 H-benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium tetrafluoroborate or O- (7-azabenzotrizol-1-yl) -N, N, N', N hexafluorophosphate '-tetramethyluronium. These coupling reactions can be carried out in any solution (liquid phase) or solid phase. The coupling reaction is preferably carried out in an inert solvent, such as halogenated hydrocarbons, for example, dichloromethane, chloroform, dipolar aprotic solvents such as acetonitrile, dimethylformamide, dimethylacetamide, ethers such as tetrahydrofuran. In many cases coupling reactions are performed in the presence of a suitable base such as a tertiary amine, e.g. triethylamine, diisopropylethylamine (DIPEA), N-methylmorpholine, N-methylpyrrolidine or 4-DMAP. The reaction temperature can vary between 0 ° C and 50 ° C and the reaction time can vary between 15 min and 24 h.

The functional groups in the building blocks that are joined together can be protected to avoid the formation of unwanted links. Suitable protecting groups that can be used are mentioned for example in Greene, "Protective Groups in Organic Chemistry", John Wiley & Sons, New York (1981) and "The Peptides: Analysis, Synthesis Biology", Vol. 3, Academic Press, New York (1981), hereinafter simply referred to as Greene, the disclosures of which are incorporated herein by reference. The carboxyl groups can be protected as an ester which can be cleaved to give the carboxylic acid. Protecting groups that can be used include 1) alkyl esters such as methyl, trimethylsilyl and tert-butyl; 2) aralkyl esters such as benzyl and substituted benzyl; or 3) esters that can be cleaved by soft reducing or soft base means such as trichloroethyl and phenacyl esters. 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, and 9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate groups such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4) cyclic alkyl carbamate groups such as cyclopentyl-oxycarbonyl and adamantyloxycarbonyl; 5) alkyl groups such as triphenylmethyl and benzyl; 6) trialkylsilyl such as trimethylsilyl; and 7) thiol containing such groups as phenylthiocarbonyl and dithiasuccinoyl. Interesting amino protecting groups are Boc and Fmoc. Preferably the a-amino protecting group is cleaved before the next coupling step. When the Boc group is used, the methods of choice are trifluoroacetic acid, pure or in dichloromethane, or HCl in dioxane or in ethyl acetate. The resulting ammonium salt is then neutralized either before coupling or in situ with basic solutions such as aqueous 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 20-22 ° C. Other functional groups which can undesirably interfere with the reactions during the synthesis process, for example during the coupling reaction of the building blocks, can also be protected. For example, hydroxyl groups can be protected by protecting groups such as those mentioned i.a. in Greene, "Protective Groups in Organic Chemistry," John Wiley & Sons, New York (1981). The hydroxy protecting groups comprise substituted methyl ethers, for example methoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl, 2- (trimethylsilyl) ethoxymethyl, t-butyl and other lower alkyl ethers, such as isopropyl, ethyl and especially methyl, benzyl and triphenylmethyl; tetrahydropyranyl; ethers of substituted ethyl, for example, 2,2,2-trichloroethyl; silyl ethers, for example, trimethylsilyl, t-butyldimethylsilyl and t-butyldiphenylsilyl; and esters prepared by the reaction of the hydroxyl group with a carboxylic acid, for example, acetate, propionate, benzoate and the like. Other amino groups can be protected by protecting groups that can be separated selectively. For example, when Boc is used as the α-amino protecting group, the following side chain protecting groups are suitable: portions of p-toluenesulfonyl (tosyl) can be used to protect other amino groups; Benzyl ethers (Bn) can be used to protect hydroxy groups; and benzyl esters can be used to protect other carboxyl groups. Or when Fmoc is chosen for a-amino protection, usually tert-butyl-based protecting groups are acceptable. For example, Boc can be used for other amino groups; tert-butyl ethers for hydroxyl groups; and tert-butyl esters for other carboxyl groups. Any of the protecting groups can be eliminated at any stage of the synthesis process but preferably, the protecting groups of any of the functionalities not involved in the reaction steps are eliminated after the completion of the construction of the macrocycle. The removal of protecting groups can be effected in any way that arises from the choice of protecting groups, these forms are well known to those skilled in the art.

The building blocks P1, P2 and P3 for the compounds (I-c) and (l-d) can be prepared starting from intermediates known in the art. A certain amount of these syntheses are described in more detail below.

Synthesis of building blocks P2 The building blocks P2 contain a pyrrolidine portion, a cyclopentane portion, or a cyclopentene portion substituted with a -O-Rr group. The Rr group can be coupled to any of these rings at any convenient stage of the synthesis of compounds according to the present invention. One method consists in first coupling the Rr group to the appropriate ring and then adding the other desired building blocks, ie P1 and P3, followed by the formation of the macrocycle. Another method consists in coupling the building blocks P2, which do not carry the substituent Rr, and P1, and adding the Rr group either before or after the formation of the macrocycle.

Synthesis and introduction of the P2 substitute The desired quinazoline group on the cyclic P2 scaffold can be introduced by various methods at any convenient stage of the synthesis.

Scheme 1 exemplifies the introduction of a P2 substituent by means of a Mitsunobu reaction. Mitsunobu, 1981, Synthesis, January, 1-28; Rano et al., Tetrahedron Lett., 1995, 36, 22, 3779-3792; Krchnak et al., Tetrahedron Lett, 1995, 36, 5, 6193-6196; Richter et al., Tetrahedron Lett., 1994, 35, 27, 4705-4706).

SCHEME 1 1 C The treatment of the appropriate cyclic hydroxy substituted p2 scaffold (1a) with the desired quinazolinol (1b) in the presence of triphenylphosphine and an activating agent of the diethyl azodicarboxylate type (DEAD), diisopropyl azodicarboxylate (DIAD) or the like, provides the alkylated compound (1c) ). The hydroxy group of the cyclic scaffold (1a) can be transformed, alternatively, into any other suitable leaving group such as a sulfonic acid derivative of the tosylate, mesylate or triflate type or the like by subjecting the alcohol to the appropriate sulfonylation conditions, type treatment with the desired acid anhydride or halide in a pyridine type solvent or using the desired sulfonic acid and triphenyl phosphine in the presence of DEAD in a toluene type solvent, or the hydroxy group can be converted to a halide by treatment of the alcohol with a suitable halogenating agent, for example the bromide can be prepared using a reagent such as phosphorus tribromide or similar. The leaving group obtained can then be replaced by a desired quinazolinol to give the alkylated derivative (le). An inverse strategy can be used alternatively where the hydroxy compound is used as a nucleophile and treated with a base such as sodium hydride or potassium t-butoxide or the like, in a solvent such as dimethylformamide (DMF) followed of the reaction of the resulting alkoxide with an alkylating agent Q-Lg, where Lg is a suitable leaving group such as a halide of the chloride, bromide or iodide type or a sulfonic acid derivative or the like and Q is a quinazoline derivative, provides the Desired substituted derivative (sic). An example applied to a proline derivative is described in E. M. Smith et al. in J. Med. Chem. (1988), 31, 875-885. It will be apparent that the above methods for introducing the quinazoline group to the cyclic P2 scaffold can be performed at any convenient stage of the synthesis of compounds according to the present invention. For example, the substituent R8 can be introduced into a suitable cyclic scaffold before the introduction of the other components of the compound or a protected hydroxy cyclic scaffold can be used through the synthesis and the quinazoline group introduced as the last step of the synthesis. An example of the synthesis of substituted quinazoline derivatives is shown in Scheme 2.

SCHEME 2 The transformation of a nitro substituted benzoic acid derivative (2a) into the corresponding benzamide for example by subjecting the acid to the Vilsmeyer conditions followed by the reduction of the nitro group using conditions of the catalytic hydrogenation type on Raney-nickel gives the corresponding amine (2 C). The amine obtained can be subsequently coupled to a heterocyclic carboxylic acid (2d) under peptide coupling conditions, such as with HOBt and EDAC or any other suitable coupling agent well known in the art. The ring closure and dehydration can then be effected by treatment with a base such as sodium hydrogen carbonate which gives the quinazoline derivative (2f). The quinazoline derivative (2f) can be coupled to the hydroxy group of a P2 scaffold in a Mitsunobu reaction as described above, or the hydroxy group of the quinazoline can be displaced by a suitable leaving group such as a chloride, bromide or iodide, by the treatment of quinazoline (2f) with an appropriate halogenating agent, for example phosphoryl chloride or the like. In addition, 8-methyl quinazoline derivatives can be obtained from an alternate tri-substituted acid or amide, prepared as illustrated in scheme 2A.

SCHEME 2A The condensation of ethylpropionyl acetate and ethoxymethylenemalonitrile in the presence of a suitable base, preferably ethoxide, such as sodium ethoxide, in e.g. ethanol gives the tetra-substituted benzoic acid derivative (2Aa). Hydrolysis of the ethyl ester effected by treatment with a base such as lithium hydroxide followed by the decarboxylation step achieved by heating the acid obtained then gives the tri-substituted phenol derivative (2Ab). The alkylation of the hydroxy function using for example methyl iodide in the presence of a base such as potassium carbonate or the like gives the corresponding alkoxy derivative (2Ac). The tri-substituted amide (2Ad) can subsequently be obtained together with the corresponding acid (2Ae) by hydrolysis of the cyano group carried out by heating a solution of the cyano derivative in e.g. water and ethanol in the presence of a base of the hydroxide type of sodium. The amide (2Ad) can then be reacted with a desired acid under peptide coupling conditions as described in Scheme 2 to give the substituted 8-methyl quinazolinol and, if desired, reacted subsequently to the corresponding 4-halo derivative. The acid (2Ae) obtained in scheme 2A can also be used for the preparation of the 8-methyl substituted quinazoline derivatives, which is illustrated in scheme 2B.

SCHEME 2B The protection of the acid function of the acid (2Ae), for example as the methyl ester, can be effected by subjecting the acid to the alkylation conditions such as the treatment with methyl iodide in the presence of a base such as potassium carbonate. The amino function of the obtained ester derivative can then be coupled with a desired acid using any conventional peptide coupling technique such as the use of the acid chloride in the presence of a base such as triethylamine or the like, which gives the amide (2Bb) . The hydrolysis of the methyl ester by treatment with a base of the lithium hydroxide type followed by heating of the acid obtained in the presence of formamide gives quinazolinol (2Bc). As described above, quinazolinol can be further reacted to give the corresponding 4-halo derivative. A variety of carboxylic acids with the general structure (2d) can be used in Scheme 2. These acids are available either commercially or in the literature. An example of the preparation of 2- (substituted) -amino-carboxy-aminothiazole derivatives, following the procedure of Berdikhina et al. Chem. Heterocycl. Compd. (Engl. Transí.) (1991), 427-33 is shown below.

SCHEME 3 R 'is d-C6 alkyl; R "is d-Cß alkyl or H Thiourea (3c) can be formed with different alkyl substituents R 'and R" by the reaction of the appropriate amine (3a) with tert-butylisothiocyanate in the presence of a base of the diisopropylethylamine type in a dichloromethane solvent followed by removal of the tert-butyl group under acidic conditions. Alternatively, thiourea (3c) can be formed by the reaction of the amine (3a) with thiocarbonyldiimidazole and thereafter with a saturated solution of ammonia in methanol. Subsequent condensation of the obtained thiourea derivative (3c) with 3-bromopyruvic acid gives the acid (3d). The 4-substituted thiazole-2-carboxylic acids to be used in the reaction with the amine 2c in scheme 2 can be prepared as illustrated in scheme 4.

SCHEME 4 4a 4b 4c 4d Condensation of the ethyl thiooxamate (4a) with a desired a-bromoketone (4b) followed by hydrolysis of the ester effected by treatment with a base such as lithium hydroxide gives the thiazole carboxylic acid (4d). The a-bromo ketones (4b) are commercially available or can be prepared by a-bromination of the corresponding ketone according to known procedures.

Synthesis and introduction of building blocks P1 Useful amino acids for the preparation of P1 fragments are available either commercially or in the literature, see for example WO 00/09543 and WO00 / 59929. Scheme 5 shows an example of the preparation of a sulfonamide derivative to be used as a P1 fragment.

SCHEME 5 The sulfonamide group can be introduced into an amino acid (6a) suitably protected by treatment of the amino acid with a coupling agent, for example N, N'-carbonyldiimidazole (CDI) or the like, in a THF type solvent followed by the reaction with the sulfonamide desired (5b) in the presence of a strong base such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU). Alternatively, the amino acid can be treated with the desired sulfonamide (5b) in the presence of a diisopropyl ethylamine type base followed by treatment with a PyBOP® type coupling agent to effect the introduction of the sulfonamide group. The elimination of the amino protecting group by the standard methods and the subsequent coupling to a P2 portion or its precursor. The building blocks P1 for the preparation of the compounds according to the general formula I where A is an ester can be prepared, for example, by reacting the amino acid (5a) with the amine or the appropriate alcohol under standard conditions for the formation of the ester. A general example of the coupling of a constructor block P1 to the acid function of the scaffold P2 is shown in scheme 7.

SCHEME 7 Q is a quinazoline derivative or a protecting group of hydroxy groups A 'is a protected carboxylic acid or a substituted amide The coupling of the building block P1 (7b), prepared as described above, to the acid function of the portion P2 using standard methods for the formation of the amide bond, such as using a coupling agent such as HATU in the presence of a base such as diisopropylamine in a solvent type dimethylformamide, gives the amide (7c). Alternatively, the sulfonamide group can be introduced at a later stage of the synthesis, for example as the last step. In this case A 'in scheme 7 is a carboxylic acid protected in an appropriate form, for example a methyl ester, and deprotected in an appropriate manner, for example with aqueous lithium hydroxide, before coupling the sulfonamide group.

Introduction of an α-unsaturated alkyl chain attached to urea on a heterocyclic P2 scaffold The alkyl chain linked by a urea functionality to the P2 scaffold can be introduced as described in Scheme 10.

SCHEME 10 Q is a quinazoline derivative or a protecting group of hydroxy groups; Rx is an unsubstituted, 5- to 8-membered alkyl chain; A 'is a protected carboxylic acid or a substituted amide.

The reaction of a hydrazine derivative (10a) with a formylating agent such as chloroformate p-nitrophenyl, carbonyl diimidazole, phosgene or the like in the presence of a sodium hydrogen carbonate-like base followed by the addition of the building block P2 gives the derivative of urea (10c). Alkenyl amines suitable for use in scheme 10 can be prepared for example by alkylation of a desired tert-butylcarbamate; A general example is shown in scheme 11.

SCHEME 11 n is 1, 2, 3 or 4 Reaction of a desired amine, R5-NH2, with tert-butyl dicarbonate gives the protected boc amine (11a). The alkylation of the carbamate obtained with an α-unsaturated alkylating agent (11 b) such as an alkenyl halide, for example bromide or chloride, followed by removal of the boc group using standard conditions such as treatment with a TFA solution in a dichloromethane type solvent, gives the free amine (11c). The group A or Rt1 can be connected to the building block P1 at any stage of the synthesis, that is, before or after the cyclization, or before or after the cyclization and reduction as described hereinabove. The compounds of formula (I) wherein A or Rt1 represents -NHS02R2, said compounds which are represented by the formula (lk-1), can be prepared by linking group A or Rt1 to P1 by forming an amide bond between both portions . Similarly, compounds of formula (I) wherein A or Rt1 represents -OR1, ie compounds (l-k-2), can be prepared by linking group A or Rt1 to P1 by forming an ester linkage. In one modality, -OR1 groups 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: G-COOH + H -SO2R "(2a) (2b) (l-k-1) The Intermediary (2a) can be coupled to the amine (2b) by an amide formation reaction such as any of the methods for the formation of an amide bond described hereafter. In particular, (2a) can be treated with a coupling agent, for example N, N'-carbonyl-diimidazole (CDI), EEDQ, IIDQ, EDCI or benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (commercially available as PyBOP®), in a solvent such as an ether, e.g. THF, or a halogenated hydrocarbon, eg. dichloromethane, chloroform, dichloroethane, and reacted with the desired sulfonamide (2b), preferably after reacting (2a) with the coupling agent. The reactions (2a) with (2b) 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-ene (DBU). The intermediary (2a) can also become an activated form, eg. an activated form of the general formula G-CO-Z, where Z represents halo, or the portion of an active ester, e.g. Z is an aryloxy group such as phenoxy, p-nitrophenoxy, pentafluorophenoxy, trichlorophenoxy, pentachlorophenoxy and the like; or Z may be the portion of a mixed anhydride. In one embodiment, G-CO-Z is an acid chloride (G-CO-CI) or a mixed acid anhydride (G-CO-O-CO-R or G-CO-O-CO-OR, R being in the latter, for example, C- alkyl, such as methyl, ethyl, propyl, i-propyl, butyl, t-butyl, i-butyl, or benzyl). The activated form G-CO-Z is reacted with the sulfonamide (2b). The activation of the carboxylic acid in (2a) as described in the above reactions can lead to an internal cyclization reaction to an azalactone intermediate of formula where L, Rr, Rq, R5, n are as previously specified and where stereogenic centers may have the stereochemical configuration as specified above, for example as in (I-a) or (l-b). The intermediates (2a-1) can be isolated from the reaction mixture, using conventional methodology, and the isolated intermediate (2a-1) is then reacted with (2b), or the reaction mixture containing (2a-1) can be further reacted with (2b) without isolation of (2a-1) . In one embodiment, where the reaction with the coupling agent is carried out in a water-immiscible solvent, the reaction mixture containing (2a-1) can be washed with water or slightly basic water to remove all water-soluble collateral products . The solution obtained in this way is then reacted with (2b) without further purification steps. On the other hand, the isolation of (2a-1) can provide certain advantages in the sense that the isolated product, after optional further purification, can be reacted with (2b), resulting in fewer side products and easier processing of the reaction. The intermediate (2a) can be coupled with the alcohol (2c) by an ester-forming reaction. For example, (2a) and (2c) are reacted together with removal of water, either physically, e.g., by azeotropic removal of water, or chemically using a dehydrating agent. The Intermediary (2a) can also be converted into an activated form G-CO-Z, such as the activated form mentioned above, and then reacted with the alcohol (2c). The ester formation reactions are preferably carried out in the presence of a base such as an alkali metal carbonate or hydrogen carbonate, e.g. potassium hydrogen carbonate and sodium, or a tertiary amine such as the amines mentioned herein in relation to the formation reactions of amide, in particular a trialkylamine, e.g. triethylamine. The solvents which can be used in the ester formation reactions comprise ethers such as THF; halogenated hydrocarbons such as dichloromethane, CH 2 Cl 2; hydrocarbons such as toluene; polar aprotic solvents such as DMF, DMSO, DMA; and similar solvents.

Synthesis of compounds containing a carbocyclic P2 unit A typical route to compounds containing a saturated carbocyclic P2 scaffold, ie L is CH in the general formula I, is shown in Scheme 14.

SCHEME 14 Rx is an alkyl chain of 5-8 members? -unsaturated; A 'is a protected carboxylic acid, substituted amide The saturated cycloalkyl scaffold (14b) can be prepared, for example, from 3,4-bis (methoxycarbonyl) cyclopentanone (14a), described by Rosenquist et al. in Acta Chem. Scand. 46 (1992) 1127-1129 for the reduction of the keto group with a reducing agent type sodium borohydride in a methanol type solvent followed by the hydrolysis of the esters and finally the ring closure in acetic anhydride in the presence of pyridine. The provided bicyclic acid (14b) can then be coupled to the amine function of the desired hydrazine derivative (14c) using standard peptide coupling conditions with HATU and diisopropyl amine in a dimethylformamide type solvent to give (14d). The lactone opening of (14d) with for example lithium hydroxide gives the acid (14e) which can then be coupled to the amino group of a building block P1 or a precursor of a desired P1 fragment (14f), using coupling conditions of conventional peptides. The introduction of the R8 group of the carbocycle can then be carried out for example by a Mitsunobu reaction with the appropriate alcohol as described above or by any other suitable method previously described. Scheme 15 shows an alternative route to compounds of formula I comprising saturated P2 scaffold where the building blocks are introduced in the reverse order, ie the P1 fragment is introduced before the hydrazine portion.

SCHEME 15 A 'is a protected carboxylic acid, substituted amide The protection of the acid group of (15a) for example as the tert-butyl ester by treatment with di-tert-butyl dicarbonate in the presence of a dimethylaminopyridine type base and triethylamine in a dichloromethane type solvent gives the ester (15b). The lactone opening using for example lithium hydroxide and the subsequent coupling of a building block P1 (15c) as described in scheme 12 or directly by the amine group of the P1 fragment gives 15d. The introduction of the R8- group as described above followed by the removal of the acid protecting group by subjecting the ester to the acid conditions trifuloroacetic acid type and trityt silane in a solvent such as methylene chloride and finally the coupling of the hydrazine portion (15e) using the peptide coupling conditions as described above gives the hydrazine derivative (15f).

An unsaturated P2 scaffold useful in the preparation of compounds of formula I can be prepared as illustrated in scheme 16.

SCHEME 16 A bromination-elimination reaction of 3,4-bis (methoxycarbonyl) -cyclopentanone (15a) as described in Dolby et al. in J. Org. Chem. 36 (1971) 1277-1285 followed by reduction of the keto function with a sodium borohydride reducing agent gives the unsaturated hydroxy compound (15b). Selective hydrolysis of the ester using, for example, lithium hydroxide in a solvent such as a mixture of dioxane and water, gives the hydroxy substituted monoester derivative (15c). A scaffold P2 where Rq is different from hydrogen, such as a methyl, can be prepared as shown in scheme 17.

SCHEME 17 17g 17h 17i Oxidation of commercial 3-methyl-3-buten-1-ol (17a) by the use of an oxidizing agent type pyridinyl chlorochromate followed by treatment with acetyl chloride, bromine and methanol gives the a-bromo ester (17c). The obtained ester (17c) can then be reacted with the enolate (17e), obtained for example by treating the corresponding tert-butyl ester with a base such as lithium diisopropyl amide in a tetrahydrofuran type solvent, to give the alkylated compound (17f) The tert-butyl ester (17e) can be prepared by treating the corresponding acid (17d) available commercially with tert-butyl dicarbonate in the presence of a dimethylaminopyridine type base. Cyclization of (17f) by an olefin metathesis reaction performed as described above provides a cyclopentene derivative (17g). The stereoselective epoxidation of (17g) can be carried out using the asymmetric epoxidation method to give the epoxide (17h). Finally, the addition of a base type DBN (1, 5-diazabicyclo- [4.3.0] non-5-ene) gives the alcohol (17i). Optionally, the double bond of the compound (17i) can be reduced, for example, by catalytic hydrogenation using a catalyst of the palladium-on-carbon type, which provides the corresponding saturated compound. The obtained cyclic scaffolds can then be used, as described above, to complete the synthesis of the compounds of formula I. An example is shown in scheme 18.

SCHEME 18 Q is a quinazoline derivative; Rx is an alkyl chain of 5 to 8 members? -unsaturated A 'is a protected carboxylic acid, substituted amide The amino group of a building block P1 or its suitable precursor (18b) can be coupled to the acid of the cyclopentene derivative (18a) using standard amide coupling conditions such as the use of HATU in the presence of a base of the diisopropyl phenylamine type or similar, followed by the introduction of the quinazoline group for example by Mitsunobu conditions as described above to give (18d). The hydrolysis of the remaining ester and the subsequent amide coupling of an optionally unsaturated α-unsaturated amine (18e) followed by manipulations of the P1 part gives cyclopentene-containing compounds (18f) according to the general formula I.

Macrocyclization The macrocycle present in the compounds of the invention is typically formed by an olefin metathesis reaction (macrocyclization).

The quinazoline group of the cyclic P2 scaffold can be introduced by any of the strategies described before or after macrocycle formation. A typical pathway to macrocyclic urea compounds is shown in Scheme 19.

SCHEME 19 19a 19b Q is a derivative of quinazollna or a protective group of hydroxy groups n = 1, 2, 3 or 4 The compound (19a) prepared as described above by the use of vinyl ethyl ester cyclopropyl glycine as portion P1 can be transformed into a macrocyclic compound (19b) by performing an olefin metathesis reaction. A base catalyst Ru such as as reported by. Miller, S.J., Blackwell, H.E .; Grubbs, R.H. J. Am. Chem. Soc. 118, (1996), 9606-9614, Kingsbury, JS, Harrity, JPA, Bonitatebus, PJ, Hoveyda, AH, J. Am. Chem. Soc. 121, (1999), 791- 799 and Huang et al., J. Am. Chem. Soc. 121, (1999), 2674-2678 can be used to effect the metathesis reaction. It will further be recognized that catalysts containing other transition metals such as Mo can also be used for this reaction. Optionally the double bond is reduced using standard hydrogenation methods well known in the art thus giving the corresponding saturated macrocyclic derivative. The macrocyclization described in Scheme 19 can also be applied to compounds comprising a saturated or unsaturated carbocyclic P2 scaffold as exemplified in Scheme 20.

SCHEME 20 20c 20d Q is a quinazoline derivative or a hydroxy group protecting group n = 1, 2, 3 or 4 The coupling of the hydrazine derivative (20b) to a building block P2-P1 (21a), prepared as desired in scheme 13 or 14, using standard peptide coupling conditions such as with HATU in the presence of a suitable base per example, diisopropylamine gives the intermediate (20c). Closing the ring of (20c) by a metathesis reaction as described in scheme 18 gives the macrocyclic compound (20d). When the intermediates in the schemes described above contain a functional group or functional groups, these are adequately protected whenever appropriate and then deprotected by methods recognized by those skilled in the art. For a broad description see for example Bodanzky or Greene mentioned above.

Synthesis of the building blocks P3 The building blocks P3 can be generated according to methodologies known in the art. One of these methodologies is shown in Scheme 28 below and employs monoacylated amines, such as trifluoroacetamide or Boc-protected amine.

SCHEME 28 where R is t-butoxy, trifluoromethyl; R5 and n are as defined in the present invention; and LG is a leaving group, such as a halogen. The aminoacylated amines (18a) are treated with a strong base such as sodium hydride and then reacted with C3-6 haloalkenyl (28b) to form the corresponding protected amine (28c). The deprotection of (28c) gives the building block P3 or (28d). The deprotection will depend on the functional group R, so if R is t-butoxy, the deprotection of the corresponding Boc-protected amine can be achieved by treatment with acid, for example, trifluoroacetic acid. Alternatively, when R is for example trifluoromethyl, the elimination of the R group is achieved with a base, e.g. sodium hydroxide.

Scheme 29 exemplifies even another method for preparing a P3 building block. where X is halogen, n is as defined in the present invention A Gabriel synthesis of primary C3-6 alkenylamines, which can be carried out by treating phthalimide (29a) with a base, such as potassium hydroxide, and a C3-6 haloalkenyl (29b), followed by hydrolysis of the N-alkyl imide intermediate to generate a primary C3-6 alkenylamine (29c). The coupling of the building block P3 to the portion P2-P1 will be obtained by the formation of an amide bond as explained herein.

Formation of the macrocycle The formation of the macrocycle can be carried out by an olefin metathesis reaction in the presence of a suitable metal catalyst such as, for example, the base catalyst Ru reported by Miller, S.J., Blackwell, H.E .; Grubbs, R.H. J. Am. Chem. Soc. 118, (1996), 9606-9614, Kingsbury, JS, Harrity, JPA, Bonitatebus, PJ, Hoveyda, AH, J. Am. Chem. Soc. 121, (1999), 791-799 and Huang et al., J. Am. Chem. Soc. 121, (1999), 2674-2678, for example a Hoveyda-Grubbs catalyst. Air-stable ruthenium catalysts such as Bis (tricyclohexylphosphine) -3-phenyl-1 H -inden-1-ylidene ruthenium chloride (Neolyst M1®) or Bis (tricyclohexylphosphine) [(phenylthio) methylene] ruthenium dichloride (IV ) can be used for large-scale production. In addition, other catalysts containing other transition metals such as Mo can be used for this reaction. The metathesis reactions can be carried out in a suitable solvent such as, for example, ethers. THF, dioxane; halogenated hydrocarbons, eg. dichloromethane, CHCl3, 1,2-dichloroethane and the like, hydrocarbons, e.g. toluene In a preferred embodiment, the metathesis reaction is carried out in toluene. These reactions are carried out at elevated temperatures under a nitrogen atmosphere. Optionally the double bond is reduced by standard hydrogenation methods well known in the art, e.g. with hydrogen in the presence of a noble metal catalyst such as Pd or Pt. In the following schemes, a number of specific synthetic routes for preparing the compounds of formula (I) or particular subgroups of compounds are described in some detail. of formula (I). In the schemes 30-33.

SCHEME 30 The compounds of the present invention can be synthesized, as shown in Scheme 30, from compounds of Formula A, B and F. Lactone A is coupled to a C3-6alkenylamine of structure B, in the presence of peptide coupling agent. , such as HATU or EDCI / HOAt in the presence of a base, such as DIPEA, to form a compound of Formula C. The subsequent opening of lactone with ethyl ester of 1- (amino) -2- (vinyl) cyclopropane-carboxylic acid in the presence of a peptide coupling agent, such as HATU or EDCI / HOAt in the presence of a base, such as DIPEA, gives a compound of Formula E. Compounds E can be coupled to a quinazoline of Formula F using a reaction of Mitsunobu type. The resulting olefin G can be subjected to ring closure using an olefin metathesis catalyst, such as the Hoveyda-Grubbs catalysts, or Bis (tricyclohexyl-phosphine) [(phenylthio) methylene] ruthenium (IV) dichloride, Bis (tricyclohexyl-phosphine) -3-phenyl-1 H-inden-1-ylidene ruthenium dichloride (IV) (Neolyst M1®), in an appropriate solvent such as 1,2-dichloroethane, dichloromethane or toluene, to form a compound of Formula H, which can be hydrolyzed to the corresponding acid of Formula I. The acid of formula I is coupling with R6SO2NH2, in the presence of the peptide coupling agent, such as CDI or EDAC, and in the presence of a base such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or DMAP to give a compound of Formula J.

SCHEME 31 In Scheme 31, a compound of Formula K is reacted with a chloroquincoline L in the presence of a base, such as NaH or tBuOK, to form a compound of Formula M. The resulting acid M can be treated with the ethyl ester of the acid. - (amino) -2- (vinyl) cyclopropanecarboxylic or the corresponding tosylate in the presence of a peptide coupling agent, such as HATU or EDCI / HOAt and in the presence of a base, such as DIPEA, to give a product of Formula N. Deprotection of the Boc portion of the compound of Formula N can be carried out by treatment with an acid, such as TFA, in a solvent such as methylene chloride to give the free amine of Formula O. Then, the urea of Formula P can be prepared from the compound of Formula O by treatment with phosgene, or an equivalent of phosgene, and an amine of Formula B, in the presence of a base, such as NaHCO 3. The resulting diolefin P can be subjected to ring closure using an olefin metathesis catalyst, such as the Hoveyda-Grubbs catalysts or β / s bichloride (tricyclohexylphosphine) [(phenylthio) -methylenejuthenium (IV), β / 2-bichloride. s (tricyclohexylphosphine) -3-phenyl-1 H -inden-1-ylidenedrhenium (IV) (Neolyst M1®), in an appropriate solvent such as 1,2-dichloroethane, dichloromethane or toluene, to form a compound of Formula Q, which can be hydrolyzed to the corresponding acid of Formula R. The acid of formula R is coupled with R6SO2NH2, in the presence of a peptide coupling agent, such as CDI or EDAC, and in the presence of such a base such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or DMAP to give a compound of Formula S. An alternative method for the synthesis of the compound of Formula Q is depicted in Scheme 32 below.

SCHEME 32 Accordingly, Boc-hydroxyproline is treated with the 1- (amino) -2- (vinyl) cyclopropane-carboxylic acid ethyl ester in the presence of a peptide coupling agent, such as HATU or EDCI / HOAt and in the presence of a base, such as DIPEA, to give the ester (1). Protection of the free hydroxyl group with p-nitrobenzoyl chloride followed by removal of the Boc gives the free amine (3). Next, the urea of Formula T can be prepared from (3) by treatment with phosgene, or an equivalent of phosgene, and an amine of Formula B, in the presence of a base, such as NaHCO 3. The resulting diolefin T can be subjected to ring closure using an olefin metathesis catalyst, such as the Hoveyda-Grubbs catalysts, or ß / s (tricyclohexylphosphine) [(phenylthio) methylene] ruthenium (IV) dichloride, ß-dichloride. / s (tricyclohexylphosphine) -3-phenyl-1 H-inden-1-ylidenedrhenium (IV) (Neolyst M1®) in an appropriate solvent such as 1,2-dichloroethane, dichloromethane or toluene, to form a compound of Formula U, which can be deprotected using a hydride, such as lithium hydroxide, to give the corresponding alcohol of Formula V. The introduction of the quinazoline P2 can be carried out starting from the compound of Formula V and a chloroisoquinoline L, in the presence of a base , such as NaH or tBuOK to give a compound of Formula Q. An alternative method for the synthesis of the compound of Formula Q is depicted in Scheme 33 below.

SCHEME 33 Accordingly, the proline derivative (1) is protected with p-nitrobenzoic acid followed by removal of the Boc to give the free amine (5). Next, the urea of Formula W can be prepared from (5) by treatment with phosgene, or an equivalent of phosgene, and an amine of Formula B, in the presence of a base, such as NaHCO 3. The compound of Formula W can be deprotected using a hydroxide, such as lithium hydroxide, to give the corresponding alcohol of Formula X. The introduction of isoquinoline P2 can be carried out starting from the compound of Formula X and a hydroxyisoquinoline F, using a Mitsunobu reaction. , to give a compound of Formula Y. The resulting diolefin Y may be subjected to ring closure using an olefin metathesis catalyst, such as the Hoveyda-Grubbs catalyst or the like, in an appropriate solvent such as 1-2. dichloroethane, dichloromethane or toluene, to form a compound of Formula Q. In schemes 28-33 above (only) R3 corresponds to the current R5, X corresponds to L, R4a corresponds to R9, R4b and R4b 'correspond to R6 and R11, R5 corresponds to R1 and R6 corresponds to R2, according to defined above for the compounds of formula (I) or any of its subgroups. The reactions of the above schemes can be carried out in a suitable solvent in the presence of a base such as alkali metal carbonate or hydroxide, e.g. sodium, potassium or cesium carbonate; or an organic base such as a trialkylamine, e.g. triethylamine. Suitable solvents for this reaction are, for example, ethers, e.g. THF, dioxane; halogenated hydrocarbons, eg. dichloromethane, CHCl3, toluene, polar aprotic solvents such as DMF, DMSO, DMA and the like. The compounds of formula (I) can be converted to one another following the reactions of transformation of functional groups known in the art, comprising those described hereafter. An amount of the intermediates used to prepare the compounds of formula (I) are known compounds or are analogs of known compounds, which can be prepared following modifications of methodologies known in the art readily accessible to those skilled in the art. Next, a number of intermediary preparations are given in some detail.

The compounds of formula (I) can be converted into the corresponding form of N-oxide following the procedures known in the art for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction, in general, can be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide. Suitable inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or alkaline earth metal peroxides, eg, sodium peroxide, potassium peroxide; suitable organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or substituted halo benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, eg. tert-butyl hydroperoxide. Suitable solvents are, for example, water, lower alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, for example 2-butanone, halogenated hydrocarbons, eg. dichloromethane, and mixtures of said solvents. The pure stereochemically isomeric forms of the compounds of formula (I) can be obtained by the application of procedures known in the art. The diastereomers can be separated by physical methods such as selective crystallization and chromatographic techniques, eg, countercurrent distribution, liquid chromatography and the like.

The compounds of formula (I) can be obtained as racemic mixtures of enantiomers which can be separated from one another following the resolution procedures known in the art. The racemic compounds of formula (I), which are sufficiently basic or acidic, can be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid, respectively the chiral base. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali or acid. An alternative way of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography, in particular liquid chromatography using a chiral stationary phase. Said pure stereochemically isomeric forms can also be derived from the corresponding pure stereochemically isomeric forms of the starting materials, provided that the reaction occurs stereospecifically. Preferably if a stereoisomer is desired, said compound can be synthesized by stereospecific methods of preparation. These methods can advantageously employ enantiomerically pure starting materials. In another aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as specified herein, or a compound of any of the subgroups of compounds of formula (I) as specified herein, and a vehicle acceptable for pharmaceutical use. A therapeutically effective amount in this context is an amount sufficient to act prophylactically against viral infection, to stabilize or reduce viral infection, and in particular viral HCV infection, in infected subjects or subjects who are at risk of becoming infected. . In still another aspect, this invention relates to a method for preparing a pharmaceutical composition as specified herein, comprising intimately admixing 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. Therefore, the compounds of the present invention or any subgroup thereof may be formulated into various pharmaceutical forms for the purpose of administration. As suitable compositions, mention may be made of all the compositions usually employed to administer drugs in systemic form. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in the form of the addition salt or metal complex, as the active ingredient is combined in an intimate mixture with a vehicle acceptable for pharmaceutical use, said vehicle may have a Wide variety of shape depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in of unit dosage suitable, particularly, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media can be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs. , emulsions and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrants and the like in the case of powders, pills, capsules, and tablets. Due to the ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the vehicle will usually comprise sterile water, at least in large part, although other ingredients, for example, to aid in solubility, may also be included. Injectable solutions, for example, can be prepared in cases where the vehicle comprises saline, glucose solution or a mixture of saline and glucose. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are preparations in solid form which are intended to be converted, shortly before use, into liquid form preparations. In compositions suitable for percutaneous administration, the vehicle optionally comprises a penetration enhancing agent and / or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, said additives do not introduce a significant damaging effect on the skin. The compounds of the present invention can also be administered by oral inhalation or insufflation by means of methods and formulations employed in the art for administration by this route. Thus, in general the compounds of the present invention can be administered to the lungs in the form of a solution, a suspension or a dry powder, with a solution being preferred. Any system developed for the administration of solutions, suspensions or dry powders by oral inhalation or insufflation are suitable for the administration of the present compounds. In this way, 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 vehicle acceptable for pharmaceutical use. Preferably, the compounds of the present invention are administered by inhalation of a solution in nebulized or aerosolized doses. It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form to facilitate administration and uniformity of dosage. The unit dosage form as used herein refers to physically discrete units suitable as unit doses, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including corrugated or coated tablets), capsules, pills, suppositories, powder packets, seals, injectable solutions or suspensions and the like, and their segregated multiples. The compounds of formula (I) show antiviral properties. Viral infections and their associated diseases treatable through the use of 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), encephalitis St. Louis, 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, liver disease in the final stage, and HCC; and for the other pathogenic flaviviruses, the diseases include yellow fever, dengue fever, hemorrhagic fever and encephalitis. An amount of the compounds of this invention are also active against the mutated strains of HCV. Moreover, many of the compounds of this invention exhibit a favorable pharmacokinetic profile and have attractive properties in terms of bioavailability, including an acceptable average life time, AUC (area under the curve) and peak values and missing unfavorable phenomena such as rapid onset. insufficient and tissue retention.

The in vitro antiviral activity against the HCV of the compounds of formula (I) was tested in a cellular HCV 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 (incorporated herein by reference), which is further exemplified in the examples section. This model, while not a complete infection model for HCV, is widely accepted as the strongest and most efficient model of replication of autonomous HCV RNA normally available. Compounds that exhibit anti-HCV activity in this cellular model are considered 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 HCV functions from those that exert cytotoxic or cytostatic effects in the HCV replicon model, and consequently cause a decrease in HCV RNA or enzyme concentration of the HCV. united reporter. The assays are known in the art for the evaluation of cellular cytotoxicity based for example on the activity of mitochondrial enzymes using fluorogenic redox dyes such as resazurin. Furthermore, there are cell counter-traces for the evaluation of the non-selective inhibition of gene activity of the bound reporter, such as firefly luciferase. Suitable cell types can be equipped by stable transfection with a luciferase reporter gene whose expression depends on a constitutively active gene promoter, and said cells can be used as a counter-tracer to eliminate non-selective inhibitors. Due to their antiviral properties, particularly their anti-HCV properties, the compounds of formula (I) or any of their subgroups, their prodrugs, N-oxides, addition salts, quaternary amines, metal complexes and stereochemically isomeric forms, are useful in the treatment of individuals who experience 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. Thus, the compounds of the present invention or any of its subgroups can be used as medicaments. Said use as a medicament or method of treatment comprises the systemic administration to subjects infected by virus or subjects susceptible to viral infections of an amount effective to combine the conditions associated with the viral infection, in particular the HCV infection. The present invention also relates to the use of the present compounds or any of its subgroups in the preparation of a medicament for the treatment or prevention of viral infections, particularly HCV infection. The present invention also relates to a method for treating a warm-blooded animal infected with a virus, or at risk of infection by a virus, in particular by HCV, said method comprising the administration of an anti-viral 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. It is generally contemplated that an antiviral effective daily amount would be from 0.01 mg / kg to 500 mg / kg of body weight, more preferably from 0.1 mg / kg to 50 mg / kg of body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals during the day. Said sub-doses may be formulated as 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 to be treated, the severity of the condition to be treated, the age, weight, sex, extent of the disorder, and the general physical condition of the particular patient as well as another medication that the individual may be taking, as is well known to those skilled in the art. Moreover, it is evident that said effective daily amount can be decreased or increased depending on the response of the treated subject and / or depending on the evaluation of the intervening professional prescribing the compounds of the present invention. The effective daily amount ranges mentioned herein are, therefore, only as guides.

In addition, the combination of the previously known anti-HCV compound, such as, for example, interferon-a (IFN-a), pegylated interferon-a and / or ribavirin, and a compound of formula (I) can be used as a medicament in a combination therapy. The term "combination therapy" refers to a product that mandatorily 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. Thus, to combat or treat HCV infections, the compounds of formula (I) can be co-administered, in combination for example, interferon-a (IFN-a), pegylated interferon-a and / or ribavirin, as thus also therapeutic products based on antibodies directed with HCV epitopes, small interfering RNA (Si RNA), ribozymes, DNAzymes, antisense RNA, small molecular antagonists of for example NS3 protease, NS3 helicase and NS5B polymerase. Accordingly, the present invention relates to the use of a compound of formula (I) or any of its subgroups as defined above for the preparation of a medicament useful for inhibiting HCV activity in a mammal infected with HCV virus, where said medicament is used in a combination therapy, said combination therapy preferably comprising a compound of formula (I) and IFN-a (pegylated) and / or ribavirin, and optionally an anti-HIV compound. For example, in drugs prone to rapid metabolism by Cyp3A4, the Dosage with HIV inhibitors such as ritonavir may allow administration of lower dosage regimens.

EXAMPLES The following examples are intended to illustrate the present invention and not limit it. The examples show the preparation of building blocks that are coupled to any other suitable building block described herein and not simply the components that are shown in the exemplified end products of formula I.

EXAMPLE 1 1-Bromo-3-methylbutan-2-one (1) To an ice-cooled solution of 3-methyl-2-butanone (25.8 g, 300 mmol) in EtOH (250 ml) was added dropwise bromine (12.9 ml, 250 mmol) and the mixture was stirred for two hours in a ice bath. Petroleum ether (600 ml) was added. The organic phase was washed twice with water. The combined aqueous phases were extracted twice with petroleum ether. The combined organic phases were washed twice with a cold sodium carbonate solution and with brine. The organic phase was dried on sodium sulphate and evaporated under reduced pressure (room temperature). Yield: 50%.

EXAMPLE 2 Ethyl 4-l-propylthiazole-2-carboxylate (2) To a boiling solution of ethyl thiooxamate (16.0 g, 120 mmol) in EtOH, 1-bromo-3-methyl-2-butanone was added dropwise over a period of 15 minutes. The mixture was refluxed for 1.5 hour. The solution was added to 300 ml of ice water and basified with concentrated ammonia solution. The mixture was extracted twice with ethyl acetate. The organic phase was washed with brine, dried with sodium sulfate and evaporated under reduced pressure. The product was purified by chromatography on a column of silica gel eluted with hexane and 20% ethyl acetate. Yield: 15.2 g, 67%. 1 H-NMR-CDCl 3 1.35 (d, 6 H), 1.42 (t, 3 H), 3.25 (m, 1 H), 4.49 (m, 2 H) 7.20 (s, 1 H) EXAMPLE 3 4-Isopropylthiazole-2-carboxylic acid (3) To a solution of ethyl 4-isopropylthiazole-2-carboxylate (9.1 g, 46 mmol) in THF (100 ml) and MeOH (30 ml) was added a solution of lithium hydroxide (1.16 g, 48.5 mmol) and the mixture was stirred. stirred for two days at room temperature. The mixture was acidified with 2M hydrochloric acid and extracted four times with diethyl ether. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. Yield: 7.1 g, 90%.

EXAMPLE 4 4-Methoxy-2-nitro-benzamide (4) To an ice-cooled suspension of 4-methoxy-2-nitro-benzoic acid (14.1 g, 71.5 mmol) and a few drops of DMF in DCM (150 mL) was added oxalyl chloride (19.0 g, 150 mmol) dropwise. and the mixture was stirred for two hours at room temperature. The solvent was evaporated and added water The product was filtered and washed with water and hexane. The product was dried under vacuum. Yield: 10 g, 71%.

EXAMPLE 5 4-Methoxy-2-amino-benzamide (5) A suspension of 4-methoxy-2-nitro-benzamide (6.9 g, 35.1 mmol) in EtOH (200 ml) was hydrogenated with Ni Raney (4.0 g) for two days at room temperature and 3.52 kg / cm2. The catalyst was filtered and washed with DMF. The solvent was evaporated under reduced pressure. Yield: 5.6g, 95%.

EXAMPLE 6 4- (2-Carbamoyl-5-methoxy-phenyl) -amide of 4-isopropylthiazole-2-carboxylic acid (6) To a cooled solution of 4-methoxy-2-aminobenzamide (5.6 g, 33.7 mmol), 4-isopropylthiazole-2-carboxylic acid (7.1 g, 42 mmol) and Hobt hydrate (6.4 g, 42 mmol) in DMF (150 ml ) EDAC (8.6 g, 45 mmol) and TEA (6.4 ml, 45 mmol) were added and the mixture was stirred overnight at room temperature. An aqueous solution of citric acid was added to the 2. 5% (600 ml) and the mixture was extracted three times with ethyl acetate. The organic phase was washed with brine and saturated sodium hydrogen carbonate.

The solution was dried over sodium sulfate and evaporated under reduced pressure. Yield: 9.0 g, 91%.

EXAMPLE 7 2- (4-lsopropylthiazol-2-yl) -7-methoxy-quinazolin-4-ol (7) A mixture of 4-isopropyl-2-carboxylic acid (2-carbamoyl-5-methoxy-phenyl) -amide (9.0 g, 28.2 mmol) and sodium carbonate (7.5 g, 71 mmol) in EtOH, 50/50 water ( 300 ml) was refluxed for two hours. The mixture was cooled and acidified with citric acid and extracted four times with ethyl acetate. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was crystallized from EtOH. Yield: 4.8 g, 60%. 1 H-NMR-DMSO-D 6 d 1.30 (d, 6H), 3.10 (m, 1 H), 3.90 (s, 3H), 7.10 (dd, 1 H) 7.16 (d, 1 H), 7.62 (d, 1 H), 8.02 (d, 1 H).

EXAMPLE 8 (2-Carbamoyl-phenyl) -amide of 4-isopropylthiazole-2-carboxylic acid (8) 2-Aminobenzamide (2.04 g, 15 mmol) was reacted with 4-isopropylthiazole-2-carboxylic acid (2.5 g, 14.6 mmol) as described in Example 6 which gave the title compound (2.4 g, 56%) .

EXAMPLE 9 2- (4-lsopropylthiazol-2-yl) -quinazolin-4-ol (9) 4-Isopropylthiazole-2-carboxylic acid (2-carbamoyl-phenyl) -amide (2.4 g, 8.3 mmol) was treated according to the procedure described in Example 7 which gave the title compound (1.7 g, 77% ). 1 H-NMR CDCl 3 d 1.33 (d, 6 H), 3.12 (m, 1 H), 7.55 (t, 1 H), 7.65 (s, 1 H), 7.72 (d, 1 H), 7.82 (t, 1 H ), 8.14 (d, 1 H).

EXAMPLE 10 2-Amino-5-methoxy-benzamide (10) Catalytic hydrogenation of 5-methoxy-nitro-benzamide (3.6 g) on Raney-nickel gave the title compound (2.75 g, 90%).

EXAMPLE 11 7-Methoxy-2-phenyl-quinazolin-4-ol (11) The treatment of 2-amino-5-methoxy-benzamide according to the procedure described by Raid J. Abdel-Khalil, Wolfgang Voelter and Muhammad Saeed in Tetrahedron Letters 45 (2004) 3475-3476 for the preparation of 2-phenyl-quinazoline 4-ol gave the title compound.

EXAMPLE 12 frans- (3 4 /?) - Bis (methoxycarbonyl) cyclopentanol (12) Sodium borohydride (1.11 g, 0.029 mol) was added to a stirred solution of (1 R, 2S) -4-oxo-cyclopentane-1,2-dicarboxylic acid dimethyl ester (4.88 g, 0.0244 mol) in methanol (300 ml). at 0 ° C. After 1 hour the reaction was quenched with 90 ml brine, concentrated and extracted with ethyl acetate. The organic phases were combined, dried, filtered and concentrated. The crude product was purified by flash column chromatography (toluene / ethyl acetate 1: 1) which gave the title compound (3.73 g, 76%) as a yellow oil.

EXAMPLE 13 3-Oxo-2-oxa-bicichlor-2,2 -pheptane-5-carboxylic acid (13) Sodium hydroxide (1 M, 74 ml, 0.074 mol) was added to a stirred solution of 12 (3.73 g, 0.018 mol) in methanol (105 ml) at room temperature. After 4 h, the reaction mixture was neutralized with 3M HCl, evaporated and co-evaporated with toluene several times. Pyridine (75 ml) and Ac2O (53 ml) were added and the reaction mixture was allowed to stir overnight at room temperature. The mixture was then coevaporated with toluene and purified by flash column chromatography (ethyl acetate + 1% acetic acid) which gave the title compound (2.51 g, 88%) as a yellow oil.

EXAMPLE 14 3-Oxo-2-oxa-biciclof2.2.nheptane-5-carboxylic acid fer-Butyl ester (14) DMAP (14 mg, 0.115 mmol) and Boc2O (252 mg, 1.44 mmol) were added to a stirred solution of 13 (180 mg, 1.15 mmol) in 2 ml of CH2Cl2 under an atmosphere of inert argon at 0 ° C. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated and the crude product was purified by flash column chromatography (gradient toluene / ethyl acetate 15: 1, 9: 1, 6: 1, 4: 1, 2: 1) which gave the compound of title (124 mg, 51%) in the form of white crystals. 1 H-NMR (300 MHz, CD 3 OD) d 1.45 (s, 9 H), 1.90 (d, J = 11.0 Hz, 1 H), 2.10-2.19 (m, 3 H), 2.76-2.83 (m, 1 H), 3.10 (s, 1 H), 4.99 (s, 1 H). 13 C-NMR (75.5 MHz, CD3OD) d 27.1, 33.0, 37.7, 40.8, 46.1, 81.1, 81.6, 172.0, 177.7.

Alternative method for the preparation of compound 14 13 14 Compound 13 (13.9 g, 89 mmol) was dissolved in dichloromethane (200 ml) and then cooled to about -10 ° C under nitrogen. Isobutylene was then bubbled into the solution until the total volume had risen to approximately 250 ml which gave a "cloudy solution". BF3 x Et2O (5.6 mL, 44.5 mmol, 0.5 eq.) Was added and the reaction mixture was maintained at about -10 ° C under nitrogen. After 10 min, a clear solution was obtained. The reaction was monitored by TLC (EtOAc-Toluene 3: 2 was acidified with a few drops of acetic acid and hexane-EtOAc 4: 1, staining with basic permanganate solution). At 70 minutes only traces of compound 13 remained and saturated aqueous NaHCO3 (200 ml) was added to the reaction mixture, which was then vigorously stirred for 10 min. The organic layer was washed with saturated NaHCO3 (3 x 200 ml) and brine (1 x 150 ml), then dried with sodium sulfite, filtered and concentrated in an oil containing small droplets. After the addition of hexane to the residue the product cracked. Adding more hexane and heating to reflux gave a clear solution of the which crystallized the product. The crystals were collected by filtration and washed with hexane (ta), then dried in air for 72 h giving colorless needles (12.45 g, 58.7 mmol, 66% from the first crop).

EXAMPLE 15 (1 2 4S) -2 - ((1 /? 2S) -1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -4-hydroxy-cyclopentanecarboxylic acid fer-Butyl ester (15) Compound 14 (56 mg, 0.264 mmol) was dissolved in dioxane / water 1: 1 (5 ml) and the mixture was cooled to 0 ° C. 1 M Lithium hydroxide (0.52 ml, 0.520 mmol) was added and the mixture was stirred at 0 ° C for 45 minutes, after which the mixture was neutralized with 1 M hydrochloric acid and evaporated and coevaporated with toluene. The crystalline residue was dissolved in DMF (5 ml) and (1α, 2S) -1-amino-2-vinylcyclopropanecarboxylic acid ethyl ester hydrochloride (60 mg, 0.313 mmol) and diisopropylethylamine (DIEA) (138 μl, 0.792 mmol) and the solution was cooled to 0 ° C. HATU (120 mg, 0.316 mmol) was added and the mixture was stirred for 0.5 h at 0 ° C and for another 2 h at room temperature. The mixture was then evaporated and extracted with EtOAc, washed with brine, dried, filtered and concentrated. The purification by flash column chromatography (toluene / EtOAc 1: 1) gave the title compound (86 mg, 89%) as a colorless oil. The obtained oil was crystallized from ethyl acetate-hexane.

EXAMPLE 16 2- (1-Ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -4- (7-methoxy-2-phenyl-quinazolin-4-yloxy) -cyclopentanecarboxylic acid tert-butyl ester (16) Compound 15 (700 mg, 1.9 mmol), 7- methoxy-2-phenyl-quinazolin-4-ol (670 mg, 2.66 mmol) and triphenyl phosphine (1245 mg, 4.75 mmol) were dissolved in THF (50 mL) and they were cooled to 0 ° C. Diisopropyl azidocarboxylate (960 mg, 4.75 mmol) was added slowly and the suspension was allowed to reach room temperature. After 12 h, the solvent was removed under reduced pressure and the residue was placed in ether and filtered. Purification by column chromatography (SiO2; 1% methanol in dichloromethane) gave the pure title compound (778 mg, 68%). MS (M + H) + 603.

EXAMPLE 17 2- (1-Ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -4- (7-methoxy-2-phenyl-quinazolin-4-yloxy) -cyclopentanecarboxylic acid (17) Compound 16 (780 mg, 1.29 mmol) was dissolved in dichloromethane (20 ml) and triethylsilane (0.4 ml). Trifluoromethanesulfonic acid was added dropwise at room temperature. The mixture was then left for 2 h at room temperature. Removal of the solvent gave the pure title product (700 mg, 99%). MS (M + H) + 546.

EXAMPLE 18 Ethyl ester of acid 1-. { r2-hex-5-enyl-methyl-carbamoyl) -4- (7-methoxy-2-phenyl-quinazol-n-4-yloxy) -cyclopentancarbon-p-amino} -2-vinyl-cyclopropanecarboxylic (18) Compound 17 (700 mg, 1.28 mmol), N-methyl-1 -hexene hydrochloride (291 mg, 1.94 mmol), diisopropylethylamine (750 mg, 5.8 mmol) and HATU (736 mg, 1.94 mmol) were dissolved in DMF ( 30 ml) and the mixture was stirred at room temperature overnight. The solvent was removed and the residue was partitioned between dichloromethane and aqueous sodium bicarbonate. The organic phase was collected and the crude product was purified by column chromatography (silica gel, 2% methanol in dichloromethane, 4% methanol in dichloromethane) Evaporation of the solvent gave the pure title compound (700 mg, 85% MS (M + H) + 641.

EXAMPLE 19 Ethyl ester of 17- (7-methoxy-2-phenyl-quinazolin-4-yloxy-13-methyl-2.14-dioxo-3,13-diaza-tricyclop 3.3.0.0 * 4,6 * 1octadec-7 en-4-carboxylic (19s) Compound 18 (700 mg, 1.1 mmol) and the Hoveyda-Grubbs catalyst, 1st generation (55 mg, 0.091 mmol) were dissolved in degassed and dried 1, 2-dichloroethane (1000 ml). The mixture was heated to reflux temperature overnight under an argon atmosphere. Evaporation of the solvent and purification by column chromatography (silica gel, ether) gave 240 mg (40%) of the pure title compound. MS (M + H) + 613.

EXAMPLE 20 Acid 17- (7-methoxy-2-phenyl-quinazolin-4-yloxy-13-methyl-2,14-dioxo-3,13-diaza-tricyclo H3.3.0.0 * 4.6 * 1octadec- 7-en-4-carboxylic (20) Compound 19 (240 mg, 0.39 mmol) was dissolved in 40 ml of a solvent mixture (THF 2: methanol 1: methanol 1). Aqueous lithium hydroxide (1.9 ml, 1 M) was added and the reaction mixture was heated at 40 ° C overnight. Purification by HPLC and column chromatography (silica gel, 5% methanol in dichloromethane) gave the title compound (75 mg, 33%).

MS (M + H) + 585.

EXAMPLE 21 I17- (7-Methoxy-2-phenyl-quinazolin-4-yloxy) -13-methyl-2,14-dioxo-3.13-diazatrichichlori3.3.0.0 * 4,6 * loctadec-7-en- 4-carbonn-amide of cyclopropanesulfonic acid (21) Compound 20 (75 mg, 0.13 mmol) and N, N, -carbonyldiimidazole (43 mg, 0.26 mmol) in THF (7 ml) were heated at reflux for 2 hours. Optionally, the formed azalactone can be isolated. Then DBU (29 μl), and cyclopropanesulfonamide, prepared as described in WO03 / 053349, (47 mg, 0.39 mmol) were added and the mixture was stirred at 60 ° C overnight. The reaction mixture was diluted with ethyl acetate (25 ml) and washed with 0.5 M citric acid. Purification by HPLC gave 30 mg of the pure title compound. MS (M + H) + 688.

EXAMPLE 22 2- (1-Ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -4-r2- (4-isopropyl-thiazol-2-yl) -7-methoxy-quinazolin-4-yloxy-cyclopentanecarboxylic acid (22) Compound 15 (850.0 mg, 2.30 mmol), PPh3 (1.60 g, 6 mmol), and the thiazole quinazoline 7 (820 mg, 2.72 mmol) were dissolved in THF (30 ml) in an ice bath. DIAD (1.18 ml, 6 mmol) was added dropwise. After stirring for 30 min, the mixture was stirred at RT for 2 days and then concentrated in vacuo. Flash column chromatography (silica, EtOAc-hexane) gave the Mitsunobu product. To a solution of this product (1.04 g, 1.60 mmol) and triethylsilane (460 mg, 4.00 mmol) in DCM (30 mL), TFA (30 mL) was added dropwise at RT. The mixture was stirred for 2 hours at room temperature, evaporated under reduced pressure, and coevaporated twice with toluene. Flash column chromatography (silica, 94/6 DCM-MeOH) gave the title compound as a white solid (950 mg, 70%).

EXAMPLE 23 Ethyl ester of 1- (. {2-Hex-5-enyl-methyl-carbamoyl) -4-f2- (4-isopropyl-thiazol-2-yl) -7-methoxy-quinazolin-4-yloxy-1-cyclopentanecarbonyl acid } -amino) -2- vinyl-cyclopropanecarboxylic (23) To a solution of carboxylic acid 22 (1.60 mmol), N-methyl-5-hexenylamine HCl salt (360 mg, 2.40 mmol), and HATU (920 mg, 2.40 mmol) in 35 ml of DMF, in a bath of ice, DIEA (1.30 ml, 7.2 mmol) was added and stirred for 30 min. The mixture was stirred at RT for 3 hours and then a saturated aqueous sodium hydrogen carbonate solution was added. The mixture was extracted three times with ethyl acetate. The organic phase was washed with brine, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by column chromatography on silica gel eluted with hexane-ethyl acetate (920 mg, 83%).

EXAMPLE 24 Ethyl ester of 17-r2- (4-lsopropyl-thiazol-2-yl) -7-methoxy-quinazolin-4-yloxy1-13-methyl-2.14-dioxo-3.13-diaza-tricichlori3.3.0.0 * 4.6 * 1octadec-7-en-4-carboxylic acid (24) The diene 23 (900 mg) was dissolved in 900 ml of DCE in a refluxing operation. The system was evacuated successively and filled with 3x argon. 2a catalyst added. Hoveyda-Grubbs generation (90 mg) and the system was evacuated and filled with argon twice. The mixture was refluxed at 90 ° C overnight, concentrated, and subjected to flash column chromatography (silica, EtOAc-hexane) to give the title compound as a gray-brown solid (380 mg, 46%). %). MS (M + H) + 662.

EXAMPLE 25 Ethyl ester of 1 - [(3-oxo-2-oxa-bicycloi2.2.nheptane-5-carbonyl) -aminol-2-vinyl-cyclopropanecarboxylic acid (25) To a solution of 13 (857 mg, 5.5 mmol), in DMF (14 ml) and DCM (25 ml) at room temperature, were added the ethyl ester hydrochloride of 1-amino-2-vinyl-cyclopropanecarboxylic acid, prepared according to it was described in WO03 / 099274, (1.15 g, 6.0 mmol), HATU (2.29 g, 6.0 mmol) and DIPEA (3.82 mL, 22 mmol). The reaction was stirred under N2 atmosphere at room temperature for 1 hour. The LC / MS analysis showed complete conversion and the reaction mixture was concentrated in vacuo. The residue was redissolved in DCM (100 ml) and 0.1 M HCl (aq) and separated. The organic phase was washed with NaHCO3 (aq) and brine, dried (MgSO) and filtered. Removal of the solvent in vacuo gave the white compound (1.6 g, 99%). LC / MS > 95%, m / z (ESI 294 (MH +) EXAMPLE 26 2- (1-Ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -4-hydroxy-cyclopentanecarboxylic acid diisopropylethylamine salt (26) To a solution of 25 (800 mg, 2.73 mmol) in water (15 ml) in a 20 ml microwave reaction vessel was added DIPEA (1.2 ml, 6.8 mmoles) and a stir bar. The reaction vessel was sealed and the immiscible suspension stirred vigorously before insertion into the microwave cavity. After 1 min of pre-stirring, the reaction was irradiated for 40 min at a fixed temperature of 100 ° C. After cooling to 40 ° C, the clear solution was concentrated in vacuo, and the residual brown oil was co-evaporated 3x with MeCN to remove any residual water. The crude title compound, in the form of a DIPEA salt, was immediately transferred to the next step. LC / MS > 95%, m / z (ESI +) = 312 (MH +).

EXAMPLE 27 Ethyl ester of acid 1-. { f2- (Hex-5-enyl-methyl-carbamoyl) -4-hydroxy-cyclopentancarbonin-amino} -2-inyl-cyclopropanecarboxylic (27) The crude compound 26 (5.5 moles) was dissolved in DCM (50 ml) and DMF (14 ml) followed by the addition of HATU (2.09 g, 5.5 mmol), N-methyl-N-hex-5-enylamine (678 mg, 6.0 mmoles) and DIPEA (3.08 ml, 17.5 mmoles) at room temperature. The reaction was stirred at room temperature for 1 hour. The LC / MS analysis showed complete conversion of the starting materials and the reaction mixture was concentrated in vacuo. The residue was redissolved in EtOAc (100 mL) and the organic phase was washed with 0.1 M HCl (aq), K2CO3 (aq) and brine, dried (MgSO4) and filtered. Removal of the solvent in vacuo gave an oil which was purified by flash chromatography (silica, EtOAc: MeOH) to give the title compound (1.65 g, 74%). TLC (Silica): MeOH: EtOAc 5:95, Rf = 0.5. LC / MS > 95%, m / z (ESI 407 (MH +).

EXAMPLE 28 Ethyl ester of acid 1-. { [2- (Hex-5-enyl-methyl-carbamoyl) -4- (2-phenyl-quinazolin-4-yloxy) -cyclopentancarbon-1-amino} -2-vinyl-cyclopropanecarboxylic (28) Compound 27 (0.15 g, 0.37 mmol) was dissolved in DMF and the solution was cooled to 0 ° C. NaH (60% in mineral oil, 0.04 g, 1.10 mmol) was added in one portion. After 0.5 hour 4-chloro-2-phenyloquinazoline (purchased from Aldrich) (0.98 g, 0.41 mmol) was added and after stirring at 0 ° C for 0.5 hour the reaction mixture was allowed to warm to room temperature. After stirring at room temperature for 2 hours, the reaction was quenched with citric acid (5%, ac) and extracted with EtOAc (3 x 20 ml). The combined organic phases were washed with citric acid (5%, ac, 2 x 20 ml), H2O (2 x 20 ml). The organic phase was then dried over MgSO 4, filtered and evaporated. Purified by flash chromatography with DCM / MeOH to give 166 mg of product (9) / hydrolyzate (48/52). This mixture was used in the next step.

EXAMPLE 29 Acid 1-. { f2- (hex-5-enyl-methyl-carbamoyl) -4- (2-phenyl-quinazolin-4-yloxy) -cyclopentan-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic (29) Compound 28 (0.17 g, 0.27 mmol) was dissolved in DMF (2.5 mL) and transferred to a microwave vessel. LiOH (aq, 2 M, 8 ml) was added and the reaction was heated in the microwave at 130 ° C for 1 h. The reaction was quenched with HCl (aq, 1 M) to pH 1 and extracted with DCM (3 x 20 ml). The combined organic phases were washed with HCl (aq, 1 M, 20 ml) and H 2 O (3 x 30 ml). The aqueous phase was back extracted with DCM (2 x 30 ml). The organic phases were dried over MgSO 4, filtered and evaporated. They were purified by flash chromatography (DCM / MeOH) to give the title compound (0.08 g, 49%).

EXAMPLE 30 4- (2-Phenyl-quinazol-n-4-yloxy) -cyclopentan-1,2-dicarboxylic acid (1-cyclopropanesulfoncarbonyl-2-vinylcyclopropyl) -amide-1-2- (hex-5-enylmethylamide) ( 30) Compound 29 (0.05 g, 80.70 μmol) was dissolved in DMF / DCM (1: 3, 1200 μl) and transferred to a vessel loaded with EDAC. The mixture was allowed to incubate for 10 min at room temperature. The addition of DMAP was followed by 20 min incubation at room temperature. A mixture of cyclopropanesulfonamide, prepared as described in WO03 / 053349, (39.1 mg, 0.32 mmol) and DBU (49.1 mg, 0.32 mmol) in DCM / DMF (1: 1, 800 μl) was added to the activated compound 10. The reaction mixture it was heated in the microwave for 30 minutes at 100 ° C. After evaporation of the solvents in vacuo, the residue was redissolved in DCM. The organic phase was washed with HCl (1 M, 3 x 20 ml). The aqueous phase was then back-extracted with DCM (1 x 20 ml). The combined organic phases were washed with HCl (1 M, ac), brine and water. The organic phase was dried over MgSO4 and evaporated. Dry in vacuo to give the title compound (50 mg, 90%).

EXAMPLE 31 ri3-Meti 1-2.14-dioxo-17- (2-phenylqui nazol in-4-yloxy) 3.13-diazatrichiclo13.3.0.0 * 4,6 * loctadec-7-en-4-carbon Pamida of cyclopropanesulfonic acid (31) A solution of compound 30 (0.02 g, 25.80 μmol) in dry DCE (15 ml) was added to a dry microwave vessel, loaded with Hoveyda Grubbs second generation catalyst (83.1 mg, 5.0 μmol). The solution was degassed with nitrogen gas before being heated in the microwave for 10 min at 150 ° C. After evaporation of the solvent, purification was carried out on LC prep which gave the title compound (3.00 mg, 29%).

EXAMPLE 32 Ethyl ester of acid 1-. { f4- (2-Chloro-quinazolin-4-yloxy) -2- (hex-5-enyl-methylcarbamoyl) -cyclopentancarbonin-amino} -2-vinyl-cyclopropanecarboxylic (32) Compound 27 (0.49 g, 1.21 mmol) was dissolved in DMF (1 ml) and transferred to a 20 ml microwave reaction vessel equipped with a magnetic stir bar and aqueous LiOH (2 M, 10.5 ml) was added. . The reaction vessel was sealed and the immiscible suspension stirred vigorously before insertion into the microwave cavity. The reaction was irradiated for 30 minutes up to 130 ° C. The reaction mixture was cooled to 40 ° C and the clear solution was acidified to pH 2 with aqueous HCl (1 M, 24 ml) and extracted 3x with EtOAc (20 ml). The combined organic phases were washed with brine, dried (MgSO4) and filtered. The solvent was removed in vacuo which gave the acid (0.41 g, 90%). The crude acid (410 mg, 1.09 mmol) was dissolved in DMF (1.5 ml) and DCM (4.5 ml) followed by the addition of EDAC (417 mg, 2.18 mmol) at room temperature. The mixture was allowed to incubate with stirring at room temperature. After 10 min, DMAP (133 mg, 1.09 mmol) was added followed by another 20 minutes of incubation at room temperature. Next, a premixed solution of cyclopropanesulfonic acid amide, prepared as described in WO03 / 053349, (527 mg, 4.36 mmol) and DBU (663 mg, 4.36 mmol) in DMF (2 ml) and DCM (2 ml) were added. ml) followed by heating in the microwave to 100 ° C for 30 minutes. The resulting red solution was concentrated in vacuo and redissolved in EtOAc (20 mL). The organic phase was washed with 1 M HCl (aq) (3x 10 ml) and brine (10 ml), dried (MgSO4) and filtered. The solvent was removed in vacuo and the residue was purified by chromatography (silica, EtOAc: MeOH, 97.5: 2.5) to give the sulfonamide derivative (0.40 g, 77%). LC / MS > 95%, m / z (ESI +) = 482 (MH +). The sulfonamide derivative (0.33 g, 0.69 mmol) was dissolved in DMF (9 mL) and the solution was cooled to 0 ° C. NaH (60% in mineral oil, 0.04 g, 1.10 mmol) was added in portions. After 0.5 h, 2,4-dichloro-quinazoline (0.15 g, 0.75 mmol) was added and after stirring at 0 ° C for 1 hour the reaction was allowed to warm to room temperature. The reaction was quenched by the addition of citric acid (5%, ac) and extracted with DCM (3 x 20 ml). The combined organic phases were washed with citric acid (5%, ac, 2 x 20 ml), H2O (2 x 20 ml). The organic phase was then dried over MgSO4? filtered and evaporated to give the title compound (0.38 g, 79%).

EXAMPLE 33 1 - [(1-Cyclopropanesulfonylaminocarbonyl-2-vinyl-cyclopropyl) amide] 2- (hex-5-enyl-methyl-amide) of 4-r2- (4-methyl-piperazin-1-yl) -quinazolin- 4-haloxy-1-cyclopentan-1,2-dicarboxylic acid (33) Compound 32 (0.03 g, 46.6 μmoles) was charged in a microwave vessel together with 1-methyl-piperazine (0.5 ml). The mixture was heated pure for 10 min at 120 ° C in the microwave system. The reaction was quenched by the addition of citric acid (5%, ac) to pH 5 and extracted with DCM (15 ml x 2). The combined organic phases were washed with citric acid (10 ml x 3). The aqueous back-extracted phase was washed with DCM (20 ml x 2) and the combined organic phases were dried over Na 2 SO 4, filtered and evaporated which gave the title compound (27 mg, 82%).

EXAMPLE 34 { 13-Methyl-17-f2- (4-methyl-piperazin-1-yl) quinazolin-4-yloxy-2,1,1-dioxo-3.13-diaza-tricyclic 13.3.0.0 * 4,6 * 1octadec-7-ene4- carbonyl} -cyclopropanesulfonic acid amide (34) A solution of compound 33 (23.5 mg, 32.2 μmol) in dry DCE (20 ml) was added to two dry microwave containers each loaded with Hoveyda Grubbs second generation catalyst (2.6 mg, 4.2 μmol). The solution was degassed with nitrogen gas before being heated in the microwave for 10 min at 150 ° C. The two batches were combined after heating and the solvents were evaporated. Purification on LC prep gave the title compound (5.00 mg, 22%).

EXAMPLE 35 1 - [(1-Cyclopropanesulfonylaminocarbonyl-2-vinyl-cyclopropyl) -amide 2- (hex-5-enyl-methyl-amide) of 4- (2-Morpholin-4-yl-quinazolin-4-yloxy) ) - cyclopentan-1,2-dicarboxylic (35) Compound 32 (0.03 g, 46.6 μmol) was loaded into a microwave flask together with morpholine (0.5 ml). The mixture was heated pure for 10 min at 120 ° C in the microwave system. To quench the reaction, citric acid (5%, ac) was added at pH 5 and extracted with DCM (15 ml x 2). The combined organic phases were washed with citric acid (10 ml x 3). The aqueous phase back-extracted with DCM (20 ml x 2) and the combined organic phases were dried over Na 2 SO 4, filtered and evaporated, which gave the title compound (17 mg, 52%).

EXAMPLE 36 RI3-Methyl-17- (2-morpholin-4-yl-quinazolin-4-yloxy) -2,14-dioxo-3,13-diazatricyclo3.3.0.0 * 4.6 * 1octadec-7 Cyclopropanesulfonic acid-4-carbonyl-1-amide (36) A solution of compound 35 (17 mg, 24.5 μmol) in dry DCE (15 ml) was added to a dry microwave flask loaded with Hoveyda Grubbs second generation catalyst (3.8 mg, 6.1 μmol). The solution was degassed with nitrogen gas before being heated in the microwave for 10 min at 150 ° C. Evaporation of the solvents followed by purification over LC prep gave the title compound (9.2 mg, 56%).

EXAMPLE 37 Acid 1-. { [2- (Hex-5-enyl-methyl-carbamoyl) -4-hydroxy-cyclopentanecarbonyl-amino} -2-vinyl-cyclopropanecarboxylic (37) Compound 27 (493 mg, 1.21 mmol) was dissolved in DMF (1 ml) and transferred to a 20 ml microwave reaction vessel equipped with a magnetic stir bar and aqueous LiOH (2 M, 10.5 ml) was added. . The reaction vessel was sealed and the immiscible suspension stirred vigorously before insertion into the microwave cavity. The reaction was irradiated for 30 minutes up to 130 ° C. The reaction mixture was cooled to 40 ° C and the clear solution was acidified to pH 2 with aqueous HCl (1M, 24 ml) and extracted with EtOAc (3x20 ml). The combined organic phases were washed with brine, dried (MgSO4) and filtered. The solvent was removed in vacuo to give the title compound (410 mg, 90%). LC / MS > 95%, m / z (ESI 379 (MH +).

EXAMPLE 38 4-Chloro-2- (4-isopropyl-thiazol-2-yl) -quinazoline (38) Compound 9 (100 mg, 0.37 mmol) was added to phosphorous oxychloride (2 ml) and heated to 100 ° C for 2 hours. The reaction mixture was then poured onto ice with vigorous stirring and made basic with NaOH (aq). The resulting suspension was extracted with ether (3x20 ml) and the combined organic phases were dried (MgSO4) and filtered. Removal of the solvent in vacuo gave the title compound in quantitative yield. LC / MS > 95%, m / z (ESI +) = 290 (MH +).

EXAMPLE 39 4-Chloro-2- (4-isopropyl-thiazol-2-yl) -7-methoxy-quinazoline (39) Compound 7 (300 mg, 1 mmol) was added to phosphorous oxychloride (6 ml) and heated to 90 ° C for 4 h. The reaction mixture was then poured into ice with vigorous stirring and made basic with NaOH (ac). The resulting suspension was extracted with ether (3x50 ml) and the combined organic phases were dried (MgSO 4) and filtered. Removal of the solvent in vacuo gave the title compound in quantitative yield. LC / MS > 95%, m / z (ESI 320 (MH +).

EXAMPLE 40 1- (. {2- (Hex-5-enyl-methyl-carbamoyl) -4- [2- (4-isopropyl-thiazol-2-yl) -quinazin-4-yloxp-cyclopentanecarbonyl acid} -amino) -2-vinyl-cyclopropanecarboxylic (40) Compound 37 (26 mg, 70 μmol) was dissolved in THF (3 ml, dried with molecular sieve). To this solution was added NaH (60% in oil, 8.2 mg, 210 μmol) and the reaction was incubated for 10 min at room temperature. To the reaction mixture was then added compound 39 (17.6 mg, 61 μmol) followed by incubation at room temperature for 16 h. To the reaction was added 0.1M HCl (aq) and EtOAc, the phases were separated and the aqueous phase was extracted with another portion of EtOAc. The organic phases The combined contents were dried (MgSO4), filtered and concentrated in vacuo which gave a crude product which was subsequently purified by flash chromatography (silica; DCM.MeOH) to give the title compound (30 mg, 78%). LC / MS > 95%, m / z (ESI +) = 632 (MH +).

EXAMPLE 41 1- (. {2- (Hex-5-enyl-methyl-carbamoyl) -4-f2- (4-isopropyl-thiazol-2-yl) -7-methoxy-quinazolin-4-yloxyl-cyclopentanecarbonyl acid .}. -amino) -2-vinyl-cyclopropanecarboxylic (41) The procedure described in Example 40 was followed but with the use of the quinazoline derivative 38 instead of 39 which gave the title compound. LC / MS > 95%, m / z (ESI +) = 662 (MH +).

EXAMPLE 42 1-f (1-cyclopropanesulfonylaminocarbonyl-2-vinyl-cyclopropyl) -amido-2- (hex-5-enyl-methyl-amide) of 4-r2- (4-lsopropyl-thiazol-2-yl) -quinazolin - 4-yloxy-1-cyclopentan-1,2-dicarboxylic acid (42) Compound 40 (25 mg, 0.0395 mmol) was dissolved in DMF: DCM (1: 4, 700 μL), followed by the addition of EDAC (15.2 mg, 0.079 mmol) at 25 ° C. The mixture was incubated for 10 minutes, followed by the addition of DMAP (4.8 mg, 0.0395 mmol) and another 20 minutes of incubation. A premixed solution of cyclopropylsulfonamide, prepared as described in WO03 / 053349, (19.3 mg, 0.158 mmol) and DBU (23.8 μL, 0.158 mmol) was added in DCM: DMF (1: 1, 200 μL), followed by heating in the microwave up to 100 ° C for 30 minutes. The resulting red color solution was concentrated in vacuo which gave a crude product which was subsequently purified by LCEM Prep to give the compound. MS-103-156 (19 mg, 65%), m / z (ESI +) = 735.28 (MH +).

EXAMPLE 43 1-f (1-cyclopropanesulfonylaminocarbonyl-2-vinyl-cyclopropyl) -amide 2- (hex-5-enyl-methyl-amide) of 4-f2- (4-lsopropyl-thiazol-2-yl) -7 acid -methoxy-quinazolin-4-yloxy-1-cyclopentan-1,2-dicarboxylic acid (43) The procedure described in Example 42 was followed but with the use of compound 41 instead of compound 40, which gave the title compound (12.3 mg, 36%). M / z (ESI 765.28 (MH +).

EXAMPLE 44 { 17-f2- (4-isopropyl-thiazol-2-yl) -quinazolin-4-yloxp-13-methyl-2,14-dioxo-3.13-diaza-triciclof13.3.0.0 * 4,6 * 1octadec-7- in-4-carbonyl-cyclopropan-sulfonic acid amide (44) Compound 42 (14.9 mg, 0.02 mmol) was dissolved in dry DCE (8 ml) under nitrogen, followed by the addition of the second generation Hoveyda-Grubbs catalyst (3.17 mg, 0.005 mmol) dissolved in dry DCE (4 ml). The mixture was heated in the microwave to 150 ° C for 10 minutes and then concentrated in vacuo which gave a crude product which was purified by LCEM Prep to give the title compound (9 mg, 64%). Mz (ESI +) = 707.27 (MH +).

EXAMPLE 45 { 17-f2- (4-isopropyl-thiazol-2-yl) -7-methoxy-quinazolin-4-yloxy1-13-methyl-2.14-dioxo-3,13-diaza-triciclof13.3.0.0 * 4, 6 * 1octadec-7-en-4-carbonyl > -cyclopropanesulfonic acid amide (45) The procedure described in Example 44 was followed but with the use of compound 43 (12.3 mg, 0.016 mmol) in place of compound 42, which gave the title compound (4.7 mg, 40%). M / z (ES l 737.11 (MH +).

EXAMPLE 46 2- (1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (46) Boc-protected proline (4 g, 17.3 mmol), HATU (6.9 g, 18.2 mmol) and 1-amino-2-vinyl-cyclopropanecarboxylic acid ethyl ester prepared as described in WO03 / were dissolved in DMF (60 ml). 099274, (3.5 g, 18.3 mmol) and cooled to 0 ° C in an ice bath. Diisopropylethylamine (DIPEA) (6ml) was added. The ice bath was removed and the mixture was left at room temperature overnight. Then dichloromethane (-80 ml) was added and the organic phase was washed with aqueous sodium hydrogen carbonate, citric acid, water, brine and dried over sodium sulfate. Purification by flash chromatography (ether? 7% methanol in ether) gave the pure title compound (6.13 g, 96%) EXAMPLE 47 2- (1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -4- (4-nitro-benzoyloxy) -pyrrolidine-1-carboxylic acid tert-butyl ester (47) Compound 46 (6.13 g, 16.6 mmol), 4-nitrobenzoic acid (4.17 g, 25 mmol) and PPh3 (6.55 g, 25 mmol) were dissolved in THF (130 mL). The solution was cooled to ~0 ° and diisopropyl azidocarboxylate (5.1 g, 25 mmol) was slowly added. The cooling was then removed and the mixture was left overnight at room temperature. Aqueous sodium hydrogen carbonate (60 ml) was added and the mixture was extracted with dichloromethane. Purification by flash chromatography (pentan-ether, 2: 1 → pentane-ether, 1: 2 → 2% methanol in ether) gave the pure title compound (6.2 g, 72%).

EXAMPLE 48 5- (1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -pyrrolidin-3-yl ester of 4-nitro-benzoic acid (48) Compound 47 (6.2 g, 12 mmol) was dissolved in a cold ice-cold mixture of 33% trifluoromethanesulfonic acid in dichloromethane. The ice bath was then removed and the mixture was left at room temperature for -1.5 h. The solvent was evaporated and 0.25 M sodium carbonate was added and the mixture was extracted with dichloromethane. Evaporation gave the title compound (4.8g, 95%) as a yellowish powder.

EXAMPLE 49 5- (1-Ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -1- (hex-5-enyl-methyl-carbamoyl) -pyrrolidin-3-yl ester of 4-n-tro-benzoic acid (49) Compound 48 (4.5 g, 10.8 mmol) was dissolved in THF (160 ml). One teaspoon of sodium hydrogen carbonate was added followed by phosgene (11.3 ml, 20% in toluene). The mixture was stirred vigorously for 1 hour. The mixture was filtered and redissolved in dichloromethane (160 ml). Sodium hydrogen carbonate (~ one tablespoon) was added followed by amine hydrochloride (2.9 g, 21.6 mmol). The reaction was left at room temperature overnight. Purification by flash chromatography (ether? 3% methanol in ether) gave the pure title compound (5.48 g, 91%), EXAMPLE 50 Ethyl ester of 13-methyl-17- (4-nitro-benzoyloxy) -2,14-dioxo-3, 13,15-triaza-tricyclic acid 13.3.0.0 * 4,6 * 1octadec-7-en-4 -carboxylic (50) Compound 49 (850 mg, 1.53 mmol) was dissolved in degassed 1.5 I and dried over 1,2-dichloroethane and refluxed under argon atmosphere overnight. Debugger was added (MP-TMT, P / N 800470 from Argonaut technologies, ~ Y? spoonful) and the mixture was stirred for 2 hours, filtered and concentrated by reduced pressure. The crude product crystallized Starting from dichloromethane / n-hexane to give the title compound (6O0mg, 74%).

EXAMPLE 51 17-Hydroxy-13-methyl-2,14-dioxo-3,13,15-triazatriciclofi 3.3.0.0 * 4.6 * 1octadec-7-en-4-carboxylic acid ethyl ester (51) Compound 50 (200 mg, 0.38 mmol) was dissolved in a methanol / THF / water mixture, 1: 2: 1, (20 ml) and cooled on an ice bath. Lithium hydroxide (1.9 ml, 1 M) was added slowly. The mixture was stirred for 4 hours at 0 ° C, then neutralized with aqueous acetic acid (20 ml) and extracted with dichloromethane. The organic phase was washed with bicarbonate, water, brine and dried over magnesium sulfate. Purification by chromatography (2% methanol in dichloromethane 4 4%) gave the title compound as a grayish powder (80%).

EXAMPLE 52 17- (7-Methoxy-2-phenyl-quinazolin-4-yloxy-13-methyl-2,14-dioxo-3,13.15-triaza-tricycloM 3.3.0.0 * 4,6 * 1octadec-7-en acid -4-carboxylic acid (52) Compound 51 (220 mg, 0.58 mmol), compound 11 (220 mg, 0.87 mmol) and triphenylphosphine (228 mg, 0.87 mmol) were suspended in dry THF (20 ml) and cooled to 0 ° C. Diisopropyl azidocarboxylate (176 mg, 0.87 mmol) was added dropwise. After the addition, the reaction mixture was allowed to reach room temperature and left overnight. The solvent was removed and aqueous sodium hydrogen carbonate was added and the mixture was extracted with dichloromethane. The organic phase was collected and the solvent was removed. The obtained crude product was dissolved in a mixture of 10 ml of THF / methanol / water (2: 1: 1). Aqueous lithium hydroxide (1 mL, 1M) was added and the mixture was heated to 50 ° C overnight. Then water (20 ml) was added and the volume reduced by half. Aqueous lithium hydroxide (1 mL, 1 M) was added and the aqueous phase was washed with several portions of dichloromethane. The aqueous phase was then acidified with citric acid and extracted with dichloromethane. Evaporation of the solvent and purification by HPLC gave the pure title compound (79 mg, 23%). M + H + 586.

EXAMPLE 53 RI7- (7-methoxy-2-phenyl-quinazolin-4-yloxy) -13-methyl-2.14-dioxo-3.13.15-triazatrichichlori3.3.0.0 * 4.6 * loctadec-7-en-4- cyclopropan sulfonic acid carbonin-amide (53) Compound 52 (79 mg, 0.13 mmol) and N, N-carbonyldiimidazole (33 mg, 0.2 mmol) were dissolved in THF (5 ml) in a sealed microwave tube under nitrogen atmosphere. The mixture was heated to 100 ° C for 10 min and then allowed to cool. A mixture of DBU (62 mg, 0.4 mmol) and cyclopropanesulfonamide (45 mg, 0.4 mmol) in THF (5 ml) were added. Then heating was continued at 100 ° C for 60 min. After cooling, the solvent was removed and the residue was dissolved in ethyl acetate.

The organic phase was washed with? 5M citric acid. Purification by HPLC gave the pure title compound (29 mg, 32%). MS (M + H) + 689.

EXAMPLE 54 Hept-6-enal (54) To a solution of hept-6-en-1-ol (1 ml, 7.44 mmol) and N-methylmorpholine N-oxide (1308 g, 11.17 mmol) in DCM (17 ml) were added standardized molecular sieves (3.5 g, 4 g. TO). The mixture was stirred for 10 min at room temperature under nitrogen atmosphere before tetrapropylammonium perruthenate (TPAP) (131 mg, 0.37 mmol) was added. After stirring for another 2.5 h the solution was filtered through celite. The solvent was then carefully evaporated and the remaining liquid was purified by flash column chromatography (DCM) to give the volatile title compound (620 mg, 74%) as an oil.

EXAMPLE 55 Ter-butyl ester of acid? -Hept-6-en- (E) -ylidene-hydrazinecarboxylic acid (55) k " To a solution of 54 (68 mg, 0.610 mmol) and tert-butyl carbazate (81 mg, 0.613 mmol) in MeOH (5 mL) were added standardized molecular sieves (115 mg, 3Á). The mixture was stirred for 3 hours after which it was filtered through celite and evaporated. The residue was dissolved in dry THF (3 ml) and AcOH (3 ml). NaBH3CN (95 mg, 1.51 mmol) was added and the solution was stirred overnight. The reaction mixture was diluted with saturated NaHCO3 solution (6 mL) and EtOAc (6 mL). The organic phase was washed with brine, saturated NaHC03, brine, dried over MgSO4 and evaporated. The cyanoborane adduct was hydrolyzed by treatment with MeOH (3 ml) and 2 M NaOH (1.9 ml). The mixture was stirred for 2 hours and the MeOH was evaporated, H20 (5 ml) and DCM (5 ml) were added and the aqueous phase was extracted three times with DCM. The combined organic phases were dried and evaporated. Purification by flash column chromatography (toluene / ethyl acetate 9: 1 with 1% triethylamine and toluene / ethyl acetate 6: 1 with 1% triethylamine) gave the title compound (85 mg, 61%) as of an oil.

EXAMPLE 56? / - (fer-Butyl) -? R-isopropylthiourea (56) To a solution of tert-butylisothiocyanate (5.0 mL, 39 mmol) in CH 2 Cl 2 (200 mL) were added isopropylamine (4.0 mL, 47 mmol) and diisopropylethylamine (DIEA) (6.8 mL, 39 mmol), and the mixture was stirred at rt. for 2 hours. The reaction mixture was diluted with EtOAc, washed with 10% citric acid (2x), saturated NaHCO 3 (2x), H 2 O (2x), and brine (1x). The organic layer was dried (MgSO4) and evaporated to give compound 94 (3.3 g, 52%) as a white solid which was used without further purification.

EXAMPLE 57: Msopropylthiourea (57) Compound 56 (3.3 g, 20 mmol) was dissolved in conc. HCl. (45 ml) and the solution was refluxed for 40 min. The mixture was allowed to cool to rt and then cooled in an ice bath and basified to pH 9.5 with solids and saturated NaHCO 3, after which the product was extracted into EtOAc (3x). The combined organic phases were washed with H20 (2x) and brine (1x), dried (MgSO), and evaporated to give the crude title compound (2.1 g, 90%) which was used without further purification.

EXAMPLE 58 2- (lsopropylamino) -1,3-thiazole-4-carboxylic acid bromide (58) A suspension of compound 57 (2.1 g, 18 mmol) and 3-bromopyruvic acid (3.0 g, 18 mmol) in dioxane (180 mL) was heated to 80 ° C. Upon reaching 80 ° C the mixture became clear, and soon after the product began to precipitate as a white solid. After 2 h of heating, the reaction mixture was cooled to rt and the precipitate was filtered and collected. This gave the pure title compound (4.4 g, 94%).

EXAMPLE 59 (2S, 4R) -2 - ((1S, 2R) 1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -4-hydroxy-pyrrolidin-1-carboxylic acid tert-butyl ester (59) A solution of HATU (6 g), diisopropylethylamine (6.8 ml), ethyl ester of (1R, 2S) -1-amino-2-vinyl-cyclopropanecarboxylic acid (1.5 g) and BOC- L-hydroxyproline (1.6 g) in dichloromethane was stirred for 1 hour. The mixture was extracted with DCM-NaHCO3 (aq), dried and concentrated. Purity HPLC approx. 90% (M + H) + 369.1.

EXAMPLE 60 (1S, 2R) -1-r (2S, 4R) - (4-Hydroxy-pyrrolidine-2-carbonyl) -aminol-2-vinyl-cyclopropanecarboxylic acid ester (60) Compound 59 was maintained in 30% trifluoroacetic acid in dichloromethane and 1% MeOH for 2 hours before being concentrated to dryness. The residue was redissolved in dichloromethane and during stirring 1N NaOH was added at pH 10-11. The organic layer was separated and concentrated which gave 1.6 g of the title compound. HPLC purity ca. 90% (M + H) + 269.1.

EXAMPLE 61 Dimethyl ester of (Rac) -4-oxocyclopent-2-en-1 acid. 2-dicarboxylic (61) Dimethyl ester of (1 /? 2S) -4-oxo-cyclopentan-1,2-dicarboxylic acid (4.8 g, 23.8 mmol) and CuBr2 (11.9 g, 53.2 mmol) were dissolved in dry THF (70 mL) and the The mixture was refluxed for two hours at 90 ° C. The formed CuBr was filtered and the organic phase was concentrated. CaCO3 (2.7 g, 27.2 mmol) and DMF (70 ml) were added and the mixture was kept at 100 ° C for one hour. The dark brown mixture was poured into ice (35 g) and the formed precipitate was filtered. The aqueous layer was extracted with ethyl acetate (1 x 300ml + 3 x 150 ml). The organic phases were dried, filtered and concentrated. Purification by flash chromatography (toluene / EtOAc 9: 1) gave 2 (2.1 g, 45%) as yellow crystals.

EXAMPLE 62 Dimethyl ester of ((1S.4K) &(1 4S)) - 4-hydroxy-cyclopent-2-en-1,2-dicarboxylic acid (62) To a cold (-30 ° C) solution of compound 61 (3.18 g, 16.1 mmol) dissolved in MeOH (23 mL), NaBH4 (0.66 g, 17.5 mmol) was added.

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

EXAMPLE 63 2-methyl ester of acid (1S.4) & (1 /? 4S) -4-hydroxy-cyclopent-2-en-1,2-dicarboxylic (63) To a freezing solution of 62 (3.4 g, 22 mmol) dissolved in dioxane and water (1: 1, 110 ml), LiOH (0.52 g, 22 mmol) was added. After two and a half hours the mixture was co-evaporated with toluene and methanol. Purification by flash chromatography (toluene / ethyl acetate 3: 1 + 1% HOAc) gave the title compound (1.0 g, 27%) as yellow-white crystals. 1 H-NMR (300 MHz, CD 3 OD): d 1.78-1.89 (m, 1 H), 2.70-2.84 (m, 1 H), 3.56-3.71 (m, 1 H), 3.76 (s, 3 H), 4.81- 4.90 (m, 1 H), 6.76-6.81 (m, 1 H). 13 C-NMR (75.5 MHz, CDCl 3): d 38.0, 48.0, 52.4, 75.7, 137.0, 146.2. 165.0 178.4.

EXAMPLE 64 Methyl ester of ((3S.5 /?) &(3 /? 5S)) - 5 - ((1 2S) -1-tert-butoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -3-hydroxyethyl ester Cyclopent-1-enecarboxylic (64) Reaction of compound 63 (50 mg, 37 mmol) with (1 R, 2 S) -1-amino-2-vinyl-cyclopropanecarboxylic acid tert-butyl ester according to the method described for the preparation of 59 gave the compound of title in the form of a slightly yellowish oil (50 mg, 38%). 1 H-NMR (300 MHz, CDCl 3): d [(1.38 & 1.42) s, 9H], 1.75-1.83 (m, 1H), 2.00--2.21 (m, 3H), 3.55-3.63 (m, 1 H) , [(3.77 &3.82) s, 3H], 4.20-4.38 (m, 1H), 4.65-4.80 (m, 1H), 5.13-5.20 (m, 1 H), 5.22-5.38 (m, 1 H) , 5.60-5.82 (m, 1 H), 6.95-6.96 (m, 2H).

EXAMPLE 65 Hex-5-enyl-methylamide of 3-oxo-2-oxa-bicyclo [2.2.-n-heptane-5-carboxylic acid (65) To HATU (2.17 g, 5.7 mmol) and N-methyl hex-5-enylamine hydrochloride (6.47 mmol) in 5 ml of DMF, under argon in an ice bath, 7R4R5R3-oxo-2-oxa-bicyclo acid was added. [2.2.1] heptane-5-carboxylic acid (835.6 mg, 5.35 mmol) in 11 ml of DMF followed by DIEA (2.80 ml, 16 mmol). After stirring for 40 min, the mixture was stirred at rt for 5 h. The solvent was evaporated, the residue was dissolved in EtOAc (70 ml) and washed with saturated NaHCO 3 (10 ml). The aqueous phase was extracted with EtOAc (2 x 25 ml). The organic phases were combined, washed with saturated NaCl (20 ml), dried over Na 2 SO 4, and evaporated. Flash column chromatography (150 g silica gel, 2/1 EtOAc-petroleum ether (PE), TLC detection by aqueous KMn04, Rf 0.55 in 4/1 EtOAc-PE) gave the title compound as an oil yellow color (1.01 g, 75%).

EXAMPLE 66 1 - [(1-Cyclopropanesulfonylaminocarbonyl-2-vinylcyclopropyl) -amide-2- (hex-5-enyl-methyl) -amide of 4-hydroxycyclopentane-1,2-dicarboxylic acid (66) LiOH solution (0.15M, 53 ml, 8 mmol) was added to lactone amide 65 (996 mg, 3.96 mmol) in an ice bath and stirred for 1 h. The The mixture was acidified to pH 2-3 with 1N HCl and evaporated, co-evaporated with toluene several times, and dried under vacuum overnight, hydrochloride (1-amino-2-vinyl-cyclopropanecarbonyl) was added. amide of (1, 2S) -cyclopropanesulfonic acid (4.21 mmol) and HATU (1.78 g, 4.68 mmol). The mixture was cooled in an ice bath under argon, and DMF (25 ml) and then DIEA (2.0 ml, 11.5 mmol) were added. After stirring for 30 min, the mixture was stirred at rt for 3 hours. After evaporation of the solvent, the residue was dissolved in EtOAc (120 ml), washed successively with 0.5 N HCl (20 ml) and saturated NaCl (2 x 20 ml), and dried over Na2SO4. Flash column chromatography (200g YMC silica gel, 2-4% MeOH in CH 2 Cl 2 gave white solids (1.25 g, 66%).

EXAMPLE 67 (17-hydroxy-13-methyl-2.14-dioxo-3,13-diazatricichlori3.3.0.0 * 4,6 * 1octadec-7- in-4-carbonyl) -amide of cyclopropanesulfonic acid (67) The cyclopentanol 66 (52.0 mg, 0.108 mmol) was dissolved in 19 ml of 1,2-dichloroethane (bubbled with argon before use). The second generation Hoveyda-Grubbs catalyst (6.62 mg, 10 mol%) was dissolved in DCE (2 x 0.5 ml) and added. The green solution was bubbled with Ar for 1 min. The aliquots (4 ml each) were transferred to five microwave tubes of 2 to 5-ml. To the last tube was added 0.8 ml of rinse with solvent. Each tube was heated by microwaves (ta up to 160 ° C in 5 min). All aliquots were combined and the solvent was evaporated. Flash column chromatography (silica gel, 3-7% MeOH in CH 2 Cl 2) gave 24.39 mg of solids (Rf 0.28 in 10% MeOH-CH 2 Cl 2 with two spots). The solids were combined with a 9.66-mg sample and subjected to a second chromatography (2? 8% MeOH in EtOAc) to give the creamy solids (23 mg) with 80% of the desired compound (yield 26%).

EXAMPLE 68 N.N-Dimethyl-thiourea (68) Dimethylamine (2M in THF, 27.5 mL, 55 mmol) was added to a stirred solution of thiocarbonyldiimidazole (10 g, 56.1 mmol) in dry THF (50 mL). The reaction mixture was made transparent by the aggregate and stirred at 50 ° C for 2 hours. After the reaction mixture had reached rt, it was evaporated on silica and purified by flash chromatography (MeOH: DCM 2:98). The solvent was removed by rotary evaporation and the remaining product was dried under high vacuum before being added to a MeOH solution. (125 ml) saturated with NH3. The reaction mixture was stirred for 60 hrs until TLC indicated complete consumption of the starting material and the LC-MS showed the product peak. The product precipitated while removing the solvent by rotary evaporation. The remaining solvent was diluted with diethyl ether and the white crystals were filtered and dried to give a yield of 1.16 g (20%). The remaining oil was purified by flash chromatography (MeOH: DCM 5:95) and another 1.87 g (32%) was obtained.

EXAMPLE 69 2-Dimethylamino-thiazole-4-carboxylic acid * HBr (69) 3-Bromopyruvic acid (2.94 g, 17.6 mmol) was added to a stirred solution of N, N-dimethyl thiourea (1.87 g, 17.6 mmol) in dry THF (60 mL). The reaction mixture was stirred at rt for 4 hrs. The precipitate that formed was filtered, washed with cold THF and dried under high vacuum. The LC-MS showed the product peak. The title compound was obtained as a white solid (2.64 g, 59%).

EXAMPLE 70 { 13-methyl-2,14-dioxo-17-f2- (5H-pyrazol-1-yl) -quinazolin-4-yloxy-3,13-diazatricyclo3.3.0.0 * 4,6 * loctadec-7 -in-4-carbonyl) -cyclopropanesulfonic acid amide (70) The title compound was synthesized analogously to the previous one using 2-pyrazoline in the procedure of Example 33.

EXAMPLE 71 f17- (2-isopropylamino-quinazolin-4-yloxy) -13-methyl-2,14-dioxo-3,13-diazatrichichlori3.3.0.0 * 4,6 * loctadec-7-en- 4-carbonin-amide of cyclopropan-sulfonic acid (71) The above compound was synthesized analogously to the previous one using isopropylamine in the procedure of Example 33.

EXAMPLE 72 [13-Methyl-2,14-dioxo-17-r 2 -pyrrolidin-1-yl) -quinazolin-4-yloxy-3,13-diazatricyclo-f 13.3.0.0 * 4, 6 * 1octac -7-en-4-carbonyl-cyclopropanesulfonic acid amide (72) The above compound was synthesized analogously to the previous one using pyrrolidine in the procedure of Example 33 EXAMPLE 73 { 17-f2- (4-cyano-phenyl) -quinazolin-4-yloxy-13-methyl-2,14-dioxo-3,13-diazatricyclo-f13.3.0.0 * 4,6 * loctadec- 7-en-4-carbonyl} -Cyclopropanesulfonic acid amide (73) The above compound was synthesized analogously to the previous one using 4-cyanobenzoic acid in Examples 6 and 7.

EXAMPLE 74 Ethyl ester of 4-amino-5-cyano-2-hydroxy-3-methylbenzoic acid (74) To a solution of sodium ethoxide (1.3 L) (prepared fresh by the addition of sodium metal (7.9 g, 0.35 mol) to ethanol (1.3L)) at 0 ° C was added ethylpropionyl acetate (25 g, 0.17 mol ) and the solution was stirred at RT for 1 h. To the above solution was added ethoxymethylene malononitrile (21 g, 0. 17 mol) at RT and the reaction mixture was refluxed at 80 ° C for 2 hours. The reaction mixture was cooled, neutralized to pH = 7 by the addition of 1.5 N HCl and concentrated in vacuo. The obtained residue was diluted with water (100 ml) and filtered. The solid was washed with water and dried under vacuum at 50 ° C to give the crude product (27 g). The crude solid was washed with 5% ethyl acetate in petroleum ether which gave the pure title compound (22.5 g, 59%).

EXAMPLE 75 4-Amino-5-cyano-2-hydroxy-3-methylbenzoic acid (75) To a solution of LiOHxH2O (8.4 g, 0.2 mol) in ethanol / water (1: 1, 300 ml) was added compound 74 (22 g, 0.1 mol) at RT and the reaction mixture was refluxed at 80 ° C for 4h The reaction mixture was concentrated in vacuo, the residue obtained was diluted with water (100 ml), washed with petroleum ether / ethyl acetate (1: 1, 2 × 200 ml). The aqueous layer was separated, acidified to pH = 5 using 1.5 N HCl and the obtained solid product was filtered. The aqueous layer was back extracted with ethyl acetate (2x300 ml), dried and concentrated to give more product. The combined products were washed with 5% ethyl acetate in petroleum ether to give the pure title compound (19 g, > 95%).

EXAMPLE 76 2-amino-4-hydroxy-3-methylbenzonitrile (76) A mixture of compound 75 (19 g, 0.1 mol) in quinoline (50 ml) was heated to 170 ° C for 2 hours (until the effervescence ceased). The reaction mixture was cooled to RT and the aqueous NaOH solution was added (1M, 500 ml) followed by petroleum ether (500 ml). The reaction mixture was stirred for 15 min and the aqueous layer was separated. The aqueous layer was subsequently washed with petroleum ether (2x300 ml) to remove quinoline completely. The aqueous layer was acidified with 1.5 N HCl until pH = 5. the solid was filtered and dried in vacuo. The solid obtained subsequently was washed with 5% ethyl acetate in petroleum ether to give the pure title compound (12 g, 82%).

EXAMPLE 77 2-amino-4-methoxy-3-methylbenzonitrile (77) A mixture of compound 76 (12 g, 0.08 mol), K2CO3 (11 g, 0.08 mol) in dry DMF (200 ml) was stirred for 15 min at RT. Mel (13.6 g, 0.096 mol) was added thereto and the mixture was stirred for 4 h at RT. The reaction mixture was diluted with water (800 ml), extracted with 30% ethyl acetate in petroleum ether (3x300 ml). The combined organic layers were washed with water and brine, dried and concentrated to give a crude product. The crude product was washed with petroleum ether to give the pure title compound (12 g, 93%).

EXAMPLE 78 2-amino-4-methoxy-3-methyl-benzamide and (78-amide) and 2-amino-4-methoxy-3-methyl-benzoic acid (78-acid) A mixture of 2-amino-4-methoxy-3-methyl-benzonitrile (9.4 g, 58 mmol) in EtOH (150 mL) and 2M sodium hydroxide solution (150 mL) was added. reflux for 8 hours. The mixture was diluted with water and extracted three times with a mixture of ethyl acetate-THF (9: 1). The organic phase was washed with water, dried with sodium sulfate and evaporated under reduced pressure. The product was crystallized from diethyl ether which gave the title amide (5.6 g, 58%). 1H-NMR dmso-d6 d 7.6 (br s, 1 H), 7.44 (d, 1 H), 6.82 (br, 1 H), 6.42 (s, 2H), 6.20 (d, 1 H), 3.78 ( s, 3H), 1.84 (s, 3H). The combined aqueous phases were acidified with citric acid and extracted three times with ethyl acetate, dried with sodium sulfate and evaporated under reduced pressure which gave the title acid (3.2 g, 30%). 1H-NMR dmso-d6 d 7.60 (d, 1 H), 6.32 (d, 1 H), 3.78 (s, 3H), 1.90 (s, 3H) EXAMPLE 79 4-isopropylthiazole-2-carboxylic acid 6-carbamoyl-3-methoxy-2-methyl-phenyl) -amide (79) To a stirred mixture of 2-amino-4-methoxy-3-methyl-benzamide (2.0 g, 11 mmol), 4-isopropyl-thiazole-2-carboxylic acid (2.4 g, 14 mmol) and Hobt-hydrate (2.2 g) , 14 mmol) in dry DMF (80 ml) was added EDAC (2.88 g, mmol) and TEA (2.1 ml, 15 mmol) and the mixture was stirred overnight. An aqueous solution of 5% citric acid was added and the mixture was extracted three times with ethyl acetate. The organic phase was washed with saturated sodium hydrogen carbonate solution (twice) and brine, dried with sodium sulfate and evaporated under reduced pressure which gave the title compound (3.1 g).

EXAMPLE 80 2- (4-isopropylthiazol-2-yl) -7-methoxy-8-methylquinazolin-4-ol (80) The above amide (79) (3.0 g, 9 mmol) was refluxed for three hours in a mixture of sodium carbonate (2.4 g, 22.5 mmol) in EtOH (70 mL) and water (70 mL). The mixture was acidified with 5% citric acid and extracted three times with a mixture of ethyl acetate-THF (4: 1). The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was purified by column chromatography on silica gel eluted with DCM containing 3% MeOH which gave the title compound (1.95 g). 1 H-NMR dmso-d 6 d 12 (s, 1 H), 8.0 (d, 1 H), 7.60 (s, 1 H), 7.32 (d, 1 H), 3.96 (s, 3 H) 2.40 (s, 3 H) ).

EXAMPLE 81 Methyl ester of 2-amino-4-methoxy-3-methylbenzoic acid (81) To a solution of 2-amino-4-methoxy-3-methyl benzoic acid (3.1 g, 17.1 mmol) in dry DMF (40 mL) was added potassium carbonate (2.4 g, 17.1 mmol) and the mixture was stirred at room temperature. environment for 30 minutes. Methyl iodide (3.1 g, 22 mmol) was added and the mixture was stirred for three hours at room temperature. A 5% aqueous solution of citric acid was added and the mixture was extracted three times with ethyl acetate. The organic phase was washed with water, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by column chromatography on silica gel eluted with hexane-ethyl acetate which gave the title compound (2.75 g).

EXAMPLE 82 2-Benzoylamino-4-methoxy-3-methylbenzoic acid methyl ester (82) To a cold solution of the previous ester (81) (1.5 g, 7.68 mmol) and TEA (2 ml) in dry DCM (30 ml) was added benzoyl chloride (1.4 g)., 10 mmol) and the mixture was stirred for four hours at room temperature. Benzoyl chloride (0.14 g, 1 mmol) was added and the mixture was stirred for an additional hour at room temperature. A 5% aqueous solution of citric acid was added and the mixture was extracted three times with ethyl acetate. The organic phase was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, dried with sodium sulfate and evaporated under reduced pressure. The product was purified by column chromatography on silica gel eluted with hexane-ethyl acetate which gave the title compound (1.6 g).

EXAMPLE 83 7-Methoxy-8-methyl-2-phenylquinazolin-4-ol (83) A mixture of the above acid (82) (1.5 g, 5 mmol) in EtOH (6 ml) and 1 m LiOH solution (6 ml) was stirred for two hours at 60 ° C. A 5% aqueous solution of citric acid was added and the mixture was extracted three times with ethyl acetate. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The residue was stirred with formamide for five hours at 150 ° C. The formamide was distilled under reduced pressure and the product was purified by column chromatography on silica gel eluted with hexane-ethyl acetate which gave the title compound (0.2 g). 1 H-NMR d 12.40 (s, 1 H), 8.21 (m, 2 H), 8.02 (d, 1 H), 7.50 (m, 3 H), 7. 22 (d, 1 H) 3.96 (d, 3H), 2.47 (d, 3H).

EXAMPLE 84 2- (1-Ethoxycarbonyl-2-vinylcyclopropylcarbamoyl) -4- (7-methoxy-8-methyl-2-phenyl-quinazolin-4-yloxy) -cyclopentanecarboxylic acid tert-butyl ester (84) Quinazolinol derivative (83) (480 mg, 1.8 mmol) was coupled to compound 15 (0.55 mg, 1.5 mmol) as described in example 16, which gave the title compound (700 mg, 75%) MS (M + H +) 616.

EXAMPLE 85 2- (1-Ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -4- (7-methoxy-8-methyl-2-phenyl-quinazolin-4-yloxy) -cyclopentanecarboxylic acid (85) Compound 84 (0.68 mg) was treated as described in Example 17, which gave the title compound (620 mg, 100%).

EXAMPLE 86 Ethyl ester of acid 1-. { [2-Hex-5-enyl-methyl-carbamoyl) -4- (7-methoxy-8-methyl-2-phenyl-quinazolin-4-yloxy) -cyclopentanecarbon-p-amino) -2-vinyl-cyclopropanecarboxylic (86 ) N-Methyl-1-hexenylamine (192 mg, 1.7 mmol) was coupled to compound 85 (615 mg, 1.1 mmol) as described in Example 18, which gave the title compound (490 mg, 68%). MS (M + H +) 655.

EXAMPLE 87 Ethyl ester of 17- (7-methoxy-8-methyl-2-phenyl-quinazolin-4-yloxy) -13-methyl-2.14-dioxo-3,13-diaza-triciclof13.3.0.0 * 4, 6 * 1octadec-7-en-4-carboxylic acid (87) A metathesis reaction of ring closure of compound 86 (480 mg, 0.73 mmol) was performed as described in Example 19, which gave the title compound (290 mg, 46%). MS (M + H +) 627.

EXAMPLE 88 17- (7-Methoxy-8-methyl-2-phenyl-quinazolin-4-yloxy) -13-methyl-2,14-dioxo-3,13-diaza-tricycloH 3.3.0.0 * 4.6 * 1octadec-7- acid en-4-carboxylic (88) The ethyl ester of compound 87 (280 mg, 0.45 mmol) was hydrolyzed as described in example 20, which gave the title compound (210 mg, 78%). MS (M + H +) 599.

EXAMPLE 89 f17- (7-methoxy-8-methyl-2-phenyl-quinazolin-4-yloxy) -13-methyl-2.14-dioxo-3,13-diaza-tricyclic 13.3.0.0 * 4.6 * 1octadec-7 Cyclopropane-sulfonic acid-4-carbonin-amide (89) Cyclopropanesulfonamide (202 mg) was coupled to acid 88 (200 mg) as described in example 21, which gave the title compound (100 mg, 42%). MS (M + H +) 702.

EXAMPLE 90 2- (4-Fluoro-benzoylamino) -4-methoxy-3-methyl-benzoic acid methyl ester (90) 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 (81) (878 mg, 4.5 mmol) was added and the mixture refluxed for 5 h. 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, eluted with ether-pentane 1: 1 which gave the pure title compound (870 mg, 61%). MS (M + H +) 318.

EXAMPLE 91 2- (4-Fluoro-benzoylamino) -4-methoxy-3-methyl-benzoic acid (91) LiOH (1 M, 4 mL) was added to a solution of 2- (4-fluoro-benzoylamino) -4-methoxy-3-methyl-benzoic acid methyl ester (90) (870 mg, 2.7 mmol), in tetrahydrofuran (15 ml), water (7.5 ml) and methanol (7.5 ml). The mixture was heated to 50 ° C for 4 h. Water (30 ml) was then added and the volume reduced by half. Acidification with acetic acid followed by filtration gave the pure title compound (830 mg, 100%). MS (M + H +) 304.

EXAMPLE 92 2- (4-Fluoro-phenyl) -7-methoxy-8-methyl-quinazolin-4-ol (92) 2- (4-Fluoro-benzoylamino) -4-methoxy-3-methyl-benzoic acid (91) (830 mg, 2.7 mmol) was heated to 150 ° C in formamide (20 ml) during 4 h. The excess formamide was removed by distillation. Water was added and the precipitated product was filtered to give the pure title compound (642 mg, 83%). MS (M + H +) 285.

EXAMPLE 93 Acid 17- (7-methoxy-8-methyl-2-phenyl-quinazolin-4-yloxy) -13-methyl-2.14-dioxo- 3.13.15-triaza-tricichlori3.3.0.0 * 4.6 * 1octadec-7 -en-4-carboxylic (93) Quinazolinol derivative (83) (449 mg, 1.7 mmol) was coupled to compound 51 (400 mg, 1.1 mmol) followed by hydrolysis of the ethyl ester as described in Example 52, which gave the title compound (112 mg, 17%). MS (M + H +) 600.

EXAMPLE 94 Ri7- (7-methoxy-8-methyl-2-phenyl-quinazolin-4-yloxy) -13-methyl-2,14-dioxo- 3.13 5-triaza-tricichlori3.3.0.0, 6 * loctadec-7 -4-carbon-p-cyclopropane-sulfonic acid amide (94) Cyclopropanesulfonamide (115 mg, 0.95 mmol) was coupled to acid 93 (112 mg, 0.19 mmol) as described in example 53, which gave the title compound (25 mg, 19%). MS (M + H +) 703.

EXAMPLE 95 Acid 17- [2- (4-lsopropyl-thiazol-2-yl) -7-methoxy-8-methyl-quinazolin-4-yloxy-13-methyl-2.14-dioxo-3.13.15-triaza- tricichlori3.3.0.0 * 4.6 * 1octadec-7-en-4-carboxylic acid (95) Quinazolinol derivative (98) (141 mg, 0.5 mmol) was coupled to compound 51 (170 mg, 0.45 mmol) followed by hydrolysis of the ethyl ester as described in Example 52, which gave the title compound (125 mg, Four. Five%). MS (M + H +) 618.

EXAMPLE 96. { 17-f2- (4-isopropyl-thiazol-2-yl- (7-methoxy-8-methyl-quinazolin-4-yloxy) -13-methyl-2.14-dioxo-3.13.15-triaza-triciclof13.3.0.0 * 4,6 * cyclopropanesulfonic acid loctadec-7-in-4-carboniD-amide (96) Cyclopropanesulfonamide (61 mg, 0.5 mmol) was coupled to acid 95 (125 mg, 0.2 mmol) as described in example 53, which gave the title compound (52 mg, 36%). MS (M + H +) 721.

EXAMPLE 97 17-r2- (4-Fluoro-phenyl) -7-methoxy-8-methyl-quinazolin-4-yloxy-3-methyl-2.14-dioxo-3,13,15-triaza-tricichlori3.3.0.0 * acid 4,6 * 1octadec-7-en-4-carboxylic acid (97) Quinazolinol derivative (92) (141 mg, 0.5 mmol) was coupled to compound 51 (170 mg, 0.45 mmol) as described in example 52, which gave crude ethyl ester of the title compound. The crude ester was purified by flash chromatography on silica gel eluted with 5-15% MeOH in diethyl ether, the residue obtained was dissolved in dichloromethane and filtered to remove traces of silica, which gave the ethyl ester of the title compound ( 135 mg, 46%). The ethyl ester was then hydrolyzed as described in Example 52, which gave the title compound (125 mg, 100%) MS (M + H) +618.3.

EXAMPLE 98 { 17-f2- (4-Fluoro-phenyl- (7-methoxy-8-methyl-quinazolin-4-yloxy) -13-methyl-2.14-dioxo-3,13,15-triaza-tricyclo [13.3.0.0 * 4 , 6 * loctadec-7-in-4-carbonyl.} - cyclopropanesulfonic acid amide (98) Did you receive? (iui? μi? μapsuii? pamiua ^ or i mg, 0.5 mmol) to acid 97 (125 mg, 0.2 mmol) as described in example 53, which gave the title compound (52 mg, 36%). MS (M + H +) 721.

EXAMPLE 99 5- (1-Ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -1-rhept-6-enyl- (4-methoxy-benzyl) -carbamoin-pyrrolidin-3-yl ester of 4-nitro-benzoic acid (99) To a solution of compound 48 (4.5 g, 10.8 mmol) in THF (160 ml) were added NaHCO 3 (1 tablespoon) and phosgene in toluene (1.93 M, 11.5 ml, 22 mmol). The mixture was stirred vigorously for 1 h at room temperature, and then filtered and evaporated. The residue was dissolved in CH2Cl2 (160 ml), and NaHCO3 (1 tablespoon) and hept-5-enyl- (p-methoxybenzyl) -amine (4.3 g, 18.5 mmol) were added. After stirring overnight at room temperature the reaction mixture was filtered and evaporated to dryness. Flash column chromatography on silica gel (EtOAc: toluene 25:75 → 40:60) gave the title compound (6.59 g, 90%) as a light brown syrup.

EXAMPLE 100 Ethyl ester of 18-Hydroxy-14- (4-methoxy-benzyl) -2,15-dioxo-3, 14.16-triaza-tricycloid acid 14.3.0.0 * 4,61 nonadec-7-en-4- carboxylic (100) Compound 99 (1g, 1.48 mmol) was dissolved in 1,2-dichloroethane (2 I). The mixture was degassed for 15 min using a stream of argon. The Hoveyda-Grubbs (II) catalyst (50 mg, 5% by mole) was added and the mixture refluxed for 4 h. The solvent was evaporated and the crude ester was dissolved in tetrahydrofuran (100 ml), methanol (50 ml) and water (50 ml). The mixture was cooled to 0 ° C on an ice bath. Aqueous lithium hydroxide (20 ml, 1M) was added and the mixture was stirred at 0 ° C for 4 h. The volume was then doubled with water and the mixture was acidified with acetic acid. Extraction (dichloromethane) followed by flash chromatography (1~5% methanol in ether) gave the pure title compound (450 mg, 61%). MS (M + H) + 500.

EXAMPLE 101 Ethyl ester of 18- [2- (4-fluoro-phenyl) -7-methoxy-8-methyl-quinazolin-4-yloxy-14- (4-methoxy-benzyl) -2,15-dioxo-3 acid , 14,16-triaza-tricycloM4.3.0.0 * 4.6 * 1nonadec-7-en-4-carboxylic (101) Quinazolinol derivative (92) (125 mg, 0.44 mmol) was coupled to compound 100 (200 mg, 0.4 mmol) as described in example 52. The obtained crude product was purified by flash chromatography on silica gel eluted with 1% of MeOH in diethyl ether, which gave the title compound (240 mg, 78%). MS (M + H) + 766.3.

EXAMPLE 102 18- [2- (4-Fluoro-phenyl) -7-methoxy-8-methyl-quinazolin-4-yloxyl-14- (4-methoxy-benzyl) -2,15-dioxo-3,14 acid, 16-triaza-triciclof14.3.0.0 * 4,6 * 1nonadec-7- en-4-carboxylic (102) The ethyl ester of compound 101 (240 mg, 0.31 mmol) was hydrolyzed as described in example 20, which gave the title compound (200 mg, 86%). MS (M + H +) 738.

EXAMPLE 103 f18-f2- (4-fluoro-phenyl) -7-methoxy-8-methyl-quinazolin-4-yloxy-1- (4-methoxy-benzyl) -2.15-dioxo-3.14.16-triaza-tricycloi4. 3.0.0 * 4.6 * 1nonadec-7-in-4-carbonyl-cyclopropanesulfonic acid (103) Cyclopropanesulfonamide (99 mg, 0.8 mmol) was coupled to acid 102 (200 mg, 0.27 mmol) as described in example 21. Purification by HPLC gave the title compound (75 mg, 33%). MS (M-H) - 839.

EXAMPLE 104. { 18- 2- (4-fluoro-phenyl) -7-methoxy-8-methyl-quinazolin-4-yloxp-2,15-dioxo- S. .ie-triaza-triciclof ^ .S00 .e ^ nonadec ^ -en ^ -carbonyl amide of cyclopropan-sulfonic acid (104) Compound 103 (75 mg, 0.09 mmol) was stirred for 2 hours in a mixture of dichloromethane-trifluoroacetic acid; 2: 1 Evaporation and purification by HPLC gave the pure title compound (25 mg, 38%). MS (M-H) "719.0.

EXAMPLE 105 4-Chloro-2-methylphenyl ester of etensulfonic acid (105) To a stirred mixture of 4-chloro-2-methylphenol (24.7g, 173mmol) in acetone (10 ml), dichloroethane (25 ml) and water (45 ml) at 0-5 ° C was added dropwise dropwise 2-chloro-1-ethane sulfonyl chloride (28.2 g, 173 mmol) and a 25% sodium hydroxide solution (60 g) for approximately one hour. The mixture was stirred for one hour at 5o and for one hour at room temperature. Water was added and the mixture was extracted twice with DCM. The organic phase was dried with sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with hexane-ethyl acetate which gave the title compound (33.4 g, 83%).

EXAMPLE 106 4-Chloro-2-methyl-5-nitrophenyl ester of etensulfonic acid (106) Compound 105 (33.2 g, 142 mmol) was dissolved in cold concentrated sulfuric acid (70 ml) and 98% nitric acid (9.8 g) was added dropwise while cooling to maintain the temperature below 10 ° C. The mixture was stirred for one hour at about 5 ° C. The mixture was added to ice water and extracted three times with ethyl acetate. The organic phase was washed twice with brine, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by column chromatography on silica gel eluted with hexane-ethyl acetate.

Yield: 30 g = 75% EXAMPLE 107 4-Chloro-2-methyl-5-nitrophenol (107) A solution of compound 106 (27.8 g, 100 mmol) and potassium carbonate (27.6 g, 200 mmol) in 1/1 water ethanol (600 mL) was refluxed for one hour. Citric acid (5%) was added and the mixture was extracted three times with DCM. The organic phase was dried with sodium sulfate and evaporated under reduced pressure which gave the title compound (19 g, 100%). 1 H-NMR CDCl 3 d 2.30 (s, 3 H), 7.24 (s, 1 H), 7.40 (s, 1 H).

EXAMPLE 108 1-Chloro-4-methoxy-5-methyl-2-nitrobenzene (108) To a stirred solution of 4-chloro-2-methyl-5-nitrophenol (18.8 g, 100 mmol) in DMF (200 mL) was added potassium carbonate (13.8 g, 100 mmol) and methyl iodide (21.3 g.150). mmol). The mixture was stirred during approximately two hours at room temperature. 5% citric acid was added and the mixture was extracted three times with ethyl acetate. The organic phase was washed with brine, dried with sodium sulfate and evaporated under reduced pressure which gave the title compound (20 G, 100%).

EXAMPLE 109 4-methoxy-5-methyl-2-nitro-benzonitrile (109) A mixture of compound 108 (20 g, 100 mmol) and copper cyanide (11.25 g, 125 mmol) in n-methyl-pyrrolidone-2 (60 ml) was stirred for 20 h at 140-150 ° C. The mixture was diluted with ethyl acetate, filtered and washed four times with water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with hexane-ethyl acetate which gave the title compound (8 g, 41%). 1 H-NMR CDCl 3 d 2.38 (s, 3 H), 4.00 (s, 3 H), 7.61 (s, 1 H), 7.73 (s, 1 H) EXAMPLE 110 4-methoxy-5-methyl-2-nitrobenzamide (110) To a mixture of 4-methoxy-5-methyl-2-nitro-benzonitrile (8 g, 40 mmol) and water (50 ml) was added concentrated sulfuric acid (65 ml) and the mixture was stirred for 2.5 hours at 100- 110 ° C. The mixture was allowed to settle overnight, filtered, washed with water and dried which gave the title compound (7 g, 83%).

EXAMPLE 111 4-methoxy-5-methyl-2-amino-benzamide (111) Compound 110 (7.0 g, 33.3 mmol) was hydrogenated in EtOH (200 ml) and Ni Raney (5.0 g) overnight at room temperature at 50 kg / cm2. The catalyst was filtered and washed with dioxane and ethanol. The solvent was removed at The product was isolated by column chromatography on silica gel eluted with dichloromethane and 3% methanol. Yield: 3.4 g = 56%.

EXAMPLE 112 7-methoxy-6-methyl-2-phenyl-quinazoline-4-ol (112) To a mixture of compound 111 (1.8 g, 10 mmol), benzoic acid (1.46 g, 12 mmol) and Hobt-hydrate (1.87 g, 12 mmol) in dry DMF (60 mL) was added EDAC (2.4 g, 12.5 mmol). ) and TEA (1.75 ml, 12.5 mmol) and the mixture was stirred at room temperature for 60 h. 5% citric acid was added and the mixture was evaporated three times with ethyl acetate. The organic phase was washed with brine and saturated sodium hydrogen carbonate solution. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The residue was refluxed for two hours with sodium carbonate (2.65 g, 25 mmol) in 100 ml ethanol-water 1/1. 5% citric acid was added and the mixture was extracted three times with ethyl acetate including 10% THF. Silica gel was added, the solvent was evaporated and the product was purified by column chromatography on silica gel eluted with hexane-ethyl acetate. Yield: 1.3 g = 50% 1 H-NMR dmso-d 6 d 2.21 (s, 3 H), 3.96 (s, 3 H), 7.17 (s, 1 H), 7.58 (m, 3 H), 7.82 (s, 1 H), 8.18 (m, 2 H) .

EXAMPLE 113 17- (7-Methoxy-6-methyl-2-phenyl-quinazolin-4-yloxy) -13-methyl-2,14-dioxo- 3.13.15-triaza-tricichlori3.3.0.0 * 4.6 * 1octac acid -7-en-4-carboxylic (113) Quinazolinol derivative (112) (480 mg, 1.8 mmol) was coupled to compound 15 (550 mg, 1.5 mmol) as described in Example 16, followed by removal of the boc group as described in Example 17, coupling N-methyl-1-hexenylamine as described in example 18, a ring closure metathesis reaction as described in example 19 and hydrolysis of the ethyl ester as described in example 52, which gave the title compound (290 mg, 30%). MS (M + H) + 599.

EXAMPLE 114 f17- (7-methoxy-6-methyl-2-phenyl-quinazolin-4-yloxy) -13-methyl-2,14-dioxo- 3.13.15-triaza-tricyclole 3.3.0.0 * 4, 6 * 1octac -7-on-4-carbonyl-cyclopropane-sulfonic acid (114) Cyclopropanesulfonamide (202 mg, 1.67 mmol) was coupled to acid 113 (200 mg, 0.33 mmol) as described in Example 89, which gave the title compound (90 mg, 38%). MS (M + H) + 702.

EXAMPLE 115 4-Methoxy-3-methyl-2- (5-methyl-pyridine-2-carbonyl) -amino-benzoic acid methyl ester (115) Methyl ester of 2-amino-4-methoxy-3-methyl-benzoic acid (400 mg, 2 mmol) and 5-methyl-pyridine-2-carboxylic acid (280 mmol, 2 mmol) where it was dissolved in dichloromethane (8 ml ) and pyridine (1 ml). Phosphorous oxychloride (0.37 ml) was added while cooling on an ice bath. The mixture was left at 0 ° C for 1 hour then allowed to reach room temperature. Aqueous sodium hydroxide (20 ml, 1 M) was added and the mixture was extracted with dichloromethane. Purification by column chromatography on silica gel (ether-pentane 1: 1) gave the pure title compound (410 mg, 65%). MS (M-H) + 315.1 EXAMPLE 116 4-Methoxy-3-methyl-2 - [(5-methyl-pyridine-2-carbonyl) -amino-1-benzoic acid (116) Compound 115 (620 mg, 1.9 mmol) was hydrolyzed by the procedure described in Example 91, which gave the pure title compound (590 mg, 100%). MS (M-H) + 301.1.

EXAMPLE 117 7-methoxy-8-methyl-2- (6-methyl-pyridin-2-yl) -quinazolin-4-ol (117) Compound 116 was heated in formamide at 150 ° C for 5-6 h. Water was then added and the precipitated product was filtered to give the pure title compound (397 mg, 71%). MS (M-H) + 282.1 EXAMPLE 118 17-R7-Methoxy-8-methyl-2- (6-methyl-pyridin-2-yl) -quinazolin-4-yloxy-13-methyl-2,14-dioxo-3,13,15 acid -triaza-tricichlori3.3.0.0 * 4.6 * loctadec-7-en-4- carboxylic (118) Quinazolinol derivative (117) (198 mg, 0.7 mmol) was coupled to compound 51 (268 mg, 0.7 mmol) followed by hydrolysis of the ethyl ester as described in example 52 which gave the title compound (50 mg, 10 mg). %). MS (M + H) + 615.3.

EXAMPLE 119. { 17-yl-methoxy-8-methyl-2- (6-methyl-pyridin-2-yl) -quinaolin-4-yloxp-13-methyl-2.14-dioxo-3.13.15-triazatriciclof13.3.0.0 * 4, 6 * 1octadec-7-en-4-carbonyl) - cyclopropanesulfonic acid amide (119) Compound 118 (50 mg, 0.08 mmol) was reacted with cyclopropan sulfonic acid amide (44 mg, 0.36 mmol) according to the procedure described in Example 53 which gave the title compound (13 mg, 22%) . MS (M-H) + 718.2 EXAMPLE 120 Acid 17- (7-methoxy-6-methyl-2-phenyl-quinazolin-4-yloxy) -13-methyl-2,14-dioxo- 3.13.15-triaza-tricichlori3.3.0.0 * 4.6 * 1octac -7-en-4-carboxylic (120) Quinazolinol derivative 112 (200 mg, 0.53 mmol) was coupled to compound 51 (268 mg, 0.7 mmol) followed by hydrolysis of the ethyl ester as described in example 52 which gave the title compound (36 mg, 11%) . MS (M-H) + 600.

EXAMPLE 121 | [17- (7-methoxy-6-methyl-2-pheny1-quinazolin-4-yloxy) -13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo [13.3. 0.0 * 4,6 * 1octadec-7-in-4-carbonn-amide of cyclopropane-sulfonic acid (121) Reaction of acid 120 (36 mg, 0.06 mmol) with cyclopropansulfonic acid amide according to the procedure described in Example 53, gave the title compound (8 mg, 19%). MS (M-H) + 703.

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 g.

° 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 was left in the water for a few hours, filtered and washed with cold water and diethyl ether. The product [C] was dried under vacuum. Performance: 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 formed amide [C] (1 eq) was added to a suspension of sodium carbonate (2.5 eq) in a 1: 1 mixture of water and EtOH and the mixture was refluxed for two hours. The EtOH was removed under reduced pressure, a 5% citric acid solution was added and the mixture was allowed to settle overnight. The product [D] was isolated by filtration, then washed with water and diethyl ether and dried in vacuo.

EXAMPLE 122 7-methoxy-8-methyl-2-pyridin-3-yl-quinazolin-4-ol (122) The general procedure described above was continued using 2-amino-4-methoxy-3-methyl benzamide as benzamide derivative and nicotinyl chloride hydrochloride as acid chloride, which gave the title compound (2.5g, 92%), [ M + H] = 268.

EXAMPLE 123 7-methoxy-8-methyl-2-pyridin-4-yl-quinazolin-4-ol (123) The general procedure described above was continued using 2-amino-4-methoxy-3-methyl benzamide as benzamide derivative and isonicotinoyl chloride hydrochloride as acid chloride, which gave the title compound (1.6 g, 60%), [M + H] = 268.

EXAMPLE 124 7-methoxy-8-methyl-2-ethyl-quinazolin-4-ol (124) The general procedure described above was continued using 2-amino-4-methoxy-3-methyl benzamide as a benzamide derivative [A] and acetic acid chloride as acid chloride [B], which gave the title compound (2.2 g , 100%). 1 H-NMR DMSO-D6 d 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, 1 H).

EXAMPLE 125 7-Methoxy-8-methyl-2- (4-methoxyphenyl) -quinazolin-4-ol (125) The general procedure described above was continued using 2-amino-4-methoxy-3-methyl benzamide as a benzamide derivative [A] and 4-methoxybenzoic acid chloride as acid chloride [B], which gave the title compound ( 5.5 g, 92%). 1 H-NMR DMSO-D 2.38 (s, 3 H), 3.82 (s, 3 H), 3.92 (s, 3 H), 7.04 (d, 2 H), 7.20 (d, 1 H), 8.00 (d, 1 H) , 8.20 (d, 2H), 12.18 (s.1 H).

EXAMPLE 126 8-methoxy-2-phenyl-quinazolin-4-ol (126) The general procedure described above was continued using 2-amino-4-methoxy-3-methyl benzamide as a benzamide derivative [A] and benzoyl chloride as acid chloride [B], which gave the title compound (2.0 g , 80%), [M + H] = 253. 1 H-NMR DMSO-D 6 d 3.97 (s, 3 H), 7.39-7.72 (m, 6 H), 8.19 (m, 2 H), 12.48 (s, 1 H).

EXAMPLE 127 2- (3-Fluoro-phenyl) -7-methoxy-8-methyl-quinazolin-4-ol (127) The general procedure described above was continued using 2-amino-4-methoxy-3-methyl benzamide as a benzamide derivative [A] and benzoyl 3-fluoro-chloride as acid chloride [B], which gave the title compound (2.1 g, 73%), [M + H] = 271.

EXAMPLE 128 2- (3,5-difluoro-phenyl) -7-methoxy-8-methyl-quinazolin-4-ol (128) The general procedure described above was continued 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 compound of the title (2.1 g, 85%), [M + H] = 303.

EXAMPLE 129 7-methoxy-8-methyl-quinazolin-4-ol (129) The title compound was formed as a bi-product when the reaction of the ring closure, step [B] to [C], in the general procedure was carried out in DMF rather than in EtOH.

EXAMPLE 130 17-R7-Methoxy-2- (4-methoxy-phenyl) -8-methyl-quinazolin-4-yloxy-13-methyl-2.14-dioxo-3.13.15-triaza-triciclof13.3.0.0 * 4.6 acid * 1octadec-7-en-4-carboxylic (130) Quinazolinol derivative (125) (281 mg, 0.949 mmol) was coupled to alcohol 51 (300 mg, 0.791 mmol) followed by hydrolysis of the ethyl ester as described in Example 52 which gave the title compound (185 mg, 47 mg). %). MS (M + H) = 630 EXAMPLE 131. { 17-f7-methoxy-2- (4-methoxy-phenyl) -8-methyl-quinazolin-4-yloxy1-13-methyl-2,14-dioxo-3,13,15-triaza-tricichlori3.3.0.0 * 4.6 * 1octadec-7-en-4-carbonyl} -cyclopropanesulfonic acid amide (131) The acid (130) (70 mg, 0.111 mmol) was dissolved in DCM (2 ml). EDAC (26 mg, 0.133 mmol) was added and the mixture was stirred at room temperature overnight. Cyclopropanesulfonic acid amide (15 mg, 0.122 mmol) and DBU (35 μl, 0.233 mmol) were added and the reaction mixture was stirred at room temperature overnight. 5% citric acid was added to the reaction mixture, and the mixture was extracted with brine, dried over Na 2 SO 4 and purified by column chromatography (DCM / MeOH 20: 1) to give the title compound (29 mg, 36%). MS (M + H) = 733 EXAMPLE 132 { 17-r7-methoxy-2- (4-methoxy-phenyl) -8-methyl-quinazolin-4-yloxp-13-methyl-2.14-d -oxo-3,13,15-triaza-tricyclop3.3.0.0 * 4.6 * 1octadec-7-en-4-carbonyl > -amide of 1-methyl-cyclopropanesulfonic acid (132) The acid (130) (35 mg, 0.056 mmol) was dissolved in DCM (2 ml). EDAC (13 mg, 0.067 mmol) was added and the mixture was stirred at room temperature overnight. Cyclopropan sulfonic acid methylamide (8.2 mg, 0.061 mmol) and DBU (18 μl, 0.117 mmol) were added and the reaction mixture was stirred at room temperature overnight. 5% citric acid was added to the reaction mixture, and the mixture was extracted with brine, dried over Na2SO4 and purified by HPLC to give the title compound (9 mg, 22%). MS (M + H) = 747.

EXAMPLE 133 2- (1-Ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -4-f7-methoxy-2- (4-methoxy-phenyl) -8-methyl-quinazolin-4-yloxy-1-cyclopentanecarboxylic acid tert-butyl ester ( 133) Alcohol 15 (550 mg, 1.5 mmol), quinazolinol 125 (533 mg, 1.8 mmol) and triphenyl phosphine (990 mg, 3.75 mmol) were dissolved in THF (40 mL) and cooled to 0 ° C. Diisopropyl azidocarboxylate (0.74 ml, 3.75 mmol) was added slowly and the suspension was allowed to reach room temperature. After 12 h, the solvent was removed under reduced pressure and the residue was placed in ether and filtered. Purification by column chromatography (Si02; toluene / EtOAc 9: 1 → 4: 1) gave the title compound (919 mg, 95%). MS (M + H) + 646.

EXAMPLE 134 2- (1-Ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -4-f7-methoxy-2- (4-methoxy-phenyl) -8-methyl-quinazolin-4-yloxy-1-cyclopentanecarboxylic acid ( 134) Compound 133 (915 mg, 1417 mmol) was dissolved in dichloromethane (20 ml) and triethylsilane (0.56 ml) was added. TFA (20 ml) dropwise at room temperature and the mixture was left for 3 h at room temperature. Removal of the solvent gave the title compound (737 mg, 88%) MS (M + H) + 590.

EXAMPLE 135 Ethyl ester of 1- (. {2- (Hex-5-enyl-methyl-carbamoyl) -4-r7-methoxy-2- (4-methoxy-phenyl) -8-methyl-quinazolin-4-} Ioxy-1-cyclopentanecarbonyl.] - amino) -2-vinyl-cyclopropanecarboxylic (135) The acid 134 (723 mg, 1.227 mmol) was dissolved in DMF (25 ml). Diisopropyl ethylamine (633 mg, 4.91 mmol) was added and the reaction mixture was placed in an ice bath. N-methyl-1-hexene hydrochloride (266 mg, 1.78 mmol) and HATU (676 mg, 1.78 mmol) were added and the mixture was stirred at room temperature for 1 hour. The solvent was removed and the residue was partitioned between EtOAc and aqueous sodium bicarbonate. The organic phase was collected and the crude product was purified by column chromatography (silica gel, heptane / EtOAc 80: 20 → 50: 50). Evaporation of the solvent gave the title compound (585 mg, 70%). MS (M + H) + 685.

EXAMPLE 136 Ethyl ester of 17-f7-methoxy-2- (4-methoxy-phenyl) -8-methyl-quinazolin-4-yloxy1-13-methyl-2.14-dioxo-3.13-diaza-triciclof13.3.0.0 * 4.6 * 1octadec-7-en-4-carboxylic acid (136) Diene 135 (585 mg, 0.854 mmol) and the second generation Hoveyda-Grubbs catalyst (50 mg) were dissolved in degassed and dried 1,2-dichloroethane (500 ml). The mixture was heated to reflux temperature overnight under an argon atmosphere. Evaporation of the solvent and purification by column chromatography (silica gel; heptane / EtOAc 70:30) gave the title compound (420 mg, 75%). MS (M + H) + 658.

EXAMPLE 137 17-R7-Methoxy-2- (4-methoxy-phenyl) -8-methyl-quinazolin-4-yloxy-13-n-ethyl-2.14-dioxo-3.13-diaza-tricyclo3.3.0.0 * 4.6 * 1-octadec acid -7-en-4-carboxylic (137) Compound 136 (420 mg, 0.639 mmol) was dissolved in 96 ml of a solvent mixture (THF 2: methanol 1: water 1). Aqueous lithium hydroxide (6.4 ml, 1 M) was added and the reaction mixture was heated at 50 ° C overnight. Purification by column chromatography (silica gel, 5% methanol in dichloromethane) gave the title compound (230 mg, 57%). MS (M + H) + 629.

EXAMPLE 138. { 17-r7-methoxy-2- (4-methoxy-phenyl) -8-methyl-quinazolin-4-yloxp-13-methyl-2.14-dioxo-3,13-diaza-triciclof13.3.0.0 * 4, 6 * 1octadec-7-en-4-carbonyl > -cyclopropanesulfonic acid amide (138) Acid 137 (130 mg, 0.207 mmol) and N, N, -carbonyldiimidazole (43 mg, 0.26 mmol) in THF (7 mL) were heated at reflux for 2 hours. DBU (29 μl), and then cyclopropanesulfonamide, prepared as described in WO03 / 053349, (28 mg, 0.23 mmol) was added and the mixture was stirred at 60 ° C overnight. The reaction mixture was diluted with ethyl acetate (25 ml) and washed with 0.5 M citric acid. Purification by HPLC gave 30 mg of the title compound. MS (M + H) + 732.

EXAMPLE 139 2,4-Dichloro-7-methoxy-8-methylquinazoline (139) Trichloromethyl chloroformate (3.60 ml, 29.8 mmol) was added under nitrogen to a solution of 6-cyano-3-methoxy-2-methylaniline (77) (3.2 g, 19.7 mmol) in acetonitrile (0.809 g, 19.7 mmol). The resulting reaction mixture was heated in a sealed tube at 130 ° C. After 12 h, the reaction mixture was cooled successively to room temperature, partitioned between ice water and EtOAc, dried (Na 2 SO 4) and evaporated. Purification by column chromatography (gradient EtOAc / CH2Cl2, 1: 9 to 1: 1) gave the title compound (3.17 g, 85%) as an orange solid: m / z = 243 (M + H) +.

EXAMPLE 140 2-Chloro-4-hydroxy-7-methoxy-8-methylquinazoline (140) A solution of NaOH (1.58 g, 39.6 mmol) in water (40 ml) was added to 2,4-dichloro-7-methoxy-8-methylquinazoline (139) (3.2 g, 13.05 mmol) in THF (20 ml). The resulting mixture was heated at 40 ° C for 24 h. Then, the reaction mixture was cooled to room temperature, the THF was evaporated and more water (30 ml) was added. The precipitate was filtered. Then, the pH of the filtrate was adjusted to 5 with AcOH to give a solid which was then filtered and washed successively with water and isopropyl ether to give the title compound (2.91 g, 99%) as a yellowish powder: m / z = 225 (M + H) +.

EXAMPLE 141 4-Hydroxy-2- (3-isopropylpyrazol-1-yl) -7-methoxy-8-methylquinazoline (141) A mixture of 2-chloro-4-hydroxy-7-methoxy-8-methylquinazoline (140) (502 mg, 2.23 mmol) and 3-isopropyraphole (500 mg, 4.55 mmol) was heated at 155 ° C for 10 min. Then, the reaction mixture was cooled successively to room temperature, partitioned between CH2Cl2 and water, dried (Na2SO4) and evaporated. The residue was triturated in ether and filtered to give the title compound (422 mg, 63%) as white needles: m / z = 299 (M + H) +.

EXAMPLE 142 2- (Hex-5-enyl-methyl-carbamoyl) -4-hydroxy-cyclopentanecarboxylic acid (142) A solution of LiOH (105 mg in 4 ml of water) was added at 0 ° C to the lactone amide (65). After 1 h, the conversion was complete (HPLC). The mixture was acidified to pH 2-3 with 1N HCl, extracted with EtOAc, dried (MgSO4), evaporated, co-evaporated with toluene several times, and dried under high vacuum overnight to give the compound of the title (520 mg, 88%), m / z = 270 (M + H) +.

EXAMPLE 143 Ethyl ester of acid 1-. { [2- (Hex-5-enyl-methyl-carbamoyl) -4-hydroxy-cyclopentan-carbonyl] -amino} -2-vinyl-cyclopropanecarboxylic acid (143) Hydrochloride of 1- (amino) -2- (vinyl) -cyclopropanecarboxylic acid ethyl ester (4.92 g, 31.7 mmol) and HATU (12.6 g, 33.2 mmol) were added to the acid (142) (8.14 g, 30.2 mmol). The mixture was cooled in an ice bath under argon, and then DMF (100 ml) and DIPEA (12.5 ml, 11.5 mmol) were added. After 30 min at 0 ° C, the solution was stirred at room temperature for another 3 hours. Then, the reaction mixture was partitioned between EtOAc and water, washed successively with 0.5 N HCl (20 ml) and saturated NaCl (2 x 20 ml), and dried (Na 2 SO). Purification by flash chromatography (EtOAc / CH2Cl2 / Petroleum ether, 1: 1: 1) gave the title compound (7.41, g 60%) as a colorless oil, m / z = 407 (M + H) + .

EXAMPLE 144 Ethyl ester of 1- (. {2- (hex-5-enyl-methyl-carbamoyl) -4-r2- (3-isopropyl-pyrazol-1-yl) -7-methoxy-8-methyl- quinazolin-4-yloxyl-cyclopentanecarbonyl.} - amino) -2-vinyl-cyclopropanecarboxylic acid (144) DIAD was added (280 μL, 1.42 mmol) at -20 ° C under nitrogen atmosphere to a solution of alcohol (143) (367 mg, 0.90 mmol), 4-hydroxy-2- (3-isopropylpyrazol-1-yl) -7-methoxy-8 -methylquinazoline (141) (270 mg, 0.90 mmol) and triphenylphosphine (288 mg, 1.42 mmol) in dry DMF (35 mL). After 2 h, the solution was warmed to room temperature. After 12 h, the reaction mixture was partitioned between ice water and ether, the organic layer was dried (Na2SO4) and evaporated. The residue was purified by column chromatography (gradient AcOEt / CH2Cl2, 1: 9 to 10: 0) to give the title compound (230 mg, 34%), m / z = 687 (M + H) +.

EXAMPLE 145 Ethyl ester of 17- [2- (3-lsopropyl-pyrazol-1-yl) -7-methoxy-8-methyl-quinazolin-4-yloxy-1, 13-methyl-2,14-dioxo-3,13-diaza - tricichlori3.3.0.0 * 4.6 * 1octadec-7-en-4-carboxylic (145) A solution of diene (144) (230 mg, 0.335 mmol) and first generation Hoveyda-Grubbs catalyst (60.8 mg, 0.101 mmol) in dry, degassed 1,2-dichloroethane (230 ml) was heated at 80 ° C under nitrogen for 18 h. Then, the solvent was evaporated and the residue was purified by silica gel chromatography (ether) to give the white compound, m / z = 659 (M + H) +.

EXAMPLE 146 Acid 17- [2- (3-isopropylpyrazol-1-yl) -7-methoxy-8-methylquinazolin-4-yloxy-13-methyl-2,14-dioxo-3,13-diazatricycloi 13.3.0.04 61octac 7-en-4-carboxylic acid (146) A solution of the lithium hydroxide hydrate (796 mg, 18.6 mmol) in water (10 ml) was added to a stirred solution of the ester (145) (346 mg, 0. 526 mmol) in THF (30 ml). After 5 days at room temperature, the reaction mixture was concentrated in vacuo. The pH was adjusted to 4 with 1 N HCl and the resulting solution was extracted successively with AcOEt, washed with brine, dried (Na 2 SO 4) and evaporated. The residue was purified by column chromatography (CH2Cl2 / MeOH, 97.5: 2.5) then triturated in isopropyl ether to give the title compound as a solid, m / z = 631 (M + H) +.

EXAMPLE 147? / - [17-r2- (3-isopropylpyrazol-1-yl) -7-methoxy-8-methylquinazolin-4-yloxp-13-methyl-2,14-dioxo-3.13-diazatricycloH3.3.0.04, 61octadec-7-en-4- carbonylKciclopropyl) sulfonamide (147) A solution of the acid (146) (53 mg, 0.084 mmol), and carbonyldiimidazole (29.4 mg, 0.181 mmol) in dry THF (10 mL) was stirred under reflux under nitrogen for 2 hours. The reaction mixture was cooled to room temperature and cyclopropylsulfonamide (50.3 mg, 0.415 mmoles) and DBU (34.1 mg, 0.224 mmoles) were added. This solution was heated at 50 ° C for 15 h. Then, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between AcOEt and dilute HCl, the organic layer was washed with brine, dried (Na2SO4) and evaporated. Purification by flash chromatography (EtOAc / CH 2 Cl 2, 2: 8) gave the desired product which was then dissolved in a minimum of ethanol and diluted with water. Filtration of the precipitate gave the title compound (14.8 mg, 24%) as a white powder, m / z = 734 (M + H) +. 1 H NMR (CDCl 3): 0.96-2.05 (m, 20H), 2.20-2.80 (m, 10H), 2.90-3.60 (m, 4H), 3.99 (s, 3H), 4.60 (t, J = 12 Hz , 1 H), 5.04 (t, J = 10 Hz, 1 H), 5.65 (m, 1 H), 5.94 (m, 1 H), 6.20-6.60 (m, 2H), 7.12 (d, J = 8.8 Hz, 1 H), 7.95 (d, J = 8.8 Hz, 1 H), 8.56 (s, 1 H), 10.9 (width s, 1 H).

EXAMPLE 148 2-ethoxy-4-hydroxy-7-methoxy-8-methylquinazoline (148) Quinazolinol (140) (530 mg, 2.36 mmol) was added in small amounts to freshly prepared EtONa (740 mg of Na added in 20 ml of EtOH). The resulting solution was heated to reflux and after 24 h, the reaction mixture was cooled to room temperature and evaporated. The residue was re-dissolved in water (10 ml) and the pH of the resulting solution adjusted to 5 with AcOH. The precipitate was collected by filtration, washed with ice water and dried to give the title compound (534 mg, 96.6%) as a white solid, m / z = 235 (M + H) +.

EXAMPLE 149 Acid 17-f2-ethoxy-7-methoxy-8-methylquinazolin-4-yloxy-M3-methyl-2,14-dioxo-3,13-diazatricycloM3.3.0.04,61octadec-7-en-4-carboxylic acid (149) The reaction of quinazolinol (148) and alcohol (143) according to the procedure described in Examples 144-146 gave the title compound m / z = 567 (M + H) +.

EXAMPLE 150? / - rI7-r2-ethoxy-7-methoxy-8-methylquinazolin-4-yloxyl-13-methyl-2,14-dioxo-3,13-d-azatricicof 13.3.0.04 6 octadec-7-en -4-carbonin (cyclopropyl) sulfonamide (150) The acid (149) was reacted with cyclopropylsulfonamide according to the procedure described in example 147, which gave the title compound, m / z = 670 (M + H) +. 1 H NMR (CDCl 3): EXAMPLE 151 17- (7-Methoxy-8-methyl-quinazolin-4-yloxy) -13-methyl-2,14-dioxo-3,13,15-triaza-tricyclop acid 3.3.0.0 * 4, 6 * 1 octadec 7-en-4-carboxylic (126) Quinazolinol derivative (126) (460 mg, 2.4 mmol) was coupled to alcohol 15 (740 mg, 2 mmol) as described in example 16, followed by removal of the boc group as described in example 17, coupling N-methyl-1-hexenylamine as described in example 18, a ring closure metathesis reaction as described in example 19 and hydrolysis of the ethyl ester as described in example 52, which gave the title compound (82 mg, 8%), MS (M + H) 523.

EXAMPLE 152 f17- (7-methoxy-8-methyl-quinazolin-4-yloxy) -13-methyl-2,14-dioxo-3,13,15-triaza-triciclof13.3.0.0 * 4,6 * 1octadec- 7-in-4-carbonn-amide of cyclopropane-sulfonic acid (152) A solution of the acid (151) (81 mg, 0.155 mmol) and EDC (40 mg, 0.21 mmol) in dry DCM (2 mL) was stirred at room temperature overnight. Cyclopropylsulfonamide (48mg, 0.4mmol) and DBU (76mg, 0.5mmol) were added and the mixture was stirred at room temperature for 6 hours. 5% citric acid was added and the mixture was extracted three times with ethyl acetate. The organic phase was washed with 5% citric acid and brine, dried with sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with ether-methanol which gave the title compound (32 mg, 31%), MS (M + H) 626.

EXAMPLE 153 Acid 17-f2- (4-fluoro-phenyl) -7-methoxy-8-methyl-quinazolin-4-yloxyM 3-methyl-2.14-dioxo-3.13.15-triaza-tricichlori3.3.0.0 * 4, 6 * 1-octadec-7-en-4-carboxylic acid (153) Quinazolinol derivative (92) (520 mg, 1.8 mmol) was coupled to alcohol 15 (550 mg, 1.5 mmol) as described in example 16, followed by removal of the boc group as described in example 17, coupling N-methyl-1-hexenylamine as described in example 18, a ring closure metathesis reaction as described in example 19 and hydrolysis of the ethyl ester as described in example 52, which gave the title compound (185 mg, 20%), MS (M + H) 617.

EXAMPLE 154. { 17-f2- (4-fluoro-phenyl) -7-methoxy-8-methyl-quinazolin-4-yloxy-1, 13-methyl-2.14-dioxo-3,13.15-triaza-tricyclop3.3.0.0 * 4,6 * loctadec-7-en-4-carbonil} -cyclopropanesulfonic acid amide (154) A solution of the acid (153) (92 mg, 0.15 mmol) and EDC (38 mg, 0.2 mmol) in dry DCM (2 ml) was stirred at room temperature overnight. Cyclopropylsulfonamide (48 mg, 0.4 mmol) and DBU (76 mg, 0.5 mmol) were added and the mixture was stirred at room temperature for 6 hours. 5% citric acid was added and the mixture was extracted three times with ethyl acetate. The organic phase was washed with 5% citric acid and brine, dried with sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with ether-methanol which gave the title compound (70 mg, 65%), MS (M + H) 720.

EXAMPLE 155 2- (1-Ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -4-r2- (3-fluoro-phenyl) -7-methoxy-8-methyl-quinazolin-4-yloxy) -cyclopentanecarboxylic acid tert-butyl ester (155) PPh3 (787 mg, 3.0 mmol) was added to a stirred solution of alcohol 15 (550 mg, 1.5 mmol) and quinazolinol 127 (430 mg, 1.5 mmol) in a mixture of dry THF (40 mL) and dry DMF (10 mL). ml). The reaction mixture was placed under an inert atmosphere (N2) at room temperature and DIAD (591 μL, 3.0 mmol) was added. The reaction mixture was stirred for 18 h where after the solvents were evaporated. The residue was dissolved in CHCl3 and washed with brine in a separatory funnel. The organic phase was dried with Na 2 SO 4, evaporated on silica and purified by flash chromatography (heptane: ethyl acetate 2: 1 to 1: 1) which gave the title compound as a white-beige solid (896 mg, 94%), LREM (M + H) 634.

EXAMPLE 156 2- (1-Ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -4-f2- (3-fluoro-phenyl) -7-methoxy-8-methyl-quinazolin-4-yloxyl-cyclopentanecarboxylic acid (156) Compound 155 (0.896 g, 1.41 mmol) was dissolved in a mixture of DCM (30 ml), TFA (10 ml), a few drops of TES and one drop of H20. The reaction was stirred for 30 minutes followed by removal of the solvent by filtration. The crude residue was divided between CHCl3 and saturated NaHC03 (ac). The organic phase was dried (Na 2 SO) and evaporated which gave the compound (0.81 g, 99%) as a white solid. LREM (M + H) 578.

EXAMPLE 157 Ethyl ester of acid 1-. { [4-f2- (3-fluoro-phenyl) -7-methoxy-8-methyl-quinazolin-4-yloxy] -2- (hex-5-enyl-methyl-carbamoyl) -cyclopentancarbonan-amino} -2-vinyl-cyclopropanecarboxylic acid (157) Compound 156 (0.81 g, 1.40 mmol) and hex-5-enyl-methyl-amine hydrochloride (272 mg, 1.82 mmol) was dissolved in dry DMF (50 mL). DIEA (975 μL, 5.6 mmol) was added and the reaction flask was placed in an ice bath. After 10 minutes HATU (559 mg, 1.47 mmol) was added to the solution. The reaction flask was allowed to reach room temperature and stirring was continued for 3 hours before the solvent was removed by evaporation. The crude product was extracted with CHCl3 and washed with saturated NaHCO3 (aq). The organic phase was dried (Na 2 SO), evaporated on silica and purified by flash chromatography (heptane: ethyl acetate 1: 1) to give the title compound (0.716 g, 76%), LREM (M + H) 673 .

EXAMPLE 158 Ethyl ester of 17-f2- (3-fluoro-phenyl) -7-methoxy-8-methyl-quinazolin-4-yloxyl-13-methyl-2,14-dioxo-3,13-diaza-trichlori3 acid. 3.0E0 * 4,6 * 1octadec-7-en-4-carboxylic (158) Diene 157 (0.70 g, 1041 mmol) was dissolved in dry DCE (0.7 L). The solution was placed under an inert atmosphere (N2) and catalyst (second generation Hoveyda Grubbs, 70 mg, 0.113 mmol) was added to the solution. The reaction mixture was refluxed for 16 h, cooled to room temperature and evaporated on silica by rotary evaporation. The product was purified by flash chromatography (heptane: ethyl acetate 1: 1) which gave the title compound (0.466 g, 70%), LREM (M + H) 645.

EXAMPLE 159 17-r2- (3-Fluoro-phenyl) -7-methoxy-8-methyl-quinazolin-4-yloxy-M3-methyl-2.14-dioxo-3.13-diaza-tricichlori3.3.0.0 * 4.6 * loctadec-7 acid -en-4-carboxylic (159) The ethyl ester 158 (460 mg, 0.713 mmol) was dissolved in THF: MeOH: H 2 O (2: 1: 1, 100 ml) and LiOH (1 M) (7.13 ml mg, 7.13 mmol) was added to the solution. The reaction was heated to 50 ° C for 16 hours. Then THF and MeOH were removed by rotary evaporation and the remaining solution was acidified with 20 ml of 10% citric acid (aq). The aqueous phase was extracted with CHCl3 (3x50 ml) and the organic phase was washed with brine. The organic phase was dried with Na 2 SO 4, filtered and concentrated by rotary evaporation. The product was obtained as a white solid (0.363 g, 82%), LREM (M + H) 617.

EXAMPLE 160 { 17-f2- (3-fluoro-phenyl) -7-methoxy-8-methyl-quinazolin-4-yloxy-1, 13-methyl-2.14-dioxo-3,13-diaza-triciclof13.3.0.0 * 4,6 * 1octadec-7-en-4-carbonyl) -cyclopropanesulfonic acid amide (160) A mixture of the acid 159 (200 mg, 0.324 mmol) and CDI (105 mg, 0.649 mmol) in dry THF (12 ml) was heated to reflux for 2 hours under N2. The reaction mixture was cooled to 50 ° C and a premixed solution of cyclopropyl sulfonamide (118 mg, 0.973 mmol) and DBU (138 μL, 0.908 mmol) in 2 mL of dry THF was added to the reaction mixture. The reaction was stirred at 50 ° C for 18 h. The solution was poured into a separatory funnel and acidified with ca. 20 ml of 10% citric acid (ac). Additional brine (20 ml) and EtOAc (40 ml) were added. The mixture was extracted with EtOAc and washed with brine, then dried with Na 2 SO 4, filtered and the solvent removed by rotary evaporation. The crude product was purified by HPLC on an Ace-5 C8 column (100x21.2 mm) with a gradient ranging from 35 to 60% acetonitrile (0.1% TFA) in H20 (0.1% TFA) for 8 minutes. The title compound was obtained as a white solid (144 mg, 62%), LREM (M + H) 720. 13C NMR (CDCI3, 500 MHz) d 6.1, 6.6, 9.6, 21.1, 24.1, 25.8, 27.5, 31.0, 32.4, 34.3, 34.9, 35.8, 44.8, 44.8, 47.5, 48.3, 56.2, 109.6, 112.3, 1 15.3 * , 115.4 *, 117.6 *, 117.8 *, 120.9, 122.4, 124.2, 124.3, 129.9 *, 130.0 *, 132.9, 140.7, 149.8, 158.2, 161.3, 162.0, 166.3, 168.2, 173.6, 179.6. (* = carbon doublets).

EXAMPLE 161 (17-r2- (3-Fluoro-phenyl) -7-methoxy-8-methyl-quinazolin-4-yloxyM3-methyl-2.14-dioxo-3,13-diazatricicof 13.3.0.0 * 4.6 * loctadec-7- en-4-carbonyl> - 1-methyl-cyclopropanesulfonic acid amide (161) A mixture of the acid 159 (100 mg, 0.162 mmol) and CDI (53 mg, 0.325 mmol) in dry THF (7 mL) was heated to reflux for 2 hours under N2. The reaction mixture was cooled to 50 ° C and a premixed solution of methyl-cyclopropyl sulfonamide (66 mg, 0.486 mmol) and DBU (69 μL, 0.454 mmol) in dry THF (1 mL) was added to the reaction mixture. The reaction was stirred at 50 ° C for 18 h. The solvent was evaporated and the residue was dissolved in CHCl3 and washed with citric acid (10% aq). The organic phase was dried with Na2S04 > it was filtered and the solvent was removed by rotary evaporation. The crude product was purified by HPLC on an Ace-5 C8 column (100x21.2 mm) with a gradient ranging from 35 to 60% acetonitrile (0.1% TFA) in H20 (0.1% TFA) for 8 minutes. The product was obtained as a white solid (23 mg, 19%). LREM (M + H) 734. 13 C NMR (CDCl 3, 500 MHz) d 9.6, 12.5, 14.4, 18.2, 22.3, 23.9, . 9, 27.5, 32.4, 34.1, 35.2, 35.9, 36.3, 44.3, 44.9, 47.4, 48.1, 56.1, 76.7, 109. 8, 112.0, 115.0 *, 115.2 *. 117.1 *, 117.3 *, 121.8, 122.0, 124.0, 124.9, 129.9 *, 129.9 *, 132.7, 141.0 *, 141.0 *, 151.4, 157.9, 160.8, 162.2, 166.1, 167.9, 173. 4, 180.4. (* = carbon doublets).

EXAMPLE 162 (17-r2- (3-Fluoro-phenyl) -7-methoxy-8-methyl-quinazolin-4-yloxy-13-methyl-2.14-dioxo-3,13-diazatricyclo [13.3.0.0 * 4,6 * 1octadec-7-en-4-carbonyl) -amide of propan-2-sulfonic acid (162) A mixture of the acid 159 (71 mg, 0.115 mmol) and CDI (37 mg, 0.228 mmol) in dry THF (10 mL) was heated to reflux for 2 hours under N2. The reaction mixture was cooled to 50 ° C and a premixed solution of methyl-cyclopropyl sulfonamide (43 mg, 0.349 mmol) and DBU (49 μL, 0.322 mmol) in 2 mL of dry THF was added to the reaction mixture. The reaction was stirred at 50 ° C for 18 h. The solvent was evaporated and the residue was dissolved in CHCl3 and washed with citric acid (10% aq). The organic phase was dried with Na 2 SO, filtered and the solvent was removed by rotary evaporation. The crude product was purified by HPLC on an Ace-5 C8 column (100x21.2 mm) with a gradient ranging from 35 to 60% acetonitrile (0.1% TFA) in H20 (0.1% TFA) for 8 hours. minutes The product was obtained as a white solid (30 mg, 36%), LREM (M + H) 722. 13 C NMR (CDCl 3, 500 MHz) d 9.7, 15.0, 16.8, 20.8, 24.1, 26.0, 27.7, 32.8, 34.2, 35.4, 36.0, 44.4, 44.8, 47.4, 48.2, 53.3, 56.2, 76.8, 110.0, 112.2, 115.1 *. 115.3 *, 117.3 *. 117.4 *. 121.9, 122.1, 124.2, 124.7, 130.0, 133.2, 141.2, 151.5, 158.1, 161, 0, 162.3, 166.2, 169.5, 173.6, 180.5. (* = carbon doublets).

EXAMPLE 163 Ethyl ester of 17-f2- (3-fluoro-phenyl) -7-methoxy-8-methyl-quinazolin-4-yloxy-13-methyl-2,14-dioxo-3.13.15-triaza-tricyclo3 acid. 3.0.0 * 4.6 * 1octadec-7-en-4-carboxylic (163) PPh3 (415 mg, 1.58 mmol) was added to a stirred solution of alcohol 51 (300 mg, 0.79 mmol) and quinazolinol 127 (247 mg, 0.87 mmol) in dry THF (35 ml) and dry DMF 7 ml. The reaction was placed under an inert atmosphere (N2) at room temperature. DIAD (311 μL, 1.58 mmol) was added. The reaction mixture was stirred for 18 h. A precipitation formed in the flask and more white solid was precipitated after the addition of 40 ml of diethyl ether. The precipitation was filtered and washed with diethyl ether and dried in vacuo which gave the pure title compound (381 mg, 75%). LREM (M + H) 646.

EXAMPLE 164 17- [2- (3-Fluoro-phenyl) -7-methoxy-8-methyl-quinazolin-4-yloxyl-13-methyl-2.14-dioxo-3,13,15-triaza-tricyclop3.3.0 acid. 0 * 4.6 * loctadec-7-en-4-carboxylic (164) The ethyl ester 163 was reacted as described in example 159. Due to the problems of solubility and a slow reaction, the reaction was kept working for 40h. The LC-MS showed that no starting material was subtracted but almost two thirds of the starting material had decomposed. The precipitation that formed after acidification was filtered, washed with water and dried under high vacuum. The yield of the product was estimated at approximately 35% by weight and HPLC. LREM (M + H) 618.

EXAMPLE 165. { 17- [2- (3-Fluoro-phenyl) -7-methoxy-8-methyl-quinazolin-4-yloxp-13-methyl-2.14-dioxo-3,13,15-triaza-tricichlori3.3.0.0 * 4.6 * 1octadec-7-in-4-carbonyl} -cyclopropanesulfonic acid amide (165) The acid 164 was reacted according to the procedure described in example 160. The crude product was purified by HPLC on a column Ace-5 C8 (100x21.2 mm) with a gradient ranging from 35 to 60% acetonitrile in 5 mM ammonium acetate buffer solution, pH 6.8, 5% acetonitrile, for 8 minutes. The title compound was obtained as a white solid in (28 mg, 47%), LREM (M + H) 721. 1 H NMR (CDCl 3 + drops of MeOD, 400 MHz) d 0.95- 1.05 (m, 1 H), 1.07-1.17 (m, 1 H), 1.17-1.26 (m, 1 H), 1.27-1.52 (m, 3H), 1.52-1.77 (m, 3H), 1.90 (dd, 1 H, J = 8.9, 5.8), 1.99 (bs, 1H), 2.33 (bs, 1 H), 2.46- 2.65 (m, 3H), 2.66 (s, 3H), 2.88 (s, 3H), 2.95 (bs, 1 H) , 3.10 (bs, 1 H), 3.69- 3.80 (m, 2H), 4.01 (s, 3H), 4.22 (dd, 1 H, J = 11.3, 3.8), 4.72 (dd, 1 H, J = 9.5, 6.6), 5.17 (dd, 1 H, J = 10.5, 10.5), 5.68- 5.77 (m, 1 H), 6.10 (bs, 1 H), 7.17 (d, 1 H, J = 7.8), 7. 21 (d, 1 H, J = 8.6), 7.45- 7.52 (m, 1 H), 7.97 (d, 1 H, J = 9.3), 8.26 (d, 1 H, J = 10.7), 8.37 (d, 1 H, J = 7.8).

EXAMPLE 166 2- (1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -4- [2- (3, 5-difluoro-phenyl) -7-methoxy-8-methyl-quinazolin-4-yloxfl acid tert-butyl ester - cyclopentanecarboxylic (166) X Alcohol 15 and quinazolinol 128 was reacted according to the same procedure described in example 155 which gave the title compound as a white solid slightly contaminated with triphenyl phosphine oxide (1245 g,> 100). %), LREM (M + H) 652.

EXAMPLE 167 2- (1-Ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl) -4- [2- (3,5-difluorophenyl) -7-methoxy-8-methyl-quinazolin-4-ylox acid 1-cyclopentanecarboxylic acid (167) The tert-butyl ester 166 as described in Example 156 which gave the title compound as a white solid (still slightly contaminated with POPH3) in > 100% performance LREM (M + H) 596.

EXAMPLE 168 Ethyl ester of 1-fr4- [2- (3,5-Difluoro-phenyl) -7-methoxy-8-methyl-quinazolin-4-yloxy1-2- (hex-5-enyl-methyl-carbamoyl) -cyclopentanecarbonyl-amino} -2-vinyl-cyclopropane-carboxylic acid (168) The acid 167 was reacted with hex-5-enyl-methyl-amine hydrochloride according to the same procedure described in example 157, which gave the title compound (0.838 g, 81%), LREM (M + H 691.

EXAMPLE 169 Acid 17-f2- (3,5-Difluoro-phenyl) -7-methoxy-8-methyl-quinazolin-4-yloxy-13-13-methyl-2.14-dioxo-3.13-diaza-tricycloH3.3.0.0 * 4.6 * 1octadec-7-en-4-carboxylic acid (169) A ring closure metathesis reaction was performed with diene 168 according to the procedure described in example 158, which gave the title compound slightly contaminated (0.509g, 66%), LREM (M + H) 635.

EXAMPLE 170 { 17-f2- (3,5-difluoro-phenyl) -7-methoxy-8-methyl-quinazolin-4-yloxyM3-methy1- 2.14-dioxo-3,13-diaza-trichlori3.3.0.0 * 4.6 * loctadec-7-en-4-carbonylV cyclopropanesulfonic acid amide. MV065673 The reaction of acid 169 with cyclopropane sulphonic acid amide according to the procedure described in Example 159, followed by purification on HPLC using an Ace-5 C8 column (100x21.2 mm) and a buffer solution of ammonium acetate. mM, pH 6.8, 5% acetonitrile, ranging from 35 to 60% acetonitrile, gave the title compound as a white solid (8 mg, 7%). LREM (M + H) 738. 1 H NMR (CDCl 3 + drops of MeOD, 500 MHz) d 0.92- 2.57 (m, 8H), 1.71- 1.95 (m, 4H), 2.57 (bs, 1 H), 2.27-3.35 (m, 3H), 2.63 (s, 3H), 2.82-2.97 (m, 3H), 3.09 (s, 3H) ), 3.42- 3.58 (m, 2H), 4.02 (s, 3H) 4.56 (t, 1 H, J = 11. 7), 5.10 (bs, 1 H), 5.61- 5.65 (m, 1 H), 5.94 (bs, 1 H), 6.93 (dd, 1 H, J = 7.4, 7. 4), 7.25 (d, 1 H, J = 9.4), 8.04 (d, 1 H, J = 9.0), 8.11 (d, 2H, J = 9.0).

EXAMPLE 171 Ethyl ester of 14- (4-methoxy-benzyl) -18- (7-methoxy-8-methyl-2-phenyl-quinazolin-4-yloxy) -2,15-dioxo-3,14,16 -triaza-tricichlori4.3.0.0 * 4,6 * lnonadec- 7-en-4-carboxylic acid (171) Quinazolinol derivative 83 (352 mg, 0.1.2 mmol) was coupled to alcohol 100 (600 mg, 1.2 mmol) using the Mitsunobu conditions described in Example 52. The obtained crude product was purified by flash chromatography on silica gel eluted with 1% MeOH in diethyl ether, which gave the title compound (842 mg, 93%). MS (M + H) + 748.3 EXAMPLE 172 Ethyl ester of 14- (4-methoxy-benzyl) -18- (7-methoxy-8-methyl-2-phenyl-quinazolin-4-yloxy) -2,15-dioxo-3,14,16- triaza-tricichlori4.3.0.0 * 4,6 * 1nonadec- 7-en-4-carboxylic (172) The ethyl ester of compound 171 (842 mg, 1.3 mmol) was hydrolyzed as described in Example 20. After 4 h the volume was reduced by half and then doubled with water. Acidification with acetic acid followed by filtration of the precipitated product gave the title compound EMR-489 (688 mg, 85%). MS (M + H) + 720.3 EXAMPLE 173 H 4 - (4-methoxy-benzyl) -18- (7-methoxy-8-methyl-2-phenyl-quinazolin-4-yloxy) -2,15-dioxo-3,14,16-triaza-tricyclo [ 14.3.0.0 * 4,6 * cyclopropanesulfonic acid 1-nonadec-7-en-4-carbonyl-1-amide (173) Cyclopropanesulfonamide (102 mg, 0.84 mmol) was coupled to acid 172 (300 mg, 0.42 mmol) as described in example 53. Purification by HPLC gave the title compound (157 mg, 45%), MS (MH) + 823.3.

EXAMPLE 174 f18- (7-methoxy-8-methyl-2-phenyl-quinazolin-4-yloxy) -2,15-dioxo-3,14,16-triazatricyclo [14.3.0.0 * 4.6 * 1nonadec- 7-in-4-carbonyl-1-cyclopropanesulfonic acid (174) Compound 173 (150 mg, 0.18 mmol) was stirred for 30 minutes in a mixture of dichloromethane-trifluoroacetic acid; 2: 1 Evaporation and purification by column chromatography (5% methanol in ether) gave the title compound (81 mg, 62%). MS (M-H) + 703 EXAMPLE 175 [14- (4-methoxy-benzyl) -18- (7-methoxy-8-methyl-2-phenyl-quinazolin-4-yloxy) -2.15-dioxo-3,14,16-triaza-triciclof14.3.0 .0 * 4,6 * 1-methyl-cyclopropanesulfonic acid 1nonadec-7-in-4-carbonyl-amide (175) One-cyclopropanesulfonic acid 1-methyl-amide (218 mg, 1.62 mmol) was added to acid 172 (388 mg, 0.54 mmol) as described in example 53. Purification by column chromatography gave the title compound (150 mg , 33%), MS (MH) + 837.

EXAMPLE 176 f18- (7-methoxy-8-methyl-2-phenyl-quinazolin-4-yloxy) -2,15-dioxo-3.14.16-triazatricyclo- [14.3.0.0 * 4,6 * 1nonadec-7 1-Methyl-cyclopropane-sulfonic acid-4-carbonin-amide (176) Compound 175 (150 mg, 0.18 mmol) was stirred for 30 minutes in a mixture of dichloromethane-trifluoroacetic acid; 2: 1 Evaporation and purification by column chromatography (5% methanol in ether) gave the title compound (74 mg, 57%), MS (M-H) + 717.3.

EXAMPLE 177 ri8- (7-methoxy-8-methyl-2-phenyl-quinazolin-4-yloxy) -2.15-dioxo-3,14,16-triazatricyclo-ri4.3.0.0 * 4,6 * 1nonadec- 7-en-4-carbonin-amide of 1-methyl-cyclopropane-sulfonic acid The quinazolinol derivative 123 (155 mg, 0.58 mmole) was coupled to alcohol 51 (200 mg, 0.53 mmole) using the conditions of Mitsunobu as described in example 52. The desired product precipitated from the reaction mixture and was collected by filtration to give the pure title compound (152 mg, 45%), MS (M + H) + 629.3 EXAMPLE 178 17- (7-Methoxy-8-methyl-2-pyridin-4-yl-quinazolin-4-yloxy) -13-methyl-2.14-dioxo-3.13,15-triaza-tricichlori3.3.0.0 * 4.6 acid * 1octadec-7-en-4-carboxylic acid (178) The ethyl ester of compound 177 (152 mg, 0.24 mmol) was hydrolyzed according to the procedure described for compound 20. The product decomposed in part during the reaction. Purification by chromatography (0 to 15% methanol in ether + 0.1% acetic acid) gave the pure title compound (46%), MS (M + H) + 601.

EXAMPLE 179 f17- (7-methoxy-8-methyl-2-pyridin-4-yl-quinazolin-4-yloxy) -13-methyl-2,14-dioxo-3,13,15-triaza-trichlori3 .3.0.0 * 4,6 *] octadec-7-en-4-carbonin-amide of cyclopropanesulfonic acid (179) Acid 178 (67 mg, 0.11 mmol) and EDAC (26 mg, 0.13 mmol) were dissolved in dichloromethane (3 mL). After stirring at room temperature for 5 h the mixture was diluted with dichloromethane (10 ml) and the organic phase was washed with water and dried (sodium sulfate). The volume was then reduced to 2 ml and cyclopropyl sulfonamide (20 mg, 0.17 mmol) and DBU (36 mg, 2.3 mmol) were added. The mixture was allowed to stir overnight at room temperature and then washed using 5% aqueous citric acid. Purification by chromatography (0 to 2% methanol in dichloromethane gave the title compound (57 mg, 73%), MS (M + H) + 704.

BIOLOGICAL EXAMPLE 1 Activity of the compounds of formula (I) Replicon assay The compounds of formula (I) were examined for their activity in the inhibition of HCV RNA replication in a cellular assay. The test showed that the compounds of formula (I) exhibited activity against the functional HCV replicons in a cell culture. The cellular assay was based on a bicistronic expression construct, as described in Lohmann et al. (1999) Science vol. 285 pp. 110-113 with modifications described by Krieger et al. (2001) Journal of Virology 75: 4614- 4624, in a multi-target tracking strategy. In essence, the method consisted of the following. The assay used the stably transfected cell line Huh-7 luc / neo (hereinafter referred to as Huh-Luc). This cell line harbors an RNA encoding a bicistronic expression construct comprising the wild-type NS3-NS5B regions of HCV type 1b translated from an Internal Ribosomal Entry Site (IRES) of the encephalomyocarditis virus (EMCV), preceded by a indicator portion (FfL-luciferase), and a selectable marker portion (neoR, neomycin phosphotransferase). The construction is limited by 5 'and 3' NTR (non-translated regions) of HCV type 1 b. The continued culture of the replicon cells in the presence of G418 (neoR) depends on the replication of the HCV RNA. Stably transfected replicon cells that express HCV RNA, which replicates autonomously and at high levels, which encode, among others, luciferase, are used to screen antiviral compounds. The replicon cells were plated in 384 well plates in the presence of the test and control compounds, which were added in various concentrations. Following the three-day incubation, HCV replication was measured by assaying the luciferase activity (using reactive substrates from the standard luciferase assay and a Perkin Elmer ViewLux ™ ultraHTS microplate imaging). The replicon cells of the control cultures have high luciferase expression in the absence of any inhibitor. The inhibitory activity of compound on luciferase activity was monitored in Huh-Lucs cells, allowing to obtain a dose-response curve for each test compound. The EC50 values were then calculated, which value represents the amount of the compound required to decrease the level of luciferase activity detected by 50%, or more specifically, the ability to replicate the genetically linked HCV replicon RNA.

BIOLOGICAL EXAMPLE 2 Activity of the compounds of formula (I) Inhibition Assay The objective of this in vitro assay is to measure the inhibition of HCV NS3 / 4A protease complexes by the compounds of the present invention. This test provides an indication of how effective the compounds of the present invention would be in inhibiting the NS3 / 4A proteolytic activity of HCV. Inhibition of the full length hepatitis C protease NS3 enzyme was measured essentially as described in Polyakov, 2002 Prot Expression & Purification 25 363 371. Briefly, the hydrolysis of a depsipeptide substrate, Ac-DED (Edans) EEAbu [COO] ASK (Dabcil) -NH2 (AnaSpec, San Jose, USA), was measured in spectrofluorometric form in the presence of a cofactor peptide, KKGSWIVGRIVLSGK (Ake Engstrom, Department of Medical Biochemistry &Microbiology, Uppsala University, Sweden). [Landro, 1997 #Biochem 36 9340-9348]. The enzyme (1 nM) was incubated in 50 mM HEPES, pH 7.5, 10 mM DTT, 40% glycerol, 0.1% n-octyl-D-glucoside, with 25 μM NS4A cofactor and inhibitor at 30 ° C for 10 min , after which the reaction was initiated by adding the substrate 0.5 μM. The inhibitors were dissolved in DMSO, sonicated for 30 sec. and they waved with vortex. The solutions were stored at -20 ° C between measurements. The final concentration of DMSO in the test sample was adjusted to 3.3%. The hydrolysis rate was corrected by the internal filter effects according to published procedures. [Liu, 1999 Analytical Biochemistry 267 331-335]. Ki values were estimated by non-linear regression analysis (GraFit, Erithacus Softwson, Staines, MX, United Kingdom), using a model for competitive inhibition and a fixed value for Km (0.15 μM). A minimum of two replicates was performed for all measurements. The following table 1 lists the representative compounds that were prepared according to the previous examples. The activities of the compounds tested are also described in Table 1. The legend for the values A, B, C, D, E and F is as follows: - the value A corresponds to an ECso > 10 μM; - the B value corresponds to an EC5o between 10 μM and 1 μM; - the C value corresponds to an EC50 between 0.99 μM and 200 nM; - the D value corresponds to an EC50 between 199 nM and 0.5 nM; - the value E corresponds to a K > 1 μM; the F value corresponds to a Ki between 1 μM and 100 nM; the G value corresponds to a Ki between 99.9 nM and 5 nM; the H value corresponds to a Ki between 4.9 nM and 0.1 nM.

TABLE 1

Claims (28)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula I: and its N-oxides, salts and stereoisomers, wherein A is OR1, NHS (= 0) pR2, wherein: R1 is hydrogen, C6 alkyl, C0-C3 alkylenecarbocyclyl, C0-C3 alkylene heterocyclyl; R2 is CrC6 alkyl, C0-C3 alkylenecarbocyclyl, C0-C3 alkylene heterocyclyl; p is independently 1 or 2; n is 3, 4, 5 or 6; - denotes an optional double link; L is N or CRz; Rz is H or forms a double bond with carbon with an asterisk; Rq is H or when L is CRz, Rq can also be CrC6 alkyl; R r is quinazolinyl, optionally substituted with one, two or three substituents each independently selected from C-C alkyl, CrC 6 alkoxy, hydroxyl, halo, C? -C6 haloalkyl > amino, mono- or dialkylamino, mono- or dialkylaminocarbonyl, C 1 -C 6 alkylcarbonylamino, C 0 -C 3 alkylenecarbocyclyl and C 0 -C 3 alkylene heterocyclyl; R 5 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl; and where each alkyl of CrC6, alkylene C0-C3-carbocyclyl or alkylene C0-

C3-heterocyclyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of halo, oxo, nitrile, azido, nitro, C-? -C6 alkyl, C0-C3 alkylene-carbocyclyl, C0-C3 alkylene-heterocyclyl, NH2C (= 0) -, Y-NRaRb, YO-Rb, YC (= 0) Rb, Y- (C = 0) NRaRb, Y-NRaC (= O) Rb, Y-NHS (= Op) Rb, YS ( = 0) pRb and YS (= 0) pNRaRb, YC (= 0) ORb, Y-NRaC (= 0) ORb; And independently it is a C3 bond or alkylene; Ra is independently H, CrC6 alkoxy, C?-C3 alkyl or: Rb is independently H, C-i-Cß alkyl, C-i-C alco alkoxy, C 0 -C 3 alkylenecarbocyclyl or C 0 -C 3 alkylene-heterocyclyl; or Ra and Rb together with the nitrogen to which they are attached are joined to form a heterocyclyl group. 2. The compound according to claim 1, further characterized by having the partial structure:

3. The compound according to claim 1, further characterized in that n is 4 or 5.

4. The compound according to claim 3, further characterized in that adjacent to the cyclopropyl moiety is a double bond.

5. The compound according to claim 1, further characterized in that R5 is hydrogen or methyl.

6. The compound according to claim 1, further characterized in that A is -OH or -NHS (= 0) 2-cyclopropyl.

7. The compound according to claim 1, further characterized in that A is cyclopropyl substituted with NHS (= 0) 2-C -Cß alkyl-

8. The compound according to claim 1, further characterized by having the formula: where n, A, L, Rq and R5 are as defined in claim 1, and R6 is hydrogen, CrC6 alkyl, CrC6 alkoxy > C0-C3-carbocyclyl alkylene, Co-C3-heterocyclyl alkylene, hydroxy, bromo, chloro or fluoro; R9 is hydrogen, C 1 -C 7 alkyl, C 1 -C 6 alkoxy, NR a R b, C 0 -C 3 alkylenecarbocyclyl, C 0 -C 3 alkylene heterocyclyl; wherein said carbocyclyl or heterocyclyl R9 is optionally substituted with R10; R10 is Ci-Cß alkyl, Cn-C3 alkylene-cycloalkyl, C0-C3 alkylene-heterocyclyl, CrC6 alkoxy, d-Cß alkoxy-C-? -C6 alkyl, amino, amido, azido, mercapto, cyano, sulfonyl, (C 1 -C 3 alkyl) sulfonyl, nitro, hydroxy, carboxy, mercapto, halo, C? -C6 haloalkyl, CrC? haloalkyloxy; Ra and Rb are as defined in claim 1; R 1 is hydrogen or C 1 -C 2 alkoxy.

9. The compound according to claim 8, further characterized in that R6 is CrC3 alkyl, chloro or fluoro, preferably bromine or hydrogen.

10. The compound according to claim 8, further characterized in that R11 is hydrogen or methoxy.

11. The compound according to claim 8, further characterized in that R9 is phenyl or heteroaryl, any one being optionally substituted with one or two R10; where R10 is hydrogen, CrC6 alkyl, C3-C7 cycloalkyl, C3-C heterocyclyl, C-? - C6 alkoxy, halo, amino optionally mono- or di-substituted with C-? -C6 alkyl, or optionally mono- or di-substituted amido with C? -C6 alkyl.

12. The compound according to claim 11, further characterized in that R9 is phenyl, pyridyl, thiazolyl, oxazolyl or pyrazolyl, each of which is optionally substituted with R0 as defined.

13. The compound according to claim 12, further characterized in that R10 is hydrogen, fluoro, difluoro, methyl, ethyl, isopropyl, tert-butyl, alkoxy of CrC6, amino, mono- or dialkylamino of Ci-Cß, pyrrolidinyl, piperinyl, piperazinyl, N-methylpiperazinyl, morpholinyl or mono- or di-alkylamido of C C6.

14. - The compound according to claim 13, further characterized in that R10 is hydrogen, fluoro or methoxy.

15. The compound according to claim 12, further characterized in that R9 is selected from

16. - The compound according to claim 12, further characterized in that R9 is selected from:

17. - A compound that has the formula

18. A compound that has the formula:

19. - A compound that has the formula:

Since it has the form:

21. - A compound that has the formula:

22. - A compound that has the formula:

23. A compound that has the formula:

24. - A compound that has the formula:

25. - A pharmaceutical composition comprising a compound according to any of claims 1-24, and a vehicle acceptable for pharmaceutical use.

26. A pharmaceutical composition according to claim 25, further comprising another HCV antiviral drug, selected from nucleoside analogue polymerase inhibitors, protease inhibitors, ribavirin and interferon.

27. The compound according to any of claims 1-24 for use in therapy.

28. The use of a compound according to any of claims 1-24 for the manufacture of a medicament useful for the prophylaxis or treatment of infections by flaviviurs, including HCV.