MX2007002450A - Hcv inhibiting bi-cyclic pyrimidines. - Google Patents

Abstract

The present invention relates to the use of bi-cyclic pyrimidines as inhibitors of HCV replication as well as their use in pharmaceutical compositions aimed to treat or combat HCV infections. In addition, the present invention relates to processes for preparation of such pharmaceutical compositions. The present invention also concerns combinat ions of the present bi-cyclic pyrimidines with other anti-HCV agents.

Description

PIR.ftfliDINAS BICICLICAS INHIBIDORAS DEL VIRUS DE LA HEPATITIS C (DESCRIPTIVE MEMORY The present invention relates to the use of bicyclic pyrimidines as inhibitors of HCV replication as well as its use in pharmaceutical compositions intended to treat or fight infections with HCV. In addition, the present invention is > refers to the processes of the preparation of such pharmaceutical compositions. The present invention it also deals with the combinations of the present bicyclic pyrimidines with other anti-HCV agents.

After its discovery in 1989 as the agent implicated I in most non-A, non-B viral hepatitis (Choo et al., Science 244, 359-362, 1989), the hepatitis C virus (HCV) has become the center of medical research (Lauer, G.M. and Walker, B.D., New Eng J Med. 345, 41-52, 2001). HCV is a member of the Flaviviridae virus family of the genus hepacivirus, and is closely related to the genus of flavivirus, which includes several involved in human diseases, such such as the dengue virus and the yellow fever virus, and with the family of pestivirus of animals, which includes bovine viral diarrhea virus (BVDV). i HCV is a single-stranded RNA virus, in a positive sense, with an I genome of around 9,600 bp. The genome comprises 5 'and 3' untranslated regions, which adopt the RNA secondary structures and a central open reading frame encoding a single polyprotein of about 3,010-3,030 amino acids. Polyprotein codes ten products genes that are generated from the precursor polyprotein by a orchestrated series of co-and post-translational endoproteolytic cleavages mediated by both host and viral proteases. Proteins structural structures include the nucleocapsid protein and two envelope glycoproteins E1 and E2. Non-structural proteins (NS) encode some essential viral enzymatic functions (helicase, polymerase, protease), as well as proteins of unknown function. The Replication of the viral genome is mediated by the RNA-dependent RNA polymerase, encoded by the non-structural protein 5b (NS5B). In addition to polymerase, the functions of the protease and helicase, both encoded in The bifunctional NS3 protein has been shown to be essential for the replication of HCV RNA in infection models in chimpanzees (Kolykhalov, A.A., Mihalik, K., Feinstone, S.M., and Rice, C.M. J. Virol. 74, 2046-2051, 2000). In addition to the serine protease of NS3, HCV also encodes a metalloproteinase in the NS2 region.

HCV replicates with preference in hepatocytes but is not directly cytopathic and leads to a persistent infection. In particular, the lack of a vigorous response of T lymphocytes and the high propensity of viruses to mutate seem to promote a high incidence of chronic infection. There are 6 main genotypes of HCV and more than 50 subtypes, which have different geographical distribution. Type 1 HCV is the predominant genotype in the United States. UU and Europe. For example, type HCV accounts for 70 to 75 percent of all HCV infections in the United States. The great genetic heterogeneity of HCV has important clinical and diagnostic consequences, which perhaps explain the difficulties in the development of vaccines and the lack of responses to therapy. It is estimated that 170 million people worldwide are infected with 'the virus of hepatitis C virus (VHC). After the initial acute infection, most infected individuals develop chronic hepatitis, which can progress to hepatic fibrosis leading to cirrhosis, end-stage liver disease and HCC (hepatocellular carcinoma) (National Institutes of Health Consensus Development Conference Statement: Management of Hepatitis C.

Hepatology, 36, 5 Suppl. S3-S20, 2002). Liver cirrhosis due to infection with HCV is responsible for approximately 10,000 deaths per year in U.S.A. alone, and is the main cause of liver transplants. HCV transmission can occur through contact with contaminated blood or blood products, for example after a blood transfusion or use of intravenous drugs. The introduction of diagnostic tests for blood screening has led to a downward trend in the incidence of post-transfusion HCV. However, given the slow evolution to terminal liver disease, existing infections will continue to signify a serious medical problem and an economic burden for decades (Kim, W.R. Hepatology, 36, 5 Suppl.S30-S34, 2002).

The treatment of this chronic disease is an unsatisfied clinical need, since the current therapy is only partially effective and limited by its undesirable side effects. I Current therapies for HCV are based on interferon alfa (pegylated) (IFN-a) in combination with ribavirin. This combined therapy produces a sustained virological response in more than 40% of patients infected by genotype 1 viruses and approximately 80% of those infected by genotypes 2 and 3. In addition to its limited efficacy over the HCV type 1, combination therapy has important side effects and has poor tolerance in many patients. For example, in pegylated interferon and ribavirin registered tests, significant side effects resulted in discontinuation of treatment in approximately 10 to 14 percent of patients. The most important side effects of combination therapy include flu-like symptoms, hematologic abnormalities, and neuropsychiatric symptoms. The development of more effective, convenient and better tolerated treatments is an important objective of public health. Asij there is a great medical need for low molecular weight compounds that produce the inhibition of HCV replication. By inhibiting HCV replication, a rapid reduction in the viral load of patients infected with the hepatitis C virus is achieved. The reduction in viral load is a test of the principle of the clinical antiviral activity of HCV inhibitors. By maintaining low to undetectable levels of viral load, the evolution of the disease is delayed or even stopped, and in this way the development of chronic hepatitis, liver fibrosis, cirrhosis, end-stage liver disease and HCC is prevented. (hepatocellular carcinoma). The resistance of viruses, and in particular of HCV, against inhibitors is also a cause of therapy failure. Many patients receiving anti-HCV therapy do not respond fully to treatment, mainly because of the resistance of the viruses to one or more drugs used. In addition, it has been shown that the resistant virus is transferred to recently infected individuals, which produces severely limited therapeutic options for these patients without prior treatment with the drugs. Accordingly, there is a need in the art for new compounds for antiviral therapy, more especially for hepatitis therapy. The need in the art is particularly critical for compounds that are not only active on the wild-type HCV virus, but also on the increasingly common resistant HCV virus. The compounds used in the present invention are derivatives of pinmidine or triazine. PCT publication WO01 / 47921 discloses pyrimidine and triazine compounds which are inhibitors of kinase activities associated with various inflammatory diseases. In addition, PCT publications WO00 / 12497 and WO02 / 076976 disclose quinazoline derivatives that are inhibitors of the TGFβR kinase receptor and of TGF-β mediated signaling.

WO04 / 087056 refers to bicyclic pyrimidine inhibitors of TGF-ß, in which a pyrimidine nucleus is bridged to the positions (5) and (6) and are also replaced in positions (2) and (4) with substituents comprising aromatic radicals. These compounds are useful for treating subjects with conditions relieved by inhibition of TGFß activity. I WO03 / 097615 relates to methods of treating disorders fibroproliferative agents associated with the TGF-β signaling system, Administration of small non-peptidic molecules that inhibit TGF-β which bind specifically to the TGF-β type I receptor (TGFβ-R1). The inhibitors are quinazoline derivatives. WO04 / 065392 refers to condensed pyridines and pyrimidines and to its use as ligands of AUK-5 receptors. These compounds are therapeutically active, in particular for the treatment or prophylaxis of disorders characterized by overexpression of transforming growth factor I (TGF-β). Pharmaceutical compositions are disclosed for use in such therapies. I WO03 / 078426 discloses azolylaminopiazines as inhibitors of protein kinase, compositions acceptable for pharmaceutical use that comprise said compounds, and methods of using the compositions for the treatment of different diseases,! conditions or disorders.

WO03 / 078427 discloses azolyl amines as inhibitors of protein kinase, pharmaceutically acceptable compositions I comprising said compounds, and methods employing those compositions for the treatment of different diseases, conditions or disorders. WO2003077921 discloses azinylaminoazoles as inhibitors of protein kinase, compositions acceptable for pharmaceutical use comprising said compounds, and methods employing those compositions for the treatment of different diseases, conditions or disorders. WO03 / 078423 discloses compounds useful as inhibitors of protein kinases, pharmaceutically acceptable compositions comprising said compounds, and methods employing those compositions for the treatment of different diseases, conditions or disorders. WO02 / 22601 describes pyrazole compositions comprising a pharmaceutically acceptable carrier and compounds useful as protein kinase inhibitors, especially as inhibitors of aurora-2 and GSK-3, for the treatment of diseases such as cancer, diabetes and Alzheimer's The compounds of the present invention are pyrimidine derivatives that contain a fused ring that bridges the positions 5 and 6. The compounds are of the formula or its pharmaceutically acceptable salt, wherein the fused ring bridging positions 5 and 6 of the pyrimidine ring is saturated, or unsaturated or aromatic. The fused ring is an optionally substituted ring and contains 4-7 members, wherein each member is independently C, N, O or S. However, if said fused ring contains 6 members, it is not aromatic. Each Air1 and Air2 is independently an aromatic radical! optionally substituted or an optionally substituted heteroaromatic radical wherein said heteroaromatic radical contains one or more O, S, and / or N; typically these radicals contain 5-12 members; 1; R is H, or optionally substituted alkyl (1-10C), alkenyl (2-10C), or alkynyl (2-10C). The compounds useful in this invention are pyrimidine derivatives containing a bridge in the 5-6 positions and fundamental substituents in the positions corresponding to positions 2 and 4 of the pyrimidine. Other non-interfering substituents can also be included. The present invention relates to the use of a compound of formula or its salt acceptable for pharmaceutical use; where the fused ring joining through positions 5 and 6 of the pyrimidine ring is an optionally substituted saturated, unsaturated or aromatic ring containing 4-7 members, where X is an atom selected from N, O or S; n is 0, 1, 2, or 3; each of Air1 and Ar2 is independently an optionally substituted aromatic radical or an optionally substituted heteroaromatic radical wherein said heteroaromatic radical contains one or more O, S, and / or N, and these aromatic or heteroaromatic radicals contain 5-12 members; R1 is H, or optionally substituted alkyl (1-10C), alkenyl (2-10C), or alkynyl (2-10C); with the proviso that if said fused ring joining by means of a bridge the positions 5 and 6 of the pyrirmidine ring contains 6 members, it is not an aromatic ring; for the manufacture of a medicament useful for inhibiting the activity of HCV, preventing or treating conditions associated with HCV, in a mammal infected with HCV. In one embodiment of the present invention, the use of a compound of formula (1) is provided for the manufacture of a medicament useful for preventing the progression of the disease to chronic hepatitis, liver fibrosis, cirrhosis, liver disease in terminal stage, HCC (hepatocellular carcinoma) and others similar in a mammal infected with HCV.

In one embodiment of the present invention, there is provided the use of a compound of formula (1) for the manufacture of a medicament useful for treating chronic hepatitis, liver fibrosis, cirrhosis, end-stage liver disease, HCC (hepatocellular carcinoma) and similar in a mammal infected with HCV. The compounds useful in this invention are pyrimidine derivatives containing a bridge in the 5-6 positions and fundamental substituents in the positions corresponding to positions 2 and 4 of the pyrimidine. Other non-interfering substituents may also be included. In one embodiment of the present invention, Air1 and Air2 are each independently an optionally substituted aromatic radical or optionally substituted heteroaromatic radical wherein said heteroaromatic radical contains one or two O, S, and / or N, and these aromatic or heteroaromatic radicals contain -12 members. In one embodiment, the present invention relates to the use of a compound of formula or its salt acceptable for pharmaceutical use; wherein the fused ring that I bridged the positions 5 and 6 of the pyrimidine ring is an optionally substituted saturated, unsaturated or aromatic ring containing 5-6 members, wherein X is an atom selected from N or O; n is O, 1, or 2; each of Air1 and Air2 is independently an optionally substituted aromatic radical or optionally substituted heteroaromatic radical, wherein said heteroaromatic radical contains one or two N atoms, and these aromatic or heteroaromatic radicals contain 5-7 members. R1 is H, or optionally substituted alkyl (1-1 OC); with the proviso that if said fused ring joining by means of a bridge the positions 5 and 6 of the pyrirmidine ring contains 6 members, it is not an aromatic ring; for the manufacture of urji drug useful for inhibiting the activity of HCV, preventing or treating conditions associated with HCV in a mammal infected with HCV. In one embodiment, the present invention relates to the use of a compound of formula (1) or its salt acceptable for pharmaceutical use; wherein the fused ring joining by a bridge the positions 5 and 6 of the pyrimidine ring is an optionally substituted saturated, unsaturated or aromatic ring containing 5-6 members, wherein: X is an atom selected from N or O; n is 0, 1, or 2; i R1 is H, or optionally substituted (1-6C) alkyl; with the proviso that said fused ring attached by means of a bridge to positions 5 and 6 of the pyrirmidine ring contains 6 members, is not an aromatic ring; for the manufacture of a medicament useful for inhibiting the activity of HCV in or preventing or treating the diseases associated with HCV in a mammal infected with HCV. In one embodiment, the present invention relates to the use of a compound of formula or its salt acceptable for pharmaceutical use; wherein the fused ring that binds to positions 5 and 6 of the pyrimidine ring is an optionally substituted unsaturated or saturated or aromatic ring containing 5-6 members where: X is a selected atom of N u | O; i n is 0, 1, or 2; R1 is H, or optionally substituted alkyl (1-6C); every R3 is, independently! hydrogen, halo, cyano, nitro, i (1-6C) alkyl, polyhaloalkyl (1-6C), -COR, -CONR2l -COOR, -OR, -OCOR, -NR2, or -NRCOR; every R4 is, independently! hydrogen, halo, cyano, nitro, polyhaloalkyl (1-6C) or alkyl (1-6C); wherein each R is independently hydrogen, hydroxy, amino, mono- or dialkylamine (1-6C), cycloalkyl (3-7C), Het or (1-6C) alkyl optionally substituted with one or more substituents selected from hydroxy I, cycloalkyl ( 3-7C), amine, mono- or dialkyl amino (1-6C) and Het, Het is a 5 or 6 membered heterocyclic ring saturated, I partially unsaturated or completely unsaturated containing 1 to 2 heteroatoms, each independently selected from nitrogen, oxygen and sulfur, and where the Het group as a whole may optionally be substituted with one, two or three substituents independently selected from the group consisting of halo, (1-6C) alkyl, hydroxy and oxo; with the proviso that if said fused ring unites by means of a bridge positions 5 and 6 of the pyrimidine ring contains 6 members, it is not an aromatic ring; for the manufacture of a drug useful to inhibit the HCV activity, prevent or treat diseases associated with HCV, in a mammal infected with HCV. i In one embodiment, the present invention relates to the use of a compound of formula or its salt acceptable for pharmaceutical use; where the fused ring that joins by a bridge positions 5 and 6 of the pyrimidine ring together with the pyrimidine ring forms a group i selected from i wherein any of these groups may be optionally substituted with one or two selected substituents of (1-6C) alkyl, phenyl and benzyl; R3 is hydrogen, halo, (1-6C) alkyl, -CF3, -COR, -CONR2 or -COOR; each R 4a and R b are, independently, hydrogen or halo; wherein each R is independently hydrogen, hydroxy, amino, mono- or dialkylamino (1-6C), cycloalkyl (3-7C), Het or (1-6C) alkyl optionally substituted with one or more substituents selected from hydroxy, cycloalkyl (3 -7C), amino, mono- or dialkyl amino (1-6C) and Het; Het is a group selected from where the Het group can be optionally substituted with one or two substituents, each one independently selected from the group that consists of (1-6C) alkyl and oxo; for the manufacture of a useful medicament I to inhibit HCV activity, prevent or treat conditions associated with HCV, in a mammal infected with HCV.

In one embodiment, the present invention relates to the use of a compound of formula or its salt acceptable for pharmaceutical use; where the fused ring linking by means of a bridge positions 5 and 6 of the pyrimidine ring together with the pyrimidine ring forms a group selected from wherein any of these groups may be optionally substituted with one or two (1-6C) alkyl; R3 is hydrogen, (1-6C) alkyl, or | C0NR2; I each R4a and R4b is independently hydrogen or halo; wherein each R is independently hydrogen, hydroxy, amino, mono- or dialkylamino (1-6C), or (1-6C) alkyl optionally substituted with a hydroxy; for the manufacture of a medicament useful for the inhibition of HCV activity, for preventing or treating conditions associated with HCV, in a mammal infected with HCV. As used in the present specification, a "non-interfering substituent" is a substituent i that allows the ability of the compound of formula (1) to inhibit HCV activity to remain qualitatively intact. Thus, substituents can alter the degree of inhibition, but while the compound of formula (1) retains the ability to inhibit activity, the substituent will be classified as "non-interfering".

As used herein, the term "alkyl," "alkenyl," and "alkynyl" includes straight chain substituents, branched chain and monovalent cyclics, which contain C + H when not they are replaced. Examples include methyl, ethyl, isobutyl, cyclohexyl, cyclopentylethyl, 2-propenyl, 3-butinyl and the like. Generally, Alkyl, alkenyl and alkynyl substituents contain 1-10C (alkyl) or 2-10C (alkenyl or alkynyl). Preferably they contain 1-6C (lower alkyl) or 2-6C (alkenyl or lower or lower alkynyl).

Heteroalkyl, heteroalkenyl and heteroalkynyl are defined similarly but may contain 1 or more, heteroatoms O, S or N or combinations thereof within the skeletal residue.

As used in the present specification, "acyl" embraces The definitions of alkyl, alkenyl, alkynyl, and heteroacyl include Heteroforms reacted, each of which is coupled to a waste additional through the carbonyl group.

"Aromatic" rest or "aryl" residue refers to bicyclic groups fused or monocyclic such as phenyl or naphthyl; "heteroaromatic" it also refers to monocyclic or fused bicyclic ring systems containing one or more heteroatoms selected from O, S and N.

Inclusion of a hetero atom allows the inclusion of 5-member rings as well as 6-membered rings. Thus, the systems typical aromatics / heteroaromatics include pyridyl, pyrimidyl, indolyl, benzoimidazolyl, benzotriazolyl, isoquinolyl, quinolyl, benzothiazolyl, benzofuranyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, and the like.

Since tautomers are theoretically possible, phthalimide is also considered aromatic. Any bicyclic fused or monocyclic system having the characteristics of aromaticity in terms of electron distribution throughout the annular system is included in this definition. Generally, ring systems contain rings of 5-12 member atoms. Similarly, "arylalkyl" and "heteroarylalkyl" refers to aromatic and heteroaromatic systems that are coupled to another residue through a carbon chain, including substituted or unsubstituted, saturated or unsaturated, carbon chains, generally 1 -8C, or its heteroforms. These carbon chains may also include a carbonyl group, thus allowing them to provide substituents such as an acyl or heteroacyl moiety. The term "polyhaloalkyl (1-6C)" as a group or part of a group is defined as mono- or polyhalo-substituted (1-6C) alkyl, in particular (1-6C) 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. Preferred is trifluoromethyl. Also included are perfluoroalkyl groups (1-6C), which are alkyl groups (1-6C) where all hydrogen atoms are replaced with fluorine atoms, eg. pentafluoroethyl. In the case where more than one halogen atom is attached to an alkyl group within the definition of polyhaloalkyl (1-6C), the halogen atoms may be the same or different. In general, any alkyl, alkenyl, alkynyl, acyl, or aryl group contained in a substituent may be optionally substituted by additional substituents. The nature of these substituents is similar to those listed with respect to the primary substituents. Thus, when one embodiment of a substituent is alkyl, this alkyl may be optionally substituted by the remaining substituents listed as substituents where this makes chemical sense, and where the size limit of the alkyl per se does not mine; for example, alkyl substituted by alkyl or alkenyl would simply extend the upper limit of the carbon atoms for these embodiments. However, alkyl substituted by aryl, amino, alkoxy and the like would be included. The characteristics of the compounds of the invention are defined by formulas (1), (2) and (3) and the nature of the substituents is less important as long as the substituents do not interfere with the established biological activity of this basic structure. The term halo is generic for fluoro, chloro, bromo and iodo. As used hereinbefore, the term oxo or (= O) forms a carbonyl group when attached to a carbon 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. The radicals used in the definitions of the variables include all possible isomers unless otherwise indicated. For example, pyridyl includes 1-pyridyl, 2-pyridyl, 3-pyridyl and 4-pyridyl; Pentyl includes 1 -pentyl, 2-pentyl and 3-pentyl.

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

Non-interfering substituents j on Air1 or Air2, include, but without limitation, alkyl, alkenyl, alkynyl, ijialo, -OR, -NR2, -SR, -SOR, -SO2R, -OCOR, -NRCOR, -NRCONR2, -NRCOOR, -OCONR2, -RCO, -COOR, I -NORROR, -NRSO2R, -SO3R, -CONR2, SO2NR2, where each R is independently H or alkyl (1-8C), -CN, -CF3, and NO2, and substituents Similar. Non-interfering substituents of Air1 or Air2, include, but are not limited to, alkyl, alkenyl, alkynyl, halo, -OR, -NR2, -SR, -SOR, -SO2R, -OCOR, -NRCOR, -NRCONR2, -NRCOOR, -OC? NR2, -RCO, -COR, -COOR, -NRSOR, -NRSO2R, -SO3R, -CONR2, SO2'NR2, wherein each R is independently H or alkyl (1-8C), -CN, -ICF3, and NO2, and similar substituents. Preferred embodiments for R are H, (1-10C) alkyl or a heteroatom containing their derivative forms, each optionally substituted, especially (1-4C) alkyl; alkoxy (1-8C), acylamido, aryloxy, arylalkyloxy, especially in which the aryl group is a phthalimido group and alkyl or arylalkyl amine.

Preferably Ar1 and Ar2 are optionally substituted phenyl, e these modalities may be optionally substituted with such a group as alkyl, alkenyl, alkynyl, aryl, -O-aryl, -O-alkylaryl, -O-aroyl, -NR-aryl, -N-alkylaryl, -NR-aroyl, halo, -OR, -NjR- ,, - SR, -OOCR, -NROCR, -RCO, -COOR, -CONR2I and / or SO2NR2, wherein each R is independently H or alkyl (1-8C), and / or -CN, -CF3, and / or NO2. Each of these embodiments may be optionally substituted with one or more groups such as alkyl, alkenyl, alkynyl, aryl, -O-aryl, -O-alkylaryl, -O-aroyl, -NR-aryl, -N-alkylaryl, - NR-aroyl, halo, -OR, -NR2, -SR, -OOCR, -OCOR, -NROCR, -NRCOR, -RCO, -COR, -COOR, -CONR2, and / or SO2NR2, where each R is independently H or alkyl (1-8C),? and / or by -CN, -CF3, and / or NO2.

Alkyl, alkenyl, alkynyl and aryl moieties can subsequently be replaced by similar substituents. Preferred substituents on | Ar1 or Ar2 include alkyl, alkenyl, alkynyl, halo, -OR, -SR, -NR2 wherein R is H or (1-4C) alkyl; and / or arylamino, arylalkylamino, which includes the alkylamino substituted by more than one aryl group. As stated above any aryl or alkyl group included within a substituent may be substituted in a similar manner.

These substituents can occupy all available positions of the ring, preferably positions 1-2 or more preferably only one position. Any of the aryl groups, which include those represented in the formulas (1), (2) and (3), especially the phenyl groups, may also comprise two substituents which, when together, form a carbocyclic ring of 7 members or a heterocyclic aliphatic ring. The I bridge between positions 5 and 6 of the pyrimidine ring forms a fused ring system where, if the fused ring contains 6 members, it is not aromatic. However, the bridge may contain pi links and contain one or more heteroatoms selected from N, O and SI Preferred modalities include those in which the bridge produces a 5-member ring that optionally contains one or two nitrogens, a nitrogen and an oxygen, a oxygen, an additional double bond, a saturated bridge, or a ring of 6 members formed by a bridge, which is saturated. In one modality, the 6-member saturated ring generated by the bridge contains one or two nitrogens. The ring formed by the bridge may be substituted. The 1 substituents described above for Air1 and Air2 can be present also as fused ring systems.

Whenever used herein, the terms "compounds of formula (1)", "compounds of formula (2)", "compounds of formula (3)", or "the present compounds" or similar terms, these include the compounds of formulas (1), (2), and (3), their prodrugs,? / - oxides, addition salts, quaternary amines, complexes metals and stereochemically isomeric forms. comprises the compounds of formula (1) or any subgroup of compounds of formula (1) specified herein, which they include compounds of formula (2) and (3), as well as the? / - oxides, salts, as their possible stereoisomeric forms. Another modality comprises the compounds of formula (1) or any subgroup of compounds of formula (1)) specified herein, as well as the salts and their possible stereoisomeric forms.

Salts of the compounds of formula (1) for therapeutic use are those in which the counterion is acceptable for pharmaceutical use. However, salts of acids and bases which are not acceptable for pharmaceutical use can also be used, for example, in the preparation or purification of the compound acceptable for pharmaceutical use, All salts, acceptable for pharmaceutical use or not acceptable are included within of the scope of the present invention. Addition salts with acids and bases acceptable for pharmaceutical use as mentioned hereinabove comprise the forms of addition salts with non-toxic therapeutically active acids and bases which the compounds of formula (1) are capable of forming. Acid addition salts with acids acceptable for pharmaceutical use can be conveniently obtained by treating the basic form with such an appropriate acid. Suitable acids comprise, for example, inorganic acids such as hydrohalic acids, e.g., hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and other similar acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (ie, ethanedioic acid), malonic, succinic (ie, butanedioic acid), benzoic, maleic, fumaric, malic acid hydroxybutanedioic), tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and similar acids.

Conversely, said salt forms can be converted by treatment with an appropriate base into the free base form. The compounds of formula (1) contain an acidic proton which can be converted into addition salt forms with non-toxic amines or metals by treatment with appropriate inorganic and organic bases. Thus, if a carboxyl group is present in the compound of formula (1), the compound can also be provided as a salt with a cation acceptable for pharmaceutical use. Suitable basic 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, eg . benzathine salts,? / - methyl-D-glucamine, hydrabamine, and salts with amino acids such as, for example, arginine, lysine and the like. The term "addition salts" as used hereinbefore also encompasses the solvates, which the compounds of formula (1) as well as their salts, are capable of forming. Such solvates are for example hydrates, alcoholates and the like. The compounds of formula (1) may also be provided in the form of a "prodrug," which is designed to release the compound of formula (1) when administered to a subject. The term "prodrug" as used herein means acceptable derivatives for pharmaceutical use such as esters, amides and phosphates, such that the in vivo biotransformation product of the resulting derivative is the active drug as defined in the compounds of formula (I). Goodman and Gilman's reference (The Pharmacological Basis of Therapeutics, 8th ed, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", p. 13-15) describes the general assumptions incorporated herein by reference. Preferably, the prodrugs have excellent aqueous solubility, high bioavailability and rapid metabolism in vivo to the active inhibitors. The prodrugs of a compound of the present invention can be prepared by functionally modifying the groups present in the compound such that the modifications are separated, by routine or in vivo manipulation, to the original compound. The designs of prodrug forms are well known in the art, and depend on the substituents contained in the compound of formula (1). For example, a sulfhydryl-containing substituent may be coupled to a carrier that produces the biologically inactive compound until deleted by endogenous enzymes or, for example, by enzymes directed to a particular receptor or located in the subject. Preferred prodrugs acceptable for pharmaceutical use are hydrolysable in vivo and derived from the compounds of formula (1) having a hydroxy or carboxyl group. An ester that can be converted in vivo is an ester, which is hydrolyzed in the human or animal body to produce the original acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include alkoxymethyl esters, for example methoxymethyl esters, alkanoyloxymethyl for example pivaloyloxymethyl esters, phthalidyl, cycloalkoxycarbonyloxyalkyl esters, for example esters of 1 - . 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl for example 5-methyl-1,3-dioxolen-2-onylmethyl and alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyl, which can be formed with any carboxy group in the compounds of this invention. An in vivo hydrolysable ester of a compound of the formula (1) containing a hydroxy group includes inorganic esters such as phosphate esters and α-acyloxyalkyl ethers and related compounds resulting from the in vivo hydrolysis of the ester to the original hydroxy group . Examples of α-acyloxy alkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy. A selection of in vivo hydrolysable esters 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 to the ring nitrogen atom by means of a methylene group of the 3- or 4-position of the benzoyl ring. The term "quaternary amine" as used herein, hereinafter, defines quaternary ammonium salts, which compounds of formula (1) are capable of forming by a reaction between a basic nitrogen of a compound of formula (1) and an appropriate quaternizing agent, such as, for example, an alkyl halide, aryl halide or optionally substituted arylalkyl halide, e.g. Methyl iodide or benzyl iodide. Other reagents with 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 counter-additions 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 (1) wherein one or more nitrogen atoms are oxidized to so-called? / - oxides. It will be considered that the compounds of formula (1) can have metal bonds, chelants, properties to form complexes and therefore can exist as metal complexes or metal chelates.

Such metal derivatives of the compounds of formula (1) should be included within the scope of the present invention. Some of the compounds of formula (1) may also exist in their tautomeric forms. Such forms, although not explicitly indicated in the above formula, must be included in the scope of the present invention. The compounds of formula (1) have several centers of chirality and exist as isomeric stereochemical forms. The term "isomeric stereochemical forms" as used herein defines all possible forms of compounds obtained from the same atoms linked by the same sequence of bonds but with different three-dimensional structures which are not interchangeable, which the compounds may possess. of formula (1). With reference to the cases where (f?) Or (S) is used to designate the absolute configuration of a chiral atom within a C, the designation is made taking into consideration the total compound and not the isolated substituents. In the case that any of the substituents of formula (1) contain chiral centers, such as have some of the compounds of formula (1) include all their stereoisomeric forms, both as isolated stereoisomers and mixtures of these stereoisomeric forms. Said mixtures may contain all the diastereomers and / or enantiomers of the basic molecular structure of said compound. All isomeric stereochemical forms of the compounds of the present invention in pure forms or in mixtures with others should be included within the scope of the present invention Pure stereoisomeric forms of the compounds and intermediates as mentioned herein are defined as isomers essentially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates. In particular, the term "stereochemically pure" refers to the compounds or intermediates having a stereoisomeric excess of at least 80% (ie minimum of 90% of one isomer and maximum of 10% of the other possible isomer) to a stereoisomeric excess of 100% (ie 100% of an isomer and nothing of the other), more in particular, compounds or intermediates having a stereoisomeric excess of 90% to 100%, even with more particularity that has a stereoisomeric excess of 94% to 100% and more in particular having a stereoisomeric excess of 97% to 100%. The terms "enantiomerically pure" and "diastereomerically pure" should be understood in the same manner, but taking into account the enantiomeric excess and the diastereomeric excess, respectively, of the mixture in question. The pure stereoisomeric forms of the compounds and intermediates of this invention can be obtained by the application of methods known in the art. For example, the enantiomers can be separated from each other by selective crystallization of their diastereomeric salts with optically active acids or bases. Their examples are tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid, and alkanesulfonic acid. Alternatively, the enantiomers can be separated by chromatographic techniques employing stationary chiral phases. Said stereochemically pure isomeric forms can be derived from the stereochemically pure isomeric forms of the appropriate starting materials, provided by the reaction that occurs stereospecifically. Preferably, if a specific isomer is desired, said compound will be synthesized by stereospecific preparation methods.

These methods will advantageously employ enantiomerically pure starting materials. The diastereomeric racemates of the compounds of formula (1) can be obtained separately by conventional methods. Suitable physical separation methods that can be used advantageously are, for example, selective crystallization and chromatography, e.g. column chromatography. For some compounds of formula (1), their prodrugs, N-oxides, salts, solvates, quaternary amines, or metal complexes and the intermediates employed in their preparation, the absolute stereochemical configuration is not determined experimentally. A person skilled in the art is able to determine the configuration > of such compounds using methods known in the art, such as, for example, X-ray diffraction. The present invention should include all isotopes of atoms appearing in the present compounds. Isotopes include atoms that have the same atomic number but different mass numbers. By way of example, but without limitation, the isotopes of hydrogen include tritium and deuterium. Carbon isotopes include C-13 and C-14.

Synthesis of the compounds of the invention A number of synthetic routes can be used to produce the compounds of the invention. In general, they can be synthesized by reactions known in the art. Any method of synthesis known in the art may be employed. However, the following synthetic routes are convenient for the preparation of the compounds of the invention. Typical compounds of the invention are shown below: ESQUE A A (Synthesis of Compounds 1 and 26): This general scheme was used to prepare compounds 1 and 16.

Preparation of the compound of formula (I): 2.53 g of 4-amino-5-imidazolecarboxamide were dissolved in 30 ml of chloroform and 30 ml of dimethylformamide. To this solution were added to 0 ° C 3.02 ml of 3-chlorobenzoyl chloride, followed by 5.4 ml of di-isopropylethylamine. The reaction mixture was allowed to warm to temperature environment and kept at that temperature throughout the night. Mix reaction was diluted with chloroform and washed with water, aqueous solution of 10% sodium carbonate and brine. The organic phases were dried with anhydrous sodium sulfate and filtered. The gross residue obtained after the concentration was removed in a minimum amount of chloroform and chromatography on silica gel, using ethyl acetate, 5% methanol to give 4.81 g of the compound of formula (I).

Biaaprara Note: For the synthesis of compound 16, methyl-4-amino-5-imidazolecarboxamide was used.

Preparation of the compound of formula (II): 2.74 g of the compound of formula (I) were suspended in 75 ml of ethanol, 5 ml of 10 N sodium hydroxide were added to the reaction mixture and the reaction mixture was refluxed during the reaction mixture. four hours. After cooling to room temperature the reaction mixture was concentrated to remove the ethanol and then diluted with water. Then the solution was acidified by the addition of 1 N hydrochloric acid at 0 ° C, at pH 6.5. The white precipitate that formed was collected by filtration, washed with water and ether and dried under high vacuum to give 0.84 g of the compound of formula (II).

Preparation of the compound of formula (III): 0.84 g of the compound of formula (II) were suspended in 60 ml of chloroform, to this suspension were added 1.1 ml of thionyl chloride and 2 ml of dimethylformamide. The resulting mixture was refluxed under nitrogen for three hours. The reaction mixture was cooled to room temperature and concentrated to a yellow residue. The residue was removed in chloroform and ice was added to the reaction mixture. The cold solution was washed with aqueous 5% sodium carbonate solution and brine. The organic phases were dried with anhydrous sodium sulfate and filtered. After concentration, the residue that was obtained was treated with cold ethyl acetate. A white solid was separated This solid was filtered and washed with ethyl acetate, to give 0.46 g of the compound of formula (III).

Preparation of the compound of formula (1): i i 0.46 g of the compound of formula (III) were dissolved in 10 ml of dry dimethylformamide, to this solution 0.67 ml of di-isopropylethylamine was added. The reaction mixture was heated to 60 ° C, and a solution of 0.21 g of 4-aminopyridine was added thereto. The reaction mixture was heated to reflux for one hour. After cooling to room temperature the reaction mixture was concentrated to a minimum volume and the product purified by preparative reverse-phase HPLC, using a C18 Vydac® column, with a gradient of water, acetonitrile (both containing 0.1% trifluoroacetic acid) . 15 mg of the compound of formula (1) were obtained after lyophilization of the fractions containing the desired product. Analysis: 1 H NMR d6 DMSO, 1 CMS, M + 323.

Preparation of the compound of formula (26): Compound 26 was prepared according to the procedures described in scheme A, employing! N-1-phenyl-2-aminoimidazole-3-carboxamide and benzoyl chloride.

SCHEME B (Synthesis of compounds 3, S-15 and 17): Preparation of 3-amino-4-cyano-5-methyl isoxazole: Hydroxylamine hydrochloride (12.78 g, 0.184 mol) was dissolved in 40 ml of water was treated with sodium hydroxide (7.36 g, 0.184 mol). 60 ml of ethanol (anhydrous) were added and while stirring, (l-ethoxyethylidene) malonitrile (25 g, 0.184 mol) was carefully added. The reaction mixture was heated at 50 ° C for 30 min, then stirred overnight at room temperature. The ethanol was removed in vacuo, the filtered solid product was washed with water, dried under vacuum to obtain 21.93 g (96.8% yield). Note: For the synthesis of 7 and 11, the corresponding ethylhydroxylamine was used and for the synthesis of 9, the corresponding phenylhydroxylamine was used.

Preparation of, N- (3-chlorobenzoyl) -4-cyano-3-methyl-5-carboxamide: 3-Amino-4-cyano-5-methylisoxazole (6.0 g, 0.0487 mol) was suspended in acetonitrile / tetrahydrofuran (30 ml. / 10 ml). Added Preparation of 3-methyl-6- (3-chlorophenyl) isoxazole [5,4d] pyrimidone: i N- (3-chlorobenzoyl) J4-cyano-3-methyl-5-carboxamide I (1.0 g, 15 mmol) was suspended in 20 ml of 1 M sodium hydroxide and treated with 8 ml of 30% hydrogen peroxide. The mixture was refluxed overnight. The cooled reaction mixture was placed in ice bath and treated with 1 M hydrochloric acid at pH 6. The product was filtered as a white precipitate and dried in vacuo to give 537 mg (53% yield). isoxazolf5,4dlpyrimidine: 3-Methyl-6- (3-chlorophenyl) isoxazole [5,4d] pyrimidone was suspended (535 mg, 2.04 mmol) in phosphorus oxychloride (6 ml) and heated to reflux for 4 hours. The excess of phosphorus oxychloride was removed, then ice and chloroform (10 ml) were added, it was made alkaline with saturated sodium bicarbonate, the product was extracted in chloroform and | the extracts were dried with sodium sulfate (anh.). The product was purified! by chromatography on silica gel eluting with chloroform. 200 mg of the product were obtained.

Preparation of 3-methyl-4- (4-aminopyridyl) -6- (3-chlorophenyl) isoxazole [5,4-d1-pyrimidine (17): 4-aminopyridine (80.6 mg, 0.859 mmol) was dissolved in N -methylpyrrolidone, diisopropylethylamine (149 microliters) was added followed by 3-methyl-4-chloro-6- (3-chlorophenyl) -soxazole [5,4-d] pyrim! dina (120 mg, 0.428 mmoles). The mixture was heated to 50 ° C with stirring for 1 hour. The product was purified by preparative HPLC on (C18 column.

ESQUE A C (Synthesis of Compounds 2 and 4) Preparation of 2-phenyl-pyrrole [2,3-dlpyrimidinone: Benzamidine hydrochloride (4.0 g, 0.25 mol) was dissolved in 64 ml of ethanol. To this solution was added 8.0 ml of a 25% by weight I I sodium methoxide solution. The reaction was stirred at room temperature for 5 hours, and filtered. Then the filtrate was added to ethyl 2-cyano-4.4-diethoxybutyrate (4.80 g, 0.21 mol). This solution was refluxed for 5 hours. The half of the solvent under reduced pressure, then 80 ml of water with ice and the pH was adjusted to 7 with acetic acid. [Then the material was refrigerated for 6 hours and the product was isolated by vacuum filtration.

Note: For the synthesis of compound 4, 3-chlorobenzamidine was used. i Preparation of 4-chloro-2-phenyl-pyrrole [2,3-d1-pyrimidine: 1 I 2-phenyl-pyrrole [2,3-d] pyrimidinone (1.0 g 4! 73 mmol) was treated with phosphorus oxychloride (7 ml. , 27.7 mmol) and refluxed for 5 hours. The excess phosphorus oxychloride was removed under reduced pressure and then extracted with chloroform, washed with sodium bicarbonate. The organic phase was dried with sodium sulfate i (anh), then concentrated to dryness to give the product.

Preparation of 4- (4-aminopyridyl) -2-phenyl-pyrrole [2,3-dlpyrimidine] I L 4-Chloro-2-phenyl-pyrrol [2,3-d] pyrimidine (0.12 g, 1.27 mmol) was dissolved in 4 ml of NMP. N, N'-Diisopropylethylamine (0.229 ml) I was added followed by 4-aminopyridine (0.15 g, 0.635 mmol). The reaction mixture was refluxed for 2 hours, cooled and purified by preparative HPLC.

D SCHEME (Synthesis of Compound 18): Preparation of acetylmethyl dimethylmalonate: Dimethyl malonate (5 g,!. 189 mol) was treated with carbonate of potassium (34.78 g, 0.25 mol), sodium iodide (1.00 g, 0.0067 mol) and then heated while chloroacetone (23.1 g, 0.25 moles) was added quickly at one time. The reaction mixture was heated at 100 ° C for 20 min. To The cooled reaction mixture was added 50 ml ethanol and the filtrate was washed with ethanol. The ethanol was removed from the filtrate in vacuo. The product was isolated I by vacuum distillation. 11.26 g of the product were obtained (32% of performance).

IV Preparation of the compound of formula (IV): Ethylene glycol (3.90 g, 0.0628 moles), malonate of acetylmethyldimethyl (11.26 g, 0.06 moles), and p-toluenesulfonic acid (0.21 g, 0.0011 moles) in 25 ml of benzene. The reaction mixture was heated to reflux and water was collected in a trap; Dean Stark throughout the night j. The reaction mixture was washed with 10% sodium bicarbonate (2 x 10 ml) and the benzene was dried with sodium sulfate. The solvent was removed to obtain the product as an oil, 14.1 g.

Preparation of the compound of formula (V): i The protected dimethyl malonate derivative (5.0 g, 0.0215 mol) was [dissolved in methanol (20 ml), 3-chlorobenzamidine hydrochloride was added, followed by 25% sodium methoxide (16 ml, 0.0646 moles). The mixture of The reaction was stirred at room temperature for 3 days. The mixture was diluted with water (50 ml) and 60 ml of 1 M HCl was added and stirred for 1 hour at ambient temperature, then 4 ml of concentrated HCl was added and stirred throughout the night, to give the final product. Methanol was removed under vacuum, and the product was obtained by filtration and drying under vacuum. 5 g of the product were obtained.

Preparation of 6-methyl-2-chlorophenyl-furanof3,2-dlpyrimidone: 6-Hydroxy-5-acetylmethyl-2- (3-chlorophenyl) pyrimidone (5.0 g) was treated with concentrated sulfuric acid (80 ml). The reaction mixture was stirred at room temperature for 4 hours, then neutralized with sodium carbonate and extracted with chloroform, the chloroform extract was washed with water, dried with sodium sulfate (anh) and the solvent was removed to give the product (1.10g).

Preparation of 6-methyl-4-chloro-2-chlorophenyl-furan [3,2-d1-pyrimidine: I-6-methyl-2-chlorophenyl-furan [3,2-d] pyrimidone (480 mg, 1.84 mmol) was suspended in dichloromethane (4 ml). Thionyl chloride (1.6 ml, 22.5 mmol) and dimethylformamide (0.5 ml) were added, the mixture was heated to reflux for 3 hours. The excess solvent was removed, the residue was treated with ice, extracted into chloroform, washed with 10% sodium bicarbonate and water, dried with sodium sulfate (anh) and the solvent was removed to give 480 mg Preparation of 6-methyl 4- (4-aminopyridyl) -2-chlorophenylfuranof3,2-dlpyrimidine (18): I 6-methyl-4-chloro-2-chlorophenyl-furan [3,2-d] pyrimidine (480 mg, 1.72 mmoles, 1 eq), BINAP (8 mg, 0.013 mmol, 0.0075 eq), Pd2 (dba) 3 (3.9 mg, O.0043 mmol, 0.0025 eq), sodium t-butoxide (231 mg, 2.4 mmol, 1.4 eq), 4-aminopyridine (194 mg, 2.06 mmol, 1.2 eq) were combined in 5 ml of dioxane and heated at 50 ° C for 5 hours. The product was isolated by Preparative HPLC on C18 column.

SCHEME E (Synthesis of compound 19) Preparation of ethyl 2-methyl-5-ethoxy-4-oxazole-4-carboxylate: Diethyl acetamidomalonate (15.0 g, 69.1 mmol) was dissolved in 60 ml of chloroform and then treated with 60 g of phosphorus pentoxide. The The reaction mixture was refluxed for 6 hours and then cooled to room temperature. ambient. This solution was treated with sodium hydroxide (1 M) to neutralize the reaction mixture. The organic phase was washed with water and dried with sodium sulfate (anh). The crude product was vacuum distilled to isolate the product. 8.26 g of the product were obtained (60% yield) Preparation of 2-methyl-5-ethoxy-4-oxazole-4-carboxylic acid: Ethyl 2-methyl-5-ethoxy-4-oxazole-4-carboxylate (8.26 g, 41.5 mmol) was treated with 74 ml of a 15% KOH solution. This solution was refluxed for 15 minutes and then cooled and acidified using a 10% HCl solution. The product was collected by vacuum filtration.

Preparation of 2-methyl-5-ethoxy-4-oxazole-4-carbonyl chloride 2-Methyl-5-ethoxy-4-oxazole-4-carboxylic acid (2.56 g, 14. 9 mmol) in dichloromethane. Two drops of dimethylformamide were added and the reaction was cooled in an ice bath. Oxalyl chloride added dropwise (12 mL, 22.3 mmol). The ice bath was removed and the reaction was stirred at room temperature for 2 hours. The solvent at reduced pressure I was removed. 'Preparation of 4- (3-chlorobenzamidinamide) -2-methyl-5-ethoxy-4-oxazole-4-carbonyl chloride: 3-chlorobenzamidine (2.29 g, 14.8 mmol) was dissolved in 40 ml of DCM and it was brought to 0 ° C. Then 15 ml of a 2.0 M sodium hydroxide solution was added. 2-Methyl-5-ethoxy-4-oxazole-4-carbonyl chloride (2.8 g, 14.8 mmol) dissolved in 30 ml of water was added dropwise. DCM to the reaction mixture and stirred at room temperature for 3 hours. The organic solvent was washed with water followed by sodium bicarbonate, then dried with sodium sulfate and concentrated.

Preparation of the compound of formula (VI): 4- (3-Chlorobenzamidinamide) -2-methyl-5-ethoxy-4-oxazole-4-carbonyl chloride (2.0 g, 6.5 mmol) was dissolved in 30 ml of toluene and I refluxed for 1.5 hours. The solvent was then removed under reduced pressure.

Preparation of 7-methyl-2- (3-chlorophenyl) -oxazole [2.3d] pyrimidone: 1.86 g, 5.93 mmol, of the oxazole ester were treated with 0.86 g, 15.4 mmol of KOH in 20 l of ethanol. This solution was stirred at room temperature overnight. The organic solvent was evaporated under reduced pressure I and the compound was dissolved in water and acidified with a 15% HCl solution. The solid product was collected by vacuum filtration.

Preparation of 7-methyl-4-chloro-2- (3-chlorophenyl) -oxazolf2.3d1pyrimidine: i 7-Methyl-2- (3-chlorophenyl) -oxazoo [2.3d] pyrimidone (1.32 g, 5. 06 mmol) with phosphorus oxychloride (13.2 ml, 141.7 mmol and refluxed for three hours) The reaction was cooled, the solvent was removed under reduced pressure and the residue was taken up in chloroform, ice was added to the organic solvent, then the The organic solvent was washed with sodium bicarbonate, dried with sodium sulfate and then concentrated.The crude product was purified by flash column chromatography. ? aOtBu dioxane Preparation of 7-methyl-4- (4-aminopyridyl) -2- (3-chlorophenyl) -oxazole [2,3-d1-pyrimidine (19): were combined 7-methyl-4-chloro-2- (3-chlorophenyl) -oxazole [2.3d] pyrimidine (0.100 g, 0.358 mmol), 4-aminopyridine (0.040g, 0.430mmol), sodium t-butoxide (0.048g, 0.501 mmol), Bis (diphenylphosphino) -1.1 '-bubfethyl (0.0009 g, 0.0014 mmol), and Pd2 (dba) 3 (0.0004 g, 0.0043 mmol) and dissolved in 2 ml of dry dioxane and refluxed for 3.5 hours. The reaction was cooled, then filtered with Celite®, and then purified by HPLC.

SCHEME F To a solution of methyl 2-oxocyclopentaryl carboxylate (4.10 g, 28.9 mmol, 1 eq) in dry ethanol (20 ml) was added a solution of 2-fluoro-5-chlorobenzamidine (5.0 g, 28.9 mmol). 1 eq) in ethanol (20 ml) and the reaction mixture was heated at 80 ° C overnight. The mixture of The reaction was cooled to room temperature (La.) And the white precipitate was filtered and washed with cold ethyl acetate (2 x 20 ml). The crude residue was divided into chloroform and water. The aqueous phase was acidified to pH 4 and the product was extracted with chloroform (3 x 50 ml). The organic phases were combined, washed with brine, dried with MgSO 4, filtered and concentrated in vacuo to 20 gave a crude white solid (VI) (4.5 g, 60%) which was not purified subsequently. Preparation of the compound of formula (VII): A suspension of the compound of formula (VI) (200 mg, 0.757 mmol) in POCI3 (5 ml) was stirred at reflux for 1 h. The solution was cooled to room temperature and concentrated under reduced pressure to give a solid white, which was dissolved in dry methylene chloride. The solution cooled to 0 ° C ice was added followed by saturated solution of. NaHCO3. The phases The organic extracts were combined, washed with brine, dried with MgSO, filtered and concentrated in vacuo to give a crude white solid, which was not purified later.

Preparation of the compound of formula (20): (Buchwald general reaction procedure): The crude chloride imino compound of formula (VII) (210 mg, 0.76 mmol, 1 eq) was dissolved in dioxane (5 ml) and to this solution was added Pd (OAc) 2 (9 mg, 0.04 mmol, 0.05 eq) followed by BINAP (35 mg, 0.056 mmol, 0. 075 eq), 4-amino-3-picoline (82 mg, 0.760 mmol, 1 eq) and Cs CO3 (370 mg, I 1.13 mmol, 1.5 eq). The reaction mixture was heated at 80 ° C for 15 h. The The reaction mixture was cooled to t.a and filtered with Celite® and the crude product was purified by flash column chromatography (ethyl acetate: hexane 3: 2) to | give the compound of formula (20) (110 mg, 41%).

Preparation of the compound of formula (IX): To a suspension of the compound of formula (VIII) (100 mg, 0.25 mmol, 1 eq) in MeOH (5 ml) was added a solution of NaOH (aq) 1N (500 μl, 0. 50 mmol, 2 eq) and the reaction mixture was refluxed for 2 h. The mixture was cooled to La. and concentrated in vacuo. Water (10 ml) was added to the crude material and the aqueous phase was acidified to pH 4. The solid was filtered, washed with water (2 x 5 ml) and dried overnight to give a compound of formula (IX) (50 mg, 52%) as a colored solid cream.

Preparation of the compound of formula (21): To a suspension of the compound of formula (IX) (50 mg, 0.13 mmol, 1 eq) in dry DMF (2 ml) was added 1-1'-carbonyldiimidazole (42 mg, 0.26 mmol). , 2 eq) and the reaction mixture was heated at 70 ° C for 2 h. The mixture was cooled to t.a. and NH3 (g) and was bubbled for 10 min. The reaction mixture was stirred at t.a. for 1 more hour The reaction was concentrated in vacuo. Water (10 ml) was added to the crude material and the solid was filtered, washed with water (2 x 5 ml) and dried overnight to give the compound of formula (21) (30 mg, 60%) as a colored solid cream.

Additional compounds prepared in accordance with Scheme F The compound of formula (32) was prepared according to the processes described in Scheme F, for the preparation of the compound of formula (VIII), using 4-aminopyridine-3-carboxylic acid ethyl ester. The compound of formula (36) was prepared by the method described for the synthesis of the compound of formula (20) using 4-amino-3-trifluoromethyl-picoline instead of 4-amino-3-picoline. The compound of formula (35) was prepared by the method described for the synthesis of the compound of formula (21) using methyl amine instead of ammonia. The compound of formula (37) was prepared by the method described for the synthesis of the compound of formula (21) using pyrrolidine instead of ammonia. The compound of formula (41) was prepared by the method described for the synthesis of the compound of formula (21) using cyclopropylamine instead of ammonia. The compound of formula (42) was prepared by the method described for the synthesis of the compound of formula (21) using cyclopropylmethylamine instead of ammonia The compound of formula (51) was prepared by the method described for the synthesis of the compound of formula ( 21) using 2-amino-ethanol in place of ammonia The compound of formula (52) was prepared by the method described for the synthesis of the compound of formula (21) using 1-amino-propan-2- (S) -ol Instead of ammonia, the compound of formula (53) was prepared by the method described for the synthesis of the compound of formula (21) using 3-amino-propane 1, 2 (S) -diol instead of ammonia. The compound of formula (54) was prepared by the method described for the synthesis of the compound of formula (21) using HO-NH2 instead of ammonia. The compound of formula (55) was prepared by the method described for the synthesis of the compound of formula (21) using 1-amino-propan-2- (R) -ol in place of ammonia. The compound of formula (56) was prepared by the method described for the synthesis of the compound of formula (21) using N-methylethylenediamine instead of ammonia. The compound of formula (58) was prepared by the method described for the synthesis of the compound of formula (21) using hydrazine instead of ammonia. The compound of formula (67) was prepared by the method described for the synthesis of the compound of formula (21) using benzamidine. The compound of formula (68) was prepared by the method described for the synthesis of the compound of formula (21) using methylamine instead of ammonia and benzamidine instead of 2-F, 3-CI-benzamidine. The compound of formula (69) was prepared by the method described for the synthesis of the compound of formula (21) using? /,? / '- dimethyl-1,3-propanediamine instead of ammonia. The compound of formula (70) was prepared by the method described for the synthesis of the compound of formula (21) using 4- (3-aminopropyl) morpholine in place of ammonia. The compound of formula (71) was prepared by the method described for the synthesis of the compound of formula (21) using 1- (3-aminopropyl) imidazole in place of ammonia. The compound of formula (72) was prepared by the method described for the synthesis of the compound of formula (21) using 1- (3-aminopropyl) -2-pyrrolidinone in place of ammonia. The compound of formula (73) was prepared by the method described for the synthesis of the compound of formula (21) using 2- (2-aminoethyl) -1-methylpyrrolidine in place of ammonia. The compound of formula (74) was prepared by the method described for the synthesis of the compound of formula (21) using 1- (3-aminopropyl) -2-pipecoline in place of ammonia. The compound of formula (75) was prepared by the method described for the synthesis of the compound of formula (21) using 1- (2-aminoethyl) pyrrolidine in place of ammonia. The compound of formula (78) is prepared by the method described for the synthesis of the compound of formula (21) using 1- (2-aminoethyl) piperdine instead of ammonia. The compound of formula I (79) was prepared by the method described for the synthesis of the compound of formula (21) using? /,? / - diethyletenediamine instead of ammonia.

SCHEME G (Synthesis of the Compound of formula (22), (24), (25) and (30)) Preparation of the compound of formula (X): To a solution of 2-fluoro-5-chlorobenzamidine (1.79 g, 10.4 mmol, 1 eq) in EtOH (10 ml) was added solid NaOEtj (705 mg, 10.4 mmol, 1 eq) followed by methyl-4-oxo-3. -piperidine carboxylate. HCl (2.0 g, 10.4 mmol, 1 eq). The reaction mixture was heated at 70 ° C for 2 h, then cooled to t.a. The precipitate was filtered and washed with ethyl acetate (2 x 20 ml) to give a white solid (2.2 g, 76%) which was not further purified.

Preparation of the compound of formula (XI): To a suspension of the compound of formula (X) (300 mg, 1.08 mmol, 1 eq) in dry THF (10 ml) was added a solution of Boc2O (258 mg, 1.18 mmol, 1.1 eq) in dry THF (10 ml) at rt The reaction mixture was stirred at t.a. for 2 h and then the solution was concentrated in vacuo to give a crude residue, which was purified by flash column chromatography to give the compound of formula (XI) (320 mg, 79%) as a white solid.

Preparation of the compound of formula (XII): To a solution of PPh3 (813 mg, 3.03 mmol, 5 eq) in dry dioxane (20 ml) was added NBS (540 mg, 3.03 mmol, 5 eq) in one time eleven and the suspension was stirred at ta for 30 min. A solution of the compound of formula (XI) (230 mg, 0.61 mmol, 1 eq) in dry dioxane (5 ml) was added and the reaction mixture was heated at 80 ° C for 45 min. The reaction mixture was cooled to t.a. and Et3N (160 μL, 1.21 mmol, 2 eq) was added. The mixture was concentrated in vacuo and the brutp residue was purified by flash column chromatography (1: 9 ethyl acetate: hexane) to give the compound of formula (XII) (72 mg, 30%).

Preparation of the compound of the formula (Xlll): To a solution of the compound of the formula (XII) (72 mg, 0.16 mmol, 1 eq) in dry dioxane (2 ml) was added Pd (OAc) 2 (2 mg, 0.008 mmol, 0. 05 eq) followed by BINAP (8 mg, 0.001 mmol, 0.075 eq), 4-amino-3-piccoline (18 mg, 0.16 mmol, 1 eq) and Cs2CO3 (80 mg, 0.24 mmol, 1.5 eq). The reaction mixture was heated at 80 ° C for 15 h. The reaction mixture was cooled to t.a I and filtered with Celite® and the crude material was purified by flash column chromatography (7: 3 / ethyl acetate: hexane) to give the compound of formula (Xlll) (65 mg, 85%).

Preparation of the compound of formula (22): To a solution of the compound of formula (Xlll) (65 mg, 0.14 mmol, 1 eq) in dry dioxane (2 ml) was added a solution of 4M HCl in dioxane (1 ml). The resulting suspension was stirred at t.a for 2 h. The precipitate was filtered and washed with chloroform (1 x 5 ml), ethyl acetate (1 x 5 ml) and cold methanol (1 x 2 ml) to give the compound of formula (22) (35 mg, 68%) as a white solid.

Preparation of the compound of formula (24): The compound of formula (24) was prepared according to the procedure described in Scheme G, using ethyl 1-benzyl-4-oxopiperidine-3-carboxylate and benzamidine.

Preparation of the compound of formula (25): The compound of formula (25) was prepared according to procedure described in Scheme G, using benzamidine.

Preparation of the compound of formula (30): The compound of formula (30) was prepared according to procedure described in Scheme G, employing ethyl 1-benzyl-4-oxopiperidin-3-carboxylate.

SCHEME H I (Synthesis of the Compound of formula (23)) Preparation of the compound of the formula (XIV): i To a solution of ethyl ethyl? / -benzyl-3-joxo-4-piperidinecarboxylate. HCl (2 g, 6.73 mmol, 1 eq) in ethanol (60 ml) was added Pd / C 10%. The air was evacuated and replaced with hydrogen by a balloon. The reaction mixture was allowed to stir at t.a. for 4 h. The reaction mixture was filtered with a bed of Celite® to give the compound of formula (XIV), which is not purified later.

Preparation of the f? Nilula compound (XV): To a solution of 2-fluoro-5-chlorobenzamidine (1.16 g, 6.71 mmol, 1 eq) in EtOH (10 ml) was added NaOEtlsolide (457 mg, 6.71 mmol, 1 eq) followed by the compound of formula (XIV) (1.39 g, 6.71 mmol, 1 eq). The reaction mixture was heated at 70 ° C for 2 h and then cooled to t.a. The precipitate was filtered and washed with ethyl acetate (2 x 20 ml) to give the compound of formula (XV) (1.12 g, 60%) as a white solid which is not purified later.

Preparation of the compound of formula (XVI): To a suspension of crude compound of formula (XV) (1.12 mg, 4. 01 mmol, 1 eq) in dry THF (10 ml) was added a solution of Boc2O (960 mg, 4.42 mmol, 1.1 eq) in dry THF (10 ml) at t.a. The reaction mixture is it stirred at t.a. for 2 h and then the solution was concentrated in vacuo to give a crude residue which was purified by flash column chromatography to give the compound I of formula (XVI) (750 mg, 50%) as a white solid.

Preparation of the compound of formula (XVII): To a solution of PPh3 (2.28 g, 8.70 mmol, 5 eq) in dry dioxane (20 ml) was added NBS (1.55 mg, 8.71 mmol, 5 eq) all at once and the suspension he stirred to ta for 30 min. A solution of the compound of formula (XVI) (660 mg, 1.74 mmol, 1 eq) in dry dioxane (5 ml) was added and the reaction mixture was heated at 80 ° C for 45 min. The reaction mixture was cooled to RT. and 2 eq of Et3N were added. The mixture mixture was concentrated in vacuo and the crude residue was purified by flash column chromatography (ethyl acetate: hexane 1: 9) to give the compound of formula (XVII) (230 mg, 30%).

Preparation of the compound of formula (XVIII): To a solution of the compound of formula (XVII) (230 mg, 0.52 mmol, 1 eq) in dry dioxane (5 ml) was added Pd (OAc) 2 (6 mg, 0.03 mmol, 0.05 eq) followed by BINAP (8 mg, 0.004 mmol, 0.075 eq), 4-amino-3-picoline (67 mg, 0.62 mmol, 1.2 eq) and Cs2C03 (271 mg, 0 83 mmol, 1.5 eq). The reaction mixture i was heated at 80 ° C for 15 h. The reaction mixture was cooled to t.a. and filtered with Celite® and the crude material was purified by flash column chromatography (9: 1 ethyl acetate: hexane) to give the compound of formula (XVIII) (38 mg, 16%).

Preparation of the compound of formula (23): To a solution of the compound of formula (XVIII) (38 mg, 0.08 mmol, 1 eq) in dry dioxane (2 ml) was added to a solution of 4 M HCl in dioxane (1 ml). ). The resulting suspension was stirred at t.a. for 2 h. The precipitate was filtered and washed with chloroform (1 x 3 ml), ethyl acetate (1 x 3 ml) and cold methanol (1 x 1 ml) to give the compound of formula (23) (32 mg, 95%). as a white solid SCHEME I (Synthesis of the compound of formula (27)) Amide of 2-amino-thiophene-3-darboxylic acid: 1,4-dithian-2,5-diol (4.56 g, 30 mmol) and 2-cyanoacetamide (2.52 g, 30 mmol) in ethanol (50 ml) were combined. Triethylamine (6 ml) was added and heated at 70 ° C for 1 hour. The volume of the solventa under vacuum was reduced, and the product was isolated by filtration. The product was recrystallized from ethanol to give 2.71 g of product (64% yield). 2- (2-Fluoro-benzoylamino) -thiophene-3-carboxylic acid amide: 2-Amino-thiophene-3-carboxylic acid amide (8.73 g, 61.4 mmol) was dissolved in pyridine (100 mL), cooled at 0 ° C and 2-fluorobenzoyl chloride was added dropwise during 20 min, then the reaction was allowed to warm to room temperature with stirring overnight. The pyridine was removed in vacuo, methane and water were added. The product precipitated as a gray solid and was washed with dilute hydrochloric acid and air dried. The dichloromethane phase was separated, washed with dilute hydrochloric acid and water, dried with sodium sulfate (anh.) And the solvent was removed to give 12.45g of the total product (77% yield) 2- (2-Fluoro-phenyl) -3H-thienof2,3-d] pyrimidin-4-one: 2- (2-Fluoro-benzoylamino) -thiophene-3-carboxylic acid amide (8.56 g, 32.4 mmol) was dissolved in a mixture of 20 ml of 1M sodium hydroxide and 60 ml of ethanol. The mixture was refluxed for 4 hours. The reaction mixture was cooled and poured into ice. The solution was acidified with dilute hydrochloric acid and the product was isolated by filtration. It was then dried under vacuum and 5.42 g of the product were obtained (Yield: 68%). 4-Chloro-2- (2-fluoro-phenyl) -thieno [2,3-d-pyrimidine: 2- (2-fluoro-phenyl) -3H-thieno [2,3-d] pyrimidin-4-one was dissolved ( 900 mg, 3.65 mmol) in chloroform and thionyl chloride (0.532 ml, 7.30 mmol) was added to the mixture followed by 1 ml of dimethylformamide. The reaction mixture was heated to reflux for 2.5 hours, the cold mixture was washed with 10% sodium carbonate, the chloroform solution was dried with sodium sulfate (anh) and the solvent was removed. The crude product was chromatographed on silica gel, eluting with chloroform. After removal of the solvent, 438 mg of the product were obtained (yield: 45%). [2- (2-Fluoro-phenyl) -thieno [2,3-dlpyrimidin-4-ill-pyridin-4-yl-amine: 4-chloro-2- (2-fluoro-phenyl) -thieno [2] was combined , 3-d] pyrimidine (110 mg, 0.41 mmol) and 4-aminopyridine (78 mg, 0.830 mmol) in isopropanol (3 ml), then 4 drops of 4 M HCl / dioxane were added and the reaction mixture was heated to 80 ° C for 7 hours. The reaction mixture was cooled and the product isolated by filtration, washed with a minimum amount of cold methanol and dried under vacuum to give 116 mg of product (yield: 86%).

SCHEME J I I (Synthesis of the compound of formula (28)) MH; 5-Amino-1,3-dimethyl-1 H-pyrazole-4-carbonitrile: Methylhydrazine (5 g, 108.5 mmol) was added dropwise to a solution of (l-ethoxyethylidene) -malonitrile (14.7 g, 108.5 mmol) in 250 ml of ethanol. The mixture was heated to reflux for 2.5 hours. The mixture of The reaction was allowed to cool, the volume was reduced to approximately 70 ml and the The product was isolated by filtration, washed with cold ethanol and dried to obtain 13. 5g of product (yield: 91%).

N- (4-Cyano-2,5-dimethyl-2H-pyrazol-3-yl) -2-fluoro-benzamide 5-Amino-1,3-dimethyl-1 H-pyrazole-4-carbonitrile (10 g, 73.4 mmol) was suspended in pyridine (90 ml) and 2-fluorobenzoyl chloride was added dropwise while the mixture was cooled. React in an ice bath. The reaction mixture was stirred overnight at room temperature. Most of the pyridine was removed and 100 ml of cold water was added to the precipitate of the product. The product was isolated by filtration, washed with cold water and a small amount of cold ethanol and dried under vacuum to obtain 9.15 g of product (yield: 50%). 6- (2-Fluoro-phenyl) -1,3-dimethyl-1,5-dihydro-pyrazole [3,4-dlpyrimidin-4-one]: N- (4-Cyano-2,5-dimethyl-2H-pyrazole- 3-Lyl) -2-fluoro-benzamide (5.0 g, 19.36 mmol) was suspended in 38 ml of 1M sodium hydroxide and heated at 90 ° C for 3 hours followed by the addition of 30% hydrogen peroxide (10 ml) and then it heated throughout the night. The reaction mixture was cooled to room temperature and acidified with dilute hydrochloric acid. The product was isolated by filtration, washed with water and dried overnight under vacuum to obtain 3.39 g of product. (Performance 67%). 4-Chloro-6- (2-fluoro-phenyl) -1,3-dimethyl-1 H-pyrazole [3,4-dlpyrimidine: I) 6- (2-fluoro-phenyl) -1,3, 3-dimethyl- 1, 5-dihydro-pyrazol [3,4-d] pyrimidin-4-one (2.0 g, 7.74 mmol) with 40 ml of phosphorus oxychloride and heated to reflux overnight. The excess phosphorus oxychloride was removed under vacuum and ice water was added to the residue. The product was extracted with ethyl acetate, washed with 10% sodium carbonate and water, then dried with sodium sulfate (anh) and the solvent was removed to give the crude product. 4 The crude product was chromatographed on a column of silica gel, eluting with chloroform to give 1.10 g of the pure product (yield: 51%). i f6- (2-Fluoro-phenyl) -1,3-dimethy1-1 H-pioiazoir-3,4-d1-pyrimidin-4-yl-pyridin-4-yl-amine: I 4-chloro-6-2-fluoro was combined phenyl) -1,3-dimethyl-1 H -pyrazolo [3,4-d] -pyrimidine (84 mg, 0.304 mmol) and 4-aminopyridine (57 mg, 0. 608 mmoles) in 4 ml of isopropanol, 3 drops of 4M HCl / dioxane were added and the reaction mixture was heated at 80 ° C for 5 hours. The reaction mixture was cooled and the product was filtered to obtain 83 mg after vacuum drying (yield: 81%)? SCHEME K (Synthesis of the compound of formula (29)) 5-Amino-1-butyl-3-methyl-1 H-pyrazole-4-carbonitrile: Butylhydrazine oxalate (14.25 g, 80 mmol) and (1-ethoxyethyl) -malonitrile (10.82 g, 80 mmol) in ethanol were combined. (200 ml), and the mixture was treated with diisopropylethylamine (10.39 'g, 80 mmol). The mixture was refluxed for 2 hours, then stirred at room temperature overnight. Most of the solvent was removed under vacuum and triturated with chloroform, some solid was filtered and the chloroform filtrate was preserved. The chloroformic filtrate was washed with water, dried with sodium sulfate (anh.) And the solvent was removed to give the product as a solid, 13.13 g (yield: 74%). N- (2-Butyl-4-cyano-5-methyl-2H-pyrazol-3-yl) -2-fluoro-benzamide: 5-Amino-1-butyl-3-methyl-1 H-pyrazole-4-carbonitrile (10.0 g, 56 mmol) was dissolved in a dichloromethane / pyridine mixture (45 ml / 15 ml) and cooled to 0 ° C and 2-fluorobenzoyl chloride (8.87 g, 56 mmol) was added dropwise and the The reaction mixture was stirred for 1 hour at 0 ° C, and at room temperature overnight. The solvent was removed in vacuo. The residue was taken up in ethyl acetate, washed with dilute hydrochloric acid, 0.1 M sodium hydroxide and water, and dried with sodium sulfate (anh). The solvent was removed and the solid was triturated in 30% ethyl acetate / hexanes. The product was filtered to obtain 4.16 g of the product (yield: 24%). 1-Butyl-6- (2-fluoro-phenyl) -3-methyl-1,5-dihydro-pyrazolf-3,4-d-pyrimidin-4-one: N- (2-butyl-4-cyano-5-methyl) was suspended -2H-pyrazol-3-yl) -2-fluoro-benzamide (4.0 g, 13.3 mmol) in 26 mL of 1 M sodium hydroxide, and 30% hydrogen peroxide (10 mL) and ethanol (5 mL) were added. ). The reaction mixture was refluxed for 4 hours, then more 30% hydrogen peroxide (10 ml) was added and it was heated to reflux overnight. The reaction mixture was cooled and acidified with dilute hydrochloric acid to pH 6.0. The product was collected by filtration and dried under vacuum to obtain 1.29 g of product (yield: 32%). 1 - . 1-Butyl-4-chloro-6- (2-fluoro-phenyl) -3-methyl-1 H-pyrazolf3.4-dlpyrimidine: 1-Butyl-6- (2-fluoro-phenyl) -3-met was dissolved 1-l, 5-dihydro-pyrazolo [3,4-d] -pyrimidin-4-one (1.23 g, 4.1 mmol) in phosphorus oxychloride (15 ml) and heated to reflux overnight. The excess phosphorus oxychloride was removed in vacuo, the residue was treated with ice water, the product was extracted into ethyl acetate, washed with water and saturated sodium chloride, then dried with sodium sulfate (anh.) and the solvent was removed to give the crude product. The product was chromatographed on a silica gel column, eluting with chloroform to give 723 mg of the purified product (yield: 55%).

RI-Butyl-6- (2-fluoro-phenyl) -3-methyl-1 H-pyrazolf-3,4-dl-pyrimidin-4-yl-1-pyridin-4-yl-amine: 1-butyl-4-chloro was combined -6- (2-fluoro-phenyl) -3-methyl-1H-pyrazolo [3,4-d] -pyrimidine (100 mg, 0.31 mmol) and 4-aminopyridine (58 mg, 0.626 mmol) in ethylene glycol and dimethoxy ether and was heated to reflux for 4 hours. The reaction mixture was cooled and the product was isolated by filtration, washed with minimal amount of solvent and dried to give 132 mg of product. 50 mg of this material was subjected to purification by reverse phase HPLC on a C18 column, eluting with a gradient of water / acetonitrile / trifluoroacetic acid 0.1%.

SCHEME L (Synthesis of the compound of formula (9)) 2- (Ethoxy-phenyl-methylene) -malononitrile: The orthobenzoate was refluxed overnight triethyl (25 g, 0.112 mol), malonitrile (9.07 g, 0.1/37 mol) and acetic anhydride (50 ml). The excess acetic anhydride was removed in vacuo and the product was chromatographed on silica gel eluting with 30% ethyl acetate / hexanes to give 21.7 g of product (yield: 97%). 5-Amino-3-phenyl-isoxazole-4-carbonitrile: Hydroxylamine hydrochloride was suspended in. Water (30 ml) and sodium hydroxide (4.4 g, 0.11 mol) and then ethanol (40 ml) were added, followed by the one-time addition of 2- (ethoxy-phenyl-methylene) -malononitrile (21.7 g, 0.11 g. 5 moles). The reaction mixture was heated at 50 ° C for 2 hours. The ethanol was removed in vacuo and the precipitate was filtered. The precipitate was redissolved in 50% ethyl acetate / hexanes and chromatographed on silica gel to give 8.2 g of product after removal of the solvent (yield: 40%). The rest of the sequence was carried out by analogy with the replacement of methyl 10 phenyl analog.

ESQUEJA M (Synthesis of the compound of formula (80)) , c CN 20 1 H-Pyrrole-2-carbonitrile: Pyrrole-2-carboxaldehyde (3.00 g, 0.0316 mole) was combined with hydroxylamine-O-sulfonic acid (12.5 g, 0.11 mole) in 100 ml of water and kilili stirred at room temperature overnight. The reaction mixture was cooled to 0 ° C and a solution of potassium hydroxide (12.06 g, 0.603 mol) in 80 ml of water was added dropwise over 1 hour. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was extracted with dichloromethane (3 x 100 ml), the extract was dried with sodium sulfate (anh.). The solvent was removed to give 3.36 g of product as a liquid (yield: 100%). 1 - . 1 -Amino-1 H-pyrrole-2-carbonitrile: 1 H-pyrrole-2-carbonitrile (3.36 g, 36.5 mmoles) was dissolved in 100 ml of dimethylformamide, potassium carbonate (7.51 g, 54.75 mmoles) was added to the solution. ) followed by O- (4-nitro-2-trifluoromethyl-phenyl) -hydroxylamine (12.15 g, 54.73 mmol). The mixture was stirred at room temperature overnight. 80 ml of water were added and the precipitate was filtered. The pH of the filtrate was adjusted to 10, and extracted with ethyl acetate (3 x 100 ml). The extract was washed with water and saturated sodium chloride and dried with sodium sulfate. The solvent was removed under vacuum to give 6.31 g of product containing residual dimethyl formamide. The yield was estimated by 64% NMR.

Amide of 1-amino-1 H-pyrrole-2-carboxylic acid: 1-amino-1 H-pyrrole-2-carbonitrile (2.52 g, 23.5 mmol) was suspended in 75 ml of water, treated with potassium hydroxide ( 32 g, 0.57 mol), 30% hydrogen peroxide (2 ml) and stirred overnight at room temperature. The ~ rfezcla de eá ^ ^ I I P ^^^ ^ íF. ^^^^ yp ^? pdirniéñt ^^^^)! 1- (5-Chloro-2-fluoro-benzoylamino) -1H-pyrrole-2-carboxylic acid amide: The amide of 1-amino-1 H-pyrrole-2-carboxylic acid was dissolved (1.25 g, 10 mmol) partially in 45 ml of acetonitrile, was added triethylamine (1.39 ml, 10 mmol) followed by the dropwise addition of 5-chloro-2-fluorobenzoyl chloride (1.93 g, 10 mmol) in 3 ml of chloroform. The The reaction mixture was stirred at room temperature overnight, the solvent was removed in vacuo and the residue was taken up in chloroform, washed with 10% sodium bicarbonate, water, and dried with sodium sulfate (anh.) . HE obtained a crystallized solid after parking. The product was obtained by chromatography of the silica gel filtrate eluting with 3% methanol / chloroform. 600 mg of product were obtained (yield: twenty-one%). 2- (5-Chloro-2-fluoro-phenyl) -3H-pyrroir2"1-f1f1.2,4ltriazin-4-one.

The 1- (5-chloro-2-fluoro-benzoylamino) -1H-pyrrole-2-carboxylic acid amide (200 mg, 0.71 mmol) was dissolved in 5 ml of 28% ammonium hydroxide in sealed tube and it was heated at 80 ° C overnight The solution was purged with nitrogen to remove the excess ammonia and acidified with 1 M hydrochloric acid until pH 2. The product was isolated by filtration, washed with water and dried under vacuum to give 90 mg of product (yield: 48%). 4-Chloro-2- (5-chloro-2-fluoro-phenyl) -pyrrole [2,1-firi, 2,4-ltriazine: 2- (5-Chloro-2-fluoro-phenyl) was added. { 3H-pyrrole [2, 1 -f] [1, 2,4] triazin-4-one (60 mg, 0.228 mmol) to phosphorus oxychloride (1 ml). 57 I microliters of N, N-dimethylaniline (catalyst) was added and heated at 110 ° C for all night. The excess phosphorus oxychloride was removed in vacuo, and the residue was treated with ice, and the product was extracted with chloroform. The chloroform extract was dried with sodium sulfate (anh.) | and the solvent was removed to give the crude product. The product was purified by chromatography on silica gel eluting with chloroform to give 36 mg of product (yield: 56%). f2- (5-Chloro-2-fluoro-phenyl) -pyrrolf2,1-f1f1.2.41triazin-4-ill- (3-methyl-pyridin-4-yl) -amine: 4-chloro-2- ( 5j-chloro-2-fluoro-phenyl) -pyrrole [2,1-f] [1, 2,4] triazine (30 mg, 0.106 mmol), cesium carbonate (48.5 mg, 0.149 mmol), palladium (II) acetate (1.19 mg, 0.00.53 mmol), BINAP (4.96 mg, 0.0080 mmol), and 4-amino-picoline (13.8 mg, 0.128 mmol) in 4 ml of dioxane (anh.) and heated to 90 ° C with stirring overnight. The mixture of The reaction was filtered to remove the solid material, the filtrate was evaporated to dryness, the residue was dissolved in chloroform (8 ml), washed with 0.5 M sodium hydroxide (1 ml), dried with sodium sulfate (anh. ), evaporated to dryness and then the residue was redissolved in dimethylformamide and purified by reverse phase HPLC and the product isolated.

SCHEME W (Synthesis of the compounds of formula (81) and (82)) dioxane 5- (2-Fluoro-phenyl) -4H- [1,4,4-triazol-l, 5-a1-pyrimidin-7-one: 3-amino-1, 2,4-triazdl (3.64 g, 43.25 mmol) and 2- were combined. Fluorobenzoyl acetate (10 g, 47.57 mmol) in acetic acid (45 ml) and refluxed overnight. The reaction mixture was cooled and the product was filtered, washed with diethyl ether to give 3.47 g (35% yield). 7-Chloro-5- (2-fluoro-phenyl) -f 1, 2,41-triazol [1, 5-alpyrimidine: i I was suspended 5- (2-fluoro-phenyl) -4H- [1,2,4] triazole [1,5-a] pyrimidin-7-one (840 mg, 3.64 mmol) in phosphorus oxychloride (5 ml) and heated to reflux for 45 min. The excess phosphorus oxychloride was removed in vacuo, the residue was treated with ice, the product was extracted with chloroform, then the chloroform was washed with 10% sodium bicarbonate, dried with sodium sulfate and the solvent was removed at room temperature. vacuum to give 420 mg of product (yield 46%). f5- (2-Fluoro-phenyl) -f1,2,4-triazolf-1,5-al? irimidin-7-ill-pyridin-4-yl-amine: 7-chloro-5- (2-fluoro-phenyl) - [1, 2,4] triazole [1,5-ajpyrimidine (124 mg, 0.5 mmol) in dioxane (5 ml), 4-aminopyridine (56.4 mg, 0.6 mmol), sodium t-butoxide (67 mg, 0.7 mmol), BINAP (2.3 mg, 0.00375 mmol), and Pd2 (dba) 3 (1.14 mg, 0.00125 mol) and were heated at 90 ° C overnight. The dioxane was removed in vacuo, the residue was taken up in methanol, filtered and purified reverse phase HPLC and the fractions were lyophilized to obtain the product as trifluoroacetate salt. The compound of formula (81) was prepared according to procedures similar to those described above, using 5-chloro-2-fluorobenzoyl ethyl acetate. The compound of formula (83) was prepared according to procedures similar to those described above, employing 4-aminopyrimidine.

SCHEME O (Synthesis of compounds of formula (60) and (61)) Preparation of 4,4-dimethylcyclohexanone: Ref: Tetrahedron Lett., 1992, 33 (35), 5009. A solution of 4,4-dimethylcyclohexen-2-one (10 g, 78.11 mmol) and triethylamine (10.89 ml, 78.11 mmol ) in 100% ethanol (30 ml) was subjected to hydrogenation at 206.8 kPa (30 psi) in a Parr apparatus, at room temperature overnight. Filtering the contents with Celite® and evaporating the filtrate gave a clean product as a colorless oil (10.08 g [99% yield]).

Preparation of 3,3-dimethylhexanedioic acid: Ref: J. Med. Chem. 1970, 13 (3), 531. To a solution of 4,4-dimethylcyclohexanone (2 g, 15.85 mmol) in glacial AcOH (100 ml) was added. added a solution of CrO3 (4.75 g, 47.54 mmol) in glacial AcOH (20 mL) and water (20 mL). The mixture was stirred at 60 ° C overnight, then cooled and diluted with 40% aqueous NaOH solution to pH 14. The mixture was washed with diethyl ether (4 x 100 ml), and the aqueous phase was returned to acidify with concentrated HCl (aq) to pH 1. The solution was extracted with diethyl ether (4 x 100 ml); the organic extracts were dried (brine and MgSO4) and evaporated to give the crude diacid which was directly esterified.

Preparation of 3,3-dimethylhexanodioic acid dimethyl ester: i Crude 3,3-dimethylhexanedioic acid was dissolved in methanol (50 ml) and thionyl chloride (1 ml) was added and the solution was heated at 60 ° C. 6h, then cooled and evaporated to give the crude diester, which was purified by chromatography (hexane / ethyl acetate 1: 1) to give the pure product as a colorless oil (2.90 g, 91% yield after two steps) .

Preparation of 4,4-dimethyl-2-oxo-cyclopentanecarboxylic acid methyl ester: Ref: J. Chem. Soc. Perkin Trans. 1, 1984, 799. To a solution of dimethyl ester delj 3,3-dimethylhexanedioic acid (2.90 g, 14.36 mmol) and methanol (100 μl) in dry toluene (10 ml) was added metallic sodium (0.66 g, 28.72 mmol). The mixture was heated to reflux overnight, then cooled and evaporated. The residue was purified by chromatography (hexane / ethyl acetate 1: 1) to give the desired cyclized product as a colorless oil (2.08 g, 85% yield).

Preparation of 2- (5-chloro-2-fluoro-phenyl) -6,6-dimethyl-6,7-dihydro-5H-cyclo-pentapyrimidin-4-or. A solution of 4,4-dimethyl-2-oxo-cyclopentane-carboxylic acid methyl ester (2.08 g, 12.21 mmol) and 5-chloro-2-fluoro-benzamidine (2.32 g, 13.44 mmol) in 100% ethanol ( 40 ml) was heated to reflux overnight, then cooled and evaporated. The residue was dissolved in 1 N NaOH (aq.) (50 ml) and washed with methylene chloride, (2 x 50 ml). The aqueous phase was then acidified with glacial acetic acid until pH 4 and extracted with methylene chloride (2 x 100 ml). The organic extracts were dried (brine and MgSO4) and evaporated to give the crude product, which was purified by chromatography (CH2Cl2, 0-10% MeOH) to give the desired product as a solid cream (2.10 g, 59% yield). ).

Preparation of 2- (5-chloro-2-fluoro-phenyl) -4-iodo-6,6-dimethyl-6,7-dihydro-5H-cyclopentapyrimidine: A suspension of 2- (5-chloro-2-fluoro- phenyl) -6,6-dimethyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ol (2.10 g, 7.16 mmol) in phosphorus oxychloride (40 ml) was heated at reflux for 2 h, then cooled and evaporated. The residue was dissolved in methylene chloride and the solution was filtered with a short pad of silica gel. The filtrate was evaporated to give the residue which was suspended in hydroiodic acid (10 ml) and heated at 90 ° C with sodium iodide (5.37 g, 35.82 mmol) for 3 h. The mixture was cooled and diluted with water (50 ml). An aqueous solution of sodium thiosulfate (50 ml) was added and the mixture was stirred vigorously with methylene chloride (3 x 100 ml). The organic extracts were dried with MgSO and evaporated to give a crude product, which was purified by flash chromatography (CH2CI2) to give the desired iodinated product as a solid cream (1.75 g, 66% yield).

Preparation of [2- (5-chloro-2-fluoro-phenyl) -6,6-dimethyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ill- (3-methyl-pyridin-4-yl) -amine : To a solution of 2- (5-chloro-2-fluoro-phenyl) -4-iodo-6,6-dimethyl-6,7-dihydro-5H-cyclopentapyrimidine (100 mg, 0.25 mmol), 3-methyl- pyridin-4-ylamine (30 mg, 0.27 mmol), Pd (OAc) 2 (3 mg, 12.42 μmol) and phthac-BINAP (12 mg, 18.63 μmol) in dry dioxane (3 ml) was added Cs2CO3 (121 mg, 0.37 mmol). The mixture was heated for 48 h at 8 ° C, cooled and evaporated. Purification by HPLC produced, after lyophilization, the desired product of formula (60) as the TFA salt, which was a white solid (6.4 mg). The same procedure was used to prepare the compound of formula (61).

SCHEME P (Synthesis of compounds of formula (62) to (66)) Preparation of 4-f2- (5-chloro-2-fluoro-phenyl) -6,6-dimethyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino-1-nicotinic acid methyl ester: IA a solution of 2 - (5-chloro-2-fl? Oro-phenyl) -4-iodo-6,6-dimethyl- 6,7-dihydro-5H-cyclopentapyrimidine (500 mg, 1.24 mmol), 4-amino-nicotinic acid methyl ester (208 mg, 1.37 mmol), Pd (OAc) 2 (14 mg, 62.09 μmol) and Rac. BINAP (60 mg, 93.14 μmol) in dry dioxane (10 ml) was added Cs2CO3 (607 mg, 1.86 mmol). The mixture was heated for 12 h at 85 ° C, cooled and evaporated The residue was purified by chromatography (CH 2 Cl 2, 0-10% MeOH) to give the desired product (178 mg, 34% yield).

Preparation of 4- [2- (5-chloro-2-fluoro-phenyl) -6,6-dimethyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylaminol-nicotinic acid: To a solution of methyl ester - [2- (5-Chloro-2-fluoro-phenyl) -6,6-dimethyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino] -nicotinic acid (178 mg, 0.42 mmol) in dioxane (10 ml. NaOH (aq) was added (451 μl solution, 0.44 mmol, 0.97 N). The mixture was heated at 60 ° C for 1 h, then cooled, and HCl (aq.) Was added (425 μl solution, 0.44 mmol, 1.03 N). In addition, the acid was precipitated from the solution and filtered and dried in vacuo, to give 137 mg of product.

Preparation of 4- [2- (5-chloro-2-fluoro-phenyl) -6,6-dimethyl-617-dihydro-5H-cyclopentapyrimidin-4-ylaminol-nicotinamide: A suspension of 4- [2- (5 -chloro-2-fluoro-phenyl) -6,6-dimethyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino] -nicotinic acid (25 mg, 60.56 μmol) and carbonyldiimidazole (20 mg, 121.11 μmol) in DMF dry (3 ml) was heated at 70 ° C for 1 h and then cooled to rt A stream of gaseous NH3 was passed through the solution for 30 min, which resulted in the conversion of the clean product to the amide. Evaporation of the solution, followed by purification by HPLC, after freeze drying, produced the pure amide of formula (62) as a TFA salt (20 mg). The compounds of formula (63) to (66) were prepared using the same procedure.

SCHEME Q (Synthesis of compounds of formula (76) and (77)) Methyl ester of 4- [6 -! (5-chloro-2-fluoro-phenyl) -3-methyl-1-isoxazolfd ^ -dl-pyrimidin ^ -ylaminol-nicotinic acid: 1-4-chloro-6- (5- chloro-2-fluoro-phenyl) -3-methyl-isoxazole [5,4-d] pyrimidine! (prepared by the method employed for the compound of formula (43) (298 mg, 1 mmol) was dissolved in dioxane (4 ml), and BINAP (4.67 mg, 0.0075 mmol), methyl ester of 4-amino-nicotinic acid (182 mg, 1.2 mmol), cesium carbonate (456 mg, 1.4 mmol), and Pd2 (dba) 3 (2.29 mg, 0.0025 mmol) were added to the mixture and heated to 90 ° C. C throughout the night. The dioxane was removed in vacuo and the residue triturated with ethyl acetate (5 ml) and the product it was isolated by filtration. 525 mg of solid were obtained, which also contained I I and cesium carbonate as a by-product. 4-f6- (5-Chloro-2-fluoro-phenyl) -3-methyl-isoxazolf-5,4-d-pyrimidin-4-ylamino-nicotinic acid: I! I The methyl ester of 4- [6- (5-chloro-2-fluoro-phenyl) -3-methyl-isoxazole [5,4-d] pyrimidin-4-ylamino] -nicotinic acid methyl ester (525 mg) was suspended in methanol (4 ml), 1 M sodium hydroxide solution (4 ml) was added and then heated at 70 ° C for 30 min. The methanol was removed in vacuo and the solution acidified to pH 4 with 6 M hydrochloric acid. The solid was filtered, washed with water and dried in an oven to give 137 mg of product. 4- [6- (5-Chloro-2-fluoro-phenyl) -3-methyl-isoxazole [5,4-dl-pyrimidin-4-ylamino-N-cyclopropyl-nicotinamide: 4- [6- (5- chloro-2-fluoro-phenyl) -3-methyl-isoxazole [5,4-d] -pyrimidin-4-ylamino] -nicotinic acid (130 mg, 0.325 mmol) with carbonyl diimidazole (105 mg, 0.650 mmol) in 2 ml of dimethylformamide and heated at 70 ° C for 1 hour. The mixture was cooled to room temperature, cyclopropylamine (74 mg, 1.3 mmol) was added and stirred for 1 hour at room temperature. The solution was filtered and the filtrate was subjected to a purification by reverse phase HPLC. After lyophilization of the fractions containing the pure product, 13.7 mg of pure product were obtained. The compound of formula (77) was prepared using the procedure described above, employing methylamine.

SCHEME R (Synthesis of the compound of formula (33)) 2- (5-Chloro-2-fluorophenyl) -5,7-dihydrofuro [3,4-dlpyrimidin-4-ol: To a suspension of 4-oxo-tetrahydrofuran-3-carboxylic acid methyl ester (prepared from according to Dow? l, P .; Choi, SC, Tetrahedron, 1991, 47, 4847-4860; 800 mg, 5.55 mmol, 1eq) in ethanol (20 ml) was added! a solution of 2-fluoro-5-chlorobenzamidine (961 mg, 5.55 mmol, 1 eq) in EtOH (10 ml). The reaction mixture was heated at 80 ° C overnight. The reaction mixture was cooled to t.a. and the white precipitate was filtered and washed with cold ethyl acetate (2 x 20 ml). The crude residue was divided between chloroform and water. The aqueous phase was acidified to pH 4 and the product was extracted with chloroform (3 x 50 ml). The organic phases were combined, washed with brine, dried with MgSO, filtered, concentrated in vacuo to give the crude solid, which was purified by flash column chromatography (5% MeOH in EtOAc) to give the white solid 2- ( 5-chloro-2-fluorophenyl) -5,7-dihydrofuro [3,4-d] pyrimidin-4-ol (440mg, 30%). 4-Chloro-2- (5-chloro-2-fluorophenyl) -5,7-} dihydrofuro [3,4-dlpyrimidine: ii A suspension of 2- (5-chloro-2-fluorophenyl) -5,7-dihydrofuro [3,4-d] pyrimidin-4-ol (100 mg, 0.36 mmol, 1 eq) in POCI3 (5 ml) was stirred at reflux for 1 h. The solution was then cooled to room temperature and concentrated under reduced pressure to give the white solid which was dissolved in dry methylene chloride. The solution was cooled to 0 ° C and ice was added followed by saturated NaHCO3 solution. The organic phase was separated, washed with brine, dried (MgSO4), filtered and evaporated in vacuo to give a crude white solid, which was purified by flash column chromatography (EtOAc: Hexane 1: 9) to give the reaction medium. -chloro-2- (5-chloro-2-fluorophenyl) -5,7-dihydrofuro [3,4-d] pyrimidine (78mg, 73%) as a white solid. 2- (5-Chloro-2-fluorophenyl) -4-iodo-5,7-idihydrofurof3,4-dlpyrimidine: IA a suspension of 4-chloro-2- (5-chloro-2-fluorophenyl) -5, 7- dihydrofuro [3,4-d] p rimidine (78 mg, 0.275 mmol, 1 eq) in Hl (aq) 57% (2 ml) at rt Nal (206 mg, 1.37 mmol, 5 eq) was added. The reaction mixture was stirred at t.a. overnight and then poured into ice. The product was extracted with chloroform and the aqueous phase was neutralized with NaHCO3 and extracted later with chloroform. The organic phases were combined, washed with brine, dried (MgSO), filtered and evaporated in vacuo to provide a crude residue of 2- (5-chloro-2-fluorophenyl) -4-iodo-5,7-dihydrofuro [3,4-d] pyrimidine, which was not subsequently purified. [2- (5-Chloro-2-fluorophenyl) -5,7-dihydrofuro [3,4-dl-pyrimidin-4-yn- (3-methyl-pyridin-4-yl) -amine, compound of formula (33 ): To a solution of 2- (5-chloro-2-fluorophenyl) -4-iodo-5,7-dihydrofuro [3,4-d] pyrimidine (80 mg, 0.21 mmol, 1 eq) in anhydrous dioxane (5%). ml) Pd (OAc) 2 (2 mg, 0.01 mmol, 0.05 eq) was added followed by BINAP (10 mg, 0. 02 mmol, 0.075 eq), 4-amine-3-picoline (25 mg, 0.23 mmol, 1.2 eq) and Cs2CO3 (100 mg, 0.32 mmol, 1.5 eq). The reaction mixture was heated to 80 ° C for 15 h. The reaction mixture was cooled to t.a. and leaked with Celite® and the crude material was purified by flash column chromatography (ethyl acetate: hexane 9: 1) to give [2- (5-chloro-2-fluorophenyl) -5,7-dihydrofuro [3,4-d] pyrimidin-4-yl] - (3-methyl-pyridine -4-yl) -amine, composed of formula (33) (20 mg, 26%) as a white solid.

SCHEME S Ethyl 4- [2- (5-chloro-2-fluoro-phenyl) -5,7-d? Hydro-furo [3,4-dl-pyrimidin-4-ylamino-nicotinic acid ester:! Following the general reaction procedure employed I during the synthesis of [2- (5-chloro-2-fluorophenyl) -5j7-dihydrofuro [3,4-d] p? Rimidin-4-yl] - (3-methyl- pyridin-4-yl) -amine, ie a compound of formula (33), was isolated Ethyl 4- [2- (5-chloro-2-fluoro-phenyl) -5,7-dihydro-furo [3,4-d] pyrimidin-4-ylamino] -nicotinic acid ester with a 73 Performance% 4- [2- (5-Chloro-2-fluoro-phenyl) -5,7-dihydro-furo [3,4-d1-pyrimidin-4-ylamino-nicotinic acid: To a suspension of 4- [2- (5-chloro-2-fluoro-phenyl) -5,7-dihydro-furo [3,4-d] pyrimidin-4-ylamino] -ethyl ester Cotinic (60 mg, 0.14 mmol, 1 eq) in MeOH (5 ml) was added to a solution of 1 N NaOH (aq) (300 μl, 0.30 i mmol, 2 eq) and the reaction mixture was heated to reflux for 2 h. The solution was cooled to t.a. and concentrated on vacuo. Water (20 ml) was added to the crude material and the aqueous phase was acidified to pH 4. The solid was filtered, washed with water (2 x 5 ml) and dried overnight to provide 4- [2- (5-chloro-2-fluoro- phenyl) -5,7-dihydro-furo [3,4-d] pyrimidin-4-ylamino] -nicotinic acid (50 mg, 90%). 4- [2- (5-Chloro-2-fluoro-phenyl) -5,7-dihydro-furo [3,4-dl-pyrimidin-4-ylaminol-nicotinic acid amide, compound of formula (34): To a suspension of 4- [2- (5-chloro-2-fluoro-phenyl) -5,7-dihydro-furo [3,4-d] pyrimidin-4-ylamino] -nicotinic acid (50 mg, 0.13 mmol , 1 eq) in DMF (2 mL) was added 1-1 '-carbonyldiimidazole (50 mg, 0.31 mmol, 2.4 eq) and the reaction mixture was heated at 70 ° C for 2 h. The mixture was cooled to t.a. and i i was bubbled with NH 3 (g) for 10 min. The reaction mixture was stirred at t.a. for an additional hour. The reaction was concentrated in vacuo and the residue was triturated with water (2 x 5 ml). To the crude residue was added 1 M NaOH (5 ml) and the suspension was heated at 100 ° C for 2 h. The reaction mixture was cooled to room temperature and neutralized with 1 N HCl and the solid was filtered to give 4- [2- (5-chloro-2-fluoro-phenyl) -5,7-dihydroamide. -furo [3,4-d] pyrimidin-4-ylamino] -nicotinic acid, compound of formula (34) (25 mg, 50%) as a white solid.

SCHEME T 2- (5-chloro-2-fluorophenyl) -5,6,7,8-tetrahydroquinazolin-4-ol: To a solution of methyl-2-oxocyclopentanecarboxylate (2 g, 11.8 mmol, 1 eq) in dry ethanol (20 g. ml) was added a solution of 2-fluoro-5-chlorobenzamidine (2.04 g, 11.8 mmol, 1 eq) in ethanol (20 ml) and the reaction mixture was heated at 80 ° C overnight. The reaction mixture was cooled to t.a. and the solvent was removed in vacuo to give the crude residue, which was purified by recrystallization from hot ethyl acetate to give 2- (5-chloro-2-fluorophenyl) -5,6,7,8-tetrahydroquinazolin-4- ol (2.56 g, 78%) as a white solid. 4-chloro-2- (5-chloro-2-fluorophenyl) -5,6,7,8-tetrahydroquinazoline: A suspension of 2- (5-chloro-2-fluorophenyl) -5,6,7,8-tetrahydroquinazolin -4-ol (500 mg, 1.89 mmol) in POCI3 (6 mL) was stirred at reflux for 1 h. The solution was then cooled to room temperature and concentrated under reduced pressure to give a white solid, which was dissolved in methylene chloride. The solution was cooled to 0 ° C and ice was added followed by saturated NaHCO3 solution. The organic phase was separated, washed with brine, dried (MgSO), filtered and evaporated in vacuo to provide a crude white solid 4-chloro-2- (5-chloro-2-fluorophenyl) -5, 6.7, 8-tetrahydroquinazolin, which was not purified subsequently. 1 2- (5-chloro-2-fluorophenyl) -4-voldo-5,6,7,8-tetrahydroquinazoline: To a suspension of 4-chloro-2- (5-chloro-2-fluorophenyl) -5,6, 7,8-tetrahydroquinazoline (534 mg, 1.89 mmol, 1 eq) in a solution of 57% Hl in water (10 ml) at and Nal (1.42 g, 9.47 mmol, 5 eq) was added. The reaction mixture was stirred at t.a. overnight and then poured into ice. The product was extracted with chloroform and the aqueous phase was neutralized with NaHCO3 and then extracted with more chloroform. The organic phases were combined, washed with brine, dried (MgSO), filtered and evaporated in vacuo to give a crude white solid 2- (5-chloro-2-fluorophenyl) -4-iodo-5, 6.7, 8-tetrahydro-quinazoline, which was not purified subsequently. r2- (5-Chloro-2-fluorophenyl) -5,6,7,8-tetrahydroquinazolin-4-yl-1- (3-methylpyridin-4-yl) -amine, compound of formula (38): 2- Crude (5-chloro-2-fluorophenyl) -4-iodo-5,6,7,8-tetrahydroquinazoline (130 mg, 0.35 mmol, 1 eq) was dissolved in dioxane (5 ml) and Pd (OAc) was added to this solution. ) 2 (4 mg, 0.02 mmol, 0.05 eq) followed by BINAP (16 mg, 0.03 mmol, 0.075 eq), 4-amino-3-picoline (49 mg, 0.45 mmol, 1.3 eq) and Cs2CO3 (170 mg, 0.52) mmol, 1.5 eq). The reaction mixture was heated at 80 ° C for 15 h. The reaction mixture was cooled to t.a. and filtered with Celite® and the crude material was purified by flash column chromatography (ethyl acetate: hexane 1: 1) to give [2- (5-chloro-2-fluorophenyl) -5, 6,7,8- tetrahydroquinazolin-4-yl] - (3-methylpyridin-4-yl) -amine, compound of formula (38) (110 mg, 86%).

SCHEME U (Synthesis of the compounds of formula (50), (40), (45), (57), (59)) Ethyl ester of 4-r2- (5-chloro-2-fluorophenyl) -5,6,7,8-tetrahydroquinazolin-4-ylaminol-nicotinic acid: Following the general reaction procedure used during the synthesis of [2- (5- chloro-2-fluorophenyl) | 5,6,7,8-tetrahydroquinazolin-4-yl] - (3-methylpyridin-4-yl) -amine, ie the compound of formula (38), the ethyl ester was isolated of 4- [2- (5-chloro-2-fluorophenyl) -5,6,7,8-tetrahydroquinazolin-4-ylaminol-nicotinic acid in 67% yield. ilaminol-nicotinic, 50: To a suspension of 4- [2- (5-chloro-2-fluorophenyl) -5,6,7,8-tetrahydroquinazolin-4-ylamino]! -nicotinic acid ethyl ester (150 mg, 0.35 t mmol, 1 eq ) in MeOH (5 ml) was added a solution of NaOH (aq) 1 N (423 μl, 0. 42 mmol, 1.2 eq) and the reaction mixture was refluxed for 1 h. The solution cooled to t.a. and concentrated on vacuo. Water (20 ml) was added to the material crude and the aqueous phase was acidified to pH 4. The solid was filtered, washed with water (2 x 5 ml) and dried overnight to give 4- [2- (5-chloro-2-fluorophenyl) -5,6,7,8-tetrahydroquinazolin-4-ylamino] -nicotinic acid, composed of I formula (50) (132 mg, 94%), as a cream-colored solid. 4- [2- (5-Chloro-2-fluorophenyl) -5,6,7,8-tetrahydroquinazolin-4-ylaminol-N-cyclopropyl nicotinamide, compound of formula (45): To a suspension of 4- [2 [- (5-chloro-2-fluorophenyl) -5,6,7,8-tetrahydro-quinazolin-4-ylamino] -nicotinic acid (40 mg, 0.10 mmol, 1 eq) in DMF dry (1 ml) was added triethylamine (15 μl, 0.1 μl 1 mmol, 1.1 eq) followed by cyclopropylamine (70 μl, 0.10 mmol, 10 eq). To the suspension was added PyBrOP solution (56 mg, 0.21 mmol, 1.2 eq) in DMF (500 μl) dropwise.

The reaction mixture was stirred at room temperature for 16 h. The The reaction was concentrated in vacuo and the residue was triturated with ether (2 x 20 ml). The crude residue i was purified by flash column chromatography (0-5% MeOH in I CHCl3) to give 4- [2- (5-chloro-2-fluorophenyl) -5,6,7,8-tetrahydroquinazolin-4-ylamino] -N-cyclopropynicotinamide, compound of formula (45), (15 mg, 34%) as a white solid. The compound of formula (40) was prepared by the method described in the synthesis of the compound of formula (45) using methylamine instead of cyclopropylamine. The compound of formula (57) was prepared by the method described in the synthesis of the compound of formula (45) using 1-amino-propan-2- (S) -ol in place of cyclopropylamine. The compound of formula (59) was prepared by the method described in the synthesis of the compound of formula (45) using? /,? / - diethyletenediamine instead of cyclopropylamine.

SCHEME V (Synthesis of the compound of formula (39) 2- (5-Chloro-2-fluorophenyl) -6,7-dihydrofuror3,2-d1-pyrimidin-4-ol: To a solution of 2-fluoro-5-chlorobenzamidine (1.05 g, 6.08 mmol, 1.2 eq) in EtOH (20 ml 3-Oxo-tetrahydrofuran-2-carboxylic acid ethyl ester (prepared in accordance with Moyer, MP, Feldman, PL, Rapoport, HJOrg.Chem, 1985, 50, 5223-5230, 800 mg, 5.06 mmol) was added. 1 eq) in ethanol (5 ml). The reaction mixture was heated at 80 ° C overnight. The reaction mixture was cooled to t.a. and the crude residue was purified by flash column chromatography (5% MeOH in CHCl3) to give a white solid 2- (5-chloro-2-fluorophenyl) -6,7-dihydrofuro [3,2-d] pyrimidin-4 -ol (650 mg, 53%). 4-Chloro-2- (5-chloro-2-fluorophenyl) -6,7-dihydrofuro [3,2-d1-pyrimidine: A suspension of 2- (5-chloro-2-fluorophenyl) -6,7-dihydrofide [3 , 2-d] pyrimidin-4-ol (100 mg, 0.36 mmol, 1 eq) in POCI3 (5 mL) was stirred at reflux for 1 h. The solution was cooled to t.a. and concentrated under reduced pressure to give a white solid which was dissolved in methylene chloride. The solution was cooled to 0 ° C and ice was added followed by saturated NaHCO3 solution. The organic phase was separated, washed with brine, dried (MgSO), filtered and evaporated in vacuo to give a crude white solid which was purified by flash column chromatography (1: 9 EtOAc: Hexane) to give 4-chloro -2- (5-chloro-2-fluorophenyl) -6,7-dihydrofuro [3! 2-d] pyrimidine (78 mg, 73%) as a white solid. 2- (5-Chloro-2-fluorophenyl) -4-iodo-6,7-dihydrofurof3,2-d1pyrimidine: To a suspension of 4-chloro-2- (5-chloro-2-fluorophenyl) -6,7- dihydrofuro [3,2-d] pyrimidine (80 mg, 0.28 mmol, 1 eq) in a Hl solution 57% in water (2 ml) at t.a. Nal (206 mg, < 1.41 mmol, 5 eq) was added. The reaction mixture was stirred at t.a. overnight and then poured into ice. The product was extracted with chloroform and the aqueous phase was neutralized with NaHCO3 and subsequently extracted with more chloroform. The organic phases were combined, washed with brine, dried (MgSO), filtered and evaporated in vacuo to give a crude residue 2- (5-chloro-2-fluoro-phenyl) -4-iodo-6,7-dihydrofide [3,2-d] pyrimidine, which was not purified subsequently. r2- (5-Chloro-2-fluorophenyl) -6,7-dihydrofuro [3,2-dlpyrimidin-4-in- (3-methyl-pyridin-4-yl) -amine, compound of formula (39): A a solution of 2- (5-chloro-2-fluorophenyl) -4-iodo-6,7-dihydrofuro [3,2-d] pyrimidine (106 mg, 0.28 mmol, 1 eq) in dioxane (5 ml) was added Pd (OAc) 2 (3 mg, 0.01 mmol, 0.05 eq) followed by BINAP (13 mg, 0.02 mmol, 0.075 eq), 4-amino-3-picoline (40 mg, 0.37 mmol, 1.3 eq) and Cs2CO3 (138 mg, 0.42 mmol, 1.5 eq). The reaction mixture was heated at 80 ° C for 15 h. The reaction mixture was cooled to t.a. and filtered with Celite® and the crude material was purified by flash column chromatography (ethyl acetate: hexane 4: 1 -100% ethyl acetate) to give [2- (5-chloro-2-fluorophenyl) -6, 7- dihydro [3,2-d] pyrimidin-4-yl] - (3-methyl-pyridin-4-yl) -amine, is deir the compound of formula (39) (30 mg, 30%) as a white solid.

SCHEME W (Synthesis of the compound of formula Ethyl ester of 4-f2- (5-chloro-2 ^ fluorophenyl) -6.7-dihydrofuroy3,2-dlpyrimidin-4-ylaminol-nicotinic acid: (To a solution of 4-clqro-2- (5-chloro-2- fluorophenyl) -6,7-dihydrofuro [3,2-d] pyrimidine (320 mg, 1 13 mmol, 1 eq) in dioxane (5 ml) was added Pd (OAc) 2 (13 mg, 0.06 mmol, 0.05 eq) followed by BINAP (53 mg, 0.08 mmol, 0.075 eq), 4-aminonicotinic acid ethyl ester (206 mg, 1.24 mmol, 1.1 eq) and Cs2CO3 (478 mg, 1.46 mmol, 1.5 eq) The reaction mixture was heated at 80 ° C for 15 h. The reaction mixture was cooled to rt and filtered with Celite® and the crude material was purified by flash column chromatography (0-5% MeOH in CHCl3) to give ethyl 4-ethyl ester. [2- (5-chloro-2-fluorophenyl) -6,7-dihydrofuro [3,2-d] pyrimidin-4-ylamino] -nicotinic acid (100 mg, 21%) as a white solid. 4-r2- (5-chloro-2-fluorophenyl) -6,7-dihydrofuro [3,2-dlpyrimidin-4-ylaminol-nicotinic acid: To a suspension of 4- [2- (5-chloro-2-ethyl ester -fluorophenol) -6,7-dihydrofuro [3,2-d] pyrimidin-4-ylamino] -nicotinic acid (100 mg, 0.24 mmol, 1 eq) in MeOH (5 mL) was added a solution of NaOH (aq. ) 1 N (290 μl, 0.29 mmol, 1.2 eq) and the reaction mixture was refluxed for 5 h. The solution was cooled to t.a. and concentrated on vacuo. Water (20 ml) was added to the crude material and the aqueous phase was acidified to pH 4. The solid was filtered, washed with water (2 x 5 ml) and dried overnight to provide 4- [2- acid. (5- chloro-2-fluorophenyl) -6,7-dihydrofuro [3,2-d] pyrimidin-4-ylamino] -nicotinic acid (88 mg, 94%) as a cream-colored solid. 4-22- (5-Chloro-2-fluorophenyl) -6,7-dihydrofuror3,2-d1-pyrimidin-4-ylaminol-N-methyl nicotinamide, compound of formula (44): To a suspension of 4- [2- (5-chloro-2-fluorophenyl) -6,7-dihydrofuro [3,2-d] pyrimidin-4-ylamino] -nicotinic acid (7.5 mg, 0.19 mmol, 1 eq) in I DMF (2 ml) was added triethylamine (30 μl, 0.21 mmol, 1.1 eq) followed by methylamin (1.17 ml, 3.89 mmol, in 2 M THF solution, 20 eq). To suspension was added a solution of PyBrOP (100 mg, 0.21 mmol, 1.2 eq) in DMF (1 ml) dropwise. The reaction mixture was stirred at temperature environment for 16 h. The reaction was concentrated in vacuo and the residue was triturated in ether (2 x 20 ml). The crude residue was purified by flash column chromatography (5% MeOH in CHCl3) to give 4- [2- (5-chloro-2-fluorophenyl) -6,7-dih drofuro [3,2-d] pyrimidin-4-ylamino] -N-methylnicotinamide, ie the! compound of formula (44) (20 mg, 26%) as a white solid.

SCHEME X; (Synthesis of the compound of formula (43)) 2- (5-Chloro-2-fluorophenyl) -5-methyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ol: To a solution of 2-fluoro-5-chlorobenzamide (1.95 g, 11.27 mmol, 1.1 eq) in EtOH (20 ml) was added a solution of ethyl ester of acid 2-methyl-5-oxo-cyclopentanecarboxylic acid (preparadol according to Wang, C; Gu, X .; Yu, M.S .; Curran, D.P .: Tetrahedron, 1998, 29, 8355-8370; 1.60 g, 10. 26 mmol, 1 eq) in ethanol (5 ml). The reaction mixture was heated at 80 ° C overnight. The reaction mixture was cooled to t.a. and the solvent is removed in vacuo to give the crude residue, which was purified by Recrystallization from hot ethyl acetate to give 2- (5-chloro-2-fluorophenyl) -5-methyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ol (1.0 g, 35%) as a crystalline white solid and the filtrate was then purified by flash chromatography on column to give another 850 mg of 2- (5-chloro-2-Jfluorophenyl) -5-methyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ol. 2- (5-Chloro-2-fluorophenyl) -4-iodo-5-methyl-6,7-dihydro-5H-I cyclopentapyrimidine: i A suspension of 2- (5-chloro-2-fluoro-phenyl) -5-methyl-6 , 7-dihydro-i 5H-cyclopentapyrimidin-4-ol (200 mg, 0.72 mmol, '1 eq) in POCI3 (5 mL) was stirred reflux for 1 h. The solution was then cooled to room temperature and concentrated under reduced pressure to give a white solid. The residual POCI3 was eliminated as azeotrope with chloroform. A urja iminochloride suspension! Crude in a solution of Hl 57% in water (5 ml) at t.a. Nal (540 mg, 3.60 mmol, 5 eq) was added. The reaction mixture was stirred at t.a. overnight and then poured into ice. The product was extracted with chloroform and the aqueous phase was neutralized with NaHCO3 and then extracted with chloroform. The organic phases were combined, washed with brine, dried (MgSO), filtered and evaporated in vacuo to give a crude residue of 2- (5-chloro-2-fluorophenyl) -4-iodo-5-methyl-6, 7-dihydro-5H-cyclopentapyrimidine, which was not subsequently purified. r2- (5-Chloro-2-fluorophenyl) -5-methyl-6,7-dihydro-5H-cyclopentapyrimidin-1-yl-methyl-pyridin-1-yi-amine, compound of formula (43): To a solution of 2 - (5-chloro-2-fluorophenyl) -4-iodo-5-methyl-6,7-dihydro-5H-cyclopentapyrimidine (275 mg, 0.71 mmol, 1 eq) in dioxane (5 ml) was added Pd (OAc) 2 (8 mg, 0.04 mmol, 0.05 eq) followed by BINAP (33 mg, 0.05 mmol, 0.075 eq), 4-amino-3-picoline (84 mg, 0.78 mmol, 1.1 eq) and Cs2C03 (347 mg, 1.06 mmol) , 1.5 eq). The reaction mixture was heated at 80 ° C for 15 h. The reaction mixture was cooled to t.a. and filtered with Celite® and the crude material was purified by flash column chromatography (ethyl acetate: hexane 1: 1-100% ethyl acetate) to give [2- (5-chloro-2-fluorophenyl) -5- meth1l-6,7-d, hydro-5H-cyclopentapyrimidin-4-yl] - (3-methyl-pyridin-4-yl) -amine, compound of formula (43) (250 mg, 96%). eleven SCHEME Y (Synthesis of the compounds of formula (48), (49), (47). (46)) Ethyl 4- [2- (5-chloro-2-fluoro-phenyl) -5-methyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylaminol-nicotinic acid ester, compound of formula (48): Following the general reaction procedure of the synthesis of [2- (5-chloro-2-fluorophenyl) -5-methyl-6,7-dihydro-5H-cyclopentapyrimidin-4-yl] - (3-methyl-pyridin-4-yl) -amine, ie the compound of formula (43), the ethyl ester of 4- [2- (5-chloro-2-fluoro-phenyl) -5-methyl-6,7-dihydro-5H-cyclopentapyrimidin-4- was isolated ilamno] -n-trinic, compound of formula (48), with 68% yield. 4- [2- (5-Chloro-2-fluorophenyl) -5-methyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylaminol-nicotinic acid, compound of formula (49): To a suspension of 4-ethyl ester - [2- (5-chloro-2-fluoro-phenyl) -5-methyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino] -nicotinic acid (180 mg, 0.42 mmol, 1 eq) in MeOH (5 ml) was added a solution of 1 N NaOH (aq) (634 μL, 0.63 mmol, 1.5 eq) and the reaction mixture was heated to reflux for 1 h. The solution was cooled to t.a. and concentrated on vacuo. Water (20 ml) was added to the crude material and the aqueous phase was acidified to pH 4. The solid was filtered, washed with water (2 x 5 ml) and dried overnight to give the acid 4- [2 - (5-chloro-2-fluorophenyl) -5-methyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylaminoj-nicotinic, compound of formula (49) (160 mg, 95%) as a white solid. 4-f2- (5-Chloro-2-fluorophenyl) -5-methyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylaminol-N-methyl-nicotinamide, compound of formula (47): To a suspension of 4- [2- (5-Chloro-2-fluorophenyl) -5-methyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino] -nicotinic acid (20 mg, 0.05 mmol, 1 eq) in DMF (2 ml) was added triethylamine (8 μl, 0.05 mmol, 1.1 eq) followed by 2 M methylamine solution (250 μl, 3.89 mmol, in THF, 10 eq). To this suspension was added a solution of PyBOP (40 mg, 0.08 mmol, 1.5 eq) in DMF (1 ml) dropwise. The reaction mixture was stirred at temperature environment for 16 h. The reaction was concentrated in vacuo and the residue was triturated with ether (2 x 20 ml). The crude residue was purified by flash chromatography column (100% ethyl acetate) to give 4- [2- (5-chloro-2-fluorophenyl) -5-methyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino] -N-met L-nicotinamide, is say, a compound of formula (47), (12mg, 58%) as a white solid. The compound of formula (46) was prepared by the method described in the synthesis of the compound of formula (47) using ammonia instead of methylamine. The compounds of formula (1) can be converted to each other following the transformation reactions of known functional groups in the art, comprising those described herein to continuation. Many of the intermediates t used to prepare the compounds of formula (1) are known compounds or are analogs of known compounds, which can be prepared by following Modifications of methodologies known in the easily accessible technique for the experts.

The compounds of formula (1) can be converted to the! corresponding? / - oxide forms following procedures known in the art for converting a trivalent nitrogen into its? / -oxide form. Said? / -oxidation reaction can generally be carried out by the reaction of the starting material of formula (1) 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, the appropriate organic peroxides may comprise peroxyacids such as, for example, benzenecarboxylic acid or halo-substituted benzenecarboxyloxy acid, e.g., 3-chlorobenzene-carboperoxoic acid, peroxoalkanoic acids, e.g., peroxoacetic acid, alkylhydroperoxides, e.g., tert-butyl hydroperoxide. Suitable solvents are, for example, water, lower alcohols, eg, ethanol and the like, hydrocarbons, e.g. toluene, ketones, eg, 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents. The stereochemically pure isomeric forms of the compounds of formula (1) can be obtained by application of procedures known in the art. The diastereomers can be separated by physical methods such as selective crystallization and chromatographic techniques, e.g., countercurrent distribution, liquid chromatography and the like. The compounds of formula (1) can be obtained as racemic mixtures of enantiomers, which can be separated from each other following the resolution procedures known in the art. The racemic compounds of formula (1), which are sufficiently basic or acidic, can be converted into the corresponding diastereomeric salt forms by the reaction of a suitable chelating acid with the respective chiral base. Said diastereomeric salt forms are successively separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by means of alkalis or acids. An alternative form of separation of enantiomeric forms of the compounds of formula (1) includes liquid chromatography, in particular liquid chromatography employing a chiral stationary phase. Said stereochemically pure isomeric forms can also be derived from the corresponding stereochemically pure isomeric forms of the appropriate starting materials, provided by the reactions that occur in stereospecific form. Preferably, if a specific stereoisomer is desired, said compound can be synthesized by stereospecific methods of preparation. These methods may advantageously employ enantiomerically pure starting materials. The form of administration and formulation of the compounds useful in this invention and their related compounds will depend on the nature of the disease., the severity of the disease, the particular subject to be treated and the criteria of the professionals, the formulations will depend on the mode of administration. The compounds of the present invention or any of its subgroups can be formulated into different dosage forms according to the purposes of administration. As suitable compositions, all of the compositions usually employed for the systemic administration of drugs can be mentioned in order to prepare the pharmaceutical compositions of this invention. invention, a therapeutically effective amount of the particular compound, optionally forms of addition salts or metal complexes, such as active ingredient combined in intimate admixture with an acceptable vehicle I for pharmaceutical use, this vehicle can take a variety of forms depending on the form of preparation desired for administration. A therapeutically effective amount in this context is a quantity enough to act prophylactically, stabilize or reduce viral infection, and in particular the viral infection with HCV, or 'prevent the evolution of disease towards chronic hepatitis, liver fibrosis, cirrhosis, end-stage liver disease, HCC (hepatocellular carcinoma) and others similar, I in infected subjects or subjects at risk of infection. Pharmaceutical compositions are desirable in forms of Suitable unit doses, particularly, for oral, rectal, and percutaneous administration or parenteral injection To prepare the compositions in oral dosage form I, any of the usual pharmaceutical media such as, for example, water, glycols, oils, alcohols and other similar substances, in the case of oral liquids, preparations such as as suspensions, syrups, elixirs, emulsions and solutions; or vehicles solids such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like, in the case of powders, pills, capsules and tablets Due to the ease of administration, the tablets and I capsules represent the most advantageous oral dosage forms, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will comprise sterile water, at least for the most part, although other ingredients may be included, for example, to improve solubility. Injectable solutions, for example, can be prepared in such a way that the vehicle comprises saline solution, glucose solution or a mixture of saline and glucose. Injectable suspensions may also be prepared using suitable liquid carriers, suspending agents and the like. Also included are preparations in solid form intended to be converted, rapidly before use, to 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 a minor proportion, such that the additives do not introduce an effect significant detrimental effect on the skin. Since the compounds of the invention are small molecules, they are conveniently administered by oral administration by means of their composition with excipients suitable for pharmaceutical use as provided by tablets, capsules, syrups and the like. Formulations suitable for oral administration may also include minor components such as buffers, flavoring agents and the like. Generally, the amount of active ingredient in the formulations will be in the range of 5% -95% of the total formulation, but a wide variation is allowed depending on the vehicle. Suitable carriers include sucrose, pectin, magnesium stearate, lactose, peanut oil, olive oil, water and the like. The compounds useful in this invention can also be administered by suppositories or other transmucosal vehicle. Generally, such formulations will include excipients that facilitate the passage of the compound through the mucosa such as detergents acceptable for pharmaceutical use. The compounds can also be administered topically, for topical conditions such as psoriasis, or in formulations intended to penetrate the skin. These include lotions, creams, ointments and the like, which can be formulated by known methods. The compounds can also be administered by injections, including intravenous, intramuscular, subcutaneous or intraperitoneal injection. The general formulations for such a luso are liquid formulations in isotonic vehicles such as Hank's solution or solution of Ringer The compounds of the present invention can also be administered orally by inhalation or insufflation by means of methods and formulations employed in the art for administration by this manner.

Thus, the compounds in general of the present invention can be administered in the lungs in the form of a solution, suspension or dry powder, the solution being the preferred form. Any system developed for the administration of solutions, suspensions or dry powders by means of oral inhalation or insufflation suitable for the administration of the present compound. Thus, the present invention also provides a pharmaceutical composition adapted for administration by inhalation or insufflation through the mouth comprising a compound of formula (1) 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. Alternative formulations include nasal sprays, liposomal formulations, slow release formulations and the like, as are known in the art. Any suitable formulation can be used. A compendium of formulations known in the art is found in Remington's Pharmaceutical Sciences, latest edition, Mack Publishing Company, Easton, PA. Reference to this manual is common in the art. It is especially advantageous to formulate the pharmaceutical compositions mentioned above in unit dosage form for ease of administration and uniformity of dosage. Unit dosage forms as used herein refer to discrete units suitable as unit dosages, each unit containing a predetermined amount of active component calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, suppositories, packaged powder, wafers, injectable solutions or suspensions and the like, and segregated multiples thereof. The dosage of the compounds of the invention will depend on many factors that will vary from patient to patient. However, it is generally considered that the oral daily dose will use 0.001-100 mg / kg total body weight, preferably 0.01-50 mg / kg and more preferably about 0.01 mg / kg-10 mg / kg. The dosage regimen will vary, however, depending on the conditions that will be treated and the professional's criteria. In general it is considered that the effective daily amount of an antiviral should be from 0.01 mg / kg to 500 mg / kg body weight, more preferably from 0.1 mg / kg to 50 mg / kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at an appropriate interval throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 1 to 1000 mg, and in particular 5 to 200 mg of active ingredient per unit dosage form. The exact dosage and the frequency of administration depend on the particular compound of formula (I) used, the particular condition being treated, the severity of the disease treated, the age, weight, sex, extent of the disorder and general condition of the patient. in particular, as well as other medication that the individual may be taking, as is known to those skilled in the art. Furthermore, it is clear that said effective daily amount can be decreased or increased according to the response of the treated subject and / or according to the evaluation of the physicians who prescribe the compounds of the present invention. The effective daily amount ranges mentioned above are therefore only guidelines. Due to its favorable antiviral properties, as will be evident in the examples, the compounds of the present invention are useful for the treatment of individuals infected with HCV and for the prophylaxis of these individuals. In general, the compounds of the present invention may be useful for the treatment of warm blooded animals infected with flaviviruses. Conditions that can be prevented or treated with the compounds of the present invention are especially diseases associated with HCV and other pathogenic flaviviruses, such as yellow fever, dengue fever (types 1-4), St. Louis encephalitis, encephalitis. Japanese, Murray Valley encephalitis, West Nile virus and Kunjin virus. Conditions associated with HCV include progressive liver fibrosis, inflammation and necrosis that lead to cirrhosis, end-stage liver disease, and HCC; and for the other pathogenic flaviruses the conditions include yellow fever, dengue fever, hemorrhagic fever and encephalitis. The compounds of the present invention or any of its subgroups can therefore be used as medicines against the diseases mentioned above. Said use as a medicine or method of treatment comprises the systemic administration to subjects infected with HCV of an amount effective to combat the diseases associated with HCV and other pathogenic flaviviruses. Accordingly, the compounds of the present invention can be used in the manufacture of a medicament useful for treating diseases associated with HCV and other pathogenic flaviviruses. In one embodiment, the invention relates to the use of a compound of formula (1) or any of its subgroups as defined herein for the manufacture of medicaments for treating or combating infections or diseases associated with HCV infection in a mammal. This invention also relates to a method for treating flaviviral infection, or a disease associated with flavivirus infection, comprising administering to an mammal in need thereof an effective amount of a compound of formula (1) or its subgroup such as was defined herein. In another embodiment, the present invention relates to the use of the formula (1) or any of its subgroups as defined herein for the manufacture of a medicament useful for the inhibition of HCV activity in a mammal infected with flavivirus. , in particular HCV. In another embodiment, the present invention relates to the use of the formula (1) or any of its subgroups as defined herein for the manufacture of a medicament useful for the inhibition of HCV activity in a mammal infected with flavivirus, where HCV is inhibited in its replication.

It must be taken into account that the compounds of formula (1) are can be administered as individual active components, or as mixtures of several modalities of this formula. The compounds of the invention can be used as sole therapeutic agents or in combination with other therapeutic agents.

As such, the combination of the anti-HCV compounds previously known, such as, for example, interferon-a (IFN-a), Pegylated interferon-a and / or ribavirin, and a compound of the present invention can be used as a medicine in combination therapy. The term "combination therapy" refers to products that contain (a) a compound of the present invention, and (b) optionally another anti-HCV compound, as a combined preparation for simultaneous, separate or sequential use in the treatment of infections with HCV, in particular for the treatment of infections with HCV type 1. Thus, to combat or treat infections with HCV, the compounds of This invention can be co-administered in combination with, for example, interferon-a (IFN-a), pegylated interferon-a and / or ribavirin, as well as therapies based on antibodies directed against HCV epitopes, small RNA interference (if RNA), ribozymes, DNAzymes, antisense RNA, I small antagonist molecules of, for example, the protease NS3, helicase NS3 and polymerase NS5B.

Accordingly, the present invention relates to the use of a compound of formula (1) or any of its subgroups as defined herein for the manufacture of a medicament useful for the inhibition of HCV activity in a mammal infected with the HCV virus, wherein said medicament is used for combination therapy, said combination therapy preferably comprising a compound of formula (1) and IFN-a (pegylated) and / or ribavirin, and poly an anti-HIV compound. The person skilled in the art will appreciate that the compounds of formula (1) can be tested in cellular HCV replicon systems 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 will be exemplified later in the Examples section. This model, although not for complete HCV infection, is widely accepted as the most robust and efficient model of autonomous replication of currently available HCV RNA Compounds that exhibit anti-HCV activity in this cellular model are considered as candidates for the subsequent development for the treatment of HCV infections in mammals. It will be considered 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 as a consequence cause a decrease in HCV RNA or concentration of the linked indicator enzyme. Assays j are known in this field for the evaluation of cellular cytotoxicity based, example, in the activity of mitochondrial enzymes using dyes Fluorogenic redox such as resazurin. In addition, there are counter-controls of cells for the evaluation of inhibition no | selective activity of linked indicator gene, such as firefly luciferase. The cell types can be prepared by stable transfection with a gene Luciferase indicator, whose expren depends on a promoter gene constitutively active, and such cells can be used as countercontrol to eliminate non-selective inhibitors. All patents, applications, patents and articles mentioned above or below are incorporated by reference herein.

EXAMPLES The following examples are intended to illustrate this invention and not to limit it to them.

EXAMPLE 1 Activity of the compounds of formula (1) in HCV replicon assays Stable replicon indicators cellular samples: The compounds of the present invention were examined for determine the activity of inhibiting the replication of HCV RNA in a cellular assay. The test showed that 'the present compounds presented activity against the functional replicons of HCV in a culture cell phone. The cellular assay was based on the expression of a construction bicetronics, as described by Lohmann et al.! (1999) Science vol. 285 pp. 110-113 with modifications described by Kriéger et al. (2001) Journal of Virology 75: 4614-4624, in a multi-objective detection strategy. In essence, the method was the following. The assay used the stably transfected cell line Huh-7 luc / neo (hereinafter referred to as Huh-Luc). This cell line contained an RNA that encoded a bicistronic expression construct comprising NS3-NS5B wild type HCV type 1 b regions Translated from an Internal Ribosome Entry Site (IRES) of the I encephalomocarditis virus (VEC), preceded by a portion of the reporter gene (FfL-luciferase) and a selectable marker portion (neoR, neomycin phosphotransferase). The construction was limited by RNTs (non-translated regions) 5 'and 3' of HCV type 1 b. The cultivation! The continuation of replicon cells in the presence of G418 (neoR) was dependent on the replication of HCV RNA. The stably transfected replicon cells expressing the HCV RNA, which replicated autonomously and at high levels, coding, among others, the luciferase, were used for the selection of the antiviral compounds.

Experimental method of the cell assay: The replicon cells were placed in 384-well plates in the presence of the control and test compounds, which were added in different concentrations. After a three-day incubation, HCV replication was measured by means of a luciferase activity assay (using standard, substrates and reagents from the luciferase assay and the Perkin Elmer ViewLuxT ultraHTS microplate reader). The replicon cells from the control cultures had high luciferase expression in the absence of any inhibitor. The inhibitory activity of the compound on the luciferase activity was myonitored on the Huh-Luc cells, allowing the realization of a dose-response curve for each compound. The EC50 values were then calculated, value representing the amount of compound required to decrease to 50% the level of the luciferase activity detected or, more specifically, the ability of the replicon of the genetically linked HCV RNA to replicate. In the following table, column 1 provides an identification number, column 2 shows the results of the Huh7-Luc test described above. 10

Claims (1)

1. NOVELTY OF THE INVENTION i CLAIMS 1. - The use of the compound of formula or its salt acceptable for pharmaceutical use; where 'the fused ring which is linked via a bridge to the 5 and β positions of the pyrimidine ring is I an aromatic or unsaturated or saturated, optionally substituted ring containing 4-7 members, where X is an atom selected from N, O or S; n is 0, 1, 2 or 3; Ar1 and A 2 is independently an optionally substituted aromatic radical or an optionally substituted heteroaromatic radical, wherein said heteroaromatic radical contains one or more O, S, and / or i. N, and this aromatic or heteroaromatic radical contains 5-12 members; R is i H, or optionally substituted alkyl (1-10C), alkenyl (2-10C), or alkynyl (2-1 OC); with the proviso that if said fused ring joining by means of a bridge the positions 5 and 6 of the pirirmidine ring contains 6 members, it is not an aromatic ring; for the manufacture of a medicament useful for inhibiting the activity of HCV in a mammal infected with HCV. 2 - . 2 - The use of the compound of formula or its salt acceptable for pharmaceutical use; wherein the fused ring that is bonded via a bridge to positions 5 and 6 of the pyrimidine ring is an optionally substituted saturated or unsaturated or saturated ring containing 5-6 members, where: X is an atom selected from N or O; n is 0, 1, or 2; R1 is H, or optionally substituted alkyl (1-6C); each R3 is, independently, hydrogen, halo, cyano, nitro, alkyl (1-6C), polyhaloalkyl (1-6C), -COR, -CONR2, -COOR, -OR, -OCOR, -NR2 or -NRCOR; each R 4 is, independently, hydrogen, halo, cyano, nitro, polyhaloalkyl (1-6 C) or (1-6C) alkyl; wherein each R is independently hydrogen, hydroxy, amino, mono- or dialkylamino (1-6C), cycloalkyl (3-7C), Het, or (1-6C) alkyl optionally substituted with one or more substituents selected from hydroxy, cycloalkyl ( 3-7C), amino, mono- or dialkyl amino (1-6C), and Het; Het is a 5 or 6 membered heterocyclic ring saturated, partially unsaturated or completely unsaturated containing 1 to 2 heteroatoms, each independently selected from nitrogen, oxygen and sulfur, and where the Het group as a whole may optionally be substituted with one, two or three substituents independently selected from the group consisting of halo, (1-6C) alkyl, hydroxy and oxo; with the proviso that if said fused ring joining by means of a bridge the positions 5 and 6 of the pyrimidine ring contains 6 members, it is not an aromatic ring; for the manufacture of a medicament useful for inhibiting HCV activity, preventing or treating diseases associated with HCV, in a mammal infected with HCV. I 3.- The use of a compound of formula or its salt acceptable for pharmaceutical use; wherein the fused ring linking by means of a bridge the positions 5 and 6 of the pyrimidine ring together with the pyrimidine ring forms a group selected from wherein any of these groups may be optionally substituted with one or two substituents selected from alkyl (1-6C), phenyl and benzyl; R3 is hydrogen, halo, (1-6C) alkyl, -CF3, -COR, -CONR2, or -COOR; each R 4a and R b is independently hydrogen or halo; wherein each R is independently hydrogen, hydroxy, amino, mono- or dialkylamino (1-6C), amino, cycloalkyl (3-7C), Het, or (1-6C) alkyl optionally substituted with; one or more substituents selected from hydroxy, cycloalkyl (3-7C), amino, mono- or dialkyl amino (1-6C), and Het; Het is a group selected from wherein the Het group may be optionally substituted with one or two substituents independently selected from the group consisting of (1-6C) alkyl and oxo; for the manufacture of a medicament useful for inhibiting HCV activity, preventing or treating diseases associated with HCV, in a mammal infected with HCV. 4. The use claimed in any of claims 1 to 3, wherein the compound is I 5. - The use claimed in any of claims 1 to 3, wherein the compound is of claims 1 to 3, wherein the compound is 7. - The use claimed in any of claims 1 to 3, wherein the compound is 1 8. - The use claimed in any of claims 1 to 3, wherein the compound is 9. - The use claimed in any of claims 1 to 3, wherein the compound is 10. - The use claimed in any of claims 1 to 3, wherein the compound is 11. - The use claimed in any of claims 1 to 3, wherein the compound is 12. - The use claimed in any of claims 1 to 3, wherein the drug is useful for preventing the progression of the disease to chronic hepatitis, liver fibrosis, cirrhosis, terminal liver disease, HCC (hepatocellular carcinoma) and the like , in a mammal infected with HCV. 13. The use claimed in any of claims 1 to 3, wherein the medicament is useful for treating chronic hepatitis, cirrhosis, end-stage liver disease, HCC (hepatocellular carcinoma) and the like, in a mammal infected with VHC.