ES2394436T3 - Aminopyrimidine 4,6-pharmaceutically active disubstituted derivatives as protein kinase modulators - Google Patents

Abstract

Compounds having the general formula (I) wherein R1, R2 and R4 are each -HR3 is a substituted phenylR5 is a substituted or unsubstituted phenylR6 is selected from the group consisting of: -H, C1-C8 linear or branched alkyl, substituted or unsubstituted, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryls, substituted or unsubstituted heterocyclyl, substituted or unsubstituted pyrrolidinyl, C3-C8 substituted or unsubstituted cycloalkyl, disubstituted cyclohexyl, cyclopentyl, C5-C12 substituted or unsubstituted cycloalkyl, adamantyl group (CH2) q- substituted or unsubstituted, being that an integer from 1 to 3 under the proviso that R6 is selected as a methylene chain from the group - (CH2) q-, R17 or R19 are selected to be a methylene chain from the group - (CH2) s-, where s is an integer from 1 to 3 or a group - (CH2) tA-, t is an integer from 1 to 3 and A is selected from O or N, respectively, and R6 and R17 or R6 and R19 together form a 5 or 8 member ring system ros, or R6 represents - (CH2) pZ, wherein p is an integer from 0 to 6 and Z selected from the group comprising: substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, -N (R7R8 ), wherein R7 and R8 independently represent each other -H, or C1-C6 substituted or unsubstituted linear linear alkyl, or Z is selected from - (CR9R10R11), where R9, R10 and R11 are independently selected from each other. group consisting of: -H, linear or branched, C1-C8 substituted or unsubstituted alkyl, substituted or unsubstituted aryl or -N (R12R13), wherein R12 and R13 independently represent each other -H or C1-C6 linear or branched alkyl substituted or unsubstituted, under the exception that if Z represents - (CR9R10R11) as defined above, p is selected to be an integer from 0 to 6, and if Z is selected from substituted or unsubstituted aryl, substituted or substituted heteroaryl, substituted heterocyclyl or unsubstituted or -N (R7R8) as defined above, p is selected to be an integer from 1 to 6; L is selected from the group comprising: -NR14-SO2-, -NR14-SO-, where R14 is selected from -H, C1-C6 substituted or unsubstituted linear or branched alkyl, -SO2-R15 or -R15-SO2-, wherein R15 is selected from C1-C6 alkyl or C1-C6 linear or branched substituted alkylene substituted ono, or R14 represents a - (CH2) r-COOR16, where r is an integer from 0 to 6 and R16 selected from -Ho C1-C6 substituted or unsubstituted linear or branched alkyl.

Description

[0001] The present invention relates to 4,6-disubstituted aminopyrimidine derivatives and / or pharmaceutically acceptable salts thereof, the use of said derivatives as pharmaceutical agents, especially for the prevention and / or treatment of infectious diseases, including opportunistic diseases, prion diseases, immune diseases, autoimmune diseases, bipolar and clinical disorders, cardiovascular diseases, cell proliferation diseases, diabetes, inflammations, transplant rejections, erectile dysfunction, neurodegenerative diseases and cerebral stroke. In addition, the present invention is directed towards pharmaceutical compositions containing at least one of the 4.6 disubstituted aminopyrimidine derivatives and / or pharmaceutically acceptable salts thereof.

[0002] One of the most important and fundamental processes in biology is the division of cells during the cell cycle. This process ensures the controlled production of later generations of cells with biologically defined functions. It is a highly regulated phenomenon and responds to a diverse series of cellular signals both within the cell and from external sources. Cyclin-dependent kinases (CDK) play a key role in cell cycle regulation. These complexes consist of two components: a catalytic subunit (the kinase) and a regulatory subunit (the cyclin). To date, eleven kinase subunits have been identified ((S. Mani et al., Exp. Opin. Invest. Drugs 2000, 9 (8), 1849-1870, JC Sergere et al., Biochem. Biophys. Res Commun. 2000, 276, 271-277, D. Hu et al, J. Biochem. Chem. 2003, 278 (10), 8623-8629).

[0003] It is known that CDKs play a role in the regulation of cell proliferation. Therefore, CDK inhibitors could be useful in the treatment of proliferative cell disorders such as cancer, neurofibromatosis, psoriasis, fungal infections, endotoxic shock, transplant rejection, vascular smooth cell proliferation associated with arteriosclerosis, pulmonary fibrosis , arthritis, glomerulonephritis and post surgical stenosis and restenosis (US Patent No. 6,114,365). It is also known that CDKs play a role in apoptosis. In this case, CDK inhibitors could be useful in the treatment of cancer, autoimmune diseases such as systemic lupus erythematosus, autoimmune glomerlulonephritis, rheumatoid arthritis, psoriasis, inflammatory bowel diseases and autoimmune diabetes and neurodegenerative diseases such as Alzheimer's disease, AIDS-associated dementia, amyotrophic lateral sclerosis, pigmentary retinitis, spinal muscular atrophy and cerebellar degeneration; myelodysplastic syndromes, aplastic anemia, ischemia lesions associated with myocardial infarction, stroke and reperfusion lesions, arrhythmias, atherosclerosis, liver lesions caused by toxins or alcohol; hematological lesions such as chronic anemia and aplastic anemia, degenerative lesions of the musculoskeletal system, such as osteoporosis and arthritis, cystic fibrosis, multiple sclerosis, kidney diseases and cancer pains, and for the treatment of cardiovascular diseases (US Pat. No. 6,107,305 and WO 02/100401). It is also known that CDK inhibitors could be used for the treatment of infectious diseases caused by viruses, such as EBV, HBV, HCV, HIV (WO 02/100401).

[0004] It was recently described that HIV-1 replication could be affected by CDK inhibitors (C. de la Fuenta, Current HIV research, 2003, 1 (2), 131-152; YK Kim et al., Molecular and Cellular Biology, 2002, 22 (13), 4622-4637). According to reports, especially CDK 9 is essential for HIV-1 replication (HS Mancebo et al, Genes Dev. 1997, 11 (20): 2633-44, O. Flores et al., Proc Natl. Acad. Sci. US A. 1999, 6 (13): 7208-13).

[0005] Most CDK inhibitors, such as olomoucin, roscovitine, CYC202, purvalanol, indolinone, paullones and 7-hydroxy-staurosporine, are aimed at inhibiting CDK1 and CDK2 in order to Create antitumor activity. (Current opinion in Pharmacalogy, 2003, 3, 1-9). M. Huwe et al. (A.Huwe et al., Angew Chem Int Ed Engl. 2003; 42 (19): 2122-38) offers a glossary of known CDK inhibitors. Flavopyridol is considered low molecular weight, but not selective for CDK, including CDK9 (W. Filgueira de Azevedo et al., Biochem.and Biophys. Res. Commun. 2002, 293 (1), 566-571). Other compounds that have been shown to inhibit CDKs include staurosporine, fascaplisin and hymenialdisin.

[0006] The use of derived 4-aminopyrimidine as a neuroprotective agent is described in WO 02/12198. These compounds generally contain as a basic residue a substituted amine in position for the aniline part of the molecule, and it is proven that these compounds do not inhibit MEK ½ kinase activity in P19 neurons. U.S. Patent No. 3,950.25 describes the use of 4-amino-6-aryl-irimidine as inhibitors of platelet aggregation and bronchodilators. U.S. Patent No. 3,478,030 describes the synthesis of the benzamide substituted anilinoaminopyrimidine derivatives. These compounds are used as potent dilators of the coronary arteries. WO 02/79197 describes the use of arylsubstituted derivatives of 2-aminopyrimidines as protein kinase inhibitors, for example as an inhibitor of JNK, GSK-3, Src, Lck or CDK2.

[0007] There is a great unmet medical need to develop CDK inhibitors, which are useful in treating various conditions associated with the activation of CDKs, in particular in relation to the activity of CDK9 kinase that is associated with HIV replication.

[0008] It is an object of the present invention to provide pharmaceutically acceptable compounds and / or salts thereof that can be used as active pharmaceutical agents, especially for the prevention and / or treatment of infectious diseases, including opportunistic diseases, cryonic diseases, immune diseases. , autoimmune diseases, bipolar and clinical disorders, cardiovascular diseases, cell proliferation diseases, diabetes, inflammations, transplant rejections, erectile dysfunction, neurodegenerative diseases and cerebral stroke, treatment methods for said diseases, as well as compositions including at least one of these compounds and / or pharmaceutically acceptable salts thereof as pharmaceutical active ingredients. Another objective of the present invention is to provide a means and method that are capable of enriching especially nucleotide binding proteins such as kinase proteins from a protein source such as a proteome, a cell lysate or a tissue lysate.

[0009] This objective is met with the compounds and / or a pharmaceutically acceptable salt thereof according to independent claim 1, the compounds of the present invention for use as active pharmaceutical agents according to independent claim 21, the use of the compounds of the present invention for the preparation of a pharmaceutical composition for the prevention and / treatment of infectious diseases, including opportunistic diseases, prion diseases, immune diseases, autoimmune diseases, bipolar and clinical disorders, cardiovascular diseases, cell proliferation diseases, diabetes, inflammations, transplant rejections, erectile dysfunction, neurodegenerative diseases and cerebral stroke, the use of compounds according to the present invention as protein kinase inhibitors in pharmaceutical compositions, the medium according to claim 45, and a method to enrich, purify ar or reduce nucleotide binding proteins.

[0010] Other advantageous features, aspects and details of the invention are evidenced in the dependent claims, the description, the examples and the drawings.

[0011] The novel 4,6-disubstituted aminopyrimidine compound according to the present invention is defined by the general formula (I)

wherein R1, R2 and R4 are each -H R3 is a substituted phenyl R5 is a substituted or unsubstituted phenyl R6 is selected from the group consisting of:

-

H, C1-C8 linear or branched, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted pyrrolidinyl, C3-C8 substituted or unsubstituted cycloalkyl, desistuted cyclohexyl, cyclopentyl, C5-C12 substituted or unsubstituted bicycloalkyl, adamantyl of the group - (CH2) q- substituted or unsubstituted, being an integer from 1 to 3 under the proviso that if R6 is selected as a methylene chain of the group - (CH2) q-, R17 or R19 must be a methylene chain of the group - (CH2) s-, in which s is an integer from 1 to 3 or a group - (CH2) tA-, t is an integer from 1 to 3 and A is selected from O or N, respectively, and R6 and R17 or R6 and R19 together form a 5 or 8 member ring system, or R6 represents - (CH2) pZ, where p is an integer from 0 to 6 and Z selected from the group consisting of:

Substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl,

-

N (R7R8), representing R7 and R8 independently of each other at -H, or C1-C6 linear or branched alkyl substituted or unsubstituted, or Z being selected from - (CR9R10R11), R9, R10 and R11 being independently selected from yes from the group consisting of:

-

H, linear or branched, C1-C8 substituted or unsubstituted alkyl, substituted or unsubstituted aryl or -N (R12R13), R12 and R13 independently representing each other at -H or C1-C6 linear or branched alkyl, substituted or not substituted, under the proviso that Z represents - (CR9R10R11) as defined above, p must be an integer from 0 to 6, and if Z is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl or -N (R7R8) as defined above, p is selected as an integer from 1 to 6;

-

L is in the meta or para position of the phenyl represented by R5 and is selected from the group consisting of:

-NR14-SO2-, -NR14-SO-,

R14 being selected from -H, C1-C6 linear or branched alkyl, substituted or unsubstituted, -SO2-R15 or -R15-SO2-, R15 being selected from C1-C6 alkyl or C1-C6 linear or branched alkyl, substituted or unsubstituted, or representing R14 to - (CH2) r-COOR16, where r is an integer from 0 to 6 and R16 selected from -H or C1-C6 linear or branched alkyl, substituted or unsubstituted,

NR17 -CO-, R17 being selected from -H, C1-C6 linear or branched alkyl, substituted or unsubstituted, or a group to (CH2) s-, being an integer from 1 to 3, and in which R6 and R17 both represent a methylene chain group, R6 and R17 can together form a 5 or 8 member ring system:

-SO2-NR18-,

R18 being selected from -H, or C1-C6 linear or branched alkyl, substituted or unsubstituted,

-CO-NR19-,

R19 being selected from -H, C1-C6 linear or branched alkyl, substituted or unsubstituted, or a group (CH2) tA-, where t is an integer from 1 to 3 and has selected from N or O, and in which if R6 represents a group - (CH2) q- and R19 represents a group - (CH2) tA-, R6 and R19 can together form a 5 or 8 member ring system

 -NH-CO-NH-, -NH-CS-NH-, -NH-CO-O-,

-CO-, -CO-O-, -SO-, -SO2-, -SO3- or and m is 1, and / or stereoisomeric forms and / or pharmaceutically acceptable salts thereof.

[0012] In another preferred embodiment of the present invention, R6, R6 ', R7, R7' independently represent each other -H, C1-C6 linear or branched alkyl, the aryl group -OR1, -O- (CH2) s , which may optionally be substituted by at least one of the groups R6, R6 ', R7 or R7'; -N (R1) 2, -CH = CH -COOR1 - (CH2) qCOOR1 representing in these cases R1 independently of each other -H or C1-C6 linear or branched alkyl.

[0013] In another embodiment of the present invention, the compound of the present invention defined by a general formula (I) represents a chiral compound. The compound may be racemate or enantiomer of R or S.

[0014] As used in the present invention, the terms C1-C8 linear or branched alkyl, C2-C6 linear or branched alkenyl or C2-C6 aquinyl should include the following alkyls, alkenyls or alkyls:

-

CH3, -C2H5, -C3H7, -CH (CH3) 2, -C4H9, -CH2-CH (CH3) 2, -CH (CH3) -C2H5, -C (CH3) 3, -C5H11, -CH (CH3) -C3H7, -CH2-CH (CH3) -C2H5, -CH (CH3) -CH (CH3) 2, -C (CH3) 2-C2H5, -CH2-C (CH3) 3, -CH (C2H5) 2, -C2H4CH (CH3) 2, -C6H13, -C3H6-CH (CH3) 2, -C2H4-CH (CH3) -C2H5, -CH (CH3) -C4H9, -CH2-CH (CH3) -C3H7, CH (CH3 ) -CH2-CH (CH3) 2, -CH (CH3) -CH (CH3) -C2H5, -CH2-CH (CH3) -CH (CH3) 2, -CH2-C (CH3) 2-C2H5, C ( CH3) 2-C3H7, -C (CH3) 2-CH (CH3) 2, -C2H4-C (CH3) 3, -CH (CH3) -C (CH3) 3, - (CH2) 6-CH3, -CH (CH3) (CH2) 4-CH3, - (CH2) 2 CH (CH3) - (CH2) 2-CH3, - (CH2) 3-CH (CH3) -C2H5, - (CH2) 4-CH (CH3) 2, -C (CH3) 2 (CH2) 3-CH3, -CH2-C (CH3) 2- (CH2) 2-CH3, - (CH2) 2-C, (CH3) 2-C2H5, - (CH2) 4-CH (CH3) 2, - (CH2) 3-C (CH3) 3, -CH (C2H5) - (CH2) 3-CH3, - (CH2) 3-CH (C2H5) -CH3, -C (C2H5 ) 3, -CH2-C (C2H5) 2-CH3, - (CH2) 2-CH (C2H5) 2, -CH (C3H7) - (CH2) 2-CH3, -CH2-CH (C3H7) -C2H5, - (CH2) 2-CH (C3H7) -CH3, - (CH2) 7-CH3, -CH (CH3) - (CH2) 5-CH3, - (CH2) 2-CH (CH3) - (CH2) 3-CH3 , - (CH2) 3-CH (CH3) - (CH2) 2-CH3, - (CH2) 4-CH (CH3) -C2H5, - (CH2) 5CH (CH3) 2, - (CH2) 4-C ( CH3) 3, -CH (C2H5) - (CH2) 4-CH3, - (CH2) 2-CH (C2H5) - (CH2) 2-CH3, - (CH2) 3CH (C2H5) 2, -CH (C3H7) - (CH2) 3-CH3, -CH2-CH (C3H7) - (CH2) 2-CH3, - (CH2) 2-CH (C3H7) -C2H5, - (CH2) 3-CH (C3H7) -CH3, -CH = CH2, -CH2-CH = CH2, -C (CH3) = CH2, -CH = CH-CH3, -C2H4-CH = CH2, -CH2-CH = CH-CH3, - CH = CH-C2H5, -CH2-C (CH3) = CH2, -CH (CH3) -CH = CH, -CH = C (CH3) 2, C (CH3) = CH-CH3, -CH = CH-CH = CH2, -C3H6-CH = CH2, -C2H4-CH = CH-CH3, -CH2-CH = CH-C2H5, -CH = CH-C3H7, -CH2-CH = CH-CH = CH2, -CH = CHCH = CH-CH3, -CH = CH-CH2-CH = CH2, -C (CH3) = CH-CH = CH2, -CH = C (CH3) -CH = CH2, -CH = CH-C (CH3) = CH2, -C2H4-C (CH3) = CH2, -CH2-CH (CH3) -CH = CH2. -CH (CH3) -CH2-CH = CH2, -CH2 CH = C (CH3) 2, -CH2-C (CH3) = CHCH3, -CH (CH3) -CH = CH-CH3, -CH = CH-CH (CH3) 2, -CH = C (CH3) -C2H5, C (CH3) = CH-C2H5, -C (CH3) = C (CH3) 2, -C (CH3) 2-CH = CH2, -CH ( CH3) -C (CH3) = CH2, -C (CH3) = CH-CH = CH2, -CH = C (CH3) -CH = CH2, -CH = CH-C (CH3) = CH2, -C4H8-CH = CH2, -C3H6-CH = CH-CH3, -C2H4-CH = CH-C2H5, -CH2-CH = CH-C3H7, -CH = CH-C4H9, -C3H6-C (CH3) = CH2, -C2H4- CH (CH3) -CH = CH2, -CH2-CH (CH3) -CH2-CH = CH2, -CH (CH3) -C2H4-CH = CH2, - C2H4-CH = C (CH3) 2, -C2H4-C (CH3) = CH-CH3, -CH2-CH (CH3) -CH = CH-CH3, -CH (CH3) CH2-CH = CH-CH3, -CH2-CH = CH-CH (CH3) 2, -CH2 -CH = C (CH3) -C2H5, CH2-C (CH3) = CH-C2H5, -CH (CH3) -CH = CH-C2H5, -CH = CH-CH2-CH (CH3) 2, -CH = CH -CH (CH3) -C2H5, -CH = C (CH3) -C3H7, -C (CH3) = CH-C3H7, -CH2-CH (CH3) -C (CH3) = CH2, -CH (CH3) -CH2 -C (CH3) = CH2, -CH (CH3) -CH (CH3) -CH = CH2, -CH2-C (CH3) 2-CH = CH2, C (CH3) 2-CH2-CH = CH2, -CH2 -C (CH3) = C (CH3) 2, -CH (CH3) -CH = C (CH3) 2, -C (CH3) 2-CH = CH-CH3, -CH (CH3) -C (CH3) = CH-CH3, -CH = C (CH3) -CH (CH3) 2, -C (CH3) = CHCH (CH3) 2, -C (CH3) = C (CH3) -C2H5, -CH = CH-C ( CH3) 3, -C (CH3) 2-C (CH3) = CH2, -CH (C2H5) C (CH3) = CH2, -C (CH3) (C2H5) -CH = CH2, -CH (CH3) -C (C2H5) = CH2, -CH2-C (C3H7) = CH2. -CH2C (C2H5) = CH-CH3, -CH (C2H5) -CH = CH-CH3, -C (C4H9) = CH2, -C (C3H7) = CH-CH3, -C (C2H5) = CH-C2H5, C (C2H5) = C (CH3) 2, -C [C (CH3) 3] = CH2, -C [CH (CH3) (C2H5)] = CH2, -C [CH2-CH (CH3) 2] = CH2 , -C2H4-CH = CH-CH = CH2, -CH2-CH = CH-CH2-CH = CH2, -CH = CHC2H4-CH = CH2, -CH2-CH = CH-CH = CH-CH3, -CH = CH-CH2-CH = CH-CH3, -CH = CH-CH = CH-C2H5, -CH2-CH = CH-C (CH3) = CH2, -CH2-CH = C (CH3) -CH = CH2, - CH2-C (CH3) = CH-CH = CH2, -CH (CH3) -CH = CH-CH = CH2, -CH = CHCH2-C (CH3) = CH2, -CH = CH-CH (CH3) -CH = CH2, -CH = C (CH3) -CH2-CH = CH2. -C (CH3) = CH-CH2-CH = CH2, -CH = CH-CH = C (CH3) 2, -CH = CH-C (CH3) = CH-CH3, -CH = C (CH3) -CH = CH-CH3, -C (CH3) = CH-CH = CH-CH3, -CH = C (CH3) -C (CH3) = CH2, -C (CH3) = CH-C (CH3) = CH2, - C (CH3) = C (CH3) -CH = CH2, -CH = CH-CH = CH-CH = CH2, -C: CH, -C: C-CH3, -CH2-C: CH, -C2H4-C : CH, -CH2-C: CH3, -C: C-C2H5, -C3H6-C: CH, -C2H4-C: CH3, CH2-C: C-C2H5, -C: C-C3H7, -CH (CH3 ) -C: CH, -CH2-CH (CH3) -C: CH, -CH (CH3) -CH2-C: CH, -CH (CH3) C: C-CH3, -C4H8-C: CH, -C3H6 -C: CH3, -C2H4-C: C-C2H5, -CH2-C: C-C3H7, -C: C-C4H9, -C2H4-CH (CH3) -C: CH, -CH2-CH (CH3) - CH2-C: CH, -CH (CH3) -C2H4-C: CH, -CH2-CH (CH3) -C: C-CH3, -CH (CH3) -CH2-C: C-CH3, -CH (CH3 ) -C: C-C2H5, -CH2-C: C-CH (CH3) 2, -C: C-CH (CH3) -C2H5, -C: C-CH2-CH (CH3) 2, C: CC ( CH3) 3, -CH (C2H5) -C: C-CH3, -C (CH3) 2-C: C-CH3, -CH (C2H5) -CH2-C: CH, -CH2-CH (C2H5) -C : CH, -C (CH3) 2-CH2-C: CH, -CH2-C (CH3) 2-C: CH, -CH (CH3) -CH (CH3) -C: CH, -CH (C3H7) - C: CH, -C (CH3) (C2H5) -C: CH, -C = CC = CH, -CH2-C: CC: CH, -C: CC: C-CH3, -CH (C: CH) 2 , -C2H4-C: CC: CH, CH2-C: C-CH2-C: CH. -C: C-C2H4-C: CH, -CH2-C: CC: C-CH3, -C: C-CH2-C: CCH3, -C: CC: C-C2H5, -C: C-CH (CH3 ) -C: CH, -CH (CH3) -C: CC: CH, -CH (C: CH) -CH2-C: CH, C (C: CH) 2-CH3, -CH2-CH (C: CH ) 2, -CH (C: CH) -C: C-CH3, -C: C-CH = CH2, -CH = CH-C: CH, -CH2-C: C-CH = CH2, -CH2-CH = CHC: CH, -C: C-CH = CH-CH3, -CH = CH-C: C-CH3, -C: C-CH2-CH = CH2, -CH = CH-CH2-C: CH, - C: C-CH2 C: CH, -C (CH3) = CH-C: CH, -CH = C (CH3) -C: CH, -C: CC (CH3) = CH2, and C: CC: CC: CH .

[0015] The term C1-C6 substituted or unsubstituted alkyl, linear or branched, or C2-C4 linear or branched alkenyl includes the respective subgroups of the groups mentioned above.

[0016] The term C3-C8 cidoalkyl denotes the following cidoalkyl:

[0017] The term C5-C12 bicycloalkyl should include the following bicycloalkyl:

[0018] The term aryl denotes an aromatic 6 or 10-membered mono- or bicyclic aromatic ring system such as phenyl, naphthyl, 3-chlorophenyl, 2,6-dibromophenyl, 2,4,6-tribromophenyl, 4,7-dichloronaphthyl , and preferably phenyl or naphthyl.

[0019] The term "heterocycle" should include a 5- or 10-membered mono- or bicyclic ring system, containing one to three heteroatoms independently selected from oxygen, sulfur or nitrogen and is preferably selected from the group consisting of: aciridinyl, acetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperadizinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl or morpholinyl.

[0020] The term heterocyclyl is further composed of all heteroaryls as defined below, all double bonds of the corresponding heteroaryls being substituted by single bonds.

[0021] The term "heteroaryl" denotes a partially or totally unsaturated 5- or 10-membered mono- or bicyclic ring system containing one to three heteroatoms independently selected from oxygen, sulfur.

or nitrogen and is preferably selected from the group consisting of:

Pyrrolyl, furanyl, thiophenyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyridinyl, pyridyl, pyrimidinyl, pyrimidyl, pyrazinyl, pyrazyl, pyradizinyl, piradizilo, 3-methylpyridyl, benzothienyl, 4etilbenzotienilo, 3,4-diethylfuranyl, pyrrolyl, tetrahydroquinolyl, quinolyl, tetrahydroisoquinolinyl, isoquinolinyl, benzoimidazolyl, benzothiazolyl, benzooxizolyl, benzo [1,3] dioxolyl, indolyl, benzofuranyl, benzothiophenyl, indazolyl or chrom-2-onyl.

[0022] It is understood that the term heteroaryl is also composed of a ring system of 5 to 10 partially unsaturated membranes, in which one to 4 double bonds of the ring system are replaced by a single bond and containing the ring system At least one double bond.

[0023] In another preferred embodiment of the present invention, R3 and R5 in the compounds according to the general formula (I) represent the phenyl, each phenyl being partially or totally independently substituted with each other with members selected from the group consisting of :

C1-C6 substituted or unsubstituted linear or branched alkyl, preferably C1-C4 substituted or unsubstituted linear or branched alkyl, more preferably -CH3, C1-C6 linear or branched alkoxy, preferably C1-C4 linear or branched alkoxy, more preferably - OCH3, -O- (CH2) u-phenyl, being an integer from 0 to 6, preferably from 0 to 4, more preferably from 0 to 2, -NR20R21, R20 and R21 being independently selected from each other from -H or C1-C6 substituted or unsubstituted linear or branched alkyl, more preferably between -H or C1-C4 substituted or unsubstituted linear or branched alkyl, and more preferably even -H, -COOR22, R22 representing C1-C6 linear or branched alkyl substituted or unsubstituted, preferably C1-C4 linear or branched alkyl substituted or unsubstituted, more preferably -CH3, or the phenyl is substituted with heteroaryl selected from benzoimidazolyl, benzothiazolyl or benzoxazolyl and each phenyl being preferent It is mono-, di- or trisubstituted, more preferably mono- or disubstituted.

[0024] In another preferred embodiment of the present invention, R 3 in the compounds according to the present invention replaces the phenyl, the phenyl being substituted in this embodiment partially or totally with members of the group consisting of:

-

F, -Cl, -Br, -I, preferably -F or -Cl, -CN, -NO2, C1-C6 substituted or unsubstituted linear or branched alkyl, preferably C1-C4 substituted or unsubstituted linear or branched alkyl, C2 -C6 linear or branched alkenyl, preferably C2-C4 linear or branched alkenyl, substituted or unsubstituted phenyl, preferably unsubstituted phenyl, C1-C6 linear or branched alkoxy, preferably C1-C4 linear or branched alkoxy, -O- (CH2) vR, v being an integer from 0 to 6, preferably from 0 to 4 and R being selected from the group consisting of: Phenyl, -O-phenyl, C1-C4 linear or branched haloalkyl substituted or unsubstituted, heterocyclyl, or -NR23R24, R23 and R24 being independently selected from each other from -H or C1-C6 substituted or unsubstituted linear or branched alkyl, preferably from -H or C1-C4 substituted or unsubstituted linear or branched alkyl, C1-CS linear or branched haloalkyl, preferably C1-C4 linear or branched haloalkyl, C1-C6 linear or branched thioalkyl, preferably C1-C4 linear or branched thioalkyl, - (CH2) wQ, where w is selected as an integer from 0 to 6, preferably from 0 to 4 and Q being selected from heterocyclyl, -OH, -NR25R26, where R25 is and R26 independently selected from each other from -H, C1-C6 substituted or unsubstituted linear or branched alkyl, preferably -H or C1-C4 substituted or unsubstituted linear or branched alkyl, or - (CH2) and -OCH3, being and selected as an integer from 0 to 6, preferably from 0 to 4, or representing Q to C1-C6 linear or branched alkoxy, preferably C1-C4 linear or branched alkoxy, - (CH2) and-COR27, being and an integer from 0 to 6, preferably from 0 to 4, and R27 being selected from the group consisting of: -H, C1-C6 substituted or unsubstituted linear or branched alkyl, preferably C1-C4 substituted or unsubstituted linear or branched alkyl, -OR28, R28 being selected from -H or C1-C6 substituted linear or branched alkyl or unsubstituted, preferably C1-C4 linear or branched alkyl substituted or unsubstituted, or R28 being selected from -NR29R30, R29 and R30 being independently selected from each other from -H, C1-C6 alkyl or C3-C8 linear or branched cycloalkyl substituted or unsubstituted, preferably between -H, C1-C4 alkyl or C4-C6 substituted or unsubstituted linear or branched cycloalkyl, -CH = CH-COOH, -CH = CH-COOCH3 or -NH-T-R31, T being selected between -CO- or -SO2 and R31 representing C1-C6 substituted or unsubstituted linear or branched alkyl, preferably C1-C4 linear or branched alkyl, and the mono-, di- or trisubstituted phenyl, preferably mono- or disubstituted, and being particularly preferred within this embodiment that the phenyl is substituted with the members of the group consisting of: -F, -Cl, -CN, -C2H5, -CH (CH3) 2, -CH = CH2, -OCH3, -OC2H5, -OCH (CH3) 2, -O-phenyl, -O-CH2-phenyl, -O (CH2) 2-O-phenyl, -O- (CH2) 2-N (CH3) 2, -O- (CH2) 3-N (CH3) 2, -O- (CH2) 3-NH2, -O CF3, -OH, -CH2-OH, -CH2-OCH3, -SCH3, -NH2, -N (CH3) 2, -CH2-NH2, -CH2-N (CH3) 2, -CH = CH-COOH, - CH = CH-COOCH3, -COOH, (CH2) 2-COOH, -COOCH3, -CF3, phenyl, -C (O) -H, -C (O) -CH3, -C (O) -NH2, -C (O) -NHCH (CH3) 2, -NH-CO-CH3, -NH-SO2-CH3, -CH2-N (CH3) - (CH2) 2-O-CH3,

the phenyl is preferably substituted with -OCH3, -O-CH2-phenyl, -OH, -OCH (CH3) 2 or -NH2.

[0025] In another preferred embodiment of the present invention, R5 in the composition according to the general formula (I) represents substituted or unsubstituted phenyl, preferably unsubstituted phenyl.

[0026] It is especially preferred that R5 in the compounds according to the general formula (I) represents a substituted phenyl, that the phenyl is partially- or totally substituted with C1-C6 linear or branched alkyl substituted or unsubstituted, preferably with C1 -C4 linear or branched alkyl substituted or unsubstituted, more preferably with -CH3 or phenyl is partially- or totally substituted with -O- (CH2) or -phenyl, being an integer from 0 to 6, preferably from 0 to 4, more preferably even from 0 to 2, and most preferably it is 1, and the phenyl is preferably monosubstituted.

[0027] In another preferred embodiment of the present embodiment, L in the compounds according to the general formula (I) is selected from the group consisting of:

-

NR14-SO2-, R14 being selected from -H, C1-C4 substituted or unsubstituted linear or branched alkyl, -SO2-R15-, -R15-SO2-, R15 being selected from C1-C4 linear or branched alkylene substituted or not substituted, or representing R14 to - (CH2) r-COOR16, where r is an integer from 0 to 4 and R16 is selected from –H or C1-C4 substituted or unsubstituted branched linear alkyl,

-

NR17-CO-, R17 being selected from -H, C1-C4 substituted or unsubstituted linear or branched alkyl, or a group (CH2) s-, being s an integer from 1 to 3, preferably s must be 1, and being that if R6 represents a group - (CH2) q-, in which q is an integer from 1 to 3, preferably q must be 2 and R17 must represent a methylene chain of the group - (CH2) s-, R6 and R17 should together form a 5 or 8 member ring system, preferably R6 and R17 will together form a 5 member ring system

-SO2-NR18-, R18 being selected from -H or C1-C4 substituted or unsubstituted linear or branched alkyl,

-CO-NR19-, R19 being selected from -H, C1-C4 substituted or unsubstituted linear or branched alkyl, or a group (CH2) tA- in which t is an integer from 1 to 3 and A is selected from N or O, and being that R6 represents a group - (CH2) q- in which q is an integer from 1 to 3, preferably q must be 2 and R19 represent a group - (CH2) t-A-, being t selected 2 and representing A to O, R6 and R19 can together form a system 6-member rings

-NH-CO-NH-, -SO2- or

and within this embodiment it is especially preferred that if R5 represents phenyl, L is preferably in the meta or para position of the phenyl.

[0028] In another preferred embodiment of the present invention, L in the compounds according to the general formula (I) is selected from the group consisting of:

-NR14-SO2-, R14 being selected from -H, - (CH2) 2-CH3, -SO2-R15 or -R15-SO2-, R15 representing C1-C4 linear or branched substituted or unsubstituted alkylene or - (CH2) 2-CH3, or - (CH2) r-COOR16, where r selected as an integer from 0 to 2, preferably 1, and representing R16 to -CH3, -NR17-CO-, -SO2-NR18-, -CO-NR19-, representing R17, R18 and R19 at -H, -NH-CO-NH- or -SO2-, being that within this embodiment it is especially preferred that L be selected from -NH-SO2-, -NH-CO-, -CO-NH-, -SO2-NH-NH-CO-NH- or -SO2-.

[0029] In another preferred embodiment of the present invention, R6 in the compounds according to the general formula (I) is selected from the group consisting of:

-

H, C1-C8 substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted pyrrolidinyl, C3-C8 substituted or unsubstituted cycloalkyl, disubstituted cyclohexyl, cyclopentyl, C5 -C12 substituted or unsubstituted bicycloalkyl, substituted or unsubstituted adamantyl, or - (CH2) pZ, where p is an integer from 0 to 4 and Z being selected from the group consisting of: substituted or unsubstituted aryl, preferably unsubstituted aryl , substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, -N (R7R8), representing R7 and R8 independently of each other at -H, or C1-C6 linear or branched alkyl, or representing Z a - (CR9R10R11), being R9, R10 and R11 independently selected from the group consisting of: -H, C1-C4 substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted aryl or -N (R12R13), representing R12 and R13 independently from each other at -H or -C4 substituted or unsubstituted linear or branched alkyl, and in which if Z is selected from substituted or unsubstituted aryl, preferably unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl , p cannot be selected 0.

[0030] In another preferred embodiment of the present invention, R6 in the compound according to the general formula (I) is selected from the group consisting of:

-

H, C1-C6 substituted or unsubstituted linear or branched alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, C3-C8 substituted or unsubstituted cycloalkyl, C5-C12 unsubstituted bicycloalkyl, preferably bicyclo [2.2.1] unsubstituted heptanyl, unsubstituted adamantyl or - (CH2) pZ, where p is an integer from 0 to 2 and Z being selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted heterocyclyl, - N (R7R8), representing R7 and R8 independently of each other at -H, C1-C4 linear or branched alkyl substituted or unsubstituted, or representing Z a (CR9R10R11), R9, R10 and R11 being independently selected from the group consisting of: -H, C1-C6 substituted or unsubstituted linear or branched alkyl, unsubstituted aryl or -N (R12R13), R12 and R13 independently representing each other at -H or C1-C4 linear or branched substituted or unsubstituted alkyl replaced.

[0031] In another preferred embodiment according to the present invention, R6 in the compounds according to the general formula

(I)

 represents -H or C1-C6 linear or branched alkyl, preferably -H, -CH3, -C2H5, -C3H7, -CH (CH3) 2, C (CH3) 3 or -CH2-C (CH3) 3, more preferably -H, -CH3 or -C (CH3) 3.

[0032] In another preferred embodiment according to the present invention, R6 in the compounds according to the general formula

(I)

 represents the substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl or naphthyl, being that if R6 represents the substituted naphthyl, the naphthyl is partially- or totally substituted with -OH or C1-C4 linear or branched alkoxy, preferably –OH and the naphthyl being preferably monosubstituted, or in the case that R6 represents the substituted phenyl, the phenyl must be partially- or totally substituted with the members of the group consisting of:

Phenyl, C1-C6 substituted or unsubstituted linear or branched alkyl, preferably C1-C4 substituted or unsubstituted linear or branched alkyl, more preferably -CH3, -C3H7, -CH (CH3) 2 or -C (CH3) 3, heterocyclyl substituted or unsubstituted, preferably unsubstituted morpholinyl or N-substituted piperazinyl, the N-substituted piperazinyl being substituted with C1-C4 linear or branched alkyl, preferably with -CH3,

or the phenyl being partially or totally substituted with -OH or -N (R32R33), R32 and R33 independently representing each other at -H or C1-C4 linear or branched alkyl, preferably -H or -CH3, more preferably -H .

[0033] In another preferred embodiment according to the present invention, R6 in the compounds according to the general formula

(I) represents the substituted or unsubstituted heteroaryl, the heteroaryl being selected from the group consisting of:

Pyrrolyl, thiophenyl, furanyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isothioazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrazizyl, tetrahydroquinolinyl, quinolinyl, isoquinolinyl, benzoimidazolyl, benzothiazolyl, benzooxazolyl, benzo [1,3] dioxotyl, indolyl, benzofuranyl, benzothiophenyl, indazolyl or chrom-2onyl, preferably R6 is selected from the group consisting of: imidazolyl, preferably being an N-atom of the imidazolyl substituted with C1-C4 linear alkyl or branched substituted or unsubstituted, more preferably with -CH3, pyridinyl, preferably 4-pyridinyl, tetrahydroquinolinyl, quinolinyl, benzoimidazolyl, benzothiazolyl, benzo [1,3] dioxolyl, indolyl, indazolyl or chrom-2-onyl.

[0034] In another preferred embodiment according to the present invention, R6 in the compounds according to the general formula

(I) represents substituted or unsubstituted heterocyclyl, the heterocyclyl being selected from the following group consisting of:

Aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, preferably R6 is selected from azetidinyl, pyrrolidinyl, preferably 2-pyrrolidinyl or 2-piperidinyl, 3-piperidinyl or 4-piperidinyl, preferably 2-piperidinyl.

It is especially preferred within the embodiment described above that R 6 in the compounds according to the general formula (I) represents the partially- or fully substituted heterocyclyl, preferably partially- or totally substituted piperidinyl, more preferably N-substituted piperidinyl, substituted with C1-C4 linear or branched alkyl substituted or unsubstituted, preferably -CH3, or -N-COOR34, R34 representing -H or C1-C4 linear or branched alkyl substituted or unsubstituted preferably - (CCH3) 3.

[0035] In another preferred embodiment of the present invention, R 6 in the compounds according to the general formula (I) represents the substituted or unsubstituted C 3 -C 8 cycloalkyl, preferably substituted or unsubstituted cyclopentyl or cyclopentyl, with cyclopentyl or partial cyclohexyl being - or fully substituted with C1-C6 substituted or unsubstituted alkyl, -OH, -NH2 or -NH-COOR35, R35 representing -H or C1-C6 linear or branched alkyl substituted or unsubstituted, preferably C1-C4 linear alkyl or branched, more preferably -C (CH3) 3, and cyclopentyl being

or the cyclohexyl preferably substituted with -NH2, and the cyclopentyl or cyclohexyl being preferably mono-, di- or trisubstituted, more preferably monosubstituted.

[0036] In another preferred embodiment of the present invention, R6 in the components according to the general formula (I) represents a - (CH2) p-Z, p being selected from 1 or 2 and Z being selected from the group consisting of:

Substituted or unsubstituted phenyl, being that in the event that the phenyl is substituted it is substituted by C1-C4 substituted or unsubstituted linear or branched alkyl, preferably -CH3, substituted or unsubstituted heterocyclyl, preferably substituted or unsubstituted piperidinyl, more preferably N-substituted or unsubstituted 2-piperidinyl, being, and in the case that 2-piperidinyl is N-substituted, it is substituted with -COOR36, R36 representing C1-C6 linear or branched substituted or unsubstituted alkyl, preferably C1-C4 linear or branched alkyl, more preferably -C (CH3) 3, or representing Z to -N (R7R8), R7 and R8 independently representing each other at -H, or C1-C4 linear or branched alkyl, preferably -H, - CH3 or -C2H5, or R6 representing a - (CH2) pZ, p being selected as an integer from 0 to 2 and Z being selected - (CR9R10R11), R9, R10 and R11 being selected independently of each other from the group consisting of: - H, C1-C5 linear alkyl or branched substituted or unsubstituted, preferably -CH3, -CH (CH3) 2, or -CH (CH3) -C2H5, substituted or unsubstituted aryl, or -N (R12R13), representing R12 and R13 independently of each other -H or C1-C4 substituted or unsubstituted linear or branched alkyl, preferably -H or -CH3.

[0037] In another preferred embodiment of the present invention, m in the components according to the general formula (I) must be 1, R1, R2 and R4 represent -H, R3 represents the monosubstituted phenyl, R5 represents the monosubstituted phenyl or unsubstituted, L is selected from the group consisting of:

-NH-CO-, -NH-SO2-, -SO2-NH-, -CO-NH- or -SO2- and R6 is selected from the group consisting of: -H, C1-C4 linear or branched alkyl substituted or unsubstituted , monosubstituted phenyl, substituted or unsubstituted heterocyclyl, the heterocyclyl being preferably selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl, substituted or unsubstituted heteroaryl, with heteroaryl being selected from imidazolyl, pyridinyl, tetrahydroquinolinyl, benzylzolzole, benzolinyl, benzolinyl, benzolinyl, benzolinyl, benzolinyl, benzylzolzole 1,3] dioxolyl, indolyl, indazolyl or chrom-l, indolyl, indazolyl or chrom-2-onyl or R6 representing C3-C8 substituted cycloalkyl

or not substituted.

[0038] Especially preferred compounds of the general formula (I) are represented by the following sub-formula

in which A-A * represents -CH2-CH2-, -CH = CH-, -NH-CH2-, -CH2-NH-, -N = CH-, -CH = N-, -N = N-, R * is a substituted or unsubstituted aryl, substituted or unsubstituted linear or branched alkyl, substituted heteroaryl or unsubstituted, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkyl, C2-C6 alkenyl or C2-C6 alkynyl, R ** represents hydrogen, substituted or unsubstituted linear or branched alkyl or a substituent selected from (Sub). R2, R3, and R4 have the meaning as defined above.

R * is preferably C1-C6 substituted or unsubstituted alkyl and more preferably methyl. R3 preferably represents phenyl,

[0039] In another preferred embodiment of the present invention, the compounds according to the general formula (I) are chiral compounds. It should be understood that these chiral compounds according to the present invention represent a racemate, or an S or R enantiomer or a mixture of isomers respectively.

[0040] As used herein, the term "substituent" or "Sub" or the possibility that a residue may also be substituted with another group refers to the following list of substituents that may be present independently of each other. :

-

H, -OH, -OCH3, -OC2H5, -OC3H7, -O-cycle-C3H5, -OCH (CH3) 2, -OC (CH3) 3, -OC4H9, -OPh, -OCH2-Ph, -OCPh3, - SH, -SCH3, -SC2H5, -SC3H7, -S-cycle-C3H5, -SCH (CH3) 2, -SC (CH3) 3, -NO2, -F, -Cl, -Br, -I, -N3, -CN, -OCN, -NCO, -SCN, -NCS, -CHO, -COCH3, -COC2H5, -COC3H7, -CO-cycle-C3H5, -COCH (CH3) 2, COC (CH3) 3, -COOH, -COCN, -COOCH3, -COOC2H5, -COOC3H7, -COO-cycle-C3H5, -COOCH (CH3) 2, -COOC (CH3) 3, -OOC-CH3, -OOC-C2H5, -OOC-C3H7, -OOC -cycle-C3H5, -OOC-CH (CH3) 2, -OOC-C (CH3) 3, -CONH2, -CONHCH3, -CONHC2H5, -CONHC3H7, -CONH-cycle-C3H5, -CONH [CH (CH3) 2 ], -CONH [C (CH3) 3], -CON (CH3) 2, -CON (C2H5) 2, -CON (C3H7) 2, -CON (cycle-C3H5) 2, -CON [CH (CH3) 2 ] 2, WITH [C (CH3) 3] 2, -NH2, -NHCH3, -NHC2H5, -NHC3H7, -NH-cycle-C3H5, -NHCH (CH3) 2, -NHC (CH3) 3, N (CH3) 2, -N (C2H5) 2, -N (C3H7) 2, -N (cycle-C3H5) 2, -N [CH (CH3) 2] 2, -N [C (CH3) 3] 2, -SOCH3, -SOC2H5, -SOC3H7, -SO-cycle-C3H5, -SOCH (CH3) 2, -SOC (CH3) 3, -SO2CH3, -SO2C2H5, -SO2C3H7, -SO2-cycle-C3H5, -SO2CH (CH3) 2, -SO2C (CH3) 3, -SO3H, -SO3CH3, -SO3C2H5, -SO3C3H7, -SO3-cycle-C3H5, -SO3CH (CH3) 2, - SO3C (CH3) 3, -OCF3, -OC2F5, -O-COOCH3, -O-COOC2H5, -O-COOC3H7, -O-COO-cycle-C3H5, -O-COOCH (CH3) 2, -O-COOC ( CH3) 3, - NH-CO-NH2, -NH-CO-NHCH3, -NH-CO-NHC2H5, -NH-CO-NHC3H7, -NHCO-NH-cycle-C3H5, -NH-CO-NH [CH ( CH3) 2], -NH-CO-NH [C (CH3) 3], -NH-CO-N (CH3) 2, -NHCO-N (C2H5) 2, -NHCO-N (C3H7) 2, -NH -CO-N (Cyclo-C3H5) 2, -NH-CO-N [CH (CH3) 2] 2, -NH-CO-N [C (CH3) 3] 2. -NH-CS-NH2, -NH-CSNHCH3, -NH-CS-NHC2H5, -NH-CS-NHC3H7. -NH-CS-NH-Cyclo-C3H5, -NH-CSNH [CH (CH3) 2] -NH-CS-NH [C (CH3) 3], -NH-CS-N (CH3) 2, -NH- CS-N (C2H5) 2, -NH-CS-N (C3H7) 2, -NH-CSN (cycle-C3H5) 2, -NH-CS-N [CH (CH3) 2] 2, -NH-CS- N [C (CH3) 3] 2, -NH-C (= NH) -NH2, -NH-C (= NH) -NHCH3, -NHC (= NH) -NHC2H5, -NH-C (= NH) - NHC3H7, -NHC (= NH) -NH-cycle-C3H5, -NH-C (= NH) -NH [CH (CH3) 2], -NHC (= NH) -NH [C (CH3) 3], - NH-C (= NH) -N (CH3) 2, -NH-C (= NH) -N (C2H5) 2, -NH-C (= NH) -N (C3H7) 2, -NH-C (= NH) N (cyclo-C3H5) 2, -NH-C (= NH) -N [CH (CH3) 2] 2. -NH-C (= NH) -N [C (CH3) 3] 2, -O-CO-NH2, -O-CO-NHCH3, -O-CO-NHC2H5, -O-CO-NHC3H7, -O- CO-NH-Cyclo-C3H5, -O-CO-NH [CH (CH3) 2], -O-CO-NH [C (CH3) 3], -O-CON (CH3) 2, -O-CO- N (C2H5) 2, -O-CO-N (C3H7) 2, -O-CO-N (cycle-C3H5) 2, -O-CON [CH (CH3) 2] 2, -O-CON [C ( CH3) 3] 2, -O-CO-OCH3, -O-CO-OC2H5, -O-CO-OC3H7, -O-CO-O-cycle-C5H5, -O-COOCH (CH3) 2, -OCO- OC (CH3) 3, -CH2F -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br -CHBr2, -CBr3, -CH2I -CHI2, -Cl3, -CH2-CH2F -CH2-CHF2, -CH2 -CF3, -CH2-CH2Cl, -CH2-CHCl2, -CH2-CCl3, -CH2-CH2Br -CH2-CHBr2, -CH2-CBr3, -CH2-CH2I -CH2-CHI2, -CH2-Cl3, -CH3, - C2H5, -C3H7, -Cyclo-C3H5, -CH (CH3) 2, -C (CH3) 3, -C4H9, CH2-CH (CH3) 2, -CH (CH3) -C2H5, -C (CH3) 3, -Ph, -CH2-Ph, -CPh3, -CH = CH2, -CH2-CH = CH2, C (CH3) = CH2, -CH = CH-CH3, -C2H4-CH = CH2, -CH = C (CH3 ) 2, -C = CH, -C: C-CH3, -CH2-C: CH.

[0041] In another embodiment of the present description, the compound according to the general formula (I) is selected from the group of components represented in Table 2.

[0042] In another aspect of the present invention, the novel compounds according to the general formula (I) are used as active pharmaceutical agent. Diabetes, inflammation, transplant rejection, erectile dysfunction, neurodegenerative diseases and cerebral stroke.

Infectious diseases including opportunistic infections

[0043] In another aspect of the present invention, the compounds according to the general formula (I) are for the preparation of a pharmaceutical composition for the prevention and / or treatment of infectious diseases, including opportunistic diseases and infections. The term infectious diseases includes infections caused by viruses, bacteria, prions, fungi and / or parasites. Especially indicated for the treatment of infectious diseases caused by viruses. In a preferred embodiment of this aspect, infectious viral diseases, including opportunistic diseases, are caused by retroviruses, human endogenous retroviruses (HERVs), hepadnaviruses, herpesviruses, flaviviridae, and / or adenovirus. Preferably, the viruses are selected by lentivirus or oncoretrovirus, the lentivirus being preferably selected from the group consisting of: HIV-1, HIV-2, feline immunodeficiency virus (VIF), bovine immunodeficiency virus (VIB), Apes immunodeficiency (VIS), HIV and VIS chimeras (HIVS), caprine arthritis encephalitis virus (VAEC), maedi / visna virus (VMV) or equine infectious anemia virus (VAIE), preferably HIV-1 and HIV-2, and the oncoretrovirus is preferably selected from HTLV-I, HTLV-II or bovine leukemia virus (VLB), preferably HTLV-I and HTLV-II.

[0044] Hepadnavirus is preferably selected from HBV, squirrel hepatitis virus (GSHV) or marmot hepatitis virus (WHV), preferably HBV, herpesvirus is selected from the group consisting of: Herpes virus type I simplex (HSV I), herpes simplex virus type II (HSV II), Epstein-Barr virus (EBV), chickenpox zoster virus (VZV), human cytomegalovirus (CMVH) or human herpesvirus 8 (VHH -8), preferably CMVH, and flaviviridae are selected from HCV, West Nile virus or yellow fever.

[0045] It should be understood that all the aforementioned viruses also include drug resistant virus strains.

[0046] Examples of infectious diseases are AIDS, alveolar hydatid disease (AHD, echinococcosis), amebiasis (entamoeba histolytica infection), angiostrongylus infection, anisakiasis, anthrax, babesiosis (babesia infection), balantidium infection (balantidiasis), Baylisascaris infection (raccoon earthworm), bilharzia (schistosomiasis), blastocystis hominis infection (blastomycosis), boreliosis, botulism, “Brainerd” diarrhea, brucellosis, BSE (spongiform bovine encephalopathy), candidiasis, capillariasis (CF infection) (chronic fatigue syndrome), Chagas disease (American trypanosomiasis), chicken pox (varicella zoster virus), chlamydia pneumoniae infection, cholera, chronic fatigue syndrome, JCC (Creutzfeldt-Jakob disease), clonorchiasis (clonorchis infection) , CLM (cutaneous migrans larva, hookworm infection), coccidioidomycosis, conjunctivitis, coxsackievirus A16 (ma disease nos, feet and mouth), cryptococcosis, cryptosporidium infection (cryptosporidiosis), culex mosquito (vector of the West Nile virus), cutaneous migrans larva (CLM), cyclosporiasis (cyclopora infection), cysticercosis (neurocysticercosis), cytomegalovirus infection dengue / dengue fever, dipylidium infection (dog and cat tapeworm), ebola hemorrhagic fever, echinococcosis (alveolar hydatid disease), encephalitis, entamoeba coli infection, disparate entamoeba infection, entamoeba hartmanni infection, entamoeba histolytica infection (amebiasis), entamoeba polecki infection, enterobiasis (pinworm infection), enterovirus (non-polio) infection, Epstein-Barr virus infection, escherichia coli infection, food infection, foot and mouth disease, fungal dermatitis, gastroenteritis, group A streptococcal disease, group B strep disease, Hansen's disease (leprosy), p syndrome hantavirus ulcer, lice infestation (pediculosis) helicobacter pylori infection, hematologic disease, Hendra virus infection, hepatitis (HCV, HBV), shingles (shingles), HIV infection, human parainfluenza virus infection, influenza, isosporiasis (isospora infection), lassa fever, leishmaniasis, kala-azar (kala azar, leishmania infection), leprosy, lice (body lice, head lice, pubic lice), Lyme disease, malaria, fever Marburg hemorrhagic disease, measles, meningitis, mosquito-borne diseases, mycobacterium avium complex infection (MAC), naegleria infection, nosocomial infections, non-pathogenic intestinal amoeba infection, onchocerciasis (river blindness), opistorchiasis (opisthorchis infection) , parvovirus infection, plague, plague, PCP (pneumocystis carinii pneumonia), polio, Q fever, rabies, respiratory syncytial virus (RSV) infection, fever and rheumatic, Rift Valley fever, river blindness (onchocerciasis), rotavirus infection, ascaris infection, salmonellosis, salmonella enteritidis, scabies, shigellosis, shingles, sleeping sickness, smallpox, streptococcal infection, dipylidium infection ( tapeworm infection), tetanus, toxic shock syndrome, tuberculosis, ulcers (peptic ulcer disease), valley fever, vibrio parahaemolyticus infection, vibrio vulnificus infection, viral hemorrhagic fever, warts, water-borne infectious diseases, virus infection West Nile (West Nile encephalitis), whooping cough, yellow fever.

Bacterial infections

[0047] As described above, the compounds according to the general formula (I) are also useful for the preparation of a pharmaceutical composition for the prevention and / or treatment of infectious diseases caused by bacteria, including opportunistic diseases and opportunistic infections, being selected Infectious diseases caused by bacteria, including opportunistic diseases, selected from tuberculosis, leprosy or meningitis caused by mycobacterium. An advantage of the inventive compounds disclosed here is their use against drug resistant bacteria strains.

Prion diseases

[0048] Another aspect of the present invention is directed to the use of at least one compound of the general formula (I) and / or pharmaceutically acceptable salts thereof for the prevention and / or treatment of cryonic diseases.

[0049] Prions are infectious agents that do not have a genome based on nucleic acid. Apparently a single protein acts as an infectious agent. A prion has been defined as "small, infectious protein particle that resists inactivation by procedures that modify nucleic acids." The discovery that proteins alone can transmit an infectious disease has been a considerable surprise to the scientific community. Cryonic diseases are often called "transmissible spongiform encephalopathies" because of the post-mortem appearance of the brain with large vacuoles in the cortex and cerebellum. It is likely that most species of mammals develop these diseases. Prion diseases are a group of neurodegenerative disorders in humans and animals, and cryonic diseases can manifest themselves in the form of sporadic, genetic or infectious disorders.Examples of prion diseases acquired by exogenous infection are bovine spongiform encephalitis (BSE) in cattle and new variant of Creutzfeld-Jakob disease (vECJ) caused by BSE, as well as animal scrapie, Examples of cryonic diseases in humans include kuru, sporadic Creutzfeldt-Jakob disease (eECJ), familial ECJ (fECJ) , Iatrogenic ECJ (iECJ), Gerstmann-Sträussler-Scheinker disease (GSS), fata family insomnia l (IFF), and especially the new CJD variant (nvECJ or vECJ).

[0050] The name "prion" is used to describe the causative agents that are the basis of transmissible spongiform encephalopathies. A prion is suggested as a novel infectious particle that differs from viruses and viroids. It consists only of a single protein that resists more inactivation procedures such as heat, radiation and proteases. This last characteristic has caused it to be called protease resistant isoform of the prion protein. The protease resistant isoform has been proposed to slowly catalyze the conversion of normal prion protein to the abnormal form.

[0051] The term "isoform" in the context of prions means two proteins with exactly the same amino acid sequence but that form radically different tertiary structure molecules. The normal cellular isoform of the cryonic protein (PrPc) has a high content of a-helices, a low content of B sheets, and is much more resistant to protease digestion.

[0052] With the use given here, the term "prion diseases" refers to encephalopathies transmissible spongiform. Examples of cryonic diseases include scrapie (sheep, goats), Mink transmissible encephalopathy (ETM), CWD (chronic cachexia; mule deer, deer, elk), BSE (encephalopathy bovine spongiform; cows, cattle), ECJ (Creutzfeld-Jacob disease), vECJ, GSS (Gerstmann Sträussler-Scheinker syndrome), IFF (fatal familial insomnia), kuru and Alpers syndrome. BSE, VECJ and ECJ are preferred.

Immune diseases

[0053] Another aspect of the present invention is directed to the use of at least one of the compounds of the general formula (I) and or pharmaceutically acceptable salts thereof for the prevention and / or treatment of immunological, neuroimmunological and autoimmune diseases.

[0054] Immune diseases are, for example, asthma and diabetes, rheumatic and autoimmune diseases, AIDS, rejection of transplanted organs and tissues (see below), rhinitis, chronic obstructive pulmonary diseases, osteoporosis, ulcerative colitis, sinusitis, lupus erythematosus, infection recurrent, atopic dermatitis / eczema and occupational allergies, food allergies, drug allergies, severe anaphylactic reactions, anaphylaxis and other manifestations of allergic diseases, as well as uncommon problems such as primary immunodeficiencies, including antibody deficiency states, cellular immunodeficiencies (e.g. eg, severe combined immunodeficiency, DiGeorge syndrome, hyper-IgE syndrome, Wiskott-Aldrich syndrome, ataxiatelangiectasia), autoimmune cancers, and white cell defects.

[0055] In autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis (RA), multiple sclerosis (MS), autoimmune or type 1 diabetes mellitus, autoimmune glomerulonephritis, scleroderma, pernicious anemia, alopecia, pemphigus, vulgar pemphigus, myasthenia gravis, myasthenia gravis Pernicious anemia, alopecia, pemphigus, pemphigus vulgaris, myasthenia gravis, inflammatory bowel diseases, Crohn's disease, psoriasis, autoimmune thyroid diseases and Hashimoto's disease, dermatomyositis, goodpasture syndrome, myasthenia pseudoparalitica, sympathetic ophthalmia, chronic phacogenic hepatitis uveitis , primary biliary cirrhosis, autoimmune hemolytic anemia, Werlof's disease, specific cells uncontrollably attack the body's own tissues and organs (autoimmunity), producing inflammatory reactions and other serious symptoms and diseases.

[0056] Hashimoto's thyroiditis is one of the most common autoimmune diseases. "Autoimmune disease" refers to a category of more than 80 chronic conditions, all very different in nature, that can affect anything from the endocrine glands (such as the thyroid) to organs such as the kidneys, or also the digestive system.

[0057] There are many different autoimmune diseases and each of them can affect the body differently. For example, the autoimmune reaction in multiple sclerosis is directed towards the brain, and in Crohn's disease towards the intestine. In other autoimmune diseases, such as systemic lupus erythematosus (lupus), affected tissues and organs may vary in individuals with the same disease. A person with lupus may have affected skin and joints, while another may have affected skin, kidneys and lung. In the long run, damage to certain tissues of the immune system may be permanent, as in the case of the destruction of insulin-producing cells in the pancreas in type 1 diabetes mellites.

Bipolar and clinical disorders

[0058] Another aspect of the present invention is directed to the use of at least one compound of the general formula (I) and / or pharmaceutically acceptable salts thereof for the prevention and / or treatment of bipolar and clinical disorders.

[0059] The term "bipolar and clinical disorders" refers to adjustment disorders, anxiety disorders, delirium, dementia, amnesic disorders and other cognitive disorders, disorders normally diagnosed for the first time in early childhood, childhood or adolescence, dissociative disorders , eating disorders, factitious disorders, impulse control disorders, mental disorders due to a general medical condition, mood disorders, other conditions that may be a focus of clinical care, personality disorders, schizophrenia and other psychotic disorders, sexual disorders and of gender identity, sleep disorders, somatoform disorders, substance-related disorders, generalized anxiety disorder, panic disorders, phobias, agoraphobia, obsessive-compulsive disorders, stress, acute stress disorders, anxiety neurosis, nervousness, phobias, posttraumatic stress disorder, disorder Posttraumatic stress (PTSD), abuse, ADHD, obsessive-compulsive disorders (OCD), manic-depressive psychosis, specific phobias, social phobias, adaptation disorders with anxiety traits.

[0060] Examples of anxiety disorders are: acute stress disorders, agoraphobia without a history of panic disorders, anxiety disorders due to general medical conditions, generalized anxiety disorders, obseVISo-compulVISos disorders, panic disorders with agoraphobia, disorders of panic without agoraphobia, posttraumatic stress disorders, specific phobias, social phobia, substance-induced anxiety disorder.

[0061] Examples of delirium, dementia, amnesia and other cognitive disorders are: delirium due to a general medical condition, delirium from substance intoxication, delirium from substance withdrawal syndrome, delirium due to multiple etiologies, Alzheimer's, Creutzfeldt- Jakob, head trauma, Huntington's disease, HIV disease, Parkinson's disease, Pick's disease, substance-induced vascular dementia due to other general medical conditions, dementia due to multiple etiologies, amnesia disorder due to a general medical condition, disorder of persistent substance-induced amnesia.

[0062] Examples of disorders normally diagnosed for the first time in early childhood, childhood or adolescence are: mental retardation, learning disorders, math disorder, reading disorder, written expression disorder, learning disorder, motor skills, developmental coordination disorder, communication disorders, expressive language disorder, phonological disorder, receptive-expressive language disorder, stuttering, pervasive developmental disorders, Asperger's disorder, autism disorder, childhood disintegrative disorder, disorder of Rett, pervasive developmental disorder, attention deficit / hyperactivity disorder (ADHD), behavior disorder, oppositional defiant disorder, eating disorder in childhood or early childhood, pica, mericism disorder, tic disorders, motor disorder or Chronic vowel, Tourette's disorder, elimination disorder, encopresis, enur esis, selective mutism, separation anxiety disorder, reactive attachment disorder in childhood or early childhood, stereotyped movement disorder.

[0063] Examples of dissociative disorders are: dissociative amnesia, depersonalization disorder, dissociative leak and dissociative identity disorders.

[0064] Examples of eating disorders are anorexia nervosa and bulimia nervosa.

[0065] Examples of mood disorders are: humor episode, major depression episode, manic episode, mixed episode, depressive disorders, dysthymic disorders, major depression disorder, single episode, recurrent bipolar disorders, bipolar disorders I, bipolar disorders II , cyclothymic disorder, mood disorder due to a general medical condition, substance-induced mood disorder.

[0066] Examples of schizophrenia and other psychotic disorders are: schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, delusions, hallucinations, substance-induced psychotic disorder.

[0067] Examples of sexual and gender identity disorders are: female sexual arousal disorder, orgasmic disorders, premature ejaculation, sexual pain disorders, dyspareunia, vaginismus, sexual dysfunction due to a general medical condition, female dyspareunia, disorder of the Female hypoactive sexual desire, male erectile disorder, male hypoactive sexual desire disorder, male dyspareunia, other female sexual dysfunctions, other male sexual dysfunctions, substance-induced sexual dysfunctions, sexual dysfunction, paraphilias, exhibitionism, fetishism, frotism, pedophilia, masochism, sadism, transvestite fetishism, voyeurism, paraphilia, gender identity disorder.

[0068] Examples of sleep disorders are: dysomnias, sleep disorder related to breathing, sleep disorder related to heart rhythm, hypersomnia, hypersomnia associated with another mental disorder, insomnia, insomnia related to other mental disorders, narcolepsy, dysomnia, parasomnia, disorder due to nightmares, night terror disorder, sleepwalking disorder, parasomnia. [0069] Examples of somatoform disorders are: body dysmorphic disorder, hypochondria, pain disorder, somatization disorder, undifferentiated somatoform disorder.

[0070] Examples of substance-related disorders are: alcohol-related disorders, amphetamine-related disorders, caffeine-related disorders, cannabis-related disorders, cocaine-related disorders, hallucinogen-related disorders, inhalation-related disorders, disorders related to nicotine, opioid-related disorders, psychotic disorder, psychotic disorder, phencyclidine-related disorder, abuse, persistent amnesic disorder, anxiety disorder, persistent dementia, dependence, intoxication, intoxication delirium, mood disorder, psychotic disorder, withdrawal syndrome , delirium from withdrawal syndrome, sexual dysfunction, sleep disorder.

Cardiovascular diseases

[0071] The compounds of the invention are also useful for the prevention and / or treatment of cardiovascular diseases, such as congenital heart disease, aneurysm, stable angina, non-stable angina, angina pectoris, angioneurotic edema, aortic valve stenosis, aneurysm aortic, arrhythmia, arrhythmogenic dysplasia of the right ventricle, arteriosclerosis, arteriovenous malformations, atrial fibrillation, Behcet syndrome, bradycardia, cardiac tamponade, cardiomegaly, congestive cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, cerebral vascular disease, cardiovascular disease of Churg-Strauss, diabetes, Ebstein's anomaly, Eisenmenger complex, cholesterol, embolism, bacterial endocarditis, fibromuscular dysplasia, congenital heart defects, heart disease, congestive heart failure, heart valve disease, heart attack aco, epidural hematoma, subdural hematoma, Hippel-Lindau disease, hyperemia, hypertension, pulmonary hypertension, hypertrophic growth, left ventricle hypertrophy, right ventricle hypertrophy, right heart hypoplasia syndrome, hypotension, intermittent claudication, ischemic heart disease, Klippel-Trenaunay-Weber syndrome, lateral medullary syndrome, lateral mitral valve prolapse Long QT syndrome, moyamoya disease, mucocutaneous lymph node syndrome, myocardial infarction, myocardial ischemia, myocarditis, pericarditis, peripheral vascular diseases, phlebitis , polyarthritis nodosa, pulmonary atresia, Raynaud's disease, restenosis, Sneddon syndrome, stenosis, superior vena cava syndrome, X syndrome, tachycardia, Takayasu arthritis, hereditary hemorrhagic telangiectasia, telangiectasis, temporal arthritis, Tetralogy of Fallot, thromboangeitis obliterans trom Bosis, thromboembolism, tricuspid atresia, varicose veins, vascular diseases, vasculitis, vasospasm, ventricular fibrillation, Williams syndrome, peripheral vascular disease, varicose veins and leg ulcers, deep vein thrombosis, WolffParkinson-White syndrome.

[0072] Preferably congenital diseases in adults, aneurysms, angina, angina pectoris, arrhythmias, prevention of cardiovascular diseases, cardiomyopathies, congestive heart failure, myocardial infarction, pulmonary hypertension, hypertrophic growth, restenosis, stenosis, thrombosis and arteriosclerosis.

Proliferative diseases

[0073] In another embodiment, the proliferative cell disease is cancer, which is preferably selected from the group consisting of:

[0074] Proliferative disorders and cancers are preferably selected from the group consisting of adenocarcinoma, choroidal melanoma, acute leukemia, acoustic neurinoma, anal ampular carcinoma carcinoma, astrocytoma, basal cell carcinoma, pancreas cancer, desmoid tumor, bladder cancer , bronchial carcinoma, breast cancer, Burkitt lymphoma, endiometer cancer, ependymoma, types of epithelial cancer, Ewing tumors, gastrointestinal tumors, gastric cancer, gallbladder cancer, uterine cancer, cervical cancer, cervical gioblastomas, tumors gynecological, tumors in ears, nose and throat, hematologic malignancies, hair cell leukemia, urethral cancer, skin cancer, scrotum cancer, brain tumors (gliomas), brain metastases, testicular cancer, pituitary tumor, carcinoids, Kaposi's sarcoma , laryngeal cancer, germ cell tumor, bone cancer, colorectal carcinoma, tumors in head and neck (tumors in the ear, nose and throat), colon carcinoma, craniopharyngiomas, oral cancer (cancer in the mouth or on the lips), cancer of the central nervous system, liver cancer, liver metastases, leukemia, tumor in eyelids, lung cancer, lymph node cancer (Hodgkin's / Non-Hodgkin's), lymphomas, stomach cancer, malignant melanoma, tumors in the gastrointestinal tract, breast carcinoma, rectal cancer, medulloblastomas, melanoma, meningiomas, Hodgkin's disease, mycosis fungoides, nasal cancer, neurinoma, neuroblastoma, renal cancer, renal cell carcinoma, non-Hodgkin lymphomas, oligodendroglioma, esophageal carcinoma, osteolytic carcinomas and osteoplastic carcinoma, osteosarcomas, ovarial carcinoma, pancreatic carcinoma, penile cancer ,, plasmocytoma, prostate cancer, pharyngeal cancer, rectal carcinoma, retinoblastoma, vaginal cancer, thyroid carcinoma, Schneeberger's disease, esophageal cancer, s pinaliomas, T-cell lymphoma (mycosis fungoides), tinoma, fallopian carcinoma, eye tumors, urethral cancer, urological tumors, urothelial carcinoma, vulva cancer, presence of warts, soft tissue tumors, soft tissue sarcoma, Wilm tumor, cervical carcinoma and tongue cancer.

[0075] Preferably the following types of cancer: bladder, breast, central nervous system, colon, gastric, lung, kidney, melanoma, head and neck, ovaries, cervix, glioblastoma, pancreas, prostate, stomach, scrotum, leukemia, lymphoma of Hodgkin, liver and kidney cancer.

Diabetes

[0076] In another preferred embodiment, said diabetes is selected from type I or type II diabetes.

Inflammation

[0077] In another preferred embodiment, said inflammation is preferably mediated by the cytokines TNF-a, IL1β, GM-CSF, IL-6 and / or IL-8.

[0078] As described above, the compounds according to the general formula (I) are pharmaceutically active agents for the prevention and / or treatment of inflammatory diseases. Therefore, these compounds are used for the preparation of a pharmaceutical formula for the prevention and / or treatment of inflammations and inflammatory diseases in mammals, including humans.

[0079] Inflammatory diseases may emanate from infectious and non-infectious inflammatory conditions that may result from an infection caused by an invading organism or by irritating, traumatic, metabolic, allergic, autoimmune or idiopathic causes as shown in the following list.

I. Acute infections

A. Viral B. Bacterial

II. Non-infectious causes III. Chronic diseases (granulomatous)

A. Bacterial C. Fungal

B. Spirocetal D. Idiopathic

IV. Allergic, immune and idiopathic disorders

A. Hypersensitive reactions

B. Immune and idiopathic disorders

V. Other inflammatory conditions

A. Parasitic infections

B. Causes for inhalation: - injuries due to thermal effects

-

 allergy to pollution and inhalation

-

 carcinogens

C. Radiation injuries: - Radionecrosis

[0080] Accordingly, the compounds disclosed herein can be used for the prevention and / or treatment of inflammations caused by invading organisms such as viruses, bacteria, prions and parasites, as well as for the prevention and / or treatment of inflammations caused. for irritative, traumatic, metabolic, allergic, autoimmune or idiopathic reasons.

[0081] Consequently, the disclosed compounds are useful for the prevention and / or treatment of inflammatory diseases that are initiated or caused by viruses, parasites and bacteria that are connected or involved with inflammations.

 [0082] The following bacteria are known to cause inflammatory diseases: mycoplasma pulmonis (eg chronic lung disease (CLD), chronic murine respiratory disease) ureallasic ureaplasma (cause pneumonia in newborns), mycoplasma py chlamydia pneumoniae (cause asthma chronic), C. Pneumoniae (cause atherosclerosis, from pharyngitis to pneumonia with empyema, coronary heart disease in humans), heliobacter pilori (coronary heart disease in humans, stomach ulcers).

[0083] The following viruses are known to cause inflammatory diseases: herpesvirus, especially cytomegalovirus (causes coronary heart disease in humans).

[0084] The compounds disclosed herein are useful for the prevention and / or treatment of inflammatory diseases caused and / or induced and / or initiated and / or aggravated by the bacteria or viruses mentioned above.

[0085] In addition, the compounds of the formula (I) are useful for the prevention and / or treatment of inflammatory diseases of the central nervous system (CNS), inflammatory rheumatic diseases, inflammatory diseases of the blood vessels, inflammatory diseases of the ear medium, inflammatory bowel diseases, inflammatory skin diseases, inflammatory uveitis disease, inflammatory diseases of the larynx.

[0086] Examples of inflammatory diseases of the central nervous system (CNS) are disorders caused by algae, prototecosis, bacterial disorders, abscess formation, bacterial meningitis, idiopathic inflammatory disorders, eosinophilic meningoencephalitis, feline polioencephalomyelitis, granulomatous meningoencephalomyelitis, meningitis, responsive meningitis steroids, various meningitis / meningoencephalitis, greyhound meningoencephalitis, necrotizing encephalitis, carlin encephalitis, pyogranulomatous meningoencephalomyelitis, idiopathic cerebelitis, CNS mycotic diseases, parasitic encephalomyelitis, prion protein-induced encephalophaloses, spongiform encephaloptosis, spongiform encephalitis, spongiform infections , encephalitiozoonosis, trypanosomiasis, acantamebiasis, babesiosis, leismaniasis, rickettsian disorders, toxoplasmosis, neosporosis, sarcocystosis, encephalithozoonosis, trypanosus myiasis, Acanthamebiasis, babesiosis, leishmaniasis, Rickett's disease, Rocky Mountain spotted fever, canine ehrlichiosis, Salmonella, viral disorders, Aujeszky's disease, Borna's disease, encephalomyelitis caused by canine herpes virus, encephalomyelitis caused by canine distemper, encephalitis caused by canine distemper for canine distemper in immature animals, encephalomyelitis caused by multifocal canine distemper in mature animals, encephalitis, for canine distemper, relapsing chronic encephalomyelitis, post-vaccine encephalitis caused by canine distemper, immunodeficiency virus, feline infectious peritonitis, feline leukemia virus, infectious hepatitis canine, La Crosse virus, encephalitis virus, encephalitis parvovirus, rabies, post-vaccine rabies, tick-borne encephalitis in dogs.

[0087] Examples of inflammatory rheumatic diseases are rheumatoid arthritis, scleroderma, lupus, polymyositis, dermatomyositis, psoriasic arthritis, ankylosing spondylitis, Reiter's syndrome, juvenile rheumatoid arthritis, bursitis, tendonitis (tendonitis) and fibromiositis.

[0088] Examples of inflammatory diseases of the blood vessels are vasculitis, autoantibodies in vasculitis, mocroscopic polyangitis, giant cell arthritis, Takayasu arthritis, vasculitis of the central nervous system, thromboangitis obliterans (Buerger's disease), secondary vasculitis in bacterial infections, fungal and parasitic, rheumatoid arthritis vasculitis, vasculitis in systemic lupus erythematosus, vasculitis in inflammatory idiopathic myopathies, recurrent polychondritis, systemic vasculitis in sarcoidosis, vasculitis and malignancy, and drug-induced vasculitis.

[0089] Examples of inflammatory diseases of the middle ear are acute suppurating otitis media, bullous myringitis, granular myringitis and chronic suppurating otitis media that can manifest as mucosal disease, cholesteatoma, or both.

[0090] Examples of inflammatory bowel diseases are ulcerative colitis, Crohn's disease.

[0091] Examples of inflammatory skin diseases are acute inflammatory dermatoses, hives, spongy dermatitis, allergic contact dermatitis, irritant contact dermatitis, atopic dermatitis, erythema multiforme (minor MS), Stevens-Johnson syndrome (SSJ, major MS ), toxic epidermal necrolysis, (NET), chronic inflammatory dermatosis, psoriasis, lichen planus, discoid lupus erythematosus and acne vulgaris.

[0092] Uveitis are inflammations located in and / or over the eye and can be associated with inflammations in any other part of the body. In most cases, patients who have uveitis as part of a disease in any other part of the body are aware of this medical condition. Most patients with uveitis have no apparent associated systemic ailment. The causes of uveitis can be infectious causes, masquerade syndromes, diseases suspected of being autoimmune, and / or syndromes limited mainly to the eye.

[0093] The following viruses are associated with inflammations: human immunodeficiency virus-1, herpes simplex, shingles virus and cytomegalovirus.

[0094] Inflammations caused, induced, initiated or aggravated by bacteria or spirochetes are tuberculosis, leprosy, proprionibacterium, syphilis, Whipple's disease, leptospirosis, brucellosis and Lyme disease.

[0095] Inflammation caused, induced, initiated or aggravated by parasites (protozoa or helminths) are toxoplasmosis, Acanthameba, toxocariasis, cysticercosis, onchocerciasis.

[0096] Examples of inflammatory diseases caused, induced, initiated and / or aggravated by fungi are histoplasmosis, cocciodio-mycosis, candidiasis, aspergillosis, sporotrichosis, blastomycosis and cryptococcosis.

[0097] Masquerade syndromes are, for example, leukemia, lymphoma, retinitis pigmentosa and retinoblastoma.

[0098] Diseases suspected of being autoimmune may be selected from the group consisting of ankylosing spondylitis, Behcet's disease, Crohn's disease, hypersensitive drug hypersensitive reaction, interstitial nephritis, juvenile rheumatoid arthritis, Kawasaki disease, multiple sclerosis , psoriasic arthritis, Reiter's syndrome, recurrent polychondritis, sarcoidosis, Sjogren's syndrome, systemic lupus erythematosus, ulcerative colitis, vasculitis, vitiligo, Vogt Koyanagi Harada syndrome.

[0099] Syndromes limited primarily to the eye are, eg, acute multifocal placoid pigment epitheliopathy, acute retinal necrosis, chorioretinopathy in pelleted (birdshot), Fuch's heterochromic cyclitis, glaucomatoclitic crisis, lens-induced uveitis, multifocal choroiditis, parsy multifocal planitis, serpiginous choroiditis, sympathetic ophthalmia and trauma.

[0100] Examples of inflammatory diseases of the larynx are gastroesophageal reflux disease (laryngopharyngeal), pediatric laryngitis, acute laryngeal infections in adults, chronic diseases (granulomatous), allergic, immune and idiopathic disorders and various inflammatory conditions.

[0101] Pediatric laryngitis is known as acute (viral or bacterial) infection, such as laryngotracheitis (croup), supraglotitis (epiglottitis), diphtheria, and non-infectious causes are, for example, spasmodic croup and traumatic laryngitis.

[0102] Acute laryngeal infections in adults are, for example, viral laryngitis, common upper respiratory infection, laryngotracheitis, herpes simplex, bacterial laryngitis, supraglotitis, laryngeal abscess and gonorrhea.

[0103] Chronic (granulomatous) diseases can be selected from the group consisting of bacterial diseases, tuberculosis, leprosy, scleroma, actinomycosis, tularemia, glanders, spirochetal diseases (syphilis), fungal diseases (fungal), candidiasis, blastomycosis, histoplasmosis, coccidiidomycosis, aspergillosis, idiopathic diseases, sarcoidosis and Wagner's granulomatosis.

[0104] Allergic, immune and idiopathic disorders are, for example, hypersensitive reactions, angioedema, Stevens-Johnson syndrome, immune and idiopathic disorders, infections of the immunocompromised hosts, rheumatoid arthritis, systemic lupus erythematosus, cicatricial pengifoid, recurrent polychondritis, syndrome of Sjogren and amyloidosis.

[0105] Various inflammatory conditions are, for example, parasitic infections, trichinosis, leishmaniasis, inhalation laryngitis, acute thermal illness, allergy to pollution and inhalation, carcinogens, radiation ailments, radiation laryngitis, radionecrosis, vocal abuse, hemorrhage of the vocal cords, dysphonia of muscular tension, and contact ulcer and granuloma.

Transplant Rejection

[0106] A transplant rejection occurs when the transplant recipient's immune system attacks the transplanted organ or tissue. No two people (except identical twins) have identical tissue antigens. Therefore, in the absence of immunosuppressive drugs, the transplanted organs and tissues will always cause an immune response against foreign tissue (rejection) that can result in the destruction of the transplant. Although the typing of the tissue ensures that the organ or tissue is as similar as possible to the recipient's tissues, no match is perfect unless the donor is an identical twin, and the possibility of transplant rejection remains.

[0107] The inventive compounds of the general formula (I) are used as immunosuppressive drugs and / or anti-rejection drugs to prevent transplant rejection.

[0108] An example of transplant rejection is graft versus host disease (GVHD) that can occur after a bone marrow transplant. The donor's immune cells in the transplanted marrow produce antibodies against the host's tissues (transplanted patient) and attack the patient's vital organs. A transplant rejection (also known as graft / organ rejection) can usually occur when tissues or organs that need blood supply are transplanted. Such organs especially include internal organs such as heart, lung, liver, kidney, pancreas, spleen, skin, tissue, bone marrow, spinal cord, hormone-producing glands, gonads and gonads.

Neurodegenerative diseases

[0109] Another aspect of the present invention is directed to at least one of the compounds of the general formula (I) and / or pharmaceutically acceptable salts thereof for use in the prevention and / or treatment of neurodegeneration and neurodegenerative disorders.

[0110] Among the hundreds of different neurodegenerative disorders, attention has been given only to a few, including Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis.

[0111] It is worth mentioning that the same neurodegenerative process can affect different areas of the brain, causing a given disease to appear very different from the symptomatic point of view.

[0112] Neurodegenerative disorders of the central nervous system (CNS) can be grouped into diseases of the cerebral cortex (Alzheimer's disease), basal ganglia (Parkinson's disease), brain and cerebellar trunk or spinal cortex (sclerosis) amyotrophic lateral).

[0113] Examples for neurodegeneration and neurodegenerative disorders are: Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, AIDS-associated dementia, pigment retinitis, muscular spinal atrophy and cerebellar degeneration, ataxia / tremor associated with Xfragile syndrome ( FXTAS), progressive supranuclear paralysis (PSP) and striatonigral degeneration (SND) that is included with olivopontocerebellar degeneration (OPCD), and Shy Drager syndrome (SDS) in a syndrome known as multiple systemic atrophy (MSA).

[0114] In another aspect of the present invention, the compounds according to the general formula (I), as well as the pharmaceutically acceptable salts thereof are for use as an inhibitor of a protein kinase, preferably as an inhibitor for cellular protein kinase . Table 1 represents a list with all currently known protein kinases in a preferred embodiment of this aspect, said protein kinase is selected from the group consisting of:

Cyclin-dependent protein kinase (CDK), protein kinase C, c-Raf, Akt, CKI, IKK

 0 $ 3

kinases / ERKs, MAP kinases / JNKs, EGF receptor, InsR, PDGF receptor, c-Met, p70S6K, ROCK, Rsk1, Src,

Abl, p56Lck, c-kit, CaMk2 & D0N & D0N & 6. R * 6.-3� \ ¡/ D SURWH¯QD TXLQDVD GHSHQGLHQWH GH

Cyclin can be selected from the group consisting of: CDK1, CDK2, CDK3, CDK4, CDK5, CDK6,

CDK7, CDK8, CDK9, CDK10, CDK11, CrkRS (Crk7, protein kinase 7 associated with CDC2), CDKL1 (kinase

cyclin dependent 1); KKIALRE, CDKL2 (cyclin-dependent kinase 2), KKIAMRE, CDKL3 (kinase

cyclin-dependent 3), NKIAMRE, CDKL4, similar to cyclin-dependent kinase 1, CDC2L1 (cycle 2 of

cell division 1), PITSLRE B, CDC2L1 (cycle 2 of cell division 1), PITSLRE A, CDC2L5 (cycle 2 of

cell division 5), PCTK1 (PCTAIRE protein kinase 1), PCTK2 (PCTAIRE protein kinase 2), PCTK3

(PCTAIRE protein kinase 3) or PFTK1 (PFTAIRE protein kinase 1).

[0115] As used herein, a "kinase inhibitor" refers to any compound capable of downregulating, decreasing, suppressing or otherwise regulating the amount and / or activity of a kinase. Inhibition of these kinases can be achieved by any of the variety of mechanisms known in the species, including but not limited to direct binding to the polypeptide kinase, denaturing or inactivating the kinase or inhibiting gene expression (eg. mRNA transcription, translation to a nascent polypeptide, and / or modifications in the final polypeptide to a mature protein), which encodes the kinase. Generally, kinase inhibitors can be proteins, polypeptides, nucleic acids, small molecules or other chemical media. As used herein, the term "inhibit" or "inhibition" refers to the ability of a compound to regulate, decrease, reduce, suppress, inactivate or at least partially inhibit the activity of an enzyme or protein and / or virus replication.

[0116] A method of prevention and / or treatment of infectious diseases, including opportunistic diseases, in mammals, especially in humans, is also disclosed, the method of which is to administer to mammals a quantity of at least one compound according to the general formula (I ), effective in the prevention and / or treatment of such infectious diseases, including opportunistic diseases. Among the revealed methods are infectious diseases, including opportunistic diseases, caused by viruses. Infectious diseases caused by viruses, including opportunistic diseases, are caused by retroviruses, hepadnaviruses, herpesviruses, flaviridae and / or adenoviruses. In a preferred embodiment of this method, the retroviruses are selected from lentiviruses or oncoretroviruses, with the lentivirus being selected from the group consisting of: HIV-1, HIV-2, VIF, VIB, VIS, HIVS, VAEC, VMV or VAIE , preferably between HIV-1 or HIV-2, the oncoretrovirus being selected from the group consisting of: HTLV-I, HTLV-II or VLB. In another preferred embodiment of this method, the hepadnavirus is selected from HBV, GSHV or WHV, preferably HBV, the herpes virus is selected from the group consisting of :: HSV I, HSV II, VEB, VVZ, HCMV or VHH 8 , preferably HCMV and flaviviridae is selected from HCV, West Nile fever or yellow fever.

[0117] Methods for the prevention and / or treatment of infectious diseases including opportunistic diseases, prion diseases, immunological diseases, autoimmune diseases, bipolar disorders, cardiovascular diseases, proliferative cell diseases, diabetes, inflammation, transplant rejection, dysfunction are also revealed. erectile, neurodegenerative diseases, and stroke in mammals, especially in humans. The methods include the administration of an amount to the mammal of at least one compound according to the general formula (I) and / or the pharmaceutically acceptable salts thereof, effective for the prevention and / or treatment of said infectious diseases, including opportunistic diseases, prion diseases, immunological diseases, autoimmune diseases, bipolar disorders, cardiovascular diseases, proliferative cell diseases, diabetes, inflammation, transplant rejection, erectile dysfunction, neurodegenerative diseases, and stroke.

[0118] The specific diseases mentioned as infectious diseases, including opportunistic diseases, prion diseases, immunological diseases, autoimmune diseases, bipolar disorders, cardiovascular diseases, proliferative cell diseases, inflammation, transplant rejection, erectile dysfunction, neurodegenerative diseases, and stroke, are selected from the groups revealed above.

[0119] Compounds explicitly shown in Table 2 should preferably be used within the methods

or the indications revealed here. Another aspect of the present invention is that at least one of the compounds according to the general formula (I) used as a pharmaceutically active agent can be administered in combination with other therapeutic compounds.

[0120] For the indication of HIV compounds according to the general formula (I), preferably those that fall under the range of activity "a" for CDK9, as shown in Table 2, can be administered in combination with selected antiretroviral drugs between the following VIFe classes:

1) Nucleoside reverse transcriptase inhibitors (INTR)

2) Non-nucleoside reverse transcriptase inhibitors (INNTR),

3) Protease inhibitors (IP),

4) Fusion inhibitors or

5) Immunity stimuli.

[0121] Thus, another aspect of the present invention relates to combinations of drugs composed of at least one of the compounds according to the general formula (I) and / or pharmaceutically acceptable salts thereof, with at least one drug. antiretroviral, especially at least one of the drugs mentioned above.

[0122] The pharmaceutical compositions according to the present invention include at least one of the compounds according to the present invention, such as an active ingredient together with at least one pharmaceutically acceptable (non-toxic) carrier, excipient and / or diluent. The pharmaceutical compositions of the present invention can be prepared in a conventional solid or liquid carrier or diluent, and a conventional pharmaceutically made adjuvant with an appropriate dosage level in the usual manner. Preferred preparations are adapted for oral application. This form of administration includes, for example, pills, tablets, film-coated tablets, capsules, powders and deposits.

[0123] In addition, the present invention also includes pharmaceutical preparations for parenteral application, including dermal, intradermal, intragastral, intracutaneous, intravasal, intravenous, intramuscular, intraperitoneal, intranasal, intravaginal, intrabucal, percutaneous, rectal, subcutaneous, sublingual, topical application or transdermal, the preparations containing, apart from the typical conductors and / or diluents, at least one of the compounds according to the present invention and / or an acceptable pharmaceutical salt thereof as active ingredient.

[0124] The pharmaceutical composition according to the present invention contains at least one of the compounds according to the present invention and / or a pharmaceutically acceptable salt thereof as an active ingredient that will be administered in the typical manner in suitable carrier materials according to the form of administration. provided, eg for oral administration in the form of tablets, capsules (either filled with solids, filled with semi-solids or filled with liquids), constitutional powders, gels, elixirs, dispersible granules, syrups, suspensions and the like, in congruence with conventional pharmaceutical practices. For example, for administration in the form of tablets or capsules, the active component of the drug can be combined with any pharmaceutically non-toxic oral carrier, preferably with an inert carrier such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (capsules filled with liquids) and the like. In addition, binders, lubricants, desenteros agents and dyes can be incorporated into the tablet or capsule. The powders and tablets may contain from about 5 to about 95% of the weight of the disubstituted 4.6 pyramide derivative, according to the general formula (I) or analogous compounds thereof or the corresponding pharmaceutical active salt as active ingredient.

[0125] Appropriate binders include starch, gelatin, natural sugars, corn syrup, natural and synthetic gums such as acacia, sodium alginate, carboxymethyl cellulose, polyethylene glycol and waxes. As suitable lubricants, boric acid, sodium benzoate, sodium acetate, sodium chloride and the like can be mentioned. Suitable deserts include starch, methyl cellulose, guar gum and the like. Sweetening and flavoring agents, as well as preservatives, may also be included if they are considered appropriate. The desenteros, diluents, lubricants, binders, etc. They are discussed in more detail below.

[0126] In addition, the pharmaceutical compositions of the present invention may be formulated in the form of sustained release to provide a controlled release of one or more of the active components or ingredients to optimize the therapeutic effect (s), p .ej antihistamine activity and the like. Suitable dosage forms for sustained release include tablets with layers of varying disintegration time or controlled release polymer matrices impregnated with the active components and in the form of a tablet or capsules containing said encapsulated or impregnated polymeric matrices.

[0127] Liquid form preparations include solutions, suspensions and emulsions. As an example, water or water / propylene glycol solutions for parenteral injections or the addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions can be mentioned. Liquid form preparations may also include solutions for nasal administration.

[0128] Aerosol preparations suitable for inhalation may include solutions and solids in the form of powders which may be presented in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, eg nitrogen.

[0129] For the preparation of suppositories, a slowly melting wax is melted, such as a mixture of fatty acylglycerides, eg cocoa butter, and then the active ingredient is dispersed homogeneously therein, eg. stirring The melted homogeneous mixture is then poured into molds of convenient size, allowed to cool allowing solidification.

[0130] Also included are preparations in solid form to convert into liquid form just before use, either for oral or parenteral use. Such liquid forms include solutions, suspensions and emulsions.

[0131] The compounds according to the present invention can also be administered transdermally. The transdermal compositions may be in the form of cream, lotion, aerosol and / or emulsion and may be included in a transdermal patch of the matrix type or deposit of those commonly used in this matter.

[0132] The term capsule as mentioned herein refers to a specific container or wrapper made eg. of methyl cellulose, polyvinyl alcohols or denatured gelatins or starch to maintain or contain the Compositions consisting of the active ingredient (s). Hard coated capsules are manufactured typically of a mixture of jellies of relatively high resistance of bones or swine skin. The capsule itself may contain small amounts of dyes, opacifying agents, plasticizers and / or preservatives

[0133] Under the tablet is meant a solid, compressed or modulated dosage form, which contains the active ingredients with suitable diluents. The tablet can be prepared by compressing the mixture or the granules obtained by wet granulation, dry granulation or by well-known compaction to people with usual experience.

[0134] Oral gels refer to the active ingredient dispersed or dissolved in a semi-solid hydrophilic matrix.

[0135] Powders for constitution refers to a mixture of powders containing the active ingredients and suitable diluents that can be suspended, eg, in water or juice:

[0136] Suitable diluents are substances that normally form the bulk of the composition or dosage form. Suitable diluents include sugars such as lactose, sucrose, mannitol and sorbitol, starches derived from wheat, corn, rice and potatoes, and cellulose such as microcrystalline cellulose. The amount of the diluent in the composition may vary from about 5% to 96% of the weight of the total composition, preferably between 25 and 75% of the weight, and more preferably from 30 to 60% of the weight.

[0137] The term "desenteros" refers to the materials added to the composition so that they do not break (disintegrate) and discloses the pharmaceutically active ingredients of a medicament. Suitable deserts include "cold water soluble" starches, modified starches such as sodium carboxymethyl starch, natural and synthetic gums such as garrofín gum, karaya, guar, tragacanth and agar, cellulose derivatives such as methylcellulose and sodium carboxymethyl cellulose, microcrystalline celluloses and crosslinked microcrystalline celluloses such as croscarmellose sodium, alginates such as alginic acid and sodium alginate, clays such as bentonites, and effervescent mixtures. The amount of the desentero in the composition can vary from about 2 to 20% of the weight of the composition, more preferably about 5 to 10% of the weight.

[0138] Binders are substances that agglutinate or "stick" dust particles together and make them coalesce forming granules that serve as "adhesives" in the formulation. The binders join the cohesive force already available in the diluent or augmentation agent. Suitable binders include sugars such as sucrose, starches derived from wheat, corn, rice and potatoes, natural gums such as acacia, gelatin and tragacanth, seaweed derivatives such as alginic acid, sodium alginate and calcium and ammonium alginate, cellulose materials such as methylcellulose, sodium carboxymethylcellulose and hydroxypropylmethylcellulose, polyvinyl pyrrolidone and organic compounds such as magnesium aluminum silicate. The amount of binder in the composition may vary from 2 to about 20% of the weight of the composition, preferably from about 3 to about 10% and more preferably from 3 to 6% of the weight.

[0139] Lubricants refers to the class of substances that are added to the dosage to enable the exit of the mold or matrix to tablets, granules, etc. After being compressed, reducing friction and preventing deterioration. Suitable lubricants include metal stearates such as magnesium stearate, calcium stearate or potassium stearate, stearic acid, high melting waxes and other water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycol and D , L-leucine. Lubricants are usually added in the last step before compression, as they have to be present on the surface of the granules. The amount of lubricants in the composition may vary from 0.2 to 5% of the weight of the composition, preferably between 0.5 and 2% of the weight, and more preferably between 0.3 and 1.5% of the weight of the composition. .

[0140] Anti-caking agents are materials that prevent the caking of the components of the pharmaceutical composition and improve the flow characteristics of the granulate so that it flows smoothly and evenly. Suitable anti-caking agents include silicone dioxide and talc. The amount of anti-caking agent in the composition can vary from 0.1 to 5% of the weight of the final composition, preferably between 0.5 and 2% of the weight.

[0141] Coloring agents are excipients that give color to the composition or dosage form. Such excipients may include a food grade dye absorbed by a suitable absorbent such as clay or aluminum oxide. The amount of the coloring agent may vary from 0.1 to 5% of the weight of the composition, preferably between 0.1 and 1% of the weight.

[0142] Nucleotide binding proteins play an important role in the metabolism of an organism. For example, enzymes in the protein kinase family are essential switches of the cell signal transduction mechanism in all eukaryotic cells. They are involved in the control of numerous physiological and pathophysiological processes in eukaryotic organisms and therefore represent an important class of target drug for a variety of indications such as cancer and inflammatory and infectious diseases. Efficient and selective enrichment is a prerequisite for the subsequent identification of protein kinase targets through the proteomic-based approach. Efficient preracing techniques are described in WO 04/013633.

[0143] In view of the needs mentioned above, the present invention presents a means for the separation of at least one nucleotide binding protein from a protein pool, the medium is composed of at least one compound of the general formula (II ) and / or (III)

where R1, R2, R3, R4, R5, R6, L and m has the meaning defined in claim 1,

R37

 and R38 are independent of each other, selected from

-L *, C1-C6 substituted or unsubstituted alkyl-L *, C3-C8 substituted or unsubstituted cycloalkyl-L *, heterocyclyl-L * substituted or unsubstituted, aryl-L * substituted or unsubstituted, or heteroaryl-L * substituted or unsubstituted; L * is selected from -X1-H, -X3, -X1-X3; X1 and X2 are independently selected from each other from -NH-, -S-, -O-, -N (C1-C6alkyl) -, -COO-, - O-CO-, -CO-NH-, -NH-CO-, -O-CO-NH-, -NH-CO-O-, -NH-CO-NH-, -O-CO-O-, - NH-C (NH) -NH-, -NH-SO2-, SO2-NH-; X1-H and Y1-H are independently selected from each other from -NH2, -SH, -OH, -N (C1-C6 alkyl) H, -COOH, -CO-NH2, -O-CO-NH2, -NH-SO2H, -NH-SO3H, -SO2-NH2, -NH-C (NH) -NH2, X3 is selected from - (CH2) to-X4, - (CH2) to-CO-X4, - (CH2) to-NH-SO2-X4, - (CH2) to-Y1-H. - (CH2) a-X2 (CH2) b-X4, - (CH2) a-X2- (CH2) b-Y1-H; X4 is selected from -Cl, -Br, -I, -N3, -OOC-C1-C6 alkyl, -O-SO2-CH3, -O-SO2-p-C6H4-CH3; a and b are independent of any other integer from 1-10; immobilized in a material support.

[0144] It is preferred that the compounds according to the general formula (II) and / or (III) are linked in a manner Covalent to material support. Subjects of this invention are novel compounds according to formula (II) and (III), thus as the compounds bound to a material support. Likewise, the non-components are also revealed. immobilized on a material support according to formula (II) or (III). It is clear that to get such a covalent bond with the support material a radical, preferably a hydrogen, must be replaced in the compound respective to form such a link with the support material. It is also preferable that these compounds are linked to the support material by a group Y1 as defined above. Therefore, all compounds according to the present invention related to the group -NH2, -SH, -OH, -N (C1-C6 alkyl) H, -COOH, -NH-SO2H, - NH-SO3H, -NH-C (NH) -NH2, can be immobilized in a support material. Especially all components explicitly mentioned in Table 2, related to the group -NH2, -SH, - OH, -NH (C1-C6 alkyl), -COOH, -NH-SO2H, -NHSO3H, -NH-C (NH) -NH2, can be immobilized in a support material. Saying Support material is preferably composed of modified sepharose and sepharose or it can be any other known common support material, preferably a solid support material that can be used for column chromatography

[0145] In another embodiment of this medium, R1, R2 and R4 in the compounds according to the general formula (II) and / or (III) are independent of each other; R3 represents substituted phenyl, with phenyl being partially- or totally substituted with members of the group consisting of: C1-C4 linear or branched alkoxy, -OCH2-phenyl, or -NH2, and the phenyl being preferably monosubstituted; R5 represents substituted or unsubstituted phenyl, with phenyl being preferably substituted with C1-C4 linear alkyl or branched substituted or unsubstituted, L is selected from the group consisting of:

-NH-CO-, -NH-SO2-, -SO2-, -SO2-NH- or -CO-NH-, and m must be 1 and R6 is selected from the group consisting of: -H, C1-C4 alkyl linear or branched substituted or unsubstituted, monosubstituted phenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl

or C3-C8 substituted or unsubstituted cycloalkyl, and R37 must be

or where R38 is selected from C3-C8 substituted or unsubstituted cycloalkyl-L *, preferably C3-C8 unsubstituted cycloalkyl-L *, from substituted or unsubstituted aryl-L *, C1-C6 substituted or unsubstituted C1-C6 , substituted or unsubstituted heterocyclyl-L *, the heterocyclyl being selected from pyrrolidinyl or piperidinyl.

[0146] In another preferred embodiment of this medium, X1 in the compounds according to the present general formula (II) and / or (III) is selected -NH- or -O-, Y1-H is selected -NH2 or -N ( C1-C6 alkyl) H and preferably -NH2, a and b are selected as an integer from 1 to 6, preferably from 2 to 4, independent of each other.

[0147] In another preferred embodiment of this medium, at least one compound according to the general formula (II) and / or (III) immobilized on a material support is selected from the list of compounds of claim 20 and preferably is 3- Amino -N- {4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -phenyl} -propionamide (compound 102) and 4-Amino-N- (4- {6- [2- (3 -amino-propoxy) -phenyl] -pyrimidine-4-ylamino} -phenyl) -benzamide (compound 103).

[0148] In a preferred embodiment of this medium, the support material is composed of or consists of sepharose, preferably modified sepharose as obtainable from semers in Amersham Biosciences. Another modified sepharose material that could be used as a support material is EAH-sepharose 4B and ECH sepharose 4C, which are also available from Amersham Biosciences.

[0149] According to another embodiment of this medium, the support material is composed of or consists of ferro- and ferrimagnetic particles such as known from WO 01/71732, incorporated herein by reference as regards the properties of the ferroimagnetic particles. The ferro- or ferrimagnetic particles may be composed of glass or plastic. The ferro- or ferrimagnetic particles that can be used with the present invention can be porous. Ferro- or ferrimagnetic glass particles can represent approximately 30 to 50% of the weight of Fe3O4 and approximately 50 to 70% of the weight of SiO2. The ferroimagnetic particles used herein preferably have an average size of 5 to 25 Pm in diameter, more preferably 6 to 15 Pm, and particularly 7 to 10 Pm. The total surface area of the ferro- or ferrimagnetic particles may be 190 m2 / g or larger, eg in the range of 190 to 270 m2 / g (as determined according to the Brunaur Emmet Teller (BET) method). ).

[0150] These magnetic particles facilitate the purification, separation and / or evaluation of biomolecules such as protein kinases. The magnetic particles (or beads) that link a molecule of interest can be accumulated and recovered, by applying an external magnetic field to a container containing the particles. Unbound molecules and supernatant liquid can be separated from particles or discarded, and molecules bound to magnetic particles can be extracted in an enriched state.

[0151] In another preferred embodiment of this medium, the compounds according to the general formula (II) and / or (III), in which at least one of these compounds is bound to the support material, can be used to enrich the protein nucleotide binding, preferably an ATP binding protein, more preferably a kinase, and mostly a protein kinase from a pool of different proteins, such as a proteome, a cell lysate or a tissue lysate.

[0152] According to another preferred aspect of the present invention, an ex vivo method for enriching, purifying or depleting at least one nucleotide binding protein, preferably an ATP binding protein, more preferably a kinase, and mostly a protein kinase, from a pool of proteins containing at least one of said nucleotide binding proteins, the method consisting of the following steps:

a) Immobilize at least one compound of the general formula (II) and / or (III)

wherein R1, R2, R3, R4, R5, R6, L and m have the meanings as defined in claim 1, R37 and R38 are independently selected from each other from

-

L *, C1-C6 substituted or unsubstituted alkyl-L *, C3-C8 substituted or unsubstituted cycloalkyl-L *, substituted or unsubstituted heterocyclyl-L *, substituted or unsubstituted aryl-L *, or heteroaryl-L * substituted or unsubstituted; L * is selected from -X1-H, -X3, -X1-X3; X1 and X2 are independently selected from each other from -NH-, -S-, -O-, -N (C1-C6 alkyl) -, -COO-, -O-CO-, -CONH-, -NH- CO-, -O-CO-NH-, -NH-CO-O-, -NH-CO-NH-, -O-CO-O-, -NH-C (NH) -NH-, -NH-SO2 -, -SO2-NH-; X1-H and Y1-H are independently selected from each other from -NH2, -SH, -OH, -N (C1-C6 alkyl) H, -COOH, -CONH2, -O-CO-NH2, -NH- SO2H, -NH-SO3H, -SO2-NH2, -NH-C (NH) -NH2, X3 is selected from - (CH2) a-X4, - (CH2) a-CO-X4, - (CH2) a- NH-SO2-X4, - (CH2) a-Y1-H, - (CH2) a-X2 (CH2) b-X4, - (CH2) a-X2- (CH2) b-Y1-H; X4 is selected from -Cl, -Br, -I, -N3, -OOC-C1-C6 alkyl, -O-SO2-CH3, - O-SO2-P-C6H4-CH3; a and b are independently of each other, integers from 1 to 10 in the support material;

b) contacting the pool of proteins containing at least one nucleotide binding protein in contact with at least one immobilized compound in the support material according to the general formula (II) and / or according to the general formula (III); Y

c) separating unbound proteins to at least one compound according to general formula (II) and / or according to general formula (III) in the support material of at least one nucleotide binding protein bound to at least one of said compounds immobilized in the support material; Y

d) releasing and collecting at least one nucleotide binding protein bound to at least one of the compounds according to the general formula (II) and / or according to the general formula (III) immobilized in the support material of at least one of said compounds compounds.

[0153] According to a preferred embodiment of the method, in the compounds according to the general formula (II) and / or (III), R1, R2 and R4 are independent of each other; [0154] R3 represents substituted phenyl, the phenyl being partially- or totally substituted with members of the group consisting of: C1-C4 linear or branched alkoxy, phenyl-OCH2-, or -NH2, and the phenyl being preferably monosubstituted;

[0155] R5 represents substituted or unsubstituted phenyl, with phenyl being preferably substituted with C1-C4 linear or branched alkyl substituted or unsubstituted,

[0156] L is selected from the group consisting of:

-

NR14-SO2-, -NR14-SO-, -NR17-CO-, -SO2-NR18-, -CO-NR19-, with R14, R17, R18, and R19 having the meaning defined in claim 1, and where m is selected 1 and R6 is selected from the group consisting of: -H, C1-C4 substituted or unsubstituted linear or branched alkyl, monosubstituted phenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl or C3-C8 substituted or unsubstituted cycloalkyl replaced, and R37 is selected

Or where

R38

 is selected from C3-C8 substituted or unsubstituted cycloalkyl-L *, preferably C3-C8 unsubstituted cycloalkyl-L *, or from substituted or unsubstituted aryl-L *, C1-C6 substituted or unsubstituted alkyl-L *, heterocyclyl -L * substituted or unsubstituted, the heterocyclyl being selected from pyrrolidinyl or piperidinyl.

[0157] According to another preferred embodiment of said method, in the compounds according to the general formula (II) and / or (III), X1 is selected from -NH- or -O-, Y1-H is selected from -OH, - NH2 or -N (C1-C6 alkyl) H, preferably -NH2, and a and b are independently selected from each other from 1 to 6, preferably from 2 to 4.

[0158] The compounds immobilized in the support material are preferably selected from the list of compounds of claim 20, and especially preferred are the 3-amino-N- {4- [6- (2-methoxyphenyl) -pyrimidine- 4-ylamino] -phenyl} -propionamido (compound 102) and 4-amino-N- (4- {6- [2- (3-amino-propoxy) -phenyl] pyrimidine-4-ylamino} -phenyl) -benzamide (compound 103).

[0159] In another preferred embodiment of the present invention, the method further includes the step of collecting at least one released nucleotide binding protein, eg the ATP binding protein, especially the protein kinase.

[0160] The method according to the present invention can be implemented using any of the means and materials described with reference to the first aspect of the present invention.

[0161] In another preferred aspect of the method according to the present invention in step c) the separation of unbound proteins to at least one immobilized compound in the support material of at least one nucleotide binding protein bound to at least one of said compounds immobilized in the support material is carried out by means of a buffer wash containing 5 to 500mM hepes pH 6.5-8.5 or 5 to 500mM Tris-HCl pH 6.8 to 9.0, 0 to 2500mM NaCl, 0 to 5% triton X-100 , 0 to 500mM EDTA, and 0 to 200mM EGTA. In another preferred embodiment, the buffer contains 20mM hepes / NaOH pH 7.5, 100mM NaCl, 0.15% triton X-100, 1 mM EDTA, and 1 mM EGTA.

[0162] In another preferred embodiment of the method according to the present invention, in step d) the release of at least one nucleotide binding protein, eg, the protein kinase, bound to at least one of the immobilized compounds in the material of support, is carried out by means of a buffer wash containing 5 to 500mM hepes pH 6.5-8.5 or 5 to 500mM Tris-HCl pH 6.8 to 9.0, 0 to 1000mM NaCl, 0 to 5.0% triton X-100, 0-5% SDS, 0 to 500mM EDTA, 0 to 200mM EGTA, 1 to 100mM ATP, 1 to 200mM MgCl2 and 0.1 to 10mM of at least one of the compounds immobilized in the support material. In another preferred embodiment, the buffer contains 50mM hepes pH 7.5, 150mM NaCl, 0.25% triton X-100, 1mM EDTA, 1mM EGTA, 10mM ATP, 20mM MgCl2 and 1mM of at least one of the immobilized compounds in the support material. In another preferred embodiment of the method of the present invention, the protein reserve is a proteome, cell lysate or tissue lysate. In another embodiment of the method according to the present invention, the ATP binding protein is a protein kinase. In a preferred embodiment of the method according to the present invention, the protein pool contains 0.5 to 5M, preferably 0.5 to 3M, and more preferably 0.75 to 2M of a salt, and preferably is an alkali metal salt, preferably NaCl.

In a preferred embodiment of the present invention, at least one nucleotide binding protein, preferably an ATP binding protein, it is enriched with at least 100 times more of the stock of proteins, preferably between 100 and 1000 times more. In another preferred embodiment, at least nucleotide binding protein, preferably a binding protein ATP is enriched with at least 104 times more and preferably up to 106 times more. In another aspect of the present invention, the invention contains a kit that includes the medium as summarized previously.

Description of figures: [0163] Figures 1a-1c shows the representative compounds of the general formula (I); Figure 2 shows the kinase activity in different amounts of CDK9wt and KRDN (K48R / D167N); Figure 3 shows the effect of the selected compounds depending on the transcriptional activity

NfKb; Figure 4 shows the effect of the selected compounds on HBV; Figure 5 shows the effect of the selected compounds on HCMV replication; Experimental part: Analytical methods: [0164] LC / MS data have been obtained using a Micromass ZQ instrument with atmospheric pressure, ionization

chemical or electrospray ionization under the conditions described below.

LC-MS standard acidity conditions (Method A1)

HPLC Configuration [0165]

Solvents: Acetonitrile (far UV grade) with 0.1% (V / V) formic acid Water (High purity via Elga UHQ unit) with 0.1% formic acid Column: Phenomenex Luna 5P C18 (2), 30X4.6mm. Addition rate: 2ml / min

Gradient:

A: Water / formic acid B: MeCN / formic acid

Time

TO% B%

0.00

80 twenty

2.50

0.00  100

3.50

0.00  100

3.60

80  twenty

4.50

 80  twenty

LC-MS standard acidity conditions (Method A2) HPLC configuration [0166]

Solvents: Acetonitrile (far UV grade) with 0.1% (V / V) formic acid Water (High purity via Elga UHQ unit) with 0.1% formic acid Column: Phenomenex Luna 5P C18 (2), 30X4.6mm. Addition rate: 2ml / min Gradient: A: Water / formic acid B: MeCN / formic acid Time A% B%

0.00 95 5

3.50 5 95

5.50 5 95

5.60

95 5

6.50

95 5

UV detection via HP or Waters DAD

[0167] The purity is given by the integral in the 210-400 nm window. If necessary, specific wavelength traces can be extracted from the DAD data. ELS detection optional using Polymer Labs ELS-1000.

Detection: Micromass Platform or ZQ, both LC-MS single quadruple instruments. [0168]

Scanning range for MS Data (m / z)

Principle (m / z 100 End (m / z) 650

With + ve / -ve switch lonization by electrospray or APCI, depending on the type of compounds.

LC-MS standard basic conditions (Method B1)

HPLC Configuration [0169]

Solvents: Acetonitrile (far UV grade) Water (High purity via Elga UHQ unit) with 10mM bicarbonate ammonium (ammonium acid carbonate) Column: - Waters Xterra MS 5P C18, 50 x 4.6mm. Addition rate: - 2ml / min

Gradient:

- A: Water NH4HCO3 B: NH4HCO3 MeCN

Time

TO% B%

0.00

80 twenty

2.50

0 100

3.50

0 100

3.60

80 twenty

4.50

80 twenty

LC-MS standard basic conditions (Method 82) HPLC configuration [0170]

Solvents: Acetonitrile (far UV grade) Water (High purity via Elga UHQ unit) with 10mM bicarbonate ammonium (ammonium acid carbonate) Column: - Waters Xterra MS 5P C18, 100 x 4.6mm. Addition rate: - 2ml / min Gradient: - A: Water / NH4HCO3 B: MeCN / NH4HCO3 Time A% B%

0.00 95 5

3.50 5 95

5.50 5 95

5.60

95 5

6.50

95 5

UV detection via HP or Waters DAD

[0171] The purity is given by the integral in the 210-400 nm window.

[0172] If necessary, specific wavelength traces can be extracted from the DAD data. Optional ELS detection using Polymer Labs ELS-1000.

Detection: Micromass Platform or ZQ, both LC-MS single quadruple instruments. [0173]

Scanning range for MS Data (m / z)

Beginning (m / z) 100 End (m / z) 650

With + ve / -ve switch

lonization by electrospray or APCI, depending on the type of compounds. All reagents have been obtained commercially and have been directly used. DMF and THF have been dried with 4A molecular sieves (Fisher Scientific). Column chromatography has used Silica Gel 60 (Fluka). TLC has been removed using precoated plastic sheets Polygram SIL G / UV254 (Macherey-Nagel).

LC-MS standard basic conditions (Method C1)

[0174] The conditions for the basic basic conditions LC-MS for method C1 are the same as for method A1, with the difference that for the method C1 no buffer has been used as ammonium bicarbonate (ammonium acid carbonate ) or formic acid.

LC-MS standard basic conditions (Method C1)

[0175] The conditions for the basic basic conditions LC-MS for method C2 are the same as for method A2, with the difference that for the method C2 no buffer has been used as formic acid.

Standard conditions for flash chromatography

[0176] Flash chromatography was done using a SiO2 column and using the following solvents:

Petroleum ether (bp 40-60), ethyl acetate, methanol

LC-MS standard neutral conditions (Method D1) HPLC configuration [0177]

Solvents: Acetonitrile (Lichrosolv Merck) Water (Lichrosolv Merck) with 1 mM ammonium acetate pH 6.8 Column: - Waters XTerra MS C18 3.5 Pm, 3.0 x 50 mm. Addition rate: - 0.8 ml / min Gradient: -A: Water / NH4Oac B: MeCN Time A% B%

0.00 98 2

5.00

5 95

6.50

5 95

6.60 98 2

8.00 98 2

LC-MS standard neutral conditions (Method D2)

HPLC configuration [0178]

Solvents: Acetonitrile (Lichrosolv Merck) Water (Lichrosolv Merck) with 1 mM ammonium acetate pH 6.8 Column: - Waters XTerra MS C18 2.5 Pm, 3.0 x 30 mm. Addition rate: - 0.8 ml / min Gradient: -A: Water / NH4OAc B: MeCN Time A% B%

0.00

100 0

1.50

100 0

8.50 30 70

8.60 5 95

10.60 5 95

10.70 100 0

12.00 100 0

Standard neutral LC-MS conditions (Method D3)

HPLC configuration

[0179]

Solvents: Acetonitrile (Lichrosolv Merck) Water (Lichrosolv Merck) with 1 mM ammonium acetate pH 6.8 Column: - Bonus RP 3.5 Pm, 4.6 x 75 mm. Addition rate: -0.8 ml / min Gradient: -A: Water / NH4OAc B: MeCN Time A% B%

0.00

100 0

1.50

100 0

8.50 15 85

8.60 2 98

11.60 2 98

11.70 100 0

13.50 100 0

UV detection via Waters 2996 PDA

[0180] For purity fixation, the wavelength at 215, 254 and 310 nm is extracted from the PDA data and an average purity is calculated from the peak areas.

Detection: Micromass Platform or ZQ, both LC-MS single quadruple instruments. [0181]

Scanning range for MS Data (m / z)

Beginning (m / z) 100 End (m / z) 650

With + ve / -ve switch lonization by electrospray or APCI, depending on the type of compounds.

Synthesis of the compounds

[0182] The synthesis of the inventive 4.6 substituted pyrimidines according to the present invention has been preferably carried out according to the general synthetic sequence shown in scheme 1, involving in a first step the animation of the pyrimidine ring followed by the Suzuki reaction or a Reverse order of reaction steps:

Scheme 1

[0183] Hal represents -Cl, -Br or -I. R2 and R4 are R3, R5, R6 and L has the meaning defined in claim 1, and is selected 1. In the case that protective groups have been used, a final deprotection step can be followed.

[0184] The introduction of the amino group can be preformed by known methods (JE Arrowsmith et al., Journal of Medicinal Chemistry 1989, 32 (3), 562-568, JR Porter et al, Bioorganic Medicinal Chemistry Letters 2002, 12 (12 ), 1595-1598):

[0185] For example, as shown in scheme 1, the animation is performed upon reaching equimolar amounts of 4,6-pyrimidine dihalogenated and a compound in a polar solvent, and in the presence of an organic base or an organic or inorganic acid. at temperatures between 50 and 120 ° C. Preferably, the polar solvent is Nmethyl-2-pyrrolidinone (NMP) or a lower alcohol, such as isopropanol or butanol, the organic base is selected for example from N, N-diisopropylethylamine (DIPEA), N-methyl-piperidine or NEt3, the acid can be selected for example from HCl, H2SO4, CH3COOH and the reaction takes place at a temperature between 60 and 110 ° C, preferably between 70 and 100 ° C. It should be understood that the reaction temperature depends on the reactivity of the amino between 80 and 110 ° C are preferred and in these cases a solvent with higher cooking point such as butanol

o NMP has the ability to offer good performance with the desired compounds.

[0186] The introduction of R3 into the pyrimidine shell as shown in scheme 1, is preferably performed by Suzuki coupling at temperatures between 60 and 110 ° C, preferably at temperatures between 70 and 100 ° C, more preferably between 75 and 90 ° C. (I. Minoru, K. Machiko, T. Masanao, Synthesis 1984, 936-938; J. P. Wolfe, R. A. Singer, B. H. Yang and S. L. Buchwald, Journal of the American Chemical Society 1999, 121, 9550-9561).

[0187] The reaction takes place in organic solvents such as DME, DMF, THF, dioxane or methanol or this reaction takes place in a mixture of organic solvents and water, such as DMF / water, DME / water or THF / water, in the presence of a base such as NaHCO3, NaOH, TIOH, NaOMe, K2CO3, K3PO4, NEt3, Cs2CO3 or Tl2CO3 and in the presence of a catalyst such as PdCl2 (dppf) {[1,1'-bis- (diphenylphosphino) ferrocene] dichloropalladium II} , Pd (PPh3) 4 or PdCl2 (PPh3) 2 or a catalyst / binding system / ligation system such as Pd (OAc) 2 / PPh3, Pd (OAc) 2 / 2- (Dicyclohexylphosphino) -biphenyl or Pd (OAc) 2 / tris (2,4,6-trimethoxyphenyl) phosphine. R3 containing a boron compound used for this reaction is selected from the group consisting of: R3B (OH) 2, R3B (OPri) 2, R3-9-BBN (9-BBN = 9-borabcycle [3.3. 1] nonanol) or

 [0188] The chemistry described above can take place in either order and derivatization can take place after amination and before / after subsequent Suzuki cross coupling. Other suitable methods will be apparent to the chemist experienced in the work, since they will be the methods for the preparation of the starting materials and the intermediates. If protective groups have been used, an unprotective step may optionally be taken at the end to obtain known unprotective reactions to a person with subject matter skills.

[0189] For example, inventive compounds according to the present invention, such as amide derivatives, sulphonamide derivatives, urea derivatives or guanidine derivatives, can be prepared from suitably functionalized anilines that react with the appropriate agent. The amides and sulfoamides can be linked as shown in scheme 2 or the reserve amide can be linked as described in the scheme

3. The introduction and removal of protection groups (PG) may be necessary for the different synthetic steps. This includes for example the use of t-butylcarbamate (BOC) amino acid protection with standard conditions for introduction and extraction.

Scheme 2

D represents -OH or -Hal. R2, R3, R4, R5 and R6 have meanings as defined in claim 1, wherein R2 and R4 represent -H. The reaction described in scheme 2 takes place in the presence of an inert solvent such as THF or CH2Cl2, in the presence of an organic base such as NEt3, DIPEA or 2,4,6-trimethylopyridine (TMP) and at temperatures between -5 ° C and 60 ° C, preferably at temperatures between 10 and 50 ° C, more preferably the reaction will take place at temperatures between 20 and 45 ° C. In the event that D represents -OH, the amine is coupled in the presence of a coupling agent selected from the group consisting of:

N - [(1-H-benzotriazol-1-yl) -dimethylamino) methylene] -N-methylomethanamio hexaphlorophosphate N-oxide (HBTU), O (3,4-dihydro-4-oxo-1,2,3-benzotriazine -3-yl) 1,1,3,3-tetramethiuronium hexifluorophosphate (HDTU), O- (benzotriazol1-yl) -1,1,3,3-bis (pentamethylene) uranium hexafluorophosphate (HBPipU) or benzotriazol-1-yl -N-oxy-tris (pyrrolidino) phosphonium hexaflurophosphate (PyBOP). Other coupling methods will be apparent to a chemist experienced in the art.

[0190] As mentioned above, the reverse amide can be linked according to the procedure described in scheme 3:

[0191] R2, R3, R4, R5 and R6 have the meaning as defined in claim 1, representing R2 and R4 at -H, and representing Hal at -Cl, -Br or -I.

[0192] In a first step of the reaction, a dihalogenated 4,6-pyrimidine reacts with an aminoalkyl compound, the reaction taking place in the presence of a base, such as DIPEA or an acid such as HCl, H2SO4, in the presence of a solvent such as NMP or DMF and at temperatures between 60 and 140 ° C, preferably at temperatures between 80 and 120 ° C, more preferably at temperatures between 90 and 110 ° C. The second step of the reaction takes place in the presence of a base such as LiOH, and in the presence of a solvent / water mixture selected from the group consisting of: THF / water, DME / water or DMF / water. The third step of the reaction, the coupling amine as shown in scheme 3, takes place under the same conditions as described for the corresponding reaction step in scheme 2. The coupling agent is selected from the group consisting of : HBTU, HDTU, HBPipU or PyBOP. Other suitable coupling methods will be apparent to the chemist with experience in the field. The introduction of R3 into the pyrimidine framework is performed as described for the corresponding reaction step in scheme 1.

[0193] According to scheme 3, the order of the reaction steps can also be reversed.

[0194] If protection groups have been used, a final deprotection step can be carried out according to the general deprotection reactions known to the person skilled in the art.

[0195] Scheme 4 shows a reaction procedure for the synthesis of alkylated sulfonamide derivatives according to the present invention:

Scheme 4

[0196] Hal represents -Cl, -Br, or -I. R2, R4, R5 and R6 have the meaning as defined in claim 1, preferably R2 and R4 represent -H, and R14 is selected C1-C5 substituted or unsubstituted linear or branched alkyl or - (CH2) r-COOR16, R14, R16 and r having the meaning as defined in claim 1.

[0197] The alkylated sulfonamide derivatives according to the present invention can be prepared by a corresponding sulfonamide reaction with, for example, an alkyl halide or similar reagent in possession of a leaving group in an aprotic polar solvent such as DMF, THF, NMP or dioxane, in the presence of a strong base such as NaH, NaNH2, LiNH2 or KotBu at temperatures between -20 and 80 ° C, preferably at temperatures between 0 and 60 ° C, more preferably at temperatures between 20 and 40 ° C. The intermediates obtained can then be transformed into the desired products as described in scheme 4, while the corresponding reaction conditions are described in scheme 1.

Scheme 4

[0198] Hal represents -Cl, -Br, or -I. R2, R4, R5 and R6 have the meaning as defined in claim 1, representing R2 and R4 at -H, and R14 being selected from C1-C6 substituted or unsubstituted linear or branched alkyl or - (CH2) r-COOR16, having R14, R16 and r meanings different from those defined in claim 1.

[0199] The alkylated sulfonamide derivatives according to the present invention can be prepared by a reaction of the corresponding sulfonamide with, for example, an alkyl halide or a similar reagent in possession of a leaving group in an aprotic polar solvent such as DMF, THF, NMP or dioxane, in the presence of a strong base such as NaH, NaNH2, LiNH2 or KotBu at temperatures between -20 and 80 ° C, preferably at temperatures between 0 and 60 ° C, more preferably at temperatures between 20 and 40 ° C. The intermediaries obtained can be then transformed into the desired products as described in scheme 4, while the conditions of Corresponding reactions are described in scheme 1.

[0200] Scheme 5

[0201] R2, R3, R4 and R5 have the meaning as defined in claim 1, representing R2 and R4 at -H, and PG at protective group that is defined below. X represents a starting group as halogen.

[0202] Guanidine derivatives can be prepared by reacting an amine compound with a benzotriazole derivative as shown in scheme 5. This reaction takes place in the presence of a base as NEt3, DIPEA, N-methyl-piperidine, or N-ethylomorpholine and an organic solvent selected from the group to be It comprises: CH2Cl2, CHCl3, THF, DMF, dioxane, ether-methyl-tert-butyl (MTBE) or diisopropylether (DIPE). This The reaction takes place under heating, preferably at a temperature of the solvent reflux used. Protective groups known in peptide chemistry are used for the protection of amino acids. Preferably carbamate protective groups are used, more preferably a carbamate group is used tert-butyl (BOC) The protective group can be introduced using (BOC) 2O, BOC-ONH2, BOC-N3 or BOC-O-CHCl-CCl3, preferably (BOC) 2O. The BOC group is introduced under the basic conditions in a polar solvent, water or a mixture of water and solvent. The division of the protective group is performed under acidic conditions such as HCl in EtOAc, Me3SiJ in CHCl3, H2SO4 in dioxane or trifluroacetic acid in CH2Cl2, being preferred as a solvent / mixing agent, use trifluroacetic acid in CH2Cl2. This reaction takes place at temperatures between 0 and 60 ° C,

Scheme 7

[0203] Hal represents -Cl, -Br or -I, R2, R4, R5, R6, L and m have the meaning as defined in claim 1, R2 and R4 being in this case -H. For this reaction an organic base selected from NEt3, DIPEA or N-methyl-piperidine is used, and the reaction It takes place in a polar solvent such as isopropanol, butanol or NMP. For microwave conditions a power of 100 to 300, preferably 150 to 250 watts, and the reaction takes place at temperatures between 140 and 220 ° C, preferably at temperatures between 150 and 170 ° C. The preferred reaction time is 30 min to 140 min.

Scheme 8

[0204] R2, R3, R4, R5 and R6 are defined in claim 1, representing R2 and R4 at -H and D being selected - OH or -Hal.

[0205] The synthesis of urea derivatives according to the present invention has taken place according to the two procedures Synthetics shown in scheme 9: The urea derivative can be obtained by reacting a compound amine with an isocinate using a solvent as dioxane and at a temperature of 60 to 100 ° C, preferably 70 to 90 ° C.

Scheme 9

[0206] R2, R3, R4, R5 and R6 have the meaning as defined in claim 1. The second synthetic process begins when an amine compound reacts to an equimolar amount of phenyl chloroformate, this reaction taking place in the presence of a base such as pyridine, NEt3 or DIPEA, and a solvent such as THF, DMF, dioxane or MTBE. The reaction is performed at a temperature between 0 and 60 ° C, preferably at a temperature between 10 and 40 ° C, more preferably between 20 and 30 ° C. In a second step of the reaction, an amine compound containing R6 reacts with the carbamate derivative to obtain the desired product. This reaction is performed in a solvent such as THF, DMF, dioxane or MTBE and the reaction takes place at temperatures between 20 and 100 ° C, preferably at temperatures between 30 and 80 ° C, more preferably between 40 and 60 ° C.

R2, R4, R5, R6, R19, L and m have the meaning as defined in claim 1, representing R2 and R4 at -H. n is selected 1-8. NaH is used as a base in organic solvents such as THF and DMF. The amination takes place under acid catalysis according to scheme 1.

[0207] The synthesis of the amide derivatives according to the present invention using a different method for step of the amination is shown in scheme 10.

[0208] The amination reaction takes place in a polar solvent, using 1 equivalent of the nitroaniline derivative and 2 equivalents of the 4,6-pyrimidine dihalogenated derivative in the presence of a base. The preferred polar solvent is N-methyl-2-pyrrolidinone (NMP) or a lower alcohol such as isopropanol or butanol, the organic base is selected between N, N-diisopropylethylamine (DIPEA), N-methyl-piperidine or NEt3. This reaction is performed using the following microwave conditions as described by G. Luo et al, Tetrahedron Letters 2002, 43, 5739-5743.

[0209] As a next reaction step a Suzuki coupling is made under the conditions described in the Scheme 1. The following reduction step can be performed as described by loffe et al., Russian Chemical Review 1966, 35, 19. The last reaction step is analogous to that described in scheme 2.

Scheme 10

[0210] R2, R3, R4, R5 and R6 have the meaning as defined in claim 1, D is defined as in scheme 2 and Hal is defined as in scheme 1.

Scheme 10A

[0211] R1, R2, R3, R4, R5 and R14 have the meaning as defined in the claim, representing R2 and R4 at -H, and PG and PG 'represent protective groups, where PG = PG' or PG '= H , as defined below. n is selected from 1 to 8. For the protection of amino function, general protective groups are used. Preferably, the phthaloyl protective group, but also carbamates such as carbamate-t-butyl (BOC) or a 9H-fluorenyl-9-ylmethyl carbamate group (FMOC). The phthaloyl group can be introduced using phthalic anhydride, phthalimide-NCO2Et, or (CH3OOC) C6H4COCl in organic solvents and at elevated temperatures, preferably using a base. The BOC group can be introduced using (BOC) 2O, BOC-ONH2, BOC-N3 or BOC-O-CHCl-CCl3, preferably (BOC) 2O. The BOC group is introduced into a polar solvent, water or a mixture of water and solvent under basic conditions. The FMOC group can be introduced using FMOCCl, FMOC-N3, FMOC-OBt (Bt = benzotriazol-1-yl), FMOC-OSu (Su = suquinimidyl) or FMOC-OC6F5. The FMOC group is introduced under basic conditions in a polar solvent or a mixture of water and solvent, using a NaHCO3 base.

Scheme 10B

[0212] R1, R2, R3, R4 and R5 have the meaning as defined in claim 1, representing R2 and R4 at -H, and PG to the protective group, preferably a carbamate such as t-butyl carbamate (BOC). n is selected from 1

8. The hydrolysis of the ester group is carried out in an organic solvent and water such as THF / water with a base such as LiOH. The coupling of the amides takes place according to the general EDC · HCl / HOBt methods of the coupling conditions in organic solvents such as DMF at room temperature.

[0213] The compounds according to the present invention, representing L a -NH-SO2- can be synthesized as described in Scheme 11:

Scheme 11

[0214] Bn = Benzyl; R2, R3, R4 and R6 have the meaning as defined in claim 1.

[0215] In a first step of the reaction, the compound benzyl ether can be synthesized using the conditions as described by O. Mitsunobu et al., Synthesis, 1981, 1-28: Amino-nitrophenol is reactivated with benzyl alcohol in the presence of trialkyl- or triarylphosphine, such as triphenylphosphine and in the presence of an azodicarboxylate alkyl such as diethyl dicarboxylate (DEAD) in a solvent such as dichloromethane to obtain benzyl ether. The animation of this intermediary can take place under the conditions as described in scheme 1. The following reduction of Zn can be performed as described by Ioffe et al., Russian Chemical Review 1966, 35. 19. The last two steps of the reaction , shown in scheme 11, can be similarly shaped as described in scheme 2 or in scheme 1 (Suzuki reaction). The synthesis of the compounds of the general formula (II) is represented in scheme 12:

Scheme 12

[0216] R1, R2, R4, R5, R6, L and m have the meaning as defined in claim 1; X1 represents -NH-, -S- or -O-, Y1-H, a and b have the meaning defined in claim 58, PG represents the protective group as defined in scheme 6 and Hal represents -Cl, -Br or -I.

[0217] In a first step of the reaction a derivative pyrimidine reacts with an alkyl halide derivative according to the scheme below, in a polar aprotic solvent such as DMF, THF, NMP or dioxane, in the presence of a strong base such as NaH, NaNH2, LiNH2 or KOtBu, at temperatures between 0 and 50 ° C, preferably at temperatures between 10 and 40 ° C, more preferably at temperatures between 20 and 30 ° C. The intermediates obtained can then be transformed into the desired product, dividing the group protective as described for the corresponding reaction in scheme 6.

Preparation of the compounds:

[0218] The LC-MS data for each compound mentioned below is explicitly shown in Table 2,

IA) Preparation of compounds 24, 25 and 72 (according to scheme 1):

[0219] To a solution of 4,6-Dichloropyrimidine (0.67mmol) in iPrOH (5mL), NEt3 (1.3mmol) was added at room temperature followed by the amino (0.67mmol) and the mixture was heated to 80 ° C for 18 hours. The solvent was evaporated under reduced pressure and the solid residue suspended in H2O (~ 5mL). The solid was filtered off, washed with water (2x), Et2O (3x) and then dried to get the product.

IB) Preparation of compound 309 (according to scheme 1):

[0220] 4,6-Dichloropyrimidine (1.5 mmol), methyl 4-aminobenzoate (1.5 mmol) and a solution of 3M HCl (4 drops) they were suspended in iPrOH (16 ml) and heated in a personal chemical optimization microwave system to 100 ° C for 1200 s. Upon standing at room temperature a settling formed which was filtered. The solvent in the tank was evaporated under reduced pressure and results in the intermediate product of 71% of a cream-colored solid. A suspension of what last (0.38 mmol), 2- (4,4,5,5, -tetrametyl-1,3,2-dioxiborolan-2-yl) aniline (0.38 mmol), sodium carbonate (1.14 mmol) , and Pd (PPh3) 2Cl2 (2 mol%) was heated in a mixture of DME / EtOH / water (4 ml / 0.5 ml / 0.5 ml) in a system of personal microwave of chemical optimization at 100 ° C for 1500 s. The reaction mixture was poured into a saturated aqueous NH4Cl solution (20 ml) and extracted with EtOAc (3x). The Combined organic layers were dried (Na2SO4) and the solvent was evaporated under reduced pressure. The crude product was purified by the preparation-HPLC (XTerra Prep MS C18 5 μm, 19 x 150 mm, gradient of MeCN water for 13 min) and compound 309 was achieved in 37%.

IC) Preparation of compound 306 (according to scheme 1):

[0221]

a) Preparation of [4- (6-Chloro-pyrimidine-4-ylamino) -butyl] -carbamic acid tert-butyl ester

4,6-Dichloropyrimidine (4.14 mmol) and tert-butyl 4-aminobutylcarbamate (4.14 mmol) were dissolved in 13 ml of 2propanol and 3 drops of 3M aqueous HCl were added. The mixture was heated in a personal chemical optimization microwave system at 100 ° C for 900 s. The reaction mixture was poured into a dilute solution with aqueous NH4Cl saturation (50 ml) and extracted with EtOAc (2x). Drying of the organic layer (Na2SO4) and evaporation of the solvent under reduced pressure with the result of crude product that was used in DMSO (2.5 ml) and purified by prep.-HPLC (XTerra Prep MS C18 5 μm, 19 x 150 mm, gradient of MeCN water for 14 min), obtaining 41% of a white solid. b) Preparation of compound 306

[0222] The carbamate shown above (0.65 mmol), 2-methoxyphenylboronic acid (0.67 mmol), sodium carbonate (1.95 mmol) and Pd (PPh3) 2Cl2 (5 mol%) were suspended in a mixture of DMF / EtOH / water (15 ml / 2 ml / 2 ml). The mixture was heated in a personal chemical optimization microwave system at 130 ° for 720 s. The reaction mixture was poured into a dilute solution with aqueous NH4Cl saturation (50 ml) and extracted with EtOAc (2x). Drying of the organic layer (Na2SO4) and evaporation of the solvents under reduced pressure with the result of crude product that was used in DMSO (1.5 ml) and purified by prep.-HPLC (ZORBAX Bonus-RP Prep C18 5 μm , 21.2 x 150 mm, gradient of MeCN water for 14 min), obtaining 22% of a pale yellow solid.

IIA) Preparation of compounds 1-17, 18-22, 28, 31, 32, 35, 39, 40, 51, 52, 55-59, 62, 63, 67, 69, 73, 75-77, 85, 92-102, 104-110, 114-119, 121-146, 149-160, 162-193, 197, 200, 202-205, 214, 215, 331-376 (Suzuki coupling according to scheme 1):

[0223] To a solution of the intermediate product obtained by method of preparation I (0.35mmol) in a worn DMF was added a boron compound (0.38mmol) followed by NaHCO3 (0.88mmol) dissolved in H2O (~ 1ml) worn, PdOAc2 (0,035mmol) and PPh3 (0,07mmol). The mixture was heated at 80-90 ° C (oil bath temperature) under a nitrogen atmosphere for 18h. After cooling to room temperature, the mixture was diluted with EtOAc (m30mL), washed with H2O (3x-5mL) and dried (MgSO4). The solvent was evaporated under reduced pressure and the residue purified by flash chromatography. The following alternative manufacturing procedure can be used: Upon completion of the reaction, the solvents were evaporated under reduced pressure and the residue was partitioned between EtOAc / H2O. The H2O layer was separated and extracted with EtOAc (2x). The combined extracts and the organic layer were dried (MgSO4), the solvent was evaporated under reduced pressure and the residue purified by flash chromatography. 2 (Dicyclocyclohexylphosphino) biphenyl was used in some cases as a binder instead of triphenylphosphine to facilitate the purification process.

IIB) Preparation of compounds 265, 293, 305, 318, 319, 322 (according to scheme 1):

[0224] 4,6-Dichloropyrimidine (0.72mmol), 2-methoxyphenylboronic acid (0.66 mmol), sodium carbonate (1.97 mmol) and Pd (PPh3) 2Cl2 (3 mol%) were suspended in a mixture of DMF / EtOH / water (2.5 ml / 0.38 ml / 0.38 ml). The mixture was heated in a personal chemical optimization microwave system at 130 ° for 900 s. IPrOH (5 ml) and the corresponding aniline derivative (0.66 mmol) were added and the mixture was treated with conc. HCl stirring to reach a pH of 1-2, The mixture was then heated in the microwave at 150 ° C for 900s. The solvent was evaporated under reduced pressure and the solid residue suspended in H2O (10 mL). The mixture reached pH = 6-7 with a saturated NaHCO3 solution and was extracted with EtOAc (3 x 20 ml). The organic materials were washed with saline and dried over Na2SO4. After evaporating the solvent, the residue was introduced into DMSO and evaporated by prep.-HPLC (XTerra Prep MS C18 5 μm, 19 x 150 mm, MeCN water gradient for 13 min). In the case of products with an acid group in the aniline part, the corresponding methyl esters were prepared by treatment with TMSCHN2 (2-4 eq.) In DCM / MeOH (2 mL / 1 mL) at room temperature.

IIC) Preparation of compounds 268, 307 and 313 (according to scheme 1 & 2):

[0225] 6-Nitroindoline (1.2 mmol) was dissolved in DCM (8 ml), treated with pyridine (2.4 mmol) and cooled to 0 ° C. MeSO2Cl (1.3 mmol) was added dropwise and the mixture was allowed to stir at room temperature overnight. 0.5 M HCl solution (10 ml) was added and the mixture was extracted twice with DCM (10 ml) and twice with EtOAc (10 ml). The organic materials were washed with saline, dried over Na2SO4 and evaporated. The dried residue was dissolved in MeOH (5 ml) and THF (4 ml). Pd / C (100 mg) was added and the mixture was removed under an atmosphere of hydrogen at room temperature for 5 h. The mixture was filtered through a pad of Celite that was washed with an abundant amount of MeOH and EtOAc. The filtrate was concentrated in vacuo and the residue dried. The crude derivative 6-amino indoline and 4,6-dichlorpyrimidine (1.5 mmol) were dissolved in isopropanol (6 ml) and concentrated HCl (0.4 ml) and the mixture was heated to reflux for 2.5 h. For the precipitation of the intermediate product, the mixture was stored overnight in the refrigerator. The precipitate (HCI salt) was filtered, washed with a small amount of cold isopropanol and dried. The intermediate product (0.17 mmol), the corresponding methoxyphenylboronic acid (0.2 mmol), NA2CO3 (0.58 mmol) and Pd (PPh3) 2Cl2 (3 mol%) were suspended in a mixture of DMF / EtOH / water (1.5 ml / 0.3 ml / 0.2 ml). The mixture was heated in the microwave at 125 ° C for 1200 s. H2O (30 ml) was added and the mixture was extracted twice with EtOAc (40 ml). Saturated NH4Cl solution (20 ml) was added to the water phase and extracted again with EtOAc (40 ml). The organic materials were washed with saline and dried over Na2SO4. After evaporating the solvent, the residue was introduced into DMSO and evaporated by prep.-HPLC (XTerra Prep MS C18 5 μm, 19 x 150 mm, MeCN water gradient for 13 min).

III) Preparation of compounds 29, 36, 37, 41, 42, 45-50, 52, 61, 64, 65, 70, 71, 84, 87, 89 and 97 (formation of amide compound according to scheme 2) :

[0226] To an solution of an amine compound (0.24mmol) in THF (4mL) was added an acid compound (0.26mmol) at room temperature followed by NEt3 (0.36mmol) and HBTU (0.25mmol) . The mixture was stirred at room temperature for 1 h and then at ~ 40 ° C (oil bath temperature) for 18 h. After cooling to room temperature, the mixture was diluted with water (5mL), extracted with EtOAc (3x) and the combined extract dried (MgSO4). The solvent was evaporated under reduced pressure and the residue purified by flash chromatography.

IV) Preparation of compounds 23, 33 and 34 (formation of sulfonamide compound according to scheme 2):

[0227] To a mixture of N- [6- (2-Methoxy-phenyl) -pyrimidin-4-yl] -benzene-1,4-diamine (0.229mmol) in CH2Cl2 (6mL) and cooled to ~ 0 ° C under nitrogen atmosphere Et3N (0.274mmol) was added followed by sulfonylchlorite (0.252mmol). The mixture was allowed to warm to room temperature and then stirred for 60h. The solvent was evaporated under reduced pressure and the solid residue suspended in water extracted with EtOAc (3x). The combined extracts were dried (MG2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography to get the product.

VA) Preparation of compounds 44, 54, 72, 88, 147, 148, 161, 194-196, 198, 199, 201, 206-213 (according to scheme 3):

[0228] The ester compound, 4- (6-Chloro-pyrimidine-4-yl-amino) -methyl ester benzoic acid was prepared according to method I. The reaction was performed in NMP as a solvent using iPr2NEt as a base at 100-110 ° C (oil bath temperature) for 18h. The product was precipitated after adding water to the reaction mixture and then separated by filtration, washing with water (2x), diethylether (2x) and drying. The ester compound was isolated as a pale brown solid with a yield of 77%. OH (d6 DMSO): 3.80 (3H, s, COOMe), 6.85 (1H, s), 7.75 (2H, d), 7.90 (2H, d), 8.55 (1H, s), 10.15 (1H, s , NH). To a solution of 4- (6-Chloro-pyrimidin-4-yl-amino) -methyl ether of benzoic acid (0.1g, 0.38mmol) in THF (3mL) was added LiOHxH2O (0.017g, 0.42mmol) dissolved in H2O (1mL) and the mixture was stirred at room temperature for 18h. The reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (2x). The H2O layer was acidified (2.5 MHCI) and extracted with EtOAc (3x). The combined organic layers were dried (MgSO4) and the solvent evaporated under reduced pressure to obtain 4- (6-Chloro-pyrimidin-4-yl-amino) -benzoic acid as a pale yellow solid. OH (d6 DMSO): 6.95 (1H, s), 7.80 (2H, s), 7.95 (2H, s), 8.65 (1H, s) 10.30 (1H, s) 12.75 (1H, bs, COOH )

a) Starting from the above mentioned 4- (6-Chloro-pyrimidine-4-yl-amino) -benzoic acid were synthesized the following compounds according to method III. b) Starting from the above mentioned 4- (6-Chloro-pyrimidine-4-yl-amino) - benzoic acid amides (compound 72 and compound 88) the following compounds 44 and 54 were synthesized according to method II:

VB) Preparation of compounds 226, 231 and 330 (according to scheme 3):

[0229] 4,6-dichloropyrimidine (1.8 mmol), 2-methoxyphenylboronic acid (1.8 mmol), sodium carbonate (5.4 mmol) and Pd (PPh3) 2Cl2 (2 mol%) were suspended in a mixture DMF / EtOH / water (12 ml / 1.8 ml / 1.8 ml). The mixture was heated in a personal chemical optimization microwave system at 130 ° for 600 s. The solution was poured into a saturated aqueous NH4Cl solution (25 ml) and extracted with EtOAc (3x). The combined organic layers were dried (Na2SO4) and the solvent was evaporated under reduced pressure to obtain the crude product. This material (1.8 mmol) was dissolved in iPrOH (10 ml), methyl 4-aminobenzoate (2.4 mmol) and a solution of 3M HCl solution (6 drops) was added. The mixture was then heated in the microwave at 120 ° for 900 s and then cooled to room temperature. The precipitate was filtered, washed with iPrOH and dried. Thus the intermediate product was achieved with a yield of 49% (in 2 steps). This last compound (1.2 mmol) was then dissolved in THF / water (3 ml / 6 ml) and lithium hydroxide was added

(3.58 mmol). Removing the reaction mixture at room temperature for 16 hours, complete conversion was achieved and the solution reached a pH = 1 by the addition of a 3M HCl solution. A precipitate formed and filtration produced 4- [6- (2-methoxy-phenyl) -pyrimidine4-yl-amine] -benzoic acid with a quantitative yield. This pyrimidine derivative (0.22 mmol) then reacted with different amines (0.22 mmol) in DMF (1.5 ml) with EDC · HCl (0.28 mmol) and HOBt (0.07 mmol). After stirring for 4-20 h the reaction was poured into water (15 ml) and extracted with EtOAc (3x). The organic layer was dried (Na2SO4) and the solvent was evaporated under reduced pressure. Purification by the preparation-HPLC (XTerra Prep MS C18 5 μm, 19 x 150 mm, MeCN water gradient for 13 min) or flash chromatography (SiO2) and compounds 231, 226 and 330 were achieved with a yield of up to 81%

VIA) Preparation of compounds 26 and 27 (according to scheme 4 & 8)

[0230] To a mixture of N- [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] -benzene-1,4-diamine (0.68mmol) in DMF (4.6mL), under atmosphere of nitrogen at room temperature NaH (0.75mmol) was added and the mixture was stirred for 30min. Mel (0.68mmol) was added dropwise and the reaction mixture was stirred for 42h. The mixture was then diluted with H2O ((7 mL) and extracted with EtOAc (3x). The combined extracts were dried (MG2SO4) and the solvent was evaporated under reduced pressure. The residue was triturated with Et2O to obtain the product as a brown solid.

[0231] This compound is prepared according to the procedure described for compound 26 but instead of the compound of diamine N- {4- [6- (4-Hydroxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -4-methyl-benzenesulfonamide is used. THF was used as solvent and 1 eq of Bromoacetic acid methyl ester as alkylating agent. The reaction was carried out at 50-60 ° C (oil bath temperature) for 18h. The crude reaction mixture was purified by flash chromatography to get the product as a solid. pale yellow.

VIB) Preparation of compounds 234, 327, 328 and 329 (according to scheme 8A)

[0232] It was added to a solution of the proline derivative (0.22 mmol) (prepared analogously to the compound described in M. Tamaki, G. Han, V. J. Hruby, J. Org. Chem. 2001, 66, 3593-3596; J. A. Gómez-Vidal, R. B. Silverman, Org. Lett. 2001, 3, 2481-2484; DJ Abraham, M. Mokotoff, L. Sheh, JE Simmons, J. Med. Chem. 1983, 26, 549554) and 4- [6- (2-methoxyphenyl) -pyrimidine-4-yl-amino] -benzoic acid ( 0.22 mmol) in DMF (1.5 ml) EDC · HCl (0.28 mmol) and HOBt (0.07 mmol) and the reaction was stirred at room temperature for 4 to 18 h. The solution was poured into NH4Cl water (15 ml) and extracted with EtOAc (3x). The combined organic layers are dried (Na2SO4) and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography (SiO2, c-hexane / EtOAc, 1: 2) and the result was compound 234 with a yield of 40%.

Compound 234 (0.16 mmol) was dissolved in DCM (4 ml) and treated with TFA (4 ml). After stirring for one hour at room temperature, the solvent was evaporated under reduced pressure and the residue was purified by flash chromatography (SiO2, DCM / MeOH 95: 5 + 0.5 vol% NEt3) to obtain compound 327 in 76% . The following reaction of compound 327 (0.11 mmol) in THF / water 1: 2 with LiOH (0.44 mmol) at room temperature for 48 hours gave after purification by prep. -HPLC (ZORBAX Bonus-RP Prep C18 5 μm, 21.2 x 150 mm, gradient of MeCN water for 15 min) compound 328. To a solution of compound 234 (0.89 mmol) in THF (3 ml) Water (6 ml) and lithium hydroxide (3.55 mmol) were added and the reaction was stirred at room temperature for 40 h. The reaction mixture was cooled to 0 ° C and 3M HCl solution was added to form a precipitate. The desired intermediate product was achieved by filtration and drying of the solid by 88%. The latter (0.19 mmol) was dissolved in DMF (7 ml), methyl 6-aminobenzoate (0.24 mmol), EDC · HCl (0.24 mmol) and HOBt (0.06 mmol) were added and removed the reaction for 4 h. Another part of methyl 6-aminobenzoate (0.12 mmol), EDC · HCl (0.12 mmol) and HOBt (0.03 mmol) was added and the reaction was stirred for another 15 h. Water (25 ml) was added and the solution was extracted with EtOAc (3x). The combined organic layers were dried (Na2SO4) and the solvent was evaporated under reduced pressure. Purification by flash chromatography (SiO2, DCM / MeOH 95: 5) achieved the product in 89%. To a solution of this compound (0.024 mmol) in DCM (1 ml) was added TFA (1 ml) and the reaction was stirred at room temperature for 30 min. After evaporation of the solvent under reduced pressure and drying of the resulting oil, the crude product was dissolved in THF (1 ml). Water (2 ml) and lithium hydroxide (1.00 mmol) were added and the reaction was stirred at room temperature for 64 h. The solvent was evaporated under reduced pressure and the resulting mixture purified by prep.-HPLC (XTerra Prep MS C18 5 μm, 19 x 150 mm, MeCN water gradient for 13 min). Compound 329 was obtained with 73%.

VII) Preparation of compounds 30, 66, 68, 81-83, 86, 90-91 (according to scheme 6 by deprotection of protected substituents):

[0233] BOC protected compounds can be synthesized according to the reaction protocol described in the scheme

6.

[0234] To a solution of the N-Boc compound (0.07mmol) in TFA / CH2Cl2 (1mL, 1: 1) a few drops of water were added and the mixture was stirred at room temperature for 2-18h. The reaction mixture was diluted with toluene (5 mL) and the solvents evaporated under reduced pressure. The residue was partitioned between EtOAc / NaHCO3 (saturated aqueous solution), (~ 15m, 1: 1). The organic layer was dried (Na2SO4) and the solvent was evaporated under reduced pressure to obtain the product.

VII) Preparation of compounds 43, 60, 74, 78-80 (according to scheme 7):

[0235] To a mixture of 6-Chloro-pyrimidine-4-yl-aryl-amino (0.3mmol) in i-PrOH (1mL) in the microwave was added amino (0.685g, 0.6mmol) followed by i -Pr2NEt (0.6mmol). The reaction mixture was heated under microwave conditions (200W, t = 160 ° C) for 2h and 15min and then, after cooling to room temperature, diluted with EtOAc / H2O (~ 12m, 2: 1). The organic layer was separated and the H2O layer extracted with EtOAc (2x). The combined organic layers were dried (MgSO4), the solvent was evaporated under reduced pressure and the residue purified by flash chromatography to obtain the product.

IXA) Preparation of compounds 38 and 111-113 (according to scheme 9):

[0236] To a suspension of one amino (0.17mmol) in dioxane (2ml) was added isocyanate (0.19mmol) and the mixture was heated at 80-90 ° C (oil bath temperature) for 24h. The solvent was evaporated under reduced pressure and the residue purified by flash chromatography to get the product. An alternative method for synthesizing urea derivatives according to the present invention is described below: Pyridine (0.7mMol) was added to a suspension of an amino (0.3mMol) as indicated in Scheme 9 in dry THF (3 mL), followed by phenylchloroformate (0.3mMol). The mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the residue divided into EtOAc: H2O. The organic layer was dried (MgSO4), the solvent was removed and the carbamate obtained was used in the next step without further purification. An amino compound (0.10mMol) was added to a solution of carbamate (0.07mMol) in dry THF (2.5 mL) and the mixture was heated at 50 ° C for 72 hours. After cooling to room temperature a precipitate appeared which was collected by filtration and washed with Et2O to achieve the desired product with a yield of 59% and a purity of 100% by LC / MS.

IXB) Preparation of compounds 292, 323-326 (according to scheme 9A):

[0237] 4,6-Dichloropyrimidine (3.7 mmol), 2-hydroxyphenylboronic acid (1.2 mmol), sodium carbonate (3.7 mmol) and Pd (PPh3) 2Cl2 (2 mol%) were suspended in a mixture DMF / EtOH / water (12 ml / 1.8 ml / 1.8 ml). The mixture was heated in a personal chemical optimization microwave system at 100 ° for 1500 s. The reaction mixture was poured into a saturated aqueous NH4Cl solution (40 ml) and extracted with EtOAc (3x). The combined organic layers were dried (Na2SO4) and the solvent was evaporated under reduced pressure to obtain the crude product. Flash chromatography achieved the intermediate product as a light yellow powder with a yield of 68%. To a suspension of NaH (3.10 mmol) in dry DMF (1.0 ml) under nitrogen at 0 ° C was added a solution of the intermediate described above (0.97 mmol) in dry DMF (1.5 ml). The resulting mixture was stirred at 0 ° C for 15 min. The corresponding 2-chloro- or 2-bromoethylaminos (as hydrochloride or hydrobromide salts) were then added (1.26 mmol) and the reaction was stirred at 0 ° C for 3 h, then the cooling bath was removed and allowed to cool. The reaction will be heated to room temperature. After 4 hours the reaction was diluted with EtOAc (20 ml) and water (10 ml) was added carefully. After extraction with EtOAc (3x) and drying of the organic layers (Na2SO4) the crude product was obtained with evaporation of the solvent under reduced pressure. This intermediate (0.18 mmol) was dissolved without further purification in iPrOH (2.4 ml), methyl 4-aminobenzoate (0.23 mmol) and a 3M HCl solution (2 drops) were added and the reaction was heated in a Personal chemical optimization microwave system at 100 ° C for 1200 s. The precipitate (if it was formed on standing at 4 ° C for 18 hours, otherwise the solvent was evaporated under reduced pressure) was filtered and the solid dissolved in EtOAc (20 ml) and saturated aqueous NaHCO3 solution (10 ml). The crude product was achieved by separating the organic layer after drying (Na2SO4) and evaporation of the solvent. The latter was purified by flash chromatography (SiO2, DCM / MeOH 14: 1 with 0.5 vol% NEt3) and the product was obtained in a yield of 59-78%.

X) Preparation of compound 53 (according to scheme 5):

[0238] To a solution of N- [6- (2-Methoxy-phenylpyrimidine-4-yl] -benzene-1,4-diamine (0.29mmol) in CH2Cl2 (10mL) and cooled, NEt3 (0.29mmol) the 5-chloro-benzotriazole carboxamidine derivative (0.29) was added as shown in scheme 5.

The mixture was heated at reflux for 5 hours. The solvent was evaporated and the residue purified by flash chromatography to obtain the product of the BOC protected compound as a white solid. OH (d6 DMSO): 1.50 (9H, s, Boc), 1.60 (9H, s, Boc), 4.00 (3H, s MeO), 7.15 (1H, t), 7.25 (1H, d), 7.50-7.60 (4H, m),

7.80 (2H, d), 8.05 (1H, d), 8.80 (1H, s), 9.75 (1H, s), 10.00 (1H, s) 11.55 (1H, s).

[0239] To a solution of the BOC protected compound (0.11mmol) in CH2Cl2 (1.5m), TFA (1.5 mL) was added at room temperature and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc / H2O (15mL, 2: 1v / v) and the H2O layer neutralized with solid NaHCO3. The organic layer was separated and the H2O layer extracted with EtOAc (3x). The combined organic layers were dried (Mga2SO4) and the solvent was evaporated under reduced pressure to obtain the crude product. The material was suspended in water, filtered off, washed with water (2x), Et2O (3x) and then dried to get the product.

XIA) Preparation of compound 119 (according to scheme 10):

[0240] 2-Methyl-4-nitroaniline (1mMol) was reacted with 4,6-dichloropyrimidine (1mMol) in the presence of DIPEA (2mMol) under microwave conditions. Suzuki coupling was performed on this substrate as described above. above. A reduction in hydrogen transfer was performed following a standard protocol (S. Hanessian et al., synthesis 1981, 396). The intermediate obtained was reacted with pivalochlorite using the conditions described in scheme 2,

XIB) Preparation of compound 320 and (3- {6- [3- (4-Amino-butan-1-sulfonylamino) -4-methyl-phenylamino] pyrimidine-4-yl} -phenyl) -carbamic acid 9H-fluoren- 9-ylmetilester (according to scheme 10A):

[0241]

a) Preparation of 4- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -butan-1-sulfonic acid {5- [6- (2-methoxy-phenyl) pyrimidine4-ylamino] - 2-methyl-phenyl} -amide and [3- (6- {3- [4- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -butan-1sulfonylamino] 4-methyl-phenylamino } -pyrimidine-4-yl) -phenyl] -carbamic acid 9H-fluoren-9-ylmetilester Potassium 4- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -butan-1- sulphonate (prepared according to Jiang, J., Wang, W. Sane, DC and Wang, B. Bioorg. Chem. 2001, 29, 357-379) to 4- (1,3-dioxo-1,3-dihydro-isoindol2yl ) -butan-1-sulfonyl chlorite analogically to the compounds described in the above-mentioned reference method. Sulfonyl chlorite (0.26 mmol) and N1- [6- (2-methoxy-phenyl) -pyrimidine-4-yl] -4-methyl-benzene-1,3-diamine (0.22 mmol; prepared according to Scheme 1) or {3- [6- (3-amino-4-methyl-phenylamino) -pyrimidine-4-yl] -phenyl} -carbamic acid 9H-fluoren-9-ylmethyl ester (0.22 mmol; prepared according to scheme 1), were suspended in 15 ml of abs. CH2Cl2, Pyridine (2.2 mmol) was added and the mixture was stirred at room temperature for 7 days. After evaporating the solvent under reduced pressure and the yellow residue, it was introduced in DMSO (2ml) and evaporated by means of prep.-HPLC (XTerra Prep MS C18 5 μm, 19 x 150 mm, MeCN water gradient for 14 min) obtaining a 70% cream powder. b) Preparation of compound 320 and (3- {6- [3- (4-Amino-butan-1-sulfonylamino) -4-methyl-phenylamino] -pyrimidine4-yl} -phenyl) -carbamic acid 9H-fluoren-9 -ylmetilester

Compound 320

[0242] Any N-protected sulfonamide shown above (91.9 μmol) was dissolved in 10 ml of EtOH. Hydrazine monohydrate (3.7 mmol) was added and the mixture was stirred at room temperature for 6 days. The solvent was evaporated under reduced pressure and the residue was redissolved in MeOH (3x) and the solvents were evaporated. The yellow residue was introduced in DMSO (3 ml) and purified by prep.-HPLC (5 μm ZorbaxBonus-RP C18, 21.2 x 150 mm, MeCN water gradient for 14 min) to obtain 92% color powders pale yellow.

XII) Preparation of compound 120 (according to scheme 11):

[0243] To a solution of 4-amino, 2-nitrophenol (1 mmol), triphenyl phosphin (1.2 mmol) and benzylalcohol (1.2 mmol) in dichloromethane (5 ml) at room temperature under a nitrogen atmosphere, a solution of diethylazodicarboxylate (1.2 mmol) in dry dichlormethane (2 ml) was added. The resulting mixture was stirred at room temperature for 18 hours. Evaporation under reduced pressure resulted in a gum that was purified by column chromatography (SiO2; diethylether) to achieve 4-benzyloxy-3-nitro-aniline, yield 85%. OH (d6 DMSO): 5.24 (2H, s), 5.30 (2H, s), 6.85 - 6.95 (1H, m, ArH) 7.10 (1H, s, ArH), 7.20 (1H, d, ArH), 7.30-7.80 (5H, m, ArH) [0244] The reaction of 4-benzyloxy-3-nitro-aniline with 4,6-dichloropyrimidine to achieve 4- (4'benzyloxy-3-nitrophenyl) amino-6-chloro- Pyrimidine is made by the method of preparation 1, OH (d6 DMSO): 5.34 (2H, s, CH2Ar), 6.84, (1H, s, HetH), 7.30-7.75 (7H, m, ArH), 8.30 (1H, m, ArH), 8.55 (1H, s, Het H), 10.10 (1H, s, NH)

[0245] To a solution of 4- (4'benzyloxy-3-nitrophenyl) amino-6-chloro-pyrimidine (4.91 g) and sulfuric acid (8 ml) in ethanol (300 ml) was added zinc powder (4.49 g). The mixture was heated under reflux for 18 hours, cooled to room temperature and basified with sodium hydrogen carbonate. After evaporation under reduced pressure the residue was dissolved in ethyl acetate and water. The organic phase was separated, washed with water, dried (MgSO4) and evaporated under reduced pressure. The residue was then subjected to column chromatography (SiO2; ethyl acetate: petroleum ether (40/60) 1: 1) to give 4- (3'-amino-4'benzyloxyphenyl) amino-6-chloro-pyrimidine, 21% OH (d6 DMSO): 4.84 (2H, s, NH2), 5.00 (2H, s, CH2Ph), 6.50 - 6.60 (2H, m, ArH), 6.70 - 6.80 (2H, m, ArH and HetH), 7.20 - 7.50 (5H, m, ArH), 8.30 (1H, s, HetH), 9.45 (1H, s, NH)

[0246] To a solution of 4- (3’benzyloxy-4-benzyloxyphenyl) amino-6-chloro-pyrimidine (630 mg) in dry dichloromethane was added pyridine (8 ml) followed by sulfonylchlorite (0.3 ml). The mixture was stirred at room temperature overnight and evaporated under reduced pressure. The residue was dissolved in water and the dichloromethane and the organic phase were separated, washed with water, dried (MgSO4) and evaporated under reduced pressure. The residue was then subjected to column chromatography (SiO2; ethyl acetate: petroleum ether (40/60) 1: 1) to obtain N- {5- [6-chloropyrimidine-4-ylamino] -2-benzyloxy-phenyl} -methanesulfonamide ( 200 mg) OH (d6 DMSO): 3.14 (3H, s, SO2Me), 5.40 (2H, s, CH2Ph), 6.94 (1H, s, HetH), 7.30 - 7.40 (1H, m, ArH), 7.50 - 7.85 (7H, m, ArH), 8.70 (1H, s, HetH), 9.30 (1H, s, NH), 10.00 (1H, s, NH).

[0247] The reaction of N- {5- [6-chloropyrimidine-4-ylamino] -2-benzyloxy-phenyl} -methanesulfonamide with 3 aminobenzene boronic acid was carried out analogously to preparation method 2 to give compound 120: N- {5- [6- (3-Aminophenyl) -pyrimidine-4-ylamino] -2-benzyloxyphenyl} -methanesulfonamide, OH (d6 DMSO): 2.90 (3H, s, SO2Me), 5.15, (2H, s, CH2Ph), 5.25 (2H, s, NH2), 6.60 - 6.70 (1H, m, ArH), 7.00 (1H, s, HetH), 7.05 - 7.15 (3H, m, ArH) 7.25 - 7.60 (8H, m, ArH), 8.55 (1H, s, HetH) 9.00 (1H, s, NH), 9.50 (1, s, NH)

XIII) Preparation of compound 103 (according to scheme 12):

[0248] NaH (0.22mMol) was added to a solution of the pyrimidine derivative as detailed in Scheme 12 in dry DMF (2mL) under nitrogen. The solution was stirred at room temperature for 30 minutes. N-protected alkyl chlorine (0.22mMol) was added and the mixture was heated at 80 ° C for 18 hours. The solution was allowed to cool to room temperature. Extraction was performed in EtOAc: H2O. The organic phase was dried (MgSO4), the solvent was removed in vacuo to obtain the crude product that was purified by column chromatography to reach the desired intermediate. The intermediate product was dissolved in a solution of 50% TFA (2ml) in DCM plus 2 drops of H2O and the mixture was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue was suspended in EtOAc. The organic phase was washed with NaHCO3 (saturated aqueous), the organic layer was dried (MgSO4) and the solvent was evaporated to give a residue that was dissolved in 1 mL 2.5 M HCl. The solution was evaporated in vacuo to give a solid that was triturated with Et2O and dried to give the desired compound as a hydrochloric salt with a total yield of 23%.

Materials and methods:

Cloned from CDK9 and Cyclin T1:

[0249] Both cDNA fragments were cloned by PCR to pDONR201 vectors using the system of input recombination (Invitrogen) following the manufacturer's recommendations. The fragments were subcloned to an input-adapted vector (pPM7) for the production of the recombinant adenovirus. All plasmids were verified by restriction digestion and sequential analysis.

Expression and purification of CDK9 / Cyclin T1 proteins:

[0250] Expression and purification was performed initially as described by Cotten et al. (M. Cotten et al., Nucleic acids research, 2003, 31 (28), 128).

Kinase assay using CDK9 / Cyclin T1:

[0251] Kinase assays were initially performed as described by Cotten et al (M. Cotten et al., Nucleic acids research, 2003, 31 (28), 128).

Kinase assays to determine the activity of CDK2 / Cyclin A and CDK5 / p35:

[0252] Kinase assays were performed as described by the manufacturer's recommendations (Proqinase for CDK2 / CyclinA and Upsate for CDK5 / p35).

General Kinase Assay:

[0253] The inhibitory effect of 4,6-disubstituted aminopyrimidine derivatives on protein kinase activity as shown in Table 1 can be measured according to the following protocol:

Reaction Volume:

40 μl

Reaction time: Reaction temperature: Test plate: PH MultiScreen plate: Filter wash solution: Scintillation liquid: Controls: Negative control (C-): Positive control (C +):

60min ambient temperature bottom plate U-hole 96 (Greiner, 650161) Well filter plates 96 MAPH (Millipore, MAPHNOB50) 0.75% H3PO4 Supermix liquid scintillator (PerkinElmer, 1200439) 100mM EDTA (Ethylenediaminetetraacetic acid), no inhibitor no Inhibitor

Reaction buffer:

[0254]

 20mM Tris (Tris (hydroxymethyl) aminomethane hydrochloride), pH 7.5  10mM MgCl2 1 mM DTT

Final test concentrations:

[0255]

Kinase: Use the kinase concentration, yield 10% ATP turnover.  ATP: 1 μM  Adenosine 5 ’- [y-33P] triphosphate: 12.5 μCi / ml (Amersham Biosciences, BF1000) Substrate: 10 μM myelin basic protein (Invitrogen, 13228-010)

Pipetting Sequence:

[0256]

1) Add 10 μl of substrate 4 times concentrated + ATP 4 times concentrated in reaction buffer 3 times concentrated to each test plate. 2) Add 10 μl of inhibitor 4 times concentrated in 4% DMSO in H2O to each well except to wells of Cy C + 3) Add 10 μl of 4% DMSO in H2O to wells of C- and C + 4) Add 10 μl 500mM ETDA in H2O to the wells of C-5) Add 10 μl 50 μCi / ml Adenosine 5 '- [y-33P] triphosphate in H2O to each well 6) Add 10 μl of kinase 4 times concentrated in the reaction buffer to each well 7) Incubate 1 hour at room temperature 8) Add 10 μl of 50mM ETDA in H2O to each well except those of C- 9) Prepare MAPH plates by adding 200μl 0.75% H3PO4 to each well 10) Evacuate 0.75 % H3PO4 using a Millipore 11 vacuum station) Add 60μl 0.75% H3PO4 to each well of the MAPH filter plate. 12) Transfer 30 μl of sample per well of the test plate to the corresponding well of the MAPH filter plate 13) Incubate 30 min at room temperature 14) Wash each well of the MAPH 3x filter plates with 200 μl 0.75% H3PO4 using the Millipore vacuum station. 15) Add 260μl of scintillation fluid to each well of the MAPH filter plate. 16) Seal the MAPH filter plate 17) Store the MAPH filter plate for 30 min in the dark 18) Quantify the radioactivity

[0257] Access numbers were obtained from the NCBI public data bank (http://www.ncbi.nlm.nih.gov/).

Determination of phosphorylation of the C-terminal domain of RNA polymerase II:

[0258] The phosphorylation state of the C-terminal domain of RNA polymerase II is determined by Western Blot techniques. PM1 cells were placed in 6-well plates with a density of 5x105 per well. After overnight incubation the cells were treated with the compound as indicated in the respective experiment. The cells were sedimented and lysed with 300 μL 3x Laemmli buffer followed by 30 minutes of denaturation at 65 ° C. After separation of the equal volumes of lysis by SDS-PAGE, the proteins were transferred to nitrocellulose membranes (Schleicher & Schuell) and verified with anti-SER2 (H5), anti-SER5 (H14) or RNA Poll 11 antibodies purchased from Eurogentec and Santa Cross respectively. The amount of the reactive protein was visualized by ECL detection methods (Amersham).

Growth test using Alamar Blue ™:

[0259] PM1 cells were introduced into 12-well plates at a density of 1.5x105 per well with RPMI 1640 containing 10% FCS (fetal bovine serum), 1% L-Glutamine and 1% Na-Pyruvate (Sigma). The cells were incubated with compound for 2 to 3 days (37 ° C, 6% CO2) followed by dissociation and renewal of the medium containing the compound. In each of these time points an aliquot of cells served as a data point for relative growth (given in% of the DMSO control [= 100%]). The number of cells is determined by adding 10 μL Alamar Blue ™ (Biozol) to 100 μL of the aliquot of the cell following the manufacturer's instructions.

HIV reproduction assay in PM1 cells:

[0260] PM1 cells were introduced into 12-well plates at a density of 1.5x105 per well with RPMI 1640 containing 10% FCS (fetal bovine serum), 1% L-Glutamine and 1% Na-Pyruvate (Sigma). The cells had previously been infected with HIV-1 BaL for 3 hours at a concentration of approximately 5x108 μg p24 / cell. After adding the respective compounds the cells were incubated for 6 to 10 days. During this incubation the cells were transferred and the medium containing the compound was renewed. The concentration of p24 in the supernatants is determined at each of these time points using a previously described ELISA assay (Bevec et al., Proceedings of the National Academy of Sciences U.S.A. 1992, 89 (20), 9870-9874).

NFKB dependent transcriptional activity:

[0261] The NIH 3T3 75E11 / 300D8 cell line used is described elsewhere (J. Eickhoff et al., Journal of Biological Chemistry, 2004, 279 (10), 9642-9652).

HBV Reproduction:

[0262] To test anti-HBV activities the compound of the cell line that produces HBV -HepG2-2,2,15 was used

(M.A. Sells, PNAS 1987, 84, 1005-1009). 1.0x104 cells were seeded in 96-well microtiter plates in a DMEM medium supplemented with 10% FCS. After incubation at 37 ° C in a 5% CO2 atmosphere for 24 hours, the medium was replaced by fresh medium with the appropriate diluted compound content. 3 days later the medium was replaced by a fresh medium containing inhibitor and the cells were incubated for a further 3 days. Then 200 µl of lysis buffer was added per well (50mM Tris-Cl 7.5; 1mM EDTA 8.0; 0.5% NP40). The lysate was centrifuged (15000rpm, 10min, 4 ° C) to remove cell debris and nucleic acids. Cellular and viral RNA was removed by adding 2μl of RNase. 100μl of the samples were deposited on a nylon membrane not charged and previously wetted with PBS (phosphate buffered saline) by means of a drying chamber of wells 96 (MINlfold Dot-Blot, Schleicher & Schüll). After another wash with 200μl of PBS per well, the membrane was treated twice with 0.5M NaOH, 1.5M NaCl (2min) and 4 times with 0.5M Tris 7.5, 3M NaCl (1min). Nucleic acids were fixed by UV treatment and used for hybridization with an HBV fragment prepared from the HBV plasmid of the length of the pTHBV1.3 overgenome (LG Guidotti et al., Journal of Virology 1995., 69 (10), 6158 - 6169). The fixed membrane was prehybridized in a standard hybridization buffer (50% formamide, 5xSSPE, 10xDenhards, 1% SDS, 100μg / ml salmon sperm DNA) for at least 3 hours at 42 ° C and hybridized overnight against the HBV labeled fragment. Preparation of the HBV fragment with the "DNA random base labeling system" (Invitrogen) was performed according to the manufacturer's instructions. The hybridized filters were washed at room temperature with 2xSSC, at 62 ° C with 2xSSC, 0.5% SDS and at 62 ° C with 0.5xSSC, 0.5% SDS. Each washing step was performed twice. The intensity of HBV DNA was quantified by a phosphorus imager (Fuji). To verify cell viability, 0.5x104 HepG2-2,2.15 cells were seeded in 96 well microtiter plates in a DMEM medium supplemented with 10% fetal bovine serum. After incubation at 37 ° C for 24 hours, the medium was replaced by a fresh medium containing compound. 3 days later the medium was replaced again with a fresh medium containing inhibitor and the cells were incubated for a further 3 days at 37 ° C. After the incubation period a 1/10 volume of Alamar Blue solution (Serotec) containing a growth-dependent indicator was added and the cells were incubated for 3h at 37 ° C. The absorbance was monitored at the wavelength of 570nm and 600nm.

HCMV Reproduction:

[0263] Cell cultures of human foreskin fibroblasts were cultured in DMEM with a content of 10% of FCS For HCMV reproduction assays, HFF cells were infected with a strain HCMV AD169 producing EGFP (HCMV AD169-GFP; 27). 1 hour after infection, the medium was changed to a medium containing the indicated concentration of the compound (0.3μM, 1μM and 3μM respectively) After 7 days incubation, the cells were lysed (in 25mM Tris, pH 7.5, 2mM DTT, 1% Triton X-100 and 10% glycerol) and the EGFP content was analyzed in a Wallac Victor fluorescence detector.

HCV replicon assays:

[0264] Compounds were tested for their activity in the HCV reproduction system described by Bartenschlager et al. (Lohmann et al, Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 285, 110, 1999).

Affinity chromatography experiments:

Immobilization of the compound:

[0265] Coupling to epoxy groups: 500 μl of Sepharose 6B (Amersham Biosciences) was resuspended epoxy-activated, balanced at 50% DMF / 0.1M Na2CO3 in 1ml 20mM compound 102 or 20mM compound 103 respectively, dissolved in 50% DMF (Dimethylfomamide) / 0.1M Na2CO3. 5 μl 10M NaOH was added followed by an overnight incubation at 30 ° C stirring permanently in the dark. After washing three times in 1ml 50% DMF / 0.1M Na2CO3 drops were incubated in 1ml 1M ethanolamine for 6 hours at 30 ° C with permanent stirring at dark followed by the following steps: 50% DMF / 0.1M Na2CO3, then H2O, then 0.1M NaHCO3 pH 8.0 / 0.5M NaCl followed by 0.1 M NaAc pH 4.0 / 0.1 M NaCl and finally three times in the chromatographic buffer (see below) containing 150mM NaCl. As a control matrix, Sepharose 6B epoxy activated with 1 m ethanolamine was incubated and He also treated as described above. The drops were stored in 20% ethanol at 4 ° C in the dark.

[0266] Carbodiimide coupling: ECH-Sepharose 4B (Amersham Biosciences) was washed according to manufacturer's instructions and balanced to 50% DMF / 50% ethanol. 2.5ml of dried drops were resuspended in 5ml 15mM compound 102 or compound 103 respectively, were dissolved in 50% DMF / 50% ethanol and at 750 µl 1 M 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) was then added dropwise, dissolved in 50% DMF / 50% ethanol. The suspension was incubated overnight at room temperature with an extreme permanent rotation on end and then washed three times with 15ml 50% DMF / 50% ethanol before adding 5ml 33% DMF / 33% ethanol / 34% 1 M ethanolamine pH 8.0 and 650 μl EDC. After 2 hours of incubation at room temperature with a rotation permanent end to end, the drops were washed three times with 15ml 50% DMF / 50% ethanol, twice with 15ml 0.5M NaCl and once with 15ml 20% ethanol. Control drops were incubated with 5ml 1M ethanolamine instead of the compound and treated in the same way. The drops were stored in 20% ethanol at 4 ° C in the dark.

Affinity chromatography and preparative gel electrophoresis.

[0267] 1.25 x 109 PM1 cells were lysed in 15ml buffer containing 50mM HEPES pH 7.5, 400mM NaCl, 0.5% Triton X-100, 1mM EDTA, 1mM EGTA, 3mM MgCl2, 1mM DTT plus additives (10mM Sodiofluorid, 1mM ortovanadat, 10μg / ml aprotinin, 10μg / ml leupeptin, 1mM PMSF), purified by centrifugation and adjusted to 1M NaCl. The filtered lysate was loaded with a flow rate of 100 μl / min on a 25mM x 5mM chromatography column containing 500μl Compound 102 or Compound 103 matrix respectively, equilibrated to chromatographic buffer (20mM HEPES pH 7.5, 0.25% Triton X-100 , 1mM EDTA, 1mM EGTA) containing 1M NaCl. The column was washed with 25 column volumes, equilibrated to the chromatographic buffer containing 150 mM NCl and bound proteins were eluted in the same buffer containing 200μM Compound 102 or 200 µM Compound 103 respectively 10mM ATP and 20mM MgCl2 with a flow rate of 50μl / min. The volume of the protein containing fractions was reduced to 1/5 in a SpeedVac concentrator prior to precipitation according to Wessel & Flügge (Wessel et al., 1984). Precipitated proteins were dissolved in 16-BAC sample buffer and after reduction / alkylation separated by 2-dimensional 16-BAC / SDS-PAGE (Daub et al., Journal of Virology 2002, 76, 8214-8137). Coomassie impregnated points were selected and subjected to analysis by mass spectrometry.

Results:

Expression and kinase activity of CDK9 / CiclinaT1:

[0268] The CDK9 / CiclinaT1 complexes of the HEK293 cells dissolved completely. CDK9 / CiclinaT1 proteins were almost completely precipitated and eluted by streptavidin drops (data not shown). The image of the enrichment of the absorbed blots for the protein by PonceauS can be reached. In the eluent the CDK9 / CiclinaT1 proteins can be seen while they are not visible in the cells or extract. The nitrocellulose assay with antibodies against CDK2 and CDK4 revealed that these kinases do not contaminate purifications (data not shown). As shown in Figure 2, the result of increasing amounts of CDK9 wt proteins incubated with substrates (ATP and GST-CTDII) was the incorporation of radioactive phosphate. As expected, the mutation of the kinase critical domain residues (K48R and D167N) within CDK9 did not reveal phosphate incorporation, which means that these mutations make the kinase inactive. Additionally, preincubation of EDTA completely inhibited activity.

[0269] These results show that the purification of CDK9 / CiclinaT1 proteins using adenovirus leads to an active and pure enzyme. The alleged contamination with another protein kinase can be ruled out because purification of the mutated CDK9 resulted in negligible kinase activity.

[0270] Table 2 shows the semi-maximum constant inhibition values (IC50) of the 4,6-substituted aminopyrimidine derivatives CDK9 and CDK2 respectively.

Table 2: Inhibitory effect on CDK9 and CDK2 of some derivatives of 4.6 aminopyrimidine disubstitutes

Activity range "A" means that the compounds have an IC 50 between 1 to 1000 nM, activity range "b" means that the compounds have an IC 50 between 1000 to 10000 nM and activity range "c" means that The compounds have an IC50 between 10000 and 250000 nM. All values refer to LCMS (M + H) + if not

explicitly indicates as (M-H) "

1: Composite Number

2: Method of synthesis of  agree with 3: Tiem retention rate (minutes)

scheme 1-12

4: LC method

5: CDK9 (rank from 6: CDK4 (rank from 7: CDK2 (rank from

activity)

activity)

activity)

one

2 LCMS 3 4 Nomenclature 5 6

(one)

one 447 1.3 A1 N- {4- [6- (4-Methoxy-phenyl) -pyrimidine-4-ylamino] -phenyl} -4-methylbenzene-sulfonamide C

(2)

one 447 1.45 A1 N- {4- [6- (3-Methoxy-phenyl) -pyrimidine-4-ylamino] -phenyl} -4-methylbenzenesulfonamide C

(3)

one 385 0.94 A1 N- {5- [6- (4-methoxy-phenyl) -pyrimidine-4-ylamino] -2-methyl-phenyl} -methane sulfonamide b

(4)

one 488 1.16 A1 4-Amino-N- {4- [6- (2-benzyloxy-phenyl) -pyrimidine-4-yl-amino] -phenyl} benzamide a

(5)

one 447 1.16 A1 N- {4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -phenyl} -4-methylbenzene sulfonamide a

(6)

one 412 0.8 A1 4-Amino-N- {4- [6 - (4-methoxy-phenyl) -pyrimidine-4-yl-amino] -phenyl} benzamide a

(7)

one 383 1.95 B1 [6- (2-Benzyloxy-phenyl) -pyrimidine-4-yl] - (2-pyridin-4-yl-ethyl) -amine  a

(8)

one 412 0.76 A1 4-Amino-N- {4- [6 - (2-methoxy-phenyl) -pyrimidine-4-yl-amino] -phenyl} benzamide a

(9)

361 0.78 A1 1- {4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -phenyl} -pyrrolidine-2one a  a

(10)

 one 335 0.44 A1 N- {4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -phenyl} -acetamide  a b

(eleven)

 one 433 1.07 A1 N- {4- [6- (4-hydroxy-phenyl) -pyrimidine-4-ylamino] -phenyl} -4-methylbenzenesulfonamide a

(12)

 one 370 1.57 B1 N- {5- [6- (3-amino-phenyl) -pyrimidine-4-ylamino] -2-methyl-phenyl} -methane sulfonamide a

(13)

 one 292 1.27 B1 [6- (3-amino-phenyl) -pyrimidine-4-yl] - (2-pyridine-4-yl-ethyl) -amine  b

(14)

 one 321 1.52 B1 4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -benz-amide  a C

(fifteen)

 one 336 2.21 B1 4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -benzoic acid methyl ester a

(16)

 one 398 1.51 B1 4-Amino-N- {4- [6- (4-hydroxy-phenyl) -pyrimidine-4-yl-amino] -phenyl} benzamide b

(17)

 one 487 (MH) " 1.24  A1 3- (4- {6- [4- (toluene-4-sulfonylamino) -phenylamino] -pyrimidine-4-yl} phenyl) propionic

(18)

 one 489 1.6 A1 N- {4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -phenyl} -4-methyl-N-propylbenzenesulfonamide

(19)

 one 377 1.02 A1 N- {4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -phenyl} -2,2-dimethylpropionamide

(twenty)

 one 412 1.05 A1 2-amino-N- {4- [6- (2-methoxy-phenyl) -pyrimidine-4-ylamino] -phenyl} benzamide

(twenty-one)

 one 397 1.52 B1 4-Amino-N- {4- [6- (3-amino-phenyl) -pyrimidine-4-y] amino] -phenyl} benzamide

(22)

 one 293 1.61 B1 N- [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] -benzene-1,4-diamine

(2. 3)

 1 +2 476 2.38 B1 4-isopropyl-N- {4- [6- (2-methoxy-phenyl) -pyrimidine-4-ylamino] -phenyl} benzenesulfon-amide

(96)

 one 461 2.24 B1 N- (4- [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] -methyl-amino} -phenyl) -4-methylbenzenesulfon-amide

(24)

 one 373 (MH) " 2.02  B1 N- [4- (6-Chloro-pyrimidine-ylamino) -phenyl] -4-methyl-benzenesulfonamide

(25)

 one 338 (MH) " 1.57  B1 4-Amino-N- [4- (6-chloro-pyrimidine-4-ylamino) -phenyl] -benzamide

(26)

 1 +4 +8 307  1.79 B1 N- [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] -N-methyl-benzene-1,4-diamine

(27)

 1 +4 +8 505 1.28 A1 [{4- [6- (4-Hydroxy-phenyl) -pyrimidine-4-ylamino] -phenyl} - (toluene-4-sulfonyl) amino acid methyl ester

(28)

 one 519 2.36 A1 [{4- [6- (2-Methoxy-phenyi) -pyrimidine-4-ylamino] -phenyl} - (toluene-4sulfonyl) -amino] -methyl ester of acetic acid

(29)

 1 +2 504 2.33 B1 (S) -2- {4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -phenyl} carbamoylpiperidine-1-carboxylic acid tert-butyl ester

(30)

 1 +6 404 1.55 B1 (S) -piperidine-2-carboxylic {4- [6- (2-methoxy-phenyl) -pyrimidine-4 -lamino] -phenyl} -amide

(31)

 one 442 1.78 B1 4-Amino-N- {4- [6- (2,4-dimethoxy-phenyl) -pyrimidine-4-ylamino] -phenyl} benzamide

(32)

 one 408 1.91 B1 4-Amino-N- {4- [6 - ((E) -styryl) -pyrimidine-4-ylamino] -phenyl} -benzamide

(33)

 1 +2 371 1.81 B1 N- (4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -phenyl} methanesulfonamide

(3. 4)

 1 +2 509 2.4 B1 Biphenyl-4-sulfonic acid {4- [6- (2-methoxy-phenyl) -pyrimidine-4-yl-amino] phenyl} -amide

(35)

 one 454 2.12 B1 4-Amino-N- {4- [6- (5-isopropyl-2-methoxy-phenyl) -pyrimidine-4-ylamino] phenyl} -benzamide

(36)

 1 +2 415 1.21 A1 Bicyclo [2,2,1] heptane-2-carboxylic {4- [6- (2-methoxy-phenyl) -pyrimidine4-ylaminoj-phenyl} -amide

(37)

 1 +2 453 1.38 A1 N- {4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -phenyl} -3-methyl-2-phenylbutyramide

(38)

 1 +9 418  1.09 A1 1-Cydohexyl-3- {4- [6- (2-methoxy-phenyl) -pyrimidine-4-amino] -phenyl} -urea a b

(39)

 one 446 2.01 B1 4-Amino-N- {4- [6- (5-chloro-2-methoxy-phenyl) -pyrimidine-4-amino] -phenyl} -benzamide b C

(40)

 one 487 1.43 B1 (E) -3- (3- {6- [4- (toluene-4-sulfonylamino) -phenylamino] pyrimidine-4-yl} phenyl) acrylic C C

(41)

 1 +2 403  2.13 B1 Cyclohexanecarboxylic {4- [6- (2-methoxy-phenyl) -pyrimidine4-ylamino] phenyl} amide b C

(42)

 1 +2 391  2.07 B1 N- {4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino) -phenyl} -3,3-dimethyl-butyramide b b

(43)

 7 417 1.87 B1 4-Amino-N44- [6- (cyclohexylmethyl-amino) -pyrimidine-4-amino] -phenyl} -benzamide b C

(44)

 1 +3 403  2.13 B1 N-cyclohexyl-4- [6- (2-methoxy-phenyl) -pyrimidine-4-ylamino] benzamide a b

(Four. Five)

 1 +2 453  2.48 B1 4-tert-butyl-N- {4- [6- (2-methoxy-phenyl) -pyrimidine-4-ylamino] phenyl} -benzamide b C

(46)

 1 +2 378  1.68 B1 2-dimethylamino-N- {4- [6- (2-methoxy-phenyl) -pyrimidine-4-amino] -phenyl} -acetamide a  b b

(47)

 1 +2 504 2.12 B1 (1- {4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -phenylcarbamoyl} -cyclopentyl) -carbamic tert-butyl ester a C

(48)

 1 +2 518  2.18 B1 2- ({4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -phenylcarbamoyl} -methyl) -piperidine-1-carboxylic acid tert-butyl ester b b

(49)

 1 +2 495  1.83 B1 N- {4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -phenyl} -4- (4-methyl-piperazin-1-yl) -benzamide a b

(fifty)

 1 +2 398  1.66 B1 N- {4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -phenyl} isonicotinamide b C

(51)

 one 442 1.58 B1 4-Amino-N- {4- [6- (2,6-dimethoxy-phenyl) -pyrimidine-4-amino] -phenyl} -benzamide b C

(52)

 1 +2 397 2 B1 4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -N-phenylbenzamide a C

(53)

 1 +5 3.35  1.02 A1 N- {4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -phenyl} guanidine b b

(54)

 1 +3 377  2.02 B1 N-tert-butyl-4- [6- (2-methoxy-phenyl) -pyrimidine-4-ylamino] benzamide b b

(55)

 one 426 1.81 B1 4-Amino-N- {4- [6- (2-ethoxy-phenyl) -pyrimidine-4-yl-amino] phenyl} -benzamide a b

(56)

 one 442 1.69 B1 4-Amino-N- {4- [6- (2,3-dimethoxy-phenyl) -pyrimidine-4-amino] -phenyl} -benzamide b b

(57)

 one 442 1.71 B1 4-Amino-N44- [6- (2,5-dimethoxy-phenyl) -pyrimidine-4-amino] -phenyl} -benzamide C C

(58)

 one 440 1.87 B1 4-Amino-N- {4- [6- (2-isopropoxy-phenyl) -pyrimidine-4-ylamino] -phenyl} -benzamide a a

(59)

 one 418 1.45 B1 N- {4- [6- (2-Methoxy-phenyl) -pyrimidine ^ -lamino] -phenyl} -2piperidine-2-yl-acet-arnide a  a b

(60)

 7 365 1.01 B1 4-Amino-N- {4- [6- (2-hydroxy-ethylamino) -pyrimidine-4-amino] -phenyl} -benzamide b C

(97)

 1 +2 427 1.62 A1 4-Amino-N- {4- [2-amino-6- (2-methoxy-phenyl) -pyrimidine-4-amino] -phenyl} -benzamide b C

(61)

 1 +2 455 2.48 B1 Adamantane-1-carboxylic {4- [6- (2-methoxy-pheny0pyrimidine-4-ylamino] -phenyl} -amide b C

(62)

 one 395 2.58 B1 (4-Benzoxazol-2-yl-phenyl) - [6- (2-methoxy-phenyl) -pyrimidine4-yl] -amine C C

(63)

 one 394 1.88 B1 [4- (1H-benzimidazol-2-yl) -phenyl] - [6- (2-methoxy-phenyl) pyrimidine-4-yl] -amine a a

(64)

 1 +2 418 (MH) " 1.74  A1 3-diethylamino-N- {4- [6- (2-methoxy-phenyl) -pyrimidine-4-amino] -phenyl} -propionamide a  b b

(65)

 1 +2 452 1.98 B1 (S) -1,2,3,4-tetrahydro-isoquinoline ine-3-carboxylic acid {4- [6- (2-methoxy-phenyl) -pyrimidine-4-ylamino] -phenyl} -Amide a  C b

(66)

 1 +6 418  1.97 B1 1-amino-cyclohexanecarboxylic acid {4- [6- (2-methoxyphenyl) -pyrimidine-4-ylamino] -phenyl} -amide a  b b

(67)

 one 383 1.35 B1 4-Amino-N- [4- (6-pyridin-4-yl-pyrimidine-4-ylamino) -phenyl] benzamide C C

(87)

 1 +2 418  1.59 B1 1-methyl-piperidine-3-carboxylic acid {4- [6- (2-methoxyphenyl) -pyrimidine-4-ylamino] -phenyl} -amide a  b b

(98)

one 448 2.43 B1 Quinoline-2-carboxylic acid {4- [6- (2-methoxy-phenyl) pyrimidine-4-ylamino] -phenyl) -amide a C

(68)

 1 +6 404  1.82 B1 1-amino-cyclopentanecarboxylic acid {4- [6- (2-methoxy-phenyl) -pyrimidine-4-ylamino] -phenyl} -amide a  b b

(69)

 one 404 1.53 B1 (R) -piperidine-2-carboxylic {4- [6- (2-methoxy-phenyl) pyrimidine-4-ylamino] -phenyl} -amide a  a b

(70)

 1 +2 401  1.59 B1 1-methyl-1 H-imidazol-4-carboxylic {4- [6- (2-methoxyphenyl) -pyrimidine-4-ylamino] -phenyl} -amide a b

(71)

 1 +2 411  1.99 B1 N- {4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] phenyl} -2-phenyl-acetamide a b

(72)

 1 +3 305  1.55 C1 N- [4- (6-Chloro-pyrimidine-4-ylamino) -phenyl] -2,2-dimethylpropionamide C

(73)

 one 348 1.57 B1 2,2-DimethyI N- [4- (6-pyridin-3-yl-pyrimidine-4-ylamino) phenyl] -propionamide C

(74)

 7 381 (MH) " 1.26  B1 2,2-Dimethyl-N44- [6- (1-methyl-piperidin-4-ylamino) pyrimidine-4-ylamino] -phenyl} -Dropionamide C C

(75)

 one 389 (MH) " 1.12  B1 3- {6- [4- (2,2-Dimethyl-propionylamino) -phenylamino] pyrimidine-4-yl} -benzoic acid C

(76)

 one 380 (MH) " 1.67 B1 4-Amino-N- [4- (6-phenyl-pyrimidine-4-ylamino) -phenyl] benzamide b C

(77)

 one 386 (MH) " 1.64 B1 4-Amino-N- [4- (6-thiophen-2-yl-pyrimidine-4-ylamino) phenyl] -benzamide b C

(78)

 7 369 1.47 B1 2,2-Dimethyl-N- {4- [6- (4-methyl-piperazin-1-yl) pyrimidine-4-ylamino] -phenyl} -propionamide C

(79)

 7 329 1.12 B1 N- {4- [6- (2-Amino-ethylamino) -pyrimidine-4-ylamino] phenyl} -2,2-dimethyl-propionamide C C

(80)

 7 342 (MH) " 1.24 B1 N- {4- [6- (3-hydroxy-propylamino) -pyrimidine-4-ylamino] -phenyl} -2,2-dimethyl-propionamide C C

(81)

 1 +6 426 1.74 B1 (S) -2-Amino-N- {4- [6- (2-methoxy-phenyl0-pyrimidine-4ylarnino] -phenyl} -2-phenyl-acetamide a  b b

(82)

 1 +6 440 1.86 B1 (S) -N- {4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] phenyl} -2-methylamino-2-phenyl-acetamide a  b b

(83)

 1 +6 416 (MH) " 1.45 B1 (R, R) / (S, S) -N- (2-Amino-cyclohexyl) -4- [6- (2-methoxy-phenyl) -pyrimidine-4-ylamino] -benzamide a  b b

(84)

 1 +2 454 2.42 B1 Benzothiazol-2-carboxylic {4- [6- (2-methoxy-phenyl) pyrimidine-4-ylamino] -phenyl} -amide b C

(85)

 one 453 2.31 B1 N- {4- [6- (2-benzyloxy-phenyl) -pyrimidine-4-ylamino] phenyl} -2,2-dimethyl-propionamide a b

(86)

 1 +6 402 (MH) " 1.41 B1 4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -Npiperidin-3-yl-benzamide a  a a

(89)

 1 +2 418 1.44 B1 1-methyl-piperidine-4-carboxylic {4- [6- (2-methoxyphenyl) -pyrimidine-4-ylamino] -phenyl} -amide a  b b

(90)

 1 +6 374 (MH) " 1.34 B1 (S) -azetidin-2-carboxylic {4- [6- (2-methoxy-phenyl) pyrimidine-4-y (arnino] -phenyl} -amide a b

(91)

 1 +6 388 (MH) " 1.56 B1 (R) -pyrrolidine-2-carboxylic {4- [6- (2-methoxy-phenyl) pyrimidine-4-ylamino] -phenyl} -amide a  b b

(92)

 one 307 1.54 B1 [6- (4-Methoxy-phenyl) -pyrimidine-4-yl] - (2-pyridin-4-yl-ethyl) amine C C

(93)

 one 307 1.49 B1 [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] - (2-pyridin-4-yl-ethyl) amine b C

(94)

 one 293 1.79 B1 2- [6- (2-Pyridin-4-yl-ethylamino) -pyrimidine-4-yl] -phenol  b C

(95)

 one 397 1.8 B1 4- [6- (2-Benzyloxy-phenyl) -pyrimidine-4-ylamino] -benzamide a  b a

(99)

 one 335 1.72 B1 6- (2-lsopropoxy-phenyl) -pyrimidine-4-yl] - (2-pyridin-4-ylethyl) -amine a b

(100)

385 1.83 B1 N- {5- [6- (3-Methoxy-phenyl) -pyrimidine-4-ylamino] -2-methyl-phenyl} -methane-sulfonamide b b

(101)

454 2.08 B1 2-dimethylamino-N- {4- [6- (2-methoxy-phenyl) -pyrimidine-4-amino] -phenyl} -2-phenyl-acetamide a b

(102)

 one 364 1.33 C1 3-amino-N- {4- [6- (2-methoxy-phenyl) -pyrimidine-4-ylamino] -phenyl} -propionamide a  a b

(103)

 1 +12 455 1.37 C1 4-Amino-N- (4- {6- [2- (3-amino-propoxy) -phenyl] pyrimidine-4-ylamino} -phenyl) -benzamide a  C b

(104)

 one 412 0.76 B1 N- {3- [6- (3-methanesulfonylamino ^ -methyl-phenylamino) pyrimidine-4-yl] -phenyl} -acetamide a  C b

(105)

 one 371 1.54 B1 N- {5- [6- (3-hydroxy-phenyl) -pyrimidine-4-ylam  a C The

(106)

 one 355 1.7 B1 N- [2-methyl-5- (6-phenyl-pyrimidine-4-ylamino) -phenyl] methanesulfonamide a  C a

(107)

 one 423 2.16 B1 N- {2-methyl-5- [6- (3-trifluoromethyl-phenyl) -pyrimidine-4-amino] -phenyl} -methanesulfonamide C C C

(108)

 one 448 1.45 B1 N- {5- [6- (3-methanesulfonylamino-phenyl) -pyrimidine-4 -lamino] -2-methyl-phenyl} -methanesulfonamide b a

(109)

 one 432 1.71 B1 N- {5- [6- (3-amino-phenyl) -pyrimidine-4-ylamino] -2-methylphenyl} -benzene-sulfonamide a b

(110)

one 357 1.26 B1 N- [5 - ([4,5 '] bipyrimidinayl-6-ylamino) -2-methyl-phenyl] methanesulfonamide b b

(111)

 1 +9 456 1.84 B1 1-benzo [1,3] dioxol-5-yl-3- {4- [6- (2-methoxy-phenyl) pyrimidine-4-ylamino] -phenyl} -urea C

(112)

 1 +9 440 1.93 B1 1- {4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -phenyl} -3- (4-methyl-benzyl) -urea a C

(113)

 1 +9 392 1.81 B1 1-tert-butyl-3- {4- [6- (2-methoxy-phenyl) -pyrimidine-4-ylamino] phenyl} -urea a B

(114)

 one 415 2.08 B1 2,2-Dimethyl-N- {4- [6- (2-trifluoroimethyl-phenyl) -pyrimidine-4-amino-phenyl} -propionamide C C

(115)

 one 321 1.47 B1 3- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -benzamide  a a

(116)

 one 398 1.61 B1 Propane-1-sulfonic acid {5- [6- (3-amino-phenyl) pyrimidine-4-ylamino] -2-methyl-phenyl} -amide a a

(117)

 one 342 1.07 C1 4- [6- (3-amino-phenyl) -pyrimidine-4-ylamino] -benzenesulfonamide b a

(118)

392 1.66 B1 N- {4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -phenyl} -2-methyl-2-methylamino-propionamide a  a b

(119)

 1 +10 391  1.76 C1 N- {4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -3-methylphenyl} -2,2-dimethyl-propionamide C C

(120)

 1 +11 462  1.68 C1 N- {5- [6- (3-amino-phenyl) -pyrimidine-4-ylamino] -2-benzyl-oxyphenyl} -methane-sulfonamide b b

(121)

 one 356 1.21 C1 N- {3- [6- (3-amino-phenyl) -pyrimidine-4-ylamino] -phenyl} methanesulfonamide a b

(122)

 one 377 1.82 C1 N- {3- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -phenyl} -2,2-dimethyl-propionamide b b

(123)

one 307 1.35 C1 N * 1 * - [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] -2-methylbenzene-1,4-diamine b b

(124)

 one 293 1.43 C1 N- [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] -benzene-1, 3diamine a  b a

(125)

 one 482 1.03 B1 4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -N- (4-morpholin-4-yl-phenyl) -benzamide a B

(126)

 one 373 2.08 B1 2,2-Dimethyl-N- {446- (2-vinyl-phenyl) -pyrimidine-4-ylamino] phenyl} -propionamide b C

(127)

 one 365 2.03 B1 N- {4- [6- (2-Fluoro-phenyl) -pyrimidine-4-ylamino] -phenyl} -2,2-dimethyl-propionamide C C

(128)

 one 404 1.92 B1 (S) -piperidine-2-carboxylic {3- [6- (2-methoxy-phenyl) pyrimidine-4-ylamino] -phenyl} -amide a  b a

(129)

one 465 1.26 B1 2-oxo-2H-chromene-3-carboxylic acid {4- [6- (2-methoxyphenyl) -pyrimidine-4-ylamino] -phenyl} -amide C

(130)

one 441 1.89 C1 Benzo [1,3] dioxol-5-carboxylic acid {4- [6- (2-methoxyphenyl) -pyrimidine-4-ylamino] -phenyl} -amide a b

(131)

 one 375 2.13 C1 N- {4- [6- (2-ethyl-phenyl) -pyrimidine-4-ylamino] -phenyl} -2,2-dimethyl-propionamide C B

(132)

 one 423 2.19 C1 N- [4- (6-Biphenyl-2-yl-pyrimidine-4-ylamino) -phenyl] -2,2-dimethyl-propionamide C

(133)

 one 436 1.07 C1 1H-lendole-3-carboxylic acid {4- [6- (2-methoxy-phenyl) pyrimidine-4-ylamino] -phenyl} -amide a b

(135)

one 419 1.7 B1 N - ((1 R, 2R) / (1 S, 2S) -2-hydroxy-cyclohexyO-4- [6- (2methoxy-phenyl) -pyrimidine-4-ylamino] -benz-amide a b

(136)

 one 413 0.91 B1 N- (4-hydroxy-phenyl) -4- [6- (2-methoxy-phenyl) -pyrimidine-4-amino] -benz-amide a b

(137)

 one 439 1.54 A1 N- (4-Isopropyl-phenyl) -4- [6- (2-methoxy-phenyl) -pyrimidine-4 -lamino] -benz-amide b C

(138)

 one 437 1.34 B1 1H-Benzoimidazol-5-carboxylic acid {4- [6- (2-methoxyphenyl) -pyrimidine-4-ylamino] -phenyl} -amide b C

(139)

one 463 1.53 A1 1-Hydroxy-naphthalene-2-carboxyIic {4- [6- (2-methoxyphenyl) -pyrimidine-4-ylamino] -phenyl} -amide acid a b

(140)

one 406 1.82 B1 {4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -phenyl} -amide (2S, 3S) -2-Amino-3-methyl-amide a  b b

(141)

 one 437 2.02 B1 1 H-lndazole-3-carboxylic acid {4- [6- (2-methoxy-phenyl) pyrimidine-4-ylamino] -phenyl} -amide b

(142)

one 483 2.89 B1 Quinoline-8-sulfonic acid {5- [6- (3-amino-phenyl) pyrimidine-4-ylamino] -2-methyl-phenyl} -amide a C

(143)

 one 392 1.69 B1 (S) -2-Amino-N- {4- [6- (2-methoxy-phenyl) -pyrimidine-4-amino] -phenyl} -3-methyl-butyramide a  b b

(144)

one 436 1.43 A1 1-methyl-1 H-imidazol-4-sulfonic acid {5- [6- (3-aminophenyl) -pyrimidine-4-ylamino] -2-methyl-phenyl} -amide a a

(145)

 one 463 2.3 B1 3-hydroxy-naphthalene-2-carboxylic {4- [6- (2-methoxy-phenyl) pyrimidine-4-ylamino] -phenylj-amide b

(146)

476 1.81 C1 2-amino-N- {4- [6- (2-methoxy-phenyl) -pyrimidine-4-yl-amino] phenyl} -2-naphthalen-2-yl-acetamide a b

(147)

 3 391 1.63 B1 {4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -phenyl} morpholin-4-yl-methanone b b

(148)

3 418 1.76 C1 N - ((1 S, 2R) / (1 R, 2S) -2-Amino-cyclohexylH-i6- (2methoxy-phenyl) -pyrimidine-4-ino ylam] -benz-amide a b

(149)

 one 426 1.69 B1 4-Amino-N- {4- [6- (2-methoxy-phenyl) -5-methyl-pyrimidine-4-amino] -phenyl} -benzamide C

(150)

 one 357 1.64 B1 3- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -benzenesulfonamide a  C a

(151)

 one 398 1.95 B1 4-Amino-N- {4- [6- (2-hydroxy-phenyl) -pyrimidine-4-ylamino] phenyl} -benzamide C C

(152)

 one 307 1.51 B1 N- [6- (2-Methoxy-phenyl) -5-methyl-pyrimidine-4-yl] -benzene-1,4-diamine C C

(153)

 one 399 1.61 C1 Propane-2-sulfonic acid {4- [6- (2-methoxy-phenyl) -pyrimidine4-yl-amino] -phenyl} -amide a a

(154)

 one 399 1.6 C1 Propane-1-sulfonic acid {4- [6- (2-methoxy-phenyl) -pyrimidine4-yl-amino] -phenyl} -amide a a

(155)

 one 433 1.79 C1 N- {4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -phenyl} benzenesulfonamide a a

(156)

 one 461 2.09 C1 N- {5- [6- (2-benzyloxy-phenyl) -pyrimidine-4-ylamino] -2-methylphenyl} -methane-sulfonamide a a

(157)

 one 398 1.7 C1 N- {5- [6- (3-dimethylamino-phenyl) -pyrimidine-4-sulfonamide ylam a b

(158)

 one 413 1.78 C1 N- {5- [6- (2-lsopropoxy-phenyl) -pyrimidine-4-ylamino] -2-methylphenyl} -methanesulfonamide a a

(159)

 one 519 2.31 B1 N-Bis-propane-1-sulfonic acid {4- [6- (2-methoxy-phenyl) -5-methyl-pyrimidine-4-yl-amino] -phenyl} -amide C

(160)

 one 413 1.85 B1 Propane-1-sulfonic acid {4- [6- (2-methoxy-phenyl) -5-methylpyrimidine-4-ylamino] -phenyl} -amide C

(161)

3 418 1.57 B1 N- (1 R, 2R) / (1S, 2S) (2-Amino-cyclo-hexyl) -4- [6- (4-methoxy-phenyl) -pyrimidine-4-ylamino] -benz-amide a b

(162)

 one 385 1.55 C1 N- {5- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -2-methyl-phenyl} methane sulfonamide a a

(163)

 one 380 1.58 C1 N- {5- [6- (3-cyano-phenyl) -pyrimidine-4-ylamino] -2-methyl-phenyl} methane sulfonamide b b

(164)

 one 480 1.95 B1 (S) -piperidine-2-carboxylic {4- [6- (2-benzyloxy-phenyl) pyrimidine-4-ylamino] -phenyl} -amide a a

(165)

 one 383 1.49 C1 N- {5- [6- (3-formyl-phenyl) -pyrimidine-4-ylamino] -2-methyl-phenyl} methane sulfonamide b b

(166)

385 1.34 C1 N- {5- [6- (2-hydroxymethyl-phenyl) -pyrimidine-4-ylamino] -2-methylphenyl} -methane sulfonamide b

(167)

404 1.61 B1 (S) -piperidine-2-carboxylic {4- [6- (4-methoxy-phenyl) pyrimidine-4-ylamino] -phenyl} -amide b

(168)

402 1.5 B1 (S) -piperidine-2-carboxylic {4- [6- (3-formyl-phenyl) -pyrimidine4-ylamino] -phenyl} -amide b b

(169)

417 1.72 B1 (S) -piperidine-2-carboxylic {4- [6- (3-dimethyl-amino-phenyl) pyrimidine-4-yl-amino] -phenyl-amide b

(170)

 one 404 1.36 B1 (S) -piperidine-2-carboxylic {4- [6- (2-hydroxy-methyl-phenyl) pyrimidine-4-yl-amino] -phenyl-amide b

(171)

405 1.45 B1 (S) -piperidine-2-carboxylic {4- [6- (2-methoxy-pyridin-3-yl) pyrimidine-4-yl-amino] -phenyl-amide a  b

(172)

405 1.45 B1 (S) -piperidine-2-carboxylic {4- [6- (6-methoxy-pyridin-3-yl) pyrimidine-4-ylamino] -phenyl-amide b

(173)

480 2.1 B1 (S) -piperidine-2-carboxylic {4- [6- (4-benzyloxy-phenyl) pyrimidine-4-ylamino] -phenyl} -amide C

(174)

466 1.94 B1 (S) -piperidine-2-carboxylic {4- [6- (4-phenoxy-phenyl) -pyrimidine4-ylamino] -phenyl} -amide a b

(175)

385 1.16 C1 N- {5- [6- (4-hydroxymethyl-phenyl) -pyrimidine-4-ylamino] -2-methylphenyl} -methane-sulfonamide b

(176)

386 1.43 C1 N- {5- [6- (2-Methoxy-pyridin-3-yl) -pyrimidine-4-ylamino] -2-methylphenyl} -methanesulfonamide a b

(177)

 one 431 1.3 C1 (S) -piperidine-2-carboxylic {4- [6- (4-acetylamino-phenyl) pyrimidine-4-ylamino] -phenyl} -amide b

(178)

467 1.37 B1 (S) -piperidine-2-carboxylic {4- [6- (3-methanesulfonyl-aminophenyl) -pyrimidine-4-ylamino] -phenyl} -amide a

(179)

416 1.43 B1 (S) -piperidine-2-carboxylic {4- [6- (3-acetyl-phenyl) -pyrimidine4-yl-amino] -phenyl} -amide C

(180)

485 1.62 B1 (S) -piperidine-2-carboxylic {4- [6- (4-cyclopentyl-carbamoylphenyl) -pyrimidine-4-yl-amino] -phenyl} -amide b

(181)

371 1.89 C1 N- {5- [6- (2-hydroxy-phenyl) -pyrimidine-4-ylamino] -2-methyl-phenyl} methane-sulfonamide a a

(182)

439 1.85 C1 (E) -3- {3- [6- (3-Methanesulfonylamino-4-methyl-phenyl-amino) pyrimidine-4-yl] -phenyl} -acrylic acid methyl ester b b

(183)

385 1.34 C1 N- {5- [6- (3-hydroxymethyl-phenyl) -pyrimidine-4-ylamino] -2-methylphenyl} -methane-sulfonamide b b

(184)

413 2.22 C1 N-Butyl-3- [6- (2-methoxy-phenyl) -pyrimidine-4-ylamino] benzenesulfonamide a b

(185)

 one 356 1.81 C1 (3-methanesulfonyl-phenyl) - [6- (2-methoxy-phenyl) -pyrimidine-4-yl] amine a a

(186)

433 1.59 B1 (S) -piperidine-2-carboxylic {4- [6- (2,3-dimethoxy-phenyl) pyrimidine-4-ylamino] -phenyl} -amide b b C

(187)

433 1.64 B1 (S) -piperidine-2-carboxylic {4- [6- (2,4-dimethoxy-phenyl) pyrimidine-4-ylamino] -phenylj-amide a  a b

(188)

432 1.85 B1 (S) -piperidine-2-carboxylic {4- [6- (2-isopropoxy-phenyl) pyrimidine-4-ylamino] -phenyl} -amide a  a b

(189)

420 1.63 B1 (S) -piperidine-2-carboxylic {4- [6- (2-methylsulfanyl-phenyl) pyrimidine-4-ylamino] -phenyl} -amide a  a B

(190)

 one 458 1.84 B1 (S) -piperidine-2-carboxylic {4- [6- (2-trifluoromethoxy-phenyl) pyrimidine-4-ylarnino] -phenyl} -amide b b

(191)

 one 422 1.55 B1 (S) -piperidine-2-carboxylic {4- [6- (5-acetyl-thio-fen-2-yl) pyrimidine-4-ylamino] -phenyl} -amide b

(192)

 one 408 1.65 B1 (S) -piperidine-2-carboxylic {4- [6- (2-chloro-phenyl) -pyrimidine4-yl-amino] -phenyl} -amide a C

(193)

 one 404 1.31 B1 (S) -piperidine-2-carboxylic {4- [6- (3-hydroxy-methyl-phenyl) pyrimidine-4-ylamino] -3henyl} -amide b

(194)

3 404 1.34 B1 N - ((1R, 2R) / (1S, 2S) -2-Amino-cyclo-hexyl) -4- [6- (3-hydroxyPhenyo-pyrimidine-4-yl-amino] -benzamide b

(195)

3 481 1.36 B1 N - ((1R, 2R) / (1S, 2S) -2-amino-cyclohex-yl) -4- [6- (3-methanesulfonylamino-phenyl) -pyrimidine-4-ylamino] -benzamide a b

(196)

 3 445 1.44 B1 4- [6- (2-Acetyl-amino-phenyl) -pyrimidine-4-yl-amino] -N - ((1 R, 2R) / (1 S, 2S) -2-amino-cyclohexyl) -benz- amide C

(197)

 one 399 1.71 B1 N- {5- [6- (2-Methoxymethyl-phenyl) -pyrimidine-4-ylamino] -2-methylphenyl} -sulfonamide met b

(198)

3 494 1.91 B1 N - ((1 R, 2R) / (1 S, 2S) -2-Amino-cyclohexyl) -4- [6- (2-benzyloxy-phenyl) -pyrimidine-4-yl-benzamide aminoj a  a a

(199)

3 446 1.81 B1 N - ((1 R, 2R) / (1 S, 2S) -2-amino-cyclohex-yl) -4- [6- (2isopropanol-poxy-phenyl) -pyrimidine-4-ylamino] -benzamide a  b b

(200)

 one 426 1.75 B1 4-Amino-N- {4- [6- (4-methoxy-phenyl) -5-methyl-pyrimidine-4-amino] -phenyl} -benzamide C

(201)

3 446 1.67 B1 3- {6- [4 - ((1R, 2R) / (1S-2S) -2-Amiho-cyclohexylcarbamoylphenylamino] -pyrimidine-4-yl} -benzoic acid methyl ester b

(202)

 one 406 1.26 B1 (S) -piperidine-2-carboxylic {4- [6- (4-methoxy-phenyl) pyrimidine-4-ylamino] -phenyl} -amide C

(203)

 one 418 1.48 B1 (S) -piperidine-2-carboxy ic {4- [6- (3-methoxymethyl-phenyl) pyrimidine-4-ylamino] -jhenyl} -amide b

(204)

 one 307 1.59 B1 N- [6- (2-Methoxy-phenyl) -2-methyl-pyrimidine-4-yl] -benzene-1,4-diamine C

(205)

 one 307 1.68 B1 N- [6- (4-methoxy-phenyl) -2-methyl-pyrimidine-4-yl] -benzene-1,4-diamine C

(206)

3 403 1.27 B1 N - ((1R, 2R) / (1S, 2S) -2-Amino-cyclohexyl) -4- [6- (3-aminophenyl) -pyrimidine-4-ylamino] -benzamide b

(207)

 3 445 1.3 B1 4- [6- (3-Acetylamino-phenyl) -pyrimidine-4-ylamino] -N - ((1R, 2R) / (1S, 2S) -2-amino-cyclohexyl-benzamide b

(208)

3 494 2.09 B1 N - ((1R, 2R) / (1S, 2S) -2-Amino-cyclohexyl) -4- [6- (4-benzyloxy-phenyl) -pyrimidine-4-ylamino] -benzamide C

(209)

3 413 1.59 B1 N - ((1R, 2R) / (1S, 2S) -2-Amino-cyclohexyl) -4- [6- (3-cyanophenyl) -pyrimidine-4-ylamino] -benzamide b

(210)

3 432 1.49 B1 N - ((1R, 2R) / (1S, 2S) -2-Amino-cyclohexyl) -4- [6- (2-methoxymethyl-phenyl) -pyrimidine-4-ylamino] -benzamide b

(211)

 3 431 1.58 B1 (S) -piperidine-2-carboxylic {4- [6- (3-dirnethylaminomethylfenil) -pyrimidine-4-ylamino] -phenyl} -amide b

(212)

3 439 1.53 B1 N - ((1R, 2R) / (1S, 2S) -2-Amino-cyclohexyl) -4- (6-quinolin-3yl-pyrimidine-4-ylamino) -benzamide C

(213)

3 420 1.28 B1 N - ((1R, 2R) / (1S, 2S) -2-Amino-cyclohexyl) -4- (2, -methoxy [4,5 '] bipyrimidinayl-6-ylamino) -benzamide C

(214)

 one 342 1.31 B1 3- [6- (3-amino-phenyl) -pyrimidine-4-ylamino] benzenesulfonamide a b

(215)

 one 357 1.45 B1 3- [6- (4-Methoxy-phenyl) -pyrimidine-4-ylamino] benzenesulfonamide a a

(216)

 one 418 2.43 B2 (R, R) -N- (2-Amino-cyclohexyl) -4- [6- (2-hydroxymethyl-phenyl) pyrimidine-4-ylamino] -benzamide

(217)

 one 420 3.05 B2 N- (2-diethylamino-ethyl) -4- [6- (2-methoxy-phenyl) -pyrimidine-4-amino] -benzamide  b

(218)

 one 404 3.1 B2 (R, R) -N- (2-Amino-cyclohexyl) -4- [6- (2-hydroxy-phenyl) pyrimidine-4-ylamino] -benzamide  b

(219)

one 419 1.46 B1 (R, R) -N- (2-Amino-cyclohexyl) -4- [6- (2-methoxy-pyridin-3-yl) pyrimidine-4-ylamino] -benzamide  C

(220)

 one 445 1.76 B1 (R, R) -N- (2-Amino-cyclohexyl) -4- [6- (5-dimethylaminomethylpyridin-3-yl) -pyrimidm-ylamino] -benzamide

(221)

459 1.28 B1 (R, R) -5- {6- [4- (2-Amino-cyclohexylcarbamoyl) -phenylamino] pyrimidine-4-yl} -pyridine-2-carboxylic acid dimethylamide

(222)

 one 434 1.78 B1 (R, R) -N- (2-Amino-cyclohexyl) -4- [6- (6-methylsulfanyl-pyridin3-yl) -pyrimidine-4-ylamino] -benzamide

(223)

 one 417 1.41 B1 (R, R) -N- (2-Amino-cyclohexyl) -4- [6- (5-aminomethyl-pyridin-3yl) -pyrimidine-4-ylamino] -benzamide

(224)

 one 434 1.59 B1 (R, R) -N- (2-Amino-cyclohexyl) -4- [6- (4-methylsulfanyl-pyridin3-yl) -pyrimidine-4-ylamino] -benzamide  b

(225)

418 1.26 B1 N- (2-Amino-cyclohexyl) -4- [6- (5-hydroxymethyl-pyridin-3-yl) pyrimidine-4-ylamino] -benzamide

(226)

390 5.33 D2 rac-4- [6- (2-methoxy-phenyl) -pyrimidine-4-ylamino] -N-pyrrolidin3-yl-benzanriide

(227)

 one 431 2.85 B2 (R, R) -N- (2-Amino-cyclohexyl) -4- [6- (5-dimethylamino-pyridin3-yl) -pyrimidine-4-ylamino] -benzamide

(228)

one 436 1.52 B1 (R, R) -4- [6- (5-acetyl-thiophene-2-yl) -pyrimidine-4-ylamino] -N- (2-amino-cyclohexyl) -benzamide

(229)

496 3.66 B2 6- (2-Methoxy-phenyl) -pyrimidine-4-yl] - [3- (piperidine-1-sulfonyl) phenyl] -arnine N- (2-diethylamino-ethyl) -benzamide  a

(230)

one 430 1.43 B1 (R, R) -4- [6- (2-Acetyl-phenyl) -pyrimidine-4-ylamino] -N- (2-amino-cyclohexyl) -benzamide

(231)

398 6.63 D2 4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -N-pyridin-3-ylbenzamide

(232)

 one 446 2.73 B2 N- (1-Acetyl-piperidin-3-yl) -4- [6- (2-methoxy-phenyl) -pyrimidine-4-lamino] -benzamide

(233)

 one 431 2.89 B2 (R, R) -N- (2-Amino-cyclohexyl) -4- [6- (2-dimethylamino-phenyl) pyrimidine-4-ylamino] -benzamide  b

(2. 3. 4)

 8A 548 7.55 D2 4- {4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] benzoylamino} -pyrrolidine-1, 2-methyl ester 1-tert-butyl ester 2-dicarboxylate

(233)

 one 431 2.89 B2 (R, R) -N- (2-Amino-cyclohexyl) -4- [6- (2-dimethylamino-phenyl) pyrimidine-4-ylamino] -benzamide  b

(2. 3. 4)

 8A 548 7.55 D2 4- {4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] benzoylamino} -pyrrolidine-1, 2-methyl ester 1-tert-butyl ester 2-dicarboxylate

(235)

 one 391 3.06 B2 2-Chloro-5- [6- (2-methoxy-phenyl) -pyrimidine-4-ylamino] benzenesulfonamide

(236)

 one 425 3.75 B2 [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] - [3- (piperidine-1-sulfonyl) phenyl] -amine

(237)

 one 397 3.29 B2 N-allyl-3- [6- (2-methoxy-phenyl) -pyrimidine-4-ylamino] benzenesulfonamide

(238)

 one 447 3.56 B2 N-Benzyl-3- [6- (2-methoxy-phenyl) -pyrimidine-4-ylamino] benzenesulfonamide

(239)

 one 411 3.8 B2 [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] - [3- (pyrroiidine-1-sulfonyl) phenyl] -amine

(240)

 one 427 3.31 B2 [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] - [3- (morpholine-4-sulfony0phenyl] -amine

(241)

 one 371 3.08 B2 3- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -N-methylbenzenesulfonamide

(242)

 one 399 2.83 B2 N- [6- (2-Methoxy-pheny0-pyrimidine-4-yl] -N- (3-sulfamoylpheny0-acetamide

(243)

 one 437 3.84 B2 N, N-diallyl-3- [6- (2-methoxy-phenyl) -pyrimidine-4-ylamino] benzenesulfonamidel

(244)

 one 433 3.24 B2 3- [6- (2-Benzyloxy-Phenyo-pyrimidine-4-ylamino] benzenesulfonamide

(245)

 one 465 3.69 B2 [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] - [4- (4-nitrobenzenesulfonyl) -phenyl] -amine

(246)

 one 410 3.98 B2 [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] - (4trifluoromethanesulfonyl-phenyl) -amine

(247)

 one 356 3.07 B2 (4-methanesulfonyl-phenyl) - [6- (2-methoxy-phenyl) -pyrimidine-4-yl] amine

(248)

 one 452 2.34 B2 N- (3,4-dimethyl-isoxazol-5-yl) -4- [6- (2-methoxy-phenyl) pyrimidine-4-ylarnino] -benzenesulfonamide

(249)

 one 399 3.37 B2 4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -N-propylbenzenesulfonamide

(250)

 one 357 2.84 B2 4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] benzenesulfonamide

(251)

 one 385 3.38 B2 4- [6- (2-Methoxy-phenyl) -pyrimWin-4-ylamino] -N, N-dimethylbenzenesulfonam

(252)

 one 415 3.09 B2 N- (2-methoxy-ethyl) -4- [6- (2-methoxy-phenyl) -pyrimidine-4-amino] -benzenesulfonamide

(253)

 one 432 3.49 B2 [6- (2-Benzyloxy-phenyl) -pyrimidine-4-yl] - (3-methanesulfonylphenyl) -amine

(254)

 one 342 3.31 B2 2- [6- (3-methanesulfonyl-phenylamino) -pyrimidine-4-yl] -phenol

(255)

 one 341 2.62 B2 [6- (3-amino-phenyl) -pyrimidine-4-yl] - (3-methanesulfonyl-phenyl) amine

(256)

 one 372 2.42 B2 5- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -2-methylbenzenesulfonic acid

(257)

 one 386 2.77 B2 2- {3- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] benzenesulfonyl} -ethanol

(258)

 one 374 3.1 B2 (2-Fluoro-5-methanesulfonyl-phenyl) - [6- (2-methoxy-phenyl) pyrimidine-4-yl] -amine

(259)

 one 341 2.97 B2 [6- (2-amino-phenyl) -pyrimidine-4-yl] - (3-methanesulfonyl-phenyl) amine

(260)

 one 410 3.92 B2 [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] - (3trifluoromethanesulfonyl-phenyl) -amine

(261)

 one 418 3.54 B2 (3-methanesulfonyl-phenyl) - [6- (2-phenoxy-phenyl) -pyrimidine-4-yl] amine

(262)

 one 398 3.55 B2 [6- (2-Butoxy-phenyl) -pyrimidine-4-yl] - (3-methanesulfonyl-phenyl) amine

(263)

 one 368 3.29 B2 (3-ethenesulfonyl-phenyl- [6- (2-methoxy-phenyl) -pyrimidine-4-yl] amine

(264)

 one 420 1.81 B1 (S) -piperidine-2-carboxylic {4- [6- (4-methylsulfanyl-phenyl) pyrimidine-4-ylamino] -phenyl} -amide

(265)

 one 370 & 372 4.28  D1 2-Chloro-4- [6- (2-methoxy-phenyl) -pyrimidine-4-ylamino] -benzoic acid methyl ester

(266)

 one 384 3.82 B2 [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] - (4-phenoxy-benzyl) -amine

(267)

 one 350 3.98 D1 4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -3-methyl-benzoic acid methyl ester

(268)

 1 +2 382 5.87 D2 [6- (3-amino-phenyl) -pyrimidine-4-yl] - (1-methanesulfonyl-2, 3dhydro-1 / - / - indole-6-yl) -amine

(269)

 one 385 3.36 B2 3- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -piperidine-1 carboxylate tert-butyl ester

(270)

 one 336 2.11 B2 {4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -phenyl} -acetic acid

(271)

 one 318 2.87 B2 (1H-lndazol-6-yl) - [6- (2-methoxy-phenyl) -pyrimidine-4-yl] -amine

(272)

 one 348 3.81 B2 1- {4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -phenyl} -butan-1one

(273)

 one 285 2.49 B2 [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] -piperidin-3-yl-amine

(274)

 one 382 3.98 B2 {4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -phenyl} -phenylmethanone

(275)

 one 369 3.9 B2 N- [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] -A / -phenyl-benzene-1,3-diamine

(276)

 one 364 3.31 B2 (3- [1,3] dioxan-2-yl-phenyl) - [6- (2-methoxy-phenyl) -pyrimidine-4-yl] amine

(277)

 one 308 3.46 B2 (3-methoxy-phenyl) - [6- (2-methoxy-phenyl) -pyrimidine-4-yl] -amine

(278)

 one 308 3.29 B2 (4-methoxy-phenyl) - [6- (2-methoxy-phenyl) -pyrimidine-4-yl] -amine

(279)

 one 369 3.81 C2 N- [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] -W-phenyl-benzene-1,4-diamine

(280)

 one 363 3.16 B2 [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] - (4-morpholin-4-yl-phenyl) amine  b

(281)

 one 296 3.43 B2 (2-fluoro-phenyl) - [6- (2-methoxy-phenyl) -pyrimidine-4-yl] -amine

(282)

 one 375 3.41 B2 (1-Benzyl-piperidin-4-yl) - [6- (2-methoxy-phenyl) -pyrimidine-4-yl] amine

(283)

 one 334 4.29 B2 (4-butyl-phenyl) - [6- (2-methoxy-phenyl) -pyrimidine-4-yl] -amine

(284)

 one 370 3.98 B2 [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] - (4-phenoxy-phenyl) -amine

(285)

 one 371 2.66 B2 4 - {[6- (2-methoxy-phenyl) -pyrimidine-4-ylamino] -methyl} benzenesulfonamide

(286)

 one 395 3.17 B2 rac-1-dimethylamino-3- {4- [6- (2-methoxy-phenyl) -pyrimidine-4-amino] -phenoxy} -3-propan-2-ol

(287)

 one 307 2.72 B1 N- [6- (4-Methoxy-phenyl) -5-methyl-pyrimidine-4-yl] -benzene-1,4amine

(288)

 one 292 2.45 B1 N- [6- (3-amino-phenyl) -5-methyl-pyrimidine-4-yl] -benzene-1, 4amine

(289)

 one 285 2.5 B2 [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] -piperidin-4-yl-amine

(290)

 one 461 3.98 B2 4- [6- (2-Benzyloxy-phenyl) -pyrimidine-4-ylamino] -piperidine-1-carboxylic acid tert-butyl ester

(291)

 one 284 3.5 B2 Cyclohexyl- [6- (2-methoxy-phenyl) -pyrimidine-4-yl] -amine

(292)

 9A 433 (MH) " 7.05  D2 4- {6- [2- (2-morpholin-4-yl-ethoxy) -phenyl] -pyrimidine-4-ylamino} benzoic methyl ester

(293)

 one 366 3.75 D1 2-methoxy-4- [6- (2-methoxy-phenyl) -pyrimidine-4-ylamino] benzoic acid methyl ester

(294)

 one 412 2.42 B2 {4- [6- (2-Benzyloxy-phenyl) -pyrimidine-4-ylamino] -phenyl} -acetic acid b

(295)

 one 323 3.6 B2 [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] - (3-nitro-phenyl) -amine

(296)

 one 308 2.79 B2 {3- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -phenyl} -methanol

(297)

 one 354 3.87 B2 [6- (2-Benzyloxy-phenyl) -pyrimidine-4-yl] -phenyl-amine

(298)

 one 278 3.43 B2 [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] -phenyl-amine

(299)

 one 296 3.45 B2 (4-fluorophenyl) - [6- (2-methoxy-phenyl) -pyrimidine-4-yl] -amine

(300)

 one 370 4.07 B2 [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] - (3-phenoxy-phenyl) -amine

(301)

 one 324 3.71 B2 [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] - (3-methylsulfanyl-phenyl) amine

(302)

 one 361 3.32 B2 [6- (2-Benzyloxy-phenyl) -pyrimidine-4-yl] -piperidin-4-yl-amine

(303)

 one 294 2.89 B2 3- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -phenol

(304)

 one 320 3.31 B2 1- {4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -phenyl} -ethanone

(305)

 one 356 and 358 2.42  D1 2-Chloro-4- [6- (2-methoxy-phenyl) -pyrimidine-4-ylamino] -benzoic acid

(306)

 one 371 (MH) " 4.93 D1 {4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -butyl} -carbamic tert-butyl ester

(307)

 1 +2 473 8.87 D3 [6- (2-Benzyloxy-phenyl) -pyrimidine-4-yl] - (1-methanesulfonyl-2, 3dihydro-1H-indole-6-yl) -amine

(308)

 one 385  3.41 B2 4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -piperidine-1 carboxylate tert-butyl ester

(309)

 one 321  7.42 D2 4- [6- (2-Amino-phenyl) -pyrimidine-4-ylamino] -benzoic acid methyl ester

(310)

 one 324 3.8 B2 [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] - (4-methylsulfanyl-phenyl) amine

(311)

 one 273 2.2 D1 N 1- [6- (2-methoxy-phenyl) -pyrimidine-4-ylamino] -butane-1,4-diamine

(312)

 one 471  3.74 B2 1- {4- [6- (2-Benzyloxy-phenyl) -pyrimidine-4-ylamino] -phenoxy} -3-dimethylamino-propan-2-ol

(313)

 1 +2 397 3.6 D1 (1-Methanesulfonyl-2,3-dihydro-1H-indol-6-yl) - [6- (2-methoxyphenyl) -amine pyrimidine

(314)

 one 445  2.69 B2 N- (2-Amino-cyclohexyl) -4- [6- (benzotriazol-1-yloxy) pyrimidine-4-ylamino] -benzamide

(315)

 one 545  2.02 B2 (2- {4- [6- (benzotriazol-1-yloxy) -pyrimidine-4-ylamino] benzoylamino} -cyclohexyl) -carbamic tert-butyl ester

(316)

 one 320  3.41 C2 1- {3- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -phenyl} -ethanone

(317)

 one 361  3.96 C2 [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] - (4-piperidin-1-yl-phenyl) amine

(318)

 one 352  3.72 D1 3-hydroxy-4- [6- (2-methoxy-phenyl) -pyrimidine-4-ylamino] benzoic acid methyl ester

(319)

 one 352  4.25 D1 2-hydroxy-4- [6- (2-methoxy-phenyl) -pyrimidine-4-ylamino] benzoic acid methyl ester

(320)

 10A 442 5.87 D4 4-amino-butane-1-sulfonic acid {5- [6- (2-methoxy-phenyl) pyrimidine-4-ylamino] -2-methyl-phenyl} -amide

(321)

 one (3- {6- [3- (4-Amino-butane-1-sulfonylamino) -4-methylphenylamino] -pyrimidine-4-yl} -phenyl) -carbamic 9H-fluoren-9-methyl ester

(322)

 one 366  4.22 D1 3-methoxy-4- [6- (2-methoxy-phenyl) -pyrimidine-4-ylamino] benzoic acid methyl ester

(323)

 9A 434 5.67 D3 4- {6- [2- (2-Piperidin-1-yl-ethoxy) -phenyl] -pyrimidine-4-ylamino} benzoic methyl ester

(324)

 9A 393 5.37 D3 4 - {- 6- [2- (2-dimethylamino-ethoxy) -phenyl] -pyrimidine-4-ylamino} benzoic acid methyl ester

(325)

 9A 449 5.2 D3 4 - {- 6- [2- (2-diisopropylamino-ethoxy) -phenyl] -pyrimidine-4-amino-} -benzoic acid methyl ester

(326)

 9A 422 5.67 D3 4 - {- 6- [2- (2-diethylamino-ethoxy) -phenyl] -pyrimidine-4-ylamino} benzoic acid methyl ester

(327)

8A 448 4.03 D2 (S, S) -4- {4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] benzoylamino} -pyrrolidine-2-carboxylic acid methyl ester

(328)

8A 434 4.52 D5 (S, S) -4- {4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] benzoylamino} -pyrrolidine-2-carboxylic acid

(329)

 8A 547 5.95 D3 acid

(330)

 3 389  7.32 D2 N-cyclopentyl-4- [6- (2-methoxy-phenyl) -pyrimidine-4-ylamino] benzamicle

(331)

 one 357  2.82 B2 3- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] benzenesulfonamide  C

(332)

 one 356  3.70 B2 (3-methanesulfonyl-phenyl- [6- (2-methoxy-phenyl) -pyrimidine-4-yl] amine

(333)

 one 386  2.77 B2 2- {3- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] benzenesulfoyl} -ethanol

(334)

463 2.70 B2 N- (4,6-dimethyl-pyrimidine-2-yl) -4- [6- (2-methoxy-phenyl) pyrimidine-4-ylamino] -benzenesulfonamide

(335)

 one 440  2.54 B2 4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -A / -thiazol-2-ylbenzenesulfonamide

(336)

 one 375  3.63 B2 (1-Benzyl-piperidin-3-yl) - [6- (2-methoxy-phenyl) -pyrimidine-4-yl] amine

(337)

 one 313  2.62 B2 3- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -azepan-2-one

(338)

 one 433  3.49 B2 4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -N-phenylbenzenesulfonamide

(339)

 one 332  3.77 B2 rac- [6- (2-methoxy-phenyl) -pyrimidine-4-yl] - (1,2,3,4-tetrahydronaphthalen-1-yl) -amine

(340)

 one 341  2.89 B2 [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] - (2,2,6,6-tetramethylpiperidin-4-yl) -amine

(341)

 one 371  3.07 B2 4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -N-methylbenzenesulfonamide  b

(342)

 one 366  3.24 B2 (1,1-dioxo-1H-1A 6-benzo [b] thiophen-6-yl) - [6- (2-methoxy-phenyl) pyrimidine-4-yl] -amine C

(343)

 one 399  2.12 B2 N-Acetyl-4- [6- (2-methoxy-phenyl) -pyrimidine-4-ylamino] benzenesulfonamide

(344)

463 3.32 B2 N- (2,6-dimethyl-pyrimidine-4-yl) -4- [6- (2-methoxy-phenyl) pyrimidine-4-ylamino] -benzenesulfonamide

(3. 4. 5)

 one 425  3.73 B2 [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] - [4- (piperidine-1-sulfonyl) phenyl] -amine

(346)

477 3.89 B2 3- {3- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -phenoxy} piperidine-1-carboxylic acid tert-butyl ester

(346)

 one 374  2.86 B2 [6- (2-Fluoro-6-methoxy-phenyl) -pyrimidtn-4-yl] - (3methanesulfonyl-phenyl) -amine  b

(348)

 one 374  3.18 B2 [6- (4-Fluoro-2-methoxy-phenyl) -pyrimidine-4-yl] - (3methanesulfonyl-phenyl) -amine

(349)

 one 374 3.20 B2 [6- (5-Fluoro-2-methoxy-phenyl) -pyrimidine-4-yl] - (3methanesulfonyl-phenyl) -amine

(350)

 one 279 2.80 B2 [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] -pyridin-3-yl-amine

(351)

 one 322 2.81 B2 2- {4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -phenyl} -ethanol b

(352)

 one 431 2.38 B2 (9,9-Dioxo-9,10-dihydro-9X6-thia-10-aza-phenanthren-3yl) - [6- (2-methoxy-phenyl) -pyrimidine-4-yl] -amine

(353)

 one 332 2.99 B2 [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] - (1-methyl-1H-indazol-6-yl) arnine  b

(354)

one 336 3.81 B2 Benzo [1L2,5] thiadiazol-4-yl- [6- (2-methoxy-phenyl) -pyrimidine4-yl] -amine

(355)

 one 336 3.62 B2 Benzo [1,2,5] thiadiazol-5-yl- [6- (2-methoxy-phenyl) -pyrimidine-4-yl] -amine

(356)

 one 377 3.53 B2 rac- [6- (2-methoxy-phenyl) -pyrimidine-4-yl] - [3- (piperidin-3-yloxy) phenyl] -amine

(357)

502 4.24 B2 6- (2-Methoxy-phenyl) -pyrimidine-4-yl] - {1- [6- (2-methoxy-phenyl) pyrimidine-4-yl] -1H-ndazol-5-yl} -amine

(358)

 one 317 3.06 B2 1H-lndol-5-YO- [6- (2-methoxy-Phenyo-pyrimidine-4-yl] -amine

(359)

 one 340 2.74 B2 (3-methanesulfinyl-phenyl) - [6- (2-methoxy-phenyl) -pyrimidine-4-yl] amine

(360)

 one 318 2.74 B2 (1H-lndazol-5-yl) - [6- (2-methoxy-phenyl) -pyrimidine-4-yl] -amine

(361)

 one 342 401 B2 4- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -thiophene-3-carboxylic acid methyl ester

(362)

 one 370 2.80 B2 4-methanesulfonyl-benzyl- [6- (2-methoxy-phenyl) -pyrimidine-4-yl] amine

(363)

 one 352 3.37 B2 (5-Chloro-1H-indazol-3-yl) - [6- (2-methoxy-phenyl) -pyrimidine-4-yl] amine

(364)

 one 283 3.19 B2 [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] - (5-methyl-isoxazol-3-yl) amine

(365)

 one 385 3.45 B2 3- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -N, N-dimethylbenzenesulfonamide

(366)

 one 385 3.27 B2 N-Ethyl-3- [6- (2-methoxy-phenyl) -pyrimidine-4-ylamino] benzenesulfonamide

(367)

 one 399 3.46 B2 3- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -N-propylbenzenesulfonamide

(368)

 one 331 3.24 B2 [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] - (2-methyl-1H-indole-5-yl) amine

(369)

 one 413 (MH) '' 3.12 B2 N- (2-methoxy-ethyl) -3- [6- (2-methoxy-phenyl) -pyrimidine-4-amino] -benzenesulfonamide

(370)

 one 413 3.5 B2 N-tert-butyl-3- [6- (2-methoxy-phenyl) -pyrimidine-4-ylamino] benzenesulfonamide

(371)

 one 293 2.71 B2 [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] -pyridin-2-ylmethyl-amine

(372)

 one 293 2.61 B2 [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] -pyridin-3-ylmethyl-amine

(372)

 one 293 2.61 B2 [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] -pyridin-3-ylmethyl-amine

(373)

 one 293 2.59 B2 [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] -pyridin-4-ylmethyl-amine

(374)

 one 371 3.15 B2 5- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -2-methylbenzenesulfonamide

(375)

 one 429 3.45 B2 N- (2-methoxy-ethyl) -5- [6- (2-methoxy-phenyl) -pyrimidine-4 -lamino] -2-methyl-benzenesulfonamide

(376)

 one 415 3.03 B2 N- (2-hydroxy-ethyl) -5- [6- (2-methoxy-phenyl) -pyrimidine-4 -lamino] -2-methyl-benzenesulfonamide

(377)

 one 348 2.17 A2 N, N-diethyl-N '- [6- (2-methoxy-phenyl) -pyrimidine-4-yl] -benzene-1,4-diamine

(378)

 one 528 3.78 A2 1- (4-Chloro-3-trifluoromethyl-phenyl) -3- [5- [6- (2-methyl-phenyl) pyrimidine-4-ylamino] -2-methyl-phenyl} -urea

(379)

 one 431 3.27 A2 1-cyclohexyl-3- {5- [6- (2-methoxy-phenyl) -pyrimidine-4-ylamino] -2-methyl-phenyl} -urea

(380)

 one 346 3.14 A2 [6- (2-Methoxy-phenyl) -pyrimidine-4-yl] - (4-pyrrolidin-1-yl-phenyl) amine

(381)

 one 326 2.74 A2 4-Chloro-N-1- [6- (2-methoxy-phenyl) -pyrimidine-4-yl] -benzene-1,3-diamine

(382)

 one 391 3.35 A2 1-Isopropyl-3- {5- [6- (2-methoxy-phenyl) -pyrimidine-4-ylamino] -2-methyl-phenyl} -urea

(383)

 one 462 2.80 A2 1- {5- [6- (2-Methoxy-phenyl) -pyrimidine-4-ylamino] -2-methyl-phenyl} 3- (2-morpholin-4-yl-ethyl) -urea

(384)

 one 2.79 A2 1- (2-dimethylamino-ethyl) -3- {5- [6- (2-m phenyl} -urea

(385)

 one 356 3.81 A2 (4-Chloro-3-nitro-phenyl) - [6- (2-methoxy-phenyl) -pyrimidine-4-yl] amine

RNA polymerase II phosphorylation:

[0271] To find out if the compounds according to general formula (I) have the intrinsic ability to penetrate cells and act against target cellular proteins, especially CDK 9, the effect of compound 30 on phosphorylation of RNA-dependent polymerase was investigated from CDK9. When testing blots with antibodies against phosphorylated forms of RNA polymerase II, it was shown that serine 2 phosphorylation was especially decreased while antibodies that recognized serine 5 phosphorylation showed no difference. These results indicate that the kinases responsible for the phosphorylation of this site, for example CDK7, are not touched. Additionally, a reduction in the molecular weight of RNA polymerase II was observed indicating that phosphorylation decreases (data not shown).

Growth of PM1 cells:

[0272] The growth of PM1 cells is not generally affected by the 4,6-disubstituted aminopyrimidine derivatives as shown in the results summarized in Table 3. In fact, only a small part of the compound appears to significantly influence the PM1 cell growth. These compounds, compound 9 and compound 28 had a tendency to inhibit CDK2 potently. Therefore, the observed effect on growth may be rather a cell cycle arrest than toxicity towards the cells. Additionally, no correlation has been observed between CDK9 inhibition and toxicity.

Table 3: Growth inhibition by the compounds described (the numbers are growth rates compared to rates of DMSO treated cells given in%).

Compound No.

Growth after 7 days [% at t 1 μM]

Compound 9, 28

: fifty

Compound 1, 2, 3, 4, 5, 6, 8, 10, 11, 15, 18, 19, 20, 22, 25, 30

51 - 100

Compound 7, 17, 21, 29

101 - 150

Reproduction of HIV in PM1 cells:

[0273] Compounds according to general formula (I) are potent inhibitors of HIV reproduction. Table 4 shows the inhibition of HIV reproduction (% DMSO control [= 0%]) in the cell culture of Compound 4, Compound 12, Compound 13, Compound 14, Compound 16, Compound 27, Compound 31, Compound 32, Compound 38, Compound 58, Compound 59, Compound 82, Compound 83, Compound 86, Compound 91, Compound 95, Compound 109, Compound 112 and Compound 116.

[0274] It is evident from the representative examples in Table 4 of the most effective compounds that were tested for inhibiting HIV reproduction are compound 4, compound 12, compound 14, compound 27, compound 58, compound 82, compound 83, compound 86, compound 95, compound 112 and compound 116 that reduce HIV reproduction by more than 60%. With compound 13, compound 16, compound 31, compound 32, compound 38, compound 59, compound 91 and compound 109, satisfactory results were obtained in terms of inhibition of HIV reproduction (between 20 and 60% inhibition) .

Table 4: Relative inhibition of HIV reproduction

Compound

[%] Inhibition of HIV reproduction

Compound 13, 16, 31, 32, 38, 59, 91, 109

20 - 60

Compound 4, 12, 14, 27, 58, 82, 83, 86, 95, 112, 116

61 - 95

Selection panel data:

[0275] Table 5 shows the inhibitory effect of the 4,6-disubstituted aminopyrimidine derivatives selected in the activity of certain protein kinases. The activity of these protein kinases is shown as% inhibition with the presence of 10 µM of the compound compared to DMSO (0% inhibition).

Table 5: Selection panel data (% inhibition) of selected 4,6-disubstituted aminopyrimidine derivatives (Cpd = Compound, na = not available; inhibition greater than 80%: a; inhibition between 80 and 50%: b ;

inhibition between 50 and 30%: c;).

[0276] These data show that 4,6-disubstituted aminopyrimidine derivatives have an inhibitory effect on the protein kinase activity of several protein kinases such as Abl, CDK1, CDK5, EGFR. GSK-3ß, PDGFR, c-kit and p56Lck. Additionally c-Src, RSK1 and cMet were affected by some cpds in their activity (table 5).

Impact on NFKB-dependent transcriptional activity:

[0277] It is known that CDK9 regulates NFKB-dependent transcriptional activity. Studies were conducted with compound 4, compound 7 and compound 30 to assess its effect on NFKB-dependent transcriptional activity. Compound 30 was able to affect the NFKB-dependent promoter activity stimulated by TNF-a at the final concentration of 1μM as shown in Figure 3. Interestingly, no inhibition is observed under unstimulated conditions. Compound 4 and compound 7 inhibited NFKB with less efficiency by reflecting the IC50 values of these compounds in CDK9 / Cyclin T1. An assessment of these three compounds was performed showing EC50 values of approximately 2 μM for compound 4 and 1 μM for compound 30,

HBV Reproduction

[0278] The 4,6-disubstituted aminopyrimidine derivatives selected were tested in a HBV reproduction assay. The result shown in Figure 4 is that only compound 7 inhibited reproduction without affecting the viability in these cells. Compound 30 was inactive in these assays indicating that other protein kinase targets that CDK9 (especially other CDKs) may be important for HBV reproduction. This is emphasized by flavopyridol that inhibits reproduction but is a more or less nonspecific inhibitor of CDKs.

HCMV Reproduction:

[0279] 4,6-Disubstituted aminopyrimidine derivatives were identified as potent inhibitors of HCMV reproduction in cell cultures (see Figure 5): Compound 4, compound 6 and compound 30 showed inhibition of HCMV reproduction (using the strain AD 169 in HFF cells).

Affinity chromatography and preparative gel electrophoresis:

[0280] Compound 102 or compound 103 known as cyclin 9 dependent kinase inhibitors (CDK9) was covalently coupled to ECH-Sepharose and used as a means for affinity chromatography as described above. The results of the analysis by mass spectrometry showed that both affinity media were able to isolate CDK9 from the crude lysates of PM1 cells. In addition, both affinity media described herein were able to identify additional targets for these compound molecules known to inhibit CDK9. Particularly Ca2 + / Calmodulin protein-dependent kinase II (CaMK2y), Ca2 + / Calmodulin protein-dependent kinase II O (CaMK2O), cyclin-dependent kinase 2 (CDK2) and mixed lineage kinase kinase (MRK-beta) , ZAK) were especially linked to compound 102. On the contrary, kinase 3 beta glycogen synthase (CSK3�) and tyrosine kinase c-Src (CSK) were especially linked to compound 103. LCMS analysis of eluents reproduced these results. In addition, the following protein kinases were identified in this last set of experiments: For compound 102 Ca2 + / Calmodulin-dependent protein kinase II (CaMK2�) mixed lineage kinase (MLK, MRK-alpha), the kinase was identified as src, the kinase as human cdc2 (similar to CDC2L5), CrkRS (Crk7, protein kinase 7 related to CDC2) and male germ cell associated kinase (MAK). For compound 103 Ca2 + / Calmodulin-dependent protein kinase II � (CaMK2�), glycogen synthase kinase 3 (GSK3a), cyclin-dependent kinase 2 (CDK2), CrkRS (Crk7, kinase 7 related to CDC2) were detected and a growth factor receptor similar to growth factor receptor 3 (FGFR-3).

References: [0281]

Prenzel N, Fischer OM, Streit S, Hart S, Ullrich A. The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification. Endocr Relat Cancer. 2001 May; 8 (1): 11-31, Review Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome Science 2002 Dec 6; 298 (5600): 1912-34. Review Blume-Jensen P, Hunter T. Onycogenic Kinase Signaling. Nature 2001 May 17; 411 (6835): 355-65. Review Flores O, Lee G, Kessler J, Miller M, Schlief W, Tomassini J, Hazuda D. Host-cell positive transcription elongation factor b kinase activity is essential and limiting for HIV type 1 replication. Proc Natl Acad Sci U S

A. 1999 Jun 22; 96 (13): 7208-13. Mancebo HS, Lee G, Flygare J, Tomassini J, Luu P, Zhu Y, Peng J, Blau C, Hazuda D, Price D, Flores O.P- TEFb kinase is required for HIV Tat transcriptional activation in vivo and in vitro. Genes Dev. 1997 Oct 15; 11 (20): 2633-44. Zhu Y, Pe’ery T, Peng J, Ramanathan Y, Marshall N, Marshall T, Amendt B, Mathews MB, Price DH. Transcription elongation factor P-TEFb is required for HIV-1 tat transactivation in vitro. Genes Dev. 1997 Oct 15; 11 (20): 2622-32, Shim EY, Walker AK, Shi Y, Blackwell TK.CDK-9 / cyclin T (P-TEFb) is required in two postinitiation pathways for transcription in the C. elegans embryo. Genes Dev. 2002 Aug 15; 16 (16): 2135-46. Hampsey M, Reinberg D. Tails of intrigue: phosphorylation of RNA polymerase II mediates histone methylation.Cell. 2003 Dec 16; 113 (4): 429-32, Review.

Bieniasz PD, Grdina TA, Bogerd HP, Cullen BR.Recruitment of cyclin T1 / P-TEFb to an HIV type 1 long terminal repeat promoter proximal RNA target is both necessary and sufficient for full activation of transcription. Proc Natl Acad Sci US A. 1999 Jul 6; 96 (14): 7791-6 Bevec D, Dobrovnik M, Hauber J, Bohnlein E. Inhibition of human immunodeficiency virus type 1 replication in human T cells by retroviral-mediated gene transfer of to dominant-negative Rev trans-activator. Proc Natl Acad Sci U S A. 1999 Jun 22; 1992 Oct 15; 89 (20): 9870-4. Sells MA, Zelent AZ, Shvartsman M, Acs G. Replicative intermediates of hepatitis B virus in HepG2 cells that produces infectious virions. J Virol. 1988 Aug; 62 (8): 2836-44. Sells MA, Chen ML, Acs G (1987): Production of hepatitis B virus particles in HepG2 cells transfected with the cloned hepatitis B virus DNA, PNAS, 84, p.1005-1009. Guidotti LG, Matzke B, Schaller H, Chisari FV. High-level hepatitis B virus replication in transgenic mice. J Virol. 1995 Oct; 69 (10): 6158-69. Brignola PS, Lackey K, Kadwell SH, Hoffman C, Horne E, Carter HL, Stuart JD, Blackburn K, Moyer MB, Alligood KJ, Knight WB, Wood ER. Comparison of the biochemical and kinetic properties of the type 1 receptor tyrosine kinase intracellular domains. Demonstration of differential sensitivity to kinase inhibitors. J Biol Chem. 2002 Jan 11; 277 (2): 1576-85. Epub 2001 Nov 05. Huwe A, Mazitschek R, Giannis A.Small molecules as inhibitors of cyclin-dependent kinases. Angew Chem Int Ed Engl. 2003 May 16; 42 (19): 2122-38.

Claims (58)

1. Compounds that have the general formula (I) wherein R1, R2 and R4 are each -H R3 is a substituted phenyl R5 is a substituted or unsubstituted phenyl R6 is selected from the group consisting of:

-

H, C1-C8 linear or branched, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted pyrrolidinyl, C3-C8 substituted or unsubstituted cycloalkyl, disubstituted cyclohexyl, cyclopentyl, C5-C12 substituted or unsubstituted bicycloalkyl, adamantyl of the group - (CH2) q- substituted or unsubstituted, being an integer from 1 to 3 under the proviso that if R6 is selected as a methylene chain of the group - (CH2 ) q-, R17 or R19 are selected to be a methylene chain of the group - (CH2) s-, where s is an integer from 1 to 3 or a group - (CH2) tA-, t is an integer from 1 at 3 and A is selected from O or N, respectively, and R6 and R17 or R6 and R19 together form a 5 or 8 member ring system, or R6 represents - (CH2) pZ, where p is an integer of 0 at 6 and Z selected from the group comprising: substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, het substituted or unsubstituted erocyclyl, -N (R7R8), wherein R7 and R8 independently represent each other -H, or C1-C6 substituted or unsubstituted linear or branched alkyl, or Z is selected from - (CR9R10R11), wherein R9, R10 and R11 are independently selected from each other from the group consisting of: -H, linear or branched, C1-C8 substituted or unsubstituted alkyl, substituted or unsubstituted aryl or -N (R12R13), where R12 and R13 represent independently of each other -H or C1-C6 substituted or unsubstituted linear or branched alkyl, with the proviso that if Z represents - (CR9R10R11) as defined above, p is selected to be an integer from 0 to 6, and if Z is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl or -N (R7R8) as defined above, p is selected to be an integer from 1 to 6; L is selected from the group comprising: -NR14-SO2-, -NR14-SO-, wherein R14 is selected from -H, C1-C6 substituted or unsubstituted linear or branched alkyl, -SO2-R15 or -R15-SO2 -, wherein R15 is selected from C1-C6 alkyl or C1-C6 substituted or unsubstituted linear or branched alkylene, or R14 represents a - (CH2) r-COOR16, where r is an integer from 0 to 6 and R16 selected of -H

or C1-C6 substituted or unsubstituted linear or branched alkyl, -NR17 -CO-, wherein R17 is selected from -H, C1-C6 substituted or unsubstituted linear or branched alkyl, or a group to (CH2) s-, where s is an integer from 1 to 3, and where R6 and R17 both represent A group of a methylene chain, R6 and R17 can together form a 5 or 8 member ring system: -SO2-NR18-, wherein R18 is selected from -H, or C1-C6 linear or branched alkyl, substituted or unsubstituted, -CO-NR19-, wherein R19 selected from -H, C1-C6 linear or branched alkyl, substituted or unsubstituted, or a group (CH2) tA-, where t is an integer from 1 to 3 and A is selected from N or O, and where if R6 represents a group (CH2) q- and R19 represents a group - (CH2) tA-, R6 and R19 can together form a 5 or 8 member ring system  -NH-CO-NH-, -NH-CS-NH-, -NH-CO-O-, -CO-, -CO-O-, -SO-, -SO2-, -SO3- or and m is 1, and / or stereoisomeric forms and / or pharmaceutically acceptable salts thereof. 2. The compound according to claim 1, wherein R3 and R5 represent phenyl, wherein each phenyl is independently of the other partially or completely substituted with members selected from the group consisting of: C1-C6 substituted or unsubstituted linear or branched alkyl, C1-C6 linear or branched alkoxy, -O- (CH2) u-Phenyl, wherein u is an integer from 0 to 6, -NR20R21, where R20 and R21 are independently selected from each other yes between -H or C1-C6 linear or branched alkyl, -COOR22, where R22 represents C1-C6 linear alkyl or branched substituted or unsubstituted, or the phenyl is substituted with heteroaryl selected from benzoimidazolyl, benzothiazolyl or benzoxazolyl 3. The compound according to claim 1 or claim 2, wherein the phenyl represented by R3 is partially or completely substituted with members of the group consisting of:

-

F, -Cl, -Br, -I, -CN, -NO2, C1-C6 linear or branched substituted or unsubstituted alkyl, C2-C6 linear or branched alkenyl, substituted phenyl

or unsubstituted, C1-C6 linear or branched alkoxy, -O- (CH2) vR, where v is an integer from 0 to 6, and R is selected from the group consisting of: Phenyl, -O-phenyl, C1-C4 linear or branched haloalkyl, heterocyclyl, or -NR23R24, wherein R23 and R24 are independently selected from each other from -H or C1-C6 linear or branched alkyl C1-C6 linear or branched haloalkyl, C1-C6 linear or branched thioalkyl, - (CH2) wQ, where w is selected to be an integer from 0 to 6, and Q is selected from heterocyclyl, -OH, -NR25R26, where R25 and R26 are independently selected from each other of -H, C1- C6 linear or branched alkyl, or - (CH2) and O-CH3, where y is selected to be an integer from 0 to 6, or Q represents C1-C6 linear or branched alkoxy, (CH2) and-COR27, where and it is an integer from 0 to 6, and R27 is selected from the group comprising: -H, C1-C6 linear or branched alkyl, -OR28, wherein R28 is selected from -H or C1-C6 linear or branched alkyl, or R 28 is selected from -NR29R30, wherein R29 and R30 are independently selected from each other of -H, C1-C6 alkyl or C3-C8 linear or branched cycloalkyl, -CH = CH-COOH, -CH = CH-COOCH3 or - NH-T-R31, where T is selected from -CO- or -SO2 and R31 represents C1-C6 linear or branched alkyl, and where the phenyl is mono-, di- or trisubstituted

Four.

 The compound according to claim 3, wherein the phenyl is substituted with members of the group consisting of:

-F, -Cl, -CN, -C2H5, -CH (CH3) 2, -CH = CH2, -OCH3, -OC2H5, -OCH (CH3) 2, -O-Phenyl, -O-CH2-Phenyl, - O- (CH2) 2O-Phenyl, -O- (CH2) 2-N (CH3) 2, -O- (CH2) 3-N (CH3) 2, -O- (CH2) 3-NH2, -OCF3, -OH, -CH2-OH, -CH2-OCH3, -SCH3, -NH2, -N (CH3) 2, -CH2-NH2, -CH2-N (CH3) 2, -CH = CH-COOH, -CH = CH-COOCH3, -COOH, - (CH2) 2-COOH, -COOCH3, -CF3, Phenyl, -C (O) -H, -C (O) -CH3, -C (O) -NH2, -C ( O) -NHCH (CH3) 2, -NH-CO-CH3, -NH-SO2-CH3, -CH2-N (CH3) - (CH2) 2-O-CH3,

5.

 The compound according to any one of claims 1 to 4, wherein the phenyl represented by R5 is partially or totally substituted with C1-C6 linear or branched alkyl, or the phenyl is partially or totally substituted with O- (CH2) or Phenyl, where u is an integer from 0 to 6.

6.

 The compound according to any one of claims 1-5, wherein L is selected from the group comprising:

-NR14-SO2-, wherein R14 is selected from -H, C1-C4 linear or branched alkyl, -SO2-R15- or -R15-SO2-, wherein R15 is selected from C1-C4 alkyl or C1-C4 linear or branched substituted or unsubstituted alkylene, or R14 represents - (CH2) r-COOR16, where r is an integer from 0 to 4 and R16 is selected from -H or C1-C4 branched linear alkyl, -NR17-CO-, where R17 is selected from -H , C1-C4 linear or branched alkyl, or a group - (CH2) s-, where s an integer from 1 to 3, and where if R6 represents a group - (CH2) q-, where q is a integer from 1 to 3, and R17 represents a methylene chain of the group - (CH2) s-, R6 and R17 can together form a 5 to 8 member ring system -SO2-NR18-, where R18 is selected from - H or C1-C4 linear or branched alkyl, -CO-NR19-, wherein R19 selected from -H, C1-C4 linear or branched alkyl, or a group - (CH2) tA-, where t is an integer of 1 at 3 and A is selected from N or O, and where R6 represents a group - (CH2) q- where q is an integer from 1 to 3, and R19 represents a group - (CH2) tA-, where t is selected to be 2 and A represents O, R6 and R19 can together form a 6-member ring system -NH-CO-NH-, -SO2- or

7.

 The compound according to claim 6, wherein L is selected from the group consisting of:

NR14-SO2-, where R14 is selected from -H, - (CH2) 2-CH3, -SO2-R15, where R15 represents - (CH2) 2-CH3, or - (CH2) r- COOR16, where r is selected to be an integer from 0 to 2, and R16 represents -CH3, -NR17-CO-, -SO2-NR18-, -CO-NR19-, where R17, R18 and R19 represent -H, -NH-CO-NH- or -SO2-

8.

 The compound according to any one of claims 1 to 7, wherein R6 is selected from the group comprising:

-H, C1-C8 linear or branched alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, substituted pyrrolidinyl, C3-C8 substituted or unsubstituted cycloalkyl, disubstituted cyclohexyl, cyclopentyl, C5-C12 bicycloalkyl substituted or unsubstituted, substituted or unsubstituted adamantyl, or - (CH2) pZ, wherein p is an integer from 0 to 4 and Z is selected from the group comprising: substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, heterocyclyl substituted or unsubstituted, N (R7R8), where R7 and R8 independently represent each other -H, or C1-C6 linear or branched alkyl, or Z represents - (CR9R10R11), where R9, R10 and R11 are selected independently of each other from the group consisting of: -H, C1-C4 linear or branched alkyl, substituted or unsubstituted aryl or -N (R12R13), wherein R12 and R13 independently represent each other -H or C1-C4 alkyl linear or branched, and wherein if Z is selected from substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, p cannot be selected to be 0.

9.

 The compound according to claim 8, wherein R6 is selected from the group consisting of:

-H, C1-C6 linear or branched alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, C3-C8 substituted or unsubstituted cycloalkyl, C5-C12 unsubstituted bicycloalkyl, unsubstituted adamantyl or - (CH2) pZ, wherein p is an integer from 0 to 2 and Z is selected from the group comprising: substituted or unsubstituted phenyl, substituted or unsubstituted heterocyclyl, -N (R7R8), wherein R7 and R8 independently represent one from the other -H, C1-C4 linear or branched alkyl, or Z represents (CR9R10R11), wherein R9, R10 and R11 are independently selected from each other from the group consisting of: -H, C1-C6 linear or branched alkyl, unsubstituted aryl or -N (R12R13), wherein R12 and R13 independently represent each other -H or C1-C4 linear or branched alkyl.

10.

 The compound according to claim 9, wherein R6 represents -H or C1-C6 linear or branched alkyl.

eleven.

 The compound according to claim 9, wherein R6 represents substituted or unsubstituted aryl, such as substituted or unsubstituted phenyl or naphthyl, wherein if R6 represents substituted naphthyl, the naphthyl is partially or completely substituted with -OH or C1-C4 linear or branched alkoxy,

or wherein if R6 represents substituted phenyl, the phenyl is partially or completely substituted with members of the group comprising: Phenyl, C1-C6 linear or branched alkyl, substituted or unsubstituted heterocyclyl, N-substituted piperazinyl, wherein the N-substituted piperazinyl is substituted with C1-C4 linear or branched alkyl, or the phenyl is partially or completely substituted with -OH or -N (R32R33), wherein R32 and R33 independently represent each other -H or C1-C4 linear or branched alkyl.

12.

 The compound according to claim 9, wherein R6 represents substituted or unsubstituted heteroaryl, wherein the heteroaryl is selected from the group comprising:

Pyrrolyl, thiophenyl, furanyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, isotioazolilo, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyradizinyl, tetrahydroquinolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzo [1,3] dioxotilo, indolyl, benzofuranyl, benzothiophenyl, indazolyl or chrom-2onyl,

13.

 The compound according to claim 9, wherein R6 represents substituted or unsubstituted heterocyclyl, wherein the heterocyclyl is selected from the group comprising:

aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl

14.

 The compound according to claim 13, wherein R6 represents partially or completely substituted heterocyclyl, substituted with C1-C4 linear or branched alkyl, or -N-COOR34, wherein R34 represents -H or C1-C4 linear or branched alkyl.

fifteen.

The compound according to claim 9, wherein R6 represents substituted or unsubstituted C3-C8 cycloalkyl.

16.

The compound according to claim 9, wherein R6 represents - (CH2) p-Z, wherein p is selected to be 1 or 2 and Z is selected from the group comprising:

Substituted or unsubstituted phenyl, where in the case that the phenyl is substituted, it is substituted with C1-C4 linear or branched alkyl, substituted or unsubstituted heterocyclyl, or Z represents -N (R7R8), where R7 and R8 represent independently of each other -H, or with C1-C4 linear or branched alkyl, or R6 represents - (CH2) pZ, in where p is selected to be an integer from 0 to 2 and z is selected to be - (CR9R10R11), where R9, R10, R11 are independently of each other selected from the group consisting of: -H, or C1-C5 linear or branched alkyl, substituted or unsubstituted aryl, or - N (R12R13), wherein R12 and R13 independently represent each other -H or C1-C4 linear or branched alkyl,

17.

 The compound according to any one of claims 1-16, wherein m is selected to be 1, R1, R2 and R4 represent -H, R3 represents monosubstituted phenyl, R5 represents monosubstituted or unsubstituted phenyl, L is selected from the group that understands:

-NH-CO-, -NH-SO2-, -SO2-NH-, -CO-NH- or -SO2- and R6 is selected from the group consisting of: -H, C1-C4 linear or branched alkyl, monosubstituted phenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl, wherein the heteroaryl is selected from imidazolyl, pyridinyl, tetrahydroquinolinyl, quinolinyl, benzoimidazolyl, benzothiazolyl, benzo [1,3] dioxolyl, indolyl, indazolyl or -chromen-2-onyl or R6 represents substituted or unsubstituted C3-C8 cycloalkyl.

18.

The compound according to any one of claims 1 to 17, wherein the compound represents a chiral compound.

19.

 The compound according to claim 18, wherein the compound represents a racemate, or an S or an R enantiomer or a mixture of isomers.

twenty.

 The compound according to any one of claims 1 to 19, wherein the compound is selected from the group of compounds consisting of:

Compound 1: N- {4- [6- (4-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -4-methyl-benzenesulfonamide, Compound 2: N- {4- [6- (3-Methoxy-phenyl) -pyrimidin-4 -lamino] -phenyl} -4-methyl-benzenesulfonamide, Compound 3: N- {5- [6- (4-Methoxy-phenyl) -pyrimidin-4 -lamino] -2-methylphenyl} -methanesulfonamide, Compound 4: 4-Amino-N- {4- [6- (2-benzyloxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -benzamide, Compound 5: N- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4 -lamino] -phenyl} -4-methyl-benzenesulfonamide, Compound 6: 4-Amino-N- {4- [6- (4-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -benzamide, Compound 8: 4-Amino-N- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -benzamide, Compound 9: 1- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -pyrrolidin-2-unon, Compound 10: N- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -acetamide, Compound 11: N- {4- [6- (4-Hydroxy-phenyl) -pyrimidin-4 -lamino] -phenyl} -4-methyl-benzenesulfonamide, Compound 12: N- {5- [6- (3-Amino-phenyl) -pyrimidin-4 -lamino] -2-methyl-phenyl} -methanesulfonamide, Compound 16: 4-Amino-N- {4- [6- (4-hydroxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -benzamide, Compound 17: 3- (4- {6- [4-Toluene-4-sulfonylamino) -phenylamino] -pyrimidin-4-yl) -phenyl) -propionic acid, Compound 18: N- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4 -lamino] -phenyl} -4-methyl-N-propyl-benzenesulfonamide, Compound 19: N- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -2,2-dimethyl-propionamide, Compound 20: 2-Amino-N- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -benzamide, Compound 21: 4-Amino-N- {4- [6- (3-amino-phenyl) -pyrimidin-4-ylamino] -phenyl} -benzamide, Compound 23: 4-Isopropyl-N- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4 -lamino] -phenyl} -benzenesulfonamide, Compound 27: [{4- [6- (4-Hydox-phenyl) -pyrimidin-4-ylamino] -phenyl} - (toluene-4-sulfonyl) -amino] -acetic acid methyl ester, Compound 28: [{4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} - (toluene-4-sulfonyl) -amino] -acetic acid methyl ester, Compound 29: (S) -2- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenylcarbamoyl} -piperidine-1-carboxylic acid tert-butyl ester, Compound 30: (S) -Piperidine-2-carboxylic acid N- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -amide Compound 31: 4-Amino-N- {4- [6- (2,4-dimethoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -benzamide, Compound 33: N- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4yl-amino] -phenyl} -methanesulfon-amide, Compound 34: Biphenyl-4-sulfonic acid - {4- [6- (2-Methoxy-phenyl) -pyrimidin-4 -lamino] -phenyl} -amide, Compound 35: 4-Amino-N- {4- [6- (5-isopropyl-2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -benzamide, Compound 36: Bicyclo [2.2.1) heptane-2-carboxylic acid {4- [6- (2-Methoxyphenyl) -pyrimidin-4-ylamino] -phenyl} amide, Compound 37: N- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -3-methyl-2-phenyl-butyramide, Compound 38: 1-Cyclohexyl-3- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -urea, Compound 39: 4-Amino-N- {4- [6- (5-chloro-2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -benzamide, Compound 40: E-3- (3- {6- [4- (Toluene-4-sulfonylamino) -phenylamino] -pyrimidin-4-yl} -phenyl) -acrylic acid, Compound 41: Cyclohexanecarboxylic acid {4- [6- (2-Methoxy phenyl) -pyrimidin-4-ylamino] -phenyl} -amide, Compound 42: N- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -3,3-dimethyl-butyramide, Compound 44: N-Cyclohexyl- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzamide, Compound 45: 4-tert-Butyl-N- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -benzamide, Compound 46: 2-Dimethylamino-N- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -acetamide, Compound 47: (1- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenylcarbamoyl-cyclopentyl) -carbamic acid tert-butyl ester Compound 48: 2 - ({4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenylcarbamoyl} -methyl) piperidine-1-acid carboxylic tert-butyl ester, Compound 49: N- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -4- (4-methyl-piperazin-1-yl) -benzamide, Compound 50: N- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -isonicotinamide, Compound 51: 4-Amino-N- {4- [6- (2,6-dimethoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -benzamide, Compound 52: {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -N-phenyl-benzamide, Compound 53: N- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -guanidine, Compound 54: N-tert-Butyl-4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzamide, Compound 55: 4-Amino-N- {4- [6- (2-ethoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -benzamide, Compound 56: 4-Amino-N- {4- [6- (2,3-dimethoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -benzamide, Compound 57: 4-Amino-N- {4- [6- (2,5-dimethoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -benzamide, Compound 58: 4-Amino-N- {4- [6- (2-isopropoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -benzamide, Compound 59: N- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -2-piperidine-2-yl-acetamide, Compound 61: Adamantane-1-carboxylic acid- {4- (6- (2-Methoxyphenyl) -pyrimidin-4-yl-amino] -phenyl} -amide, Compound 62: (4-Benzoxazol-2-yl-phenyl) - [6- (2-Methoxy-phenyl) -pyrimidin-4-yl] -amino, Compound 63: [4- (1H-Benzimidazol-2-yl) -phenyl] - [6- (2-Methoxy-phenyl) -pyrimidin-4-yl] -amino, Compound 64: 3-Diethylamino-N- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -propion amide, Compound 65: (S) -1,2,3,4-Tetrahydro-isoquinoline-3-carboxylic acid- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4 -lamino] phenyl} amide, Compound 66: 1-amino-cyclohexane- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} amide carboxylic acid, Compound 68: 1-Amino-cyclopentanecarboxylic acid {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} amide, Compound 69: (R) -piperidine-2-carboxylic acid {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -amide, Compound 70: 1-Methyl-4H-imidazol-4-carboxylic acid {4- [6- (2-Methoxyphenyl) -pyrimidin-4-ylamino] -phenyl} amide, Compound 71: N- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl) -2-phenyl-actetamide, Compound 76: 4-Amino-N- [4- (6-phenyl-pyrimidin-4-ylamino) -phenyl] -benzamide, Compound 81: (S) -2-Amino-N- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -2-phenyl-acetamide, Compound 82: (S) -N- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl) -2-methylamino-2-phenyl-acetamide, Compound 83: (R, R) / (SS) -N- (2-Amino-cyclohexyl) -4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzamide, Compound 84: Benzothiazole-2-carboxylic acid - {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} amide, Compound 85: N- {4- [6- (2-Benzyloxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -2,2-dimethyl-propionamide, Compound 86: 4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -N-piperidin-3-yl-benzamide. Compound 87: 1-methyl-piperidine-3-carboxylic acid {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} amide. Compound 89: 1-methyl-piperidine-4-carboxylic acid {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-yl] -amino] -phenyl} amide, Compound 90: (S) -Azetidine-2-carboxylic acid (4- [6- (2-methoxy-phenyl) -pyrimidin-4-ii] -amino] -phenyl} -amide, Compound 91: (R) -pyrrolidine-2-carboxylic acid {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-yl] -amino] -phenyl} -amide, Compound 95: 4- [6- (2-Benzyloxy-phenyl) -pyrimidin-4-ylamino] -benzamide, Compound 96: N- (4 - {[6- (2-Methoxy-phenyl) -pyrimidin-4-yl] -methyl-amino} -phenyl) -4-methyl-benzenesulfonamide, Compound 98: Quinoline-2-carboxylic acid {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -amide, Compound 100: N- {5- [6- (3-Methoxy-phenyl) -pyrimidin-4-ylamino] -2-methylphenyl} -methane sulfonamide, Compound 101: 2-Dimethylamino-N- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -2-phenyl-acetamide, Compound 102: 3-Amino-N- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -propion-amide, Compound 103: 4-Amino-N- (4- {6- [2- (3-amino-propoxy) -phenyl] -pyrimidin-4-ylamino} -phenyl) -benzamide, Compound 104: N- {3- [6- (3-Methanesulfonylamino-4-methyl-phenylamino) -pyrimidin-4-yl] -phenyl} -acetamide, Compound 105: N- {5- [6- (3-Hydroxy-phenyl) -pyrimidin-4-ylamino] -2-methylphenyl} methanesulfonamide, Compound 107: N- {2-Methyl-5- [6- (3-trifluoromethyl-phenyl) -pyrimidin-4-ylamino] -phenyl} -methanesulfonamide, Compound 108: N- {5- [6- (3-Methanesulfonylamino-phenyl) -pyrimidin-4-ylamino] -2-methyl-phenyl) methanesulfonamide, Compound 109: N- {5- [6- (3-Amino-phenyl) -pyrimidin-4-ylamino] -2-methyl-phenyl} -benzene-sulfonamide, Compound 111: 1-Benzo [1,3] dioxol-5-yl-3- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -urea, Compound 112: 1- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -3- (4-methyl-benzyl) -urea, Compound 113: 1-tert-Butyl-3- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -urea, Compound 114: 2,2-Dimethyl-N- {4- [6- (2-trifluoromethyl-phenyl) -pyrimidin-4-ylamino] -phenyl} -propionamide, Compound 115: 3- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzamide, Compound 116: Propane-1-sulfonic acid {5- [6- (3-amino-phenyl) -pyrimidin-4-ylamino] -2-methyl-phenyl} -amide, Compound 117: 4- [6- (3-Amino-phenyl) -pyrimidin-4-ylamino] -benzenesulfonamide, Compound 118: N- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -2-methyl-2-methylamino-propionamide, Compound 119: N- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -3-methylphenyl} -2,2-dimethyl-propionamide, Compound 120: N- {5- [6- (3-Amino-phenyl) -pyrimidin-4-ylamino] -2-benzyloxyphenyl} -methanesulfonamide, Compound 121: N- {3- [6- (3-Amino-phenyl) -pyrimidin-4-ylamino] -phenyl} -methanesulfon-amide, Compound 122: N- {3- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl) -2,2-dimethyl-propionamide, Compound 125: 4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -N- (4-morpholin-4-yl-phenyl) -benzamide, Compound 126: 2,2-Dimethyl-N- {4- [6- (2-vinyl-phenyl) -pyrimidin-4-ylamino] -phenyl} -propionamide, Compound 127: N- {4- [6- (2-Fluoro-phenyl) -pyrimidin-4-ylamino] -phenyl} -2,2-dimethyl-propionamide, Compound 128: (S) -Piperidine-2-carboxylic acid {3- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} amide, Compound 129: 2-oxo-2H-chromene-3-carboxylic acid {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} amide, Compound 130: Benzo [1,3] dioxoe-5-carboxylic acid {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} amide, Compound 131: N- {4- [6- (2-Ethyl-phenyl) -pyrimidin-4-ylamino] -phenyl} -2,2-dimethyl-propion-amide, Compound 132: N- [4- (6-Biphenyl-2-yl-pyrimidin-4-ylamino) -phenyl] -2,2-dimethyl-propion-amide, Compound 133: 1H-indole-3-carboxylic acid {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -amide, Compound 135: N - ((1R, 2R) / (1 S, 2S) -2-Hydroxy-cyclohexyl) -4- [6- (2-Methoxyphenyl) -pyrimidin-4-ylamino] benzamide, Compound 136: N- (4-Hydroxy-phenyl) -4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzamide, Compound 137: N- (4-Isopropyl-phenyl) -4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzamide, Compound 138: 1H-Benzoimidazol-5-carboxylic acid {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} amide, Compound 139: 1-Hydroxy-naphthalene-2-carboxylic acid {4- [6- (2-Methoxyphenyl) -pyrimidin-4-ylamino] -phenyl} amide, Compound 140: (2S, 3S) -2-Amino-3-methyl-pentanoic acid {4- [6- (2-Methoxyphenyl) -pyrimidin-4-ylamino] -phenyl} amide, Compound 141: 1H-indazole-3-carboxylic acid {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -amide, Compound 142: Quinoline-8-sulfonic acid {5- [6- (3-amino-phenyl) -pyrimidin-4-ylamino] -2-methyl-phenyl) amide, Compound 143: (S) -2-Amino-N- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -3-methyl-butyramide, Compound 144: 1-Methyl-1H-imidazol-4-sulfonic acid {5- [6- (3-amino-phenyl) -pyrimidin-4-ylamino] -2-methylphenyl} -amide, Compound 145: 3-Hydroxy-naphthalene-2-carboxylic acid {4- [6- (2-Methoxyphenyl) -pyrimidin-4-ylamino] -phenyl} amide, Compound 146: 2-amino-N- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -2-naphthalene-2-yl-acetamide, Compound 147: {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -morpholin-4-yl-methanone, Compound 148: N - ((1S, 2R) / (1R, 2S) -2-amino-cyclohexyl) -4- [6- (2-methoxyphenyl) -pyrimidin-4-ylamino] benzamide, Compound 150: 3- [6- (2-methoxy-phenyl) -pyrimidin-4-ylamino] -benzenesulfonamide, Compound 151: 4-amino-N- {4- [6- (2-hydroxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -benzamide, Compound 153: Propane-2-sulfonic acid {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -amide, Compound 154: Propane-1-sulfonic acid {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -amide, Compound 155: N- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -benzene sulfonamide, Compound 156: N- {5- [6- (2-Benzyloxy-phenyl) -pyrimidin-4-ylaminol-2-methylphenyl} -methanesulfonamide, Compound 157: N- {5- [6- (3-dimethylamino-phenyl) -pyrimidin-4-ylamino] -2-methylphenyl} -methanesulfonamide, Compound 158: N- {5- [6- (2-Isopropoxy-phenyl) -pyrimidin-4-ylamino] -2-methylphenyl} -methanesulfonamide, Compound 161: N- (2-amino-cyclohexyl) -4- [6- (4-Methoxy-phenyl} -pyrimidin-4-ylamino] -benzamide, Compound 162: N- {5- [6- (2-methoxy-phenyl) -pyrimidin-4-ylamino] -2-methylphenyl} -methanesulfonamide, Compound 163: N- {5- [6- (3-Cyano-phenyl) -pyrimidin-4-y) anino] -2-methyl-phenyl} -methane sulfonamide, Compound 164: (S) -Piperidine-2-carboxylic acid {3- [6- (2-benzyloxy-phenyl) -pyrimidin-4-ylamino] -phenyl} amide, Compound 165: N- {5- [6- (3-Formyl-phenyl) -pyrimidin-4-ylamino] -2-methyl-phenyl} -methane sulfonamide, Compound 166: N- {5- [6- (2-Hydroxymethyl-phenyl) -pyrimidin-4-ylamino] -2-methylphenyl} -methanesulfonamide, Compound 167: (S) -Piperidine-2-carboxylic acid {3- [6- (4-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} amide, Compound 168: (S) -Piperidine-2-carboxylic acid {3- [6- (3-formyl-phenyl) -pyrimidin-4-ylamino] -phenyl} -amide, Compound 169: (S) -Piperidine-2 carboxylic acid {3- [6- (3-dimethylamino-phenyl) -pyrimidin-4-ylamino] -phenylol} amide, Compound 170: (S) -Piperidine-2-carboxylic acid {3- [6- (2-hydroxymethyl-phenyl) -pyrimidin-4-ylamino] -phenyl} amide, Compound 173: (S) -Piperidine-2-carboxylic acid {3- [6- (4-benzyloxy-phenyl) -pyrimidin-4-ylamino] -phenyl} amide, Compound 174: (S) -Piperidine-2-carboxylic acid {3- [6- (4-phenoxy-phenyl) -pyrimidin-4-yl-amino] -phenyl} amide Compound 175: N- {5- (6- (4-Hydroxymethyl-phenyl) -pyrimidin-4-ylamino] -2-methylphenyl} -methanesulfonamide, Y Compound 177: (S) -Piperidine-2-carboxylic acid (4- [6- (4-acetylamino-phenyl) -pyrimidin-4-ylamino] -phenyl} amide, Compound 178: (S) -Piperidine-2-carboxylic acid {4- [6- (3-methanesulfo-nylamino-phenyl) -pyrimidin-4-ylamino] - phenyl} -amide, Compound 179: (S) -Piperidine-2-carboxylic acid {4- [6- (3-acetyl-phenyl) -pyrimidin-4-ylamino] -phenyl} -amide, Compound 180: (S) -Piperidine-2-carboxylic acid {4- [6- (4-cyclopentylcar-bamoyl-phenyl) -pyrimidin-4-ylamino] phenyl} -amide, Compound 181: N- {5- [6- (2-Hydroxy-phenyl) -pyrimidin-4-ylamino] -2-methylphenyl} -methanesulfonamide, Compound 182: (E) -3- {3- [6- (3-Methanesulfonylamino-4-methyl-phenyl-amino) -pyrimidin-4-yl] -phenyl} -acrylic acid methyl ester, Compound 183: N- {5- [6- (3-Hydroxymethyl-phenyl) -pyrimidin-4-ylamino] -2-methylphenyl} -methanesulfonamide, Compound 184: N-Butyl-3- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzenesulfonamide, Compound 185: (3-Methanesulfonyl-phenyl) - [6- (2-Methoxy-phenyl) -pyrimidin-4-yl] -amine, Compound 186: (S) -Piperidine-2-carboxylic acid {4- [6- (2,3-dimethoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} amide, Compound 187: (S) -Piperidine-2-carboxylic acid {4- [6- (2,4-dimethoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} amide, Compound 188: (S) -Piperidine-2-carboxylic acid {4- [6- (2-isopropoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} amide, Compound 189: (S) -Piperidine-2-carboxylic acid {4- [6- (2-methylsulfanyl-phenyl) -pyrimidin-4-ylamino] -phenyl} - amide, Compound 190: (S) -Piperidine-2-carboxylic acid {4- [6- (2-trifluoromethoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} amide, Compound 192: (S) -Piperidine-2-carboxylic acid {4- [6- (2-chloro-phenyl) -pyrimidin-4-ylamino] -phenyl} -amide, Compound 193: (S) -Piperidine-2 carboxylic acid {4- [6- (3-hydroxymethyl-phenyl) -pyrimidin-4-ylamino] -phenyl} amide, Compound 194: N - ((1S, 2S) / (1R, 2R) -2-Amino-cyclohexyl) -4- [6- (3-hydroxyphenyl) -pyrimidin-4-ylamino] benzamide, Compound 195: N - ((1S, 2S) / (1R, 2R) -2-Amino-cyclohexyl) -4- [6- (3-methanesulfonyl-amino-phenyl) -pyrimidin- 4-ylamino] -benzamide, Compound 196: 4- [6- (2-Acetylamino-phenyl) -pyrimidin-4-ylamino] -N - ((1S, 2S) / (1R, 2R) -2-amino-cyclohexyl) - benzamide, Compound 197: N- {5- [6- (2-Methoxymethyl-phenyl) -pyrimidin-4-ylamino] -2-methylphenyl} -methanesulfonamide, Compound 198: N - ((1R, 2R) / (1S, 2Sr2-Amino-cyclohexyl) -4- [6- (2-benzyloxyphenyl) -pyrimidin-4-yl-amino] benzamide, Compound 199: N - ((1R, 2R) / (1S, 2S) -2-Amino-cyclohex-yl) -4- [6- (2-isopro-poxy-phenyl) -pyrimidin-4-ylamino] - benzamide, Compound 201: 3- {6- [4 - ((1R, 2R) / (1S, 2S) -2-Amino-cyclohexylcarbamoyl) -phenylamino] -pyrimidin-4-yl} benzoic methyl ester, Compound 202: (S) -Piperidine-2-carboxylic acid {4- [6- (4-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -amide, Compound 203: (S) -Piperidine-2-carboxylic acid {4- [6- (3-Methoxymethyl-phenyl) -pyrimidin-4-ylamino] -phenyl} amide, Compound 206: N - ((1R, 2R) / (1S, 2S) -2-Amino-cyclohexyl) -4- [6- (3-amino-phenyl) -pyrimidin-4-ylamino] benzamide, Compound 207: 4- [6- (3-Acetylamino-phenyl) -pyrimidin-4-ylamino] -N - ((1R, 2R) / (1S, 2S) -2-amino-cyclohexyl) -

benzamide,

Compound

 208: N - ((1R, 2R) / (1S, 2S) -2-Amino-cyclohexyl) -4- [6- (4-benzyloxyphenyl) -pyrimidin-4-ylamino]

benzamide,

Compound

 209: N - ((1R, 2R) / (1  S, 2S) -2-Amino-cyclohexyl) -4- [6- (3-cyano-phenyl) -pyrimidin-4-ylamino]

benzamide,

Compound 210: N - ((1R, 2R) / (1S, 2S) -2-Amino-cyclohexyl) -4- [6- (2-Methoxymethyl-phenyl) -pyrimidin-4-ylamino] - benzamide, Compound 211: (S) -Piperidine-2-carboxylic acid {4- [6- (3-dimethylaminomethyl-phenyl) -pyrimidin-4-ylamino] - phenyl} -amide, Compound 214: 3- [6- (3-Amino-phenyl) -pyrimidin-4-ylamino] -benzenesulfonamide, Compound 215: 3- [6- (4-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzenesulfonamide, Compound 216: (R, R) -N- (2-Amino-cyclohexyl) -4- [6- (2-hydroxymethyl-phenyl) -pyrimidin-4-ylamino] -benzamide, Compound 217: N- (2-Diethylamino-ethyl) -4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzamide, Compound 218: (R, R) -N- (2-Amino-cyclohexyl) -4- [6- (2-hydroxy-phenyl) -pyrimidin-4-ylamino] -benzamide, Compound 228: (R, R) -4- [6- (5-Acetyl-thiophen-2-yl) -pyrimidin-4-ylamino] -N- (2-amino-cyclohexyl) -benzamide, Compound 229: [6- (2-Methoxy-phenyl) -pyrimidin-4-yl] - [3- (piperidine-1-sulfonyl) -phenyl] -amine N- (2-diethylamino- ethyl) -benzamide, Compound 230: (R, R) -4- [6- (2-Acetyl-phenyl) -pyrimidin-4-ylamino] -N- (2-aminocyclohexyl) -benzamide, Compound 231: 4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -N-pyridin-3-yl-benzamide, Compound 232: N- (1-Acetyl-piperidin-3-yl) -4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzamide, Compound 233: (R, R) -N- (2-Amino-cyclohexyl) -4- [6- (2-dimethylamino-phenyl) -pyrimidin-4-ylamino] -benzamide, Compound 234: 4- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzoylamino} -pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, Compound 235: 2-Chloro-5- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzenesulfonamide, Compound 236: [6- (2-Methoxy-phenyl) -pyrimidin-4-yl] - [3- (piperidine-1-sulfonyl) -phenyl] -amine, Compound 237: N-Allyl-3- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzenesulfonamide, Compound 238: N-Benzyl-3- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzenesulfonamide, Compound 239: [6- (2-Methoxy-phenyl) -pyrimidin-4-yl] - [3- (pyrrolidine-1-sulfonyl) -phenyl] -amine, Compound 240: [6- (2-Methoxy-phenyl) -pyrimidin-4-yl] - [3- (morpholine-4-sulfonyl) -phenyl] -amine, Compound 241: 3- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -N-methyl-benzenesulfonamide, Compound 243: N, N-Diallyl-3- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzenesulfonamide, Compound 244: 3- [6- (2-Benzyloxy-phenyl) -pyrimidin-4-ylamino] -benzenesulfonamide, Compound 245: [6- (2-Methoxy-phenyl) -pyrimidin-4-yl] - [4- (4-nitrobenzenesulfonyl) -phenyl] -amine, Compound 246: [6- (2-Methoxy-phenyl) -pyrimidin-4-yl] - (4-trifluoromethanesulfonyl-phenyl) -amine, Compound 247: (4-Methanesulfonyl-phenyl) - [6- (2-Methoxy-phenyl) -pyrimidin-4-yl] -amine, Compound 248: N- (3,4-Dimethyl-isoxazol-5-yl) -4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzenesulfonamide, Compound 249: 4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -N-propyl-benzenesulfonamide, Compound 250: 4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzenesulfonamide, Compound 251: 4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -N, N-dimethyl-benzenesulfonamide, Compound 252: N- (2-Methoxy-ethyl) -4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzenesulfonamide, Compound 253: [6- (2-Benzyloxy-phenyl) -pyrimidin-4-yl] - (3-methanesulfonylphenyl) -amine, Compound 254: 2- [6- (3-Methanesulfonyl-phenylamino) -pyrimidin-4-yl] -phenol, Compound 255: [6- (3-Amino-phenyl) -pyrimidin-4-yl] - (3-methanesulfonyl-phenyl) -amine, Compound 256: 5- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -2-methylbenzenesulfonic acid, Compound 257: 2- {3- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzenesulfonyl) -ethanol, Compound 258: (2-Fluoro-5-methanesulfonyl-phenyl) - [6- (2-Methoxy-phenyl) -pyrimidin-4-yl] -amine, Compound 259: [6- (2-Amino-phenyl) -pyrimidin-4-yl] - (3-methanesulfonyl-phenyl) -amine, Compound 260: [6- (2-Methoxy-phenyl) -pyrimidin-4-yl] - (3-trifluoromethanesulfonyl-phenyl) -amine, Compound 261: (3-Methanesulfonyl-phenyl) - [6- (2-Phenoxy-phenyl) -pyrimidin-4-yl] -amine, Compound 262: [6- (2-Butoxy-phenyl) -pyrimidin-4-yl] - (3-methanesulfonyl-phenyl) -amine, Compound 263: (3-Etenosulfonyl-phenyl- [6- (2-Methoxy-phenyl) -pyrimidin-4-yl] -amine, Compound 264: (S) -Piperidine-2-carboxylic acid {4- [6- (4-methylsulfanyl-phenyl) -pyrimidin-4-ylamino] -phenyl) - amide, Compound 265: 2-Chloro-4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzoic acid methyl ester, Compound 267: 4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -3-methyl-benzoic methyl ester, Compound 272: 1- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -butan-1-one, Compound 274: {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -phenyl-methanone, Compound 292: 4- {6- [2- (2-Morpholin-4-yl-ethoxy) -phenyl] -pyrimidin-4-ylamino) -benzoic acid methyl ester, Compound 293: 2-Methoxy-4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzoic acid methyl ester, Compound 305: 2-Chloro-4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzoic acid, Compound 309: 4- [6- (2-Amino-phenyl) -pyrimidin-4-ylamino] -benzoic acid methyl ester, Compound 316: 1- {3- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -phenyl} -ethanone, Compound 318: 3-Hydroxy-4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzoic acid methyl ester, Compound 319: 2-Hydroxy-4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzoic acid methyl ester, Compound 320: 4-Amino-butane-1-sulfonic acid {5- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -2-methyl-phenyl} amide, Compound 321: (3- {6- [3- (4-Amino-butane-1-sulfonylamino) -4-methylphenylamino] -pyrimidin-4-yl} -phenyl) carbamic acid 9H-fluoren-9-ylmethyl ester, Compound 322: 3-Methoxy-4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzoic acid methyl ester, Compound 323: 4- {6- [2- (2-Piperidin-1-yl-ethoxy) -phenyl] -pyrimidin-4-ylamino} -benzoic acid methyl ester, Compound 324: 4 - {- 6- [2- (2-Dimethylamino-ethoxy) -phenyl] -pyrimidin-4-ylamino} -benzoic acid methyl ester, Compound 325: 4 - {- 6- [2- (2-Diisopropylamino-ethoxy) -phenyl] -pyrimidin-4-ylamino} -benzoic acid methyl ester, Compound 326: 4 - {- 6- [2- (2-Diethylamino-ethoxy} -phenyl] -pyrimidin-4-ylamino} -benzoic acid methyl ester, Compound 327: (S, S) -4- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzoylamino} -pyrrolidine-2- carboxylic methyl ester, Compound 328: (S, S) -4- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzoylamino} -pyrrolidine-2-carboxylic acid Compound 329: (S, S) -6 - [(4- {4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzoylamino} -pyrrolidine-2-carbonyl) -amino] -hexanoic acid, Compound 330: N-Cyclopentyl-4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzamide, Compound 331: 3- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzenesulfonamide, Compound 332: (3-Methanesulfonyl-phenyl) - [6- (2-Methoxy-phenyl) -pyrimidin-4-yl] -amine, Compound 333: 2- {3- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzenesulfoyl} -ethanol, Compound 334: N- (4,6-Dimethyl-pyrimidin-2-yl) -4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzenesulfonamide, Compound 335: 4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -N-thiazol-2-yl-benzenesulfonamide, Compound 338: 4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -N-phenyl-benzenesulfonamide, Compound 341: 4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -N-methyl-benzenesulfonamide, Compound 343: N-Acetyl-4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzenesulfonamide, Compound 344: N- (2,6-Dimethyl-pyrimidin-4-yl) -4- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzenesulfonamide, Compound 345: [6- (2-Methoxy-phenyl) -pyrimidin-4-yl] - [4- (piperidine-1-sulfonyl) -phenyl] -amine, Compound 347: [6- (2-Fluoro-6-Methoxy-phenyl) -pyrimidin-4-yl] - (3-methanesulfonyl-phenylamine, Compound 348: [6- (4-Fluoro-2-Methoxy-phenyl) -pyrimidin-4-yl] - (3-methanesulfonyl-phenyl) -amine, Compound 349: [6- (5-Fluoro-2-Methoxy-phenyl) -pyrimidin-4-yl] - (3-methanesulfonyl-phenyl) -amine, Compound 362: 4-Methanesulfonyl-benzyl- [6- (2-Methoxy-phenyl) -pyrimidin-4-yl] -amine, Compound 365: 3- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -N, N-dimethyl-benzenesulfonamide, Compound 366: N-Ethyl-3- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzenesulfonamide, Compound 367: 3- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -N-propyl-benzenesulfonamide, Compound 369: N- (2-Methoxy-ethyl) -3- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzenesulfonamide, Compound 370: N-tert-Butyl-3- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -benzenesulfonamide, Compound 374: 5- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -2-methyl-benzenesulfonamide, Compound 375: N- (2-Methoxy-ethyl) -5- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -2-methyl-benzenesulfonamide, Compound 376: N- (2-Hydroxy-ethyl) -5- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -2-methyl-benzenesulfonamide, Compound 378: 1- (4-Chloro-3-trifluoromethyl-phenyl) -3- {5- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -2-methyl-phenyl} urea, Compound 379: 1-Cyclohexyl-3- {5- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -2-methyl-phenyl} -urea, Compound 380: [6- (2-Methoxy-phenyl) -pyrimidin-4-yl] - (4-pyrrolidin-1-yl-phenyl) -amine, Compound 382: 1-Isopropyl-3- {5- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -2-methyl-phenyl} -urea, Compound 383: 1- {5- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -2-methylphenyl} -3- (2-morpholin-4-ylethyl) urea, Compound 384: 1- (2-Dimethylamino-ethyl) -3- {5- [6- (2-Methoxy-phenyl) -pyrimidin-4-ylamino] -2-methyl-phenyl) -urea,

twenty-one.

 A compound according to one of claims 1 to 20 for use as a pharmaceutically active agent.

22

 The use of at least one compound according to any one of claims 1 to 21 for the preparation of a pharmaceutical composition for the prophylaxis and / or treatment of infectious diseases, including opportunistic diseases, prion diseases, immunological diseases, autoimmune diseases, bipolar disorders. and clinical, cardiovascular diseases, cell proliferation diseases, diabetes, inflammations, transplant rejections, erectile dysfunction, neurodegenerative diseases and cerebral stroke.

2. 3.

 The use according to claim 22, wherein infectious diseases, including opportunistic diseases, are virally induced infectious diseases, including opportunistic diseases.

24.

 Use according to claim 23, wherein virally induced infectious diseases, including opportunistic diseases, are caused by retroviruses, human endogenous retroviruses, lentiviruses, oncoretroviruses, hepadnaviruses, herpesviruses, flaviviridae, and / or adenoviruses.

25.

 The use according to claim 24, wherein the lentivirus, oncoretrovirus, hepadnavirus, herpesvirus is selected from the group comprising: HIV-1, HIV-2, IVF, BIV, SIVs, SHIVs, CAEV, VMV or EIAV, HTLV- I, HTLV-II

or BLV, HBV, GSHV or WHV, HSV I, HSV II, EBV, VZV, HCMV or HHV 8.

26.

 The use according to claim 22 or 24, wherein the infectious disease including opportunistic infections is selected from the group consisting of AIDS, alveolar hydatid disease (AHD, echinococcosis), amebiasis (histolytic entamoeba infection), angiostrongylus infection, anisakiasis , anthrax, babesiosis (babesia infection), balantidium infection (balantidiasis), baylisascaris infection (raccoon worm), bilharzia (schistosomiasis), blastocystis hominis infection (blastomycosis), boreliosis, botulism, “Braineris” diarrhea, bruce BSE (bovine spongiform encephalopathy), candidiasis, capillariasis (capillary infection), CFS (chronic fatigue syndrome), Chagas disease (American trypanosomiasis), chicken pox (varicella zoster virus), chlamydia pneumoniae infection, cholera, fatigue syndrome chronic, ECJ (Creutzfeldt-Jakob disease), clonorchiasis (clonorchis infection), CLM (larva migra ns cutaneous, hookworm infection), coccidioidomycosis, conjunctivitis, coxsackievirus A16 (hand, foot and mouth disease), cryptococcosis, cryptosporidium infection (cryptosporidiosis), Culex mosquito (vector of West Nile virus), cutaneous migrans larva (CLM) , cyclosporiasis (cyclospora infection), cysticercosis (neurocysticercosis), cytomegalovirus infection, dengue / dengue fever, dipylidium infection (dog and cat tapeworm), ebola hemorrhagic fever, echinococcosis (alveolar hydatid disease), encephalitis, infection entamoeba coli, disparate entamoeba infection, entamoeba hartmanni infection, entamoeba histolytica infection (amebiasis), entamoeba polecki infection, enterobiasis (pinworm infection), enterovirus (non-polio) infection, Epstein-Barr virus infection, Escherichia coli infection, food infection, foot and mouth disease, fungal dermatitis, gastroenterit is, group A strep disease, group B strep disease, Hansen's disease (leprosy), hantavirus pulmonary syndrome, lice infestation (pediculosis) helicobacter pylori infection, hematologic disease, Hendra virus infection, hepatitis (HCV , HBV), shingles (shingles), HIV infection, human ehrlichiosis, human parainfluenza virus infection, influenza, isosporiasis (isospora infection), lassa fever, leishmaniasis, kala-azar (kala azar, leishmania infection), leprosy, lice (body lice, head lice, pubic lice), Lyme disease, malaria, Marburg hemorrhagic fever, measles, meningitis, mosquito-borne diseases, infection by mycobacterium avium complex (MAC), naegleria infection , nosocomial infections, non-pathogenic intestinal amoeba infection,

onchocerciasis (river blindness), opistorchiasis (opisthorchis infection), parvovirus infection, plague, plague, PCP (pneumocystis carinii pneumonia), polio, Q fever, rabies, respiratory syncytial virus (RSV) infection, rheumatic fever, fever of the Rift Valley, river blindness (onchocerciasis), rotavirus infection, ascaris infection, salmonellosis, salmonella enteritidis, scabies, shigellosis, shingles, sleeping sickness, smallpox, streptococcal infection, dipylidium infection (tapeworm infection) , tetanus, toxic shock syndrome, tuberculosis, ulcers (peptic ulcer disease), valley fever, vibrio parahaemolyticus infection, vibrio vulnificus infection, viral hemorrhagic fever, warts, water-borne infectious diseases, West Nile virus infection ( West Nile encephalitis), whooping cough, yellow fever, tuberculosis, leprosy, microbacterial-induced meningitis.

27.

 The use according to claim 22, wherein the prion disease is selected from the group comprising Tembladera, TME, CWD, BSE CJD, vCJD, GSS, FFI, Kuru, and Alpers Syndrome.

28.

 The use according to claim 22, wherein the immunological disease and / or the autoimmune disease is selected from the group comprising:

asthma, diabetes, rheumatic diseases, AIDS, rejection of transplanted organs and tissues, rhinitis, chronic obstructive pulmonary diseases, osteoporosis, ulcerative colitis, sinusitis, lupus erythematosus, recurrent infections, atopic dermatitis / eczema and occupational allergies, food allergies, drug allergies , severe anaphylactic reactions, anaphylaxis, manifestations of allergic diseases, primary immunodeficiencies, antibody deficiency states, cell-mediated immunodeficiencies, severe combined immunodeficiency, DiGeorge syndrome, Hyper-IgE syndrome, Wiskott-Aldrich syndrome, ataxiatelangiectasia, autoimmune cancers, white cell defects, autoimmune diseases, systemic lupus erythematosus, rheumatoid arthritis (RA), multiple sclerosis (MS), autoimmune or type 1 diabetes mellitus, autoimmune glomerulonephritis, scleroderma, pernicious anemia, alopecia, pemphigus, pemphigus myasthenia grav e, intestinal inflammatory diseases, Crohn's disease, psoriasis, autoimmune thyroid diseases, Hashimoto's disease, dermatomyositis, goodpasture syndrome, myasthenia gravis pseudoparalitic, sympathetic ophthalmia, phacogenic uveitis, aggressive chronic hepatitis, primary biliary cirrhosis, hemolytic autoimmune anemia, Werlof

29.

 The use according to claim 22, wherein the bipolar and / or clinical disorder is selected from the group comprising: adaptation disorders, anxiety disorders, delusions, dementia, amnesic disorders and other cognitive disorders, disorders normally diagnosed for the first time in early childhood, childhood or adolescence, dissociative disorders, eating disorders, mood disorders, impulse control disorders, mental disorders due to a general medical condition, mood disorders, other conditions that may be a focus of clinical care , personality disorders, schizophrenia and other psychotic disorders, sexual and gender identity disorders, sleep disorders, somatoform disorders, substance-related disorders, generalized anxiety disorder, panic disorders, phobias, agoraphobia, obsessive-compulsive disorders, stress , acute stress disorder, ansied neurosis ad, nervousness, phobias, post-traumatic stress disorders, post-traumatic stress disorders (PTSD), abuse, ADHD, obsessive-compulsive disorders (OCD), manic-depressive psychosis, specific phobias, social phobias, adaptation disorders with anxiety traits.

30

 The use according to claim 29, wherein anxiety disorders, delusions, dementia, amnesic disorders and other cognitive disorders, disorders normally diagnosed for the first time in early childhood, childhood or adolescence, dissociative disorders, eating disorders, disorders of the mood, schizophrenia and other psychotic disorders, sexual and gender identity disorders, sleep disorders, somatoform disorders, substance-related disorders are selected from the group comprising: acute stress, agoraphobia without a history of panic disorders, anxiety disorders due to general medical conditions, generalized anxiety disorders, obsessive-compulsive disorders, panic disorders with agoraphobia, panic disorders without agoraphobia, post-traumatic stress disorders, specific phobias, social phobia, substance-induced anxiety disorder, delusions due to mé condition general dica, delusions from substance intoxication, delusions from substance withdrawal syndrome, delusions due to multiple etiologies, Alzheimer's, Creutzfeldt-Jakob disease, head trauma, Huntington's disease, HIV disease, Parkinson's disease, Pick's disease, Substance-induced vascular dementia due to other general medical conditions, dementia due to multiple etiologies, amnesia disorder due to a general medical condition, substance-induced persistent amnesia disorder, mental retardation, learning disorders, math disorder, reading, written expression disorder, learning disorder, motor disorder, coordination development disorder, communication disorders, expressive language disorder, phonological disorder, receptive-expressive language disorder, stuttering, generalized disorders of the development, Asperger disorder, tra autism storno, childhood disintegrative disorder, Rett disorder, generalized developmental disorder, attention deficit / hyperactivity disorder (ADHD), behavior disorder, oppositional defiant disorder, childhood or early childhood eating disorder, itches, disorder mericism, tic disorders, chronic motor or vocal tic disorder, Tourette disorder, elimination disorders, encopresis, enuresis, selective mutism, separation anxiety disorder, reactive attachment disorder in childhood or early childhood, stereotyped movement disorder , dissociative amnesia disorder

depersonalization, dissociative identity disorders, anorexia nervosa, bulimia nervosa, mood episodes, major depression episode, hypomanic episode, mixed episode, depressive disorders, dysthymic disorder, major depression disorder, single episode, recurrent bipolar disorders, bipolar disorders I, bipolar disorders II, cyclothymic disorder, mood disorder due to a general medical condition, substance-induced mood disorder, schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to a general medical condition, delusions, hallucinations, substance-induced psychotic disorder, female sexual arousal disorder, orgasmic disorders, premature ejaculation, sexual pain disorders, dyspareunia, vaginismus, sexual dysfunction due to a general medical condition, di female spareunia, female hypoactive sexual desire disorder, male erectile disorder, male hypoactive sexual desire disorder, male dyspareunia, other female sexual dysfunctions, other male sexual dysfunctions, substance-induced sexual dysfunctions, sexual dysfunction, paraphilia, exhibitionism, fetishism, frotteurism , pedophilia, masochism, sadism, cross-dressing fetishism, voyeurism, paraphilia, gender identity disorder, dysomnias, sleep related breathing disorder, sleep disorder related to heart rhythm, hypersomnia, hypersomnia associated with another mental disorder, insomnia, insomnia related to other mental disorders, narcolepsy, dysomnia, parasomnia, nightmare disorder, night terror disorder, sleepwalking disorder, parasomnia, body dysmorphic disorder, conversion disorder, hypochondria, pain disorder, somatization disorder, disorder s omatoform undifferentiated, alcohol-related disorders, amphetamine-related disorders, caffeine-related disorders, cannabis-related disorders, cocaine-related disorders, hallucinogen-related disorders, inhalation-related disorders, nicotine-related disorders, opioid-related disorders , psychotic disorder, psychotic disorder, phencyclidine-related disorder, abuse, persistent amnesic disorder, anxiety disorder, persistent dementia, dependence, intoxication, intoxication delusions, mood disorder, psychotic disorder, withdrawal syndrome, delusions by syndrome of withdrawal, sexual dysfunction, sleep disorder.

31.

 The use according to claim 22, wherein the cardiovascular diseases are selected from the group consisting of:

adult congenital heart disease, aneurysm, stable angina, non-stable angina, angina pectoris, angioneurotic edema, aortic valve stenosis, aortic aneurysm, arrhythmia, arrhythmogenic right ventricular dysplasia, arteriosclerosis, arteriovenous malformations, atrial fibrillation, Behcet syndrome , bradycardia, cardiac tamponade, cardiomegaly, congestive cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, prevention of cardiovascular diseases, carotid stenosis, cerebral hemorrhage, Churg-Strauss syndrome, diabetes, Ebstein's anomaly, Eisenmenger complex, cholesterol embolism, endocardium , fibromuscular dysplasia, congenital heart defects, heart disease, congestive heart failure, heart valve diseases, heart attack, epidural hematoma, subdural hematoma, Hippel-Lindau disease, hyperemia, hypertension, pulmonary hypertension, cre hypertrophic foundation, left ventricular hypertrophy, right ventricular hypertrophy, hypoplastic left heart syndrome, hypotension, intermittent claudication, ischemic heart disease, Klippel-Trenaunay-Weber syndrome, lateral spinal syndrome, mitral valve prolapse long QT syndrome, Moyamoya diseases, mucocutaneous lymph node syndrome, myocardial infarction, myocardial ischemia, myocarditis, pericarditis, peripheral vascular diseases, phlebitis, polyarteritis nodosa, pulmonary atresia, Raynaud's disease, restenosis, Sneddon syndrome, stenosis, superior vena cava, syndrome X, tachycardia, Takayasu arteritis, hereditary hemorrhagic telangiectasia, telangiectasis, temporal arteritis, tetralogy of fallot, thromboangiitis obliterans, thrombosis, thromboembolism, tricuspid atresia, varicose veins, vascular diseases, vasculitis, ventricular fibrosis ar, Williams syndrome, peripheral vascular disease, varicose veins and leg ulcers, deep vein thrombosis, WolffParkinson-White syndrome.

32

 The use according to claim 22, wherein the proliferative disease is selected from the group comprising:

adenocarcinoma, choroidal melanoma, acute leukemia, acoustic neurinoma, ampullary carcinoma, anal carcinoma, astrocytoma, basal cell carcinoma, pancreas cancer, desmoid tumor, bladder cancer, bronchial carcinoma, breast cancer, Burkitt lymphoma, body cancer, syndrome CUP carcinoma of unknown primary), colorectal cancer, small bowel cancer, small intestine tumors, ovarian cancer, endometrial cancer, ependymoma, epithelial cancer types, Ewing tumors, gastrointestinal tumors, gastric cancer, gallbladder cancer biliary, gallbladder carcinomas, uterine cancer, cervical cancer, cervical gioblastomas, gynecological tumors, tumors in ears, nose and throat, hematological malignancies, hair cell leukemia, urethral cancer, skin cancer, scrotum cancer, tumors Cerebral (gliomas), brain metastases, testicular cancer, pituitary tumor, carcinoids, Kaposi's sarcoma, canine Cer larynx, germ cell tumor, bone cancer, colorectal carcinoma, head and neck tumors (tumors of the ear, nose and throat area), colon carcinoma, craniopharyngiomas, oral cancer (cancer in the mouth area or lips), cancer of the central nervous system, liver cancer, liver metastases, leukemia, tumor in the eyelids, lung cancer, cancer of the lymph nodes (Hodgkin's / Non-Hodgkin's), lymphomas, stomach cancer, malignant melanoma, malignant neoplasm, malignant tumors in the gastrointestinal tract, breast carcinoma, rectal cancer, medulloblastomas, melanoma, meningiomas, Hodgkin's disease, fungoid mycoses, nasal cancer, neurinoma, neuroblastoma, renal cancer, renal cell carcinoma, non-Hodgkin's lymphomas, oligodendroglioma , esophageal carcinoma, osteolytic carcinomas and osteoplastic carcinomas, osteosarcomas, ovarian carcinoma, pancreatic carcinoma, penile cancer, plasmacytoma, cancer prostate cancer, pharyngeal cancer, rectal carcinoma, retinoblastoma, vaginal cancer, thyroid carcinoma, Schneeberger's disease, esophageal cancer, spinaliomas, T-cell lymphoma (fungoid mycosis), thymoma, fallopian tube carcinoma, eye tumors , deurethral cancer, urological tumors, urothelial carcinoma, vulvar cancer, appearance of warts, soft tissue tumors, soft tissue sarcoma, Wilm tumor, cervical carcinoma and tongue cancer.

33.

 The use according to claim 22, wherein said diabetes is selected from Type I diabetes or Type II diabetes.

3. 4.

 The use according to claim 22, wherein said inflammation is mediated by cytokines TNF-a, IL-1β, GM-CSF, IL-6 and / or IL-8.

35

 The use according to claim 22 or 34 wherein the inflammatory disease is caused, induced, initiated and / or enhanced by bacteria, viruses, prions, parasites, fungi, and / or caused by irritative, traumatic, metabolic, allergic reasons, autoimmune, or idiopathic.

36.

The use according to claim 35 wherein the viruses and bacteria are selected from the group comprising human immunodeficiency virus-I, herpes virus, herpes simplex virus, herpes zoster virus, mycoplasma pulmonis cytomegalovirus, ureaplasma urealyticum, mycoplasma pneumoniae, chlamydia pneumoniae, C. pneumoniae, Helicobacteri pylori, and propriono bacteria.

37.

 The use according to any of claims 22, 34-36, wherein the inflammatory disease is selected from the group comprising inflammatory diseases of the central nervous system (CNS), inflammatory rheumatic diseases, inflammatory diseases of the blood vessels, inflammatory diseases of the middle ear, inflammatory bowel diseases, inflammatory skin diseases, inflammatory uveitis disease, inflammatory diseases of the larynx.

38.

 The use according to claim 37 wherein the inflammatory diseases of the central nervous system (CNS), the rheumatic inflammatory diseases, the inflammatory diseases of the blood vessels, the inflammatory diseases of the middle ear, the inflammatory diseases of the intestine, the inflammatory diseases of the skin, uveitis inflammatory disease, inflammatory diseases of the larynx are selected from the group comprising:

abscesses, Acanthameba, Acanthamebiasis, acne vulgaris, actinomycosis, acute inflammatory dermatosis, acute laryngeal infections of adults, acute multifocal placoid pigment epitheliopathy, acute (thermal) lesion, acute retinal necrosis, acute suppurative otitis media, algae disorders, dermatitis allergic contact, amyloidosis, angiodema, ankylosing spondylitis, aspergillosis, atopic dermatitis, Aujeszky's disease, autoantibodies in vasculitis, babesiosis, bacterial disorders, bacterial laryngitis, bacterial meningitis, Behcet's disease, pellet choroidopathy, blastomycosis, boroscopic disease bullous myringitis, bursitis, candidiasis, canine distemper encephalomyelitis, canine distemper encephalomyelitis in canine animals, canine ehrlichiosis, canine herpes virus encephalomyelitis, chloesteatoma, chronic diseases (granulomatous), chronic inflammatory dermatosis, chronic recurrent otitisomyelitis a chronic suppurative, scarring pemphigoid, coccidiomycosis, coccidiodomycosis, common upper respiratory infection, contact ulcer and granuloma, Crohn's disease, cryptococcosis, cysticercosis, dermatomyositis, diphtheria, discoid lupus erythematosus, drug-induced vasculitis, hypersensitivity reaction , eosinophilic meningoencephalitis, erythema multiforme (minor MS), feline leukemia virus, feline immunodeficiency virus, feline infectious peritonitis, feline polioencephalomyelitis, feline spongiform encephalopathy, fibromyalgia, Fuch heterochromic cyclitis, gastroesophageal laryngitis (gastroesophageal laryngitis) of giant cells, glanders, glaucomatocicitic crisis, granular myringitis gonorrhea, granulomatous meningoencephalomyelitis, herpes simplex, histoplasmosis, idiopathic diseases, inflammatory idiopathic disorders, immune and idiopathic infections, immunocomp host infections Rometido, canine infectious hepatitis, inhalation laryngitis, interstitial nephritis, irritant contact dermatitis, juvenile rheumatoid arthritis, Kawasaki disease, La Crosse encephalitis virus, larynx abscesses, laryngotracheitis (croup), leishmaniasis, lens-induced uveitis, leprosy , leptospirosis, leukemia, lichen planus, lupus, lyme disease, lymphoma, meningitis, meningoencephalitis in greyhounds, different meningitis / meningoencephalitis, microscopic polyangiitis, multifocal choroiditis, multifocal distemper encephalomyelitis in adult animals, multiple sclerosis, muscular tension dysphonia fungal diseases (fungi), fungal diseases of the CNS, necrotizing encephalitis, neosporosis, old dog encephalitis, onchocerciasis, parasitic encephalomyelitis, parasitic infections, pars planitis, parvovirus encephalitis, pediatric laryngitis, contamination and inhalation allergy, polymyositis, canine distemper encephalitispost-vaccination, post-vaccine rabies, prion protein-induced diseases, prototecosis, protozoic encephalitis-encephalomyelitis, psoriasis, psoriatic arthritis, pug dog encephalitis, pyogranulomatous meningoencephalomyelitis, rabies, radiation injuries, radiation laryngitis, radionecrosis, recurrent polychondritis Reiter, retinitis pigmentosa, retinoblastoma, rheumatoid arthritis, rickettsial disorders, Rocky Mountain fever, salmon poisoning, sarcocystosis, sarcoidosis, schistosomiasis, scleroderma, scleroma, serpiginous choroiditis, agitated dog disease, Sjogrenic syndrome, croup Spirochetes (syphilis), spongiotic dermatitis, sporotrichosis, steroid-sensitive meningitis-arteritis, Stevens-Johnson syndrome (SSJ, MS major), supraglotitis (epiglottitis), sympathetic ophthalmia, Syngamus laryngeus, syphilis, systemic lupus erythematosus, systemic vasculitis in the sarcoids is, Takayasu arteritis, tendinitis (tendinitis), thromboangiitis obliterans (Buerger's disease), tick-borne encephalitis in dogs, toxic epidermal necrolysis (NET), toxocariasis, toxoplasmosis, trauma, traumatic laryngitis, trichinosis, trypanosomiasis, tuberculosis ulcerative colitis, urticaria (hives), vasculitis, vasculitis and malignant neoplasms, vasculitis and rheumatoid arthritis, vasculitis in systemic lupus erythematosus, vasculitis in idiopathic inflammatory myopathies, vasculitis of the central nervous system, vasculitis secondary to a bacterial, fungal and parasitic infection viral, viral laryngitis, vitiligo, voice abuse, bleeding from the vocal cords, Vogt Koyanagi Harada syndrome, Wegener granulomatosis, and Whipple's disease.

39.

 The use according to claim 22, wherein the transplant rejection is selected from the group comprising rejection of the heart transplant, rejection of the heart-lung transplant, rejection of the lung transplant, rejection of the liver transplant, rejection of the transplant of the kidney, rejection of the pancreas transplant, rejection of the spleen transplant, rejection of the skin transplant, rejection of the tissue transplant, rejection of the bone marrow transplant, rejection of the spinal cord transplant, rejection of the transplant of hormone-producing glands, rejection of transplantation of gonads and gonads, graft versus host diseases and host graft diseases.

40

 The use according to claim 22, wherein the neurodegenerative diseases are selected from the group comprising:

Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, AIDS-related dementia, retinitis pigmentosa, spinal muscular atrophy and cerebellar degeneration, ataxia / tremor associated with X-fragile syndrome (FXTAS), progressive supranuclear paralysis (PSP ), and striatonigral degeneration (SND) which is included with olivopontocerebellar degeneration (OPCD), and Shy Drager syndrome (SDS) in a syndrome known as multiple systemic atrophy (MSA).

41.

 The compound for use according to any one of claims 1 to 21 for the use of protein kinase inhibitor.

42

 The compound for use according to claim 41, wherein said cellular protein kinase is selected from the group comprising: Cyclin dependent protein kinase (CDK), protein kinase C, c-Raf, Akt, CKI, IKK� , MAP kinasesEERKs, MAP kinasesEJNKs, EGF receptor, InsR, PDGF receptor, c-Met, p70S6K, ROCK, Rsk1, Src, Abl, p56Lck, c-kit, CaMk2�, CaMk2O, CaMk2y, CSK or GSK-3a yß, MLK , MRK-alpha, yes, CSK, protein kinase similar to human cdc2 (similar to CDC2L5), Crk7, MAK and growth factor receptor similar to fibroblast growth factor receptor 3 (FGFR-3).

43

 The compound for use according to claim 42, wherein said cyclin dependent protein kinase is selected from the group comprising:

CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, CDK11, CrkRS (Crk7, protein kinase 7 associated with CDC2), CDKL1 (similar to cyclin-dependent kinase 1); KKIALRE, CDKL2 (similar to cyclin dependent kinase 2), KKIAMRE, CDKL3 (similar to cyclin dependent kinase 3), NKIAMRE, CDKL4, similar to cyclin dependent kinase 1, CDC2L1 (similar to cell division cycle 2 1), PITSLRE B, CDC2L1 (similar to cycle 2 of cell division 1), PITSLRE A, CDC2L5 (similar to cycle 2 of cell division 5), PCTK1 (PCTAIRE protein kinase 1), PCTK2 (PCTAIRE protein kinase 2), PCTK3 (PCTAIRE protein kinase 3) or PFTK1 (PFTAIRE protein kinase 1).

44.

 The pharmaceutical composition comprising at least one compound according to any one of claims 1 to 21 as an active ingredient, together with at least one pharmaceutically acceptable carrier, excipient and / or diluent.

Four. Five.

 A means for separating at least one nucleotide that binds to the protein from a set of proteins, the medium comprising at least one compound of general formula (II) and formula (III)

where R1, R2, R3, R4, R5, R6, L and m have the meaning defined in claim 1, R37 and R38 are independent selected from each other of -L *, C1-C6 substituted or unsubstituted alkyl-L *, C3-C8 substituted or unsubstituted cycloalkyl-L *, heterocyclyl-L * substituted or unsubstituted, aryl-L * substituted or unsubstituted, or heteroaryl-L * substituted or unsubstituted; L * is selected from -X1-H, -X3, -X1-X3; X1 and X2 are independently selected from each other from -NH-, -S-, -O-, -N (C1-C6 alkyl) -, -COO-, -O-CO-, - CO-NH-, -NH-CO-, -O-CO-NH-, -NH-CO-O-, -NH-CO-NH-, -O-CO-O-, -NH-C (NH) -NH-, -NH-SO2-, -SO2-NH-; X1-H and Y1-H are independently selected from each other from -NH2, -SH, -OH, -N (C1-C6 alkyl) H, -COOH, - CO-NH2, -O-CO-NH2, -NH-SO2H, -NH-SO3H, -SO2-NH2, -NH-C (NH) -NH2, X3 is selected from - (CH2) to-X4, - (CH2) to-CO-X4, - (CH2) to-NH-SO2-X4, - (CH2) to-Y1-H. - (CH2) a-X2- (CH2) b-X4, - (CH2) aX2- (CH2) b-Y1-H; X4 is selected from -Cl, -Br, -I, -N3, -OOC-C1-C6 alkyl, -O-SO2-CH3, -O-SO2-p-C6H4-CH3; a and b are independent of each other any other integer from 1-10; immobilized in a support material. 46. The medium according to claim 45, wherein R1, R2 and R4 are independently selected the from each other of -H or C1-C4 linear or branched alkyl; R3 represents substituted phenyl, wherein the phenyl is partially or totally substituted with members of the group that consists of: C1-C4 linear or branched alkoxy, -OCH2-Phenyl, or -NH2; R5 represents substituted or unsubstituted aryl, L is selected from the group comprising: -NH-CO-, -NH-SO2-, -SO2-NH-, -CO-NH-, -NH-CO-NH-, -NH-CO-O-, -NH-CS-NH-, -NH -C (NH) -NH-, -CO-, -COO-, -SO-, -SO2-, -SO3- m is selected to be 1 and R6 is selected from the group comprising: -H, C1-C4 linear or branched alkyl, monosubstituted phenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl or C3-C8 substituted or unsubstituted cycloalkyl, and R37 is selected to be or where R38  is selected from C3-C8 substituted or unsubstituted cycloalkyl-L *, substituted or unsubstituted aryl-L *, C1-C6 substituted or unsubstituted alkyl-L *, substituted or unsubstituted heterocyclyl-L *, wherein the heterocyclyl is selected from pyrrolidinyl or piperidinyl.

47

 The medium according to claims 45 or 46, wherein X1 is selected to be -NH- or -O- Y1-H is selected to be -NH2 or -N (C1-C6 alkyl) H a and b are independently selected one of the another to be an integer from 1 to 6.

48.

 The medium according to claim 47, wherein at least one of the compounds 1-205, is immobilized in a support material.

49.

 The medium according to any of claims 45 to 48, wherein the compound is covalently linked through the group Y1 with the support material.

fifty.

 The medium according to claim 49, wherein the support material comprises sepharose and modified sepharose.

51.

 The medium according to any of claims 45 to 50, wherein the protein set is a proteome, a cell lysate or a tissue lysate.

52

 The medium according to any of claims 45 to 51, wherein the nucleotide that binds to the protein is a protein binding ATP.

53.

 A method for enriching, purifying or depleting ex-vivo at least one nucleotide that binds with proteins of a set of proteins that contains at least one nucleotide that binds with proteins, the method comprising the following steps:

a) immobilize at least one compound of the general formula (II) and / or the general formula (III) where R1, R2, R3, R4, R5, R6. L and m have the meanings as defined in claim 1, R37  and R38 are independently selected from each other from -L *, C1-C6 substituted or unsubstituted alkyl-L *, C3-C8 substituted or unsubstituted cycloalkyl-L *, heterocyclyl-L * substituted or unsubstituted, aryl-L * substituted or unsubstituted, or heteroaryl-L * substituted or unsubstituted; L * is selected from -X1-H, -X3, -X1-X3; X1 and X2 are independently selected from each other from -NH-, -S-, -O-, -N (C1-C6 alkyl) -, -COO-, -O- CO-, -CO-NH-, -NH-CO-, -O-CO-NH-, -NH-CO-O-, -NH-CO-NH-, -O-CO-O-, -NH- C (NH) -NH-, -NH-SO2-, -SO2- NH-; X1-H and Y1-H are independently selected from each other from -NH2, -SH, -OH, -N (C1-C6 alkyl) H, - COOH, -CO-NH2, -O-CO-NH2, -NH-SO2H, -NH-SO3H, -SO2-NH2, -NH-C (NH) -NH2, X3 is selected from - (CH2) a-X4, - (CH2) a-CO-X4, - (CH2) a-NH-SO2-X4, - (CH2) a-Y1-H, - (CH2) a- X2- (CH2) b-X4, (CH2) a-X2- (CH2) b-Y1-H; X4 is selected from -Cl, -Br, -I, -N3, -OOC-C1-C6 alkyl, -O-SO2-CH3, -O-SO2-p-C6H4-CH3; a and b are independent of each other any other integer from 1-10; in a support material; b) putting the set of proteins containing at least one nucleotide that binds with the protein in contact with at least one compound according to the general formula (II) and / or according to the general formula (III) immobilized in the material support; and c) separating unbound proteins from at least one compound according to the general formula (II) and / or according to the general formula (III) in the support material of the at least one nucleotide that binds to the bound protein with the at least one mentioned compound immobilized in the support material; and d) Releasing and collecting the at least one nucleotide that binds with the protein bound to the at least one compound according to the general formula (II) and / or according to the general formula (III) immobilized in the support material from the at least one of the mentioned compounds. 54. The method according to claim 53, wherein R1, R2, R3 are independently selected from each other of -H; R3 represents phenyl, in which the phenyl is partially or completely substituted with members of the group consisting of: C1-C4 linear or branched alkoxy, -OCH2-Phenyl, or -NH2; R5 represents substituted or unsubstituted phenyl, L is selected from the group comprising: -NH-CO-, -SO2-, -NH-SO2-, -SO2-NH- or -CO-NH-, and m is selected to be 1 and R6 is selected from the group comprising: -H, C1-C4 linear or branched alkyl, monosubstituted phenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted heteroaryl or C3-C8 substituted or unsubstituted cycloalkyl, and R37 is selected for be or where R38 is selected from C3-C8 substituted or unsubstituted cycloalkyl-L *, substituted or unsubstituted heterocyclyl-L *, in where the heterocyclyl is selected from pyrrolidinyl or piperidinyl.

55.

 The method according to claims 53 or 54, wherein X1 is selected to be -NH- or -O-, Y1-H is selected to be -OH, -NH2 or -N (C1-C6 alkyl) H, a and b are independently of each other selected to be an integer from 1 to 6.

56.

 The method according to any of claims 53 a55, wherein at least one of the compounds of claim 53, 54 or 55 is immobilized in the support material.

57.

 The method according to any of claims 53 to 56, wherein the nucleotide that binds to the Protein is a protein binding ATP,

58.

 The method according to any one of claims 53 to 57, wherein the support material comprises sepharose and modified sepharose.