MX2008009462A - 7h-pyrido[3,4-d]pyrimidin-8-ones, their manufacture and use as protein kinase inhibitors - Google Patents

Abstract

Objects of the present invention are the compounds of formula (I) their pharmaceutically acceptable salts, enantiomeric forms, diastereoisomers and racemates, the preparation of the above compounds, medicaments containing them and their manufacture, as well as the use of the above compounds in the control or prevention of illnesses such as cancer.

Description

7H-PIRIDO [3,4-D] PYRIMIDIN-8-ONAS, ITS MANUFACTURE AND USE AS PROTEIN KINASE INHIBITORS FIELD OF THE INVENTION The present invention relates to novel 7H-pyrido [3, 4-d] pyrimidin-8-one derivatives, to a process for their manufacture, pharmaceutical compositions containing them and their manufacture as well as the use of these compounds as pharmaceutically active agents.

BACKGROUND OF THE INVENTION Protein kinases are enzymes that catalyze the transfer of an ATP phosphate group to an amino acid residue, such as tyrosine, serine, threonine, or histidine in a protein. The regulation of these protein kinases is essential for the control of a wide variety of cellular events including proliferation and migration. Inappropriate activation of tyrosine kinases is known to be involved in a variety of disease states including inflammatory, immune, CNS disorders, or oncological disorders, or bone diseases. See for example Susva,. , et al., Trends Pharmacol. Sci. 21 (2000) 489-495; Biscardi, J.S., et al., Adv. Cancer Res. 76 (2000) 61-119. Tyrosine kinases are a class of protein kinases. The Src family consisting of at least eight members (Src, Ref .: 193446 Fyn, Lyn, Yes, Lck, Fgr, Hck and Blk) participating in a variety of signaling pathways represents the major family of cytoplasmic protein tyrosine kinases (Schwartzberg, PL, Oncogene 17 (1998) 1463-1468). The prototype member of this tyrosine kinase family is Src, which is involved in proliferation and migration responses in many cell types (Sawyer, T., et al., Expert Opin, Investigation Drugs 10 (2001) 1327-1344) . Src activity has been shown to be elevated in different tumors, for example, breast tumors, colon (> 90%), pancreatic (> 90%) and liver tumors (> 90%). The highly increased Src activity is also associated with metastasis (> 90%) and is of reserved prognosis. The antisense Src message prevents the growth of colon neoplastic cells in transgenic mice (Staley, C.A., Cell Growth Differ., (1997) 269-274), suggesting that Src inhibitors may delay tumor growth. Moreover, in addition to its role in cell proliferation, Src also acts on stress response trajectories, including the response to hypoxia. Studies in transgenic mice with neoplastic colon cells expressing Src antisense message have reduced vascularization (Ellis, LM, et al., J. Biol. Chem. 273 (1998) 1052-1057), suggesting that Src inhibitors they could be an i-angiogenic as well as anti-proliferative. Src breaks E-oadherin that associates cell-cell interactions (Avizienyte, E., et al., Nature Cell Bio 4 (2002) 632-638). A low molecular weight inhibitor Src prevents this disruption by thereby reducing the cancer cell metastasis (Nam, J.S., et al., Clin Cancer Res. 8 (2002) 2430-2436). Src inhibitors can prevent secondary injury resulting from a VEGF-mediated increase in vascular permeability such as that seen after stroke (Eliceiri, BP, et al., Mol.Cell., 4 (1999) 915-924).; Paul, R., et al., Nat. Med. 7 (2001) 222-227). Src blocking prevents dissociation of the complex involving Flk, VE cadherin, and β-catenin with the same kinetics with which VEGF-mediated VP / edema is prevented and account for the Src requirement in VEGF-mediated permeability and provides a basis for the inhibition of Src as a therapeutic option for patients with acute myocardial infarction (Vfeis, S., et al., J. Clin.Research 113 (2004) 885-894). Src also plays a role in osteoporosis. Transgenic mice genetically produced to be deficient in the production of Src were found to exhibit osteopetrosis, insufficiency for bone resorption ^ Soriano, P., et al., Cell 64 (1991) 693-702; Boyce, B.F., et al., J. Clin., Invest. 90 (1992) 1622-1627). This defect was characterized by a lack of osteoclast activity. Since the osteoclasts normally express high level is Src, the inhibition of Src kinase activity may be useful in the treatment of osteoporosis (Missbach, M., et al., Bone 24 (1999) 437- Inhibitors of Low molecular weight protein kinases are widely known in the state of the art.For the inhibition of src and other kinases such inhibitors are based on, that is, 8H-pyrido [2,3-d] pyrimidin-7-one derivatives ( see for example, WO 96/34867, WD 96/15128, US 5,733,914, WO 02/018379, WO 02/018380, WO 2005/034869, Klutchko, SR, et al., J. Med. Chem. 41 (1998) 3276-3292 or Blankley, CJ, J. Med. Chem. 41 (1998) 1752-1763) or 3,4-dihydro-lH-pyrimido [4,5-d] pyrinddin-2-one derivatives (see for example, WO 99/61444, WO 00/024744, WO 01/029041, WO 01/029042, WO 2004/011465, WO 2004/041821, WO 2004/041823, WO 2004/075852, WO 2004/089955 or WO 2005/011597). Some pyrido-pyriduiddinone derivatives are known from cross coupling reaction studies ( Sakamoto, T., et al., Chemical &; Pharmaceutical Bulletin 30 (19S2) 2410-2416).

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to pyrido [3,4-d] pyrimidin-8-one derivatives of the general formula I Formula I, wherein R 1 is halogen, alkyl, alkoxy, halogenated alkyl or halogenated alkoxy; R 2 is hydrogen, halogen, alkyl, alkoxy, halogenated alkyl or halogenated alkoxy; R3 is alkyl that is optionally substituted one or more times with cyano, -0R, -NRR ', -C (0) NRR', -NR-C (O) -alkyl, -S (0) 2NRR ', -NR- S (O) 2-alkyl, heteroaryl, heterocyclyl, unsubstituted phenyl or phenyl substituted one or more times with halogen, alkyl, alkoxy or cyano; R4 is a) alkyl wherein the alkyl is optionally substituted one or more times with -OR or -NRR '; b) phenyl wherein the phenyl is optionally substituted one or more times with alkyl, alkoxy, heterocyclyl, -C (0) NRR ', -NR-C (O) -alkyl, -S (0) -alkyl, -S ( O) 2NR-alkyl or -NR-S (O) 2 -alkyl, and wherein all the alkyl and alkoxy groups are optionally substituted one or more times with -OR or -NRR '; or c) heterocyclyl; R and R 'are hydrogen or alkyl; and all pharmaceutically acceptable salts thereof. The compounds according to this invention show activity as protein kinase inhibitors, in particular as inhibitors of family src tyrosine kinase (especially as src and lck inhibitors) and additionally as inhibitors of Abl, PDGFR, Raf tyrosine kinase inhibitors, and by thus, they can be useful for the treatment of tyrosine kinase-mediated diseases. The family of tyrosine kinases plays an important role in the regulation of cell signaling and cell proliferation by phosphorylating tyrosine residues of peptides and proteins. Inadequate activation of tyrosine kinases is known to be involved in a variety of disease states including inflammatory, immune, 13NC disorders, or oncological disorders, or bone diseases. See for example Susva, M., et al., Trains Pharmacol. Sci. 21 (2000) 489-495; Biscardi, J.S., et al., Adv. Cancer Res. 76 (2 00) 61-119. The inhibition of Src, Abl, PDGFR and Raf kinase exerts an antiproliferative effect on tumor cell lines. This indicates that Src, Abl, PDGFR and Raf kinase inhibitors may be useful in the treatment of for example, hyperproliterative diseases such as cancer and in particular colorectal, breast, lung, prostate, pancreatic, gastric, bladder tumors. ovary, melanoma, neuroblastoma, cervical, kidney or kidney, leukemia or lymphoma. Src family kinases are also known to be involved in a variety of other disease states. The compounds of the present invention can also be used as inhibitors of the Src family kinase, especially as inhibitors of Src kinase, in the prevention and therapy of, for example, transplant rejection, inflammatory bowel syndrome, rheumatoid arthritis, psoriasis, restenosis, allergic asthma, Alzheimer's disease, Parkinson's disease, stroke, osteoporosis and benign. The kinases of the Abl family are also known to be involved in a variety of other disease states. The compounds of the present invention can also be used as inhibitors of kinases of the Abl family, especially as inhibitors of Abl kinase, in the prevention and therapy of, for example, neurodegenerative disease, rheumatoid arthritis and diabetes, including type I diabetes or type II. The kinases of the PDGFR family are also known to be involved in a variety of other disease states. The compounds of the present invention can also be used as kinase inhibitors of the PDGFR family, especially as inhibitors of PDGFR kinase, in the prevention and therapy of, for example, diabetes, including type I or type II diabetes, restenosis (e.g. , restenosis induced by valvuloplasty injury), atherosclerosis or pulmonary fibrosis. The objects of the present invention are the compounds of formula I and their tautomers, pharmaceutically acceptable salts, enantiomeric forms, diastereoisomers and racemates, their use for the inhibition of tumor growth, the preparation of the aforementioned compounds, drugs containing them and their manufacture as well as the use of the aforementioned compounds in the control or prevention of diseases, especially of tumors such as coloreetal, breast, lung, prostate, pancreatic, gastric, bladder, ovarian, melanoma, neuroblastoma, cervical, kidney or kidney tumors, leukemia or lymphoid tumors, or in the manufacture of corresponding medications.

DETAILED DESCRIPTION OF THE INVENTION 1. Definitions: The term "halogen" means fluorine, chlorine or bromine, preferably fluorine or chlorine and especially chlorine. The term "alkyl" as used herein means a straight chain or branched chain, saturated hydrocarbon containing from 1 to 4, preferably 1 to 3, carbon atoms. Examples of such alkyl groups include such as methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-butyl and t-butyl, preferably methyl. The term "alkoxy" as used herein means an alkyl-O- group wherein the alkyl is defined as above. Examples of such alkoxy groups include methoxy, ethoxy, n-propoxy and isopropoxy, preferably methoxy. The term "halogenated alkyl" as used herein means an alkyl group as defined above that is substituted one or more times, preferably one up to six and especially one up to three times, by halogen, preferably by fluorine or chlorine, especially by fluorine. Examples are difluoromethyl, trifiuoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, and the like, especially trifluoromethyl. The term "halogenated alkoxy" as used herein means an alkoxy group as defined above that is substituted one or more times by halogen, preferably by fluorine or chlorine, especially fluorine. Examples are difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy and the like, especially trifluoromethoxy. The term "heteroaryl" means a mono or bicyclic aromatic ring with 5 to 10, preferably 5 to 6, ring atoms, containing up to 3, preferably 1 or 2 heteroatoms independently selected from N, O or S and the atoms in the ring. remaining ring being carbon atoms. Such heteroaryl groups can optionally be substituted one to three, preferably one up to twice by alkyl, preferably by methyl. Examples of such heteroaryl groups include pyrrolyl, imidazolyl, pyrazolyl, methylpyrazolyl, dimethylpyrazolyl, triazolyl, tetrazolyl, furanyl, oxazolyl, isoxazolyl, thienyl, methylthienyl, thiazolyl, methyl thiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, indazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, quinolyl, isoquinolyl, quinazolinyl and the like, preferably pyrazolyl, methylpyrazolyl or dimethylpyrazolyl, and especially dimethylpyrazolyl. The term "heterocyclyl" means a monocyclic hydrocarbon ring, saturated with 5 to 6 ring atoms containing up to 3, preferably 1 or 2 heteroatoms independently selected from N, O or S and the remaining ring atoms being carbon atoms. Such a saturated heterocyclic group can optionally be substituted one to three, preferably one up to twice by alkyl, preferably by methyl. Examples of such saturated heterocyclic groups are tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperazinyl, N-methyl-piperazinyl, piperidyl, pyrrolidinyl, and the like, preferably tetrahydrofuranyl, tetrahydropyranyl, morpholinyl or N-methyl-piperazinyl. As used herein, the term "a therapeutically effective amount" of a compound means an amount of compound that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. The determination of a therapeutically effective amount is within the skill of the art. The therapeutically effective amount or dose of a compound according to this invention can vary within wide limits and can be determined in a manner known in the art. Such doses will be adjusted to the individual requirements in each particular case including the specific compounds to be administered, the route of administration, the condition to be treated, as well as the patient to be treated. In general, in the case of oral or parenteral administration to human adults weighing approximately 70 Kg, a daily dose of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, would be appropriate, although the upper limit may be exceeded when indicated. The daily dose can be administered as a single dose or in divided doses, or for parenteral administration, this can be given as a continuous infusion. R1 is halogen, alkyl, alkoxy, halogenated alkyl or halogenated alkoxy, preferably halogen, alkyl or alkoxy, and more preferably halogen or alkyl. R2 is hydrogen, halogen, alkyl, alkoxy, halogenated alkyl or halogenated alkoxy, preferably hydrogen. R3 is alkyl that is optionally substituted one or more times, preferably one up to two times, with cyano, -OR, -NRR ', -C (0) NRR', -NR-C (O) -alkyl, -StO) 2RR ', -NR-S <; 0) 2-alkyl, heteroaryl, heterocyclyl, unsubstituted phenyl or phenyl substituted one or more times, preferably one up to two times, with halogen, alkyl, alkoxy or cyano. If the alkyl in the definition of R 3 is substituted, this is preferably substituted with -OR, -C (0) I 1RR ', heteroaryl (preferably dimethylpyrazolyl), heterocyclyl (preferably tetrahydrofuranyl) or phenyl substituted one to two times with alkoxy.

R4 is a) alkyl wherein the alkyl is optionally substituted one or more times, preferably one up to two times, with -OR or -NRR '; b) phenyl wherein the phenyl is optionally substituted one or more times, preferably one up to two times, with alkyl, alkoxy, heterocyclyl (preferably morpholinyl or N-methyl-piperazinyl), -C. { 0) NRR ', -NR-C (O) -alkyl, -S (0) -alkyl, -S (0) 2 NR-alkyl or -NR-S (0) 2-alkyl, preferably with alkyl, alkoxy, heterocyclyl , -S (0) -alkyl or -S (0) 2 NR-alkyl, and wherein all the alkyl and alkoxy groups, preferably the alkyl, alkoxy or -S (O) 2 NR-alkyl group, are optionally substituted one or more times, preferably one up to two times, with -OR or -NRR '; or c) heterocyclyl, preferably tetrahydrofuranyl. R and R 'are hydrogen or alkyl. One embodiment of the invention are the compounds of the formula I, wherein R 1 is halogen or alkyl; R2 is hydrogen; R3 is alkyl that is optionally substituted one or more times with -OR, -C (0) NRR ', heteroaryl, heterocyclyl, unsubstituted phenyl or phenyl substituted one or more times with alkoxy; and R4 is a) alkyl wherein the alkyl is optionally substituted one or more times with -OR or -NRR '; b) phenyl wherein the phenyl is optionally substituted one or more times with alkyl, alkoxy, heterocyclyl, -S (0) -alkyl or -S (0) 2 NR-alkyl, and wherein all the alkyl and alkoxy groups are optionally substituted one or more times with -0R or -NRR '; or c) heterocyclyl. Another embodiment of the invention are the compounds of the formula I, wherein R 1 is halogen. Another embodiment of the invention are the compounds of the formula I, wherein R 1 is alkyl. Another embodiment of the invention are the compounds of the formula I, wherein R4 is a) alkyl wherein the alkyl is optionally substituted one or more times with -OR or -NRR '; or b) heterocyclyl. Another embodiment of the invention are the compounds of the formula I, wherein R 4 is alkyl wherein the alkyl is optionally substituted one or more times with -OR or -NRR '. Another embodiment of the invention are the compounds of the formula I, wherein R 1 is halogen or al-chyl; R2 is hydrogen; R3 is alkyl that is optionally substituted one or more times with -0R, -C (0) NRR ', heteroaryl, heterocyclyl, unsubstituted phenyl or phenyl substituted one or more times with alkoxy; and R 4 is alkyl wherein the alkyl is optionally substituted one or more times with -OR or -NRR '. Such compounds, for example, can be selected from the group consisting of: 2- (2-Hydroxy-1-hydroxymethyl-ethylamino) -7-methyl-6-o-tolyl-7H-pyrido [3,4-d] pyrimidine -8-ona; 7- (1, 5-Dimethyl-lH-pyraz-ol-3-ylmethyl) -2- (2-hydroxy-l-hydroxymethyl-ethylamino) -6-o-tolyl-7H-pyrido [3,4-d] pyrimidin-8-one; and 3- [6- (2-chloro-phenyl) -2- (2-hydroxy-l-hydroxymethyl-ethylamino) -8-oxo-8H-pyrido [3,4-d] pyrimidin-7-yl] -propionamide .

Another embodiment of the invention are the compounds of the formula I, wherein R 4 is phenyl wherein the phenyl is optionally substituted one or more times with alkyl, alkoxy, heterocyclyl, -S (O) -alkyl or -S (O) 2NR -alkyl, and wherein all the alkyl and alkoxy groups are optionally substituted one or more times with -OR or -NRR '. Another embodiment of the invention are the compounds of the formula I, wherein R 1 is halogen or alkyl; R2 is hydrogen; R3 is alkyl that is optionally substituted one or more times with -0R, -C (0) NRR ', heteroaryl, heterocyclyl, unsubstituted phenyl or phenyl substituted one or more times with alkoxy; and R 4 is phenyl wherein the phenyl is optionally substituted one or more times with alkyl, alkoxy, heterocyclyl, -S (0) -alkyl or -S (0) 2 NR-alkyl, and wherein all the alkyl and alkoxy groups are optionally substituted one or more times with -0R or -NRR '. Such compounds, for example, can be selected from the group consisting of: 7-Methyl-2- (4-morpholin-4-yl-phenylamino) -6-o-tolyl-7H-pyrido [3,4-d] pyrimidine -8-ona; 2- (3-Hydroxymethyl-phenylamino) -7-methyl-6-o-tolyl-7H-pyrido [3,4-d] pyrimidin-8-one; 7-Methyl-2- [4- (4-methyl-piperazin-1-yl) -phenylamino] -6-o-tolyl-7H-pyrido [3,4-d] pyrimidin-8-one; 2-. { 2- [4- (2-Hydroxy-ethylsulfamoyl) -phenylamino] -8-oxo-6-o-tolyl-8H-pyrido [3,4-d] pyrimidin-7-yl} -acetamide; N- (2-Hydroxy-ethyl) -4- (7-methyl-8-oxo-6-o-tolyl-7,8-dihydro-pyrido [3,4-d] pyrimidin-2-ylamino) -benzenesulfonamide; 2- [4- (2-Diethylamino-ethoxy) -phenylamino] -7-methyl-6-o-tolyl-7H-pyrido [3,4-d] pyrimidin-B-one; 2- [2- (3-Methansulfinyl-phenylamino) -8-oxo-6-o-tolyl-8 H -pyrido [3,4-d] pyrimidin-7-yl] -acetamide; 2- (3-Methansulfinyl-phenylamino) -7-methyl-6-o-tolyl-7H-pyrido [3,4-d] pyrimidin-8-one; 7- (1, 5-Dimethyl-lH-pyrazol-3-ylmethyl) -2- (4-morpholin-4-yl-phenylamino) -6-o-tolyl-7H-pyrido [3,4-d] pyrimidine- 8-one; 7- (3-Hydroxy-propyl) -2- [4- (4-methyl-piperazin-1-yl) -phenylamino] -6-o-tolyl-7H-pyrido [3,4-d] pyrimidine-8- ona; N- (2-Hydroxy-ethyl) -4-. { 7- (3-hydroxy-propyl) -8-oxo-6-o-tolyl-7,8-dihydro-pyrido [3,4-d] pyrimidin-2-ylamino] -benzenesulfonamide; 2- [4- (2-Diethylamino-ethoxy) -phenylamino] -7- (3-hydroxy-propyl) -6-o-tolyl-7H-pyrido [3,4-d] pyrimidin-8-one; 7- (3-Hydroxy-propyl) -2- (3-methanesulfinyl-phenylamino) -6-0-tolyl-7H-pyrido [3,4-d] pyrimidin-8-one; 7- (3-Methoxy-benzyl) -2- [4- (4-methyl-piperazin-1-yl) -phenylamino] -6-o-tolyl-7H-pyrido [3,4-d] pyrimidine-8- ona; N- (2-Hydroxy-ethyl) -4- [7- (3-methoxy-benzyl) -8-0x0-6-0-tolyl-7,8-dihydro-pyrido [3,4-d] pyrimidin-2 -ylamino] -benzenesulfonamide; 2- [4- (2-Diethylamino-ethoxy) -phenylamino] -7- (3-methoxy-benzyl) -6-o-tolyl-7H-pyrido [3,4-d] pyrimidin-8-one; 2- (3-Methansulfinyl-phenylamino) -7- (3-methoxy-benzyl) -6-0-tolyl-7H-pyrido [3,4-d] pyrimidin-8-one; 3- [2- (3-Hydroxymethyl-phenylamino) -8-oxo-6-o-tolyl-8 H -pyrido [3,4-d] pyrimidin-7-yl] -propionamide;3-. { 2- [4- (2-Hydroxy-ethylsulfamoyl) -phenylamino] -8-0x0-6-0-tolyl-8H-pyrido [3,4-d] pyrimidin-7-yl} -propionamide; 3- [2- (3-Methansulfinyl-phenylamino) -8-oxo-6-o-tolyl-8 H -pyrido [3,4-d] pyrimidin-7-yl] -propionamide; 6- (2-Chloro-phenyl) -7- (1, 5-dimethyl-1H-pyrazol-3-ylmethyl) -2- [4- (4-methyl-piperazin-1-yl) -phenylamino] -7H- pyrido [3,4-d] pyrimidin-8-one; 6- (2-Chloro-phenyl) -2- [4- (2-diethylamino-ethoxy) -phenylamino] -7- (1, 5-dimethyl-lH-pyrazol-3-ylmethyl) -7H-pyrido [3, 4-d] pyrimidin-8-one; 6- (2-Chloro-phenyl) -7- (1, 5-dimethyl-lH-pyrazol-3-ylmethyl) -2- (3-methanesulfinyl-phenylamino) -7H-pyrido [3,4-d] pyrimidine- 8-one; 6- (2-Chloro-phenyl) -7- (3-hydroxy-propyl) -2- [4- (4-methyl-piperazin-1-yl) -phenylamino] -7H-pyrido [3, 4-d] pyrimidin-8-one; 6- (2-Chloro-phenyl) -7- (3-methoxy-benzyl) -2- [4- (4-methyl-piperazin-1-yl) -phenylamino] -7H-pyrido [3, 4-d] pyrimidin-8-one; 4- [6- (2-Chloro-phenyl) -7- (3-methoxy-benzyl) -8-oxo-7,8-dihydro-pyrido [3,4-d] pyrimidin-2-ylamino] -N- (2-hydroxy-ethyl) -benzenesulfonamide; 6- (2-Chloro-phenyl) -2- [4- (2-diethylamino-ethoxy) -phenylamino] -7- < 3-methoxy-benzyl) -7H-pyrido [3,4-d] pyrimidin-8-one; 6- (2-Chloro-phenyl) -2- (3-methanesulfinyl-phenylamino) -7- (3-methoxy-benzyl) -7H-pyrido [3,4-d] pyrimidin-8-one; 6- (2-Chloro-phenyl) -2- (3-hydroxymethyl-phenylamino) -7- (tetrahydro-furan-2-ylmethyl) -7H-pyrido [3,4-d] pyrimidin-8-one; 6- (2-Chloro-phenyl) -2- [4- (4-methyl-piperazin-1-yl) -phenylamino] -7- (tetrahydro-furan-2-ylmethyl) -7H-pyrido [3, 4- d] pyrimidin-8-one; 4- [6- (2-Chloro-phenyl) -8-OXO-7- (tetrahydro-furan-2-ylmethyl) -7,8-dihydro-pyrido [3,4-d] pyrimidin-2-ylamino] - N- (2-hydroxy-ethyl) -benzenesulfonamide; 6- (2-Chloro-phenyl) -2- [4- (2-diethylamino-ethoxy) -phenylamino] -7- (tetrahydro-furan-2-ylmethyl) -7H-pyrido [3,4-d] pyrimidine- 8-one; and 6- (2-Chloro-phenyl) -2- (3-methanesulfinyl-phenylamino) -7- (tetrahydro-furan-2-ylmethyl) -7H-pyrido [3,4-d] pyrimidin-8-one.

Another embodiment of the invention are the compounds of the formula I, wherein R 4 is heterocyclyl. Another embodiment of the invention are the compounds of the formula I, wherein R 1 is halogen or alkyl; R2 is hydrogen; R3 is alkyl that is optionally substituted one or more times with -0R, -C (0) NRR ', heteroaryl, heterocyclyl, unsubstituted phenyl or phenyl substituted one or more times with alkoxy; and R 4 is heterocyclyl. Such compounds, for example, can be selected from the group consisting of: 2- [8-0x0-2- (tetrahydro-pyran-4-ylamino) -o-tolyl-8H-pyrido [3,4-d] pyrimidine -7-yl] -acetamide; 7-Methyl-2- (tetrahydro-pyran-4-ylamino) -6-o-tolyl-7H-pyrido [3,4-d] pyrimidin-8-one; 7- (1, 5-Dimethyl-lH-pyrazol-3-ylmethyl) -2- (tetrahydro-pyran-4-ylamino) -6-o-tolyl-7H-pyrido [3,4-d] pyrimidine-8- ona; 7- (3-Hydroxy-propyl) -2- (tetrahydro-pyran-4-ylamino) -6-o-tolyl-7H-pyrido [3,4-d] pyrimidin-8-one; 7- (3-Methoxy-benzyl) -2- (tetrahydro-pyran-4-ylamino) -6-o-tolyl-7H-pyrido [3,4-d] pyrimidin-8-one; 3 - [8-0x0-2- (tetrahydro-pyran-4-ylamino) -6-o-tolyl-8 H -pyrido [3,4-d] pyrimidin-7-yl] -propionamide; 2- [6- (2-Chloro-phenyl) -8-oxo-2- (tetrahydro-pyran-4-ylamino) -8 H -pyrido [3,4-d] pyrimidin-7-yl] -acetamide; 6- (2-Chloro-phenyl) -7- (1, 5-dimethyl-lH-pyrazol-3-ylmethyl) -2- (tetrahydro-pyran-4-ylamino) -7H-pyrido [3,4-d] pyrimidin-8-one; 6- (2-Chloro-phenyl) -7- (3-hydroxy-propyl) -2- (tetrahydro-pyran-4-ylamino) -7H-pyrido [3,4-d] pyrimidin-8-one; 6- (2-Chloro-phenyl) -7- (3-methoxy-benzyl) -2- (tetra-pyro-pyran-4-ylamino) -7H-pyrido [3,4-d] pyrimidin-8-one; and 6- (2-Chloro-phenyl) -7- (tetrahydro-furan-2-ylmethyl) -2- (tetrahydro-pyran-4-ylamino) -7H-pyrido [3,4-d] pyrimidin-8-one .

Another embodiment of the invention are the compounds of the formula I, wherein R 1 is halogen or alkyl; R2 is hydrogen; R3 is alkyl; and R4 is a) alkyl wherein the alkyl is optionally substituted one or more times with -OR or -NRR '; b) phenyl wherein the phenyl is optionally substituted one or more times with alkyl, alkoxy, heterocyclyl, -S (O) -alkyl or -S (0) 2 NR-alkyl, and wherein all the alkyl and alkoxy groups are optionally substituted one or more times with -OR or -NRR '; or c) heterocyclyl. Another embodiment of the invention are the compounds of the formula I, wherein R3 is alkyl that is substituted once with -OH. Another embodiment of the invention are the compounds of the formula I, wherein R 1 is halogen or alkyl; R2 is hydrogen; R3 is alkyl that is substituted once with -OH; and R4 is a) alkyl wherein the alkyl is optionally substituted one or more times with -OR or -NRR '; b) phenyl - wherein the phenyl is optionally substituted one or more times with alkyl, alkoxy, heterocyclyl, -S (O) -alkyl or -S (O) 2 NR-alkyl, and wherein all the alkyl and alkoxy groups are optionally substituted one or more times with -OR or -NRR '; or c) heterocyclyl.

Another embodiment of the invention are the compounds of the formula I, wherein R3 is alkyl that is substituted once with -C (0) NRR '; and R and R 'are hydrogen. Another embodiment of the invention are the compounds of the formula I, wherein R 1 is halogen or alkyl; R2 is hydrogen; R3 is alkyl that is substituted once with -C (0) NRR '; R4 is a) alkyl wherein the alkyl is optionally substituted one or more times with -0R or -NRR '; b) phenyl wherein the phenyl is optionally substituted one or more times with alkyl, alkoxy, heterocyolyl, -S (0) -alkyl or -S (?) 2 NR-alkyl, and wherein all the alkyl and alkoxy groups are optionally substituted one or more times with -0R or -NRR '; or c) heterocyclyl; and R and R 'are hydrogen Another embodiment of the invention are the compounds of the formula I, wherein R3 is alkyl that is substituted once with heteroaryl. Another embodiment of the invention are the compounds of the formula I, wherein R 1 is halogen or alkyl; R2 is hydrogen; R3 is alkyl that is substituted once with heteroaryl; and R4 is a) alkyl wherein the alkyl is optionally substituted one or more times with -0R or -NRR '; b) phenyl wherein the phenyl is optionally substituted one or more times with alkyl, alkoxy, heterocyclyl, -S < 0) -alkyl or -S (O) 2 NR-alkyl, and wherein all the alkyl and alkoxy groups are optionally substituted one or more times with -OR or -NRR '; or c) heterocyclyl. Another embodiment of the invention are the compounds of the formula I, wherein R3 is alkyl that is substituted once with heterocyclyl. Another embodiment of the invention are the compounds of the formula I, wherein R 1 is halogen or alkyl; R2 is hydrogen; R3 is alkyl that is substituted once with heterocyclyl; and R4 is a) alkyl wherein the alkyl is optionally substituted one or more times with -OR or -NRR '; b) phenyl wherein the phenyl is optionally substituted one or more times with alkyl, alkoxy, heterocyclyl, -S (0) -alkyl or -S (0) 2 NR-alkyl, and wherein all the alkyl and alkoxy groups are optionally substituted one or more times with -0R or -NRR '; or c) heterocyclyl. Another embodiment of the invention are the compounds of the formula I, wherein R3 is alkyl that is substituted once with substituted phenyl one or more times with alkoxy. Another embodiment of the invention are the compounds of the formula I, wherein R 1 is halogen or alkyl; R2 is hydrogen; R3 is alkyl that is substituted once with substituted phenyl one or more times with alkoxy; and R4 is a) alkyl wherein the alkyl is optionally substituted one or more times with ~ 0R or -NRR '; b) phenyl wherein the phenyl is optionally substituted one or more times with alkyl, alkoxy, heterocyclyl, -S (O) -alkyl or -S (O) 2 NR-alkyl, and wherein all the alkyl and alkoxy groups are optionally substituted one or more times with -0R or -NRR '; or c) heterocyclyl. Another embodiment of the invention is a process for the manufacture of the compounds of the formula I, which comprises the steps of (a) reacting a compound of the formula VIII formula VIII, wherein R1, R2 and R3 have the meaning given above by formula I and L is a starting group selected from alkylsulfonyl or alkylsulfinyl, preferably L is alkylsulfonyl and more preferably methylsulfonyl, with a compound of the formula Villa R4-NH2 formula Villa, wherein R4 has the meaning given above by formula I, to give the respective compound of the formula Formula I, wherein R 1, R 2, R 3 and R 4 have the meaning given above. By the formula I, (b) the compound of the formula I is isolated from the reaction mixture, and (c) if desired, converted to a pharmaceutically acceptable salt. The derivatives of the general formula I or a pharmaceutically acceptable salt thereof can be prepared by any process known to be applied by the preparation of compounds chemically related by one skilled in the art. Such processes, when used to prepare the derivatives of formula I, or a pharmaceutically acceptable salt thereof, are provided as a further feature of the invention and are illustrated by the following representative examples of reaction scheme 1, in which, unless to be stated otherwise R1, R2, R3 and R4 have the meaning given herein before formula I. The necessary starting materials can be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described within the accompanying examples. Alternatively the necessary starting materials are obtained by procedures analogous to those illustrated which are within the ordinary experience of organic chemistry.

Reaction scheme 1 meaning as previously given by the formula I, X - is bromine or iodine and n is 1 or 2.

Step 1 The methyl ester of 5-bromo-2-methylsulfanyl-pyrimidine-4-carboxylic acid is a known compound. The free carboxylic acid can be prepared from the mucobromic acid and S-methylisothiourea under basic conditions. It can also be converted to the methyl ester by standard procedures, for example by condensation with methanol in the presence of anhydrous hydrochloric acid.

Step 2 The substituted phenylacetylenes of formula III are well known in the art and can be prepared from the corresponding bromo- or iodoarenes of the formula II and an ethyne protected by the so-called Sonogashira reaction. This coupling reaction is carried out with a copper catalyst such as Cul or CuCl, and a palladium catalyst such as PdCl2 (PPh3) 2 or PdCl2 (PhCN) 2 / PtBu3, and a base such as di-isopropyl amine, diethyl amine or triethyl amine, which may also serve as the solvent, or in an inert solvent such as tetrahydrofuran (THF), dioxane,?,? - dimethylformamide (DMF) or acetonitrile. The reaction proceeds at room temperature or higher, up to 160 ° C. A suitable protected group in ethyne is the trimethylsilyl group which can be further divided by treatment with a fluoride containing tetrabutyl ammonium fluoride type reagent in an inert aprotic solvent such as tetrahydrofuran, or by a strong base such as potassium hydroxide in solvents. of alcohol like methanol. This deprotection reaction is preferably done at moderate to low temperatures in the range of -30 ° C to 50 ° C.

Step 3 The coupling of the phenylacetylenes of the formula III to the methyl ester of 5-bromo-2-methylsulfanyl-pyrimidine-4-carboxylic acid can be achieved under conditions of the so-called Sonogashiro reaction as described by step 2. Alternatively, the ethynyl arene can first be converted to a Zn or alkynyl-Sn derivative plus reagents derived by procedures known in the art: ethynyl arene is deprotonated with a strong base such as butyl lithium to form an alkynyl-Li intermediate that is reacted with ZnCl2 or Bu3SnCl to provide the desired zinc or tin intermediate. This can then be coupled to the methyl ester of 5-bromo-2-methylsulfanyl-pyrimidine-4-carboxylic acid under standard cross-coupling conditions, for example, by catalysis by a palladium phosphine complex such as Pd (PPh3) 4 or PdCl2 (PPh3) 2 or Pd2 (dba) 3 / PtBu3 in solvents such as dimethyl acetamide, THF, or toluene.

Step 4 The cyclization of the ethynylpyrimidine derivatives of the formula IV to pyranone derivatives of the formula V can be achieved under acidic conditions, optionally in the presence of water. This can be carried out by a solvent such as tetrahydrofuran, dioxane, N-methylpyrrolidinone or sulfolane. Suitable acids for this reaction may be trifluoroacetic acid, hydrochloric acid, sulfuric acid, toluene sulfonic acid, methanesulfonic acid, or polyphosphoric acid. The reaction can optionally be catalyzed by mercury salts such as HgO. Alternatively, a Lewis acid such as ZnBr2 is employed in an inert solvent such as tetrahydrofuran.

Step 5 The pyranone derivatives of the formula V are reacted with amines R3NH2 of the formula Va to provide open ring pyrimidine carboxamides of the formula VI. This can be achieved by heating the pure reaction partners in an excess of the amine, or in an inert solvent such as dichloromethane, tetrahydrofuran (THF), ethanol, xylene, or N-methylpyrrolidinone (NP) at a temperature in the range of 40. ° C up to 170 ° C. Optionally, an acid can be added to facilitate the reaction.

Step 6 The pyrimidine carboxamides of formula VI are again cyclized to pyrimidopyridones of formula VII by heating in the presence of an acid. In principle, the same conditions apply as described in step 4.

Step 6a Alternatively, in certain cases the direct conversion of pyrimidine caboxylates of the formula IV to the pyrimidopyridones of the formula VII is possible by heating with the appropriate amine R3NH2 of the formula Va pure or in an inert solvent such as dichloromethane, tetrahydrofuran (THF) ), xylene, ethanol or N-methylpyrrolidinone (NMP). Optionally, an acid such as trifluoroacetic acid or hydrochloric acid, or a transition metal catalyst such as a palladium phosphine complex can be added to facilitate the reaction.

Step 7 The methylthio group of pyrimidopyridones VII is converted in a starting group by oxidation to a methylsulfinyl or methylsulfonyl group. Oxidants suitable for this purpose are meta-chloroperbenzoic acid or 3-phenyl-2- (toluene-4-sulfonyl) -oxaziridine in solvents such as mixtures of dichloromethane or THF, or Oxone or sodium periodate in methanol or THF / water. The oxidation reaction is carried out at temperatures in the range of -20 ° C to 60 ° C, and the resulting methylsulfinyl- or methylsulfonyl-pyrimidopyridones of formula VIII (n = 1 or 2) can optionally be used directly without isolation in the step 8 Step 8 The methylsulfinyl or methylsulfonyl group of compounds of the formula VIII is displaced by an amine RNH2 of the formula Villa to provide the final products of the formula I by heating the pure reactants, or diluting with an inert solvent such as N-methylpyrrolidioneone, dimethylacetamide, sulfolane, dichloromethane, tetrahydrofuran (THF) or acetonitrile. An acid such as trifluoroacetic acid or anhydrous hydrochloric acid can be added to facilitate the reaction. The reaction is carried out at elevated temperatures in the range of 60 ° C to 180 ° C. Alternatively, the amines R4NH2 can be deprotonated by a strong base such as lithium hexamethyldisilazide or lithium diisopropylamide and reacted with compounds of the formula VIII at temperatures between -50 ° C and room temperature in an inert solvent such as diethyl ether or THF The compounds according to the present invention can exist in the form of their pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to conventional acid addition salts that retain the biological efficacy and properties of the compounds of the formula I and are formed of non-toxic or suitable inorganic or organic bases or of inorganic or organic acids . Examples of basic addition salts include those derived from sodium, potassium, ammonium, quaternary ammonium hydroxides (such as, for example, tetramethylammonium idroxide), especially sodium. Examples of acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. The chemical modification of a pharmaceutical compound (this is a drug) in a salt is a well known technique for pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. See, for example, Stahl, P. H., and Wermuth, G., (editors), Handbook of Pharmaceutical Salts, Verlag Helvetica Chimica Acta (VHCA), Zürich, (2002) or Bastin, R.J., et al., Organic Proc. Res. Dev. 4 (2000) 427-435. The compounds of the formula I may contain one or more chiral centers and may then be presented in a remymic form or in an optionally active form. The racemates can be prepared according to known methods in the enantiomers. For example, diastereomeric salts that can be prepared by crystallization are formed from the racemic mixtures by reaction with an optionally active acid such as for example D- or L-canf-or sulfonic acid.

Alternatively, the separation of the enantiomers can also be performed by using chromatography in chiral HPLC phase which are commercially available. Medicaments containing a compound of the present invention or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are an object of the present invention, as is a process for their production, which comprises linking one or more compounds of the present invention and / or pharmaceutically acceptable salts and, if desired, one or more other therapeutically valuable substances in a galenic administration form together with one or more therapeutically inert carriers. One embodiment of the invention is a pharmaceutical composition, containing one or more compounds according to formula I, together with pharmaceutically acceptable excipients. Another embodiment of the invention is a pharmaceutical composition, which contains one or more compounds according to formula I, for the inhibition of tumor growth. Another embodiment of the invention is a pharmaceutical composition, containing one or more compounds according to formula I, for the treatment of cancer. Another embodiment of the invention is a medicament containing one or more compounds of the formula I as active ingredients together with pharmaceutically acceptable adjuvants for the treatment of colorectal, breast, lung, prostate, pancreatic, gastric, veg, ovarian cancer. , melanoma, neuroblastoma, cervical, kidney or kidney, leukemia or lymphoma. Another embodiment of the invention is the use of a compound according to formula I, for the manufacture of corresponding medicaments for the inhibition of tumor growth.

Another embodiment of the invention is the use of a compound according to formula I, for the manufacture of corresponding medicaments for the treatment of cancer. Another embodiment of the invention is the use of the compounds of the formula I as anti-proliferative agents. Another embodiment of the invention is the use of one or more compounds of the formula I for the treatment of cancer.

Pharmacological activity The compounds of the formula I and their pharmaceutically acceptable salts possess valuable pharmacological properties. The compounds have been found to exhibit activity as tyrosine kinase inhibitors of the Src family. Accordingly, the compounds of the present invention are useful in the therapy and / or prevention of proliferative diseases such as cancer. The activity of the present compounds is as demonstrated for example by the following biological assay: Parameters of the Src Inhibitor Assay: Reaction mixture: ATP 5 μ? Peptide (Ro + Jal33-Ro): 10 μ? Jal33-Ro 196 nM Ro 9.8 μ? PT66 230 ng / ml Test buffer 4 mM MgC12 2 mM TCEP 50 mM HEPES 0, 1% Tween 20 pH 7.3 Enzyme: 2.5 U / ml Inhibitor: max. 25μ? min. 0.42 nM Material: Phosphotyrosine antibody for Lck Cisbio Mab PT66-K, labeled Eu For Src EG &G Wallac PT66 EU-1024 (all commercially available). gone: RO: NH2-A-E-E-E-I-Y-G-E-F-E-A-K-K-K-K-CONH2 / and Jal33-Ro: Jal33-G-aminocaprilic acid-A-E-E-E-I-Y- G-E-F-E-A-K-K-K-K-CONH2, wherein Ja 133 is succinimide ester Red light cycler 640-N-hydroxy; therefore, both peptides were synthesized by an optimized solid phase peptide synthesis protocol (Merrifield, Fed. Proc. Fed. Amer. Soc.Exp.Biol. 21 (1962) 412) on a Zinsser SMP350 peptide synthesizer. In short, the peptide was assembled into 160 mg (22.8 μl scale) of a Rink ligature modified polystyrene solid phase by repeatedly conjugating a twenty fold excess of amino acids each protected by Fmoc-unstable groups to the Temporary piperidine and tert-Bu-, BOC- and O-tert-Bu- unstable to permanent acid depending on the side chain function. The substrate sequence AEEEIYGEFEAKKKK was N-terminal additionally mounted with the spacer amino acids aminocaprylic acid and glycine. After cleavage of the temporary protected group from the N-terminus, the still bound and protected peptide was labeled with a quantity 1.5 v «z of succinimide ester of Light-Red Cycler 640-N-hydroxy (purchased from Roche Diagnostics GmbH) and triethylamine. After 3 hrs., the resin was washed with Dimethylformamide and Isopropanol until the eluate of the blue resin becomes colorless. The fully protected and labeled peptide was removed from the solid phase and freed from the permanent protecting groups by treating with a mixture of 80% trifluoroacetic acid, 10% Ethanedithiol, 5% Thioanisole and 5% Water. The substrate was finally isolated by a preparative reverse phase HPLC purification. The purification provides 12.2 mg of pure blue single-spike material RP-CLAR (lyophilized). The identity was demonstrated by MALDI mass spectroscopy [2720.0].

Enzymes: Upstate Lck (p56lck, active), Upstate Src (p60c ~ src, partially purified) were purchased from UBI, Upstate Biotech, Inc.

Fluorescence test solved in time: Reader: Perkin Elmer multi-label counter, Wallac Viktor 1420-040; liquid handling system: Beckman Coulter, Biomek 2000. ATP, Tween ™ 20, 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid (HEPES) were purchased from Roche Molecular Biochemicals, MgCl2 and MnCl2 were purchased from Merck Eurolab, hydrochloride Tris (2-carboxyethyl) phosphine (TCEP) was purchased from Pierce, low volume fluorescent plates from 384 wells were purchased from Falcon.

Test Description: In the first the enzyme is previously incubated for 15 min. at 15 ° C in aqueous solution with corresponding amounts of inhibitors according to this invention. Then the phosphorylation reaction is initiated by adding a reaction mixture, which contains ATP, Peptide and PT66, and subsequent stirring. The procedure of this reaction is monitored immediately using resolution time fluorescence spectroscopy in a suitable well plate reader. The IC50 values can be obtained from the reaction ratios when using a non-linear curve fitting (XLfit software (ID Business Solution Ltd., Guilford, Surrey, UK)). The results are shown in Table 1.

Table 1 IC50 determination for Abl kinase inhibitors Abl assay was done using corresponding fusion protein for Abl mouse (final 27), fluorescein eticfuetado peptide substrate (with an EAIYAAPFAKKK sequence) and quantified by IMAP fluorescent polarization technology from Molecular Devices . The compounds were tested in serial dilutions in 384-well plates. The kinase reaction was performed in KAB buffer solution (10 mM HEPES, pH 7, 50 mM NaCl, 5 mM MgCl 2, 1 mM DTT, 0.1 mM NaV04, 0.02% ESA), in the presence of 22.8uM ATP, incubated 37 ° C for 60 minutes. The reaction was stopped by lAP bed mixing (at 1: 400 dilution). After incubation at room temperature for 3 hours, the reaction product was analyzed in LJL Acquest (excitation 485nM and emission 530nM). The FP reader (in mP) was used to calculate the reaction ratio.

The trial was semi-automated by the Tanatee Quadra work station. Results are shown in table 2.

Table 2 IC50 determination for PDGFR kinase inhibitors Principle of the assay The PDGFR assay was carried out with fluorescein labeled peptide substrate, human recombinant beta PDGFR (with a peptide sequence of ALTSNQEYLDLSMPL) and test compounds (in serial dilution) using plates of 384 wells. The kinase reaction was performed in MOPS buffer solution (MOPS 20 niM pH 7.1, 5 mM sodium acetate, 6.25 nM MgCl2, 0.5 mM EDTA, 1 mM DTT, NaV040.04 mM, 0.02% BSA), in the presence of 48uM of ATP, incubated at room temperature for 60 minutes. The reaction was stopped by the IMAP Bed Link System (Molecular Devices). After incubation at room temperature for 2 hours, the reaction product was analyzed in LJL Acquest. FP (in mP) was used to calculate the reaction ratio. The test was semi-automated by the Tomtec Quadra workstation. The results are shown in Table 3.

Table 3 Antiproliferative activity The activity of the compounds present as antiproliferative agents can be demonstrated by the following biological assays: CellTiter-Glo ™ assay in HCT 116 cells The CellTiter-Glo ™ luminescent cell viability assay (Promega) is a homogeneous method to determine the number of viable cells in the culture based on the quantification of the ATP present, which indicates the presence of metabolically active cells. HCT 116 cells (human colon carcinoma, ATCC-No, CC1-247) are cultured in RPMI 1640 medium with GlutaMAX ™ I (Invitrogen, Cat-No, 61870-010), 5% fetal calf serum (FCS, For its acronym in English, Sigma Cat-No, F4135 (FBS)); 100 units / ml of penicillin / 100 g ml of streptomycin (= Pen / strep of Invitrogen Cat. No. 15140). For the assay the cells are seeded in 384 well plates, 1000 cells per well, in the same medium. The next day the test compounds were added in various concentrations in the range from 30 μ? up to 0.0015 μ? (10 concentrations, dilution 1: 3). After 5 days the CellTiter-Glo ™ assay is done according to the manufacturer's instructions (CellTiter-Glo ™ luminescent viability assay, from Promega). In brief: the cell plate is equilibrated at room temperature for approximately 30 minutes and such CellTiter-Glo ™ reagent is added. The contents are carefully mixed for 15 minutes to induce cell lysis. After 45 minutes the luminescent signal is measured in Victor 2, (Sweep Multiple Well Spectrophotometer, Wallac).

Details: day day: - Medium: RPMI 1640 with GlutaMAX ™ 1 (Invitrogen, Cat-Nr. 61870), 5% FCS (Sigma Cat.-No.F4135), Pen / strep (Invitrogen, Cat No. 15140). - HCT116 (ATCC-No, CCl-247): 1000 cells in 60 μ? per plate well of 384 wells (Greiner 781098, transparent white layer) - After the incubated plates are sown 24 h at 37 ° C, 5% C02 2nd day; Induction (Treatment with compounds, 10 concentrations); In order to achieve a final concentration of 30 μ? as the highest concentration 3.5 μ? of 10 mM compound reserve solution is added directly to 1-63 μ? medium. Then step e) of the dilution procedure described below is followed. In order to achieve the second highest for the lowest concentrations, a serial dilution with dilution steps of 1: 3 is followed according to the procedure (ae) as described hereinafter: a) for the second concentration higher add 1? μ? of 10 mM reserve solution of the compound at 20 μ? of dimethylsulfoxide (DMSO) b) dilute 8x 1: 3 (always 10 μm for 20 μm DMSO) in this DMSO dilution lane (results in 9 wells with concentrations of 3333.3 μm to 0.51 μm) c) dilute each concentration 1: 47.6 (3.5 μ? dilution of the compound to 163 μ? of medium) d) add 10 μ? of-each concentration at 60 μ? of medium in the cell plate resulting in the final concentration of DMSO: 0.3% in each well and resulting in final concentration 10 of the compounds in the range from 30 μ? up to 0.0015 μ ?.

- Each compound is tested in triplicate. - Incubate 120 h (5 days) at 37 ° C, C02 5% Analysis: - Add 30 μ? of CellTiter-Glo ™ reagent (prepared from CellTiter-Glo ™ buffer solution and CellTiter-Glo ™ substrate (lyophilized) purchased from Promega) per well, - Stir 15 minutes at room temperature - Incubate an additional 45 minutes at room temperature without agitation Measurement: - Victor 2 (Wallac) multiple well scanning spectrophotometer, luminescence mode (0.5 sec / reading, 477 nm) - Determine IC50 using non-linear curve equipment (XLfit software (ID Business Solution Ltd., 3uilford, Surrey, RU)) The compounds according to this invention and their pharmaceutically acceptable salts can be used as medicaments, for example, in the form of pharmaceutical compositions. The pharmaceutical compositions can be administered orally, for example in the form of tablets, coated tablets, dragees, hard and soft gelatin capsules, solutions, emulsions or suspensions. The administration can, however, also be carried out rectally, for example in the form of suppositories, or parenterally, for example in the form of injection solutions. The pharmaceutical compositions mentioned above can be obtained by processing the compounds according to this invention with pharmaceutically inert, inorganic or organic carriers. Lactose, corn starch or derivatives thereof, talc, stearic acids or their salts and the like can be used, for example, as carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid polyols and l < jui-dos and the like. Depending on the nature of the active substance usually, however, carriers are not required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid and liquid polyols and the like. The pharmaceutical compositions can, therefore, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffer solutions, masking agents or antioxidants. They may also contain other therapeutically valuable substances. The pharmaceutical compositions comprise, for example, the following: a) Tablet formulation (wet granulation): Manufacturing process: 1. Mix points 1, 2, 3 and 4 and granulate with purified water. 2. Dry the granules at 50 ° C. 3. Pass the granules through the appropriate grinding equipment. 4. Add point 5 and mix for three minutes; Compress in a suitable press. b) Capsule formulation: Manufacturing process: 1. Mix points 1, 2 and 3 in a suitable mixer for 30 minutes. 2. Add points 4 and S and mix for 3 minutes. 3. Fill in a capsule.

The following examples are provided to aid the understanding of the present invention, the actual scope of which is set forth in the appended claims. It is understood that the modifications can be made in the established procedures without departing from the spirit of the invention.

Experimental procedures: Experimental methods The 1H-RM spectra were recorded using a Bruker 250 Avance spectrometer. The chemical changes were reported in parts per million (ppm) on the scale d in relation to the internal trimethylsilane standard. The identification and purity were determined by analytical LC-MS performed in a system 10? using a Phenomenex Oemini Column C18 (5 | im, 30mmx2.Omm), mobile phase 5-95% acetonityl / water (containing 0.05% ammonia) for 4.5 min, maintained for 1.5min, flow ratio, lml / min, detection of diode configuration at 210-220nm. The mass spectrometer has a micromass platform LC that operates in negative ion and positive switch electro-worm modes. The analytical 3C was carried out in an Agilent 6890N GC system using a Z5-5 column (15m, 0.32mm x 0.25mm), 50 ° C maintained for 2.5 min, 50 ° C-275 ° C for 10 min, 1 ml / min, injector temperature 300 ° C, detection of flame ionization at 300 ° C. Microwave reactions were carried out in heavy wall Smith glass process vials with aluminum screw caps fixed with a silicone septum. Microwave heating was performed in a Personal Chemistry Creator EXP system at the specific temperature and for the specified duration. All reactions were carried out under a nitrogen atmosphere.

Synthesis of key intermediates Example A Methyl ester of 5-bromo-2-methylsulfanylpyrimidine-4-carboxylic acid Triethylamine (161.5 ml, 1.16 mol) was added dropwise over 25 min to a stirred suspension of 5-methylisothiourea iodide (85.0 g, 0.39 mol) and mucobromic acid (100.0 g, 0.39 mol) in water (500 ml). During this time an exotherm was observed (20 ° C to 50 ° C). The mixture was stirred for 18 h at room temperature, then made acidic at 0-5 ° C until pH 2 using 10% hydrochloric acid. The resulting precipitate was collected by filtration and dried in vacuo to give 5-bromo-2-methylsulfanyl-pyrimidine-4-carboxylic acid (71.4g) as a brown solid, which was used without further purification. Acetyl chloride (6.26 ml, 0.088 mol) was added dropwise at 0-5 ° C to methanol (100 ml). The mixture was stirred at 0-5 ° C for 5 min. 5-Bromo-2-methylsulfanylpyrimidine-4-carboxylic acid (20 g, 0.08 mol) was added in portions at 0-5 ° C then the mixture was heated under reflux for 1 h, during which time the thickened mixture dissolves, then it was cooled to room temperature and poured into saturated aqueous sodium hydrogen carbonate solution (100ml). The product was extracted into dichloromethane (3xl00ml), the extracts were washed with water (100 ml), dried (MgSO 4) and evaporated in vacuo. The residue solid was crystallized from hexane to give the methyl ester of 5-bromo-2-methylsulfanylpyrimidine-4-carboxylic acid (12.27g) as an opaque white crystalline solid, m.p. 67-70 ° C; 250 MHz 1 H-RM (CDC13) d (ppm): 2.6 (s, 3 H) (-SCH 3), 4.05 (s, 3 H) (-OCH 3), 8.7 (s, 1 H) (Ar H); m / z (M + H) + 249; purity CLAR 96%; CLAR retention time 1.58min. The substituted phenylacetylenes of the formula II are known in the literature or were prepared according to the following examples Bl and B2: Example Bl l-ethynyl-2-methylbenzene The 2-iodotoluene (81.5ml, 0.64mol) and trimethylsilylacetylene (99ml, 0.71mol) were dissolved in triethylamine (250ml). Triphenylphosphine (0.427g, 1.6 mmol), copper iodide (I) (0.3g, 1.6 mmol) and fristriphenylphosphinpalladium (II) bichloride (0.53g, 0.71mmol) were added and the mixture was heated under reflux for 18h. The mixture was cooled to room temperature and carefully added to 10% hydrochloric acid (480ml) and the product was extracted into hexane (3x200ml). The extracts were washed with 10% hydrochloric acid (200ml) and water (2x200ml) then dried (MgSO4) and evaporated in vacuo to give trimethyl- (2-methylphenyl) ethinylsilane (114.06g) as a yellow oil, which was used without additional purification. Potassium hydroxide (100g, 1.8mol) was added in 4 portions to a stirred solution of trimethyl- (2-methylphenyl) ethynylsilane (114.0 g, 0.61 mol) in methanol (400ml) at 0 ° C. The mixture was stirred at 0 ° C until the reaction was complete (by ccd 1: 1 ethyl acetate: hexane). The mixture was neutralized by the addition of 10% hydrochloric acid and the product was extracted into dichloromethane (2xl50ml). The combined extracts were dried (MgSO) and evaporated in vacuo. The residue oil was purified by short path distillation (Kugelrohr) to give l-ethynyl-2-methylbenzene (52.03g) as a clear oil, e.g. 45 ° C / 12mBar. 250 MHz 1 H-NMR (CDC13) d (ppm): 2.35 (s, 3 H) (ArCH 3), 3.2 (s, 1 H) (CH), 7.0-7.2 (m, 3 H) (3 x Ar H), 7.4 (m , 1H) (ArH); purity GC 98%, retention time GC 7.94min.

Example B2 l-chloro-2-ethynylbenzene The 2-Bromochlorobenzene (54.1ml, 0.46mol) and trimethylsilylacetylene (72ml, 0.51mol) were dissolved in triethylamine (250ml). Triphenylphosphine (0.4g, 1.5mmol), copper (I) iodide (0.3g, 1.6mmol) and bistriphenylphosphinepalladium (II) dichloride (0.5g, 0.67mmol) were added and the mixture was heated under reflux for 18h. The reaction mixture was cooled to room temperature and carefully added to 10% hydrochloric acid (480ml). The product was extracted into hexane (3x200ml), the extracts were washed with 10% hydrochloric acid (200ml) and water (2x200ml) then dried (MgSO4) and evaporated in vacuo to give (2-chlorophenylethynyl) -trimethylsilane (95.4g. ) as an orange oil, which was used without further purification. The potassium hydroxide (77.5 g, 1.38 mol) was added in 4 portions to a stirred solution of (2-chlorophenylethynyl) -trimethylsilane (95.0 g, 0.46 mol) in methanol (250 ml) at 0 ° C. The mixture was stirred at 0 ° C until the reaction was complete (by ccd 1: 1 ethyl acetate: hexane). The mixture was neutralized by the addition of 10% hydrochloric acid and the product was extracted into dichloromethane (2xl50ml). The combined extracts were dried (MgSO4) and evaporated in vacuo. The residue oil was purified by short path distillation (Kugelrohr) to give l-chloro-2-ethynylbenzene (41.23g) as a clear oil. e.g. 38 ° C / 10mBar. 250 MHz 1 H-RM (CDC13) d (ppm): 3.25 (s, 1H) (CH), 7.1-7.5 (m, 4H) (ArH); GC purity 89%, retention time GC 2.67 min.

Example Cl 2-methylsulfanyl-6- (2-methylphenyl-pyrano [3,4-d] pyrimidin-8-one) A mixture of l-ethynyl-2-methylbenzene (0.53g, 4.6mmol), 5-bromo-2-methylsulfanylpyrimidine-4-carboxylic acid methyl ester (1.0 g, 3.8mmol), triethylamine (2.5ml), triphenylphosphine ( 0.125g, 0.48mmol), copper iodide (I) (0.025g, 0.13mmol), bistriphenylphosphinepalladium (II) dichloride (0.10g, 0.14mmol) and dimethylformamide (1ml) was stirred in a Smith wall process vial Weighed and irradiated with microwaves to maintain 100 ° C for 20 min. The cooled mixture was diluted with dichloromethane (20ml) and washed with 5% hydrochloric acid (20ml), water (20ml), saturated aqueous sodium hydrogen carbonate solution (20ml) and water (20ml) then dried (MgSO4) and evaporated in vacuo. The residue oil was purified by flash column chromatography on silica using a 1: 4 mixture of hexane and dichloromethane as eluent. The appropriate fractions were combined and the solvents were removed in vacuo to give 2-methylsulfanyl-5- (2-methylphenyl) ethynylpyrimidine-4-carboxylic acid methyl ester (0.9g) as an orange oil. 250 MHz 1 H-NMR (CDC13) d (ppm): 2.45 (s, 3 H) (ArCH 3), 2.55 (s, 3 H) (-SCH 3), 3.95 (s, 3 H) (CO2CH 3), 7.05-7.25 (m, 3H) (3 x ArH), 7.45 (m, 1H) (ArH), 8.7 (s, 1H) (ArH); m / z (M + H) + 299, purity CLAR 96%, retention time HPLC 4.15 min. A mixture of 2-methylsulfanyl-5- (2-methylphenyl) ethynylpyrimidine-4-carboxylic acid methyl ester (5.0 g, 16. 8mmol) (prepared in a manner similar to that described above), 50% (v / v) trifluoroacetic acid in dichloromethane (15ml) and water (1ml) was stirred in a heavy wall Smith process vial and irradiated up to 120 ° C for 45min. The mixture was evaporated in vacuo to dryness and the residue oil was purified by flash column chromatography on silica using a 3: 7 mixture of hexane and dichloromethane as eluent. The appropriate fractions were combined and the solvents were removed in vacuo to give 2-methylsulfanyl-6- (2-methylphenyl-pyrano [3,4-d] pyrimidin-8-one (3.75g) as an orange oil 250 MHz 1H -NMR (CDC13) d (ppm): 2.45 (s, 3H) (ArCH3), 2.65 (s, 3H) (-SCH3), 6.45 (s, 1H) (= CHAr), 7.15-7.45 (m, 4H) (4 x ArH), 8.85 (s, 1) (ArH), m / z (M + H) + 285, purity CLAR 98%, retention time CLAR 3.64 min.

Example C2 6- (2-chlorophenyl) -2-methylsulfanylpyrano [3,4-d] pyrimidin-8-one A mixture of l-chloro-2-ethynylbenzene (0.63g, 4.6 mmol), 5-bromo-2-methylsulfanylpyrimidine-4-carboxylic acid methyl ester (1.0 g, 3.8 mmol), triethylamine (2.5 ml), triphenylphosphine ( 0.125g, 0.48mmol), copper iodide (I) (0.025g, 0.13mmol), bistriphenylphosphinepalladium (II) bichloride (0.10g, 0.14mmol) and dimethylformamide (1ml) was stirred in a Smith heavy wall process vial and irradiated with microwaves to maintain 100 ° C for 20min. The mixture was diluted with dichloromethane (20ml) and washed with 5% hydrochloric acid (20ml), water (20ml), saturated aqueous sodium acid carbonate solution (20ml) and water (20ml) then dried (MgSO4). and evaporated in vacuo. The residue oil was purified by flash column chromatography on silica using a 1: 4 mixture of hexane and dichloromethane as eluent. The appropriate fractions were combined and the solvents were removed in vacuo to give 5- (2-chlorophenylethynyl) -2-methylsulfanylpyrimidine-4-carboxylic acid methyl ester (0.9 g) as a yellow oil. 250 MHz ^ i-NMR (CDC13) d (ppm): 2.5 (s, 3H) (-SCH3), 3.9 (s, 3H) (-C02CH3), 7.1-7.5 (m, 4H) (ArH), 8.65 ( s, 1H) (ArH); m / z (M + H) + 319, purity CLAR 91%, retention time HPLC 4.08 min. A mixture of 5- (2-chloro-phenylethynyl) -2-methylsulfanyl-pyrimidine-4-carboxylic acid methyl ester (5.0 g, 9.4 mmol) (prepared in a manner similar to that described above), trifluoroacetic acid 50% (v / v) in dichloromethane (15ml) and water (1ml) was stirred in a heavy wall Smith process vial and irradiated up to 120 ° C for 45 min. The mixture was evaporated in vacuo to dryness and the residue oil was purified by flash column chromatography on silica using a 3: 7 mixture of hexane and dichloromethane as eluent. The appropriate fractions were combined and the solvents were removed in vacuo to give 6- (2-chlorophenyl) -2-methylsulfanylpyrano [3,4-d] pyrimidin-8-one (3.15 g) as a pale yellow oil. 250 MHz 1 H-NMR (CDCl 3) d (ppm): 2.65 (s, 3 H) (-SCH 3), 6.95 (s, 1 H) (= CHAr), 7.25-7.4 (m, 3 H) (ArH), 7.65 (m , 1H) (ArH), 8.85 (s, 1H) (ArH); m / z (M + H) + 305, CIAR purity 100%, retention time HPLC 3.66 min.

Example D Amides of 2-Methylsulfanyl-5- (2-oxo-2-o-tolyl-ethyl) -pyrimidine-4-carboxylic acid A mixture of 2-methylsulfanyl-6- (2-methylphenyl) -pyrano [3,4-d] pyrimidin-8-one (0.5g, 1.8mmol), the appropriate amine (3.6 mmol) and dichloromethane (3.5ml) are stirred in a heavy wall Smith process vial and irradiated to 120 ° C for 15 min. The mixture was diluted with dichloromethane (10ml), washed with water (2x10 ml) then dried (MgSO 4) and evaporated in vacuo to give the desired amide as dark oil in each case, which was used without further purification.

Synthesized compounds: Example E 7 -situitudo-2-methylsiolfanyl-6-o-tolyl-7H-pyrido [3,4-d] pyrimdin-8-ones A mixture of the appropriate amide (1.8 mmol) (prepared in (D)) and 10% trifluoroacetic acid (v / v) in dichloromethane (4 ml) was stirred in a heavy-wall Smith process vial and irradiated up to 120 °. C for 20min. The mixture was emptied into saturated aqueous sodium hydrogen carbonate solution (20ml) and the product was extracted into dichloromethane (2x2Oml). The combined extracts were dried (MgSO4) and evaporated in vacuo to give the desired lactam, which was used without further purification.

Synthesized compounds: Example F 2-Methanesulfonyl-7-substituted-6-o-tolyl-7H-pyrido [3,4-d] irimidin-8-ones The appropriate lactam (0.7mmol) (prepared in (E)) was dissolved in chloroform (4 ml). 3-Chloroperoxybenzoic acid (mCPBA) (1.0 mmol) was added and the mixture was stirred at room temperature for 1 h. A second portion of 3-chloroperoxybenzoic acid was added and the mixture was stirred for an additional 18h. The mixture was emptied into saturated aqueous sodium sulfite solution (25ml) and the product was extracted into dichloromethane (2xl5ml). The combined extracts were washed with 2M aqueous sodium carbonate solution (25ml), then dried (MgSO4) and evaporated in vacuo. The residue oil was purified by flash column chromatography on silica using dichloromethane as eluent. The appropriate fractions were combined and the solvent was removed in vacuo to give the desired sulfone.

Synthesized compounds: Example G 5- [2- (2-Chloro-phenyl) -2-oxo-ethyl] -2-methylsulfanyl-pyrimidine-4-carboxylic acid amides The synthesis was carried out according to the method described in (D) above using 5- (2-chloro-phenylethynyl) -2-methylsulfanyl-pyrimidine-4-carboxylic acid methyl ester and the appropriate amines.

Synthesized compounds Example H 6- (2-Chloro-phenyl) -7-substituted-2-methylsulfanyl-7H-pyrido [3,4-d] irimidin-8-ones The synthesis was carried out according to the method described in (E) above using the appropriate amine synthesized in (G).

Synthesized compounds: Example I 6- (2-Chloro-phenyl) -2-methanesulfonyl-7-substituted-7H-pyrido [3,4-d] irimidin-8-ones The synthesis was carried out according to the method described in (F) above using the appropriate lactam synthesized in (H).

Synthesized compounds Synthesis of final products A mixture of the appropriate sulfone (0.4mmol) from Example F or I, the amine designated RNH2 (0.8mmol) and N-methylpyrrolidinone (O.lml) was stirred in a Smith heavy wall process vial. Trifluoroacetic acid (0.12 mmol) was added and the mixture was irradiated to 120 ° C for 2 h. The resulting oil was diluted in methanol and applied directly for preparative HPLC purification. Fractions containing product were pooled and evaporated and optionally further purification by chromatography on silica in ethyl acetate / hexane mixtures to give the appropriate 7H-pyrido [3,4-d] pyrimidin-8-one derivatives.

Synthesized compounds: Examples 1-47: 7Í It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (9)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A compound according to formula I, characterized in that R1 is halogen, alkyl, alkoxy, halogenated alkyl or halogenated alkoxy; R 2 is hydrogen, halogen, alkyl, alkoxy, halogenated alkyl or halogenated alkoxy; R3 is alkyl that is optionally substituted one or more times with cyano, -OR, -NRR ', -C (0) NRR', -NR-C (?) -alkyl, -S (0) 2NRR ', -NR- S (O) 2-alkyl, heteroaryl, heterocyclyl, unsubstituted phenyl or phenyl substituted one or more times with halogen, alkyl, alkoxy or cyano; R4 is a) alkyl wherein the alkyl is optionally substituted one or more times with -OR or -NRR '; b) phenyl wherein the phenyl is optionally substituted one or more times with alkyl, alkoxy, heterocyclyl, -C < 0) NRR ', -NR-C (O) -alkyl, -S < ?) -alkyl, -S (0) 2NR-alkyl or -NR-S (O) 2 -alkyl, and wherein all the alkyl and alkoxy groups are optionally substituted one or more times with -0R or -NRR '; or c) heterocyclyl; R and R 'are hydrogen or alkyl; and all pharmaceutically acceptable salts thereof.
2. 2. The compounds according to claim 1, characterized in that R1 is halogen or alkyl R2 is hydrogen; R3 is alkyl that is optionally substituted one or more times with -OR, -C (0) NRR ', heteroaryl, heterocyclyl, unsubstituted phenyl or phenyl substituted one or more times with alkoxy; and R4 is a) alkyl wherein the alkyl is optionally substituted one or more times with -OR or -NRR '; b) phenyl wherein the phenyl is optionally substituted one or more times with alkyl, alkoxy, heterocyclyl, -S (0) -alkyl or -S (0) 2 NR-alkyl, and wherein all the alkyl and alkoxy groups are optionally substituted one or more times with -OR or -NRR ', - or c) heterocyclyl.
3. 3. The compounds according to any of claims 1 to 2, characterized in that R4 is a) alkyl wherein the alkyl is optionally substituted one or more times with -OR or -NRR '; or b) Eterocyclyl.
4. 4. The compounds according to any of claims 1 to 2, characterized in that R4 is phenyl wherein the phenyl is optionally substituted one or more times with alkyl, alkoxy, heterocyclyl, -S (0) -alkyl or -S (O ) 2NR-alkyl, and wherein all the alkyl and alkoxy groups are optionally substituted one or more times with -OR or -NRR '.
5. 5. The compounds according to claim 1, characterized in that they are selected from the group consisting of: 2- (2-Hydroxy-l-hydroxymethyl-ethylamino) -7-methyl-6-o-tolyl-7H-pyrido [3 , 4-d] pyrimidin-8-one; 7- (1, 5-Dimethyl-1H-pyrazol-3-ylmethyl) -2- (2-hydroxy-1-hydroxymethyl-ethylamino) -o-tolyl-7H-pyrido [3,4-d] pyrimidine-8 -one; 3- [6- (2-chloro-phenyl) -2-. { 2-hydroxy-l-hydroxymethyl-ethylamino) -8-oxo-8 H -pyrido [3,4-d] pyrimidin-7-yl] -propionamide; 7- ethyl-2- (4-morpholin-4-yl-phenylamino) -6-o-tolyl-7H-pyrido [3, -d] pyrimidin-8-one; 2- (3-Hydroxymethyl-phenylamino) -7-methyl-6-o-tolyl-7H-pyrido [3,4-d] pyrimidin-8-one; 7-Methyl-2- [4- (4-methyl-piperazin-1-yl) -phenylamino] -6-o-tolyl-7H-pyrido [3,4-d] pyrimidin-8-one; 2- . { 2- [4- (2-Hydroxy-ethylsulfamoyl) -phenylamino] -8-oxo-6-o-tolyl-8H-pyrido [3,4-d] pyrimidin-7-yl} -acetamide; N- (2-Hydroxy-ethyl) -4- (7-methyl-8-oxo-6-o-tolyl-7,8-dihydro-pyrido [3,4-d] pyrimidin-2-ylamino) -benzenesulfonamide; 2- [4- (2-Diethylamino-ethoxy) -phenylamino] -7-methyl-6-o-tolyl-7H-pyrido [3,4-d] pyrimidin-8-one; 2- [2- (3-Methansulfinyl-phenylamino) -8-oxo-¾-o-tolyl-8 H -pyrido [3,4-d] pyrimidin-7-yl] -acetamide; 2- (3-Methansulfinyl-phenylamino) -7-methyl-6-o-tolyl-7H-pyrido [3,4-d] pyrimidin-8-one; 7- (1, 5-Dimethyl-1H-pyrazol-3-ylmethyl) -2- (4-morpholin-4-yl-phenylamino) -6-o-tolyl-7H-pyrido [3,4-d] pyrimidine- 8-one; 7- (3-Hydroxy-propyl) -2- [4- (4-methyl-piperazin-1-yl) -phenylamino] -6-o-tolyl-7H-pyrido [3,4-d] pyrimidine-8- ona; N- (2-Hydroxy-ethyl) -4- [7- (3-hydroxy-propyl) -8-oxo- € -o-tolyl-7,8-dihydro-pyrido [3,4-d] pyrimidin-2 -ylamino] -benzenesulfonamide; 2- [4- (2-Diethylamino-ethoxy) -phenylamino] -7- (3-hydroxy-propyl) -6-o-tolyl-7H-pyrido [3,4-d] pyrimidin-8-one; 7- (3-Hydroxy-propyl) -2- (3-methanesulfinyl-phenylamino) -6-o-tolyl-7H-pyrido [3,4-d] pyrimidin-8-one; 7- (3-Me oxy-benzyl) -2- [4- (4-methyl-piperazin-1-yl) -phenylamino] - * 6-Q-tolyl-7H-pyrido [3,4-d] pyrimidine-8- ona; N- (2-Hydroxy-ethyl) -4- [7- (3-methoxy-benzyl) -8-oxo-6-o-tolyl-7,8-dihydro-pyrido [3,4-d] pyrimidin-2 -ylamino] -benzenesulfonamide; 2- [4- (2-Diethylamino-ethoxy) -f-enylamino] -7- (3-methoxy-benzyl) -6-o-tolyl-7H-pyrido [3,4-d] pyrimidin-8-one; 2- (3-ethansulfinyl-phenylamino) -7- (3-me oxy-benzyl) -6-o-tolyl-7H-pyrido [3,4-d] pyrimidin-8-one; 3 - [2- (3-Hydroxymethyl-phenylamino) -8-oxo-6-o-tolyl-8-H-pyrido [3,4-d] pyrimidin-7-yl] -propionamide; 3 - . { 2- [4- (2-Hydroxy-ethylsulfamoyl) -phenylamino] -d-??? - 6-β-tolyl-8H-pyrido [3,4-d] pyrimidin-7-yl} -propionamide; 3 - [2- (3-Methansulfinyl-phenylamino) -8-oxo-6-o-tolyl-8 H -pyrido [3,4-d] pyrimidin-7-yl] -propionamide; 6- (2-Chloro-phenyl) -7- (1, 5-dimethyl-1H-pyrazol-3-ylmethyl) -2- [4- (4-methyl-piperazin-1-yl) -phenylamino] -7H- pyrido [3,4-d] pyrimidin-8-one; 6- (2-Chloro-phenyl) -2- [4- (2-diethylamino-ethoxy) -phenylamino] -7- (1,5-dimethyl-1H-pyrazol-3-ylmethyl) -7H-pyrido [3, 4-d] pyrimidin-8-one; 6- (2-Chloro-phenyl) -7- (1, 5-dimethyl-lH-pyrazol-3-ylmethyl) -2- (3-methanesulfinyl-phenylamino) -7H-pyrido [3,4-d] pyrimidine- 8-one; 6- (2-Chloro-phenyl) -7- (3-hydroxy-propyl) -2- [4- (4-methyl-piperazin-1-yl) -phenylamino] -7H-pyrido. { 3, 4-d] pyrimidin-8-one; 6- (2-Chloro-phenyl) -7- (3-methoxy-benzyl) -2- [4- (4-methyl-piperazin-1-yl) -phenylamino] -7H-pyrido [3, 4-d] pyrimidin-8-one; 4- [6- (2-Chloro-f-enyl) -7- (3-methoxy-benzyl) -> 8-??? -7, β-dihydro-pyrido [3,4-d] pyrimidin-2- ilamino] -N- (2-hydroxy-ethyl) -benzenesulfonamide; 6- (2-Chloro-phenyl) -2- [4- (2-diethylamino-ethoxy) -phenylamino] -7- (3-methoxy-benzyl) -7H-pyrido [3,4-d] pyrimidine-8- ona; 6- (2-Chloro-phenyl) -2- (3-methanesulfinyl-phenylamino) -7- (3-methoxy-benzyl) -7H-pyrido [3,4-d] pyrimidin-8-one; 6- (2-Chloro-phenyl) -2- (3-hydroxymethyl-phenylamino) -7- (tetrahydro-furan-2-ylmethyl) -7H-pyrido [3,4-d] pyrimidin-8-one; 6- (2-Chloro-phenyl) -2- [4- (4-methyl-piperazin-1-yl) -phenylamino] -7- (tetrahydro-furan-2-ylmethyl) -7H-pyrido [3, 4- d] pyrimidin-8-one; 4- [6- (2-Chloro-phenyl) -8-oxo-7- (tetrahydro-furan-2-ylmethyl) -7,8-dihydro-pyrido [3,4-d] pyrimidin-2-ylamino] - N- (2-hydroxy-ethyl) -benzenesulfonamide; 6- (2-Chloro-phenyl) -2- [4- (2-diethylamino-ethoxy) -phenylamino] -7- (tetrahydro-furan-2-ylmethyl) -7H-pyrido [3,4-d] pyrimidine- 8-one; 6- (2-Chloro-phenyl) -2- (3-methanesulfinyl-phenylamino) -7- (tetrahydro-furan-2-ylmethyl) -7H-pyrido [3,4-d] pyrimidin-8-one; 2- [8 - ??? - 2- (tetrahydro-pyran-4-ylamino) -6-o-tolyl-8H-pyrido [3,4-d] pyrimidin-7-yl] -acetamide; 7-Methyl-2- (tetrahydro-pyran-4-ylamino) -6-o-tolyl-7H-pyrido. { 3, 4-d] pyrimidin-8-one; 7- (1, 5-Dimethyl-lH-pyrazol-3-ylmethyl) -2- (tetrahydro-pyran-4-ylamino) -6-o-tolyl-7H-pyrido [3,4-d] pyrimidine-8- ona; 7- (3-Hydroxy-propyl) -2- (tetrahydro-pyran-4-ylamino) -6-o-tolyl-7H-pyrido [3,4-d] pyrimidin-8-one; 7- (3-Methoxy-benzyl) -2- (tetrahydro-pyran-4-ylamino) -6-o-tolyl-7H-pyrido [3,4-d] pyrimidin-8-one; 3- [8-0x0-2- (tetrahydro-pyran-4-ylamino) -6-o-tolyl-8 H -pyrido [3,4-d] pyrimidin-7-yl] -pro-ionamide; 2- [6- (2-Chloro-phenyl) -8-oxo-2- (tetrahydro-pyran-4-ylamino) -8 H -pyrido [3,4-d] pyrimidin-7-yl] -acetamide; 6- (2-Chloro-phenyl) -7- (1, 5-dimethyl-lH-pyrazol-3-ylmethyl) -2- (tetrahydro-pyran-4-ylamino) -7H-pyrido [3,4-d] pyrimidin-8-one; 6- (2-Chloro-phenyl) -7- (3-hydroxy-propyl) -2- (tetrahydro-pyran-4-ylamino) -7H-pyrido [3,4-d] pyrimidin-8-one; 6- (2-Chloro-phenyl) -7- (3-methoxy-benzyl) -2- (tetrahydro-pyran-4-ylamino) -7H-pyrido [3,4-d] pyrimidin-8-one; and 6- (2-Chloro-phenyl) -7- (tetrahydro-furan-2-ylmethyl) -2- (tetrahydro-pyran-4-ylamino) -7H-pyrido [3,4-d] pyrimidin-8-one .
6. 6. A process for the manufacture of the compounds of the formula I according to claim 1, characterized in that it comprises the steps of (a) reacting a compound of the formula VIII formula VIII, wherein R1, R2 and R3 have the meaning given above by formula I according to claim 1, and L is a starting group selected from allylsulphonyl or alkylsulfinyl, with a compound of the formula Villa R4-NH2 formula Villa, wherein R has the meaning given above by formula I according to claim 1, to give the respective compound of formula I, formula I, wherein R1, R2, R3 and R4 have the meaning given above by formula I according to claim 1, (b) the compound of formula I is isolated from the reaction mixture, and (c) if It is desired to convert to a pharmaceutically acceptable salt.
7. 7. A pharmaceutical composition, characterized in that it contains one or more compounds according to any of claims 1 to 5 together with pharmaceutically acceptable adjuvants.
8. 8. The pharmaceutical composition according to claim 7, characterized in that it is for the treatment of cancer
9. 9. The use of a compound according to any of claims 1 to 5 for the manufacture of corresponding medicaments for the treatment of cancer.