EP2004651A2 - Novel cyclobutyl compounds as kinase inhibitors - Google Patents

Abstract

The invention relates to compounds of formula I, the production and use thereof for the production of a medicament for treatment of diseases, in particular, tumours and/or diseases in which protein kinases play a part in the origin or course thereof.

Description

 Novel cyclobutyl compounds as kinase inhibitors

The invention relates to compounds of the formula I ₁

wherein

R ¹ H ₁ Hal, OH, CN, NO ₂ , NH ₂ , A, Ar ₁

R ² , R ^{2 are} each independently H, A having 1, 2, 3, 4, 5 or 6 C atoms, wherein R ² and R ² together with the N-atom to which they are linked, a saturated or unsaturated mononuclear heterocycle with no or one further N, O or S atom can form,

A unbranched, branched or cyclic alkyl with 1, 2, 3,

4, 5, or 6 C atoms, wherein one or two CH groups are represented by N, wherein furthermore one or two CH ₂ groups are represented by an O, N or S atom and / or by an NH, NA, CONH , Si (CHs) ₂ , NHCO, SO ₂ , -CH = CH- or -C≡C- group and / or also 1-7 H-atoms may be replaced by Hal, and in which one or two CH ₃ groups by NH, NH _2, NAH, NA _2, NHCOOA, NHCONHA, Si _{(CH3) 3,} CN, or Ar may be substituted, Ar is a mono- or bicyclic aromatic homo- or heterocycle having 1 to 4 N, O and / or S atoms and 5 to 12 Framework atoms which are unsubstituted or mono-, di- or trisubstituted by carbonyl oxygen, Hal ₁ A, OH, OA, NH ₂ , NHA, NA ₂ , NO ₂ , CN, OCN, SCN ₁ COOH, COOA, CONH ₂ , CONHA, CONA ₂ , NHCOA, NHCOOA ₁ NHCONH ₂ , NHSO ₂ A ₁ CHO, COA, SO ₂ CH ₃ and / or SO ₂ NH ₂ may be substituted,

Hal is F, Cl, Br or I and n is 0, 1, 2 or 3, 10 and their pharmaceutically acceptable salts, derivatives, solvates and

Stereoisomers, including mixtures thereof in all ratios.

It has been found that the compounds of the formula I can inhibit, regulate and / or modulate the signal transduction mediated by protein kinases. Thus, medicaments and pharmaceutical compositions according to the invention can be used effectively for the treatment of diseases which are caused, mediated and / or propagated by protein kinases and / or by kinase-mediated signal transduction. Thus, the compounds of the invention are useful in the treatment and prophylaxis of angiogenesis, cancer, tumorigenesis, growth and spread, arteriosclerosis, ocular disorders such as age-related macular degeneration, choroidal neovascularization and diabetic retinopathy, inflammatory diseases, arthritis, thrombosis, fibrosis, Glomerulonephritis, neurodegeneration, psoriasis, restenosis, wound healing, graft rejection, metabolic and immune system disorders, including autoimmune diseases.

2Q gene, cirrhosis, diabetes and blood vessel diseases, as well

Instability and permeability (permeability) and the like in mammals. Other protein kinase inhibitors are known, for example, from WO 97/28161 or WO 02/92599. 5 Cancer is a disease whose causes include abnormal signal transduction. In particular, deregulated signal transduction via tyrosine kinases plays a central role in the growth and spread of cancer (Blume-Jensen, P. and T. Hunter, Nature 411: 355-365, 2001, Hanahan D. and RA Weinberg, Cell 100: 57 -70, 2000).

Tyrosine kinases, and in particular receptor tyrosine kinases, as well as the growth factors that bind to them, may thus be involved in deregulated apoptosis, tissue invasion, metastasis and, more generally, cancer-causing signal transduction mechanisms.

As already mentioned, one of the major mechanisms by which cell regulation is effected is the transduction of extracellular signals across the membrane, which in turn modulate biochemical pathways in the cell. Protein phosphorylation is a process by which intracellular signals are propagated from molecule to molecule, ultimately resulting in a cellular response. These signal transduction cascades are highly regulated and often overlap, as evidenced by the presence of many protein kinases as well as phosphatases. Phosphorylation of proteins occurs predominantly with serine, threonine or tyrosine residues, and protein kinases were therefore determined by their specificity of the phosphorylation site, i. H. serine / threonine kinases and tyrosine kinases. Since phosphorylation is a very widespread process in cells, and because cell phenotypes are largely influenced by the activity of these pathways, it is presently believed that a large number of disease states and / or diseases are due to either aberrant activation or functional mutations in attributed to the molecular components of kinase cascades. Consequently, considerable attention has been paid to the characterization of these proteins and compounds capable of modulating their activity (see review article: Weinstein-Oppenheimer et al., Pharm. & Therap. 88: 229-279, 2000).

Various possibilities for the inhibition, regulation and modulation of protein kinases include, for example, the provision of anti- - A -

bodies, antisense ribozymes and inhibitors. In oncology research in particular tyrosine kinases are promising targets. Thus, numerous synthetic small-molecule tyrosine kinase inhibitors for the treatment of cancer in clinical development such as Iressa ^® or Glivec ^®. However, there are still numerous problems to be solved, such as side effects, dosage, tumor resistance, tumor specificity and patient selection.

Tyrosine kinases are a class of enzymes that catalyze the transfer of the terminal phosphate of adenosine triphosphate to tyrosine residues on protein substrates. It is believed that tyrosine kinases play an important role in signal transduction in different cell functions via substrate phosphorylation. Although the exact mechanisms of signal transduction are still unclear, tyrosine kinases have been shown to be important factors in cell proliferation, carcinogenesis and cell differentiation.

The tyrosine kinases can be classified into receptor tyrosine kinases and cytosolic tyrosine kinases. The receptor tyrosine kinases have an extracellular part, a transmembrane part and an intracellular part, while the cytosolic tyrosine kinases are exclusively intracellular.

The receptor tyrosine kinases consist of a multiplicity of transmembrane receptors with different biological activity. Thus, approximately 20 different subfamilies of receptor tyrosine kinases have been identified. A tyrosine kinase subfamily designated EGFR or HER subfamily consists of EGFR, HER2, HER3 and HER4. The ligands of this receptor subfamily include epithelial growth factor (EGF), tissue growth factor (TGF-α and β),

Amphiregulin, HB-EGF, betacellulin and heregulin. The insulin subfamily, which includes InsR, IGF-IR, and IR-R, represents another The PDGF subfamily includes the PDGF-α and -ß receptor, CSFIR, c-kit and FLK-II. There is also the FLK family, which consists of the kinase domain domain receptor

(KDR) or VEGFR-2, fetal liver kinase-1 (FLK-1), fetal liver kinase-4 (FLK-4) and fms-tyrosine kinase-1 (flt-1) or VEGFR-1. The PDGF and FLK family are usually grouped together because of the similarities between the two groups in the group of split kinase domains receptor tyrosine kinases (Laird, AD and JM Cherrington, Expert, Opin. Investig., Drugs 12 (1): 51-). 64, 2003). For a detailed discussion of the receptor tyrosine kinases, see the work of Plowman et al., DN & P 7 (6): 334-339, 1994). TIE2 and its ligands angiopoietin 1 and 2 also belong to the receptor tyrosine kinases. More and more homologues of these ligands are now found, the effect of which has not yet been clearly demonstrated in detail. TIE1 is known as a homologue of TIE2. The TIE receptor tyrosine kinases are selectively expressed on endothelial cells and find their function in processes of angiogenesis and maturation of the

Blood vessels. This allows them especially in diseases of the

Vascular system and in pathologies in which vessels are used or even reshaped, a valuable goal. In addition to preventing neovascularization and maturation, stimulation of neovascularization can also be a valuable target for drugs.

Another receptor tyrosine kinase is MET. Their role in human oncogenesis, as well as the possibility of inhibiting HGF (hepatocyte growth factor) -dependent Met activation, is described by S. Berthou et al. (Oncogene 23 (31): 5387-5393, 2004).

The cytosolic tyrosine kinases also consist of a variety of subfamilies including SRC, FRK, BTK, CSK, ABL, ZAP70,

FES / FPS, FAK, JAK, ACK and LIMK. Each of these subfamilies is further subdivided into different subgroups. For example, the src

Subfamily is one of the largest subfamilies. It includes SRC, YES, FYN, LYN, LCK, BLK, HCK, FGR and YRK. The SRC enzyme subfamily has been implicated in oncogenesis. For a more detailed discussion of cytosolic tyrosine kinases, see the work of Bolen,

Oncogene, 8: 2025-2031, 1993.

5

Both the receptor tyrosine kinases and the cytosolic tyrosine kinases are involved in cell signaling pathways leading to the already mentioned conditions of affliction such as cancer, psoriasis and hyperimmune reactions.

10

The other large group of protein kinases, the serine / threonine kinases, include the checkpoint kinases CHK1 and CHK2 as well as SGK (human serum and glucocorticoid dependent kinase), of which the

_{* 5} subtypes SGK-1, -2 and -3 are known.

The invention was based on the object of finding novel compounds with advantageous therapeutic properties that can be used for the preparation of medicaments. 0

Thus, the identification and provision of chemical compounds that inhibit, regulate and / or modulate the signal transduction of various kinases is desirable and therefore an object of the present invention. 5

The compounds of the formula I according to the invention are now surprisingly characterized by three properties:

2 _Q 1. They are able to inhibit a variety of protein kinases, rather than acting specifically only on a particular kinase. This spectrum activity is of great importance in the treatment of tumor diseases, since tumor cells during their proliferation typically resort to alternative signal transduction cascades, if a certain case

35 kade is blocked. 2. They do not inhibit InsR or only to a limited extent. Substances that inhibit the IGF1 R often also inhibit the InsR because these two receptors are structurally related. However, a comparably strong inhibition of InsR is usually not desirable, as this can lead to side effects (eg onset of diabetes).

The compound known from WO 02/092599 (Ex. 64) trans-5- (3-benzyloxyphenyl) -7- (3-pyrrolidin-1-ylmethyl-cyclobutyl) -7H-pyrrolo [2,3-d] For example, pyrimidin-4-ylamine, which was later found to be particularly effective under the code designation NVP-0 ADW742 (Mitsiades et al. Cancer Cell 5: 221-230, 2004), has only about 5-fold higher selectivity for the IGF1 R in comparison with the InsR (IC ₅₀ (ELISA) IGFR = 0.165 uM, InsR = 0.76), where this ratio is as the compounds of this invention, ₅ about at 10th

3. They have an unexpectedly high solubility in aqueous, even as free bases, compared to prior art compounds

Buffer systems. High solubility under physiological conditions and associated high bioavailability are of great importance for a drug.

Major cancers that may be treated using a compound of the invention include breast cancer, prostate cancer, colorectal cancer, brain cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma, renal cell carcinoma, endometrial carcinoma, squamous cell carcinoma, bladder cancer, gastric cancer, pancreatic cancer, Liver cancer, chronic leukemia and acute leukemia.

The present invention thus relates to the use of the compounds of the formula I for the prevention and / or treatment of

Disorders related to unregulated or impaired kinase 5

Activity. In addition, the compounds of the present invention may be used to treat certain existing cancer chemotherapies and

Irradiations to achieve additive or synergistic effects and / or to increase the efficacy of certain existing cancer chemotherapies and

Restore radiation.

Description of the invention

10

It has been found that the compounds of formula I and their salts possess very valuable pharmacological properties with good compatibility. In particular, it has been found that the subject matter of the invention

In the case of good solubility, compounds of the formula I are effective kinase inhibitors, with a pronounced spectrum acridity.

In general, all residues that occur multiple times may be the same or different, i. are independent of each other. Above and below, the radicals or parameters have the meanings given for the formula I, unless expressly stated otherwise. 5 Accordingly, the invention relates in particular to those compounds of the formula I in which at least one of the radicals mentioned has one of the preferred meanings given below.

Q Hal denotes fluorine, chlorine, bromine or iodine, in particular fluorine or chlorine.

A is alkyl, is unbranched (linear), branched or cyclic, has 1, 2, 3, 4, 5 or 6 carbon atoms and may be substituted by Ar.

5 For example, A is methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1, 1-, 1, 2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1, 2,

3- or 4-methylpentyl, 1,1-, 1, 2-, 1, 3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1 methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2 or 1,2,2-trimethylpropyl.

Furthermore, A preferably denotes alkyl, in which one or two CH groups are protected by N, where furthermore one or two CH ₂ groups are represented by O, N or S atoms and / or by NH, NA, SO ₂ , CONH, Si ( CH ₃ ) ₂ , NHCO, -C≡C or -CH = CH groups and / or 1-7 H atoms may be replaced by F and / or Cl, such as methyl, ethyl, propyl, isopropyl, butyl , Isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethyl, 1, 1

Difluoromethyl, 1, 1, 1 trifluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy, and wherein one or two CH ₃ groups by OH, NH ₂ , NAH, Si (CH ₃ ) ₃ , NA ₂ or CN may be replaced.

Cycloalkyl is preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

Ar is, for example, unsubstituted phenyl, naphthyl or biphenyl, furthermore preferably, for example, by A ₁ fluorine, chlorine, bromine, iodine, hydroxyl, methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, nitro, cyano, formyl, acetyl, propionyl, trifluoromethyl, Amino, methylamino, ethylamino, dimethylamino, diethylamino, benzyloxy, methanesulfonyl, sulfonamido, methylsulfonamido, ethylsulfonamido, propylsulfonamido, butylsulfonamido, dimethylsulfonamido, phenylsulfonamido, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl mono-, di- or trisubstituted phenyl,

Naphthyl or biphenyl. Ar furthermore denotes phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-, m- or p- (N-methylamino) -phenyl, o-, m- or p- (N-methylaminocarbonyl) -phenyl, o-, m- or p-acetamidophenyl, o-, m- or p-methoxyphenyl, o-, m - or p-ethoxyphenyl, o-, m- or p-ethoxycarbonylphenyl, o-, m- or p- (N, N-dimethylamino) -phenyl, o-, m- or p- (N, N-dimethylaminocarbonyl) - phenyl, o-, m- or p- (N-ethylamino) -phenyl, o-, m- or p- (N, N-diethylamino) -phenyl, o-, m- or p-

Fluorophenyl, o-, m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- or p- (methylsulfonamido) -phenyl, o-, m- or p- (methylsulfonyl) -phenyl, more preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2, 6-, 3,4- or 3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2,4- or 2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl, 3-amino-4-chloro, 2-amino-3-chloro, 2-amino-4-chloro , 2-amino-5-chloro- or 2-amino-6-chlorophenyl, 2-nitro-4-N, N-dimethylamino or 3-nitro-4-N, N-dimethylaminophenyl, 2,3- Diamino-phenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl, 4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl, 2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl, 3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl, 3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl, 3-chloro-4-acetamidophenyl or 2, 5-dimethyl-4-c chlorophenyl, (4-methoxyphenyl) methyl, (3-methoxyphenyl) methyl, (4-methoxyphenyl) ethyl, (3-methoxyphenyl) ethyl.

Ar furthermore preferably denotes unsubstituted or mono-, di- or trihydric eg by carbonyl oxygen, F, Cl, Br, methyl, ethyl, propyl, phenyl, benzyl, -CH ₂ -cyclohexyl, hydroxyl, methoxy, ethoxy, amino, methylamino , Dimethylamino, nitro, cyano, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, acetamino,

Ureido, methylsulfonylamino, formyl, acetyl, aminosulfonyl and / or methyl thylsulfonyl-substituted 2-, 3- or 4-phenyl, 2-, 3- or 4-phenyl-methyl, 2-, 3- or 4-phenyl-ethyl, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-, 2, A- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 3- or 4-pyridylmethyl, 2-, 3- or A-pyridyl-ethyl, 2-, 4-, 5- or 6-pyrimidinyl, 2-, 3-, 5-, or 6-pyrazine-1 or 4-yl, more preferably 1, 2,3 -TriazoM-, -A- or -5-yl, 1, 2,4-triazoM-, -3- or 5-yl, 1- or 5-tetrazolyl, 1, 2, 3-oxadiazole-4 or -5 -yl, 1, 2,4-oxadiazol-3 or -5-yl, 1, 3,4-thiadiazol-2 or -5-yl, 1,2,4-thiadiazole-3 or -5 -yl, 1, 2,3-thiadiazol-4 or -5-yl, 3- or 4-pyridazinyl, 1, 2, 3, 4, 5,

6- or 7-indolyl, 2-, 3-, 4- or 5-isoindolyl, 2-, 3-, 4-, 5- or 6- indazolyl, 3-, 4-, 5- or 6-benzotriazolyl, 2 -, 6, or 8-purinyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5- , 6- or 7-benzoxazolyl, 4-, 5-, 6- or 7-benzoxazolyl-2-one, 3-, 4-, 5-, 6- or 7- benzisoxazolyl, 2-, 4-, 5-, 6- or 7-benzothiazolyl, 2-, 4-, 5-, 6- or 7- benzisothiazolyl, 4-, 5-, 6- or 7-benz-2,1,3-oxadiazolyl, 1-, 3-, 4-, 5-, 6-,

7- or 8-isoquinolinyl, 3-, A-, 5-, 6-, 7- or 8-quinolinyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6- Quinoxalinyl, A, 5-, or 6-phthalazinyl, 2-,

3, 5, 6, 7 or 8-2H-benzo [1, 4] oxazinyl, more preferably 1, 3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2, 1,3-benzothiadiazol-4- or -5-yl, 2,1,3-benzoxadiazol-5-yl or benzofuran-4, -5, -6, or -7-yl.

The heterocyclic radicals may also be partially or completely hydrogenated and are e.g. also 2,3-dihydro-2-, -3-, -A- or -5-furyl, 2,5-dihydro-2-, -3-, -A- or -5-furyl, tetrahydro-2-or 3-furyl, 1,3-dioxolan-4-yl, tetrahydro-2- or 3-thienyl, 2,3-dihydro-1-, 2-, -3-, -A- or -5-pyrrolyl , 2,5-dihydro-1-, 2-, -3-, -A- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-1-, -2- or -4 -imidazolyl, 2,3-dihydro-1-, 2-, -3-, -A- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-1 -, -2-, -3- or -4-pyridyl, 1, 2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5- or -6-pyridyl, 2 -, 3

, 5- or 6-piperidine-1 or 4-yl, 2-, 3- or 4-morpholinyl, tetrahydro-2-, -

3- or 4-pyranyl, 1, 4-dioxanyl, 1, 3-dioxane-2, -A- or -5-yl, hexahydroxy 1-, 3- or 4-pyridazinyl, hexahydro-1, -2-, -4- or -5-pyrimidinyl, 1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro- 1-, 2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1, 2,3,4-tetrahydro-1 -, - 2 -, - 3, -A, 5, 6, 7 or 8 isoquinolyl,

2-, 3-, 5-, 6-, 7- or 8-3,4-dihydro-2H-benzo [1,4] oxazinyl, more preferably 2,3-methylenedioxyphenyl, 3,4-methylenedioxyphenyl, 2,3

Ethylenedioxyphenyl, 3,4-ethylenedioxyphenyl, 3,4- (difluoromethylenedioxy) -phenyl, 2,3-dihydrobenzofuran-5- or 6-yl, 2,3- (2-oxomethylenedioxy) -phenyl or else 3,4- Dihydro-2H-1, 5-benzodioxepin-6 or -7-yl, furthermore 10 preferably 2,3-dihydrobenzofuranyl, 2,3-dihydro-benzo [1,4] dioxin-4, -5 or -6- yl or 2,3-dihydro-2-oxofuranyl.

The term "substituted" preferably refers _{* c} tion with the abovementioned substituents, where a plurality of different degrees of substitution are possible, unless otherwise indicated to the substitution.

According to the invention, all physiologically acceptable salts,

Derivatives, solvates and stereoisomers of these compounds, including

20 their mixtures in all proportions.

The compounds of formula I may have one or more chiral centers. Accordingly, they can occur in various enantiomeric forms and be in racemic or optically active form. The invention therefore also relates to the optically active forms (stereoisomers), the enantiomers, the racemates, the diastereomers and hydrates and solvates of these compounds.

30

Since the pharmaceutical activity of the racemates or stereoisomers of the compounds of the invention may differ, it may be desirable to use the enantiomers. In these

Cases may be the end product or even the intermediates in

35 enantiomeric compounds, by chemical known in the art or physical measures, separated or already used as such in the synthesis.

In the case of racemic amines diastereomers are formed from the mixture by reaction with an optically active release agent. Suitable release agents are e.g. optically active acids such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-benzenesulfonylproline) or the various optically active camphorsulfonic acids. Also advantageous is chromatographic enantiomer separation using an optically active resolving agent (e.g., dinitrobenzoylphenylglycine, cellulose triacetate or other derivatives of carbohydrates or silica gel-fixed chirally derivatized methacrylate polymers). Suitable eluents for this purpose are aqueous or alcoholic solvent mixtures, such as e.g. Hexane / isopropanol / acetonitrile, e.g. in the ratio 82: 15: 3.

An elegant method for cleaving racemates with ester groups

(e.g., acetyl ester) represents the use of enzymes, particularly esterases.

A preferred group of compounds of the formula I corresponds to the formula II

wherein R ¹ , R ² and n have the meaning given for the formula I and their pharmaceutically acceptable salts, derivatives, solvates and

Stereoisomers, including mixtures thereof in all ratios. 5

Further preferred subgroups of compounds of the formulas I and II can be expressed by the following sub-formulas A to E, which correspond to the formulas I and II, respectively, wherein, however, 10 in the case of the partial formula A

R ¹ A, unsubstituted or by A, fluorine, chlorine, bromine, iodine,

Hydroxy, methoxy, ethoxy, propoxy, butoxy, pentybxy, he-,. _C xyloxy, nitro, cyano, formyl, acetyl, propionyl, trifluoromethyl,

Amino, methylamino, ethylamino, dimethylamino, diethylamine, benzyloxy, methanesulfonyl, sulfonamido, methylsulfonamido, ethylsulfonamido, propylsulfonamido, butylsulfonamido, dimethylsulfonamido, phenylsulfonamido, carboxy,

20

Methoxycarbonyl, ethoxycarbonyl or aminocarbonyl mono- or disubstituted phenyl, indolyl, indazolyl, benzotriazolyl, benzoxazolyl-2-one, furyl, thienyl, thiazolyl, pyridyl or pyrimidinyl, 25 and R ² and n have the meaning given for the formula I .

in the partial formula B 2Q R ¹ A, unsubstituted or by A, fluorine, chlorine, bromine, iodine,

Hydroxy, methoxy, ethoxy, propoxy, butoxy, pentybxy, hexyloxy, nitro, cyano, formyl, acetyl, propionyl, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamine, benzyloxy, methanesulfonyl, sulfonamido, methylsulfo

35 namido, ethylsulfonamido, propylsulfonamido, butylsulfonamido, dimethylsulfonamido, phenylsulfonamido, carboxy, Methoxycarbonyl, ethoxycarbonyl or aminocarbonyl mono- or disubstituted phenyl, indolyl, indazolyl, benzotriazolyl, benzoxazolyl-2-one, furyl, thienyl, thiazolyl, pyridyl or pyrimidine, R ² , R ^{2 are} H or together form a butylene unit and n 1 means

in sub-formula C

R ¹ A, unsubstituted or by A, fluorine, chlorine, bromine, iodine, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentybxy, hexyloxy, nitro, cyano, formyl, acetyl, propionyl, trifluoromethyl, amino, methylamino, ethylamino , Dimethylamino, diethylamine, benzyloxy, methanesulfonyl, sulfonamido, methylsulfonamido, ethylsulfonamido, propylsulfonamido, butylsulfonamido, dimethylsulfonamido, phenylsulfonamido, carboxy, methoxycarbonyl, ethoxycarbonyl or aminocarbonyl mono- or disubstituted phenyl, indolyl, indazolyl, benzotriazolyl, benzoxazolyl- 2-one, furyl, thienyl, thiazolyl, pyridyl or pyrimidine, R ² , R ^{2 are} each independently H or straight or branched alkyl having 1, 2, 3 or 4 C atoms, wherein R ² and R ² together form an ethylene, propylene, butylene or pentylene unit and n is 1,

in the sub-formula D

R 1

Propan-1-olyl, propen-1-olyl, propyn-1-olyl, unsubstituted or by hydroxy, amino, fluorine, butoxy, acetamido, t Butoxy-carbonylamino, nitro, benzyl, (dimethylphenylsilanyl) methoxy, dimethylphenylsilanyloxy, methanesulphonyl, sulphonamido, methanesulphonamido, methyl, 2-propyl, trifluoromethyl, trifluoromethoxy, trifluoromethanesulphonic acid, benzylamino, N- Benzyl-propane-1,3-diamino, mono- or disubstituted phenyl, indolyl, indazolyl, benzofuranyl, benzotriazolyl, benzoimidazolyl-2-one, benzoxazolyl-2-one, furyl, thienyl, thiazolyl, pyridyl or pyrimidinyl, and R ² and n have the meaning given for the formula I,

in the partial formula ER ¹ propan-1-olyl, propen-1-olyl, propyn-1-olyl, unsubstituted or by hydroxy, amino, fluoro, butoxy, acetamido, t-butoxycarbonylamino, nitro, benzyl, (dimethyl-phenyl - silanyl) -methoxy, dimethyl-phenyl-silanyloxy, methanesulfonyl,

Sulfonamido, methanesulfonamido, methyl, 2-propyl, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonic acid, benzylamino, N-benzyl-propane-1,3-diamino, mono- or disubstituted phenyl, indolyl, indazolyl, benzofuranyl, benzotriazolyl, Benzoimidazolyl-2-one, benzoxazolyl-2-one, furyl, thienyl, thiazolyl, pyridyl or pyrimidinyl,

R ² , R ^{2 are} H or together form a butylene unit and n is 1

and their pharmaceutically acceptable salts, derivatives, solvates and stereoisomers, including mixtures thereof in all ratios.

Particular preference is given to sub-formulas A to E of the compounds of the formula II. Very particular preference is given to compounds selected from the group consisting of in Table 1 listed compounds and their pharmaceutically acceptable salts, derivatives, solvates and stereoisomers, including mixtures thereof in all proportions.

The melting points, solubility values and

IC50 values refer, if no anion is given, to the free base present in the trans configuration. If a compound can not be obtained in crystalline form, the material properties are given at room temperature. The solubility data refer to the conditions given in Example C. The IC50 values given were obtained by the flashplate method (see Examples B) unless otherwise stated (ELISA, see Examples B).

Table 1

Löslich¬

Schmelz¬

IC50 (μM) speed point [ ⁰ C] [μg / ml]

ng)

74.5

IGF = 0.13 (0.57 ELISA) InsR = 5.5 (ELISA) 83-84 (TFA) FAK = 14 (ELISA)

G)

42 oil (TFA)

ng)

Ci;

54 FAK = (28 ELISA)

oil

ISA)

By pharmaceutically or physiologically harmless derivatives is meant e.g. Salts of the compounds of the invention, as well as so-called prodrug compounds. Such derivatives are known in the art. An overview of physiologically acceptable derivatives is provided by Burger's Medicinal Chemistry & Drug Discovery, 5th Edition, VoI

1: Principles and Practice. By prodrug compounds is meant by e.g. Alkyl or acyl groups, sugars or oligopeptides modified compounds of formula I, which are rapidly cleaved or released in the organism to the active compounds of the invention.

These also include biodegradable polymer derivatives of the compounds of the invention, such as e.g. in Int. J. Pharm. 115: 61-67, 1995.

Suitable acid addition salts are inorganic or organic salts of all physiologically or pharmacologically acceptable acids, for example halides, in particular hydrochlorides or hydrobromides, lactates, sulfates, citrates, tartrates, maleates, fumarates, oxalates,

Acetates, phosphates, methyl sulfonates or p-toluenesulfonates.

Solvates of the compounds of the formula I mean additions of inert solvent molecules to the compounds of the formula I which form on account of their mutual attraction. Solvates are, for example, hydrates, such as monohydrates or dihydrates or alkoxides, i. Addition compounds with alcohols such as methanol or ethanol.

The term "effective amount" means the amount of a drug or pharmaceutical agent that elicits a biological or medical response in a tissue, system, animal or human, such as is sought or sought by a researcher or physician. In addition, the term "therapeutically effective amount" means an amount that, as compared to a corresponding subject who has not received that amount, results in: improved healing, healing, prevention or elimination of one

Illness, a medical condition, a medical condition, a disease, a disorder or prevention of side effects or even the reduction of the progression of a disease, a disease or a disorder. The term "therapeutically effective amount" also includes the amounts effective to increase normal physiological function.

The invention also provides mixtures of the compounds of the formula I according to the invention, e.g. Mixtures of two diastereomers e.g. in the ratio 1: 1, 1: 2, 1: 3, 1: 4, 1: 5, 1:10, 1: 100 or 1: 1000. These are particularly preferably mixtures of stereoisomeric compounds.

Furthermore, the present invention relates to a process for the preparation of compounds of formula I and their physiologically acceptable salts, derivatives, solvates and stereoisomers, characterized in that in a first step, a compound of formula VI

with a compound of formula V

V

condensed to a compound of formula IV

IV,

the further with a desired radical R ¹ to a compound of formula III

which is finally reacted with NH ₃ to give a compound of formula I.

Finally, a base or acid of the formula I can be converted into one of its salts.

The starting materials for the process according to the invention are generally known. If they are new, they can be prepared by methods known per se, as described in the literature (eg in standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg Thieme Verlag, Stuttgart, Organic Reactions, John Wiley & Sons, Inc.). , New York) are described.

The compounds of the formula I and also the starting materials for their preparation are prepared by methods known per se, as described in the literature (eg in standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg Thieme Verlag, Stuttgart, Organic Reactions, John Wiley & Sons, Inc., New York), under reaction conditions known and appropriate for the aforementioned reactions. One can also make use of known per se, not mentioned here variants. The reactions described above are usually carried out in an inert solvent. Suitable inert solvents for the reactions described above are, for example, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1, 2-dichloroethane, carbon tetrachloride, chloroform or dichloromethane; Ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; Glycol ethers, such as ethylene glycol monomethyl or monoethyl

10 ether (methyl glycol or ethyl glycol), ethylene glycol dimethyl ether (diglyme); Ketones such as acetone or butanone; Amides such as acetamide, N-methylpyrrolidone (NMP), dimethylacetamide or dimethylformamide (DMF); Nitrites such as acetonitrile; Sulfoxides such as dimethylsulfoxide (DMSO); disulphide

^ ₅ fabric; Carboxylic acids such as formic acid or acetic acid; Nitro compounds such as nitromethane or nitrobenzene; Esters such as ethyl acetate or mixtures of said solvents. Preference is given to sulfoxides such as dimethyl sulfoxide (DMSO).

20

The amount of the solvent is not critical, preferably 5 g to 500 g of solvent per g of the product to be formed may be added.

In general, working at a pressure of 1 to 200 bar, preferably 25 but at atmospheric pressure.

The reaction temperature for the reactions described above is between about -10 and 200 ^° C., depending on the conditions used.

2Q normally between -5 and 100 ^° C., preferably between 0 and 80 ^° C.

The reaction time is between a few minutes and several days, preferably in the range of several hours, depending on the conditions used. 35 The reaction may also be carried out in a heterogeneous phase, preferably using an aqueous phase and a benzene or toluene phase. Here is a phase transfer catalyst is used, such as tetrabutylammonium and optionally an acylation catalyst such as dimethylaminopyridine.

An obtained base of the formula I can be converted with an acid into the associated acid addition salt. Suitable acids for this reaction are those which yield physiologically acceptable salts. Thus, inorganic acids can be used, e.g. Sulfuric acid, hydrohalic acids such as hydrochloric acid or hydrobromic acid, phosphoric acids such as orthophosphoric acid, nitric acid, sulfamic acid, other organic acids, in particular aliphatic, alicyclic, araliphatic, aromatic or heterocyclic mono- or polybasic carboxylic, sulfonic or sulfuric acids, such as formic acid, Acetic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid,

Pimelic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, benzoic acid, salicylic acid, 2-phenylpropionic acid, citric acid,

Gluconic acid, ascorbic acid, nicotinic acid, isonicotinic acid, methane or ethanesulfonic acid, ethanedisulfonic acid, 2-hydroxyethanesulfonic acid; Benzenesulfonic acid, p-toluenesulfonic acid, naphthalene mono- and di-sulfonic acids, laurylsulfuric acid.

If desired, the free bases of the formula I can be liberated from their salts by treatment with strong bases such as sodium or potassium hydroxide, sodium or potassium carbonate, provided that no further acidic groups are present in the molecule.

Compounds of the formula I can furthermore be obtained by liberating them from one of their functional derivatives by treatment with a solvolyzing or hydrogenolysing agent. Preferred starting materials for the solvolysis or hydrogenolysis are those which otherwise correspond to the formula I but correspondingly protected instead of one or more free amino and / or hydroxyl groups

Amino and / or hydroxyl groups, preferably those which instead of an H atom, which is connected to an N atom, carry an amino-protecting group, especially those which instead of an HN group, an R'-N group in which R ^{1 represents} an amino-protecting group, and / or those which, instead of the H atom of a hydroxy group, have a hydroxyl group

10 carry a protective group, e.g. those which correspond to the formula I, but instead of a group -COOH carry a group -COOR ", in which

R "means a hydroxy protecting group.

Preferred starting materials are also the Oxadiazolderivate included in the

^ ₅ corresponding amidino compounds can be converted.

There may also be several - same or different - protected amino and / or hydroxy groups present in the molecule of the starting material. If the existing protective groups are different from each other,

In many cases they can be selectively split off.

The term "amino protecting group" is well known and refers to groups that are capable of protecting an amino group from chemical conversion.

Protect (block) but which are easily removable after the desired chemical reaction has been carried out at other points of the molecule. Typical of such groups are in particular unsubstituted or substituted acyl, aryl, aralkoxymethyl

_O0 or aralkyl groups. Moreover, because the amino protecting groups are removed after the desired reaction (or reaction sequence), their type and size is not critical; however, preference is given to those having 1-20, in particular 1-8 C atoms. The term "acyl group" is to be understood in the broadest sense in the context of the present process. He converted

35 includes acyl groups derived from aliphatic, araliphatic, aromatic or heterocyclic carboxylic acids or sulfonic acids and in particular alkoxycarbonyl, aryloxycarbonyl and especially aralkoxycarbonyl groups. Examples of such acyl groups are alkanoyl such as acetyl, propionyl, butyryl; Aralkanoyl such as phenylacetyl; Aroyl, such as benzoyl or toluyl; Aryloxyalkanoyl such as POA; Alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, BOC (tert-butyloxycarbonyl), 2-iodoethoxycarbonyl; Aralkyloxycarbonyl such as CBZ ("carbobenzoxy"), 4-methoxybenzyloxycarbonyl, FMOC; Arylsulfonyl such as Mtr. Preferred amino-protecting groups are BOC and Mtr, furthermore CBZ, Fmoc, Benzy I and acetyl.

Furthermore, free amino groups can be acylated in the usual way with an acid chloride or anhydride, or alkylated with an unsubstituted or substituted alkyl halide, or reacted with CH 3 -C (= NH) -OEt, expediently in an inert solvent such as dichloromethane or THF and / or in the presence of a base such as triethylamine or pyridine at temperatures between -60 and + 30 ⁰ C.

The term "hydroxy protecting group" is also well known and refers to groups which are suitable for protecting a hydroxy group from chemical reactions, but are readily removable after the desired chemical reaction has been carried out at other sites on the molecule. Typical of such groups are the abovementioned unsubstituted or substituted aryl, aralkyl or acyl groups, and also alkyl or silyl groups. The nature and size of the hydroxy protecting groups is not critical because they are removed after the desired chemical reaction or reaction sequence; preferred are groups having 1-20, in particular 1-10 C-atoms. Examples of hydroxy protecting groups include benzyl, 4-methoxybenzyl, p-nitrobenzoyl, p-toluenesulfonyl, tert-butyl and acetyl, with benzyl and tert-butyl being particularly preferred. The in-freedom setting of the compounds of formula I from their functional derivatives succeed - depending on the protecting group used - z. B. with strong acids, useful with TFA or perchloric acid, but also with other strong inorganic acids such as hydrochloric acid or sulfuric acid, strong organic carboxylic acids such as trichloroacetic acid or sulfonic acids such as benzene or p-toluenesulfonic acid. The presence of an additional inert solvent is possible, but not always necessary. Suitable inert solvents are preferably organic, for example

10 carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as DMF, halogenated hydrocarbons such as dichloromethane, and also alcohols such as methanol, ethanol or isopropanol, and water. Also suitable are mixtures of the abovementioned solvents.

_* c TFA is preferably used in excess without addition of another solvent, perchloric acid in the form of a mixture of acetic acid and 70% perchloric acid in the ratio 9: 1. The reaction temperatures for the cleavage are suitably between about 0 and about 50 ^° C., preferably between 15 and 30 ^° C. (room temperature).

20 temperature, RT).

The groups BOC, OBut and Mtr can z. B. preferably with TFA in dichloromethane or with about 3 to 5n HCl in dioxane at 15-30 ° C 25 th deleted, the FMOC group with an about 5- to 50% solution of dimethylamine, diethylamine or piperidine in DMF at 15-30 ⁰ C.

Hydrogenolytically removable protective groups (eg. As CBZ, benzyl or the liberation of the amidino _O0 can "from its oxadiazole derivative z. B. by treating with hydrogen in the presence of a catalyst (for. Example, a noble metal catalyst such as palladium, expediently on a support such as carbon Suitable solvents are the abovementioned ones, in particular, for example, alcohols, such as methanol or ethylene.

35 nol or amides such as DMF. The hydrogenolysis is usually at temperatures between about 0 and 100 ⁰ C and pressures between about 1 and 200 bar, preferably at 20-30 ⁰ C and 1-10 bar performed. A hydroge- nolysis of the CBZ group succeeds z. B. good at 5 to 10% Pd / C in methanol or with ammonium formate (instead of hydrogen) to Pd / C in

Methanol / DMF at 20-30 ⁰ C.

For example, esters can be saponified with acetic acid or with NaOH or KOH in water, water-THF or water-dioxane at temperatures between 0 and 100 ^° C.

Other methods of deprotection are described, for example, in Theodora W. Green, Peter G. M. Wuts: Protective Groups in Organic Synthesis, 3rd Edition John Wiley & Sons (1999).

Compounds of the formula I according to the invention can, on the basis of their

Molecular structure chiral and therefore occur in different enantiomeric forms. They may therefore be in racemic or optically active form.

Since the pharmaceutical activity of the racemates or stereoisomers of the compounds of the invention may differ, it may be desirable to use the enantiomers. In these cases, the end product or else the intermediates may already be separated into enantiomeric compounds, chemical, biochemical or physical measures known to those skilled in the art, or already be used as such in the synthesis.

By usual workup steps such as adding water to the reaction mixture and extraction, the compounds of formula I can be obtained after removal of the solvent. It may be advantageous to add a distillation or crystallization for further purification of the product. Another object of the invention are pharmaceutical compositions containing at least one compound of the invention and / or their physiologically acceptable salts, derivatives, solvates and stereoisomers, including mixtures thereof in all proportions. 5

Furthermore, a pharmaceutical preparation according to the invention, further excipients and / or adjuvants and optionally contain one or more other active pharmaceutical ingredients.

The invention further provides a process for the preparation of a medicament, which comprises reacting a compound according to the invention and / or one of its physiologically acceptable salts, derivatives, solvates and stereoisomers, including mixtures thereof

^ ₅ brings all ratios together with a solid, liquid or semi-liquid carrier or excipient in a suitable dosage form.

The invention is also a set (kit) consisting of separate

Packs of

20 a) an effective amount of a compound of the invention and / or its physiologically acceptable salts, derivatives, solvates and stereoisomers, including mixtures thereof in all proportions and b) an effective amount of another active pharmaceutical ingredient.

The kit contains suitable containers, such as boxes or boxes, individual bottles, bags or ampoules. The set may e.g. separate am-

In each of which an effective amount of a compound of the invention and / or its pharmaceutically acceptable derivatives, solvates and stereoisomers, including mixtures thereof in all proportions, and an effective amount of another drug substance is dissolved or in lyophilized form.

35 Drugs may be presented in the form of dosage units containing a predetermined amount of active ingredient per unit dose. Such a unit may for example be 0.5 mg to 1 g, preferably 1 mg to

700 mg, more preferably 5 mg to 100 mg of an inventive

Depending on the disease state treated, the compound contained

Route of administration and the age, sex, weight and condition of the patient. Preferred dosage unit formulations are those containing a daily or partial dose as indicated above or a corresponding fraction of an active ingredient. Furthermore, such drugs can be prepared by any of the methods well known in the pharmaceutical art.

Drugs may be administered by any suitable route, for example oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) routes , to adjust. Such medicines can be used with all in the pharmaceutical

The art can be prepared by known methods, for example by bringing the drug together with the carrier (s) or excipient (s).

Drugs adapted for oral administration may be administered as separate units, e.g. Capsules or tablets; Powder or granules; Solutions or suspensions in aqueous or non-aqueous liquids; edible foams or foam foods; or oil-in-water

Liquid emulsions or water-in-oil liquid emulsions are presented.

Thus, for example, in the oral administration in the form of a

Tablet or capsule, the active component with an oral, non-toxic and pharmaceutically acceptable inert carrier, such as For example, combine ethanol, glycerine, water and others. Powders are prepared by comminuting the compound to a suitable fine size and mixing it with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate such as starch or mannitol. A flavoring, preservative,

Dispersant and dye may also be present.

Capsules are made by preparing a powder mixture as described above and filling shaped gelatin shells therewith. Lubricants such as e.g. highly disperse silica, talc, magnesium stearate, calcium stearate or solid-state polyethylene glycol can be added to the powder mixture before the filling process. A disintegrants or solubilizers, e.g. Agar-agar, calcium carbonate or sodium carbonate may also be added to improve the availability of the drug after ingestion of the capsule.

In addition, if desired or necessary, suitable bonding,

Lubricants and disintegrants as well as dyes are also incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars, e.g. Glucose or beta-lactose, corn sweeteners, natural and synthetic gums, e.g. Acacia, traganth or sodium alginate, carboxymethyl cellulose, polyethylene glycol,

Waxes, etc. The lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, etc. The disintegration agents include, but are not limited to, starch, methyl cellulose, agar, bentonite, xanthan gum and others The tablets are formulated by, for example, preparing a powder mix, granulating or dry pressing, adding a lubricant and a disintegrant, and compressing the whole into tablets. A powder mixture is prepared by treating the appropriately comminuted compound with a diluent or a base as described above, and optionally with a Binders, such as carboxymethyl cellulose, an alginate, gelatin or polyvinylpyrrolidone, a Lösungsverlangsamer, such as paraffin, a resorption accelerator, such as a quaternary salt and / or an absorbent, such as bentonite, kaolin or Dikalzi- umphosphat mixed. The powder mixture can be granulated by wetting it with a binder such as syrup, starch paste, Acadia slime or solutions of cellulosic or polymeric materials and pressing it through a sieve. As an alternative to granulation, the powder mixture can be run through a tabletting machine to produce non-uniformly shaped lumps which are broken up into granules. The granules may be greased by the addition of stearic acid, a stearate salt, talc or mineral oil to prevent sticking to the tablet molds. The greased mixture is then compressed into tablets. The compounds according to the invention can also be combined with a free-flowing inert carrier and then pressed directly into tablets without carrying out the granulation or dry pressing steps. A transparent or opaque protective layer consisting of a shellac sealant, a layer of sugar or polymeric material, and a glossy layer of wax may be present. Dyes can be added to these coatings in order to differentiate between different dosing units.

Oral fluids, e.g. Solution, syrups and elixirs may be prepared in unit dosage form such that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in an aqueous solution of suitable taste, while elixirs are prepared using a non-toxic alcoholic vehicle. Suspensions can be obtained by dispersion of the compound in a non-toxic

Vehicle formulated. Solubilizers and emulsifiers, such as, for example, ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives flavoring agents such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, among others may also be added.

5

The unit dosage formulations for oral administration may optionally be encapsulated in microcapsules. The formulation may also be prepared to prolong or retard the release, such as by coating or embedding 10 particulate material in polymers, wax, and the like.

The compounds of the invention and salts, solvates and physiologically functional derivatives thereof can, be administered in the form of liposomal ^ _c menzuführsystemen, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from various phospholipids such as cholesterol, stearylamine or phosphatidylcholines.

20

The compounds of the invention as well as the salts, solvates and physiologically functional derivatives thereof can also be delivered using monoclonal antibodies as individual carriers to which the compound molecules are coupled. The connections can

25 can also be coupled with soluble polymers as targeted drug carriers. Such polymers may be polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol or polyethyleneoxidepolylysine substituted with palmitoyl radicals,

₃₀ include. Furthermore, the compounds can be attached to a class of biodegradable polymers which are suitable for the controlled release of a drug, for example polylactic acid, polyepsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals,

Polydihydroxypyrans, polycyanoacrylates and cross-linked or amphipathic

35 block copolymers of hydrogels to be coupled. Drugs adapted for transdermal administration may be administered as discrete plasters for prolonged, intimate contact with the epidermis of the recipient. For example, the drug can be delivered from the patch by iontophoresis, as generally described in Pharmaceutical Research, 3 (6): 318, 1986.

Drugs adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

For treatments of the eye or other external tissues, e.g. Mouth and skin, the formulations are preferably as a topical ointment

^ ₅ or cream applied. When formulated into an ointment, the active ingredient can be used with either a paraffinic or water miscible cream base. Alternatively, the active ingredient can be formulated into a cream with an oil-in-water cream base or a water-in-oil base.

20

The medicaments adapted for topical application to the eye include eye drops, the active ingredient being dissolved or suspended in a suitable carrier, in particular an aqueous solvent. 25

Drugs adapted for topical application in the mouth include lozenges, lozenges and mouthwashes.

2Q Drugs adapted for rectal administration may be given in the form of suppositories or enemas.

Drugs adapted for nasal administration in which the vehicle is a solid, contain a coarse powder with a partial

For example, in the range of 20-500 microns, which is in the

Way in which snuff is absorbed, administered ie by rapid inhalation via the nasal passages from a container held close to the nose with the powder. Suitable formulations for administration as a nasal spray or nasal drops with a liquid as

Vehicle include drug solutions in water or oil. 5

Drugs adapted for administration by inhalation include fine particulate dusts or mists which may be generated by various types of pressurized dosing dispensers with aerosols, nebulisers or insufflators.

Medicaments adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations A _c .

Medicinal products adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions containing the antioxidants, buffers, bacteriostats and solutes which make the formulation isotoprotein.

20 is made with the blood of the recipient to be treated included; and aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickeners. The formulations may be administered in single or multiple dose containers, e.g. sealed ampoule

25 liters and vials, and stored in the freeze-dried (lyophilized) state so that only the addition of the sterile carrier liquid, e.g. Water for injections, needed immediately before use. Prescribed injection solutions and suspensions

₃ Q pensions can be made from sterile powders, granules and tablets.

It is understood that the medicaments of the present invention, in addition to the above-mentioned components mentioned above, are others in the art

35

Means related to the particular type of pharmaceutical formulation can contain; For example, drugs suitable for oral administration may contain flavorings.

A therapeutically effective amount of a compound of the present invention

The invention depends on a number of factors, including e.g. the

The age and weight of the recipient, the exact condition of the disease requiring treatment, as well as its severity, the nature of the formulation and the route of administration, will ultimately be determined by the attending physician or veterinarian. However, an effective amount of a compound of formula I for the treatment of the diseases of the invention will generally range from 0.1 to 100 mg / kg body weight of the recipient (mammal) per day, and more typically in the range of 1 to 10 mg / kg of body weight per day. Thus, for a 70 kg adult mammal, the actual amount per day would usually be between 70 and 700 mg, this amount as a single dose per day or more commonly in a number of divided doses (such as two, three, four, five or six) per Day can be given so that the total daily dose is the same. An effective amount of one

Salt or solvate or a physiologically functional derivative thereof can be determined as the proportion of the effective amount of the compound according to the invention per se.

The compounds of the present invention exhibit beneficial biological activity which is readily detectable in enzyme assays. In such enzyme-based assays exhibit and cause the erfindungsgemä- SEN compounds preferably an inhibiting effect, which is usually by IC _ö o values in a suitable range, preferably in the micromolar range and more preferably will be documented in the nanomolar range.

The present invention provides compounds according to the invention as effectors, preferably as inhibitors of those described here Signal paths. Therefore, particularly preferred subject matter of the invention are compounds according to the invention as activators and inhibitors of serine / threonine and tyrosine kinases, preferably as inhibitors of cytosolic and receptor tyrosine kinases, in particular of the receptor tyrosine kinases.

As discussed above, the signaling pathways affected by the compounds of the present invention are relevant to various diseases. Accordingly, the compounds according to the invention are useful in the prophylaxis and / or treatment of diseases which are dependent on said signaling pathways by interaction with one or more of said signal pathways.

Another object of the present invention is therefore the use of compounds of the invention and / or their physiologically acceptable salts, derivatives, solvates and stereoisomers, including mixtures thereof in all proportions for the preparation of a

Medicament for the treatment and / or prophylaxis of diseases, in particular those diseases which are caused by kinases and / or by kinase-mediated signal transduction mediated and / or propagated.

In addition, the present compounds are useful as pharmaceutical agents for mammals, particularly for humans, in the treatment of protein kinase-related diseases. The term "protein kinase-related diseases" refers to pathological conditions that depend on the activity of one or more protein kinases The kinases are either directly or indirectly at the signal transduction pathways of various cellular activities, including proliferatron, adhesion and migration Diseases associated with tyrosine kinase activity include cancer, tumor growth,

Arteriosclerosis, diabetic retinopathy and inflammatory diseases. Usually, the diseases discussed here are divided into two groups, hyperproliferative and non-hyperproliferative diseases.

In this context, psoriasis, arthritis, inflammation,

5

Endometriosis, scarring, benign prostatic hyperplasia, immunological diseases, autoimmune diseases and immunodeficiency diseases are considered non-cancerous diseases, of which arthritis, inflammation, immunological diseases, autoimmune diseases and

Immunodeficiency diseases are usually regarded as non-hyperproliferative disorders.

In this connection, brain cancer, lung cancer, Plattene- A _c pithelkrebs, bladder cancer, stomach cancer, pancreatic cancer, liver cancer, kidney cancer, colon cancer, breast cancer, head cancer, neck cancer, oesophageal cancer, thyroid cancer, lymphoma, chronic leukemia and acute leukemia are to be regarded as cancerous diseases All of them are usually counted among the group of hyperproliferative diseases

20 will be. In particular, cancerous cell growth and in particular by

IGF-1R directly or indirectly mediated cancerous cell growth is a disease that is an object of the present invention.

The subject of the present invention is therefore the use of compounds according to the invention for the preparation of a medicament for the treatment and / or prophylaxis of said diseases as well as a method for the treatment of said diseases, comprising

₃ Q send the administration of one or more compounds of the invention to a patient in need of such administration.

The recipient or patient may be of any mammalian species, e.g. A primate species, especially humans; Rodents, including

35 lent to mice, rats, and hamsters; Rabbits; Horses, cattle, dogs,

Cats, etc. Animal models are for experimental studies of Interest, providing a model for the treatment of human disease.

The susceptibility of a particular cell to treatment with the compounds of the invention can be determined by in vitro assays. Typically, a culture of the cell is incubated with a compound of the invention at various concentrations for a time sufficient to allow the drugs to

10 induce cell death or inhibit migration, usually between about one hour and one week. Cultured cells from a biopsy sample can be used in in vitro tests. The viable cells remaining after treatment are then counted.

^ _C The dose varies depending on the specific compound used, the specific disease, the patient status, etc .. Typically, a therapeutic dose sufficient to reduce the undesired cell population in the target tissue to reduce considerably, while the viability of the patient is maintained. The treatment is generally

20 continue until there is a significant reduction, for. B. at least about 50% reduction in the specific cell count and can be continued until essentially no more unwanted cells are detected in the body.

25

Various assay systems are available for the identification of protein kinase inhibitors. In the Scintillation Proximity Assay (Sorg et al., J. of Biomolecular Screening: 7: 11-19, 2002) and the FlashPlasma

2Q te assay is the radioactive phosphorylation of a protein or peptide as a substrate with γATP measured. In the presence of an inhibitory compound, no or a reduced radioactive signal is detectable. Further, Homogeneous Time-resolved Fluorescence Resonance Energy Transfer (HTR-FRET) and Fluorescence Polarization (FP) 35 Technologies are useful as an assay method (SiIIs et al., J. of Biomolecular Screening: 191-214, 2002).

Other non-radioactive ELISA assay methods use specific phospho-antibodies (Phospho-AK). The phospho-AK binds only the phosphorylated substrate. This binding is detectable by chemiluminescence with a second peroxidase-conjugated anti-sheep antibody (Ross et al., Biochem., J. 366: 977-981, 2002).

Assay systems with which the inhibitory activity of the compounds according to the invention can be tested specifically for the protein kinases TIE2, VEGF-2, SGK1, TGFβRI, IGF1R, PDGFRβ and FAK are described in Examples B1 to B7.

There are many diseases and conditions associated with deregulation of cell proliferation and cell death (apoptosis). The

Diseases and conditions which may be treated, prevented or alleviated by compounds of the present invention include, but are not limited to, the diseases and conditions listed below. The compounds of the present invention are useful in the treatment and / or prophylaxis of a variety of disorders and disease states in which proliferation and / or migration of smooth muscle cells and / or inflammatory cells into the intimal layer of a vessel is present, resulting in limited perfusion of this vessel, e.g. In neointimal occlusive lesions. Occlusive transplant vascular diseases of interest include atherosclerosis, coronary vascular disease after transplantation, venous graft stenosis, peri-anastomotic prosthetic restenosis, restenosis after angioplasty or stent placement, and the like.

The present invention encompasses the use of the compounds of the invention for the treatment or prevention of cancer. The invention particularly relates to the use of compounds according to the invention and / or their physiologically acceptable salts, derivatives, solvates and stereoisomers, including their

Mixtures in all proportions for the manufacture of a medicament for 5

Treatment and / or prophylaxis of solid tumors, wherein the solid

Tumor is particularly preferably selected from the group consisting of brain tumor, tumor of the urogenital tract, tumor of the lymphatic system, gastric tumor, laryngeal tumor, lung tumor. Preferred may

10 also solid tumors selected from the group consisting of monocytic leukemia, lung adenocarcinoma, small cell and non-small cell lung carcinomas, renal cell carcinoma, endometrial carcinoma, multiple myeloma, prostate cancer, colorectal cancer, pancreatic cancer, glioma

.J _j - oblastomas and breast carcinoma are treated with medicaments containing compounds of the invention.

The compounds of the invention may be administered to patients for the treatment of cancer. The present compounds

By binding to protein kinases, tumor angiogenesis can influence the growth of tumors. The properties of the compounds of the present invention also make them suitable for the treatment of certain forms of blindness associated with retinal neovascularization.

The invention therefore also _{relates to} the use of compounds _{according to} the invention and / or their physiologically acceptable salts, derivatives, solvates and stereoisomers, including their salts

Mixtures in all ratios for the manufacture of a medicament for the treatment and / or prophylaxis of diseases caused, mediated and / or propagated by angiogenesis.

35 One such disease involving angiogenesis is an eye disease such as retinal vascularization, diabetic retinopathy, age-related macular degeneration, and the like.

The invention therefore also relates to the use of the compounds according to the invention for the production of a medicament for

Treatment and / or prophylaxis of the above diseases.

The use of compounds of the invention and / or their physiologically acceptable salts and solvates for the manufacture of a medicament for the treatment and / or prophylaxis of inflammatory diseases is also within the scope of the present invention. Such inflammatory diseases include, for example, rheumatoid arthritis, psoriasis, contact dermatitis, late-type hypersensitivity reaction, and the like.

Preferred is the use for the treatment of diseases, preferably from the group of hyperproliferative and non-hyperproliferative diseases.

These are cancers or non-cancerous diseases.

The invention also relates to the use of compounds according to the invention and / or their physiologically acceptable salts, derivatives, solvates and stereoisomers, including mixtures thereof in all ratios for the preparation of a medicament for the treatment of diseases selected from the group of non-cancerous diseases consisting of psoriasis, Arthritis, inflammation, endometriosis, scarring, benign prostatic hyperplasia, immunological diseases, autoimmune diseases and immunodeficiency diseases.

Another object of the invention is the use of compounds of the invention and / or their physiologically acceptable salts, derivatives, solvates and stereoisomers, including mixtures thereof in all proportions for the manufacture of a medicament for the treatment of diseases selected from the group of cancerous diseases consisting of brain cancer, lung cancer, squamous cell cancer, bladder cancer, gastric cancer, pancreatic cancer, liver cancer, kidney cancer, colorectal cancer , Breast cancer, head cancer, cervical cancer, esophageal cancer, gynecological cancer, thyroid cancer, lymphoma, multiple myeloma, chronic leukemia and acute leukemia.

The present compounds are also useful for combination with known anticancer agents. These known anticancer agents include the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, growth factor inhibitors, and the like angiogenesis inhibitors. The present compounds are particularly suitable for joint use.

Turn with radiotherapy.

"Estrogen receptor modulators" refers to compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of how it is done. "The estrogen receptor modulators include, for example, tamoxifen, raloxifene, idoxifen, LY353381, LY 117081, toremifene , Fulvestrant, 4- [7- (2,2-Dimethyl-1-oxopropoxy-4-methyl-2- [4- [2- (1-piperidinyl) ethoxy] phenyl] -2H-1-benzopyran-3-yl ] phenyl 2,2-dimethylpropanoate, 4,4'-dihydroxybenzophenone-2,4-dinitrophenylhydrazone and SH646, this list being not intended to be limiting.

"Androgen receptor modulators" refers to compounds that interfere with or inhibit the binding of androgens to the receptor, regardless of how this occurs. "Androgen receptor modulators include, for example, finasteride and other 5α-reductase modulators. Inhibitors, nilutamide, flutamide, bicalutamide, liarozole and abiraterone acetate.

"Retinoid receptor modulators" refers to compounds that interfere with or inhibit the binding of retinoids to the receptor, regardless of how this occurs Such retinoid receptor modulators include, for example, bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis Retinoic acid, α-difluoromethylmuthine, ILX23-7553, trans-N- (4'-hydroxyphenyl) -retinamide and N-4-carboxyphenylretinamide.

10 "Cytotoxic agents" refers to compounds that cause cell death or interfere with cell mitosis, primarily through direct action on cell function, including alkylating agents, tumor necrosis factors, intercalators, microtubulin inhibitors, and others

^ _c topoisomerase inhibitors.

The cytotoxic agents include, for example, tirapazimine, Sertenef, cachectin, ifosfamide, tasonermine, lonidamine, carboplatin, altretamine, prednimustine, dibromodulcite, ranitin, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improvisulfan-tosylate, trofosfate.

20 mid, Nimustin, Dibrospidium chloride, Pumitepa, Lobaplatin, Satraplatin,

Profiromycin, cisplatin, irofulvene, dexifosfamide, cis-amine dichloro (2-methylpyridine) platinum, benzylguanine, glufosfamide, GPX100, (trans, trans, trans) -bis-mu (hexane-1,6-diamine) -mu- [diamine -

25 platinum (II)] bis [diamine (chloro) platinum (II)] tetrachloride, diarizidinylspermine, arsenic trioxide, 1- (11-dodecylamino-10-hydroxyundecyl) -3,7-dimethylxanthine, zobricin, idarubicin, Daunorubicin, bisantrene, mitoxantrone, pirarubicin, pinafide, valrubicin, amrubicin, antineoplaston, 3'-desamino-3'-morpholino-13-

2 _Q deoxo-10-hydroxycarminomycin, annamycin, galarubicin, elinafide,

MEN10755 and 4-desmethoxy-3-desamino-3-aziridinyl-4-methylsulfonyl-daunorubicin (see WO 00/50032), but this is not intended to be limiting.

The microtubulin inhibitors include, for example, paclitaxel, valine

35 sulphate, S''-dideshy ^ '- desoxy-δ'-norvincaleukoblastin, docetaxol, rhizoxin, dolastatin, mivobulinisethionate, auristatin, cemadotin, RPR109881, BMS184476, vinflunine, cryptophycin, 2,3,4,5,6-pentafluoro-N- (3-fluoro-4-methoxyphenyl) benzenesulfonamide, anhydrovinblastine, N, N-dimethyl-L-valyl-L-valyl-N-methyl-L -valyl-L-prolyl-L-proline t-butylamide, TDX258 and

BMS188797. 5

Topoisomerase inhibitors are, for example, topotecan, hycaptamine, irinotecan, rubitecane, 6-ethoxypropionyl-3 ', 4'-O-exo-benzylidene-chartreusine, 9-methoxy-N, N-dimethyl-δ-nitropyrazolo [3,4, δ-kl] acridine-2

10 (6H) propanamine, 1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H, 12H-benzo [de] pyrano [3 ^l , 4 ^l : b, 7] indolizino [1, 2b] quinoline-10,13 (9H _l 15H) - dione, lurtotecan, 7- [2- (N-isopropylamino) ethyl] - (20S) camptothecin, BNP1350, BNPM 100, BN80915, BN80942, Etoposide phosphate, teniposide,

A c souzoxan, 2'-dimethylamino-2'-deoxy-etoposide ₁ GL331, N- [2-

(Dimethylamino) ethyl] -9-hydroxy-δ, 6-dimethyl-6H-pyrido [4,3-b] carbazole-1-carboxamide, asulacrine, (δa, δaB, 8aa, 9b) -9- [2-] N- [2- (dimethylamino) ethyl] -N-methylaminolethyl-δ - ^ -hydroxy-S.delta-dimethoxyphenyll-δ.Sa.β.δ.δa.θ-hexohydrofuro (3 ', 4 ^l : 6.7 ) naphtho (2,3-d) -1,3-dioxol-6-one, 2,3-

20

(Methylenedioxy) -δ-methyl-7-hydroxy-8-methoxybenzo [c] phenanthridinium,

6,9-bis [(2-aminoethyl) amino] benzo [g] isoquinoline-δ, 10-dione, δ- (3-aminopropylamino) -7,10-dihydroxy-2- (2-hydroxyethylaminomethyl) -6H - pyrazolo [4, δ, 1-de] acridin-6-one, N- [1- [2 (diethylamino) ethylamino] -7-2δ-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl] formamide, N - (2- (Dimethylamino) ethyl) acridine-4-carboxamide, 6 - [[2- (dimethylamino) ethyl] amino] -3-hydroxy-7H-indeno [2,1-c] quinoline-7 -on and Dimesna.

_{O0 Antiproliferative} agents include antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 and INX3001, and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine .

Cytarabine ocfosfate, Fosteabin Sodium Hydrate, Raltitrexed, Paltitrexide, Emi- tefur, Tiazofurin, Decitabine, Nolatrexed, Pemetrexed, Nelzarabin, T-

Deoxy-2'-methylidenecytidine, 2'-fluoromethylene-2 ^l -deoxycytidine, N- [δ- (2,3- Dihydrobenzofuryl) sulfonyl] -N '- (3,4-dichlorophenyl) urea, N6- [4-deoxy-4- [N 2 - [2 (E), 4 (E) -tetradecadienoyl] -glycylamino] -L-glycero-BL manno-heptopyranosyl] adenine, aplidine, ecteinascidin, troxacitabine, 4- [2-amino-4-0X0-4,6,7,8-tetrahydro-3H-pyrimidino [5,4-b] [1, 4] thiazine 6-yl (S) -ethyl] -2,5-thienoyl-L-glutamic acid, aminopterin, 5-fluorouracil, alanosine, 11-acetyl-8- (carbamoyloxymethyl) -4-formyl-6-methoxy-14- oxa-1,11-diazatetracyclo (7.4.1.0.0) -tetradeca-2,4,6-trien-9-ylacetic acid ester, swainsonine, lometrexol, dexrazoxane, methioninase, 2'-cyano-2'-deoxy-N4 -palmitoyl-1-BD-arabinofuranosylcytosine and 3-aminopyridine-2-carboxaldehyde thiosemicarbazone. The "antiproliferative agents" also include monoclonal antibodies to growth factors such as cetuximab, matuzumab, as well as tumor suppressor genes such as p53, which can be delivered via recombinant virus-mediated gene transfer (see, eg, US Pat. No. 6,069,134).

embodiments

Example A1: Preparation of 4-chloro-5-iodo-pyrrolo [2,3-d] pyrimidine according to the following reaction scheme:

(a) 130 ml (860 mmol) of bromoacetaldehyde diethyl acetal are treated with ethyl cyanoacetate (430 ml, 4.04 mol), sodium iodide (8.1 g, 54.04 mmol) and Potassium carbonate (115.9 g, 839 mmol) heated to reflux for 10 h. After cooling to room temperature (RT), the mixture is stirred with 800 ml of water, the aqueous phase extracted with diethyl ether, the combined organic phases dried and concentrated. Chromatography gives 124.99 g (63%) of a colorless liquid 2-cyano-4,4-diethoxy-butyric acid ethyl ester.

(b) 3.3 g (99 mmol) of sodium in 75 ml of ethanol are added at 0 ^° C. and 7.5 g (99 mmol) of thiourea and 2-cyano-4,4-diethoxybutyric acid ethyl ester (20, 6 g, 90 mmol), when the sodium has completely reacted. The mixture is then heated to reflux for 10 h and, after cooling, the solvent is removed in vacuo. The residue is partitioned between water and ether and, after phase separation, the aqueous phase is acidified with 5.7 ml (99 mmol) of acetic acid. The product precipitates, is filtered off and dried in vacuo. This gives 21, 73 g (93%) of 6-amino-5- (2,2-diethoxy-ethyl) -2-mercapto-pyrimidin-4-ol in the form of a beige-colored

Powder used in the subsequent reaction without further purification. , becomes.

(c) To a suspension of 50 g of Raney nickel in water and 50 ml of ammonia (26% in water) are added 35.5 g (187 mmol) of 6-amino-5- (2,2-diethoxy-ethyl) - 2-mercapto-pyrimidin-4-ol and heated for one

Hour to reflux. It is filtered hot and the ammonia evaporated. The aqueous residue is mixed with 100 ml of 3N HCl and stirred for 48 hours at RT. The precipitated product is filtered off and washed with water and ether. This gives 15.46 g (83.5%) of a colorless solid 7H-pyrrolo [2,3-d] pyrimidin-4-ol, whose melting point is above 300 ⁰ C.

(d) The mixture of 5 g (37 mmol) of 7H-pyrrolo [2,3-d] pyrimidin-4-ol in 50 ml of POCb is heated until the starting material is completely in

Solution is. Then without further heat for 45 minutes stirred and finally the POCb removed in vacuo. The residue is taken up in ice-water, alkalized with NaHCO ₃ and extracted with ether. The organic phase is dried and concentrated.

This gives 5.28 g (93%) of 4-chloropyrrolo [2,3-d] pyrimidine in the form of a greenish solid, which melts at 187-188 ⁰ C.

(e) Dissolve 5 g (32.56 mmol) of 4-chloro-pyro [3-d] pyrimidine and 11 g (50 mmol) of N-iodo-succinimide in 60 ml of DMF and stir at RT for 10 hours. the. It is worked up with aqueous sodium thiosulfate solution and extracted with ether. The organic phase is washed with aqueous sodium thiosulphate solution and ammonium chloride solution. The finally remaining solid is recrystallized from methanol. This gives 7 g (77%) of 4-chloro-5-iodo-pyrrolo [2,3-d] pyrimidine in the form of a slightly brownish solid which melts at 195-196 ° C.

Example A2: Preparation of carbamic acid (3-hydroxycyclobutylmethyl) tert-butyl ester according to the following reaction scheme:

CH ₂ NHBOC

(A) 50 g (0.54 mol) of S-methylene-cyclobutancarbonitril are dissolved in 600 ml of water and 50 ml of ether, cooled to 5 ⁰ C and treated with 100 mg (0.4 mmol) of osmium (IV) oxide. Now 260 g (1, 2 mol) of sodium periodate is added at the indicated temperature protionsweise and allowed to warm to rt. The organic phase is extracted with dichloromethane and chromatographed on silica gel after drying and concentration. This gives 25 g (49%) of S-oxo-cyclobutancarbonitril as colorless crystals (mp. 51 ⁰ C). (b) 25 g (0.26 mol) of S-oxo-cyclobutanecarbonitrile are dissolved in 350 ml of THF and added dropwise to a suspension of 40 g (1:05 mol) of lithium aluminum hydride in 350 ml of THF. After two hours, the mixture is cooled to 0 ⁰ C and treated with water, filtered and the residue concentrated to ckene to TRO. Chromatography over silica gel gives 20 g

(70%) 3-aminomethylcyclobutanol as a colorless oil. (This alanate reduction yields only the syn product in a substrate-controlled process.)

(c) 10 g (0.1 mol) of 3-aminomethylcyclobutanol are dissolved in 200 ml of THF and 33 g (0.15 mol) of di-tert-butyl dicarbonate and 14 ml (0.1 mol) of triethylamine added. After stirring for 10 h at RT, the mixture is concentrated to dryness and fractionated on silica gel. This gives 11 g (55%) of carbamic acid (3-hydroxy-cyclobutylmethyl) tert-butyl ester in the form of colorless crystals, which melt at 109-110 ⁰ C.

Example A3: Inversion of the absolute configuration at the carbinol center according to Mitsunobu according to the following reaction scheme (optional):

(a) Cis-carbamic acid (3-hydroxy-cyclobutylmethyl) tert-butyl ester is dissolved in THF and dissolved in THF in the presence of triphenylphosphine.

Nitrobenzoic acid cooled to 0 ⁰ C. At this temperature you give Diisopropylazodicarboxylat added dropwise and allowed to warm to rt. After 12 h, the batch is worked up with 5% sodium bicarbonate solution. After phase separation and chromatography, 4-nitrobenzoic acid S-tert-butoxycarbonylamino-methyl-cyclobutyl ester is obtained.

(b) The ester is dissolved in methanol and stirred in the presence of 1 N sodium hydroxide solution for 12 h at RT. The alcohol is removed in vacuo and the aqueous residue exhaustively extracted with dichloromethane. The organic phase is dried, concentrated and the residue is chromatographed on silica gel. Trans -carbamic acid (3-hydroxycyclobutylmethyl) tert-butyl ester is obtained.

Example A4 Preparation of 7 - (- 3-aminomethyl-cyclobutyl) -5- (3-fluorophenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine According to the Reaction Scheme:

(A) 1.81 g (5.4 mmol) of triphenylphosphine are placed in 60 ml of THF and cooled to -65 ° C. Now 1.1 ml (5.6 mmol) of diisopropyl azodi carboxylate are added dropwise. After 10 minutes, the 4-chloro-5-iodopyrrolo [2,3-d] pyrimidine is added, and after a further 15 minutes, the cis-carbamic acid dissolved in 5 ml of THF 3-hydroxy-cyclobutylmethyl tert. butyl ester too. The mixture is then stirred for 10 h at 50 ° C. After distilling off the solvent is chromatographed on silica gel. This gives 1.5 g of a light oil. This reaction leads to an inversion at the carbinol center, so that the radicals on the four-membered ring are trans to each other. The stereochemistry can be determined by NOE-NMR measurements.

(b) 600 mg (1.3 mmol) of carbamic acid [3- (4-chloro-5-iodopyrrolo [2,3-d] pyrimidin-7-yl) -cyclobutylmethyl] tert. butyl ester and 370 mg (1.7 mmol) of 2- (3-fluorophenyl) -4,4,5,5-tetramethyl- [1,2,2] dioxaborolane are mixed with 450 mg of sodium carbonate (5 mmol) in 15 ml DME and 10 ml of water submitted. To this suspension is added 31 mg (0.03 mmol) of tetrakis (triphenylphosphine) palladium and heated for 10 h at reflux. The product carbamic acid {3- [4-chloro-5- (3-fluoro-phenyl) -pyrrolo [2,3-d] pyrimidin-7-yl] -cyclobutylmethyl} tert-butyl ester is obtained by chromatography on silica gel.

(c) 500 mg (1.2 mmol) of carbamic acid {3- [4-chloro-5- (3-fluoro-phenyl) -pyrrolo [2,3-d] pyrimidin-7-yl] -cyclobutylmethyl} tert. Butyl ester are dissolved in 30 ml of ammonia water (32%) and 10 ml of THF and heated together with 42 mg (0.2 mmol) of copper sulfate for 10 h in a closed vessel at 100 ⁰ C. The batch is neutralized and extracted with ethyl acetate. Chromatography on silica gel gives 130 mg (36%) of 7- (3-aminomethyl-cyclobutyl) -5- (3-fluorophenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine as a colorless solid , Mp .: 101-102 ⁰ C.

Example A5: Preparation of 5- (3-fluorophenyl) -7- (3-pyrrolidin-1-ylmethyl-cyclobutyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine according to the following reaction scheme:

250 mg (mmol) of 7- (3-aminomethyl-cyclobutyl) -5- (3-fluoro-phenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine are dissolved in 10 ml of dioxane and dissolved in the presence of Triethylamine with 1, 4-dibromobutane for 10 h at 80 ⁰ C stirred.

There are obtained 5- (3-fluoro-phenyl) -7- (3-pyrrolidin-1-ylmethyl-cyclobutyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine in 56% yield.

Example A6: Preparation of 3- [4-amino-7- (3-pyrrolidin-1-ylmethyl-cyclobutyl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl] -phenol according to the following reaction scheme:

(a) First, analogously to Example A3 (b) and (c) from 2- (3-benzyloxy-phenylH ^ .δ.δ-tetramethyl-ti .S ^ Jdioxaborolan and carbamic acid [3- (4-chloro-δ-iodo -pyrrolo ^ .S-dJ-pyrimidine ^ -yO-cyclobutylmethyl tert -butyl ester, 5- (3-benzyloxyphenyl) -7- (3-pyrrolidin-1-ylmethyl-cyclobutyl) -7H-pyrrolo [2,3-d ] pyrimidin-4-ylamine. (B) 500 mg of this compound are dissolved in 10 ml of methanol and reacted with 25 ml of hydrogen to 100 mg of palladium on carbon. You get

250 mg (86%) of 3- [4-amino-7- (3-pyrrolidin-1-ylmethyl-cyclobutyl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl] -phenol as a colorless solid ( mp.

193 - 194 ⁰ C).

3- [4-Amino-7- (3-pyrrolidin-1-ylmethyl-cyclobutyl) -7H-pyrrolo [2,3-d] pyrimidin-5-yl] -phenol has pronounced spectrum activity (IC ₅₀ in μM), which gives the compound a great therapeutic importance. The inhibition constants can be determined according to Examples B1 to B8 given below:

ICso kinase

0.06 IGF

1, 8 FAK

0.52 TIE

0.18 VEGF

0.097 PDGF

11.6 SGK

0.12 TGF

The solubility of the compound is determined as described in Example C. It is 1071 μg / ml in phosphate buffer (37 ^° C., pH 7.0).

Example B: Inhibition of Various Protein Kinases (IC ₅ o)

B1a: Inhibition of IGF1R (FlashPlate Assay)

The test plates used are 96-well Flashplate microtiter plates from Perkin Eimer (USA). Into the assay plate are the components of the kinase

33 reaction pipetted. The IGF1 R kinase is treated with radioactively labeled P- ATP in the presence and absence of test substances in a total volume of 100 .mu.l at room temperature together with biotinylated poly-Iy (Glu ₁ Tyr) 4: 1 1 hr. Incubated. The reaction is treated with 25 μl of a 200 mM

EDTA solution stopped. After incubation for a further 30 min at room temperature, the supernatants are aspirated and the wells are extracted three times with each

100 .mu.l 0.9% NaCl solution washed. The radioactivity is measured with a Topcount scintillation counter (PerkinElmer, USA). IC ₅ o values are calculated with the computer program RS1.

B1b: inhibition of IGF1R (ELISA assay)

Cultured human tumor cells expressing the IGF1 receptor (IGF1R) (e.g., MCF-7 or Calu-6) are stimulated with human IGF1, the natural ligand of IGF1R. The stimulation induces autophosphorylation of tyrosine residues in the cytoplasmic IGF1R domain which triggers signal transduction cascades leading to apoptosis inhibition and cell proliferation.

The amount of phosphorylated IGF1 R is determined by a receptor-specific capture ELISA or a LUMINEX analog assay.

The IGF1 R from cell lysates is bound by means of a specific antibody to a 96-well ELISA plate or LUMINEX beads ("capturing"), and the tyrosine phosphorylation with a biotin-labeled anti-phosphotyrosine antibody and a streptavidin-peroxidase conjugate In order to determine the activity of kinase inhibitors, cells are pre-treated with increasing concentrations of these compounds for 45 min and then stimulated with IGF1 for 5 min Activity of the ligand IGF1 checked and measured a concentration series of an IGF1R reference inhibitor. B2a: Inhibition of FAK (FlashPlate Assay) 384-well flashplate microtiter plates from Perkin Elmer (USA) serve as test plates. The components of the kinase reaction are pipetted into the assay plate. The FAK kinase is incubated with radioactively labeled ³³ P-ATP in the presence and absence of test substances in a total volume of 100 μl at room temperature together with biotinylated poly (Glu ₁ Tyr) 4: 1 3 h. The reaction is stopped with 25 μl of a 200 mM EDTA solution. After incubation for a further 30 min at room temperature, the supernatants are filtered off with suction and the wells are washed three times with 100 μl each of 0.9% NaCl solution. The radioactivity is measured with a Topcount scintillation counter (PerkinElmer, USA). IC ₅₀ values are calculated with the computer program RS1.

B2b: inhibition of FAK (ELISA assay)

Cultured human cells which have amplification of the FAK (focal adhe- sion kinase) gene (e.g., Calu-6 or HT-29) exhibit constitutive FAK activation associated with increased tyrosina- tophosphorylation. Activated FAK promotes invasive growth of

Tumor cells and inhibits anoikis.

The amount of phosphorylated FAK is determined by a specific capture ELISA or a LUMINEX analog assay. FAK from cell lysates is bound by means of a specific antibody to a 96-well ELISA plate or LUMINEX beads ("capturing"), and the tyrosine phosphorylation with a biotin-labeled anti-phosphotyrosine antibody and a streptavidin-peroxidase Conjugate detected by a chemiluminescent method or by means of a fluorescently labeled anti-phosphotyrosine antibody.

To determine the activity of kinase inhibitors, cells are pretreated with increasing concentrations of these compounds for 45 min, and then FAK phosphorylation is determined. As internal control, a concentration series of a reference inhibitor is measured. B3: Inhibition of VEGF-2 (FlashPlate Assay) 384-well flashplate microtiter plates from Perkin Elmer (USA) serve as test plates. The components of the kinase reaction are pipetted into the assay plate. The VEGF-2 kinase is incubated with radioactively labeled ³³ P-ATP in the presence and absence of test substances in a total volume of 100 μl at room temperature together with biotinylated poly (Glu, Tyr) 4: 1 3 h. The reaction is treated with 25 μl of a

10 200 mM EDTA solution stopped. After incubation for a further 30 min at room temperature, the supernatants are filtered off with suction and the wells are washed three times with 100 μl each of 0.9% NaCl solution. The radioactivity is measured with a Topcount scintillation counter (PerkinElmer, USA). IC ₅₀ -

< _| c values are calculated with the computer program RS1.

B4: Inhibition of TIE2 (FlashPlate Assay)

The test plates are 384-well Flashplate microtiter plates from the company

Perkin bucket (USA). In the assay plate are the components of the

20

Kinase reaction pipetted. The Tl E2 kinase is labeled with radioactivity

³³ P-ATP in the presence and absence of test substances in a total volume of 100 .mu.l at room temperature together with biotinylated poly-Iy (Glu, Tyr) 4: 1 3 hrs. Incubated. The reaction is treated with 25 μl of a 200 mM

25 EDTA solution stopped. After incubation for a further 30 min at room temperature, the supernatants are filtered off with suction and the wells are washed three times with 100 μl each of 0.9% NaCl solution. The radioactivity is measured with a Topcount scintillation counter (PerkinElmer, USA). IC ₅ o values

3Q are calculated with the computer program RS1.

B5: Inhibition of SGK1 (FlashPlate Assay)

The test plates are 384-well Flashplate microtiter plates from the company

Perkin bucket (USA). In the assay plate are the components of the

35

Kinase reaction pipetted. The SGK1 kinase is labeled with radioactivity P-ATP in the presence and absence of test substances in a total volume of 100 .mu.l at room temperature together with biotinylated poly-Iy (Glu, Tyr) 4: 1 3 hrs. Incubated. The reaction is treated with 25 μl of a 200 mM

EDTA solution stopped. After incubation for a further 30 min at room temperature, the supernatants are aspirated and the wells are extracted three times with each

100 .mu.l 0.9% NaCl solution washed. The radioactivity is measured with a Topcount scintillation counter (PerkinElmer, USA). IC ₅ o values are calculated with the computer program RS1. 0

B6: Inhibition of PDGFRβ (FlashPlate Assay)

The test plates used are 96-well Flashplate microtiter plates from Perkin Eimer (USA). The components of the kinase reaction are pipetted into the assay plate. The PDGFRβ kinase is incubated with radioactively labeled ³³ P-ATP in the presence and absence of test substances in a total volume of 100 μl at room temperature for 3 hours (here autophosphorylation of the kinase). The reaction is stopped with 150 μl of a 60 mM EDTA solution. After incubation for a further 30 min at room temperature, the supernatants are removed by suction and the wells are washed three times with 200 μl each time

Washed 0.9% NaCl solution. The radioactivity is measured with a Topcount scintillation counter (PerkinElmer, USA). ICso values are calculated with the computer program RS1. 5

B7: Inhibition of TGFßRI (FlashPlate Assay)

The test is carried out as described in Example B1b for IGF1 R. A biotinylated TGFβRI kinase is added. Q The kinase assay is performed as a 384-well flashplate assay.

The components of the kinase reaction are pipetted into the assay plate. The TGFßRI kinase is incubated with radioactively labeled ³³ P-ATP in the presence and absence of test substances together with biotinylated substrate in a total volume of 35 μl for 45 min. The reaction is stopped with 25 μl 200 mM EDTA solution, after 30 min at room temperature. filtered off with suction and washed the wells with three times with 100 .mu.l 0.9% NaCl solution. The radioactivity is measured with a Topcount scintillation counter (PerkinElmer, USA). IC ₅₀ values are with the

Computer program RS1 calculated.

B8: inhibition of InsR (ELISA assay)

Cultured human cells expressing the insulin receptor (InsR)

(e.g., HepG2) are stimulated with human insulin, the natural ligand of InsR. The stimulation induces autophosphorylation of tyrosine residues in the cytoplasmic InsR domain which triggers signal transduction cascades that trigger various biological responses of the cells. The amount of phosphorylated InsR is determined by a receptor-specific capture ELISA or a LUMINEX analog assay. The insr from cell lysates is bound by means of a specific antibody to a 96-well ELISA plate or LUMINEX beads ("capturing"), and the tyrosine phosphorylation with a biotin-labeled anti-body

Phosphotyrosine antibodies and a streptavidin-peroxidase conjugate detected by a chemiluminescence method or by means of a fluorescently labeled anti-phosphotyrosine antibody. To determine the activity of kinase inhibitors, cells are pretreated with increasing concentrations of these compounds for 45 min and then stimulated with insulin for 5 min. As an internal control, the biological activity of the ligand insulin is checked and a concentration series of a reference inhibitor measured.

Further physicochemical data and inhibition constants of compounds according to the invention are listed in Table 1. Example C: Determination of the Solubility in Phosphate Buffer by the Shake Flask Method

It is as in Glömme et al. (J. Pharm. Sci. 94 (1): 1-16, 2005). The concentration is determined by HPLC

UV detection against a standard solution.

Buffer: 3.954 g sodium dihydrogen phosphate monohydrate + 6.024 g sodium chloride + 950 ml ultrapure water. Adjustment of pH 7.0 with 0.1 M NaOH or 0.1 M HCl.

Procedure: ₅ The samples were shaken at 37 ° C and 450 rpm for 24 h. After about 7 h, the pH of the samples was checked and readjusted if necessary. It was checked if the sample was still in excess. Shortly before the end of the 24h shaking time, the samples were again checked for pH and precipitate. 0

Used devices:

Ultrapure water System: MiIIiQ Gradient, Millipore, Device: F3PN37462D Shakers: TiMix control, Bühler 5 Incubation hood: TH 15, Bühler pH Meter: 766 Calimatic Knick Instrument: pH 1 pH Electrode: InLab 423 Mettler

HPLC: Column: LiChroCart 125-4 LiChrospher 100 RP-18 Q Flow: 1, 000 ml / min

eluent:

Eluent A: 2 ml of diethylamine, for synthesis + 1000 ml of methanol, LiChrosolv

Eluent B: 5 g ammonium acetate, for analysis + 5

5 ml of methanol, LiChrosolv + 995 ml ultrapure water Example C1: Solubilities of compounds of the invention

By the method described above, the following solubilities are obtained:

Example C2: Solubilities of structurally similar compounds of the prior art (comparative example)

By the method described above, the following solubilities are obtained:

It is clear that the solubility of the inventive Verbindun- ₀ of the prior art gene that of the compounds to the 5 to

Exceeds 1000 times.

The following examples relate to pharmaceutical preparations: 5

Example D1: Injection glasses

A solution of 100 g of an active ingredient according to the invention and 5 g of disodium hydrogen phosphate is adjusted to pH 6.5 in 3 L bidistilled water with 0 2 N hydrochloric acid, filtered sterile, filled into injection jars, lyophilized under sterile conditions and sealed sterile. Each injection jar contains 5 mg of active ingredient.

_c Example D2: Suppositories

A mixture of 20 g of an active ingredient according to the invention is melted with 100 g of soya lecithin and 1400 g of cocoa butter, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.

0 _. , , _ _. ..

Example D3: Solution

A solution of 1 g of an active ingredient according to the invention, 9.38 g of NaH 2 PO 4 .2H 2 O, 28.48 g of Na 2 HPO 4 .12H 2 O and 0.1 g of benzaldehyde chloride in 940 ml of bidistilled water is prepared. Adjust to 5 pH 6.8, make up to 1 L and sterilize by irradiation. This solution can be used in the form of eye drops. Example D4: ointment

500 mg of an active ingredient according to the invention are mixed with 99.5 g of Vaseline under aseptic conditions.

Example D5: tablets

A mixture of 1 kg of active ingredient, 4 kg of lactose, 1, 2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed in the usual way into tablets, such that each tablet contains 10 mg of active ingredient.

Example D6: dragees

Tablets are pressed analogously to Example 5e, which are then coated in the usual way with a coating of sucrose, potato starch, talc, tragacanth and dyestuff.

Example D7: Capsules

2 kg of active ingredient in the usual way in hard gelatin capsules filled, so that each capsule contains 20 mg of the active ingredient.

Example D8: Ampoules

A solution of 1 kg of an active compound according to the invention in 60 L of double distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed sterile. Each vial contains 10 mg of active ingredient.

Claims

claims

1. Compounds of the formula I ₁

wherein

R ^{1 '} H ₁ Hal, OH, CN, NO ₂ , NH ₂ , A, Ar,

R ² , R ^{2 are} each independently H, A having 1, 2, 3, 4, 5 or 6 0 C atoms, wherein R ² and R ² together with the N-atom to which they are linked, a saturated or unsaturated mononuclear heterocycle with no or one further N, O or S atom can form,

A is unbranched, branched or cyclic alkyl having 1, 2, 3, 5

4, 5, or 6 C atoms, wherein one or two CH groups are represented by N, wherein furthermore one or two CH ₂ groups are represented by an O, N or S atom and / or by an NH, NA, CONH , Si (CH ₃ ) ₂ , NHCO, SO ₂ , -CH = CH- or -C≡C- group ° and / or 1-7 H atoms may be replaced by Hal, and wherein one or two CH ₃ - Groups may be replaced by NH, NH ₂ , NAH, NA ₂ , NHCOOA, NHCONHA, Si (CH ₃ ) ₃ , CN or Ar, Ar 5 is a mononuclear or dinuclear aromatic homo- or heterocycle having 1 to 4 N, O and / or S atoms and 5 to 12 Framework atoms which are unsubstituted or mono-, di- or trisubstituted by carbonyl oxygen, Hal, A, OH, OA, NH ₂ , NHA, NA ₂ , NO ₂ , CN, OCN, SCN, COOH, COOA, CONH ₂ , CONHA, CONA ₂ , NHCOA ₁ NHCOOA, NHCONH ₂ , NHSO ₂ A, CHO, COA, SO ₂ CH ₃ and / or SO ₂ NH ₂ may be substituted,

Hal is F, Cl, Br or I and n is O, 1, 2 or 3, and their pharmaceutically acceptable salts, derivatives, solvates and

Stereoisomers, including mixtures thereof in all ratios.

2. Compounds according to claim 1, which correspond to the formula II

wherein R ¹ , R ² and n have the meaning given for the formula I and their pharmaceutically acceptable salts, derivatives, solvates and stereoisomers, including mixtures thereof in all ratios.

3. Compounds according to one or more of claims 1 to 2, wherein the unspecified radicals have the meaning given in the formula I according to claim 1, wherein, however in the sub-formula A

R ¹ A ₁ unsubstituted or by A, fluorine, chlorine, bromine, iodine,

Hydroxy, methoxy, ethoxy, propoxy, butoxy, pentybxy, hexyloxy, nitro, cyano, formyl, acetyl, propionyl, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, benzyloxy, methanesulfonyl, sulfonamido, methylsulfonamido, Ethylsulfonamido, propylsulfonamido, butylsulfonamido, dimethylsulfonamido, phenylsulfonamido, carboxy, methoxycarbonyl, ethoxycarbonyl or aminocarbonyl mono- or disubstituted phenyl, indolyl, indazolyl, benzotriazolyl, benzoxazolyl-2-one, furyl, thienyl, thiazolyl, pyridyl or pyrimidinyl and R ² and n have the meaning given for the formula I,

in the subformula B

R ¹ A, unsubstituted or by A, fluorine, chlorine, bromine, iodine,

Hydroxy, methoxy, ethoxy, propoxy, butoxy, pentybxy, hexyloxy, nitro, cyano, formyl, acetyl, propionyl, trifluoromethyl, amino, methylamino, ethylamino, dimethylamino, diethylamino, benzyloxy, methanesulfonyl, sulfonamido, methylsulfonamido, Ethylsulfonamido, propylsulfonamido, butylsulfonamido, dimethylsulfonamido, phenylsulfonamido, carboxy, methoxycarbonyl, ethoxycarbonyl or aminocarbonyl mono- or disubstituted phenyl, indolyl, indazolyl, benzotriazolyl, benzoxazolyl-2-one, furyl, thienyl, thiazolyl, pyridyl or pyrimidinyl,

R ² , R ^{2 are} H or together form a butylene unit and n is 1 means

in sub-formula C

R ¹ A, unsubstituted or by A, fluorine, chlorine, bromine, iodine, hydroxy, methoxy, ethoxy, propoxy, butoxy, pentybxy, hexyloxy, nitro, cyano, formyl, acetyl, propionyl, trifluoromethyl, amino, methylamino, ethylamino , Dimethylamino, diethylamine, benzyloxy, methanesulfonyl, sulfonamido, methylsulfonamido, ethylsulfonamido, propylsulfonamido, butylsulfonamido, dimethylsulfonamido, phenylsulfonamido, carboxy, methoxycarbonyl, ethoxycarbonyl or aminocarbonyl mono- or disubstituted phenyl, indolyl, indazolyl, benzotriazolyl, benzoxazolyl- 2-one, furyl, thienyl, thiazolyl, pyridyl or pyrim- idinyl, R ^{2 '} , R ^{2 "are} each independently H or straight or branched alkyl having 1, 2, 3 or 4 C atoms, wherein R ² and R ² together form an ethylene, propylene, butylene or pentylene unit and n is 1,

in the sub-formula D

R ^{1 is} propan-1-olyl, propen-1-olyl, propyn-1-olyl, unsubstituted or by hydroxy, amino, fluorine, butoxy, acetamido, t-butoxycarbonylamino, nitro, benzyl, (dimethylphenylsilanyl) -methoxy, dimethylphenylsilanyloxy, methanesulfonyl, sulfonamido, methanesulfonamido, methyl, 2-propyl, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonic acid, benzylamino, N-benzyl-propane-1,3-diamino, mono- or disubstituted phenyl, indolyl , Indazolyl, benzofuranyl, benzotriazolyl, Benzoimidazolyl-2-one, benzoxazolyl-2-one, furyl, thienyl,

Thiazolyl, pyridyl or pyrimidinyl and R ² and n have the meaning given for the formula I,

in the sub-formula E

R ^{1 is} propan-1-olyl, propen-1-olyl, propyn-1-olyl, unsubstituted or by hydroxy, amino, fluorine, butoxy, acetamido, t-butoxycarbonylamino, nitro, benzyl, (dimethylphenylsilanyl) -methoxy, dimethylphenylsilanyloxy, methanesulfonyl, sulfonamido, methanesulfonamido, methyl, 2-propyl, trifluoromethyl, trifluoromethoxy, trifluoromethanesulfonic acid, benzylamino, N-benzyl-propane-1,3-diamino, mono- or disubstituted phenyl, indolyl, indazolyl, benzofuranyl, benzotriazolyl, benzoimidazolyl-2-one, benzoxazolyl-2-one, furyl, thienyl, thiazolyl, pyridyl or pyrimidinyl,

R ² , R ^{2 are} H or together form a butylene unit and n is 1

and their pharmaceutically acceptable salts, derivatives, solvates and stereoisomers, including mixtures thereof in all ratios.

4. A process for the preparation of compounds of formula I and their physiologically acceptable salts, derivatives, solvates and stereoisomers, characterized in that a compound of formula VI

with a compound of formula V

V

is condensed to a compound of formula IV

which further with a desired radical R ¹ to a compound of formula III

which is finally reacted with NH ₃ to give a compound of the formula I, and that, if appropriate, a base or acid of the formula I is converted into one of its salts.

5. Compounds according to one or more of claims 1 to 3 and / or their physiologically acceptable salts, derivatives, solvates and

20 stereoisomers, including mixtures thereof in all ratios as a drug.

6. Medicaments containing at least one compound according to one or more of claims 1 to 3 and / or their physiologically acceptable salts, derivatives, solvates and stereoisomers, including their salts

Mixtures in all ratios, and optionally excipients and / or adjuvants.

³⁰ 7. A pharmaceutical composition containing at least one compound according to one or more of claims 1 to 3 and / or their physiologically acceptable salts, derivatives, solvates and stereoisomers, including mixtures thereof in all proportions and at least one further Arz-

35 active agent.

8. Set (kit) consisting of separate packages of a) an effective amount of a compound according to one or more of claims 1 to 3 and / or their physiologically acceptable salts, derivatives, solvates and stereoisomers, including mixtures thereof in all proportions and b) an effective amount of another active pharmaceutical ingredient.

9. Compounds according to one or more of claims 1 to 3 and their physiologically acceptable salts, derivatives, solvates and stereoisomers, including mixtures thereof in all proportions as inhibitors of protein kinases.

10. Use of compounds according to one or more of claims 1 to 3 and / or their physiologically acceptable salts, derivatives, solvates and stereoisomers, including mixtures thereof in all proportions for the preparation of a medicament for prophylaxis or

Treatment of diseases in which the inhibition of protein

Kinases leads to the improvement of the clinical picture.

11. Use of compounds according to one or more of claims 1 to 3 and / or their physiologically acceptable salts, derivatives, solvates and stereoisomers, including mixtures thereof in all proportions for the preparation of a medicament for the prophylaxis or treatment of cancer, tumor growth, tumor angiogenesis , Arteriosclerosis, diabetic retinopathy and inflammatory diseases.

12. Use of compounds according to one or more of claims 1 to 3 and / or their physiologically acceptable salts, derivatives, solvates and stereoisomers, including mixtures thereof in all

Conditions for the preparation of a medicament for prophylaxis or

Treatment of breast cancer, brain cancer, prostate cancer, colorectal cancer, small cell lung cancer, non-small cell lung cancer, multiple myeloma and renal cell carcinoma and endometrial carcinoma.