MX2007005338A - Novel anthranilamide pyridinureas as vegf receptor kinase imhibitors - Google Patents

Abstract

The invention relates to novel anthranilamide pyridinureas as VEGF receptor kinase inhibitors, their production and use as pharmaceutical agents for preventing or treating diseases that are triggered by persistent angiogenesis.

Description

NOVEDOSAS PIRIDINUREA ANTRANI LAMI DAS AS KINASE INHIBITORS OF RECEPTORS OF THE VASCULAR ENDOTHELIUM GROWTH FACTOR (VEGF) Field of the Invention The invention relates to novel pyridinurea anthranilamides as inhibitors of VEGF receptor kinases, their production and use as pharmaceutical agents to prevent or treat diseases that are triggered by persistent angiogenesis. BACKGROUND OF THE INVENTION It is known that many diseases are associated with persistent angiogenesis, for example, diseases such as tumor growth or metastasis; psoriasis; arthritis, such as rheumatoid arthritis, hemangioma, endometriosis, angiofibroma; ophthalmological diseases, such as diabetic retinopathy, neovascular glaucoma; kidney diseases, such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathic syndrome, transplant rejections and glomerulopathy; fibrotic diseases, such as liver cirrhosis, mesangial cell proliferative diseases and arteriesclerosis. Lymphangiogenesis is a process that accompanies tumor growth and metastasis. It is important in lymphedema, lymphangiectasia, lymphangioma, and lymphoma, and in asthmatic disease, where the lymphatic vessels are chronically overexpressed in the lung. Persistent angiogenesis is induced by VEGF factor through its receptors. For VEGF to be able to exert this action, it is necessary for VEGF to bind to the receptor and for tyrosine phosphorylation to be induced. Direct or indirect inhibition of the VEGF receptor can be used to prevent or treat such diseases and other VEGA-induced vascular permeable vascular and angiogenesis conditions, such as tumor vascularization. For example, it is known that the growth of tumors can be inhibited by soluble receptors and antibodies against VEGF, one example being Avastin®, whose treatment paradigm has been introduced in human cancer therapy. The anthranilic acid amides which are effective in the treatment of psoriasis; arthritis, such as rheumatoid arthritis, hemangioma, angiofibroma; ophthalmological diseases, such as diabetic retinopathy, neovascular glaucoma; kidney diseases, such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathic syndrome, transplant rejections and glomerulopathy; fibrotic diseases, such as liver cirrhosis, mesangial cell proliferative diseases, arteriosclerosis, damage to nervous tissue, and to inhibit reocclusion of vessels after balloon catheterization, in the implantation of vascular prostheses or after using mechanical devices to maintain open vessels, such as, for example, Stents, as described in WO 00/27820. The anthranilic acid amides which are effective in the treatment of tumor growth or metastasis, psoriasis, Kaposi's sarcoma, restenosis, such as, for example, stent-induced restenosis, endometriosis, Crohn's disease, Hodgkin's disease, leukemia; arthritis, such as rheumatoid arthritis, hemangioma, angiofibroma; ophthalmological diseases, such as diabetic retinopathy, neovascular glaucoma; kidney diseases, such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathic syndrome, transplant rejections and glomerulopathy; fibrotic diseases, such as liver cirrhosis, mesangial cell proliferative diseases, arteriosclerosis, damage to nervous tissue, and to inhibit reocclusion of vessels after balloon catheterization, in the implantation of vascular prostheses or after using mechanical devices to maintain open vessels, such as, for example, Stents, as immunosuppressive agents, as a support in a scarless healing, in senile keratosis and in contact dermatitis, also described in WO 04/13102. However, there remains a desire to produce compounds that are as effective as possible in as wide a range of indications as possible. Constant blocking of VEGF-mediated signal transduction is desirable to reduce persistent angiogenesis and lymphangiogenesis. Compounds suitable for longer term treatments should exhibit little or no potential drug-drug interaction. The cytochrome P450 isoenzymes play a fundamental role in the degradation of pharmaceutical agents. The problem is also complicated by the fact that patients can express different relative amounts of isoenzymes. An inhibition of these isoenzymes can result in undesired interactions between pharmaceutical agents, especially in the case of multimorbid patients (patients with multiple disease states). For example, the inhibition of cytochrome P450 isoenzymes responsible for the metabolism of the related agent could lead to systemic toxic concentrations. There are other problems in a combination therapy with other medications, since the inhibition of the cytochrome P450 isoenzymes responsible for the metabolism of said co-medications could lead to toxic systemic concentrations of said co-medication. This is especially the case with cytostatics co-administered in the case of a cancer therapy. Accordingly, it has now been surprisingly found that the compounds of the general formula (I), which are described below, have more advantageous physicochemical and / or pharmacokinetic properties and prevent, for example, the tyrosine phosphorylation or stop the persistent angiogenesis. and hence the growth and spread of tumors, whereby they are particularly distinguished by a potent inhibition of VEGF receptor kinases and a reduced potential of drug-drug interactions, specifically a reduced inhibition of cytochrome P450 isoenzymes 2C9 and 2C19 . Detailed Description of the Invention The compounds of formula (I) are then suitable, for example, for the treatment or prevention of diseases for which an inhibition of angiogenesis and / or VEGF receptor kinases is beneficial. In one aspect of the invention, a pyridinurea anthranilamide compound of formula (I) is provided: (I), wherein: X is CH or N, preferably CH; is hydrogen or fluorine; preferably hydrogen; they are, independently of each other, CH or N, where only a maximum of two nitrogen atoms are contained in the ring; preferably A, E and Q are, each, CH; is aryl or heteroaryl, which may be optionally substituted at one or more sites in the same manner, or differently, with halogen, hydroxy, Ci-C12-alkyl, C2-C6-alkenyl, d-C12-alkoxy, halo- dC6-alkyl, = 0, -S02R6, -OR5, -SOR4, -COR6, -C02R6 or -NR7R8, wherein d-C12-alkyl can be substituted with -NR7R8; preferably the heteroaryl is optionally substituted at one or more sites in the same manner, or differently, with halogen, hydroxy, dC ^ -alkyl, C2-C6-alkenyl, d-C12-alkoxy, halo-d-C6- alkyl, = 0, -S02R6, -OR5, -SOR4, -COR6, -C02R6 or -NR7R8, wherein C12-alkyl can be substituted with -NR7R8; more preferably the heteroaryl is substituted at one or more sites in the same manner, or differently, with halogen, hydroxy, d-C12-alky, C2-C6-alkenyl, d-C12-alkoxy, halo-C, -C6-alkyl, = 0, -S02R6, -OR5, -SOR4, -COR6, -C02R6 or -NR7R8, wherein d-C12-alkyl can be substituted with -NR7R8; even more preferably quinolinyl, isoquinolinyl or indazolyl which may be optionally substituted at one or more sites in the same manner, or differently, with halogen, hydroxy, dC 2 -alkyl, C 2 -C 6 -alkenyl, d-C 12 -alkoxy, halo-d-Ce-alkyl, = 0, -S02R6, -OR5, -SOR4, -COR6, -C02R6 or -NR7R8, wherein d-C12-alkyl can be substituted with -NR7R8; even more preferably quinolinyl, isoquinolinyl or indazolyl substituted at one or more sites in the same manner, or differently, with halogen, hydroxy, C12-alkyl, C2-C6-alkenyl, dC2-alkoxy, halo-d- C6-alkyl, = 0, -S02R6, -OR5, -SOR4, -COR6, -C02R6 or -NR7R8, wherein d-C12-alkyl can be substituted with -NR7R8; more particularly preferred indazolyl substituted with d-C12-alkyl, particularly 2-methyl-indazolyl and 1-methyl indazolyl; form, together with the nitrogen atom to which they are attached, a 3-8 membered heterocycloalkyl ring, preferably a 4-7 membered heterocycloalkyl ring, which optionally may contain at least one additional heteroatom, such as nitrogen, oxygen or sulfur, and which may be optionally substituted at one or more sites in the same manner, or differently, with halogen, cyano, d-Ci2-alkyl, d-C12-alkoxy, halo-Ci-C6-alkyl, C C3-dialkylketal, d-C3-cyclic ketal, = 0, -OR5, -SR4, -SOR4, -S02R6, -COR6 or -C02R6, wherein the d-C12 alkyl may also be optionally substituted with a group -OR5; more preferably, R2 and R3 form, together with the nitrogen atom to which they are attached, a 5- or 6-membered heterocycloalkyl ring, which contains no or at least one additional heteroatom, such as nitrogen, oxygen or sulfur, and which may be optionally substituted at one or more sites in the same manner, or differently, with halogen, cyano, Ci-Ci2-alkyl, CrCi2-alkoxy, halo-d-Cg-alkyl, d-C3-dialkylketal, Ci -C3-cyclic ketal, = 0, -OR5, -SR4, -SOR4, -S02R6, -COR6 or -C02R6, wherein the C, -C2 alkyl may also be optionally substituted with a group -OR5; is d-C12-alkyl, C3-C8-cycloalkyl, aryl or heteroaryl; preferably C 12 -alkyl; more preferably -CH3; is hydrogen, d-C 12 -alkyl, C 3 -C 8 -cycloalkyl or halo-C C 6 -alkyl; preferably -CH3 or hydrogen; more preferably hydrogen; is hydrogen, CrC ^ -alkyl, C3-C8-cycloalkyl, halo-d-C6-alkyl, aryl or -NR7Re; preferably C C ^ -alkyl or -NR7R8; more preferably -CH3; they are, independently of each other, hydrogen, -S02R6, -COR6, aryl, C3-C8-cycloalkyl, CrC12-alkyl, halo-CC ^ -alkyl or d-C12-alkoxy, where C, -C12- alkyl may be optionally substituted with -OR5 or -N (CH3) 2, or R7 and R8 may also be chosen such that they provide a cycloalkyl ring of 3-8 members, preferably a cycloalkyl ring of 4-7 members, more preferably a 5-6 membered cycloalkyl ring, which optionally may contain at least one additional heteroatom, such as nitrogen, oxygen or sulfur, and may be optionally substituted at one or more sites in the same way, or differently, with halogen, cyano, d-C12-alkyl, d-Ci2-alkoxy, halo-C, -C6-alkyl, = 0, -OR5, COR6, -SR4, -SOR4 or -S02R6; preferably R7 and R8 are, independently of each other, hydrogen, COR6, -S02R6, CC ^ -alkyl; more preferably hydrogen or CrC ^ -alkyl; more preferably hydrogen or -CH3, and also isomers, diastereoisomers, enantiomers, tautomers and salts thereof. In a second aspect of the present invention, there is provided a pharmaceutical agent comprising at least one compound of formula (I) or an isomer, diastereoisomer, enantiomer, tautomer or salt thereof. In a third aspect of the present invention, there is provided a pharmaceutical agent comprising at least one compound of formula (I), or an isomer, diastereomer, enantiomer, tautomer or salt thereof, and at least one carrier, diluent or excipient acceptable for pharmaceutical use. In a fourth aspect of the present invention, there is provided a pharmaceutical agent comprising at least one compound of formula (I), or an isomer, diastereomer, enantiomer, tautomer or salt thereof, for use in the prevention or treatment of diseases associated with persistent angiogenesis and / or diseases associated with excessive lymphangiogenesis. In a fifth aspect of the present invention, there is provided a pharmaceutical agent comprising at least one compound of formula (I), or an isomer, diastereomer, enantiomer, tautomer or salt thereof, for use in the prevention or treatment of tumor growth or metastasis; psoriasis; Kaposi's sarcoma; restenosis including restenosis induced by a Stent; Crohn's disease; Hodgkin's disease; leukemia; arthritis including rheumatoid arthritis, hemangioma, angiofibroma; endometriosis; ophthalmologic diseases including diabetic retinopathy, neovascular glaucoma; cornea transplants; kidney diseases, including glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathic syndrome, transplant rejections and glomerulopathy; fibrotic diseases, including liver cirrhosis; mesangial cell proliferative diseases; arteriesclerosis; damage to nervous tissue, and to inhibit reocclusion of vessels after balloon catheterization; in the implantation of vascular prostheses or after using mechanical devices to keep the vessels open, as immunosuppressive agents as a support in scar-free healing; senile keratosis; contact dermatitis; and asthma. In a sixth aspect of the present invention, there is provided a pharmaceutical agent comprising at least one compound of formula (I), or an isomer, diastereomer, enantiomer, tautomer or salt thereof, for use as inhibitors of kinase of VEGF-3 receptors in lymphangiogenesis. In a seventh aspect of the present invention, there is provided a pharmaceutical agent comprising at least one compound of formula (I), or an isomer, diastereomer, enantiomer, tautomer or salt thereof, for use in a method for treatment of the body of an animal or human being. In an eighth aspect of the present invention, there is provided a pharmaceutical agent comprising at least one compound of formula (I), or an isomer, diastereomer, enantiomer, tautomer or salt thereof, for use in the preparation of a pharmaceutical product for the prevention or treatment of a disease in which inhibition of angiogenesis and / or lymphangiogenesis and / or VEGF receptor kinases is beneficial. In a ninth aspect of the present invention, there is provided a pharmaceutical agent comprising at least one compound of formula (I), or an isomer, diastereomer, enantiomer, tautomer or salt thereof, for use as an inhibitor of tyrosine kinases VEGFR-1 and VEGFR-2. In a tenth aspect of the present invention, a compound of general formula is provided ( neither ). wherein A, E, Q, W, X, R2 and R3 are as defined for formula (I) above and Ry is H or C6-alkyl, as an intermediate for the preparation of a compound of formula Preferably, R 'is H or C1-C2-alkyl, W is hydrogen and X is CH; more preferably, Ry is H or -CH3, W is hydrogen and X is CH. In a eleventh aspect of the present invention, there is provided the use of a compound of general formula (III), wherein A, E, Q, W, X, R2 and R3 are as defined for formula (I) above and Ry is H or CrC6-alkyl, as an intermediate for the preparation of a compound of formula (I). In a twelfth aspect of the present invention, there is provided a process for the preparation of a compound of formula (I), wherein all substituents are as described in claim 1, wherein a compound of formula (III), in where A, E, Q, W, X, R2 and R3 are as defined in claim 1 and Ry is H or CrCValkyl, is reacted with an amine of formula R1NH2 wherein R1 is as defined in claim 1. In a thirteenth aspect of the present invention, there is provided a process for the preparation of a compound of formula (I), wherein all substituents are as described in claim 1, wherein a compound of formula (II): wherein A, E, Q, W, X, and R1 are as defined in claim 1 and M represents halogen: (i) is first converted to an amine and then converted to a compound of formula (I) by reaction with a carbamoyl chloride of formula CICONR R3, wherein R2 and R3 are as defined in claim 1; or, alternatively, (i) is reacted with a compound of the formula H2NCONR2R3, wherein R2 and R3 are as defined in claim 1, or alternatively, (iii) is first converted to an amine and then converted to in a compound of formula (I) by a first reaction with a compound of formula CIC02Ph and then by reaction with a compound of formula HNR2R3, wherein R2 and R3 are as defined in claim 1. Preferably a compound of formula (I ) is prepared using the process (i). As used herein, the term "alkyl" is defined in each case as a substituted or unsubstituted straight or branched chain alkyl group, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl or hexyl, heptyl, octyl, nonyl, decyl, undecyl or dodecyl. As used herein, the term "alkoxy" is defined in each case as a straight or branched chain alkoxy group, such as, for example, methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, tert-butyloxy, pentyloxy, isopentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy or dodecyloxy. As used herein, the term "cycloalkyl" is defined as a monocyclic alkyl ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, and also as bicyclic rings or tricyclic rings, such as , for example, adamantanyl. The cycloalkyl group may also contain one or more heteroatoms, such as oxygen, sulfur and / or nitrogen, such that a heterocycloalkyl ring is formed. As used herein, the term "heterocycloalkyl", as used herein, for example as used in the definition of "R2 and R3 form, together with the nitrogen atom to which they are attached, a heterocycloalkyl ring 3-8 membered "is defined as a monocyclic alkyl ring containing a nitrogen atom and optionally containing at least one additional heteroatom, such as oxygen, sulfur and / or nitrogen, where it will be understood that said nitrogen atom binds the Heterocycloalkyl ring with the rest of the molecule. Preferred 3-8 membered heterocycloalkyl rings, preferably 4-7 membered heterocycloalkyl rings. Even more 5 or 6 membered heterocycloalkyl rings are preferred. For example, a heterocycloalkyl ring such as one selected from the following list may be mentioned: It will be understood that any of the above structures may contain at least one additional heteroatom, such as nitrogen, oxygen or sulfur. In particular, the following heterocycloalkyl rings may be mentioned: tetrahydrofuran, tetrahydropyran, pyrrolidine, piperidine, morpholine, piperazine and thiomorpholine. The heterocycloalkyl ring may be optionally substituted at one or more sites in the same manner, or differently, with, for example, halogen, cyano, CVC ^ -alkyl, dC ^ -alkoxy, halo-C C6-alkyl, = 0 , -OR5, -SR4, -SOR4 or -S02R6, -COR6, -C02R6, wherein the C12 alkyl may also be optionally substituted with a group -OR5. It will be understood that the substitution in any of the aforementioned heterocycloalkyl rings can be in any of the carbon atoms of the heterocycloalkyl ring and / or in any of the heteroatoms of the heterocycloalkyl ring. Preferably the heterocycloalkyl ring is substituted at one or two sites. As used herein, the term "cycloalkenyl" is defined in each case as cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl or cyclodecenyl, whereby the bond can be made with the double bond and with the single bonds. As used herein, the term "halogen" is defined in each case as fluorine, chlorine, bromine or iodine, with fluorine being preferred for the compounds of formula (I) and with chlorine and bromine being preferred as a substitute for M in the compounds of formula (II). As used herein, the term "halo-C Cg-alkyl" is defined as a C C6 alkyl group wherein some or all of the hydrogen atoms are replaced by halogen atoms, preferably replaced by one or more hydrogen atoms. fluorine. The CF3 group is preferred.

As used herein, the term "alkenyl" is defined in each case as a straight or branched chain alkenyl group containing 2-6, preferably 2-4 carbon atoms. For example, the following groups may be mentioned: vinyl, propen-1-yl, propen-2-yl, but-1-en-1-yl, but-1-en-2-yl, but-2-en- 1 -yl, but-2-en-2-yl, 2-methyl-prop-2-en-1-yl, 2-methyl-prop-1-en-1-yl, but-1-en-3- ilo, but-3-en-1-yl and allyl. As used herein, the term "aryl" is defined in each case to have between 3 and 12 carbon atoms, preferably 6-12 carbon atoms, such as, for example, cyclopropenyl, cyclopentadienyl, phenyl, tropyl, cyclooctadienyl, indenyl, naphthyl, azulenyl, biphenyl, fluorenyl, anthracenyl, etc., phenyl being preferred. As used herein, the term "d-CV, as used herein, for example in the context of the definitions of" CrCi2-alkyl "and" CrC12-alkoxy ", is to be construed as an alkyl group or alkoxy containing a finite number of carbon atoms between 1 and 12, ie 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. term ', -? ^ "should be interpreted as any subrange included in it, for example C1-C12, C2-C11 C3-C10, C4-Cg Cs-Cg, C6-C7, C1-C2, C1-C3 C1- C5 Ci-C6, Ci-C7, Ci-Ce, C1-C9, Ci-C10, CrC "; preferably C: -C2, C -C3, C1-C4, C1-C5, C ^ Ce: more preferably C ° 3 Similarly, as used herein, the term "C2-C6", as used herein, for example in the context of the definitions of "C2-C6-alkenyl", should be interpreted as a alkenyl group containing a finite number of carbon atoms between 2 and 6, ie 2, 3, 4, 5 or 6 carbon atoms. It is further considered that said term "C2-C6" should be interpreted as any subrange included therein, for example C2-C6, C3-C5i C3-C C2-C3 C2-C, C2-C5; preferably C2-C3 Further, as used herein, the term "?, -? ß", as used herein, for example in the context of the definitions of "halo-d-C6-alkyl", it should be interpreted as a haloalkyl group containing a finite number of carbon atoms between 1 and 6, ie 1, 2, 3, 4, 5 or 6 carbon atoms. It is further considered that said term "C, -C6" should be interpreted as any subrange included therein, for example C ^ -C6 C2-C5, C3-C4, C, -C2, C1-C3, C, -C4, C, -C5, CrC6; more preferably C C-. As used herein, the term "heteroaryl" as defined in each case, is an aromatic ring system containing, in the ring, at least one heteroatom which may be identical or different, and which comprises 3-16 atoms in the ring, preferably 5 or 6 atoms or 9 or 10 atoms, said heteroatom being for example oxygen, nitrogen or sulfur, and can be monocyclic, bicyclic or tricyclic, and in each case can be benzocondensed. Preferably, the heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc., and benzo derivatives thereof, such as, for example, benzofuranyl, benzothienyl , benzoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl, indolyl, isoindolyl, etc .; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof, such as, for example, quinolinyl, isoquinolinyl, etc .; or azocinyl, indolizinyl, purinyl, etc., and benzo derivatives thereof; or cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naftpyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl or oxepinyl, etc. More preferably, the heteroaryl is selected from quinolinyl, isoquinolinyl, or indazolyl. More preferably still, the heteroaryl is indazolyl. As used herein, the term "C C3-dialkylketal" represents a group that is formed when two Ci-C3-alkoxy groups are attached, preferably through their oxygen atoms, to the same carbon atom. Preferably, the group Ci-C3-alkoxy is -OCH3. As used herein, the term "cyclic CVC3-cet.al" is defined as a 5-6 membered ring that is formed when a CVCs-dioxyalkyl group, such as ethane-1,2-dioxy or propan- 1,3-dioxy, is attached through the oxygen atoms to the same carbon atom. Examples of cyclic d-C3-ketals are 1,3-dioxolane or 1,3-dioxane rings. Preferably, the Cr C3-cyclic ketal is -0 (CH2) 20- such that a 1,3-dioxolane ring is formed. The aryl group and the heteroaryl group can each be substituted in the same way, or differently, at one or more sites with halogen, hydroxy, CVC ^ -alkyl, C2-C6-alkenyl, d-dz- alkoxy, halo-d-C6-alkyl, = 0, -S02R6, -OR5, -SOR4, -COR6, -C02R6 or -NR7R8, wherein the d-d2-alkyl can be substituted with -NR7R8. It will be understood that the substitution in the aryl group and the heteroaryl group can be in any of the carbon atoms and / or in any of the heteroatoms of the group. Preferably the aryl group and the heteroaryl group is substituted at one or two sites. If an acid group is included, those salts of organic and inorganic bases which are physiologically acceptable, such as, for example, the alkali salts and readily soluble alkaline earth salts as well as N-methyl-glucamine, dimethyl glucamine, are suitable as salts. , ethyl-glucamine, lysine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-amine-methane, aminopropanediol, Sovak base and 1-amino-2,3,4-butanediol. If a basic group is included, the physiologically acceptable salts of organic and inorganic acids are suitable, such as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, succinic acid, fumaric acid. The compounds of general formula (I) according to the invention also contain the possible tautomeric forms and comprise the E isomers or Z isomers or, if there are one or more stereogenic centers, racemates and / or enantiomers and / or diastereoisomers. Accordingly, a molecule with a single stereogenic center can be a mixture of enantiomers (R, S) or can be an individual (R) or (S) enantiomer. A molecule with more than one stereogenic center may comprise a mixture of diastereoisomers or may comprise a single diastereomer, whereby diastereomers may also exist as mixtures of enantiomers or as individual enantiomers. An embodiment of the present invention comprises compounds of formula (I) wherein X is CH. In one embodiment, W is hydrogen. In one embodiment, A, E and Q are, each, CH.

In one embodiment, X is CH, W is hydrogen and A, E and Q are each CH. In one embodiment, R1 is aryl or heteroaryl, which may be optionally substituted at one or more sites in the same manner, or differently, with halogen, hydroxy, C, -C12-alkyl, C2-C6-alkenyl, d- C12-alkoxy, halo-Ci-C6-alkyl, = 0, -S02R6, -OR5, -SOR4, -COR6, -C02R6 or -NR7R8, wherein d-C12-alkyl can be substituted with -NR7R8. In another embodiment, R1 is heteroaryl optionally substituted at one or more sites in the same manner, or differently, with halogen, hydroxy, Ci-C2-alkyl, C2-C6-alkenyl, d-C12-alkoxy, halo- dCe-alkyl, = 0, -S02R6, -OR5, -SOR4, -COR6, -C02R6 or -NR7R8, wherein C, -Ci2-alkyl can be substituted with -NR7R8. In a preferred embodiment, R1 is heteroaryl substituted at one or more sites in the same manner, or differently, with halogen, hydroxy, dC ^ -alkyl, C2-C6-alkenyl, d-C12-alkoxy, halo-d -C6-alkyl, = 0, -S02R6, -OR5, -SOR4, -COR6, -C02R6 or -NR7R8, wherein the CC2-alkylene can be substituted with -NR7R8. In a more preferred embodiment, R1 is quinolinyl, isoquinolinyl or indazolyl which may be optionally substituted at one or more sites in the same manner, or differently, with halogen, hydroxy, Ci-C12-alkyl, C2-C6-alkenyl, dC, 2-alkoxy, halo-C, -C6-alkyl, = 0, -S02R6, -OR5, -SOR4, -COR6, -C02R6 or -NR7R8, where Ci-Ci2-alkyl can be substituted with -NR7R8. In an even more preferred embodiment, R1 is quinolinyl, isoquinolinyl or indazolyl substituted at one or more sites in the same manner, or differently, with halogen, hydroxy, d-C12-alkyl, C2-C6-alkenyl, Ci-C12 -alkoxy, halo-C, -C6-alkyl, = 0, -S02R6, -OR5, -SOR4, -COR6, -C02R6 or -NR7R8, wherein the dC ^ -alkyl can be substituted with -NR7R8. In a still more preferred embodiment, R 1 is indazolyl substituted with C Ci 2 -alkyl, particularly R 1 is 2-methyl-indazolyl or 1-methyl-indazolyl. In one embodiment, R2 and R3 form, together with the nitrogen atom to which they are attached, a 5- or 6-membered heterocycloalkyl ring, which contains no or at least one additional heteroatom, such as nitrogen, oxygen or sulfur, and which can optionally being substituted at one or more sites in the same manner, or differently, with halogen, cyano, d-Ci2-alkyl, d-C12-alkoxy, halo-d-C6-alkyl, dd-dialkyl-ketal, d-C3 cyclic ketal, = 0, -OR5, -SR4, -SOR4, -S02R6, -COR6 or -C02R6, wherein the d-C12 alkyl may also be optionally substituted with a group -OR5. In one embodiment, R 4 is d-C 12 -alkyl. In a preferred embodiment, R4 is -CH3.

In one embodiment, R5 is -CH3 or hydrogen. In a preferred embodiment, R5 is hydrogen.

In one embodiment, R6 is C, -Ci2-alkyl or -NR7R8. In a preferred embodiment, R6 is C-alkyl. In a more preferred embodiment, R6 is -CH3. In one embodiment, R7 and R8 are, independently of each other, hydrogen, COR6, S02R6, Ci2-alkyl. In a preferred embodiment, R7 and R8 are, independently of each other, hydrogen CH3. In one embodiment: X is CH, W is hydrogen, A, E and Q are, each, CH, R1 is aryl or heteroaryl, which may be optionally substituted at one or more sites in the same manner, or differently, with halogen, hydroxy, C2-C6-alkenyl, C, -C12-alkoxy, halo-C, -C6-alkyl, = 0, -S02R6, -OR5, -SOR4, -COR6, -C02R6 or -NR7R8, wherein the CC ^ -alkyl can be substituted with -NR7R8, R2 and R3 form, together with the nitrogen atom to which they are attached, a 3-8 membered heterocycloalkyl ring, preferably a 4-7 membered heterocycloalkyl ring, more preferably a 5- or 6 membered heterocycloalkyl ring, which optionally may contain at least one additional heteroatom, such as nitrogen, oxygen or sulfur, and which may be optionally substituted at one or more sites in the same manner, or differently, with halogen, cyano, C, -C, 2-alkyl, C , -C12-alkoxy, halo-CrC6-alkyl, CrC3-dialkyl-ketal, d-Cs-cyclic ketal, = 0, -OR5, -SR4, -SOR4, -S02R6, -COR6 or -C02R6, wherein the C, -C12 alkyl may also be optionally substituted with a group -OR5, R4 is CrC12-alkyl, C3-C8-cycloalkyl , aryl or heteroaryl, R5 is hydrogen, Ci-C ^ -alkyl, C3-C8-cycloalkyl or halo-C, -C6-alkyl, R6 hydrogen, dC ^ -alkyl, C3-C8-cycloalkyl, halo-d-Ce -alkyl, aryl or -NR7R8, R7 and R8 are, independently of each other, hydrogen, -S02R6, -COR6, aryl, C3-C8-cycloalkyl, CC ^ -alkyl, halo-CrC ^ -alkyl or Ci-Ci2-alkoxy, where C, - C alkyl may be optionally substituted with -OR5 or -N (CH3) 2, or R7 and may also be chosen such that they provide a cycloalkyl ring of 3-8 members, preferably a cycloalkyl ring of 4-7 members, more preferably a 5-6 membered cycloalkyl ring, which optionally may contain at least one additional heteroatom, such as nitrogen, oxygen or sulfur, and may be optionally substituted at one or more sites in the same way, or differently, with halogen, cyano, d-C12-alkyl, d-C12-alkoxy, halo-C, -C6-alkyl, = 0, -OR5, COR6, -SR4, -SOR4 or -S02R6, and also isomers, diastereomers, enantiomers, tautomers and you come out of them. In a preferred embodiment: X is CH, W is hydrogen, A, E and Q are, each, CH, R1 is heteroaryl, which may be optionally substituted at one or more sites in the same manner, or differently, with halogen, hydroxy, dC ^ -alkyl, C2-C6-alkenyl, d-C12-alkoxy, halo-C, -C6-alkyl, = 0, -S02R6, -OR5, -SOR4, -COR6, -C02R6 or -NR7R8 , wherein C C 12 -alkyl can be substituted with -NR 7 R 8, R 2 and R 3 form, together with the nitrogen atom to which they are attached, a 3-8 membered heterocycloalkyl ring, preferably a 4-7 membered heterocycloalkyl ring, more preferably a 5- or 6-membered heterocycloalkyl ring, which optionally may contain at least one additional heteroatom, such as nitrogen, oxygen or sulfur, and which may be optionally substituted at one or more sites in the same manner, or differently, with halogen , cyano, d- Ci2-alkylo, CrC12-alkoxy, halo-d-C6-alkylo, d-C3-dialkylacetal, d-C3-cyclic ketal, = 0, -OR5, -SR 4, -SOR4, -S02R6, -COR6 or -C02R6, wherein the d-d2 alkyl may also be optionally substituted with a group -OR5; R4 is d-Ci2-alkyl, C3-C8-cycloalkyl, heteroaryl or heteroaryl, R5 is hydrogen, d-C12-alkylo, C3-C8-cycloalkyl or halo-Ci-C6-alkylo , Hydrogen R6, C12-alkyl, C3-C8-cycloalkyl, halo-d-C6-alkyl, aryl or -NR7R8, R7 and R8 are, independently of each other, hydrogen, -S02R6, -COR6, aryl, C3-C8-cycloalkyl, C-C12-alkyl, halo-CrC ^ -alkyl or Ci-Ci2-alkoxy, where the C ^ -alkyl can be optionally substituted with -OR5 or -N (CH3) 2, or R7 and R8 can also be chosen such that they provide a cycloalkyl ring of 3-8 members, preferably a cycloalkyl ring of 4-7 members , more preferably a 5-6 membered cycloalkyl ring, which optionally may contain at least one additional heteroatom, such as nitrogen, oxygen or sulfur, and may be optionally substituted at one or more sites in the same manner, or in a different manner, with halogen, cyano, Ci-Ci2-alkyl, Ci-C12-alkoxy, halo-d-C6-alkyl, = 0, -OR5, COR6, -SR4, -SOR4 or -S02R6, and also isomers, diastereoisomers, enantiomers , tautomeros and salts thereof. In an even more preferred embodiment: X is CH, W is hydrogen, A, E and Q are each CH, R1 is quinolinyl, isoquinolinyl or indazolyl which may be optionally substituted at one or more sites in the same manner, or in a different manner, with halogen, hydroxy, C, -C12-alkyl, C2-C6-alkenyl, Ci-Ci2-alkoxy, halo-CrCValkyl, = 0, -S02R6, -OR5, -SOR4, -COR6, -C02R6 or -NR7R8, where C C 12 -alkyl can be substituted with -NR 7 R 8, form, together with the nitrogen atom to which they are attached, a 3-8 membered heterocycloalkyl ring, preferably a 4-7 membered heterocycloalkyl ring, more preferably a 5- or 6-membered heterocycloalkyl ring, which optionally may contain at least one additional heteroatom, such as nitrogen, oxygen or sulfur, and which may be optionally substituted at one or more sites in the same manner, or differently, with halogen, cyano, C Ci2-alkyl, CrCi2-alkoxy, halo-Ci-C6-alkyl, CrC3-dialkyl ketal, CC 3-cyclic ketal, = 0, -OR5, -SR4, -SOR4, -S02R6, -COR6 or -C02R6, wherein the C, -C12 alkyl may also be optionally substituted with a group -OR5; is CC ^ -alkyl, C3-C8-cycloalkyl, aryl or heteroaryl, R5 is hydrogen, CrC12-alkyl, C3-C8-cycloalkyl or halo-CrC6-alkyl, R6 hydrogen, CrC12-alkyl, C3-C8-c Chloralkyl, halo-C Ce-alkyl, aryl or -NR7R8, R7 and R8 are, independently of each other, hydrogen, -S02R6, -COR6, aryl, C3-C8-cycloalkyl, C12-alkyl, halo-Ci12-alkyl, or C, -C12-alkoxy, wherein C, -C 12 -alkyl can be optionally substituted with -OR 5 or -N (CH 3) 2, or R 7 and R 8 can also be chosen such that they provide a cycloalkyl ring of 3-8 members, preferably a cycloalkyl ring of 4- 7 members, more preferably a cycloalkyl ring of 5-6 members, which optionally may contain at least one additional heteroatom, such as nitrogen, oxygen or sulfur, and may be optionally substituted at one or more sites in the same manner, or different, with halogen, cyano, CrCi2-alkyl, CrC ^ -alkoxy, halo-Ci-C6-alkyl, = 0, -OR5, COR6, -SR4, -SOR4 or -S02R6 'and also isomers, diastereoisomers, enantiomers, tautomers and salts thereof. In a more preferred embodiment: X is CH, W is hydrogen, A, E and Q are each CH, R1 is quinolinyl, isoquinolinyl or indazolyl which is substituted at one or more sites in the same way, or differently , with halogen, hydroxy, CrC ^ -alkyl, C2-C6-alkenyl, C-C12-alkoxy, halo-C, -C6-alkyl, = 0, -S02R6, -OR5, -SOR4, -COR6, -C02R6 or -NR7R8, where the CrC12-alkyl can be substituted with -NR7R8, R2 and R3 form, together with the nitrogen atom to which they are attached, a 5- or 6-membered heterocycloalkyl ring, which optionally can contain at least one additional heteroatom, such as nitrogen, oxygen or sulfur, and which may be optionally substituted at one or more sites in the same manner, or differently, with halogen, cyano, CrC 2 -alkyl, CrC ^ -alkoxy, halo-Ci-C6-alkyl , C C3-dialkylketal, d-C3-cyclic ketal, = 0, -OR5, -SR4, -SOR4, -S02R6, -COR6 or -C02R6, wherein Ci-C2-alkyl may also be optionally substituted with a group -OR5; R4 is Ci-C12-alkyl, C3-C8-cycloalkyl, aryl or heteroaryl, R5 is hydrogen, d-C12-alky, C3-C8-cycloalkyl or halo-C Ce-alkyl, R6 hydrogen, dC ^ -alkyl , C3-C8-cycloalkyl, halo-d-Ce-alkyl, aryl or -NR7R8, R7 and R8 are, independently of each other, hydrogen, -S02R6, -COR6, aryl, C3-C8-cycloalkyl, dC ^ -alkyl, halo-C12-alkyl or d-C12-alkoxy, where d-C12 - alkyl may be optionally substituted with -OR5 or -N (CH3) 2, or R7 and R8 may also be chosen such that they provide a cycloalkyl ring of 3-8 members, preferably a cycloalkyl ring of 4-7 members, more preferably a 5-6 membered cycloalkyl ring, which optionally may contain at least one additional heteroatom, such as nitrogen, oxygen or sulfur, and may be optionally substituted at one or more sites in the same manner, or differently, with halogen , cyano, d-C12-alkylene, dC2-alkoxy, halo-dC6-alkyl, = 0, -OR5, COR6, -SR4, -SOR4 or -S02R6, and also isomers, diastereoisomers, enantiomers, tautomers and salts thereof. In an even more preferred embodiment: X is CH, W is hydrogen, A, E and Q are, each, CH, R1 is indazolyl which may be optionally substituted at one or more sites in the same manner, or in a different manner, with halogen, hydroxy, Ci-C12-alkyl, C2-C6-alkenyl, d-Ci2-alkoxy, halo-d-C6-alkyl, = 0, -S02R6, -OR5, -SOR4, -COR6, -C02R6 or - NR7R8, where d-C12-alkyl can be substituted with -NR7R8, R2 and R3 form, together with the nitrogen atom to which they are attached, a 5- or 6-membered heterocycloalkyl ring, which optionally can contain at least one additional heteroatom, such as nitrogen, oxygen or sulfur, and which may be optionally substituted at one or more sites in the same manner, or differently, with halogen, cyano, d-C12-alkyl, d-C12-alkoxy, halo-d -C6-alkyl, dC3-dialkylketal, dC3-cyclic ketal, = 0, -OR5, -SR4, -SOR4, -S02R6, -COR6 or -C02R6, wherein the d-C12 alkyl may also be optionally substituted with a group -O R5; R4 is d-Ci2-alkyl, C3-C8-cycloalkyl, aryl or heteroaryl, R5 is hydrogen, d-C12-alkyl, C3-C8-cycloalkyl or halo-d-C6-alkyl, R6 hydrogen, dC ^ -alkyl, C3-C8-cycloalkyl, halo-d-C6-alkyl, aryl or -NR7R8, R7 and R8 are, independently together, hydrogen, -S02R6, -COR6, aryl, C3-C8-cycloalkyl, d-Ci2-alkyl, halo-d-C12-alkyl or d-C12-alkoxy, where d-C12-alkyl may be substituted optionally with -OR5 or -N (CH3) 2, or R7 and R8 may also be chosen such that they provide a cycloalkyl ring of 3-8 members, preferably a cycloalkyl ring of 4-7 members, more preferably a cycloalkyl ring of 5-6 members, which optionally may contain at least one additional heteroatom, such as nitrogen, oxygen or sulfur, and may be optionally substituted at one or more sites in the same manner, or differently, with halogen, cyano, d- C12-alkyl, d-C12-alkoxy, halo-CC6-alkyl, = 0, -OR5, COR6, -SR4, -SOR4 or -S02R6, and also isomers, diastereoisomers, enantiomers, tautomers and salts thereof . In an even more preferred embodiment: X is CH, W is hydrogen, A, E and Q are each CH, R1 is indazolyl substituted with d-C12-alkyl, optionally containing a substituent of a halogen atom, R2 and R3 form, together with the nitrogen atom to which they are attached, a 5- or 6-membered heterocycloalkyl ring, which optionally may contain at least one additional heteroatom, such as nitrogen, oxygen or sulfur, and which may be optionally substituted in one or more sites in the same way, or differently, with halogen, cyano, C C 12 -alkyl, dC ^ -alkoxy, halo-C, -C 6 -alkyl, d-d-dialkylketal, d-C 3 -cyclic ketal, = 0, -OR5, -SR4, -SOR4, -S02R6, -COR6 or -C02R6, wherein the d-C12 alkyl may also be optionally substituted with a group -OR5; R4 is CrCi2-alkyl, R5 is hydrogen, R6 is Ci-C12-alkyl, and also isomers, diastereoisomers, enantiomers, tautomers and salts thereof. Some specific examples of compounds of the present invention include the following: (4- {[[2- (2-methyl-2H-indazol-6-ylcarbamoyl) -phenylamino] -methyl} -pyridin-2-yl) -amide of 4-hydroxy-4-methyl-piperidin -1-carboxylic acid (4- {[2- (2-methyl-2H-yndazol-6-ylcarbamoyl) -phenylamino] -methyl} - pyridin-2-yl) -amide 4-hydroxy-piperidin-1-carboxylic acid, (4- {[[2- (2-methyl-2H-indazol-6-ylcarbamoyl) -phenylamino] -methyl} -pi din-2-yl) -am 4-hydroxy-4-trifluoromethyl-piperidin-1-carboxylic acid, (4- {[[2- (2-methyl-2H-indazol-6-ylcarbamoyl) -phenylamino] -methyl. 1-Oxo-thiomorpholine-4-carboxylic acid (4 { [2- (2-methyl-2H-yndazol-6-ylcarbamoyl) -phenylamino] -amide. 1, 1-dioxo-thiomorpholine-4-carboxylic acid methyl, 4-pyridin-2-yl) -amide, (4 { [2- (2-methyl-2H-indazol-6-ylcarbamoyl) 4-methyl-piperazine-1-carboxylic acid (4-phenyl) -methyl] -methyl] -pyridin-2-yl) -amide, (4- {[2- (1-methy1-H -indazole 4-methyl-piperazine-1-carboxylic acid (6-ylcarbamoyl) -phenylamino] -methyl] -pyridin-2-yl) -amide; - { [2- (1-methyl-1 H-indazol-6-ylcarbamoyl) -phenylamino] -methyl} 4- (2-hydroxy-ethyl) -piperazin-1-carboxylic acid (4-pyridyl-2-yl) -amide. (4- (2-methyl-2H-indazol-6) 4- (2-hydroxy-ethyl) -piperazin-1-carboxylic acid (4-yl.) [2- (4- (2-hydroxy-ethyl) -piperazin-1-carboxylic acid) -phenyl-2-yl) -amide. 2-Methyl-2H-indazol-6-ylcarbamoyl) -phenylamino] -methyl] -pyridin-2-yl) -amide of 4-methanesulfonyl-piperazine-1-carboxylic acid, (4- { [2- (1-Methyl-1 H -indazol-6-ylcarbamoyl) -phenylamino] -methyl] -pyridin-2-yl) -amide of morpholine-4-carboxylic acid, (4- { [2- (2 methyl-2H-indazol-6-ylcarbamoyl) -phenylamino] -methyl] -pyridin-2-yl) -amide of morpholine-4-carboxylic acid, (4- { [2- (7- methoxy-5-quinolin-3-ylcarbamoyl) -phenylamino] -methyl] -pyridin-2-yl) -am of morpholin-4-carboxylic acid, (4-. 2,6-dimethyl-morpholine-4-carboxylic acid {2- [1- (1-methyl-1 H -indazol-6-ylcarbamoyl) -phenylamino] -methyl] -pyridin-2-yl) -amide, (4- {[2- (2-methyl-2H-indazol-6-ylcarbamoyl) -phenylamino] -methyl} - pyridin-2-yl) -am of 2,6-acid dimethyl-morpholine-4-carboxylic, (4-. { [2- (2-methyl-2H-indazol-6-ylcarbamoyl) -phenylamino] -methyl} 3-Hydroxy-pyrrolidin-1-carboxylic acid (4 { [3-fluoro-2- (2-methyl-2H-nitrozol-6-carbamoyl) -pyridin-2-yl) -am of morpholine-4-carboxylic acid, morpholine-4 (4- {[[2- (isoquinolin-3-ylcarbamoyl) -phenylamino] -methyl] -pyridin-2-yl) -ami} -carboxylic, morpholine-4-carboxylic acid (4- { [2- (3,6-difluoro-quinolin-2-ylcarbamoyl) -phenylamino] -methyl} - pyridin-2-yl) -amide, and (4-. {[[2- (3-Fluoro-6-methoxy-quinolin-2-ylcarbamoyl) -phenylamino] -methyl] -pyridin- of morpholine-4-carboxylic acid The compounds of formula (I ) can be used as pharmaceutical agents based on their inhibitory activity in relation to the phosphorylation of VEGF receptors On the basis of their action profile, the compounds according to the invention are suitable for preventing or treating diseases that are caused or promoted by persistent angiogenesis Since the compounds of formula (I) are identified as inhibitors of VEG tyrosine kinases FR-1 and VEGFR-2, are particularly suitable for preventing or treating those diseases that are caused or promoted by a persistent angiogenesis that is triggered through the VEGF receptor or by an increase in vascular permeability. The present invention also provides the use of the compounds of formula (I) as inhibitors of the tyrosine kinases VEGFR-1 and VEGFR-2, or KDR and FLT. The term "diseases that are caused or promoted by persistent angiogenesis" is especially associated with diseases such as tumor growth or metastasis, psoriasis, Kaposi's sarcoma, restenosis, such as, for example, stent-induced restenosis, endometriosis, disease of Crohn's disease, Hodgkin's disease, leukemia; arthritis, such as rheumatoid arthritis, hemangioma, angiofibroma; ophthalmological diseases, such as diabetic retinopathy, neovascular glaucoma; cornea transplants; kidney diseases, such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathic syndrome, transplant rejections and glomerulopathy; fibrotic diseases, such as liver cirrhosis, mesangial cell proliferative diseases, arteriesclerosis, damage to nervous tissue, and to inhibit reocclusion of vessels after balloon catheterization treatment, in the implantation of vascular prostheses or after using mechanical devices for keep the vessels open, such as, for example, Stents, as immunosuppressive agents, as a support in scarless healing, in senile keratosis, in contact dermatitis and in asthma. In the treatment of damage to nerve tissue, the rapid formation of scars at the sites of the lesion with the compounds according to the invention can be prevented, that is, the formation of scars can be prevented before the axons are reconnected. . Accordingly, reconstruction of the nerve compounds is facilitated. The formation of ascites in patients, especially in patients suffering from tumors caused by metastasis, can also be suppressed with the compounds according to the invention. The edema induced by VEGF can also be suppressed. The treatment with the compounds of formula (I) allows to achieve not only a reduction in the size of the metastasis but also a reduction in the number of metastases. Lymphangiogenesis plays an important role in lymphogenic metastasis (Karpanen, T. et al., Cancer Res. 2001 Mar 1, 61 (5): 1786-90, Veikkola, T., et al., EMBO J. 2001, Mar. 15; 20 (6): 1223-31).

The compounds of formula (I) also show excellent action as inhibitors of VEGFR-3 kinase and are therefore also suitable as effective inhibitors of lymphangiogenesis. The compounds of formula (I) are then effective in the prevention or treatment of diseases that are associated with excessive lymphangiogenesis, such as lymphedema, lymphangiectasia, lymphangioma and lymphangiosarcoma, and also asthma. The lymphatic growth around the tumors can facilitate the metastatic expansion of malignant cells that end up killing the patient. This process can be effectively avoided by the compounds of this invention. Therefore, the compounds are not only effective in inhibiting the growth of metastases, but they can also be effective in reducing the number of metastases. This invention also provides the use of the compounds of formula (I) as inhibitors of the tyrosine kinase VEGFR-3 (FLT-4). A further object of this invention is also a pharmaceutical agent for preventing or treating diseases that are associated with excessive lymphangiogenesis, such as metastasis growth, lymphedema, lymphangiectasia, lymphangioma and lymphangiosarcoma and also asthma. In addition, the invention relates to the use of the compounds of general formula (I) for the preparation of a pharmaceutical agent for use in or for the prevention or treatment of tumor growth or metastasis, of psoriasis, Kaposi's sarcoma, restenosis, such as, for example, restenosis induced by a Stent, endometriosis, Crohn's disease, Hodgkin's disease, leukemia; arthritis, such as rheumatoid arthritis, hemangioma, angiofibroma; ophthalmological diseases, such as diabetic retinopathy, neovascular glaucoma; cornea transplants; kidney diseases, such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathic syndrome, transplant rejections and glomerulopathy; fibrotic diseases, such as liver cirrhosis, mesangial cell proliferative diseases, arteriosclerosis, damage to nervous tissue, and to inhibit reocclusion of vessels after balloon catheterization treatment, in the implantation of vascular prostheses or after using mechanical devices for keep the vessels open, such as, for example, Stents, as immunosuppressive agents, as a support in scarless healing, in senile keratosis, in contact dermatitis, and also in asthma. To use the compounds of formula (I) as pharmaceutical agents, the latter are brought into the form of a pharmaceutical preparation, which in addition to the active ingredient for enteral or parenteral administration contains suitable inert organic or inorganic pharmaceutical carrier materials, such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talcum, vegetable oils, polyalkylene glycols, etc. The pharmaceutical preparations can be found in a solid form, for example as tablets, coated tablets, suppositories, capsules, or in a liquid form, for example as solutions, suspensions or emulsions. They may also contain, in addition, adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, salts for changing the osmotic pressure or buffers. For parenteral administration, solutions or suspensions for injections, especially aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are especially suitable. As vehicle systems, surfactant adjuvants such as salts of bile acids or animal or plant phospholipids, and also mixtures thereof as well as liposomes or components thereof can also be used. For oral administration, tablets are especially suitable, coated tablets or capsules with vehicles or binders with talc and / or hydrocarbons, such as, for example, lactose, corn starch or potato starch. The administration may also be effected in a liquid form, such as, for example, as a juice, to which a sweetener may optionally be added or, if necessary, one or more flavoring substances. The dosage of the active ingredients may vary depending on the method of administration, the age and weight of the patient, the type and severity of the disease to be treated and similar factors. The daily dose is 0.5-1000 mg, preferably 50-200 mg, whereby the dose can be administered as a single dose that will be administered once or can be divided into 2 or more daily doses. A further object of this invention is then a pharmaceutical agent comprising a compound of formula (I) in combination with at least one vehicle or excipient acceptable for pharmaceutical use. Compounds of formula (I) are obtained, for which a compound of general formula (II): (II). wherein A, E, Q, W, X and R1 are as defined supra for the general formula (I) and M represents halogen, (i) is first converted to an amine and then, by reaction with a carbamoyl chloride of formula CICONR2R3, wherein R2 and R3 are as defined above for the general formula (I), converted to a urea of general formula (I), or (ii) is reacted with a urea of general formula H2NCONR2R3, wherein R2 and R3 are as defined above for the general formula (I), or (ii) is first converted to an amine, then converted to a compound of the formula (I) by a first reaction with a compound of the formula CIC02Ph and then by reaction with a compound of formula HNR2R3, wherein R2 and R3 are as defined supra for the general formula (I); or a compound of the general formula (III), wherein A, E, Q, W, X, R2 and R3 are as defined for the general formula (I) and RY represents H or Ci- Ce-alkyl, is reacted with an amine of general formula R1NH2 wherein R1 is as defined supra for general formula (I): (ni) There are many methods known to the person skilled in the art which are described in the literature for the formation of amides. For example, it is possible to start from the corresponding ester. The ester can be reacted according to J. Org. Chem. 1995, 8414 with trimethylaluminum and the corresponding amine in solvents, such as toluene or 1,2-dichloroethane, at temperatures between 0 ° C and the boiling point of the solvent. If the molecule contains two ester groups, both are converted to the same amide. Instead of trimethylaluminum, hexamethyldisilazide sodium can also be used. However, for the formation of the amide all the processes that are known to the person skilled in the art of peptide chemistry are also available. For example, the corresponding acid, obtained from the corresponding ester by saponification, can be reacted with the amine in polar aprotic solvents, such as, for example, dimethylformamide, by an activated acid derivative, which can be obtained, for example, with hydroxybenzotriazole and a carbodiimide, such as, for example, diisopropylcarbodiimide, at temperatures between 0 ° C and the boiling point of the solvent, preferably at 80 ° C, or else with preformed reagents, such as, for example, HATU (0-6 hexafluorophosphate). (7-azabenzotriazol-1-yl) -1, 1, 3,3-tetramethyluronium) (Chem. Comm. 1994, 201), at temperatures between 0 ° C and the boiling point of the solvent, preferably at room temperature. The addition of a base is necessary, such as N-methylmorpholine. The formation of the amide can also take place with the acid halide, mixed acid anhydride, imidazolide or azide. Urea of aryl or heteroarylamines can be prepared by a variety of methods known in the literature, which are also known to the person skilled in the art. For example, they can be prepared by reaction of aryl or heteroarylamines with isocyanates, reaction of amines with aryl or heteroarylcarbamates, such as aryl or heteroarylphenoxycarbamates, or reaction of aryl or heteroarylamines with appropriately substituted carbamoyl chlorides or reaction of an aryl or heteroarylhalide with ureas under the effect of metal catalysts. For example, ureas of aminopyridines can be prepared by reaction of a urea with halopyridines, for which chlorine and bromopyridines are preferred, under the catalytic effect of metal complexes, for example, palladium or copper complexes. In the case of copper complexes, the use of stoichiometric amounts of the copper complexes for the reaction result would be advantageous. Copper salts suitable for the reaction are copper (I) or copper (II) salts, where copper (I) salts such as, for example, copper (I) oxide or copper (I) iodide are preferred. . In the case of copper iodide (I), the addition of an additive such as, for example,, ethylenediamine. Suitable solvents for this copper promoted coupling comprise dioxane or dimethylformamide, at temperatures up to the boiling point of the solvent, with a temperature of 120 ° C being preferred. The addition of a base, such as potassium phosphate or cesium carbonate, is also necessary. In the case of palladium catalysis, palladium complexes such as tris- (dibenzylidene ketone) -dipaladium (0) can be used. The solvents suitable for the reaction are toluene, dioxane or dimethylformamide, whereby solvent mixtures for the reaction can also be advantageous, at temperatures between room temperature and the boiling point of the solvents, a temperature of 1 10 ° being preferred. C. A coligand, such as BINAP, DPPF or Xantphos is also employed. A base is also required, the bases being suitable for the reaction, for example, cesium carbonate, potassium phosphate or sodium tert -butoxide. The initial urea materials required for the above coupling promoted by copper or palladium can be prepared in turn by reaction of the corresponding amines with the corresponding isocyanates. Solvents, such as for example dichloromethane or isopropyl alcohol, can be used at temperatures between 0 ° C and the boiling point of the solvent, with room temperature being preferred. The methods for the preparation of substituted or unsubstituted 6-aminoindazoles are well known to those skilled in the art and in the literature. They can be obtained from the reduction of the corresponding nitroindazoles by catalytic hydrogenation or other reduction methods well known to the person skilled in the art. The N-alkylation of substituted nitroindazoles can be carried out with a variety of alkylating agents known in the literature. For example, the methylation of N-1 or N-2 of a suitably functionalized 6-nitroindazole can be effected, for example, by treatment with a base, preferably Cs 2 CO 3 or NaH, and a methyl halide, preferably methyl iodide in a solvent suitable, such as N, N-dimethylformamide, at temperatures ranging from 0 ° C to 50 ° C, with 50 ° C being preferred. The 3-substituted 6-nitroindazoles can be prepared by a variety of methods. For example, alkyl substituents at position 3 can be introduced by means of standard Suzuki reactions between an appropriate 3-haloindazole, with the appropriate 3-iodoindazoles being preferred, and an alkylboronic acid, where trialkylborax can also be used. The N-protection of indazole may be advantageous for the reaction. 6-Nitroindazole-3-carboxylic acid provides an initial material suitable for the substitution of ester, amide, hydroxymethyl and alkoxymethyl in the 3-position of 6-nitroindazole, by transformations well known to the person skilled in the art, such as transesterification , amide coupling, reduction or reduction followed by alkylation. 6-Nitroindazole-3-carbaldehyde (prepared by the reaction of commercial 6-nitroindole with NaN02 in the presence of dilute aqueous hydrochloric acid according to J. Med. Chem. 2001, 44, 7, 1021) provides a useful precursor of the acid 6-Nitroindazole-3-carboxylic acid by oxidation methods well known to the person skilled in the art. In turn, 6-nitroindazole-3-carbaldehyde can also be converted into 3-hydroxymethyl-6-nitroindazole, 3-alkoxymethyl-6-nitroindazole or 3-aminomethyl-6-nitroindazole derivatives by likewise standard transformations, such as reduction, reduction followed by alkylation or reductive amination. Said standard transformations can also be applied to the synthesis of other substituted aminoindazoles. There is a variety of commercially available substituted nithrindazoles, however, they can easily be synthesized by the reaction of a suitable 2-amino-nittroluene derivative with, for example, NaN02 and aqueous hydrochloric acid. If necessary, the nitro group can be introduced after a delation reaction of a suitable 2-aminotoluene derivative by standard nitration chemistry. The preparation of the N-alkylated aminobenzimidazoles can take place from the corresponding N-alkylated nitrobenzimidazoles by standard reducing chemistry. Alkylation of a suitable functionalized nitrobenzimidazole, for example with an alkyl halide and a base, provides N 1 - and N 3 -alkylated nitrobenzimidazoles, which can be separated and isolated in their pure form by standard purification techniques. For example, the compound 6-amino-1-methyl-benzimidazole can be produced by the reaction of commercial 5-nitrobenzimidazole with Mel and Cs2CO3 in DMF followed by purification (of the resulting mixture of 5- and 6-nitro-1-methyl) -benzimidazoles) and hydrogenation in the presence of 10% Pd on carbon. Similarly, the preparation of N-alkylated aminobenzotriazoles can also be carried out from the corresponding nitrobenzotriazoles. Alkylation of a suitable functionalized nitrobenzotriazole, for example with an alkyl halide and a base, provides N1-, N2- and N3-alkylated nitrobenzotriazoles, which can be separated and isolated in their pure form by standard purification techniques. The standard reducing chemistry provides the corresponding aminobenzotriazoles. For example, 5-amino-2-methyl-benzotholol can be prepared according to a procedure described in the literature. { Eur. J. Med. C em. 1992, 27, 161-166). The preparation of 3-aminoisoquinolines which are substituted in the 7-position can be carried out by the corresponding 3-amino-1-bromo-substituted isoquinoline 7 by means of reductive dehalogenation. In turn 7-substituted 3-amino-1-bromo isoquinolines can be prepared by reaction of a suitable 2-cyano-4-substituted benzenacetonitrile with HBr in acetic acid. For example, 3-amino-7-methoxyisoquinoline can be prepared in two steps (HBr-mediated cyclization followed by reductive dehalogenation) from 2-cyano-4-methoxy-benzenacetonitrile, which can be prepared according to a procedure described in the literature (Bull. Chem. Soc. Jpn. 1980, 53, 10, 2885-2890). The 1-alkyl-6-amino-quinolin-2-ones can be prepared by methods known to the person skilled in the art. For example, 6-amino-2-methyl-quinolin-2-one can be prepared according to a procedure described in the literature (J. Chem. Research, Synopses, 1997, 310-31 1). The 2-amino-3,6-disubstituted quinolines can be prepared by numerous methods. For example, the reaction of the lithium salt (generated with a base such as lithium diisopropylamide) of a suitably substituted cyanomethyl dialkylphosphonate with a suitably substituted 2-nitrobenzaldehyde derivative in a suitable solvent, such as THF, provides a suitable acrylonitrile derivative which can be cyclized in the desired 2-amino-3,6-disubstituted quinoline by treatment with a suitable reducing agent, such as iron in acetic acid. The compounds of the general formulas II and III: wherein A, E, Q, W, R1, R2 and R3 are defined in the same manner as for general formula (I), M is halogen and RY is H or CrC6-alkyl, they provide valuable intermediates for the preparation of the compounds of general formula (I) of the invention and, therefore, also constitute objects of the invention. The use of compounds of formula (II) and (III) in the production of a compound of formula (I), as well as the process previously described using these compounds in the production of a compound of formula (I) are also objects of the invention. invention. EXAMPLES Production of the compounds according to the invention The following examples explain the production of the compounds according to the invention without limiting the scope of the claimed compounds to these examples. Abbreviations The following abbreviations that are used in the invention have the meaning indicated below: Saline solution saturated aqueous solution of sodium chloride CI + chemical ionization (NH3) DCE 1,2-dichloroethane DMF N, Ndimethylformamide d6-DMSO d6-dimethylsulfoxide d doublet d doublet doublets ES + ionization by electroatomization in positive mode EtOAc ethyl acetate EtOH ethanol 1 H-NMR proton nuclear magnetic resonance spectroscopy: chemical shifts (d) are expressed in ppm. Hex n-hexane LC-ES + liquid chromatography / ionization by electroatomization in positive mode LDA Diisopropylamide lithium MeOH methanol m multiplet P.f. melting point MS mass spectrometry m / z mass / charge ratio Pd2dba3 ths- (dibenzylidene ketone) -dipallate (0) -chloroform Rt ambient temperature RT retention time (LC) s singlet THF tetrahydrofuran t triplet Xantphos 9 , 9-dimethyl-4,5-bi (diphenylphosphino) xanthene Example 1.0 Preparation of 4- (4-hydroxy-4-hydroxy-4- ({[2- (2-methyl-2H-indazol-6-ylcarbamoyl) -phenylamino] -methyl} -pyridin-2-yl) -amide -methyl-piperidin-1 -carboxylic (4- {[[2- (2-Methyl-2H-yndazol-6-ylcarbamoyl) -phenylamino] -methyl} - pyridin-2-yl) -amid of the acid was treated. -oxo-p-peridin-1-carboxylic acid (50 mg, 0.1 mmol) in dry THF under argon, at -78 ° C, by drops with methyllithium (1.5 M in diethylether, 0.2 ml, 0, 3 mmol). The reaction was stirred for 30 minutes at -78 ° C before heating to rt. The reaction was stirred overnight before partitioned between EtOAc and saturated aqueous solution of ammonium chloride. The organic phase was washed with saline, dried, filtered and concentrated under vacuum. The residue was purified by chromatography on Isolute® flash silica gel (Separtis) (gradient elution: 100% CH2Cl2 to CH2Cl2 / EtOH 10: 2) to obtain (4- {[2- (2-methylene) 2H-indazol-6-ylcarbamoyl) -phenylamino] -methyl] -pyridin-2-yl) -amide of 4-hydroxy-4-methyl-piperaden-1-carboxylic acid (12 mg, 23% ) as a solid; 1 H-NMR (300 MHz, d6-DMSO) 10, 13 (1 H, s), 9.02 (1 H, s), 8.25 (1 H, s), 8.13 (1 H, d) ), 8.10 (1 H, s), 7.94 (1 H, t), 7.80 (1 H, s), 7.72 (1 H, d), 7.64 (1 H, d) ), 7.23-7.32 (2H, m), 6.92 (1H, d), 6.66 (1H, t), 6.54 (1H, d), 4.43 (2H , d), 4.31 (1 H, s), 4.13 (3H, s), 3.68-3.74 (2H, m), 3.16-3.25 (2H, m), 1 , 35-1, 46 (4H, m), 1, 12 (3H, s); m / z Example 1.1 Preparation of 4- (4- {[2- (2-methyl-2H-indazol-6-ylcarbamoyl) -phenylamino] -methyl} - pyridin-2-yl) -amide hydroxy-piperidin-1-carboxylic (4-Oxo-p-peridin) 4- ({[2- (2-methyl-2H-indazol-6-ylcarbamoyl) -phenylamino] -methyl} - pyridin-2-yl) -amide was treated -1-carboxylic acid (50 mg, 0.1 mmol) in absolute EtOH, at 4 ° C with sodium borohydride (4 mg, 0.1 mmol). The reaction was heated to rt and stirred for 1 hour before partitioning the reaction between EtOAc and water. The organic phase was washed with saline, dried, filtered and concentrated under vacuum to obtain (4- {[2- (2-methyl-2H-indazol-6-ylcarbamoyl) -phenylamino] -methyl}. 4- pyridin-2-yl) -amide of 4-hydroxy-piperidine-1-carboxylic acid (39 mg, 78%) as a solid; 1 H-NMR (300 MHz, d6-DMSO) 10.14 (1 H, s), 9.07 (1 H, s), 8.26 (1 H, s), 8.14 (1 H, d) ), 8.10 (1 H, s), 7.94 (1 H, t), 7.79 (1 H, s), 7.71 -7.73 (1 H, m), 7.64 ( 1 H, d), 7.30-7.33 (1 H, m), 7.23-7.28 (1 H, m), 6.92-6.94 (1 H, m), 6, 66 (1 H, t), 6.54 (1 H, d), 4.68 (1 H, d), 4.43 (2 H, d), 4.13 (3 H, s), 3.79- 3.84 (2H, m), 3.60-3.67 (1 H, m), 3.00-3.08 (2H, m), 1, 70-1, 73 (2H, m), 1 , 23-1, 35 (2H, m); m / z (ES +) 500 [M + H] +. Example 1.2 Preparation of 4-hydroxy-4-hydroxy-4- ({[2- (2-methyl-2H-indazol-6-ylcarbamoyl) -phenylamino] -methyl} -pyridin-2-yl) -amide -trifluoromethyl-piperidin-1 -carboxylic acid It was treated with 4-oxo-piperdin (4- {[2- (2-methyl-2H-indazol-6-ylcarbamoyl) -phenylamino] -methyl} -. Pyridin-2-yl) -amide. -1-carboxylic acid (140 mg, 0.28 mmol) in dry THF successively with trifluoromethyltrimethylsilane (0.06 ml, 0.42 mmol) and tetra-n-butylammonium fluoride (1 M solution in THF, 0.28 ml, 0.28 mmol). The reaction was stirred at rt overnight before partitioning between EtOAc and water. The organic phase was washed with saline, dried, filtered and concentrated in vacuo. The residue was purified by Isolute® flash silica gel chromatography (Separtis) (gradient elution: 100% CH2Cl2 to CH2Cl2 / EtOH 10: 1) to obtain (4- {[2- (2-methyl-2H- 4-hydroxy-4-trifluoromethyl-piperidin-1-carboxylic acid (4 mg, 9%) nidazol-6-ylcarbamoyl) -phenyl-2-yl) -amide. solid; 1 H-NMR (300 MHz, d6-DMSO) 10.14 (1 H, s), 9.21 (1 H, s), 8.25 (1 H, s), 8, 15 (1 H, d) ), 8.10 (1 H, s), 7.95 (1 H, t), 7.80 (1 H, s), 7.72 (1 H, d), 7.63 (1 H, d) ), 7.23-7.32 (2H, m), 6.94 (1H, d), 6.66 (1H, t), 6.53 (1H, d), 6.02 (1 H, s), 4.44 (2H, d), 4.07-4.17 (5H, m), 2.95-3.05 (2H, m), 1.55-1.63 (4H, m); m / z (ES +) 568 [M + H] \ Example 2.0 Preparation of acid (4- {[[2- (2-methy1-2H-nitrazol-6-ylcarbamoyl) -phenylamide] -oxo-thiomorpholine-4-carboxylic acid A mixture of thiomorpholine-4- (2- {2-methyl-2H-indazol-6-ylcarbamoyl) -phenylamino] -methyl] -pyridin-2-yl) -amide was stirred. carboxyl (50 mg, 0.1 mmol) and sodium periodate (43 mg, 0.2 mmol) in MeOH / water (3: 1, 4 mL) overnight at rt. The reaction was partitioned between EtOAc and saline and the organic phase was dried, filtered and concentrated under vacuum to obtain (4- {[2- (2-methyl-2H-indazol-6-ylcarbamoyl) -phenylamino] 1-oxo-thiomorpholine-4-carboxylic acid (methyl) -methyl-2-yl) -amide (30 mg, 58%) as a solid; 1 H-NMR (300 MHz, d6-DMSO) 10.14 (1 H, s), 9.37 (1 H, s), 8.25 (1 H, s), 8.17 (1 H, d). ), 8.10 (1 H, s), 7.96 (1 H, t), 7.82 (1 H, s), 7.71-7.74 (1 H, m), 7.63 ( 1 H, d), 7.23-7.32 (2H, m), 6.96-6.98 (1 H, m), 6.67 (1 H, t), 6.54 (1 H, d), 4.45 (2H, d), 4.13 (3H, s), 3.99-4.04 (2H, m), 3.66-3.74 (2H, m), 2.84 -2.93 (2H, m), 2.65-2.70 (2H, m); m / z (LC-ES +) 518 [M + H] +. EXAMPLE 2.1 Preparation of (1- {[[2- (2-methyl-2H-indazol-6-ylcarbamoyl) -phenylamino] -methyl} - pyridin-2-yl) -amide of 1,1-dioxo acid -thiomorpholine-4-carboxylic acid Thiomorpholine-4-carboxylic acid (4- ({[2- (2-methyl-2H-indazol-6-ylcarbamoyl) -phenylamino] - ^ (89 mg, 0.18 mmol) in acetone (6 ml) was treated. ) and distilled water (1.5 ml) successively with 4-methylmorpholine-N-oxide (63 mg, 0.54 mmol) and osmium tetraoxide (2.5% solution in water, 0.01 ml, catalytic). The reaction was stirred overnight before being quenched with saturated aqueous sodium bisulfite solution.The mixture was extracted with CH2Cl2 and the organic phase was washed with water, dried, filtered and concentrated under vacuum to obtain (4-. 1,1-Dioxo-thiomorpholine-4-carboxylic acid (2- [2 (methyl-2H-indazol-6-ylcarbamoyl) -phenylamino] -methyl] -pyridin-2-yl) -amide (44 mg, 46%) as a solid, 1 H-NMR (300 MHz, d6-DMSO) 10.14 (1 H, s), 9.53 (1 H, s), 8.25 (1 H, s) , 8.17 (1 H, d), 8.10 (1 H, s), 7.96 (1 H, t), 7.81 (1 H, s), 7.71-7.73 (1 H, m), 7.63 (1 H, d), 7.23-7.32 (2 H, m), 6.97-6.99 (1 H, m), 6.67 (1 H, t ), 6.54 (1 H, d), 4.45 (2H, d), 4.13 (3H, s), 3.87-3.90 (4 H, m), 3.15-3.17 (4H, m); m / z (ES +) 534 [M + H] +. EXAMPLE 3.0 Preparation of (4-. {[2- (2-methy1-2H-indazol-6-ylcarbamoyl) -phenylamino] -methyl] -pyrin-2-yl ) - 4-methyl-piperazine-1-carboxylic acid anamide 2 - [(2-bromo-pyridin-4-ylmethyl) -amino] -N- (2-methyl-2H-indazol-6-yl) -benzamide (110 mg, 0.25 mmol) was suspended in dioxane (3 mi) and treated consecutively with DMF (1 ml), Pd2dba3 (5 mg, 0.005 mmol), Xantphos (9 mg, 0.015 mmol), cesium carbonate (98 mg, 0.3 mmol) and 4-methyl amide -piperazine-1-carboxylic acid (184 mg, 1.3 mmol). The reaction mixture was placed under a nitrogen atmosphere and heated for 3 hours at 1 ° C (bath temperature). With cooling, the volatiles were removed under vacuum and the residue was partitioned between CH2Cl2 and water. The organic phase was washed with saline, dried, filtered and concentrated. The residue was purified by chromatography using Flash NH2 Isolute® (Separtis) as a stationary phase (gradient elution: 100% CH 2 Cl 2 to CH 2 Cl 2 / EtOH 95: 5) to obtain (4- { [2- (2-methyl-2H 4-methyl-p-piperazin-1-carboxylic acid (-indazol-6-ylcarbamoyl) -phenylamino] -methyl] -pyridin-2-yl) -amide (28 mg , 22%) as a foam; 1 H-NMR (300 MHz, d6-DMSO) 10.14 (1H, s), 9.11 (1H, s), 8.25 (1H, s), 8.14 (1H, d), 8, 10 (1H, s), 7.95 (1H, t), 7.80 (1H, s), 7.72 (1H, d), 7.63 (1H, d), 7.23-7.32 (2H, m), 6.94 (1H, d), 6.66 (1H, t), 6.53 (1H, d), 4.43 (2H, d), 4.13 (3H, s) , 3.41-3.44 (4H, m), 2.25-2.28 (4H, m), 2.17 (3H, s); m / z (ES +) 499. The following compounds were prepared analogously from the corresponding 2-bromopyridine intermediate and the corresponding urea intermediate: Example 4.0 Preparation of (4- {[2- (2-methy1-2H-indazol-6-carbamoyl) -phenylamino] -methyl} -pyridn 2-yl) -amide of 3-hydroxy-pyrrolidin-1-carboxylic acid 2 - [(2-Bromo-pyridin-4-ylmethyl) -amino] -N- (2-methyl-2H-indazol-6-yl) -benzamide (400 mg, 0.92 mmol) was suspended in dioxane (15 mg). mi) and treated consecutively with DMF (5 ml), Pd2dba3 (19 mg, 0.02 mmol), Xantphos (32 mg, 0.06 mmol), cesium carbonate (358 mg, 1.1 mmol) and amide 3-hydroxy-pyrrolidin-1-carboxylic acid (358 mg, 2.75 mmol). The reaction mixture was placed under a nitrogen atmosphere and heated for 3 hours at 110 ° C (bath temperature). With cooling, the reaction was partitioned between EtOAc and water. The organic phase was washed with saline, dried, filtered and concentrated in vacuo. The residue was purified by Isolute® flash silica gel chromatography (Separtis) (gradient elution: 100% CH2Cl2 to CH2Cl2 / EtOH 10: 1) to obtain (4- {[2- (2-methyl-2H- 3-hydroxy-pyrrolidin-1-carboxylic acid (indazol-6-ylcarbamoyl) -phenylamino] -methyl] -pyridin-2-yl) -amide (270 mg, 61%) as a solid; 1 H-NMR (300 MHz, d6-D SO) 10.14 (1 H, s), 8.62 (1 H, s), 8.25 (1 H, s), 8.14 (1 H, d), 8.10 (1 H, s), 7.95 (1 H, t), 7.90 (1 H, s), 7.71-7.73 (1 H, m), 7.64 (1 H, d), 7.23-7.33 (2H, m), 6.93-6.95 (1 H, m), 6.67 (1 H, t), 6.53 (1 H , d), 4.93 (1 H, d), 4.43 (2 H, d), 4.26 (1 H, m), 4.13 (3 H, s), 3.40-3.48 ( 4H, m), 1, 79-1, 94 (2H, m); m / z (ES +) 486 [M + H] +. Example 5.0 Preparation of (4-. {[3-fluoro-2- (2-methyl-2H-indazol-6-carbamoyl) -phenylamino] -methyl] -pyridin-2- il) - morpholine-4-carboxylic acid amide 2 - [(2-Bromo-pyridin-4-ylmethyl) -amino] -6-fluoro-N- (2-methyl-2H-indazol-6-yl) -benzamide was suspended (227 mg, 0.5 mmol) in dioxane (4 mL) and treated sequentially with DMF (1.6 mL), Pd2dba3 (13 mg, 0.013 mmol), Xantphos (18 mg, 0.031 mmol), cesium carbonate (193 mg, 0.59 mmol. ) and morpholine-4-carboxylic acid amide (244 mg, 0.75 mmol). The reaction mixture was placed under an argon atmosphere and heated for 3 hours at 1 ° C (bath temperature). With cooling, the reaction was partitioned between EtOAc and water. The organic phase was dried, filtered and concentrated in vacuo. The residue was purified by chromatography on Isolute® flash silica gel (Separtis) (gradient elution: 100% CH2Cl2 to CH2Cl2 / EtOH 10: 1) to obtain (4- {3-fluoro-2- (2- methyl-2H-indazol-6-ylcarbamoyl) -phenylamino] -methyl] -pyridin-2-yl) -amide of morpholine-4-carboxylic acid (132 mg, 52%) as a pale yellow resin. Further purification was performed by reverse phase preparative HPLC [column: Kromasil C8 5μ, 125 x 20mm. Eluent: 38% CH3CN in H20 (containing 0.2% NH3) to 95% CH3CN in H20 (containing 0.2% NH3)]; 1 H-NMR (300 MHz, d6-DMSO) 10.43 (1 H, s), 9.15 (1 H, s), 8.26 (1 H, s), 8.23 (1 H, s). ), 8.15 (1H, d), 7.79 (1H, s), 7.64 (1H, d), 7.13-7.25 (2H, m), 6.95 (1 H, d), 6.73 (1 H, t), 6.48 (1 H, t), 6.29 (1 H, d), 4.40 (2H, d), 4, 14 (3H, s), 3.56-3.59 (4H, m), 3.42-3.45 (4H, m); m / z (ES +) 504 [M + H] +.

Example 6.0 Preparation of Morpholine-4-carboxylic acid (4- [2- (isoquinolin-3-ylcarbamoyl) -phenylamino] -methyl] -pyridin-2-yl) -amide To a stirred solution of 3-aminoisoquinoline (75 mg, 0.52 mmol) and 2- (. {2 - [(morpholin-4-carbonyl) -amino] -pyridin-4-ylmethyl methyl ester. .}. -amino) -benzoic acid (149 mg, 0.40 mmol) in DCE (6 mL) at 0 ° C, under argon, trimethylaluminum (2M in toluene, 0.4 mL, 0, 8 mmol). The reaction was heated to 120 ° C (bath temperature) for 3 hours. With cooling, the reaction was diluted with aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The organic phase was washed with water, dried and concentrated under vacuum. The residue was purified by chromatography on Isolute® (Separtis) flash NH2 (eluent: EtOAc) to obtain (4- {[2- (isoquinolin-3-ylcarbamoyl) -phenylamino] -methyl} -pyridin-2- il) -amide of morpholine-4-carboxylic acid (60 mg, 32%) as a resin; 1 H-NMR (300 MHz, d6-DMSO) 10.69 (1 H, s), 9.21 (1 H, s), 9.18 (1 H, s), 8.60 (1 H, s) ), 8, 16-8.20 (2H, m), 8.10 (1H, d), 7.96 (1H, d), 7.90 (1H, d), 7.82 (1 H, d), 7.75 (1 H, t), 7.57 (1 H, t), 7.28 (1 H, t), 6.98 (1 H, d), 6.63 (1 H, t), 6.58 (1 H, d), 4.48 (2H, d), 3.55-3.59 (4H, m), 3.41-3.45 (4H, m); m / z (ES +) 483 [M + H, 242. The following compounds were prepared analogously from 2- (. {2 - [(morpholin-4-carbonyl) -amino] -pyridin- methyl ester. 4-ylmethyl.} -amino) -benzoic acid and the corresponding amine: Production of initial compounds and intermediates If the production of intermediate compounds is not described, the latter are known or can be produced analogously to known compounds or processes described herein or in WO2004 / 013102. In particular, the intermediate compound 2 - [(2-bromopyridin-4-yl-methyl) -amino] -N- (2-methyl-2H-indazol-6-yl) -benzamide is prepared as published in WO 2004 / 013102, which is reiterated herein as Example 6A: Example 6A Step 1: Production of 2 - [(2-bromo-pyridin-4-ylmethyl) -amino] -benzoic acid methyl ester 6.04 g (40 mg) are mixed. mmol) of anthranilic acid methyl ester in 600 ml of methanol with 3.2 ml of acetic acid and 7.4 g (40 mmol) of 2-bromopyridine-4-carbaldehyde and stirred overnight at 40 ° C. To this mixture was added 3.8 g (60 mmol) of sodium cyanoborohydride and stirred overnight at 40 ° C. 3.8 g (60 mmol) of sodium cyanoborohydride was added again and stirred over the weekend at 40 ° C. It was mixed with water and concentrated largely by evaporation. The aqueous phase is extracted with ethyl acetate and the combined organic phases are dried, filtered and concentrated by evaporation. The crude product was chromatographed on silica gel with a gradient consisting of hexane and hexane / ethyl acetate 1: 3 and hexane / ethyl acetate 1: 1 as eluent. 10.0 g (78% of theory) of 2 - [(2-bromo-pihdin-4-ylmethyl) -amino] -benzoic acid methyl ester is obtained as a colorless oil. Step 2: Production of 2 - [(2-bromo-pyridin-4-ylmethyl) -amino] -benzoic acid .0 g (31.2 mmol) of 2 - [(2-bromo-pyridin-4-ylmethyl) -amino] -benzoic acid methyl ester are dissolved in 290 ml of ethanol and mixed with 31.2 ml of solution 2 M sodium hydroxide. After stirring overnight at room temperature, the ethanol is removed and the aqueous phase is stirred with ethyl acetate. The aqueous phase is acidified with concentrated hydrochloric acid. The precipitate that forms is removed by suction and dried. 5.93 g (62%) of 2 - [(2-bromo-pyridin-4-methylmethyl) -amino] -benzoic acid are accumulated in the form of a white solid. Step 3: Production of 2 - [(2 ^ romo-pyridin ^ -ylmethyl) -amino] -W- (2-methyl-2H-indazol-6-yl) -benzamide 0.500 g (1.6 mmol) of 2 - [(2-bromo-pyridin-4-ylmethyl) -amino] -benzoic acid, 0.471 g (3.2 mmol) of 2-methyl-2H-indazole-6 are stirred. -amylamine, 0.4 ml (3.68 mmol) of N-methylmorpholine and 0.729 g (1.92 mmol) of 0- (7-azabenzotriazol-1-yl) -1,1,3-tetramethyluronium hexafluorophosphate (HATU) in 25 ml of dimethylformamide for 16 hours at room temperature. The dimethylformamide is removed with an oil vacuum pump. The remaining residue is removed in saturated sodium bicarbonate solution. It is extracted three times with ethyl acetate and the combined organic phases are dried, filtered and concentrated by evaporation. The residue is subjected to chromatography on silicon gel with a gradient consisting of hexane: acetone = 100: 0 to 50:50 as eluent. This gives 0.669 g (96% of theory) of 2 - [(2-bromo-pyridin-4-ylmethyl) -amino] -V- (2-methyl-2H-indazol-6-yl) -benzamide in the form of a beige foam. Example 7.0 Preparation of 1,4-dioxa-8-aza-spiro [4,5] decan-8-carboxylic acid amide To a stirred solution of 1,4-dioxa-8-azaspiro [4.5] -decane (1.1 g, 7.67 mmol) in isopropanol (20 mL) at rt was added trimethylsilylisocyanate (1.5 mL). , 6 mmol) and the resulting solution is stirred overnight before removing the volatiles under vacuum to obtain 1,4-dioxa-8-azaspiro [4,5] decan-8-carboxylic acid amide (1.47 g, quant.); 1 H-NMR (300 MHz, d 6 -D SO) 5.96 (2H, s), 3.88 (4H, s), 3.33 (4H, t), 1.51 (4H, t). Example 7.1 Preparation of 1,4-dioxamide (4- {[[2- (2-methyl-2H-indazol-6-ylcarbamoyl) -phenylamino] -methyl} - pyridin-2-yl) -amide -8-azaspiro [4,5] decan-8-carboxylic 2 - [(2-Bromo-pyridin-4-ylmethyl) -amino] -N- (2-methyl-2H-indazol-6-yl) -benzamide (700 mg, 1.6 mmol) was suspended in dioxane (26). mi) and was treated consecutively with DMF (7 mi), Pd2dba3 (32 mg, 0.03 mmol), Xantphos (61 mg, 0.1 mmol), cesium carbonate (632 mg, 1.9 mmol) and 1,4-dioxa-8-azaspiro acid amide [4 , 5] decan-8-carboxylic acid (930 mg, 5 mmol). The reaction mixture was placed under a nitrogen atmosphere and heated for 4 hours at 1 ° C (bath temperature). With cooling, the reaction was partitioned between EtOAc and saline. The organic phase was dried, filtered and concentrated in vacuo. The residue was purified by Isolute® flash silica gel chromatography (Separtis) (gradient elution: 100% CH2Cl2 to CH2Cl2 / EtOH 10: 1) to obtain (4- {[2- (2-methyl-2H- 1,4-dioxa-8-aza-spiro [4.5] decan-8-carboxylic acid indazol-6-ylcarbamoyl) -methyl] -pyridin-2-yl) -amide (574) mg, 66%) as a solid; 1 H-NMR (300 MHz, d6-DMSO) 10.20 (1 H, s), 9.25 (1 H, s), 8.32 (1 H, s), 8.21 (1 H, d). ), 8.17 (1 H, s), 8.01 (1 H, t), 7.87 (1 H, s), 7.75-7.80 (1 H, m), 7.70 ( 1H, d), 7.30-7.40 (2H, m), 6.99-7.01 (1H, m), 6.73 (1H, t), 6.60 (1H, d), 4.50 (2H, d), 4.20 (3H, s), 3.97 (4H, s), 3.54-3.59 (4H, m), 1, 53-1, 58 (4H, m); m / z (ES +) 542 [M + H] +. Example 7.2 Preparation of 4-oxo-piperidine-1-carboxylic acid (4 ^ [2- (2 ^ netyl-2H-indazol-6 ^ carbamoyl) -phenylamino] -m It was cooled (1,4-dioxa-8- {. [2- (2-methyl-2H-indazol-6-ylcarbamoyl) -phenylamino] -methyl] -pyridin-2-yl) -amide. aza-spiro [4.5] decan-8-carboxylic acid (564 mg, 1. 04 mmol) in acetone (35 ml) at 4 ° C and treated with drops with aqueous hydrochloric acid (4 N, 9 ml). The reaction was heated to rt and stirred overnight. The reaction was basified by the addition of saturated aqueous sodium hydrogen carbonate and extracted with EtOAc. The organic phase was washed with saline, dried, filtered and concentrated under vacuum to obtain (4- {[2- (2-methy1-2H-indazol-6-ylcarbamoyl) -phenylamino] -methyl} 4-oxo-piperidine-1-carboxylic acid amide-2-yl) -amide (467 mg, 90%) as a solid; 1 H-NMR (300 MHz, d6-DMSO) 10.14 (1 H, s), 9.36 (1 H, s), 8.25 (1 H, s), 8.17 (1 H, d) ), 8.10 (1 H, s), 7.96 (1 H, t), 7.86 (1 H, s), 7.72 (1 H, d), 7.64 (1 H, d) ), 7.23-7.32 (2H, m), 6.96-6.98 (1H, m), 6.66 (1H, t), 6.55 (1H, d), 4 , 45 (2H, d), 4, 13 (3H, s), 3.72-3.76 (4H, m), 2.36-2.40 (4H, m); m / z (ES +) 498 [+ H] +. Example 8.0 Preparation of thiomorpholine-4-carboxylic acid amide To a stirred solution of thiomorpholine (1.0 g, 9.7 mmol) in isopropanol (25 ml) at rt was added trimethylsilyl isocyanate (1.9 ml, 13.45 mmol) and the resulting solution was stirred overnight. The resulting suspension was filtered and the filtrate was concentrated under vacuum to obtain thiomorpholine-4-carboxylic acid amide (1.18 g, 89%); 1 H-NMR (300 MHz, d6-DMSO) 6.00 (2H, s), 3.53-3.57 (4H, m), 2.46-2.51 (4H, m, obscured by solvent) . EXAMPLE 8.1 Preparation of thiomorpholine-4-carboxylic acid (4- {[[2- (2-methyl-2H-indazol-6-ylcarbamoyl) -phenylamino] -methyl} - pyridin-2-yl) -amide suspended 2 - [(2-bromo-pyridin-4-methylmethyl) -N- (2-methyl-2H-indazol-6-yl) -benzamide (500 mg, 1.15 mmol) in dioxane (14 mL) was treated consecutively with DMF (5 mL), Pd2dba3 (23 mg, 0.023 mmol), Xantphos (42 mg, 0.07 mmol), cesium carbonate ( 454 mg, 1.38 mmol) and thiomorpholine-4-carboxylic acid amide (511 mg, 3.5 mmol). The reaction mixture was placed under a nitrogen atmosphere and heated for 4 hours at 110 ° C (bath temperature). With cooling, the reaction was partitioned between EtOAc and water. The organic phase was washed with saline, dried, filtered and concentrated in vacuo. The residue was purified by chromatography on Isolute® flash silica gel (Separtis) (gradient elution: 100% CH2Cl2 at d- ^ C / EtOH 10: 1) to obtain (4- { [2- (2-methyl) -2H-indazol-6-ylcarbamoyl) -phenylamino] -methyl] -pyridin-2-yl) -amide of thiomorpholine-4-carboxylic acid (375 mg, 65%) as a solid; 1 H-NMR (300 MHz, d6-DMSO) 10.14 (1 H, s), 9.20 (1 H, s), 8.25 (1 H, s), 8.15 (1 H, d) ), 8.1 1 (1 H, s), 7.95 (1 H, t), 7.80 (1 H, s), 7.72 (1 H, d), 7.63 (1 H, d) ), 7.23-7.33 (2H, m), 6.95 (1H, d), 6.67 (1H, t), 6.54 (1H, d), 4.44 (2H , d), 4.13 (3H, s), 3.70-3.73 (4H, m), 2.55-2.58 (4H, m); m / z (ES +) 502 [M + H] +. Example 9.0 Preparation of 4-methyl-piperazine-1-carboxylic acid amide To a stirred solution of 1-methylpiperazine (1.66 mL, 15 mmol) in isopropanol (30 mL) at rt was added trimethylsilyl-isocyanate (2.8 mL, 21 mmol) and the resulting solution was stirred overnight.

The volatiles were removed under vacuum to obtain 4-methyl-piperazine-1-carboxylic acid amide (2.6 g, quant.) As an oil that slowly crystallized on standing; 1 H-NMR (300 MHz, CDCl 3) 4.62 (2H, s), 3.40 (4H, t), 2.39 (4H, t), 2.29 (3H, s); m / z (ES +) 143 [M + H] +. Example 10.0 Preparation of 4- (2-hydroxy-ethyl) -piperazine-1-carboxylic acid amide To a stirred solution of 1- (2-hydroxy-ethyl) -piperazine (1.95 g, 15 mmol) in isopropanol (30 mL) at rt was added thmethylsilylisocyanate (2.8 mL, 21 mmol) and the resulting solution was stirred overnight before removing the volatiles under vacuum. The residue was partitioned between CH2Cl2 and water. The aqueous phase was concentrated under vacuum to obtain 4- (2-hydroxy-ethyl) -piperazin-1-carboxylic acid amide (2.3 g, 88%); 1 H-NMR (300 MHz, d6-DMSO) 5.92 (2H, s), 4.40 (1 H, t), 3.46-3.52 (2H, m), 3.22-3, 34 (4H, m), 2.30-2.39 (6H, m); m / z (ES +) 173 [M + H] +. Example 11.0 Preparation of 4-methanesulfonyl-piperazine-1-carboxylic acid amide To a stirred suspension of / V-methanesulfonylpiperazine (1.0 g, 6.1 mmol) in isopropanol (15 mL) at rt was added trimethylsilylisocyanate (1.4 mL, 11 mmol) and the resulting suspension was stirred overnight before filtg the precipitate and dried to obtain 4-methanesulfonyl-piperazine-1-carboxylic acid amide (1.35 g, quant.) as a solid; 1 H-NMR (300 MHz, d6-DMSO) 6, 10 (2H, s), 3.37-3.40 (4H, m), 3.03-3.06 (4H, m), 2.90 (3H, s). Example 12.0 Preparation of Morpholine-4-carboxylic acid amide To a stirred solution of morpholine (1.3 ml, 15 mmol) in isopropanol (30 ml) at rt was added trimethylsilylisocyanate (2.8 ml, 21 mmol) and the resulting solution was stirred overnight before removing volatiles under vacuum to obtain morpholine-4-carboxylic acid amide (2.0 g, quant.) as a solid; 1 H-NMR (300 MHz, d6-DMSO) 6.00 (2H, s), 3.51 -3.54 (4H, s), 3.23-3.26 (4H, s). Example 13.0 Preparation of 2,6-dimethyl-morpholine-4-carboxylic acid amide To a stirred solution of 2,6-dimethylmorpholine (mixture of cis and trans isomers, 1.7 g, 15 mmol) in isopropanol (30 mL) at rt was added trimethylsilylisocyanate (2.8 mL, 21 mmol) and the resulting solution it was stirred overnight before removing the volatiles under vacuum to obtain a mixture of cis and trans isomers of 2,6-dimethyl-morpholine-4-carboxylic acid amide (2.7 g, quant.) as a solid.; m / z (ES +) 158 [M + H] +. Example 14.0 Preparation of 3-hydroxy-pyrrolidin-1-carboxylic acid amide To a stirred solution of 3-hydroxypyrrolidine (1.0 g, 11.48 mmol) in isopropanol (27 mL) at rt was added trimethylsilylisocyanate (2.14 mL, 16.07 mmol) and the resulting solution was stirred overnight . The resulting suspension was filtered and the residue was washed with isopropanol and dried to obtain 3-hydroxy-pyrrolidine-1-carboxylic acid amide (0.89 g, 60%); 1 H-NMR (300 MHz, d 6 -DMSO) 5.64 (2H, s), 4.85 (1H, d), 4.21-4.22 (1H, m), 3.22-3.28 ( 3H, m), 3.06-3.10 (1H, m), 1.79-1.90 (1H, m), 1.67-1.76 (1H, m). Example 15.0 Preparation of 2 - [(2-bromo-pyridin-4-ylmethyl) -amino] -N- (7-methoxy-isoquinolin-3-yl) -benzamide 2 - [(2-Bromo-pyridin-4-ylmethyl) -amino] -N- (7-methoxy-isoquinolin-3-yl) benzamide was prepared from 2 - [(2-bromo-pyridin- 4-ylmethyl) -amino] -benzoic acid and 3-amino-7-methoxyisoquinoline analogously to the procedures detailed in W 02004/013102, in particular example 6A, supra; 1 H-NMR (300 MHz, d 6 -DMSO) 10.62 (1H, s), 9.10 (1H, s), 8.51 (1H, s), 8.32 (1H, d), 8.11 (1H, t), 7.83-7.90 (2H, m), 7.60 (1H, s), 7.50 (1H, m), 7.38-7.41 (2H, m), 7.27 (1H, t), 6.66 (1H, t), 6.55 (1H, d), 4.54 (2H, d), 3.91 (3H, s). Example 16.0 Preparation of 2 - [(2-bromo-pyridin-4-ylmethyl) -amino] -6-fluoro-N- (2-methyl-2H-indazol-6-yl) -benzamide 2 - [(2-bromo-pyridn-4-methylmethyl) -6-fluoro-N- (2-methyl-2H-nitrozol-6-yl) was prepared; l) -benzamide from methyl 2-amino-6-fluorobenzoate by reductive amination with 2-bromo-pyridine-4-carbaldehyde, followed by subsequent amidation with 6-amino-2-methyl-indazole analogously to the procedures which are detailed in WO2004 / 013102, in particular in example 6A, supra; 1 H-NMR (300 MHz, d6-DMSO) 10.51 (1 H, s), 8.31 (1 H, d), 8.26-8.28 (2H, m), 7.65 (1 H, d), 7.59 (1 H, s), 7.40 (1 H, d), 7, 13-7.25 (2H, m), 6.73 (1 H, t), 6, 50 (1 H, t), 6.29 (1 H, d), 4.47 (2 H, d), 4, 13 (3 H, s). Example 17.0 Preparation of 2- (. {2 - [(Morpholine-4-carbonyl) -amino] -pyridin-4-ylmethyl} -amino) -benzoic acid methyl ester 2- (. {2 - [(Morpholin-4-carbonyl) -amino] -pyridin-4-ylmethyl] -amino) -benzoic acid methyl ester was prepared from 2 - [(methyl ester. 2-bromo-pyridin-4-ylmethyl) -amino] -benzoic acid and morpholine-4-carboxylic acid amide analogously to the procedures detailed in WO2004 / 013102, in particular in example 6A, supra; 1 H-NMR (300 MHz, d6-DMSO) 9.19 (1 H, s), 8.15-8.19 (2H, m), 7.79-7.84 (2H, m), 7, 29-7.34 (1 H, m), 6.92 (1 H, dd), 6.56-6.62 (2H, m), 4.50 (2H, d), 3.83 (3H, s), 3.57-3.60 (4H, m), 3.42-3.46 (4H, m). The following examples detail the biological activity and use of the compounds of the invention without limiting the scope of the claimed compounds to these examples. Inhibition of KDR kinase The kinase activity was measured with a fusion construct of the GST-kinase domain of the KDR kinase according to the following protocol to obtain concentration response curves. The components were added to a microtiter plate in the following sequence: 10 μ? of inhibitor at a final triple concentration [DMSO 3% in buffer solution (Tris-CI 40 mM, pH 7.5; 1 mM DTT, 1 mM MnCl 2, 10 mM MgCl 2, 2.5 polyethylene glycol per thousand 20,000) and 10 μM? of substrate mixture [ATP 24 μ ?, poly (Glu4Tyr 24 μg / ml) in buffer, specific activity 32? - ???? 500 cpm / pmol approximately]. The reaction was initiated by addition of 10 μ? of enzyme preparation properly diluted in buffer solution containing vanadate 10 μ ?. After incubating for exactly 10 min, the reaction was stopped by the addition of 10 μ? of detention solution (EDTA 250 mM). 10 μ? of the reaction mixture to phosphocellulose filters. The filters were washed in 0.1% phosphoric acid, dried before applying the Meltilex scintillator (Wallac, Perkin-Elmer) and the radioactivity counted. VEGFR-3 autophosphorylation MVEC (1.5 x 106 / well) was plated from a low number of passages on 48-well plates coated with collagen-G in complete EBM medium (including EGM-2, BD-Clonetech). After 5 h, the medium was changed by EBM-2 without EGM-2 but containing 0.2% BSA (poor in EBM). At 12 h the medium was removed, 250 μ? of medium poor in EBM-2 and the respective dilutions of compound in 50 μ? of poor medium in EBM-2. The solutions were carefully mixed and left for 5 min at 4 ° C before adding 200 μ? of medium poor in EBM-2 containing VEGF-C (the final concentration in the assay is 5 nM, Reliatech, Braunschweig). Next, the solution was mixed thoroughly and incubated for 15 min at room temperature. The medium was removed and the cells were washed twice with cold PBS / 2 mM vanadate. Then the cells were lysed with 100 μ? of Duschl buffer solution [Hepes 50 mM pH 7.2; 150 mM NaCl; 1 mM MgCl 2; Triton X-100 1, 5%; 10 mM Na-pyrophosphate; 100 mM Nafluoride; 10% glycerol + 2 mM orthovanadate (newly added before the experiment) and 1 tablet per 50 ml of Complete medium (Roche No. 1836145)]. For the ELISA, Fluoronic MaxiSorp-MTP plates (No. 3204006 Zinser) were coated overnight at 4 ° C with Flt-4 antibody (Flt-4 (C-20) No. sc-321 Santa Cruz); 1 g / ml in coating buffer: Na2C03 pH 9.6 100 μ? / Well). After three washes with wash buffer (0.1% Tween 20 in Na2HP04, pH 7.4), the wells were incubated with 250 μ? of blocking buffer solution (Roti Block 1/10 from Roth, Karisruhe for 1 h at room temperature). After the 3 washes with washing buffer, the cell lysates were added and the whole was incubated overnight at 4 ° C. The cavities were then washed 3 times, anti-phosphotyrosine antibody coupled to HRP (16-105, UPSTATE, dilution 1 / 20,000 in TBST + 3% Top Block No. 37766, Fluka) and incubated overnight 4 ° C. Washing with wash buffer (6x) preceded the addition of the chemiluminescence reagent BM for ELISA No. 1582950 (Roche) and measurement of the luminescence. Inhibition of cytochrome P450 Inhibition of cytochrome P450 isoenzyme was carried out according to the publication of Crespi et al. (Anal. Biochem., 1997, 248, 188-190) using human cytochrome P 450 isoenzymes (2C9 and 2C19), expressed in baculovirus / insect cells. The selected results are shown in the following table: The advantages of the compounds of the invention can be easily demonstrated in comparison with the compounds known in the previous studies.

Claims (7)

1. A compound of formula (I): (I) where: X is CH or N; W is hydrogen or fluorine; A, E and Q are, independently of each other, CH or N, where only a maximum of two nitrogen atoms is contained in the ring; R1 is aryl or heteroaryl, which may be optionally substituted at one or more sites in the same manner, or differently, with halogen, hydroxy, d-C12-alkyl, C2-C6-alkenyl, d-C12-alkoxy, Halo-C C6-alkyl, = 0, -S02R6, -OR5, -SOR4, -COR6, -C02R6 or -NR7R8, where the C12-C-alkyl can be substituted with -NR7R8; R2 and R3 form, together with the nitrogen atom to which they are attached, a 3-8 membered heterocycloalkyl ring, preferably a 4-7 membered heterocycloalkyl ring, more preferably a 5- or 6 membered heterocycloalkyl ring, which optionally may contain at least one additional heteroatom and which may be optionally substituted at one or more sites in the same manner, or differently, with halogen, cyano, dC ^ -alkyl, dC ^ -alkoxy, halo-d-C6-alkyl, Ci -C3-dialkylketal, d-C3-cyclic ketal, = 0, -OR5, -SR4, -SOR4, -S02R6, -COR6 or -C02R6, wherein d-C12 alkyl may also be optionally substituted with an -OR group; R 4 is C C 12 -alkyl, C 3 -C 8 -cycloalkyl, aryl or heteroaryl; R5 is hydrogen, CVC ^ -alkyl, C3-C8-cycloalkyl or halo-CrC6-alkyl; R6 is hydrogen, CrC ^ -alkyl, C3-C8-cycloalkyl, halo-CVCe-alkyl, aryl or -NR7R8; R7 and R8 are, independently of each other, hydrogen, -S02R6, -COR6, aryl, C3-C8-cycloalkyl, d-C12-alkyl, halo-Ci-Ci2-alkyl or alkyl may be optionally substituted with -OR5 or -N (CH3) 2, or R7 and R8 may also be chosen such that they provide a cycloalkyl ring of 3-8 members, preferably a cycloalkyl ring of 4-7 members, more preferably a cycloalkyl ring of 5-6 members, which optionally may contain at least one additional heteroatom and may be optionally substituted at one or more sites in the same manner, or differently, with halogen, cyano, CC ^ -alkyl, CC ^ -alkoxy, halo-CrCValkyl, = 0 , -OR5, -COR6, -SR4, -SOR4 or -S02R6; and as well as isomers, diastereoisomers, enantiomers, tautomers and salts thereof. 2. The compound claimed in claim 1, wherein X is CH. 3. The compound claimed in any of claims 1 or 2, wherein W is hydrogen. 4. The compound claimed in any of claims 1-3, wherein A, E and Q are, each, CH. 5. The compound claimed in claim 1, wherein X is CH, W is hydrogen, and A, E, and Q are each CH. 6. The compound claimed in any of claims 1-5, wherein R1 is heteroaryl optionally substituted at one or more sites in the same manner, or differently, with halogen, hydroxy, Ci-Ci2-alkyl, C2-C6 -alkenyl, CC ^ -alkoxy, halo-CrCe-alkyl, = 0, -S02R6, -OR5, -SOR4, -COR6, -C02R6 or -NR7R8, where C, -C12-alkyl can be substituted with -NR7R8. 7. The compound claimed in any of claims 1-5, wherein R1 is heteroaryl substituted at one or more sites in the same manner, or differently, with halogen, hydroxy, C ^ C ^ -alkyl, C2-C6 -alkenyl, C12-alkoxy, halo-CrCfs-alkyl, = 0, -S02R6, -OR5, -SOR4, -COR6, -C02R6 or -NR7R8, wherein C, -C12-alkyl can be substituted with -NR7R8. 8. The compound claimed in any of claims 1-5, wherein R1 is quinolinyl, isoquinolinyl or indazolyl which may be optionally substituted at one or more sites in the same manner, or differently, with halogen, hydroxy, d- C12-alkyl, C2-C6-alkenyl, d-dz-alkoxy, halo-d-Ce-alkyl, = 0, -S02R6, -OR5, -SOR4, -COR6, -C02R6 or -NR7R8, where Cr Ci2- alkyl can be substituted with -NR7R8. 9. The compound claimed in any of claims 1-5, wherein R1 is quinolinyl, isoquinolinyl or indazolyl substituted at one or more sites in the same manner, or in a different manner, with halogen, particularly a fluorine, chlorine, bromine or iodine atom, hydroxy, d-Ci2-alkyla, C2-C6-alkenyl, d-C12-alkoxy, halo-d-C6- alkyl, = 0, -S02R6, -OR5, -SOR4, -COR6, -C02R6 or -NR7R8, where Ci-C12-alkyl can be substituted with -NR7R8. 10. The compound claimed in any of claims 1-5, wherein R1 is indazolyl substituted with d-C12-alkyl. 11. The compound claimed in any of claims 1-5, wherein R1 is
2. 2-methyl-indazolyl or 1-methyl-indazolyl. 12. The compound claimed in any of claims 1-11, wherein R2 and R3 form, together with the nitrogen atom to which they are attached, a 5- or 6-membered heterocycloalkyl ring, containing no or at least one additional heteroatom and which may be optionally substituted at one or more sites in the same manner, or differently, with halogen, cyano, C C 12 -alkyl, C, -C 12 -alkoxy, halo-d-C 6 -alkyl, d-C 3- the alkaline, cyclic d-C3-ketal, = 0, -OR5, -SR4, -SOR4, -S02R6, -COR6, or -C02R6, wherein the C, -C12 alkyl may also be optionally substituted with a group -OR5 13. The compound claimed in any of claims 1-12, wherein R4 is C Ci2-alkyl. 14. The compound claimed in any of claims 1-12, wherein R4 is -CH3. 15. The compound claimed in any of claims 1-14, wherein R5 is -CH3 or hydrogen. 16. The compound claimed in any of claims 1-14, wherein R5 is hydrogen. 17. The compound claimed in any of claims 1-16, wherein R6 is (_V C12-alkyl or -NR7R8 18. The compound claimed in any of claims 1-16, wherein R6 is Cr C12-alkyl. 19. The compound claimed in any of claims 1-16, wherein R6 is -CH3 20. The compound claimed in any of claims 1-19, wherein R7 and R8 are, independently of each other, hydrogen, -COR6, -S02R6 or CVC ^ -alkyl 21. The compound claimed in any of claims 1-19, wherein R7 and R8 are, independently of each other, hydrogen or -CH3 22. The compound claimed in Claim 1, where: X is CH; W is hydrogen; A, E and Q are, each, CH; R1 is aryl or heteroaryl, which may be optionally substituted at one or more sites in the same manner, or differently, with halogen, hydroxy, Ci-Ci2-alkyl, C2-C6-alkenyl, CC ^ -alkoxy, halo- C, -C6-alkyl, = 0, -S02R6, -OR5, -SOR4, -COR6, -C02R6 or -NR7R8, wherein C C 12 -alkyl can be substituted with -NR 7 R 8; R2 and R3 form, together with the nitrogen atom to which they are attached, a 3-8 membered heterocycloalkyl ring, preferably a 4-7 membered heterocycloalkyl ring, more preferably a 5- or 6 membered heterocycloalkyl ring, which optionally may contain at least one additional heteroatom and which may be optionally substituted at one or more sites in the same manner, or differently, with halogen, cyano, CrC ^ -alkyl, C, -C12-alkoxy, halo-CrCe-alkyl, C C3-dialkylketal, C C3-cyclic ketal, = 0, -OR5, -SR4, -SOR4, -S02R6, - COR6 or -C02R6, where the C12 alkyl may also be optionally substituted with a group -OR5; R 4 is C, -C 12 -alkyl, C 3 -C 8 -cycloalkyl, aryl or heteroaryl; R5 is hydrogen, d-C12-alkyl, C3-C8-cycloalkyl or halo-d-C6-alkyl; R6 is hydrogen, d-C ^ -alkyl, C3-C8-cycloalkyl, halo-d-C6-alkyl, aryl or -NR7R8; R7 and R8 are, independently of each other, hydrogen, -S02R6, -COR6, aryl, C3-C8-cycloalkyl, dC ^ -alkyl, halo-d-C12-alkyl or d-Ci2-alkoxy, wherein the C C 12 -alkyl may be optionally substituted with -OR 5 or -N (CH 3) 2, or R 7 and R 8 may also be chosen such that they provide a cycloalkyl ring of 3-8 members, preferably a cycloalkyl ring of 4-7 members, more preferably a 5-6 membered cycloalkyl ring, which optionally may contain at least one additional heteroatom and may be optionally substituted at one or more sites in the same way, or differently, with halogen, cyano, d-d2-alkyl , dCi2-alkoxy, halo-dC6-alkylo, = 0, -OR5, -COR6, -SR4, -SOR4 or -S02R6; and as well as isomers, diastereoisomers, enantiomers, tautomers and salts thereof. 23. The compound claimed in claim 1, wherein: X is CH; W is hydrogen; A, E and Q are, each, CH; R1 heteroaryl substituted at one or more sites in the same manner, or differently, with halogen, hydroxy, C12-alkyl, C2-C6-alkenyl, d-Ci2-alkoxy, halo-Ce-alkyl, = 0, -S02R6, -OR5, -SOR4, -COR6, -C02R6 or -NR7R8, wherein the d-C12-alkyl can be substituted with -NR7R8; R2 and R3 form, together with the nitrogen atom to which they are attached, a
3. 3-8 membered heterocycloalkyl ring, preferably a heterocycloalkyl ring of
4. 4-7 members, more preferably a
5. 5- or
6. 6-membered heterocycloalkyl ring, which optionally may contain at least one additional heteroatom and which may be optionally substituted at one or more sites in the same manner, or differently, with halogen, cyano , d-C12-alkyl, dC ^ -alkoxy, halo-C, -C6-alkyl, d-Cs-dialkyl-ketal, C-C3-cyclic ketal, = 0, -OR5, -SR4, -SOR4, -S02R6, - COR6 0 -C02R6 wherein the CrC12 alkyl may also be optionally substituted with a group -OR5; R 4 is C C 12 -alkyl, C 3 -C 8 -cycloalkyl, aryl or heteroaryl; R5 is hydrogen, CrC2-alkyl, C3-C8-cycloalkyl or halo-Ci-C6-alkyl; R6 is hydrogen, aryl or -NR7R8; R7 and R8 are, independently of each other, hydrogen, -S02R6, -COR6, aryl, C3-C8-cycloalkyl, Ci-C12-alkyl, halo-CrC ^ -alkyl or C ^ C ^ -alkoxy, where C Ci2- alkyl may be optionally substituted with -OR5 or -N (CH3) 2, or R7 and R8 may also be chosen such that they provide a cycloalkyl ring of 3-8 members, preferably a cycloalkyl ring of 4-7 members, more preferably a 5-6 membered cycloalkyl ring, which optionally may contain at least one additional heteroatom and may be optionally substituted at one or more sites in the same way, or differently, with halogen, cyano, CC ^ -alkyl, C C 12 -alkoxy, halo-C Ce -alkyl, = 0, -OR 5, -COR 6, -SR 4, -SOR 4 or -S02R 6; and as well as isomers, diastereoisomers, enantiomers, tautomers and salts thereof. 24. The compound claimed in claim 1, wherein: X is CH; W is hydrogen; A, E and Q are, each, CH; R1 is quinolinyl, isoquinolinyl, or indazolyl which may be optionally substituted at one or more sites in the same manner, or differently, with halogen, hydroxy, C12-alkyl, C2-C6-alkenyl, CC ^ -alkoxy, halo -Ci-Ce-alkyl, = 0, -S02R6, -OR5, -SOR4, -COR6, -C02R6 or -NR7R8, where C C12-alkyl can be substituted with -NR7R8; R2 and R3 form, together with the nitrogen atom to which they are attached, a 3-8 membered heterocycloalkyl ring, preferably a 4-7 membered heterocycloalkyl ring, more preferably a 5- or 6 membered heterocycloalkyl ring, which optionally may contain at least one additional heteroatom and which may be optionally substituted at one or more sites in the same manner, or differently, with halogen, cyano, C C 12 -alkyl, d-C 12 -alkoxy, halo-d-C 6 -alkyl , C, -C3-dialkylketal, d-C3-cyclic ketal, = 0, -OR5, -SR4, -SOR4, -S02R6, - COR6 or -C02R6, wherein the d-C12 alkyl may also be optionally substituted with a group -OR5; R4 is C, -Ci2-alkyl, C3-C8-cycloalkyl, aryl or heteroaryl; R5 is hydrogen, d-C12-alkyl, C3-C8-cycloalkyl or halo-d-C6-alkyl; R6 is hydrogen, Ci-C12-alkyl, C3-C8-cycloalkyl, halo-d-C6-alkyl, aryl or -NR7R8; R7 and R8 are, independently of each other, hydrogen, -S02R6, -COR6, aryl, C3-Ci cycloalkyl, d-C12-alkyl, halo-d-C12-alkyl or C, -Ci2-alkoxy, wherein the d -C12- alkyl may be optionally substituted with -OR5 or -N (CH3) 2, or R7 and R8 may also be chosen such that they provide a cycloalkyl ring of 3-8 members, preferably a cycloalkyl ring of 4-7 members , more preferably a 5-6 membered cycloalkyl ring, which optionally may contain at least one additional heteroatom and may be optionally substituted at one or more sites in the same way, or differently, with halogen, cyano, CrC12-alkyl, CrC12-alkoxy, halo-d-C6-alkyl, = 0, -OR5, -COR6, -SR4, -SOR4 or -S02R6; and as well as isomers, diastereoisomers, enantiomers, tautomers and salts thereof. 25. The compound claimed in claim 1, wherein: X is CH; W is hydrogen; A, E and Q are, each, CH; R1 is quinolinyl, isoquinolinyl, or indazolyl which is substituted at one or more sites in the same manner, or differently, with halogen, hydroxy, Ci-C12-alkyl, C2-CB-alkenyl, d-C12-alkoxy, halo -C, -C6-alkyl, = 0, -S02R6, -OR5, -SOR4, -COR6, -C02R6 or -NR7R8, wherein the C12-alkyl can be substituted with -NR7R8; R2 and R3 form, together with the nitrogen atom to which they are attached, a 5- or 6-membered heterocycloalkyl ring, which optionally may contain at least one additional heteroatom and which may be optionally substituted at one or more sites in the same manner, or differently, with halogen, cyano, Ci-Ci2-alkyl, d-Ci2-alkoxy, halo-d-C6-alkyl d-C3-dialkyl ketal, d-C3-cyclic ketal, = 0, -OR5, -SR4 , -SOR4, -S02R6, -COR6 or -C02R6, wherein the d-C12 alkyl may also be optionally substituted with a group -OR5; R 4 is C, -Ci 2 -alkyl, C 3 -C 8 -cycloalkyl, aryl or heteroaryl; R 5 is hydrogen, d-Ci 2 -alkyl, C 3 -C 8 -cycloalkyl or halo-Ci-C 6 -alkyl; R6 is hydrogen, Ci-C2-alkyl, C3-C8-cycloalkyl, halo-Ci-C6-alkyl, aryl or -NR7R8; R7 and R8 are, independently of each other, hydrogen, -S02R6, -COR6, aryl, C3-C8-cycloalkyl, dC ^ -alkyl, halo-CrC12-alkyl or CC ^ -alkoxy, where Ci-C 2- alkyl may be optionally substituted with -O 5 or -N (CH 3) 2, or R 7 and R 8 may also be chosen such that they provide a cycloalkyl ring of 3-8 members, preferably a cycloalkyl ring of 4-7 members, more preferably a 5-6 membered cycloalkyl ring, which optionally may contain at least one additional heteroatom and may be optionally substituted at one or more sites in the same manner, or differently, with halogen, cyano, C, -C 2- alkyl, d-C12-alkoxy, halo-d-C6-alkyl, = 0, -OR5, -COR6, -SR4, -SOR4 or -S02R6; and as well as isomers, diastereoisomers, enantiomers, tautomers and salts thereof. 26. The compound claimed in claim 1, wherein: X is CH; W is hydrogen; A, E and Q are, each, CH; R1 is indazolyl which may be optionally substituted at one or more sites in the same manner, or differently, with halogen, hydroxy, d-C12-alkyl, C2-C6-alkenyl, d-C12-alkoxy, halo-d- C6-alkyl, = 0, -S02R6, -OR5, -SOR4, -COR6, -C02R6 or -NR7R8, wherein C12-alkyl can be substituted with -NR7R8; R2 and R3 form, together with the nitrogen atom to which they are attached, a 5- or 6-membered heterocycloalkyl ring, which optionally may contain at least one additional heteroatom and which may be optionally substituted at one or more sites in the same manner, or in a different way, with halogen, cyano, CrC½-alkyl, Ci-Ci2-alkoxy, halo-d-C6-alkyl, d-C3-dialkyl-ketal, d-C3-cyclic ketal, = 0, -OR5, -SR4, -SOR4, -S02R6, -COR6 or -C02R6 wherein CrC, 2 alkyl may also be optionally substituted with a group -OR5; R4 is CrC12-alkyl, C3-C8-cycloalkyl, aryl or heteroaryl; R5 is hydrogen, C C12-alkyl, C3-CB-cycloalkyl or halo-CrC6-alkyl; R6 is hydrogen, d-C12-alkyl, C3-CB-cycloalkyl, halo-Ci-C6-alkyl, aryl or -NR7R8; R7 and R8 are, independently of each other, hydrogen, -S02R6, -COR6, aryl, C3-C8-cycloalkyl, CrC12-alkyl, halo-d-C12-alkyl or d-C12-alkoxy, where C12 is - alkyl may be optionally substituted with -OR5 or -N (CH3) 2, or R7 and R8 may also be chosen such that they provide a cycloalkyl ring of 3-8 mrs, preferably a cycloalkyl ring of 4-7 mrs, more preferably a 5-6 mred cycloalkyl ring, which optionally may contain at least one additional heteroatom and may be optionally substituted at one or more sites in the same manner, or differently, with halogen, cyano, d-C12-alkyl, C C 12 -alkoxy, halo-d-C 6 -alkyl, = 0, -OR 5, -COR 6, -SR 4, -SOR 4 or -SOzR 6; and as well as isomers, diastereoisomers, enantiomers, tautomers and salts thereof. 27. The compound claimed in claim 1, wherein: X is CH; W is hydrogen; A, E and Q are, each, CH; R1 is indazolyl substituted with d-C12-alkyl; form, together with the nitrogen atom to which they are attached, a 5- or 6-mred heterocycloalkyl ring, which optionally may contain at least one additional heteroatom and which may be optionally substituted at one or more sites in the same manner, or different, with halogen, cyano, CC ^ -alkyl, CrC ^ -alkoxy, halo-Ci-CValkyl C1-C3-dialkylketal, Cs-cyclic ketal, -OR5, -SR4, -SOR4, -S02R6, -COR6 or - C02R6, wherein the C, -C12 alkyl may also be optionally substituted with a group is hydrogen; is Ci-C ^ -alkyl; and, as well as isomers, diastereoisomers, enantiomers, tautomers and salts thereof. 28. The compound claimed in claim 1, selected from the group consisting of: (4- {[[2- (2-methyl-2H-ndazol-6-ylcarbamoyl) -phenylamino] -methyl}. pyridin-2-yl) -amide of 4-hydroxy-4-methyl-piperidin-1-carboxylic acid, (4- { [2- (2-methyl-2H-indazol-6-ylcarbamoyl) -phen lamino] -methyl.}. -pihdin-2-yl) -amide of 4-hydroxy-piperidin-1-carboxylic acid, (4- { [2- (2-methyl-2H-indazol-6-ylcarbamoyl) 4-Hydroxy-4-trifluoromethyl-piperidin-1-carboxylic acid (4 { [2- (2-methyl-2H-indazole-4-hydroxy-4-pyridin-2-yl) -amide. 1-oxo-thiomorpholine-4-carboxylic acid-6-ylcarbamyl) -phenylamino] -methyl] -pyridin-2-yl) -amide, (4- { [2- (2-methyl-2H- indazol-6-ylcarbamoyl) -phenylamino] -methyl] -pyridin-2-yl) -amide of 1,1-dioxo-thiomorpholine-4-carboxylic acid, (4- { [2- (2-methyl) 4-Methyl-piperazin-1-carboxylic acid (2. 4-ylcarbamoyl) -phenylamino] -methyl]. Pyridin-2-yl) -amide, (4- { [2- (1 - methyl-1 H-indazol-6-ylcarbamoyl) -phenilami no] -methyl-4-methyl-piperazin-1-carboxylic acid (4-methyl-piperazin-1-carboxylic acid) -pyridin-2-yl) -amide. { [2- (1-methyl-1 H-indazol-6-ylcarbamoyl) -phenylamino] -metl} 4- (2-hydroxy-ethyl) -piperazine-1-carboxylic acid (4- ({2- [2-methyl-2H-indazole-6-pyridin-2-yl) -amide) 4- (2-hydroxy-ethyl) -piperazin-1-carboxylic acid (4- {. [2- (2-yl) -amino] -methyl] -methyl] -pihdin-2-yl) -amide. -methyl-2H-nitrazol-6-ylcarbamoyl) -phenollamino] -methyl] -yl-2-yl) -amide of 4-methanesulfonyl-piperazin-1 - carboxylic, (4- { [2- (1-methyl-1 H -indazol-6-ylcarbamoyl) -phenylamino] -methyl] -3-iridin-2-yl) -a of morpholin-4- carboxylic acid, (4- { [2- (2-methyl-2H-indazol-6-carbamoyl) -phenylamino] -m of morpholine-4-carboxylic acid, (4- { [2- (
7. 7-methoxy-lsoquinolin-3-ylcarbamoyl) -phenylamino] -methyl] -pyridin-2-yl) -a of morpholine-4-carboxylic acid, (4- { [2- (1 - 2,6-dimethyl-morpholin-4-carboxylic acid methyl-1 H-indazol-6-ylcarbamoyl) -phenylamino] -methyl] -pyridin-2-yl) -am, (4- { [2 2,6-Dimethyl-morpholine-4-carboxylic acid (2-methyl-2H-indazol-6-ylcarbamoyl) -phenylamino] -m, (4- { [2- (2-methyl- 2H-ynd azol-6-ylcarbamoyl) -phenylamino] -methyl} 3-hydroxy-pyrrolidin-1-carboxylic acid-pyridin-2-yl), (4- {[3-fluoro-2- (2-methyl-2H-ndazol-6-ylcarbamoyl)) -phenylamino] -m of morpholine-4-carboxylic acid, (4- {[[2- (isoquinolin-3-ylcarbamoyl) -phenylamino] -methyl} - pyridin-2-yl) -amtl of morpholin-4-carboxylic acid, (4- {[[2- (3,6-difluoro-quinolin-2-ylcarbamoyl) -phenylamino] -methyl} - pyridin-2-yl) -am morpholine-4-carboxylic acid, and (4- { [2- (3-Fluoro-6-methoxy-quinolin-2-ylcarbamoyl) -phenylamino] -methyl] -pyridin-2-yl of moryolin-4-carboxylic acid as well as isomers, diastereoisomers, enantiomers, tautomers and salts thereof 29. A pharmaceutical agent comprising at least one compound of formula (I) according to any of claims 1 to 28. 30. A pharmaceutical agent comprising at least one compound of formula (I) according to any of claims 1 to 28 and at least one vehicle acceptable for pharmaceutical use. 31. A pharmaceutical agent according to claims 29 or 30 for use in the prevention or treatment of diseases associated with persistent angiogenesis and / or diseases associated with excessive lymphangiogenesis. 32. A pharmaceutical agent according to claim 29 or 30 for use in the prevention or treatment of tumor growth or metastasis; of psoriasis; Kaposi's sarcoma; restenosis including restenosis induced by a Stent; Crohn's disease; Hodgkin's disease; leukemia; arthritis including rheumatoid arthritis, hemangioma, angiofibroma; endometriosis; ophthalmologic diseases including diabetic retinopathy, neovascular glaucoma; cornea transplants; kidney diseases, including glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathic syndrome, transplant rejections and glomerulopathy; fibrotic diseases, including liver cirrhosis; mesangial cell proliferative diseases; arteriesclerosis; damage to nervous tissue, and to inhibit reocclusion of vessels after balloon catheterization; in the implantation of vascular prostheses or after using mechanical devices to keep the vessels open, as immunosuppressive agents as a support in scar-free healing; senile keratosis; contact dermatitis; and asthma. 33. A pharmaceutical agent according to claim 29 or 30 for use as inhibitors of VEGF-3 receptor kinase in lymphangiogenesis. 34. A compound of formula (I) according to any of claims 1 to 28 for use in a method for the treatment of the body of an animal or human being. 35. A compound of formula (I) according to any of claims 1 to 28 for use in the preparation of a pharmaceutical product for the prevention or treatment of a disease in which an inhibition of angiogenesis is beneficial and / or of the lymphangiogenesis and / or of the VEGF receptor kinases. 36. A compound of formula (I) according to any of claims 1 to 28 for use as an inhibitor of the tyrosine kinases VEGFR-1 and VEGFR-2. 37. A compound of general formula (III): (??). wherein A, E, Q, W, X, R2 and R3 are as defined in formula (I) and Ry is H or C C6-alkyl, as an intermediate for the preparation of a compound of formula (I). 38. The compound claimed in claim 37, wherein Ry is H or C1-C2-alkyl. 39. The use of the compound claimed in any of claims 37 or 38, as an intermediate for the preparation of a compound of formula (I). 40. A process for the preparation of a compound of formula (I): (I) wherein all substituents are as described in claim 1, wherein a post of formula (III): (III), defined in any of claims 37 or 38, is reacted with an amine of formula R1NH2, wherein R1 is as defined in claim 1. 41. A process for the preparation of a compound of formula (I ): (i) wherein all substituents are as described in claim 1, wherein a post of formula (II): wherein A, E, Q, W, X, and R1 (n), are as defined in claim 1 and M represents halogen: (i) is first converted to an amine and then converted to a compound of formula ( I) by reaction with a carbamoyl chloride of the formula CICONR2R3, wherein R2 and R3 are as defined in claim 1; or alternatively, (ii) is reacted with a compound of the formula H2NCONR2R3, wherein R2 and R3 are as defined in claim 1; or alternatively, (ii) is first converted to an amine, then converted to a compound of formula (I) by a first reaction with a compound of formula CIC02Ph and then by reaction with a compound of formula HNR2R3, wherein R2 and R3 are as defined in claim 1. 42. The process claimed in claim 41, wherein wherein the compound of formula (II) is reacted with a compound of formula H2NCONRzR3, wherein R2 and R3 are as defined in claim 1.