JP2005538112A - VEGFR-2 and VEGFR-3 inhibitory anthranilamidopyridine - Google Patents

Abstract

VEGFR-2 and VEGFR-3 inhibitory anthranilamidopyridine amides, their production and use as agents for the treatment of diseases caused by persistent angiogenesis, and intermediates for the production of said compounds are disclosed. Said compounds are for example tumor or metastatic growth, psoriasis, Kaposi's sarcoma, restenosis, eg stent-induced restenosis, endometriosis, Crohn's disease, Hodgkin's disease, leukemia; arthritis, eg rheumatoid arthritis, hemangiomas, blood vessels Fibroma; Eye diseases such as diabetic retinopathy, neovascular glaucoma; Renal diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microvascular syndrome, graft rejection and glomerulopathy; fibrotic disease In the case of, for example, cirrhosis, glomerular stromal cell proliferation disease, arteriosclerosis, nerve tissue trauma, balloon catheter treatment, vascular prosthesis, or mechanical devices to maintain vascular opening, eg vascular after use of stents It can be used to inhibit reocclusion, as an immunosuppressant, and to maintain scarless treatment in senile keratosis and contact dermatitis. The compounds can also be used as VEGFR-3 inhibitors in lymphangiogenesis.

Description

The present invention relates to VEGFR-2 and VEGFR-3 inhibitory anthranilamidopyridines, their use as pharmaceutical agents for treating diseases induced by their production and persistent angiogenesis, and the production of compounds The intermediate product of
Persistent angiogenesis is caused by various diseases such as tumors or metastatic growth, psoriasis; arthritis such as rheumatoid arthritis, hemangiomas, angiofibromas; eye diseases such as diabetic retinopathy, neovascular glaucoma; Eg glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microvascular syndrome, graft rejection and glomerulopathy; fibrotic diseases such as cirrhosis, glomerular interstitial cell proliferation disease and cause or premise of arteriosclerosis Condition or cause worsening of those diseases.

Relentless angiogenesis is induced through its receptor by the VEGF factor. In order for VEGF to exert this effect, it must bind to the receptor and induce tyrosine phosphorylation.
Direct or indirect inhibition of the VEGF receptor (VEGF = vascular endothelial growth factor) is responsible for such diseases and other VEGF-induced pathological and vascular permeability conditions such as tumor angiogenesis. Can be used to process. For example, it is known that tumor growth can be inhibited by soluble receptors for VEGF and antibodies.

Psoriasis; arthritis such as rheumatoid arthritis, hemangioma, hemangiofibroma; eye diseases such as diabetic retinopathy, neovascular glaucoma; kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microvascular syndrome For the treatment of fibrotic diseases such as cirrhosis, glomerular stromal cell proliferation disease, arteriosclerosis, nerve tissue trauma, and after treatment of balloon catheters in vascular prostheses; Or anthranilamidopyridone used as a pharmaceutical agent for the inhibition of vascular reocclusion after use of a mechanical device, for example a stent, to maintain vascular opening is known from WO 00/27820 (eg Example 38) It has been.
The compounds known from WO00 / 27820 are generally effective in the indications shown, but their effectiveness is hardly clear.

  Anthranilic acid amides that are not only very effective in the inhibition of cytochrome P450 isoenzyme 3A4, but also have their good inhibition properties are also known from WO 00/27819 example 2.54). Cytochrome P450 isoenzyme 3A4 is one of the essential metabolic enzymes in which pharmaceutical agents are degraded. This isoenzyme inhibition leads to undesired pharmaceutical drug interactions, especially in multipathic patients (diseases with multiple disease states). There is also a problem in combination therapy with other drugs where increased toxicity occurs due to inhibition of compound degradation and associated excessive serum levels.

Thus, active ingredients that are effective on the one hand and, on the other hand, more compatible or do not show any unwanted side effects are desired.
Thus, on the one hand, more effective and on the other hand more compatible compounds are desired.

The following general formula I:

[Wherein X represents CH or N;
W represents hydrogen or fluorine;
A, B, D, E and Q, in each case, independently of one another, represent nitrogen or carbon atoms, where only a maximum of two nitrogen atoms can be present in the ring;

R ¹ represents aryl or heteroaryl, where halogen, hydroxy, C ₁ -C ₁₂ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl Aralkyloxy, C ₁ -C ₁₂ -alkoxy, halo-C ₁ -C ₆ -alkyl, cyano-C ₁ -C ₆ -alkyl, or the group ═O, —SO ₂ R ⁶ or —OR ⁵ , and so on Or optionally substituted at one or more positions, wherein said C ₁ -C ₆ -alkyl is optionally substituted by the group —OR ⁵ or —NR ⁹ R ^10. Well,
Y and Z are, in each case, independently of one another, represent bond, or a group = CO, a = CS or = SO _2,
R ² and R ³ are independently of each other hydrogen or a group -CONR ⁹ R ¹⁰ , -SO ₂ R ⁶ , -COR ¹¹ , -COC ₁ -C ₆ -alkyl, -CO-C ₁ -C _6- Alkyl-R ¹¹ , —NR ⁹ R ¹⁰ , or C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cycloalkyl, C ₃ -C ₆ -cycloalkenyl, aryl or heteroaryl (halogen, cyano, C _1- C ₁₂ -alkyl, C ₁ -C ₁₂ -alkoxy, hydroxy-C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, or group -NR ⁷ R ⁸ , -OR ⁵ , -C ₁ -C ₆ -alkyl-OR ⁵ , —SR ⁴ , —SOR ⁴ or —SO ₂ R ⁶ the same or different, optionally substituted at one or more positions; or

R ² , R ³ , Y and Z together with the nitrogen atom can contain a 3-8 membered saturated or unsaturated ring (optionally can contain additional heteroatoms in the ring, and optionally halogen, cyano , C ₁ -C ₁₂ -alkyl, C ₁ -C ₁₂ -alkoxy, halo-C ₁ -C ₆ -alkyl, hydroxy-C ₁ -C ₆ -alkyl, or the group = O, -OR ⁵ , -SR ⁴ , -SOR ⁴ or -SO ₂ R ⁶ is optionally substituted in one or more positions in the same or different manner;
R ⁴ represents C ₁ -C ₁₂ -alkyl, aryl or heteroaryl;
R ⁵ is hydrogen, C ₁ -C ₁₂ -alkyl, C ₃ -C ₁₀ -cycloalkyl, C ₁ -C ₁₂ -alkoxy, halo-C ₁ -C ₁₂ -alkyl, or halo-C ₃ -C _6- Represents cycloalkyl;

R ⁶ represents hydrogen, C ₁ -C ₁₂ -alkyl, halo-C ₁ -C ₁₂ -alkyl, aryl or heteroaryl, or the group —N ⁹ R ¹⁰ , where said aryl or heteroaryl itself is optionally May be substituted in one or more positions in the same or different manner by C ₁ -C ₁₂ -alkyl, C ₁ -C ₆ -alkoxy, halogen or halo-C ₁ -C ₆ -alkoxy ;
R ⁷ and R ⁸ independently of one another represent hydrogen or C ₁ -C ₁₂ -alkyl, and
R ⁹ and R ¹⁰ are independently of each other hydrogen, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, aryl, C ₃ -C ₈ -cycloalkyl or the group -CONR ⁷ R ⁸ , or C ₁ -C ₁₂ -alkyl (optionally substituted at one or more positions by aryl, morpholino, hydroxy, halogen, C ₁ -C ₁₂ -alkoxy or the group -NR ⁷ R ⁸ , in the same or different manner. Wherein the aryl itself is optionally substituted in the same or different manner one or more optionally by C ₁ -C ₆ -alkoxy or halo-C ₁ -C ₆ -alkyl. May be; or

R ⁹ and R ¹⁰ together form a 5-8 membered ring that can contain additional heteroatoms; and
R ¹¹ is C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxy-C ₁ -C ₆ -alkyl, hydroxy-C ₁ -C ₆ -alkoxy, C ₃ -C ₆ -cycloalkyl, phenyl Represents pyridyl, biphenyl or naphthyl, wherein said phenyl itself is substituted in one or more positions by C ₁ -C ₆ -alkyl or halo-C ₁ -C ₆ -alkyl in the same way or differently It may be]
It has now been found that the compounds of formula I, isomers, diastereomers, tautomers and salts thereof exhibit high efficacy with improved properties, ie low CYP450 3A4 inhibition.

The compounds of the invention prevent tyrosine phosphorylation or stop persistent angiogenesis and thus tumor growth and expansion, so that they are notably affected by slight inhibition of cytochrome P450 (3A4) isoforms. Differentiated.
Thus, dosing of the compounds of the present invention is not at risk even for pharmaceutical agents that are administered simultaneously and that are degraded through their isoforms.

Alkyl is in each case defined as a linear or branched alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl, undecyl or dodecyl. The
Alkoxy is in each case a linear or branched alkoxy group, for example methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, hexyloxy, peptyloxy, octyloxy , Nonyloxy, decyloxy, undecyloxy or dodecyloxy.

Cycloalkyl is defined as a monocyclic alkyl ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl or cyclodecyl, and as a bicyclic or tricyclic ring such as adamantanyl.
Cycloalkyl groups can contain one or more heteroatoms, such as oxygen, sulfur, and / or nitrogen, instead of carbon atoms. Those heterocycloalkyls having 3 to 8 ring atoms are preferred.

Cycloalkenyl is defined in each case as cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl or cyclodecenyl, whereby linkage can be made to both double and single bonds.
Halogen is defined in each case as fluorine, chlorine, bromine or iodine.
Halo-alkyl, halo-alkoxy, etc. are defined as alkyl, alkoxy, etc. being substituted at one or more positions by halogen in the same way or differently.

Alkenyl is in each case defined as a straight-chain or branched alkenyl group containing 2 to 6, preferably 4 to 6 C atoms. For example, the following groups are mentioned: vinyl, propen-1-yl, propen-2-yl, but-1-en-1-yl, but-1-en-2-yl, but-2-ene- 1-yl, but-2-en-2-yl, 2-methyl-prop-2-en-1-yl, 2-methyl-prop-1-yl, but-1-en-3-yl, but- 3-en-1-yl and allyl.
Aryl groups in each case comprise 3 to 12 carbon atoms and in each case can be benzofused.

For example, the following may be mentioned: cyclopropenyl, cyclopentadienyl, phenyl, tropyl, cyclooctadienyl, indenyl, naphthyl, azulenyl, biphenyl, fluorenyl, anthracenyl, and the like.
Heteroaryl groups in each case comprise from 3 to 16 ring atoms and contain, in place of carbon atoms, one or more heteroatoms, for example oxygen, nitrogen or sulfur, which are the same or different And can be monocyclic, bicyclic or tricyclic and, in each case, benzo-fused.

  For example, the following may be mentioned: thienyl, furanyl, prolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, and the like, and benzo derivatives thereof such as benzofuranyl, benzothienyl, benzoxazolyl, Benzimidazolyl, indazolyl, indolyl, isoindolyl, etc .; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc. and their benzo derivatives such as quinolyl, isoquinolyl, etc .; or azosinyl, indolizinyl, purinyl, etc. and their benzo Derivatives; or quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl , Carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, xanthenyl or oxepinyl, etc..

Heteroaryl groups can in each case be benzofused. For example, the following may be mentioned as 5-cyclic heteroaromatic compounds: thiophene, furan, oxazole, thiazole, imidazole, pyrazole and their benzo derivatives, and the following as 6-cyclic heteroaromatic compounds: To obtain: pyridine, pyrimidine, triazine, quinoline, isoquinoline and their benzo derivatives,
A heteroatom is defined as an oxygen, nitrogen or sulfur atom.
Is formed together with the nitrogen atom, the ring of R ^2, R ^3, Y and 3-8 membered within the meaning of Z is, C ₃ -C ₈ - cycloalkyl heteroalkyl and C ₃ -C ₈ - is defined as heteroaryl.

When acid groups are included, physiologically compatible salts of organic and inorganic bases are readily soluble alkali and alkaline earth salts, and N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, As salts such as 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-amino-methane, aminopropanediol, Sovak base and 1-amino-2,3,4-butanetriol Is appropriate.
Where basic groups are included, physiologically compatible salts of organic and inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, fumaric acid, etc. are suitable.

  The compounds of the general formula I according to the invention also include possible tautomeric forms and also comprise E-mutants or Z-isomers, or if a chiral center is present and also racemates and enantiomers. .

X represents CH,
W represents hydrogen,
A, B, D, E and Q together as a ring represent pyridyl,
R ¹ represents aryl or heteroaryl, which are halogen, hydroxy, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₄ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl Aralkyloxy, C ₁ -C ₆ -alkoxy, halo-C ₁ -C ₆ -alkyl, cyano-C ₁ -C ₆ -alkyl, or the group ═O, —SO ₂ R ⁶ or —OR ⁵ , and so on Or optionally substituted at one or more positions, wherein said C ₁ -C ₆ -alkyl is optionally substituted by the group —OR ⁵ or —NR ⁹ R ^10. Well,
Y and Z each independently represent a bond, independently of each other;

R ² and R ³ are independently of each other hydrogen or a group -CONR ⁹ R ¹⁰ , -SO ₂ R ⁶ , -COR ¹¹ , -COC ₁ -C ₆ -alkyl, -CO-C ₁ -C _6- Alkyl-R ¹¹ , —NR ⁹ R ¹⁰ , or C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -cycloalkenyl, aryl or heteroaryl (halogen, cyano, C _1- C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxy-C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, or groups -NR ⁷ R ⁸ , -OR ⁵ , -C ₁ -C ₆ -alkyl-OR ⁵ , —SR ⁴ , —SOR ⁴ or —SO ₂ R ⁶ the same or different, optionally substituted at one or more positions, or

R ² , R ³ , Y and Z together with the nitrogen atom can contain a 3-8 membered saturated or unsaturated ring (optionally can contain additional heteroatoms in the ring, and optionally halogen, cyano , C ₁ -C ₁₂ -alkyl, C ₁ -C ₁₂ -alkoxy, halo-C ₁ -C ₆ -alkyl, hydroxy-C ₁ -C ₆ -alkyl, or the group = O, -OR ⁵ , -SR ⁴ , -SOR ⁴ or -SO ₂ R ⁶ may be optionally substituted at one or more positions in the same or different manner,
R ⁴ represents C ₁ -C ₆ -alkyl, aryl or heteroaryl,
R ⁵ is hydrogen, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, C ₁ -C ₁₂ -alkoxy, C ₃ -C ₁₀ -cycloalkyl, or halo-C ₃ -C _6- Represents cycloalkyl,

R ⁶ represents hydrogen, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, aryl or heteroaryl, or the group —N ⁹ R ¹⁰ , where said aryl or heteroaryl itself is optionally May be substituted in one or more positions in the same or different manner by C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogen or halo-C ₁ -C ₆ -alkoxy ,
R ⁷ and R ⁸ independently of one another represent hydrogen or C ₁ -C ₆ -alkyl,
R ⁹ and R ¹⁰ are independently of each other hydrogen, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, aryl, C ₃ -C ₈ -cycloalkyl, or the group -CONR ⁷ R ⁸ , or C ₁ -C ₆ -alkyl (optionally substituted at one or more positions by aryl, morpholino, hydroxy, halogen or C ₁ -C ₁₂ -alkoxy or the group —NR ⁷ R ^{8 in} the same or different manner Wherein the aryl itself is optionally the same or different, optionally by C ₁ -C ₆ -alkoxy or halo-C ₁ -C ₆ -alkyl. And may be replaced with

R ¹¹ is C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxy-C ₁ -C ₆ -alkyl, hydroxy-C ₁ -C ₆ -alkoxy, C ₃ -C ₆ -cycloalkyl, phenyl represents pyridyl, biphenyl or naphthyl, wherein said phenyl itself, C ₁ -C ₆ - alkyl or halo -C _{1-C 6} - by alkyl, the same way or differently, substituted with one or more positions The resulting compounds of general formula I, as well as their isomers, diastereomers, tautomers and salts have proved advantageous.

X represents CH,
W represents hydrogen,
A, B, D, E and Q together as a ring represent pyridyl,
R ¹ represents phenyl, quinolinyl, isoquinolinyl or indazolyl, which are halogen, hydroxy, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkynyl, C ₁ -C ₆ -alkoxy, halo-C _1- C ₆ -alkyl, or cyano-C ₁ -C ₆ -alkyl may be optionally substituted in one or more positions, in the same or different manner, wherein said C ₁ -C ₆ -alkyl is Optionally, it may be substituted by the group -OR ⁵ or -NR ⁹ R ¹⁰
Y and Z, in each case, independently of one another, represent a bond or a group = CO;

R ² and R ³ are independently of each other hydrogen or a group -CONR ⁹ R ¹⁰ , -SO ₂ R ⁶ , -COR ¹¹ , -COC ₁ -C ₆ -alkyl, -CO-C ₁ -C _6- Alkyl-R ¹¹ , —NR ⁹ R ¹⁰ , or C ₁ -C ₆ -alkyl or phenyl (depending on the group —NR ⁷ R ⁸ , or —OR ⁵ , the same or different, optionally in one or more positions) Which may be substituted), or
R ² , R ³ , Y and Z together with the nitrogen atom can contain a 3-8 membered saturated or unsaturated ring (optionally can contain additional heteroatoms in the ring, and optionally halogen, cyano , C ₁ -C ₁₂ -alkyl, C ₁ -C ₁₂ -alkoxy, halo-C ₁ -C ₆ -alkyl, hydroxy-C ₁ -C ₆ -alkyl, or the group = O, -OR ⁵ , -SR ⁴ , -SOR ⁴ or -SO ₂ R ⁶ are optionally substituted in one or more positions in the same or different manner,

R ⁵ represents hydrogen or C ₁ -C ₆ -alkyl,
R ⁶ represents hydrogen, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, phenyl, benzyl, thiophenyl, or pyridyl, wherein said phenyl, benzyl, thiophenyl, or pyridyl itself is optionally May be substituted in one or more positions in the same or different manner by C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogen or halo-C ₁ -C ₆ -alkoxy ,
R ⁷ and R ⁸ independently of one another represent hydrogen or C ₁ -C ₆ -alkyl,

R ⁹ and R ¹⁰ are independently of each other hydrogen, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, phenyl, biphenyl, C ₃ -C ₈ -cycloalkyl, naphthyl, or the group —CONR ⁷ R ⁸ , or C ₁ -C ₆ -alkyl (optionally phenyl, morpholino, hydroxy, halogen, C ₁ -C ₁₂ -alkoxy or the group —NR ⁷ R ⁸ , in the same or different manner, one or more Wherein the phenyl itself is the same or different, optionally by C ₁ -C ₆ -alkoxy or halo-C ₁ -C ₆ -alkyl, Or a plurality of optionally substituted, and

R ¹¹ is C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxy-C ₁ -C ₆ -alkyl, hydroxy-C ₁ -C ₆ -alkoxy, C ₃ -C ₆ -cycloalkyl, phenyl represents pyridyl, biphenyl or naphthyl, wherein said phenyl itself, C ₁ -C ₆ - alkyl or halo -C _{1-C 6} - by alkyl, the same way or differently, substituted with one or more positions Of particular interest are those compounds of the general formula, their isomers, diastereomers, tautomers and salts.

  The compounds of the invention and their physiologically compatible salts prevent tyrosine oxidation or stop persistent angiogenesis and thus tumor growth and expansion, so that they are notably cytochrome P450 (3A4) A distinction is made by slight inhibition of the isoforms. Thus, dosing with the compounds of the present invention does not pose a risk even for pharmaceutical agents that are administered simultaneously and that are degraded through their isoforms.

The compounds of formula I and their pharmaceutically compatible salts can be used as pharmaceutical agents based on their inhibitory activity on phosphorylation of VEGF receptors. Based on their action profiles, the compounds of the invention are suitable for treating diseases caused or promoted by persistent angiogenesis.
Since compounds of formula I have been identified as inhibitors of the tyrosine kinases KDR and FLT, they are particularly caused or promoted by persistent angiogenesis induced through VEGF receptors or by increased vascular permeability Suitable for treating those diseases.
The object of the invention is also the use of the compounds of the invention as inhibitors of the tyrosine kinases KDR and FLT.
The object of the present invention is therefore also a pharmaceutical agent, or use thereof, for the treatment of tumors.

  The compounds of the present invention may be used for tumor or metastatic growth, psoriasis, Kaposi's sarcoma, restenosis, eg stent-induced restenosis, endometriosis, Crohn's disease, Hodgkin's disease, leukemia; arthritis, eg rheumatoid arthritis, hemangioma, Hemangiofibromas; ocular diseases such as diabetic retinopathy, neovascular glaucoma; renal diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microvascular syndrome, graft rejection and glomerulopathy; fibrosis In the case of diseases such as liver cirrhosis, glomerular stromal cell proliferation disease, arteriosclerosis, nerve tissue trauma, mechanical devices such as balloon catheter treatment, vascular prosthesis, or vascular opening after the use of stents such as blood vessels As a pharmaceutical agent for the prevention of re-occlusion, as an immunosuppressant and for the maintenance of scar-free treatment in senile keratosis and contact dermatitis, alone or in formulations It can be used.

In the treatment of damage to nerve tissue, rapid scar formation on the site of injury is prevented by the compounds of the present invention, that is, scar formation is prevented from occurring prior to axonal reconnection. Therefore, reconstitution of the neural compound is promoted.
Ascites formation in patients can also be inhibited by the compounds of the present invention. VEGF-induced edema can also be suppressed.
Lymphangiogenesis plays an important role in lymphatic 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 the present invention also exhibit outstanding action as VEGFR kinase 3 inhibitors and are therefore also suitable as effective inhibitors of lymphangiogenesis.
Treatment with the compounds of the present invention not only reduces the size of the transition, but also reduces the number of transitions.
Such pharmaceutical agents, their formulation and use are also an object of the present invention.

  The invention also includes tumor or metastatic growth, psoriasis, Kaposi's sarcoma, restenosis, such as stent-induced restenosis, endometriosis, Crohn's disease, Hodgkin's disease, leukemia; arthritis, such as rheumatoid arthritis, hemangiomas, blood vessels Fibroma; Eye diseases such as diabetic retinopathy, neovascular glaucoma; Renal diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microvascular syndrome, graft rejection and glomerulopathy; fibrotic disease In the case of, for example, cirrhosis, glomerular stromal cell proliferation disease, arteriosclerosis, nerve tissue trauma, balloon catheter treatment, vascular prosthesis, or mechanical devices to maintain vascular opening, for example vascular Use of a compound of general formula I as an inhibitor of reocclusion, as an immunosuppressant and for the manufacture of a pharmaceutical agent for the maintenance of scarless treatment in senile keratosis and contact dermatitis Also related to business.

Ascites formation in patients can also be inhibited by the compounds of the present invention. VEGF-induced edema can also be suppressed.
In order to use a compound of formula I as a pharmaceutical agent, the pharmaceutical agent is in the form of a pharmaceutical formulation, wherein the formulation comprises a suitable organic or inorganic in addition to the active agent for enteral or parenteral administration. Pharmaceutically inert carrier materials such as water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, and the like. The pharmaceutical preparations can be present in solid form, such as tablets, coated tablets, suppositories, or capsules, or in liquid form, such as solutions, suspensions or emulsions. They optionally further comprise adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, salts for changing the osmotic pressure, or buffers.

For parenteral administration, aqueous solutions of the active compounds are suitable, especially in injectable solutions or suspensions, in particular polyhydroxyethoxylated castor oil.
As carrier systems, surfactant adjuvants such as bile acid salts, or animal or plant phospholipids, or mixtures thereof, and liposomes or components thereof may also be used.
For oral administration, tablets, coated tablets or capsules containing talc and / or hydrocarbon vehicles or binders such as lactose, corn starch or potato starch are particularly suitable. Administration can also take place in liquid form, for example as a juice, optionally with a sweetener or, if necessary, one or more flavoring substances added.

The dosage of the active ingredient varies depending on the method of administration, the age and weight of the patient, the type and severity of the disease being treated, and similar factors. The daily dose is 0.5-1000 mg, preferably 50-200 mg, whereby the dose can be given as a single dose or divided into multiple daily doses.
The above formulations and forms for dispensing are also an object of the present invention.
Production of the compounds of the invention is carried out according to methods known in the art. For example, a compound of general formula I can have the following general formula II:

［式中、A, B, D, E, Q, W, X及びR¹は、一般式Iに示される意味を有し、そしてMはハロゲンである］で表される化合物がまず、アミンに転換され、そして次に、アシル化されるか、又はMがNHCOR’基により置換されることにより得られる。

[Wherein, A, B, D, E, Q, W, X and R ¹ have the meanings shown in general formula I, and M is halogen] Converted and then acylated or obtained by replacing M with an NHCOR ′ group.

［式中、R^yはC₁-C₆−アルキル又は水素を表し、そしてFGは脱離基、例えばハロゲン、O−トリフレート、O−メシレート、O−トシレート又はスルホンを意味する］で表される化合物がまず、アミドに転換され、そして次に、脱離基が、N(Y-R²)-R³基により置換されるか、又は下記式III ： Compounds of general formula I are also obtained as follows:

Wherein R ^y represents C ₁ -C ₆ -alkyl or hydrogen and FG represents a leaving group such as halogen, O-triflate, O-mesylate, O-tosylate or sulfone. The compound is first converted to an amide, and then the leaving group is replaced by a N (YR ² ) —R ³ group, or the following formula III:

Wherein R ² , R ³ , Y and Z have the meanings indicated in general formula I and R ^y represents C ₁ -C ₆ -alkyl or hydrogen, Saponified and then converted to an amide.
Amide formation is performed according to methods known in the art.
For amide formation it is possible to start from the corresponding ester. The ester is reacted according to J. Org. Chem. 1995, 8414 with aluminum trimethyl and its corresponding amine in a solvent such as toluene at a temperature 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 aluminum trimethyl, sodium hexamethyldisilazide can also be used.

  However, for amide formation, all steps known from peptide chemistry are also available. For example, the corresponding acid is passed through an amine and an activated acid derivative in an aprotic polar solvent, such as dimethylformamide, obtained for example with hydroxybenzotriazole and with a carbodiimide such as diisopropylcarbodiimide, and a temperature between 0 ° C. and the boiling point of the solvent. The reaction is preferably carried out at 80 ° C. However, the reaction between the carboxylic acid and the amine can also be activated by an activating reagent such as HATU (N-dimethylamino-1H-1,2,3-triazole- [4,5-b] pyridin-ylmethylene-N-methyl. Metanaminium hexafluorophosphate-N-oxide), where a polar aprotic solvent such as dimethylformamide is suitable for the reaction.

  The addition of a base such as N-methylmorpholine is necessary. The reaction proceeds at a temperature of 0-100 ° C., where the process is preferably carried out at room temperature, but in many cases heating is absolutely necessary. For amide formation, the process can also be used with acid halides, mixed anhydrides, imidazolides or azides. Pre-protection of the additional amino group, for example as an amide, is not necessary in all cases, but can conveniently affect the reaction.

In the case of bisacid chloride, a cyclic compound can be produced. In the case of a halogen acid halide, a cyclic compound can be produced. The ring closure is then completed optionally by the addition of a strong base such as sodium alcoholate. The same is true for sulfonic acid halides, where double sulfonation can also occur.
Urea is produced from an amino compound by reaction with an isocyanate. Inert solvents such as methylene chloride or dimethylformamide are used at temperatures between room temperature and 100 ° C., preferably 60 ° C. Pressurization is advantageous for the reaction.

The reaction of amide with halopyridine is carried out under a catalyst, for example with a palladium or copper catalyst. In the case of a copper catalyst (see Synlett. 2002, 427), a catalyst such as dioxane or dimethylformamide is used at a temperature up to the boiling point of the solvent, preferably 120 ° C. As the base, potassium phosphate or cesium carbonate is used. Ethylenediamine is advantageous for complexing copper (I) iodide used as a catalyst. The application of pressure is not harmful. In the case of palladium catalysts, both palladium (II) salts, such as palladium (II) acetate and palladium (O) complexes, such as palladium (O) ₂ dibenzylideneacetone ₃ (JACS 2002, 6043, THL 1999, 2035, Org. Lett 2001 , 2539, THL 2001, 4381 or THL 2001, 3681).

  As the solvent, toluene, dioxane or dimethylformamide is used at a temperature from room temperature to the boiling point of the solvent, preferably about 100 ° C. As an auxiliary ligand, BINAP, DPPF or Xanthphos is used. A base is also necessary. For this purpose, cesium carbonate, potassium phosphate or sodium-t-butyrate is used. These components can be combined by various means.

The formation of pyridine amine from its corresponding 2-halopyridine is carried out at a temperature up to 200 ° C. under a solvent such as pyridine or under a protic polar solvent such as ethylene glycol. A catalyst with a copper (I) salt is required for the reaction. Application of pressure is absolutely necessary in the case of low boiling amine reactions, but is also advantageous in conventional amines.
The ether decomposition is achieved according to known methods, for example by reaction with boron tribromide at −78 ° C. to room temperature, preferably −78 ° C., for example under an inert solvent such as methylene chloride.

General formulas II, IIa and III:

[Wherein, A, B, D, E, Q, W, X, Y, Z, R ² and R ³ have the meanings shown in general formula I, M represents halogen, and FG represents A group represented by a leaving group such as halogen, O-triflate, O-mesylate, O-tosylate or sulfone, and R ^y represents C ₁ -C ₆ -alkyl or hydrogen]. It represents a valuable intermediate product for the production of compounds of general formula I and is therefore also an object of the present invention.
Production of the compounds of the invention:
The following examples illustrate the production of the compounds of the present invention and are not intended to limit the invention.

Example 1.0: Formation of 2-{[2- (2-dimethylamino-ethylamino) -pyridin-4-ylmethyl] -amino} -N- (3-trifluoromethyl-phenyl) -benzamide :

90 mg (0.2 mmol) 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide are dissolved in 3 ml pyridine and 1 ml Mix with N, N-dimethyl-aminoethylamine and heat in a pressure vessel for 5 hours to a bath temperature of 200 ° C. After cooling, it is concentrated by evaporation and 90 mg of 2-{[2- (2-dimethylamino-ethylamino) -pyridin-4-ylmethyl] -amino} -N- (3-trifluoromethyl-phenyl ) -Benzamide is obtained.
Melting point: 100 ° C.
The following compounds are also produced analogously:

Example 2.0: Formation of 2-[(2-amino-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide :

8.747 g (19.4 mmol) of 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide in 175 mg of oxidation in 150 ml of ethanediol Heat to 80 ° C. with copper (I) in autoclave under 10 bar ammonia pressure for 23 hours. After the solvent is distilled under vacuum, the residue is purified on silica gel using an ethyl acetate: ethanol (100: 0 to 0: 100) gradient as eluent. 4.15 g (51% of theory) of 2-[(2-amino-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide (melting point: 64 ° C.) are obtained.
Similarly, the following compound is produced:

融点：202℃ Example 2.1: 2-[(2-Amino-pyridin-4-ylmethyl) -amino] -N-isoquinolin-3-yl-benzamide :

Melting point: 202 ° C

MS：m/e 358
融点：200℃ Example 2.2: 2-[(2-Amino-pyridin-4-ylmethyl) -amino] -N- (1H-indazol-5-yl) -benzamide :

MS: m / e 358
Melting point: 200 ° C

MW：372.43 Example 2.3: 2-[(2-Amino-pyridin-4-ylmethyl) -amino] -N- (2-methyl-2H-indazol-6-yl) -benzamide :

MW: 372.43

Example 3.0: Formation of 2-{[2- (3-benzyl-ureido) -pyridin-4-ylmethyl] -amino} -N- (3-trifluoromethyl-phenyl) -benzamide :

  100 mg (0.26 mmol) of 2-[(2-amino-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide in 3 ml of 2.5 ml of methylene chloride 0.29 mmol) of benzyl isocyanate is mixed together and it is stirred overnight at room temperature. After concentration by evaporation, the residue is chromatographed. 66 mg (49% of theory) of 2-{[2- (3-benzyl-ureido) -pyridin-ylmethyl] -amino} -N- (3-trifluoromethyl-phenyl) -benzamide (melting point: 153 ° C.) Get.

Similarly, the following compound is also produced:

Examples 3.15 and 3.29 are produced analogously to Example 3.0 using trimethyl isocyanate.
Example 3.30: Formation of 2-{[2- (3,3-dimethyl-ureido) -pyridin-4-ylmethyl] -amino} -N- (3-isoquinolinyl) -benzamide :

100 mg (0.23 mmol) 2-[(2-bromopyridin-4-ylmethyl) -amino] -N- (3-isoquinolinyl) -benzamide in 89 ml (0.28 mmol) cesium carbonate, 61 mg in 2 ml dioxane (0.69 mmol) N, N-dimethylurea, with 4,7 mg (0.0046 mmol) dipalladium-tribenzylideneacetone and 7.9 mg (0.014 mmol) Xanthphos, under protective gas and in a dry environment And heat to a bath temperature of 100 ° C. for 9 hours. It is then mixed with 20 ml of methylene chloride, suctioned off and concentrated by evaporation. The residue is chromatographed on silica gel using ethyl acetate as a solubilizer. 24 mg (24% of theory) of 2-{[2- (3,3-dimethyl-ureido) -pyridin-4-ylmethyl] -amino} -N- (3-isoquinolinyl) -benzamide are obtained.
(MS (CL): 441 ( M + + H)).
Similarly, the following compound is also produced:

Example 4.0: Formation of 2-[(2-Methanesulfonylamino-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide :

90 mg (0.2 mmol) 2-[(2-Bromo-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide and 23 mg (0.24 mmol) methanesulfonic acid amide Is introduced into 5 ml of dioxane and continuously mixed with 4 mg (0.02 mmol) of copper (I) iodide, 85 mg (0.4 mmol) of potassium phosphate and 2 mg (0.02 mmol) of ethylenediamine. . After stirring for 1 hour at a bath temperature of 120 ° C., it is diluted with 20 ml of water and concentrated by evaporation. It is then made alkaline with ammonia and shaken 3 times with 25 ml of ethyl acetate. The collected organic phases are washed with water, filtered and concentrated by evaporation. The residue is crystallized with ethyl acetate and a little hexane, stirred and sucked. 24 mg (26% of theory) of 2-[(2-methanesulfonylamino-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide (melting point at 214.5 ° C.) are obtained. .
Similarly, the following compound is produced:

Example 5.0: Formation of 2-[(2-bismethanesulfonylamino-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide :

193 mg (0.5 mmol) [(2-amino-pyridin-ylmethyl) -amino] -N (3-trifluoromethyl-phenyl) -benzamide in 69 ml (0.6 mmol) methanesulfonic acid in 3 ml dichloromethane Mix with chloride and 61 mg (0.6 mmol) triethylamine and stir together at room temperature for 1.5 hours. It is then washed once with dilute sodium bicarbonate solution, dried, filtered and concentrated by evaporation. The residue is chromatographed by flash chromatography (5 g of Isolute) using a gradient of cyclohexane: ethyl acetate (100: 0 to 50:50) as eluent. 80 mg (30% of theory) of 2-[(2-bismethanesulfonylamino-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide are obtained as a resin.
(MS: m / e 542).

Example 6.0: Formation of 2-[(2-butyrylamino-pyridin-4-ylmethyl) -amino] -N- (3-isoquinolinyl) -benzamide :

100 mg (0.23 mmol) 2-[(2-bromopyridin-4-ylmethyl) -amino] -N- (3-isoquinolinyl) -benzamide in 1 ml dioxane, 89 mg (0.28 mmol) cesium carbonate, 24 hours (0.69 mmol) butyramide, 4.7 mg (0.0046 mmol) dipalladium-tribenzylideneacetone and 7.9 mg (0.014 mmol) Xanthphos under cover gas and in a moisture-free environment for 25 hours Heat to 90 ° C bath temperature. It is then mixed with 20 ml of methylene chloride, sucked and concentrated by evaporation, the residue is firstly hexane, then hexane: ethyl acetate (8: 2) and then hexane: acetic acid as eluent. Chromatography on silica gel with ethyl (1: 1) and 45 mg (42% of theory) of 2-[(2-butyrylamino-pyridin-4-ylmethyl) -amino] -N- (3-isoquinolinyl ) -Benzamide (melting point: 173 ° C.).
Similarly, the following compound is produced:

同様にして、下記化合物を生成する：

Similarly, the following compound is produced:

融点：71℃。 Example 6.32: 2-{[2- (acetyl-methyl-amino) -pyridin-4-ylmethyl] -amino} -N-isoquinolin-3-yl-benzamide :

Melting point: 71 ° C.

Example 7.0: Formation of 2-{[2- (2-oxo-pyrrolidin-1-yl) -pyridin-4-ylmethyl] -amino} -N- (3-trifluoromethyl-phenyl) -benzamide :

  156 mg (0.5 mmol) of 2-{[2-oxo-pyrrolidin-1-yl] -pyridin-4-ylmethyl] -amino} -benzoic acid was added in 0.12 ml (1 mmol) of 3 in 5 ml of dimethylformamide. Aminobenzotrifluoride, 228 mg (0.6 ml mole) HATU (N-dimethylamino-1H-1,2,3-triazolo- [4,5-b] pyridin-1-ylmethylene-N-methylmethaneammonium hexafluoro Phosphate-N-oxide) and 0.14 ml N-methylmorpholine and it is stirred overnight at room temperature.

It is diluted with ethyl acetate and washed successively with saturated sodium bicarbonate solution, water and saturated saline solution. The organic phase is dried, filtered and concentrated by evaporation. The residue is chromatographed on Isolute as mobile solvent. 95 mg (42% of theory) of 2-{[2- (2-oxo-pyrrolidin-1-yl) -pyridin-4-ylmethyl] -amino} -N- (3-trifluoromethyl-phenyl) -benzamide Get.
(MS: m / e 454).
Similarly, the following compound is produced:

R², R³, Y及びZ=G

R ² , R ³ , Y and Z = G

Example 8.0 :
Analogously to Example 6.0, the following compound is produced:
2-{[2- (2-hydroxymethyl-5-oxo-pyrrolidin-1-yl) -pyridin-4-ylmethyl] -amino} -N-isoquinolin-3-yl-benzamide :

Similarly, the following compound is produced:

Example 9.0: Formation of 2-{[2- (2.5-Dioxo-pyrrolidin-1-yl) -pyridin-4-ylmethyl] -amino} -N- (3-trifluoromethyl-phenyl) -benzamide :

  193 mg (0.5 mmol) of 2-[(2-amino-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide in 0.21 ml (1.5 ml) in 20 ml chloromethane. (mmol) of triethylamine and it is mixed in portions at room temperature with a solution of 93 mg (0.6 mmol) of succinic dichloride in 3 ml of methylene chloride. After overnight stirring at room temperature, it is diluted with methylene chloride and washed successively with water, saturated sodium bicarbonate solution and saturated saline solution.

The organic phase is then dried, filtered and concentrated by evaporation. The residue is chromatographed on Isolute (Separtis Company) using a gradient of methylene chloride: ethanol (100: 0 to 95: 5). 120 mg (51% of theory) of 2-{[2- (2.5-dioxo-pyrrolidin-1-yl) -pyridin-4-ylmethyl] -amino} -N- (3-trifluoromethyl-phenyl) -benzamide Get.
(MS: m / e 468).
Similarly, the following compound is produced:

融点：201.9℃。 Example 9.1: 2-{[2- (3,5-Dioxo-morpholin-4-yl) -pyridin-4-ylmethyl] -amino} -N- (3-trifluoromethyl-phenyl) -benzamide :

Melting point: 201.9 ° C.

Example 10.0: Formation of 2-[(2- (3-chloropropanesulfonylamino-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide :

135 mg (0.35 mmol) 2-[(2-amino-pyridin-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide in 62 ml (0.35 mmol) in 10 ml dichloromethane Mix with 3-chloropropanesulfonic acid chloride and 49 μl (0.35 mmol) triethylamine and stir it at room temperature for 2 hours. It is then washed once with saturated sodium hydrogen carbonate solution, filtered and concentrated by evaporation. The residue is chromatographed by flash chromatography (5 g of Isolute) using a gradient of dichloromethane: ethanol (100: 0 to 90:10) as eluent. 67 mg (36% of theory) of 2-[(2- (3-chloropropanesulfonylamino-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide are obtained.
(MS (Cl): 491 ( 100%, M + + H-HCl).

58mg（0.11mモル）の２−[（２−（３−クロロプロパンスルホニルアミノ−ピリジン−４−イルメチル）−アミノ]−N−（３−トリフルオロメチル−フェニル）−ベンズアミドを、5mlのエタノールに懸濁し、そして5mgの水素化ナトリウム（鉱油中、55％）と共に混合する。その混合物を１時間、環流し、10mlの水と共に混合し、そして酢酸エチルにより抽出する。水性相を、硫酸ナトリウムにより飽和化し、そして酢酸エチルにより一晩、攪拌することにより、反復して抽出する。組合された抽出物を蒸発により濃縮した後、50mg（理論値の93％）の２−{[２−（１，１−ジオキソ−１λ⁶−イソチアゾリジン−２−イル）−ピリジン−４−イルメチル]−アミノ}−N−（３−トリフルオロメチル−フェニル）−ベンズアミドを得る。
(MS(Cl)：491 (100%, M^-+H))。 Example 11.0: 2-{[2- (1,1-dioxo-1λ ⁶ -isothiazolidin- 2-yl) -pyridin-4-ylmethyl] -amino} -N- (3-trifluoromethyl-phenyl) -benzamide Generate :

58 mg (0.11 mmol) 2-[(2- (3-chloropropanesulfonylamino-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide was suspended in 5 ml ethanol. Cloudy and mixed with 5 mg of sodium hydride (55% in mineral oil) The mixture is refluxed for 1 hour, mixed with 10 ml of water and extracted with ethyl acetate The aqueous phase is saturated with sodium sulfate And extracted repeatedly by stirring with ethyl acetate overnight After concentration of the combined extracts by evaporation, 50 mg (93% of theory) of 2-{[2- (1, 1-Dioxo-1λ ⁶ -isothiazolidin-2-yl) -pyridin-4-ylmethyl] -amino} -N- (3-trifluoromethyl-phenyl) -benzamide is obtained.
(MS (Cl): 491 ( 100%, M - + H)).

Example 12.0: N- [2- (2-hydroxy-ethyl) -2H-indazol-5-yl] -2-{[2- (3-methyl-ureido) -pyridin-4-ylmethyl] -amino} -benzamide :

  50 mg (0.11 mmol) N- [2- (2-methoxy-ethyl) -2H-indazol-5-yl] -2-{[2- (3-methyl-ureido) -pyridin-4-ylmethyl]- Amino} -benzamide is introduced into 5 ml of methylene chloride and with 0.56 ml of boron tribromide (1M in methylene chloride) at −78 ° C. under argon and in a moisture-free environment. Mix little by little. It is stirred for a further 15 minutes, the cold bath is removed and then it is stirred for a further 2 hours.

It is then mixed with water, flushed with methylene chloride, made alkaline with sodium hydrogen carbonate solution and extracted twice with 15 ml of ethyl acetate each time. The collected organic phases are dried, filtered and concentrated by evaporation. The residue was chromatographed on silica gel using a gradient of methylene chloride: ethanol (100: 0 to 90:10) as eluent and 27 mg of N- [2- (2-hydroxy-ethyl) -2H -Indazol-5-yl] -2-{[2- (3-methyl-ureido) -pyridin-4-ylmethyl] -amino} -benzamide.
Similarly, the following compound is produced from the corresponding methoxy compound.

Generation of intermediate compounds:
Example A :
If the production of intermediate compounds is not described, then those compounds are known or can be produced analogously to known compounds or methods described herein.
Stage 1:

で表される２−ブロモピリジン−５−カルバルデヒドの生成は、F.J. Romero-Salguerraなど., THL 40,859 (1999) に従って行われる。 a) The following formula:

2-bromopyridine-5-carbaldehyde is produced according to FJ Romero-Salguerra et al., THL 40,859 (1999).

で表される２−ブロモ−イソニコチン酸の生成： b) The following formula:

Formation of 2-bromo-isonicotinic acid represented by:

  160 g (0.93 mol) of 2-bromo-4-methyl-pyridine is added dropwise to 152 g (0.96 mol) of potassium permanganate in 4 L of water. It is then stirred at reflux for 1 hour, after which 152 g (0.96 mol) of potassium permanganate are added all at once. After a further 2 hours of stirring under reflux, it is sucked hot over celite and washed with water. The aqueous phase is shaken 3 times with dichloromethane. The aqueous phase is concentrated by evaporation to half its original volume and the pH is set to 2 with concentrated hydrochloric acid. The precipitated solid is aspirated and dried at 70 ° C. under vacuum. 56.5 g of white solid product accumulates.

で表される２−ブロモ−４−ヒドロキシメチル−ピリジンの生成： Following formula:

Formation of 2-bromo-4-hydroxymethyl-pyridine represented by:

30.2 ml (295 mmol) of triethylamine is added to 56.5 g (280 mmol) of 2-bromo-isonicotinic acid in 1.2 L of THF. It is then cooled to −10 ° C. and mixed little by little with 38.2 ml (295 mmol) of isobutyl chloroformate. Stirring is continued for 1 hour at −10 ° C., after which it is cooled to −70 ° C. and mixed little by little with 590 ml (590 mmol) of LiAlH ₄ solution (1M in THF). Stirring is continued for 1 hour at -70 ° C, after which it reaches -40 ° C. Add 600 ml of 50% acetic acid. It is stirred overnight at room temperature. Insoluble components are aspirated and the filtrate is concentrated by evaporation. The residue is purified on silica gel with hexane and hexane / ethyl acetate (1: 1). 28.0 g of a solid white oil accumulates.

で表される２−ブロモ−４−ホルミル−ピリジンの生成： Following formula:

Formation of 2-bromo-4-formyl-pyridine represented by:

149 g (1714 mmol) of manganese dioxide is added within 6 hours in a measured amount to 28.0 g (148.9 mmol) of 2-bromo-4-hydroxymethyl-pyridine in 500 ml of dichloromethane. Stirring is then continued at room temperature for 48 hours. It is sucked onto celite and concentrated by evaporation. 16.4 g of a solid white oil accumulates.
2-Bromo-4-formyl-pyridine can also be produced in two steps from 2-bromo-4-picoline according to THL 42,6815 (2001).

で表される２−[（６−ブロモ−ピリジン−３−イルメチル）−アミノ]−N−イソキノリン−３−イル−ベンズアミドの生成： Stage 2:
Following formula:

Formation of 2-[(6-bromo-pyridin-3-ylmethyl) -amino] -N-isoquinolin-3-yl-benzamide represented by:

3.46 g (13.17 mmol) of 2-amino-N-isoquinolin-3-yl-benzamide are introduced into 50 ml of methanol, 1.5 ml of glacial acetic acid and 2.45 g (13.17 mmol) of 2-bromopyridine- Mix with 5-carbaldehyde and stir at room temperature for 24 hours under argon and in a moisture-free environment. It is then mixed with 828 mg (13.17 mmol) sodium cyanoborohydride and stirred for a further 24 hours at room temperature. After concentration by evaporation under vacuum, the residue is taken up in dilute sodium hydrogen carbonate solution and sucked. The residue obtained is adsorbed and precipitated in a little ethyl acetate and suctioned repeatedly. The residue obtained in this case is chromatographed on silica gel using hexane: ethyl acetate (1: 1) as eluent. 3.27 g (57% of theory) of 2-[(6-Bromo-pyridin-3-ylmethyl) -amino] -N-isoquinolin-3-yl-benzamide are obtained.
Similarly, the following compound is produced:

2-[(2-Bromo-pyridin-4-ylmethyl) -amino] -N-isoquinolin-3-yl-benzamide:

2-[(2-Bromo-pyridin-4-ylmethyl) -amino] -N- (3-trifluoromethyl-phenyl) -benzamide:

Example B:
First stage:
Following formula:

Formation of 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -benzoic acid methyl ester represented by:
In 600 ml methanol 6.04 g (40 mmol) anthranilic acid methyl ester was mixed with 3.2 ml acetic acid and 7.4 g (40 mmol) 2-bromopyridine-4-carbaldehyde and overnight at 40 ° C. Stir. 3.8 g (60 mmol) sodium cyanoborohydride is added thereto and stirred at 40 ° C. overnight. 3.8 g (60 mmol) of sodium cyanoborohydride are added again and stirred at 40 ° C. over the weekend. It is mixed with water and concentrated by evaporation. The aqueous phase is extracted with ethyl acetate and the combined organic phases are dried and concentrated by evaporation. The crude product is chromatographed on silica gel using a gradient consisting of hexane and hexane / ethyl acetate (1: 1) as eluent. 10.0 g (78% of theory) of 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -benzoic acid methyl ester are obtained as a colorless oil.

で表される２−[（２−ブロモ−ピリジン−４−イルメチル）−アミノ]−安息香酸： Example C:
First stage:
Following formula:

2-[(2-Bromo-pyridin-4-ylmethyl) -amino] -benzoic acid represented by:

  10.0 g (31.2 mmol) of 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -benzoic acid methyl ester is dissolved in 290 ml of ethanol and mixed with 31.2 ml of 2M sodium hydroxide solution To do. After stirring overnight at room temperature, the ethanol is flushed and the aqueous phase is shaken with ethyl acetate. The aqueous phase is acidified with concentrated hydrochloric acid. The precipitate formed is sucked and dried. 5.93 g (62%) of 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -benzoic acid accumulates in the form of a white solid.

で表される２−［（２−ブロモ−ピリジン−４−イルメチル）−アミノ］−N−（２−メチル−2H−インダゾール−６−イル）−ベンズイミドの生成： Second stage:
Following formula:

Formation of 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -N- (2-methyl-2H-indazol-6-yl) -benzimide represented by:

  0.500 g (1.6 mmol) 2-[(2-Bromo-pyridin-4-ylmethyl) -amino] -benzoic acid, 0.471 g (3.2 mmol) 2-methyl-2H-indazole in 25 ml dimethylformamide -6-ylamine, 0.4 ml (3.68 mmol) N-methylmorpholine and 0.729 g (1.92 mmol) O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyl Uronium hexafluorophosphate (HATU) is stirred at room temperature for 16 hours. Dimethylformamide is drained under oil pump vacuum. The remaining residue is drained into 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 chromatographed on silica gel using a gradient consisting of hexane: acetone (100: 0 to 50:50) as eluent. 0.669 g (96% of theory) of [(2-Bromo-pyridin-4-ylmethyl) -amino] -N- (2-methyl-2H-imidazol-6-yl) -benzimide was converted to a beige foam. Get in the form of

Similarly, the following compound is also produced:
2-[(2-Bromo-pyridin-4-ylmethyl) -amino] -N- (1-methyl-1H-indazol-6-yl) -benzamide:

2-[(2-Bromo-pyridin-4-ylmethyl) -amino] -N- (1H-indazol-6-yl) -benzamide:

2-[(2-Bromo-pyridin-4-ylmethyl) -amino] -N- (1H-indazol-5-yl) -benzamide:

で表される２−{[２−（２−オキソ−ピロリジン−１−イル）−ピリジン−４−イルメチル]−アミノ｝−安息香酸メチルエステルの生成： Example D:
Following formula:

Formation of 2-{[2- (2-oxo-pyrrolidin-1-yl) -pyridin-4-ylmethyl] -amino} -benzoic acid methyl ester represented by:

  870 mg (2.78 mmol) 2-[(2-bromo-4-ylmethyl) -amino] -benzoic methyl ester, 53 mg (0.28 mmol) copper (I) iodide, 1.126 g (5.5 mmol) phosphorus Potassium acid and 0.26 ml (3.6 mmol) pyrrolidin-2-one are refluxed for 8 hours under 15 ml dioxane. After adding water, dioxane is distilled under vacuum, made alkaline with about 12% ammonia solution and shaken several times with ethyl acetate. The collected ethyl acetate phases are washed, dried, filtered and concentrated by evaporation. As a residue, 700 mg (77% of theory) of 2-{[2- (2-oxo-pyrrolidin-1-yl) -pyridin-4-ylmethyl] -amino} -benzoic acid methyl ester as crude product Which is used in the next step without further purification.

Similarly, the following compounds survive:

で表される２−{[２−（２−オキソ−ピロリジン−１−イル）−ピリジン−４−イルメチル]−アミノ}−安息香酸の生成： Stage 3:
Following formula:

Formation of 2-{[2- (2-oxo-pyrrolidin-1-yl) -pyridin-4-ylmethyl] -amino} -benzoic acid represented by:

  700 mg (2.15 mmol) of 2-{[2- (2-oxo-pyrrolidin-1-yl) -pyridin-4-ylmethyl] -amino} -benzoic acid methyl ester in 2.7 ml of 1N in 15 ml of methanol With sodium hydroxide solution and reflux for 1 hour. After the methanol is distilled under vacuum, it is diluted with water and shaken once with ethyl acetate. The aqueous phase is mixed with 5 ml of 1M citric acid solution and stirred overnight. The solid precipitate is aspirated and dried very quickly. 600 mg of 2-{[2- (2-oxo-pyrrolidin-1-yl) -pyridin-4-ylmethyl] -amino} -benzoic acid is obtained, which is used as the crude product in the next step.

R², R³, Y及びZ＝G Similarly, the following compound is produced:

R ² , R ³ , Y and Z = G

Example E:
Following formula:

2-[(2-Bromo-pyridin-4-ylmethyl) -amino] -N- (1-methyl-1H-indazol-5-yl) -benzamide and 2-[(2-bromo-pyridine- Formation of 4-ylmethyl) -amino] -N- (2-methyl-2H-indazol-5-yl) -benzamide:
4.22 g (10 mmol) of 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -N- (1H-indazol-5-yl) -benzamide was cooled in 30 ml of dimethylformamide with ice. While mixing with 3.6 g (11 mmol) of cesium carbonate and 0.68 ml (11 mmol) of methyl iodide, it is stirred overnight at room temperature.

  It is then stirred into 250 ml of ice-cold water, stirring is continued for 15 minutes and it is aspirated. The filter cake is dried very quickly and chromatographed on silica gel using an ethyl acetate: hexane (1: 1 to 100: 0) gradient as eluent. 1.79 g (41% of theory) of 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -N- (1-methyl-1H-indazol-5-yl) -benzamide (melting point: 173.8 ° C. ) And 830 mg (19% of theory) of 2-[(2-bromo-pyridin-4-ylmethyl) -amino] -N- (2-methyl-2H-indazol-5-yl) -benzamide (melting point: 183.8 C).

Similarly, the following compound is produced:
2-[(2-bromo-pyridin-4-ylmethyl) -amino] -N- (1-isopropyl-1H-indazol-5-yl) -benzamide;
2-[(2-Bromo-pyridin-4-ylmethyl) -amino] -N- (2-isopropyl-2H-indazol-5-yl) -benzamide;
2-[(2-Bromo-pyridin-4-ylmethyl) -amino] -N- (1-ethyl-1H-indazol-5-yl) -benzamide;
2-[(2-Bromo-pyridin-4-ylmethyl) -amino] -N- (2-ethyl-2H-indazol-5-yl) -benzamide;
2-[(2-bromo-pyridin-4-ylmethyl) -amino] -N- (1- [2-methoxyethyl] -1H-indazol-5-yl) -benzamide;

2-[(2-Bromo-pyridin-4-ylmethyl) -amino] -N- (2- [2-methoxyethyl] -2H-indazol-5-yl) -benzamide;
2-[(2-bromo-pyridin-4-ylmethyl) -amino] -N- (1- [cyanomethyl] -1H-indazol-5-yl) -benzamide;
2-[(2-bromo-pyridin-4-ylmethyl) -amino] -N- (2- [cyanomethyl] -2H-indazol-5-yl) -benzamide;
2-[(2-bromo-pyridin-4-ylmethyl) -amino] -N- (1- [2-dimethylaminoethyl] -1H-indazol-5-yl) -benzamide;
2-[(2-Bromo-pyridin-4-ylmethyl) -amino] -N- (2- [2-dimethylaminoethyl] -2H-indazol-5-yl) -benzamide;

2-[(2-Bromo-pyridin-4-ylmethyl) -amino] -N- (1-methyl-1H-indazol-6-yl) -benzamide;
2-[(2-Bromo-pyridin-4-ylmethyl) -amino] -N- (2-methyl-2H-indazol-6-yl) -benzamide;
2-[(2-Bromo-pyridin-4-ylmethyl) -amino] -N- (1-isopropyl-1H-indazol-6-yl) -benzamide;
2-[(2-Bromo-pyridin-4-ylmethyl) -amino] -N- (2-isopropyl-2H-indazol-6-yl) -benzamide;
2-[(2-Bromo-pyridin-4-ylmethyl) -amino] -N- (1-ethyl-1H-indazol-6-yl) -benzamide;

2-[(2-Bromo-pyridin-4-ylmethyl) -amino] -N- (2-ethyl-2H-indazol-6-yl) -benzamide;
2-[(2-bromo-pyridin-4-ylmethyl) -amino] -N- (1- [2-methoxyethyl] -1H-indazol-6-yl) -benzamide;
2-[(2-bromo-pyridin-4-ylmethyl) -amino] -N- (2- [2-methoxyethyl] -2H-indazol-6-yl) -benzamide;
2-[(2-bromo-pyridin-4-ylmethyl) -amino] -N- (1- [cyanomethyl] -1H-indazol-6-yl) -benzamide;
2-[(2-Bromo-pyridin-4-ylmethyl) -amino] -N- (2- [cyanomethyl] -2H-indazol-6-yl) -benzamide;
2-[(2-bromo-pyridin-4-ylmethyl) -amino] -N- (1- [2-dimethylaminoethyl] -1H-indazol-6-yl) -benzamide; and 2-[(2-bromo -Pyridin-4-ylmethyl) -amino] -N- (2- [2-dimethylaminoethyl] -2H-indazol-6-yl) -benzamide.

The following sample applications illustrate the biological effects and uses of the compounds of the invention, but they are not intended to limit the invention.
Solutions required for testing :
Stock solution:
Stock solution A: 3 mmol ATP in water, pH 7.0 (−70 ° C.);
Stock solution B: g-33P-ATP 1 mCi / 100 μl:
Stock solution C; poly- (Glu4Tyr) 10 mg / ml water:
Solution for dilution:
Substrate solvent: 10 mmol DTT, 10 mmol manganese chloride, 100 mmol magnesium chloride;
Enzyme solution: 120 mmol Tris / HCl, pH 7.5, 10 μM sodium vanadium oxide.

Sample application 1 :
Inhibition of KDR- and FLT-kinase activity in the presence of the compounds of the invention:
In a single-point tapered microtiter plate (no protein binding), 10 μl substrate mixture (10 μl ATP stock solution A + 25 μCi g-33P-ATP (approximately 2.5 μl stock solution B) +30 μl poly- (Glu4Tyr) stock solution C + 1.21 ml substrate solvent), 10 μl inhibitor solution (substance corresponding to dilution, 3% DMSO in substrate solvent as control), and 10 μl enzyme stock solution (KDR or FLT-1 kinase)), 1.25 ml Add to enzyme solution (rare) at 4 ° C. It is mixed well and incubated for 10 minutes at room temperature. Next, 10 μl of stop solution (250 mmol EDTA, pH 7.0) is added, mixed and 10 μl of the solution is transferred to a P81 phosphocellulose filter. It is then washed several times with 0.1M phosphoric acid. The filter paper is dried, coated with Meltilex and measured by a microbeta counter.

IC50 values are determined from the inhibitor concentration required to inhibit phosphate incorporation to 50% of uninhibited incorporation after removal of blank readings (response stopped by EDTA).
The results of kinase inhibition IC50 at μM are shown in the table below.

Sample application 2 :
Cytochrome P450 inhibition:
Cytochrome P450 inhibition was performed using baculovirus / insect cell-expressed human cytochrome P450 isoenzyme (3A4) according to Crespi et al. (Anal. Biochem., 248, 188-190 (1997)). The results are shown in the following table.

  Compared to the known compounds, the superior action of the compounds of the invention can be clearly seen from the above results.

Claims (11)

The following general formula I:

[Wherein X represents CH or N;
W represents hydrogen or fluorine;
A, B, D, E and Q, in each case, independently of one another, represent nitrogen or carbon atoms, where only a maximum of two nitrogen atoms can be present in the ring;
R ¹ represents aryl or heteroaryl, which are halogen, hydroxy, C ₁ -C ₁₂ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl, Similarly, by aralkyloxy, C ₁ -C ₁₂ -alkoxy, halo-C ₁ -C ₆ -alkyl, cyano-C ₁ -C ₆ -alkyl, or the group = O, -SO ₂ R ⁶ or -OR ⁵ Or, alternatively, optionally substituted at one or more positions, wherein said C ₁ -C ₆ -alkyl may optionally be substituted by the group —OR ⁵ or —NR ⁹ R ^10. Often;
Y and Z, in each case, independently of one another, represent a bond or a group = CO, = CS or = SO ₂ ;
R ² and R ³ are independently of each other hydrogen or a group -CONR ⁹ R ¹⁰ , -SO ₂ R ⁶ , -COR ¹¹ , -COC ₁ -C ₆ -alkyl, -CO-C ₁ -C _6- Alkyl-R ¹¹ , —NR ⁹ R ¹⁰ , or C ₁ -C ₆ -alkyl, C ₃ -C ₁₀ -cycloalkyl, C ₃ -C ₆ -cycloalkenyl, aryl or heteroaryl (halogen, cyano, C _1- C ₁₂ -alkyl, C ₁ -C ₁₂ -alkoxy, hydroxy-C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, or group -NR ⁷ R ⁸ , -OR ⁵ , -C ₁ -C ₆ -alkyl-OR ⁵ , —SR ⁴ , —SOR ⁴ or —SO ₂ R ⁶ the same or different, optionally substituted at one or more positions; or
R ² , R ³ , Y and Z together with the nitrogen atom can contain a 3-8 membered saturated or unsaturated ring (optionally can contain additional heteroatoms in the ring, and optionally halogen, cyano , C ₁ -C ₁₂ -alkyl, C ₁ -C ₁₂ -alkoxy, halo-C ₁ -C ₆ -alkyl, hydroxy-C ₁ -C ₆ -alkyl, or the group = O, -OR ⁵ , -SR ⁴ , -SOR ⁴ or -SO ₂ R ⁶ is optionally substituted in one or more positions in the same or different manner;
R ⁴ represents C ₁ -C ₁₂ -alkyl, aryl or heteroaryl;
R ⁵ is hydrogen, C ₁ -C ₁₂ -alkyl, C ₃ -C ₁₀ -cycloalkyl, C ₁ -C ₁₂ -alkoxy, halo-C ₁ -C ₁₂ -alkyl, or halo-C ₃ -C _6- Represents cycloalkyl;
R ⁶ represents hydrogen, C ₁ -C ₁₂ -alkyl, halo-C ₁ -C ₆ -alkyl, aryl or heteroaryl, or the group —N ⁹ R ¹⁰ , where said aryl or heteroaryl itself is optionally May be substituted in one or more positions in the same or different manner by C ₁ -C ₁₂ -alkyl, C ₁ -C ₆ -alkoxy, halogen or halo-C ₁ -C ₆ -alkoxy ;
R ⁷ and R ⁸ independently of one another represent hydrogen or C ₁ -C ₁₂ -alkyl; and
R ⁹ and R ¹⁰ are independently of each other hydrogen, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, aryl, C ₃ -C ₈ -cycloalkyl or the group -CONR ⁷ R ⁸ , or C ₁ -C ₁₂ -alkyl (optionally substituted at one or more positions by aryl, morpholino, hydroxy, halogen, C ₁ -C ₁₂ -alkoxy or the group -NR ⁷ R ⁸ , in the same or different manner. Wherein the aryl itself is optionally substituted in the same or different manner one or more optionally by C ₁ -C ₆ -alkoxy or halo-C ₁ -C ₆ -alkyl. May be; or
R ⁹ and R ¹⁰ together form a 5-8 membered ring that can contain additional heteroatoms; and
R ¹¹ is C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxy-C ₁ -C ₆ -alkyl, hydroxy-C ₁ -C ₆ -alkoxy, C ₃ -C ₆ -cycloalkyl, phenyl represents pyridyl, biphenyl or naphthyl, wherein said phenyl itself, C ₁ -C ₆ - alkyl or halo -C _{1-C 6} - by alkyl, the same way or differently, substituted with one or more positions It may be]
And isomers, diastereomers, tautomers and salts thereof. X represents CH,
W represents hydrogen,
A, B, D, E and Q together as a ring represent pyridyl,
R ¹ represents aryl or heteroaryl, which are halogen, hydroxy, C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₄ -C ₆ -alkenyl, C ₂ -C ₆ -alkynyl Aralkyloxy, C ₁ -C ₆ -alkoxy, halo-C ₁ -C ₆ -alkyl, cyano-C ₁ -C ₆ -alkyl, or the group ═O, —SO ₂ R ⁶ or —OR ⁵ , and so on Or optionally substituted at one or more positions, wherein said C ₁ -C ₆ -alkyl is optionally substituted by the group —OR ⁵ or —NR ⁹ R ^10. Well,
Y and Z each independently represent a bond, independently of each other;
R ² and R ³ are independently of each other hydrogen or a group -CONR ⁹ R ¹⁰ , -SO ₂ R ⁶ , -COR ¹¹ , -COC ₁ -C ₆ -alkyl, -CO-C ₁ -C _6- Alkyl-R ¹¹ , —NR ⁹ R ¹⁰ , or C ₁ -C ₆ -alkyl, C ₃ -C ₆ -cycloalkyl, C ₃ -C ₆ -cycloalkenyl, aryl or heteroaryl (halogen, cyano, C _1- C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxy-C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, or groups -NR ⁷ R ⁸ , -OR ⁵ , -C ₁ -C ₆ -alkyl-OR ⁵ , —SR ⁴ , —SOR ⁴ or —SO ₂ R ⁶ the same or different, optionally substituted at one or more positions, or
R ² , R ³ , Y and Z, together with the nitrogen atom, can contain a 3-8 membered saturated or unsaturated ring (optionally can contain additional heteroatoms in the ring, and optionally, halogen, cyano , C ₁ -C ₁₂ -alkyl, C ₁ -C ₁₂ -alkoxy, halo-C ₁ -C ₆ -alkyl, hydroxy-C ₁ -C ₆ -alkyl, or the group = O, -OR ⁵ , -SR ⁴ , -SOR ⁴ or -SO ₂ R ⁶ may be optionally substituted in one or more positions in the same or different manner,
R ⁴ represents C ₁ -C ₆ -alkyl, aryl or heteroaryl,
R ⁵ is hydrogen, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, C ₁ -C ₁₂ -alkoxy, C ₃ -C ₁₀ -cycloalkyl, or halo-C ₃ -C _6- Represents cycloalkyl,
R ⁶ represents hydrogen, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, aryl or heteroaryl, or the group —N ⁹ R ¹⁰ , where said aryl or heteroaryl itself is optionally May be substituted in one or more positions in the same or different manner by C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogen or halo-C ₁ -C ₆ -alkoxy ,
R ⁷ and R ⁸ independently of one another represent hydrogen or C ₁ -C ₆ -alkyl,
R ⁹ and R ¹⁰ are independently of each other hydrogen, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, aryl, C ₃ -C ₈ -cycloalkyl, or the group -CONR ⁷ R ⁸ , or C ₁ -C ₆ -alkyl (optionally substituted at one or more positions by aryl, morpholino, hydroxy, halogen or C ₁ -C ₁₂ -alkoxy or the group —NR ⁷ R ^{8 in} the same or different manner Wherein the aryl itself may be the same or different, optionally by C ₁ -C ₆ -alkoxy or halo-C ₁ -C ₆ -alkyl. And may be replaced with
R ¹¹ is C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxy-C ₁ -C ₆ -alkyl, hydroxy-C ₁ -C ₆ -alkoxy, C ₃ -C ₆ -cycloalkyl, phenyl represents pyridyl, biphenyl or naphthyl, wherein said phenyl itself, C ₁ -C ₆ - alkyl or halo -C _{1-C 6} - by alkyl, the same way or differently, substituted with one or more positions The obtained compound of claim 1 and isomers, diastereomers, tautomers and salts thereof. X represents CH,
W represents hydrogen,
A, B, D, E and Q together as a ring represent pyridyl,
R ¹ represents phenyl, quinolinyl, isoquinolinyl or indazolyl, which are halogen, hydroxy, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkynyl, C ₁ -C ₆ -alkoxy, halo-C _1- C ₆ -alkyl, or cyano-C ₁ -C ₆ -alkyl may be optionally substituted in one or more positions, in the same or different manner, wherein said C ₁ -C ₆ -alkyl is Optionally, it may be substituted by the group -OR ⁵ or -NR ⁹ R ¹⁰
Y and Z, in each case, independently of one another, represent a bond or a group = CO;
R ² and R ³ are independently of each other hydrogen or a group -CONR ⁹ R ¹⁰ , -SO ₂ R ⁶ , -COR ¹¹ , -COC ₁ -C ₆ -alkyl, -CO-C ₁ -C _6- Alkyl-R ¹¹ , —NR ⁹ R ¹⁰ , or C ₁ -C ₆ -alkyl or phenyl (depending on the group —NR ⁷ R ⁸ , or —OR ⁵ , the same or different, optionally in one or more positions) Which may be substituted), or
R ² , R ³ , Y and Z together with the nitrogen atom can contain a 3-8 membered saturated or unsaturated ring (optionally can contain additional heteroatoms in the ring, and optionally halogen, cyano , C ₁ -C ₁₂ -alkyl, C ₁ -C ₁₂ -alkoxy, halo-C ₁ -C ₆ -alkyl, hydroxy-C ₁ -C ₆ -alkyl, or the group = O, -OR ⁵ , -SR ⁴ , -SOR ⁴ or -SO ₂ R ⁶ may be optionally substituted in one or more positions in the same or different manner,
R ⁵ represents hydrogen or C ₁ -C ₆ -alkyl,
R ⁶ represents hydrogen, C ₁ -C ₆ -alkyl, halo-C ₁ -C ₆ -alkyl, phenyl, benzyl, thiophenyl, or pyridyl, wherein the phenyl, benzyl, thiophenyl, and pyridyl itself are optionally May be substituted in one or more positions in the same or different manner by C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, halogen or halo-C ₁ -C ₆ -alkoxy ,
R ⁷ and R ⁸ independently of one another represent hydrogen or C ₁ -C ₆ -alkyl,
R ⁹ and R ¹⁰ are independently of each other hydrogen, C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, phenyl, biphenyl, C ₃ -C ₈ -cycloalkyl, naphthyl, or the group —CONR ⁷ R ⁸ , or C ₁ -C ₆ -alkyl (optionally phenyl, morpholino, hydroxy, halogen, C ₁ -C ₁₂ -alkoxy or the group —NR ⁷ R ⁸ , in the same or different manner, one or more Wherein the phenyl itself is the same or different, optionally by C ₁ -C ₆ -alkoxy or halo-C ₁ -C ₆ -alkyl, Or a plurality of optionally substituted, and
R ¹¹ is C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, hydroxy-C ₁ -C ₆ -alkyl, hydroxy-C ₁ -C ₆ -alkoxy, C ₃ -C ₆ -cycloalkyl, phenyl represents pyridyl, biphenyl or naphthyl, wherein said phenyl itself, C ₁ -C ₆ - alkyl or halo -C _{1-C 6} - by alkyl, the same way or differently, substituted with one or more positions 3. A compound according to claim 1 or 2 and the isomers, diastereomers, tautomers and salts thereof obtained.   A pharmaceutical agent comprising at least one compound of general formula I.   Tumor or metastatic growth, psoriasis, Kaposi's sarcoma, restenosis, eg stent-induced restenosis, endometriosis, Crohn's disease, Hodgkin's disease, leukemia; arthritis, eg rheumatoid arthritis, hemangioma, angiofibroma; ocular disease , Eg diabetic retinopathy, neovascular glaucoma; renal diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microvascular syndrome, graft rejection and glomerulopathy; fibrotic diseases such as cirrhosis, thread In the case of spherical interstitial cell proliferative disorder, arteriosclerosis, nerve tissue trauma, inhibition of vascular reocclusion after use of balloon catheter treatment, vascular prosthesis, or vascular opening, eg, use of a stent, 5. A pharmaceutical agent according to claim 4 for use as an immunosuppressant and for the maintenance of scarless treatment in senile keratosis and contact dermatitis.   6. A pharmaceutical agent according to claim 5 for use as a VEGFR (vascular endothelial growth factor receptor) kinase 3-inhibitor of lymphangiogenesis.   7. A pharmaceutical agent according to any one of claims 4 to 6 comprising a compound according to any one of claims 1 to 3 together with a suitable formulation and vehicle.   Use of a compound of formula I according to any one of claims 1 to 3 as an inhibitor of tyrosine kinases KDR and FLT.   Use of a compound of general formula I according to any one of claims 1 to 3 in the form of pharmaceutical preparations for enteral, parenteral and oral administration.   Tumor or metastatic growth, psoriasis, Kaposi's sarcoma, restenosis, eg stent-induced restenosis, endometriosis, Crohn's disease, Hodgkin's disease, leukemia; arthritis, eg rheumatoid arthritis, hemangioma, angiofibroma; ocular disease , Eg diabetic retinopathy, neovascular glaucoma; renal diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microvascular syndrome, graft rejection and glomerulopathy; fibrotic diseases such as cirrhosis, thread In the case of spherical interstitial cell proliferative disorder, arteriosclerosis, nerve tissue trauma, inhibition of vascular reocclusion after use of balloon catheter treatment, vascular prosthesis, or vascular opening, eg, use of a stent, Use of a compound according to any one of claims 1 to 3 as an immunosuppressant and for the maintenance of scar-free treatment in senile keratosis and contact dermatitis. The following general formulas II, IIa and III:

[Wherein, A, B, D, E, Q, W, X, Y, Z, R ² and R ³ have the meanings shown in general formula I, M represents halogen, and FG represents Represents a leaving group such as halogen, O-triflate, O-mesylate, O-tosylate or sulfone, and R ^y represents C ₁ -C ₆ -alkyl or hydrogen]
A compound as an intermediate product for the production of a compound of general formula I according to the invention represented by: