3-amino-pyrazolo[3,4b]pyridines as inhibitors of protein tyrosine kinases, their production and use as pharmaceutical agents

This application claims the benefit of the filing date of U.S. Provisional Application Ser. No. 60/636,690 filed Dec. 17, 2004 which is incorporated by reference herein.

The invention relates to compounds of general formula (I), production and use as inhibitors of protein tyrosine kinases, in particular Eph (erythropoetin-producing hepatoma amplified sequence) receptors for treating various diseases.

Protein tyrosine kinases catalyze the phosphorylation of specific tyrosine radicals in various proteins. Such phosphorylation reactions play a role in a number of cellular processes that are involved in the regulation of growth and the differentiation of cells. Protein tyrosine kinases are divided into receptor- and non-receptor tyrosine kinases. The family of receptor tyrosine kinases (RTKs) consists of 58 kinases (Manning, G. et al. 2002, Science 298, 1912-1934). RTKs have an extracellular ligand binding domain, a transmembrane domain and an intracellular domain, which generally contains tyrosine kinase activity. RTKs mediate the signal relay of extracellular stimulators such as, e.g., growth factors. The ligand bond results in the dimerization of RTKs and the reciprocal auto-phosphorylation of their intracellular domains. Based on the cell type, specific intracellular binding proteins are thus recruited (i.a., non-receptor tyrosine kinases), via which a signal processing is carried out in the cells (Schlessinger, J. 2000, Cell 103, 211-225). The latter include receptor families of growth factors such as EGF (epidermal growth factor), VEGF (vascular endothelial growth factor), FGF (fibroblast growth factor), PDGF (platelet derived growth factor) and NGF (nerve growth factor), as well as the insulin receptors and the large family of ephrin receptors, etc.

The ephrin (Eph) receptors make up the largest family within the RTKs. They are divided according to their sequential affinity and their ligand specificity into the group of EphA receptors (9 members) and EphB receptors (6 members) (Kullander, K. and Klein, R. 2002, Nat. Rev. Mol. Cell. Biol. 3, 475-486; Cheng, N. et al. 2002, Cyt. and Growth Factor Rev. 13, 75-85). Eph receptors are activated by membrane-fixed ligands of the EphrinA or EphrinB family. EphrinAs are anchored via glycolipids (GPI) in the cell membrane, while EphrinBs have a transmembrane region and an intracellular domain. The interaction between ephrins and the Eph receptors results in a bi-directional signal transfer in the ephrin-expressing cells and in the cells that carry the Eph receptor. Ephrins and Eph receptors play a role in a number of morphogenetic processes in embryonic development and in the adult organism. They are involved in embryonic pattern formation, in the development of the vascular system (Gerety, S. S. et al., 1999, Mol. Cell. 4, 403-414) and in creating neuronal circuits (Flanagan, J. G. and Vanderhaeghen, P., 1998, Annu. Rev. Neurosci. 21, 306-354). In the adult organism, they are involved in the neovascularization process, e.g., in tumor development and in endometriosis, as well as in the morphogenesis of the intestinal epithelium (Battle, E. et al. 2002, Cell 111:251-63). On the cellular plane, they mediate migration, adhesion and juxtacrine cell contacts. Elevated expression of Eph receptors, such as, e.g., EphB2 and EphB4, was also observed in various tumor tissues, such as, e.g., breast tumors and tumors of the intestine (Nakamoto, M. and Bergemann, A. D. 2002, Mic. Res. Tech. 59, 58-67). Knock-out mice of EphB2, EphB3 and EphB4 show defects in the formation of the vascular system. The embryonic mortality of the EphB4-I-mice in embryonic stage d14 shows the special role of EphB4 in this process (Gerety, S. S. et al. 1999, Mol. Cell. 4, 403-414). A modulation of these receptors, e.g., by the inhibition of their kinase activity, results, for example, in that the tumor growth and/or the tumor metastasizing is suppressed either by a direct antitumoral action or by an indirect antiangiogenic action.

Non-receptor tyrosine kinases are present intracellularly in soluble form and are involved in the processing of extracellular signals (e.g., of growth factors, cytokines, antibodies, adhesion molecules) within the cell. They include, i.a., the families of Src (sarcoma) kinases, the Tec (tyrosine kinases expressed in hepatocellular-carcinoma) kinases, the Abl (Abelson) kinases and the Brk (breast-tumor kinase) kinases, as well as the focal adhesion kinase (FAK).

A modified activity of these protein tyrosine kinases can result in the most varied physiological disorders in the human organism and thus cause, e.g., inflammatory, neurological and oncological diseases.

Pyrazolopyridines are described as antimicrobial substances (e.g., Attaby et al., Phosphorus, Sulfur and Silicon and the Related Elements (1999), 149, 49-64; ibid. (1999), 155, 253-270).

In U.S. Pat. No. 5,478,830, pyrazolopyridines are disclosed.

DE 30 01 498 A1 (Agfa-Gevaert AG) discloses pyrazoles that can be used for photographic materials.

Pyrazolopyridines that have an antiphlogistic and in particular antithrombotic action are described in DE 26 43 753 A1 (Dr. Karl Thomae GmbH). The disclosed substituents are always linked via a nitrogen atom to the pyridine in 6-position.

F. E. Goda et al. 2004, Bioorganic & Medicinal Chemistry, 12(8), pp. 1845-1852, discloses pyrazolopyridines that have an antimicrobial action.

B. Narsaiah et al. 2001, Journal of Fluorine Chemistry, 109, 183-7 describes various pyrazolopyridines that are substituted with CF 3 .

WO 01/19828 A2 discloses a pyrazolopyridine that is substituted with a diaminopyrazolyl group and a methyl group. The substances that are described in this patent can be used as hair dyes.

In WO 01/19828 (BASF AG), the bases for the most varied kinase inhibitors are disclosed. The description contains pyrazolopyridines (structure 95, page 101). In the examples, however, no pyrazolopyridines are disclosed, and the production of the pyrazolopyridines claimed therein is not described.

In other prior art, reference is made to suitable spots in the text. No Eph-receptor inhibitors are described under the receptor tyrosine kinase inhibitors, however.

The object of this invention is to provide compounds that inhibit protein tyrosine kinases, in particular Eph receptors.

In a first embodiment of this invention, it was now found that compounds of general formula (I)

in which

R 1 stands for C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkinyl, C 3 -C 10 -cycloalkyl, C 3 -C 10 -heterocycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with K, whereby C 3 -C 10 -heterocycloalkyl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and C 3 -C 10 -cycloalkyl and/or C 3 -C 10 -heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO 2 — groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring, K stands for halogen, hydroxy or the group —O—R 3 , or for C 3 -C 10 -cycloalkyl, C 3 -C 10 -heterocycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with L, whereby the C 3 -C 10 -heterocycloalkyl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and C 3 -C 10 -cycloalkyl and/or C 3 -C 10 -heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO 2 — groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring, L stands for C 1 -C 6 -alkyl or for the group —COR 4 or —NR 5 R 6 , R 2 stands for C 1 -C 6 -alkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with M, R 3 stands for C 1 -C 6 -alkyl, aryl or —(CH 2 ) n -aryl that optionally is substituted in one or more places, in the same way or differently, with the group —NR 5 R 6 , R 4 stands for hydrogen, hydroxy, C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy, M stands for cyano, halogen, hydroxy, nitro or for C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, or C 2 -C 6 -alkinyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, or C 1 -C 6 -alkoxy, or for the group —O—R 3 or —COR 4 , R 5 and R 6 , independently of one another, stand for hydrogen, C 1 -C 6 -alkyl or for the group —COR 4 , and n stands for 1 to 4,

as well as their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts, with the stipulation that if

R 1 stands for methyl, then R 2 cannot simultaneously stand for methyl, —CH 2 —O—CH 3 , phenyl, chlorophenyl, or benzofuranyl or furanyl that is substituted with hydroxy and/or methoxy, or if R 1 stands for —CH 2 —O—CH 3 , then R 2 cannot simultaneously stand for methyl, or if R 1 stands for —CH═CH-phenyl, then R 2 cannot simultaneously stand for phenyl, or if R 1 stands for —CH═CH-chlorophenyl, then R 2 cannot simultaneously stand for phenyl or chlorophenyl, or if R 1 stands for —CH═CH-methoxyphenyl, then R 2 cannot simultaneously stand for phenyl or methoxyphenyl, or if R 1 stands for phenyl, then R 2 cannot simultaneously stand for —CF 3 or phenyl, or if R 1 stands for chlorophenyl, then R 2 cannot simultaneously stand for chlorophenyl, or if R 1 stands for hydroxyphenyl, then R 2 cannot simultaneously stand for heterocycloalkyl or for —COO-tert-butyl-substituted heterocycloalkyl, or if R 1 stands for benzyloxyphenyl, then R 2 cannot simultaneously stand for —COO-tert-butyl-substituted heterocycloalkyl,

inhibit protein tyrosine kinases, in particular Eph receptors.

Compounds of the above-mentioned general formula I, in which

R 1 stands for C 1 -C 6 alkyl, C 3 -C 10 -cycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with K, K stands for halogen, hydroxy or morpholinyl, piperazinyl, piperidinyl or phenoxy that optionally is substituted in one or more places, in the same way or differently, with L, L stands for C 1 -C 6 -alkyl or —COO—C 1 -C 6 alkyl, R 2 stands for C 1 -C 6 alkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with M, M stands for cyano, halogen, hydroxy, nitro or for C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, or C 2 -C 6 -alkinyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, or C 1 -C 6 -alkoxy, or for the group —O—C 1 -C 6 -alkyl, —O—(CH 2 ) n —N(C 1 -C 6 -alkyl) 2 , —CO—C 1 -C 6 -alkyl, —O-phenyl or —O—(CH 2 ) n -phenyl, and n stands for 1 to 4,

as well as their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts, are preferred.

Compounds of the above-mentioned general formula I, in which

R 1 stands for tert-butyl, cyclopropyl, cyclohexyl, cyclohexanone, 1,4-dioxa-spiro[4.5]dec-8-yl, phenyl, 1,3-benzodioxolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with K, K stands for halogen, hydroxy or morpholinyl, piperazinyl, piperidinyl, methoxy or phenoxy that optionally is substituted in one or more places, in the same way or differently, with L, L stands for methyl or —COO-tert-butyl, R 2 stands for isopropyl, phenyl, quinolinyl, imidazolyl, indolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with M, and M stands for cyano, halogen, hydroxy, nitro, methyl, —CF 3 or for methoxy or for the group —CO-methyl, —O—(CH 2 ) 3 —N(methyl) 2 , phenoxy or benzyloxy,

as well as their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts, are especially preferred.

In addition, compounds of the above-mentioned general formula I, in which

R 1 stands for C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkinyl, C 3 -C 10 -cycloalkyl, C 3 -C 10 -heterocycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with K, whereby the C 3 -C 10 -heterocycloalkyl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and C 3 -C 10 -cycloalkyl and/or C 3 -C 10 -heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO 2 — groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring, K stands for halogen, hydroxy or the group —O—R 3 or —NR 5 R 6 or for C 3 -C 10 -cycloalkyl, C 3 -C 10 -heterocycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with L, whereby the C 3 -C 10 -heterocycloalkyl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and C 3 -C 10 -cycloalkyl and/or C 3 -C 10 -heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO 2 — groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring, L stands for C 1 -C 6 -alkyl or the group —COR 4 or —NR 5 R 6 , R 2 stands for C 1 -C 6 -alkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with M, R 3 stands for C 1 -C 6 -alkyl, aryl or —(CH 2 ) n -aryl that optionally is substituted in one or more places, in the same way or differently, with the group —NR 5 R 6 , R 4 stands for hydrogen, hydroxy, C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy, M stands for cyano, halogen, hydroxy, nitro or for C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl or C 2 -C 6 -alkinyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, or C 1 -C 6 -alkoxy, or for the group —O—C 1 -C 6 -alkyl, —O—(CH 2 ) n —NR 5 R 6 or —COR 4 , R 5 and R 6 , independently of one another, stand for hydrogen, C 1 -C 6 -alkyl or for the group —COR 4 , and n stands for 1 to 4,

as well as their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts, are preferred.

In addition, those compounds of the above-mentioned general formula I, in which

R 1 stands for C 1 -C 6 alkyl, C 3 -C 10 -cycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with K, K stands for halogen, hydroxy or morpholinyl, piperazinyl, piperidinyl or phenyoxy that optionally is substituted in one or more places, in the same way or differently, with L, L stands for C 1 -C 6 -alkyl or —COO—C 1 -C 6 alkyl, R 2 stands for C 1 -C 6 alkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with M, M stands for cyano, halogen, hydroxy, nitro or for C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, or C 2 -C 6 -alkinyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, or C 1 -C 6 -alkoxy, or for the group —O—C 1 -C 6 -alkyl, —O—(CH 2 ) n —N(C 1 -C 6 -alkyl) 2 or —CO—C 1 -C 6 -alkyl, and n stands for 1 to 4,

as well as their solvates, hydrates, stereoisomers, diastereomers, enantiomers, and salts, are preferred.

Those compounds of the above-mentioned general formula, in which

R 1 stands for C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, cyclohexanone, 1,4-dioxa-spiro[4.5]dec-8-yl, phenyl, 1,3-benzodioxolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with K, K stands for halogen, hydroxy or morpholinyl, piperazinyl, piperidinyl, methoxy or phenoxy that optionally is substituted in one or more places, in the same way or differently, with L, L stands for C 1 -C 6 -alkyl or —COO—C 1 -C 6 alkyl, R 2 stands for C 1 -C 6 -alkyl, phenyl or quinolinyl, imidazolyl, indolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with M, M stands for cyano, halogen, hydroxy, nitro or for C 1 -C 6 -alkyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, or C 1 -C 6 -alkoxy, or for the group —O—C 1 -C 6 -alkyl, —O—(CH 2 ) n —N(C 1 -C 6 -alkyl) 2 or —CO—C 1 -C 6 -alkyl, and n stands for 1 to 4,

as well as their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts, are especially preferred.

Those compounds of general formula I, in which

R 1 stands for tert-butyl, cyclopropyl, cyclohexyl, cyclohexanone, 1,4-dioxa-spiro[4.5]dec-8-yl, phenyl, 1,3-benzodioxolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with K, K stands for halogen, hydroxy or morpholinyl, piperazinyl, piperidinyl, methoxy or phenoxy that optionally is substituted in one or more places, in the same way or differently, with L, L stands for methyl or —COO-tert-butyl, R 2 stands for isopropyl, phenyl, quinolinyl, imidazolyl, indolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with M, and M stands for cyano, halogen, hydroxy, nitro, methyl, —CF 3 or for methoxy or for the group —CO-methyl, —O—(CH 2 ) 3 —N(methyl) 2 , phenoxy or benzyloxy,

as well as their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts, are very highly preferred.

The intermediate products that are preferably used for the production of the compounds of general formula I according to the invention in accordance with this first embodiment of the invention are the following compounds of general formulas II and III

in which

X stands for halogen or —O—SO 2 —C m F 2m+1 , m stands for 1 to 4, R 1a stands for C 1 -C 6 -alkyl, C 1 -C 6 -alkenyl, C 2 -C 6 -alkinyl, C 3 -C 10 -cycloalkyl, C 3 -C 10 -heterocycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with K a , whereby the C 3 -C 10 -heterocycloalkyl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and C 3 -C 10 -cycloalkyl and/or C 3 -C 10 -heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO 2 — groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring, K a stands for halogen, hydroxy, the group —O—R 3a , —COR 4a or —NR 5a R 6 a, or for C 3 -C 10 -cycloalkyl, C 3 -C 10 -heterocycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with L a , whereby the C 3 -C 10 -heterocycloalkyl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and C 3 -C 10 -cycloalkyl and/or C 3 -C 10 -heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO 2 — groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring, L a stands for C 1 -C 6 -alkyl or the group —COR 4a or —NR 5a R 6a , R 2a stands for C 1 -C 6 -alkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with M a , R 3a stands for trimethylsilyl (TMS), tert-butyl-dimethylsilyl (TBDMS), tert-butyl-diphenylsilyl (TBDPS), triethylsilyl (TES), C 1 -C 2 -alkyl, C 3 -C 6 -allyl, benzyl or for the group —COR 4a or for C 1 -C 6 -alkyl, aryl or —(CH 2 ) n -aryl that optionally is substituted in one or more places, in the same way or differently, with the group —NR 5a R 6a , R 4a stands for hydrogen, C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy, M a stands for cyano, halogen, hydroxy, nitro or for C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, or C 2 -C 6 -alkinyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, or C 1 -C 6 -alkoxy, or for the group —O—R 3a or —COR 4a , R 5a and R 6a , independently of one another, stand for hydrogen, C 1 -C 6 -alkyl or for the group COR 4a , and n a stands for 1 to 4,

as well as their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts.

Alkyl is defined in each case as a straight-chain or branched alkyl radical, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl and decyl.

Alkoxy is defined in each case as a straight-chain or branched alkoxy radical, such as, for example, methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy or decyloxy.

The alkenyl substituents are in each case straight-chain or branched, whereby, for example, the following radicals are meant: 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-yl, but-3-en-1-yl, or allyl.

Alkinyl is defined in each case as a straight-chain or branched alkinyl radical that contains 2-6, preferably 2-4, C atoms. For example, the following radicals can be mentioned: acetylene, propin-1-yl, propin-3-yl, but-1-in-1-yl, but-1-in-4-yl, but-2-in-1-yl, but-1-in-3-yl, etc.

Heterocyclyl or C 3 -C 10 -heterocycloalkyl stands for an alkyl ring that comprises 3-10 carbon atoms and is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and the C 3 -C 10 -heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO 2 — groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring. Only those combinations are meant, however, that are useful from the viewpoint of one skilled in the art, in particular in reference to ring strain.

As heterocyclyls, there can be mentioned, e.g.: oxiranyl, oxethanyl, aziridinyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, dioxanyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, quinuclidinyl, etc.

Cycloalkyls are defined as monocyclic C 3 -C 10 alkyl rings, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, but also bicyclic rings or tricyclic rings, such as, for example, adamantanyl or 1,4-dioxa-spiro[4,5]dec-8-yl. The cycloalkyl rings can be unsubstituted or substituted in one or more places.

An aryl radical in each case has 6-12 carbon atoms, such as, for example, naphthyl, biphenyl and in particular phenyl.

The heteroaryl radical in each case comprises 3-16 ring atoms and instead of carbon contains one or more of the heteroatoms that are the same or different from the group oxygen, nitrogen or sulfur, can be monocyclic, bicyclic or tricyclic and in addition in each case can be benzocondensed. Only those combinations are meant, however, that are useful from the viewpoint of one skilled in the art, in particular in reference to ring strain.

The heteroaryl rings can be unsubstituted or substituted in one or more places.

For example, there can be mentioned: thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl as well as benzo derivatives thereof, such as, e.g., 1,3-benzodioxolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, indazolyl, indolyl, isoindolyl, oxepinyl, azocinyl, indolizinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, purinyl, or quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, etc.

Halogen is defined in each case as fluorine, chlorine, bromine or iodine.

In an additional embodiment of this invention that achieves the object, there are, according to a 1 st aspect, compounds of general formula (I),

in which

R 1 stands for C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkinyl, C 3 -C 10 -cycloalkyl, C 3 -C 10 -heterocycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with K, whereby the C 3 -C 10 -heterocycloalkyl and/or the heteroaryl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and the C 3 -C 10 -heterocycloalkyl and/or heteroaryl can be linked only via a carbon ring atom with the pyrazolopyridine, and C 3 -C 10 -cycloalkyl and/or C 3 -C 10 -heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO 2 — groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring, or stands for a C 3 -C 10 -cycloalkyl, aryl, C 3 -C 10 -heterocycloalkyl or heteroaryl that is substituted with the group —O—(CH 2 ) n —O—, whereby the terminal oxygen atoms of the —O—(CH 2 ) n —O— group are linked to the same or a directly adjacent C 3 -C 10 -cycloalkyl ring-, aryl ring-, C 3 -C 10 -heterocycloalkyl ring- or heteroaryl ring-carbon atom, K stands for halogen, hydroxy or the group —OR 3 , —COR 4 or —NR 5 R 6 , or for C 3 -C 10 -cycloalkyl, C 3 -C 10 -heterocycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with L, whereby the C 3 -C 10 -heterocycloalkyl and/or the heteroaryl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and C 3 -C 10 -cycloalkyl and/or C 3 -C 10 -heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO 2 — groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring, L stands for C 1 -C 6 -alkyl or the group —COR 4 , —OR 3 or —NR 5 R 6 , R 2 stands for C 1 -C 6 alkyl, C 3 -C 10 -cycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with M, R 3 stands for C 1 -C 6 -alkyl, aryl or —(CH 2 ) n -aryl that optionally is substituted in one or more places, in the same way or differently, with the group —NR 5 R 6 , R 4 stands for hydrogen, hydroxy, C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy, M stands for amino, cyano, halogen, hydroxy, or nitro or for C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, or C 2 -C 6 -alkinyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, nitro, or C 1 -C 6 -alkoxy, or for the group —OR 3 , —COR 4 , or —CO—N—R 7 , R 5 and R 6 , independently of one another, stand for hydrogen, C 1 -C 6 -alkyl or for the group —COR 4 , and R 7 stands for hydrogen, or NH 2 , n stands for 1 to 4,

with the stipulation that if

R 1 stands for methyl, then R 2 cannot simultaneously stand for methyl, —CH 2 —O—CH 3 , phenyl, chlorophenyl, benzofuranyl that is substituted with hydroxy and/or methoxy, —CF 3 or furanyl, or if R 1 stands for —CH 2 —O—CH 3 , then R 2 cannot simultaneously stand for methyl, or if R 1 stands for —CH═CH-phenyl, then R 2 cannot simultaneously stand for phenyl, or if R 1 stands for —CH═CH-chlorophenyl, then R 2 cannot simultaneously stand for phenyl or chlorophenyl, or if R 1 stands for —CH═CH-methoxyphenyl, then R 2 cannot simultaneously stand for phenyl or methoxyphenyl, or if R 1 stands for phenyl, then R 2 cannot simultaneously stand for —CF 3 , methyl, methoxyphenyl or phenyl, or if R 1 stands for methoxyphenyl, then R 2 cannot simultaneously stand for —CF 3 , or if R 1 stands for methylphenyl, then R 2 cannot simultaneously stand for —CF 3 , or if R 1 stands for chlorophenyl, then R 2 cannot simultaneously stand for chlorophenyl or —CF 3 , or if R 1 stands for dichlorophenyl, then R 2 cannot simultaneously stand for trimethoxyphenyl, or if R 1 stands for bromophenyl, then R 2 cannot simultaneously stand for trimethoxyphenyl, or if R 1 stands for alkyl, alkenyl, aryl, aralkyl, cycloalkyl, or for an alkyl that is substituted with phenyl or p-methoxyphenyl, then R 2 cannot simultaneously also stand for alkyl, alkenyl, aryl, aralkyl, cyano, a heterocyclic radical or cycloalkyl, or if R 1 stands for a lower alkyl radical, alkoxy or aryloxy, then R 2 simultaneously cannot stand for a lower alkyl radical, or if R 1 stands for hydroxyphenyl, then R 2 cannot simultaneously stand for heterocyclyl or a —COO-tert-butyl-substituted heterocycloalkyl, or if R 1 stands for benzyloxyphenyl, then R 2 cannot simultaneously stand for a —COO-tert-butyl-substituted heterocycloalkyl,

as well as their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts.

In an alternate embodiment,

R 1 =methyl, then R 2 is not=methyl or ethyl, or if R 2 =methyl, then R 1 is not=methyl or ethyl, or if R 1 =chlorophenyl, then R 2 is not=chlorophenyl or methylchlorophenyl, or if R 2 =chlorophenyl, then R 1 is not=—CH 2 -phenyl, or if R 1 =methyl, then R 2 is not=chlorophenyl, furanyl, methylchlorophenyl or methylfuranyl, or if R 2 =chlorophenyl or furanyl, then R 1 is not=methyl or ethyl, or if R 1 =—CH═CH-phenyl, then R 1 is not=phenyl, or methylphenyl, or if R 2 =phenyl, then R 1 is not=—C 1-3 -alkyl-phenyl, C 2-3 -alkenyl-phenyl, C 2-3 -alkinyl-phenyl, or —CH═CH-methylphenyl, or if R 1 =—CH═CH-methoxyphenyl, then R 2 is not=phenyl, methylphenyl, methoxyphenyl, ethoxyphenyl, hydroxyphenyl, or methoxyphenyl with an additional methyl substituent, or if R 2 =phenyl or methoxyphenyl, then R 1 is not=—C 1-3 -alkyl-methoxyphenyl, C 2-3 -alkenyl-methoxyphenyl, or C 2-3 -alkinyl-methoxyphenyl, or if R 1 =—CH═CH-chlorophenyl, then R 2 is not=phenyl, methylphenyl, chlorophenyl, or methylchlorophenyl, or if R 2 =phenyl or chlorophenyl, then R 1 is not=—C 1-3 -alkyl-chlorophenyl, C 2-3 -alkenyl-chlorophenyl, C 2-3 -alkinyl-chlorophenyl, or —CH═CH-methylphenyl, or if R 1 =methyl, then R 2 is not=—CH 2 —O—CH 3 , —CH 2 —CH 2 —O—CH 3 , or —CH 2 —O—CH 2 —CH 3 , R 2 =—CH 2 —O—CH 3 , then R 1 is not=methyl or ethyl, or if R 1 =phenyl, then R 2 is not=—CF 3 or C 1-2 -alkyl that is optionally substituted with halogen, preferably with 3 F groups, or if R 2 =—CF 3 , then R 1 is not=phenyl or —CH 2 -phenyl, or if R 1 =methylphenyl, then R 2 is not=—CF 3 or C 1-2 -alkyl optionally substituted with halogen, preferably with 3 F groups, or if R 2 =—CF 3 , then R 1 is not=phenyl, methylphenyl, ethylphenyl, or —CH 2 -methylphenyl, or if

R 1 =methoxyphenyl, then R 2 is not=—CF 3 or C 1-2 -alkyl optionally substituted with halogen, preferably with 3 F groups, or if

R 2 =—CF 3 , then R 1 is not=methoxyphenyl, ethoxyphenyl, or hydroxyphenyl, or if R 1 =chlorophenyl, then R 2 is not=—CF 3 or C 1-2 -alkyl optionally substituted with halogen, preferably with 3 F groups, or if R 2 =—CF 3 , then R 1 is not=chlorophenyl, or if R 1 =phenyl, then R 2 is not=phenyl or methylphenyl, or if R=phenyl, then R 1 is not=—CH 2 -phenyl, or if R 1 =methyl, then R 2 is not=benzofuranyl that is substituted with hydroxy and/or methoxy or ethoxy, or benzofuranyl that is substituted with hydroxy and/or methoxy and an additional methyl, or if R 2 =benzofuranyl that is substituted with hydroxy and/or methoxy, then R 1 is not=methyl or ethyl, or if R 2 =methyl, then R 2 is not=—CF 3 or C 1-2 -alkyl optionally substituted with halogen, preferably with 3 F groups, or if R 2 =—CF 3 , then R 1 is not=methyl or ethyl, or if R 1 =—CH 2 —O—CH 3 , then R 2 is not=methyl or ethyl, or if R 2 =methyl, then R 1 is not=—CH 2 —O—CH 3 , —CH 2 —CH 2 —O—CH 3 , —CH 2 —O—CH 2 —CH 3 , —CH═CH—O—CH 3 , —CH 2 —O—CH═CH 2 , —C≡C—O—CH 3 , or —CH 2 —O—C≡C, or if R 1 =methyl, then R 2 is not=phenyl or methylphenyl, or if R 2 =phenyl, then R 1 is not=methyl or ethyl, or if R 1 =dichlorophenyl, then R 2 is not=trimethoxyphenyl, or a dimethoxyhphenyl group that additionally is substituted with a hydroxy or ethoxy group, or a trimethoxyphenyl that is substituted with a methyl group, or if R 1 =bromophenyl, then R 2 is not=trimethoxyphenyl or a dimethoxyphenyl group that additionally is substituted with a hydroxy or ethoxy group, or trimethoxyphenyl that is substituted with a methyl group, or if R 1 =hydroxyphenyl, then R 2 is not=piperidine or methylpiperidine, or if R 1 =phenyl, then R 2 is not=methoxyphenyl, ethoxyphenyl, or hydroxyphenyl, or if R 2 =methoxyphenyl, then R 1 is not=phenyl or —CH 2 -phenyl, or if R=methyl, then R 1 is not=—CH 2 -phenyl, or if R 1 =phenyl, then R 2 is not=methyl or ethyl, or if R 1 stands for an unsubstituted alkyl, alkenyl, aryl, aralkyl or cycloalkyl group, then R 2 is not an unsubstituted alkyl, alkenyl, aryl, aralkyl or cycloalkyl group, or if R 1 stands for diaminopyrazolyl-, then R 2 - is not methyl or ethyl, or if R 1 stands for hydrogen, an optionally substituted alkyl, aralkyl-, cycloalkyl-, or aryl radical, for example, a methyl, ethyl or propyl group that is substituted with a phenyl, methylphenyl, p-nitrophenyl, -methylnitrophenyl, p-methoxyphenyl, p-ethoxyphenyl, or p-hydroxyphenyl ring then R 2 is not hydrogen, an optionally substituted alkyl-, aralkyl-, cyclo-alkyl-, aryl- or heterocyclic radical or a cyano group, or if R 1 stands for a lower alkyl radical (for example, methyl or ethyl), an alkoxy or aryloxy group or a primary, secondary or tertiary amino group, then R 2 is not a lower alkyl radical (for example, a methyl or ethyl group) or a phenyl, —CH 2 -phenyl or methylphenyl,

as well as their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts.

The above-described disclaimer was introduced based on the prior art below.

A pyrazolopyridine with R 1 =methyl and R 2 =methyl is described by, for example, Kaupp., G. et al. 2003, European Journal of Organic Chemistry, (8) pp. 1545-1551, Gamal, A., 1994, Zagazig Journal of Pharmaceutical Sciences, 3(2) 148-53, Kalme, Z. A. et al., 1992, Khimiya Geterotsiklicheskikh Soedinenii, (9), 1218-22, El-Dean, A. M. Kamal et al., 1991, Bulletin of the Faculty of Science, Assiut University, 20(1), 15-21 or by El-Dean, A. M. et al, 1991, Indian Journal of Chemistry, 30B (9), 878-82.

A pyrazolopyridine with R 1 =chlorophenyl and R 2 =chlorophenyl is known by Gamal et al., 2001, Journal of Saudi Chemical Society, 5(2), pp. 183-187.

Mohamed, A. et al., 2000, Phosphorus, Sulfur and Silicon, 167, 161-179 describes pyrazolopyridines in which R 1 =methyl and at the same time R 2 =chlorophenyl, and R 1 =methyl and at the same time R 2 =furanyl. Attaby, Fawzy A. et al., 1999, Phosphorus, Sulfur and Silicon, 149, 49-64 show that these substances have antimicrobial properties.

Attaby, Fawzy A. et al., 1999, Phosphorus, Sulfur and Silicon, 155, 253-270 disclose, for example, pyrazolopyridines with antimicrobial action in which R 1 =—CH═CH-phenyl and at the same time R 2 =phenyl, R 1 =—CH═CH-methoxyphenyl and at the same time R 2 =phenyl or methoxyphenyl, R 1 =—CH═CH-chlorophenyl and at the same time R 2 =phenyl or chlorophenyl. Sanna, Eldin M. et al., 1998, Egyptian Journal of Pharmaceutical Sciences, 39, (1-3), 197-209 describe the same compounds and show that these substances have antibacterial properties.

Arustamova, I. S. et al., 1999, Chemistry of Heterocyclic Compounds, 35(1), 58-63 describes pyrazolopyridines in which R 1 =methyl and at the same time R 2 =—CH 2 —O—CH 3 .

Lacan, M. and Tabakovic, K. (1975) Chroatica Chemica Acta 47 (2), 127-133 disclose pyrazolopyridines in which R 1 stands for methyl while at the same time R 2 also stands for methyl.

Chandra, Sheker Reddy et al., 1997, Journal of Fluorine Chemistry, 86(2) 127-130 describes pyrazolopyridines in which R 1 =methyl and at the same time R 2 =methyl, R 1 =phenyl and at the same time R 2 =—CF 3 , R 2 =methylphenyl and at the same time R 2 =—CF 3 , R 1 =methoxyphenyl and at the same time R 2 =—CF 3 , as well as R=chlorophenyl and at the same time R 2 =—CF 3 .

Abdel, Hafez et al., 1993, Collection of Czechoslovak Chemical Communications, 58(5), 1198-202; Deeb, Ali, 1991, Collection of Czechoslovak Chemical Communications, 56(7), 1560-3 disclose a pyrazolopyridine with R 1 =phenyl and at the same time R 2 =phenyl.

Gohar, Abdel Kerim et al., 1987, Archiv der Pharmazie (Weinheim, Germany), 320(9), 823-9 disclose pyrazolopyridines in which R 2 =methyl and at the same time R 2 =benzofuranyl that is substituted with hydroxy and/or methoxy.

Balicki, R. et al., 1979, Polish Journal of Chemistry, 53(7-8), 1515-25 describes a pyrazolopyridine in which R 1 =methyl and at the same time R 2 =—CF 3 .

Pejcic, Marijan et al., 1977, Acta Pharmaceutica Jugoslavia, 27(3), 143-6 disclose pyrazolopyridines with antibacterial properties, in which R 1 =methyl and at the same time R 2 =—CH 2 —O—CH 3 , and R 1 =—CH 2 —O—CH 3 and at the same time R 2 =methyl.

Bomika, Z. et al., 1976, Khimiya Geterotsiklicheskikh Soedinenii, (8), 1085-8 describes a pyrazolopyridine in which R 1 =phenyl and at the same time R 2 =phenyl, R 1 =methyl and at the same time R 2 =phenyl.

Yoshida, Kei et al., 1976, Yakugaku Zasshi, 96(1), 33-6 describes a pyrazolopyridine in which R 1 =methyl and at the same time R 2 =—CH 2 —O—CH 3 .

DE 30 01 498 A1 (Agfa-Gevaert AG) discloses pyrazoles that can be used for photographic materials. The patent discloses pyrazolopyridines in which R 1 stands for an unsubstituted alkyl, alkenyl, aryl, aralkyl or cycloalkyl group, and R 2 simultaneously stands for an unsubstituted alkyl, alkenyl, aryl, aralkyl or cycloalkyl group.

Described in DE 26 43 753 A1 (Dr. Karl Thomae GmbH) are pyrazolopyridines that have an antiphlogistic and in particular antithrombotic action. The disclosed substituents are always linked via a nitrogen atom to the pyridine (of the pyrazolopyridine) at 6-position.

F. E. Goda et al. 2004, Bioorganic & Medicinal Chemistry, 12(8), pp. 1845-1852 discloses pyrazolopyridines that have an antimicrobial action. In this case, R 1 stands for dichlorophenyl, and R 2 simultaneously stands for trimethoxyphenyl (compound 5b) or R 1 stands for bromophenyl, and R 2 then simultaneously stands for trimethoxyphenyl (compound 5c). Compounds 3a to 5a in Table 1 on page 1846 relate to precursors of pyrazolopyridines, but not pyrazolopyridines themselves.

Registry Number 774531-14-5 discloses a pyrazolopyridine in which R 1 =hydroxyphenyl and at the same time R 2 is a piperidine. Registry Number 692775-16-9 discloses a pyrazolopyridine in which R 1 =phenyl and at the same time R 2 is a methoxyphenyl. Registry Number 201224-90-0 discloses a pyrazolopyridine in which R 1 =methoxyphenyl and at the same time R 1 is a —CF 3 .

B. Narsaiah et al. 2001, Journal of Fluorine Chemistry, 109, 183-7 describes different CF 3 -substituted pyrazolopyridines. In this case, R 2 stands for —CF 3 while R 1 either stands for phenyl, methylphenyl or chlorophenyl.

WO 01/19828 A2 discloses a pyrazolopyridine that is substituted with a diaminopyrazolyl- (at R 1 -position) and a methyl group (at R 1 -position). The diaminopyrazolyl is linked via the nitrogen atom to the pyridine (of the pyrazolopyridine) at 6-position. The substances that are described in this patent can be used as hair dyes.

German laid-open specification DE2160780 discloses pyridinopyrazoles for use as diazo components in which R 1 stands for phenyl or methyl and at the same time R 2 stands for phenyl or methyl.

German laid-open specification DE2238400 pyrazolopyridines as dyes in which R 1 stands for hydrogen, an optionally substituted alkyl-, aralkyl-, cycloalkyl-, or aryl radical, and R 2 stands for hydrogen, an optionally substituted alkyl-, aralkyl-, cyclo-alkyl-, aryl- or heterocyclic radical or a cyano group. Which substitutions may be suitable is not defined in the application. In the examples, for R 1 , there is only one ethyl group that is substituted with a phenyl ring, a p-nitrophenyl and a p-methoxyphenyl. For R 2 , there are no examples with substitutions. Also, for R 2 defined as a heterocyclic radical, there are no definitions and also no examples.

German laid-open specification DE2355967 discloses polycyclic dyes in whose production pyrazolopyridines are used in which R 1 stands for a lower alkyl radical (in the examples, methyl is mentioned), an alkoxy or aryloxy group or a primary, secondary or tertiary amino group, and R 2 simultaneously stands for a lower alkyl radical (in the examples, methyl and phenyl are mentioned for R 2 ).

None of the above-mentioned publications and patents disclose Eph-receptor inhibitors.

According to this embodiment, compounds of general formula I in a 2 nd aspect, according to claim 1 , in which

R 1 stands for C 1 -C 6 alkyl or C 3 -C 10 -cycloalkyl that optionally is substituted in one or more places, in the same way or differently, with K, whereby the C 3 -C 10 -cycloalkyl optionally is interrupted by one or more —(CO)—, —SO— or —SO 2 — groups in the ring, and optionally one or more double bonds can be contained in the ring, or for aryl, C 3 -C 10 -heterocycloalkyl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with K, whereby the C 3 -C 10 -heterocycloalkyl and/or the heteroaryl itself is interrupted by at least one nitrogen/oxygen and/or sulfur, and the C 3 -C 10 -heterocycloalkyl and/or heteroaryl can be linked only via a carbon ring atom with the pyrazolopyridine, or for a C 3 -C 10 -cycloalkyl, aryl, C 3 -C 10 -heterocycloalkyl or heteroaryl that is substituted with the group —O—(CH 2 ) n —O—, whereby the terminal oxygen atoms of the —O—(CH 2 ) n —O— group are linked with the same or a directly adjacent C 3 -C 10 -cycloalkyl ring-, aryl ring-, C 3 -C 10 -heterocycloalkyl ring- or heteroaryl ring-carbon atom, K stands for halogen, hydroxy or the group —OR 3 , —COR 4 or for C 3 -C 10 -cycloalkyl, C 3 -C 10 -heterocycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with L, whereby the C 3 -C 10 -heterocycloalkyl and/or the heteroaryl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and C 3 -C 10 -cycloalkyl and/or C 3 -C 10 -heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO 2 — groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring, R 2 stands for C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with M, whereby the heteroaryl is interrupted by at least one nitrogen, oxygen and/or sulfur, R 3 stands for C 1 -C 6 -alkyl, aryl or —(CH 2 ) n -aryl, M stands for amino, cyano, halogen, hydroxy, nitro or for C 1 -C 6 -alkyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, nitro, or C 1 -C 6 -alkoxy, or for the group —O—C 1 -C 6 -alkyl, —O—(CH 2 ) n —NR 5 R 6 , —COR 4 —O-phenyl, —O—(CH 2 ) n -phenyl or —CO—N—R 7 ,

as well as their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts, are also subjects of the invention.

According to this embodiment, compounds of general formula I in a 3 rd aspect, according to the 2 nd aspect, in which

R 1 stands for C 1 -C 6 alkyl or C 3 -C 10 -cycloalkyl that optionally is substituted in one or more places, in the same way or differently, with K, whereby the C 3 -C 10 -cycloalkyl optionally is interrupted by one or more —(CO)—, —SO— or —SO 2 groups in the ring, and optionally one or more double bonds can be contained in the ring, or R 1 stands for aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with K, whereby the heteroaryl itself is interrupted by at least one nitrogen, oxygen and/or sulfur, and the heteroaryl can be linked only via a carbon ring atom with the pyrazolopyridine, or R 1 stands for a C 3 -C 10 -cycloalkyl, aryl or heteroaryl that is substituted with the group —O—(CH 2 ) n —O—, whereby the terminal oxygen atoms of the —O—(CH 2 ) n —O— group are linked with the same or a directly adjacent C 3 -C 10 -cycloalkyl ring-, aryl ring- or heteroaryl ring-carbon atom, K stands for halogen, hydroxy or the group —OR 3 , —COR 4 or for C 3 -C 10 -cycloalkyl, or C 3 -C 10 -heterocycloalkyl that optionally is substituted in one or more places, in the same way or differently, with L, whereby the C 3 -C 10 -heterocycloalkyl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and C 3 -C 10 -cycloalkyl and/or C 3 -C 10 -heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO 2 — groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring, L stands for C 1 -C 6 -alkyl or the group —COR 4 , —OR 3 , R 3 stands for C 1 -C 6 -alkyl or aryl, M stands for amino, cyano, halogen, hydroxy, or nitro or for C 1 -C 6 -alkyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, nitro, or C 1 -C 6 -alkoxy, or for the group —O—C 1 -C 6 -alkyl, —O—(CH 2 ) n —NR 5 R 6 , —CO—C 1 -C 6 -alkyl, —O-phenyl, —O—(CH 2 ) n -phenyl or —CO—N—R 7 ,

as well as their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts, are another subject of this invention.

According to this embodiment, compounds of general formula I in a 4 th aspect, according to the 3 rd aspect, in which

R 1 stands for C 1 -C 6 alkyl, C 3 -C 10 -cycloalkyl that optionally is substituted in one or more places, in the same way or differently, with K, whereby the C 3 -C 10 -cycloalkyl optionally is interrupted by one or more —(CO)— groups in the ring, or for aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with K, whereby the heteroaryl itself is interrupted by at least one nitrogen, and the heteroaryl can be linked only via a carbon ring atom with the pyrazolopyridine, or for a C 3 -C 10 -cycloalkyl, aryl or heteroaryl that is substituted with the group —O—(CH 2 ) n —O—, whereby the terminal oxygen atoms of the —O—(CH 2 ) n —O— group are linked to the same or a directly adjacent C 3 -C 10 -cycloalkyl ring-, aryl ring- or heteroaryl ring-carbon atom, K stands for halogen, hydroxy or for the group —OR 3 , or C 3 -C 10 -heterocycloalkyl that optionally is substituted in one or more places, in the same way or differently, with L, whereby the C 3 -C 10 -heterocycloalkyl itself is interrupted by at least one of the following atoms nitrogen and/or oxygen in the ring, L stands for C 1 -C 6 -alkyl or —COO—C 1 -C 6 -alkyl, R 2 stands for C 1 -C 6 alkyl, C 3 -C 6 -cycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with M, whereby the heteroaryl is interrupted by at least one nitrogen, M stands for amino, cyano, halogen, hydroxy, nitro or for C 1 -C 6 -alkyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, nitro or C 1 -C 6 -alkoxy, or for the group —O—C 1 -C 6 -alkyl, —O—(CH 2 ) n —N(C 1 -C 6 -alkyl) 2 , —CO—C 1 -C 6 -alkyl, phenoxy, benzyloxy or —CO—N—NH 2 ,

as well as their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts, are also another subject of this invention.

According to this embodiment, compounds of general formula I in a 5 th aspect, according to one of aspects 1 to 4, in which

M stands for amino, cyano, halogen, hydroxy, or nitro or for C 1 -C 6 -alkyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, nitro or C 1 -C 6 -alkoxy, or for the group —O—C 1 -C 6 -alkyl, —O—(CH 2 ) n —N(C 1 -C 6 -alkyl) 2 or —CO—C 1 -C 6 -alkyl,

as well as their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts, are another subject of this invention.

According to this embodiment, compounds of general formula I in a 6 th aspect, according to the 4 th aspect, in which

R 1 stands for C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, cyclohexanone, 1,4-dioxa-spiro[4.5]dec-8-yl, phenyl, 1,3-benzodioxolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with K, K stands for halogen, hydroxy, C 1 -C 6 -alkoxy or morpholinyl, piperazinyl, piperidinyl, or phenoxy that optionally is substituted in one or more places, in the same way or differently, with L, R 2 stands for C 1 -C 6 -alkyl, phenyl or quinolinyl, imidazolyl, indolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with M, M stands for amino, cyano, halogen, hydroxy, nitro, C 1 -C 6 -alkyl, —CF 3 , or for C 1 -C 3 -alkoxy, or for the group —CO—C 1 -C 6 -alkyl, —O—(CH 2 ) n —N(C 1 -C 6 -alkyl) 2 , phenoxy or benzyloxy,

as well as their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts, are another subject of this invention.

According to this embodiment, compounds of general formula I in a 7 th aspect, according to the 6 th aspect, in which

R 1 stands for C 3 -C 6 alkyl, cyclopropyl, cyclohexyl, cyclohexanone, 1,4-dioxa-spiro[4.5]dec-8-yl, phenyl, 1,3-benzodioxolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with K, K stands for halogen, hydroxy, or methoxy, or morpholinyl, piperazinyl, piperidinyl or phenoxy that optionally is substituted in one or more places, in the same way or differently, with L, L stands for C 1 -C 3 -alkyl or —COO—C 3 -C 5 -alkyl, R 2 stands for isopropyl, phenyl, quinolinyl, imidazolyl, indolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with M, and M stands for cyano, halogen, hydroxy, nitro, methyl, —CF 3 or for methoxy or for the group —CO—C 1 -C 3 -alkyl or —O—(CH 2 ) 3 —N(methyl) 2 ,

as well as their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts, are another subject of this invention.

According to this embodiment, compounds of general formula (I), in an 8 th aspect, according to the 7 th aspect, in which

R 1 stands for tert-butyl, cyclopropyl, cyclohexyl, cyclohexanone, 1,4-dioxa-spiro[4.5]dec-8-yl, phenyl, 1,3-benzodioxolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with K, L stands for methyl or —COO-tert-butyl, R 2 stands for isopropyl, phenyl, quinolinyl, imidazolyl, indolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with M, and M stands for cyano, halogen, hydroxy, nitro, methyl, —CF 3 or for methoxy or for the group —CO-methyl or —O—(CH 2 ) 3 —N(methyl) 2 ,

as well as their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts, are another subject of this invention.

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R 1 stands for C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkinyl, C 3 -C 10 -cycloalkyl, C 3 -C 10 -heterocycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with K, whereby the C 3 -C 10 -heterocycloalkyl and/or the heteroaryl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and the C 3 -C 10 -heterocycloalkyl and/or heteroaryl can be linked only via a carbon ring atom with the pyrazolopyridine, and C 3 -C 10 -cycloalkyl and/or C 3 -C 10 -heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO 2 — groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring, or for a C 3 -C 10 -cycloalkyl, aryl, C 3 -C 10 -heterocycloalkyl or heteroaryl that can be substituted with the group —O—(CH 2 ) n —O—, whereby the terminal oxygen atoms of the —O—(CH 2 ) n —O— group are linked with the same or a directly adjacent C 3 -C 10 -cycloalkyl ring-, aryl ring-, C 3 -C 10 -heterocycloalkyl ring- or heteroaryl ring-carbon atom,

are a subject of the invention.

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R 1 stands for C 1 -C 6 alkyl or C 3 -C 10 -cycloalkyl that optionally is substituted in one or more places, in the same way or differently, with K, whereby the C 3 -C 10 -cycloalkyl optionally is interrupted by one or more —(CO)—, —SO— or —SO 2 — groups in the ring and optionally one or more double bonds can be contained in the ring, or for aryl, C 3 -C 10 -heterocycloalkyl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with K, whereby the C 3 -C 10 -heterocycloalkyl and/or the heteroaryl itself is interrupted by at least one nitrogen, oxygen and/or sulfur, and the C 3 -C 10 -heterocycloalkyl and/or heteroaryl can be linked only via a carbon ring atom with the pyrazolopyridine, or for a C 3 -C 10 -cycloalkyl, aryl, C 3 -C 10 -heterocycloalkyl or heteroaryl that is substituted with the group —O—(CH 2 ) n —O—, whereby the terminal oxygen atoms of the —O—(CH 2 ) n —O— group are linked with the same or a directly adjacent C 3 -C 10 -cycloalkyl ring-, aryl ring-, C 3 -C 10 -heterocycloalkyl ring- or heteroaryl ring-carbon atom,

are another subject of the invention.

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R 1 stands for C 1 -C 6 alkyl, C 3 -C 10 -cycloalkyl that optionally is substituted in one or more places, in the same way or differently, with K, whereby the C 3 -C 10 -cycloalkyl optionally is interrupted by one or more —(CO)—, —SO— or —SO 2 — groups in the ring, and optionally one or more double bonds can be contained in the ring, or for aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with K, whereby the heteroaryl itself is interrupted by at least one nitrogen, oxygen and/or sulfur, and the heteroaryl can be linked only via a carbon ring atom with the pyrazolopyridine, or for a C 3 -C 10 -cycloalkyl, aryl or heteroaryl that is substituted with the group —O—(CH 2 ) n —O—, whereby the terminal oxygen atoms of the —O—(CH 2 ) n —O— group are linked with the same or a directly adjacent C 3 -C 10 -cycloalkyl ring-, aryl ring- or heteroaryl ring-carbon atom,

are another subject of the invention.

In another subject of the invention according to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R 1 stands for C 1 -C 6 alkyl, C 3 -C 10 -cycloalkyl that optionally is substituted in one or more places, in the same way or differently, with K, whereby the C 3 -C 10 -cycloalkyl optionally is interrupted by one or more —(CO)— groups in the ring, or for aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with K, whereby the heteroaryl itself is interrupted by at least one nitrogen, and the heteroaryl can be linked only via a carbon ring atom with the pyrazolopyridine, or for a C 3 -C 10 -cycloalkyl, aryl or heteroaryl that is substituted with the group —O—(CH 2 ) n —O—, whereby the terminal oxygen atoms of the —O—(CH 2 ) n —O— group are linked with the same or a directly adjacent C 3 -C 10 -cycloalkyl ring-, aryl ring- or heteroaryl ring-carbon atom.

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R 1 stands for C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, cyclohexanone, 1,4-dioxa-spiro[4.5]dec-8-yl, phenyl, 1,3-benzodioxolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with K, are a preferred subject of the invention.

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R 1 stands for C 3 -C 6 alkyl, cyclopropyl, cyclohexyl, cyclohexanone, 1,4-dioxa-spiro[4.5]dec-8-yl, phenyl, 1,3-benzodioxolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with K, are a preferred subject of the invention.

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R 1 stands for tert-butyl, cyclopropyl, cyclohexyl, cyclohexanone, 1,4-dioxa-spiro[4.5]dec-8-yl, phenyl, 1,3-benzodioxolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with K, are a preferred subject of the invention.

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R 1 stands for C 1 -C 6 -alkyl that optionally is substituted in one or more places, in the same way or differently, with K, and especially preferably tert-butyl, are an especially preferred subject of the invention.

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R 1 stands for C 3 -C 6 -cycloalkyl that optionally is substituted in one or more places, in the same way or differently, with K, and especially preferably cyclopropyl and/or cyclohexyl, are an especially preferred subject of the invention.

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R 1 stands for C 3 -C 10 -cycloalkyl that optionally is substituted in one or more places, in the same way or differently, with K, which is interrupted by one or more —(CO)— groups in the ring, are an especially preferred subject of the invention. R 1 is then especially preferred for cyclohexanone.

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R 1 stands for a C 3 -C 10 -cycloalkyl, aryl or heteroaryl that is substituted with the group —O—(CH 2 ) n —O—, whereby the terminal oxygen atoms of the —O—(CH 2 ) n —O— group are linked with the same or a directly adjacent C 3 -C 10 -cycloalkyl ring-, aryl ring- or heteroaryl ring-carbon atom, are an especially preferred subject of the invention. R 1 then especially preferably stands for 1,4-dioxa-spiro[4.5]dec-8-yl and/or 1,3-benzodioxolyl.

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R 1 stands for aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with K, whereby the heteroaryl itself is interrupted by at least one nitrogen, and the heteroaryl can be linked only via a carbon ring atom with the pyrazolopyridine, are an especially preferred subject of the invention. R 1 then especially preferably stands for phenyl and/or pyridinyl.

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R 1 stands for a C 3 -C 10 -heterocycloalkyl and/or heteroaryl, whereby the C 3 -C 10 -heterocycloalkyl and/or heteroaryl is linked only via a carbon ring atom with the pyrazolopyridine, are another subject of the invention.

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R 1 is substituted in one or more places, in the same way or differently, with K, are an especially preferred subject of the invention. According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R 1 is substituted in one place with K, are an especially preferred subject of the invention.

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which K stands for halogen, hydroxy or the group —OR 3 , —COR 4 or —NR 5 R 6 , or for C 3 -C 10 -cycloalkyl, C 3 -C 10 -heterocycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with L, whereby the C 3 -C 10 -heterocycloalkyl and/or the heteroaryl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and C 3 -C 10 -cycloalkyl and/or C 3 -C 10 -heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO 2 — groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring, are a subject of the invention.

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which K stands for halogen, hydroxy or the group —OR 3 , —COR 4 or C 3 -C 10 -cycloalkyl, C 3 -C 10 -heterocycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with L, whereby the C 3 -C 10 -heterocycloalkyl and/or the heteroaryl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and C 3 -C 10 -cycloalkyl and/or C 3 -C 10 -heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO 2 — groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring, are another subject of this invention.

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which K stands for halogen, hydroxy or the group —OR 3 , —COR 4 or for C 3 -C 10 -cycloalkyl, or C 3 -C 10 -heterocycloalkyl that optionally is substituted in one or more places, in the same way or differently, with L, whereby the C 3 -C 10 -heterocycloalkyl itself is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and C 3 -C 10 -cycloalkyl and/or C 3 -C 10 -heterocycloalkyl optionally can be interrupted by one or more —(CO)—, —SO— or —SO 2 — groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring, are another subject of this invention.

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which K stands for halogen, hydroxy or for the group —OR 3 , or for C 3 -C 10 -heterocycloalkyl that optionally is substituted in one or more places, in the same way or differently, with L, whereby the C 3 -C 10 -heterocycloalkyl itself is interrupted by at least one of the following atoms nitrogen and/or oxygen in the ring, are a preferred subject of the invention.

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which K stands for halogen, hydroxy, C 1 -C 6 -alkoxy or morpholinyl, piperazinyl, piperidinyl, or phenoxy that optionally is substituted in one or more places, in the same way or differently, with L, are a preferred subject of the invention.

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which K stands for halogen, hydroxy, methoxy or morpholinyl, piperazinyl, piperidinyl or phenoxy that optionally is substituted in one or more places, in the same way or differently, with L, are a preferred subject of the invention.

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which L stands for C 1 -C 6 -alkyl or the group —COR 4 , —OR 3 or —NR 5 R 6 , are a subject of the invention. According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which L stands for C 1 -C 6 -alkyl or the group —COR 4 or —OR 3 , are another subject of the invention. According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which L stands for C 1 -C 6 -alkyl or —COO—C 1 -C 6 alkyl, are another subject of this invention. According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which L stands for C 1 -C 3 -alkyl or —COO—C 3 -C 5 -alkyl, are a preferred subject of the invention. According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which L stands for methyl or —COO-tert-butyl, are another preferred subject of the invention.

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R 2 stands for C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with M, are a subject of the invention.

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R 2 stands for C 1 -C 6 -alkyl, C 3 -C 10 -cycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with M, whereby the heteroaryl is interrupted by at least one nitrogen, oxygen and/or sulfur, are another subject of this invention.

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R 2 stands for C 1 -C 6 alkyl, C 3 -C 6 -cycloalkyl, aryl or heteroaryl that optionally is substituted in one or more places, in the same way or differently, with M, whereby the heteroaryl is interrupted by at least one nitrogen, are another subject of this invention.

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R 2 stands for C 1 -C 6 -alkyl, phenyl or quinolinyl, imidazolyl, indolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with M, are a preferred subject of this invention.

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R 2 stands for isopropyl, phenyl, quinolinyl, imidazolyl, indolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with M, are another preferred subject of this invention.

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R 2 stands for isopropyl, phenyl, quinolinyl, imidazolyl, indolyl or pyridinyl that optionally is substituted in one or more places, in the same way or differently, with M, are another preferred subject of this invention.

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R 3 stands for C 1 -C 6 -alkyl, aryl or —(CH 2 ) n -aryl that optionally is substituted in one or more places, in the same way or differently, with the group —NR 5 R 6 are a subject of the invention. According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R 3 stands for C 1 -C 6 -alkyl, aryl or —(CH 2 ) n -aryl, are another subject of this invention. According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R 3 stands for C 1 -C 6 -alkyl or aryl, are another subject of this invention. According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R 3 stands for C 1 -C 6 -alkyl or phenyl, are a preferred subject of this invention. According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R 3 stands for C 1 -C 3 -alkyl or phenyl, are another preferred subject of this invention. According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R 3 stands for C 1 -C 3 -alkyl, are another preferred subject of this invention.

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R 4 stands for hydrogen, hydroxy, C 1 -C 6 -alkyl or C 1 -C 6 -alkoxy, are a subject of the invention. According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R 4 stands for hydrogen, hydroxy, C 1 -C 3 -alkyl or C 1 -C 3 -alkoxy, are another subject of this invention.

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which M stands for amino, cyano, halogen, hydroxy, nitro or for C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkinyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, nitro, C 1 -C 6 -alkoxy or for the group —OR 3 , —COR 4 , or —CO—N—R 7 , are a subject of the invention.

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which M stands for amino, cyano, halogen, hydroxy, nitro or for C 1 -C 6 -alkyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, nitro, or C 1 -C 6 -alkoxy or for the group —O—C 1 -C 6 -alkyl, —O—(CH 2 ) n —NR 5 R 6 , —COR 4 , —O-phenyl, —O—(CH 2 ) n -phenyl or —CO—N—R 7 , are another subject of this invention. Compounds of general formula (I), according to one of aspects 1 to 8, in which M stands for amino, cyano, halogen, hydroxy, nitro or for C 1 -C 6 -alkyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, nitro, or C 1 -C 6 -alkoxy, or for the group —O—C 1 -C 6 -alkyl, —O—(CH 2 ) n —NR 5 R 6 , —COR 4 or —CO—N—R 7 , are another preferred subject of this invention.

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which M stands for amino, cyano, halogen, hydroxy, nitro or for C 1 -C 6 -alkyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, nitro, C 1 -C 6 -alkoxy or for the group —O—C 1 -C 6 -alkyl, —O—(CH 2 ) n —NR 5 R 6 , —CO—C 1 -C 6 -alkyl, —O-phenyl, O—(CH 2 ) n -phenyl or —CO—N—R 7 , are another subject of this invention. According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which M stands for amino, cyano, halogen, hydroxy, nitro or for C 1 -C 6 -alkyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, nitro, or C 1 -C 6 -alkoxy or for the group —O—C 1 -C 6 -alkyl, —O—(CH 2 ) n —NR 5 R 6 , —CO—C 1 -C 6 -alkyl or —CO—N—R 7 are another preferred subject of this invention.

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which M stands for amino, cyano, halogen, hydroxy, or nitro or for C 1 -C 6 -alkyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, nitro or C 1 -C 6 -alkoxy, or for the group —O—C 1 -C 6 -alkyl, —O—(CH 2 ) n —N(C 1 -C 6 -alkyl) 2 , —CO—C 1 -C 6 -alkyl, phenoxy, benzyloxy or —CO—N—NH 2 , are another subject of this invention. According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which M stands for amino, cyano, halogen, hydroxy, or nitro or for C 1 -C 6 -alkyl that optionally is substituted in one or more places, in the same way or differently, with amino, cyano, halogen, hydroxy, nitro or C 1 -C 6 -alkoxy, or for the group —O—C 1 -C 6 -alkyl, —O—(CH 2 ) n —N(C 1 -C 6 -alkyl) 2 , —CO—C 1 -C 6 -alkyl or —CO—N—NH 2 , preferably without —CO—N—NH 2 , are another preferred subject of this invention.

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which M also stands for amino, cyano, halogen, hydroxy, nitro, C 1 -C 6 -alkyl, —CF 3 , or for C 1 -C 3 -alkoxy or for the group —CO—C 1 -C 6 -alkyl, —O—(CH 2 ) n —N(C 1 -C 6 -alkyl) 2 , phenoxy or benzyloxy, are another preferred subject of this invention. According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which M stands for amino, cyano, halogen, hydroxy, nitro, C 1 -C 6 -alkyl, —CF 3 , or for C 1 -C 3 -alkoxy, or for the group —CO—C 1 -C 6 -alkyl or —O—(CH 2 ) n —N(C 1 -C 6 -alkyl) 2 , are another preferred subject of this invention.

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which M stands for cyano, halogen, hydroxy, nitro, methyl, —CF 3 or for methoxy or for the group —CO—C 1 -C 3 -alkyl or —O—(CH 2 ) 3 —N(methyl) 2 are another preferred subject of this invention.

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which M also stands for cyano, halogen, hydroxy, nitro, methyl, —CF 3 or for methoxy or for the group —CO-methyl or —O—(CH 2 ) 3 —N(methyl) are another preferred subject of this invention.

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which R 2 according to general formula (I) is substituted in one or more places, in the same way or differently, with M, are another subject of this invention. Compounds of general formula (I), according to one of aspects 1 to 8, in which R 2 is an aryl or heteroaryl, and the aryl or heteroaryl is substituted in one or more places, in the same way or differently, with M, are another subject of this invention. Compounds of general formula (I), according to one of aspects 1 to 8, in which R 2 is an aryl or heteroaryl, and the aryl or heteroaryl is substituted in one or more places, in the same way or differently, and at least one time in meta-position with M, are another subject of this invention. Compounds of general formula (I), according to one of aspects 1 to 8, in which R 2 is an aryl, and the aryl is substituted in one or more places, in the same way or differently, and at least one time in meta-position with M, are another preferred subject of this invention. Compounds of general formula (I), according to one of aspects 1 to 8, in which R 2 is a phenyl and is substituted in one or more places, in the same way or differently, and at least one time in meta-position with M, are another preferred subject of this invention. Compounds of general formula (I), according to one of aspects 1 to 8, in which R 2 is substituted in several places, in the same way or differently, and at least one time in meta-position with M, are another subject of this invention. Compounds of general formula (I), according to one of aspects 1 to 8, in which R 2 is substituted in several places, in the same way or differently, and twice in meta-position with M, are another preferred subject of this invention. Compounds of general formula (I), according to one of aspects 1 to 8, in which R 2 is the same and is substituted twice in meta-position with M, are another preferred subject of this invention. Compounds of general formula (I), according to one of aspects 1 to 8, in which R 2 is substituted one time in meta-position with M, are another preferred subject of this invention.

Compounds of general formula (I), according to one of aspects 1 to 8, in which R 5 and R 6 , independently of one another, stand for hydrogen, C 1 -C 6 -alkyl or for the group —COR 4 , are a subject of the invention. Compounds of general formula (I), according to one of aspects 1 to 8, in which R 5 and R 6 , independently of one another, stand for hydrogen or C 1 -C 6 -alkyl, are another subject of this invention.

R 7 according to general formula (I), according to one of aspects 1 to 8, stands for hydrogen or NH 2 .

According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which n stands for 1 to 4, are a subject of the invention. According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which n means 1 to 3, are another subject of this invention. According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which n means 1 to 2, are another subject of this invention. According to this embodiment, compounds of general formula (I), according to one of aspects 1 to 8, in which n means 1, are another subject of this invention

Another subject of this invention according to this embodiment is the use of the compounds of general formula I in a 9 th aspect, according to one of aspects 1 to 8, whereby if

R 1 stands for alkyl, alkenyl, aryl, aralkyl, cycloalkyl, or for a phenyl substituted alkyl or p-methoxyphenyl, then R 1 can simultaneously also stand for alkyl, alkenyl, aryl, aralkyl, cyano, a heterocyclic radical or cycloalkyl, or if R 1 stands for a lower alkyl radical, alkoxy or aryloxy, then R 1 can simultaneously also stand for a lower alkyl radical,

for the production of a pharmaceutical agent.

Another preferred subject of this invention according to this embodiment is the use of the compounds of general formula I in a 10 th aspect, according to one of aspects 1 to 8, for the production of a pharmaceutical agent.

Another subject of this invention according to this embodiment is the use of the compounds of general formula I in an 11 th aspect, according to one of aspects 1 to 8, whereby if

R 1 stands for methyl, then R 2 can simultaneously also stand for methyl, —CH 2 —O—CH 3 , phenyl, chlorophenyl, hydroxy- and/or methoxy-substituted benzofuranyl, —CF 3 or furanyl, or if R 1 stands for —CH 2 —O—CH 3 , then R 2 can simultaneously also stand for methyl, or if R 1 stands for —CH═CH-phenyl, then R 2 can simultaneously also stand for phenyl, or if R 1 stands for —CH═CH-chlorophenyl, then R 2 can simultaneously also stand for phenyl or chlorophenyl, or if R 1 stands for —CH═CH-methoxyphenyl, then R 2 can simultaneously also stand for phenyl or methoxyphenyl, or if R 1 stands for phenyl, then R 1 can simultaneously also stand for —CF 3 , methyl, methoxyphenyl or phenyl, or if R 1 stands for methoxyphenyl, then R 1 can simultaneously also stand for —CF 3 , or if R 1 stands for methylphenyl, then R 1 can simultaneously also stand for —CF 3 , or if R 1 stands for chlorophenyl, then R 2 can simultaneously also stand for chlorophenyl or —CF 3 , or if R 1 stands for dichlorophenyl, then R 2 can simultaneously also stand for trimethoxyphenyl, or if R 1 stands for bromophenyl, then R 2 can simultaneously also stand for trimethoxyphenyl, or if R 1 stands for alkyl, alkenyl, aryl, aralkyl, cycloalkyl, or for a phenyl -substituted alkyl or p-methoxyphenyl, then R 2 can simultaneously also stand for alkyl, alkenyl, aryl, aralkyl, cyano, a heterocyclic radical or cycloalkyl, or if R 1 stands for a lower alkyl radical, alkoxy, aryloxy or a primary, secondary or tertiary amino group, then R 2 can simultaneously also stand for a lower alkyl radical, or if R 1 stands for hydroxyphenyl, then R 2 can simultaneously also stand for heterocyclyl or —COO-tert-butyl-substituted heterocycloalkyl, or if R 1 stands for benzyloxyphenyl, then R 2 can simultaneously also stand for —COO-tert-butyl-substituted heterocycloalkyl, or if R 1 stands for a C 3 -C 10 -heterocycloalkyl or a heteroaryl, then the C 3 -C 10 -heterocycloalkyl and/or the heteroaryl can be linked via a carbon ring atom to the pyrazolopyridine,

for the production of a pharmaceutical agent for treating diseases in which angiogenesis, lymphangiogenesis or vasculogenesis plays a role, vascular diseases, diseases that are caused by a hyperproliferation of body cells, as well as chronic or acute neurodegenerative diseases.

Another preferred subject of this invention according to this embodiment is the use of the compounds of general formula I in a 12 th aspect, according to the 11 th aspect, for the production of a pharmaceutical agent for treating diseases in which angiogenesis, lymphangiogenesis or vasculogenesis plays a role, diseases that are caused by a hyperproliferation of body cells, as well as chronic or acute neurodegenerative diseases.

Another preferred subject of this invention according to this embodiment is the use of the compounds of general formula I in a 13 th aspect, according to one of aspects 1 to 8, for the production of a pharmaceutical agent for treating diseases in which angiogenesis, lymphangiogenesis or vasculogenesis plays a role, vascular diseases, diseases that are caused by a hyperproliferation of body cells, as well as chronic or acute neurogenerative diseases.

Another subject of this invention according to this embodiment is the use of the compounds of general formula I in a 14 th aspect, according to one of aspects 1 to 8, for diagnostic purposes in vitro or in vivo for identifying receptors in tissues by means of autoradiography or PET.

The intermediate products that are preferably used for the production of the compounds of general formula (I) according to the invention in a 15 th aspect, according to one of aspects 1 to 8, according to this embodiment of the invention, are the following compounds:

in which

X stands for halogen or —O—SO 2 —C m F 2m+1 , preferably for perfluoroalkylsulfonyl, m stands for 1 to 4, and R 1a and R 2a have the same meaning as R 1 and R 2 , according to one of aspects 1 to 8, whereby K, however, also can stand for group —COR 4 , and R 3 also can stand for the group trimethylsilyl (TMS), tert-butyl-dimethylsilyl (TBDMS), tert-butyl-diphenylsilyl (TBDPS), triethylsilyl (TES), C 1 -C 2 -alkyl, C 3 -C 6 -allyl, benzyl or for the group —COR 4a ,

as well as their solvates, hydrates, stereoisomers, diastereomers, enantiomers and salts as intermediate products for the production of compounds of general formula (I).

Another subject of the invention according to this embodiment is the use of the compounds of general formulas (II) and/or (III) in a 16 th aspect, according to the 15 th aspect, as intermediate products for the production of compounds of general formula (I).

According to this embodiment, pharmaceutical agents in a 17 th aspect, which contain at least one compound of general formula I according to one of aspects 1 to 8, whereby if

R 1 stands for alkyl, alkenyl, aryl, aralkyl, or cycloalkyl, or for a phenyl; substituted alkyl or p-methoxyphenyl, then R 2 can also simultaneously stand for alkyl, alkenyl, aryl, aralkyl, cyano, a heterocyclic radical or cycloalkyl, R 1 stands for a lower alkyl radical, alkoxy, aryloxy, or a primary, secondary or tertiary amino group, then R 2 can also simultaneously stand for a lower alkyl radical,

are another subject of the invention.

According to this embodiment, pharmaceutical agents in aspect 18 that contain at least one compound of general formula I according to one of aspects 1 to 8 are another preferred subject of the invention.

According to this embodiment, compounds according to aspects 1 to 8 or pharmaceutical agents according to aspects 17 or 18 with suitable formulation substances and vehicles in aspect 19 are another preferred subject of the invention.

Alkyl is defined in each case as a straight-chain or branched alkyl radical, such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl and decyl.

The alkyl group of R 1 has the meaning that is mentioned in the paragraph above, but C 1 -C 6 -alkyl groups are preferred. Preferred for the alkyl group R 1 are C 1 -C 5 -alkyl groups, still more preferred are C 3 -C 5 -alkyl groups, and especially preferred is a C 4 -alkyl group, in particular a tert-butyl group. Alkyl group R 2 has the meaning that is mentioned in the paragraph above, but C 1 -C 6 -alkyl groups are preferred, C 2 -C 4 -alkyl groups are especially preferred, and a C 3 -alkyl group, in particular an isopropyl group, is quite especially preferred. Alkyl groups R 3 , R 4 , R 5 , R 6 , L and M have the meaning that is mentioned in the paragraph above, but C 1 -C 6 -alkyl groups are preferred, C 1 -C 3 -alkyl groups are especially preferred, and a methyl group is quite especially preferred.

Alkoxy is defined in each case as a straight-chain or branched alkoxy radical, such as, for example, methyloxy, ethyloxy, propyloxy, isopropyloxy, butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy or decyloxy.

The alkoxy groups K, R 4 and M have the meaning that is mentioned in the paragraph above, but C 1 -C 6 -alkoxy groups are preferred, C 1 -C 3 -alkoxy groups are especially preferred, and a methoxy group is especially preferred.

The alkenyl substituents are in each case straight-chain or branched, whereby, for example, the following radicals are meant: 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-yl, but-3-en-1-yl, or allyl.

Alkinyl is defined in each case as a straight-chain or branched alkinyl radical that contains 2-6, preferably 2-4, C atoms. For example, the following radicals can be mentioned: acetylene, propin-1-yl, propin-3-yl, but-1-in-1-yl, but-1-in-4-yl, but-2-in-1-yl, but-1-in-3-yl, etc.

Heterocyclyl or C 3 -C 10 -heterocycloalkyl stands for an alkyl ring that comprises 3-10 carbon atoms, preferably for an alkyl ring that comprises 3 to 10 carbon atoms, and especially preferably for an alkyl ring that comprises 5 to 6 carbon atoms, and said alkyl ring is interrupted by at least one of the following atoms nitrogen, oxygen and/or sulfur in the ring, and optionally can be interrupted by one or more —(CO)—, —SO— or —SO 2 — groups that are the same or different in the ring, and optionally one or more double bonds can be contained in the ring. Only those combinations are meant, however, that are useful from the viewpoint of one skilled in the art, in particular in reference to ring strain.

As heterocyclyls, there can be mentioned, e.g.: oxiranyl, oxethanyl, aziridinyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, dioxanyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, quinuclidinyl, etc.

Cycloalkyls are defined as monocyclic C 3 -C 10 alkyl rings, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, but also bicyclic rings or tricyclic rings, such as, for example, adamantanyl, and in the first embodiment of this invention. The cycloalkyl rings can be unsubstituted or substituted in one or more places. Cycloalkyls, according to this embodiment of the invention, contain C 3 -C 10 hydrocarbon atoms; cycloalkyls with C 3 -C 6 -hydrocarbon atoms are preferred.

An aryl radical in each case has 6-12 carbon atoms, such as, for example, naphthyl, biphenyl and in particular phenyl. The radical can be monocyclic or bicyclic, for example naphthyl, biphenyl and in particular phenyl.

The heteroaryl radical in each case comprises 3-16 ring atoms, preferably 5 to 10 ring atoms, and especially preferably 5 to 7 ring atoms, and instead of carbon contains one or more of the heteroatoms that are the same or different from the group oxygen, nitrogen or sulfur, can be monocyclic, bicyclic or tricyclic, and in addition in each case can be benzocondensed. Only those combinations are meant, however, that are useful from the viewpoint of one skilled in the art, in particular in reference to ring strain.

The heteroaryl rings can be unsubstituted or substituted in one or more places.

For example, there can be mentioned: thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl as well as benzo derivatives thereof, such as, e.g., benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, indazolyl, indolyl, isoindolyl, oxepinyl, azocinyl, indolizinyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, purinyl, or quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, etc.

Halogen is defined in each case as fluorine, chlorine, bromine or iodine. A fluorine, chlorine or bromine atom is preferred. The fluorine atom and the chlorine atom are especially preferred.

As used in this application, for example in connection with the definition of “C 1 -C 6 -alkyl”, “C 1 -C 6 ” refers to an alkyl group with a finite number of 1 to 6 carbon atoms, i.e., 1, 2, 3, 4, 5, or 6 carbon atoms. In addition, the definition of “C 1 -C 6 ” is interpreted such that any possible partial area, such as, for example, C 1 -C 6 , C 2 -C 6 , C 3 -C 6 , C 4 -C 6 , C 5 -C 6 , C 1 -C 2 , C 1 -C 3 , C 1 -C 4 , C 1 -C 5 , C 1 -C 6 , is co-contained.

Analogously thereto, “C 2 -C 6 ,” for example in connection with the definition of “C 2 -C 6 -alkenyl” and “C 2 -C 6 -alkinyl,” refers to an alkenyl group or an alkinyl group with a finite number of 2 to 10 carbon atoms, i.e., 2, 3, 4, 5 or 6 carbon atoms. The definition of “C 2 -C 6 ” is interpreted such that any possible partial area, such as, for example C 2 -C 6 , C 3 -C 6 , C 4 -C 6 , C 5 -C 6 , C 2 -C 3 , C 2 -C 4 , C 2 -C 8 , C 2 -C 6 , preferably C 2 -C 4 , is co-contained.

In addition, “C 1 -C 6 ,” for example in connection with the definition of “C 1 -C 6 -alkoxy,” refers to an alkoxy group with a finite number of 1 to 6 carbon atoms, i.e., 1, 2, 3, 4, 5 or 6 carbon atoms. The definition of “C 1 -C 6 ” is interpreted such that any possible partial area, such as, for example, C 1 -C 6 , C 2 -C 8 , C 3 -C 4 , C 1 -C 2 , C 1 -C 3 , C 1 -C 4 , C 1 -C 5 , C 1 -C 6 , is co-contained in the definition.

All area information of the application not explicitly cited here is defined analogously to the areas “C 1 -C 6 ,” “C 2 -C 6 ,” and “C 1 -C 6 ” that are mentioned above by way of example.

The above-cited definitions relate to the compounds of general formula (I). The definitions are not such that they can be used for interpretation of the excluded (disclaimed) prior art. If, for example, a cycloalkyl is mentioned in the prior art that is cited here, cycloalkyl is not defined such that substituted cycloalkyl could also be co-contained (as mentioned in this application in the case of the definitions on page 32, lines 13 to 18, in particular line 16). The definition of this cycloalkyl depends solely on the original document of the prior art made available to the public.

The Following Information Relates Equally To The Two Embodiments Of The Invention

Isomers are defined as chemical compounds of the same summation formula but of different chemical structure. In general, constitutional isomers and stereoisomers are distinguished.

Constitutional isomers have the same summation formula, but are distinguished by the way in which their atoms or atom groups are linked. These include functional isomers, position isomers, tautomers or valence isomers.

Stereoisomers basically have the same structure (constitution)—and thus also the same summation formula—but are distinguished by the spatial arrangement of the atoms. In general, configuration isomers and conformation isomers are distinguished. Configuration isomers are stereoisomers that can be converted into one another only by bond breaking. These include enantiomers, diastereomers and E/Z (cis/trans) isomers. Enantiomers are stereoisomers that behave toward one another like image and mirror image and do not have any plane of symmetry. All stereoisomers that are not enantiomers are referred to as diastereomers. E/Z (cis/trans) isomers on double bonds are a special case. Conformation isomers are stereoisomers that can be converted into one another by the rotation of single bonds.

To differentiate the types of isomerism from one another, see also the IUPAC Rules, Section E (Pure Appl. Chem. 45, 11-30, 1976).

The compounds of general formula I according to the invention also contain the possible tautomeric forms and comprise the E or Z isomers, or, if a chiral center is present, also the racemates and enantiomers. Double-bond isomers are also defined among the latter.

The compounds according to the invention can also be present in the form of solvates, in particular of hydrates, whereby the compounds according to the invention consequently contain polar solvents, in particular water, as structural elements of the crystal lattice of the compounds according to the invention. The proportion of polar solvent, in particular water, can be present in a stoichiometric or else unstoichiometric ratio. In the case of stoichiometric solvates, hydrates, we also speak of hemi- (semi), mono-, sesqui-, di-, tri-, tetra-, penta-, etc., solvates or hydrates.

If an acid group is included, the physiologically compatible salts of organic and inorganic bases are suitable as salts, such as, for example, the readily soluble alkali and alkaline-earth salts, as well as N-methyl-glucamine, dimethyl-glucamine, ethyl-glucamine, lysine, 1,6-hexadiamine, ethanolamine, glucosamine, sarcosine, serinol, tris-hydroxy-methyl-amino-methane, aminopropanediol, Sovak base, or 1-amino-2,3,4-butanetriol.

If a basic group is included, the physiologically compatible salts of organic and inorganic acids, such as hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, tartaric acid, i.a., are suitable.

Functional groups can optionally be protected by protective groups during the reaction sequence. Such protective groups can be, i.a., esters, amides, ketals/acetals, nitro groups, carbamates, alkyl ethers, allyl ethers, benzyl ethers or silyl ethers. As components of silyl ethers, i.a., the following compounds, such as, e.g., trimethylsilyl (TMS), tert-butyl-dimethylsilyl (TBDMS), tert-butyl-diphenylsilyl (TBDPS), triethylsilyl (TES), etc., can occur. Their production is described in the experimental part.

The compounds of general formula I according to the invention inhibit protein tyrosine kinases, in particular Eph receptors, and this also accounts for their action in, for example, the treatment of diseases, in which angiogenesis, lymphangiogenesis or vasculogenesis plays a role, vascular diseases, diseases that are caused by hyperproliferation of body cells or chronic or acute neurodegenerative diseases. These compounds of general formula (I) of the two embodiments of the invention can accordingly be used for the production of a pharmaceutical agent. These compounds of general formula (I) of the two embodiments of the invention can also be used in particular for the production of a pharmaceutical agent for treating the above-cited diseases.

Treatments are performed preferably on humans but also on related mammal species such as, e.g., dogs and cats.

Angiogenic and/or vasculogenic diseases can be treated by the growth of the blood vessels being inhibited (antiangiogenic) or promoted (proangiogenic). Antiangiogenic uses are carried out, e.g., in the case of tumor angiogenesis, endometriosis, in diabetes-induced or other retinopathies or in age-related macular degeneration.

Proangiogenic uses are carried out in, e.g., myocardial infarction or acute neurodegenerative diseases by ischemias of the brain or neurotraumas.

Vascular diseases are defined as stenoses, arterioscleroses, restenoses or inflammatory diseases, such as rheumatic arthritis.

Hyperproliferative diseases are defined as solid tumors, non-solid tumors or non-carcinogenic cell hyperproliferation, whereby solid tumors are defined as, i.a., breast tumors, colon tumors, kidney tumors, lung tumors and/or brain tumors. Non-solid tumors are defined as, i.a., leukemias, and non-carcinogenic cell hyperproliferation is defined as psoriasis, eczema, and scleroderma in the skin or benign hypertrophy of the prostate.

Chronic neurodegenerative diseases are defined as, i.a., Huntington's disease, amyotrophic lateral sclerosis, Parkinson's disease, AIDS-induced dementia or Alzheimer's disease.

Use of the compounds of general formula I according to the two embodiments of the invention can also be used for diagnostic purposes in vitro or in vivo for identifying corresponding receptors in tissues by means of autoradiography and/or PET.

In particular, the substances can also be radiolabeled for diagnostic purposes.

To use the compounds according to the invention 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 application contains suitable pharmaceutical, organic or inorganic inert carrier materials, such as, for example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. The pharmaceutical preparations can be present in solid form, for example as tablets, coated tablets, suppositories or capsules, or in liquid form, for example as solutions, suspensions or emulsions. They optionally contain, moreover, adjuvants, such as preservatives, stabilizers, wetting agents or emulsifiers, salts for changing the osmotic pressure, or buffers.

These pharmaceutical preparations are also subjects of this invention.

For parenteral application, in particular injection solutions or suspensions, in particular aqueous solutions of the active compounds in polyhydroxyethoxylated castor oil, are suitable.

As carrier systems, surface-active adjuvants, such as salts of bile acids or animal or plant phospholipids, but also mixtures thereof as well as liposomes or their components, can also be used.

For oral application, in particular tablets, coated tablets or capsules with talc and/or hydrocarbon vehicles or hydrocarbon binders, such as, for example, lactose, corn or potato starch, are suitable. The application can also be carried out in liquid form, such as, for example, as a juice, to which optionally a sweetener is added.

The enteral, parenteral and oral applications are also subjects of this invention.

The dosage of the active ingredients can vary depending on the method of administration, age and weight of the patient, type and severity of the disease to be treated and similar factors. The daily dose is 0.5-1,000 mg, whereby the dose can be given as an individual dose to be administered once or divided into two or more daily doses.

Pharmaceutical agents for treating the above-cited diseases that preferably contain at least one compound according to general formula (I), as well as pharmaceutical agents with suitable formulation substances and vehicles, are also subjects of the two embodiments of this invention.

If the production of the starting compounds is not described, the latter are known to one skilled in the art or can be produced analogously to known compounds or processes that are described here. It is also possible to perform all reactions described here in parallel reactors or by means of combinatory operating procedures.

According to commonly used methods, such as, for example, crystallization, chromatography or salt formation, the isomer mixtures can be separated into enantiomers or E/Z isomers.

The production of salts is carried out in the usual way by a solution of the compound of formula I being mixed with the equivalent amount of or an excess of a base or acid, which optionally is in solution, and the precipitate being separated, or the solution being worked up in the usual way.

Production of the Compounds of the Invention According to the Two Embodiments of the Invention

Y stands for a C 1 -C 6 -alkyl radical, and X stands for halogen or perfluoroalkylsulfonyl.

In the two embodiments, substituents R 1a and R 2a have the meaning that is described in general formulas II and III.

Substituents R 1 and R 2 have the meaning that is described in general formula I.

The production of the compounds of general formula I is carried out in the way shown in process variant I. By reaction of aldehyde R 2a —CHO with the methylketone R 1a C(O)CH 3 , cyanoacetic acid ester as well as ammonium acetate, first the pyridones of general formula II are produced. Compounds of general formula II are then converted into the compounds of general formula III, in which X has the meaning of halogen or perfluoroalkylsulfonyl. The addition of hydrazine to compounds of general formula III ultimately results in compounds of general formula IV, from which then the compounds of general formula I can be produced optionally by further modifications of radicals R 1a and R 2a . These modifications contain, e.g., the cleavage of protective groups, but also substitutions, additions, e.g., of carbonyl groups or nitrites, alkylations, reductive aminations, acetylations of OH— or NH— groups and other reactions. Radicals R 1a and R 2a can also already correspond to later radicals R 1 and R 2 , however, such that then the compounds of general formula I are produced directly by adding hydrazine to compounds of general formula III.

A mixture that consists of 20 ng/ml of recombinant EphB4 kinase (related to ProQinase GmbH, Freiburg, Germany), 2.67 μg/ml of polyGluAlaTyr, 2 μmol of ATP, 25 mmol of HEPES (pH 7.3), 5 mmol of MgCl 2 , 1 mmol of MnCl 2 , 2 mmol of DTT, 0.1 mmol of NaVO 4 , 1% (v/v) glycerol, 0.02% NP40, EDTA-free protease inhibitors (Complete Fa. [Company] Roche, 1 tablet in 50 ml) is incubated at 20° C. for 10 minutes. Test substances are dissolved in 100% DMSO and introduced in 0.017× volume before the beginning of the reaction. 60 minutes after the addition of 1.7× volume of a solution of 50 mmol of Hepes, pH 7.0, 0.2% BSA, 0.14 μg/ml of PT66-europium, 3.84 μg/ml of SA-XL665, and 75 mmol of EDTA, the batch is measured in a Discovery HTRF-measuring device of the PerkinElmer Company.

The following compounds, i.a., inhibit the EphB4 kinase with an IC 50 that is less than 10 μmol: Examples 6, 12, 14, 16, 33, 35, 39, 40, 41, 51, etc. The IC 50 of compound 6 is, for example, 6.1 μm.

This illustrates that the substances according to the invention inhibit protein tyrosine kinases, in particular Eph receptors, and here in particular EphB4.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The preceding preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.

In the foregoing and in the examples, all temperatures are set forth uncorrected in degrees Celsius and, all parts and percentages are by weight, unless otherwise indicated.

The entire disclosures of all applications, patents and publications, cited herein and of corresponding German application No. 10 2004 061 288.9, filed Dec. 14, 2004, and U.S. Provisional Application Ser. No. 60/636,690, filed Dec. 17, 2004, are incorporated by reference herein.

The preceding examples can be repeated with similar success by substituting the generically or specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention and, without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.