HK1090643B

HK1090643B - Novel pyridopyrazines and use thereof as kinase modulators

Info

Publication number: HK1090643B
Application number: HK06111425.6A
Authority: HK
Inventors: E‧京特; E‧克劳斯; I‧塞佩尔特; U-R‧拉普; L‧维克斯莱尔
Original assignee: 赞塔里斯有限公司
Priority date: 2003-05-23
Filing date: 2004-05-19
Publication date: 2010-12-10

Description

Novel pyridopyrazines and their use as kinase modulators

The present invention relates to pyrido [2, 3-b ] pyrazine-type kinase modulators and their preparation and use as medicaments for the modulation of misguided cell signaling processes, in particular for influencing the function of tyrosine and serine/threonine kinases and for the treatment of malignant or benign tumors and other diseases based on pathological cell proliferation such as restenosis, psoriasis, arteriosclerosis and cirrhosis of the liver.

Activation of protein kinases is a major event in the process of cell signal transduction. Abnormal kinase activation is observed in different pathological states. Thus, directed inhibition of kinases is a fundamental therapeutic goal.

Phosphorylation of proteins is generally initiated by extracellular signals and represents a common mechanism for controlling various cellular events such as metabolic processes, cell growth, cell migration, cell differentiation, membrane transport and apoptosis. The kinase protein family is responsible for protein phosphorylation. These enzymes catalyze the conversion of phosphate to specific substrate proteins. Based on the specificity of the substrate, kinases are divided into two main classes, tyrosine kinases and serine/threonine kinases. Receptor tyrosine kinases and cytoplasmic tyrosine and serine/threonine kinases are important proteins in cell signal transduction. Over-expression or degradation of these proteins plays an important role in diseases based on pathological cell proliferation. These include, inter alia, metabolic, connective and vascular diseases, as well as malignant and benign tumors. They often appear as carcinogens in the initiation and progression of tumors, for example as abnormal, constitutively active kinase proteins. The consequences of this excessive kinase activation are, for example, uncontrolled growth of the cells and reduced cell death. Stimulation by tumor-inducing growth factors may also be responsible for kinase overstimulation. The development of kinase modulators is therefore of particular interest for all pathogenic processes affected by kinases.

The present invention is therefore directed to the generation of novel compounds suitable as modulators of receptor tyrosine kinases and cytoplasmic tyrosine and serine/threonine kinases. Since not all of the kinases linked to one another in a misdirected signal transduction cascade-for example in the case of Raf/Mek/Erk-have to be present as oncogenic kinases or as constitutively active enzymes, the inactive kinases are also to be regarded as target proteins for therapy in the context of the present invention, i.e.the novel compounds can be linked to active as well as inactive kinases and thus influence signal transduction.

Pyrido [2, 3-b ] pyrazine derivatives substituted in position 6 or 7 are widely used as pharmaceutically active compounds and synthetic members in pharmaceutical chemistry. For example, patent WO99/17759 describes pyrido [2, 3-b ] pyrazines having carbamates substituted in the 6-position, in particular by alkyl-, aryl-and heteroaryl groups. These compounds are useful for modulating the function of serine-threonine protein kinases.

Patent WO04/005472 by White et al describes, inter alia, pyrido [2, 3-b ] pyrazines substituted with carbamate in the 6-position, which act as antibacterial substances inhibiting the growth of bacteria. No antitumor effect is described.

Patents WO03/084473(Barnett et al), WO03/086394(Bilodeau et al) and WO03/086403(Lindsley et al) describe specific diphenylquinoxalines as inhibitors of the activity of the serine/threonine kinase Akt and pyrido [2, 3-b ] pyrazines with specific alkylpyrrolidine, alkyl-piperidine or alkylsulfonamide groups located on the benzene ring, which may also carry urea or carbamate substituents in the 6 or 7 position. The use of these compounds in the treatment of cancer is given. No clear indications are given for the biological action of the pyrido [2, 3-b ] pyrazine compounds of the examples described therein. Furthermore, they have significant structural differences from the pyrido [2, 3-b ] pyrazines according to the present invention described in the present invention.

In addition, Delorme et al, WO03/024448, describes pyrido [2, 3-b ] pyrazines substituted with amide-and acrylamide, also containing carbamate as an additional substituent, and are useful as histone deacetylase inhibitors for the treatment of cell proliferative diseases.

Other publications (C.simple, Jr.; J.Med.chem, 1990, 3044-. The antitumor effect is neither disclosed nor evident.

The synthesis of other derivatives of 6-ethylcarbamate-substituted pyrido [2, 3-b ] pyrazines is described in the publication by R.D.Elliott (J.org.chem.1968, 2393-2397). The biological effects of these compounds are neither described nor apparent.

The publication c.simple, jr., j.med.chem.1968, 1216-1218 describes the synthesis and study of 6-ethylcarbamate-substituted pyrido [2, 3-b ] pyrazines as potential antimalarial agents. The antitumor effect was neither described nor evident.

It has now surprisingly been found that novel compounds from the pyrido [2, 3-b ] pyrazine series, substituted in position 6 or 7 by, for example, urea, thiourea, guanidine or amidine, are suitable for the production of medicaments for the modulation of misdirected cell signaling processes, in particular for influencing the function of tyrosine and serine/threonine kinases and for the treatment of malignant or benign tumors, such as breast, prostate, lung, skin and ovarian cancers and other diseases based on pathological cell proliferation. According to this aspect, the present application describes novel compounds from the pyrido [2, 3-b ] pyrazine series of the general formula I

Wherein the substituents R1-R4 have the following meanings:

r1 and R2 may be independently of each other:

(i) hydrogen

(ii) Hydroxy radical

(iii) Halogen, e.g. chlorine or bromine

(iv) Alkyl, wherein alkyl is saturated and may contain 1 to 8C atoms,

(v) unsubstituted or substituted aryl, where the aryl radicals may have one or more of the same or different F, Cl, Br, I, CF₃、CN、NH₂NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-NH₂NH-alkyl-OH, N (alkyl)₂NHC (O) -alkyl, NHC (O) -cycloalkyl, NHC (O) -heterocyclyl, NHC (O) -aryl, NHC (O) -heteroaryl, NHC (O) -alkyl-aryl, NHC (O) -alkyl-heteroaryl, NHSO (O) -alkyl-aryl₂Alkyl, NHSO₂Cycloalkyl, NHSO₂-heterocyclic radical, NHSO₂Aryl, NHSO₂Heteroaryl, NHSO₂Alkyl-aryl, NHSO₂-alkyl-heteroaryl、NO₂SH, S-alkyl, S-aryl, S-heteroaryl, OH, OCF₃O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aryl, O-alkyl-heteroaryl, O-alkyl-OH, O- (CH)₂)_n-O, OC (O) -alkyl, OC (O) -cycloalkyl, OC (O) -heterocyclyl, OC (O) -aryl, OC (O) -heteroaryl, OC (O) -alkyl-aryl, OC (O) -alkyl-heteroaryl, OSO₃H、OSO₂Alkyl, OSO₂Cycloalkyl, OSO₂-heterocyclic radical, OSO₂Aryl, OSO₂Heteroaryl, OSO₂Alkyl-aryl, OSO₂Alkyl-heteroaryl, OP (O) (OH)₂C (O) -alkyl, C (O) -aryl, C (O) -heteroaryl, CO₂H、CO₂Alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂Aryl, CO₂-heteroaryl, CO₂-alkyl-cycloalkyl, CO₂-alkyl-heterocyclyl, CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl, C (O) -NH₂C (O) NH-alkyl, C (O) NH-cycloalkyl, C (O) NH-heterocyclyl, C (O) NH-aryl, C (O) NH-heteroaryl, C (O) NH-alkyl-cycloalkyl, C (O) NH-alkyl-heterocyclyl, C (O) NH-alkyl-aryl, C (O) NH-alkyl-heteroaryl, C (O) N (alkyl)₂C (O) N (cycloalkyl)₂C (O) N (aryl)₂C (O) N (heteroaryl)₂SO-alkyl, SO-aryl, SO₂Alkyl, SO₂Aryl, SO₂NH₂、SO₂NH-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl, SO₂NH-alkyl-aryl, SO₃H、SO₂O-aryl, SO₂O-alkyl-aryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents, n can have the value 1, 2 or 3, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkyl-cycloalkyl, alkyl-heterocyclyl, alkyl-aryl and alkyl-heteroaryl substituents, which themselves can in turn be substituted,

(vi) unsubstituted or substituted heteroaryl, wherein the heteroaryl can have one or more of the same or different F, Cl, Br, I, CF₃、CN、NH₂NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-NH₂NH-alkyl-OH, N (alkyl)₂NHC (O) -alkyl, NHC (O) -cycloalkyl, NHC (O) -heterocyclyl, NHC (O) -aryl, NHC (O) -heteroaryl, NHC (O) -alkyl-aryl, NHC (O) -alkyl-heteroaryl, NHSO₂Alkyl, NHSO₂Cycloalkyl, NHSO₂-heterocyclic radical, NHSO₂Aryl, NHSO₂Heteroaryl, NHSO₂Alkyl-aryl, NHSO₂-alkyl-heteroaryl, NO₂SH, S-alkyl, S-aryl, S-heteroaryl, OH, OCF₃O-alkyl, O-cycloalkyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aryl, O-alkyl-heteroaryl, OC (O) -alkyl, OC (O) -cycloalkyl, OC (O) -heterocyclyl, OC (O) -aryl, OC (O) -heteroaryl, OC (O) -alkyl-aryl, OC (O) -alkyl-heteroaryl, OSO₃H、OSO₂Alkyl, OSO₂Cycloalkyl, OSO₂-heterocyclic radical, OSO₂Aryl, OSO₂Heteroaryl, OSO₂Alkyl-aryl, OSO₂Alkyl-heteroaryl, OP (O) (OH)₂C (O) -alkyl, C (O) -aryl, C (O) -heteroaryl, CO₂H、CO₂Alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂Aryl, CO₂-heteroaryl, CO₂-alkyl-cycloalkyl, CO₂-alkyl-heterocyclyl, CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl, C (O) -NH₂C (O) NH-alkyl, C (O) NH-cycloalkyl, C (O) NH-heterocyclyl, C (O) NH-aryl, C (O) NH-heteroaryl, C (O) NH-alkyl-cycloalkyl, C (O) NH-alkyl-heterocyclyl, C (O) NH-alkyl-aryl, C (O) NH-alkyl-heteroaryl, C (O) N (alkyl)₂C (O) N (cycloalkyl)₂C (O) N (aryl)₂C (O) N (heteroaryl)₂、SO₂NH₂、SO₂NH-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl, SO₂NH-alkyl-aryl, SO₃H、SO₂O-alkyl, SO₂O-aryl, SO₂O-alkyl-aryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents, and the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituents may themselves be substituted in sequence,

(vii) OR5 wherein R5 can be alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl OR alkylheteroaryl and the alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl OR alkylheteroaryl substituents themselves can be substituted in sequence,

(viii) SR6, wherein R6 can be alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaryl and the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaryl substituents can themselves be substituted in sequence,

(ix) NR7R8 where R7 and R8 can be, independently of one another, hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylcyclyl, alkylheterocyclyl, alkylaryl or alkylheteroaryl, and the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaryl substituents can themselves be substituted in turn, or R7 and R8 together form a cycloalkyl or heterocyclyl where the cycloalkyl and heterocyclyl can themselves be substituted in turn.

R3 and R4 can, independently of one another, be hydrogen or NR9R10, with the proviso that when R3 ═ NR9R10, R4 ═ H, when R4 ═ NR9R10, R3 ═ H,

wherein R9 can be hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaryl, and the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, alkylcycloalkyl, alkylheterocyclyl, alkylaryl or alkylheteroaryl substituents can in turn be substituted on their own part,

r10 may be

-C (Y) NR11R12, wherein Y is O, S, R11 and R12 may be independently of each other

(i) Hydrogen

(ii) Unsubstituted or substituted alkyl, where the alkyl may have one or more of the same or different F, Cl, Br, I, CF₃、CN、NH₂NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, N (alkyl)₂NHC (O) -alkyl, NHC (O) -cycloalkyl, NHC (O) -heterocyclyl, NHC (O) -aryl, NHC (O) -heteroaryl, NHC (O) -alkyl-aryl, NHC (O) -alkyl-heteroaryl, NHSO₂Alkyl, NHSO₂Cycloalkyl, NHSO₂-heterocyclic radical, NHSO₂Aryl, NHSO₂Heteroaryl, NHSO₂Alkyl-aryl, NHSO₂-alkyl-heteroaryl, NO₂SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF₃O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aryl, O-alkyl-heteroaryl, OC (O) -alkyl, OC (O) -cycloalkyl, OC (O) -heterocyclyl, OC (O) -aryl, OC (O) -heteroaryl, OC (O) -alkyl-aryl, OC (O) -alkyl-heteroaryl, OSO₃H、OSO₂Alkyl, OSO₂Cycloalkyl, OSO₂-heterocyclic radical, OSO₂Aryl, OSO₂Heteroaryl, OSO₂Alkyl-aryl, OSO₂Alkyl-heteroaryl, OP (O) (OH)₂C (O) -alkyl, C (O) -aryl, C (O) -heteroaryl, CO₂H、CO₂Alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂Aryl, CO₂-heteroaryl, CO₂-alkyl-cycloalkyl, CO₂-alkyl-heterocyclyl, CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl, C (O) -NH₂C (O) NH-alkyl, C (O) NH-cycloalkyl, C (O) NH-heterocyclyl, C (O) NH-aryl, C (O) NH-heteroaryl, C (O) NH-alkyl-cycloalkyl, C (O) NH-alkyl-heteroar-kylCyclyl, C (O) NH-alkyl-aryl, C (O) NH-alkyl-heteroaryl, C (O) N (alkyl)₂C (O) N (cycloalkyl)₂C (O) N (aryl)₂C (O) N (heteroaryl)₂SO-alkyl, SO-aryl, SO₂Alkyl, SO₂Aryl, SO₂NH₂、SO₂NH-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl, SO₂NH-alkyl-aryl, SO₃H、SO₂O-alkyl, SO₂O-aryl, SO₂An O-alkyl-aryl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituent,

(iii) unsubstituted or substituted cycloalkyl, wherein the cycloalkyl can have one or more of the same or different F, Cl, Br, I, NH₂NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, N (alkyl)₂NHC (O) -alkyl, NHC (O) -cycloalkyl, NHC (O) -heterocyclyl, NHC (O) -aryl, NHC (O) -heteroaryl, NHC (O) -alkyl-aryl, NHC (O) -alkyl-heteroaryl, NHSO₂Alkyl, NHSO₂Cycloalkyl, NHSO₂-heterocyclic radical, NHSO₂Aryl, NHSO₂Heteroaryl, NHSO₂Alkyl-aryl, NHSO₂-alkyl-heteroaryl, OH, O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-aryl, O-alkyl-heteroaryl, OC (O) -alkyl, OC (O) -cycloalkyl, OC (O) -heterocyclyl, OC (O) -aryl, OC (O) -heteroaryl, OC (O) -alkyl-aryl, OC (O) -alkyl-heteroaryl, OSO₃H、OSO₂Alkyl, OSO₂Cycloalkyl, OSO₂-heterocyclic radical, OSO₂Aryl, OSO₂Heteroaryl, OSO₂Alkyl-aryl, OSO₂Alkyl-heteroaryl, OP (O) (OH)₂、CO₂H、CO₂Alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂Aryl, CO₂-heteroaryl, CO₂-alkylcycloalkyl, CO₂-alkyl-hetero-cyclic group, CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl, C (O) -NH₂C (O) NH-aryl, C (O) NH-cycloalkyl, C (O) NH-heterocycleC (O) NH-aryl, C (O) NH-heteroaryl, C (O) NH-alkyl-cycloalkyl, C (O) NH-alkyl-heterocyclyl, C (O) NH-alkyl-aryl, C (O) NH-alkyl-heteroaryl, C (O) N (alkyl)₂C (O) N (cycloalkyl)₂C (O) N (aryl)₂C (O) N (heteroaryl)₂An alkyl or aryl substituent,

(iv) unsubstituted or substituted heterocyclyl, wherein the heterocyclyl may have one or more of the same or different OH, O-alkyl, O-aryl, NH₂NH-alkyl, NH-aryl, alkyl-aryl or aryl substituents,

(v) unsubstituted or substituted aryl, where the aryl radicals may have one or more of the same or different F, Cl, Br, I, CF₃、CN、NH₂NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-NH₂NH-alkyl-OH, N (alkyl)₂NHC (O) -alkyl, NHC (O) -cycloalkyl, NHC (O) -heterocyclyl, NHC (O) -aryl, NHC (O) -heteroaryl, NHC (O) -alkyl-aryl, NHC (O) -alkyl-heteroaryl, NHSO₂Alkyl, NHSO₂Cycloalkyl, NHSO₂-heterocyclic radical, NHSO₂Aryl, NHSO₂Heteroaryl, NHSO₂Alkyl-aryl, NHSO₂-alkyl-heteroaryl, NO₂SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF₃O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aryl, O-alkyl-heteroaryl, O-alkyl-OH, O- (CH)₂)_n-O, OC (O) -alkyl, OC (O) -cycloalkyl, OC (O) -heterocyclyl, OC (O) -aryl, OC (O) -heteroaryl, OC (O) -alkyl-aryl, OC (O) -alkyl-heteroaryl, OSO₃H、OSO₂Alkyl, OSO₂Cycloalkyl, OSO₂-heterocyclic radical, OSO₂Aryl, OSO₂Heteroaryl, OSO₂Alkyl-aryl, OSO₂Alkyl-heteroaryl, OP (O) (OH)₂C (O) -alkyl, C (O) -aryl, C (O) -heteroaryl, CO₂H、CO₂Alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂Aryl, CO₂-heteroaryl, CO₂-alkyl-cycloalkyl, CO₂-alkyl-heterocyclyl, CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl, C (O) -NH₂C (O) NH-alkyl, C (O) NH-cycloalkyl, C (O) NH-heterocyclyl, C (O) NH-aryl, C (O) NH-heteroaryl, C (O) NH-alkyl-cycloalkyl, C (O) NH-alkyl-heterocyclyl, C (O) NH-alkyl-aryl, C (O) NH-alkyl-heteroaryl, C (O) N (alkyl)₂C (O) N (cycloalkyl)₂C (O) N (aryl)₂C (O) N (heteroaryl)₂SO-alkyl, SO-aryl, SO₂Alkyl, SO₂Aryl, SO₂NH₂、SO₂NH-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl, SO₂NH-alkyl-aryl, SO₃H、SO₂O-alkyl, SO₂O-aryl, SO₂An O-alkylaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituent, n may have a value of 1, 2 or 3,

(vi) unsubstituted or substituted heteroaryl, wherein the heteroaryl can have one or more of the same or different F, Cl, Br, I, CF₃、CN、NH₂NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-NH₂NH-alkyl-OH, N (alkyl)₂NHC (O) -alkyl, NHC (O) -cycloalkyl, NHC (O) -heterocyclyl, NHC (O) -aryl, NHC (O) -heteroaryl, NHC (O) -alkyl-aryl, NHC (O) -alkyl-heteroaryl, NHSO₂Alkyl, NHSO₂Cycloalkyl, NHSO₂-heterocyclic radical, NHSO₂Aryl, NHSO₂Heteroaryl, NHSO₂Alkyl-aryl, NHSO₂-alkyl-heteroaryl, NO₂SH, S-alkyl, S-aryl, S-heteroaryl, OH, OCF₃O-alkyl, O-cycloalkyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aryl, O-alkyl-heteroaryl, OC (O) -alkyl, OC (O) -cycloalkyl, OC (O) -heterocyclylOC (O) -aryl, OC (O) -heteroaryl, OC (O) -alkyl-aryl, OC (O) -alkyl-heteroaryl, OSO₃H、OSO₂Alkyl, OSO₂Cycloalkyl, OSO₂-heterocyclic radical, OSO₂Aryl, OSO₂Heteroaryl, OSO₂Alkyl-aryl, OSO₂Alkyl-heteroaryl, OP (O) (OH)₂C (O) -alkyl, C (O) -aryl, C (O) -heteroaryl, CO₂H、CO₂Alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂Aryl, CO₂-heteroaryl, CO₂-alkyl-cycloalkyl, CO₂-alkyl-heterocyclyl, CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl, C (O) -NH₂C (O) NH-alkyl, C (O) NH-cycloalkyl, C (O) NH-heterocyclyl, C (O) NH-aryl, C (O) NH-heteroaryl, C (O) NH-alkyl-cycloalkyl, C (O) NH-alkyl-heterocyclyl, C (O) NH-alkyl-aryl, C (O) NH-alkyl-heteroaryl, C (O) N (alkyl)₂C (O) N (cycloalkyl)₂C (O) N (aryl)₂C (O) N (heteroaryl)₂、SO₂NH₂、SO₂NH-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl, SO₂NH-alkyl-aryl, SO₃H、SO₂O-alkyl, SO₂O-aryl, SO₂O-alkyl-aryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents,

(vii) -C (O) -R17, wherein R17 can be alkyl, aryl or heteroaryl and the alkyl and aryl substituents can themselves be substituted in sequence,

(viii) or R11 and R12 together may be cycloalkyl or heterocyclyl,

may be-C (Y) NR13R14, wherein Y is NH, R13 and R14 may be independently of each other

(i) Hydrogen

(ii) Unsubstituted or substituted alkyl, where the alkyl may have one or more of the same or different F, Cl, Br, I, CF₃、CN、NH₂NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroAryl, NH-alkyl-heteroaryl, N (alkyl)₂NHC (O) -alkyl, NHC (O) -cycloalkyl, NHC (O) -heterocyclyl, NHC (O) -aryl, NHC (O) -heteroaryl, NHSO₂Alkyl, NHSO₂Cycloalkyl, NHSO₂Aryl, NHSO₂-heteroaryl, NO₂SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF₃O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-aryl, O-alkyl-heteroaryl, OC (O) -alkyl, OC (O) -cycloalkyl, OC (O) -heterocyclyl, OC (O) -aryl, OC (O) -heteroaryl, OSO₂Alkyl, OSO₂Cycloalkyl, OSO₂Aryl, OSO₂Heteroaryl, C (O) -alkyl, C (O) -aryl, CO₂H、CO₂Alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂Aryl, CO₂-heteroaryl, CO₂-alkyl-cycloalkyl, CO₂-alkyl-heterocyclyl, CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl, C (O) -NH₂C (O) NH-alkyl, C (O) NH-cycloalkyl, C (O) NH-heterocyclyl, C (O) NH-aryl, C (O) NH-heteroaryl, C (O) NH-alkyl-cycloalkyl, C (O) NH-alkyl-heterocyclyl, C (O) NH-alkyl-aryl, C (O) NH-alkyl-heteroaryl, C (O) N (alkyl)₂C (O) N (cycloalkyl)₂C (O) N (aryl)₂C (O) N (heteroaryl)₂SO-alkyl, SO-aryl, SO₂Alkyl, SO₂Aryl, SO₂NH₂、SO₃H. Alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents,

(iii) unsubstituted or substituted cycloalkyl, wherein the cycloalkyl can have one or more of the same or different F, Cl, Br, I, NH₂NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, N (alkyl)₂NHC (O) -alkyl, NHC (O) -cycloalkyl, NHC (O) -heterocyclyl, NHC (O) -aryl, NHC (O) -heteroaryl, NHSO₂Alkyl, NHSO₂Cycloalkyl, NHSO₂Aryl, NHSO₂Heteroaryl, OH, O-Alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-aryl, O-alkyl-heteroaryl, OC (O) -alkyl, OC (O) -cycloalkyl, OC (O) -heterocyclyl, OC (O) -aryl, OC (O) -heteroaryl, OSO₂Alkyl, OSO₂Cycloalkyl, OSO₂Aryl, OSO₂-heteroaryl, CO₂H、CO₂Alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂Aryl, CO₂Heteroaryl, C (O) -NH₂C (O) NH-alkyl, C (O) NH-cycloalkyl, C (O) NH-heterocyclyl, C (O) NH-aryl, C (O) NH-heteroaryl, C (O) NH-alkyl-aryl, C (O) NH-alkyl-heteroaryl, C (O) N (alkyl)₂An alkyl or aryl substituent,

(iv) unsubstituted or substituted heterocyclyl, wherein the heterocyclyl may have one or more of the same or different OH, O-alkyl, O-aryl, NH₂NH-alkyl, NH-aryl, alkyl or aryl substituents,

(v) unsubstituted or substituted aryl, where the aryl radicals may have one or more of the same or different F, Cl, Br, I, CF₃、CN、NH₂NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-NH₂NH-alkyl-OH, N (alkyl)₂NHC (O) -alkyl, NHC (O) -cycloalkyl, NHC (O) -heterocyclyl, NHC (O) -aryl, NHC (O) -heteroaryl, NHSO₂Alkyl, NHSO₂Aryl, NHSO₂-heteroaryl, NO₂SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF₃O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aryl, O-alkyl-heteroaryl, O-alkyl-OH, O- (CH)₂)_n-O, OC (O) -alkyl, OC (O) -cycloalkyl, OC (O) -heterocyclyl, OC (O) -aryl, OC (O) -heteroaryl, OSO₂Alkyl, OSO₂Cycloalkyl, OSO₂Aryl, OSO₂Heteroaryl, C (O) -alkyl, C (O) -aryl, C (O) -heteroaryl, CO₂H、CO₂Alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂Aryl, CO₂-heteroaryl, CO₂-alkyl-cycloalkyl, CO₂-alkyl-heterocyclyl, CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl, C (O) -NH₂C (O) NH-alkyl, C (O) NH-cycloalkyl, C (O) NH-heterocyclyl, C (O) NH-aryl, C (O) NH-heteroaryl, C (O) NH-alkyl-cycloalkyl, C (O) NH-alkyl-heterocyclyl, C (O) NH-alkyl-aryl, C (O) NH-alkyl-heteroaryl, C (O) N (alkyl)₂C (O) N (cycloalkyl)₂C (O) N (aryl)₂C (O) N (heteroaryl)₂SO-alkyl, SO-aryl, SO₂Alkyl, SO₂Aryl, SO₂NH₂、SO₂NH-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl, SO₃H、SO₂O-alkyl, SO₂O-aryl, SO₂An O-heteroaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituent, n may have a value of 1, 2 or 3,

(vi) unsubstituted or substituted heteroaryl, wherein the heteroaryl can have one or more of the same or different F, Cl, Br, I, CF₃、CN、NH₂NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, N (alkyl)₂NHC (O) -alkyl, NHC (O) -cycloalkyl, NHC (O) -heterocyclyl, NHC (O) -aryl, NHC (O) -heteroaryl, NHSO₂Alkyl, NHSO₂Aryl, NHSO₂-heteroaryl, NO₂SH, S-alkyl, S-aryl, OH, OCF₃O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, OC (O) -alkyl, OC (O) -cycloalkyl, OC (O) -heterocyclyl, OC (O) -aryl, OC (O) -heteroaryl, OSO₂Alkyl, OSO₂Cycloalkyl, OSO₂Aryl, OSO₂Heteroaryl, C (O) -alkyl, C (O) -aryl, C (O) -heteroaryl, CO₂H、CO₂Alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂Aryl, CO₂-heteroaryl, CO₂-alkyl-cycloalkyl, CO₂-alkyl heteroCyclic radical, CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl, C (O) -NH₂C (O) NH-alkyl, C (O) NH-cycloalkyl, C (O) NH-heterocyclyl, C (O) NH-aryl, C (O) NH-heteroaryl, C (O) NH-alkyl-cycloalkyl, C (O) NH-alkyl-heterocyclyl, C (O) NH-alkyl-aryl, C (O) NH-alkyl-heteroaryl, C (O) N (alkyl)₂C (O) N (cycloalkyl)₂C (O) N (aryl)₂C (O) N (heteroaryl)₂、SO₂Alkyl, SO₂Aryl, SO₂NH₂、SO₂NH-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl, SO₃H、SO₂O-alkyl, SO₂O-aryl, SO₂An O-heteroaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituent,

(vii) or R13 and R14 together may be cycloalkyl or heterocyclyl,

may be-C (NR15) R16 wherein R15 is H and R16 may be

(i) Unsubstituted or substituted alkyl, where the alkyl may have one or more of the same or different F, Cl, Br, I, CF₃、NH₂NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, N (alkyl)₂NHC (O) -alkyl, NHC (O) -cycloalkyl, NHC (O) -heterocyclyl, NHC (O) -aryl, NHC (O) -heteroaryl, NHSO₂Alkyl, NHSO₂Cycloalkyl, NHSO₂Aryl, NHSO₂-heteroaryl, NO₂SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF₃O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-aryl, O-alkyl-heteroaryl, OC (O) -alkyl, OC (O) -cycloalkyl, OC (O) -heterocyclyl, OC (O) -aryl, OC (O) -heteroaryl, OSO₂Alkyl, OSO₂Cycloalkyl, OSO₂Aryl, OSO₂Heteroaryl, C (O) -alkyl, C (O) -aryl, CO₂H、CO₂Alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂-an aryl group,CO₂-heteroaryl, CO₂-alkyl-cycloalkyl, CO₂-alkyl-heterocyclyl, CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl, C (O) -NH₂C (O) NH-alkyl, C (O) NH-cycloalkyl, C (O) NH-heterocyclyl, C (O) NH-aryl, C (O) NH-heteroaryl, C (O) NH-alkyl-cycloalkyl, C (O) NH-alkyl-heterocyclyl, C (O) NH-alkyl-aryl, C (O) NH-alkyl-heteroaryl, C (O) N (alkyl)₂C (O) N (cycloalkyl)₂C (O) N (aryl)₂C (O) N (heteroaryl)₂SO-alkyl, SO-aryl, SO₂Alkyl, SO₂Aryl, SO₂NH₂、SO₃H. Alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituents,

(ii) unsubstituted or substituted cycloalkyl, wherein the cycloalkyl can have one or more of the same or different F, Cl, Br, I, NH₂NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, N (alkyl)₂NHC (O) -alkyl, NHC (O) -cycloalkyl, NHC (O) -heterocyclyl, NHC (O) -aryl, NHC (O) -heteroaryl, NHSO₂Alkyl, NHSO₂Cycloalkyl, NHSO₂Aryl, NHSO₂-heteroaryl, OH, O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-aryl, O-alkyl-heteroaryl, OC (O) -alkyl, OC (O) -cycloalkyl, OC (O) -heterocyclyl, OC (O) -aryl, OC (O) -heteroaryl, OSO₂Alkyl, OSO₂Cycloalkyl, OSO₂Aryl, OSO₂-heteroaryl, CO₂H、CO₂Alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂Aryl, CO₂Heteroaryl, C (O) -NH₂C (O) NH-alkyl, C (O) NH-cycloalkyl, C (O) NH-heterocyclyl, C (O) NH-aryl, C (O) NH-heteroaryl, C (O) NH-alkyl-aryl, C (O) NH-alkyl-heteroaryl, C (O) N (alkyl)₂An alkyl or aryl substituent,

(iii) unsubstituted or substituted heterocyclyl, wherein the heterocyclyl may have one or more of the same or different OH, O-alkyl, O-aryl, NH₂NH-alkyl, NH-aryl, alkyl or aryl substituents,

(iv) unsubstituted or substituted aryl, where the aryl radicals may have one or more of the same or different F, Cl, Br, I, CF₃、NH₂NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-NH₂NH-alkyl-OH, N (alkyl)₂NHC (O) -alkyl, NHC (O) -cycloalkyl, NHC (O) -heterocyclyl, NHC (O) -aryl, NHC (O) -heteroaryl, NHSO₂Alkyl, NHSO₂Aryl, NHSO₂-heteroaryl, NO₂SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF₃O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aryl, O-alkyl-heteroaryl, O-alkyl-OH, O- (CH)₂)_n-O, OC (O) -alkyl, OC (O) -cycloalkyl, OC (O) -heterocyclyl, OC (O) -aryl, OC (O) -heteroaryl, OSO₂Alkyl, OSO₂Cycloalkyl, OSO₂Aryl, OSO₂Heteroaryl, C (O) -alkyl, C (O) -aryl, C (O) -heteroaryl, CO₂H、CO₂Alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂Aryl, CO₂-heteroaryl, CO₂-alkyl-cycloalkyl, CO₂-alkyl-heterocyclyl, CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl, C (O) -NH₂C (O) NH-alkyl, C (O) NH-cycloalkyl, C (O) NH-heterocyclyl, C (O) NH-aryl, C (O) NH-heteroaryl, C (O) NH-alkyl-cycloalkyl, C (O) NH-alkyl-heterocyclyl, C (O) NH-alkyl-aryl, C (O) NH-alkyl-heteroaryl, C (O) N (alkyl)₂C (O) N (cycloalkyl)₂C (O) N (aryl)₂C (O) N (heteroaryl)₂SO-alkyl, SO-aryl, SO₂Alkyl, SO₂Aryl, SO₂NH₂、SO₂NH-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl, SO₃H、SO₂O-alkyl, SO₂O-aryl, a,SO₂An O-heteroaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituent, n may have a value of 1, 2 or 3,

(v) unsubstituted or substituted heteroaryl, wherein the heteroaryl can have one or more of the same or different F, Cl, Br, I, CF₃、NH₂NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, N (alkyl)₂NHC (O) -alkyl, NHC (O) -cycloalkyl, NHC (O) -heterocyclyl, NHC (O) -aryl, NHC (O) -heteroaryl, NHSO₂Alkyl, NHSO₂Aryl, NHSO₂-heteroaryl, NO₂SH, S-alkyl, S-aryl, OH, OCF₃O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, OC (O) -alkyl, OC (O) -cycloalkyl, OC (O) -heterocyclyl, OC (O) -aryl, OC (O) -heteroaryl, OSO₂Alkyl, OSO₂Cycloalkyl, OSO₂Aryl, OSO₂Heteroaryl, C (O) -alkyl, C (O) -aryl, C (O) -heteroaryl, CO₂H、CO₂Alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂Aryl, CO₂-heteroaryl, CO₂-alkyl-cycloalkyl, CO₂-alkylheterocyclyl, CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl, C (O) -NH₂C (O) NH-alkyl, C (O) NH-cycloalkyl, C (O) NH-heterocyclyl, C (O) NH-aryl, C (O) NH-heteroaryl, C (O) NH-alkyl-cycloalkyl, C (O) NH-alkyl-heterocyclyl, C (O) NH-alkyl-aryl, C (O) NH-alkyl-heteroaryl, C (O) N (alkyl)₂C (O) N (cycloalkyl)₂C (O) N (aryl)₂C (O) N (heteroaryl)₂、SO₂Alkyl, SO₂Aryl, SO₂NH₂、SO₂NH-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl, SO₃H、SO₂O-alkyl, SO₂O-aryl, SO₂An O-heteroaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl substituent,

the term "alkyl" includes aliphatic saturated or unsaturated for the purposes of the present inventionAnd hydrocarbon radicals, which may be branched or unbranched and unsubstituted or mono-or polysubstituted, having 1 to 8C atoms, e.g. C_1-8Alkyl radical, C_2-8-alkenyl and C_2-8-alkynyl. In this connection, alkenyl has at least one C-C double bond and alkynyl has at least one C-C triple bond. The alkyl group is preferably selected from the group consisting of methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 2-hexyl, n-octyl, ethenyl (ethenyl), ethynyl, propenyl (-CH), and allyl (-CH)₂CH＝CH₂、-CH＝CH-CH₃、-C(＝CH₂)-CH₃) Propynyl (-CH)₂-C≡CH、-C≡C-CH₃) Butenyl, butynyl, pentenyl, pentynyl, hexenyl, hexynyl, heptenyl, heptynyl, octenyl and octynyl.

The term "cycloalkyl" refers to a cyclic hydrocarbon group having 3 to 12 carbon atoms, which may be saturated or unsaturated, for the purposes of the present invention. Can be attached to the compounds of the general structure I via any of the possible ring atoms of the cycloalkyl group. Cycloalkyl groups may also be part of a bi-or polycyclic ring system.

The term "heterocyclyl" represents a 3-, 4-, 5-, 6-, 7-or 8-membered ring organic group containing at least 1 heteroatom, suitably 2, 3, 4 or5, the heteroatoms being the same or different, the cyclic group being saturated or unsaturated but not aromatic. Can be attached to the compounds of the general structure I via any of the possible ring atoms of the heterocyclic group. Heterocyclyl groups may also be part of a bi-or polycyclic ring system. Preferred heteroatoms are nitrogen, oxygen and sulfur. Preferred heterocyclyl groups are selected from tetrahydrofuran, tetrahydropyran, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl.

The term "aryl" refers to aromatic hydrocarbons having 6 to 14 carbon atoms, especially phenyl, naphthyl and anthracenyl, which are used for the purposes of the present invention. This group may also be fused with other saturated, (partially) unsaturated or aromatic ring systems. Can be attached to the compounds of the general structure I via any of the possible ring atoms of the aryl group.

The term "heteroaryl" denotes a 5-, 6-or 7-membered cyclic aromatic radical which contains at least 1 heteroatom, where appropriate also 2, 3, 4 or5, which heteroatoms are identical or different. Can be attached to the compound of general structure I via any of the possible ring atoms of the heteroaryl group. Heterocycles can also be di-or polycyclic ring systems. Preferred heteroatoms are nitrogen, oxygen and sulfur. Preferred heteroaryl groups are selected from pyrrolyl, furanyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 2, 3-naphthyridinyl, indolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, carbazolyl, phenazinyl, phenothiazinyl, acridinyl.

For the purposes of the present invention, the terms "alkyl-cycloalkyl", "alkyl-heterocyclyl", "alkyl-aryl" or "alkyl-heteroaryl" mean that alkyl and cycloalkyl, heterocyclyl, aryl and heteroaryl have the meanings defined above, cycloalkyl, heterocyclyl, aryl or heteroaryl being interrupted by C_1-8-alkyl is attached to a compound of general structure I.

For the purposes of the present invention, the terms substitution in relation to "alkyl", "cycloalkyl", "heterocyclyl", "aryl", "heteroaryl", "alkyl-cycloalkyl", "alkyl-heterocyclyl", "alkyl-aryl" and "alkyl-heteroaryl" means with F, Cl, Br, I, CN, CF, in addition to those explicitly defined in the above description or in the claims₃、NH₂NH-alkyl, NH-aryl, N (alkyl)₂、NO₂SH, S-alkyl, OH, OCF₃O-alkyl, O-aryl, OSO₃H、OP(O)(OH)₂、CHO、CO₂H、SO₃H or alkyl in place of one or more hydrogen groups. The substituents may be the same or different, and the substitution may occur at any possible position of the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups.

Groups substituted more than once are understood to mean those groups which are substituted more than once, for example twice or three times, on different or the same atoms, for example on the same atomThree times on one C atom, like CF₃、-CH₂CF₃Or at a different position is-CH (OH) -CH ═ CH-CHCl₂. More than one substitution with the same or different substituents is possible.

In which the compounds of the general formula I according to the invention have at least one asymmetric center, they can be present in the form of their racemates, in the form of pure enantiomers and/or diastereomers or in the form of mixtures of these enantiomers and/or diastereomers. Any mixing ratio of the stereoisomers is possible in the mixture.

Thus, for example, the compounds of the formula I according to the invention which have one or more chiral centers and are present as racemates can be separated in a manner known per se into their optical isomers, for example enantiomers or diastereomers. This separation can be carried out by column separation on a chiral phase, or recrystallization from optically active solvents or using optically active acids or bases or by derivatization with optically active reagents, for example optically active alcohols, followed by removal of the group.

It is possible, among other things, that the compounds of the invention may exist in tautomeric forms.

The compounds of the general formula I according to the invention can be converted with inorganic or organic acids into their physiologically tolerated salts if they contain sufficient bases, for example primary, secondary or tertiary amines. The pharmaceutically acceptable salts of the compounds of the general formula I according to the invention are preferably salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, formic acid, acetic acid, trifluoroacetic acid, sulfoacetic acid, oxalic acid, malonic acid, maleic acid, succinic acid, tartaric acid, racemic acid, malic acid, embonic acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid or aspartic acid. Salts formed are in particular the hydrochloride, bromate, sulfate, bisulfate, phosphate, methanesulfonate, toluenesulfonate, carbonate, bicarbonate, formate, acetate, trifluoromethanesulfonate, sulfoacetate, oxalate, malonate, maleate, succinate, tartrate, malate, embonate, mandelate, fumarate, lactate, citrate, glutamate and aspartate. The stoichiometry of the salts formed with the compounds of the invention may furthermore be an integer or non-integer multiple thereof.

The compounds of the general formula I according to the invention can be converted with inorganic or organic bases into their physiologically tolerable salts if they contain sufficient acidic groups, for example carboxyl groups. Examples of suitable inorganic bases are sodium hydroxide, potassium hydroxide, calcium hydroxide, and examples of organic bases are ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dibenzylethylenediamine, and lysine. The stoichiometry of the salts formed with the compounds of the invention may furthermore be an integer or non-integer multiple thereof.

Likewise, preference is given to solvates, in particular hydrates of the compounds of the invention, which can be obtained, for example, by recrystallization from solvents or aqueous solutions. In these cases, one, two, three or any number of solvent or water molecules can be combined with the compounds of the present invention to yield solvates and hydrates.

Chemical species are known to form solids in various ordered states, which are referred to as polymorphs or variants. The various variations of polycrystalline material may vary widely in their physical properties. The compounds of formula I of the present invention can exist in various polymorphic forms, and particular variants may be metastable.

The preparation of the substituted pyrido [2, 3-b ] pyrazines according to the invention is illustrated below.

The compounds of the general formula I can be obtained by the following method (methods 1 to 5):

scheme 1

The parent compounds for alternative examples of pyrido [2, 3-b ] pyrazines according to the invention according to general formula I, wherein the substituents R1 and/OR R2 are the groups OR5, SR6, NR7R8, can be obtained according to the procedures of scheme 2 OR known to the person skilled in the art, for example.

Scheme 2

The parent compounds for the alternative examples of pyrido [2, 3-b ] pyrazines according to the invention according to formula I, wherein the substituent R9 is not equal to H, can be obtained according to the procedure of, for example, scheme 3.

Scheme 3

The reaction of the parent compounds 4, 7 and 13 in schemes 1-3 to obtain substituted pyrido [2, 3-b ] pyrazines according to the invention according to general formula I can be carried out according to the procedure of scheme 4, for example.

Scheme 4

Alternative examples of pyrido [2, 3-b ] pyrazines according to the invention according to general formula I (wherein the substituents R1 and R2 may be selected from the group substituted by carboxylate-, carboxamide-, sulfonate-or sulfonamide) can be obtained according to the procedures of scheme 5 or known to the person skilled in the art, for example.

Scheme 5

R17 ═ alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkyl-aryl, alkyl-heteroaryl.

The starting materials are commercially available or can be prepared by methods known per se. Starting materials 4, 7 and 10-13 are valuable intermediates for preparing the pyridopyrazines of the general formula I according to the invention.

For the preparation of the starting and target substances, the preparation can be carried out, for example, in the following basic literature, the content of which is incorporated in the disclosure of the present application.

1) Houben-Weyl, Methoden der Organischen Chemie, volume 4/1a, p.343-350

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General procedure for the preparation of compounds of the general formula I:

scheme 1: stage 1

2, 6-diamino-3-nitropyridine or 2-amino-3, 5-dinitropyridine is dissolved in a suitable inert solvent such as methanol, ethanol, dimethylformamide or dioxane. After addition of a catalyst such as Raney nickel, palladium on carbon or platinum (IV) dioxide, the reaction mixture is placed in hydrogen with the gas pressure adjusted between 1 and 5 bar. The reaction mixture is left to react for several hours, for example 1-16 hours, at a temperature in the range of 20 ℃ to 60 ℃. After the reaction is complete, the insoluble residue is filtered and the filter medium may, for example, comprise silica gel, diatomaceous earth or commercially available glass fiber filters and washed with a suitable solvent. The crude product was used in the solution of the following reaction without additional purification.

Stage 2

The 1, 2-dione derivative is added to a suitable inert solvent such as methanol, ethanol, dioxane, toluene or dimethylformamide. Immediately after reduction of the solution of the crude product contained in one of the above-mentioned solvents, 2, 3, 6-triaminopyridine or 2, 3, 5-triaminopyridine is added to introduce the 1, 2-dione, suitably with addition of an acid, such as acetic acid, or a base, such as potassium hydroxide. The reaction mixture is left to react for some time, for example 20 minutes to 40 hours, at a temperature in the range of 20 ℃ to 80 ℃. After the reaction is complete, any precipitate which has separated out is filtered off and the filter medium can, for example, comprise commercially available filter paper and washed with a suitable solvent, the residual solid being dried under vacuum or the solvent being removed from the reaction mixture under vacuum. In the case of dimethylformamide, the reaction mixture is stirred into a large volume of water, the precipitate which has separated off is filtered off, or the aqueous phase is extracted with a suitable organic solvent, for example dichloromethane or ethyl acetate, and the organic phase is concentrated in vacuo. The residual crude product is purified by recrystallization from a suitable solvent, such as dioxane, or by column or flash chromatography on silica gel or alumina. Mixtures of methanol and dichloromethane can be used as, for example, the mobile phase.

Scheme 2: stage 1

The solution of the crude product in one of the above solvents is reduced and then 2, 3, 6-triaminopyridine or 2, 3, 5-triaminopyridine is added directly. After addition of an oxalic acid derivative, such as diethyl oxalate or oxalyl chloride, the reaction mixture is left to react for some time, such as 10 minutes to 24 hours, at a temperature in the range of 20 ℃ to 150 ℃, where appropriate with addition of an acid, such as hydrochloric acid, sulfuric acid or glacial acetic acid. After the reaction is complete, the precipitate which has been separated off is filtered, and the filter medium can, for example, comprise a commercially available filter paper and is washed with a suitable solvent, and the remaining solid is dried under vacuum or the solvent is removed from the reaction mixture in vacuo. In the case of dimethylformamide, the reaction mixture is stirred into a large volume of water, the precipitate which has separated off is filtered off, or the aqueous phase is extracted with a suitable organic solvent, for example dichloromethane or ethyl acetate, and the organic phase is concentrated in vacuo. The residual crude product is purified by recrystallization from a suitable solvent, such as dioxane or toluene, or by column or flash chromatography on silica gel or alumina. Mixtures of methanol and dichloromethane can be used as, for example, the mobile phase.

Stage 2

The diketone derivative 8 is added to a suitable inert solvent such as dimethylformamide, dioxane or toluene, or without any solvent. A chlorinating agent such as phosphoryl chloride or thionyl chloride is added at room temperature, leaving the reaction mixture to react for some time, for example 1 hour to 24 hours, at a temperature in the range of 20 ℃ to 100 ℃. After completion of the reaction, the reaction mixture is poured into water and neutralized with a suitable aqueous base such as sodium hydroxide solution. The precipitate which has been separated off is filtered off and the filter medium can, for example, comprise a commercially available filter paper and is washed with the corresponding solvent, the remaining solid is dried under vacuum or the aqueous phase is extracted with a suitable organic solvent, for example dichloromethane or ethyl acetate, and the organic phase is concentrated in vacuo. The residual crude product is purified by recrystallization from a suitable solvent, such as dioxane or toluene, or by column or flash chromatography on silica gel or alumina. Mixtures of methanol and dichloromethane can be used as, for example, the mobile phase.

Stage 3

Intermediate 9 can be reacted with a suitable alcohol, thiol or amine, where appropriate with a suitable base, preferably sodium hydride, pyridine, triethylamine, potassium carbonate or sodium methoxide, in methanol, in a suitable inert solvent, for example dimethylformamide, dimethyl sulfoxide, methanol or toluene, or in a base as solvent, for example pyridine or triethylamine, or without any solvent. The reaction mixture is left to react for some time, for example 30 minutes to 2 days, at a temperature in the range of 20 ℃ to 140 ℃. After the reaction is completed, the precipitate which has been removed is filtered, and the filter medium may, for example, comprise a commercially available filter paper and washed with a suitable solvent, and the residual solid is dried under vacuum, or the solvent is removed from the reaction mixture under vacuum. When dimethylformamide or dimethyl sulfoxide is used, the reaction mixture is stirred into a large volume of water, the precipitate which has separated off is filtered off, or the aqueous phase is extracted with a suitable organic solvent, for example dichloromethane or ethyl acetate, and the organic phase is concentrated in vacuo. The residual crude product is purified by recrystallization from a suitable solvent, such as dioxane or toluene, or by column or flash chromatography on silica gel or alumina. Mixtures of methanol and dichloromethane can be used as, for example, the mobile phase.

Scheme 3: stage 1

Intermediates 4 and 7 can be reacted with the appropriate, suitable chloride, bromide or tosylate, where appropriate with a suitable base, preferably sodium hydride, pyridine, triethylamine, potassium carbonate or sodium methoxide, in methanol, in a suitable inert solvent, for example dimethylformamide, dimethyl sulfoxide, methanol, or in a base as solvent, for example pyridine or triethylamine, or without any solvent. The reaction mixture is left to react for some time, for example 1 to 24 hours, at a temperature in the range of 20 to 150 ℃. Alternatively, intermediates 4 and 7 can be reacted with the appropriate aryl bromide or aryl iodide and a suitable catalyst such as palladium acetate or Pd₂(dba)₂And a suitable ligand such as BINAP, and a suitable base such as potassium carbonate or sodium tert-butoxide, in a suitable solvent such as toluene or dioxane. The reaction mixture is left to react for some time, for example 10 hours to 30 hours, at a temperature in the range of 60 ℃ to 120 ℃. After the reaction is complete, the precipitate which has been separated off is filtered, the filter medium may, for example, comprise a commercially available filter paper and is washed with a suitable solvent, and the solid residue is dried under vacuumOr any catalyst residue which may be present is filtered and washed with a suitable solvent and the solvent is removed in vacuo or the solvent is removed from the reaction mixture in vacuo. When dimethylformamide or dimethyl sulfoxide is used, the reaction mixture is stirred into a large volume of water, the precipitate which has separated off is filtered off, or the aqueous phase is extracted with a suitable organic solvent, for example dichloromethane or ethyl acetate, and the organic phase is concentrated in vacuo. The residual crude product is purified by recrystallization from a suitable solvent such as EtOH, or by column or flash chromatography on silica gel or alumina. Mixtures of methanol and dichloromethane can be used as, for example, the mobile phase.

Scheme 4: stage 1

The products obtained from the basic process can be converted in a subsequent reaction into the subsequent products of the formula I according to the invention in accordance with the basic process in a procedure known to the skilled worker.

Thus, if the product is a derivative of compound 14, as shown in scheme 4, then after completion of the basic reaction, the reaction product 4, 7 or 13 can be reacted with a suitable isocyanate and, if appropriate, a suitable base, preferably sodium hydride, potassium hexamethyldisilazide, pyridine, triethylamine or potassium carbonate, in a suitable inert solvent such as dimethylformamide, dimethyl sulfoxide, acetonitrile, dichloromethane, 1, 2-dichloroethane or dioxane, or in a base as solvent such as pyridine or triethylamine, or without a solvent. The reaction mixture is left to react for several hours, for example 1-24 hours, at a temperature in the range of 0 to 80 ℃. After the reaction is complete, the precipitate which has been separated off is filtered, and the filter medium can, for example, comprise a commercially available filter paper and is washed with a suitable solvent, and the remaining solid is dried under vacuum or the solvent is removed from the reaction mixture in vacuo. When dimethylformamide or dimethyl sulfoxide is used, the reaction mixture is stirred into a large volume of water, the precipitate which has separated off is filtered off, or the aqueous phase is extracted with a suitable organic solvent, for example dichloromethane or ethyl acetate, and the organic phase is concentrated in vacuo. The residual crude product is purified by recrystallization from a suitable solvent such as ethanol or ethyl acetate, or by column or flash chromatography on silica gel or alumina. Mixtures of methanol and dichloromethane can be used as, for example, the mobile phase.

Another possibility is that if the product is a derivative of compound 15, as shown in scheme 4, after the basic reaction is complete the reaction product 4, 7 or 13 will be reacted with phosgene or carboxydiimidazole and the appropriate amine in a suitable inert solvent such as dimethylformamide, tetrahydrofuran, toluene, dichloromethane or acetonitrile. Suitable bases can be used, preferably pyridine, sodium hydrogen carbonate, triethylamine, N-methylmorpholine or sodium acetate. The reaction mixture is left to react for some time, for example 15 minutes to 24 hours, at a temperature in the range of 0 to 60 ℃. After the reaction is complete, any precipitate which has separated off is filtered, the filter medium can, for example, comprise a commercially available filter paper and is washed with a suitable solvent, and the remaining solid is dried under vacuum or the solvent is removed from the reaction mixture in vacuo. When dimethylformamide is used, the reaction mixture is stirred into a large amount of water, the precipitate which has separated off is filtered off, or the aqueous phase is extracted with a suitable organic solvent, for example dichloromethane or ethyl acetate, and the organic phase is concentrated in vacuo. The residual crude product is purified by recrystallization from a suitable solvent such as ethanol or ethyl acetate, or by column or flash chromatography on silica gel or alumina. Mixtures of methanol and dichloromethane can be used as, for example, the mobile phase.

Thus, if the product is a derivative of compound 16, as shown in scheme 4, then after completion of the basic reaction, the reaction product 4, 7 or 13 can be reacted with a suitable isocyanate, if appropriate with a suitable base, preferably sodium hydride, triethylamine, potassium carbonate or pyridine, in a suitable inert solvent, for example dimethylformamide, tetrahydrofuran, acetone or toluene, or in a base as solvent, for example pyridine or triethylamine, or without a solvent. The reaction mixture is left to react for some time, for example 30 minutes to 90 hours, at a temperature in the range of 0 to 115 ℃. After the reaction is complete, any precipitate which has separated off is filtered, the filter medium can, for example, comprise a commercially available filter paper and is washed with a suitable solvent, and the remaining solid is dried under vacuum or the solvent is removed from the reaction mixture in vacuo. In the case of dimethylformamide, the reaction mixture is stirred into a large volume of water, the precipitate which has separated off is filtered off, or the aqueous phase is extracted with a suitable organic solvent, for example dichloromethane or ethyl acetate, and the organic phase is concentrated in vacuo. The residual crude product is purified by recrystallization from a suitable solvent such as ethanol or ethyl acetate, or by column or flash chromatography on silica gel or alumina. Mixtures of methanol and dichloromethane can be used as, for example, the mobile phase.

Another possibility is that if the product is a derivative of compound 17, as shown in scheme 4, after the basic reaction is complete the reaction product 4, 7 or 13 will be reacted with thiophosgene or thiocarboxydiimidazole and the appropriate amine in a suitable inert solvent such as dimethylformamide, tetrahydrofuran, toluene, dichloromethane, ethanol or acetonitrile. Suitable bases can be used, preferably pyridine, sodium hydrogen carbonate, potassium carbonate, triethylamine or imidazole. The reaction mixture is left to react for several hours, for example 1 to 24 hours, at a temperature in the range of-10 to 80 ℃. After the reaction is complete, any precipitate which has separated off is filtered, the filter medium can, for example, comprise a commercially available filter paper and is washed with a suitable solvent, and the remaining solid is dried under vacuum or the solvent is removed from the reaction mixture in vacuo. In the case of dimethylformamide, the reaction mixture is stirred into a large volume of water, the precipitate which has separated off is filtered off, or the aqueous phase is extracted with a suitable organic solvent, for example dichloromethane or ethyl acetate, and the organic phase is concentrated in vacuo. The residual crude product is purified by recrystallization from a suitable solvent such as ethanol or ethyl acetate, or by column or flash chromatography on silica gel or alumina. Mixtures of methanol and dichloromethane can be used as, for example, the mobile phase.

Thus, if the product is a derivative of compound 18, as shown in scheme 4, then after completion of the basic reaction, the reaction product 4, 7 or 13 can be reacted with a suitable aminonitrile, if appropriate with a suitable base, preferably triethylamine or pyridine, or with a suitable acid, preferably hydrochloric acid, in a suitable inert solvent, for example acetone, toluene, chlorobenzene, ethanol, tetrahydrofuran or dimethylsulfoxide, or in a base as solvent, for example pyridine or triethylamine, or without a solvent. The reaction mixture is left to react for several hours, for example 2 to 140 hours, at a temperature in the range of 20 to 135 ℃. After the reaction is complete, any precipitate which has separated off is filtered, the filter medium can, for example, comprise a commercially available filter paper and is washed with a suitable solvent, and the remaining solid is dried under vacuum or the solvent is removed from the reaction mixture in vacuo. The residual crude product is purified by recrystallization from a suitable solvent, such as dioxane, or by column or flash chromatography on silica gel or alumina or by HPLC. Mixtures of methanol and dichloromethane can be used as mobile phase, for example, or mixtures of acetonitrile and water can be used as mobile phase in HPLC purification.

Another possibility is that, if the product is a derivative of compound 19, as shown in scheme 4, after the basic reaction has been completed, the reaction product 4, 7 or 13 can be reacted with a suitable nitrile, if appropriate with a suitable base, preferably sodium hydride, pyridine, triethylamine or potassium hexamethyldisilazane, or with a suitable catalyst, for example aluminum trichloride, trimethylaluminum, glacial acetic acid or sulfuric acid, in a suitable inert solvent, for example dioxane, toluene or ethanol, or in a base as solvent, for example pyridine or triethylamine, or without a solvent. The reaction mixture is left to react for some time, for example 30 minutes to 24 hours, at a temperature in the range of 0 to 200 ℃. After the reaction is complete, any precipitate which has separated off is filtered, the filter medium can, for example, comprise a commercially available filter paper and is washed with a suitable solvent, and the remaining solid is dried under vacuum or the solvent is removed from the reaction mixture in vacuo. The residual crude product is purified by recrystallization from a suitable solvent, such as dioxane, or by column or flash chromatography on silica gel or alumina or by HPLC. Mixtures of methanol and dichloromethane can be used as mobile phase, for example, or mixtures of acetonitrile and water can be used as mobile phase in HPLC purification.

Scheme 5: stage 1

Thus, if the product is a derivative of compound 21 or 24, as shown in scheme 5, then after completion of the basic reaction, the reaction product 20 or 23 can be reacted with a suitable phosgene, if appropriate with a suitable base, preferably sodium hydride, potassium hydroxide, pyridine, triethylamine or potassium carbonate, in a suitable inert solvent, for example tetrahydrofuran, toluene, acetonitrile, dichloromethane, acetone or dioxane, or in a base as solvent, for example pyridine or triethylamine, or without a solvent. The reaction mixture is left to react for some time, for example 30 minutes to 12 hours, at a temperature in the range of 0 to 110 ℃. After the reaction is complete, any precipitate which has separated off is filtered, the filter medium can, for example, comprise a commercially available filter paper and is washed with a suitable solvent, and the remaining solid is dried under vacuum or the solvent is removed from the reaction mixture in vacuo. Alternatively, the reaction mixture is stirred into a large volume of water, the precipitate which has separated is filtered, or, after neutralization with a suitable aqueous acid such as hydrochloric acid, the aqueous phase is extracted with a suitable organic solvent such as diaminomethane or ethyl acetate, and the organic phase is concentrated in vacuo. The residual crude product is purified by recrystallization from a suitable solvent, such as ethanol, or by column or flash chromatography on silica gel or alumina. Mixtures of methanol and dichloromethane can be used as, for example, the mobile phase.

Another possibility is that if the product is a derivative of compound 22 or 25 as shown in scheme 5, after the basic reaction is complete the reaction product 20 or 23 will be reacted with a suitable sulfonyl chloride, if appropriate, and a suitable base, preferably sodium hydride, potassium hydroxide, pyridine, triethylamine or potassium carbonate, in a suitable inert solvent such as tetrahydrofuran, toluene, acetonitrile, dichloromethane, acetone, dimethylformamide or dioxane, or in a base as solvent such as pyridine or triethylamine, or in the absence of a solvent. The reaction mixture is left to react for some time, for example 30 minutes to 16 hours, at a temperature in the range of 0 to 80 ℃. After the reaction is complete, any precipitate which has separated off is filtered, the filter medium can, for example, comprise a commercially available filter paper and is washed with a suitable solvent, and the remaining solid is dried under vacuum or the solvent is removed from the reaction mixture in vacuo. Alternatively, the reaction mixture is stirred into a large volume of water, the precipitate which has separated is filtered off, or, after neutralization with a suitable aqueous acid, for example hydrochloric acid, the aqueous phase is extracted with a suitable organic solvent, for example dichloromethane or ethyl acetate, and the organic phase is concentrated in vacuo. In the case of dimethylformamide, the reaction mixture is stirred into a large volume of water, the precipitate which has separated off is filtered off, or the aqueous phase is extracted with a suitable organic solvent, for example dichloromethane or ethyl acetate, and the organic phase is concentrated in vacuo. The residual crude product is purified by recrystallization from a suitable solvent, such as ethanol, or by column or flash chromatography on silica gel or alumina. Mixtures of methanol and dichloromethane can be used as, for example, the mobile phase.

OH, SH and NH under some of the reaction conditions already mentioned₂The radical may suffer from undesirable side reactions. They are therefore preferably provided with a protecting group, or in NH₂Neutral NO₂By substitution, since subsequent elimination of the protecting group or NO₂The radical is reduced. Thus, in the above-described modification, at least one OH group in the starting material can be substituted, for example, by benzyloxy and/or at least one SH group can be substituted, for example, by S-benzyl and/or at least one NH group₂The radicals being capable of being substituted by NO₂And (4) substituting the group. At least one-preferably all-benzyloxy group can be eliminated subsequently with, for example, hydrogen and palladium on carbon and/or at least one-preferably all-S-benzyl group can be eliminated with, for example, sodium in aqueous ammonia and/or at least one-preferably all-NO can be eliminated with hydrogen and Raney nickel₂Reduction of the radical to NH₂。

OH, NH under some of the reaction conditions already mentioned₂And COOH groups may suffer from undesirable side reactions. It will therefore preferably comprise at least one OH and/or at least one NH₂The starting and intermediate products of the group and/or of the at least one COOH group are converted into the corresponding carboxylic esters and carboxamide derivatives. In the above-mentioned modification process, at least one OH group and/or at least one NH group is present₂The starting and intermediate species of the group can be converted into carboxylic acid esters or carboxylic amine derivatives by reaction with an active carboxyl group, for example phosgene. In the above-described modification processes, the starting and intermediate compounds having at least one COOH group can be converted into carboxylic acid esters or carboxylic amine derivatives by reaction with an activating agent, such as thionyl chloride or carbonyldiimidazole, followed by reaction with a suitable alcohol or amine.

The pyrido [2, 3-b ] pyrazine derivatives of the general formula I according to the invention are suitable as active ingredients in pharmaceuticals, for modulating misdirected cell signaling processes, in particular affecting the function of tyrosine and serine/threonine kinases, and for the treatment of malignant or benign tumors such as breast, prostate, lung, skin and ovarian cancers in humans, mammals and poultry and other diseases based on pathological cell proliferation such as restenosis, psoriasis, arteriosclerosis and cirrhosis. The mammal may be a domestic animal such as a horse, cow, dog, cat, rabbit, sheep, and the like.

The medical role of the pyrido [2, 3-b ] pyrazine derivatives of the invention may be based, for example, on the modulation of signal transduction through interaction with receptor tyrosine kinases and cytoplasmic tyrosine and serine/threonine kinases. In addition, other known and unknown mechanisms of action that control the oxidative process are also possible.

Another aspect of the present invention is to provide a method for controlling tumors in humans, mammals and poultry, characterized in that at least one pyrido [2, 3-b ] pyrazine derivative of the general formula I is administered to humans, mammals or poultry in an amount effective for tumor treatment. The therapeutically effective dose of the particular pyrido [2, 3-b ] pyrazine derivatives of the invention administered for therapy depends inter alia on the nature and stage of the tumor, the age and sex of the patient, the mode of administration and the duration of the treatment. The medicaments of the present invention may be administered in the form of liquid, semi-solid and solid medicaments. This takes place in each case in the form of aerosols, powders, dusting powders and dusting powders, tablets, coated tablets, emulsions, foams, solutions, suspensions, gels, ointments, pastes, pills, lozenges, capsules or suppositories.

The pharmaceutical preparations contain, in addition to at least one of the components according to the invention, suitable auxiliary substances, depending on the pharmaceutical preparation used, such as, inter alia, solvents, solution promoters, cosolvents, emulsifiers, wetting agents, antifoams, gelling agents, thickeners, film formers, binders, buffers, salt formers, drying agents, flow control agents, fillers, preservatives, antioxidants, colorants, mold release agents, lubricants, disintegrants and taste masking and odor agents. The choice of auxiliary substances and the amounts thereof depends on the medicament chosen and is based on prescriptions known to the skilled person.

The medicament of the invention can be applied to the skin in a suitable dosage form as a solution, suspension, emulsion, foam, ointment, paste or plaster for application to the skin; as tablets, troches, coated tablets, gargles or mouthwashes by oral and lingual mucosa from the mouth, buccal, lingual or sublingual administration; as enteric tablets, coated tablets, capsules, solutions, suspensions or emulsions to be administered enterally through the gastric and intestinal mucosa; rectally administered through the rectal mucosa as a suppository, rectal capsule or ointment; nasally as drops, ointments or sprays through the nasal mucosa; administered as an aerosol or inhalant by the pulmonary route or by inhalation through the bronchial and alveolar epithelium; administered from conjunctiva through conjunctiva as eye drops, eye ointments, eye tablets, eye sheets, or eye washes; intravaginal administration of pessaries, ointments and vaginal douches through the mucosa of the reproductive organs; administered as a pessary by intrauterine route; administered from the urethra through the urinary tract as a douche, ointment or bougie; administered into an artery as an injection; administered intravenously as an injection or infusion solution; intradermally administered as an injection or implant under the skin; administered subcutaneously as an injection or implant into the skin; administered intramuscularly as an injection or implant into the muscle; administered intraperitoneally as an injection or infusion solution into the abdominal cavity.

The medical action of the compounds of the general structure I according to the invention can be prolonged by suitable methods according to the actual therapeutic requirements. This object can be achieved by chemical and/or pharmaceutical methods. Examples of achieving prolonged action are the use of implants and liposomes, the formation of salt and low solubility complexes, or the use of crystalline suspensions.

Particularly preferred medicaments in this connection are those which contain at least one pyrido [2, 3-b ] pyrazine derivative of the general structure I below, in the form of the free base or of other physiologically tolerable acid pharmaceutically acceptable salts thereof:

1-allyl-3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) thiourea (example 1)

1-allyl-3- (3-naphthalen-2-ylpyrido [2, 3-b ] pyrazin-6-yl) thiourea (example 2)

1-allyl-3- [3- (4-methoxyphenyl) pyrido [2, 3-b ] pyrazin-6-yl ] thiourea (example 3)

1-allyl-3- [3- (4-hydroxyphenyl) pyrido [2, 3-b ] pyrazin-6-yl ] thiourea hydrochloride (example 4)

1- (2-Methylallyl) -3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) thiourea (example 5)

1- (2-Methylallyl) -3- (3-naphthalen-2-ylpyrido [2, 3-b ] pyrazin-6-yl) thiourea (example 6)

1- [3- (4-methoxyphenyl) pyrido [2, 3-b ] pyrazin-6-yl ] -3- (2-methylallyl) thiourea (example 7)

1- (3-Naphthalen-2-ylpyrido [2, 3-b ] pyrazin-6-yl) -3- (4-nitrophenyl) thiourea (example 8)

1- [3- (4-methoxyphenyl) pyrido [2, 3-b ] pyrazin-6-yl ] -3- (4-nitrophenyl) thiourea (example 9)

1-tert-butyl-3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) thiourea (example 10)

1-cyclopropyl-3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) thiourea (example 11)

1-methyl-3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) thiourea (example 12)

1-benzyl-3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) thiourea (example 13)

1- (4-fluorophenyl) -3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) thiourea (example 14)

1-cyclohexyl-3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) thiourea (example 15)

1-isopropyl-3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) thiourea (example 16)

1-Furan-2-ylmethyl-3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) thiourea (example 17)

1-methyl-3- [3- (4-nitrophenyl) pyrido [2, 3-b ] pyrazin-6-yl ] thiourea (example 18)

1- [3- (4-hydroxyphenyl) pyrido [2, 3- ] pyrazin-6-yl ] -3-methylthiourea (example 19)

1-allyl-3- [3- (4-nitrophenyl) pyrido [2, 3-b ] pyrazin-6-yl ] -thiourea (example 20)

Ethyl 4- [6- (3-allylthiourea) pyrido [2, 3-b ] pyrazin-3-yl ] -benzoate (example 21)

1-allyl-3- [3- (3-hydroxyphenyl) pyrido [2, 3-b ] pyrazin-6-yl ] thiourea (example 22)

1-allyl-3- (3-benzo [1, 3] dioxol-5-ylpyrido [2, 3-b ] pyrazin-6-yl) thiourea (example 23)

1- [3- (4-hydroxyphenyl) pyrido [2, 3-b ] pyrazin-6-yl ] -3-prop-2-ynyl (propylyl) thiourea (example 24)

1-allyl-3- [3- (4-hydroxyphenyl) pyrido [2, 3-b ] pyrazin-6-yl ] thiourea (example 25)

1- [3- (4-hydroxyphenyl) pyrido [2, 3-b ] pyrazin-6-yl ] -3- (propenyl) thiourea (example 26)

1-allyl-3- [2, 3-bis (4-hydroxyphenyl) pyrido [2, 3-b ] pyrazin-6-yl ] thiourea (example 27)

1- [2, 3-bis (4-hydroxyphenyl) pyrido [2, 3-b ] pyrazin-6-yl ] -3- (propenyl) thiourea (example 28)

1-allyl-3- [2- (4-hydroxyphenyl) pyrido [2, 3-b ] pyrazin-6-yl ] thiourea (example 29)

1-allyl-3- [3- (4-nitrophenyl) pyrido [2, 3-b ] pyrazin-7-yl ] thiourea (example 30)

1-cyclopropyl-3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) urea (example 31)

1-allyl-3- [3- (4-hydroxyphenyl) pyrido [2, 3-b ] pyrazin-6-yl ] urea (example 32)

1- (3-Phenylpyrido [2, 3-b ] pyrazin-6-yl) -3-p-tolylurea (example 33)

1- (4-chloro-3-trifluoromethylphenyl) -3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) urea (example 34)

1- (2-Morpholin-4-ylethyl) -3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) urea (example 35)

1-phenethyl-3- (3-phenylpyrido [2, 3- ] pyrazin-6-yl) urea (example 36)

1- (2, 3-Dipyridin-2-ylpyrido [2, 3-b ] pyrazin-6-yl) -3-ethylurea (example 37)

1- (2, 3-Dimethylpyrido [2, 3-b ] pyrazin-6-yl) -3-ethylurea (example 38)

Exemplary embodiments

As is evident from the description of the individual chemical names identified below, the following compounds can be synthesized according to the general synthetic methods on which the synthetic schemes 1-4 are based. In addition, their NMR spectrum data and melting points are also attached. The structures of these compounds are evident from the general formula II and the substituents R1, R2, R3, R4 and R5 and Y in Table 1 below.

The chemicals and solvents used can be obtained commercially from common suppliers (Acros, Aldrich, Fluka, Lancaster, Maybrid, Merck, Sigma, TCI, etc.) or synthetically.

The present invention is explained in more detail by way of the following examples, but the present invention is not limited thereto.

Example 1:

preparation of 3-phenylpyrido [2, 3-b ] pyrazin-6-ylamine (reaction shown in scheme 1, stages 1 and 2)

A solution of 1.22g of 2, 6-diamino-3-nitropyridine (7.92mmol) in 210ml of ethanol was hydrogenated at 50 ℃ and 5 bar using Raney nickel as catalyst. After the hydrogenation was complete, the catalyst was filtered by suction through a glass fiber filter. Before filtration, 1.68g of benzoyl formaldehyde hydrate (11.03mmol) were added to 50ml of ethanol in a receiver. The catalyst was then filtered under nitrogen as a blanket gas and the hydrogenation solution was drawn directly into the reaction flask. The green-blue reaction mixture was heated under nitrogen at reflux for 30 minutes. The mixture was cooled and the solvent was removed in vacuo. Finally a brown solid is obtained. Purification by column chromatography on silica gel (mobile phase dichlorotetraalkyl/methanol mixture) gave a pale yellow crystalline solid.

Preparation of 1-allyl-3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) thiourea (reaction shown in scheme 4, 1 st stage)

0.246g of sodium hydride (6.14mmol) was added to 5ml of anhydrous dimethylformamide under nitrogen as a protective gas. The mixture was cooled to 0 ℃ in an ice bath. 1.05g of 3-phenylpyrido [2, 3-b ] pyrazin-6-ylamine (4.72mmol) was dissolved in 5ml of anhydrous dimethylformamide and added dropwise. The cooling bath was removed, leaving the mixture to stir at RT for 30 minutes. The mixture was then cooled to 0 ℃ again in an ice bath and 0.469g of allyl isothiocyanate (4.72mmol) dissolved in 4ml of anhydrous dimethylformamide was added dropwise. After the addition was complete, the cooling bath was removed, leaving the mixture to stir at room temperature for 1.5 hours. For the stepwise establishment, we poured the mixture into about 250ml of distilled water and filtered off the precipitated orange solid by suction. Purification by column chromatography several times (mobile phase dichloromethane/methanol mixture) followed by preparative HPLC gave a yellow solid.

Melting point: 239-

¹H-NMR(d₆-DMSO)：δ＝4.40(m，2H)，5.30(d，1H)，5.60(d，1H)，6.07-6.17(m，1H)，7.55-7.70(m，4H)，8.35(d，2H)，8.45(d，1H)，9.50(s，1H)，11.35(s，1H)，12.55(m，1H)。

The following examples were synthesized according to example 1 and general synthesis:

example 2: 1-allyl-3- (3-naphthalen-2-ylpyrido [2, 3-b ] pyrazin-6-yl) thiourea

Melting point: 242 ℃ 243 ℃ (decomposition)

¹H-NMR(d₆-DMSO)：δ＝4.42(m，2H)，5.37(d，1H)，5.65(d，1H)，6.07-6.19(m，1H)，7.57-7.68(m，3H)，7.97-8.05(m，1H)，8.07-8.19(m，2H)，8.40-8.52(m，2H)，8.99(s，1H)，9.70(s，1H)，11.36(s，1H)，12.56(t，1H)。

Example 3: 1-allyl-3- [3- (4-methoxyphenyl) pyrido [2, 3-b ] pyrazin-6-yl ] thiourea

Melting point: 240 ℃ in 241 deg.C (decomposition)

¹H-NMR(d₆-DMSO)：δ＝3.87(m，3H)，4.36-4.42(m，2H)，5.32(d，1H)，5.60(d，1H)，6.06-6.16(m，1H)，7.16(d，2H)，7.60(d，1H)，8.32(d，2H)，8.42(d，1H)，9.56(s，1H)，11.29(s，1H)，12.56(m，1H)。

Example 4: 1-allyl-3- [3- (4-hydroxyphenyl) pyrido [2, 3-b ] pyrazin-6-yl ] thiourea hydrochloride

Melting point: 160-

¹H-NMR(d₆-DMSO)：δ＝4.36-4.43(m，2H)，5.31(d，1H)，5.59(d，1H)，6.05-6.16(m，1H)，6.97(d，2H)，7.57(d，1H)，8.20(d，2H)，8.40(d，1H)，9.41(s，1H)，10.17(bs，1H)，11.24(s，1H)，12.56(m，1H)。

Example 5: 1- (2-methylallyl) -3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) thiourea

Melting point: 225 + 226 deg.C (decomposition)

¹H-NMR(d₆-DMSO)：δ＝1.90(s，3H)，4.30-4.35(m，2H)，5.01(s，1H)，5.22(s，1H)，7.55-7.80(m，4H)，8.30-8.38(m，2H)，8.45(d，1H)，9.52(s，1H)，11.32(s，1H)，12.65(m，1H)。

Example 6: 1- (2-methylallyl) -3- (3-naphthalen-2-ylpyrido [2, 3-b ] pyrazin-6-yl) thiourea

Melting point: 239-

¹H-NMR(d₆-DMSO)：δ＝1.94(s，3H)，4.32(m，2H)，5.07(s，1H)，5.28(s，1H)，7.60-7.69(m，3H)，8.00-8.05(m，1H)，8.07-8.12(m，1H)，8.14(d，1H)，8.42-8.51(m，2H)，8.98(s，1H)，9.68(s，1H)，11.32(s，1H)，12.78(m，1H)。

Example 7: 1- [3- (4-methoxyphenyl) pyrido [2, 3-b ] pyrazin-6-yl ] -3- (2-methylallyl) thiourea

Melting point: 251 + 252 deg.C (decomposition)

¹H-NMR(d₆-DMSO)：δ＝1.92(s，3H)，3.85(s，3H)，4.27-4.35(m，2H)，5.02(s，1H)，5.24(s，1H)，7.15(d，2H)，7.58(d，1H)，8.31(d，2H)，8.41(d，1H)，9.46(s，1H)，11.29(s，1H)，12.68(m，1H)。

Example 8: 1- (3-naphthalen-2-ylpyrido [2, 3-b ] pyrazin-6-yl) -3- (4-nitrophenyl) thiourea

Melting point: 260 ℃ 261 ℃ (decomposition)

¹H-NMR(d₆-DMSO)：δ＝7.61-7.68(m，3H)，7.72(d，2H)，7.75(d，1H)，8.01-8.06(m，1H)，8.16(m，2H)，8.26(d，2H)，8.53(d，1H)，8.58(d，1H)，9.04(s，1H)，9.62(s，1H)，9.76(s，1H)，11.81(s，1H)。

Example 9: 1- [3- (4-methoxyphenyl) pyrido [2, 3-b ] pyrazin-6-yl ] -3- (4-nitrophenyl) thiourea

Melting point: 250 + 251 deg.C (decomposition)

¹H-NMR(d₆-DMSO)：δ＝3.85(s，3H)，7.17(d，2H)，7.71(d，2H)，8.21(d，2H)，8.22-8.27(m，1H)，8.36-8.42(m，3H)，9.53(s，1H)，9.65(s，1H)，11.77(s，1H)。

Example 10: 1-tert-butyl-3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) thiourea

Melting point: 227 deg.C (decomposition)

¹H-NMR(d₆-DMSO)：δ＝1.65(s，9H)，7.53-7.69(m，4H)，8.34(d，2H)，8.41(d，1H)，9.51(s，1H)，10.98(s，1H)，12.75(s，1H)。

Example 11: 1-cyclopropyl-3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) thiourea

Melting point: 233 ℃ above and 234 ℃ below

¹H-NMR(d₆-DMSO)：δ＝0.70-0.80(m，2H)，0.91-1.00(m，2H)，3.20-3.28(m，1H)，7.51-7.72(m，4H)，8.36(d，2H)，8.45(d，1H)，9.52(s，1H)，11.31(s，1H)，12.45(s，1H)。

Example 12: 1-methyl-3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) thiourea

Melting point: 253 temperature 254 DEG C

¹H-NMR(d₆-DMSO)：δ＝3.25(s，3H)，7.59-7.67(m，4H)，8.38(d，2H)，8.46(d，1H)，9.52(s，1H)，11.31(s，1H)，12.10(s，1H)。

Example 13: 1-benzyl-3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) thiourea

Melting point: 232 ℃ plus 233 DEG C

¹H-NMR(d₆-DMSO)：δ＝4.96(m，2H)，7.37-7.48(m，3H)，7.54-7.67(m，6H)，8.32(d，2H)，8.47(d，1H)，9.52(s，1H)，11.43(s，1H)，12.91(s，1H)。

Example 14: 1- (4-fluorophenyl) -3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) thiourea

Melting point: 225 ℃ C. 226 ℃ C

¹H-NMR(d₆-DMSO)：δ＝7.33(m，2H)，7.57-7.65(m，3H)，7.70-7.81(m，3H)，8.34(d，2H)，8.54(d，1H)，9.57(s，1H)，11.62(s，1H)。

Example 15: 1-cyclohexyl-3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) thiourea

Melting point: 230 ℃ and 232 DEG C

¹H NMR(d₆-DMSO)：δ＝1.50-1.75(m，6H)，1.80-2.00(m，4H)，7.55-7.70(m，4H)，8.37(d，2H)，8.45(d，1H)，9.55(s，1H)，11.20(s，1H)，12.80(s，1H)。

Example 16: 1-isopropyl-3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) thiourea

Melting point: 229 ℃ 230 DEG C

¹H NMR(d₆-DMSO)：δ＝1.40(d，6H)，4.40-4.50(m，1H)，7.58-7.66(m，4H)，8.36(d，2H)，8.44(d，1H)，9.52(s，1H)，11.20(s，1H)，12.48(s，1H)。

Example 17: 1-furan-2-ylmethyl-3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) thiourea

Melting point: 250 deg.C (decomposition)

¹H NMR(d₆-DMSO)：δ＝4.95(s，2H)，6.55(m，1H)，6.68(d，1H)，7.59-7.68(m，4H)，7.74(d，1H)，8.37(d，2H)，8.48(d，1H)，9.55(s，1H)，11.45(s，1H)，12.83(s，1H)。

Example 18: 1-methyl-3- [3- (4-nitrophenyl) pyrido [2, 3-b ] pyrazin-6-yl ] thiourea

Melting point: 270 deg.C

¹H NMR(d₆-DMSO)：δ＝3.25(s，3H)，7.70(d，1H)，8.44(d，2H)，8.50(d，1H)，8.64(d，2H)，9.64(s，1H)，11.38(s，1H)，12.03(s，1H)。

Example 19: 1- [3- (4-hydroxyphenyl) pyrido [2, 3- ] pyrazin-6-yl ] -3-methylthiourea

Melting point: 282 deg.C

¹H NMR(d₆-DMSO)：δ＝3.25(s，3H)，6.98(d，2H)，7.57(d，1H)，8.26(d，2H)，8.40(d，1H)，9.45(s，1H)，10.18(s，1H)，11.25(s，1H)，12.10(s，1H)。

Example 20: 1-allyl-3- [3- (4-nitrophenyl) pyrido [2, 3-b ] pyrazin-6-yl ] -thiourea

Melting point: 244 deg.C (decomposition)

¹H NMR(d₆-DMSO)：δ＝4.40(s，2H)，5.36(d，1H)，5.59(d，1H)，6.08-6.15(m，1H)，7.71(d，1H)，8.46(d，2H)，8.51(d，1H)，8.60(d，2H)，9.64(s，1H)，11.45(s，1H)，12.51(t，1H)。

Example 21: ethyl 4- [6- (3-allylthiourea) pyrido [2, 3-b ] pyrazin-3-yl ] -benzoate

Melting point: 223 ℃ 224-

¹H NMR(d₆-DMSO)：δ＝1.39(t，3H)，4.35-4.42(m，4H)，5.35(d，1H)，5.60(d，1H)，6.08-6.15(m，1H)，7.68(d，1H)，8.17(d，2H)，8.47(d，2H)，8.50(d，1H)，9.60(s，1H)，11.40(s，1H)，12.52(t，1H)。

Example 22: 1-allyl-3- [3- (3-hydroxyphenyl) pyrido [2, 3-b ] pyrazin-6-yl ] thiourea

Melting point: 205 deg.C (decomposition)

¹H NMR(d₆-DMSO)：δ＝4.41(s，2H)，5.33(d，1H)，5.58(d，1H)，6.07-6.15(m，1H)，6.99(d，1H)，7.42(t，1H)，7.64(d，1H)，7.72(s，1H)，7.77(d，1H)，8.46(d，1H)，9.45(s，1H)，9.80(s，1H)，11.37(s，1H)，12.55(s，1H)。

Example 23: 1-allyl-3- (3-benzo [1, 3] dioxol-5-ylpyrido [2, 3-b ] pyrazin-6-yl) thiourea

Melting point: 218 at 220 deg.C (decomposition)

¹H NMR(d₆-DMSO)：δ＝4.40(s，2H)，5.31(d，1H)，5.60(d，1H)，6.08-6.20(m，3H)，7.16(d，1H)，7.61(d，1H)，7.90(s，1H)，7.96(d，1H)，8.43(d，1H)，9.49(s，1H)，11.34(s，1H)，12.58(s，1H)。

Example 24: 1- [3- (4-hydroxyphenyl) pyrido [2, 3-b ] pyrazin-6-yl ] -3-prop-2-ynylthiourea

Melting point: 350 deg.C (decomposition)

¹H NMR(d₆-DMSO)：δ＝2.09(s，1H)，2.44(s，2H)，6.99(d，2H)，7.19(s，1H)，7.44(s，1H)，8.24(d，2H)，8.26(d，1H)，9.29(s，1H)，10.08(s，1H)，11.81(s，1H)。

Example 25: 1-allyl-3- [3- (4-hydroxyphenyl) pyrido [2, 3-b ] pyrazin-6-yl ] thiourea

Melting point: 230 ℃ (decomposition)

¹H NMR(d₆-DMSO)：δ＝4.40(s，2H)，5.34(d，1H)，5.60(d，1H)，6.07-6.15(m，1H)，6.98(d，2H)，7.58(d，1H)，8.24(d，2H)，8.42(d，1H)，9.45(s，1H)，10.19(s，1H)，11.34(s，1H)，12.60(s，1H)。

Example 26: 1- [3- (4-hydroxyphenyl) pyrido [2, 3-b ] pyrazin-6-yl ] -3- (propenyl) thiourea

Melting point:

¹H NMR(d₆-DMSO)：δ＝2.12(d，3H)，5.17(m，1H)，6.96(d，2H)，7.22-7.26(m，1H)，7.59(d，1H)，8.25(d，2H)，8.45(d，1H)，9.48(s，1H)，10.20(s，1H)，11.56(s，1H)，14.67(s，1H)。

example 27: 1-allyl-3- [2, 3-bis (4-hydroxyphenyl) pyrido [2, 3-b ] pyrazin-6-yl ] thiourea

Melting point: 270 deg.C (decomposition)

¹H NMR(d₆-DMSO)：δ＝4.40(s，2H)，5.25(d，1H)，5.50(d，1H)，6.02-6.13(m，1H)，6.74(d，2H)，6.76(d，2H)，7.31(d，2H)，7.36(d，2H)，7.62(d，1H)，8.42(d，1H)，9.78(s，1H)，9.85(s，1H)，11.30(s，1H)，12.47(s，1H)。

Example 28: 1- [2, 3-bis (4-hydroxyphenyl) pyrido [2, 3-b ] pyrazin-6-yl ] -3- (propenyl) thiourea

Melting point: 240 deg.C (decomposition)

¹H NMR(d₆-DMSO)：δ＝2.05(d，3H)，5.10-5.18(m，1H)，6.74(d，2H)，6.76(d，2H)，7.20-7.26(m，1H)，7.34(d，2H)，7.39(d，2H)，7.63(d，1H)，8.45(d，1H)，9.79(s，1H)，9.89(s，1H)，11.55(s，1H)，14.56(d，1H)。

Example 29: 1-allyl-3- [2- (4-hydroxyphenyl) pyrido [2, 3-b ] pyrazin-6-yl ] thiourea

Melting point: 260 deg.C (decomposition)

¹H NMR(d₆-DMSO)：δ＝4.40(s，2H)，5.28(d，1H)，5.48(d，1H)，6.03-6.12(m，1H)，6.96(d，2H)，7.66(d，1H)，8.16(d，2H)，8.43(d，1H)，9.52(s，1H)，10.06(s，1H)，11.31(s，1H)，12.40(s，1H)。

Example 30: 1-allyl-3- [3- (4-nitrophenyl) pyrido [2, 3-b ] pyrazin-7-yl ] thiourea

Melting point: 250 deg.C (decomposition)

¹H NMR(d₆-DMSO)：δ＝4.23(s，2H)，5.19(d，1H)，5.29(d，1H)，5.90-6.00(m，1H)，8.46(d，2H)，8.55(s，1H)，8.64(d，2H)，8.92(s，1H)，9.23(s，1H)，9.77(s，1H)，10.35(s，1H)。

Example 31: 1-cyclopropyl-3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) urea

Melting point: 158 ℃ and 160 DEG C

¹H NMR(d₆-DMSO)：δ＝0.52-0.60(m，2H)，0.72-0.82(m，2H)，2.70-2.79(m，1H)，7.57-7.65(m，3H)，7.71(d，1H)，8.34(d，2H)，8.38(d，1H)，9.21(s，1H)，9.46(s，1H)，10.12(s，1H)。

Example 32: 1-allyl-3- [3- (4-hydroxyphenyl) pyrido [2, 3-b ] pyrazin-6-yl ] urea

Melting point: 240 deg.C (decomposition)

¹H NMR(d₆-DMSO)：δ＝3.98(s，2H)，5.19(d，1H)，5.37(d，1H)，5.96-6.05(m，1H)，6.97(d，2H)，7.59(d，1H)，8.22(d，2H)，8.33(d，1H)，9.38(s，1H)，9.45(s，1H)，10.13(s，1H)，10.18(s，1H)。

Example 33: 1- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) -3-p-toluyl urea

Melting point: 298-

¹H-NMR(d₆-DMSO)：δ＝2.29(s，3H)，7.20(d，2H)，7.52(d，2H)，7.59-7.67(m，3H)，7.80(d，1H)，8.38(d，2H)，8.44(d，1H)，9.59(s，1H)，10.36(s，1H)，11.46(s，1H)。

Example 34: 1- (4-chloro-3-trifluoromethylphenyl) -3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) urea

Melting point: 250 deg.C

¹H-NMR(d₆-DMSO)：δ＝7.58-7.67(m，3H)，7.74(d，1H)，7.80(d，1H)，7.87(d，1H)，8.21(s，1H)，8.39(d，2H)，8.48(d，1H)，9.53(s，1H)，10.55(s，1H)，11.82(s，1H)。

Example 35: 1- (2-morpholin-4-ylethyl) -3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) urea

Melting point: 226 deg.C

¹H-NMR(d₆-DMSO)：δ＝2.45-2.67(m，6H)，3.40-3.48(m，2H)，3.60-3.69(m，4H)，7.55-7.70(m，4H)，8.30-8.40(m，3H)，9.29(s，1H)，9.42(s，1H)，10.18(s，1H)。

Example 36: 1-phenethyl-3- (3-phenylpyrido [2, 3- ] pyrazin-6-yl) urea

Melting point: 250 deg.C (decomposition)

¹H NMR(d₆-DMSO)：δ＝2.88-2.95(m，2H)，3.52-3.60(m，2H)，7.18(t，1H)，7.28(t，2H)，7.42(d，2H)，7.58-7.68(m，4H)，8.37(d，3H)，9.25(s，1H)，9.48(s，1H)，10.18(s，1H)。

Example 37: 1- (2, 3-dipyridin-2-ylpyrido [2, 3-b ] pyrazin-6-yl) -3-ethylurea

Melting point: 236 ℃ plus 237 DEG C

¹H NMR(d₆-DMSO)：δ＝1.13-1.22(m，3H)，3.28-3.39(m，2H)，3.60-3.69(m，4H)，7.31-7.39(m，2H)，7.79(d，1H)，7.91-7.99(m，4H)，8.26(d，1H)，8.29(d，1H)，8.47(d，1H)，9.08(s，1H)，10.20(s，1H)。

Example 38: 1- (2, 3-dimethylpyrido [2, 3-b ] pyrazin-6-yl) -3-ethylurea

Melting point: 246-248 DEG C

¹H NMR(d₆-DMSO)：δ＝1.17(t，3H)，2.64(s，3H)，2.67(s，3H)，3.24-3.40(m，2H)，7.55(d，1H)，8.24(d，1H)，9.14(s，1H)，9.91(s，1H)。

Table 1:

R3/R4: hydrogen or

Examples	R1	R2	R3	R4	R5
Examples	R1	R2	R3	R4	R5	1	Ph	H	Y＝S	H	-CHCH＝CH
2	2-naphthyl radical	H	Y＝S	H	-CHCH＝CH	1	Ph	H	Y＝S	H	-CHCH＝CH
2	2-naphthyl radical	H	Y＝S	H	-CHCH＝CH	3	4-Meo-Ph	H	Y＝S	H	-CHCH＝CH
4	4-HO-Ph	H	Y＝S	H	-CHCH＝CHHCl salt	3	4-Meo-Ph	H	Y＝S	H	-CHCH＝CH
4	4-HO-Ph	H	Y＝S	H	-CHCH＝CHHCl salt	5	Ph	H	Y＝S	H	-CHC(CH)＝CH
6	2-naphthyl radical	H	Y＝S	H	-CHC(CH)＝CH	5	Ph	H	Y＝S	H	-CHC(CH)＝CH
6	2-naphthyl radical	H	Y＝S	H	-CHC(CH)＝CH	7	4-Meo-Ph	H	Y＝S	H	-CHC(CH)＝CH
8	2-naphthyl radical	H	Y＝S	H	-Ph-p-NO	7	4-Meo-Ph	H	Y＝S	H	-CHC(CH)＝CH
8	2-naphthyl radical	H	Y＝S	H	-Ph-p-NO	9	4-Meo-Ph	H	Y＝S	H	-Ph-p-NO
10	Ph	H	Y＝S	H	-C(CH)	9	4-Meo-Ph	H	Y＝S	H	-Ph-p-NO

Examples	R1	R2	R3	R4	R5
Examples	R1	R2	R3	R4	R5	11	Ph	H	Y＝S	H	-cyclopropyl group
12	Ph	H	Y＝S	H	-CH	11	Ph	H	Y＝S	H	-cyclopropyl group
12	Ph	H	Y＝S	H	-CH	13	Ph	H	Y＝S	H	-benzyl radical
14	Ph	H	Y＝S	H	-Ph-p-F	13	Ph	H	Y＝S	H	-benzyl radical
14	Ph	H	Y＝S	H	-Ph-p-F	15	Ph	H	Y＝S	H	-cyclohexyl radical
16	Ph	H	Y＝S	H	-CH(CH)	15	Ph	H	Y＝S	H	-cyclohexyl radical
16	Ph	H	Y＝S	H	-CH(CH)	17	Ph	H	Y＝S	H	-1-furan-2-ylmethyl
18	4-NO-Ph	H	Y＝S	H	-CH	17	Ph	H	Y＝S	H	-1-furan-2-ylmethyl
18	4-NO-Ph	H	Y＝S	H	-CH	19	4-HO-Ph	H	Y＝S	H	-CH
20	4-NO-Ph	H	Y＝S	H	-CHCH＝CH	19	4-HO-Ph	H	Y＝S	H	-CH
20	4-NO-Ph	H	Y＝S	H	-CHCH＝CH	21	4-COEt-Ph	H	Y＝S	H	-CHCH＝CH
22	3-HO-Ph	H	Y＝S	H	-CHCH＝CH	21	4-COEt-Ph	H	Y＝S	H	-CHCH＝CH
22	3-HO-Ph	H	Y＝S	H	-CHCH＝CH	23	3-benzo [1, 3]]-dioxol-5-yl	H	Y＝S	H	-CHCH＝CH
24	4-HO-Ph	H	Y＝S	H	-propyn-2-yl	23	3-benzo [1, 3]]-dioxol-5-yl	H	Y＝S	H	-CHCH＝CH
24	4-HO-Ph	H	Y＝S	H	-propyn-2-yl	25	4-HO-Ph	H	Y＝S	H	-CHCH＝CH
26	4-HO-Ph	H	Y＝S	H	-CH＝CHCH	25	4-HO-Ph	H	Y＝S	H	-CHCH＝CH
26	4-HO-Ph	H	Y＝S	H	-CH＝CHCH	27	4-HO-Ph	4-OH-Ph	Y＝S	H	-CHCH＝CH
28	4-HO-Ph	4-OH-Ph	Y＝S	H	-CH＝CHCH	27	4-HO-Ph	4-OH-Ph	Y＝S	H	-CHCH＝CH
28	4-HO-Ph	4-OH-Ph	Y＝S	H	-CH＝CHCH	29	H	4-OH-Ph	Y＝S	H	-CHCH＝CH

Examples	R1	R2	R3	R4	R5
Examples	R1	R2	R3	R4	R5	30	4-NO-Ph	H	H	Y＝S	-CHCH＝CH
31	Ph	H	Y＝O	H	-cyclopropyl group	30	4-NO-Ph	H	H	Y＝S	-CHCH＝CH
31	Ph	H	Y＝O	H	-cyclopropyl group	32	4-HO-Ph	H	Y＝O	H	-CHCH＝CH
33	Ph	H	Y＝O	H	-p-tolyl radical	32	4-HO-Ph	H	Y＝O	H	-CHCH＝CH
33	Ph	H	Y＝O	H	-p-tolyl radical	34	Ph	H	Y＝O	H	-Ph-p-Cl-m-CF
35	Ph	H	Y＝O	H	-CHCH-morpholin-4-yl	34	Ph	H	Y＝O	H	-Ph-p-Cl-m-CF
35	Ph	H	Y＝O	H	-CHCH-morpholin-4-yl	36	Ph	H	Y＝O	H	-phenethyl group
37	2-pyridyl group	2-pyridyl group	Y＝O	H	-ethyl radical	36	Ph	H	Y＝O	H	-phenethyl group
37	2-pyridyl group	2-pyridyl group	Y＝O	H	-ethyl radical	38	Methyl radical	Methyl radical	Y＝O	H	-ethyl radical

Biological Effect of the Compounds of the invention

The inhibitory effect of the compounds of the invention on the following human serine/threonine and tyrosine kinases was determined by routine kinase assays: PKB/Akt1, c-Raf-Mek-Erk, B-Raf-Mek-Erk, MAPKs, PDGFRbeta, Flt-3, c-Kit, c-Abl, KDR, FGFR1 and IGF 1R. Full-length kinases and truncated fragments-but at least the cytoplasmic kinase domain-were used. The kinase was combined with GST (glutathione-S-transferase) or HIS Tag in Sf9 cell culture medium to prepare recombinant fusion proteins. Depending on the type of substrate, different kinase reactions were performed in sandwich ELISA formates or by simple substrate uptake experiments on 96-well flashplates (perkin elmer).

The experiments on the substance in the c-Raf-Mek-Erk cascade are described in detail below. Selected experimental results of the c-Raf-Mek-Erk experiment are then presented.

The operation is as follows: C-Raf-Mek-Erk ELISA

Potential inhibitors were first studied at a concentration of 20 μ g/ml in an initial single dose assay on 96-well microtiter plates (MTPs). Substances with 70% inhibition were used for dose effect studies.

Reconstitution of the c-Raf-Mek-Erk cascade was quantified without the aid of ELISA on cells. Recombinant kinase proteins were prepared using the following: 1) constitutively active GST-c-Raf-DD from Sf9 cells, 2) inactive GST-Mek1 from e.coli and 3) inactive His-Erk2 from e.coli.

Typical kinase experiments were carried out in a final volume of 50. mu.l, in each case 20-150ng of Raf, Mek, Erk protein, 1mM ATP, 10mM MgCl₂150mM NaCl, 25mM glycerol beta-phosphate, 25mM Hepes pH 7.5. Each test substance was pre-incubated with three kinases separately for 30 minutes at room temperature before the kinase reaction. For the kinase reaction, the kinases preincubated with the test substances were combined and incubated at 26 ℃ for 30 minutes. The reaction was stopped by a final concentration of 2% SDS and heating in a heating block at 50 ℃ for 10 minutes.

For immunodetection, the reaction mixture was transferred to 96-well MTPs coated with anti-Erk Ab (K-23, Santa Cruz Biotechnology), incubated for 60 min at room temperature and washed 3 times with TBST. anti-phosphor-ErkAb (#9106, New England Biolabs) 1: 500 in 50. mu.l TBST/1% BSA was added and incubated overnight at 4 ℃. After washing MTPs 3 times with TBST, a second anti-mouse IgG was added^PODThe conjugate (# NA931, Pharmacia) was 1: 2500, incubated at room temperature for 1 hour, and washed again 3 times with TBST. For colorimetric detection of kinase reaction, 50. mu.l OPD (o-phenylenediamine dihydrochloride) chromogen buffer was aspirated into each well and incubated at 37 ℃ for 30 minutes. The colour reaction was then determined at 492nm in an ELISA reader.

The experimental determination of the dose response plots was performed with the same experimental design with a 10 semilog gradient concentration from 31.6pM to 100 μ M. IC (integrated circuit)₅₀Values were calculated in GraphPadPrism.

The compounds of the present invention show potent inhibition of Erk phosphorylation, IC thereof₅₀The value was 400nM (see typical embodiments 4 and 12).

Claims

1. Pyrido [2, 3-b ] pyrazine derivatives of general formula I,

wherein the substituents R1-R4 have the following meanings:

r1 is:

(i) the presence of hydrogen in the presence of hydrogen,

(i v) alkyl, wherein alkyl is saturated and contains 1 to 8C atoms,

(v) unsubstituted or substituted aryl, said aryl being phenyl, naphthyl or anthracenyl, wherein the aryl has one or more NO's, which are the same or different₂SH, S-alkyl, OH, O-alkyl, O-cycloalkyl, O- (CH)₂)_n-O、CO₂H、CO₂Alkyl, CO₂-cycloalkyl, SO₂Alkyl, SO₃H or SO₂An O-alkyl substituent, n has the value 1, 2 or 3, said alkyl being an aliphatic saturated or unsaturated, branched or unbranched hydrocarbon radical having 1 to 8C atoms, said cycloalkyl being a saturated or unsaturated, cyclic hydrocarbon radical having 3 to 12C atoms,

(vi) heteroaryl, which is a 5-, 6-or 7-membered cyclic aromatic radical, containing at least 1 heteroatom, which is identical or different and is selected from the group consisting of nitrogen, oxygen and sulfur,

r2 is:

(i) the presence of hydrogen in the presence of hydrogen,

(iv) alkyl, wherein alkyl is saturated and contains 1 to 8C atoms,

(v) unsubstituted or substituted aryl, which is phenyl, naphthyl or anthracenyl, wherein aryl has one or more identical or different SH, S-alkyl, OH, O-alkyl or O-cycloalkyl substituents, the alkyl being an aliphatic saturated or unsaturated, branched or unbranched hydrocarbon radical having 1 to 8C atoms, the cycloalkyl being a saturated or unsaturated, cyclic hydrocarbon radical having 3 to 12C atoms,

r3 is NR9R10,

wherein R9 is a hydrogen atom,

r10 is-C (Y) NR11R12, wherein Y is O or S, R11 is hydrogen and R12 is

(i) The presence of hydrogen in the presence of hydrogen,

(ii) unsubstituted or substituted alkyl, which is an aliphatic saturated or unsaturated, branched or unbranched hydrocarbon radical having 1 to 8C atoms, wherein alkyl has one or more identical or different heterocyclyl or heteroaryl substituents, which heterocyclyl is a saturated or unsaturated, 3-, 4-, 5-, 6-, 7-or 8-membered ring nonaromatic organic radical which contains at least 1 heteroatom, which heteroatom is identical or different and is selected from the group consisting of nitrogen, oxygen and sulfur, which heteroaryl is a 5-, 6-or 7-membered ring aromatic radical which contains at least 1 heteroatom, which heteroatom is identical or different and is selected from the group consisting of nitrogen, oxygen and sulfur,

(iii) cycloalkyl which is a saturated or unsaturated cyclic hydrocarbon group having 3 to 12C atoms,

(v) unsubstituted or substituted aryl, which is phenyl, naphthyl or anthracenyl, wherein the aryl has one or more of the same or different F, Cl, Br, I, CF₃、NO₂Or an alkyl substituent, said alkyl being an aliphatic saturated or unsaturated, branched or straight-chain hydrocarbon radical having 1 to 8C atoms,

R4＝H，

or a pharmacologically tolerable salt thereof, wherein the salt is obtained by neutralizing basic compounds with inorganic and organic acids or by neutralizing acidic compounds with inorganic or organic bases.

2. Pyrido [2, 3-b ] of the formula I according to claim 1]Pyrazine derivatives characterised in that the alkyl group is methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 2-hexyl, n-octyl, ethenyl (ethenyl), ethynyl, propenyl (-CH)₂CH＝CH₂、-CH＝CH-CH₃、-C(＝CH₂)-CH₃) Propynyl (-CH)₂-C≡CH、-C≡C-CH₃) Butenyl, butynyl, pentenyl, pentynyl, hexenyl, hexynyl, heptenyl, heptynyl, octenyl or octynyl.

3. Pyrido [2, 3-b ] pyrazine derivatives of general formula I according to claim 1, characterized in that the heterocyclic group is tetrahydrofuran, tetrahydropyran, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl.

4. Pyrido [2, 3-b ] pyrazine derivatives of the general formula I according to claim 1, characterized in that the heteroaryl group is pyrrolyl, furanyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 2, 3-naphthyridinyl, indolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, carbazolyl, phenazinyl, phenothiazinyl or acridinyl.

5. Pyrido [2, 3-b ] pyrazine derivatives of general formula I according to any of claims 1 to 4, in particular one of the following compounds:

1-allyl-3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) thiourea

1-allyl-3- (3-naphthalen-2-ylpyrido [2, 3-b ] pyrazin-6-yl) thiourea

1-allyl-3- [3- (4-methoxyphenyl) pyrido [2, 3-b ] pyrazin-6-yl ] thiourea

1-allyl-3- [3- (4-hydroxyphenyl) pyrido [2, 3-b ] pyrazin-6-yl ] thiourea hydrochloride

1- (2-methylallyl) -3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) thiourea

1- (2-methylallyl) -3- (3-naphthalen-2-ylpyrido [2, 3-b ] pyrazin-6-yl) thiourea

1- [3- (4-methoxyphenyl) pyrido [2, 3-b ] pyrazin-6-yl ] -3- (2-methylallyl) thiourea

1- (3-naphthalen-2-ylpyrido [2, 3-b ] pyrazin-6-yl) -3- (4-nitrophenyl) thiourea

1- [3- (4-methoxyphenyl) pyrido [2, 3-b ] pyrazin-6-yl ] -3- (4-nitrophenyl) thiourea

1-tert-butyl-3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) thiourea

1-cyclopropyl-3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) thiourea

1-methyl-3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) thiourea

1-benzyl-3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) thiourea

1- (4-fluorophenyl) -3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) thiourea

1-cyclohexyl-3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) thiourea

1-isopropyl-3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) thiourea

1-furan-2-ylmethyl-3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) thiourea

1-methyl-3- [3- (4-nitrophenyl) pyrido [2, 3-b ] pyrazin-6-yl ] thiourea

1- [3- (4-hydroxyphenyl) pyrido [2, 3] pyrazin-6-yl ] -3-methylthiourea

1-allyl-3- [3- (4-nitrophenyl) pyrido [2, 3-b ] pyrazin-6-yl ] -thiourea

Ethyl 4- [6- (3-allylthiourea) pyrido [2, 3-b ] pyrazin-3-yl ] -benzoate

1-allyl-3- [3- (3-hydroxyphenyl) pyrido [2, 3-b ] pyrazin-6-yl ] thiourea

1-allyl-3- (3-benzo [1, 3] dioxol-5-ylpyrido [2, 3-b ] pyrazin-6-yl) thiourea

1- [3- (4-hydroxyphenyl) pyrido [2, 3-b ] pyrazin-6-yl ] -3-prop-2-ynylthiourea

1-allyl-3- [3- (4-hydroxyphenyl) pyrido [2, 3-b ] pyrazin-6-yl ] thiourea

1- [3- (4-hydroxyphenyl) pyrido [2, 3-b ] pyrazin-6-yl ] -3- (propenyl) thiourea

1-allyl-3- [2, 3-bis (4-hydroxyphenyl) pyrido [2, 3-b ] pyrazin-6-yl ] thiourea

1- [2, 3-bis (4-hydroxyphenyl) pyrido [2, 3-b ] pyrazin-6-yl ] -3- (propenyl) thiourea

1-allyl-3- [2- (4-hydroxyphenyl) pyrido [2, 3-b ] pyrazin-6-yl ] thiourea

1-cyclopropyl-3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) urea

1-allyl-3- [3- (4-hydroxyphenyl) pyrido [2, 3-b ] pyrazin-6-yl ] urea

1- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) -3-p-toluyl urea

1- (4-chloro-3-trifluoromethylphenyl) -3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) urea

1- (2-morpholin-4-ylethyl) -3- (3-phenylpyrido [2, 3-b ] pyrazin-6-yl) urea

1-phenethyl-3- (3-phenylpyrido [2, 3- ] pyrazin-6-yl) urea

1- (2, 3-dipyridin-2-ylpyrido [2, 3-b ] pyrazin-6-yl) -3-ethylurea

1- (2, 3-dimethylpyrido [2, 3-b ] pyrazin-6-yl) -3-ethylurea.

6. Medicament comprising at least one compound of general formula I according to any one of claims 1 to 5.

7. The medicament according to claim 6, wherein the compound is present in the composition in combination with at least one other pharmaceutically active ingredient and/or a pharmaceutical carrier and/or diluent or other excipient.

8. Process for the manufacture of a medicament according to claim 6 or 7, characterized in that one or more of the pyrido [2, 3-b ] pyrazine derivatives of the general formula I according to any of claims 1 to 5 are processed with conventional pharmaceutical carriers and/or diluents or other auxiliary substances into pharmaceutical preparations or converted into therapeutically usable forms.

9. Use of pyrido [2, 3-b ] pyrazine derivatives of general formula I according to any of claims 1 to 5 as therapeutically active ingredient in the manufacture of a medicament for influencing the function of active or inactive tyrosine and serine/threonine kinases.

10. Use according to claim 9 for the treatment of diseases based on pathological cell proliferation.

11. Use according to claim 10, wherein the disease of pathological cell proliferation is restenosis, psoriasis, arteriosclerosis or cirrhosis of the liver.

12. Use according to claim 9 for the treatment of malignant or benign tumors.

13. The use according to claim 12, wherein the malignant or benign tumor is a breast, prostate, lung, skin or ovarian tumor.

14. Use according to any one of claims 9 to 13 for influencing the function of active or inactive tyrosine and serine/threonine kinases in humans, mammals and poultry and for treating diseases based on pathological cell proliferations and malignant or benign tumors.

15. The use according to claim 9, wherein the tyrosine and serine/threonine kinases are c-Raf, B-Raf, Mek, MAPKs, PDGFRbeta, Flt-3, IGF1R, PKB/Akt1, c-Kit, c-Abl, FGFR1 or KDR.