HK1193033A

HK1193033A - Pyridopyrazine derivatives and their use

Info

Publication number: HK1193033A
Application number: HK14106521.9A
Authority: HK
Inventors: M．格拉驰; I．赛佩特; L．布鲁门斯泰因; G.穆勒; E．贡特尔; T.舒斯特; M．特费尔
Original assignee: 阿特纳赞塔里斯有限公司
Priority date: 2011-04-06
Filing date: 2012-04-04
Publication date: 2014-09-12

Description

Pyridopyrazine derivatives and their use

Description of the invention

Technical Field

The present invention relates to pyridopyrazine derivatives having novel biological effects and their use for the treatment of physiological and/or pathophysiological states mediated and/or modulated by signaling pathways in mammals and in particular in humans.

Prior Art

The signaling cascades ras-Raf-Mek-Erk and PI3K-Akt play key roles in cell growth, cell proliferation, apoptosis, cell adhesion, cell migration and glucose metabolism. Thus, both the ras-Raf-Mek-Erk and PI3K-Akt signaling pathways have been shown to be fundamentally involved in the pathogenesis of diseases such as cancer, neurodegenerative and inflammatory diseases. The individual components of these signaling cascades are therefore important therapeutic attack points for intervention in a variety of disease processes (Weinstein-Oppenheimer c.r. et al 2000, Chang f. et al 2003, Katso r. et al 2001 and Lu y. et al 2003).

The molecular and biochemical properties of these two signaling pathways are first described separately below.

Various growth factors, cytokines, and oncogenes transduce their growth-promoting signals by activating G-protein coupled ras, which leads to activation of serine-threonine kinase Raf and activation of mitogen-activated protein kinase kinases 1 and 2(MAPKK1/2 or Mek1/2), and to phosphorylation and activation of MAPKs 1 and 2 (also known as extracellular signal-regulated kinases (Erk1 and 2)). In contrast to other signaling pathways, the ras-Raf-Mek-Erk signaling pathway binds to a number of proto-oncogenes, including ligands, tyrosine kinase receptors, G-proteins, kinases, and nuclear transcription factors. Tyrosine kinases such as EGFR (Mendelsohn j. et al, 2000) often mediate constitutive activation signals to the downstream ras-Raf-Mek-Erk signaling pathway in neoplastic events caused by overexpression and mutation. Ras mutations occur in 30% of all human tumors (Khleif s.n. et al, 1999, Marshall c, 1999), with a maximum incidence of 90% being found in pancreatic cancer (friessh. et al, 1996, Sirivatanauksorn v. et al, 1998). Deregulated expression and/or activation of c-Raf has been described in a variety of tumours (Hoshino r. et al, 1999, McPhillips f. et al, 2001). B-Raf point mutations were detected in 66% of all human malignant melanomas, 14% of all ovarian cancers and 12% of all colon cancers (Davies h. et al, 2002). It is therefore not surprising that Erk1/2 is primarily involved in various cellular processes, such as cell growth, cell proliferation, and cell differentiation (Lewis t.s. et al, 1998, Chang f. et al, 2003).

In addition, members of Raf kinases also have anti-apoptotic functions independent of Mek-Erk, molecular steps of which have not been fully described. Ask1, Bcl-2, Akt, and Bag1 have been described as potential interaction partners independent of the Raf activity of Mek-Erk (Chen J et al, 2001, tropipmaier J. et al, 2003, Rapp u.r. et al, 2004, Gotz r. et al, 2005). It is currently hypothesized that both the Mek-Erk-dependent and Mek-Erk-independent signal transduction mechanisms control the activation of downstream ras and Raf stimuli.

The isozyme of phosphatidylinositol 3-kinase (PI3Ks) acts primarily as a lipid kinase and promotes phosphorylation of the second messenger lipid PtdIns (phosphatidylinositol) D3 to PtdIns (3) P, PtdIns (3,4) P₂、PtdIns(3,4,5)P₃Phosphatidylinositol phosphate. Class I PI3Ks is structurally composed of catalytic subunits (p110 α, β, γ, δ) and regulatory subunits (p85 α, β or p101 γ). Furthermore, class II (PI3K-C2 α, PI3K-C2 β) and class III (Vps34P) enzymes belong to the P13 kinase family (Wymann nM. P. et al, 1998, Van Haesebroeck B. et al, 2001). PIP increase triggered by PI3Ks activates the proliferating ras-Raf-Mek-Erk signaling pathway by coupling of ras on the one hand (Rodriguez-Viciana p. et al, 1994), and on the other hand stimulates the anti-apoptotic signaling pathway by recruiting Akt to the cell membrane and consequent over-activation of this kinase (Alessi d.r. et al, 1996, changh.w. et al, 1997, Moore s.m. et al, 1998). Thus, the activation of PI3Ks is consistent with at least two key mechanisms of tumor formation, namely cell growth and cell differentiation and inhibition of apoptosis. In addition, PI3K also has protein-phosphorylation properties (Dhand et al, 1994, Bondeva T. et al, 1998, Bondev A. et al, 1999, Van Haesebroeck B. et al, 1999), which can trigger, for example, PI3 Ks-intrinsically regulated serine autophosphorylation. In addition, PI3Ks is also known to have kinase-independent regulatory effector properties, for example during cardiac contractile control (crowower m.a. et al, 2002, Patrucco et al, 2004). In addition, PI3K δ and PI3K γ have also been shown to be specifically expressed on hematopoietic cells and thus constitute potential points of attack for isozyme-specific PI3K δ and PI3K γ inhibitors in the treatment of inflammatory diseases such as rheumatism, asthma and allergy, and B and T cell lymphomas (Okkenhaug k et al, 2003, Ali k et al, 2004, sujobrt p. et al, 2005). PI3K α (Shayesteh l. et al, 1999, Ma y.y. et al, 2000, Samuels y. et al, 2004, Campbell i.g. et al, 2004, Levine d.a.,2005), which was recently identified as a primary oncogene, is considered as an important target in the treatment of neoplastic diseases. The target PI3K type is therefore of great importance for active substance development (Chang F).&Lee j.t. et al, 2003).

Kinases related to PI3K (PIKK) are also of great interest, including the serine/threonine kinases mTOR, ATM, ATR, h-SMG-1 and DNA-PK (Chiang g.g. 2004). Their catalytic regions have high sequence homology with the catalytic region of PI3 Ks.

Furthermore, the loss of the tumor suppressor protein PTEN-whose function is the reversal of phosphorylation initiated by PI3K (Li j et al, 1997, tack p.a. et al, 1997) promotes excessive activation of Akt and its downstream cascade components and thus reinforces the importance of PI3K as a target molecule for tumor therapy.

Various inhibitors of the individual components of the ras-Raf-Mek-Erk and PI3K-Akt signaling pathways have been disclosed and claimed.

The current state of development in the field of kinase inhibitors, in particular ras-Raf-Mek-Erk and PI3K-Akt pathways, is described in reviews by h.t. arkenau et al, 2011, m.s. chapman & j.n.miner,2011 and p.liu et al, 2009. These publications contain an exhaustive list of disclosed low molecular ras-Raf-Mek-Erk-and PI3K inhibitors.

The kinase inhibitor sorafenib (Bay 43-9006; WO99/32111, WO03/068223), approved in 2006, showed a relatively non-specific inhibition pattern of serine/threonine and tyrosine kinases such as Raf, VEGFR2/3, Flt-3, PDGFR, c-Kit and others. The inhibitors are valued in angiogenesis-induced advanced tumor diseases (e.g. in renal cell carcinoma) and in melanomas with high B-Raf mutation rates. Inhibition of kinases in the PI3K-Akt signaling pathway by Bay43-9006 has not been described. Other Raf-specific inhibitors such as PLX-4032 and GSK2118436(Arkenau h.t. et al, 2011) are currently in clinical evaluation.

Several Mek1/2 inhibitors (AZD-6244, XL-518, GSK1120212 and others) are currently undergoing clinical trials (review by MS Chapman & JN Miner, 2011). However, neither interaction of these Mek inhibitors with Erk1 or Erk2 nor their ability to inhibit or simultaneously modulate any PI3K-Akt signaling pathway is disclosed.

Patent specification WO2009/077766 describes pyrido [2,3-b ] pyrazines as RAF inhibitors.

Furthermore, patent specifications WO2008/040820, WO2008/009908 and WO2005/123733 describe pyrido [2,3-b ] pyrazines as agrochemical fungicides and herbicides, respectively.

Korean invention KR2008004646 relates to 2-alkenyloxy-3-ethynylpyrido [2,3-b ] pyrazine derivatives and pharmaceutically acceptable salts thereof that inhibit the expression of hypoxia inducible transcription factor 1(HIF-1) gene.

Patent specifications WO04/104002 and WO04/104003 describe pyrido [2,3-b ] pyrazines which may be substituted in the 6-or 7-position by a urea, thiourea, amidine or guanidine group. These compounds have the property of being inhibitors or modulators of kinases, particularly tyrosine and serine/threonine kinases, and specify their use as medicaments. However, the use of these compounds as lipid kinase modulators (alone or in combination with tyrosine and serine/threonine kinases) has not been described.

Furthermore, patent specification WO99/17759 describes pyrido [2,3-b ] pyrazines which, among other groups, have alkyl-, aryl-and heteroaryl-substituted carbamates in the 6-position. These compounds are intended to be used for the modulation of serine threonine protein kinases.

Patent specification WO05/007099 describes urea-substituted pyrido [2,3-b ] pyrazines and the like as inhibitors of the serine/threonine kinase PKB. The use of these compounds in the treatment of cancer diseases is described in particular. However, no specific examples of urea-substituted pyridopyrazines having these biological properties are given.

Further examples of pyrido [2,3-b ] pyrazines substituted in the 6-and 7-positions by urea are given in patent specification WO 05/056547. The compounds of this patent specification are described as inhibitors of protein kinases, particularly GSK-3, Syk and JAK-3. Among other things, the use of these compounds in the treatment of proliferative diseases is given. The use of these compounds as lipid kinase modulators (alone or in combination with serine/threonine kinases) has not been described.

Patent application WO04/005472 describes, among other things, pyrido [2,3-b ] pyrazines substituted in the 6-position by carbamates, which act as antibacterial substances inhibiting the growth of bacteria. No antitumor effect is mentioned.

Patent specifications WO03/084473, WO03/086394 and WO03/086403 describe certain diphenylquinoxalines and pyrido [2,3-b ] pyrazines having specific alkylpyrrolidine, alkylpiperidine or alkylsulfonamide groups in the phenyl ring, which may additionally have a urea or carbamate substituent in the 6-or 7-position, as inhibitors of the activity of the serine/threonine kinase Akt. The use of these compounds in the treatment of cancer diseases is described in particular. No definitive indications are given for the biological effects of the pyrido [2,3-b ] pyrazines described herein as examples.

Patent specification WO03/024448 describes amide and acrylamide-substituted pyrido [2,3-b ] pyrazines, which may also contain carbamates as additional substituents and which can be used as histone deacetylase inhibitors for the treatment of cell proliferative diseases.

Publications (s.laufer, j.med.chem.2010,53(3),1128-1137) describe pyridylpyridopyrazines as lead compounds for novel p38 α mitogen-activated protein kinase inhibitors.

Pyrido [2,3-b ] pyrazines as promoters of tubulin polymerization are described in another publication (M.R.Dobler, Pest Management Science,2010,66(2), 178-185).

The synthesis of 6-ethylcarbamate-substituted pyrido [2,3-b ] pyrazine derivatives is described as an example in the publication (sample c. et al. 1990). The antitumor effect is not disclosed or made apparent.

The synthesis of additional derivatives of 6-ethylcarbamate-substituted pyrido [2,3-b ] pyrazines is described in a publication by r.d.elliott (j.org.chem.1968). The biological effects of these compounds are not described or disclosed.

The synthesis and study of 6-ethylcarbamate-substituted pyrido [2,3-b ] pyrazines as potential antimalarial drugs is described in the publication by temperature (1968). The antitumor effect is not disclosed or made apparent.

Several PI3K inhibitors (NVP-Bez-235, GDC-0941, XL-147 and others) were subjected to clinical trials (reviewed by Maira s.m., et al, 2010).

Description of the invention

It is an object of the present invention to provide novel compounds useful for treating or preventing physiological and/or pathophysiological conditions in mammals, particularly humans, mediated by a signaling pathway selected from the group consisting of the PI3K-Akt signaling pathway and the ras-Raf-Mek-Erk signaling pathway.

The object of the present invention was surprisingly achieved in one aspect by the preparation of compounds of the general formula (I)

Wherein the substituents R1, R2, X have the following meanings:

x: o or S

R1

(I) Unsubstituted or substituted alkyl, wherein the alkyl may be substituted by one or more, 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-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, SO₂O-alkyl-aryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, n may have a value of 1,2 or 3, and the alkyl-, cycloalkyl-, heterocyclyl-, aryl-, heteroaryl-, alkyl-cycloalkyl-, alkyl-heterocyclyl-, alkyl-aryl-and alkyl-heteroaryl substituents may themselves in turn be substituted,

(II) unsubstituted or substituted aryl, whichWherein said aryl group may be substituted by one or more, 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-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、O-CH₂-CH₂-O-CH₂-CH₂-O-CH₂-CH₂-OH; OC (O) -alkyl, OC (O) -cycloalkyl, OC (O) -heterocyclyl, OC (O) -aryl, OC (O) -heteroaryl, OC (O) -alkyl-aryl, OC (O) -alkyl-heteroaryl, OC (O) -NH-alkyl, OSO₃H、OSO₂Alkyl, OSO₂Cycloalkyl, OSO₂-heterocyclic radical, OSO₂Aryl, OSO₂Heteroaryl, OSO₂Alkyl-aryl, OSO₂Alkyl-heteroaryl, OP (O) (OH)₂C (O) -alkyl, C (O) -aryl, C (O) -heteroaryl, O-CO₂Alkyl, 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)₂、C(O) N (cycloalkyl)₂C (O) N (aryl)₂C (O) N (heteroaryl)₂SO-alkyl, SO-aryl, SO₂Alkyl, SO₂-a heterocyclic group; SO (SO)₂Aryl, SO₂NH₂、SO₂NH-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl, SO₂NH-alkyl-aryl, SO₃H、SO₂O-alkyl, SO₂O-aryl, SO₂O-alkyl-aryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, n may have a value of 1,2 or 3, and the alkyl-, cycloalkyl-, heterocyclyl-, aryl-, heteroaryl-, alkyl-cycloalkyl-, alkyl-heterocyclyl-, alkyl-aryl-and alkyl-heteroaryl substituents may themselves in turn be substituted,

(III) unsubstituted or substituted heteroaryl, wherein said heteroaryl may be substituted by one or more, 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, OSO₂-alkyl-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)₂Si (alkyl) 3, SO₂NH₂、SO₂NH-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl, SO₂NH-alkyl-aryl, SO3H, SO₂O-alkyl, SO₂O-aryl, SO₂O-alkyl-aryl, alkyl, cycloalkyl, heterocyclyl, alkyl-cycloalkyl, alkyl-heterocyclyl, alkyl-aryl, alkyl-heteroaryl, aryl or heteroaryl, and the alkyl-, cycloalkyl-, heterocyclyl-, alkyl-cycloalkyl, alkyl-heterocyclyl, alkyl-aryl, alkyl-heteroaryl, aryl-and heteroaryl substituents may themselves in turn be substituted,

and R2:

(I) unsubstituted or substituted alkyl, wherein the alkyl may be substituted by one or more, 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-heteroaromaticsRadical, 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-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, SO₂O-alkyl-aryl, cycloalkyl or heterocyclyl,

(II) unsubstituted or substituted cycloalkyl, wherein the cycloalkyl may be substituted by one or more, identical 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) -arylNHC (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-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)₂Alkyl or aryl, or a pharmaceutically acceptable salt thereof,

their physiologically tolerated salts, their racemate forms, their pure enantiomeric and/or diastereomeric forms or the forms of mixtures of these enantiomers and/or diastereomers or their tautomeric forms;

it can be used for the preparation of a medicament for the treatment or prevention of a physiological and/or pathophysiological state in a mammal mediated by a signaling pathway selected from the group consisting of the PI3K-Akt signaling pathway and the ras-Raf-Mek-Erk signaling pathway.

In a preferred embodiment, compounds of the general formula (I) are prepared which can be used for the preparation of a medicament for the treatment or prophylaxis of a signal transduction pathway mediated by a signal transduction pathway selected from the group consisting of the PI 3K-t signal transduction pathway and the Raf-Mek-Erk signal transduction pathway in a mammal, wherein alkyl is 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, (-CH2CH = CH 2; -CH = CH-CH3, -C (= CH2) -CH3), propynyl (-CH 2-C.ident.CH, -C.ident.CH 3), butenyl, butynyl (butynyl), pentenyl, pentynyl (pentynyl), hexenyl, hexynyl (hexynyl), heptenyl, heptynyl (heptynyl), octynyl (Ak3-K-t signal transduction pathway and the Raf-Meras-Erk-signal transduction pathway Physiological and/or pathophysiological states of (a).

In a further preferred embodiment, compounds of the general formula (I) are prepared for the aforementioned use, wherein the heterocyclic group is selected from the group consisting of "tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl".

In a further preferred embodiment, compounds of the general formula (I) are prepared for the aforementioned use, wherein the heteroaryl group is selected from the group consisting of "pyrrolyl, furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 2, 3-naphthyridinyl, indolyl, indazolyl, indolizinyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, carbazolyl, phenazinyl, phenothiazinyl, acridinyl".

In a further preferred embodiment, compounds of the general formula (I) are prepared for the aforementioned applications, wherein alkyl is 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, vinyl (ethenyl), ethynyl, (-CH2CH = CH 2; -CH = CH-CH3, -C (= CH2) -CH3), propynyl (-CH 2-C.ident.CH, -C.ident.C-CH 3), butenyl, butynyl, pentenyl, pentynyl, hexenyl, hexynyl, heptynyl, octenyl, octynyl", and/or wherein the heterocyclyl is selected from the group consisting of "tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl", and/or the heteroaryl group is selected from the group consisting of "pyrrolyl, furanyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 2, 3-naphthyridinyl, indolyl, indazolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalyl, quinazolinyl, carbazolyl, phenazinyl, phenothiazinyl, acridinyl".

The object of the present invention is surprisingly achieved in another aspect by the preparation of a pyridopyrazine compound selected from the group consisting of:

the compound 1: 1-ethyl-3- {3- [1- (3,4, 5-trimethoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -urea

The compound 2, 1-ethyl-3- [3- (1-pyridin-2-ylmethyl-1H-pyrazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

The compound 3:1- {3- [1- (3-difluoromethoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-urea

The compound 4: 1-ethyl-3- {3- [1- (3-hydroxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -urea

Compound 5- [3- (1-benzo [1,3] dioxol-5-ylmethyl-1H-pyrazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-ethyl-thiourea

The compound 6: 1-ethyl-3- {3- [1- (4-trifluoromethoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -urea

Compound 7 1- {3- [1- (3, 4-dimethoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3- (2-methoxy-ethyl) -thiourea

Compound 8- {3- [1- (3-chloro-4-fluoro-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-urea

The compound 9: 1-ethyl-3- {3- [1- (3-phenyl-propyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -urea

Compound 10- {3- [1- (4-cyano-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-urea

The compound 11- {3- [1- (4-difluoromethoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-urea

Compound 12 1- {3- [1- (3, 5-dimethyl-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-thiourea

The compound 13 1-ethyl-3- {3- [1- (3-methyl-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -urea

Compound 14 1-ethyl-3- [3- (1-pyridin-4-ylmethyl-1H-pyrazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 15 1-ethyl-3- {3- [1- (4-methyl-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -urea

The compound 16: 1-ethyl-3- {3- [1- (4-phenyl-butyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -urea

Compound 17: 1-ethyl-3- {3- [1- (4-hydroxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -urea

Compound 18- {3- [1- (4-chloro-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-urea

Compound 19 1- {3- [1- (2, 5-dimethoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-thiourea

Compound 20 1-Ethyl-3- {3- [1- (4-methyl-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

The compound 21- {3- [1- (3-benzyloxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-thiourea

Compound 22- {3- [1- (4-bromo-3-methyl-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-urea

Compound 23-Ethyl-3- {3- [1- (4-methoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

Compound 24: 1-ethyl-3- [3- (1-pyridin-3-ylmethyl-1H-pyrazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 25 1-Ethyl-3- {3- [1- (3-fluoro-5-methyl-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

Compound 26 1- {3- [1- (2, 3-dimethoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-thiourea

The compound 27- {3- [1- (3-difluoromethoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-thiourea

Compound 28 1- {3- [1- (3, 4-dimethoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-thiourea

Compound 29, 1-ethyl-3- {3- [1- (2-fluoro-3-methoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

Compound 30: 1-ethyl-3- [3- (1-phenyl-1H-pyrazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 31- [3- (1-benzyl-1H-pyrazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3- (2-methoxy-ethyl) -thiourea

Compound 32- {3- [1- (3-methoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3- (2-methoxy-ethyl) -thiourea

Compound 33- {3- [1- (3-methoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-methoxymethyl-thiourea

Compound 34- [3- (1-benzyl-1H-pyrazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-methoxymethyl-thiourea

Compound 35- {3- [1- (3, 4-dimethoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-methoxymethyl-thiourea

Compound 36-Ethyl-3- {3- [1- (3-hydroxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

Compound 37 1- {3- [1- (3-dimethylamino-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-thiourea

Compound 38- {3- [1- (3-chloro-4-fluoro-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-thiourea

Compound 39 1- {3- [1- (3, 5-dimethoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-thiourea

Compound 40: 1-ethyl-3- {3- [1- (3-methoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

The compound 41: 1-ethyl-3- {3- [1- (3-methyl-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

Compound 42- {3- [1- (3, 4-dimethoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-urea

Compound 43 1-Ethyl-3- {3- [1- (2,3, 4-trimethoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

Compound 44-Ethyl-3- {3- [1- (3-phenyl-propyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

Compound 45- [3- (1-benzyl-1H-pyrazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-ethyl-thiourea

Compound 46 1-ethyl-3- {3- [1- (3,4, 5-trimethoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

Compound 47- {3- [1- (3-methoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3- (2,2, 2-trifluoro-ethyl) -thiourea

Compound 48 1-Ethyl-3- {3- [1- (2-fluoro-3-methyl-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

Compound 49 1- {3- [1- (3-ethoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-thiourea

Compound 501- {3- [1- (4-chloro-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-thiourea

Compound 51- {3- [1- (3-methyl-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3- (2,2, 2-trifluoro-ethyl) -thiourea

Compound 52 1-Ethyl-3- {3- [1- (2-methyl-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

Compound 53 1-ethyl-3- [3- (1-phenethyl-1H-pyrazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 54-Ethyl-3- {3- [1- (4-hydroxy-3-methoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -urea

Compound 55, 1-ethyl-3- {3- [1- (4-hydroxy-3-methoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

Compound 56 1-ethyl-3- {3- [1- (3-hydroxy-4-methoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -urea

Compound 57 1-Ethyl-3- {3- [1- (3-hydroxy-4-methoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

Compound 58 1- {3- [1- (3, 5-dichloro-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-urea

Compound 59 1- {3- [1- (3, 5-dichloro-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-thiourea

Compound 60 1- {3- [1- (3-amino-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-urea

Compound 61- {3- [1- (3-amino-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-thiourea

Compound 62-Ethyl-3- [3- (1-pyridazin-3-ylmethyl-1H-pyrazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 63, 1-Ethyl-3- [3- (1-pyridazin-3-ylmethyl-1H-pyrazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 64: 1-ethyl-3- {3- [1- (3-methanesulfonyl-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -urea

Compound 65 1-Ethyl-3- {3- [1- (3-methanesulfonyl-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

Compound 66 1-ethyl-3- (3- {1- [3- (2-methoxy-ethoxy) -benzyl ] -1H-pyrazol-4-yl } -pyrido [2,3-b ] pyrazin-6-yl) -urea

Compound 67, 1-Ethyl-3- (3- {1- [3- (2-methoxy-ethoxy) -benzyl ] -1H-pyrazol-4-yl } -pyrido [2,3-b ] pyrazin-6-yl) -thiourea

Compound 68: 1-ethyl-3- (3- {1- [3- (4-methyl-piperazin-1-ylmethyl) -benzyl ] -1H-pyrazol-4-yl } -pyrido [2,3-b ] pyrazin-6-yl) -urea

Compound 69 1-Ethyl-3- (3- {1- [3- (4-methyl-piperazin-1-ylmethyl) -benzyl ] -1H-pyrazol-4-yl } -pyrido [2,3-b ] pyrazin-6-yl) -thiourea

Compound 70 mono- (3- {4- [6- (3-ethyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-ylmethyl } -phenyl) phosphate

Compound 71 mono- (3- {4- [6- (3-ethyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-ylmethyl } -phenyl) phosphate

Compound 72- [3- (1-benzyl-1H-pyrazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3- (2-methoxy-ethyl) -urea

Compound 73:1- {3- [1- (3-methoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3- (2-methoxy-ethyl) -urea

Compound 74- {3- [1- (3, 4-dimethoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3- (2-methoxy-ethyl) -urea

Compound 75- [3- (1-benzyl-1H-pyrazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3- (2, 2-dimethoxy-ethyl) -thiourea

Compound 76 1- (2, 2-dimethoxy-ethyl) -3- {3- [1- (3-methoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

Compound 77 1- {3- [1- (3, 4-dimethoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3- (2, 2-dimethoxy-ethyl) -thiourea

Compound 78: 1-ethyl-3- (3- {1- [2- (2-methoxy-ethoxy) -ethyl ] -1H-pyrazol-4-yl } -pyrido [2,3-b ] pyrazin-6-yl) -urea

Compound 79 1-ethyl-3- (3- {1- [2- (2-methoxy-ethoxy) -ethyl ] -1H-pyrazol-4-yl } -pyrido [2,3-b ] pyrazin-6-yl) -thiourea

Compound 80-Ethyl-3- [3- (1- {2- [2- (2-methoxy-ethoxy) -ethoxy ] -ethyl } -1H-pyrazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 81-Ethyl-3- [3- (1- {2- [2- (2-methoxy-ethoxy) -ethoxy ] -ethyl } -1H-pyrazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 82 1-Ethyl-3- (3- {1- [2- (2-hydroxy-ethoxy) -ethyl ] -1H-pyrazol-4-yl } -pyrido [2,3-b ] pyrazin-6-yl) -urea

The compound 83 1-ethyl-3- (3- {1- [2- (2-hydroxy-ethoxy) -ethyl ] -1H-pyrazol-4-yl } -pyrido [2,3-b ] pyrazin-6-yl) -urea

Compound 84, 1- [3- (1-benzyl-1H- [1,2,3] triazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-ethyl-urea

Compound 85- [3- (1-benzyl-1H- [1,2,3] triazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-ethyl-urea

Compound 86-Ethyl-3- {3- [1- (3-methoxy-benzyl) -1H- [1,2,3] triazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -urea

The compound 87, 1-ethyl-3- {3- [1- (3-methoxy-benzyl) -1H- [1,2,3] triazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

Compound 88 1- {3- [1- (3, 4-dimethoxy-benzyl) -1H- [1,2,3] triazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-urea

Compound 89 1- {3- [1- (3, 4-dimethoxy-benzyl) -1H- [1,2,3] triazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-thiourea

Compound 190: 1-ethyl-3- {3- [1- (4-methoxy-cyclohexylmethyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

Compound 191-Ethyl-3- {3- [1- (5-methoxy-pentyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

Compound 192, 1-ethyl-3- [3- (2-methoxy-ethyl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 193- [6- (3-Ethyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -acetamide

Compound 210-Ethyl-3- {3- [1- (4-hydroxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

Compound 211, 1-ethyl-3- (3- {1- [ 4-methoxy-3- (2-methoxy-ethoxy) -benzyl ] -1H-pyrazol-4-yl } -pyrido [2,3-b ] pyrazin-6-yl) -urea

Compound 212- [6- (3-ethyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylic acid

Compound 213 1-ethyl-3- [3- (5-methyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 214 1-ethyl-3- [3- (5-methyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 215- [6- (3-Ethyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylic acid

Compound 216 (2- {4- [6- (3-ethyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -ethyl) -carbamic acid tert-butyl ester

Compound 217- {4- [6- (3-ethyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -propionamide

Compound 218, sodium 4- {4- [6- (3-ethyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-ylmethyl } -phenol

Compound 219 1-Ethyl-3- {3- [1- (4-methoxymethyloxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

Compound 220 (4- {4- [6- (3-ethyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-ylmethyl } -phenoxy) -acetic acid

Compound 221, 1-ethyl-3- (3- {1- [4- (2-hydroxy-ethoxy) -benzyl ] -1H-pyrazol-4-yl } -pyrido [2,3-b ] pyrazin-6-yl) -thiourea

Compound 222, 1-Ethyl-3- (3- {1- [4- (2-methoxy-ethoxy) -benzyl ] -1H-pyrazol-4-yl } -pyrido [2,3-b ] pyrazin-6-yl) -thiourea

Compound 223 1- (3- {1- [4- (2-dimethylamino-ethoxy) -benzyl ] -1H-pyrazol-4-yl } -pyrido [2,3-b ] pyrazin-6-yl) -3-ethyl-thiourea

Compound 224 1-Ethyl-3- (3- {1- [4- (2-morpholin-4-yl-ethoxy) -benzyl ] -1H-pyrazol-4-yl } -pyrido [2,3-b ] pyrazin-6-yl) -thiourea

Compound 225 1-Ethyl-3- [3- (1- {4- [2- (2-hydroxy-ethoxy) -ethoxy ] -benzyl } -1H-pyrazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 226 dimethylamino-acetic acid 4- {4- [6- (3-ethyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-ylmethyl } -phenyl ester

Compound 227, 2-amino-3-hydroxy-propionic acid 4- {4- [6- (3-ethyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-ylmethyl } -phenyl ester

Compound 228- {3- [1- (4-dimethylamino-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-thiourea

Compound 229: 1-ethyl-3- {3- [1- (4-methanesulfonyl-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

Compound 230, 1-allyl-3- [3- (5-methyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

The compound 231, 1-allyl-3- [3- (5-methyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 232, 1-allyl-3- [3- (4-methyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 233 1-allyl-3- [3- (4-methyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 234, {5- [6- (3-allyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophen-2-ylmethyl } -carbamic acid tert-butyl ester

Compound 235 {5- [6- (3-allyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophen-2-ylmethyl } -carbamic acid tert-butyl ester

Compound 236-allyl-3- [3- (5-hydroxymethyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 237, 1-allyl-3- [3- (5-hydroxymethyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 238- [6- (3-allyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylic acid

Compound 239- [6- (3-allyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylic acid

Compound 240, tert-butyl 4- [6- (3-allyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazole-1-carboxylate

Compound 241- [6- (3-allyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazole-1-carboxylic acid tert-butyl ester

Compound 242- {4- [6- (3-allyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -acetic acid ethyl ester

Compound 243 {4- [6- (3-allyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -acetic acid ethyl ester

Compound 244- {4- [6- (3-allyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -propionamide

Compound 245- {4- [6- (3-allyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -propionamide

Compound 246 (2- {4- [6- (3-allyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -ethyl) -carbamic acid tert-butyl ester

Compound 247 (2- {4- [6- (3-allyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -ethyl) -carbamic acid tert-butyl ester

Compound 248 methyl 5- [6- (3-allyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -2-methyl-furan-3-carboxylate

Compound 249 methyl 5- [6- (3-allyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -2-methyl-furan-3-carboxylate

Compound 250, 1-allyl-3- [3- (5-isopropyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 251, 1-allyl-3- [3- (5-isopropyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 252 1- [3- (5-ethoxymethoxymethyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-allyl-urea

Compound 253- [3- (5-ethoxymethoxymethyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-allyl-thiourea

Compound 254, 1-allyl-3- [3- (5-trimethylsilyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 255-allyl-3- [3- (5-trimethylsilyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 256, 1-allyl-3- [3- (5-methyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 257, 1-allyl-3- [3- (5-methyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 258 1-allyl-3- (3-thiazol-5-yl-pyrido [2,3-b ] pyrazin-6-yl) -urea

The compound 259, 1-allyl-3- (3-thiazol-5-yl-pyrido [2,3-b ] pyrazin-6-yl) -thiourea

Compound 260: 1-allyl-3- [3- (2-methyl-thiazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 261, 1-allyl-3- [3- (2-methyl-thiazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 262 1-allyl-3- [3- (1-isopropyl-1H-pyrazol-3-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 263 1-allyl-3- [3- (1-isopropyl-1H-pyrazol-3-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 264 1-allyl-3- [3- (5-hydroxymethyl-thiophen-3-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 265-1-allyl-3- [3- (5-hydroxymethyl-thiophen-3-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 266- [6- (3-allyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylic acid ethyl ester

Compound 267 ethyl 4- [6- (3-allyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylate

Compound 268- [6- (3-allyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylic acid

Compound 269, 4- [6- (3-allyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylic acid

Compound 270 1-allyl-3- [3- (4-methyl-thiazol-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 271, 1-allyl-3- [3- (4-methyl-thiazol-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 272, 1-allyl-3- (3-furan-3-yl-pyrido [2,3-b ] pyrazin-6-yl) -urea

Compound 273:1 allyl-3- (3-furan-3-yl-pyrido [2,3-b ] pyrazin-6-yl) -thiourea

Compound 274 1-allyl-3- [3- (1-methyl-1H-imidazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

The compound 275 1-allyl-3- [3- (1-methyl-1H-imidazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 276, 1-allyl-3- [3- (1-methyl-1H- [1,2,3] triazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 277, 1-allyl-3- [3- (1-methyl-1H- [1,2,3] triazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 278: 1-allyl-3- (3-isoxazol-4-yl-pyrido [2,3-b ] pyrazin-6-yl) -urea

Compound 279, 1-allyl-3- (3-isoxazol-4-yl-pyrido [2,3-b ] pyrazin-6-yl) -thiourea

Compound 280: 1-allyl-3- [3- (1H-imidazol-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

The compound 281, 1-allyl-3- [3- (1H-imidazol-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 282- [3- (6-chloro-pyridin-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-allyl-urea

Compound 283- [3- (6-chloro-pyridin-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-allyl-thiourea

Compound 284, 1-cyclopentyl-3- [3- (5-methyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 285: 1-cyclopentyl-3- [3- (5-methyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 286 1-cyclopentyl-3- [3- (4-methyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 287 Compound 220 1-cyclopentyl-3- [3- (4-methyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 288 {5- [6- (3-cyclopentyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophen-2-ylmethyl } -carbamic acid tert-butyl ester

Compound 289, {5- [6- (3-cyclopentyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophen-2-ylmethyl } -carbamic acid tert-butyl ester

Compound 290: 1-cyclopentyl-3- [3- (5-hydroxymethyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 291 1-cyclopentyl-3- [3- (5-hydroxymethyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 292, 5- [6- (3-cyclopentyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylic acid

Compound 293- [6- (3-cyclopentyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylic acid

Compound 294- [6- (3-cyclopentyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazole-1-carboxylic acid tert-butyl ester

Compound 295: {4- [6- (3-cyclopentyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -acetic acid ethyl ester

Compound 296: {4- [6- (3-cyclopentyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -acetic acid ethyl ester

Compound 297, 3- {4- [6- (3-cyclopentyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -propionamide

Compound 298:3- {4- [6- (3-cyclopentyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -propionamide

Compound 299 (2- {4- [6- (3-cyclopentyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -ethyl) -carbamic acid tert-butyl ester

Compound 300 methyl 2-methyl-5- [6- (3-cyclopentyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -furan-3-carboxylate

Compound 301 methyl 2-methyl-5- [6- (3-cyclopentyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -furan-3-carboxylate

The compound 302- [3- (5-isopropyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-cyclopentyl-urea

Compound 303- [3- (5-isopropyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-cyclopentyl-thiourea

Compound 304- [3- (5-ethoxymethoxymethyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-cyclopentyl-urea

Compound 305- [3- (5-ethoxymethoxymethyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-cyclopentyl-thiourea

Compound 306 1-cyclopentyl-3- [3- (5-trimethylsilyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 307, 1-cyclopentyl-3- [3- (5-trimethylsilyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 308 1-cyclopentyl-3- [3- (5-methyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 309 1-cyclopentyl-3- [3- (5-methyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 310 1-cyclopentyl-3- (3-thiazol-5-yl-pyrido [2,3-b ] pyrazin-6-yl) -urea

Compound 311, 1-cyclopentyl-3- (3-thiazol-5-yl-pyrido [2,3-b ] pyrazin-6-yl) -thiourea

Compound 312-cyclopentyl-3- [3- (2-methyl-thiazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 313 1-cyclopentyl-3- [3- (2-methyl-thiazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 314 1-cyclopentyl-3- [3- (1-isopropyl-1H-pyrazol-3-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 315 1-cyclopentyl-3- [3- (1-isopropyl-1H-pyrazol-3-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 316 1-cyclopentyl-3- [3- (5-hydroxymethyl-thiophen-3-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 317 1-cyclopentyl-3- [3- (5-hydroxymethyl-thiophen-3-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 318- [6- (3-cyclopentyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylic acid ethyl ester

Compound 319, 4- [6- (3-cyclopentyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylic acid ethyl ester

Compound 320- [6- (3-cyclopentyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylic acid

Compound 321- [6- (3-cyclopentyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylic acid

Compound 322, 1-cyclopentyl-3- [3- (4-methyl-thiazol-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 323 1-cyclopentyl-3- [3- (4-methyl-thiazol-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 324 1-cyclopentyl-3- (3-furan-3-yl-pyrido [2,3-b ] pyrazin-6-yl) -urea

Compound 325 1-cyclopentyl-3- (3-furan-3-yl-pyrido [2,3-b ] pyrazin-6-yl) -thiourea

Compound 326: 1-cyclopentyl-3- [3- (1-methyl-1H-imidazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 327: 1-cyclopentyl-3- [3- (1-methyl-1H-imidazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 328 1-cyclopentyl-3- [3- (1-methyl-1H- [1,2,3] triazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 329 1-cyclopentyl-3- [3- (1-methyl-1H- [1,2,3] triazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 330 1-cyclopentyl-3- (3-isoxazol-4-yl-pyrido [2,3-b ] pyrazin-6-yl) -urea

The compound 331: 1-cyclopentyl-3- (3-isoxazol-4-yl-pyrido [2,3-b ] pyrazin-6-yl) -thiourea

Compound 332 1-cyclopentyl-3- [3- (1H-imidazol-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 333-cyclopentyl-3- [3- (1H-imidazol-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 334, 1- [3- (6-chloro-pyridin-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-cyclopentyl-urea

Compound 335- [3- (6-chloro-pyridin-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-cyclopentyl-thiourea

Compound 336: 1-cyclopropyl-3- [3- (5-methyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 337: 1-cyclopropyl-3- [3- (5-methyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] thiourea

Compound 338 1-cyclopropyl-3- [3- (4-methyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 339: 1-cyclopropyl-3- [3- (4-methyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 340 {5- [6- (3-cyclopropyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophen-2-ylmethyl } -carbamic acid tert-butyl ester

Compound 341 {5- [6- (3-cyclopropyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophen-2-ylmethyl } -carbamic acid tert-butyl ester

Compound 342-cyclopropyl-3- [3- (5-hydroxymethyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 343, 1-cyclopropyl-3- [3- (5-hydroxymethyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 344- [6- (3-cyclopropyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylic acid

Compound 345- [6- (3-cyclopropyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylic acid

Compound 346 tert-butyl 4- [6- (3-cyclopropyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazole-1-carboxylate

Compound 347- [6- (3-cyclopropyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazole-1-carboxylic acid tert-butyl ester

Compound 348 {4- [6- (3-cyclopropyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -acetic acid ethyl ester

Compound 349 {4- [6- (3-cyclopropyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -acetic acid ethyl ester

Compound 350- {4- [6- (3-cyclopropyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -propionamide

Compound 351, 3- {4- [6- (3-cyclopropyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -propionamide

Compound 352 (2- {4- [6- (3-cyclopropyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -ethyl) -carbamic acid tert-butyl ester

Compound 353 (2- {4- [6- (3-cyclopropyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -ethyl) -carbamic acid tert-butyl ester

Compound 354 methyl 5- [6- (3-cyclopropyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -2-methyl-furan-3-carboxylate

Compound 355 methyl 5- [6- (3-cyclopropyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -2-methyl-furan-3-carboxylate

Compound 356, 1-cyclopropyl-3- [3- (5-isopropyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 357-cyclopropyl-3- [3- (5-isopropyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 358-cyclopropyl-3- [3- (5-ethoxymethoxymethyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 359 1-cyclopropyl-3- [3- (5-ethoxymethoxymethyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 360 1-cyclopropyl-3- [3- (5-trimethylsilyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 361, 1-cyclopropyl-3- [3- (5-trimethylsilyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 362-cyclopropyl-3- [3- (5-methyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 363 1-cyclopropyl-3- [3- (5-methyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 364: 1-cyclopropyl-3- (3-thiazol-5-yl-pyrido [2,3-b ] pyrazin-6-yl) -urea

Compound 365 1-cyclopropyl-3- (3-thiazol-5-yl-pyrido [2,3-b ] pyrazin-6-yl) -thiourea

Compound 366-cyclopropyl-3- [3- (2-methyl-thiazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 367: 1-cyclopropyl-3- [3- (2-methyl-thiazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 368-cyclopropyl-3- [3- (1-isopropyl-1H-pyrazol-3-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 369-cyclopropyl-3- [3- (1-isopropyl-1H-pyrazol-3-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 370 1-cyclopropyl-3- [3- (5-hydroxymethyl-thiophen-3-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 371 1-cyclopropyl-3- [3- (5-hydroxymethyl-thiophen-3-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 372- [6- (3-cyclopropyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylic acid ethyl ester

Compound 373- [6- (3-cyclopropyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylic acid ethyl ester

Compound 374- [6- (3-cyclopropyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylic acid

Compound 375- [6- (3-cyclopropyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylic acid

Compound 376-cyclopropyl-3- [3- (4-methyl-thiazol-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 377-cyclopropyl-3- [3- (4-methyl-thiazol-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 378, 1-Ethyl-3- (3-furan-3-yl-pyrido [2,3-b ] pyrazin-6-yl) -Urea

Compound 379-cyclopropyl-3- (3-furan-3-yl-pyrido [2,3-b ] pyrazin-6-yl) -thiourea

Compound 380: 1-cyclopropyl-3- [3- (1-methyl-1H-imidazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 381 1-cyclopropyl-3- [3- (1-methyl-1H-imidazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 382 1-cyclopropyl-3- [3- (1-methyl-1H- [1,2,3] triazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 383, 1-cyclopropyl-3- [3- (1-methyl-1H- [1,2,3] triazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 384 1-cyclopropyl-3- (3-isoxazol-4-yl-pyrido [2,3-b ] pyrazin-6-yl) -urea

Compound 385, 1-cyclopropyl-3- (3-isoxazol-4-yl-pyrido [2,3-b ] pyrazin-6-yl) -thiourea

Compound 386: 1-cyclopropyl-3- [3- (1H-imidazol-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 387 1-cyclopropyl-3- [3- (1H-imidazol-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 388- [3- (6-chloro-pyridin-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-cyclopropyl-urea

Compound 389- [3- (6-chloro-pyridin-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-cyclopropyl-thiourea

Compound 390-Ethyl-3- [3- (5-methyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -Urea

Compound 391-Ethyl-3- [3- (5-methyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] Thiourea

Compound 392, 1-ethyl-3- [3- (4-methyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 393 1-ethyl-3- [3- (4-methyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 394 [ 5- [6- (3-ethyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophen-2-ylmethyl ] -carbamic acid tert-butyl ester

Compound 395, {5- [6- (3-ethyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophen-2-ylmethyl } -carbamic acid tert-butyl ester

Compound 396:

1-ethyl-3- [3- (5-hydroxymethyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 397 1-Ethyl-3- [3- (5-hydroxymethyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -Thiourea

Compound 398, 5- [6- (3-ethyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylic acid

Compound 399:5- [6- (3-ethyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylic acid

Compound 400- [6- (3-ethyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazole-1-carboxylic acid tert-butyl ester

Compound 401, tert-butyl 4- [6- (3-ethyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazole-1-carboxylate

Compound 402 {4- [6- (3-ethyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -acetic acid ethyl ester

Compound 403 {4- [6- (3-ethyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -acetic acid ethyl ester

Compound 404, 3- {4- [6- (3-ethyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -propionamide

Compound 405 3- {4- [6- (3-ethyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -propionamide

Compound 406 (2- {4- [6- (3-ethyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -ethyl) -carbamic acid tert-butyl ester

Compound 407 (2- {4- [6- (3-ethyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -ethyl) -carbamic acid tert-butyl ester

Compound 408, methyl 5- [6- (3-ethyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -2-methyl-furan-3-carboxylate

Compound 409 methyl 5- [6- (3-ethyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -2-methyl-furan-3-carboxylate

Compound 410 1-ethyl-3- [3- (5-isopropyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

The compound 411, 1-ethyl-3- [3- (5-isopropyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 412- [3- (5-ethoxymethoxymethyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-ethyl-urea

Compound 413 1- [3- (5-ethoxymethoxymethyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-ethyl-thiourea

Compound 414-Ethyl-3- [3- (5-trimethylsilyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 415 1-Ethyl-3- [3- (5-trimethylsilyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 416 1-ethyl-3- [3- (5-methyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 417, 1-ethyl-3- [3- (5-methyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 418 1-ethyl-3- (3-thiazol-5-yl-pyrido [2,3-b ] pyrazin-6-yl) -urea

Compound 419: 1-ethyl-3- (3-thiazol-5-yl-pyrido [2,3-b ] pyrazin-6-yl) -thiourea

The compound 420, 1-ethyl-3- [3- (2-methyl-thiazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 421, 1-ethyl-3- [3- (2-methyl-thiazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 422 1-ethyl-3- [3- (1-isopropyl-1H-pyrazol-3-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 423-ethyl-3- [3- (1-isopropyl-1H-pyrazol-3-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 424-Ethyl-3- [3- (5-hydroxymethyl-thiophen-3-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 425: 1-ethyl-3- [3- (5-hydroxymethyl-thiophen-3-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 426- [6- (3-Ethyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylic acid ethyl ester

Compound 427, ethyl 4- [6- (3-ethyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylate

Compound 428- [6- (3-ethyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylic acid

Compound 429- [6- (3-Ethyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylic acid

Compound 430: 1-ethyl-3- [3- (4-methyl-thiazol-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 431 1-ethyl-3- [3- (4-methyl-thiazol-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 432 1-Ethyl-3- (3-furan-3-yl-pyrido [2,3-b ] pyrazin-6-yl) -Urea

Compound 433: 1-ethyl-3- (3-furan-3-yl-pyrido [2,3-b ] pyrazin-6-yl) -thiourea

Compound 434 1-ethyl-3- [3- (1-methyl-1H-imidazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 435: 1-ethyl-3- [3- (1-methyl-1H-imidazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 436, 1-ethyl-3- [3- (1-methyl-1H- [1,2,3] triazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 437 1-Ethyl-3- [3- (1-methyl-1H- [1,2,3] triazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -Thiourea

Compound 438 1-ethyl-3- (3-isoxazol-4-yl-pyrido [2,3-b ] pyrazin-6-yl) -urea

Compound 439 1-ethyl-3- (3-isoxazol-4-yl-pyrido [2,3-b ] pyrazin-6-yl) -thiourea

The compound 440 1-ethyl-3- [3- (1H-imidazol-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 441, 1-ethyl-3- [3- (1H-imidazol-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 442- [3- (6-chloro-pyridin-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-ethyl-urea

Compound 443, 1- [3- (6-chloro-pyridin-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-ethyl-thiourea

Compound 444- [3- (5-methyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-pentyl-urea

Compound 445- [3- (5-methyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-pentyl-thiourea

Compound 446- [3- (4-methyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-pentyl-urea

Compound 447- [3- (4-methyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-pentyl-thiourea

Compound 448 {5- [6- (3-pentyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophen-2-ylmethyl } -carbamic acid tert-butyl ester

Compound 449 {5- [6- (3-pentyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophen-2-ylmethyl } -carbamic acid tert-butyl ester

Compound 450- [3- (5-hydroxymethyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-pentyl-urea

Compound 451- [3- (5-hydroxymethyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-pentyl-thiourea

Compound 452 5- [6- (3-pentyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylic acid

Compound 453- [6- (3-pentyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylic acid

Compound 454, tert-butyl 4- [6- (3-pentyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazole-1-carboxylate

Compound 455- [6- (3-pentyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazole-1-carboxylic acid tert-butyl ester

Compound 456 {4- [6- (3-pentyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -acetic acid ethyl ester

Compound 457 {4- [6- (3-pentyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -acetic acid ethyl ester

Compound 458, 3- {4- [6- (3-pentyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -propionamide

Compound 459 3- {4- [6- (3-pentyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -propionamide

Compound 460 (2- {4- [6- (3-pentyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -ethyl) -carbamic acid tert-butyl ester

Compound 461 (2- {4- [6- (3-pentyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -ethyl) -carbamic acid tert-butyl ester

Compound 462 methyl 2-methyl-5- [6- (3-pentyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -furan-3-carboxylate

Compound 463 methyl 2-methyl-5- [6- (3-pentyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -furan-3-carboxylate

Compound 464-1- [3- (5-isopropyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-pentyl-urea

Compound 465 1- [3- (5-isopropyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-pentyl-thiourea

The compound 466- [3- (5-ethoxymethoxymethyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-pentyl-urea

The compound 467- [3- (5-ethoxymethoxymethyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-pentyl-thiourea

Compound 468 1-pentyl-3- [3- (5-trimethylsilyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 469 1-pentyl-3- [3- (5-trimethylsilyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 470: 1-pentyl-3- [3- (5-methyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 471, 1-pentyl-3- [3- (5-methyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 472-pentyl-3- (3-thiazol-5-yl-pyrido [2,3-b ] pyrazin-6-yl) -urea

Compound 473: 1-pentyl-3- (3-thiazol-5-yl-pyrido [2,3-b ] pyrazin-6-yl) -thiourea

Compound 474-pentyl-3- [3- (2-methyl-thiazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 475 1-pentyl-3- [3- (2-methyl-thiazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 476, 1-pentyl-3- [3- (1-isopropyl-1H-pyrazol-3-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 477-pentyl-3- [3- (1-isopropyl-1H-pyrazol-3-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 478: 1-pentyl-3- [3- (5-hydroxymethyl-thiophen-3-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

The compound 479: 1-pentyl-3- [3- (5-hydroxymethyl-thiophen-3-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 480- [6- (3-pentyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylic acid ethyl ester

Compound 481 ethyl 4- [6- (3-pentyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylate

Compound 482- [6- (3-pentyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylic acid

Compound 483- [6- (3-pentyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylic acid

Compound 484-pentyl-3- [3- (4-methyl-thiazol-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 485 1-pentyl-3- [3- (4-methyl-thiazol-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

The compound 486, 1-pentyl-3- (3-furan-3-yl-pyrido [2,3-b ] pyrazin-6-yl) -urea

Compound 487 1-pentyl-3- (3-furan-3-yl-pyrido [2,3-b ] pyrazin-6-yl) -thiourea

Compound 488: 1-pentyl-3- [3- (1-methyl-1H-imidazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 489 1-pentyl-3- [3- (1-methyl-1H-imidazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 490-pentyl-3- [3- (1-methyl-1H- [1,2,3] triazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

The compound 491, 1-pentyl-3- [3- (1-methyl-1H- [1,2,3] triazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 492-pentyl-3- (3-isoxazol-4-yl-pyrido [2,3-b ] pyrazin-6-yl) -urea

Compound 493 1-pentyl-3- (3-isoxazol-4-yl-pyrido [2,3-b ] pyrazin-6-yl) -thiourea

Compound 494, 1-pentyl-3- [3- (1H-imidazol-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 495: 1-pentyl-3- [3- (1H-imidazol-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

The compound 496- [3- (6-chloro-pyridin-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-pentyl-urea

The compound 497- [3- (6-chloro-pyridin-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-pentyl-thiourea

Compound 498, 1-cyclopropylmethyl-3- [3- (5-methyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 499-cyclopropylmethyl-3- [3- (5-methyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] thiourea

Compound 500 1-cyclopropylmethyl-3- [3- (4-methyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 501 1-cyclopropylmethyl-3- [3- (4-methyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 502 {5- [6- (3-cyclopropylmethyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophen-2-ylmethyl } -carbamic acid tert-butyl ester

Compound 503- [6- (3-Cyclopropylmethyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophen-2-ylmethyl } -carbamic acid tert-butyl ester

Compound 504 1-cyclopropylmethyl-3- [3- (5-hydroxymethyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 505 1-cyclopropylmethyl-3- [3- (5-hydroxymethyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 506- [6- (3-cyclopropylmethyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylic acid

Compound 507- [6- (3-cyclopropylmethyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylic acid

Compound 508, 4- [6- (3-cyclopropylmethyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazole-1-carboxylic acid tert-butyl ester

Compound 509- [6- (3-cyclopropylmethyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazole-1-carboxylic acid tert-butyl ester

Compound 510 {4- [6- (3-cyclopropylmethyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -acetic acid ethyl ester

Compound 511- {4- [6- (3-Cyclopropylmethyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -acetic acid ethyl ester

Compound 512- {4- [6- (3-cyclopropylmethyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -propionamide

Compound 513 3- {4- [6- (3-cyclopropylmethyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -propionamide

Compound 514 (2- {4- [6- (3-cyclopropylmethyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -ethyl) -carbamic acid tert-butyl ester

Compound 515 (2- {4- [6- (3-cyclopropylmethyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -ethyl) -carbamic acid tert-butyl ester

Compound 516 methyl 5- [6- (3-cyclopropylmethyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -2-methyl-furan-3-carboxylate

Compound 517 methyl 5- [6- (3-cyclopropylmethyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -2-methyl-furan-3-carboxylate

Compound 518 1-cyclopropylmethyl-3- [3- (5-isopropyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 519, 1-cyclopropylmethyl-3- [3- (5-isopropyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 520- [3- (5-ethoxymethoxymethyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-cyclopropylmethyl-urea

Compound 521- [3- (5-ethoxymethoxymethyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-cyclopropylmethyl-thiourea

Compound 522 1-cyclopropylmethyl-3- [3- (5-trimethylsilyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 523 1-Cyclopropylmethyl-3- [3- (5-trimethylsilyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 524, 1-cyclopropylmethyl-3- [3- (5-methyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 525 1-cyclopropylmethyl-3- [3- (5-methyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 526, 1-cyclopropylmethyl-3- (3-thiazol-5-yl-pyrido [2,3-b ] pyrazin-6-yl) -urea

Compound 527, 1-cyclopropylmethyl-3- (3-thiazol-5-yl-pyrido [2,3-b ] pyrazin-6-yl) -thiourea

Compound 528: 1-cyclopropylmethyl-3- [3- (2-methyl-thiazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 529 1-cyclopropylmethyl-3- [3- (2-methyl-thiazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 530, 1-cyclopropylmethyl-3- [3- (1-isopropyl-1H-pyrazol-3-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 531-cyclopropylmethyl-3- [3- (1-isopropyl-1H-pyrazol-3-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 532-cyclopropylmethyl-3- [3- (5-hydroxymethyl-thiophen-3-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 533: 1-cyclopropylmethyl-3- [3- (5-hydroxymethyl-thiophen-3-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 534- [6- (3-Cyclopropylmethyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylic acid ethyl ester

Compound 535 ethyl 4- [6- (3-cyclopropylmethyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylate

Compound 536- [6- (3-cyclopropylmethyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylic acid

Compound 537:4- [6- (3-cyclopropylmethyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylic acid

Compound 538 1-cyclopropylmethyl-3- [3- (4-methyl-thiazol-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 539 1-cyclopropylmethyl-3- [3- (4-methyl-thiazol-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 540, 1-cyclopropylmethyl-3- (3-furan-3-yl-pyrido [2,3-b ] pyrazin-6-yl) -urea

Compound 541 1-cyclopropylmethyl-3- (3-furan-3-yl-pyrido [2,3-b ] pyrazin-6-yl) -thiourea

Compound 542: 1-cyclopropylmethyl-3- [3- (1-methyl-1H-imidazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

The compound 543, 1-cyclopropylmethyl-3- [3- (1-methyl-1H-imidazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 544 1-cyclopropylmethyl-3- [3- (1-methyl-1H- [1,2,3] triazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 545 1-cyclopropylmethyl-3- [3- (1-methyl-1H- [1,2,3] triazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 546: 1-cyclopropylmethyl-3- (3-isoxazol-4-yl-pyrido [2,3-b ] pyrazin-6-yl) -urea

Compound 547 1-cyclopropylmethyl-3- (3-isoxazol-4-yl-pyrido [2,3-b ] pyrazin-6-yl) -thiourea

Compound 548: 1-cyclopropylmethyl-3- [3- (1H-imidazol-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 549 1-cyclopropylmethyl-3- [3- (1H-imidazol-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 550- [3- (6-chloro-pyridin-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-cyclopropylmethyl-urea

Compound 551- [3- (6-chloro-pyridin-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-cyclopropylmethyl-thiourea

Compound 552 1-allyl-3- {3- [4- (2-methoxy-ethoxy) phenyl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

The compound 553, 1-allyl-3- {3- [4- (2-dimethylamino-ethoxy) -phenyl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

Compound 554: 1-allyl-3- {3- [4- (2-morpholin-4-yl-ethoxy) -phenyl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

Compound 555 Ethyl-carbamic acid 4- [6- (3-allyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -phenyl ester

Compound 556 methanesulfonic acid 4- [6- (3-allyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -phenyl ester

Compound 557-allyl-3- {3- [4- ((2S,3R,4S,5S,6R) -3,4, 5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy) -phenyl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

Compound 558 1-allyl-3- {3- [1- (3-phenyl-propyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

The compound 559: 1-allyl-3- {3- [1- (3-methanesulfonyl-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

Compound 560 1-allyl-3- {3- [1- (3-hydroxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

Compound 561, 1-allyl-3- [3- (1-propyl-1H-pyrazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 562 1-allyl-3- [3- (1H-pyrazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 563 1-allyl-3- [3- (1-benzyl-1H-pyrazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 564, 1-allyl-3- {3- [1- (4-methoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

Compound 565, 1-allyl-3- {3- [1- (3, 4-dimethoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } thiourea

Compound 566 1-allyl-3- [3- (1-benzo [1,3] dioxol-5-ylmethyl-1H-pyrazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 567 1-allyl-3- {3- [1- (4-fluoro-3-methoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

Compound 568 1-allyl-3- {3- [1- (3-difluoromethoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

The compound 569-allyl-3- [3- (1- {2- [2- (2-methoxy-ethoxy) -ethoxy ] -ethyl } -1H-pyrazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 570, 1-allyl-3- [3- (3, 4-dimethoxy-phenyl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 571, 1-allyl-3- [3- (3-hydroxy-4-methoxy-phenyl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 572 1-allyl-3- [3- (3, 5-dichloro-4-hydroxy-phenyl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 573-allyl-3- [3- (4-amino-phenyl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 574 1-allyl-3- [3- (3-chloro-4-hydroxy-phenyl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 575, 1-allyl-3- [3- (3-chloro-4-hydroxy-5-methoxy-phenyl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 576-allyl-3- [3- (2, 3-dihydro-benzofuran-5-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 577 mono- {4- [6- (3-allyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -phenyl } phosphate

Compound 578, 4- [6- (3-allyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -phenyl 2, 2-dimethyl-propionate

The compound 579, 1-allyl-3- [3- (4- {2- [2- (2-hydroxy-ethoxy) -ethoxy ] -ethoxy } -phenyl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

Compound 580-allyl-3- {3- [1- (3-methoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

Compound 581, tert-butyl 4- [6- (3-cyclopentyl-thioureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazole-1-carboxylate

Compound 582 (2- {4- [6- (3-cyclopentyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -ethyl) -carbamic acid tert-butyl ester

To avoid ambiguity, a specific unambiguous compound should be unambiguously defined by a chemical structure when the chemical structure and the chemical name of the compound shown above are erroneously not matched to each other.

The compounds of the aforementioned general formula and preferred embodiments having the general formula (I) and the specifically specified pyridopyrazines 1-89, 190-193, 210-582 are hereinafter collectively referred to as "compounds of the invention".

The expressions and terms indicated for explaining the compounds of the invention having the general formula (I), the preferred embodiments and the compounds 1 to 89, 190-193, 210-582 have essentially the following meanings, unless otherwise stated in the specification and the claims:

in the context of the present invention, the expression "alkyl" includes acyclic saturated or unsaturated hydrocarbon radicals, which may be branched or linearAnd having 1 to 8 carbon atoms, i.e. C_1-8-alkanyl radical, C_2-8Alkenyl and C_2-8-alkynyl. Alkenyl has at least one C-C double bond and alkynyl has at least one C-C triple bond. Alkynyl groups may additionally have at least one C-C double bond. Preferred alkyl groups are methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 2-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, ethenyl (ethenyl), ethynyl, propenyl (-CH), propenyl (-CH (-CO-O-H), tert-butyl, n-pentyl, isopentyl, neopentyl₂CH=CH₂；-CH=CH-CH₃、-C(=CH₂)-CH₃) Propynyl (-CH)₂-C≡CH、-C≡C-CH₃) Butenyl, butynyl, pentenyl, pentynyl, hexenyl, hexynyl, heptenyl, heptynyl, octenyl, octadienyl, and octynyl.

For the purposes of the present invention, the expression "cycloalkyl" means a cyclic, non-aromatic hydrocarbon having from 1 to 3 rings, having from 3 to 20, preferably from 3 to 12 carbon atoms, which may be saturated or unsaturated, more preferably is (C)₃-C₈) A cycloalkyl group. The cycloalkyl group can be part of a bicyclic or polycyclic ring system wherein, for example, the cycloalkyl group is fused to an aryl, heteroaryl, or heterocyclyl group as defined herein through any possible and desired ring member. The bonding to the compounds of the general formula (I) can be effected via any of the possible ring members of the cycloalkyl group. Preferred cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclohexenyl, cyclopentenyl and cyclooctadienyl.

The expression "heterocyclyl" denotes a 3-to 14-membered, preferably 3-, 4-, 5-, 6-, 7-or 8-membered, cyclic organic group comprising at least 1 heteroatom, optionally 2,3,4 or 5 heteroatoms, especially nitrogen, oxygen and/or sulfur atoms, which heteroatoms are identical or different, and which cyclic group is saturated or unsaturated, but not aromatic. Heterocyclyl may also be part of a bicyclic or polycyclic ring system in which, for example, the heterocyclyl is fused to an aryl, heteroaryl or cycloalkyl group as defined herein through any possible and desired ring member. The bonding to the compounds of the general formula (I) can be effected via any of the possible ring members of the heterocyclic group. Preferred heterocyclyl groups are tetrahydrofuranyl, pyrrolidinyl, imidazolidinyl, thiazolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiapyrrolidinyl, oxapiperazinyl, oxapiperidinyl and oxadiazolyl.

In the context of the present invention, the expression "aryl" means an aromatic hydrocarbon having from 3 to 14 carbon atoms, preferably from 5 to 14 carbon atoms, more preferably from 6 to 14 carbon atoms. Aryl may also be part of a bicyclic or polycyclic ring system, wherein, for example, aryl is fused to a heterocyclyl, heteroaryl or cycloalkyl group as defined herein, for example to tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, thiazolidine, tetrahydropyran, dihydropyran, piperidine, furan, thiophene, imidazole, thiazole, oxazole, isoxazole, by any possible and desired ring member. The bonding to the compounds of the general formula (I) can be effected via any of the possible ring members of the aryl group. Preferred aryl groups are phenyl, biphenyl, naphthyl and anthracenyl, but indanyl, indenyl or 1,2,3, 4-tetrahydronaphthyl are likewise preferred.

The expression "heteroaryl" denotes a 5-, 6-or 7-membered cyclic aromatic radical which comprises at least 1 heteroatom, which may, where appropriate, also comprise 2,3,4 or 5 heteroatoms, in particular nitrogen, oxygen and/or sulfur, which heteroatoms are identical or different. The number of nitrogen atoms is preferably 0 to 3, and the number of oxygen atoms and sulfur atoms is preferably 0 or 1. Heteroaryl may also be part of a bicyclic or polycyclic ring system, wherein, for example, heteroaryl is fused to a heterocyclyl, aryl or cycloalkyl group as defined herein through any possible and desired ring member. The bonding to the compounds of the general formula (I) can be effected via any of the possible ring members of the heteroaryl group. Preferred heteroaryl groups are pyrrolyl, furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazole, tetrazole, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, 2, 3-naphthyridinyl, indolyl, indazolyl, indolizinyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, carbazolyl, phenazinyl, phenoxazinyl, phenothiazinyl and acridinyl.

For the purposes of the present invention, the expressions "alkyl-cycloalkyl", "cycloalkylalkyl", "alkyl-heterocyclyl", "heterocyclylalkyl", "alkyl-aryl", "arylalkyl", "alkyl-heteroaryl" and "heteroarylalkyl" mean that alkyl, cycloalkyl, heterocyclyl (heterocycl), aryl and heteroaryl are each as defined herein, and that said cycloalkyl, heterocyclyl, aryl and heteroaryl are each defined by alkyl, preferably C₁-C₈-alkyl, more preferably C₁-C₅-alkyl groups are bound to compounds of general formula (I).

The terms substituted in relation to "alkyl", "cycloalkyl", "heterocyclyl", "aryl", "heteroaryl", "alkyl-cycloalkyl", "alkyl-heterocyclyl", "alkyl-aryl" and "alkyl-heteroaryl" are understood in the sense of the present invention to be that one or more hydrogen radicals are substituted by: F. cl, Br, I, CN, CF₃、NH₂NH-alkyl, NH-aryl, N (alkyl)₂、NO₂SH, S-alkyl, SO₂Alkyl, OH, OCHF₂O-CH 2-Oalkyl, O-CH2-OMe, O-alkyl, OCF₃、OMe、OEt、O-CH2-CH2-NMe2、O-CH2-CH2-OMe；O-CH2-CH2-OH、O-CH₂-CH₂-O-CH₂-CH₂-OH、O-CH₂-CH₂-O-CH₂-CH₂-OMe; o-alkyl-aryl, O-aryl, -O-CH-O-; OC (O) -alkyl, OSO₃H、OP(O)(OH)₂NC (O) O-alkyl, CHO, CO₂H. C (O) O-alkyl, C (O) NH2, SO₃H. Alkyl, alkyl-OH, heterocyclyl or 4-methyl-piperazin-1-ylmethyl, unless explicitly defined above in the description and in the claims. The substituents may be the same or different, and the substitution may occur at any arbitrary and possible position of the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups.

In the context of the present invention, the expression "halogen" includes the halogen atoms fluorine, chlorine, bromine and iodine.

Polysubstituted radicals are to be understood as meaning those which are polysubstituted, for example disubstituted, trisubstituted, for example, as in CF, on different or identical atoms₃、-CH₂CF₃In which case they are trisubstituted on the same C atom, or as in-CH (OH) -CH = CH-CHCl₂In the case of (A) is trisubstituted in different positions. The polysubstitution may be carried out by the same or different substituents.

As long as the compounds of the invention have at least one asymmetric center, they may be present in the form of their racemates, in the form of the pure enantiomers and/or diastereomers or in the form of mixtures of these enantiomers and/or diastereomers. The mixture may be present in any mixing ratio of the stereoisomers.

Thus, for example, the compounds of the invention which have one or more chiral centers and which are present as racemates thereof can be separated into their optical isomers, i.e. enantiomers or diastereomers, by methods known per se. The separation may be performed by: the residue is separated by column separation with a chiral phase or by recrystallization from an optically active solvent or by using an optically active acid or base or by derivatization with an optically active reagent (e.g., an optically active alcohol).

The compounds of the invention may exist as "pure" E or Z isomers in the form of their double bond isomers, or as mixtures of these double bond isomers.

The compounds of the invention may exist in tautomeric forms whenever possible.

If they have sufficiently basic groups, for example primary, secondary or tertiary amines, inorganic and organic acids can be used to convert the compounds of the invention into their physiologically compatible salts. Pharmaceutically acceptable salts of the compounds of the present invention are formed with the following acids: hydrochloric acid, bromic 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, methylenepamoic acid (embonic acid), mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, or aspartic acid. Salts formed include hydrochloride, hydrobromide, sulfate, bisulfate, phosphate, methanesulfonate, toluenesulfonate, carbonate, bicarbonate, formate (formiate), acetate, trifluoromethanesulfonate, sulfoacetate (sulfoacetate), oxalate, malonate, maleate, succinate, tartrate, malate, methylenepamoate (embonate), mandelate, fumarate, lactate, citrate, glutamine, aspartate and the like. The stoichiometry of the salt of the compound of the invention formed may be an integer or non-integer multiple of 1.

If they contain sufficiently acidic groups, for example carboxyl or phenolic groups, inorganic and organic bases can be used, for example, to convert the compounds of the invention into their physiologically compatible salts. Possible inorganic bases are, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, and possible organic bases are ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dibenzylethylenediamine and lysine. The stoichiometry of the salt of the compound of the invention formed may be an integer or non-integer multiple of 1.

Also preferred are solvates, and in particular hydrates, of the compounds of the invention, which may be obtained, for example, by crystallization from a solvent or from an aqueous solution. Herein, one, two, three or any number of solvent or water molecules may be combined with the compounds of the present invention to form solvates and hydrates.

It is known that chemicals form solids that exist in different ordered states, which are referred to as polymorphic forms or variants. The various modifications of polymorphic substances may vary widely in their physical properties. The compounds of the invention may exist in a variety of polymorphic forms, in which case certain variants may be metastable.

The compounds of the invention may likewise be present in any prodrug form, for example esters, carbonates, carbamates, ureas, amides or phosphates, in which the actual biologically active form is released only by catabolism.

It is also known that chemical substances are converted in vivo into metabolites, which optionally may also induce the desired biological effect, possibly even in a more distinct form.

The corresponding prodrugs and metabolites of the compounds of the present invention should also be considered to be within the scope of the present invention.

It has now surprisingly and advantageously been established that the compounds of the invention can simultaneously act on or have a modulating or inhibiting effect on one or more signalling pathways or enzymes. In this context, it has been found that the compounds of the invention can exert or have a modulating or inhibiting effect with high selectivity.

Such simultaneous, e.g., dual, modulation or inhibition of one or more signaling pathways, e.g., the ras-Raf-Mek-Erk signaling pathway and the PI3K-Akt signaling pathway, is advantageous over having only a single modulation or inhibition of the signaling pathway, as it may lead to synergistic therapeutic effects, e.g., enhanced apoptosis and more rapid and effective tumor regression.

This surprisingly advantageous effect of the compounds of the invention makes it possible to seek a variety of therapeutic approaches in physiological and/or pathophysiological states or clinical phenomena which are sensitive to or mediated by the treatment or modulation of one or more signaling pathways.

It was also surprisingly and advantageously determined that: the compounds of the invention may also act doubly selective or have modulating or inhibiting effects on the PI3K-Akt signaling pathway and the ras-Raf-Mek-Erk signaling pathway or their enzymes, and the multiple mechanisms of action and methods of treatment described above may also be achieved using such signaling pathways or enzymes, comprising a pharmacologically active amount of at least one compound selected from the group consisting of: "compounds 1,2,3,4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 190, 191, 192, 193, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 224, 223, 226, 223, 230, 235, 240, 233, 240, 233, 237, 235, 240, 237, 235, 240, 237, 244. 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 369308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 351, 349, 350, 358, 354, 355, 364, 363, 368, 363, 368, 366, 362, 363, 366, 362, 363, 360, 362, 363, 360, 150, 351, 357, 351, 357, 351, 373. 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 464, 466, 462, 467, 495, 469, 470, 475, 476, 474, 477, 486, 483, 480, 481, 495, 493, 501, 53, 498, and 498, 430, 473, 498, and 498, 502. 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, and/or compound 582 "and optionally comprising pharmaceutically compatible excipients and/or adjuvants are encompassed by the present invention.

According to the invention, the term "modulation" is understood as meaning "activation, partial activation, inhibition, partial inhibition". In such a case, one of ordinary skill in the art would be able to measure and determine the activation, partial activation, inhibition, partial inhibition by conventional measurement and determination methods. Thus, partial activation can be determined and determined relative to full activation; likewise, partial inhibition can be determined and determined relative to complete inhibition.

According to the invention, the term "inhibition and/or blocking" is understood as meaning "partial or complete inhibition and/or blocking". In such cases, one of ordinary skill in the art would be able to determine and ascertain such inhibition and/or retardation by conventional measurement and determination methods. Thus, for example, partial inhibition and/or blocking may be determined and determined relative to complete inhibition and/or blocking.

In the context of the present invention, the terms "modulate" and "inhibit and/or block" in relation to "enzyme" and/or "kinase" relate both to inactive (enzymatically inactive) and/or active (enzymatically active) forms of the respective enzyme and/or kinase. Within the scope of the present invention, this means that the compounds according to the invention may have a modulating effect on the inactive form, the active form or both forms of the enzyme and/or kinase.

In a further aspect, the object of the present invention is surprisingly achieved by the preparation of the compounds of the present invention which can be used for the preparation of a medicament for the treatment or prophylaxis of physiological and/or pathophysiological states in mammals, wherein the treatment or prophylaxis is effected by modulation of one or more signaling pathways selected from the group consisting of the "ras-Raf-Mek-Erk signaling pathway" and the "PI 3K-Akt signaling pathway".

In a further aspect, the object of the present invention is surprisingly achieved by the preparation of the compounds of the present invention, which can be used for the preparation of a medicament for the treatment or prevention of physiological and/or pathophysiological states mediated by the PI3K-Akt signaling pathway in a mammal.

In a further aspect, the object of the present invention is surprisingly achieved by the preparation of the compounds of the invention which can be used for the preparation of a medicament for the treatment or prophylaxis of physiological and/or pathophysiological states in mammals, wherein the treatment or prophylaxis is achieved by modulation of the PI3K-Akt signaling pathway and the ras-Raf-Mek-Erk signaling pathway.

In a further preferred embodiment, the compounds of the invention are prepared for the use as described above, wherein the modulation of the PI3K-Akt signaling pathway is effected by the modulation of one or more enzymes selected from the group consisting of "lipid kinases", and preferably from the group consisting of "PI 3K, PI3K α, PI3K β, PI3K γ, PI3K δ, PI3K-C2 α, PI3K-C2 β, PI3K-Vps34 p".

In a preferred embodiment, the compounds of the invention are prepared for the uses described above, wherein the modulation of the ras-Raf-Mek-Erk signaling pathway is effected by modulation of one or more enzymes selected from the group consisting of "tyrosine kinase, serine/threonine kinase, receptor tyrosine kinase, cytoplasmic serine/threonine kinase", and preferably selected from the group consisting of "Erk, Erk1, Erk 2".

In a further aspect, the object of the present invention is surprisingly achieved by the preparation of the compounds according to the invention according to the above-described aspects, preferred embodiments and uses, which compounds can be used for the preparation of a medicament for the treatment or prophylaxis of physiological and/or pathophysiological states in mammals, wherein the treatment or prophylaxis is effected by the modulation of one or more enzymes.

In a further preferred embodiment, the compounds of the invention are prepared for the use as described above, wherein at least one enzyme is selected from the group consisting of "Erk, Erk1, Erk 2" and at least one enzyme is selected from the group consisting of "PI 3K, PI3K α, PI3K β, PI3K γ, PI3K δ, PI3K-C2 α, PI3K-C2 β, PI3K-Vps34 p" in the treatment or prevention of a disease caused by modulation by two or more enzymes.

In a further preferred embodiment, the compounds of the invention are prepared for the use as described above, wherein the modulation is inhibition.

The compounds of the invention can be administered within the scope of the invention to all known mammals, in particular humans, for therapy and/or prophylaxis.

In another preferred embodiment, the compounds of the invention are prepared for the uses described above, wherein the mammal is selected from the group consisting of "human, domestic animal, livestock, pet, beef cattle, dairy cow, sheep, pig, goat, horse, pony, donkey mule (hinny), mule, hare, rabbit, cat, dog, guinea pig, hamster, rat, mouse", and preferably is human.

The compounds of the invention can be used within the scope of the invention for the treatment and/or prophylaxis of all known physiological and/or pathophysiological states.

In a preferred embodiment, the compounds of the invention are prepared for the uses described above, wherein the physiological and/or pathophysiological state is selected from the group consisting of "malignant tumors, benign tumors, inflammatory diseases, inflammation, pain, rheumatic diseases, arthritic diseases, HIV infections, neurological or neurodegenerative diseases, rheumatism, arthritis, AIDS, ARC (AIDS-related syndrome), Kaposi sarcoma, tumors originating from the brain and/or the nervous system and/or meninges, dementia, Alzheimer's disease, hyperproliferative diseases, psoriasis, endometriosis, scar formation, Benign Prostatic Hyperplasia (BPH), diseases of the immune system, autoimmune diseases, immunodeficiency diseases, colon tumors, gastric tumors, intestinal tumors, lung tumors, pancreatic tumors, ovarian tumors, prostate tumors, leukemias, Melanoma, liver tumor, kidney tumor, head tumor, larynx tumor, glioma, breast tumor, uterus cancer, endometrial cancer, cervical carcinoma of the uterus (cervico-uterine carcinosoma), brain tumor, acanthoma glandulifera cancer, bladder cancer, stomach tumor, colorectal tumor, esophageal cancer, gynecological tumor (gynecomastia tumor), ovarian tumor, thyroid cancer, lymphoma, chronic leukemia, acute leukemia, restenosis, diabetes, diabetic nephropathy, fibrotic disease, cystic fibrosis, malignant nephrosclerosis, thrombotic microangiopathy syndrome (thrombotic microangiopathy syndrome), organ transplant rejection, glomerulopathy, metabolic disease, solid/fixed tumor, rheumatoid arthritis, diabetic retinopathy, asthma, allergy, allergic disease, chronic obstructive pulmonary disease, inflammatory bowel disease, fibrosis, atherosclerosis, chronic obstructive pulmonary disease, chronic inflammatory bowel, Heart disease, cardiovascular disease, myocardial disease, vascular disease, angiogenic diseases (diseases), kidney disease, rhinitis, graves' disease, focal ischemia, heart failure, ischemia, cardiac hypertrophy, renal failure, myocardial cell dysfunction, hypertension, vasoconstriction, stroke, anaphylactic shock, platelet aggregation, skeletal muscle atrophy, obesity, overweight, glucose homeostasis (glucose homeostasis), congestive heart failure, angina, heart attack, heart infarction, hyperglycemia, hypoglycemia, hypertensive disease ".

In another aspect of the present invention, the object of the present invention is surprisingly achieved by the preparation of compounds according to the above-described aspects, preferred embodiments and uses, which compounds can be used for the preparation of a medicament for the treatment or prophylaxis of physiological and/or pathophysiological states in a mammal, wherein the medicament comprises at least one further pharmacologically active substance.

In another aspect of the present invention, the object of the present invention is surprisingly achieved by the preparation of compounds according to the above-described aspects, preferred embodiments and uses, which compounds can be used for the preparation of a medicament for the treatment or prophylaxis of physiological and/or pathophysiological states in mammals, wherein the medicament is administered before and/or during and/or after treatment with at least one further pharmacologically active substance.

In another aspect of the present invention, the object of the present invention is surprisingly achieved by the preparation of a compound according to the above-described aspects, preferred embodiments and uses, which compound can be used for the preparation of a medicament for the treatment or prophylaxis of physiological and/or pathophysiological states in a mammal, wherein the medicament is administered before and/or during and/or after treatment with radiotherapy and/or surgery.

The compounds according to the invention can be administered within the scope of the invention together with all known pharmacologically active substances in the manner of the combination therapy described.

In a preferred embodiment, the compounds of the invention are prepared for the use as described above, wherein the additional pharmacologically active substance is selected from the group consisting of "DNA topoisomerase I and/or II inhibitors, DNA intercalators, alkylating agents, microtubule destabilizers (microtubuli destabilizers), hormone and/or growth factor receptor agonists and/or antagonists, antibodies against growth factors and their receptors, kinase inhibitors, alkyl phospholipids, antimetabolites".

In a preferred embodiment, the compounds of the invention are prepared for the uses described above, wherein the additional pharmacologically active substance is selected from the group consisting of "asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, levo-asparaginase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycin), epirubicin, etoposide, 5-fluorouracil, hexamethylcyanamide, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifene, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine, vindesine, L-asparaginase, Azathioprine, 5-azacytidine, cladribine, busulfan, diethylstilbestrol, 2' -difluorodeoxycytidine, docetaxel, erythrohydroxynonyladenine (erythrohydroxyxynyladenine), ethinylestradiol, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluoroxymethyltestosterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, oxaliplatin, pentostatin, N-phosphonoacetyl-L-aspartic acid (PALA), plicamycin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, vinorelbine (vinorelbin), epothilone, gemcitabine, taxotere, NU, CCNU, DTIC, 5-fluorouracil, herceptin, avastin, Erbitux, sorafenib, gleevec, iressa, tarceva, rapamycin, perifosine, miltefosine, edelfosine, actinomycin D ".

Oral administration can be carried out, for example, as tablets, capsules, gel capsules (gel capsules), dragees, granules or powders in solid form, but also in the form of drinkable solutions. For oral administration, the novel compounds of the invention as defined above may be combined with known physiologically compatible adjuvants and excipients, such as acacia, talc, starch, sugars, e.g. mannitol, methylcellulose, lactose, gelatin, surfactants, magnesium stearate, cyclodextrins, aqueous or non-aqueous excipients, diluents, dispersants, emulsifiers, lubricants, preservatives and flavoring agents, e.g. ether oils (etheroils). The compounds of the invention may also be dispersed in a microparticle, e.g., nanoparticle composition.

Non-oral administration can be carried out, for example, by intravenous, subcutaneous or intramuscular injection of sterile aqueous or oily solutions, suspensions or emulsions, by implants or by ointments, creams or suppositories. Optionally, administration may be performed as a delayed release form. The implant may comprise an inert material, such as a biodegradable polymeric material or a synthetic silicone base such as silicone rubber. Intravaginal administration can be, for example, by a vaginal ring. Intrauterine administration may be performed, for example, by vaginal diaphragm (diaphragm) or other suitable intrauterine contraceptive device. Furthermore, transdermal administration can be provided in particular by, for example, preparations suitable for this purpose and/or by suitable means, for example plasters.

As already stated, the novel compounds according to the invention can also be combined with further pharmaceutically active substances. Within the scope of combination therapy, the individual active ingredients may be administered simultaneously or separately, and by the same route (e.g. orally) or by separate routes (e.g. orally and by injection). They may be present or administered in the same or different amounts in a unit dose. A certain dosage regimen may be applied as long as it appears appropriate. In this way, a large number of the novel compounds of the invention can be combined with one another.

The dosage may vary within wide limits depending on the type of indication, the severity of the disease, the type of administration, the age, sex, weight and sensitivity of the subject to be treated. It is within the ability of the person skilled in the art to determine a "pharmacologically effective amount" of a pharmaceutical composition of said combination. The administration may be in a single dose or in multiple divided doses.

Suitable unit doses are from 0.001mg to 100mg of active substance, i.e. at least one compound according to the invention and optionally further pharmaceutically active substances, per kg of body weight of the patient.

In another aspect of the invention, therefore, a pharmacologically active amount of at least one compound selected from the group consisting of "Compound 1,2,3,4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 190, 191, 211, 193, 210, 212, 213, 215, 217, 220, 223, 222, 224, 220, 224, 223, 220, 227. 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 319, 320, 321, 322, 338, 324, 325, 329, 327, 328, 326, 330, 331, 332, 337, 336, 338, 351, 334, 336, 340, 339, 340, 345, 353, 342, 343, 347, 343, 347, 150, 340, 342, 353, 150, 342, 343, 356. 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 413, 414, 415, 412, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 454, 453, 455, 456, 458, 457, 460, 465, 463, 467, 470, 481, 480, 478, 480, 478, 481, 480, 481, 466, 480, 481, 480, 466, 480, 485. 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 555, 556, 557, 558, 559, 560, 561, 562, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 575, 576, 577, 578, 581, 579, 580, 582, and/or pharmaceutical compounds "574 and optionally include excipients and/or adjuvants in the present invention.

Preferred and particularly preferred pharmaceutical compositions are those comprising at least one of the above-mentioned preferred compounds of the invention. The pharmaceutical composition of the invention may comprise, in addition to at least one compound of the invention as defined previously, at least one further pharmaceutically active substance as already detailed above.

The pharmaceutical compositions of the invention comprise a pharmacologically active amount of at least one of the novel compounds of the invention as defined above, preferably in a unit dose, for example as described above, and preferably in an administration form which allows oral administration.

For pharmaceutical compositions comprising the compounds of the invention and for the use of the compounds of the invention as medicaments, reference is made to the statements concerning the use of the novel compounds of the invention as such with regard to the possibilities of use and administration.

In another aspect of the invention, the object of the present invention is surprisingly solved by preparing a kit comprising a pharmacologically active amount of at least one preferred compound of the invention as shown above and a pharmacologically active amount of at least one further pharmacologically active substance as defined above.

The compounds of the invention having the general formula (I) and preferred exemplary embodiments, in particular"compounds 1,2,3,4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 190, 191, 192, 193, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 224, 223, 226, 223, 230, 235, 240, 233, 240, 233, 237, 235, 240, 237, 235, 240, 237, 244. 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 369308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 351, 349, 350, 358, 354, 355, 364, 363, 368, 363, 368, 366, 362, 363, 366, 362, 363, 360, 362, 363, 360, 150, 351, 357, 351, 357, 351, 373. 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 463, 464, 466, 462, 467, 468, 469, 470, 472, 471, 382, 186, 398, 166, 398, 410,473. 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 567, 568, 569, 570, 568, 574, 553, 571, 575, 577, 573, 57580, and 2000 (i.e.) using nomex or nosocoma, ssyp, sshinm (r) and/2000)^TM(ii)/Draw2.5; MDL).

General rules of Synthesis of the Compounds of the invention

The following explains the process for preparing the substituted pyrido [2,3-b ] pyrazines of the present invention.

The compounds of the invention can be obtained according to corresponding methods known to the person skilled in the art. Furthermore, see patent specifications WO2004/104002, WO2004/104003, WO2007/054556 and WO2008/138878 or see the corresponding processes known in the literature for the preparation of the compounds according to the invention. For the preparation of the starting compounds, intermediate compounds and pyridopyrazines of the present invention, reference is made to the following main documents, et cetera, the content of which is hereby referred to as part of the disclosure of the present application:

1) Houben-Weyl, Methods of Organic Chemistry, volume 4/1a, pages 343-350

2) Houben-Weyl, Methods of Organic Chemistry, fourth edition, volume E7b (part 2), page 579; degussa GB1184848 (1970); p.Seko, et al EP735025(1996)

3) Catarzi, et al; med, chem, 1996, 1330-1336; seydel, et al; med, chem, 1994,3016-3022

4) Houben-Weyl, Methods of Organic Chemistry, volume E9c, pages 231-

5) Houben-Weyl/Science of Synthesis, volume 16, page 1269

6)C.L.Leese,H.N.Rydon J.Chem.Soc.1955,303-309；T.S.Osdene,G.M.Timmis J.Chem.Soc.1955,2033-2035

7) He, et al, bioorg, Med, chem, Lett, 2003,13,3097-

8) M.S.A.El-Gaby, et al.Indian J.chem.Sect.B2001,40, 195-200; M.R.Myers, et al, bioorg.Med.chem.Lett.2003,13, 3091-3096; R.Renslo, et al.J.Amer.chem.Soc.1999, 121, 7459-7460; j.heterocyclic Chem.1983,20, 199-203; C.R.Hopkins, et al.Tet.Lett.2004, 45,8631-

9) J.yin, et al, org.Lett.2002,4, 3481-; O.A.El-Sayed, et al. Arch.pharm.2002,335, 403-410; c.simple, et al.J.Med.chem.1992, 35,988-

10) Thompson, et al J.Med.chem.2000,43, 4200-; n.a. dales, et al, org.lett.2001, 2313-2316; G.Dannhardt, et al. Arch.Pharm.2000, 267-274; G.S.Poindexter, et al.Bioorg.Med.chem.2004, 12, 507-; J. receivur, et al, bioorg, Med, chem, Lett, 2004,14, 5075-an 5080

11) G.Heinisch, et al. Arch.Pharm.1997, 207-210; K.Matsuno, et al.J.Med.chem.2002, 45, 4513-; papini, et al J.Med.chem.2004,47,5224-

12) L.Mao, et al Synthesis2004,15, 2535-; M.Darabantu, et al.tetrahedron 2005,61, 2897-2905; E.Ford, et al, Tet.Lett.2000,41, 3197-; T.Shiota, et al.J.org.chem.1999, 64,453-

13) J.F.Miravet, et al, org.Lett.2005,7, 4791-4794; l. Castelhano, et al, bioorg.Med.chem.Lett.2005,15,1501-1504.

14) J.W.Huffmann, et al, bioorg.Med.chem.2006,14, 247-; liu, et al, Org. & Biomolecular chem.2005,3,1525-1533

The present invention will be explained in detail according to the following examples, but is not limited to these examples.

Examples

Compound 1

1-ethyl-3- {3- [1- (3,4, 5-trimethoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -urea

¹H-NMR(DMSO-d₆):δ=10.00(s,1H),9.18(s,1H),9.08(bs,1H),8.30(m,3H),7.75(s,1H),8.35(s,1H),8.27(d,1H),7.57(m,1H),6.71(s,2H),5.35(s,2H),3.76(s,6H),3.64(s,3H),3.22(m,2H),1.19(m,3H),ppm

mp:219℃

Compound 2

1-ethyl-3- [3- (1-pyridin-2-ylmethyl-1H-pyrazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

¹H-NMR(DMSO-d₆):δ=12.24(s,1H),11.14(s,1H),9.25(s,1H),8.82(s,1H),8.55(m,1H),8.38(s,1H),8.36(m,1H),7.81(m,1H),7.53(m,2H),7.34(m,1H),7.22(m,1H),5.57(s,2H),3.37(m,2H),1.33(m,3H),ppm

Compound 3

1- {3- [1- (3-difluoromethoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-urea

¹H-NMR(DMSO-d₆):δ=10.01(s,1H),9.18(s,1H),9.09(s,1H),8.80(s,1H),8.37(s,1H),8.28(m,1H),7.57(m,1H),7.44(m,1H),7.16(m,4H),5.48(s,2H),3.33(m,2H),1.19(m,3H),ppm

mp:198℃

Compound 4

1-ethyl-3- {3- [1- (3-hydroxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -urea

¹H-NMR(DMSO-d₆):δ=10.00(s,1H),9.44(s,1H),9.09(s,1H),9.18(s,1H),9.07(s,1H),8.75(s,1H),8.35(s,1H),8.27(m,1H),7.57(m,1H),7.16(m,1H),6.74(m,1H),6.68(m,2H),5.36(s,2H),3.33(m,2H),1.19(m,3H),ppm

mp:242℃

Compound 5

1- [3- (1-benzo [1,3] dioxol-5-ylmethyl-1H-pyrazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-ethyl-thiourea

¹H-NMR(DMSO-d₆):δ=12.22(m,1H),11.14(s,1H),9.23(s,1H),8.74(s,1H),8.35(m,2H),7.53(d,1H),6.90(m,3H),6.00(s,2H),5.34(s,2H),3.73(m,2H),1.33(m,3H),ppm

mp:244℃

Compound 6

1-ethyl-3- {3- [1- (4-trifluoromethoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -urea

¹H-NMR(DMSO-d₆):δ=10.01(s,1H),9.18(s,1H),9.08(s,1H),8.80(s,1H),8.37(d,1H),7.57(d,1H),7.25(d,2H),7.38(d,2H),5.50(s,2H),3.32(m,2H),1.19(m,3H),ppm

mp:231℃

Compound 7

1- {3- [1- (3, 4-dimethoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3- (2-methoxy-ethyl) -thiourea

¹H-NMR(DMSO-d₆):δ=12.35(m,1H),11.19(s,1H),9.22(s,1H),8.61(s,1H),8.35(d,1H),8.31(s,1H),7.54(d,1H),7.03(s,1H),6.95(m,1H),6.90(m,1H),5.36(s,2H),3.84(m,2H),3.75(m,8H),3.65(m,2H),3.40(s,3H)ppm

mp:198℃

Compound 8

1- {3- [1- (3-chloro-4-fluoro-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-urea

¹H-NMR(DMSO-d₆):δ=10.01(s,1H),9.17(s,1H),9.09(s,1H),8.79(s,1H),8.37(s,1H),8.27(d,1H),7.58(m,2H),7.43(m,1H),7.37(m,1H),5.46(s,2H),3.33(m,2H),1.19(m,3H)ppm

mp:214-219℃

Compound 9

1-ethyl-3- {3- [1- (3-phenyl-propyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -urea

¹H-NMR(DMSO-d₆):δ=10.00(s,1H),9.17(s,1H),9.08(s,1H),8.69(s,1H),8.33(s,1H),8.27(d,1H),7.58(m,1H),7.30(m,2H),7.23(m,2H),7.19(m,1H),4.24(m,2H),3.32(m,2H),2.61(m,2H)2.18(m,2H9,1.19(m,3H)ppm

mp:251℃

Compound 10

1- {3- [1- (4-cyano-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-urea

¹H-NMR(DMSO-d₆):δ=10.01(s,1H),9.18(s,1H),9.09(s,1H),8.82(s,1H),8.39(s,1H),7.85(d,2H),7.59(d,1H),7.46(d,2H),5.58(s,2H),3.29(m,2H),1.19(m,3H)ppm

mp:208-215℃

Compound 11

1- {3- [1- (4-difluoromethoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-urea

¹H-NMR(DMSO-d₆):δ=10.00(s,1H),9.17(s,1H),9.08(s,1H),8.78(s,1H),8.35(s,1H),8.27(d,2H),7.57(d,1H),7.40(d,2H),7.19(m,3H),5.45(s,2H),3.32(m,2H),1.19(m,3H)ppm

mp:239℃

Compound 12

1- {3- [1- (3, 5-dimethyl-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-thiourea

¹H-NMR(DMSO-d₆):δ=12.23(m,1H),11.14(s,1H),9.24(s,1H),8.74(s,1H),8.36(m,2H),7.53(m,1H),6.95(m,3H),5.36(s,1H),3.37(m,2H),2.25(s,6H),1.33(m,3H)ppm

Compound 13

1-ethyl-3- {3- [1- (3-methyl-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -urea

¹H-NMR(DMSO-d₆):δ=10.00(s,1H),9.17(s,1H),9.08(s,1H),8.75(s,1H),8.34(m,2H),8.28(m,1H),7.57(m,1H),7.26(m,1H),7.14(m,3H),5.41(s,2H),3.33(m,2H),2.29(s,3H),1.19(m,3H)ppm

mp:208-210℃

Compound 14

1-ethyl-3- [3- (1-pyridin-4-ylmethyl-1H-pyrazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

¹H-NMR(DMSO-d₆):δ=10.02(s,1H),9.19(s,1H),9.08(s,1H),8.83(s,1H),8.55(m,2H),8.41(s,1H),8.28(m,1H),7.58(m,1H),7.22(m,2H),5.54(s,2H),3.32(m,2H),1.19(m,3H)ppm

Compound 15

1-ethyl-3- {3- [1- (4-methyl-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -urea

¹H-NMR(DMSO-d₆):δ=10.00(s,1H),9.16(s,1H),9.07(s,1H),8.74(s,1H),8.33(s,1H),8.26(d,1H),7.57(m,1H),7.23(d,2H),7.19(d,2H),5.39(s,2H),3.33(m,2H),2.28(s,3H),1.19(m,3H)ppm

mp:217-220℃

Compound 16

1-ethyl-3- {3- [1- (4-phenyl-butyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -urea

¹H-NMR(DMSO-d₆):δ=10.00(s,1H),9.15(s,1H),9.08(s,1H),8.66(s,1H),8.30(s,1H),8.26(d,1H),7.56(m,1H),7.26(m,2H),7.18(m,3H),4.24(m,2H),3.32(m,2H),2.26(m,3H),1.87(m,2H),1.57(m,2H),1.19(m,3H)ppm

mp:182℃

Compound 17

1-ethyl-3- {3- [1- (4-hydroxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -urea

¹H-NMR(DMSO-d₆):δ=9.99(s,1H),9.45(s,1H),9.16(s,1H),9.07(s,1H),8.30(s,1H),8.69(s,1H),8.26(m,1H),7.57(m,1H),7.19(d,3H),6.75(d,2H),5.30(s,2H),3.33(m,2H),1.19(m,3H)ppm

Compound 18

1- {3- [1- (4-chloro-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-urea

¹H-NMR(DMSO-d₆):δ=10.01(s,1H),9.17(s,1H),9.09(bs,1H),8.78(s,1H),8.36(s,1H),8.27(d,1H),7.57(d,1H),7.44(d,2H),7.25(d,2H),5.46(s,2H),3.31(m,2H),1.19(m,3H)ppm

mp:240-244℃

Compound 19

1- {3- [1- (2, 5-dimethoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-thiourea

¹H-NMR(DMSO-d₆):δ=12.25(m,1H),11.14(s,1H),9.24(s,1H),8.65(s,1H),8.35(m,2H),7.52(d,1H),6.99(d,1H),6.89(m,1H),6.64(m,1H),5.37(s,2H),3.80(s,3H),3.72(m,2H),3.66(s,3H),1.33(m,3H)ppm

mp:225℃

Compound 20

1-ethyl-3- {3- [1- (4-methyl-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

¹H-NMR(DMSO-d₆):δ=12.23(m,1H),11.14(s,1H),9.22(s,1H),8.75(s,1H),8.35(m,2H),7.52(d,1H),7.23(d,2H),7.17(d,2H),5.40(s,2H),3.73(m,2H),2.28(s,3H),1.33(m,3H)ppm

mp:241℃

Compound 21

1- {3- [1- (3-benzyloxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-thiourea

¹H-NMR(DMSO-d₆):δ=12.23(m,1H),11.14(s,1H),9.23(s,1H),8.77(s,1H),8.36(m,2H),7.53(m,1H),7.42(m,2H),7.36(m,2H),7.29(m,2H),9.97(m,2H),6.89(m,1H),5.42(s,2H),5.08(s,2H),3.73(m,2H),1.32(m,3H)ppm

mp:203-205

Compound 22

1- {3- [1- (4-bromo-3-methyl-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-urea

¹H-NMR(DMSO-d₆):δ=10.01(s,1H),9.17(s,1H),9.08(s,1H),8.77(s,1H),8.35(s,1H),8.27(d,1H),7.57(m,2H),7.34(m,1H),7.09(m,1H),5.40(s,2H),3.33(m,2H),2.34(s,3H),1.19(m,3H)ppm

mp:250-252℃

Compound 23

1-ethyl-3- {3- [1- (4-methoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

¹H-NMR(DMSO-d₆):δ=12.22(m,1H),11.14(s,1H),9.22(s,1H),8.73(s,1H),8.35(m,2H),7.52(d,1H),7.30(d,2H),6.93(d,2H),5.37(s,2H),3.73(m,5H),1.33(m,3H)ppm

mp:237℃

Compound 24

1-ethyl-3- [3- (1-pyridin-3-ylmethyl-1H-pyrazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

¹H-NMR(DMSO-d₆):δ=12.23(m,1H),11.15(s,1H),9.23(s,1H),8.83(s,1H),8.61(m,1H),8.54(m,1H),8.37(m,2H),7.75(m,1H),7.53(m,1H),7.41(m,1H),5.52(s,2H),3.73(m,2H),1.33(m,3H)ppm

mp:238℃

Compound 25

1-ethyl-3- {3- [1- (3-fluoro-5-methyl-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

¹H-NMR(DMSO-d₆):δ=12.23(m,1H),11.15(s,1H),9.24(s,1H),8.79(s,1H),8.36(m,2H),7.53(m,1H),6.98(m,3H),5.44(s,2H),3.73(m,2H),2.30(s,3H),1.33(m,3H)ppm

mp:257-259℃

Compound 26

1- {3- [1- (2, 3-dimethoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-thiourea

¹H-NMR(DMSO-d₆):δ=12.23(m,1H),11.14(s,1H),9.24(s,1H),8.71(s,1H),8.35(m,2H),7.53(m,1H),7.04(m,2H),6.74(m,1H),5.43(s,2H),3.82(s,3H),3.75(s,3H),3.72(m,2H),1.33(m,3H)ppm

mp:218-222℃

Compound 27

1- {3- [1- (3-difluoromethoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-thiourea

¹H-NMR(DMSO-d₆):δ=12.23(t,1H),11.15(s,1H),9.24(s,1H),8.81(s,1H),8.39(s,1H),8.36(d,1H),7.54(d,1H),7.44(t,1H),7.35(s,1H),7.23(s,1H),7.19(m,1H),7.15(m,1H),7.15(m,1H),5.49(s,2H),3.73(m,2H),1.33(t,3H)ppm

mp:207℃

Compound 28

1- {3- [1- (3, 4-dimethoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-thiourea

¹H-NMR(DMSO-d₆):δ=12.23(t,1H),11.14(s,1H),9.23(s,1H),8.73(s,1H),8.35(t,1H),7.53(d,1H),7.03(m,1H),6.94(m,1H),6.83(m,1H),5.36(s,2H),3.74(m,8H),1.33(t,3H)ppm

mp:213℃

Compound 29

1-ethyl-3- {3- [1- (2-fluoro-3-methoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

¹H-NMR(DMSO-d₆):δ=12.23(m,1H),11.14(s,1H),9.24(s,1H),8.75(s,1H),8.36(m,2H),7.54(d,1H),7.14(m,2H),6.83(m,1H),5.51(s,1H),3.85(s,4H),3.73(m,2H),1.33(t,3H)ppm

mp:215-220℃

Compound 30

1-ethyl-3- [3- (1-phenyl-1H-pyrazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

¹H-NMR(DMSO-d₆):δ=10.01(s,1H),9.1(m,2H),8.75(s,1H),8.3(m,2H),7.55(d,1H),7.3(m,5H),5.45(s,2H),3.3(s,2H),1.15(t,3H)ppm

mp:256-257℃

Compound 31

1- [3- (1-benzyl-1H-pyrazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3- (2-methoxy-ethyl) -thiourea

¹H-NMR(DMSO-d₆):δ=12.35(m,1H),11.19(s,1H),9.23(s,1H),8.69(s,1H),8.35(m,2H),7.54(d,1H),7.36(m,5H),5.46(m,2H),3.84(m,2H),3.66(m,2H),3.41(s,3H)ppm

mp:219℃

Compound 32

1- {3- [1- (3-methoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3- (2-methoxy-ethyl) -thiourea

¹H-NMR(DMSO-d₆):δ=12.36(s,1H),11.19(s,1H),9.23(s,1H),8.68(s,1H),8.34(m,2H),7.54(d,1H),7.30(t,1H),6.91(m,3H),5.42(s,2H),3.85(m,2H),3.74(m,3H),3.66(m,2H),3.42(m,3H)ppm

mp:215℃

Compound 33

1- {3- [1- (3-methoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-methoxymethyl-thiourea

¹H-NMR(DMSO-d₆):δ=12.63(m,1H),11.39(s,1H),9.27(s,1H),8.79(s,1H),8.39(m,2H),7.58(d,1H),7.28(m,1H),6.91(m,2H),5.43(s,2H),5.22(m,2H),3.74(s,3H),3.42(m,3H),3.3(s,1H)ppm

mp:187℃

Compound 34

1- [3- (1-benzyl-1H-pyrazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-methoxymethyl-thiourea

¹H-NMR(DMSO-d₆):δ=12.64(m,1H),11.38(s,1H),9.27(s,1H),8.80(s,1H),8.39(m,2H),7.58(d,1H),7.35(m,5H),5.46(s,2H),5.43(m,2H),3.41(s,3H)ppm

Compound 35

1- {3- [1- (3, 4-dimethoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-methoxymethyl-thiourea

¹H-NMR(DMSO-d₆):δ=12.63(m,1H),11.38(s,1H),9.26(s,1H),8.73(s,1H),8.37(m,2H),7.58(d,1H),7.04(s,1H),6.92(m,2H),5.35(s,2H),5.23(d,2H),3.75(m,6H),3.41(m,3H)ppm

mp:188℃

Compound 36

1-ethyl-3- {3- [1- (3-hydroxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

¹H-NMR(DMSO-d₆):δ=12.23(m,1H),11.14(s,1H),9.44(s,1H),9.23(s,1H),8.76(s,1H),8.36(m,2H),7.54(d,1H),7.17(t,1H),6.71(m,3H),5.37(s,2H),3.74(m,2H),1.33(m,3H)ppm

mp:239℃

Compound 37

1- {3- [1- (3-dimethylamino-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-thiourea

¹H-NMR(DMSO-d₆):δ=12.23(m,1H),11.14(s,1H),9.23(s,1H),8.76(s,1H),8.35(m,2H),7.54(d,1H),7.15(t,1H),6.74(s,1H),6.67(d,1H),6.58(d,1H),5.36(s,2H),3.73(m,2H),2.88(s,6H),1.33(t,3H)ppm

mp:215℃

Compound 38

1- {3- [1- (3-chloro-4-fluoro-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-thiourea

¹H-NMR(DMSO-d₆):δ=12.23(m,1H),11.16(s,1H),9.23(s,1H),8.80(s,1H),8.38(m,2H),7.60(m,1H),7.54(d,1H),7.43(m,1H),7.37(m,1H),5.46(s,2H),3.73(m,2H),1.33(t,3H)ppm

mp:235-238℃

Compound 39

1- {3- [1- (3, 5-dimethoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-thiourea

¹H-NMR(DMSO-d₆):δ=12.23(m,1H),11.14(s,1H),9.24(s,1H),8.77(s,1H),8.36(m,2H),7.54(d,1H),6.47(m,3H),5.37(s,2H),3.73(m,2H),1.33(t,3H)ppm

mp:230℃

Compound 40

1-ethyl-3- {3- [1- (3-methoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

¹H-NMR(DMSO-d₆):δ=12.23(m,1H),11.14(s,1H),9.24(s,1H),8.77(s,1H),8.36(m,2H),7.54(d,1H),7.29(t,1H),6.90(m,3H),5.43(s,2H),3.73(m,5H),1.33(t,3H)ppm

mp:217-220℃

Compound 41

1-ethyl-3- {3- [1- (3-methyl-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

¹H-NMR(DMSO-d₆):δ=12.23(m,1H),11.14(s,1H),9.23(s,1H),8.77(s,1H),8.36(m,2H),7.53(d,1H),7.26(t,1H),7.14(m,3H),5.42(s,2H),3.73(m,5H),2.30(s,3H),1.33(t,3H)ppm

mp:258-261℃

Compound 42

1- {3- [1- (3, 4-dimethoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-urea

¹H-NMR(DMSO-d₆):δ=9.99(s,1H),9.16(s,1H),9.08(s,1H),8.71(s,1H),8.31(s,1H),8.27(d,1H),7.57(d,1H),7.03(m,1H),6.94(m,1H),6.89(m,1H),5.35(s,2H),3.74(m,6H),3.33(m,2H),1.19(t,3H)ppm

mp:205℃

Compound 43

1-ethyl-3- {3- [1- (2,3, 4-trimethoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

¹H-NMR(DMSO-d₆):δ=12.23(m,1H),11.14(s,1H),9.24(s,1H),8.65(s,1H),8.35(m,2H),7.52(d,1H),6.96(d,1H),6.81(d,1H),5.35(s,2H),3.76(m,11H),1.33(t,3H)ppm

mp:213℃

Compound 44

1-ethyl-3- {3- [1- (3-phenyl-propyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

¹H-NMR(DMSO-d₆):δ=12.25(m,1H),11.14(s,1H),9.24(s,1H),8.71(s,1H),8.36(m,2H),7.53(d,1H),7.26(m,5H),4.24(t,2H),3.73(m,2H),2.61(t,2H),2.18(m,2H),1.33(t,3H)ppm

mp:206-208℃

Compound 45

1- [3- (1-benzyl-1H-pyrazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -3-ethyl-thiourea

¹H-NMR(DMSO-d₆):δ=12.23(m,1H),11.14(s,1H),9.23(s,1H),8.79(s,1H),8.36(m,2H),7.54(d,1H),7.35(m,5H),5.46(s,2H),3.73(m,2H),1.33(t,3H)ppm

mp:252℃

Compound 46

1-Ethyl-3- {3- [1- (3,4, 5-trimethoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

¹H-NMR(DMSO-d₆):δ=12.23(m,1H),11.14(s,1H),9.24(s,1H),8.75(s,1H),8.36(m,2H),7.54(d,1H),6.72(s,2H),5.36(s,2H),3.75(m,8H),3.64(m,3H),1.33(t,3H)ppm

mp:232℃

Compound 47

1- {3- [1- (3-methoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3- (2,2, 2-trifluoro-ethyl) -thiourea

¹H-NMR(DMSO-d₆):δ=12.80(t,1H),11.61(s,1H),9.27(s,1H),8.72(s,1H),8.42(d,1H),8.34(s,1H),7.58(d,1H),7.29(t,1H),6.89(m,3H),5.44(m,2H),4.80(m,2H),3.74(m,3H)ppm

mp:217℃

Compound 48

1-ethyl-3- {3- [1- (2-fluoro-3-methyl-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

¹H-NMR(DMSO-d₆):δ=12.23(t,1H),11.14(s,1H),9.24(s,1H),8.75(s,1H),8.36(m,2H),7.54(d,1H),7.27(t,1H),7.11(m,2H),5.51(s,2H),3.73(m,2H),2.25(s,3H),1.33(t,3H)ppm

mp:242-245℃

Compound 49

1- {3- [1- (3-ethoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-thiourea

¹H-NMR(DMSO-d₆):δ=12.23(t,1H),11.14(s,1H),9.24(s,1H),8.78(s,1H),8.36(m,2H),7.54(d,1H),7.27(t,1H),6.87(m,3H),5.42(s,2H),4.01(m,2H),3.73(m,2H),1.33(m,6H)ppm

mp:222℃

Compound 50

1- {3- [1- (4-chloro-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3-ethyl-thiourea

¹H-NMR(DMSO-d₆):δ=12.23(t,1H),11.15(s,1H),9.23(s,1H),8.79(s,1H),8.38(s,1H),8.36(d,1H),7.54(d,1H),7.44(m,2H),7.35(m,2H),5.47(s,2H),3.73(m,2H),1.33(t,3H)ppm

mp:249℃

Compound 51

1- {3- [1- (3-methyl-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -3- (2,2, 2-trifluoro-ethyl) -thiourea

¹H-NMR(DMSO-d₆):δ=12.8(t,1H),11.61(s,1H),9.27(s,1H),8.70(s,1H),8.42(d,1H),8.33(s,1H),7.58(d,1H),7.26(t,1H),7.13(m,3H),5.43(s,2H),4.80(m,2H),2.30(s,3H)ppm

mp:249℃

Compound 52

1-ethyl-3- {3- [1- (2-methyl-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

¹H-NMR(DMSO-d₆):δ=12.22(m,1H),11.14(s,1H),9.24(s,1H),8.69(s,1H),8.38(s,1H),8.35(d,1H),7.53(d,1H),7.23(m,2H),7.18(m,1H),7.06(d,1H),5.47(s,2H),3.72(m,2H),2.36(s,3H),1.32(t,3H)ppm

mp:252-255℃

Compound 53

1-ethyl-3- [3- (1-phenethyl-1H-pyrazol-4-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -thiourea

¹H-NMR(DMSO-d₆):δ=12.23(m,1H),11.14(s,1H),9.19(s,1H),8.57(s,1H),8.35(m,2H),7.53(d,1H),7.28(t,2H),7.21(m,3H),4,47(t,2H),3.73(m,2H),3.19(t,2H),1.33(t,3H)ppm

mp:231-233℃

Compound 54

1-ethyl-3- {3- [1- (4-hydroxy-3-methoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -urea

1H-NMR(DMSO-d6)δ=9.99(s,1H),9.16(s,1H),9.07(s,1H),9.02(s,1H),8.69,(s,1H),8.32(s,1H),8.26(m,1H),7.57(m,1H),7.00(s,1H),6.76(m,2H),5.30(s,2H),3.76(s,3H),3.32(m,2H),1.19(m,3H)ppm

m.p.:237℃

Compound 55

1-ethyl-3- {3- [1- (4-hydroxy-3-methoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

1H-NMR(DMSO-d6)δ=12.23(m,1H),11.14(s,1H),9.22(s,1H),9.02(s,1H),8.70,(s,1H),8.34(m,2H),7.53(m,1H),7.00(s,1H),6.76(m,2H),5.31(s,2H),3.75(m,5H),1.33(m,3H)ppm

m.p.:242℃

Compound 56

1-ethyl-3- {3- [1- (3-hydroxy-4-methoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -urea

1H-NMR(DMSO-d6)δ=10.00(s,1H),9.16(s,1H),9.07(s,1H),9.02(s,1H),8.70,(s,1H),8.33(s,1H),8.27(m,1H),7.57(m,1H),6.89(m,1H),6.77(m,2H),5.28(s,2H),3.74(s,3H),3.33(m,2H),1.19(m,3H)ppm

m.p.:250℃

Compound 57

1-ethyl-3- {3- [1- (3-hydroxy-4-methoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

1H-NMR(DMSO-d6)δ=12.23(m,1H),11.14(s,1H),9.23(s,1H),9.02(s,1H),8.71,(s,1H),8.35(m,2H),7.53(m,1H),6.89(m,1H),6.77(m,2H),7.12(m,1H),5.29(m,2H),3.73(m,5H),1.33(m,3H)ppm

m.p.:230℃

Compound 64

1-ethyl-3- {3- [1- (3-methanesulfonyl-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -urea

1H-NMR(DMSO-d6)δ=10.01(s,1H),9.18(s,1H),9.09(s,1H),8.84(s,1H),8.39,(s,1H),8.28(m,1H),7.91(m,2H),7.59(m,1H),5.60(s,2H),3.22(s,3H),1.19(m,3H)ppm

m.p.:218℃

Compound 65

1-Ethyl-3- {3- [1- (3-methanesulfonyl-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

1H-NMR(DMSO-d6)δ=12.23(s,1H),11.15(s,1H),9.25(s,1H),8.85(s,1H),8.42,(s,1H),8.36(m,1H),7.91(m,2H),7.67(m,2H),6.54(m,1H),5.61(s,2H),3.73(m,2H),3.22(s,3H),1.33(m,3H)ppm

Compound 66

1-ethyl-3- (3- {1- [3- (2-methoxy-ethoxy) -benzyl ] -1H-pyrazol-4-yl } -pyrido [2,3-b ] pyrazin-6-yl) -urea

1H-NMR(DMSO-d6)δ=10.00(s,1H),9.17(s,1H),9.08(s,1H),8.77(s,1H),8.35(s,1H),8.28(m,1H),7.57(m,1H),7.28(m,1H),6.89(m,3H),5.41(s,2H),4.07(m,2H),3.64(m,2H),3.32(m,2H),3.29(s,3H),1.19(m,3H)ppm

m.p.:201℃

Compound 210

1-ethyl-3- {3- [1- (4-hydroxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [2,3-b ] pyrazin-6-yl } -thiourea

1H-NMR(DMSO-d6)δ=12.22(s,1H),11.13(s,1H),9.45(s,1H),9.22(s,1H),8.70(s,1H),8.34(m,2H),7.53(m,1H),7.20(d,2H),6.75(d,1H),5.30(s,2H),3.73(m,2H),1.34(m,3H)ppm

m.p.:257℃

Compound 211

1-ethyl-3- (3- {1- [ 4-methoxy-3- (2-methoxy-ethoxy) -benzyl ] -1H-pyrazol-4-yl } -pyrido [2,3-b ] pyrazin-6-yl) -urea

1H-NMR(DMSO-d6)δ=10.01(s,1H),9.16(s,1H),9.09(s,1H),8.71(s,1H),8.33(s,1H),8.27(m,1H),7.56(m,1H),7.04(s,1H),6.95(m,1H),6.90(m,1H),5.33(s,2H),4.05(m,2H),3.74(s,3H),3.64(m,2H),3.29(s,3H),1.19(m,3H)ppm

Compound 212

4- [6- (3-ethyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -thiophene-2-carboxylic acid

1H-NMR(DMSO-d6)δ=13.41(s,1H),10.09(s,1H),9.43(s,1H),9.04(s,1H),8.89(s,1H),8.54(s,1H),8.35(d,1H),7.69(d,1H),3.36(s,2H),1.20(m,3H)ppm

mp:250 deg.C (decomposition)

Compound 213

1-ethyl-3- [3- (5-methyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

1H-NMR(DMSO-d6)δ=10.03(s,1H),9.17(s,1H),9.09(s,1H),8.29(m,1H),7.59(d,1H),7.51(s,1H),6.45(s,1H),3.32(m,2H),2.61(s,3H),1.19(m,3H)ppm

mp:242℃

Compound 396

1H-NMR(DMSO-d6)δ=10.05(s,1H),9.37(s,1H),8.94(s,1H),8.30(d,1H),8.08(d,1H),7.65(d,1H),7.12(d,1H),5.67(m,1H),4.72(d,2H),3.23(s,2H),1.20(m,3H)ppm

mp:222℃

Compound 404

3- {4- [6- (3-ethyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -propionamide

1H-NMR(DMSO-d6)δ=10.00(s,1H),9.17(s,1H),9.08(s,1H),8.60(s,1H),8.32(s,1H),8.27(d,1H),7.59(d,1H),7.43(s,1H),6.91(s,1H),4.41(m,2H),3.33(m,2H),2.72(m,2H),1.20(m,3H),ppm

mp:247℃

Compound 406:

(2- {4- [6- (3-Ethyl-ureido) -pyrido [2,3-b ] pyrazin-3-yl ] -pyrazol-1-yl } -ethyl) -carbamic acid tert-butyl ester

1H-NMR(DMSO-d6)δ=10.00(s,1H),9.17(s,1H),8.59(s,1H),8.30(m,1H),8.27(s,1H),7.57(d,1H),6.98(s,1H),4.25(m,2H),3.40(m,2H),1.35(s,10H),1.25(s,2H),.1.20(m,4H)ppm

mp:235℃

Compound 416D-1194221-Ethyl-3- [3- (5-methyl-furan-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

mp:242℃

1H-NMR(DMSO-d6)δ=10.09(s,1H),9.43(s,1H),9.04(s,1H),8.89(s,1H),8.54(s,1H),8.35(d,1H),7.69(d,1H),3.36(s,2H),1.20(m,3H)ppm

mp:250 deg.C (decomposition)

Compound 432 1-Ethyl-3- (3-furan-3-yl-pyrido [2,3-b ] pyrazin-6-yl) -Urea

1H-NMR(DMSO-d6)δ=10.05(s,1H),9.23(s,1H),9.00(s,1H),8.75(s,1H),8.32(d,1H),7.82(s,1H),7.66(d,1H),7.26(s,1H),3.33(s,2H),1.20(m,3H)ppm

mp:240℃

Evidence of kinase inhibition by Compounds of the invention

Cell-free kinase assay (using ALPHA technique)

The compounds of the invention were tested for their inhibitory effect on a variety of serine/threonine, tyrosine and lipid kinases in an enzymatic assay. Recombinant human kinases such as Erk2, PI3K α and others are used in this assay, partly full length kinases and partly shortened fragments, but which contain at least a functional kinase domain. Commercially available kinase protein (Proqinase, Upstate) was used as a recombinant fusion protein with GST (glutathione-S-transferase) or His-Tag. Passing through suitable ALPHA according to substrate type^TMBeads (Perkin-Elmer) quantitate various kinase reactions.

Testing

The substrate test is described in detail in the Erk assay below. Selected test results for Erk2 and PI3K α tests are given below. For determining IC₅₀Values, the potential inhibitory substances were studied at 10 half-log concentrations (3.16 nM-100. mu.M).

a) MAPK-ALPHAs (e.g., Erk2) test substances 0.625ng Erk2(#14-173, Upstate), 10. mu.M ATP and 15nM biotinylated MBP (myelin basic protein) substrate were applied in 384-well Optiplate (Perkin-Elmer) in 25mM Tris, 10mM MgCl (15. mu.l volume)₂、0.1%Tween-20、100μM NaVO₄2mM DTT, at pH7.5 for 1 hour. The kinase reaction was then stopped by adding 10. mu.l of a mixture of ALPHA beads (10. mu.g/ml, #6760617/Perkin-Elmer) preincubated with anti-phosphoMBP antibody (320pM, #05-429/Upstate) in 25mM Tris, 200mM NaCl, 100mM EDTA and 0.3% BSA and left overnight.

b) PI3K-ALPHAs (e.g. PI 3K. alpha.) test substances, 1ng PI 3K. alpha. (#14-602, Upstate), 100. mu.M ATP and 20. mu.M PIP₂Substrate (#64910, cayman Chemicals) was plated in 384-well Optiplate (Perkin-Elmer) on 50mM Hepes, 50mM NaCl, 5mM MgCl₂0.05% Chaps, 5mM DTT, incubated at pH7.4 for 1 hour. The kinase reaction was then stopped by adding a mixture of ALPHA beads (10. mu.g/ml, #6760603/Perkin-Elmer) preincubated with 1nM GST: Grp1 fusion protein (Upstate) and 15nM biotinylated PIP3(#10009531, Cayman Chemicals) in 50mM Hepes, 50mM NaCl,50mM EDTA and 0.1% BSA and left overnight.

The following morning fluorescence was detected in an Envision microplate detector (plate reader) (Perkin-Elmer).

Evaluation of

The% -inhibition value/amount concentration of substance was calculated from the raw data obtained by Envision microplate detector as disclosed below:

eight assays were performed for each control and two assays were performed for the test substance samples. 0% of the control contained no ATP or no substrate, and 100% of the control (fully active kinase) contained no test substance. IC determination Using GraphPadprism₅₀The value is obtained.

Compounds of the invention show IC₅₀Effective inhibition of Erk and/PI 3K with values up to 1nM (see Table 1).

TABLE 1 Erk2 andPI3K alpha kinase assay test results (IC)₅₀[μM]10 μ M or 100 μ M ATP)

Compound (I)	Erk2	PI3Kα*
			27	0.75	0.059
28	0.112	0.082
			29	0.492	0.112
40	0.336	0.168
			41	0.400	0.184
42	0.043	0.274
			45	0.272	0.249
55	0.523	0.391
			65	0.225	0.180
210	0.225	0.208

Cell experiments anti-proliferative Effect test (XTT test)

The principle of this assay is based on the reduction of the tetrazolium salt dye XTT (3' - [1- (phenylaminocarbonyl) -3, 4-tetrazolium ] -bis (4-methoxy-6-nitro) sodium benzenesulfonate, Sigma) to the formazan □ staining product by intracellular mitochondrial dehydrogenase. The dye is formed only by metabolically active cells and its photometrically measurable intensity is a quantitative indicator of the presence of viable cells. The reduction of the dye formed by the incubation of the cells with the substrate is used as a parameter for the antiproliferative effect.

Testing

Tumor cell lines (ATCC) were injected in a defined number of cells (1250 cells/well for Hct 116) into 96-well microplates, then in an incubator at 37 ℃ with 5% CO₂And incubated overnight at 95% air humidity. Test substances were prepared as stock solutions (10mM) in DMSO. To determine EC₅₀Values, potential inhibitory substances were added to cells in semilog gradient dilutions (half-log gradient dilution) to give final concentrations of 1.58nM to 50. mu.M. The cell plates were then placed in an incubator at 37 ℃ with 5% CO₂And incubated at 95% air humidity for-48 hours.

To assay the reaction, substrate XTT was mixed with PMS (N-methyl dibenzopyrazine methylsulfate, Sigma) and added to the cells to give final concentrations of 325 μ g XTT/ml and 2.5 μ g PMS/ml. Then, it was incubated at 37 ℃ under 95% air humidity for 3 hours. The formazan □ salt formed by the cellular dehydrogenase can then be determined quantitatively by absorption at 490 nm.

Evaluation of

The% inhibition value was evaluated from the optical density value measured at 490nm in each test by the following disclosure:

eight assays were performed for each control and two assays were performed for the test substance samples. 0% control contained no cells and 100% control (proliferation control) contained no test substance. EC determination Using GraphPadprism₅₀The value is obtained.

The compounds of the invention show partial effective inhibition of cell proliferation, their EC₅₀Is valued at<1 μ M (see Table 2).

TABLE 2 test results (EC) of XTT test₅₀[μM])

Compound (I)	Hct116
		27	1.53
28	1.65

29	2.56
		40	2.57
41	3.01
		42	1.98
45	1.95
		65	2.11
210	1.70

Claims

1. Use of compounds of the general formula (I) and their physiologically tolerated salts, their racemate forms, their pure enantiomeric and/or diastereomeric forms or the forms of mixtures of these enantiomers and/or diastereomers or their tautomeric forms for the preparation of a medicament:

wherein the substituents R1, R2, X have the following meanings:

x: o or S

R1

(I) Unsubstituted or substituted alkyl, wherein the alkyl may be substituted by one or more, 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-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, SO₂O-alkyl-aryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, n may have a value of 1,2 or 3, and the alkyl-, cycloalkyl-, heterocyclyl-, aryl-, heteroaryl-, alkyl-cycloalkyl-, alkyl-heterocyclyl-, alkyl-aryl-and alkyl-heteroaryl substituents may themselves in turn be substituted,

(II) unsubstituted or substituted aryl, wherein the aryl may be substituted by one or more, 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-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、O-CH₂-CH₂-O-CH₂-CH₂-O-CH₂-CH₂-OH; OC (O) -alkyl, OC (O) -cycloalkyl, OC (O) -heterocyclyl, OC (O) -aryl, OC (O) -heteroaryl, OC (O) -alkyl-aryl, OC (O) -alkyl-heteroaryl, OC (O) -NH-alkyl, OSO₃H、OSO₂Alkyl, OSO₂Cycloalkyl, OSO₂-heterocyclic radical, OSO₂Aryl, OSO₂Heteroaryl, OSO₂Alkyl-aryl, OSO₂Alkyl-heteroaryl, OP (O) (OH)₂C (O) -alkyl, C (O) -aryl, C (O) -heteroaryl, O-CO₂Alkyl, 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, SO₂-a heterocyclic group; SO (SO)₂Aryl, SO₂NH₂、SO₂NH-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl, SO₂NH-alkyl-aryl, SO₃H、SO₂O-alkyl, SO₂O-aryl, SO₂O-alkyl-aryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, n may have a value of 1,2 or 3, and the alkyl-, cycloalkyl-, heterocyclyl-, aryl-, heteroaryl-, alkyl-cycloalkyl-, alkyl-heterocyclyl-, alkyl-aryl-and alkyl-heteroaryl substituents may themselves in turn be substituted,

(III) unsubstituted or substituted heteroaryl, wherein said heteroaryl may be substituted by one or more, 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)₂Si (alkyl) 3, SO₂NH₂、SO₂NH-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl, SO₂NH-alkyl-aryl, SO3H, SO₂O-alkyl, SO₂O-aryl, SO₂O-alkyl-aryl, alkyl, cycloalkyl, heterocyclyl, alkyl-cycloalkyl, alkyl-heterocyclyl, alkyl-aryl, alkyl-heteroaryl, aryl or heteroaryl, and the alkyl-, cycloalkyl-, heterocyclyl-, alkyl-cycloalkyl, alkyl-heterocyclyl, alkyl-aryl, alkyl-heteroaryl, aryl-and heteroaryl substituents may themselves in turn be substituted,

and R2:

(I) unsubstituted or substituted alkyl, wherein the alkyl may be substituted by one or more, 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-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, SO₂-alkyl radical、SO₂Aryl, SO₂NH₂、SO₂NH-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl, SO₂NH-alkyl-aryl, SO₃H、SO₂O-alkyl, SO₂O-aryl, SO₂O-alkyl-aryl, cycloalkyl, heterocyclyl,

(II) unsubstituted or substituted cycloalkyl, wherein cycloalkyl may be substituted by one or more, identical 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-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)₂Alkyl or aryl, or a pharmaceutically acceptable salt thereof,

the medicament is for treating or preventing a physiological and/or pathophysiological condition mediated by a signaling pathway selected from the group consisting of the PI3K-Akt signaling pathway and the ras-Raf-Mek-Erk signaling pathway in a mammal.

2. Use according to claim 1, wherein the alkyl group is 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, vinyl (ethenyl), ethynyl, propenyl (-CH2CH = CH 2; -CH = CH-CH3, -C (= CH2) -CH3), propynyl (-CH 2-C.ident.CH, -C.ident.C-CH 3), butenyl, butynyl, pentenyl, pentynyl, hexenyl, hexynyl, heptynyl, octynyl".

3. The use according to any one of claims 1 to 2, wherein said heterocyclyl is selected from the group consisting of "tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl".

4. Use according to any one of claims 1 to 3, wherein the heteroaryl group is selected from the group consisting of "pyrrolyl, furanyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 2, 3-naphthyridinyl, indolyl, indazolyl, indolizinyl, benzimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, carbazolyl, phenazinyl, phenothiazinyl, acridinyl".

5. Use according to any one of claims 1 to 4, wherein the compound is selected from:

Compound 55, 1-ethyl-3- {3- [1- (4-hydroxy-3-methoxy-benzyl) -1H-pyrazol-4-yl ] -pyrido [23-b ] pyrazin-6-yl } -thiourea

Compound 258 1-allyl-3- (3-thiazol-5-yl-pyrido [2,3-b ] pyrazin-6-yl) -urea

Compound 272, 1-allyl-3- (3-furan-3-yl-pyrido [2,3-b ] pyrazin-6-yl) -urea

Compound 273: 1-allyl-3- (3-furan-3-yl-pyrido [2,3-b ] pyrazin-6-yl) -thiourea

Compound 278: 1-allyl-3- (3-isoxazol-4-yl-pyrido [2,3-b ] pyrazin-6-yl) -urea

Compound 324 1-cyclopentyl-3- (3-furan-3-yl-pyrido [2,3-b ] pyrazin-6-yl) -urea

Compound 378, 1-Ethyl-3- (3-furan-3-yl-pyrido [2,3-b ] pyrazin-6-yl) -Urea

Compound 396 1-ethyl-3- [3- (5-hydroxymethyl-thiophen-2-yl) -pyrido [2,3-b ] pyrazin-6-yl ] -urea

Compound 418 1-ethyl-3- (3-thiazol-5-yl-pyrido [2,3-b ] pyrazin-6-yl) -urea

Compound 432 1-Ethyl-3- (3-furan-3-yl-pyrido [2,3-b ] pyrazin-6-yl) -Urea

Compound 433: 1-ethyl-3- (3-furan-3-yl-pyrido [2,3-b ] pyrazin-6-yl) -thiourea

Compound 438 1-ethyl-3- (3-isoxazol-4-yl-pyrido [2,3-b ] pyrazin-6-yl) -urea

Compound 472-pentyl-3- (3-thiazol-5-yl-pyrido [2,3-b ] pyrazin-6-yl) -urea

The compound 486, 1-pentyl-3- (3-furan-3-yl-pyrido [2,3-b ] pyrazin-6-yl) -urea

Compound 487 1-pentyl-3- (3-furan-3-yl-pyrido [2,3-b ] pyrazin-6-yl) -thiourea

Compound 492-pentyl-3- (3-isoxazol-4-yl-pyrido [2,3-b ] pyrazin-6-yl) -urea

6. Use according to any one of claims 1 to 5, wherein the treatment or prevention is effected by modulation of one or more signalling pathways selected from the group consisting of the "ras-Raf-Mek-Erk signalling pathway" and the "PI 3K-Akt signalling pathway".

7. Use according to any one of claims 1 to 6, wherein the modulation of the PI3K-Akt signaling pathway and the ras-Raf-Mek-Erk signaling pathway is effected by modulation of one or more enzymes selected from the group consisting of "lipid kinase, tyrosine kinase, serine/threonine kinase, receptor tyrosine kinase, cytoplasmic serine/threonine kinase".

8. The use according to claim 7, wherein the enzyme is selected from the group consisting of "PI 3K, PI3K α, PI3K β, PI3K γ, PI3K δ, PI3K-C2 α, PI3K-C2 β, PI3K-Vps34 p".

9. The use according to claim 7, wherein the enzyme is selected from the group consisting of "Erk, Erk1, Erk 2".

10. Use according to any one of claims 1 to 9, wherein one or more enzymes are modulated.

11. Use according to any one of claims 1 to 10, wherein the modulation is inhibition.

12. The use according to any one of claims 1 to 5, wherein at least one compound is selected from the group consisting of "Compounds 1,2,3,4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 190, 191, 192, 193, 210, 212, 213, 215, 217, 220, 223, 220, 223, 222, 224, 220, 223, 220, 228. 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 335, 351, 333, 337, 336, 351, 341, 340, 345, 347, 343, 356, 343, 356, 357. 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 449, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 458, 459, 460, 461, 463, 467, 470, 481, 480, 481, 466, 481, 480, 481, 480, 478, 466, 480, 486. 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 57581, 580, and/or a compound "that selectively acts on a signal transduction pathway or on Meraf-25 or on Meraf-Rak signaling pathways or on both of Meraf-25 and/or on the signal transduction pathway, and the multiple mechanisms of action and methods of treatment may employ the signaling pathway or enzyme.

13. Use according to any one of claims 1 to 12, wherein the physiological and/or pathophysiological state is selected from the group consisting of "malignant tumors, benign tumors, inflammatory diseases, inflammation, pain, rheumatic diseases, arthritic diseases, HIV infections, neurological or neurodegenerative diseases, rheumatism, arthritis, AIDS, ARC (AIDS-related syndrome), Kaposi's sarcoma, tumors originating from the brain and/or the nervous system and/or meninges, dementia, Alzheimer's disease, hyperproliferative diseases, psoriasis, endometriosis, scarring, Benign Prostatic Hyperplasia (BPH), diseases of the immune system, autoimmune diseases, immunodeficiency diseases, colon tumors, stomach tumors, intestinal tumors, lung tumors, pancreatic tumors, ovarian tumors, prostate tumors, leukemias, melanomas, liver tumors, Renal tumor, head tumor, laryngeal tumor, glioma, breast tumor, uterine cancer, endometrial cancer, uterine cervical cancer, brain tumor, acanthosis glandulosa, bladder cancer, gastric tumor, colorectal tumor, esophageal cancer, gynecological tumor, ovarian tumor, thyroid cancer, lymphoma, chronic leukemia, acute leukemia, restenosis, diabetes, diabetic nephropathy, fibrotic diseases, cystic fibrosis, malignant nephrosclerosis, thrombotic microangiopathy syndromes, organ transplant rejection, glomerulopathy, metabolic diseases, solid/fixed tumors, rheumatoid arthritis, diabetic retinopathy, asthma, allergy, allergic diseases, chronic obstructive pulmonary disease, inflammatory bowel disease, fibrosis, atherosclerosis, cardiac diseases, cardiovascular diseases, myocardial diseases, vascular diseases, angiogenic diseases, inflammatory bowel disease, cardiovascular diseases, myocardial diseases, cardiovascular diseases, inflammatory bowel disease, renal disease, rhinitis, graves' disease, focal ischemia, heart failure, ischemia, cardiac hypertrophy, renal failure, myocardial cell dysfunction, hypertension, vasoconstriction, stroke, anaphylactic shock, platelet aggregation, skeletal muscle atrophy, obesity, overweight, glucose homeostasis, congestive heart insufficiency, angina, heart attack, heart infarction, hyperglycemia, hypoglycemia, hypertension ".

14. Use according to any one of claims 1 to 13, wherein the medicament comprises at least one further pharmacologically active substance.

15. Use according to any one of claims 1 to 13, wherein the medicament is administered before and/or during and/or after treatment with radiotherapy and/or surgery.

16. Use according to claim 14, wherein the additional pharmacologically active substance is selected from the group consisting of "DNA topoisomerase I and/or II inhibitors, DNA intercalators, alkylating agents, microtubule destabilizers (microtubuli destabilisers), hormone and/or growth factor receptor agonists and/or antagonists, antibodies against growth factors and their receptors, kinase inhibitors, alkyl phospholipids, antimetabolites", wherein the additional pharmacologically active substance is selected from the group consisting of "asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, levo-asparaginase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycin), epirubicin, etoposide, 5-fluorouracil, hexamethylcyanamide, hydroxyurea, ifosfamide, irinotecan, folinic acid, Lomustine, mechlorethamine, 6-mercaptopurine, mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifene, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine, vindesine, aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine cladribine, busulfan, diethylstilbestrol, 2' -difluorodeoxycytidine, docetaxel, erythrohydroxynonyladenine, ethisterone, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluorohydroxytestosterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, oxaliplatin, pentostatin, N-phosphonoacetyl-L-aspartate (PALA), staphyl, Precamycin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, vinorelbine, epothilone, gemcitabine, taxotere, BCNU, CCNU, DTIC, 5-fluorouracil, herceptin, avastin, erbitux, sorafenib, gleevec, Iressa, tarceva, rapamycin, perifosine, miltefosine, edelfosine, actinomycin D ".

17. Pyridopyrazines selected from the group consisting of compounds 1,2,3,4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 190, 191, 192, 193, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 226, 223, 225, 223, 230, 235, 234, 233, and 23, 27, 23, and 23, 238. 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 335, 332, 333, 334, 342, 336, 338, 339, 340, 341, 343, 347, 358, 350, 354, 353, 354, 357, 362, 363, 356, 362, 356, 363, 356, 362, 356, 363, 356, 362, 363, 367. 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 466, 463, 464, 494, 46494, 469, 470, 486, 477, 486, 481, 480, 478, 18, 492, 491, 481, 480, 481, 495, 481, 495, 481, 480, 481, 495, 496. 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 577, 576, 579, 580, 581, and/or a compound 582 ", their physiologically tolerated salts, their racemate forms, their pure enantiomeric and/or diastereomeric forms or mixtures of these enantiomers and/or diastereomers or their tautomeric forms.

18. Pharmaceutical compositions comprising a pharmacologically active amount of at least one compound according to claim 17 for the treatment or prophylaxis of physiological and/or pathophysiological states which can be treated by modulation of one or more signaling pathways selected from the group consisting of the "ras-Raf-Mek-Erk signaling pathway and the PI3K-Akt signaling pathway, wherein said physiological and/or pathophysiological states are selected from the group consisting of" malignant tumors, benign tumors, inflammatory diseases, inflammation, pain, rheumatic diseases, arthritic diseases, HIV infections, neurological or neurodegenerative diseases, rheumatic diseases, arthritis, AIDS, ARC (AIDS-related syndrome), kaposi's sarcoma, tumors of brain and/or nervous system and/or meninges origin, dementia, alzheimer's disease, hyperproliferative diseases, psoriasis, meningitis, HIV, rheumatoid arthritis, and/or rheumatoid arthritis, Endometriosis, scarring, Benign Prostatic Hyperplasia (BPH), immune system disease, autoimmune disease, immunodeficiency disease, colon tumour, gastric tumour, intestinal tumour, lung tumour, pancreatic tumour, ovarian tumour, prostate tumour, leukaemia, melanoma, liver tumour, kidney tumour, head tumour, larynx tumour, glioma, breast tumour, uterine cancer, endometrial cancer, uterine cervical cancer, brain tumour, acantho glandulifera cancer, bladder cancer, gastric tumour, colorectal tumour, oesophageal cancer, gynaecological tumour, ovarian tumour, thyroid cancer, lymphoma, chronic leukaemia, acute leukaemia, restenosis, diabetes, diabetic nephropathy, fibrotic disease, cystic fibrosis, malignant nephrosclerosis, thrombotic microangiopathy syndrome, organ transplant rejection, glomerulopathy, metabolic disease, solid/fixed tumour, Rheumatoid arthritis, diabetic retinopathy, asthma, allergy, allergic diseases, chronic obstructive pulmonary disease, inflammatory bowel disease, fibrosis, atherosclerosis, heart disease, cardiovascular disease, myocardial disease, vascular disease, angiogenic disease, kidney disease, rhinitis, graves' disease, focal ischemia, heart failure, ischemia, cardiac hypertrophy, renal failure, myocardial cell dysfunction, hypertension, vasoconstriction, stroke, anaphylactic shock, platelet aggregation, skeletal muscle atrophy, obesity, overweight, glucose homeostasis, congestive heart failure, angina, heart attack, cardiac infarction, hyperglycemia, hypoglycemia, hypertensive disease ".

19. A pharmaceutical composition comprising a pharmacologically active amount of at least one compound according to claim 17.

20. Pharmaceutical composition according to claim 19, wherein the active substance is present in a unit dose of 0.001mg to 100mg per kg body weight of the patient.

21. The pharmaceutical composition according to any one of claims 19 or 20, wherein the composition further comprises at least one pharmaceutically compatible excipient and/or adjuvant.

22. The pharmaceutical composition according to any one of claims 19 to 21, wherein the composition comprises at least one additional pharmacologically active substance.

23. The pharmaceutical composition according to claim 22, wherein the additional pharmacologically active substance is selected from the group consisting of "DNA topoisomerase I and/or II inhibitors, DNA intercalators, alkylating agents, microtubule destabilizers, hormone and/or growth factor receptor agonists and/or antagonists, antibodies against growth factors and their receptors, kinase inhibitors, alkyl phospholipids, antimetabolites" selected from the group consisting of "asparaginase, bleomycin, carboplatin, carmustine, chlorambucil, cisplatin, levoasparaginase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin (adriamycin), epirubicin, propofol, 5-fluorouracil, hexamethylcyanamide, hydroxyurea, ifosfamide, irinotecan, leucovorin, lomustine, nitrogen mustard, 6-mercaptopurine, Mesna, methotrexate, mitomycin C, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifene, streptozocin, tamoxifen, thioguanine, topotecan, vinblastine, vincristine, vindesine, aminoglutethimide, L-asparaginase, azathioprine, 5-azacytidine cladribine, busulfan, diethylstilbestrol, 2' -difluorodeoxycytidine, docetaxel, erythrohydroxynonyl adenine, ethinyl estradiol, 5-fluorodeoxyuridine monophosphate, fludarabine phosphate, fluorohydroxytestosterone, flutamide, hydroxyprogesterone hexanoate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, oxaliplatin, pentostatin, N-phosphonoacetyl-L-aspartic acid (PALA), Precamycin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, vinorelbine, epothilone, gemcitabine, taxotere, BCNU, CCNU, DTIC, 5-fluorouracil, herceptin, avastin, erbitux, sorafenib, gleevec, Iressa, tarceva, rapamycin, perifosine, miltefosine, edelfosine, actinomycin D ".

24. A kit comprising a pharmacologically active amount of at least one compound according to claim 17 and a pharmacologically active amount of at least one further pharmacologically active substance according to any one of claims 22 to 23.