CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority to U.S. 60/735,707, filed Nov. 11, 2005, which is hereby incorporated by reference in its entirety.

TECHNICAL FIELD

The present invention relates to pyridopyrazine derivatives with new biological action and their use for the treatment of physiological and/or pathophysiological states mediated and/or modulated by signal transduction pathways in mammals and in particular in humans.

PRIOR ART

The signal transduction cascades ras-Raf-Mek-Erk and PI3K-Akt play a central role in cell growth, cell proliferation, apoptosis, adhesion, migration and glucose metabolism. Consequently, the fundamental involvement in the pathogenesis of diseases such as cancer, neurodegeneration and inflammatory diseases is proven both for the ras-Raf-Mek-Erk and for the PI3K-Akt signal pathway. The individual components of these signal cascades are therefore important therapeutic points of attack for intervention in various 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 both signal pathways are first described separately hereinafter.

A plurality of growth factors, cytokines and oncogenes transduce their growth-promoting signals via the activation of G-protein coupled ras which leads to the activation of serine threonine kinase Raf and to the activation of mitogen-activated protein kinase kinase 1 and 2 (MAPKK1/2 or Mek1/2) and results in the phosphorylation and activation of MAPK 1 and 2â€”also known as extracellular signal regulated kinase (Erk1 and 2). Compared to other signal pathways, the ras-Raf-Mek-Erk signal pathway combines a large number of proto-oncogenes, including ligands, tyrosine kinase receptors, G-proteins, kinases and nuclear transcription factors. Tyrosine kinases such as, for example, EGFR (Mendelsohn J. et al., 2000) frequently mediate constitutively active signals to the downstream ras-Raf-Mek-Erk signal pathway in tumour events caused by overexpression and mutation. Ras mutations are mutated in 30% of all human tumours (Khleif S. N. et al., 1999, Marshall C., 1999), the highest incidence of 90% being found in pancreatic carcinomas (Friess H. et al., 1996, Sirivatanauksorn V. et al., 1998). For c-Raf a deregulated expression and/or activation has been described in various tumours (Hoshino R. et al., 1999, McPhillips F. et al., 2001). B-Raf point mutants were detected in 66% of all human malignant melanomas, 14% of all ovarian carcinomas and 12% of all carcinomas of the colon (Davies H. et al., 2002). It is therefore not surprising that Erk1/2 is primarily involved in many cellular processes such as cell growth, cell proliferation and cell differentiation (Lewis T. S. et al., 1998, Chang F. et al., 2003).

In addition, the members of the Raf kinases also have Mek-Erk-indepedent anti-apoptotic functions whose molecular steps have not yet been fully described. Ask1, Bc1-2, Akt and Bag1 have been described as possible interaction partners for the Mek-Erk-independent Raf activity (Chen J et al., 2001, Troppmaier J. et al., 2003, Rapp U. R. et al., 2004, Gotz R. et al., 2005). It is assumed nowadays that both Mek-Erk-dependent and Mek-Erk-independent signal transduction mechanisms control the activation of the upstream ras and Raf stimuli.

The isoenzymes of the phosphatidylinositol 3-kinases (PI3Ks) function predominantly as lipid kinases and catalyse the D3 phosphorylation of the second-messenger lipids PtdIns (phosphatidylinositol) to PtdIns(3)P, PtdIns(3,4)P₂, PtdIns(3,4,5)P₃phosphatidylinositol phosphates. The class I PI3Ks are composed structurally of the catalytic (p110alpha, beta, gamma, delta) and the regulatory (p85alpha, beta or p101gamma) subunits. Furthermore, the class II (PI3K-C2alpha, PI3K-C2beta) and class III (Vps34p) enzymes belong to the family of the P13 kinases (Wymann M. P. et al., 1998, VanHaesebroeck B. et al., 2001). The PIP increase triggered by the PI3Ks activates the proliferative ras-Raf-Mek-Erk signal pathway via the coupling of ras on the one hand (Rodriguez-Viciana P. et al., 1994) and on the other hand stimulates the anti-apoptotic signal pathway by recruiting Akt to the cell membrane and consequent overactivation of this kinase (Alessi D. R. et al., 1996, Chang H. W. et al., 1997, Moore S. M. et al., 1998). Consequently, the activation of PI3Ks fulfils at least two crucial mechanisms for tumour formation, namely the activation of cell growth and cell differentiation and the inhibition of apoptosis. In addition, PI3K also have protein-phosphorylating properties (Dhand et al., 1994, Bondeva T. et al., 1998, Bondev A. et al., 1999, VanHaesebroeck B. et al., 1999) which can trigger a PI3Ks-intrinsically regulating serine autophosphorylation for example. In addition, it is known that PI3Ks also have kinase-independent regulating effector properties, e.g. during control of cardiac contraction (Crackower M. A. et al., 2002, Patrucco et al., 2004). It is furthermore proven that PI3Kdelta and PI3Kgamma are specifically expressed on hematopoietic cells and therefore constitute potential points of attack for isoenzyme-specific PI3Kdelta and PI3Kgamma inhibitors in the treatment of inflammatory diseases such as rheumatism, asthma and allergies and in the treatment of B and T cell lymphomas (Okkenhaug K. et al., 2003, Ali K. et al., 2004, Sujobert P. et al., 2005). PI3Kalpha, which was recently identified as a proto-oncogene (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) is considered to be an important target in the treatment of tumour diseases. The importance of PI3K species as a target for the development of active substances is therefore extremely diverse (Chang F. & Lee J. T. et al, 2003).

The kinases related to PI3K (PIKK), which include the serine/threonine kinases mTOR, ATM, ATR, h-SMG-1 and DNA-PK (Chiang G. G. et al 2004) are also of great interest. Their catalytic domains have a high sequence homology to the catalytic domains of PI3Ks.

In addition, the loss of the tumour suppressor protein PTEN (Li J. et al., 1997, Steck P. A. et al., 1997)â€”whose function is the reversion of the phosphorylation initiated by the PI3Kâ€”contributes to an overactivation of Akt and its downstream cascade components and thereby emphasise the causal importance of PI3K as a target molecule for tumour therapy.

Various inhibitors of individual components of the ras-Raf-Mek-Erk and PI3K-Akt signal pathways have already been published and patented.

The present state of development in the field of kinase inhibitors, in particular of the ras-Raf-Mek-Erk and PI3K-Akt pathway, is described in the reviews of J. S. Sebolt-Leopold et al., 2004, and R. Wetzker et al., 2004. These publications contain comprehensive listings of the published patent specifications which describe the synthesis and use of low-molecular ras-Raf-Mek-Erk- and PI3K inhibitors.

The kinase inhibitor Bay 43-9006 (WO 99/32111, WO 03/068223) which is already undergoing clinical trials, shows a relatively non-specific inhibition pattern of serine/threonine and of tyrosine kinases such as Raf, VEGFR2/3, Flt-3, PDGFR, c-Kit and other kinases. Great importance is attached to this inhibitor in angiogenesis-induced advanced tumour diseases (e.g. in renal cell carcinoma) and also in melanomas having a high B-Raf mutation rate. The clinical effect of Bay 43-9006 is currently also being determined in patients presenting with refractory solid tumours in combination with, for example, Docetaxel. Mild side effects and promising anti-tumoral effects have been described so far. No inhibition of the kinases in the PI3K-Akt signal pathway has been described for Bay 43-9006.

The Mek1/2 inhibitor PD0325901 (WO 02/06213) is currently undergoing a Phase I clinical trial. The precursor substance CI-1040 (WO 00/35435, WO 00/37141) was striking because of its high Mek specificity and target affinity. However, this compound proved to be metabolically unstable in Phase I/II trials. No clinical data are available yet for the current successor substance PD0325901. However, no interaction with Erk1 or Erk2 nor any PI3K-Akt signal pathway inhibiting function or its simultaneous modulation has yet been disclosed for this Mek inhibitor.

Patent specifications WO 04/104002 and WO 04/104003 describe pyrido[2,3-b]pyrazines, which can be substituted in the 6- or 7-position with urea, thiourea, amidine or guanidine groups. These compounds possess properties as inhibitors or modulators of kinases, in particular of tyrosine and serine/threonine kinases, and a use as a medicament is specified. However, no use of these compounds as modulators of lipid kinases, alone or in combination with tyrosine and serine/threonine kinases has been described.

In addition, patent specification WO 99/17759 describes pyrido[2,3-b]pyrazines which, among other things, carry alkyl-, aryl- and heteroaryl-substituted carbamates in the 6-position. These compounds are to be used to modulate serine threonine protein kinases.

Patent specification WO 05/007099 describes, among other things, urea-substituted pyrido[2,3-b]pyrazines as inhibitors of the serine/threonine kinase PKB. A use in the treatment of cancer diseases is specified for these compounds. However, no specific examples of urea-substituted pyridopyrazines with these biological properties are given.

Further examples of pyrido[2,3-b]pyrazines substituted with urea in the 6- and 7-position are given in patent specification WO 05/056547. The compounds in this patent specification are described as inhibitors of protein kinases, in particular GSK-3, Syk and JAK-3. A use in the treatment of proliferative diseases is given for these compounds among other things. No use of these compounds as modulators of lipid kinases, alone or in combination with serine/threonine kinases is described.

The patent application WO 04/005472 describes, among other things pyrido[2,3-b]pyrazines substituted with carbamate in the 6-position which inhibit the growth of bacteria as antibacterial substances. No antitumour effect is described.

Certain diphenyl quinoxalines and pyrido[2,3-b]pyrazines with special alkylpyrrolidine, alkylpiperidine or alkyl sulfonamides group at a phenyl ring which can additionally also bear urea or carbamate substitutions in the 6- or 7-position are described in patent specifications WO 03/084473, WO 03/086394 and WO 03/086403 as inhibitors of the activity of the serine/threonine kinase Akt. A use in the treatment of cancer diseases is specified for these compounds. No defined indication of a biological effect is given for the pyrido[2,3-b]pyrazine compounds described therein as examples.

Patent specification WO 03/024448 describes amide and acrylamide-substituted pyrido[2,3-b]pyrazines which can also contain carbamates as additional substituents and can be used as histone deacetylase inhibitors for the treatment of cell proliferation diseases.

In another publication (Temple C. et al. 1990) the synthesis of a 6-ethylcarbamate-substituted pyrido[2,3-b]pyrazine derivative is described as one example. No antitumour effect is disclosed or made obvious.

The synthesis of further derivatives of 6-ethylcarbamate-substituted pyrido[2,3-b]pyrazine is described in a publication by R. D. Elliott (J. Org. Chem. 1968). No biological effect of these compounds is described or disclosed.

The publication by C. Temple (1968) describes the synthesis and investigation of 6-ethylcarbamate-substituted pyrido[2,3-b]pyrazines as potential antimalarial drugs. No antitumour effect is disclosed or made obvious.

The PI3K inhibitors published so far are undergoing preclinical trials. ICOS disclosed a PI3K inhibitor IC87114 with high PI3Kdelta isoenzyme specificity (WO 01/81346). For PI103 (WO 04/017950) Yamanouchi/Piramed describe a selectivity versus the PI3Kalpha isoform. In addition, a research environment which has attracted a great deal of attention exists in the early development of PI3K inhibitors (see the review of R. Wetzker et al., 2004).

Inhibitors of the SAPK signal pathway, either of Jnk or of p38 have been described in the literature (Gum R. J., 1998, Bennett B. L. et al 2001, Davies S. P. et al 2000). However, no PI3K-inhibiting function and also no specific inhibition of Erk1 or Erk2 or simultaneous inhibition of SAPKs, Erk1, Erk2, or PI3Ks is disclosed for these SAPK inhibitors.

DESCRIPTION OF THE INVENTION

The object of the present invention is to provide new compounds which can be used for the treatment or prevention of physiological and/or pathophysiological states in mammals, in particular in humans, which are mediated by signal transduction pathways selected from the group consisting of: â€œras-Raf-Mek-Erk signal transduction pathway, PI3K-Akt signal transduction pathway and/or SAPK signal transduction pathwayâ€ . A further object of the invention is to provide new compounds for the aforesaid uses by modulation of said signal transduction pathways. It is further the object of the present invention to provide new compounds which can be used for the treatment or prevention of physiological and/or pathophysiological states in mammals, in particular in humans, which are mediated by enzymes selected from the group consisting of: â€œATM, ATR, mTOR, DNA-PK, hSMG-1â€ . A further object of the invention is to provide new compounds for the aforesaid uses by modulation of said enzymes.

The inventive object was surprisingly achieved in one aspect by preparing a compound according to the general formula (I) [Image Omitted]
wherein the substituents R1, R2, R3, R4 have the following meaning:
R1 and R can be independently of one another
(i) hydrogen
(ii) hydroxyl
(iii) halogen
(iv) alkyl, wherein the alkyl group is saturated and can consists of 1 to 8 C atoms,
(v) unsubstituted or substituted aryl, wherein the alkyl group can be substituted with one or more, the same or different F, Cl, Br, I, CF₃, CN, NH₂, NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-NH₂, NH-alkyl-OH, N(alkyl)₂, NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHC(O)-alkyl-aryl, NHC(O)-alkyl-heteroaryl, NHSO₂-alkyl, NHSO₂-cycloalkyl, NHSO₂-heterocyclyl, NHSO₂-aryl, NHSO₂-heteroaryl, NHSO₂-alkyl-aryl, NHSO₂-alkyl-heteroaryl, NO₂, SH, S-alkyl, S-aryl, S-heteroaryl, OH, OCF₃, O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aryl, O-alkyl-heteroaryl, O-alkyl-OH, Oâ€”(CH₂)_nâ€”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, OSO₂-alkyl, OSO₂-cycloalkyl, OSO₂-heterocyclyl, OSO₂-aryl, OSO₂-heteroaryl, OSO₂-alkyl-aryl, OSO₂-alkyl-heteroaryl, OP(O)(OH)₂, C(O)-alkyl, C(O)-aryl, C(O)-heteroaryl, CO₂H, CO₂-alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂-aryl, CO₂-heteroaryl, CO₂-alkyl-cycloalkyl, CO₂-alkyl-heterocyclyl, CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl, C(O)â€”NH₂, C(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)₂, C(O)N(aryl)₂, C(O)N(heteroaryl)₂, SO-alkyl, SO-aryl, SO₂-alkyl, SO₂-aryl, 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 can have the value 1, 2 or 3 and the alkyl-, cycloalkyl-, heterocyclyl-, aryl-, heteroaryl-, alkyl-cycloalkyl-, alkyl-heterocyclyl-, alkyl-aryl- and alkyl-heteroaryl substituents for their part can in turn be substituted,
(vi) unsubstituted or substituted heteroaryl, wherein the heteroaryl group can be substituted with one or more, the same or different F, Cl, Br, I, CF₃, CN, NH₂, NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-NH₂, NH-alkyl-OH, N(alkyl)₂, NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHC(O)-alkyl-aryl, NHC(O)-alkyl-heteroaryl, NHSO₂-alkyl, NHSO₂-cycloalkyl, NHSO₂-heterocyclyl, NHSO₂-aryl, NHSO₂-heteroaryl, NHSO₂-alkyl-aryl, NHSO₂-alkyl-heteroaryl, NO₂, SH, S-alkyl, S-aryl, S-heteroaryl, OH, OCF₃, O-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, OSO₂-alkyl, OSO₂-cycloalkyl, OSO₂-heterocyclyl, OSO₂-aryl, OSO₂-heteroaryl, OSO₂-alkyl-aryl, OSO₂-alkyl-heteroaryl, OP(O)(OH)₂, C(O)-alkyl, C(O)-aryl, C(O)-heteroaryl, CO₂H, CO₂-alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂-aryl, CO₂-heteroaryl, CO₂-alkyl-cycloalkyl, CO₂-alkyl-heterocyclyl, CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl, C(O)â€”NH₂, C(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)₂, C(O)N(aryl)₂, C(O)N(heteroaryl)₂, SO₂NH₂, SO₂NH-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl, SO₂NH-alkyl-aryl, SO₃H, SO₂O-alkyl, SO₂O-aryl, SO₂O-alkyl-aryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the alkyl-, cycloalkyl-, heterocyclyl-, aryl- and heteroaryl substituents for their part can in turn be substituted,
(vii) OR5, wherein R5 can be alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkyl-cycloalkyl, alkyl-heterocyclyl, alkyl-aryl or alkyl-heteroaryl, and the alkyl-, cycloalkyl-, heterocyclyl-, aryl-, heteroaryl-, alkyl-cycloalkyl, alkyl-heterocyclyl, alkyl-aryl or alkyl-heteroaryl substituents for their part can in turn be substituted,
(viii) SR6, wherein R6 can be alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkyl-cycloalkyl, alkyl-heterocyclyl, alkyl-aryl or alkyl-heteroaryl and the alkyl-, cycloalkyl-, heterocyclyl-, aryl- and heteroaryl-, alkyl-cycloalkyl-, alkyl-heterocyclyl-, alkyl-aryl- or alkyl-heteroaryl substituents for their part can in turn be substituted,
(ix) NR7R8, wherein R7 and R8 independently of one another can be hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkyl-cycloalkyl, alkyl-heterocyclyl, alkyl-aryl or alkyl-heteroaryl and the alkyl-, cycloalkyl-, heterocyclyl-, aryl- and heteroaryl-, alkyl-cycloalkyl, alkyl-heterocyclyl, alkyl-aryl or alkyl-heteroaryl substituents for their part can in turn be substituted,
or R7 and R8 together mean cycloalkyl or heterocyclyl, wherein cycloalkyl and heterocyclyl for their part can in turn be substituted.
R3 and R4 can independently of one another mean hydrogen or NR9R10 assuming that if R3=NR9R110, R4=H, and if R4=NR9R110, R3=H,
wherein R9 can be hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, alkyl-cycloalkyl, alkyl-heterocyclyl, alkyl-aryl or alkyl-heteroaryl and the alkyl-, cycloalkyl-, heterocyclyl-, aryl- and heteroaryl-, alkyl-cycloalkyl, alkyl-heterocyclyl, alkyl-aryl or alkyl-heteroaryl substituents for their part can in turn be substituted,
and R10:
can mean â€”C(Y)NR11R12, wherein Y=O, S and R11 and R12 can be independently of one another
(i) hydrogen,
(ii) unsubstituted or substituted alkyl wherein the alkyl group can be substituted with one or more, the same or different F, Cl, Br, I, CF₃, CN, NH₂, NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, N(alkyl)₂, NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHC(O)-alkyl-aryl, NHC(O)-alkyl-heteroaryl, NHSO₂-alkyl, NHSO₂-cycloalkyl, NHSO₂-heterocyclyl, NHSO₂-aryl, NHSO₂-heteroaryl, NHSO₂-alkyl-aryl, NHSO₂-alkyl-heteroaryl, NO₂, SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF₃, O-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, OSO₂-alkyl, OSO₂-cycloalkyl, OSO₂-heterocyclyl, OSO₂-aryl, OSO₂-heteroaryl, OSO₂-alkyl-aryl, OSO₂-alkyl-heteroaryl, OP(O)(OH)₂, C(O)-alkyl, C(O)-aryl, C(O)-heteroaryl, CO₂H, CO₂-alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂-aryl, CO₂-heteroaryl, CO₂-alkyl-cycloalkyl, CO₂-alkyl-heterocyclyl, CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl, C(O)â€”NH₂, C(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)₂, C(O)N(aryl)₂, C(O)N(heteroaryl)₂, SO-alkyl, SO-aryl, SO₂-alkyl, SO₂-aryl, SO₂NH₂, SO₂NH-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl, SO₂NH-alkyl-aryl, SO₃H, SO₂O-alkyl, SO₂O-aryl, SO₂O-alkyl-aryl, cycloalkyl, heterocyclyl, aryl or heteroaryl,
(iii) unsubstituted or substituted cycloalkyl, wherein the cycloalkyl group can be substituted with one or more, the same or different F, Cl, Br, I, NH₂, NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, N(alkyl)₂, NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHC(O)-alkyl-aryl, NHC(O)-alkyl-heteroaryl, NHSO₂-alkyl, NHSO₂-cycloalkyl, NHSO₂-heterocyclyl, NHSO₂-aryl, NHSO₂-heteroaryl, NHSO₂-alkyl-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, OSO₂-alkyl, OSO₂-cycloalkyl, OSO₂-heterocyclyl, OSO₂-aryl, OSO₂-heteroaryl, OSO₂-alkyl-aryl, OSO₂-alkyl-heteroaryl, OP(O)(OH)₂, CO₂H, CO₂-alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂-aryl, CO₂-heteroaryl, CO₂-alkyl-cycloalkyl, CO₂-alkyl-heterocyclyl, CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl, C(O)â€”NH₂, C(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)₂, C(O)N(aryl)₂, C(O)N(heteroaryl)₂, alkyl, or aryl,
(iv) unsubstituted or substituted heterocyclyl, wherein the heterocyclyl group can be substituted with one or more, the same or different OH, O-alkyl, O-aryl, NH₂, NH-alkyl, NH-aryl, alkyl, alkyl-aryl or aryl,
(v) unsubstituted or substituted aryl, wherein the aryl group can be substituted with one or more, the same or different F, Cl, Br, I, CF₃, CN, NH₂, NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-NH₂, NH-alkyl-OH, N(alkyl)₂, NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHC(O)-alkyl-aryl, NHC(O)-alkyl-heteroaryl, NHSO₂-alkyl, NHSO₂-cycloalkyl, NHSO₂-heterocyclyl, NHSO₂-aryl, NHSO₂-heteroaryl, NHSO₂-alkyl-aryl, NHSO₂-alkyl-heteroaryl, NO₂, SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF₃, O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aryl, O-alkyl-heteroaryl, O-alkyl-OH, Oâ€”(CH₂)_nâ€”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, OSO₂-alkyl, OSO₂-cycloalkyl, OSO₂-heterocyclyl, OSO₂-aryl, OSO₂-heteroaryl, OSO₂-alkyl-aryl, OSO₂-alkyl-heteroaryl, OP(O)(OH)₂, C(O)-alkyl, C(O)-aryl, C(O)-heteroaryl, CO₂H, CO₂-alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂-aryl, CO₂-heteroaryl, CO₂-alkyl-cycloalkyl, CO₂-alkyl-heterocyclyl, CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl, C(O)â€”NH₂, C(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)₂, C(O)N(aryl)₂, C(O)N(heteroaryl)₂, SO-alkyl, SO-aryl, SO₂-alkyl, SO₂-aryl, SO₂NH₂, SO₂NH-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl, SO₂NH-alkyl-aryl, SO3H, SO₂O-alkyl, SO₂O-aryl, SO₂O-alkyl-aryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and n can have the value 1, 2 or 3,
(vi) unsubstituted or substituted heteroaryl, wherein the heteroaryl group can be substituted with one or more, the same or different F, Cl, Br, I, CF₃, CN, NH₂, NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-NH₂, NH-alkyl-OH, N(alkyl)₂, NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHC(O)-alkyl-aryl, NHC(O)-alkyl-heteroaryl, NHSO₂-alkyl, NHSO₂-cycloalkyl, NHSO₂-heterocyclyl, NHSO₂-aryl, NHSO₂-heteroaryl, NHSO₂-alkyl-aryl, NHSO₂-alkyl-heteroaryl, NO₂, SH, S-alkyl, S-aryl, S-heteroaryl, OH, OCF₃, O-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, OSO₂-alkyl, OSO₂-cycloalkyl, OSO₂-heterocyclyl, OSO₂-aryl, OSO₂-heteroaryl, OSO₂-alkyl-aryl, OSO₂-alkyl-heteroaryl, OP(O)(OH)₂, C(O)-alkyl, C(O)-aryl, C(O)-heteroaryl, CO₂H, CO₂-alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂-aryl, CO₂-heteroaryl, CO₂-alkyl-cycloalkyl, CO₂-alkyl-heterocyclyl, CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl, C(O)â€”NH₂, C(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)₂, C(O)N(aryl)₂, C(O)N(heteroaryl)₂, SO₂NH₂, SO₂NH-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl, SO₂NH-alkyl-aryl, SO₃H, SO₂O-alkyl, SO₂O-aryl, SO₂O-alkyl-aryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl,
(vii) â€”C(O)â€”R17, wherein R17 can be alkyl, aryl or heteroaryl and the alkyl and aryl substituents for their part can in turn be substituted,
(viii) or R11 and R12 together can mean cycloalkyl or heterocyclyl,
can mean â€”C(Y)NR13R14 wherein Yâ• NH and R13 and R14 can be independently of one another,
(i) hydrogen,
(ii) unsubstituted or substituted aryl, wherein the aryl group can be substituted with one or more, the same or different F, Cl, Br, I, CF₃, CN, NH₂, NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, N(alkyl)₂, NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHSO₂-alkyl, NHSO₂-cycloalkyl, NHSO₂-aryl, NHSO₂-heteroaryl, NO₂, SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF₃, O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-aryl, O-alkyl-heteroaryl, OC(O)-alkyl, OC(O)-cycloalkyl, OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl, OSO₂-alkyl, OSO₂-cycloalkyl, OSO₂-aryl, OSO₂-heteroaryl, C(O)-alkyl, C(O)-aryl, CO₂H, CO₂-alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂-aryl, CO₂-heteroaryl, CO₂-alkyl-cycloalkyl, CO₂-alkyl-heterocyclyl, CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl, C(O)â€”NH₂, C(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)₂, C(O)N(aryl)₂, C(O)N(heteroaryl)₂, SO-alkyl, SO-aryl, SO₂-alkyl, SO₂-aryl, SO₂NH₂, SO₃H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl,
(iii) unsubstituted or substituted cycloalkyl, wherein the cycloalkyl group can be substituted with one or more, the same or different F, Cl, Br, I, NH₂, NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, N(alkyl)₂, NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHSO₂-alkyl, NHSO₂-cycloalkyl, NHSO₂-aryl, NHSO₂-heteroaryl, OH, O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-aryl, O-alkyl-heteroaryl, OC(O)-alkyl, OC(O)-cycloalkyl, OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl, OSO₂-alkyl, OSO₂-cycloalkyl, OSO₂-aryl, OSO₂-heteroaryl, CO₂H, CO₂-alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂-aryl, CO₂-heteroaryl, C(O)â€”NH₂, C(O)NH-alkyl, C(O)NH-cycloalkyl, C(O)NH-heterocyclyl, C(O)NH-aryl, C(O)NH-heteroaryl, C(O)NH-alkyl-aryl, C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)₂, alkyl, or aryl,
(iv) unsubstituted or substituted heterocyclyl, wherein the heterocyclyl group can be substituted with one or more, the same or different OH, O-alkyl, O-aryl, NH₂, NH-alkyl, NH-aryl, alkyl, or aryl,
(v) unsubstituted or substituted aryl, wherein the aryl group can be substituted with one or more, the same or different F, Cl, Br, I, CF₃, CN, NH₂, NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-NH₂, NH-alkyl-OH, N(alkyl)₂, NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHSO₂-alkyl, NHSO₂-aryl, NHSO₂-heteroaryl, NO₂, SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF₃, O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aryl, O-alkyl-heteroaryl, O-alkyl-OH, Oâ€”(CH₂)_nâ€”O, OC(O)-alkyl, OC(O)-cycloalkyl, OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl, OSO₂-alkyl, OSO₂-cycloalkyl, OSO₂-aryl, OSO₂-heteroaryl, C(O)-alkyl, C(O)-aryl, C(O)-heteroaryl, CO₂H, CO₂-alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂-aryl, CO₂-heteroaryl, CO₂-alkyl-cycloalkyl, CO₂-alkyl-heterocyclyl, CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl, C(O)â€”NH₂, C(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)₂, C(O)N(aryl)₂, C(O)N(heteroaryl)₂, SO-alkyl, SO-aryl, SO₂-alkyl, SO₂-aryl, SO₂NH₂, SO₂NH-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl, SO₃H, SO₂O-alkyl, SO₂O-aryl, SO₂O-heteroaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and n can have the value 1, 2 or 3,
(vi) unsubstituted or substituted heteroaryl, wherein the heteroaryl group can be substituted with one or more, the same or different F, Cl, Br, I, CF₃, CN, NH₂, NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, N(alkyl)₂, NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHSO₂-alkyl, NHSO₂-aryl, NHSO₂-heteroaryl, NO₂, SH, S-alkyl, S-aryl, OH, OCF₃, O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, OC(O)-alkyl, OC(O)-cycloalkyl, OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl, OSO₂-alkyl, OSO₂-cycloalkyl, OSO₂-aryl, OSO₂-heteroaryl, C(O)-alkyl, C(O)-aryl, C(O)-heteroaryl, CO₂H, CO₂-alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂-aryl, CO₂-heteroaryl, CO₂-alkyl-cycloalkyl, CO₂-alkyl-heterocyclyl, CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl, C(O)â€”NH₂, C(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)₂, C(O)N(aryl)₂, C(O)N(heteroaryl)₂, SO₂-alkyl, SO₂-aryl, SO₂NH₂, SO₂NH-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl, SO₃H, SO₂O-alkyl, SO₂O-aryl, SO₂O-heteroaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl,
(vii) or R13 and R14 together can mean cycloalkyl or heterocyclyl,
can mean â€”C(NR15)R16, wherein R15=H and R16 can be
(i) unsubstituted or substituted alkyl, wherein the alkyl group can be substituted with one or more, the same or different F, Cl, Br, I, CF₃, NH₂, NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, N(alkyl)₂, NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHSO₂-alkyl, NHSO₂-cycloalkyl, NHSO₂-aryl, NHSO₂-heteroaryl, NO₂, SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF₃, O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-aryl, O-alkyl-heteroaryl, OC(O)-alkyl, OC(O)-cycloalkyl, OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl, OSO₂-alkyl, OSO₂-cycloalkyl, OSO₂-aryl, OSO₂-heteroaryl, C(O)-alkyl, C(O)-aryl, CO₂H, CO₂-alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂-aryl, CO₂-heteroaryl, CO₂-alkyl-cycloalkyl, CO₂-alkyl-heterocyclyl, CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl, C(O)â€”NH₂, C(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)₂, C(O)N(aryl)₂, C(O)N(heteroaryl)₂, SO-alkyl, SO-aryl, SO₂-alkyl, SO₂-aryl, SO₂NH₂, SO₃H, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl,
(ii) unsubstituted or substituted cycloalkyl, wherein the cycloalkyl group can be substituted with one or more, the same or different F, Cl, Br, I, NH₂, NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, N(alkyl)₂, NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHSO₂-alkyl, NHSO₂-cycloalkyl, NHSO₂-aryl, NHSO₂-heteroaryl, OH, O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-aryl, O-alkyl-heteroaryl, OC(O)-alkyl, OC(O)-cycloalkyl, OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl, OSO₂-alkyl, OSO₂-cycloalkyl, OSO₂-aryl, OSO₂-heteroaryl, CO₂H, CO₂-alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂-aryl, CO₂-heteroaryl, C(O)â€”NH₂, C(O)NH-alkyl, C(O)NH-cycloalkyl, C(O)NH-heterocyclyl, C(O)NH-aryl, C(O)NH-heteroaryl, C(O)NH-alkyl-aryl, C(O)NH-alkyl-heteroaryl, C(O)N(alkyl)₂, alkyl, or aryl,
(iii) unsubstituted or substituted heterocyclyl, wherein the heterocyclyl group can be substituted with one or more, the same or different OH, O-alkyl, O-aryl, NH₂, NH-alkyl, NH-aryl, alkyl or aryl,
(iv) unsubstituted or substituted aryl, wherein the aryl group can be substituted with one or more, the same or different F, Cl, Br, I, CF₃, NH₂, NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-cycloalkyl, NH-alkyl-heterocyclyl, NH-alkyl-aryl, NH-alkyl-heteroaryl, NH-alkyl-NH₂, NH-alkyl-OH, N(alkyl)₂, NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHSO₂-alkyl, NHSO₂-aryl, NHSO₂-heteroaryl, NO₂, SH, S-alkyl, S-cycloalkyl, S-heterocyclyl, S-aryl, S-heteroaryl, OH, OCF₃, O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, O-alkyl-cycloalkyl, O-alkyl-heterocyclyl, O-alkyl-aryl, O-alkyl-heteroaryl, O-alkyl-OH, Oâ€”(CH₂)_nâ€”O, OC(O)-alkyl, OC(O)-cycloalkyl, OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl, OSO₂-alkyl, OSO₂-cycloalkyl, OSO₂-aryl, OSO₂-heteroaryl, C(O)-alkyl, C(O)-aryl, C(O)-heteroaryl, CO₂H, CO₂-alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂-aryl, CO₂-heteroaryl, CO₂-alkyl-cycloalkyl, CO₂-alkyl-heterocyclyl, CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl, C(O)â€”NH₂, C(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)₂, C(O)N(aryl)₂, C(O)N(heteroaryl)₂, SO-alkyl, SO-aryl, SO₂-alkyl, SO₂-aryl, SO₂NH₂, SO₂NH-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl, SO₃H, SO₂O-alkyl, SO₂O-aryl, SO₂O-heteroaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and n can have the value 1, 2 or 3,
(v) unsubstituted or substituted heteroaryl, wherein the heteroaryl group can be substituted with one or more, the same or different F, Cl, Br, I, CF₃, NH₂, NH-alkyl, NH-cycloalkyl, NH-heterocyclyl, NH-aryl, NH-heteroaryl, NH-alkyl-aryl, NH-alkyl-heteroaryl, N(alkyl)₂, NHC(O)-alkyl, NHC(O)-cycloalkyl, NHC(O)-heterocyclyl, NHC(O)-aryl, NHC(O)-heteroaryl, NHSO₂-alkyl, NHSO₂-aryl, NHSO₂-heteroaryl, NO₂, SH, S-alkyl, S-aryl, OH, OCF₃, O-alkyl, O-cycloalkyl, O-heterocyclyl, O-aryl, O-heteroaryl, OC(O)-alkyl, OC(O)-cycloalkyl, OC(O)-heterocyclyl, OC(O)-aryl, OC(O)-heteroaryl, OSO₂-alkyl, OSO₂-cycloalkyl, OSO₂-aryl, OSO₂-heteroaryl, C(O)-alkyl, C(O)-aryl, C(O)-heteroaryl, CO₂H, CO₂-alkyl, CO₂-cycloalkyl, CO₂-heterocyclyl, CO₂-aryl, CO₂-heteroaryl, CO₂-alkyl-cycloalkyl, CO₂-alkyl-heterocyclyl, CO₂-alkyl-aryl, CO₂-alkyl-heteroaryl, C(O)â€”NH₂, C(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)₂, C(O)N(aryl)₂, C(O)N(heteroaryl)₂, SO₂-alkyl, SO₂-aryl, SO₂NH₂, SO₂NH-alkyl, SO₂NH-aryl, SO₂NH-heteroaryl, SO3H, SO₂O-alkyl, SO₂O-aryl, SO₂O-heteroaryl, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
which can be used for the production of a medicament for the treatment or prevention of physiological and/or pathophysiological states in mammals mediated by signal transduction pathways selected from the group consisting of: the â€œras-Raf-Mek-Erk signal transduction pathway, the PI3K-Akt signal transduction pathway and/or the SAPK signal transduction pathway.

In a preferred embodiment, compounds according to the general formula (I) are prepared, wherein the alkyl group is selected from the group consisting of: â€œmethyl, ethyl, n-propyl, 2-propyl, n-butyl, sec.-butyl, tert.-butyl, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl, 2-hexyl, n-octyl, ethylenyl (vinyl), ethynyl, propenyl (â€”CH2CHâ• CH2; â€”CHâ• CHâ€”CH3, â€”C(â• CH2)-CH3), propinyl (â€”CH2-Câ‰¡CH, â€”Câ‰¡Câ€”CH3), butenyl, butinyl, pentenyl, pentinyl, hexenyl, hexinyl, heptenyl, heptinyl, octenyl, octinylâ€ which can be used for the production of a medicament for the treatment or prevention of physiological and/or pathophysiological states in mammals mediated by signal transduction pathways selected from the group consisting of: the â€œras-Raf-Mek-Erk signal transduction pathway, the PI3K-Akt signal transduction pathway and/or the SAPK signal transduction pathway.

In a further preferred embodiment, compounds according to the general formula (I) are prepared for the aforementioned use, wherein the heterocyclyl group is selected from the group consisting of: â€œtetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinylâ€ .

In a further preferred embodiment, compounds according to the general formula (I) are prepared for the aforementioned use, wherein the heteroaryl group is selected from the group consisting of: â€œpyrrolyl, furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, phthalazinyl, indolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, carbazolyl, phenazinyl, phenothiazinyl, acridinylâ€ .

In a further preferred embodiment compounds according to the general formula (I) are prepared for the aforementioned use, wherein the alkyl group is selected from the group consisting of: â€œmethyl, ethyl, n-propyl, 2-propyl, n-butyl, sec.-butyl, tert.-butyl, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl, 2-hexyl, n-octyl, ethylenyl (vinyl), ethynyl, propenyl (â€”CH2CHâ• CH2; â€”CHâ• CHâ€”CH3, â€”C(â• CH2)-CH3), propinyl (â€”CH2-Câ‰¡CH, â€”Câ‰¡Câ€”CH3), butenyl, butinyl, pentenyl, pentinyl, hexenyl, hexinyl, heptenyl, heptinyl, octenyl, octinylâ€ and/or wherein the heterocyclyl group is selected from the group consisting of: â€œtetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinylâ€ and/or the heteroaryl group is selected from the group consisting of: â€œpyrrolyl, furyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, phthalazinyl, indolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, carbazolyl, phenazinyl, phenothiazinyl, acridinylâ€ .

The inventive object was surprisingly achieved in a further aspect by preparing pyridopyrazine compounds selected from the group consisting of: [Image Omitted]
which can be used for the production of a medicament for the treatment or prevention of physiological and/or pathophysiological states in mammals mediated by signal transduction pathways selected from the group consisting of: the â€œras-Raf-Mek-Erk signal transduction pathway, the PI3K-Akt signal transduction pathway and/or the SAPK signal transduction pathway.

In order to avoid ambiguities: when chemical structure and chemical name of the explicit compounds shown above erroneously do not match one another, the chemical structure shall unambiguously define the particular explicit compound.

The afore-mentioned generic compounds having the general formula (I) and preferred embodiments as well as the explicitly specified pyridopyrazine compounds 1 to 269 are hereinafter designated jointly as â€œcompounds according to the inventionâ€ .

The expressions and terms specified to explain the compounds according to the invention having the general formula (I), the preferred embodiments and compounds 1 to 269 basically have the following meanings unless specified otherwise in the description and the claims:

In the context of this invention, the expression â€œalkylâ€ encompasses acyclic saturated or unsaturated hydrocarbon radicals which may be branched or straight-chain and have 1 to 8 carbon atoms, i.e. C_1-8-alkanyls, C_2-8-alkenyls and C_2-8-alkynyls. Alkenyls have at least one Câ€”C double bond and alkynyls at least one Câ€”C triple bond. Alkynyls may additionally also have at least one Câ€”C double bond. Preferred alkyl radicals are methyl, ethyl, n-propyl, 2-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl, 2-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, ethylenyl (vinyl), ethynyl, propenyl (â€”CH₂CHâ• CH₂; â€”CHâ• CHâ€”CH₃, â€”C(â• CH₂)â€”CH₃), propynyl (â€”CH₂â€”Câ‰¡CH, â€”Câ‰¡Câ€”CH₃), butenyl, butynyl, pentenyl, pentynyl, hexenyl, hexynyl, heptenyl, heptynyl, octenyl, octadienyl and octynyl.

For the purposes of this invention, the expression â€œcycloalkylâ€ means cyclic nonaromatic hydrocarbons having 1 to 3 rings with 3 to 20, preferably 3 to 12 carbon atoms, which may be saturated or unsaturated, more preferably (C₃-C₈)cycloalkyl. The cycloalkyl radical may also be part of a bi- or polycyclic system, where, for example, the cycloalkyl radical is fused to an aryl, heteroaryl or heterocyclyl radical as defined herein by any possible and desired ring member(s).

The bonding to the compounds of the general formula (I) can be effected via any possible ring member of the cycloalkyl radical. Preferred cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclohexenyl, cyclopentenyl and cyclooctadienyl.

The expression â€œheterocyclylâ€ represents a 3- to 14-membered, preferably 3-, 4-, 5-, 6-, 7- or 8-membered, cyclic organic radical which contains at least 1 heteroatom, optionally 2, 3, 4 or 5 heteroatoms, especially nitrogen, oxygen and/or sulphur, the heteroatoms being the same or different and the cyclic radical being saturated or unsaturated but not aromatic. The heterocyclyl radical may also be part of a bi- or polycyclic system, where, for example, the heterocyclyl radical is fused to an aryl, heteroaryl or cycloalkyl radical as defined herein by any possible and desired ring member(s). The bonding to the compounds of the general formula (I) can be effected via any possible ring member of the heterocyclyl radical. Preferred heterocyclyl radicals are tetrahydrofuryl, pyrrolidinyl, imidazolidinyl, thiazolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiapyrrolidinyl, oxapiperazinyl, oxapiperidinyl and oxadiazolyl.

In the context of this invention, the expression â€œarylâ€ means aromatic hydrocarbons having 3 to 14 carbon atoms, preferably 5 to 14 carbon atoms, more preferably 6 to 14 carbon atoms. The aryl radical may also be part of a bi- or polycyclic system, where, for example, the aryl radical is fused to a heterocyclyl, heteroaryl or cycloalkyl radical as defined herein by any possible and desired ring member(s), for example to tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, thiazolidine, tetrahydropyran, dihydropyran, piperidine, furan, thiophene, imidazole, thiazole, oxazole, isoxazole. The bonding to the compounds of the general formula (I) can be effected via any possible ring member of the aryl radical. Preferred aryl radicals are phenyl, biphenyl, naphthyl and anthracenyl, but likewise indanyl, indenyl or 1,2,3,4-tetrahydronaphthyl.

The expression â€œheteroarylâ€ represents a 5-, 6- or 7-membered cyclic aromatic radical which contains at least 1 heteroatom, if appropriate also 2, 3, 4 or 5 heteroatoms, especially nitrogen, oxygen and/or sulphur, the heteroatoms being the same or different. The number of nitrogen atoms is preferably 0 to 3, that of oxygen and sulphur atoms preferably 0 or 1. The heteroaryl radical may also be part of a bi- or polycyclic system, where, for example, the heteroaryl radical is fused to a heterocyclyl, aryl or cycloalkyl radical as defined herein by any possible and desired ring member(s). The bonding to the compounds of the general formula (I) can be effected via any possible ring member of the heteroaryl radical. Preferred heteroaryl radicals are pyrrolyl, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazole, tetrazole, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, phthalazinyl, indolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, carbazolyl, phenazinyl, phenoxazinyl, phenothiazinyl, and acridinyl.

For the purposes of the present invention, the expressions â€œalkyl-cycloalkylâ€ , â€œcycloalkylalkylâ€ , â€œalkyl-heterocyclylâ€ , â€œheterocyclylalkylâ€ , â€œalkyl-arylâ€ , â€œarylalkylâ€ , â€œalkyl-heteroarylâ€ and â€œheteroarylalkylâ€ mean that alkyl, cycloalkyl, heterocycl, aryl and heteroaryl are each as defined above, and the cycloalkyl, heterocyclyl, aryl and heteroaryl radical is bonded to the compounds of the general formula (I) via an alkyl radical, preferably C₁-C₈-alkyl radical, more preferably C₁-C₄-alkyl radical.

In connection with â€œalkylâ€ , â€œcycloalkylâ€ , â€œheterocyclylâ€ , â€œarylâ€ , â€œheteroarylâ€ , alkyl-cycloalkylâ€ , â€œalkyl-heterocyclylâ€ , â€œalkyl-arylâ€ and â€œalkyl-heteroarylâ€ the term substituted is understood in the sense of this invention unless defined explicitly above in the description and the claims as the substitution of one or more hydrogen groups by F, Cl, Br, I, CN, CF₃, NH₂, NH-alkyl, NH-aryl, N(alkyl)₂, NO₂, SH, S-alkyl, OH, OCF₃, O-alkyl, O-aryl, OSO₃H, OP(O)(OH)₂, CHO, CO₂H, SO₃H or alkyl. The substituents can be the same or different and the substitutions can take place in any arbitrary and possible position of the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group.

In the context of this invention, the expression â€œhalogenâ€ encompasses the halogen atoms fluorine, chlorine, bromine and iodine.

Multiply substituted groups are to be understood as those which are multiply, e.g. doubly, triply, substituted either at different or at the same atoms, for example, triply substituted at the same C atoms as in the case of CF₃, â€”CH₂CF₃or at different positions as in the case of â€”CH(OH)â€”CHâ• CHâ€”CHCl₂. The multiple substitution can take place with the same or different substituents.

Insofar as the compounds according to the invention have at least one centre of asymmetry, they can 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 mixtures can be present in any arbitrary mixture ratio of the stereoisomers.

Thus, for example, the compounds according to the invention which have one or a plurality of centres of chirality and which occur as their racemates can be separated into their optical isomers, that is enantiomers or diastereomers, by methods known per se. The separation can be performed by column separation at chiral phases or by recrystallisation from an optically active solvent or by using an optically active acid or base or by derivatisation with an optically active reagent, such as for example, an optically active alcohol and subsequent separation of the residue.

The inventive compounds may be present in the form of their double bond isomers as â€œpureâ€ E or Z isomers, or in the form of mixtures of these double bond isomers.

As far as possible, the compounds according to the invention can be present in the form of tautomers.

If they possess a sufficiently basic group, such as for example, a primary, secondary or tertiary amine, the compounds according to the invention can be converted into their physiologically compatible salts using inorganic and organic acids. The pharmaceutically acceptable salts of the compounds according to the invention are preferably formed with hydrochloric acid, bromic acid, sulphuric acid, phosphoric acid, methane sulfonic acid, p-toluene sulfonic acid, carbonic acid, formic acid, acetic acid, trifluoroacetic acid, sulfoacetic acid, oxalic acid, malonic acid, maleic acid, succinic acid, tartaric acid, racemic acid, malic acid, embonic acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid or asparaginic acid. The salts formed include, among others, hydrochloride, hydrobromide, sulfate, hydrogen sulfate, phosphate, methane sulfonate, tosylate, carbonate, hydrogen carbonate, formiate, acetate, triflate, sulfoacetate, oxalate, malonate, maleate, succinate, tartrate, malate, embonate, mandelate, fumarate, lactate, citrate, glutaminate and aspartate. The stoichiometry of the salts of the compounds according to the invention which are formed can be integer or non-integer multiples of one.

If they contain a sufficiently acidic group, such as the carboxy group, for example, the compounds according to the invention can be converted into their physiologically compatible salts using inorganic and organic bases. Possible inorganic bases are, for example, sodium hydroxide, potassium hydroxide, calcium hydroxide, possible organic bases are ethanol amine, diethanol amine, triethanol amine, cyclohexylamine, dibenzylethylene diamine and lysine. The stoichiometry of the salts of the compounds according to the invention which are formed can be integer or non-integer multiples of one.

Likewise preferred are solvates and in particular hydrates of the compounds according to the invention, which can be obtained, for example, by crystallisation from a solvent or from aqueous solution. In this context, one, two, three or an arbitrary number of solvate or water molecules can combine with the compounds according to the invention to form solvates and hydrates.

It is known that chemical substances form solids which are present in various states of order, which are designated as polymorphous forms or modifications. The various modifications of a polymorphous substance can differ strongly in respect of their physical properties. The compounds according to the invention can be present in various polymorphous forms, in which case certain modifications can be metastable.

The compounds according to the invention can likewise be present in the form of any prodrugs such as, for example, esters, carbonates, carbamates, ureas, amides or phosphates, wherein the actually biologically active form is only released by catabolism.

It is further known that chemical substances are converted to metabolites in the body which optionally can likewise induce the desired biological effect, possibly even in a more distinct form.

Corresponding prodrugs and metabolites of the compounds according to the invention should also be considered as pertaining to the invention.

It was now surprisingly and advantageously determined that the compounds according to the invention can act simultaneously or have a modulating or inhibiting effect on two or more signal transduction pathways or enzymes. In this context, it has been found that the compounds according to the invention can act or have a modulating or inhibiting effect with high selectivity.

Such a simultaneous, for example, dual modulation or inhibition of two or more signal transduction pathways, e.g. the ras-Raf-Mek-Erk signal pathway, the PI3K-Akt signal pathway and/or the SAPK signal pathway, more especially Erk1/Erk2 and/or PI3K and/or Jnk and/or p38, is advantageous compared with merely single modulation or inhibition of a signal transduction pathway since synergistic therapeutic effects can be brought about, such as for example, intensified apoptosis and faster and more efficient tumour regression.

The surprising advantageous effects of the compounds according to the invention allow multiple therapy approaches to be pursued in physiological and/or pathophysiological states or clinical pictures which are sensitive for the treatment or modulation of, or are mediated by, two or more signal transduction pathways.

It was further surprisingly and advantageously determined that the compounds according to the invention can also act with high selectivity or have a modulating or inhibiting effect on the PI3K-Akt signal transduction pathway or enzymes thereof and that the multiple mechanisms of action and therapy approaches described above can also be used with this signal pathway or enzymes.

It was further surprisingly and advantageously determined that the compounds according to the invention can also act with high selectivity or have a modulating or inhibiting effect on the SAPK signal transduction pathway or enzymes thereof and that the multiple mechanisms of action and therapy approaches described above can also be used with this signal pathway or enzymes.

It was further surprisingly and advantageously determined that the compounds according to the invention can also act with high selectivity or have a modulating or inhibiting effect on enzymes such as ATM, ATR, mTOR, DNA-PK and/or hSMG-1 and that the multiple mechanisms of action and therapy approaches described above can also be used with this signal pathway or enzymes.

The term â€œmodulationâ€ is understood according to the invention as follows: â€œactivation, partial activation, inhibition, partial inhibitionâ€ . In this case, it is within the specialist knowledge of the average person skilled in the art to measure and determine such activation, partial activation, inhibition, partial inhibition by means of the usual methods of measurement and determination. Thus, a partial activation can be measured and determined in relation to a complete activation; likewise, a partial inhibition in relation to a complete inhibition.

The terms â€œinhibiting, inhibition and/or retardationâ€ are understood as follows according to the invention: â€œpartial or complete inhibiting, inhibition and/or retardationâ€ . In this case, it is within the specialist knowledge of the average person skilled in the art to measure and determine such inhibiting, inhibition, and/or retardation by means of the usual methods of measurement and determination. Thus, a partial inhibiting, inhibition and/or retardation, for example, can be measured and determined in relation to a complete inhibiting, inhibition and/or retardation.

The terms â€œmodulationâ€ and â€œinhibiting, inhibition and/or retardationâ€ in connection with â€œenzymesâ€ and/or â€œkinasesâ€ within the scope of this invention relate both to the inactive form (enzymatically inactive) and/or active form (enzymatically active) of the respective enzyme and/or kinase. This means within the scope of this invention that the compound according to the invention can have a modulating effect on the inactive form, active form or both forms of the enzyme and/or kinase.

In a further aspect, the inventive object was surprisingly achieved by preparing the compounds according to the invention which can be used to produce a medicament for the treatment or prevention of physiological and/or pathophysiological states in mammals, wherein the treatment or prevention is effected by modulation of the signal transduction pathway or pathways selected from the group consisting of: the â€œras-Raf-Mek-Erk signal transduction pathway, the PI3K-Akt signal transduction pathway and/or the SAPK signal transduction pathway.

In a further aspect, the inventive object was surprisingly achieved by preparing the compounds according to the invention which can be used to produce a medicament for the treatment or prevention of physiological and/or pathophysiological states in mammals, mediated by enzymes selected from the group consisting of: â€œATM, ATR, mTOR, DNA-PK, hSMG-1â€ .

In a further aspect, the inventive object was surprisingly achieved by preparing the compounds according to the invention which can be used to produce a medicament for the treatment or prevention of physiological and/or pathophysiological states in mammals, wherein the treatment or prevention is effected by modulation of one or more enzymes selected from the group consisting of: â€œATM, ATR, mTOR, DNA-PK, hSMG-1â€ .

In a preferred embodiment, the compounds according to the invention are prepared for use to produce a medicament for the treatment or prevention of physiological and/or pathophysiological states in mammals mediated by the ras-Raf-Mek-Erk signal transduction pathway, the PI3K-Akt signal transduction pathway and/or use to produce a medicament for the treatment or prevention of physiological and/or pathophysiological states in mammals, wherein the treatment or prevention is effected by modulation of the ras-Raf-Mek-Erk signal transduction pathway and the PI3K-Akt signal transduction pathway.

In a further aspect, the inventive object was surprisingly achieved by preparing the compounds according to the invention which can be used to produce a medicament for the treatment or prevention of physiological and/or pathophysiological states in mammals, mediated by the PI3K-Akt signal transduction pathway.

In a further aspect, the inventive object was surprisingly achieved by preparing the compounds according to the invention which can be used to produce a medicament for the treatment or prevention of physiological and/or pathophysiological states in mammals, wherein the treatment or prevention is effected by modulation of the PI3K-Akt signal transduction pathway.

In a preferred embodiment, the compounds according to the invention are prepared for use to produce a medicament for the treatment and/or prevention of physiological and/or pathophysiological states in mammals mediated by the SAPK signal transduction pathway and the PI3K-Akt signal transduction pathway and/or to produce a medicament for the treatment or prevention of physiological and/or pathophysiological states in mammals, wherein the treatment or prevention is effected by modulation of the SAPK signal transduction pathway and the PI3K-Akt signal transduction pathway.

In a further aspect, the inventive object was surprisingly achieved by preparing the compounds according to the invention which can be used to produce a medicament for the treatment or prevention of physiological and/or pathophysiological states in mammals, mediated by the SAPK signal transduction pathway.

In a further aspect, the inventive object was surprisingly achieved by preparing the compounds according to the invention which can be used to produce a medicament for the treatment or prevention of physiological and/or pathophysiological states in mammals, wherein the treatment or prevention is effected by modulation of the SAPK signal transduction pathway.

In a preferred embodiment, the compounds according to the invention are prepared for the uses described above, wherein the modulation of the ras-Raf-Mek-Erk signal transduction pathway is effected by modulation of one or more enzymes selected from the group consisting of: â€œtyrosine kinase, serine/threonine kinase, receptor tyrosine kinase, cytoplasmic tyrosine kinase, cytoplasmic serine/threonine kinaseâ€ and preferably selected from the group consisting of: â€œErk, Erk1, Erk2â€ .

In a further preferred embodiment, the compounds according to the invention are prepared for the uses described above, wherein the modulation of the P13K-Akt signal transduction pathway is effected by modulation of one or more enzymes selected from the group consisting of: â€œPI3K, PI3Kalpha, PI3Kbeta, PI3Kgamma, PI3Kdelta, PI3K-C2alpha, PI3K-C2beta, PI3K-Vps34pâ€ .

In a further preferred embodiment, the compounds according to the invention are prepared for the uses described above, wherein the modulation of the SAPK signal transduction pathway is effected by modulation of one or more enzymes selected from the group consisting of: â€œtyrosine kinase, serine/threonine kinase, receptor tyrosine kinase, cytoplasmic tyrosine kinase, cytoplasmic serine/threonine kinaseâ€ and is preferably selected from the group consisting of: â€œJnk, Jnk1, Jnk2, Jnk3, p38, p38alpha, p38beta, p38gamma, p38deltaâ€ .

In a further aspect, the inventive object was surprisingly achieved by preparing the compounds according to the invention according to the aspects, preferred embodiments and uses described above which can be used to produce a medicament for the treatment or prevention of physiological and/or pathophysiological states in mammals, wherein the treatment or prevention is effected by modulation of two or more enzymes.

In a further preferred embodiment, the compounds according to the invention are prepared for the uses described above, wherein in the treatment or prevention effected by modulation of two or more enzymes, at least one enzyme is selected from the group consisting of: â€œErk, Erk1, Erk2â€ and at least one enzyme is selected from the group consisting of: â€œPI3K, PI3Kalpha, PI3Kbeta, PI3Kgamma, PI3Kdelta, PI3K-C2alpha, PI3K-C2beta, PI3K-Vps34pâ€ .

In a further preferred embodiment, the compounds according to the invention are prepared for the uses described above, wherein in the treatment or prevention effected by modulation of two or more enzymes at least one enzyme is selected from the group consisting of: â€œJnk, Jnk1, Jnk2, Jnk3, p38, p38alpha, p38beta, p38gamma, p38deltaâ€ and at least one enzyme is selected from the group consisting of: â€œPI3K, PI3Kalpha, PI3Kbeta, PI3Kgamma, PI3Kdelta, PI3K-C2alpha, PI3K-C2beta, PI3K-Vps34pâ€ .

In a further preferred embodiment, the compounds according to the invention are prepared for the uses described above, wherein in the treatment or prevention effected by modulation of two or more enzymes, at least one enzyme is selected from the group consisting of: â€œErk, Erk1, Erk2â€ and at least one enzyme is selected from the group consisting of: â€œATM, ATR, mTOR, DNA-PK, hSMG-1â€ .

In a further preferred embodiment, the compounds according to the invention are prepared for the uses described above, wherein in the treatment or prevention effected by modulation of two or more enzymes, at least one enzyme is selected from the group consisting of: â€œJnk, Jnk1, Jnk2, Jnk3, p38, p38alpha, p38beta, p38gamma, p38deltaâ€ and at least one enzyme is selected from the group consisting of: â€œATM, ATR, mTOR, DNA-PK, hSMG-1â€ .

In a further preferred embodiment, the compounds according to the invention are prepared for the uses described above, wherein in the treatment or prevention effected by modulation of two or more enzymes, at least one enzyme is selected from the group consisting of: â€œPI3K, PI3Kalpha, PI3Kbeta, PI3Kgamma, PI3Kdelta, PI3K-C2alpha, PI3K-C2beta, PI3K-Vps34pâ€ and at least one enzyme is selected from the group consisting of: â€œATM, ATR, mTOR, DNA-PK, hSMG-1â€ .

In a further preferred embodiment, the compounds according to the invention are prepared for the uses described above, wherein the modulation is an inhibition.

The compounds according to the invention can be administered within the scope of this invention to all known mammals, in particular, humans, for the treatment and/or prevention.

In another preferred embodiment, the compounds according to the invention are prepared for the uses described above, wherein the mammal is selected from the group consisting of: â€œhuman, domesticated animal, cattle, pet, beef cattle, cow, sheep, pig, goat, horse, pony, donkey, hinny, mule, hare, rabbit, cat, dog, guinea pig, hamster, rat, mouseâ€ and is preferably a human.

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

In a preferred embodiment, the compounds according to the invention are prepared for the uses described above, wherein the physiological and/or pathophysiological states are selected from the group consisting of: â€œmalignant tumours, benign tumours, inflammatory diseases, inflammations, pain, rheumatic diseases, arthritic diseases, HIV infections, neurological or neurodegenerative diseases, rheumatism, arthritis, AIDS, ARC (AIDS related complex), Kaposi's sarcoma, tumours originating from the brain and/or nervous system and/or meninges, dementia, Alzheimer's disease, hyperproliferative diseases, psoriasis, endometriosis, scarring, benign prostatahyperplasia (BPH), diseases of the immune system, autoimmune diseases, immunodeficiency diseases, colon tumour, gastric tumour, intestinal tumour, pulmonary tumour, pancreatic tumour, ovarian tumour, prostatic tumour, leukaemia, melanoma, hepatic tumour, renal tumour, head tumour, throat tumour, glioma, breast tumour, uterine cancer, endometrial cancer, cervico-uterine carcinoma, brain tumour, adeno-acanthoma, cancer of the bladder, gastric tumour, colorectal tumour, oesophageal cancer, gynecological tumour, ovarian tumour, cancer of the thyroid, lymphoma, chronic leukaemia, acute leukaemia, restenosis, diabetes, diabetic nephropathy, fibrotic diseases, cystic fibrosis, malignant nephrosclerosis, thrombotic microangiopathy syndrome, organ transplant rejection, glomerulopathy, metabolic diseases, solid/fixed tumours, rheumatic arthritis, diabetic retinopathy, asthma, allergies, allergic diseases, chronic obstructive pulmonary diseases, inflammatory bowel disease, fibrosis, atherosclerosis, heart diseases, cardiovascular diseases, diseases of the myocardium, vascular diseases, angiogenetic diseases, kidney diseases, rhinitis, Grave's disease, focal ischaemia, cardiac failure, ischaemia, cardiac hypertrophia, renal failure, cardiac myocytic malfunction, high blood pressure, vasoconstriction, stroke, anaphylactic shock, platelet agglutination, skeletomuscular atrophy, obesity, overweight, glucosis homeostasis, congestive cardiac insufficiency, angina, heart attack, cardiac infarction, hyperglycaemia, hypoglycaemia, hypertensionâ€ .

In a further aspect of the present invention, the inventive object was surprisingly achieved by preparing the compounds according to the aspects, preferred embodiments and uses described above, for use for the production of a medicament for the treatment or prevention of physiological and/or pathophysiological states in mammals, wherein the medicament comprises at least one further pharmacologically active substance.

In a further aspect of the present invention, the inventive object was surprisingly achieved by preparing the compounds according to the aspects, preferred embodiments and uses described above, for use for the production of a medicament for the treatment or prevention of physiological and/or pathophysiological states in mammals, wherein the medicament is administered with at least one further pharmacologically active substance before and/or during and/or after treatment.

In a further aspect of the present invention, the inventive object was surprisingly achieved by preparing the compounds according to the aspects, preferred embodiments and uses described above, for use for the production of a medicament for the treatment or prevention of physiological and/or pathophysiological states in mammals, wherein the medicament is administered before and/or during and/or after treatment with radiation therapy and/or surgery.

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

In a preferred embodiment, the compounds according to the invention are prepared for the uses described above, wherein the further pharmacologically active substance is selected from the group consisting of: â€œDNA topoisomerase I and/or II inhibitors, DNA intercalators, alkylating agents, microtubuli destabilisors, hormone and/or growth factor receptor agonists and/or antagonists, antibodies against growth factors and their receptors, kinase inhibitors, antimetabolitesâ€ .

In a preferred embodiment, the compounds according to the invention are prepared for the uses described above, wherein the further pharmacologically active substance is selected from the group consisting of: â€œasparaginase, bleomycin, carboplatin, carmustin, chlorambucil, cisplatin, colaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin(adriamycin), epirubicin, etoposide, 5-fluorouracil, hexamethylmelamine, hydroxurea, ifosfamide, irinotecan, leucovorin, 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, 2â€²,2â€²-difluorodeoxycytidine, docetaxel, erythrohydroxynonyladenine, ethinylestradiol, 5-fluorodeoxyuridin, 5-fluorodeoxyuridin monophosphate, fludarabine phosphate, fluoxymesterone, flutamide, hydroxyprogesterone caproate, idarubicin, interferon, medroxyprogesterone acetate, megestrol acetate, melphalan, mitotane, paclitaxel, oxaliplatin, pentostatin, N-phosphonoacetyl-L-aspartate (PALA), plicamycin, semustine, teniposide, testosterone propionate, thiotepa, trimethylmelamine, uridine, vinorelbin, epothilone, gemcitabine, Taxotere, BCNU, CCNU, DTIC, 5-fluorouarcil, Herceptin, Avastin, Erbitux, Sorafenib, Gleevec, Iressa, Tarceva, rapamycin, actinomycin Dâ€ .

In a further aspect of the present invention, the inventive object was surprisingly achieved by preparing the pyridopyrazine selected from the group consisting of: [Image Omitted]

Oral administration can take place, for example, in solid form as tablet, capsule, gel capsule, dragee, granule or powder but also in the form of a potable solution. For oral administration, the new compounds according to the invention, as defined hereinbefore, can be combined with known physiologically compatible adjuvants and excipients usually used, such as gum Arabic, talc, starch, sugar such as, for example, mannite, methyl cellulose, lactose, gelatine, surfactants, magnesium stearate, cyclodextrin, aqueous or non-aqueous excipients, diluents, dispersants, emulsifiers, lubricants, preservatives and flavourings (e.g. ether oils). The compounds according to the invention can also be dispersed in a microparticle, e.g. nanoparticle composition.

Non-oral administration can be effected, for example, by intravenous, subcutaneous or intramuscular injection of sterile aqueous or oily solutions, suspensions or emulsions, by means of implants or by ointments, creams or suppositories. Optionally, administration can be effected as a retard form. Implants can contain inert materials, e.g. biologically degradable polymers or synthetic silicones such as, for example, silicone rubber. Intravaginal administration can be effected by means of vaginal rings, for example. Intrauterine administration can take place, for example, by means of diaphragms or other suitable intrauterine devices. In addition, transdermal administration can be provided, in particular by means of a formulation suitable for this purpose and/or suitable means such as plasters, for example.

As has already been explained, the new compounds according to the invention can also be combined with further pharmaceutically active substances. Within the framework of a combination therapy, the individual active constituents can be administered simultaneously or separately and either by the same pathway (e.g. oral) or by separate pathways (e.g. oral and as injection). They can be present or administered in the same or different quantities in a unit dose. A certain dosage regime can be applied insofar as this seems appropriate. In this way, a plurality of the new compounds according to the invention can be combined with one another.

The dosage can vary according to the type of indication, the severity of the disease, the type of administration, the age, sex, body weight and sensitivity of the subject to be treated over a wide range. It is within the capabilities of a person skilled in the art to determine a â€œpharmacologically effective quantityâ€ of the combined pharmaceutical composition. The administration can be made in a single dose or a plurality of separate doses.

A suitable unit dose is 0.001 mg to 100 mg of the active substance, i.e. at least one compound according to the invention and optionally a further pharmaceutically active substance, per kg body weight of a patient.

In a further aspect of the present invention, accordingly pharmaceutical compositions comprising a pharmacologically active quantity of at least one compound selected from the group consisting of: â€œcompound 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, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 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 and/or compound 269â€ and optionally pharmaceutically compatible excipients and/or adjuvants are covered by the present invention.

Preferred and particularly preferred pharmaceutical compositions are those which comprise at least one of the aforesaid preferred compounds according to the invention. Pharmaceutical compositions according to the present invention can also contain, in addition to at least one compound according to the invention, as defined previously, at least one further pharmaceutically active substance, as has been described in detail hereinbefore.

The pharmaceutical compositions according to the invention contain at least one of the new compounds according to the invention, as defined hereinbefore, in a pharmacologically active quantity, preferably in a unit dose, e.g. the aforesaid unit dose and preferably in an administration form which allows oral administration.

With regard to pharmaceutical compositions comprising compounds according to the invention and with regard to the use of the compounds according to the invention as medicaments, reference is made to the statements made in connection with the use of the new compounds according to the invention themselves with regard to the possibilities for usage and administration.

In a further aspect of the present invention, the inventive object was surprisingly solved by preparing a kit comprising a pharmacologically active quantity of at least one preferred compound according to the invention as presented above and a pharmacologically active quantity of at least one further pharmacologically active substance as defined hereinbefore.

The naming of the compounds according to the invention having the general formula (I) together with preferred exemplary embodiments and in particular compounds 1 to 269 was made using AutoNom 2000-Software (ISISâ„¢/Draw 2.5; MDL).

General Synthetic Regulations for the Compounds According to the Invention

The procedures for manufacturing substituted pyrido[2,3-b]pyrazine according to the invention are explained below.

The compounds according to the invention can be obtained according to the diagrams below (diagrams 1-7) or the corresponding procedures known to the person skilled in the art. In addition, refer to patent specifications WO2004/104002 and WO 2004/104003 or to the corresponding methods known in the literature to manufacture the compounds in accordance with the invention.

The residues X1 to X21 listed in the diagrams below correspond in their importance to the substituents defined above in conjunction with the general formula (I), for example, R-residues etc. The particular coordination is simple for the person skilled in the art to manage based on the average knowledge of the person skilled in the art. [Image Omitted]

Initial stages for selected examples of the pyrido[2,3-b]pyrazine according to the invention where the substituents R2 and R4 are to be replaced by hydrogen, can for example, be obtained according to the procedure in diagram 2 or a corresponding procedure known to the person skilled in the art. [Image Omitted]

Initial stages for selected examples of the pyrido[2,3-b]pyrazine according to the invention, where the substituents R3 and/or R4 are to be the residues OX₃, SX₄, NX₅X₆, can for example, be obtained according to the procedure in diagram 3 or a corresponding procedure known to the person skilled in the art. [Image Omitted]

For the initial stage shown above 11 the intermediate product 9 in diagram 2 or the intermediate product 21 also in diagram 6 or an appropriate substituted intermediate product can be used.

Substituted initial stages for selected examples of the pyrido[2,3-b]pyrazine according to the invention can, for example, be obtained according to the procedure in diagram 4 or a corresponding procedure known to the person skilled in the art. [Image Omitted]

Translation of initial stage 16 in diagram 4 into the pyrido[2,3-b]pyrazines substituted according to the invention, can, for example, take place according to the procedure in diagram 5 or a corresponding procedure known to the person skilled in the art. [Image Omitted]

For the initial stage shown above 16 the intermediate product 15 in diagram 4 can be used.

Selected examples of the pyrido[2,3-b]pyrazine according to the invention where the substituents R3 and/or R4 can be selected alkyl, aryl or hetero-aryl residues, can be obtained, for example, according to the procedure in diagram 6 or corresponding procedures known to the person skilled in the art. [Image Omitted]

When manufacturing the pyridopyrazine substituted for aryl, hetero-aryl according to the invention, for the initial phase shown above 21 the intermediate product 9 in diagram 2 or the intermediate product 11 in diagram 3 can be used or an appropriate substituted intermediate product.

Selected examples of the pyrido[2,3-b]pyrazine according to the invention, where the substituents R3 and/or R4 can be selected O, S, or N substituted residues, can for instance, be obtained according to the procedure in diagram 7 or appropriate procedures known to the person skilled in the art. [Image Omitted]

The cleavage of the corresponding phosphoric ester can be carried out according to procedures known or known to the person skilled in the art using methods known in the literature.

The initial compounds and intermediate stages can either be obtained on the market or manufactured according to procedures known to the person skilled in the art. The feed materials 4, 7, 9-16, 21, 24 and 26 represent valuable intermediate compounds for manufacturing pyridopyrazine according to the invention.

In order to manufacture the initial compounds, intermediate compounds and the pyridopyrazine according to the invention, refer amongst other things, to the primary literature below, the content of which is herewith to become an integral part of the disclosure of the present filing application:

1) Houben-Weyl, Methods of Organic Chemistry, Volume 4/1a, pp. 343-350
2) Houben-Weyl, Methods of Organic Chemistry, 4th edition, Volume E 7b (Part 2), p. 579; Degussa G B 1184848 (1970); p. Seko, et al. EP 735025 (1996)
3) D. Catarzi, et al.; J. Med. Chem. 1996, 1330-1336; J. K. Seydel, et al.; J. Med. Chem. 1994, 3016-3022
4) Houben-Weyl, Methods of Organic Chemistry, Volume E 9c, pp. 231-235
5) Houben-Weyl/Science of Synthesis, Volume 16, p. 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) W. He, et al. Bioorg. Med. Chem. Lett. 2003, 13, 3097-3100
8) M. S. A. El-Gaby, et al. Indian J. Chem. Sect. B 2001, 40, 195-200; M. R. Myers, et al. Bioorg. Med. Chem. Lett. 2003, 13, 3091-3096; A. R. Renslo, et al. J. Amer. Chem. Soc. 1999, 121, 7459-7460; C. O. Okafor, et al. J. Heterocyclic Chem. 1983, 20, 199-203; C. R. Hopkins, et al. Tet. Lett. 2004, 45, 8631-8633
9) J. Yin, et al. Org. Lett. 2002, 4, 3481-3484; O. A. El-Sayed, et al. Arch. Pharm. 2002, 335, 403-410; C. Temple, et al. J. Med. Chem. 1992, 35, 988-993
10) A. M. Thompson, et al. J. Med. Chem. 2000, 43, 4200-4211; 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, 507-521; J.-M. Receveur, et al. Bioorg. Med. Chem. Lett. 2004, 14, 5075-5080
11) G. Heinisch, et al. Arch. Pharm. 1997, 207-210; K. Matsuno, et al. J. Med. Chem. 2002, 45, 4513-4523; A. M. Papini, et al. J. Med. Chem. 2004, 47, 5224-5229
12) L. Mao, et al. Synthesis 2004, 15, 2535-2539; M. Darabantu, et al. Tetrahedron 2005, 61, 2897-2905; E. Ford, et al. Tet. Lett. 2000, 41, 3197-3198; T. Shiota, et al. J. Org. Chem. 1999, 64, 453-457
13) J. F. Miravet, et al. Org. Lett. 2005, 7, 4791-4794; A. L. Castelhano, et al. Bioorg. Med. Chem. Lett. 2005, 15, 1501-1504.
14) J. W. Huffmann, et al. Bioorg. Med. Chem. 2006, 14, 247-262; T. Liu, et al. Org. & Biomolecular Chem. 2005, 3, 1525-1533
General Regulations Setting Out the Compounds According to the Invention:
Diagram 1: Stage 1

2,6-diamino-3-nitropyridine or 2-amino-3,5-dinitro-pyridine is dissolved in a suitable inert solvent, such as methanol, ethanol, dimethylformamide or dioxan, for instance. After adding a catalyst, Raney nickel. palladium on carbon or platinum(IV) oxide, the reaction mass is placed in a hydrogen atmosphere with pressure of between 1 and 5 bar being set. The reaction mass is allowed to react for several hours, 1-16 hours, for example, in a temperature range between 20Â° C. and 60Â° C. When conversion is finished, the insoluble residues are filtered out, the filter medium can, for example, consist of silica gel, celite or normal glass fibre filters and rewashed using the corresponding solvent. The raw product present in solution is used for the next conversion without additional purification.

Stage 2

The 1,2-dione derivative is placed in a suitable, inert solvent, methanol, ethanol, dioxan, toluene or dimethylformamide. Immediately after reduction 2,3,6-triaminopyridine or 2,3,5-triaminopyridine is added as solution of the raw products in one of the solvents referred to above to the presented 1,2-dione, if necessary adding an acid, such as for example, acetic acid or a base, potassium hydroxide. The reaction mass is allowed to react for a period, between 20 minutes and 40 hours in a temperature range of between 20Â° C. and 80Â° C. Once conversion is finished, a possible precipitate which has separated is filtered out, the filter medium can, for instance, consist of filter paper on the market, rewashed with the corresponding solvent and the remaining solid is dried in vacuum or rather the reaction mass is released from the solvent in vacuum. Where dimethylformamide is used, the reaction mass is stirred into a large quantity of water and the precipitate separated is filtered out or rather the aqueous phase is extracted using a suitable organic solvent, such as, for example, dichloromethane or ethyl acetate and the organic phases concentrated in vacuum. Cleaning of the remaining raw product takes place by recrystallisation from a suitable solvent, dioxan, for example, or using column or rather flash chromatography on silica gel or aluminium oxide. A mixture of methanol and dichloromethane, for example, can serve as solvent.

Diagram 2: Stage 1

The pyrido-pyrazine on derivate 8 is presented in a suitable, inert solvent, dimethylformamide, dioxan or toluene or without a solvent. A chlorinating agent, phosphoryl chloride or thionyl chloride, for instance, is added at room temperature and the reaction amount is allowed to react in a temperature range of between 20Â° C. and 100Â° C. for a period, between 1 hour and 24 hours for example. When conversion is finished, the reaction mass is poured on to water and neutralised using a suitable aqueous base, caustic soda solution, for instance. A possible precipitate separated is filtered out, the filter medium can consist, for instance of filter paper on the market, is rewashed with the corresponding solvent and the remaining solid dried in vacuum or the aqueous phase is extracted in a suitable organic solvent, such as dichloromethane or ethyl acetate, for example, and the organic phases are concentrated. Cleaning of the remaining raw product takes place by recrystallisation from a suitable solvent, dioxan or toluene, for example, or using column or rather flash chromatography on silica gel or aluminium oxide. A mixture of methanol and dichloromethane, for example, can serve as solvent.

Diagram 3: Stage 1

2,3,6-triaminopyridine or 2,3,5-triaminopyridine are presented directly after reduction as a solution of the raw products in one of the solvents referred to above. Having added an oxalic acid derivative, such as oxalic acid diethylester or oxalyl chloride, for example, the reaction mass is allowed to react, if necessary by adding an acid, such as hydrochloric acid, sulphuric acid or crystalline acid for a period of time, between 10 minutes and 24 hours, for instance, in a temperature range of between 20Â° C. and 150Â° C. Once conversion is finished, a possible precipitate which has separated is filtered out, the filter medium can, for instance, consist of filter paper on the market, rewashed with the corresponding solvent and the remaining solid is dried in vacuum or rather the reaction mass is released from the solvent in vacuum. Alternatively, the reaction mass can be stirred into a large quantity of water and the precipitate separated filtered out or rather the aqueous phase, following neutralisation using an appropriate aqueous base, such as for instance, caustic soda solution, extracted using a suitable organic solvent, such as for instance, dichloromethane or ethyl acetate, and the organic phase concentrated in vacuum. Cleaning of the remaining raw product takes place by recrystallisation from a suitable solvent, dioxan or toluene, for example, or using column or rather flash chromatography on silica gel or aluminium oxide. A mixture of methanol and dichloromethane, for example, can serve as solvent.

Stage 2

The diketone derivative 10 is presented in a suitable, inert solvent, dimethylformamide, dioxan or toluene, for instance, or without a solvent. A chlorinating agent, phosphoryl chloride or thionyl chloride, for instance, is added at room temperature and the reaction amount is allowed to react in a temperature range of between 20Â° C. and 100Â° C. for a period, between 1 hour and 24 hours, for example. When conversion is finished, the reaction mass is poured on to water and neutralised using a suitable aqueous base, caustic soda solution, for instance. A possible precipitate separated is filtered out, the filter medium can consist, for instance of filter paper on the market, is rewashed with the corresponding solvent and the remaining solid dried in vacuum or the aqueous phase is extracted in a suitable organic solvent, such as dichloromethane or ethyl acetate, for example, and the organic phases are concentrated in vacuum. Cleaning of the remaining raw product takes place by recrystallisation from a suitable solvent, dioxan or toluene, for example, or using column or flash chromatography on silica gel or aluminium oxide. A mixture of methanol and dichloromethane, for example, can serve as a solvent.

Stage 3

The intermediate stage 11 can be converted using a corresponding alcohol, thiol or amine and if necessary using a suitable base, preferably sodium hydride, pyridine, triethylamine, potassium carbonate or sodium methanolate in methanol, in a suitable, inert solvent, such as dimethylformamide, dimethyl sulfoxide, methanol, toluene or in a base as solvent, such as for example, pyridine or triethylamine without solvent. The reaction mass is allowed to react for a period, between 30 minutes and 2 days, for example, in a temperature range between 20Â° C. and 140Â° C. Alternatively, the intermediate stage 11 can be converted using a corresponding amine and a suitable catalyst, such as for instance, tris(dibenzalacetone) palladium(0) or tetrakis(triphenylphosphine) palladium(0) and a suitable ligand, such as for instance, 2-(dicyclohexylphosphanyl) biphenyl or BINAP, and a suitable base, sodium tert butanolate or potassium carbonate, in a suitable solvent, such as toluene, dioxan or dimethylformamide, for instance. The reaction mass is allowed to react for a period, between 2 hours and 30 hours, for example, in a temperature range of between 60Â° C. and 120Â° C. Once conversion is finished, a possible precipitate which has separated is filtered out, the filter medium can, for instance, consist of filter paper on the market, rewashed with the corresponding solvent and the remaining solid is dried in vacuum or the reaction mass is released from the solvent in vacuum. Alternatively, the reaction mass can be stirred into a large quantity of water and the separated precipitate filtered out or the aqueous phase, following neutralisation using a suitable aqueous acid, such as for instance, caustic soda solution, extracted using a suitable organic solvent, such as for example, dichloromethane or ethyl acetate, and the organic phase concentrated in vacuum. Cleaning of the remaining raw product takes place by recrystallisation from a suitable solvent, dioxan or toluene, for example, or using column or flash chromatography on silica gel or aluminium oxide. A mixture of methanol and dichloromethane, for example, can serve as solvent.

Diagram 4: Stage 1

The intermediate stage 15 can be converted in the corresponding suitable chloride, bromide, Iodide or tosylate and if necessary using a suitable base, preferably sodium hydride, pyridine, triethylamine, sodium carbonate or sodium methanolate in methanol in a suitable, inert solvent, such as, dimethylformamide, dimethyl sulfoxide, methanol or in a base as solvent, such as, for example, pyridine or triethylamine without a solvent. The reaction mass is allowed to react for a period, between 1 hour and 24 hours for example, in a temperature range between 20Â° C. and 150Â° C. Alternatively, the intermediate stage 15 can be converted using a corresponding aryl bromide or aryl Iodide and a suitable catalyst, such as, for example, tris(dibenzalacetone)palladium(0) or tetrakis(triphenylphosphine) palladium(0) and a suitable ligand, such as for example, 2-(dicyclohexylphosphanyl) biphenyl or BINAP, and a suitable base, for example, potassium carbonate or sodium tert butanolate or in a suitable solvent, such as toluene, dioxan or dimethylformamide, for instance. The reaction mass is allowed to react for a period, between 10 hours and 30 hours, for example, in a temperature range of between 60Â° C. and 120Â° C. Once conversion is finished, a possible precipitate separated is filtered out, the filter medium can, for instance, consist of filter paper on the market, rewashed with the corresponding solvent and the remaining solid is dried in vacuum or the reaction mass is released from the solvent in vacuum. Alternatively, the reaction mass can be stirred into a large quantity of water and the precipitate separated filtered out or the aqueous phase, following neutralisation using an suitable aqueous acid, such as for example, caustic soda solution, extracted using a suitable organic solvent, such as, for example, dichloromethane or ethyl acetate, and the organic phase concentrated in vacuum. Cleaning of the remaining raw product takes place by recrystallisation from a suitable solvent, dioxan or toluene, for example, or using column or flash chromatography on silica gel or aluminium oxide. A mixture of methanol and dichloromethane, for example, can serve as solvent.

Diagram 5: Stage 1

After the basic procedure, the products which have come about according to the basic procedure can be translated in consecutive reactions into resultant products according to the invention in a procedure known to the person skilled in the art.

Thus, if the product is to be a derivative of compound 17 according to diagram 5, then the reaction product 16 can be converted using a corresponding isocyanate and if necessary a suitable base, preferably sodium hydride, potassium hexamethyldisalzide, pyridine, triethylamine or potassium carbonate, in a suitable, inert solvent, such as dimethylformamide, dimethyl sulfoxide, acetonitrile, dichloromethane, 1,2-dichloroethane or dioxan or in a base as solvent, such as for example, pyridine or triethylamine without solvent. The reaction mass is allowed to react for several hours, between 1 and 24 hours, for instance, in a temperature range between 0 and 80Â° C. Once conversion is finished, a possible precipitate which has separated is filtered out, the filter medium can, for instance, consist of filter paper on the market, rewashed with the appropriate solvent and the remaining solid is dried in vacuum or the reaction mass is released from the solvent in vacuum. Alternatively, the reaction mass can be stirred into a large quantity of water and the precipitate separated filtered out or the aqueous phase, following neutralisation using an appropriate aqueous acid, such as for example, caustic soda solution, extracted using a suitable organic solvent, such as, for instance, dichloromethane or ethyl acetate, and the organic phase concentrated in vacuum. Cleaning of the remaining raw product takes place by recrystallisation from a suitable solvent, dioxan or toluene, for example, or using column or flash chromatography on silica gel or aluminium oxide. A mixture of methanol and dichloromethane, for example, can serve as a solvent.

Or alternatively, if the product is to be a derivative of the compound 18 according to diagram 5, the reaction product 16 can be converted using phosgene or carbonyldiimidazole and a corresponding amine in a suitable, inert solvent, such as, for example, dimethylformamide, tetrahydrofuran, toluene, dichloromethane or acetonitrile. If necessary, a suitable base is used, preferably pyridine, sodium hyrdogencarbonate, triethylamine, N-methylmorpholine or sodium acetate. The reaction mass is allowed to react for a period, for example between 15 minutes and 24 hours, in a temperature range between 0 and 60Â° C. Alternatively, the reaction product 16 can be converted using a corresponding amine phenyl carbamate reagent and if necessary using a suitable base, preferably pyridine, sodium carbonate, triethylamine or sodium hydride, in a suitable, inert solvent, such as, for example, pyridine or triethylamine or without solvent. The reaction mass is allowed to react for a period, between 1 hour and 18 hours for example, in a temperature range between 0Â° C. and 120Â° C. Once conversion is finished, a possible precipitate which has separated is filtered out, the filter medium can, for instance, consist of filter paper on the market, rewashed with the corresponding solvent and the remaining solid is dried in vacuum or the reaction mass is released from the solvent in vacuum. Alternatively, the reaction mass can be stirred into a large quantity of water and the precipitate separated is filtered out or the aqueous phase, following neutralisation using a suitable aqueous acid, such as for example, caustic soda solution, extracted using a suitable organic solvent, such as, for instance, dichloromethane or ethyl acetate, and the organic phase concentrated in vacuum. Cleaning of the remaining raw product takes place by recrystallisation from a suitable solvent, dioxan or toluene, for example, or using column or flash chromatography on silica gel or aluminium oxide. A mixture of methanol and dichloromethane, for example, can serve as solvent.

Thus if the product is to be a derivative of the compound 19 according to diagram 5, the reaction product 16 can be translated using a corresponding isothiocyanate, and if necessary, a suitable base, preferably sodium hydride, triethylamine, potassium carbonate or pyridine, in a suitable, inert solvent, such as for instance dimethylformamide, tetrahydrofuran, acetone or toluene, or in a base as solvent, such as, for instance, pyridine or triethylamine or without solvent. The reaction mass is allowed to react for a period, for example between 30 minutes and 90 hours, in a temperature range between 0 and 115Â° C., Once conversion is finished, a possible precipitate which has separated is filtered out, the filter medium can, for instance, consist of filter paper on the market, rewashed with the corresponding solvent and the remaining solid is dried in vacuum or the reaction mass is released from the solvent in vacuum. Alternatively, the reaction mass can be stirred into a large quantity of water and the precipitate separated filtered out or the aqueous phase, following neutralisation using a suitable aqueous acid, such as for example, caustic soda solution, extracted using a suitable organic solvent, such as, for instance, dichloromethane or ethyl acetate, and the organic phase concentrated in vacuum. Cleaning of the remaining raw product takes place by recrystallisation from a suitable solvent, dioxan or toluene, for example, or using column or flash chromatography on silica gel or aluminium oxide. A mixture of methanol and dichloromethane, for example, can serve as a solvent.

Or alternatively, if the product is to be a derivative of the compound 20 according to diagram 5, the reaction product 16 can be translated using thiophosgene or thiocarbonyl diimidazole and a corresponding amine in a suitable, inert solvent, such as dimethylformamide, tetrahydrofuran, toluene, dichloromethane, ethanol or acetonitrile. If necessary, a suitable base, preferably pyridine, sodium hydrogencarbonate, potassium carbonate, triethylamine or imidazole is used. The reaction mixture is allowed to react for several hours, between 1 and 24 hours for example, in a temperature range between âˆ’10 and 80Â° C. Once conversion is finished, a possible precipitate which has separated is filtered out, the filter medium can, for instance, consist of filter paper on the market, rewashed with the appropriate solvent and the remaining solid is dried in vacuum or the reaction mass is released from the solvent in vacuum. Alternatively, the reaction mass can be stirred into a large quantity of water and the precipitate separated filtered out or the aqueous phase, following neutralisation using an appropriate aqueous acid, such as for example, caustic soda solution, extracted using a suitable organic solvent, such as, for instance, dichloromethane or ethyl acetate, and the organic phase concentrated in vacuum. Cleaning of the remaining raw product takes place by recrystallisation from a suitable solvent, dioxan or toluene, for example, or using column or flash chromatography on silica gel or aluminium oxide. A mixture of methanol and dichloromethane, for example, can serve as solvent.

Diagram 6: Stage 1

After the basic procedure, the products which have come about according to the basic procedure can be translated in consecutive reactions into resultant products according to the invention in a procedure known to the person skilled in the art.

Thus, if the product is to be a derivative of the compound 22 according to diagram 6, the reaction product 21 can be translated using the corresponding aryl/heteroaryl boronic acid derivatives or aryl/heteroaryl organotin compounds and a suitable catalyst, such as, for example, Pd(PPh₃)₄, [1,1â€²-bis(diphenylphosphino)ferrocene] dichloro palladium(II) or Pd₂(dba)₃and a suitable base, for example, sodium carbonate, cesium carbonate or triethylamine, in a suitable solvent, such as for instance, dimethylformamide, dimethylformamide/water, toluene, acetonitrile, dimethoxyethane or dioxan. The reaction mixture is allowed to react for a period, for instance between 6 hours and several days, in a temperature range between 60Â° C. and 120Â° C. Once conversion is finished, a possible precipitate which has separated is filtered out, the filter medium can, for instance, consist of filter paper on the market, rewashed with the corresponding solvent and the remaining solid is dried in vacuum or the reaction mass is released from the solvent in vacuum. Alternatively, the reaction mass can be stirred into a large quantity of water and the precipitate separated filtered out or the aqueous phase, following neutralisation using a suitable aqueous acid, such as for example, caustic soda solution, extracted using a suitable organic solvent, such as, for instance, dichloromethane or ethyl acetate, and the organic phase concentrated in vacuum. Cleaning of the remaining raw product takes place by recrystallisation from a suitable solvent, dioxan or toluene, for example, or using column or flash chromatography on silica gel or aluminium oxide. A mixture of methanol and dichloromethane, for example, can serve as a solvent.

Thus if the product is to be a derivative of the compound 23 according to diagram 6, the reaction product 21 can be converted using corresponding alkyl zinc halogenides and a suitable catalyst, such as, for example, Pd(PPh₃)₄, [1,1â€²-bis(diphenylphosphino)ferrocene] dichloro palladium(II) or PdCl₂(PPh₃)₂in a suitable solvent, such as for instance, dimethylformamide, tetrahydrofuran, toluene, dimethoxyethane or dioxan. The reaction mixture is allowed to react for a period, for example between 30 minutes and 48 hours, in a temperature range between room temperature and 120Â° C. Once conversion is finished, a possible precipitate which has separated is filtered out, the filter medium can, for instance, consist of filter paper on the market, rewashed with the appropriate solvent and the remaining solid is dried in vacuum or the reaction mass is released from the solvent in vacuum. Alternatively, the reaction mass can be stirred into a large quantity of water and the perpetrate separated is filtered out or the aqueous phase, following neutralisation using an appropriate aqueous acid, such as for example, dichloromethane or ethyl acetate, and the organic phase concentrated in vacuum. Cleaning of the remaining raw product takes place by recrystallisation from a suitable solvent, dioxan or toluene, for example, or using column or flash chromatography on silica gel or aluminium oxide. A mixture of methanol and dichloromethane, for example, can serve as solvent.

Diagram 7: Stage 1

After the basic procedure, the products which have come about according to the basic procedure can be translated in consecutive reactions into resultant products according to the invention in a procedure known to the person skilled in the art.

Thus, if the product is to be a derivative of the compound 25 according to diagram 7, the reaction product 24 can be converted, for example, using a corresponding chloride, bromide, Iodide and if necessary using a suitable base, preferably sodium hydride, pyridine, triethylamine, sodium carbonate or sodium methanolate in methanol in a suitable, inert solvent, such as, dimethylformamide, dimethyl sulfoxide, methanol, dioxan, tetrahydrofuran, toluene or in a base as solvent, such as, for instance, pyridine or triethylamine or without solvent. The reaction mass is allowed to react for a period, between 30 minutes and 2 days, for example, in a temperature range between 0Â° C. and 140Â° C. Alternatively, an amino substituted intermediate stage 24, for example, can be used, using a corresponding chloride, bromide or Iodide and a suitable catalyst, such as, for instance, tris(dibenzalacetone)palladium(0) or tetrakis(triphenylphosphine) palladium(0) and a suitable ligand, such as, for instance, 2-(dicyclohexylphosphanyl) biphenyl or BINAP, and a suitable base, sodium tert butanolate or potassium carbonate, in a suitable solvent, such as toluene, dioxan or dimethylformamide, for instance. The reaction mass is allowed to react for a period, between 2 hours and 30 hours, for example, in a temperature range of between 60Â° C. and 120Â° C. Once conversion is finished, a possible precipitate separated is filtered out, the filter medium can, for instance, consist of filter paper on the market, rewashed with the suitable solvent and the remaining solid is dried in vacuum or the reaction mass is released from the solvent in vacuum. Alternatively, the reaction mass can be stirred into a large quantity of water and the perpetrate separated filtered out or the aqueous phase, following neutralisation using a suitable aqueous acid, such as for instance, caustic soda solution, extracted using a suitable organic solvent, such as, for example, dichloromethane or ethyl acetate, and the organic phase concentrated in vacuum. Cleaning of the remaining raw product takes place by recrystallisation from a suitable solvent, dioxan or toluene, for example, or using column or flash chromatography on silica gel or aluminium oxide. A mixture of methanol and dichloromethane, for example, can serve as solvent.

Thus, if the product is to be a derivative of the compound 27 according to diagram 7, the reaction product 26 can be converted, for example, using a corresponding chloro-phosphoric ester and if necessary using a suitable base, preferably sodium hydride, pyridine, triethylamine, potassium carbonate or lithium diisopropylamide in a suitable, inert solvent, such as for example, dimethylformamide, dimethyl sulfoxide, methanol, dioxan, tetrahydrofuran, toluene or in a base as solvent, such as for example, pyridine or triethylamine or without solvent. The reaction mass is allowed to react for a period, between 1 hour and 24 hours for example, in a temperature range between 0Â° C. and 100Â° C. Once conversion is finished, a possible precipitate separated is filtered out, the filter medium can, for instance, consist of filter paper on the market, rewashed with the suitable solvent and the remaining solid is dried in vacuum or the reaction mass is released from the solvent in vacuum. Alternatively, the reaction mass can be stirred into a large quantity of water and the precipitate separated filtered out or the aqueous phase, following neutralisation using a suitable aqueous acid, such as for example, caustic soda solution, extracted using a suitable organic solvent, such as, for example, dichloromethane or ethyl acetate, and the organic phase concentrated in vacuum. Cleaning of the remaining raw product takes place by recrystallisation from a suitable solvent, dioxan or toluene, for example, or using column or rather flash chromatography on silica gel or aluminium oxide. A mixture of methanol and dichloromethane, for example, can serve as solvent.

Under the reaction conditions mentioned, OH, SH and NH₂groups can possibly undergo unwanted secondary reactions. It is therefore preferable to provide them with protective groups or in the case of NH₂to replace with NO₂and subsequently to split the protective group off or to reduce the NO₂group. Thus varying the procedures described above, in the initial compounds at least one OH group, for example, can be replaced by a benzyl oxy group and/or at least one SH group, for example, by an S-benzyl group and/or at least one NH₂group by a NH-benzyl group or by an NO₂group. Subsequently at least oneâ€”preferably allâ€”benzyl oxy group(s) or NH benzyl group(s) can be split off, for instance, using hydrogen and palladium on carbon and/or at least oneâ€”preferably allâ€”S-benzyl group(s), for example, using sodium in ammonia and/or at least oneâ€”preferably all NO₂group(s) are reduced, for instance using hydrogen and Raney nickel to NH₂

Under some of the reaction conditions mentioned OH, NH₂and COOH groups can possibly undergo unwanted secondary reactions. It is therefore preferable to convert initial compounds and intermediate stages containing at least one OH and/or at least one NH₂and/or at least one COOH group into corresponding carbonic ester and carboxamide derivatives. Thus varying the procedures described above, in the initial compounds and intermediate stages with at least one OH group and/or at least one NH₂group can be converted into carboxamide derivatives by transformation using an active carboxamide group. Thus varying the procedures described above the initial compounds and intermediate stages with at least one COOH group can be converted into carbonic ester or carboxamide derivatives by transformation using an activator, such as thionyl chloride or carbonyldiimidazole and a subsequent transformation using a suitable alcohol or amine. Subsequently at least oneâ€”preferably allâ€”carbonic ester or carboxamide group(s) in the initial compounds and intermediate stages can be split, for instance using diluted aqueous acids or bases to free at least oneâ€”preferably all â€”OH group(s) and/or NH₂group(s) and/or COOH groups.

The invention will be explained in detail with reference to the following examples without being restricted to these examples.

EXAMPLES

I. Manufacture of Compounds According to the Invention

According to the general synthesis regulations on which the synthesis diagrams 1-7 are based, the following compounds according to the invention were synthesised.

The initial stages for the manufacture of the compounds according to the invention can be synthesised according to procedures known to the person skilled in the artâ€”unless otherwise described.

The chemicals and solvents used were purchased commercially from the usual suppliers (Acros, Aldrich, Fluka, Lancaster, Maybridge, Merck, Sigma, TCI, etc.) or synthesised.

Example 1 1-ethyl-3-[3-(3-hydroxy-phenyl)-pyrido[2,3-b]pyrazine-6-yl]-urea (Compound 151) Manufacture of 1-(3-chloropyrido[2,3-b]pyrazine-6-yl)-3-ethyl-urea (Conversion According to Diagram 5)

100 mg 3-chloropyrido[2,3-b]pyrazine-6-yl-amine (0.55 mmol) was presented in 5 ml predried pyridine and add 44 Î¼L ethyl isocyanate (0.55 mmol) at room temperature. The mixture was stirred at 75Â° C. and then a total of 132 Î¼L ethyl isocyanate (1.65 mmol) was added again over 18 hours to the reaction mixture in small amounts. Then the volatile components were removed in vacuum. The resulting solid was cleaned through column chromatography on silica gel (solvent dichloromethane/methanol). A light yellow solid was obtained.

Refer to the following literature and the procedures known to the person skilled in the art to manufacture 3-chloropyrido[2,3-b]pyrazine-6-yl-amine:

1) T. S. Osdene, et al. J. Chem. Soc. 1955, 2033-2035; C. L. Leese, et al. J. Chem. Soc. 1955, 303-309
2) C. M. Atkinson, et al. J. Chem. Soc. 1956, 26-30; S. Goswami, et al. Molecules 2005, 10, 929-936

Manufacture of 1-ethyl-3-[3-(3-hydroxy-phenyl)-pyrido[2,3-b]pyrazine-6-yl]-urea (Conversion According to Diagram 6)

100 mg 1-(3-chloropyrido[2,3-b]pyrazine-6-yl)-3-ethyl-urea (0.40 mmol) was presented in a dimethylformamide/water mixture under nitrogen as protective gas. Then 60.3 mg 3-hydroxyphenyl boronic acid (0.44 mmol), 126 mg sodium carbonate (1.19 mmol) and 23 mg tetrakis(triphenylphosphine) palladium(0) (0.02 mmol) were added. The reaction mixture was stirred at 90Â° C. for 4 hours. The mixture was filled with water for reprocessing and the deposited solid rewashed with dichloromethane. The resulting raw product was stirred again in warm DCM, filtered off and dried. A yellow solid was obtained.

Additional compounds according to the invention were produced according to this regulation: For example, the compounds 152, 153, 154, 208, 209 and 210.

Example 2 1-ethyl-3-(3-o-tolylamino-pyrido[2,3-b]-pyrazine-6-yl)-urea (Compound 160) Manufacture of 1-ethyl-3-(3-o-tolylamino-pyrido[2,3-b]-pyrazine-6-yl)-urea (Conversion According to Diagram 3)

55 mg 1-(3-chlor-pyrido[2,3-b]pyrazine-6-yl)-3-ethyl-urea (0.22 mmol), 60 mg o-toluidine (0.56 mmol), 33 mg sodium-tert.-butylate(0.33 mmol), 29 mg tris(dibenzalacetone)palladium(0) (0.03 mmol) and 78 mg 2-(dicyclohexylphosphanyl)biphenyl (0.22 mmol) were presented in 1.5 ml predried toluene in a microwave reaction vessel under nitrogen as protective gas. The reaction mass was heated in the microwave at 100Â° C. (100 watt) for 30 minutes. Then the volatile components were removed in vacuum and the raw product was cleaned using column chromatography on silica gel (solvent dichloromethane/methanol). A yellow solid was obtained.

Additional compounds according to the invention were produced according to this regulation: For example, the compounds 161, 180, 211, 212 and 213.

Example 3 1-ethyl-3-(3-phenoxy-pyrido[2,3-b]pyrazine-6-yl)-urea (Compound 64) Manufacture of 1-ethyl-3-(3-phenoxy-pyrido[2,3-b]pyrazine-6-yl)-urea (Conversion According to Diagram 3)

19 mg sodium hydride (0.48 mmol) (60% suspension in mineral oil) was presented in 10 ml predried dimethylformamide. 37 mg phenol (0.40 mmol) was added dissolved in a little predried dimethylformamide at 0Â° C. The mixture was stirred for 1 hour at 0Â° C. Then 100 mg 1-(3-chloro-pyrido[2,3-b]pyrazine-6-yl)-3-ethyl-urea (0.40 mmol) was dissolved in a little predried dimethylformamide and dropped in at 0Â° C. The reaction mixture was stirred overnight at room temperature. When the reaction was finished the reaction solution was poured on iced water and neutralised using 1N HCl. The raw product deposited was cleaned using column chromatography on silica gel (dichloromethane/methanol). A white solid was obtained.

Additional compounds according to the invention were produced according to this regulation: For example, the compounds 67, 69, 73, 80 and 87.

Conversion using amines can be undertaken using triethylamine as a base in dioxan or without a base in dioxan. Additional compounds according to the invention were produced according to this method: For example, the compounds 59, 62, 65, 81 and 88.

II. Physico-Chemical Characterisation

II.1 ESI MS Data for Selected Compounds

TABLE 1New pyrido[2,3-b]pyrazine derivatives with relevant MS data according to thegeneral formula (I)MS m/zComp.Pyridopyrazine derivative(M + H⁺)11-Allyl-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-thiourea322.0171-(2-Morpholin-4-yl-ethyl)-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-urea379.1291-[3-(4-Hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-prop-2-inyl-336.2thiourea311-[3-(4-Hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-((E)-propenyl)-338.3thiourea351-Phenethyl-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-urea370.2361-(2,3-Di-pyridin-2-yl-pyrido[2,3-b]pyrazin-6-yl)-3-ethyl-urea372.1371-(2,3-Dimethyl-pyrido[2,3-b]pyrazin-6-yl)-3-ethyl-urea246.2381-[3-(4-Hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-methyl-urea296.1391-Allyl-3-[3-(4-phenoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-urea398.140Methansulfonic acid-4-[6-(3-allyl-ureido)-pyrido[2,3-b]pyrazin-3-yl]-400.0phenyl-ester414-Dimethylamino-benzoic acid-4-[6-(3-allyl-ureido)-pyrido[2,3-469.3b]pyrazin-3-yl]-phenyl-ester42Acetic acid-4-[6-(3-allyl-ureido)-pyrido[2,3-b]pyrazin-3-yl]-phenyl-364.1ester431-Ethyl-3-[3-(4-hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-urea310.2441-[3-(4-Amino-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-methyl-thiourea311.1451-Ethyl-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-urea294.2461-Acetyl-1-ethyl-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-urea336.3471-Allyl-3-[3-(4-fluoroo-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-urea324.0481,1-Diethyl-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-urea322.0491-(2-Chloro-ethyl)-3-[3-(4-fluoro-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-346.3urea501-Ethyl-3-[3-(4-methoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-urea324.2511-(3-Phenyl-pyrido[2,3-b]pyrazin-6-yl)-3-propyl-urea308.052[3-(3-Phenyl-pyrido[2,3-b]pyrazin-6-yl)-ureido]-acetic acid-ethyl-ester352.0531-(3-Chloro-pyrido[2,3-b]pyrazin-6-yl)-3-ethyl-urea252.1541-Ethyl-3-[3-(4-fluoro-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-urea312.2551-[3-(3-Chloro-4-fluoro-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-346.2urea564-[6-(3-Ethyl-ureido)-pyrido[2,3-b]pyrazin-3-yl]-benzoic acid338.157N-{4-[6-(3-Ethyl-ureido)-pyrido[2,3-b]pyrazin-3-yl]-phenyl}-acetamide350.9581-[3-(2,4-Difluoro-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-urea329.9591-Ethyl-3-(3-morpholin-4-yl-pyrido[2,3-b]pyrazin-6-yl)-urea303.1601-Ethyl-3-[3-(4-methyl-piperazin-1-yl)-pyrido[2,3-b]pyrazin-6-yl]-urea316.3611-Ethyl-3-[3-(2-hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-urea310.2621-Ethyl-3-[3-(2-methoxy-ethylamino)-pyrido[2,3-b]pyrazin-6-yl]-urea291.2631-[3-(4-Chloro-3-trifluoromethyl-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-294.9ethyl-urea641-Ethyl-3-(3-phenoxy-pyrido[2,3-b]pyrazin-6-yl)-urea310.2651-[3-(Cyclopropylmethyl-amino)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-287.2urea661-Ethyl-3-{3-[(pyridin-4-ylmethyl)-amino]-pyrido[2,3-b]pyrazin-6-yl}-324.2urea671-Ethyl-3-[3-(4-fluoro-benzyloxy)-pyrido[2,3-b]pyrazin-6-yl]-urea341.9681-Ethyl-3-(3-pyridin-4-yl-pyrido[2,3-b]pyrazin-6-yl)-urea295.3691-Ethyl-3-[3-(pyridin-3-yloxy)-pyrido[2,3-b]pyrazin-6-yl]-urea311.3701-Ethyl-3-[3-(tetrahydro-furan-2-ylmethoxy)-pyrido[2,3-b]pyrazin-6-318.2yl]-urea711-Ethyl-3-[3-(4-morpholin-4-yl-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-379.4urea721-Ethyl-3-(3-hydroxy-pyrido[2,3-b]pyrazin-6-yl)-urea234.3731-Ethyl-3-[3-(3-methoxy-phenylsulfanyl)-pyrido[2,3-b]pyrazin-6-yl]-355.9urea741-Ethyl-3-(3-quinolin-3-yl-pyrido[2,3-b]pyrazin-6-yl)-urea345.1751-(3-Benzo[b]thiophen-3-yl-pyrido[2,3-b]pyrazin-6-yl)-3-ethyl-urea350.1761-Ethyl-3-[3-(pyridin-2-ylsulfanyl)-pyrido[2,3-b]pyrazin-6-yl]-urea327.3771-[3-(4-Dimethylamino-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-337.2urea78N-{4-[6-(3-Ethyl-ureido)-pyrido[2,3-b]pyrazin-3-yl]-phenyl}-387.3methansulfonamide791-Ethyl-3-[3-(1H-pyrazol-4-yl)-pyrido[2,3-b]pyrazin-6-yl]-urea284.2801-(3-Benzylsulfanyl-pyrido[2,3-b]pyrazin-6-yl)-3-ethyl-urea340.0811-Ethyl-3-[3-(4-methyl-[1,4]diazepan-1-yl)-pyrido[2,3-b]pyrazin-6-yl]-330.5urea821-[3-(4-Amino-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-urea309.4831-(3-Amino-pyrido[2,3-b]pyrazin-6-yl)-3-ethyl-urea233.3841-Ethyl-3-pyrido[2,3-b]pyrazin-6-yl-urea218.3861-Ethyl-3-[3-(4-fluoro-2-hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-328.2urea871-(3-Cyclopentyloxy-pyrido[2,3-b]pyrazin-6-yl)-3-ethyl-urea302.3881-Ethyl-3-[3-(4-hydroxy-piperidin-1-yl)-pyrido[2,3-b]pyrazin-6-yl]-317.2urea89(3-Phenyl-pyrido[2,3-b]pyrazin-6-yl)-urea266.2901-Ethyl-3-(3-pyrimidin-5-yl-pyrido[2,3-b]pyrazin-6-yl)-urea296.3911-Ethyl-3-(3-pyridin-3-yl-pyrido[2,3-b]pyrazin-6-yl)-urea295.3921-Allyl-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-urea306.3931-Ethyl-3-(3-piperazin-1-yl-pyrido[2,3-b]pyrazin-6-yl)-urea302.3941-[3-(3-Chloro-pyridin-4-ylmethyl)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-329.3urea951-Ethyl-3-[3-(6-methoxy-pyridin-3-yl)-pyrido[2,3-b]pyrazin-6-yl]-urea325.3961-[3-(3,5-Dimethyl-isoxazol-4-yl)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-313.3urea971-Ethyl-3-[3-(4-trifluoromethoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-378.3urea981-Ethyl-3-(3-furan-2-yl-pyrido[2,3-b]pyrazin-6-yl)-urea284.2991-Ethyl-3-[3-(2-methoxy-pyridin-3-yl)-pyrido[2,3-b]pyrazin-6-yl]-urea325.31001-[3-(2,4-Dimethoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-urea353.91011-Ethyl-3-[3-(1H-pyrrol-2-yl)-pyrido[2,3-b]pyrazin-6-yl]-urea383.31021-Ethyl-3-[3-(6-morpholin-4-yl-pyridin-3-yl)-pyrido[2,3-b]pyrazin-6-380.3yl]-urea1031-Benzyl-3-ethyl-1-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-urea384.01041-[3-(2-Amino-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-urea309.21051-Ethyl-3-[3-(4-hydroxymethyl-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-324.2urea1061-[3-(3-Amino-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-urea309.21071-[3-(4-Acetyl-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-urea336.11081-[3-(2,3-Dihydro-benzofuran-5-yl)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-336.2urea1091-[3-(4-Benzyloxy-3-fluoro-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-418.3urea1101-(2,3-Dihydroxy-propyl)-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-urea340.01111-Ethyl-3-[3-(3-formyl-4-methoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-352.1urea1121-Ethyl-3-[3-(4-methansulfonyl-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-372.1urea113N-{4-[6-(3-Ethyl-ureido)-pyrido[2,3-b]pyrazin-3-yl]-phenyl}-409.3succinamid acid1141-Ethyl-3-(3-pyridin-4-yl-pyrido[2,3-b]pyrazin-6-yl)-urea295.3Methansulfonic acid salt1151-[3-(2,6-Dimethoxy-pyridin-3-yl)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-354.9urea1161-[3-(2,6-Dimethoxy-pyrimidin-4-yl)-pyrido[2,3-b]pyrazin-6-yl]-3-356.1ethyl-urea1171-[3-(2,4-Dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl)-pyrido[2,3-328.4b]pyrazin-6-yl]-3-ethyl-urea1181-Ethyl-3-[3-(1H-indol-5-yl)-pyrido[2,3-b]pyrazin-6-yl]-urea333.01191-(3-Chloroo-pyrido[2,3-b]pyrazin-6-yl)-3-ethyl-thiourea268.01201-Ethyl-3-{3-[4-(2-methoxy-ethoxy)-phenyl]-pyrido[2,3-b]pyrazin-6-368.4yl}-urea121Acrylic acid-4-[6-(3-ethyl-ureido)-pyrido[2,3-b]-pyrazin-3-yl]-phenyl-364.1ester1221-[3-(4-Cyano-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-urea319.11231-(3-Benzo[1,2,5]oxadiazol-4-yl-pyrido[2,3-b]pyrazin-6-yl)-3-ethyl-336.0urea1241-Ethyl-3-[3-(4-hydroxy-3-methoxy-phenyl)-pyrido[2,3-b]pyrazin-6-340.0yl]-urea1251-[3-(2,6-Dimethoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-urea354.21261-[3-(3-Acetyl-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-urea336.21271-Ethyl-3-[3-(3-morpholin-4-yl-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-379.2urea1281-[3-(6-Amino-pyridin-3-yl)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-urea310.21293-{4-[6-(3-Ethyl-ureido)-pyrido[2,3-b]-pyrazin-3-yl]-phenoxy}-382.3propionic acid1301-Isopropyl-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-urea308.21311-Cyclopentyl-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-urea333.91321-Pentyl-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-urea336.2133N-{4-[6-(3-Ethyl-ureido)-pyrido[2,3-b]pyrazin-3-yl]-phenyl}-363.2acrylamide1341-tert-Butyl-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-urea322.11351-(2-Hydroxy-ethyl)-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-urea310.21361-Cyclobutyl-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-urea319.81371-Allyl-3-[3-(4-nitro-phenyl)-pyrido[2,3-b]pyrazin-7-yl]-thiourea367.11381-Ethyl-1-(Ethylcarbamoyl)-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-365.1urea139[3-(4-Hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-carbamic acid-allyl-323.0ester140(3-Phenyl-pyrido[2,3-b]pyrazin-6-yl)-carbamic acid-ethyl-ester295.31411-Ethyl-3-[3-(4-phenyl-piperazin-1-yl)-pyrido[2,3-b]pyrazin-6-yl]-urea378.31421-(2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-3-(3-phenyl-pyrido[2,3-380.2b]pyrazin-6-yl)-urea1431,3-Bis-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-urea471.3144N-(3-Phenyl-pyrido[2,3-b]pyrazin-6-yl)-acetamidine264.81451-Ethyl-3-[3-(2-methoxy-pyridin-3-yl)-pyrido[2,3-b]pyrazin-6-yl]-341.2thiourea1461-(4-Hydroxy-butyl)-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-urea338.21471-(3-Hydroxy-propyl)-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-urea324.21481-Ethyl-3-{3-[4-(3-morpholin-4-yl-propoxy)-phenyl]-pyrido[2,3-437.3b]pyrazin-6-yl}-urea1491-Ethyl-3-[3-(4-hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-thiourea326.11501-Ethyl-3-(3-p-tolylamino-pyrido[2,3-b]pyrazin-6-yl)-urea323.21511-Ethyl-3-[3-(3-hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-urea310.21523-[6-(3-Ethyl-ureido)-pyrido[2,3-b]pyrazin-3-yl]-benzoic acid338.21531-[3-(3,4-Dimethoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-urea354.11541-[3-(4-Amino-3-methoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-339.1urea1553-[6-(3-Ethyl-ureido)-pyrido[2,3-b]-pyrazin-3-yl]-benzamide337.11561-[3-(3-Chloro-4-hydroxy-5-methoxy-phenyl)-pyrido[2,3-b]pyrazin-6-374.2yl]-3-ethyl-urea1571-Ethyl-3-(3-m-tolylamino-pyrido-[2,3-b]pyrazin-6-yl)-urea323.31581-Ethyl-3-[3-(4-methoxy-phenylamino)-pyrido[2,3-b]pyrazin-6-yl]-urea339.01591-[3-(4-Chloroo-phenylamino)-pyrido-[2,3-b]pyrazin-6-yl]-3-ethyl-urea343.11601-Ethyl-3-(3-o-tolylamino-pyrido[2,3-b]-pyrazin-6-yl)-urea323.21611-Ethyl-3-[3-(pyridin-3-ylamino)-pyrido-[2,3-b]pyrazin-6-yl]-urea310.21621-Ethyl-3-[3-(4-ethyl-phenylamino)-pyrido[2,3-b]pyrazin-6-yl]-urea337.21631-Ethyl-3-[3-(3-methoxy-4-methyl-phenylamino)-pyrido[2,3-b]pyrazin-353.36-yl]-urea1641-Ethyl-3-[3-(4-hydroxy-phenylamino)-pyrido[2,3-b]pyrazin-6-yl]-urea325.31651-Ethyl-3-[3-(5-methyl-pyridin-2-yl-amino)-pyrido[2,3-b]pyrazin-6-yl]-324.3urea1661-Ethyl-3-[3-(1-methyl-1H-pyrazol-3-ylamino)-pyrido[2,3-b]pyrazin-6-313.4yl]-urea1671-Ethyl-3-[3-(4-fluoro-phenylamino)-pyrido[2,3-b]pyrazin-6-yl]-urea327.41681-(4-Hydroxy-butyl)-3-[3-(4-hydroxy-3-methoxy-phenyl)-pyrido[2,3-384.3b]pyrazin-6-yl]-urea169Phosphoric acid-mono-{4-[6-(3-ethyl-ureido)-pyrido-[2,3-b]pyrazin-3-420.2yl]-2-methoxy-phenyl}-ester1701-[3-(2-Chloro-4-hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-344.3urea1711-[3-(4-Chloro-2-methoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-358.1urea1721-[3-(3,5-Dimethyl-1H-pyrazol-4-yl)-pyrido[2,3-b]pyrazin-6-yl]-3-312.2ethyl-urea1731-Ethyl-3-[3-(1-methyl-1H-pyrazol-4-yl)-pyrido[2,3-b]pyrazin-6-yl]-298.4urea1741-[3-(5-Cyano-thiophen-2-yl)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-urea325.31761-[3-(4-Hydroxy-3-methoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-(4-453.4morpholin-4-yl-butyl)-urea1771-[3-(3-Chloro-4-methoxy-phenylamino)-pyrido[2,3-b]pyrazin-6-yl]-3-373.4ethyl-urea1781-Ethyl-3-[3-(naphthalin-2-ylamino)-pyrido[2,3-b]pyrazin-6-yl]-urea359.31791-Ethyl-3-[3-(chinolin-3-ylamino)-pyrido[2,3-b]pyrazin-6-yl]-urea360.31801-[3-(3,5-Dimethoxy-phenylamino)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-369.3urea1811-Ethyl-3-[3-(pyrazin-2-ylamino)-pyrido[2,3-b]pyrazin-6-yl]-urea311.31821-Ethyl-3-[3-(3-isopropoxy-phenylamino)-pyrido[2,3-b]pyrazin-6-yl]-367.2urea1831-Ethyl-3-[3-(4-hydroxy-3-methoxy-phenyl)-pyrido[2,3-b]pyrazin-6-340.3yl]-urea p-Toluolsulfonate(free base)1841-[3-(2-Chloro-pyridin-4-ylamino)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-344.3urea1851-[3-(3,5-Dichloro-4-hydroxy-phenylamino)-pyrido[2,3-b]pyrazin-6-393.2yl]-3-ethyl-urea1861-[3-(3,5-Dichloro-4-hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-369.2ethyl-urea1871-[3-(3,4-Dimethoxy-phenylamino)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-369.2urea1881-Ethyl-3-[3-(3-hydroxy-4-methyl-phenylamino)-pyrido[2,3-b]pyrazin-339.16-yl]-urea1893-[6-(3-Ethyl-ureido)-pyrido[2,3-b]-pyrazin-3-ylamino]-5-421.3trifluoromethyl-benzoic acid1901-Ethyl-3-[3-(6-methoxy-pyridin-3-ylamino)-pyrido[2,3-b]pyrazin-6-340.3yl]-urea1911-[3-(3,5-Dimethyl-phenylamino)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-337.3urea1921-[3-(4-Cyano-phenylamino)-pyrido-[2,3-b]pyrazin-6-yl]-3-ethyl-urea334.11941-Ethyl-3-[3-(4-hydroxy-3-methoxy-phenyl)-pyrido[2,3-b]pyrazin-6-340.1yl]-urea Hydrochloride(free base)1951-Ethyl-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-thiourea310.21961-(3-Chloro-pyrido[2,3-b]pyrazin-6-yl)-3-cyclohexyl-urea306.21971-Ethyl-3-[3-(4-hydroxy-3-methoxy-phenylamino)-pyrido[2,3-355.3b]pyrazin-6-yl]-urea1981-Ethyl-3-[3-(4-hydroxy-3,5-dimethyl-phenyl)-pyrido[2,3-b]pyrazin-6-338.3yl]-urea1993-Ethyl-1-phenethyl-1-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-urea398.22001-Allyl-3-{3-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-pyrido[2,3-422.2b]pyrazin-6-yl}-thiourea2013-Ethyl-1-[3-(4-methoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-1-propyl-366.3urea2023-Ethyl-1-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-1-(2-piperidin-1-yl-405.4ethyl)-urea Hydrochloride(free base)203N-{4-[6-(3-Ethyl-ureido)-pyrido[2,3-b]-pyrazin-3-yl]-phenyl}-2-427.3phenyl-acetamide2041-(4-Hydroxy-butyl)-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-urea338.3Hydrochloride(free base)205Acetic acid-4-[3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-ureido]-butyl380.4ester2061-(4-Amino-butyl)-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-urea337.32071-(5-Hydroxy-pentyl)-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-urea352.32083-[6-(3-Ethyl-ureido)-pyrido[2,3-b]-pyrazin-3-yl]-N-methyl-benzamide351.22091-Ethyl-3-[3-(2-methoxy-5-methyl-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-338.1urea2101-Ethyl-3-(3-p-tolyl-pyrido[2,3-b] pyrazin-6-yl)-urea308.22111-Ethyl-3-[3-(methyl-p-tolyl-amino)-pyrido[2,3-b]pyrazin-6-yl]-urea337.12121-Ethyl-3-[3-(2-p-tolyl-ethylamino)-pyrido[2,3-b]pyrazin-6-yl]-urea351.12131-Ethyl-3-[3-(4-methyl-benzylamino)-pyrido[2,3-b]pyrazin-6-yl]-urea337.22141-Ethyl-3-[3-(3-fluoro-4-methyl-phenyl-amino)-pyrido[2,3-b]pyrazin-6-341.2yl]-urea2151-[3-(3,4-Dimethyl-phenylamino)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-337.1urea2161-Ethyl-3-[3-(4-isopropyl-phenylamino)-pyrido[2,3-b]pyrazin-6-yl]-351.1urea2171-(4-Morpholin-4-yl-butyl)-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-407.3urea218N-{4-[3-(3-Phenyl-pyrido[2,3-b]pyrazin-6-yl)-ureido]-butyl}-acetamide379.32191-[3-(3-Amino-4-methyl-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-323.3urea2201-[3-(3-Acetyl-2-fluoro-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-354.2urea2211-Ethyl-3-[3-(4-methoxy-3-methyl-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-338.3urea2221-[3-(6-Ethoxy-pyridin-3-yl)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-urea339.32231-Ethyl-3-[3-(2-fluoro-4-methyl-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-326.2urea2241-Ethyl-3-[3-(3-fluoro-4-methoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-342.1urea2251-Ethyl-3-[3-(2-fluoro-3-methoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-342.1urea2261-Ethyl-3-[3-(3,4,5-trimethoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-urea384.22271-[3-(3,5-Difluoro-2-methoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-360.3ethyl-urea2281-Ethyl-3-[3-(4-trifluoromethyl-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-362.3urea2291-Ethyl-3-[3-(2,3,4-trimethoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-urea384.32301-[3-(3-Chloro-4-methoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-358.2urea2311-Ethyl-3-[3-(3-fluoro-4-hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-328.3urea2321-Ethyl-3-[3-(6-fluoro-pyridin-3-yl)-pyrido[2,3-b]pyrazin-6-yl]-urea313.32331-[3-(2,4-Dimethyl-thiazol-5-yl)-pyrido-[2,3-b]pyrazin-6-yl]-3-ethyl-329.4urea2341-Ethyl-3-[3-(2-methoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-urea324.32351-[3-(2-Chloro-pyridin-4-yl)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-urea329.32361-[3-(5-Acetyl-thiophen-2-yl)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-urea342.32371-[3-(5-Chloro-thiophen-2-yl)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-urea334.12381-Ethyl-3-[3-(3-methoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-urea324.12391-[3-(3-Bromo-5-methoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-402.3urea2401-[3-(Benzothiazol-6-ylamino)-pyrido[2,3-b]pyrazin-6-yl]-3-ethyl-urea366.32411-Ethyl-3-[3-(4-methyl-3-trifluoroomethyl-phenylamino)-pyrido[2,3-391.4b]pyrazin-6-yl]-urea2421-[3-(3-Cyano-4-methyl-phenylamino)-pyrido[2,3-b]pyrazin-6-yl]-3-348.3ethyl-urea2431-Ethyl-3-[3-(4-phenoxy-phenylamino)-pyrido[2,3-b]pyrazin-6-yl]-urea401.32441-[3-(4-Chloro-3-methyl-phenylamino)-pyrido[2,3-b]pyrazin-6-yl]-3-357.3ethyl-urea2451-[3-(2-Chloro-4-methyl-phenylamino)-pyrido[2,3-b]pyrazin-6-yl]-3-357.1ethyl-urea2461-Ethyl-3-[3-(3-trifluoroomethyl-phenylamino)-pyrido[2,3-b]pyrazin-6-377.4yl]-urea2471-[3-(2-Chloro-4-trifluoromethoxy-phenylamino)-pyrido[2,3-b]pyrazin-427.36-yl]-3-ethyl-urea2481-[3-(4-Chloro-2-methoxy-5-methyl-phenylamino)-pyrido[2,3-387.4b]pyrazin-6-yl]-3-ethyl-urea2491-Ethyl-3-[3-(4-methylsulfanyl-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-urea340.32503-[6-(3-Ethyl-ureido)-pyrido[2,3-b]pyrazin-3-yl]-benzolsulfonamide373.3251N-{4-[3-(3-Phenyl-pyrido[2,3-b]pyrazin-6-yl)-ureido]-butyl}-415.3methansulfonamide

II.2 NMR Spectroscopic Data and Melting Points for Selected Compounds

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

Melting point: 239-240Â° C. (Decomp.)

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

Compound 2: 1-(2-methyl-allyl)-3-(3-naphth-2-yl-pyrido[2,3-b]pyrazin-6-yl)-thiohurea

Mp.: 239-240Â° C. (Decomp.)

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

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

Mp.: 251-252Â° C. (Decomp.)

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

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

Mp.: 225-226Â° C. (Decomp.)

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

Compound 5: 1-allyl-3-(3-naphth-2-yl-pyrido[2,3-b]pyrazin-6-yl)-thiourea

Mp.: 242-243Â° C. (Decomp.)

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

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

Mp.: 240-241Â° C. (Decomp.)

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

Compound 7: 1-allyl-3-[3-(4-hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-thiourea-hydrochloride

Mp.: 160-161Â° C. (Decomp.)

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

Compound 8: 1-(3-naphth-2-yl-pyrido[2,3-b]pyrazin-6-yl)-3-(4-nitro-phenyl)-thiourea

Mp.: 260-261Â° C. (Decomp.)

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

Compound 9: 1-[3-(4-methoxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-(4-nitro-phenyl)-thio-urea

Mp.: 250-251Â° C. (Decomp.)

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

Compound 10: 1-tert.butyl-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-thiourea

Mp.: 227Â° C. (Decomp.)

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

Compound 11: 1-cyclopropyl-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-thiourea

Mp.: 233-234Â° C.

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

Compound 12: 1-methyl-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-thiourea

Mp.: 253-254Â° C.

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

Compound 13: 1-benzyl-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-thiourea

Mp.: 232-233Â° C.

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

Compound 14: 1-(4-fluoro-phenyl)-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-thiourea

Mp.: 225-226Â° C.

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

Compound 15: 1-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-3-p-tolyl-urea

Mp.: 298-299Â° C.

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

Compound 16: 1-(4-chloro-3-trifluoromethyl-phenyl)-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-urea

Mp.: 250Â° C.

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

Compound 17: 1-(2-morpholin-4-yl-ethyl)-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-urea

Mp.: 226Â° C.

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

Compound 18: 1-cyclohexyl-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-thiourea

Mp.: 230-232Â° C.

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

Compound 19: 1-isopropyl-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-thiourea

Mp.: 229-230Â° C.

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

Compound 20: 1-furan-2-ylmethyl-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-thiourea

Mp.: 250Â° C. (Decomp.)

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

Compound 21: 1-cyclopropyl-3-(3-phenyl-pyrido[2,3-b]pyrazin-6-yl)-urea

Mp.: 158-160Â° C.

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

Compound 22: 1-methyl-3-[3-(4-nitro-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-thiourea

Mp.: 270Â° C.

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

Compound 23: 1-[3-(4-hydroxy-phenyl)-pyrido[2,3-]pyrazin-6-yl]-3-methyl-thiourea

Mp.: 282Â° C.

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

Compound 24: 1-allyl-3-[3-(4-nitro-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-thiourea

Mp.: 244Â° C. (Decomp.)

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

Compound 25: 1-allyl-3-[3-(4-hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-urea

Mp.: 240Â° C. (Decomp.)

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

Compound 26: 4-[6-(3-allyl-thioureido)-pyrido[2,3-b]pyrazin-3-yl]-benzoic acid ethyl ester

Mp.: 223-224Â° C.

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

Compound 27: 1-allyl-3-[3-(3-hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-thiourea

Mp.: 205Â° C. (Decomp.)

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

Compound 28: 1-allyl-3-(3-benzo[1,3]dioxol-5-yl-pyrido[2,3-b]pyrazin-6-yl)-thiourea

Mp.: 218-220Â° C. (Decomp.)

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

Compound 29: 1-[3-(4-hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-prop-2-inyl-thio-urea

Mp.: 350Â° C. (Decomp.)

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

Compound 30: 1-allyl-3-[3-(4-hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-thiourea

Mp.: 230Â° C. (Decomp.)

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

Compound 31: 1-[3-(4-hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-((E)-propenyl)-thio-urea

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

Compound 32: 1-allyl-3-[2,3-bis-(4-hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-thiourea

Mp.: 270Â° C. (Decomp.)

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

Compound 33: 1-[2,3-bis-(4-hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-3-((E)-propenyl)-thiourea

Mp.: 240Â° C. (Decomp.)

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

Compound 34: 1-allyl-3-[2-(4-hydroxy-phenyl)-pyrido[2,3-b]pyrazin-6-yl]-thiourea

Mp.: 260Â° C. (Decomp.)

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

Compound 35: 1-phenethyl-3-(3-phenyl-pyrido[2,3-]pyrazin-6-yl)-urea

Mp.: 250Â° C. (Decomp.)

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

Compound 36: 1-(2,3-di-pyridin-2-yl-pyrido[2,3-b]pyrazin-6-yl)-3-ethyl-urea

Mp.: 236-237Â° C.

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

Compound 37: 1-(2,3-dimethyl-pyrido[2,3-b]pyrazin-6-yl)-3-ethyl-urea

Mp.: 246-248Â° C.

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

Compound 85: 1-ethyl-3-(3-imidazol-1-yl-pyrido[2,3-b]pyrazin-6-yl)-urea

¹H-NMR (d₆-DMSO): Î´=1.20 (t, 3H), 3.26-3.32 (m, 2H), 7.26 (s, 1H), 7.75 (d, 1H), 8.20 (s, 1H), 8.40 (d, 1H), 8.79 (s, 1H), 8.84 (s, 1H), 9.39 (s, 1H), 10.16 (s, 1H) ppm.

Compound 137: 1-allyl-3-[3-(4-nitro-phenyl)-pyrido[2,3-b]pyrazin-7-yl]-thiourea

Mp.: 250Â° C. (Decomp.)

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

III. Evidence of the Kinase Inhibition of Compounds According to the Invention

III.1 Cell-Free Kinase Assays (Using ALPHA Technology)

The inhibitory effect of the compounds according to the invention was tested on various serine/threonine, tyrosine and lipid kinases in enzymatic assays. Recombinant human kinases such as, for example, Erk2, PI3Kalpha, -beta, -gamma, -delta, p38alpha, p38gamma, Jnk1, Jnk2 and others were used in this case, partly as full-length kinases, partly as shortened fragments, but at least consisting of the functional kinase domains. The commercial kinase proteins (Proqinase, Upstate) were used as recombinant fusion proteins with GST (glutathion-S-transferase) or His-Tag. Depending on the type of substrate, the various kinase reactions were quantified by means of suitable ALPHAâ„¢ beads (Perkin-Elmer).

Testing

The substance testing is described in detail hereinafter for the Erk assay. Selected test results of the Erk2, PD3Kalpha, p38alpha and Jnk2 assays are given below. To determine the IC₅₀value, the potential inhibitor substances were investigated in 10 semi-logarithmically graded concentrations of 3.16 nM-100 Î¼M.

a) MAPK-ALPHAs (e.g. Erk2): the test substance, 0.625 ng Erk2 (#14-173, Upstate), 10 Î¼M ATP and 15 nM biotinylated MBP (myelin basic protein) substrate were incubated on a 384-well Optiplate (Perkin-Elmer) in a volume of 15 Î¼l for 1 h in 25 mM Tris, 10 mM MgCl₂, 0.1% Tween-20, 100 Î¼M NaVO₄, 2 mM DTT at pH 7.5. The kinase reaction was then stopped by adding 10 Î¼l of the ALPHA bead mixes (10 Î¼g/ml, #6760617/Perkin-Elmer) pre-incubated with anti-phospho MBP antibody (320 pM, #05-429/Upstate) in 25 mM Tris, 200 mM NaCl, 110 nM EDTA and 0.3% BSA and left to stand overnight.

b) PI3K-ALPHAs (e.g. PI3Kalpha): the test substance, 1 ng PI3Kalpha (#14-602, Upstate), 100 Î¼M ATP and 20 Î¼M PIP₂substrate (#P4508, Echelon) were incubated on a 384-well Optiplate (Perkin-Elmer) for 1 h in 50 mM Hepes, 50 mM NaCl, 5 mM MgCl₂, 0.05% Chaps, 5 mM DTT at pH 7.4. The kinase reaction was then stopped by adding ALPHA bead mixes (10 Î¼g/ml, #6760603/Perkin-Elmer) pre-incubated with 1 nM GST:Grp1 fusion protein (Upstate) and 15 nM biotinylated PIP3 (#C-39B6/Echelon) in 50 mM Hepes, 50 mM NaCl, 50 mM EDTA and 0.1% BSA and left to stand overnight.

The fluorescence was detected the following morning in a Fusionâ„¢^aÎ±-system (Perkin-Elmer).

Evaluation

The %-inhibition values per substance concentration were calculated by means of the following formula from the raw data determined in the Fusionâ„¢ [Image Omitted] : $% â ¢ â€ƒ â ¢ Kinase â ¢ â€ƒ â ¢ {inhibition}_{(Sample)} = 100 - (100 Ã— \frac{{Mean}_{(Sample)} - {Mean}_{(0 â ¢ % â ¢ â€ƒ â ¢ Control)}}{{Mean}_{(100 â ¢ % â ¢ â€ƒ â ¢ Control)} - {Mean}_{(0 â ¢ % â ¢ â€ƒ â ¢ Control)}})$

Eight determinations were made for each control and two for the substance samples. The 0% control either contains no ATP or no substrate, the 100% control (fully active kinase) contains no test substance. The IC₅₀values were determined using GraphPadPrism.

The compounds according to the invention showed effective inhibition of Erk, PI3K, p38alpha and Jnk1+Jnk2 with IC₅₀values of up to 6 nM (see Table 2).

TABLE 2MAPK and PI3Kalpha kinase assay test results (IC50 [Î¼M] bei10 Î¼M bzw. 100 Î¼M* ATP)CompoundErk2PI3Kalphap38alphaJnk1 + Jnk2110.9>31.6>31.6250.0761.5>100>31.6300.3920.37>10021.8430.0066.2>1005.5442.53.8>1001.5469.5>1000.495>100820.9446.4>31.61.11240.0620.49>1001.01460.1551.1>1003.31470.7114.1>10014.21481.81.4>10013.71490.9543.5>100>31.615018.70.12918.1>1001510.1041.5>1002.91521.95.3>10012.11530.9390.612>1006.71540.5920.984>31.62.8155>1005>1007.81560.1380.425>1002.1157>1000.348>10028.5158>1000.186>100>31.6159>1000.147>10012.61605.82.9>31.6>31.6161>1001.1>100>100162>1000.19>100>31.616326.90.096>100>31.616419.60.444>10024.316519.41.2>10027.116613.71.3>10021.9167>1001.1>10027.31680.150.612>1002.51692.73.7>1009.51700.1032.4>31.61.11710.0843>1001.41720.414>10041730.1072.4>1002.91744.93>31.64.61750.1910.458>1002.5177>31.60.295>1003.9178>1000.164>31.62.317980.2021.48.118015.71.1>1008.61811.70.739>1004.3182>31.61.1>100211830.2032.8>1004.7184>1000.133>1006.3185>31.60.154>1004.31860.2233.8>1002.518716.60.712>31.6>100188>1002.8>100>31.618920.30.237>1006.2190>1000.271>1003119231.60.422>1001.81930.2122.2>1001.5

III.2A Cellular Assay: Testing for Anti-Proliferative Effect (XTT Assay)

The principle of this test is based on the intracellular reduction of the tetrazolium dye XTT (sodium 3â€²-[1-(phenylaminocarbonyl)-3,4-tetrazolium]-bis(4-methoxy-6-nitro)benzene sulfonic acid, Sigma) to a formazan dye by mitochondrial dehydrogenases. The dye is only formed by metabolically active cells and its photometrically measurable intensity is a quantitative indicator for the presence of living cells. The reduction of dye formation by incubation of the cells with substances serves as a parameter for the anti-proliferative effect.

Testing

The tumour cell lines (ATCC) were injected into 96-well microtitre plates in a defined cell number (5000 cells/well for BxPC3 and Hct116; 10000 cells/well for MDA MB468) and then incubated overnight in an incubator at 37Â° C., 5% CO₂and 95% air humidity. The test substances were prepared as stock solutions (10 mM) in DMSO. To determine the EC₅₀values the potential inhibitor substances were added to the cells in quarter-logarithmically graded dilutions, resulting in final concentrations of 0.28 Î¼M-50 Î¼M. The cell plates were then incubated for 45 h in an incubator at 37Â° C., 5% CO₂and 95% air humidity.

For the detection reaction the substrate XTT was mixed with PMS (N-Methyl dibenzopyrazine methylsulfate, Sigma) and added to the cells so that a final concentration of 325 Î¼g XTT/ml and 2.5 Î¼g PMS/ml was obtained. It was then incubated for 3 h at 37Â° C., 95% air humidity. The formazan salt formed by the cellular dehydrogenases could then be quantified by adsorption at 490 nm.

Evaluation

The % inhibition value was evaluated by means of the following formula from the values for the optical densities measured in each case at 490 nm: $% â ¢ â€ƒ â ¢ Inhibition â ¢ â€ƒ â ¢ of â ¢ â€ƒ â ¢ cell â ¢ â€ƒ â ¢ {proliferation}_{(Sample)} = 100 - (100 Ã— \frac{{Mean}_{(Sample)} - {Mean}_{(0 â ¢ % â ¢ â€ƒ â ¢ Control)}}{{Mean}_{(100 â ¢ % â ¢ â€ƒ â ¢ Control)} - {Mean}_{(0 â ¢ % â ¢ â€ƒ â ¢ Control)}})$

Eight determinations were made for each control and two for the substance samples. The 0% control contains no cells, the 100% control (proliferation control) contains no test substance. The EC₅₀values were determined using GraphPadPrism.

The compounds according to the invention showed partly effective inhibition of the cell proliferation with EC₅₀values of to <1 Î¼M (see Table 3).

TABLE 3XTT assay test results (EC50 [Î¼M])CompoundBxPC3MDA-MB468Hct116â€‚30124612410101.5146>50ca. 209.31500.94.32.3153>252461568.9151.4157>253.54.4164>505.2>25169nicht getestet5.72.8173nicht getestet>259175nicht getestet>504.4176nicht getestet1711.8183nicht getestet4.32.1191nicht getestet8.55.5193nicht getestet4.42.1Ly294002252017

It was surprisingly found that the PI3K inhibitor Ly294002 known from the literature only showed weak anti-proliferative effects on the cell lines used compared to the Exemplary Embodiments.

III.2B Cellular Assay: Testing for Substrate Inhibition (Western Blotting)

This method can be used to predict whether the kinase modulator under study also achieves the desired effect in a cellular context, i.e. in this case, a substrate protein downstream of the target kinase is investigated for its phosphorylation status. For this purpose, the cells incubated with substance are lysed and the total protein separated on a reducing polyacrylamide gel. The proteins are then transferred to a PVDF membrane by means of Western Blotting and the substrate bands sought are made visible with specific antibodies and a suitable detection method. The substrate proteins downstream of the target kinases are detected simultaneously with a respectively special anti-phospho-antibody and at the same time a total antibody which recognizes the substrate total protein. This simultaneous measurement can be made using the duplex technology of the ODYSSEY imagers (LiCOR). The intensity of the total substrate bands is used for normalising or quantifying the phosphorylation inhibition or activation.

Testing

Suitable tumour cell lines (e.g. BxPC3, Hct116 or MDA MB468) were injected into six-well microtitre plates in a defined cell number (e.g. 350 000 cells/well for BxPC3 and Hct116) in the respective standard complete medium and then incubated overnight at 37Â° C., 5% CO₂and 95% air humidity. The cells were then incubated for a further 24 h under serum-reduced conditions i.e. in the respective medium but with only 0.25% serum. The test substances were prepared as stock solutions (10 mM) in DMSO and incubated with the cells in final concentrations of 5, 15.8 and 50 Î¼M for 5 h. This was followed by cell lysis in 25 mM Tris, 150 mM NaCl, 10 mM Na-pyrophosphate, 2 mM EGTA, 25 mM Î²-glycerophosphate, 25 mM NaF, 10% glycerine, 0.75% NP-40, 100 Î¼M NaVO₄buffer. Following protein quantification by means of BCA (bicinchonic acid protein assay kit, Sigma) Assay, protein quantities of about 20 Î¼g per track were separated on a LÃ¤mmli polyacrylamide gel and then transferred to a PVDF membrane (Millipore) by means of Semi-Dry Western-Blotting at 0.8 mA/cm²for 1 h. This was followed by pre-hybridisation of the membrane for 1 hour in I-block reagent (Applied Biosystems) and incubation overnight with the specific antibodies. To determine the Erk and PI3K inhibition, the respectively downstream substrates Rsk1 were detected with the total antibody (Rsk #sc-231g C-21, Santa Cruz) and the phospho-antibody (Phospho-p90RSK (S380) #9341, NEB Cell Signalling) and Akt was detected with the total antibody (Akt1 #sc-1618 C-20, Santa Cruz) and the phospho-antibody (Phospho-Akt (Ser 473) #9271, NEB Cell Signaling). After washing the membrane, secondary antibody incubation was carried out with anti-rabbit IR Dye 800 (#611-732-127, Rockland) for the phospho-antibody and anti-goat Alexa Fluor 680 (#A-21081, Molecular Probes) for the total protein-antibody. After incubating for 30 min at room temperature in the dark, the hybridisation of the detection antibody on the membrane was detected by scanning in the ODYSSEY imager (LiCOR).

Evaluation

At concentrations of 5-50 Î¼M, the compounds according to the invention exhibited dual inhibition of Erk (MAPK1/2) and PI3K (see Table 4) which are indicated by inhibition of the band intensity of both corresponding phospho-substrate proteins Rsk1 and Akt. The reduction of the fluorescence intensity of the phospho-substrate bands (pRsk and pAkt) is given in the table below as % inhibition and relates to the following formula: $% â ¢ â€ƒ â ¢ Inhibition â ¢ â€ƒ â ¢ of â ¢ â€ƒ â ¢ Substrate â ¢ â€ƒ â ¢ {phosphorylation}_{(Sample)} = 100 - (100 Ã— \frac{Sample}{100 â ¢ % â ¢ â€ƒ â ¢ Control})$

The band intensity (fluorescence intensity) of the respective non-inhibited (without substance) phospho-substrates was used as 100% control.

TABLE 4Inhibition of cellular substrate phosphorylation by selected substances(bei 50 Î¼M)CompoundErk â†’ pRskPI3K â†’ pAktâ€‚3090%100%12490%90%146100%10%1500%90%17390%50%18380%80%Ly2940020%40%Wortmannin0%100%

The PI3K inhibitor Ly294002 known from the literature showed only weak PI3K inhibition compared to the pyridopyrazine derivatives, i.e. inhibition of the PI3K substrate p-Akt and as predicted, no Erk inhibition or inhibition of the Erk substrate p-Rsk. Wortmanninâ€”a further PI3K inhibitor known from the literatureâ€”showed complete inhibition of the PI3K substrate pAkt, but no Erk or p-RSK inhibition.

In contrast to Exemplary Embodiments both reference substances used here showed no dual inhibition, i.e. of Erk and PI3K simultaneously but only a PI3K inhibition.

Abbreviations

Akt of: murine Akt8 retrovirus or protein kinase B (PKB)

Ask1 apoptosis signal-regulating kinase

ATR ataxia-telangiectasia and Rad3-related

ATM Ataxia-telangiectasia mutated

Bag1 Bc1-2 associated athanogene-1

Bc1-2 B-cell leukemia/lymphoma-2 gene

DNA-PK DNA-dependent protein kinase

Erk extracellular signal-regulated kinase

Flt-3 fms like tyrosine kinase 3

GSK-3 Glycogen synthase kinase-3

hSMG-1 human ortholog of product of seven nematode gene-1

JAK-3 Janus kinase 3

JNK c-jun N-terminal kinase

MAPK mitogen activated protein kinase

Mek MAP or Erk kinase

mTOR mammalian target of rapamycin

PDGFR platelet derived growth factor receptor

PI3K phosphoinositol 3-kinase

PIKK phosphoinositol 3-kinase related kinase

PIP₂phosphatidylinositol-biphosphate

PIP₃phosphatidylinositol-triphosphate

PtdIns phosphatidylinositol

Raf rapid accelerated fibrosarcoma

Ras rat sarcoma

RTK receptor tyrosine kinase

SAPK stress-activated protein kinase

Ser Serine

Syk spleen tyrosine kinase

Thr Threonine

Tyr Tyrosine

VEGFR vascular endothelial growth factor receptor

REFERENCES

1. Alessi D R, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P, Hemmings B A. Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J. 1996 Dec. 2; 15(23):6541-51.
2. Ali K, Bilancio A, Thomas M, Pearce W, Gilfillan A M, Tkaczyk C, Kuehn N, Gray A, Giddings J, Peskett E, Fox R, Bruce I, Walker C, Sawyer C, Okkenhaug K, Finan P, Vanhaesebroeck B. Essential role for the p110delta phosphoinositide 3-kinase in the allergic response. Nature. 2004 Oct. 21; 431(7011):1007-11.
3. Bennett B L, Sasaki D T, Murray B W, O'Leary E C, Sakata S T, Xu W, Leisten J C, Motiwala A, Pierce S, Satoh Y, Bhagwat S S, Manning A M, Anderson D W. SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc Natl Acad Sci USA. 2001 Nov. 20; 98(24):13681-6.
4. Bondev A, Rubio I, Wetzker R. Differential regulation of lipid and protein kinase activities of phosphoinositide 3-kinase gamma in vitro. Biol. Chem. 1999 November; 380(11):1337-40.
5. Bondeva T, Pirola L, Bulgarelli-Leva G, Rubio I, Wetzker R, Wymann M P. Bifurcation of lipid and protein kinase signals of PI3Kgamma to the protein kinases PKB and MAPK. Science. 1998 Oct. 9; 282(5387):293-6.
6. Campbell I G, Russell S E, Choong D Y, Montgomery K G, Ciavarella M L, Hooi C S, Cristiano B E, Pearson R B, Phillips W A. Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res. 2004 Nov. 1; 64(21):7678-81.
7. Chang F, Lee J T, Navolanic P M, Steelman L S, Shelton J G, Blalock W L, Franklin R A, McCubrey J A. Involvement of PI3K/Akt pathway in cell cycle progression, apoptosis, and neoplastic transformation: a target for cancer chemotherapy. Leukemia. 2003 March; 17(3):590-603. Review
8. Chang F, Steelman L S, Lee J T, Shelton J G, Navolanic P M, Blalock W L, Franklin R A, McCubrey J A. Signal transduction mediated by the Ras/Raf/MEK/ERK pathway from cytokine receptors to transcription factors: potential targeting for therapeutic intervention. Leukemia. 2003 July; 17(7):1263-93. Review.
9. Chang H W, Aoki M, Fruman D, Auger K R, Bellacosa A, Tsichlis P N, Cantley L C, Roberts T M, Vogt P K. Transformation of chicken cells by the gene encoding the catalytic subunit of PI 3-kinase. Science. 1997 Jun. 20; 276(5320):1848-50.
10. Chen J, Fujii K, Zhang L, Roberts T, Fu H. Raf-1 promotes cell survival by antagonizing apoptosis signal-regulating kinase 1 through a MEK-ERK independent mechanism. Proc Natl Acad Sci USA. 2001 Jul. 3; 98(14):7783-8.
11. Chiang G G, Abraham R T. Determination of the catalytic activities of mTOR and other members of the phosphoinositide-3-kinase-related kinase family. Methods Mol Biol. 2004; 281:125-41.
12. Crackower M A, Oudit G Y, Kozieradzki I, Sarao R, Sun H, Sasaki T, Hirsch E, Suzuki A, Shioi T, Irie-Sasaki J, Sah R, Cheng H Y, Rybin V O, Lembo G, Fratta L, Oliveira-dos-Santos A J, Benovic J L, Kahn C R, Izumo S, Steinberg S F, Wymann M P, Backx P H, Penninger J M. Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways. Cell. 2002 Sep. 20; 110(6):737-49.
13. Davies H, Bignell G R, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett M J, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson B A, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins G J, Bigner D D, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho J W, Leung S Y, Yuen S T, Weber B L, Seigler H F, Darrow T L, Paterson H, Marais R, Marshall C J, Wooster R, Stratton M R, Futreal P A. Mutations of the BRAF gene in human cancer. Nature. 2002 Jun. 27; 417(6892):949-54.
14. Davies S P, Reddy H, Caivano M, Cohen P. Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 2000 Oct. 1; 351 (Pt 1):95-105.
15. Dhand R, Hiles I, Panayotou G, Roche S, Fry M J, Gout I, Totty N F, Truong O, Vicendo P, Yonezawa K, et al. PI 3-kinase is a dual specificity enzyme: autoregulation by an intrinsic protein-serine kinase activity. EMBO J. 1994 Feb. 1; 13(3):522-33.
16. Elliott R D, Temple C Jr, Montgomery J A. Potential folic acid antagonists. 3. Deaza analogs of methotrexate. 3. 1- and 3-Deaza analogs of 2,4-diamino-6-[(n-methylanilino)methyl]pteridine. J Org Chem. 1968 February; 33(2):533-6.
17. Friess H, Berberat P, Schilling M, Kunz J, Korc M, Buchler M W. Pancreatic cancer: the potential clinical relevance of alterations in growth factors and their receptors. J Mol Med. 1996 January; 74(1):35-42. Review.
18. Gotz R, Wiese S, Takayama S, Camarero G C, Rossoll W, Schweizer U, Troppmair J, Jablonka S, Holtmann B, Reed J C, Rapp U R, Sendtner M. Bag1 is essential for differentiation and survival of hematopoietic and neuronal cells. Nat. Neurosci. 2005 September; 8(9): 1169-78.
19. Gum R J, McLaughlin M M, Kumar S, Wang Z, Bower M J, Lee J C, Adams J L, Livi G P, Goldsmith E J, Young P R. Acquisition of sensitivity of stress-activated protein kinases to the p38 inhibitor, SB 203580, by alteration of one or more amino acids within the ATP binding pocket. J Biol Chem. 1998 Jun. 19; 273(25):15605-10.
20. Hoshino R, Chatani Y, Yamori T, Tsuruo T, Oka H, Yoshida O, Shimada Y, Ari-i S, Wada H, Fujimoto J, Kohno M. Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors. Oncogene. 1999 Jan. 21; 18(3):813-22.
21. Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield M D. Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol. 2001; 17:615-75. Review.
22. Khleif S N, Abrams S I, Hamilton J M, Bergmann-Leitner E, Chen A, Bastian A, Bernstein S, Chung Y, Allegra C J, Schlom J. A phase I vaccine trial with peptides reflecting ras oncogene mutations of solid tumors. J Immunother. 1999 March; 22(2): 155-65.
23. Levine D A, Bogomolniy F, Yee C J, Lash A, Barakat R R, Borgen P I, Boyd J. Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Clin Cancer Res. 2005 Apr. 15; 11(8):2875-8.
24. Lewis T S, Shapiro P S, Ahn N G. Signal transduction through MAP kinase cascades. Adv Cancer Res. 1998; 74:49-139. Review.
25. Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang S I, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner S H, Giovanella B C, Ittmann M, Tycko B, Hibshoosh H, Wigler M H, Parsons R. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997 Mar. 28; 275(5308):1943-7.
26. Lu Y, Wang H, Mills G B. Targeting P I3K-AKT pathway for cancer therapy. Rev Clin Exp Hematol. 2003 June; 7(2):205-28. Review.
27. Ma Y Y, Wei S J, Lin Y C, Lung J C, Chang T C, Whang-Peng J, Liu J M, Yang D M, Yang W K, Shen C Y. PIK3CA as an oncogene in cervical cancer. Oncogene. 2000 May 25; 19(23):2739-44.
28. Marshall C. How do small GTPase signal transduction pathways regulate cell cycle entry? Curr Opin Cell Biol. 1999 December; 11(6):732-6. Review.
29. McPhillips F, Mullen P, Monia B P, Ritchie A A, Dorr F A, Smyth J F, Langdon S P. Association of c-Raf expression with survival and its targeting with antisense oligonucleotides in ovarian cancer. Br J Cancer. 2001 Nov. 30; 85(11):1753-8.
30. Mendelsohn J, Baselga J. The EGF receptor family as targets for cancer therapy. Oncogene. 2000 Dec. 27; 19(56):6550-65. Review.
31. Moore S M, Rintoul R C, Walker T R, Chilvers E R, Haslett C, Sethi T. The presence of a constitutively active phosphoinositide 3-kinase in small cell lung cancer cells mediates anchorage-independent proliferation via a protein kinase B and p70s6k-dependent pathway. Cancer Res. 1998 Nov. 15; 58(22):5239-47.
32. Okkenhaug K, Vanhaesebroeck B. PI3K in lymphocyte development, differentiation and activation. Nat Rev Immunol. 2003 April; 3(4):317-30. Review.
33. Patrucco E, Notte A, Barberis L, Selvetella G, Maffei A, Brancaccio M, Marengo S, Russo G, Azzolino O, Rybalkin S D, Silengo L, Altruda F, Wetzker R, Wymann M P, Lembo G, Hirsch E. PI3Kgamma modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and -independent effects. Cell. 2004 Aug. 6; 118(3):375-87.
34. Rapp U R, Rennefahrt U, Troppmair J. Bc1-2 proteins: master switches at the intersection of death signaling and the survival control by Raf kinases. Biochim Biophys Acta. 2004 Mar. 1; 1644(2-3):149-58. Review.
35. Rodriguez-Viciana P, Warne P H, Dhand R, Vanhaesebroeck B, Gout I, Fry M J, Waterfield M D, Downward J. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature. 1994 Aug. 18; 370(6490):527-32.
36. Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell S M, Riggins G J, Willson J K, Markowitz S, Kinzler K W, Vogelstein B, Velculescu V E. High frequency of mutations of the PIK3CA gene in human cancers, Science. 2004 Apr. 23; 304(5670):554.
37. Sebolt-Leopold J S, Herrera R. Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer. 2004 December; 4(12):937-47. Review.
38. Shayesteh L, Lu Y, Kuo W L, Baldocchi R, Godfrey T, Collins C, Pinkel D, Powell B, Mills G B, Gray J W. PIK3CA is implicated as an oncogene in ovarian cancer Nat Genet. 1999 January; 21(1):99-102.
39. Sirivatanauksorn V, Sirivatanauksorn Y, Lemoine N R. Molecular pattern of ductal pancreatic cancer. Langenbecks Arch Surg. 1998 April; 383(2):105-15. Review.
40. Steck P A, Pershouse M A, Jasser S A, Yung W K, Lin H, Ligon A H, Langford L A, Baumgard M L, Hattier T, Davis T, Frye C, Hu R, Swedlund B, Teng D H, Tavtigian S V. Identification of a candidate tumour suppressor gene, MMAC 1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet. 1997 April; 15(4):356-62.
41. Sujobert P, Bardet V, Cornillet-Lefebvre P, Hayflick J S, Prie N, Verdier F, Vanhaesebroeck B, Muller O, Pesce F, Ifrah N, Hunault-Berger M, Berthou C, Villemagne B, Jourdan E, Audhuy B, Solary E, Witz B, Harousseau J L, Himberlin C, Lamy T, Lioure B, Cahn J Y, Dreyfus F, Mayeux P, Lacombe C, Bouscary D. Essential role for the p110delta isoform in phosphoinositide 3-kinase activation and cell proliferation in acute myeloid leukemia. Blood. 2005 Aug. 1; 106(3):1063-6.
42. Temple C Jr, Rener G A. Potential antimitotic agents. Synthesis of some ethyl benzopyrazin-7-ylcarbamates, ethyl pyrido[3,4-b]pyrazin-7-ylcarbamates, and ethyl pyrido[3,4-e]-as-triazin-7-ylcarbamates. J Med Chem. 1990 November; 33(11):3044-50.
43. Troppmair J, Rapp U R. Raf and the road to cell survival: a tale of bad spells, ring bearers and detours. Biochem Pharmacol. 2003 Oct. 15; 66(8):1341-5. Review.
44. Vanhaesebroeck B, Higashi K, Raven C, Welham M, Anderson S, Brennan P, Ward S G, Waterfield M D. Autophosphorylation of p110delta phosphoinositide 3-kinase: a new paradigm for the regulation of lipid kinases in vitro and in vivo. EMBO J. 1999 Mar. 1; 18(5):1292-302.
45. Vanhaesebroeck B, Leevers S J, Ahmadi K, Timms J, Katso R, Driscoll P C, Woscholski R, Parker P J, Waterfield M D. Synthesis and function of 3-phosphorylated inositol lipids. Annu Rev Biochem. 2001; 70:535-602. Review.
46. Weinstein-Oppenheimer C R, Blalock W L, Steelman L S, Chang F, McCubrey J A. The Raf signal transduction cascade as a target for chemotherapeutic intervention in growth factor-responsive tumors. Pharmacol Ther. 2000 December; 88(3):229-79. Review.
47. Wetzker R, Rommel C. Phosphoinositide 3-kinases as targets for therapeutic intervention. Curr Pharm Des. 2004; 10(16):1915-22. Review.
48. Wymann M P, Pirola L. Structure and function of phosphoinositide 3-kinases. Biochim Biophys Acta. 1998 Dec. 8; 1436(1-2):127-50. Review.