Preparation of novel naphthyridine derivatives and their use as kinase inhibitors.

Abstract

The present invention relates to kinase modulators of the naphthyridine I [R1-R3 = H, alkyl, heterocyclyl, aryl, etc., where at least one of the substituents R1-R3 has to be an NR7R8 and where R7 = H, alkyl, cycloalkyl, etc. and R8 = C(Y)NR9R10 (Y = O, S; R9, R10 = H, alkyl, cycloalkyl, etc.), C(Y)NR11R12 (Y = NH; R11, R12 = H, alkyl, cycloalkyl, etc.), C(NR13)R14 (R13 = H and R14 = alkyl, cycloalkyl, aryl, etc.); R4-R6 = H, alkyl, cycloalkyl, aryl, etc., where at least one of R4-R6 has to be an (un)substituted (hetero)aryl or NR15R16 (R15, R16 = H, alkyl, cycloalkyl, etc.; or NR15R16 = (un)substituted heterocyclyl)] and to the prepn. and use thereof as medicaments for the modulation of misdirected cellular signal transduction processes, in particular for influencing the function of tyrosine and serine/threonine kinases and for the treatment of malignant or benign tumors and other disorders based on pathol. cell proliferation, such as, for example, restenosis, psoriasis, arteriosclerosis and cirrhosis of the liver. Forty compds. I were prepd. Thus, reacting 1-(7-bromo-[1,5]naphthyridin-2-yl)-3-ethyl-urea with 4-methoxyphenylboronic acid afforded 51% 1-ethyl-3-[7-(4-methoxyphenyl)-[1,5]naphthyridin-2-yl]-urea (II). The inhibitory effect of compds. I was tested on various human serine/threonine kinases and tyrosine kinases (data given). For example, II showed dual activity against Aurora-B and Erk2. Pharmaceutical compns. comprising the compd. I, alone or in combination with other therapeutic agent, were disclosed. [on SciFinder(R)]