Substituted indolines with an inhibitory effect on various kinases and complexes of CDKs

A compound of formula

• X denotes an oxygen or sulphur atom,
• R1 denotes a hydrogen atom, C1-3-alkyl, hydroxy, C1-4-alkoxycarbonyl, or C2-4-alkanoyl group,
• R2 denotes a hydrogen, fluorine, chlorine, bromine or iodine atom, a C1-3-alkyl or nitro group,
• R3 denotes a phenyl or naphthyl group, each of which may be mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C1-3-alkyl, C1-3-alkoxy, carboxy, cyano, trifluoromethyl, nitro, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, C1-3-alkylsulphonylamino, amino-C1-3-alkyl, 2-carboxy-phenylcarbonylaminomethyl, C1-3-alkylamino-C1-3-alkyl, C2-4-alkanoylamino-C1-3-alkyl, N—(C2-4-alkanoyl)-C1-3-alkylamino-C1-3-alkyl, di-(C1-3-alkyl)-amino-C1-3-alkyl, carboxy-C2-3-alkenyl, N-(carboxy-C1-3-alkyl)-aminocarbonyl, N-(carboxy-C1-3-alkyl)-N—(C1-3-alkyl)-aminocarbonyl or imidazolyl-C1-3-alkyl groups, while the substituents may be identical or different,
• R4 denotes a hydrogen atom or a C1-3-alkyl group and
• R5 denotes a substituted phenyl or naphthyl group, which is optionally, additionally substituted by a C1-3-alkyl group, the substituted phenyl or naphthyl group being substituted in the aromatic moiety
• by a fluorine, chlorine, bromine or iodine atom, by a C1-3-alkyl, C1-3-alkoxy, cyano, nitro or trifluoromethyl group,
• by a C1-3-alkoxy group which is substituted by a carboxy, aminocarbonyl, C1-3-alkylaminocarbonyl or di-(C1-3-alkyl)-aminocarbonyl group or in the 2 or 3 position by an amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, phenyl-C1-3-alkylamino, N-(phenyl-C1-3-alkyl)-N—(C1-3-alkyl)-amino, pyrrolidino, piperidino or hexamethyleneimino group,
• by a C2-3-alkenyl group optionally substituted by a di-(C1-3-alkyl)-amino group, which may additionally be substituted in the alkenyl moiety by a chlorine or bromine atom,
• by a C2-3-alkynyl group optionally substituted by a di-(C1-3-alkyl)-amino group,
• by a C1-3-alkyl group which is substituted by a 3- to 7-membered cycloalkyleneimino group, by a dehydropiperidino, morpholino, thiomorpholino, 1-oxido-thiomorpholino, 1,1-dioxido-thiomorpholino, piperazino, N—(C1-3-alkyl)-piperazino, N—(C1-3-alkanoyl)-piperazino or N—(C1-5-alkoxycarbonyl)-piperazino group, whilst the abovementioned substituents may be substituted by a C1-3-alkyl, phenyl or phenyl-C1-3-alkyl group and the abovementioned piperidino or hexamethyleneimino groups may additionally be substituted by a C1-3-alkyl group or in the 3 or 4 position by a hydroxy, C1-3-alkoxy, hydroxy-C1-3-alkyl, carboxy, aminocarbonyl, N—(C1-3-alkyl)-aminocarbonyl or N,N-di-(C1-3-alkyl)-aminocarbonyl group,
• by a C1-3-alkyl group substituted by a hydroxy, C1-3-alkoxy, carboxy or cyano group, whilst a C1-3-alkyl group substituted by a carboxy group may additionally be substituted in the alkyl moiety by an amino or C1-5-alkoxycarbonylamino group,
• by an aminocarbonylamino, amidino or guanidino group optionally substituted by one or two C1-3-alkyl groups,
• by a piperidino, hexamethyleneimino, morpholino, piperazino or N—(C1-3-alkyl)-piperazino group,
• by a formyl, carboxy or trifluoroacetyl group,
• by a carbonyl group which
• is substituted by a C1-3-alkyl, C1-3-alkoxy-C1-3-alkyl, amino, C1-5-alkylamino or di-(C1-3-alkyl)-amino group, while the abovementioned amino and C1-3-alkylamino groups may additionally be substituted at the nitrogen atom by a carboxy-C1-3-alkyl group or by a C2-3-alkyl group which may be substituted in the 2 or 3 position by a hydroxy, C1-3-alkoxy, amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group,
• by a pyrrolidinocarbonyl, piperidinocarbonyl, hexamethyleneiminocarbonyl, morpholinocarbonyl, piperazinocarbonyl, N—(C1-3-alkyl)-piperazinocarbonyl or N-(phenyl-C1-3-alkyl)-piperazinocarbonyl group,
• by an amidosulphonyl, pyrrolidinosulphonyl, piperidinosulphonyl or hexamethyleneiminosulphonyl group, by a C1-3-alkylamidosulphonyl or di-(C1-3-alkyl)-amidosulphonyl group, wherein an alkyl moiety may be substituted in each case by a carboxy, aminocarbonyl, N—(C1-3-alkyl)-aminocarbonyl or N,N-di-(C1-3-alkyl)-aminocarbonyl group or, in the 2 or 3 position, by a C1-3-alkylamino or di-(C1-3-alkyl)-amino group,
• by an amino, C1-5-alkylamino, C3-7-cycloalkylamino, phenyl-C1-3-alkylamino, phenylamino, 6-membered heteroarylamino, amino-C1-3-alkyl, N—(C1-5-alkyl)-amino-C1-3-alkyl, di-(C1-5-alkyl)-amino-C1-3-alkyl, C3-7-cycloalkylamino-C1-3-alkyl, N—(C1-5-alkyl)-C3-7-cycloalkylamino-C1-3-alkyl, phenylamino-C1-3-alkyl, N—(C1-3-alkyl)-phenylamino-C1-3-alkyl, phenyl-C1-3-alkylamino-C1-3-alkyl or N—(C1-5-alkyl)-phenyl-C1-3-alkylamino-C1-3-alkyl group or by a 6-membered heteroarylamino-C1-3-alkyl group optionally substituted at the nitrogen atom by a C1-5-alkyl group, while the N-alkyl moiety of the abovementioned groups may be substituted in each case by a cyano, carboxy, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, 2-[di-(C1-3-alkyl)-amino]-ethylaminolocarbonyl, 3-[di-(C1-3-alkyl)-amino]-propylamincarbonyl, N-{2-[di-(C1-3-alkyl)-amino]-ethyl}-N—(C1-3-alkyl)-aminocarbonyl or N-{3-[di-(C1-3-alkyl)-amino]-propyl}-N—(C1-3-alkyl)-aminocarbonyl group or in the 2 or 3 position by a hydroxy, C1-3-alkoxy, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, pyrrolidino, piperidino, hexamethyleneimino, morpholino, piperazino or N—(C1-3-alkyl)-piperazino group and the nitrogen atom of the abovementioned amino, N—(C1-5-alkyl)-amino, C3-7-cycloalkylamino, phenyl-C1-3-alkylamino, phenylamino, 6-membered heteroarylamino, amino-C1-3-alkyl- and N—(C1-5-alkylamino)-C1-3-alkyl groups may additionally be substituted
• by a C1-5-alkoxycarbonyl group,
• by a formyl, trifluoroacetyl or benzoyl group,
• by a carboxy-C1-3-alkyl, aminocarbonyl-C1-3-alkyl, N—(C1-3-alkyl)-aminocarbonyl-C1-3-alkyl or N,N-di-(C1-3-alkyl)-aminocarbonyl-C1-3-alkyl group,
• by a C1-5-alkyl group which may be substituted, except in the 1 position, by a hydroxy, C1-3-alkoxy, amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group,
• by a C2-4-alkanoyl group which may be substituted in the alkanoyl moiety by a carboxy, hydroxy, C1-3-alkoxy, phenyl, amino, phthalimido, C1-3-alkylamino, di-(C1-3-alkyl)-amino, pyrrolidino, piperidino, hexamethyleneimino or morpholino group or by a piperazino group optionally substituted at the nitrogen atom by a C1-3-alkyl or phenyl-C1-3-alkyl group, while the alkyl moiety of the abovementioned C1-3-alkylamino- and di-(C1-3-alkyl)-amino substituents may be substituted in the 2 or 3 position by a hydroxy, C1-3-alkoxy, amino, C1-5-alkoxycarbonylamino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, phenyl, pyrrolidino, piperidino, hexamethyleneimino or morpholino group,
• by a C1-5-alkylsulphonyl group in which the alkyl moiety may be substituted except in the 1 position by a di-(C1-3-alkyl)-amino, pyrrolidino, piperidino, hexamethyleneimino or morpholino group,
• by a phenyl-(C1-3)-alkylsulphonyl or phenylsulphonyl group optionally substituted in the phenyl moiety by a fluorine, chlorine or bromine atom or by a C1-3-alkyl or C1-3-alkoxy group,
• while additionally any carboxy, amino or imino group present may be substituted by a group which can be cleaved in vivo,
• the stereoisomers and the salts thereof.