Substituted indolinones with kinase inhibitory activity

A compound of the formula

• wherein:
• X denotes an oxygen or sulphur atom,
• R1 denotes a hydrogen atom, a C1-4-alkoxy-carbonyl or C2-4-alkanoyl group,
• R2 denotes a carboxy or C1-4-alkoxy-carbonyl group or an aminocarbonyl group optionally substituted by one or two C1-3-alkyl groups, whilst the substituents may be identical or different,
• R3 denotes a hydrogen atom or a C1-6-alkyl group which may be substituted at the 2 position, in relation to the carbon atom of the R3—C(R4NR5)═ group by a fluorine, chlorine or bromine atom, by a hydroxy, C1-3-alkoxy, C1-3-alkylsulphenyl, C1-3-alkylsulphinyl, C1-3-alkylsulphonyl, phenylsulphenyl, phenylsulphinyl, phenylsulphonyl, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, C2-5-alkanoylamino or N—(C1-3-alkylamino)-C2-5-alkanoylamino group,
• R4 denotes a hydrogen atom, a C1-6-alkyl group or a C5-7-Cycloalkyl group optionally substituted by a C1-3-alkyl group wherein a methylene group in the 3 or 4 position in relation to the carbon atom of the R3—C(R4NR5)═ group may be substituted by an imino group optionally substituted by a C1-3-alkyl group,
• a phenyl or naphthyl group which may be substituted by a fluorine, chlorine, bromine or iodine atom,
• by a methoxy group optionally substituted by 1 to 3 fluorine atoms,
• by a C2-3-alkoxy which may be substituted in the 2 or 3 position by a C1-3-alkylamino, di-(C1-3-alkyl)-amino or 7-membered cycloalkyleneimino group, whilst additionally an alkyl moiety in the abovementioned alkylamino and dialkylamino groups may be substituted by a phenyl group,
• by a trifluoromethyl, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, C2-5-alkanoylamino, N—(C1-3-alkyl)-C2-5-alkanoylamino, C1-5-alkylsulphonylamino, N—(C1-3-alkyl)-C1-5-alkylsulphonylamino, phenylsulphonylamino, N—(C1-3-alkyl)-phenylsulphonylamino, aminosulphonyl, C1-3-alkylaminosulphonyl or di-(C1-3-allyl)-aminosulphonyl group, whilst additionally an alkyl moiety in the abovementioned alkylamino and dialkylamino groups may be substituted by a phenyl group,
• by a carbonyl group which is substituted by a hydroxy, C1-3-alkoxy, amino, C1-3-alkylamino or N—(C1-5-alkyl)-C1-3-alkylamino group, whilst additionally an alkyl moiety in the abovementioned groups may be substituted by a carboxy, C1-3-alkoxycarbonyl or phenyl group or in the 2 or 3 position by a di-(C1-3-alkyl)-amino, or 7-membered cycloalkyleneimino group,
• by a C1-3-alkyl group which is substituted by an amino, C1-7-alkylamino, C5-7-cycloalkylamino, C5-7-cycloalkyl-C1-3-alkylamino or phenyl-C1-3-alkylamino group which may additionally be substituted at the amino nitrogen atom by a C1-3-alkyl group wherein the hydrogen atoms are wholly or partially replaced by fluorine atoms, by a C5-7-cycloalkyl, C2-4-alkenyl or C1-4-alkyl group, whilst
• the abovementioned C1-4-alkyl substituent may in each case be additionally mono, di- or trisubstituted by a cyano, carboxy, C1-3-alkoxycarbonyl, or phenyl group, wherein the phenyl group may be substituted by fluorine, chlorine or bromine atoms, by methyl, methoxy, trifluoromethyl, cyano or nitro groups and the substituents may be identical or different, or may be substituted in the 2, 3 or 4 position by a hydroxy group,
• by a C1-3-alkyl group which may be substituted by a hydroxy, carboxy,
• by a 7-membered cycloalkenyleneimino group, wherein the abovementioned 7-membered cycloalkyleneimino group may be substituted by one or two C1-3-alkyl groups, by a C5-7-cycloalkyl or phenyl group, by a C1-3-alkyl, C5-7-cycloalkyl, phenyl, carboxy or C1-4-alkoxy-carbonyl group and by a hydroxy group and in the abovementioned cycloalkyleneimino group a methylene group adjacent to the nitrogen atom may be replaced by a carbonyl group,
• by a C1-3-alkyl group which is substituted by a 7-membered cycloalkyleneimino group, whilst a phenyl group optionally mono- or disubstituted by fluorine, chlorine or bromine atoms or by methyl or methoxy groups, wherein the substituents may be identical or different, or a thiazolo, pyrazino group, optionally substituted by a fluorine, chlorine, bromine or iodine atom or by a methyl, methoxy or amino group, may be fused to the abovementioned 7-membered cycloallyleneimino group via two adjacent carbon atoms,
• whilst additionally the abovementioned monosubstituted phenyl groups may be substituted by a fluorine, chlorine or bromine atom or by a methyl, methoxy or nitro group,
• a 5-membered heteroaromatic group which contains a sulphur and one nitrogen atom, or
• a pyrazinyl, pyrimidinyl or pyridazinyl group, which pyrazinyl, pyrimidinyl or pyridazinyl group may additionally be substituted by a chlorine or bromine atom or by a methyl group, or a phenyl ring may be fused to the abovementioned pyrazinyl, pyrimidinyl or pyridazinyl group via two adjacent carbon atoms, and
• R5 denotes a hydrogen atom or a C1-3-alkyl group
• whilst any amino or imino group present may be substituted by a group which can be cleaved in vivo selected from the group consisting of
• an acyl group selected from C2-4-alkanoyl, benzoyl, pyridinoyl, pentanoyl, hexanoyl, allyloxycarbonyl, C1-6-alkoxycarbonyl group, phenyl-C1-6-alkoxycarbonyl, C1-3-alkylsulphonyl-C2-4-alkoxycarbonyl, C1-3-alkoxy-C2-4-alkoxy-C2-4-alkoxycarbonyl and RcCO—O—(RdCRe)—O—CO-group, wherein
• Rc denotes a C1-8-alkyl, C5-7-cycloalkyl, phenyl or phenyl-C1-3-alkyl group,
• Re denotes a hydrogen atom, a C1-3-alkyl, C5-7-cycloalkyl or phenyl group and
• Rd denotes a hydrogen atom or a C1-3-alkyl group or the RcCO—O—(RdCRe)—O— group,
• or a pharmaceutically acceptable salt thereof.