CA2493721A1 - Indoline derivatives substituted in position 6, production and use thereof as medicaments - Google Patents

Indoline derivatives substituted in position 6, production and use thereof as medicaments Download PDF

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CA2493721A1
CA2493721A1 CA002493721A CA2493721A CA2493721A1 CA 2493721 A1 CA2493721 A1 CA 2493721A1 CA 002493721 A CA002493721 A CA 002493721A CA 2493721 A CA2493721 A CA 2493721A CA 2493721 A1 CA2493721 A1 CA 2493721A1
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alkyl
amino
group
carbonyl
phenyl
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Gerald Juergen Roth
Armin Heckel
Joerg Kley
Thorsten Lehmann-Lintz
Frank Hilberg
Ulrike Tontsch-Grunt
Jacobus C.A. Van Meel
Guenter Linz
Werner Rall
Peter Sieger
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Boehringer Ingelheim Pharma GmbH and Co KG
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    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

The invention relates to indoline derivatives substituted in position 6 of general formula (I) wherein R1 - R6 and X are defined in Claim 1, the tautomers, enantiomers, diastomers thereof, the mixtures and salts thereof, especially physiologically compatible salts which have valuable pharamaceutical properties, especially an inhibiting effect on various receptor tyrosine kinases and on the proliferation of enthethelial cells and various tumor cells, medicaments containing said compounds, the use thereof and a method for the production thereof.

Description

81066fft.208 Boehringer Ingelheim Pharma GmbH & Co. KG 111373-en-a.doc Indolinone derivatives substituted in the 6 position, the preparation thereof and their use as pharmaceutical compositions The present invention relates to indolinone derivatives substituted in the 6 position of general formula Ra -N
Rs ~ \ R5 -X
N

R~ CI), the tautomers, enantiomers, diastereomers, mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof which have valuable pharmacological properties, pharn-aceutical compositions containing these compounds, the use thereof and processes for the preparation thereof.
The above compounds of general formula I have valuable pharmacological properties, particularly an inhibiting effect oo various kinases, especially receptor tyrosine kinases such as VEGFR1 VEGFR2, VEGFR3, PDGFRa, PDGFR~i, FGFR1, FGFR3, EGFR, HER2, c-Kit, IGF1R and HGFR, Flt-3, as well as on the proliferation of cultivated human cells, particularly endothelial cells, e.g. in angiogenesis, but also on the ~nroliferation of other cells, particularly tumour cells.
The present invention thus relates to the ab~we compounds of general - ~ formula I which have valuable pharmacological properties, pharmaceutical compositions containing these pharmacologically active compounds, the use thereof and processes for the preparation thereof.
In the above general formula I
X denotes an oxygen or sulphur atom, R' denotes a hydrogen atom, a C~~-alkoxy-~;arbonyl, C~_3-alkyl-carbonyl, aminomethyl, C~_3-alkylaminomethyl, di-(C~_;,-alkyl)-aminomethyl or a 5- to 7-membered cycloalkyleneiminomethyl group, R2 denotes a fluorine, chlorine or bromine a':om or a cyano group, R3 denotes a phenyl or naphthyl group or a phenyl or naphthyl group mono- or disubs~~ituted by a fluorine, chlorine, bromine or iodine atom, by a trifluoromethyl C~_3-alkyl or C~_3-alkoxy group, while in the case of disubstitution the substi~:uents may be identical or different and the abovementioned unsubstituted as well as the mono- and disubstituted phenyl and naphthyl groups may additionally be substituted by a fluorine, chlorine, bromine or ioc ine atom, by a C~_3-alkyl, C~_4-alkoxy, C~_4-alko~:y-carbonyl, C~~-alkoxy-carbonyl-C~_3-alkoxy, C~_4-alkyloxy-carbonylarr~ino- C~_4-alkoxy-carbonyl-C~-3-alkylamino, C~_4-alkoxy-carbonyl-C~_3-alkyl- N-(C~_3-alkyl)-amino, aminocarbonyl, C~_3-alkylamino-carbonyl, di-(C~_3-alkyl)-aminocarbonyl, benzyloxy, carboxy, carboxy-C~_3-alkoxy, carboxy-C~_3-alkylamino, carboxy-C~_3-alkyl- N-(C~_3-alkyl)-ami io, cyano, trifluoromethyl, nitro, amino, C4_~-cycloalkylamino, C~_3-alk ~l-carbonyl-amino, N-(C~_3-alkyl)-N-(C~_3-alkyl-carbonyl)-amino, pheny-carbonylamino, N-(C~_3-alkyl)-N-(phenyl-carbonyl)-amino, benzyl-cart~onylamino, N-(C~_3-alkyl)-N-{benzyl-carbonyl)-amino, hydroxy, C1.3-alkylsulphonylamino, N-(C~_3-alkyl)-C~_3-alkylsulphonylamino, phenylsulphonylamino, N-(C,_3-alkyl)-phenylsulphonylamino, phenyl- C~_3-a Ikyl-sulphonylamino, N-{C~_3-alkyl)-N-(phenyl-C~_3-alkyl-sulphonyl)-amino, C~_3-alkylamino or dl-(C~-3-alkyl)-amino group, by a C~_3- or C4_6-alkyl group which is substituted by a hydroxy, cyano, carboxy, C~_4-alkoxy, C~_4-alkoxy-cark onyl, aminocarbonyl, (C~_3-alkyl-amino)-carbonyl, di-(C~_3-alkyl)-aminc~carbonyl, amino, C~_3-alkylamino, [di-(C~_3-alkyl)-amino], N-(C~_4-alkoxy-carbonyl)-amino, N-(C~~.-alkoxy-carbonyl)-N-(C~_3-alkyl)-amino, phenylamino, diphenylamino, N-phenyl-N-(C~_3-alkyl)-amino, benzylamino, diaenzylamino, N-benzyl-N-(C~_3-alkyl)-amino, heteroarylamino, N-hetE:roaryl-N-(C~_3-alkyl)-amino, C~~-alkyl-sulphonylamino, N-(C~_3-alkyl)-C;~_4-alkylsulphonylamino, phenyl-sulphonylamino, N-(C~_3-alkyl)-pheny sulphonylamino, phenyl-C~_3-alkyl-sulphonylamino, N-(C~_3-alkyl)-~I-(phenyl-C~_3-alkyl-sulphonyl)-amino, benzylcarbonylamino, N-(C~_3-alkyl)-N-(benzylcarbonyl)-amino, phenylcarbonylamino, N-(C~_3-alkyl)-!J-(phenylcarbonyl)-amino, 4-{C~_3-alkyl)-piperazin-1-yl-carbonyl, (C~_6-alkyl-carbonyl)-amino, N-(C~_3-alkyl)-N-(C~_6-alkyl-carbonyl)-amino, I C3_7-cycloalkyl-carbonyl)-amino, N-(C~_3-alkyl)-N-(C3_7-cycloalkyl-carbonyl)-amino, (C3_7-cycloalkyl-C~_3-alkyl-carbonyl)-amino, N-(C~_3-alkyl)-n-(C3_~-cycloalkyl-C~_3-alkyl-carbonyl)-amino, (C~~-alkoxy-C~_3-alN;yl-carbonyl)-amino, N-(C~_3-alkyl)-N-(C~_4-alkoxy-C~_3-alkyl-carbonyl)-ariino, (heteroaryl-carbonyl)-amino, N-(C~_3-alkyl)-N-(heteroaryl-carbonyl)-amino, (C3_~-cycloalkyl-sulphonyl)-amino, N-(C~_3-alkyl)-N-(C3_~-cycloalkyl-sulphonyl)-amino, (C3_7-cycloalkyl-C~_3-alkyl-sulphonyl)-amino, N-(C~_3-alkyl)-N-(C3_7-cycloalkyl-C~_3-alkyl-sulphonyl)-amino, (C~~-alkoxy-C~_3-alkyl-sulphonyl)-amino, N-(C~_3-alkyl)-N-(C~~-alkoxy-C~_3-alkyl-sulphonyl)-amino, (heteroaryl-sulphonyl)-amino, N-(C~_3-alkyl)-N-(heteroaryl-sulphonyl)-amino, tetrazolyl or heteraaryl group, by a carboxy-C2_3-alkenyl, aminocarb~nyl-C2_3-alkenyl, (C~_3-alkyl-amino)-carbonyl-C2_3-alkenyl, di-(C~_3~~alkyl)-amino-carbonyl-C2_3-alkenyl or C~_4-alkoxy-carbonyl-C2_3-alkenyl group, by a heteroaryl group or by a cycloalkyleneimino or cycloalkyl~neimino-C~_3-alkyl group with in each case 5 to 7 ring members, wherein in each case a methylene group linked to the imino group is replaced by a carbonyl or sulphonyl group or the two methylene groups linked to the imino group are each replaced by a carbonyl group or a -CH2-CH2- group linked to the imino group is replaced by the group -O-CO-, while the carbonyl group of the -O-CO- group is linked to the imino group and a phenyl ring may b~fused to the 5- to 7-membered cycloalkyleneimino group via two adjacent carbon atoms, or by a cycloalkyleneimino, cycloalkyleneiminocarbonyl, cycloalkyleneiminosulphonyl, cycloall;yleneimino-C~_3-alkyl, cycloalkyleneiminocarbonyl-C~_3-alky or cycloalkyleneiminosulphonyl-C~_3-alkyl group with 4 to 7 ring members in each case, while in each case the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be substituted by a carboxy, C~~-alkoxy-carbonyl, aminocarbonyl, C~_3-alkylaminocarbonyl, di-(C,_3-alkyl)-aminocarbonyl, phenyl-C~_3-alkylamino or N-(C;~_3-alkyl)-phenyl-C~_3-alkylamino group or may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, -NH, -N(C1_3-alkyl), -N(phenyl), -N(C~_3-alkyl-carbonyl) or -N(benzoyl)- group, while the substituents may be identical or different, R4 denotes a benzopyrazolyl group, a C3_~-cycloalkyl group which may be substi~:uted by a N-[di-(C,_3-alkyl)-amino-C~_3-alkyl-carbonyl]-amino or N-[di-(C~_3-alkyl)-amino-C~_3-alkyl-carbonyl]-N-C~_3-alkyl-amino group, while the methylene group in the 4 po: ition of a 6- or 7-membered cycloalkyl group may be substituted by an amino, C~_3-alkylamino or di-(C,_3-alkyl)-amino group or replaced by a -NH or -N(C~_3-alkyl) group, or a phenyl, naphthyl or heteroaryl group substituted by the group R9 which may additionally be mono- or disubstituted key fluorine, chlorine, bromine or iodine atoms, by C~_5-alkyl, trifluoromethyl, r~ydroxy, C~~-alkoxy, benzyloxy, carboxy, C~_4-alkoxy-carbonyl, amino, C~_3-alkylamino, di-(C~_3-alkyl)-amino, acetylamino, C,_3-alkyl-sulphonylamino, aminocarbonyl, C,_3-alkyl-aminocarbonyl, di-(C~_3-alkyl)-amioocarbonyl, aminosulphonyl, C~_3-alkyl-aminosulphonyl, di-(C~_3-alkyl)-aminosulphonyl, nitro or cyano groups, while the substituents may be ident cal or different and wherein R9 denotes a hydrogen, fluorine, chlorine, b~omine or iodine atom, a cyano, nitro, amino, C~_5-alkyl, C3_~-cycloalkyl, trifluoromethyl, phenyl, tetrazolyl or heteroaryl group, a C~_3-alkyl-sulphonyl, amino-C~_3-alkyl-sulphonyl, (C~_3-alkylamino)-C~_3-alkyl-sulphonyl or di-(C~_3-alkyl)-amino-C~_3-alkyls ulphonyl group, a C1_4-alkoxy group, a w-C~_3-alkoxy-C2_3-alN:oxy, phenyl-C~_3-alkoxy, ~-amino-C2_3-alkoxy, c~-(C~_3-alkylamino)-C;_3-alkoxy, w-[di-(C,_3-alkyl)-amino]-C2_3-alkoxy, w-(phenyl-C~_3-alkylamino)-C2_3-alkoxy, w-[N-(C~_3-alkyl)-phenyl-C~_3-alkylamino]-C2_3-alkoxy, w-(C5_~-cycloalkyleneimino)-C2_3-alkoxy or C~_3-alkylmercapto group, a carboxy or C,~-alkoxy-carbonyl group, arr inocarbonyl, C~~-alkyl-amino-carbonyl, N-(C1_5-alkyl)-C~_3-alkylamiriocarbonyl, C3_~-cycloalkyl-amino-carbonyl, N-(C~_5-alkyl)-C3_7-cycloalk~°laminocarbonyl, (phenyl-C~_3-alkyl)-amino-carbonyl, N-(C~_3-alkyl)-phenyl-C~_3-alkylamino-carbonyl group, a C~_3-alkylaminocarbonyl or N-(C~_3-alkyl)-C~~_3-alkylaminocarbonyl group, wherein one or two alkyl moieties are substituted independently of one another by a nitro, cyano, carbamoyl, N-(C~.3-alkyl)-carbamoyl, di-N-(C~_3-alkyl)-carbamoyl, carboxy or C~_4-alkoa:y-carbonyl group or in the 2 or position by an amino, (C~_3-alkyl)-amino, di-i C~_3-alkyl)-amino, (C~_4-alkoxy-carbonyl)-amino, N-(C~~-alkoxy-carbonyl)-~'-(C~_3-alkyl)-amino, piperazino, N-(C~_3-alkyl)-piperazino, a 4- to 7-memberE~d cycloalkyleneimino group, a hydroxy or methoxy group, a 4- to 7-membered cycloalkyleneiminocarbonyl group wherein the cycloalkylene moiety may be fusecd to a phenyl ring via two adjacent ring atoms or may be bridged to a a~ethylene or ethylene group via two non-adjacent ring atoms or one or two hydrogen atoms in each case may be replaced by a C~_3-alkyl group andlor in each case the methylene group in tl~e 4 position of a 6- or 7-membered cycloalkyleneiminocarbonyl group may be substituted by a carboxy, C~_4-alkoxy-carbonyl, aminocarbonyl, C~_3-alkylaminocarbonyl, di-(C~_3-alkyl)-aminocarbonyl, di-(C~_3-;~Ikyl)-amino-C~_3-alkyl, di-(C~_3-alkyl)-amino, phenyl-C~_3-alkylan- ino or N-(C~_3-alkyl)-phenyl-C~_3-alkylamino group, a hydroKy or methoxy group or replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl or -NH
group or by a nitrogen atom, the by a ~~~_3-alkyl, phenyl, C~_3-alkyl-carbonyl, C»-alkoxy-carbon ~I, di-(C~_3-alkyl)-amino-C~_3-alkyl, - ~ w-hydroxy-C2_3-alkyl or benzoyl group, a 4- to 7-membered cycloalkyleneimino group wherein a methylene group linked to the imino group by a carbonyl or sulphonyl group may be replaced or the cycloalkylene moiety may be fused to a phenyl ring or one or two hydrogen atoms in each case may be replaced by a C~_3-alkyl group andlor in each case the methylene group in ttie 4 position of a 6- or 7-membered cycloalkyleneimino group ray be substituted by a carboxy, C~~-alkoxy-carbonyl, aminocarbonyl, (;~_3-alkylaminocarbonyl, di-(C~_3-alkyl)-aminocarbonyl, phenyl-C;~_3-alkylamino or N-(C~_3-alkyl)-phenyl-C~_3-alkylamino group or replaced by an oxygen or sulphur atone, by a sulphinyl, sulphonyl, -NH, -N(C~_3-alkyl), -N(phenyl), -N(C~_3-alkyl-carbonyl) or -N(benzoyl) group, a C~~-alkyl group substituted by the group ft~o, where Rio denotes a C3_~-cycloalkyl group, while the methylene group in the 4 position of a 6- or 7-membered cycloalkyl group may be substitutE~d by an amino, C~_3-alkylamino or di-(C~_3-alkyl)-amino group or replaced by a -NH or -N(C~_3-alkyl) group or in a 5- to 7-membered cycloalkyl raroup a -(CH2)2 group may be replaced by a -CO-NH group, a -(i~H2)3 group may be replaced by a -NH-CO-NH or -CO-NH-CO group or a -(CH2)4 group may be ' replaced by a -NH-CO-NH-CO group, while in each case a hydrogen atom bonded to a nitrogen atom Tray be replaced by a C~_3-alkyl group, a phenyl, triazolyl or heteroaryl group, a hydroxy or C~_4-alkoxy group, an amino, C~_~-alkylamino, di-(C,_7-alkyl)-amino, phenylamino, N-phenyl-N-(C~_3-alkyl)-amino, N-(phenyl-C~_3-alkyl)-amino, N-(C~_3-alkyl)-N-(phenyl-C~_3-alkyl)-amino or di-(phenyl-C~_3-alkyl)-amino group, a w-hydroxy-C2_3-alkyl-amino, N-(C~_3-alkyl)-(w-hydroxy-C2_3-alkyl)-amino, di-(w-hydroxy-C2_3-alkyl)-amino or di-(c~-(C~_3-alkoxy)-C2_3-alkyl)-amino-group, a C,_3-alkyl-carbonylamino-C2_3-alkyl-amino or C~_3-alkyl-carbonyl-amino-C2_3-alkyl-N-(C~_3-alkyl)-amino c roup, a C~_4-alkyloxy-carbonyl-amino, N-(C~_~-alkyloxy-carbonyl)-N-(C~_3-alkyl)-amino or N-{w-[N-(C»-alkoxy-carbonyl)-amino]-(C~~-alkyl))-N-(C~_3-alkyl)-amino group, a C~_3-alkylsulphonylamino, N-(C~_3-alN:yl)-C~_3-alkylsulphonylamino, C~_3-alkylsulphonylamino-C2_3-alkyl-amino or C~_3-alkylsulphonyl-amino-C2_3-alkyl-N-(C~_3-alkyl)-amino clroup, a hydroxycarbonyl-C~_3-alkylamino or I~-(C~_3-alkyl)-hydroxycarbonyl-C~_3-alkyl-amino group, an N-(c~-amino-C2_3-alkyl)-N-(C~_3-alkyl ~-amino, N-(w-C~_3-alkylamino-.- C2_3-alkyl)-N-(C~_3-alkyl)-amino, N-[w-d -(C~_3-alkyl)-amino-C2_3-alkyl]-N-(C~_3-alkyl)-amino, N-(cu-C~_3-alkoxy-C2.3-alkoxy-C~_3-alkyl)-amino or N-(w-C~_3-alkoxy-C2_3-alkoxy-C~_3-alkyl)-~'-(C~_3-alkyl)-amino group, a guanidino group wherein one or two hydrogen atoms may each be replaced by a C~_3-alkyl group, a C4_~-cycloalkylamino, C4_7-cycloalkyl-C~_3-alkylamino or C4_~-cyclo-alkenylamino group wherein position 1 of the ring does not participate in the double bond and the abovementioi~ed groups may each additionally be substituted at the aminonitrogen atom by a C5_~-cycloalkyl, C2_4-alkenyl or C~~-alkyl group, a 4- to 7-membered cycloalkyleneimino group wherein the cycloalkylene moiety may be fused with a phenyl group or with an oxazolo, imidazolo, thiazolo, pyridino, pyrazino or pyrimidino group optionally substituted by a fluorine, chlorine, bromine or iodine atom or by a nitro, C1_3-alkyl, C~_3-i~IkOXy or amino group andlor one or two hydrogen atoms may each be replaced by a C~_3-alkyl, C~_4-alkoxy-carbonyl, amino, C~_3-alkylamino or di-(C~_3-alkyl)-amino group C5_~-cycloalkyl or phenyl grc up andlor the methylene group in position 3 of a 5-membered cycloalkyleneimino group may be substituted by a hydroxy, hydroxy-C~_3-alkyl, C~_4-alkoxy or C:~_3-alkoxy-C~_3-alkyl group, in each case the methylene group in position 3 or 4 of a 6- or 7-membered cycloalkyleneimino group may be substituted by a hydroxy, hydroxy-C~_3-alkyl, C~_4-alkoxy, C1.~-alkoxy-C~_3-alkyl, carboxy, C~_4-alkoxy-carbonyl, am nocarbonyl, C1_3-alkylaminocarbonyl, di-(C~_3-alkyl)-aminocarbonyl, C~_3-alkylamino, di-(C~_3-alkyl)-amino, P~-(phenyl-C,_3-alkyl)-amino or N-(C~_3-alkyl)-N-(phenyl-C~_3-alkyl)-amino group or may be replaced by an oxygen or :>ulphur atom, by a sulphinyl, sulphonyl, -NH, -N(C~_3-alkyl-), -N(~henyl), -N(phenyl-C~_3-alkyl-), -N(C~_3-alkyl-carbonyl-), -N(C~_4-hydroxy-carbonyl-), -N(C~_4-alkoxy-carbonyl-), -N(benz~yl-) or -N(phenyl-C1_3-alkyl-carbonyl-) group, while a methylene group linked to an imino-nitrogen atom of the cycloalkyleneimino group may be replaced by a carbonyl or sulphonyl group or in a 5- to 7~~membered monocyclic cyclo-alkyleneimino group or a cyclcalkyleneimino group fused to a phenyl group the two methylerie groups linked to the imino-nitrogen atom may each be replaced by a carbonyl group, and all the dialkylamino group: contained in the group R'° may also be present in quaternised form, for example as the N-methyl-(N,N-dialkyl)-ammonium group, the counter-ion preferably being selected from among the iodide, chloride, bromide, methylsulphonate, para-toluenesulphonate, or trifluoroacetate, or R9 denotes a C~_4-alkyl group which is substituted by a carboxy, C»-alk-oxy-carbonyl, aminocarbonyl, C~_3-alkylamiriocarbonyl, di-(C~_3-alkyl)-aminocarbonyl, N-[amino-C~_~-alkyl]-aminocarbonyl, N-[(C~_3-alkyl)-amino-C~_3-alkyl]-aminocarbonyl, N-[di-(C~_3-alkyl)-amino-C~_3-alkyl]-aminocarbonyl, N-[amino-C~_3-alkyl]-~~-(C~_3-alkyl)-aminocarbonyl, N-[(C~_3-alkyl)-amino-C~_3-alkyl]-N-(C~_3-alkyl)-;~minocarbonyl, N-(C3_~-cycloalkyl)-N-(C~_3-alkyl)-amino or N-[di-(C~_3-alkyl)-am no-C~_3-alkyl]-N-(C~_3-alkyl)-aminocarbonyl group or by a 4- to 7-membE:red cycloalkyleneiminocarbonyl group, while in the abovementioned cycloalkyleneimino groups one or two ,_ ~' hydrogen atoms may each be replayed by a C~_3-alkyl, carboxy, C,_4-alkoxy-carbonyl, aminocarbonyl, C~ .3-alkylaminocarbonyl or di-(C~_3-alkyl)-aminocarbonyl group or one or two hydrogen atoms, which ~~re bonded to a carbon atom not adjacent to the imino group, may bE~ replaced by an amino, C~-3-alkylamino, di-(C~_3-alkyl)-amino, phenyl-C~_3-alkylamino or N-(C~_3-alkyl)-phenyl-C~_3-alkylamino group andlor the methylene group in the 4 positic n of a 6- or 7-membered cyclo-alkyleneimino group may be replacE;d by one of the groups -S, -SO, -S02, -NH, -N(C~_3-alkyl), -N(phenyl ~, -N(C~_3-alkyl-carbonyl), -N(C~~-alkoxy-carbonyl), -N(benzoyl) or -0~~, an N-(C~_3-alkyl)-C~_3-alkyl-carbonyl-amino croup which is additionally substituted in the alkyl moiety by a carboxy or C~~-alkoxy-carbonyl group, or a group of formula - N
~ R~
wherein R7 denotes a hydrogen atom, ~ C~~-alkyl or C3_~-cycloalkyl group, a C~_3-alkyl group terminally substituted by a phenyl, heteroaryl, trifluoromethyl, aminocarbonyl, C~~-alkylamino-carbonyl, di-(C~_4-alkyl)-amino-carbonyl, C~_3-alkyl-carbonyl, C~_3-alkyl-sulphonylamino, N-(C~_3-alkyl)-C~_3-alkyl-sulphonylamino, C~_3-alkyl-aminosulphonyl or di-(C~_3-alkyl)-aminosulphonyl gn~up, a C2_3-alkyl group terminally substituted by a hydroxy or C,_3-alkoxy group, a C~_4-alkyl-carbonyl, benzylcarbonyl, heteroarylcarbonyl, heteroaryl-C~_3-alkyl-carbonyl, cycloalkyleneimino-C~_3-alkyl-carbonyl with 5 to 7 ring atoms in the cycloalkyleneimino moiety, C~_3-alkoxy-C~_3-alkyl-carbonyl amino-C~_3-alkylcarbonyl, (C~_3-alkyl)-amino-C~_3-alkyl-carbon~~l, di-(C~_3-alkyl)-amino-carbonyl-C~_3-alkyl, C~~-alkylsulphonyl, ~henylsulphonyl, heteroarylsulphonyl, heteroaryl-C~_3-alkyl-sulphonyl or benzyl-sulphonyl group or a phenylcarbonyl group optionally substituted in the phenyl moiety by one or two methoxy groups and R$ denotes a C~_3-alkyl, di-(C~_3-alkyl)-amino-C~_3-alkyl-amino-carbonyl or 1-(C~_3-alkyl)-piper din-4-yl-aminocarbonyl group, a C~~-alkyl-carbonyl group terminally substituted by a (w-alkoxy-C2_3-alkyl)-amino, C~_3-alkyl-carbonyl-amino or N-[di-(C~_3-alkyl)-amino-C~_3-alkyl]-N-(C~_3-alkyls-amino group or a Cz_a-alkyl, carbonyl, C~_4-alk~°I-carbonyl or carbonyl-C~_3-alkyl group terminally substituted b~~ one of the groups described under R'°, while R'° additionally also denotes a C~~-cycloalkyloxy group wherein the metr~ylene group may be substituted in the 4 position by a -NH or -N(C~_3-alkyl)- group, a 5- to 7-membered cyc;loalkyleneimino-amino group, while the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be substituted by a carboxy, C,_3-alko7:ycarbonyl, aminocarbonyl, C~_3-alkylaminocarbony , di-(C~_3-alkyl)-aminocarbonyl, phenyl-C~_3-alkylamino or N-(C~_3-alkyl)-phenyl-C~_3-alkylamino group or replaced by an oxygen ~r sulphur atom, by a sulphinyl, sulphonyl, -NH, -N(C~_3-alkyl), -N(phenyl), -N(C~_3-alkyl-carbonyl) or -N(benzoyl)- group, or may denote an N-(hE~teroaryl-C~_3-alkyl)-amino group, R5 denotes a hydrogen atom or a C~_3-alkyl group and R6 denotes a hydrogen atom or a vitro group, while the unsubstituted, mono- or disubstit~ited phenyl groups contained in the above definitions, whether singly bonded or fused on, may additionally be substituted by one or two fluorine, chlorine, bromine or iodine atoms or by one or two C~_5-alkyl, C~_4-alkoxy, benzyloxy, canboxy, cyano, C,.~-alkoxy-carbonyl, aminocarbonyl, C~~-alkylamino-carbonyl, di-(C~_4-alkyl)-amino-carbonyl, aminosulphonyl, C~_3-alkyl-aminosulphonyl, di-(C~_3-alkyl)-aminosulphonyl, trifluoromethyl, vitro, amino, hydroxy, C~_3-alkylsulphonylamino, C~_3-alkylamino or di-(C~_3-alkyl)-amino groups, while the substituents may be identical or different, the abovementioned alkyl groups including straight-chain and branched alkyl groups, wherein additionally one to 3 hydro~~en atoms may be replaced by fluorine atoms, while, unless otherwise stated, the expression a heteroaryl group refers to a monocyclic 5- or 6-membered heteroaryl group optionally substituted in the carbon skeleton by a C~_3-alkyl group, wherein the 6-membered heteroaryl group cone ains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C~_3-alkyl or phenyl-C~ _3-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted ky a C,_3-alkyl, amino-C~_3-alkyl, C~_ 3-alkylamino-C~_3-alkyl, di-(C~_3-alkyl)-amino-C~_3-alkyl or phenyl-C~_3-alkyl group or an oxygen cr sulphur atom and additionally contains a nitrogen atom or an imino group optionally substituted k y a C,_3-alkyl or phenyl-C~_3-alkyl group and two nitrogen atoms, and moreover a phenyl ring may be fu red to the abovementioned monocyclic heterocyclic groups via two adjacent carbon atoms and the bonding takes place via a nitrogen atom or via a carbon atom of the heterocyclic moiety or a fused-on phenyl ring, and additionally any carboxy, amino or imin ~ group present may be substituted by a group which can be cleaved in vivo, or may be present in the form of a prodrug group, e.g. in the form of ,~ group which may be converted in vivo into a carboxy group or in the form of a group which may be converted in vivo into an imino or amino group, the tautomers, enantiomers, diastereomers mixtures thereof and the salts thereof, with the exception of the compounds (Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylideneJ-6-chloro-2-indolinone and (Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-6-bromo-2-indolinone.
By a group which may be converted in-vivo into a carboxy group is meant for example a hydroxymethyl group, a carboxy group esterified with an alcohol wherein the alcoholic moiety preferably den rtes a C~_s-alkanol, a phenyl-C~_3-alkanol, a C3_9-cycloalkanol, while a C5_g-cycloalkanol may additionally be substituted by one or two C~_3-alkyl groups, a C5_8-cycloalkanol, wherein a methylene group is replaced in the 3 or 4 position by an oxygen atom or by an imino group optionally substituted by a C~_3-alkyl, phenyl-C~_3-alkyl, phenyl-C~_3-alkoxy-carbonyl or C~_s-alkyl-carbonyl group and the cycloalkanol moiety may additionally be substituted by one or tv~o C~_3-alkyl groups, a C4_~-cycloalkenol, a C3_5-alkenol, a phenyl-C3_5-alkenol, a C3_5-alkynol or phenyl-C3_5-alkynol, with the proviso that no bond to the oxygen atom starts from a carbon atom which carries a double or triple bond, a C3_8-cycloalkyl-C~_3-alkanol, a bicycloalkanol with a total of 8 to 10 carbon atoms which may additionally be substituted in the bicycloalkyl moiety by one or two C~_3-alkyl groups, a 1,3-dihydro-3-oxo-1-isobenzofuranol or an alcohol of formula Ra-CO-O-(RbCFy)-OH, wherein Ra denotes a C~_$-alkyl, C5_7-cycloalkyl, phenyl or phenyl-C~_3-alkyl group, Rb denotes a hydrogen atom, a C~_3-alkyl, C5_~-cycloalkyl or phenyl group and R~ denotes a hydrogen atom or a C~_3-alkyl group, and by a group which can be cleaved in viva from an imino or amino group is meant for example a hydroxy group, an acyl group such as the benzoyl or pyridinoyl group or a C~-~s-alkyl-carbonyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl l~roup, an allyloxycarbonyl group, a C~-~s-alkoxy-carbonyl group such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, buto;;ycarbonyl, tert.butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxy-carbonyl group, a phenyl-C~_6-alkoxy-carbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a C~_3-alkylsulphonyl-C~_4-alkoxy-carbonyl, C~ .3-alkoxy-C2~-alkoxy-C2_4-alkoxy-carbonyl or RaCO-O-(RbCR~)-O-CO-group wherein Ra denotes a C~_8-alkyl, C5_~-cycloalkyl, phenyl or phenyl-C~_3-alkyl group, Rb denotes a hydrogen atom, a C~_3-alkyl, C5_~-cycloalkyl or phenyl group and R~ denotes a hydrogen atom, a C~_3-alkyl or RaCO-O-(RbCR~)-O-group wherein Ra to R~ are as hereinbefore defined, and additionally for an amino group the phthalimido group, while the abovementioned ester groups may also be ased as a group which can be converted in vivo into a carboxy group.
Preferred prodrug groups for a carboxy group include a C~_6-alkoxy-carbonyl group such as the methoxycarbonyl, ethoxycarbonyl, n-propyloycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, n-pentyloxycarbonyl, n-hexyloxy-carbonyl or cyclohexyloxycarbonyl group or phenyl-C~_3-alkoxy-carbonyl group such as the benzyloxycarbonyl group and for an imino or amino group a C~_9-alkoxy-c~~rbonyl group such as the methoxycarbonyl, ethoxycarbonyl, n-propyl«xycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl, cyclohexyloxy-carbonyl, n-heptyloxycarbonyl, n-octyloxyc~ rbonyl or n-nonyloxycarbonyl group, a phenyl-C~_3-alkoxy-carbonyl group such as the benzyloxycarbonyl group, a phenylcarbonyl group optionally sc bstituted by a C~_3-alkyl group such as the benzoyl or 4-ethyl-benzoyl grog p, a pyridinoyl group such as the nicotinoyl group, a C~_3-alkylsulphonyl-n-C2 ;~ alkoxy-carbonyl or C~_3-alkoxy-C2_3-alkoxy-C~_4-alkoxy-carbonyl group such as the 2-methylsulphonylethoxycarbonyl or 2-(2-etl~oxy)-ethoxycarbonyl group.
Moreover, the saturated alkyl and alkoxy moieties containing more than 2 carbon atoms mentioned in the definitions above as well as the alkanoyl and unsaturated alkyl moieties which contain more than 3 carbon atoms also include the branched isomers thereof such ~~s the isopropyl, tert.butyl, isobutyl group, etc.
One sub-group of compounds of general formula I deserving special mention are those wherein X denotes an oxygen or sulphur atom, R' denotes a hydrogen atom, a C~_4-alkoxy-carbonyl, C~_3-alkyl-carbonyl, aminomethyl, C~_3-alkylaminomethyl, di-(C~_3-alkyl)-aminomethyl or a 5- to 7-membered cycloalkyleneiminomethyl group R2 denotes a fluorine, chlorine or bromine atom or a cyano group, R3 denotes a phenyl or naphthyl group or a phenyl or naphthyl group mono- or disubstituted by a fluorine, chlorine, bromine or iodine atom, by a trifluoromethyl, C,_3-alkyl or C~_3-alkoxy group, while in the case of disubstitution the substituents may be identical or different and the abovementioned unsubstituted as well as the mono- and disubstituted phenyl and naphthyl groups may additionally be substituted by a fluorine, chlorine, bromine or iodine atom, by a C~_3-alkyl, C~_4-alkoxy, benzyloxy~, carboxy, cyano, trifluoromethyl, nitro, amino, C~_3-alkyl-carbonyl-amino, C~~-alkyloxy-carbonylamino, N-(C~_3-alkyl)-N-(C~_3-alkyl-carbonyl)-amino, phenyl-carbonylamino, N-(C,_3-alkyl)-N-(phenyl-carbonyl)-amino, benzyl-carbonylamino, N-{C~_3-alkyl)-N-(benzyl-carbonyl)-amino, hyciroxy, C~_3-alkylsulphonylamino, N-(C~_3-alkyl)-N-{C~_3-alkylsulphonyl)-ariino, phenylsulphonylamino, N-(C~-3-alkyl)-N-(phenylsulphonyl)-amir o, benzylsulphonylamino, N-(C1-s-alkyl)-N-(benzylsulphonyl)-amino, C~ 3-alkylamino or di-(C~_3-alkyl)-amino group, by a hydroxy-C~-s-alkyl, cyano-C~_3-alkyl, carboxy-C~_3-alkyl, C~~,-alkoxy-C~_3-alkyl, amino-C~_3-alkyl, C- _3-alkylamino-C~_3-alkyl, [di-(C~_3-alkyl)-amino]-C~_3-alkyl, benzylamino ~C~_3-alkyl, dibenzylamino-C~_3-alkyl, N-benzyl-N-(C~_3-alkyl)-amino-(;~_~-alkyl, benzylcarbonylamino-C~_3-alkyl, N-(C~_3-alkyl)-N-(benzylcarbonyl)-amino-C~_3-alkyl, phenylcarbonylamino-C~_3-alkyl, N-(C ~_3-alkyl)-N-(phenylcarbonyl)-amino-C~_3-alkyl, phenylamino-C~_3-a kyl, diphenylamino-C~_3-alkyl, N-phenyl-N-(C~_3-alkyl)-amino-C,_3-alky , heteroarylamino-C~_3-alkyl, N-heteroaryl-N-(C~_3-alkyl)-amino-C~_3-alkyl, C~_4-alkyl-sulphonylamino-C~_3-alkyl, N-(C~_3-alkyl)-N-(C~~-alkyl-sulphonyl)-amino-C~_3-alkyl, phenyl-sulphonylamino-C~_3-alkyl, N-;C~_3-alkyl)-N-(phenyl-sulphonyl)-amino-C~_3-alkyl, benzyl-sulphonylarr~ino-C~_3-alkyl, N-(C~_3-alkyl)-N-(benzyl-sulphonyl)-amino-C1_3-alkyl, ~~~_~-alkoxy-carbonyl-C~_3-alkyl, N-(C1_4-alkoxy-carbonyl)-amino-C~_3-alkyl, N-(C~_3-alkyl)-N-(C~_a-alkoxy-carbonyl)-amino-C~_3-alkyl, aminocar~onyl-C~_3-alkyl, (C~_3- alkylamino)-carbonyl-C~-3-alkyl, di-(C~_3-alkyl)-am nocarbonyl-C~_3-alkyl, (C~_6-alkyl-carbonyl)-amino-C~_3-alkyl, N-(C~_3-alkyl)-N-(C~_6-alkyl-carbonyl)-amino-C,.3-alkyl, (C3_~-cycloalkyl-carbonyl)-amino-C~_3-alkyl, N-{C~_3-alkyl)-N-(Cs_7-cycloalkyl-carbonyl)-amino-C~_3 alkyl, {C3_7-cycioalkyl-C~_3-alkyl-carbonyi)-amino-C~_3-alkyl, N-(C~_3-alkyl)-N-(C3_7-cycloalkyl-C~_3-alkyl-carbonyl)-amino-C~_3-alkyl, {C~_a-alkoxy-C~_3-alkyl-carbonyl)-amino-C~_3-alkyl, N-(C~_3-alkyl)-N-(C~~-alkoxy-C~_3-alkyl-carbonyl)-amino-C~_3-alkyl, (heteroaryl-carbonyl)-amino-C1_3-alkyl, N-(C~_3-alkyl)-N-(heteroaryl-carbonyl)-amino-C~_3-alkyl, 4-(C~_3-alkyl)-piperazin-1-yl-carbonyl-(C~_3-alkyl), tetrazolyl-C~_3-alkyl or heteroaiyl-C~_3-alkyl group, by a carboxy-C2_3-alkenyl, aminocarbonyl-C2_3-alkenyl, (C1_3-alkyl-amino)-carbonyl-C2_3-alkenyl, di-(C~_3-alkylamino)-carbonyl-C2_3-alkenyl or C~~-alkoxy-carbonyl-C2_3-alkenyl c roup or by a cycloalkyleneimino or cycloaklyl :neimino-C~_3-alkyl group each with 5 to 7 ring members, wherein in each case one or two methylene groups adjacent to the nitrogen atom may be replaced by a carbonyl or sulphonyl group or a -CH2-CH2- grog p linked to the imino group may be replaced by the group -O-C~~-, while the carbonyl group of the -O-CO- group is linked to the imi io group, while the substituents may be identical or different, R4 denotes a benzopyrazolyl or 1-(C~_3-alkyl)-piperidin-4-yl group, a cyclohexyl group which is substituted by ~ N-[di-(C~_3-alkyl)-amino-C~_3-alkyl-carbonyl]-amino or N [di-(C~_3-alkyl)-amino-~~~_3-alkyl-carbonyl]-N-C~_3-alkyl-amino group, or a phenyl, furyl, pyrrolyl, pyridinyl or naphthy group, each of which is substituted in the carbon skeleton by a fluorine, chlorine, bromine or iod ine atom, by a C~_3-alkyl, C~~-alkoxy, cyano, nitro, carboxy or trifluc~romethyl group, by a ~-amino-C2_3-alkoxy, w-[(C~_3-alE:yl)-amino]-C2_3-alkoxy, w-[di-(C~_3-alkyl)-amino]-C2_3-alkoxy, C~_3-alkyl-s alphonyl, (C,_3-alkyl)-amino-C~_3-alkyl-sulphonyl, amino-C~_3-alkyl-sulphonyl, di-(C~_3-alkyl)-amino-C~_3-alkyl-sulphonyl, 4-(C~_3-alkyl)-piperaz no or heteroaryl group, by a C~_3-alkyl group which is termini Ily substituted by a carboxy, C~_4-alkoxy-carbonyl, amino, C~_3-alkylamino, di-(C~_3-alkyl)-amino, N-(C~_3-alkyl)-N-(w-amino-C2_3-alkyl)-amino, iV-benzyl-N-(C~_3-alkyl)-amino, N-[c~-(di-(C~_3-alkyl)-amino)-C2_3-alkyl]-I~-(C~_3-alkyl)-amino, N-[di-(C~_3-alkyl)-amino-C~_3-alkyl]-N-(C~_3-alkyl)-amino-carbonyl, N-(~-hydroxy-CZ_ 3-alkyl)-N-(C~_3-alkyl)-amino, di-(w-hydroxy-C2_3-alkyl)-amino, N-(w-C~_3-alkoxy-C2_3-alkoxy-C~_3-alkyl)-N-(C~_3-alkyl)-amino, N-(C~_4-alkoxy-carbonyl)-amino, N-(C~~-alkoxy-carbonyl)-N-(C~_3-alkyl)-amino, N-{c~-[N-(C~.~-alkoxy-carbonyl)-amino]-(C~_,4-alkyl)}-N-(C~_3-alkyl)-amino, heteroaryl, triazolyl or by a 5- to 7-mE~mbered cycloalkyleneimino or cycloalkyleneiminocarbonyl group, while in the abovementioned cycloalkyleneimino groups one or two hydrogen atoms may each be replaced by a C~_3-alkyl, C~_a-alkoxy-carbonyl, amino, C~_3-a kylamino or di-(C~_3-alkyl)-amino group andlor the methylene group in the 4 Gosition of a 6- or 7-membered cycloalkyleneimino group may be replaced by one of the groups -NH, -N(C~_3-alkyl), -N(C~~-alHoxy-carbonyl) or-O-, by a carbonyl group which is substituted by a C~_3-alkoxy, N-[amino-C~_3-alkyl]-amino, N-[(C~_3-alkyl)-amino-C~_3-alkyl]-amino, N-[di-(C~_3-alkyl)-amino-C~_3-alkyl]-amino, N-[amino-C~_3-alkyl]-N-(C~_3-alkyl)-amino, N-[(C~_3-alkyl)-amino-C~_3-alk~rl]-N-(C~_3-alkyl)-amino, N-[di-(C~_3-alkyl)-amino-C~_3-alkyl]-N-(C~_3-alkyl)-amino, N-(C3_7-cycloalkyl)-N-(C~_3-alkyl)-amino or 5- to 7-membered cyc;loalkyleneimino group, while the methylene group in tie 4 position of a 6- or 7-membered cycloalkylene grou,~ may be replaced by a -NH, -N(C~_3-alkyl) or -N(C»-alkyloxy-carbonyl)-group, or by a group of formula R$
N
~ R7 wherein R' denotes a hydrogen atom c~r a C»-alkyl, C~~-alkyl-carbonyl, benzylcarbonyl, heteroarylcart~onyl, cycloalkyleneimino-C~_3-alkyl-carbonyl with 5 to 7 ring ~~toms in the cycloalkyleneimino moiety, C~_3-alkoxy-C~_3-alkyl-c arbonyl, amino-C~_3-alkyl-carbonyl, (C~_3-alkyl)-amino-C,_3-alkyl-carbonyl, di-(C~_3-alkyl)-amino-carbonyl-C~_3-alkyl, C~_4-alkylsulphonyl, phenylsulphonyl, heteroarylsulphonyl or benzylsulphonyl group or a phenylcarbonyl group optional y substituted in the phenyl moiety by one or two methoxy groups and R$ denotes a C~_3-alkyl group, a C2_4-alkyl group terminally substituted by an amino, (C~_3-alkyl)-amino, di-(C~_3-alkyl)-amino or N-benzyl-N-(C~_3-alkyl)-amino group, an amino-carbonyl-C~_3-alkyl, (C~_3-alkyl)-amino-carbonyl-C~_3-alkyl or di-(C~_3-alkyl)-amino-carbonyl-C~_3-alkyl group, a di-(C~_3-alkyl)-amino-C,_3-alkyl-amino-carbonyl, 4-(C1_3-alkyl)-piperazin-1-yl-carbonyl, 4-(C~ -alkyl)-piperazin-1-yl-aminocarbonyl, 1-(C~_3-alkyl)-piperidin-4-yl-aminocarbonyl, 1-(C~_3-alkyl)-piperidin-4-yl-oxy-carbonyl or (pyridinyl-C~_3-alkyl)-aminocarbonyl group or a C~~-alkyl-carbonyl group terminally substituted by a hydroxy, C~~-alkyloxy, amino, (C~_3-alky I)-amino, di-(C~_3-alkyl)-amino, (w-hydroxy-C2_3-alkyl)-amino, di-(~~-hydroxy-C2_3-alkyl)-amino, (~-alkoxy-C2_3-alkyl)-amino, di-(w-alkoxy-C2_3-alkyl)-amino, C~_3-alkyl-carbonyl-amino, N-benzyl-N-(C~_3-alkyl)-amino, N-[di-(C~_3-alkyl)-amino-C~_3-alkyl]-N-(C~_3-alkyl)-amino, 1-(C~_3-alkyl)-piperidin-4-yl or heteroaryl group or by a 5- to 7-membered cycloalkyleneimino group, while the cycloalkylene group may be substituted by a C~_3-alkyl group andlor one or finro methylene groups linked to the imino group may be replaced by a csrbonyl group and/or the methylene group in the 4 position of a 6- or 7-membered cycloalkylim ino group may be replaced by an -NH, -N(C~_3-alkyl), -N(I~enzyl), -N(C~.~-alkoxy-carbonyl) or -O- andlor a phenyl ring may be fused via finro adjacent carbon atoms of the cycloalkylE neimino group, while a 2- or 3-linked pyrrolyl group may additionally be substituted at the nitrogen atom by a C~_3-alkyl group, R5 denotes a hydrogen atom or a C~_3-alkyl group and R6 denotes a hydrogen atom or a nitro grow ~, while the unsubstituted, mono- or disubstitu :ed phenyl groups contained in the above definitions may additionally be substi :uted by a fluorine, chlorine, bromine or iodine atom or by a C~_3-alkyl, C-_3-alkoxy, benzyloxy, carboxy, cyano, trifluoromethyl, nitro, amino, hydroxy, C~_3-alkylsulphonylamino, C~_3-alkylamino or di-(C~_3-alkyl)-amino group or by two methyl groups, the abovementioned alkyl groups including :straight-chain and branched alkyl groups, wherein additionally one to 3 hydrogen atoms may be replaced by fluorine atoms, while, unless otherwise stated, the expressian a heteroaryl group refers to a monocyclic 5- or 6-membered heteroaryl gn~up optionally substituted in the carbon skeleton by a C~_3-alkyl group, wher~;in the 6-membered heteroaryl group con~:ains one, two or three nitrogen atoms and the 5-membered heteroaryl group con~;ains an imino group optionally substituted by a C~_3-alkyl or phenyl-C~ _3-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted k~y a C~_3-alkyl, amino-C~_3-alkyl, [(C~_3-alkyl)-amino]-C~_3-alkyl, [di-(C~_3-alkyl)-amino]-C~_3-alkyl or phenyl-C~_3-alkyl group or an oxygen c r sulphur atom and additionally contains a nitrogen atom or an imino group optionally substituted k~y a C,_3-alkyl or phenyl-C~_3-alkyl group and two nitrogen atoms, and moreover a phenyl ring may be fu sed to the abovementioned monocyclic heterocyclic groups via two adjacent carbon atoms and the bonding takes place via a nitrogen atom or via a carbon atom of the heterocyclic moiety or a fused-on phenyl ring, and additionally any carboxy, amino or imin ~ group present may be substituted by a group which can be cleaved in vivo, the tautomers, enantiomers, diastereomers. mixtures thereof and the salts thereof, with the exception of the compounds (Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-6-chloro-2-indolinone and (Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-6-bromo-2-indolinone.
Preferred compounds of the above general formula I are those wherein X denotes an oxygen or sulphur atom, R' denotes a hydrogen atom, a C1~-alkoxy-carbonyl, C~_3-alkyl-carbonyl, aminomethyl, C~_3-alkylaminomethyl, di-(C~_~-alkyl)-aminomethyl or a 5- to 7-membered cycloalkyleneiminomethyl group R2 denotes a fluorine, chlorine or bromine atom or a cyano group, R3 denotes a phenyl or naphthyl group or a phenyl or naphthyl group mono- or disubstituted by a fluorine, chlorine, bromine or iodine atom, by a trifluoromethyl C~_3-alkyl or C~_3-alkoxy group, while in the case of disubstitution the substis.uents may be identical or different and the abovementioned unsubstituted as well as the mono- and disubstituted phenyl and naphthyl groups may additionally be substituted by a fluorine, chlorine, bromine or iodine atom, by a C~_3-alkyl, C~~-alkoxy, benzylox~~, carboxy, cyano, trifluoromethyl, nitro, amino, C,_3-alkyl-carbonyl-amino, C»-alkyloxy-carbonylamino, hydroxy, C~_3-alkylsulphonylamino, C,_3-alkylamino or di-(C~_3-alkyl)-amino group, by a hydroxy-C~_3-alkyl, cyano-C~_3-alkyl, carboxy-C~_3-alkyl, C~_a-alkoxy-C~_3-alkyl, amino-C~_3-alkyl, C~_3-aikylamino-C~_3-alkyl, [di-(C1-3-alkyl)-amino]-C~_3-alkyl, benzylamino-C~_3-alkyl, dibenzylamino-C~_3-alkyl, N-benzyl-N-(C~_3-alkyl)-amino-C:~_3-alkyl, benzylcarbonylamino-C~_3-alkyl, phenylcarbonylamino-C~_3-alkyl, phenylamino-C~_3-alkyl, diphenylamino-C~_3-alkyl, N-phenyl-l~-(C~_3-alkyl)-amino-C~_3-alkyl, heteroarylamino-C~_3-alkyl, N-heteroaryl-N-(C,_3-alkyl)-amino-C~_3-alkyl, C~~-alkyl-sulphonylamino-C~_3-alkyl, phenyl-sulphonylamino-C~_3-alkyl, benzyl-sulphonylamino-C~_3-alkyl, C~.4-alkoxy-carbonyl-C~_3-alkyl, N-(C~_4-alkoxy-carbonyl)-amino-C~_3-alk~rl, aminocarbonyl-C~_3-alkyl, (C~_3-alkylamino)-carbonyl-C~_3-alkyl, di-(C,_3-alkyl)-aminocarbonyl-C~_3-alkyl, (C~_6-alkyl-carbonyl)-amino-C~_3-alkyl N-(C~_3-alkyl)-N-(C~_6-alkyl-carbonyl)-amino-C~_3-alkyl, (C3_~-cycloalkyl-carbonyl)-amino-C~_3-alkyl, N-(C~_3-alkyl)-N-(C3_7-cycloalkyl-carbonyl)-amino-C~_3-alkyl, (C3_~-cycloalkyl-C~_3-alkyl-carbonyl)-amino~C~_3-alkyl, N-(C~_3-alkyl)-N-(C3_~-cycloalkyl-C~_3-alkyl-carbonyl)-amino~C~_3-alkyl, (C~~-alkoxy-C~_3-alkyl-carbonyl)-amino-C~_3-alkyl, N-(C~_3-al cyl)-N-(C»-alkoxy-C~_3-alkyl-carbonyl)-amino-C~_3-alkyl, (heteroaml-carbonyl)-amino-C~_3-alkyl, N-(C~_3-alkyl)-N-(heteroaryl-carbonyl)-amino-C~_3-alkyl, 4-(C~_3-alkyl)-piperazin-1-yl-carbonyl-(C~_3-alkyl), tEtrazolyl-C~_3-alkyl or imidazoyl-C~_3-alkyl group, by a carboxy-G2_3-alkenyl, aminocarbonyl-C2_3-alkenyl or C~_4-alkoxy-carbonyl-C2_3-alkenyl group or by a 5- to 7-membered cycloalkyleneimino group wherein one or two methylene groups adjacent to the nitrogen atom may be replaced by a carbonyl group or a -CH2-CH2- grou~~ linked to the imino group may be replaced by the group -O-CO-, while the carbonyl group of the -O-CO-group is linked to the imino group, while the substituents may be identical or different, R4 denotes a benzopyrazolyl or 1-(C~_3-alkyl )-piperidin-4-yl group, a cyclohexyl group which is substituted by ~ N-[di-(C~_3-alkyl)-amino-C~_3-alkyl-carbonyl]-amino or N-[di-(C~_3-alkyl)-amino-~~~_3-alkyl-carbonyl]-N-(C~_3-alkyl)-amino group, or a phenyl, furyl, pyrrolyl, pyridinyl or naphthyl group each of which may be substituted in the carbon skeleton by a fluorine, chlorine, bromine or ioc ine atom, by a C~_3-alkyl, C~_3-alkoxy, cyano, nitro, carboxy or trifluc~romethyl group, by a w-[di-(C~_3-alkyl)-amino]-C2_3-alkoxy, C~_3-alkyl-sulphonyl, di-(C~_3-alkyl)-amino-C~_3-alkyl-sulphonyl, 4-(i:~_3-alkyl)-piperazino, imidazolyl, C,_3-alkyl-imidazolyl or [di-(C~_3-alkyl)amino]-C~_3-alkyl-imidazolyl group, by a C~_3-alkyl group which is termini Ily substituted by a carboxy, C~~-alkoxy-carbonyl, amino, C~_3-alkylamino, di-(C~_3-alkyl)-amino, N-(C~_3-alkyl)-N-(~-amino-C2_3-alkyl)-amino, iV-benzyl-N-(C~_3-alkyl)-amino, N-[w-(di-(C1_3-alkyl)-amino)-C2_3-alkyl]-A'-(C~_3-alkyl)-amino, N-[di-(C~_3-alkyl)-amino-C~_3-alkyl]-N-(C~_3-alkyl)-amino-carbonyl, N-(w-hydroxy-C2_ 3-alkyl)-N-(C~_3-alkyl)-amino, di-(c~-hy~lroxy-C2_3-alkyl)-amino, N-(w-C,_3-alkoxy-C2_3-alkoxy-C~_3-alkyl)-N-(C~_3-alkyl)-amino, N-(C~_4-alkoxy-carbonyl)-amino, N-(C~_4-alkoxy-carbonyl)-N-(C~_3-alkyl)-amino, N-{w-[N-(C~_4-alkoxy-carbonyl )-amino]-(C~_ ~-al kyl )}-N-(C~_3-al kyl )-amino, pyridinyl, triazolyl, pyrrolidino, piperidino, di-(C~_3-alkyl)-piperidino, [di-(C~_3-alkyl)-amino]-piperidino, pipera~:ino, morpholino, (C~_3-alkyl)-piperazino, (C~_3-alkyl)-piperazin-1-yl~~carbonyl or 4-(C~~-alkoxy-carbonyl)-piperazino group, by a carbonyl group which is substituted by a C~_4-alkoxy, N-[di-(C~_3-alkyl)-amino-C~_3-alkyl]-amino, N-[di-~C~_3-alkyl)-amino-C~_3-alkyl]-N-(C~
3-alkyl)-amino, N-(C3_~-cycloalkyl)-N-(C~_3-alkyl)-amino, piperidino, piperazino, 4-(C~_4-alkyloxy-carbonyl;-piperazino or 4-(C~_3-alkyl)-piperazino group, or by a group of formula N
~ R~
wherein R' denotes a hydrogen atom c r a C~_3-alkyl, C~_3-alkyl-carbonyl, benzylcarbonyl, pyridinylcarbonyl, furanylcarbonyl, pyrrolidino-C~_3-alkyl-carbonyl, C~_3-alkoxy-C~_3-alkyl-carbonyl, di-(C~_3-alkyl)-amino-carbonyl-C~_3-alkyl, C~_4-alkylsulphonyl or benzylsulphonyl group or a phenylcarbonyl group optionally substituted in the phenyl moiety by one or two rr ethoxy groups and Ra denotes a C~_3-alkyl, di-(C~_ j-alkyl)-amino-C~.~-alkyl-amino-carbonyl or di-(C~_3-alkyl)-amino-carbonyl-C~_3-alkyl group, a C2_3-alkyl group terminally su bstituted by a di-(C~_3-alkyl)-amino or N-benzyl-N-(C~_3-alkyl)-amino group, a 4-(C~_3-alkyl)-piperazin-1-yl-carbonyl, 4-(C~_3-alkyl)-piperazin-1-yl-aminocarbonyl, 1-(C~_3-alkyln-piperidin-4-yl-aminocarbonyl, 1-(C~_3-alkyl)-piperidin-4-yl-oxy-carbonyl or (pyridinyl-C~_3-alkyl)-aminocarbonyl group or a C~~-alkyl-carbonyl group terminally substituted by a hydroxy, amino, di-(C~_3-alkyl)-amino, di-(w-hydroxy-C2_3-alkyl)-amino, C~_3-alkyl-carbonyl-amino, N-b ~nzyl-N-(C~_3-alkyl)-amino, N-(di-(C~_3-alkyl)-amino-C~_3-alkyl]-N-(C~_3-alkyl)-amino, imidazolyl, piperazino, 4-(C~_3-alkyl)-pipen~zin-1-yl, 4-benzyl-piperazin-1-yl, 4-(C~~-alkoxy-carbonyl)-piperazin-1-yl, 4-(C~_3-alkyl)-homo-piperazin-1-yl, morpholino, pyrrolidino, piperidino, 1-(C~_3-alkyl)-piperidin-4-yl, 4-(C~_3-alkyl)-piperidin-1-yl or phthalimido group, zg while a 2- or 3-linked pyrrolyl group may ad~~itionally be substituted at the nitrogen atom by a C~_3-alkyl group, R5 denotes a hydrogen atom or a C~_3-alkyl group and R6 denotes a hydrogen atom or a vitro grow p, while the unsubstituted, mono- or disubstitu ted phenyl groups contained in the above definitions may additionally be substituted by a fluorine, chlorine, bromine or iodine atom or by a C~_3-alkyl, C _3-alkoxy, benzyloxy, carboxy, cyano, trifluoromethyl, vitro, amino, hydroxy, C~_~-alkylsulphonylamino, C~_3-alkylamino or di-(C~_3-alkyl)-amino group or by two methyl groups, the abovementioned alkyl groups including :>traight-chain and branched alkyl groups, wherein additionally one to 3 hydrocien atoms may be replaced by fluorine atoms, while, unless otherwise stated, the expression a heteroaryl group refers to a monocyclic 5- or 6-membered heteroaryl group optionally substituted in the carbon skeleton by a C~_3-alkyl group, wherE~in the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C~_3-alkyl or phenyl-C-_3-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted ~y a C~_3-alkyl or phenyl-C~_3-alkyl group or an oxygen or sulphur atom arid additionally a nitrogen atom or an imino group optionally substituted ~y a C~_3-alkyl or phenyl-C~_3-alkyl group and two nitrogen atoms, and moreover a phenyl ring may be fu sed to the abovementioned monocyclic heterocyclic groups via twc~ adjacent carbon atoms and the bonding takes place via a nitrogen atom or via a carbon atom of the heterocyclic moiety or a fused-on phenyl ring, and additionally any carboxy, amino or imino group present may be substituted by a group which can be cleaved in vivo, the tautomers, enantiomers, diastereomers, mixtures thereof and the salts thereof, with the exception of the compounds (Z)-3-[1-(4-piperid inomethyl-phenylamino)-1-phenyl-methylidene]-6-chloro-2-indolinone and (Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-6-bromo-2-indolinone.
A first sub-group of preferred compounds of general formula I deserving special mention comprises those wherein R', R2, R3, R5, R6 and X are as hereinbeforE~ defined and R4 denotes a benzopyrazolyl or 1-(C~_3-alkyl)-piperidin-4-yl group, a cyclohexyl group which is substituted by an N-[di-(C~_3-alkyl)-amino-C,_3-alkyl-carbonyl]-amino or N-[di-(C~_3-alkyl)-amino-C~_3-alkyl-carbonyl]-N-C~_3-alkyl-amino group, or a phenyl, furyl, pyrrolyl, pyridinyl or naphthyl group, each of which may be substituted in the carbon skeleton by a fluorine, chlorine, bromine or iod ine atom, by a C~_3-alkyl, C~_3-alkoxy, cyano, nitro, carboxy or trifluc romethyl group, by a w-[di-(C~_3-alkyl)-amino]-C2_3-alkoxy, C1_3-alkyl-sulphonyl, df-(C~_3-alkyl)-amino-C1_3-alkyl-sulphonyl, 4-((;~_3-alkyl)-piperazino, imidazolyl, C~_3-alkyl-imidazolyl or [di-(C~_3-alkyl)amino]-C~_3-alkyl-imidazolyl group, by a carbonyl group which is substitu led by a C»-alkoxy, N-[di-(C~_3-alkyl)-amino-C~_3-alkyl]-amino, N-[di-(C~_3-alkyl)-amino-C~_3-alkyl]-N-C~_3-alkyl-amino, N-(C3_7-cycloalkyl)-~I-(G~_3-alkyl)-amino, piperidino, piperazino, 4-(C~~-alkyloxy-carbonyl)-piperazino or 4-(C~_3-alkyl)-piperazino group, or by a group of formula -N
~ R~
wherein R' denotes a hydrogen atom cr a C~_3-alkyl, C~_3-alkyl-carbonyl, benzylcarbonyl, pyridinylcarbo ~yl, furanylcarbonyl, pyrrolidino-C~_3-alkyl-carbonyl, C~_3-alkoxy-C~_3-alkyl-carbonyl, di-(C~_3-alkyl)-amino-carbonyl-C~_3-alkyl, C»-alkylsulphonyl or benzylsulphonyl group or a phenylcarbonyl group optionally substituted in the phenyl moiety by one or two methoxy groups and R8 denotes a C~_3-alkyl, di-(C~_ 3-alkyl)-amino-C~_3-alkyl-amino-carbonyl or di-(C~_3-alkyl)-amino-carbonyl-C~_3-alkyl group, a C2_3-alkyl group terminally su bstituted by a di-(C,_3-alkyl)-amino or N-benzyl-N-(C~_3-alkyl)-amino group, a 4-(C~_3-alkyl)-piperazin-1-yl-carbonyl, 4-(C~_3-alkyl)-piperazin-1-yl-aminocarbonyl, 1-(C~_3-alkyl s-piperidin-4-yl-aminocarbonyl, 1-(C,_3-alkyl)-piperidin-4-yl-oxy-carbonyl or (pyridinyl-C~_3-alkyl)-aminocarbonyl group or a C»-alkyl-carbonyl group terminally substituted by a hydroxy, amino, di-(C~_3-alkyl)-amino, di-(~-hydroxy-C2_3-alkyl)-amino, C~_3-alkyl-carbonyl-amino, N-bsnzyl-N-(C~_3-alkyl)-amino, N-[di-(C~_3-alkyl)-amino-C,_3-alkyl]-N-(C~_3-alkyl)-amino, imidazolyl, piperazino, 4-(C~_3-alkyl)-piper~zin-1-yl, 4-benzyl-piperazin-1-yl, 4-(C~_4-alkoxy-carbonyl)-piperazin-1-yl, 4-(C~_3-alkyl)-homo-piperazin-1-yl, morpholino, pyrrolidino, piperidino, 1-(C~_3-alkyl)-piperidin-4-yl, 4-(C~_3-alkyl)-pi~eridin-1-yl or phthalimido group, while a 2- or 3-linked pyrrolyl group may additionally be substituted at the nitrogen atom by a C~_3-alkyl group, while the unsubstituted, mono- or disubstitu red phenyl groups contained in the above definitions may additionally be substituted by a fluorine, chlorine, bromine or iodine atom or by a C~_3-alkyl, C ~_3-alkoxy, benzyloxy, carboxy, cyano, trifluoromethyl, nitro, amino, hydroxy, C~_3-alkylsulphonylamino, C1-s-alkylamino or di-(C~_3-alkyl)-amino group or by two methyl groups, the abovementioned alkyl groups including straight-chain and branched alkyl groups, wherein additionally one to 3 hydro~~en atoms may be replaced by fluorine atoms, while, unless otherwise stated, the expression a heteroaryl group refers to a monocyclic 5- or 6-membered heteroaryl group optionally substituted in the carbon skeleton by a C~_3-alkyl group, wher:in the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C~_3-alkyl or phenyl-C-_3-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted k y a C,_3-alkyl or phenyl-C~_3-alkyl group or an oxygen or sulphur atom arid additionally a nitrogen atom or an imino group optionally substituted k y a C,_3-alkyl or phenyl-C~_3-alkyl group and two nitrogen atoms, and moreover a phenyl ring may be fu red to the abovementioned monocyclic heterocyclic groups via two adjacent carbon atoms and the bonding takes place via a nitrogen atom or via a carbon atom of the heterocyclic moiety or a fused-on phenyl ring, and additionally any carboxy, amino or imino group present may be substituted by a group which can be cleave~~ in vivo, the tautomers, enantiomers, diastereomers, mixtures thereof and the salts thereof.
A second sub-group of preferred compounc s of general formula I deserving special mention are those wherein R', R2, R4, R5, R6 and X are as hereinbefor~: defined and R3 denotes a phenyl or naphthyl group or a phenyl or naphthyl group mono- or disub~tituted by a fluorine, chlorine, bromine or iodine atom, by a trifluoromethyl, C~_3-alkyl or C~_3-alkoxy group, while in the case of disubstitution the substii uents may be identical or different and the abovementioned unsubstituted as well as the mono- and disubstituted phenyl and naphthyl groups may additionally be substituted by a fluorine, chlorine, bromine or iodine atom, by a C~_3-alkyl, C~_4-alkoxy, benzylox~~, carboxy, cyano, trifluoromethyl, nitro, amino, C~_3-alkyl-carbonyl-amino, C~~-alkyloxy-carbonylamino, hydroxy, C~_3-alkylsulphonylamino, C,_3-alkylamino or di-(C~_3-alkyl)-amino group, by a hydroxy-C~_3-alkyl, cyano-C~_3-alkyl, carboxy-C~_3-alkyl, C~_a-alkoxy-C~_3-alkyl, amino-C~_3-alkyl, C,_3-alkylamino-C~_3-alkyl, [di-(C~-3-alkyl)-amino]-C~_3-alkyl, benzylamino~~C~_3-alkyl, dibenzylamino-C~_3-alkyl, N-benzyl-N-(C~_3-alkyl)-amino-C;~_3-alkyl, benzylcarbonylamino-C~_3-alkyl, phenylcarbonylamino-C,_3-alkyl, phenylamino-C~_3-alkyl, diphenylamino-C~_3-alkyl, N-phenyl-n-(C~_3-alkyl)-amino-C,_3-alkyl, heteroarylamino-C~_3-alkyl, N-hetero~~ryl-N-(C~_3-alkyl)-amino-C~_3-alkyl, C~_4-alkyl-sulphonylamino-C~_3-alkyl, phenyl-sulphonylamino-C~_3-alkyl, benzyl-sulphonylamino-C~_3-alkyl, C~.4-alkoxy-carbonyl-C~_3-alkyl, N-(C»-alkoxy-carbonyl)-amino-C~_3-alkyl, aminocarbonyl-C1_3-alkyl, (C~_3-alkylamino)-carbonyl-C~_3-alkyl, di-(C,_3-alkyl)-aminocarbonyl-C~_3-alkyl, (C~_6-alkyl-carbonyl)-amino-C~_3-alkyl N-(C~_3-alkyl)-N-(C~_6-alkyl-carbonyl)-amino-C~_3-alkyl, (C3_~-cycl~~alkyl-carbonyl)-amino-C~_3-alkyl, N-(C~_3-alkyl)-N-(C3_~-cycloalkyl-carbcmyl)-amino-C~_3-alkyl, (C3_~-cycloalkyl-C~_3-alkyl-carbonyl)-amino~~C~_3-alkyl, N-(C~_3-alkyl)-N-(C3_7-cycloalkyl-C~_3-alkyl-carbonyl)-amino~~C~_3-alkyl, (C~_4-alkoxy-C,_3-alkyl-carbonyl)-amino-C~_3-alkyl, N-(C~_3-alkyl)-N-(C~_4-alkoxy-C~_3-alkyl-carbonyl)-amino-C~_3-alkyl, (heteroar~l-carbonyl)-amino-C~_3-alkyl, N-(C~_3-alkyl)-N-(heteroaryl-carbonyl)-amino-C~_3-alkyl, 4-(C~_3-alkyl)-piperazin-1-yl-carbonyl-(C~_3-alkyl), tE;trazolyl-C~_3-alkyl or imidazoyl-C~_3-alkyl group, by a carboxy-C2_3-alkenyl, aminocarbonyl-C2_3-alkenyl or C~~-alkoxy-carbonyl-C2_3-alkenyl group or by a 5- to 7-membered cycloalkyleneimino group wherein one or two methylene groups adjacent to the nitrogen atom may be replaced by a carbonyl group or a -CH2-CH2- grou~~ linked to the imino group may be replaced by the group -O-CO-, while the carbonyl group of the -O-CO- group is linked to the imino grou ~, while the substituents may be identical or different, and the unsubstituted, mono- or disubstitut~d phenyl groups contained in the above definitions may additionally be substituted by a fluorine, chlorine, bromine or iodine atom or by a C~_3-alkyl, C _3-alkoxy, benzyloxy, carboxy, cyano, trifluoromethyl, vitro, amino, hydroxy, C~_3-alkylsulphonylamino, C~_3-alkylamino or di-(C~_3-alkyl)-amino group or by two methyl groups, the abovementioned alkyl groups including straight-chain and branched alkyl groups, wherein additionally one to 3 hydrol~en atoms may be replaced by fluorine atoms, while, unless otherwise stated, the expression a heteroaryl group refers to a monocyclic 5- or 6-membered heteroaryl gr~~up optionally substituted in the carbon skeleton by a C~_3-alkyl group, wher~:in the 6-membered heteroaryl group con~ains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C~_3-alkyl or phenyl-C,_3-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted try a C~_3-alkyl or phenyl-C~_3-alkyl group or an oxygen or sulphur atom a ~d additionally a nitrogen atom or an imino group optionally substituted ky a C~_3-alkyl or phenyl-C~_3-alkyl group and two nitrogen atoms, and moreover a phenyl ring may be fu red to the abovementioned monocyclic heterocyclic groups via two adjacent carbon atoms and the bonding takes place via a nitrogen ato ~n or via a carbon atom of the heterocyclic moiety or a fused-on phenyl ring, and additionally any carboxy, amino or imirn~ group present may be substituted by a group which can be cleaved in vivo, the tautomers, enantiomers, diastereomers, mixtures thereof and the salts thereof.
Particularly preferred compounds of the abcwe general formula I are those wherein X denotes an oxygen or sulphur atom, R' denotes a hydrogen atom, a C~.~-alkoxy-carbonyl, C~_3-alkyl-carbonyl, aminomethyl, C~_3-alkylaminomethyl, di-(C~_3-alkyl)-aminomethyl or a 5- to 7-membered cycloalkyleneiminomethyl group R2 denotes a fluorine, chlorine or bromine atom or a cyano group, R3 denotes a phenyl or naphthyl group or a phenyl or naphthyl group mono- or disubstituted by a fluorine, chlorine, bromine or iodine atom, by a trifluoromethyl, C~_3-alkyl or C~_3-alkoxy group, while in the case of disubstitution the substituents may be identical or different and the abovementioned unsubstituted as urell as the mono- and disubstituted phenyl and naphthyl groups may additionally be substituted by a C~_3-alkyl-carbonyl-amino, C~.~-~Ikyloxy-carbonylamino, benzyloxy or hydroxy group, by a hydroxy-C,_3-alkyl, carboxy-C,_3-alkyl, C~~-alkoxy-C~_3-alkyl, cyano-C~_3-alkyl, benzylamino-C~_3-alkyl, dibenzylamino-C~_3-alkyl, N-benzyl-N-(C~_3-alkyl)-amino-C~_3-alkyl, C~_4-alkoxy-C,_3-alkyl-carbonylamino-C~_3-alkyl, C3_~-cycloa kyl-carbonylamino-C1_3-alkyl, C3_,-cycloalkyl-C~_3-alkyl-carbonylamino-C 1_3-alkyl, benzylcarbonylamino-C~_3-alkyl, phenylcarbonylamino-C~_3-alkyl, heteroaryl-carbonylamino-C~_3-alkyl, phenylamino-C~_3-alkyl, did henylamino-C~_3-alkyl, N-phenyl-N-(C~_3-alkyl)-amino-C~_3-alkyl, heteroarylamino-C~_3-alkyl, N-heteroaryl-N-(C~_3-alkyl)-amino-C~_3-alkyl, C~.~-a kyl-sulphonylamino-C~_3-alkyl, phenyl-sulphonylamino-C~_3-alkyl, be ~zyl-sulphonylamino-C~_3-alkyl, C~_a-alkoxy-carbonyl-C~_3-alkyl, N-(C~.~-alkoxy-carbonyl)-amino-C~_3-alkyl, aminocarbonyl-C~_3-alkyl, (C~_3-alkylamino)-carbonyl-C~_3-alkyl, di-(C~_3-alkyl)-aminocarbonyl-C~_3-alkyl, 4-(C~_3-alkyl)-piperazin-1-yl-carbonyl-(C~_3-alkyl) or tetrazolyl-C~_3-alkyl group, by an aminocarbonyl-C2_3-alkenyl or ~~~_4-alkoxy-carbonyl-C2_3-alkenyl group or by a 5- to 7-membered cycloalkyleneimino groups, wherein one or two methylene groups adjacent to the nitrogen atom may be replaced by a carbonyl group or a -CH2-CH2- group linked to the imino group may be replaced by the group -O-CO-, while the carbonyl group of the -O-CO- group is linked to the imino group, while the substituents may be identical or different, R4 denotes a benzopyrazolyl or 1-(C~_3-alkyl)-piperidin-4-yl group, a cyclohexyl group which is substituted by a N-[di-(C~_3-alkyl)-amino-C~_3-alkyl-carbonyl]-amino or N-[di-(C~_3-alkyl)-amino-~~_3-alkyl-carbonyl]-N-(C~_3-alkyl)-amino group, or a phenyl, pyridinyl or naphthyl group or a pyrrolyl group optionally substituted at the nitrogen by a C~_3-alkyl group, each of which may be substituted by a fluorine, chlorine, bromine or iod ine atom, by a C~_3-alkyl, C1-s-alkoxy, cyano, nitro, carboxy or trifluc~romethyl group, by a w-[di-(C~_3-alkyl)-amino]-C2_3-alkoxy, C~_3-alkyl-sulphonyl, di-(C~_3-alkyl)-amino-C~_3-alkyl-sulphonyl, 4-(c~~_3-alkyl)-piperazino, imidazolyl, C~_3-alkylimidazolyl or [di-(C~_3-alkyl)-amino]-C~_3-alkyl-imidazolyl group, by a C~_3-alkyl group which is termins Ily substituted by a carboxy, C~_3-alkoxy-carbonyl, amino, C~_3-alkylamino, di-(C~_3-alkyl)-amino, N-(C~_3-alkyl)-N-(w-amino-C2_3-alkyl)-amino, iV-benzyl-N-(C~_3-alkyl)-amino, N-[w-(di-(C~_3-alkyl)-amino)-C2_3-alkyl]-A'-(C~_3-alkyl)-amino, N-[di-(C~_3-alkyl)-amino-C~_3-alkyl]-N-(C~_3-alkyl)-amino-carbonyl, N-(w-hydroxy-C2_3-alkyl)-N-(C~_3-alkyl)-amino, di-(w~ hydroxy-C2_3-alkyl)-amino, N-(w-C~_3-alkoxy-C2_3-alkoxy-C~_3-alkyl)-N-I C~_3-alkyl)-amino, N-(C~_4-alkoxy-carbonyl)-amino, N-(C~~-alkoxy-carb ~nyl)-N-(C~_3-alkyl)-amino, N-{w-[N-(C~ _4-al koxy-carbonyl )-a m ino]-(C ~ _ 3-al kyl )}-N-(C~ _3-al kyl )-ami no, pyridinyl, triazolyl, pyrrolidino, piperidino, di-(C~_3-alkyl)-piperidino, [di-(C~_3-alkyl)-amino]-piperidino, pipera::ino, morpholino, (C~_3-alkyl)-piperazino, 4-(C~_3-alkyl)-piperazino-carbonyl or 4-(C~~-alkoxy-carbonyl)-piperazino group, by a carbonyl group which is substituted by a C~_3-alkoxy, N-[di-(C~_3-alkyl)-amino-C~_3-alkyl]-amino, N-[di-i C~_3-alkyl)-amino-C~_3-alkyl]-N-(C~_3-alkyl)-amino, N-(C3_~-cycloalkyl~-N-(C~_3-alkyl)-amino, piperidino, piperazino, 4-(C~_4-alkyloxy-carbonyl;-piperazino or (C~_3-alkyl)-piperazino group, or by a group of formula -N
~ R~
wherein R' denotes a hydrogen atom, ~~ C~_3-alkyl, C~_3-alkyl-carbonyl, benzylcarbonyl, pyridinylcarbo iyl, furanylcarbonyl, pyrrolidino-C,_3-alkyl-carbonyl, C~_3-alkoxy-C~_3-alkyl-carbonyl, di-(C~_3-alkyl)-amino-carbonyl-C~_3-alkyl, C~_4-alkylsulphonyl or benzylsulphonyl group or a phenylcarbonyl group optionally substituted in the phenyl moiety by one or two methoxy groups and R8 denotes a C~_3-alkyl, w-[di-( ~~_3-alkyl)-amino]-C2_3-alkyl, di-(C~_3-alkyl)-amino-carbonyl-C~.3-alkyl, di-(C~_3-alkyl)-amino-C~_3-alkyl-amino-carbonyl or w-(N-benzyl-N-(C~_3-alkyl)-amino]-C2_3-alkyl group or a 4-(C~_3-alkyl)-piperazin-1-yl-carbonyl, 4-(C~_3-alkyl)-piperazin-1-yl-aminocarbonyl, 1-(C~_3-alkyll-piperidin-4-yl-aminocarbonyl, 1-(C~_3-alkyl)-piperidin-4-yl-oxy-carbonyl or (pyridinyl-C~_3-alkyl)-aminocarbonyl group or a C~_3-alkyl-carbonyl group terrinally substituted by a hydroxy, amino, di-(C~_3-alkyl)-amino, d -(cu-hydroxy-C2_3-alkyl)-amino, C,_3-alkyl-carbonyl-amino, N-benzyl-N-(C~_3-alkyl)-amino, N-[di-(C~_3-alkyl)-amino-C~_3-alkyl]-I~-(C~_3-alkyl)-amino, imidazolyl, piperazino, 4-(C~_3-alkyl)-piperazin-1-yl, 4-benzyl-piperazin-1-yl, 4-(C~~-alkoxy-carbonyl)-piperazin-1-yl, 4-(C1_3-alkyl)-homopiperazin-1-yl, morpholiro, pyrrolidino, piperidino-,1-(C~_3-alkyl)-piperidin-4-yl, 4-(C~_3-alN:yl)-piperidin-1-yl or phthalimido group, R5 denotes a hydrogen atom or a C~_3-alkyl group and R6 denotes a hydrogen atom or a nitro group, while the unsubstituted, mono- or disubstitu~:ed phenyl groups contained in the above definitions may additionally be substi~:uted by a cyano or a methoxy group or by two methyl groups, and the abovementioned alkyl groups include straight-chain and branched alkyl groups, wherein additionally one to 3 hydroclen atoms may be replaced by fluorine atoms, while, unless otherwise stated, the expression a heteroaryl group refers to a monocyclic 5- or 6-membered heteroaryl group optionally substituted in the carbon skeleton by a C~_a-alkyl group, wherf:in the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C~_3-alkyl or phenyl-C,_3-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C~_3-alkyl, amino-C~_3-alkyl, C~_3-alkylamino-C~_3-alkyl, di-(C~_3-alkyl )-amino-C~_3-alkyl or phenyl-C,_3-alkyl group or an oxygen or sulphur atom and additionally a nitrogen atom or an imino group optionally substituted Cy a C~_3-alkyl or phenyl-C~_3-alkyl group and two nitrogen atoms, and moreover a phenyl ring may be fu:~ed to the abovementioned monocyclic heterocyclic groups via twc~ adjacent carbon atoms and the bonding takes place via a nitrogen ato ~ or via a carbon atom of the heterocyclic moiety or a fused-on phenyl ring, and additionally any carboxy, amino or imino group present may be substituted by a group which can be cleaved in vivo, the tautomers, enantiomers, diastereomers, mixtures thereof and the salts thereof.
Most particularly preferred compounds of tfie above general formula I are those wherein X denotes an oxygen atom, R' denotes a hydrogen atom, R2 denotes a fluorine, chlorine or bromine atom or a cyano group, R3 denotes a phenyl group or a phenyl group monosubstituted by a fluorine, chlorine, bromine or iodine atom or by a C~_:;-alkoxy group, while the abovementioned unsubstituted and monosubstituted phenyl groups may additionally be substituted in the 3 or 4-posi:ion by a fluorine, chlorine or bromine atom, by a C~_3-alkoxy or C~_2-alkyl-carbonyl-amino group, by a carboxy-C,_3-alkyl, C~_4-alkoxy-carbonyl-C~_3-alkyl, aminocarbonyl-C~_3-alkyl, (C~_2-alkylamino)-carbonyl-C~_3-alkyl, di-(C~_2-alkyl)-amino-carbonyl-C~_3-alkyl, (C~_2-alkyl-carbonyl)-amino-C~_3-alkyl or (phenyl-carbonyl)-amino-C~_3-alkyl group, while the substituents may be identical or different, R4 denotes a phenyl group which is substituted by a C~_3-alkyl group terminally substituted by a di-(C~_2-alkyl)-amino group or by a group of formula -N
~ R~
wherein R' denotes a C~_2-alkyl, C~_2-al <yl-carbonyl, di-(C~_2-alkyl)-amino-carbonyl-C~_3-alkyl or C~_3-alkyisulphonyl group and R$ denotes a C~_3-alkyl or w-[di-(C~_2-alkyl)-amino]-C2_3-alkyl group or a C~_3-alkyl-carbonyl group terminally substituted by a di-(C~_2-alkyl)-amino, piperazino or 4-(i~~_3-alkyl)-piperazin-1-yl group, R5 denotes a hydrogen atom and R6 denotes a hydrogen atom, while the abovementioned alkyl groups include straight-chain and branched alkyl groups, wherein additionally one to 3 hydrogen atoms may be replaced by fluorine atoms, while additionally any carboxy, amino or imi io group present may be substituted by a group which can be cleaved in vivo, the tautomers, enantiomers, diastereomers, mixtures thereof and the salts thereof.

A first sub-group of most particularly preferred compounds of general formula I deserving special mention comprises those; wherein X, R', R2, R3, R5 and Rs are as hereinbeforE~ defined and R4 denotes a phenyl group which is substituted by a group of formula N
~ R~
wherein R' denotes a C,_2-alkyl, C~_2-al cyl-carbonyl, di-(C~_2-alkyl)-amino-carbonyl-C~_3-alkyl or C~_3-alkyisulphonyl group and R$ denotes a C~_3-alkyl or w-[di-(C~_2-alkyl)-amino]-C2_3-alkyl group or a C~_3-alkyl-carbonyl group terminally substituted by a di-(C~_2-alkyl)-amino, piperazino or 4-(c:~_3-alkyl)-piperazin-1-yl group, the abovementioned alkyl groups including :straight-chain and branched alkyl groups, wherein additionally one to 3 hydroclen atoms may be replaced by fluorine atoms, while additionally any carboxy, amino or imi ~o group present may be substituted by a group which can be cleaved in vivo, the tautomers, enantiomers, diastereomers, mixtures thereof and the salts thereof.

A second sub-group of particularly preferrec compounds of general formula I
deserving special mention comprises those wherein X, R', R2, R4, R5 and R6 are as hereinbeforE~ defined and R3 denotes a phenyl group or a phenyl grou p monosubstituted by a fluorine, chlorine or bromine atom or by a C~_3-alkox~~ group, while the abovementioned unsubstituted and monosubstituted phenyl groups are additionally substituted in the 3- or 4-position by a fluorine, chlorine or bromine atom, by a C~_3-alkoxy or C~_2-alkyl-carbony-amino group or by a carboxy-C~_3-alkyl, C~_4-alkoxy-c,~rbonyl-C~_3-alkyl, aminocarbonyl-C~_3-alkyl, (C~_2-alkylamino)-carbonyl-C,_3-alkyl, di-(C~_2-alkyl)-amino-carbonyl-C~_3-alkyl, (C~_2-alkyl-carbonyl)-amino-C~_3-alkyl or (phenyl-carbonyl)-amino-C~_3-alkyl group, while the substituents may be identic,~l or different, the abovementioned alkyl groups including :>traight-chain and branched alkyl groups, wherein additionally one to 3 hydroclen atoms may be replaced by fluorine atoms, while additionally any carboxy, amino or imioo group present may be substituted by a group which can be cleaved in vivo, the tautomers, enantiomers, diastereomers, mixtures thereof and the salts thereof.
A second sub-group of compounds of general formula I deserving particular mention comprises those wherein X denotes an oxygen atom, R' denotes a hydrogen atom, R2 denotes a bromine atom, R3 denotes a phenyl group, R4 denotes a 1-(C~_3-alkyl)-piperidin-4-yl group or a phenyl group which is substituted in the 4-position by a C~_3-alkyl group terminally substituted by a C~_3-alkylamino, di-(C~_3-alkyl)-amino, N-[w-(di-(C~_3-alkyl)-amino)-C2_3-alkyl]-N-(C~_3-alkyl)-amino or N-(C~_4-alkyloxy-carbonyl)-~~-(C~_3-alkyl)-amino group, by a 1-(C~_3-alkyl)-imidazol-2-yl or 4-( ~~_3-alkyl)-piperazin-1-yl-carbonyl group or by a group of formula -N
~ R~
wherein R' denotes a C~_3-alkyl, C~_3-al kyl-carbonyl, C~_3-alkyl-sulphonyl or benzylsulphonyl group and R$ denotes a w-[di-(C~_3-alkyl)-amino]-Cz_3-alkyl, w-[di-(C~_3-alkyl)-amino]-C~~-alkyl-carbonyl, c~-[4-(C~_3-alkyl)-piperazin-1-yl]-C~_3-alkyl-carbonyl or w-{N-[di-;C~_3-alkyl)-amino-C2_3-alkyl]-N-(C~_3-alkyl)-amino}-C~_3-alkyl-c,~rbonyl group, R5 denotes a hydrogen atom and R6 denotes a hydrogen atom, the abovementioned alkyl groups including :straight-chain and branched alkyl groups, wherein additionally one to 3 hydroclen atoms may be replaced by fluorine atoms, the tautomers, enantiomers, diastereomers, mixtures thereof and the salts thereof.
A third sub-group of compounds of general formula I deserving particular mention comprises those wherein X denotes an oxygen atom, R' denotes a hydrogen atom, R2 denotes a fluorine atom, R3 denotes a phenyl group which is optionally substituted in the 3- or 4-position by a fluorine or iodine atom or by a cyano-C~_3-alkyl, amino-C~_3-alkyl, C~_3-alkylamino-C~_3-alkyl, C~_5-alkyl-carbon~~lamino-C~_3-alkyl, C~_4-alkyloxy-carbonyl-amino-C~_3-alkyl, C»-alkyloxy-C~_3-alkyl-carbonyl-amino-C~_3-alkyl, C3_~-cycloalkyl-carbonyl-amino-C~_3-alkyl, C,_~-cycloalkyl-C~_3-alkyl-carbonyl-amino-C~_3-alkyl, N-(phenyl-carbonyl)-aminc-C~_3-alkyl, N-(benzyl-carbonyl)-amino-C~_3-alkyl, heteroaryl-carbonyl-amino ~C~_3-alkyl, N-(C~_3-alkylsulphonyl)-amino-C~_3-alkyl, N-(phenylsulphonyl)-amino-C~_3-alkyl, N-(benzylsulphonyl)-amino-C~_3-alkyl, carboxy-C~_3-alkyl, C~.~-alkoxy-carbonyl-C~_3-alkyl, aminocarbonyl-C~_3-alkyl, C~_3-alkylaminoca ~bonyl-C~_3-alkyl, di-(C~_3-alkyl)-aminocarbonyl-C~_3-alkyl, 4-(C~_3-alkyl)-pipe~azin-1-yl-carbonyl-C~_3-alkyl, 2-(aminocarbonyl)-C2_3-alkenyl or 2-(C~_3-alkyloxy-carbonyl)-C2_3-alkenyl group, or a phenyl group trisubstituted in the 3-, 4- and 5-position by fluorine atoms, R4 denotes a phenyl group which may be s~ bstituted in the 4-position by a C~_3-alkyl group terminally substituted by a pyrrolidin-1-yl, piperidin-1-yl, 4-(C~_3-alkyl)-piperazin~ 1-yl, C~_3-alkylamino, dl-(C~_3-alkyl)-amino, N-[di-(C~_3-alkyl)-amino-C2_3-alkyl]-N-(C~_3-alkyl)-amino or N-(C~_4-alkyloxy-carbonyl)-N-(C~_3-alkyl)-amino group, by a C~_3-alkyl-sulphonyl, 1-(C~_3-alky )-imidazol-2-yl or 4-(C~_3-alkyl)-piperazin-1-yl-carbonyl group or by a group of formula Ra -N
~ R~
wherein R' denotes a C1_3-alkyl, C~_3-al kyl-carbonyl, C~_3-alkyl-sulphonyl or benzylsulphonyl group and R8 denotes a C~_3-alkyl, w-[di-(~~_3-alkyl)-amino]-C2_3-alkyl, c~-[di-(C~_3-alkyl)-amino]-C~_3-alkyl-c~~rbonyl, di-(C~_3-alkyl)-amino-carbonyl-C~_3-alkyl, w-[4-(C~_3-~~Ikyl)-piperazin-1-yl]-C~_3-alkyl-carbonyl or ~-{N-[di-(C~_3-alkyl-amino-C2_3-alkyl]-N-(C~_3-alkyl)-amino}-C~_3-alkyl-carbonyl group, R5 denotes a hydrogen atom and R6 denotes a hydrogen atom, while the term heteroaryl group denotes a pyridinyl, furyl or thienyl group, while unsubstituted or monosubstituted phe iyl groups contained in the abovementioned definitions may additionall~~ be substituted by a methoxy group, the abovementioned alkyl groups include straight-chain and branched alkyl groups, wherein additionally one to 3 hydro<len atoms may be replaced by fluorine atoms, and any carboxy, amino or imino group present inay be substituted by a group which can be cleaved in vivo, the tautomers, enantiomers, diastereomers, mixtures thereof and the salts thereof.
A fourth sub-group of compounds of gener~il formula I deserving particular mention comprises those wherein X denotes an oxygen atom, R' denotes a hydrogen atom, R2 denotes a cyano group, R3 denotes a phenyl group optionally substis.uted by one or two methoxy groups, R4 denotes a phenyl group which is substituted in the 3- or 4-position by a bromine atom, by a C~_3-alkyl group terminally subst tuted by a pyrrolidin-1-yl, piperidin-1-yl, 4-(C~_3-alkyl)-piperazin~~1-yl-carbonyl, C~_3-alkylamino, di-(C~_3-alkyl)-amino, N-[di-(C~_3-alkyl)-a ~nino-C~_3-alkyl]-N-(C~_3-alkyl)-aminocarbonyl or N-(C~_4-alkyloxy-ca ~bonyl)-N-(C~_3-alkyl)-amino group, by a w-di-(C~_3-alkyl)-amino-C2_3-alko;cy, N-(di-(C~_3-alkyl)-amino-C2_3-alkyl)-amino-carbonyl, N-[di-(C~_3-alk~~l)-amino-C2_3-alkyl]-N-(C~_3-alkyl)-amino-carbonyl or 4-(C~_3-alkyl)-piperazin-1-yl-carbonyl group or by a group of formula Ra -N
~ R7 wherein R' denotes a hydrogen atom cr a C~_3-alkyl, C~_3-alkyl-carbonyl or C~_3-alkylsulphonyl group ar d R8 denotes a w-[di-(C~_3-alkyl)-amino]-(C2_3-alkyl), w-[di-(C~_3-alkyl)-amino]-C~_3-alkyl-carbonyl, w-(piperazin-1-yl)-C~_3-alkyl-carbonyl, w-[4-(C~_3-alkyl)-piperazin-1-yl]-C~_3-alkyl-carbonyl, w-[4-(C~~-alkyloxy-carbonyl)-pipE;razin-1-yl]-C,_3-alkyl-carbonyl, ~-[4-(C~_3-alkyl)-homopiperazin-1-yl]-C~_3-alkyl-carbonyl, w-morpholino-C~_3-alkyl-carbonyl or ~-{N-[di-(C~_3-alkyl)-amino-C~_3-alkyl]-N-(C~_3-alkyl)-amino[-C~_3-alkyl-carbonyl group, R5 denotes a hydrogen atom and R6 denotes a hydrogen atom, while the abovementioned alkyl groups incl~ide straight-chain and branched alkyl groups, wherein additionally one to 3 hydrogen atoms may be replaced by fluorine atoms, and additionally any carboxy, amino or imino group present may be substituted by a group which can be cleaved in vivo, their stereoisomers and their salts.
A fifth sub-group of compounds of general formula I deserving particular mention comprises those wherein X denotes an oxygen or sulphur atom, R' denotes a hydrogen atom, R2 denotes a chlorine atom, R3 denotes a phenyl group which is optionally monosubstituted in the 3- or 4-position by a chlorine or iodine atom, by a cyano, hydroxy, benzyloxy, amino or nitro group or by an aminomethyl, acetylamino, ~~henylcarbonylamino-C~_3-alkyl, C~_3-alkylsulphonylamino-C~_3-alkyl, phenylsulphonylamino-C~_3-alkyl, acetylaminomethyl, imidazol-1-yl-methyl, 2-oxo-pyrrolidin-1-yl, 2-carboxy-ethyl, 2-methoxycarbonyl-ethyl, 2-aminocarbonyl-ethyl, 2-(methylaminocarbonyl)-ethyl or 2-me:hoxycarbonyl-ethenyl group, or a 3-hydroxy-4-nitro-phenyl, 4-amino-3-nitrophenyl or 3,4-dimethoxyphenyl group, R4 denotes a 5-(4-methyl-piperazin-1-yl-carbonyl)-pyridin-2-yl, 2-[N-acetyl-N-(w-dimethylamino-C2_3-alkyl)-amino]-pyridim:-5-yl, benzo-pyrazol-6-yl, 1-methyl-2-(4-methyl-piperazin-1-yl-carbonyl)~~pyrrol-4-yl, 2-(N-dimethylamino-ethyl-N-methyl-aminocarbonyl)-pyrrol-4-yl, 1-methyl-2-(N-dimethylamino-ethyl-N-methyl-aminocarbonyl)-pyrrol-4-yl, 4-(N-dimethylamino-methylcarbonylamino)-cyclohexyl or 4-[(N-d methylamino-methylcarbonyl)-N-methyl-amino]cyclohexyl group or a phenyl group which is substituted in the 3-position by a carboxy, carboxy-C~_3-alkyl, C~~-alkoxy-carbonyl, C~_4-alkoxy-~:arbonyl-C~_3-alkyl, dimethylamino-C~_3-alkyl or pyridin-4-yl-C,_3-alkyl group or is substituted in the 4-position by a carboxy, w-[di-(C~_3-alkyl)-amino;-C2_3-alkoxy, ethoxycarbonyl, piperidin-1-yl-carbonyl, 4-(C»-alkylo~;y-carbonyl)-piperazin-1-yl-carbonyl, N-(C3_~-cycloalkyl)-N-(C~_3-a lkyl)-amino-carbonyl or N-[di-(C~_3-alkyl)-amino-C~_3-alkyl]-N-(C~_3-alkyl)-aminocarbonyl group, by a [di-(C~_3-alkyl)-amino]-C~_3-alkylsulphonyl group, by a C~_3-alkyl group terminally substituted by a carboxy, C~_4-alkyloxy-carbonyl, amino, C~_3-alkylamino, di-( ~~_3-alkyl)-amino, N-benzyl-N-(C~_3-alkyl)-amino, N-(2-hydroxyethyl)-N-(C~_3-alkyl)-amino, Di-(2-hydroxyethyl)-amino, triazolyl, N-(methoxyethoxyethyl)-N-(C~_3-alkyl)-amino, N-(amino-C~_3-alkyl)-N-(C~_3-a kyl)-amino, N-[di-(C~_3-alkyl)-amino-C~_3-alkyl]-N-(C~_3-alkyl)-amino, N-[di-(C~_3-alkyl)-amino-C~_3-alkyl]-N-(C~_3-alkyl)-amino-carbonyl, ~J-(C»-alkyloxy-carbonyl-amino-C~_3-alkyl)-N-(C~_3-alkyl)-amino, N-(C,_4-alkyloxy-carbonyl)-amino or N-(C~~-alkyloxy-carbonyl)-N-(C~_3-alkyl)-amino group, by a 1-methyl-imidazol-2-yl, 5-methyl-1H-imidazol-4-yl, 1-[di-(C~_3-alkyl)-amino-C~_3-alkyl]-imidazol-2-yl, 4-methyl-piperazin-1-yl, piperazinylcarbonyl or 4-methyl-piperazin-1-yl-carbonyl group or by a group of formula -N
~ R~
wherein R7 denotes a hydrogen atom or a C~_3-alkyl, C~_3-alkyl-carbonyl, di-(C~_3-alkyl)-amino-carbonyl-~~~_3-alkyl, benzylcarbonyl, pyridinylcarbonyl, furanylcarbonyl, methoxymethylcarbonyl, C~_4-alkylsulphonyl or benzylsulphonyl group or a phenylcarbonyl group optionally substituted in the phenyl moiety by one or two methoxy groups and R8 denotes a C~_3-alkyl, w-[di-(~~_3-alkyl)-amino]-C2_3-alkyl, w-[N-benzyl-N-(C~_3-alkyl)-amino]-C;>_3-alkyl, N-[di-(C~_3-alkyl)-amino-C~_3-alkyl]-amino-carbonyl, (py-idinyl-C~_3-alkyl)-amino-carbonyl, 1-(C~_3-alkyl)-piperidin-4-yl-am no-carbonyl-,1-(C~_3-alkyl)-piperidin-4-yl-oxy-carbonyl, 4-(C~_3-alkyl)-piperazin-1-yl-amino-carbonyl, 4-(C~_3-alkyl)-piperazin-1-yl-carbonyl or di-(C~_3-alkyl)-aminocarbonyl-C,_3-alkyl grouts or a C~_4-alkyl-carbonyl group terminally substituted by a hydroxy, amino, di-(C~_3-alkyl)-amino, N-benzyl-N-(C~_3-alkyl)-amino, di-(2-hydroxyethyl)-amino, acetylarr ino, N-[di-(C~_3-alkyl)-amino-C~_3-alkyl]-N-(C~_3-alkyl)-amino, imidazol-1-yl, piperazin-1-yl, 4-(C~_3-alkyl)-piperazin-1-yl, 4-benzyl-~iperazin-1-yl, 4-(C~~-alkyloxy-carbonyl)-piperazin-1-yl, 4-(C~.3-alkyl)-homopiperazin-1-yl, morpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl, 1-(C~_3-alkyl)-piperidin-4-yl or phthalimido group, R5 denotes a hydrogen atom and R6 denotes a hydrogen atom or a vitro grow ~, while the unsubstituted or monosubstituted phenyl groups mentioned in the above definitions may additionally be substituted by a methoxy or a cyano group or by two methyl groups, the abovementioned alkyl~groups including straight-chain and branched alkyl groups, wherein additionally one to 3 hydro~aen atoms may be replaced by fluorine atoms, and additionally any carboxy, amino or imin ~ group present may be substituted by a group which can be cleave~~ in vivo, the tautomers, enantiomers, diastereomers, mixtures thereof and the salts thereof.
Additional sub-groups of compounds of general formula I, of preferred, particularly preferred and most particularly ~~referred compounds of formula I
and the sub-groups thereof which deserve ~ pecial mention are those wherein X, R', R3, R4, R5 and R6 are each as hereinl~efore defined and R2 denotes fluorine.
Additional sub-groups of compounds of general formula I, of preferred, particularly preferred and most particularly ~~referred compounds of formula I
and the sub-groups thereof which deserve : pecial mention are those wherein X, R', R3, R4, R5 and R6 are each as hereinl~efore defined and R2 denotes chlorine.
Additional sub-groups of compounds of general formula I, of preferred, particularly preferred and most particularly ~~referred compounds of formula I
and the sub-groups thereof which deserve : pecial mention are those wherein X, R', R3, R4, R5 and R6 are each as hereinl~efore defined and RZ denotes bromine.
Additional sub-groups of compounds of general formula I, of preferred, particularly preferred and most particularly ~~referred compounds of formula I

and the sub-groups thereof which deserve ;special mention are those wherein X, R', R3, R4, R5 and R6 are each as herein Before defined and R2 denotes cyano.
The following compounds of general formul ~ I are particularly preferred:
(a) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-~nethylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone, (b) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone, (c) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-Nacetyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone, (d) 3-Z-[1-(4-(N-(4-ethyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone, (e) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-(3,4-dimethoxy-phenyl)-methylene]-6-chloro-2-in dolinone, (f) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-meihylcarbonyl)-N-methyl-amino)-anilino)-1-(3,4-dimethoxy-phenyl)-methylen~:]-6-chloro-2-indolinone, (g) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-bromo-2-indolinone, (h) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-bromo-2-indolinone, (i) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-cyano-2-indolinone, Q) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-meihylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-cyano-2-ind~~linone, (k) 3-Z-[1-(4-(N-(4-ethyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-cyano-2-indolinone, (I) 3-Z-[1-(4-(N-(dimethylamino-methylcarbcnyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone, (m) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone, (n) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone, (o) 3-Z-[1-(4-(dimethylaminomethyl)-anilino;-1-(3-fluoro-phenyl)-methylene]-6-fluoro-2-indolinone, (p) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-(3-fluoro-phenyl)-methylene]-6-fluoro-2-indolinone, (q) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-(3-fluoro-phenyl)-methylene]-6-fluoro-2-indolinone, (r) 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(4-(2-carbamoyl-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone, (s) 3-Z-[1-(4-(N-(piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone, (t) 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinone, (u) 3-Z-[1-(4-dimethylaminomethyl-anilino)-'I-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone, (v) 3-Z-[1-(4-dimethylaminomethyl-anilino)-' -(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone, (w) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-mEahylcarbonyl)-N-methyl-amino)-anilino)-1-(4-carboxymethyl-phenyl)-methylE;ne]-6-fluoro-2-indolinone, (x) 3-Z-[1-(4-dimethylaminomethyl-anilino)-' -(4-(2-methylcarbamoyl-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone, (y) 3-Z-[1-(4-dimethylaminomethyl-anilino)-' -(3-(2-carbamoyl-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone, (z) 3-Z-[1-(4-dimethylaminomethyl-anilino)-' -(3-(2-dimethylcarbamoyl-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone, (aa) 3-Z-(1-(4-(N-(2-dimethylamino-ethyl)-N ~methylsulphonyl-amino)-anilino)-1-(4-dimethylcarbamoylmethyl-phenyl)-metl~ylene]-6-fluoro-2-indolinone, (ab) 3-Z-[1-(4-(N-methyl-N-acetyl-amino)-ar~ilino)-1-(4-(2-methylcarbamoyl-ethyl)-phenyl)-methylene]-6-fluoro-2-indolin~me, (ac) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-(4-acetylamino-phenyl)-methylenE:]-6-chloro-2-indolinone, (ad) 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(4-acetylaminomethyl-phenyl)-methylene]-6-chloro-2-indolinone, (ae) 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(3-acetylaminomethyl-phenyl)-methylene]-6-fluoro-2-indolinone, (af) 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(3-benzoylaminomethyl-phenyl)-methylene]-6-fluoro-2-indolinone and (ag) 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(3-(2-acetylamino-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (ah) 3-Z-[1-(4-(N-(2-dimethylamino-ethylcar~onyl)-N-methyl-amino)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-fl uoro-2-indolinone, (ai) 3-Z-[1-(4-(pyrrolidin-1-yl-methyl)-anilino~-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone and (aj) 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinone (ak) 3-Z-[1-(4-diethylaminomethyl-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (al) 3-Z-[1-(4-(2-dimethylamino-ethyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinone (am) 3-Z-[1-(4-(pyrrolidin-1-yl-methyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinone (an) 3-Z-[1-(4-(pyrrolidin-1-yl-methyl)-aniline)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinone (ap) 3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinone (ao) 3-Z-[1-(4-(diethylaminomethyl)-anilino)~ 1-(4-(2-carboxy-ethyl)-methylene]-6-bromo-2-indolinone while additionally any carboxy, amino or imino group present may be substituted by a group which can be cleaved in vivo, and the salts thereof.
According to the invention the new compou ids may be obtained for example by the following methods known in principle from the literature:
a. reacting a compound of general formula L,~L
R' .
(V), wherein the groups Z' and R3 may optionally changE: positions, X, R2, R3 and R6 are as hereinbefore define, R'' has the meanings given for R' hereinbelore or denotes a protective group for the nitrogen atom of the lactam group, while R' may also denote a bond to a solid phase, optionally via a spacer, and Z' denotes a halogen atom, a hydroxy, alkoxy or aryl-alkoxy group, e.g. a chlorine or bromine atom, a methoxy, ethox,~ or benzyloxy group, with an amine of general formula Ra ~ N, Rs I
(V I ), wherein R4 and R5 are as hereinbefore defined, and if necessary subsequently cleaving any protective group used for the nitrogen atom of the lactam group or from a solid phase.
The protective group for the nitrogen atom c~f the lactam group may be for example an acetyl, benzoyl, ethoxycarbonyl, tert.butyloxycarbonyl or benzyloxycarbonyl group and the solid phase may be a resin such as a 4-(2',4'-dimethoxyphenylamino methyl)-phenoxy resin, while the bond is ccmveniently made via the amino group, or a p-benzyloxybenzylalcohol resin, while the bond is conveniently made via an intermediate member such as ~ 2,5-dimethoxy-4-hydroxy-benzyl derivative.
The reaction is expediently carried out in a :solvent such as dimethylformamide, toluene, acetonitrile, teirahydrofuran, dimethylsulphoxide, methylene chloride or mixtures thereof, optionally in the presence of an inert base such as triethylamine, N-ethyl-diisoprcpylamine or sodium hydrogen carbonate at temperatures between 20 and 175°C, while any protective group used may simultaneously be cleaved as a vault of transamidation.
If Z' in a compound of general formula V denotes a halogen atom, then the reaction is preferably carried out in the pres snce of an inert base at temperatures between 20 and 120°C.
If Z' in a compound of general formula V denotes a hydroxy, alkoxy or arylalkoxy group, then the reaction is prefer,~bly carried out at temperatures between 20 and 200°C.
Any protective group used is optionally sub;;equently conveniently cleaved either by hydrolysis in an aqueous or alcoholic solvent, e.g. in methanollwater, ethanollwater, isopropanollwater, tetrahydrc~furanlwater, dioxanelwater, dimethylformamidelwater, methanol or etha Col in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide at temperatures between 0 and 100°C, preferably at temperatures between 10 and 50°C, or advantageously by transamidation with an organic base such as ammonia, butylamine, dimethylamine or piperidine in ~~ solvent such as methanol, ethanol, dimethylformamide and mixtures thereof or in an excess of the amine used at temperatures between 0 and 100°C , preferably at temperatures between 10 and 50°C.
The cleaving of any solid phase used is preferably carried out using trifluoroacetic acid and water at temperaturEa between 0 and 35°C, preferably at ambient temperature.
b. In order to prepare a compound of general formula I wherein R4 contains the group R8, where R8 denotes a C~_4-alkyl-carbonyl group terminally substituted by a hydroxy, C~_3-alkyoxyl group, amino, (C~_3-alkyl)-amino, di-(C~_3-alkyl)-amino, (~-hydroxy~C2_3-alkyl)-amino, di-(~-hydroxy-C2_3-alkyl)-amino, (w-alkoxy-C;._3-alkyl)-amino, di-(~-alkoxy-C2_3-alkyl)-amino, C~_3-alkyl-carbonyl-amino, N-benzyl-N-C~_3-alkyl-amino, N-[di-(C~_3-alkyl)-aminc-C~_3-alkyl]-N-C~_3-alkyl-amino, 1-(C~_3-alkyl)-piperidin-4-yl- grow p or by a 5- to 7-membered cycloalkyleneimino group, while the cycloalkylene group may be substituted by a C~_3-alkyl group andlor one or two methylene groups linked to the imino group may be replaced by a carbonyl group andlor the methylene group in the 4 position of a 6- or 7-membered cycloalkylimino group may be replaced by a -NH, -N(C~_3-alkyl), -N(benzyl), -N(C~~-alkcxy-carbonyl) or-O- andlor a phenyl ring may be f~ sed on via two adjacent carbon atoms of the cycloalkylf:neimino group:
reacting a compound of general formula n \) R
N
\Rs R6 ~X
N

R~' (VII), wherein R2, R3, R5, R6, R' and X are as hereinbeforE: defined, R'' has the meanings given for R~ hereinbevore or denotes a protective group for the nitrogen atom of the lactam group, w hile R'' may also denote a bond to a solid phase optionally formed via a space', n denotes the number 1, 2, 3 or 4 and Z2 denotes a leaving group, for example a h alogen atom or an alkyl or arylsulphonyloxy group such as the chlorinE , bromine or iodine atom or the methylsulphonyloxy, ethylsulphonyloxy, p-tc~luenesulphonyloxy, or trifluoromethanesulphonyloxy group, with a hydroxide base such as sodium or potassium hydroxide or a compound of general formula H- R$' iVlll), wherein Ra~ denotes a C~_3-alkyloxy, amino, (C~_3-alkyl)-amino, dl-(C~_3-alkyl)-amino, (w-hydroxy-C2_3-;~Ikyl)-amino, di-(w-hydroxy-C2_3-alkyl)-amino, (c~-alkoxy-C2_3-al <yl)-amino, di-(w-alkoxy-Cz_3-alkyl)-amino, C~_3-alkyl-carbonyl-amino, N-benzyl-N-C~_3-alkyl-amino, N-[di-(C~_3-alkyl)-amine-C1_3-alkyl]-N-C~_3-alkyl-amino or a 5- to 7-membered cycloalkylerieimino group, while the cycloalkylene group may be substituted by a C~_3-alkyl group andlor one or two methylene groups linked to the imino group may be replaced by a carbonyl group andlor the methylene group in the 4 position of a 6- or 7-membered cycloalkylimino group may be replaced by a -NH, -N(C~_3-alkyl), -N(I~enzyl), -N(C~~-alkoxy-carbonyl) or -O- andlor a phenyl ring may be fused on via two adjacent carbon atoms of the cycloalkylE~neimino group, and if necessary subsequently cleaving any protective group used for the nitrogen atom of the lactam group or from a solid phase.
The reaction is expediently carried out in a :solvent such as methylene chloride, tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, dimethylsulphoxide, dimethylformamide, dir~ethylacetamide, N-methylpyrrolidone or mixtures thereof, optionally with the addition of water as cosolvent andlor with the addition of an inert auxiliary base, for example sodium hydrogen carbonate, pyridine, 2,4,6-trimethylpyridin, quinoline, triethylamine, N-ethyldiisopropylamine, N-ethyl-dicyclohexylamine, 1,4-diaza-bicyclo[2,2,2]octane or 1,8-diazabicyclo[5,4 0]undec-7-ene, at temperatures befiNeen -50°C and +100°C, preferably befiveen -10°C and +50°C, , while any protective group used may simultaneously I~e cleaved as a result of transamidation.
If it is necessary to cleave a protective group used for the nitrogen atom of the lactam group or to cleave from a solid phas ~ the same method is used as described under (a) above.
c. In order to prepare a compound of genen~l formula I wherein R3 denotes a phenyl or naphthyl group substituted by a c,~rboxy-C2_3-alkenyl, amino-carbonyl-C2_3-alkenyl, (C~_3-alkylamino)-cark~onyl-C2_3-alkenyl, di-(C~_3-alkyl-amino)-carbonyl-C2_3-alkenyl or C»-alkoxy-carbonyl-C2_3-alkenyl group, reacting a compound of general formula Ra N

\

Rs ~ -X

N
R~.
(IX), wherein R2, R4, R5, R6 and X are as hereinbefore defined, R'' has the meanings given for R' hereinbelore or denotes a protective group for the nitrogen atom of the lactam group, while R'' may also denote a bond to a solid phase optionally formed via a spacer, and Z3 denotes a leaving group, for example a halogen atom or an alkyl or arylsulphonyloxy group such as the chlorine, bromine or iodine atom or the methylsulphonyloxy, ethylsulphonyloxy, p-tc luenesulphonyloxy or trifluoromethanesulphonyloxy group, with an alkene of general formula (X), wherein R3' denotes an amino, (C~_3-alkylamino), di-(C~_3-alkylamino) or C~~.-alkoxy-group and n is the number 0 or 1.
The reaction is conveniently carried out under palladium catalysis, for example with palladium(II)-acetate, palladium(Il)-chloride, bis-(triphenylphosphine)-palladium(II)-acetate, I~is-(triphenylphosphine)-palladium(II)-chloride, palladiumlactivated charcoal, bis-[1,2-bis-(diphenylphosphino)-ethane]-palladium(0), ~iichloro-(1,2-bis-(diphenylphosphino)-ethane)-palladium(II), letrakistriphenylphosphine-palladium(0), tris-(dibenzylideneacetone)-di~alladium(0), 1,1'-bis-(diphenylphosphino)-ferrocene-dichloro-palladium(II) or tris-(dibenzylideneacetone)-dipalladium(0)-chloroform adduct in the presence of a base such as triethylamine, diisopropyl-ethylamine, lithium carbonate, potassium carbonate, sodium carbonate, c~ esium carbonate and a ligand such as triphenylphosphine, tri-ortho-tolyl-pl~osphine or tri-(tert.butyl)-phasphine in solvents such as acetonitrile, IJ-methyl-pyrrolidinone, dioxane or dimethylformamide and mixtures thereof.
If it is necessary to cleave a protective grou ~ used for the nitrogen atom of the lactam group or to cleave from a solid phase the same method is used as described under (a) above.
d. In order to prepare a compound of gener,~l formula I wherein R3 denotes a phenyl or naphthyl group substituted by carboxy-C~_3-alkyl, C~~,-alkoxy-carbonyl-C~_3-alkyl, aminocarbonyl-C~_3-alkyl, (C~_3-alkylamino)-carbonyl-C~_3-alkyl, di-(C~_3-alkyl)-amino-carbonyl-C~_3-alkyl or 4-(C~_3-alkyl)-piperazin-1-yl-carbonyl-(C~_3-alkyl) groups, hydrogenating a compound of general form.ala Rs~ O
A, r~
Ra N

\

\

Rs ~ =X

N
R'~ (XI), wherein R2, R4, R5, Rs and X are as hereinbefore defined, R'' has the meanings given for R' hereinbei~ore or denotes a protective group for the nitrogen atom of the lactam group, while R~' may also denote a bond to a solid phase optionally formed via a spacer, A denotes a C2_3-alkenyl group and R3~ denotes a hydroxy, C~_4-alkoxy, amino, (C~_3-alkylamino), di-(C~_3-alkyl)-amino or 4-(C~_3-alkyl)-piperazin-1-yl group.
The hydrogenation is preferably carried out by catalytic hydrogenation with hydrogen in the presence of a catalyst such as palladiumlcharcoal or platinum in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic. acid optionally with the addition of an acid such as hydrochloric acid at tem~~eratures between 0 and 50°C, but preferably at ambient temperature, and and sr a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
If it is necessary to cleave a protective grou ~ used for the nitrogen atom of the lactam group or to cleave from a solid phase: the same method is used as described under (a) above.

If according to the invention a compound of general formula I is obtained which contains an alkoxycarbonyl group, this may be converted by hydrolysis into a corresponding carboxy compound, on if a compound of general formula I is obtained which contains an amino or alkylamino group, this may be converted by reductive alkylation into a corresponding alkylamino or dialkylamino compound, or if a compound of general formula f is obtained which contains a dialkylamino group, this may be converted by alkylation into a corresponding trialkylammonium compound, or if a compound of general formula l is obtained which contains an amino or alkylamino group, this may be converted by acylation or sulphonation into a corresponding acyl or sulphonyl compound, or if a compound of general formula I is obtain ~d which contains a carboxy group, this may be converted by esterificatic>n or amidation into a corresponding ester or aminocarbonyl com~~ound, or if a compound of general formula I is obtain sd which contains a cyclo-alkyleneimino group in which a methylene group is replaced by a sulphur atom, this may be converted by oxidation into a corresponding sulphinyl or sulphonyl compound, or if a compound of general formula 1 is obtained which contains a nitro group, this may be converted by reduction into a corresponding amino compound, or if a compound of general formula I is obtained which contains a cyano group, this may be converted by reduction into a corresponding aminomethyl compound, or if a compound of general formula I is obtained which contains an arylalkyloxy group, this may be converted with acid into a corresponding hydroxy compound, or if a compound of general formula I is obtained which contains an alkoxycarbonyl group, this may be converted by saponification into a corresponding carboxy compound, or if a compound of general formula I is obtained wherein R4 denotes a phenyl group substituted by an amino, alkylamino, aminoalkyl or N-alkyl-amino group, this may be converted by reacting with a corresponding cyanate, iso-cyanate or carbamoyl halide into a corresponding urea compound of general formula I or if a compound of general formula I is obtain ed which contains a carbonyl group, this may be converted by reacting with phosphorus pentasulphide into a corresponding thiocarbonyl compound, or if a compound of general formula I is obtain ~d wherein Ra denotes a phenyl group substituted by an amino, alkylamino, aminoalkyl or N-alkyl-amino group, this may subsequently be converted by reacting with a corresponding compound which transfers the amidino grog p or by reacting with a corresponding nitrite into a corresponding g aanidino compound of general formula I.
The subsequent hydrolysis is preferably carried out in an aqueous solvent, e.g. in water, methanollwater, ethanol/waten, isopropanollwater, tetrahydrofuranlwater or dioxane/water, in tl~e presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulk huric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide at temperatures between 0 and 100°C, preferably at temperatures between 10 and 50°C.

The subsequent reductive alkylation is prefE;rably carried out in a suitable solvent such as methanol, methanol/water, methanollwaterlammonia, ethanol, ether, tetrahydrofuran, dioxane or dimethylf ~rmamide, optionally with the addition of an acid such as hydrochloric acid in the presence of catalytically activated hydrogen, e.g. hydrogen in the pr~;sence of Raney nickel, platinum or palladiumlcharcoal, or in the presence of a metal hydride such as sodium borohydride, lithium borohydride, sodium cyanoborohydride or lithium aluminium hydride at temperatures between 0 and 100°C, preferably at temperatures between 20 and 80°C.
The subsequent alkylation is preferably carried out in a suitable solvent such as ether, tetrahydrofuran, dioxane, dichloroinethane, acetone or acetonitrile in the presence of alkylating agents such as a kyl iodides, alkyl bromides, alkyl chlorides, alkyl-methanesulphonic acid esters, alkyl-para-toluenesulphonic acid esters or alkyl trifluoroacetates, at temkreratures between 0 and 100°C, preferably at temperatures between 20 and 60°C.
The subsequent acylation or sulphonylation is conveniently carried out with the corresponding free acid or a correspond ing reactive compound such as the anhydride, ester, imidazolide or halide thereof, preferably in a solvent such as methylene chloride, diethyl ether, tE;trahydrofuran, toluene, dioxane, acetonitrile, dimethylsulphoxide or dimethyliormamide, optionally in the presence of an inorganic or a tertiary organic base at temperatures between -20 and 200°C, preferably at temperatures k~etween 20°C and the boiling temperature of the solvent used. The reacticm with the free acid may optionally take place in the presence of an acid-activating agent or a dehydrating agent, e.g. in the presence of i: obutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2,2-~limethoxypropane, tetramethoxysilane, thionyl chloride, trimeth ylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimidelN-hydroxysu ~cinimide, N,N'-dicyclohexylcarbodiimidel1-hydroxy-benzotriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroboratE:/1-hydroxy-benzotriazole, N,N'-carbonyldiimidazole or triphenylphospl~inelcarbon tetrachloride, and optionally with the addition of a base such as pyridine, 4-dimethylamino-pyridine, N-methyl-morpholine or triethylamine, conveniently at temperatures between 0 and 150°C, preferably at temperatures between 0 and 100°C. The reaction with a corresponding reactive compound may optionally take place in the presence of a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine, N-methyl-morpholine or ~ yridine or using an anhydride in the presence of the corresponding acid at tE;mperatures befinreen 0 and 150°C, preferably at temperatures between 50 and 100°C.
The subsequent esterification or amidation s conveniently carried out by reacting a corresponding reactive carboxylic: acid derivative with a corresponding alcohol or amine as hereinbE:fore described.
The esterification or amidation is preferably carried out in a solvent such as methylene chloride, diethyl ether, tetrahydrc~furan, toluene, dioxane, acetonitrile, dimethylsulphoxide or dimethyliormamide, optionally in the presence of an inorganic or a tertiary organic base, preferably at temperatures between 20°C and the boiling temperature of the solvent used. The reaction is carried out with a corresponding acid, prefE~rably in the presence of a dehydrating agent, e.g. in the presence of i:~obutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2,2-limethoxypropane, tetramethoxysilane, thionyl chloride, trimeth ylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimidelN-hydroxysu ;cinimide, N,N'-dicyclohexylcarbodiimidel1-hydroxy-benzotriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroboratc:l1-hydroxy-benzotriazole, N,N'-carbonyldiimidazole or triphenylphosphinelcarbon tetrachloride, and optionally with the addition of a base such as pyridine, 4-dimethylaminopyridine, N-methyl-morpholine or triethylamine, conveniently at temperatures between 0 and 150°C, prefi~rably at temperatures between 0 and 100°C, and the acylation with a corresponding reactive compound such as the anhydride, ester, imidazolide or halide thereof may optionally be carried out in the presence of a tertiary orgy nic base such as triethylamine, N-ethyl-diisopropylamine or N-methyl-morpholine at temperatures between 0 and 150°C, preferably at temperatures betv~ een 50 and 100°C.
The subsequent oxidation of the sulphur atom is preferably carried out in a solvent or mixture of solvents, e.g. in water, waterlpyridine, acetone, methylene chloride, acetic acid, acetic acidl~cetic anhydride, dilute sulphuric acid or trifluoroacetic acid, conveniently at t~:mperatures between -80 and 100°C, depending on the oxidising agent used.
In order to prepare a corresponding sulphiny~l compound of general formula I
the oxidation is conveniently carried out with one equivalent of the oxidising agent used, e.g. with hydrogen peroxide in ~~lacial acetic acid, trifluoroacetic acid or formic acid at 0 to 20°C or in aceton~: at 0 to 60°C, with a peracid such as performic acid in glacial acetic acid or trilluoroacetic acid at 0 to 50°C or with m-chloroperbenzoic acid in methylene ~:hloride, chloroform or dioxane at -20 to 80°C, with sodium metaperiodate in ~ queous methanol or ethanol at -15 to 25°C, with bromine in glacial acetic a~~id or aqueous acetic acid optionally in the presence of a weak base such as sodium acetate, with N-bromosuccinimide in ethanol, with tert.buv:ylhypochlorite in methanol at -80 to -30°C, with iodobenzodichloride in aqueous pyridine at 0 to 50°C, with nitric acid in glacial acetic acid at 0 to 20°C, with ~:hromic acid in glacial acetic acid or in acetone at 0 to 20°C and with sulphurylchloride in methylene chloride at -70°C, and the thioether-chlorine complex thus obtained is conveniently hydrolysed with aqueous ethanol.
In order to prepare a sulphonyl compound cf general formula I oxidation is carried out starting from a corresponding sulphinyl compound, conveniently with one or more equivalents of the oxidisirn~ agent used, or starting from a corresponding mercapto compound, conveniently with two or more equivalents of the oxidising agent used, e.g with hydrogen peroxide in glacial acetic acidlacetic anhydride, trifluoroacetic ~~cid or in formic acid at 20 to 100°C or in acetone at 0 to 60°C, with a peracid such as performic acid or m-chloroperbenzoic acid in glacial acetic acid, trifluoroacetic acid, methylene ~o chloride or chloroform at temperatures between 0 and 60°C, with nitric acid in glacial acetic acid at 0 to 20°C, with chromic; acid, sodium periodate or potassium permanganate in acetic acid, wa:erlsulphuric acid or in acetone at 0 to 20°C.
The subsequent reduction of a nitro group i:> preferably carried out by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladiumlcharcoal or Raney nickel in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylfermamidelacetone or glacial acetic acid, optionally with the addition of ari acid such as hydrochloric acid or glacial acetic acid at temperatures between 0 and 50°C, but preferably at ambient temperature, and under a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar.
The subsequent hydrogenation of a cyano group is preferably carried out by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladiumlcharcoal or Raney nickel in a solvent such as methanol, ethanol, ethyl acetate, methylene chloride, dimethylfixmamide, dimethylformamidelacetone or glacial acetic. acid, optionally with the addition of an acid such as hydrochloric acid or glacial acetic acid at temperatures between 0 and 50°C, but preferably at ambient temperature, and under a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
Expediently, a corresponding urea compound of general formula I is subsequently prepared with an inorganic c~~anate or a corresponding isocyanate or carbamoylchloride, preferably in a solvent such as dimethylformamide and optionally in the presence of a tertiary organic base such as triethylamine at temperatures betwE:en 0 and 50°C, preferably at ambient temperature.
Expediently, a corresponding thiocarbonyl compound of general formula I is subsequently prepared with phosphorus peotasulphide or (p-methoxy-phenyl)-thionophosphine-sulphide dimer (Lawesson's reagent) preferably in a solvent such as pyridine or toluene at temp~;ratures between 80 and 120°C, preferably at 120°C.
Expediently, a corresponding guanidino coripound of general formula I is subsequently prepared by reacting with a compound which transfers the amidino group, such as 3,5-dimethylpyrazole-1-carboxylic acid amidine, preferably in a solvent such as dimethylforniamide and optionally in the presence of a tertiary organic base such as triethylamine at temperatures between 0 and 50°C, preferably at ambient temperature In the reactions described hereinbefore, any reactive groups present such as carboxy, hydroxy, amino, alkylamino or imiro groups may be protected during the reaction by conventional protecting grog ps which are cleaved again after the reaction.
For example, a protecting group for a carboKy group may be a trimethylsilyl, methyl, ethyl, tert.butyl, benzyl ortetrahydrcpyranyl group and protecting groups for a hydroxy, amino, alkylamino or imino group may be an acetyl, trifluoroacetyl, benzoyl, ethoxycarbooyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for the amino group, a phthalyl group.
Any protecting group used is optionally sub;~equently cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanollwater, tetrahydrofuranlwater or dioxan/water, in thE: presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulG huric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide at temperatures between 0 and 100°C, preferably at temperatures between 10 and 50°C.
However, a benzyl, methoxybenzyl or benz!~loxycarbonyl group is cleaved, for example, hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladiumlcharcoal in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamidelacetone or glacial acetic acid, optionally with the addition of an acid such ~~s hydrochloric acid or glacial acetic acid at temperatures between 0 and 50°C, but preferably at ambient temperature, and at a hydrogen pressure o,~ 1 to 7 bar, but preferably 3 to 5 ba r.
A methoxybenzyl group may also be cleaved in the presence of an oxidising agent such as cerium(IV)ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrilelwater at temperatures of between 0 and 50°C, but preferably at ambient temperaturE:.
A 2,4-dimethoxybenzyl group, however, is f~referably cleaved in trifluoroacetic acid in the presence of anisol.
A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxan. ethyl acetate or ether.
A phthalyl group is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethyla mine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, tol«ene/water or dioxan at temperatures between 20 and 50°C.
Moreover, chiral compounds of general formula I obtained may be resolved into their enantiomers andlor diastereomers.
Thus, for example, the compounds of general formula I obtained which occur as racemates may be separated by method ~ known per se (cf. Allinger N. L.
and Eliel E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971 ) into their optical antipodes and compounds of general formula I with at least asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g.
by chromatography andlor fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.
The enantiomers are preferably separated key column separation on chiral phases or by recrystallisation from an optic~~lly active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g.
esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, an ~ separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents.
Optically active acids in common use are e. ~. the D- and l_-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, N-acetylglutamic acid, aspartic acid, N-acetylaspartic acid or quinic acid. An optically active alcohol may be for example (+) or (-)-menthol and an optically ;active acyl group in amides, for example, may be a (+)-or (-)-menthyloxycaroonyl group.
Furthermore, the compounds of formula I ot~tained may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic a~;ids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, malefic acid, methanesul~honic acid, ethanesulphonic acid, para-toluenesulphonic acid, phenylsulphoni~; acid or L-(+)-mandelic acid.
Moreover, if the new compounds of formula I thus obtained contain a carboxy group, they may subsequently, if desired, bc; converted into the salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable salts thereof. Suitable bases for this purpose include for example sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanc~lamine.

For compounds of general formula I which contain 2 or more acidic or basic groups, salts with 2 or more inorganic or organic bases or acids may also be used (so-called disalts etc.).
The compounds of general formulae V to XI used as starting products are known from the literature in some cases or nay be obtained by methods known from the literature or may be obtained by methods described hereinbefore and in the Examples. For example, the compounds of general formula IX are described in German Patent Application 198 44 003.
As already mentioned hereinbefore, the nevi compounds of general formula I
have valuable pharmacological properties, I>articularly an inhibiting effect on various kinases, especially receptor tyrosinc: kinases such as VEGFR1, VEGFR2, VEGFR3, PDGFRa, PDGFR(3, Fc~FR1, FGFR3, EGFR, HER2, c-Kit, IGF1 R and HGFR, Flt-3, as well as on t ie proliferation of cultivated human cells, particularly endothelial cells, e.g. in angiogenesis, but also on the proliferation of other cells, particularly t~imour cells.
The biological properties of the new compounds were tested by the following standard method as described:
Human umbilical endothelial cells (HUVEC) were cultivated in IMDM (Gibco BRL), supplemented with 10 % foetal calf scrum (FBS) (Sigma), 50 pM of f3-mercaptoethanol (Fluka), standard antibiotics, 15 Nglml of endothelial cell growth factor (ECGS, Collaborative Biomedical Products) and 100 Nglml of heparin (Sigma) on gelatine-coated culture dishes (0.2 % gelatine, Sigma) at 37°C, under 5 % C02 in a water-saturated ~~tmosphere.

~s In order to investigate the inhibitory activity ~f the compounds according to the invention the cells were "starved" for 16 hours, i.e. kept in culture medium without growth factors (ECGS + heparin). Tne cells were detached from the culture dishes using trypsin/EDTA and washed once in serum-containing medium. Then they were seeded out in amounts of 2.5 x 103 cells per well.
The proliferation of the cells was stimulated with 5 nglml of VEGF165 (vas-cular endothelial growth factor; H. Weich, GBF Braunschweig) and 10 Nglml of heparin. As a control, 6 wells in each dish were not stimulated.
The compounds according to the invention ~nrere dissolved in 100%
dimethylsulphoxide and added to the culturE;s in various dilutions as triple measurements, the maximum dimethylsulptioxide concentration being 0.3 %.
The cells were incubated for 76 hours at 37'C, then for a further 16 hours 3H-thymidine (0.1 p Cilwell, Amersham) was added in order to determine the DNA synthesis. Then the radioactively labelled cells were immobilised on filter mats and the radioactivity incorporated was measured in a (3-counter. In order to determine the inhibitory activity of the cornpounds according to the invention the mean value of the non-stimulated cells was subtracted from the mean value of the factor-stimulated cells (in the presence or absence of the compounds according to the invention).
The relative cell proliferation was calculated as a percentage of the control (HUVEC without inhibitor) and the concentr,~tion of active substance which inhibits the proliferation of the cells by 50 % (ICSp) was determined.
The compounds of general formula I according to the invention have an ICSo of between 50 NM and 1 nM.
In view of their inhibitory effect on the prolifE:ration of cells, particularly endothelial and tumour cells, the compounds of general formula I are suitable for treating diseases in which the proliferation of cells, particularly endothelial cells, plays a part.
Thus, for example, the proliferation of endo~:helial cells and the concomitant neovascularisation constitute a crucial stag: in tumour progression (Folkman J. et al., Nature 339, 58-61, (1989); Hanah~ n D. and Folkman J., Cell 86, 353-365, (1996)). Furthermore, the proliferation of endothelial cells is also important in haemangiomas, in metastasisation, rheumatoid arthritis, psoriasis and ocular neovascularisation (Folkman J., Nature Med. 1, 27-31, (1995)).
The therapeutic usefulness of inhibitors of a ndothelial cell proliferation was demonstrated in the animal model for example by O'Reilly et al. and Parangi et al. (O'Reilly M.S. et al., Cell 88, 277-285, (1997); Parangi S. et al., Proc Natl Acad Sci USA 93, 2002-2007, (1996)).
The compounds of general formula I, their t;~utomers, their stereoisomers or the physiologically acceptable salts thereof are thus suitable, for example, for treating tumours (e.g. plate epithelial carcir oma, astrocytoma, Kaposi's sarcoma, glioblastoma, lung cancer, bladder cancer, head and neck carcinoma, oesophageal cancer, melanoma ovarian cancer, prostate cancer, breast cancer, small-cell lung cancer, gliom ~, colorectal cancer, pancreatic cancer, urogenital cancer and gastrointestiral cancer as well as haematological cancers such as e.g. multiple myeloma and acute myeloid leukaemia), psoriasis, arthritis (e.g. rheuma~:oid arthritis), haemangioma, angiofibroma, eye diseases (e.g. diabetic retinopathy), neovascular glaucoma, kidney diseases (e.g. glomerulonephritis), diabetic nephropathy, malignant nephrosclerosis, thrombic microangiopathic syndrome, transplant rejections and glomerulopathy, fibrotic diseases (e.g. ~;irrhosis of the liver), mesangial cell proliferative diseases, arteriosclerosis, damage to the nerve tissue and for inhibiting the reocclusion of blood vessels after treatment with a balloon catheter, in vascular prosthetics or after the fitting of mechanical devices for holding the blood vessels open (e.g. stents), or other diseases in which cell proliferation or angiogenesis are involved.

By reason of their biological properties the ~;ompounds according to the invention may be used on their own or in cc njunction with other pharmacologically active compounds, for e>:ample in tumour therapy, in monotherapy or in conjunction with other anti-tumour therapeutic agents, for example in combination with topoisomeras~ inhibitors (e.g. etoposide), mitosis inhibitors (e.g. vinblastin, taxol), compounds which interact with nucleic acids (e.g. cisplatin, cyclophosphamide, adi iamycin), hormone antagonists (e.g. tamoxifen), steroids and their analogu~;s (e.g. dexamethasone), inhibitors of metabolic processes (e.g. 5-FU etc.), cytokines (e.g.
interferons), kinase inhibitors (e.g. EGFR kinase inhibito's such as e.g. Iressa; Gleevec), receptor tyrosine kinase inhibitors with an a losteric effect, antibodies (e.g.
herceptin), COX-2 inhibitors, or in conjunction with radiotherapy, etc. These combinations may be administered either simultaneously or sequentially.

The Examples that follow are intended to ill astrate the invention more fully:
Example ~~ame 3-Z-[1-(4-(N-(2-dimethylaminc-ethyl)-N-methylsuiphonyl-amino)-1.0 anilino)-1-phenyl-methvlene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(dimethylamino-metr~ylcarbonyl)-N-methyl-amino)-anilino)-1.1 1-phenyl-methylens:]-6-chloro-2-indolinone 3-Z-[1-(4-ethoxycarbonyl-anilir o)-1-phenyl-methylene]-6-chloro-2-1.2 inc olinone 3-Z-[1-(4-(N-(dimethylamino-carl~onylmethyl)-N-methylsulphonyl-ami-1.3 no)-anilino)-1-phenyl-meihylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-Methyl-N-methylsulphonyl-amino)-anilino)-1-phenyl-1.4 methylene]-6-c:hloro-2-indolinone 3-Z-[1-(4-(N-Methyl-N-acetyl-arr ino)-anilino)-1-phenyl-methylene]-6-1.5 chloro-~'.-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-ethylsulphonyl-amino)-anilino)-1.6 1-phenyl-methylenc:]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-f~thyl)-N-propionyl-amino)-anifino)-1-1.7 phenyl-methylene:-6-chloro-2-indolinone 3-Z-[1-(4-(N-(3-dimethylamino~~ropyl)-N-methylsulphonyl-amino)-1.8 anilino)-1-phenyl-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino~ ~athyl)-N-butyryl-amino)-anilino)-1-1.9 phenyl-methylene'-6-chloro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-E thyl)-N-isobutyryl-amino)-anilino)-1-1.10 phenyl-methylene;~~-6-chloro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-etl- yl)-N-acetyl-amino)-anilino)-1-phenyl-1.11 methylene]-6-c;hloro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-benzoyl-amino)-anilino)-1-1.12 phenyl-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-et ~y1)-N-phenylacetyl-amino)-an ilino)-1-1.13 phenyl-methylene~-6-chloro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-Ethyl)-N-(pyrid-3-yl-carbonyl)-amino)-1.14 anilino)-1-phenyl-meth~rlene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-a thyl)-N-(furan-2-yl-carbonyl )-amino)-1.15 anilino)-1-phenyl-meth~rlene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-(2-methoxy-benzoyl)-amino)-1.16 anilino)-1-phenyl-methylene]-6-chloro-2-indofinone 3-Z-[1-(4-(N-(2-dimethylaminc~-ethyl)-N-propylsulphonyl-amino)-1.17 anilino)-1-phenyl-meths~lene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-isopropylsulphonyl-amino)-1.18 anilino)-1-phenyl-meth~~lene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylaminc-ethyl)-N-benzylsulphonyl-amino)-1.19 anilino)-1-phenyl-meth~~lene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(4-benzyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-1.20 anilino)-1-phenyl-meth~~lene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(morpholin-4-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1.21 1-phenyl-methylenE;]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(piperidin-1-yl-methyl carbonyl)-N-methyl-amino)-anilino)-1-1.22 phenyl-methylene:-6-chloro-2-indolinone 3-Z-[1-(4-(N-(benzylmethylamin~~-methylcarbonyl)-N-methyl-amino)-1.23 anilino)-1-phenyl-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(dimethylamino-meth yl)-anilino)-1-phenyl-methylene]-6-1.24 chloro-a'.-indolinone 3-Z-[1-(4-((2,6-dimethyl-piperi~iin-1-yl)-methyl)-anilino)-1-phenyl-1.25 methylene]-6-c:hloro-2-indolinone 3-Z-[1-(4-((N-(2-(2-methoxy-ethc ~xy)-ethyl)-N-methyl-amino)-methyl)-1.26 anilino)-1-phenyl-methy lene]-6-chloro-2-indolinone 3-Z-[1-(4-(triazol-1-yl-methyl)-ani lino)-1-phenyl-methylene]-6-chloro-2-1.27 indolinone 3-Z-[1-(4-(di-(2-hyd roxy-ethyl y-amino-methyl )-anilino)-1-phenyl-1.28 methylene]-6-c;hloro-2-indolinone 3-Z-[1-(4-(5-methyl-imidazol-4~ y1)-anilino)-1-phenyl-methylene]-6-1.29 chloro :'.-indolinone 3-Z-[1-(4-(N-tert.butoxycarbonyl-~ahylamino-methyl)-anilino)-1-phenyl-1.30 methylene]-6-c;hloro-2-indolinone 3-Z-[1-(4-(1-methyl-imidazol-2~ yl)-anilino)-1-phenyl-methylene]-6-1.31 chloro-:'.-indoiinone 3-Z-[1-(4-(morpholin-4-yl-methyl)-anilino)-1-phenyl-methylene]-6-1.32 chloro-:!-indolinone 3-Z-[1-(4-(N-benzyl-N-methyl-amino-methyl)-anilino)-1-phenyl-1.33 methylene]-6-c:hloro-2-indolinone 3-Z-[1-(4-(pyrrolidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-chloro-1.34 2-in~iolinone 3-Z-[1-(4-((4-methyl-piperazi i-1-yl)-methyl)-anilino~1-phenyl-1.35 methylene]-6-c;hloro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-butylsulphonyl-amino)-anilino)-1.36 1-phenyl-methylenc;]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methoxyacetyl-amino)-anilino)-1.37 1-phenyl-methylenc:]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino ethyl)-N-(3,4-dimethoxy-benzoyl)-1.38 amino)-anilino)-1-phenyl-m ethylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(2-hydroxy-ethyl)- ~-methyl-amino-methyl)-anilino)-1-1.39 phenyl-methylene:-6-chloro-2-indolinone 3-Z-[1-(4-(N-(2-benzylmethylamirio-ethyl)-N-propionyl-amino)-anilino)-1.40 1-phenyl-methylenc:]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-a thyl)-N-(pyrid-4-yl-carbonyl)-amino)-1.41 anilino)-1-phenyl-meth~~lene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(phthalimido-2-yl-methylcarbonyl)-N-methyl-amino)-1.42 anilino)-1-phenyl-meths~4ene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-tert.butoxycarbon yl-methylamino-methyl)-anilino)-1-1.43 phenyl-methylene: -6-chloro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-y1-methylcarbonyl)-N-methyl-amino)-1.44 anilino)-1-phenyl-meth~~lene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(di-(2-hydroxy-ethy I)-amino-methylcarbonyl)-N-methyl-1.45 amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(pyrrolidin-1-yl-meth ylcarbonyl)-N-methyl-amino)-anilino)-1.46 1-phenyl-methyfenf;]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(N-(2-dimethylamino-ethyl)-N-methyl-amino-1.47 methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-~'.-indolinone 3-Z-[1-(4-(N-(imidazol-1-yl-methyl carbonyl)-N-methyl-amino)-anilino)-1-1.48 phenyl-methylene:-6-chloro-2-indolinone 3-Z-[1-(4-(4-methyl-piperazin-1-yl-carbonyl)-anilino)-1-phenyl-1.49 methylene]-6-c;hloro-2-indolinone 3-Z-[1-(4-(N-(2-(4-tert.butoxycarb cnyl-piperazin-1-yl)-ethylcarbonyl)-N-1.50 methyl-amino)-anilino)-1-phen~~l-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(2-benzylmethylami no-ethyl)-N-acetyl-amino)-anil ino)-1-1.51 phenyl-methylene-6-chloro-2-indolinone 3-Z-[1-(4-((4-tert.butoxycarbom ~I-piperazin-1-yl)-methyl)-anil ino)-1-1.52 phenyl-methylene;-6-chloro-2-indolinone 3-Z-[1-(4-(N-(d imethylamino-m ethylcarbonyl)-N-methyl-amino)-3-1.53 methoxy-anilino)-1-phenyl-n~ethy4ene]-fi-chloro-2-indolinone 3-Z-[1-(3-(dimethylamino-methyl)-anilino)-1-phenyl-methylene]-6-1.54 chloro-~'.-indolinone 3-Z-[1-(3-(pyridin-4-yl-methyl)-an lino)-1-phenyl-methylene]-6-chloro-2-1.55 indolinone 3-Z-[1-(4-(4-methyl-piperazin-1-yl-carbonyl)-pyridin-2-yl-amino)-1-1.56 phenyl-methylene;'-6-chloro-2-indolinone 1.57 3-Z-[1-(Indazol-6-yl-amino)-1-phE:nyl-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-~ ethyl)-N-acetyl-amino)-(pyridin-3-yl-1.58 amino))-1-phenyl-meth~rlene]-6-chioro-2-indolinone trans-3-Z-[1-(4-(N-(dimethy amino-methylcarbonyl)-amino)-1.59 cyclohexylamino)-1-phenyl-rnethylene]-6-chloro-2-indolinone cis-3-Z-[1-(4-(N-(dimethylaminc~-methylcarbonyl)-N-methyl-amino)-1.60 cyclohexylamino)-1-phenyl-rnethylene]-6-chloro-2-indolinone 3-Z-[1-(4-(4-methyl-piperazin-'I-yl-carbonyl)-3-methyl-pyrrol-3-yl-1.61 amino)-1-phenyl-methy lene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(2-d imethylamino-a thyl)-N-methyl-carbamoyl)-3-methyl-1.62 pyrrol-3-yl-amino)-1-phenyl-rnethylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-1.63 phenyl-methylene:-6-chloro-2-indolinone 3-Z-[1-(4-(2-d iethylamino-et iyl-sulphonyl)-anilino)-1-phenyl-1.64 methylene]-6-c:hloro-2-indolinone 3-Z-[1-(4-(1-(2-dimethylamino-e1 hyl)-imidazol-2-yl)-anilino)-1-phenyl-1.65 methylene]-6-c:hloro-2-indolinone 3-Z-[1-(4-(piperidin-1-yl-carboy yl )-anil ino)-1-phenyl-methylene]-6-1.66 chloro-~'.-indolinone 3-Z-[1-(4-(4-tent. butoxycarbonyl-piperazin-1-yl-carbonyl )-anilino)-1-1.67 phenyl-methylene:-6-chloro-2-indolinone 3-Z-[1-(4-(N-cyclohexyl-N-me :hyl-carbamoyl)-anilino)-1-phenyl-1.68 methylene]-6-c:hloro-2-indolinone 3-Z-(1-(4-(N-(2-dimethylaminc~-ethyl-carbonyl)-N-methyl-amino)-1.69 anilino)-1-phenyl-methvleneJ-6-chloro-2-indolinone 3-Z-[1-(4-(N-(2-d imethylamino-et ~yl)-N-methyl-amino-methyl)-anilino)-1.70 1-phenyl-methylen~;]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(2-(4-methyl-piper ~zin-1-yl)-ethyl-carbonyl)-N-methyl-1.71 amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(2-d imethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-1.72 chloro-:!-indolinone 3-Z-(1-(4-((4-dimethylamino-pipE~ridin-1-yl)-methyl)-anilino)-1-phenyl-1.73 methylene]-6-c:hloro-2-indolinone 3-Z-[1-(3-methoxycarbonylmet iyl-anilino)-1-phenyl-methyleneJ-6-1.74 chloro-.!-indolinone 3-Z-[1-(3-methoxycarbonyl-anilii ~0)-1-phenyl-methylene]-6-chloro-2-1.75 ind ~linone 3-Z-[1-(4-(2-d imethylamino-etr yl)-anilino)-1-phenyl-methylene]-6-1.76 chloro ~!-indolinone 3-Z-[1-(4-(N-tert.butoxycarbon~ ~I-amino-methyl)-anilino)-1-phenyl-1.77 methyleneJ-6-c;hloro-2-indolinone 3-Z-[1-(4-(N-(dimethylamino-methylcarbonyl)-N-isopropyl-amino)-1.78 anilino)-1-phenyl-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(4-tert.butoxycarbor~yl-piperazin-1-yl-methylcarbonyl)-N-1.79 isopropyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(diethylamino-methyl)-anilino)-1-phenyl-methylene]-6-chloro-1.80 2-in~iolinone 3-Z-[1-(4-(N-propyl-N-methyl~~amino-methyl)-anilino)-1-phenyl-1.81 methylene]-6-c:hloro-2-indolinone 3-Z-[1-{4-(4-methyl-piperazin-1-yl)-anilino)-1-phenyl-methylene]-6-1.82 chloro-~'.-indolinone 3-Z-[1-(4-(N-(2-d imethylamino-a rhyl)-N-methyl-carbamoyl)-anilino)-1-1.83 phenyl-methyleney-6-chloro-2-indolinone 3-Z-[1-(4-(N-(4-tert.butoxycarbooyl-piperazin-1-yl-methylcarbonyl)-N-1.84 methyl-amino)-anilino)-1-phern~l-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(hyd roxy-methylca rbonyl )-N-methyl-amino)-anilino)-1-1.85 phenyl-methylene; -6-chloro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methyl-amino)-anilino)-1-1.86 phenyl-methylene: -6-chloro-2-indolinone 3-Z-[1-(4-(N-(N-(tert. butoxycarboi ~yl-3-amino-propyl)-N-methyl)-amino-1.87 methyl)-anilino)-1-phenyl-rrethylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-homopipe razin-1-yl-methylcarbonyl)-N-methyl-1.88 amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(dimethylamino-rr ethylcarbonyl)-N-methyl-amino)-3-1.89 cyano-anilino)-1-phenyl-m~;thylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(4-ethyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-1.90 anilino)-1-phenyl-meth~~lene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-( 1-methyl-piperidin-4-yl-methylcarbonyl)-N-methyl-amino)-1.91 anilino)-1-phenyl-meth~~lene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-amino)-anilino)-1.92 1-phenyl-methylenE~]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(3-dimethylamino-E~ropyl)-N-methyl-carbamoylmethyl)-1.93 anilino)-1-phenyl-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methyl-carbamoylmethyl)-1.94 anilino)-1-phenyl-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(4-methyl-piperazin-1-~~I-carbonylmethyl)-anilino)-1-phenyl-1.95 methylene]-6-<;hloro-2-indolinone 3-Z-[1-(4-(N-(4-dimethylamino-butyl-carbonyl)-N-methyl-amino)-1.96 anilino)-1-phenyl-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(dimethylamino-meahylcarbonyl)-N-methyl-amino)-2,3-1.97 dimethyl-anilino)-1-phenyl-roethylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperaz n-1-yl-methylcarbonyl)-amino)-2,3-1.98 dimethyl-anilino)-1-phenyl-n~ethylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-'I-yl-aminocarbonyl)-N-methyl-amino)-1.99 anilino)-1-phenyl-meth~~lene]-6-chloro-2-indolinone 3-Z-[1-(4-ethoxycarbonylmethyl-a nilino)-1-phenyl-methylene]-6-chloro-1.100 2-irnlolinone 3-Z-[1-(4-(N-( 1-methyl-piperidin-4 -yl-aminocarbonyl)-N-methyl-amino)-1.101 anilino)-1-phenyl-meth~~lene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(3-dimethylamino- propyl-carbonyl)-N-methyl-amino)-1.102 anilino)-1-phenyl-meth~~lene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-carbonyl)-N-methyl-amino)-1.103 anilino)-1-phenyl-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(N-(3-dimethylamin o-propyl)-aminocarbonyl)-N-methyl-1.104 amino)-anilino)-1-phenyl-m ethylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(pyrid in-4-yl-meths ~laminocarbonyl)-N-methyl-amino)-1.105 anilino)-1-phenyl-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(1-methyl-piperidir ~-4-oxy-carbonyl)-N-methyl-amino)-1.106 anilino)-1-phenyl-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-2.0 anilino)-1-phenyl-methylen ;]-6-chloro-5-nitro-2-indolinone 3-Z-[1-(4-(N-(dimethylamino-metl- ylcarbonyl)-N-methyl-amino)-anil ino)-2.1 1-phenyl-methylene]-6~~chloro-5-nitro-2-indolinone 3-Z-[1-(4-(dimethylamino-meth yl)-anilino)-1-phenyl-methylene]-6-2.2 chloro-5-nilro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-etl- yl )-N-acetyl-amino)-anilino)-1-phenyl-2.3 methylene]-6-chlo ~o-5-nitro-2-indolinone 3-Z-[1-(4-(N-(dimethyl-carbamc yl-methyl)-N-(2-pyrrolidin-1-yl-ethyl-3.0 carbonyl)-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(dimethyl-carbamc yl-methyl)-N-(pyrrolidin-1-yl-methyl-3.1 carbonyl)-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(dimethyl-carbamo~ rf-methyl)-N-(2-dimethylamino-ethyl-3.2 carbonyl)-amino)-anilinn)-1-phenyl-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(dimethyl-carba moyl-methyl)-N-(dimethylamino-3.3 methylcarbonyl)-amino)-anilin)-1-phenyl-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-methyl-N-methyl;.ulphonyl-amino)-anilino)-1-(3-iod-4.0 phenyl)-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(dimethylamino-methyl)-anilino)-1-(3-iod-phenyl)-methylene]-4.1 6-chloro~ 2-indolinone 3-Z-[1-(4-(N-(dimethylamino-metr ylcarbonyl)-N-methyl-amino)-anilino)-4.2 1-(4-chloro-phenyl)-meth~ylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-~;thyl)-N-acetyl-amino)-anilino)-1-(4-4.3 chloro-phenyl)-methyl:ne]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-4.4 anilino)-1-(4-chloro-phenyl)-rnethylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-(4-4.5 chloro-phenyl)-methyl:ne]-6-chloro-2-indolinone 3-Z-[1-(4-(dimethylamino-methyl)-anilino)-1-(4-chloro-phenyl)-4.6 methylene]-6-c:hloro-2-indolinone 3-Z-[1-(4-(dimethylamino-meth yl)-anilino)-1-(4-benzyloxy-phenyl)-4.7 methylene]-6-c:hloro-2-indolinone 3-Z-[1-(4-(N-(dimethylamino-meti- ylcarbonyl)-N-methyl-amino)-anilino)-4.8 1-(4-benzyloxy-phenyl)-mEahylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-4.9 anilino)-1-(4-benzyloxy-phenyl i-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-~ ethyl)-N-acetyl-amino)-anilino)-1-(4-4.10 benzyloxy-phenyl)-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-p ropyl)-N-acetyl-amino)-anilino)-1-(4-4.11 benzyloxy-phenyl)-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-a thyl)-N-acetyl-amino)-anilino)-1-(3,4-4.12 dimethoxy-phenyl)-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-4.13 anilino)-1-(3,4-dimethoxy-phenyl)-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-4.14 anilino)-1-(3,4-dimethoxy-phen~~l)-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(dimethylamino-methyl)-anilino)-1-(3,4-dimethoxy-phenyl)-4.15 methylene]-6-c:hloro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-e~:hyl)-N-methyl-carbamoyl)-anilino)-1-4.16 (3,4-dimethoxy-phenyl)-mcahylene]-6-chloro-2-indolinone 3-Z-[1-(4-(dimethylamino-methyl)-anilino)-1-(3-hydroxy-4-nitro-phenyl)-4.17 methylene]-6-c;hloro-2-indolinone 3-Z-[1-(4-(N-(dimethylamino-metr ylcarbonyl)-N-methyl-amino)-anilino)-5.0 1-(4-(imidazol-1-yl-methyl)-phen yl)-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-~;thyl )-N-acetyl-amino)-an ilino)-1-(4-5.1 (imidazol-1-yl-methyl)-phenyl)-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-5.2 anilino)-1-(4-(imidazol-1-yl-metiyl)-phenyl)-methylene]-6-chloro-2-ind ~linone 3-Z-[1-(4-(N-(3-d imethylamino-p ropyl)-N-acetyl-amino)-anilino)-1-(4-5.3 (imidazol-1-yl-methyl)-phenyl)-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(pyrrolidin-1-yl-methyl;-anil ino)-1-(4-(2-oxo-pyrrolid in-1-yl )-5.4 phenyl)-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(dimethylamino-metf ylcarbonyl)-N-methyl-amino)-anilino)-5.5 1-(4-(2-oxo-pyrrolidin-1-yl)-phenyl)-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(dimethylamino-methyl )-anilino)-1-(4-(2-oxo-pyrrolidin-1-yl)-5.6 phenyl)-methylene ]-6-chloro-2-indolinone 3-Z-[1-(4-(4-methyl-piperazin-1-yl-carbonyl )-anilino)-1-(4-(2-oxo-5.7 pyrrolidin-1-yl)-phenyl)-mE~thylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(3-dimethylamino-pn ~pyl)-N-acetyl-amino)-anilino)-1-(4-(2-5.8 oxo-pyrrolidin-1-yl)-phenyl)-rnethylene]-6-chloro-2-indolinone 3-Z-[1-(4-(2-diethylamino-eth yl-sulphonyl)-anilino)-1-(4-(2-oxo-5.9 pyrrolidin-1-yl)-phenyl)-mE thylene]-6-chloro-2-indolinone 3-Z-(1-(4-(ethylmethylamino-mei hyl)-anilino)-1-(4-(2-oxo-pyrrolid in-1-5.10 yl)-phenyl)-methyler a]-6-chloro-2-indolinone 3-Z-[1-(4-(N-tert. butoxycarbonyl-i nethylamino-methyl)-anilino)-1-(4-(2-5.11 oxo-pyrrolidin-1-yl)-phenyl)-rnethylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(dimethylamino-metf' ylcarbonyl)-N-methyl-amino)-anilino)-5.12 1-(4-amino-3-vitro-phenyl)-n~ethylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-5.13 anilino)-1-(4-amino-3-vitro-phenyl)-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(pyrrolidin-1-yl-methyl-anilino)-1-(4-amino-3-vitro-phenyl)-5.14 methylene]-6-c;hloro-2-indolinone 3-Z-[1-(4-(4-methyl-piperazin-1-yl carbonyl)-anAino)-1-(4-amino-3-nitro-5.15 phenyl)-methylene[-6-chloro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-~ahyl)-N-acetyl-amino)-anilino)-1-(4-5.16 amino-3-vitro-phenyl)-me':hylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-(4-5.17 amino-3-vitro-phenyl)-me':hylene]-6-chloro-2-indolinone 3-Z-[1-(4-(dimethylamino-m~ahyl)-anilino)-1-(4-vitro-phenyl)-5.18 methylene]-6-c;hloro-2-indolinone 3-Z-[1-(4-(N-(2-d imethylamino-e;thyl)-N-acetyl-amino)-anilino)-1-(4-5.1 9 vitro-phenyl)-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-~ -yl-methylcarbonyl)-N-methyl-amino)-5.20 anilino)-1-(4-nitro-phenyl)-niethylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(dimethylamino-metf ~ylcarbonyl)-N-methyl-amino)-an ilino)-5.21 1-(4-nitro-phenyl)-methy~lene]-6-chloro-2-indolinone 3-Z-[1-(4-(4-methyl-piperazin-1-y -carbonyl)-anilino)-1-(4-n itro-phenyl)-5.22 methylene]-6-c:hloro-2-indolinone 3-Z-[1-(4-(dimethylamino-methyl)-anilino)-1-(4-cyano-phenyl)-5.23 methylene]-6-c:hloro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-6.0 anilino)-1-phenyl-methylene]-6-bromo-2-indolinone 3-Z-[1-(4-(N-(dimethylamino-mett ylcarbonyl)-N-methyl-amino)-anilino)-6.1 1-phenyl-methylenE:]-6-bromo-2-indolinone 3-Z-[1-(4-(d imethylamino-meth yl)-anilino)-1-phenyl-methylene]-6-6.2 bromo-;'.-indolinone 3-Z-[1-(4-(N-(2-d imethylamino-etr yl)-N-acetyl-amino)-an ilino)-1-phenyl-6.3 methylene]-6-k~romo-2-indolinone 3-Z-[1-(4-methyl-piperidin-1-yl-amino)-1-phenyl-methylene]-6-bromo-2-6.4 ind ~linone 3-Z-[1-(4-(N-tert.butoxycarbonyl-~ahylamino-methyl)-anilino)-1-phenyl-6.5 methylene]-6-k~romo-2-indolinone 3-Z-[1-(4-(1-methyl-imidazol-2-yl)-anilino)-1-phenyl-methylene]-6-6.6 bromo-:'--indolinone 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-benzylsulphonyl-amino)-6.7 anilino)-1-phenyl-methy lene]-fi-bromo-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-E ethyl )-N-(n-propylsulphonyl )-amino)-6.8 anilino)-1-phenyl-methy lene]-6-bromo-2-indolinone 3-Z-[1-(4-(4-methyl-piperazin-1-yl-carbonyl)-anilino)-1-phenyl-6.9 methylene]-6-k~romo-2-indolinone 3-Z-[1-(4-(N-(3-dimethylamino~~propyl)-N-acetyl-amino)-anilino)-1-6.10 phenyl-methylene: -6-bromo-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-' -yl-methylcarbonyl)-N-methyl-amino)-6.11 anilino)-1-phenyl-meth~~lene]-6-bromo-2-indolinone 3-Z-[1-(4-(pyrrolidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-bromo-6.12 2-irniolinone 3-Z-[1-(4-(N-(N-(2-dimethy lamino-ethyl)-N-methyl-amino-6.13 methylcarbonyl)-N-methyl-amigo)-anilino)-1-phenyl-methylene]-6-bromo-:?-indolinone 3-Z-[1-(4-((4-methyl-piperazi ~-1-yl )-methyl)-anilino)-1-phenyl-6.14 methylene]-6-k~romo-2-indolinane 3-Z-[1-(4-(N-((2-dimethylaminc-ethyl)-carbonyl)-N-methyl-amino)-6.15 anilino)-1-phenyl-methy lene]-6-bromo-2-indolinone 3-Z-[1-(4-(N-(2-d imethylamino-et iyl )-N-methyl-amino-methyl )-an ilino)-6.16 1-phenyl-methylenf:]-6-bromo-2-indolinone 3-Z-[1-(4-(N-tert.butoxycarbonyl-methylamino-methyl)-anilino)-1-6.17 phenyl-methylene]-6-bromo-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-7.0 anilino)-1-phenyl-meth~~lene]-6-cyano-2-indolinone 3-Z-[1-(4-(N-(dimethylamino-mett ylcarbonyl)-N-methyl-amino)-anilino)-7.1 1-phenyl-methylenE~]-6-cyano-2-indolinone 3-Z-[1-(4-(dimethylamino-methyl)-anilino)-1-phenyl-methylene]-6-7.2 cyano-a'.-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-ett yl)-N-acetyl-amino)-anilino)-1-phenyl-7.3 methylene]-6-c:yano-2-indolinone 7.4 3-Z-[1-(4-bromo-anilino)-1-pheryl-methylene]-6-cyano-2-indolinone 3-Z-[1-(4-(N-tert. butoxycarbonyl-~ahylamino-methyl)-anilino)-1-phenyl-7.5 methylene]-6-c:yano-2-indofinone 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-cyano-7.6 2-in lolinone 3-Z-[1-(4-(2-dimethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-7.7 cyano-:'.-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-carbamoyl)-anilino)-1-phenyl-7.8 methylene]-6-c;yano-2-indolinone 3-Z-[1-(4-(4-methyl-piperazin-1-yl-carbonyl)-an ilino)-1-phenyl-7.9 methylene]-6-c;yano-2-indolinone 3-Z-[1-(4-(N-(3-dimethylamino~ propyl)-N-acetyl-amino)-anilino)-1-7.10 phenyl-methylene:-6-cyano-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-7.11 anilino)-1-phenyl-meth~~lene]-6-cyano-2-indolinone 3-Z-[1-(4-(pyrrolidin-1-yl-methyl)-a milino)-1-phenyl-methyleneJ-6-cyano-7.12 2-irniolinone 3-Z-[1-(4-(N-(N-(2-d imethylamino-ethyl)-N-methyl-amino-7.13 methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-cyano-a'.-indolinone 3-Z-[1-(4-(N-(3-d imethylamino-p ropyl )-carbamoyl )-anil ino)-1-phenyl-7.14 methylene]-6-c:yano-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-ei hyl)-N-methyl-carbamoyl)-anilino)-1-7.15 phenyl-methylene: -6-cyano-2-indolinone 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-methyl-carbamoyl)-anil ino)-1-7.16 phenyl-methylene:-6-cyano-2-indolinone 3-Z-[1-(4-(N-((2-dimethylamino-ethyl)-carbonyl)-N-methyl-amino)-7.17 anilino)-1-phenyl-meth~~lene]-6-cyano-2-indolinone 3-Z-[1-(4-(N-(4-tent.butoxycarboriyl-piperazin-1-yl-methylcarbonyl)-N-7.18 methyl-amino)-anilino)-1-phern~l-methylene]-6-cyano-2-indolinone 3-Z-[1-(3-(dimethylamino-methyl)-anilino)-1-phenyl-methylene]-6-7.19 cyano-a'.-indolinone 3-Z-[1-(3-(N-(2-d imethylamino-a :hyl )-N-methyl-carbamoyl)-anilino)-1-7.20 phenyl-methylene ~-6-cyano-2-indolinone 3-Z-[1-(4-(N-(morpholin-4-yl-metr ylcarbonyl)-N-methyl-amino)-anilino)-7.21 1-phenyl-methylen~;]-6-cyano-2-indolinone 3-Z-[1-(4-(N-(4-methyl-homopipe razin-1-yl-methylcarbonyl)-N-methyl-7.22 amino)-anilino)-1-phenyl-methylene]-6-cyano-2-indolinone 3-Z-[1-(4-(N-(4-ethyl-piperazin-1- yl-methylcarbonyl)-N-methyl-amino)-7.23 anilino)-1-phenyl-meth~~lene]-6-cyano-2-indolinone 3-Z-[1-(3-{N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-7.24 anilino)-1-phenyl-meth~~lene]-6-cyano-2-indolinone 3-Z-[1-(3-(N-(dimethylamino-metf-ylcarbonyl)-N-methyl-amino)-anilino)-7.25 1-phenyl-methylenE:]-6-bromo-2-indolinone 3-Z-[1-{3-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-amino)-anil ino)-7.26 1-phenyl-methylent;]-6-cyano-2-indolinone 3-Z-[1-(4-(N-(3-dimethylamino-yropyl)-N-methyl-carbamoylmethyl)-7.27 anilino)-1-phenyl-meth~~lene]-6-cyano-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methyl-carbamoylmethyl)-7.28 anilino)-1-phenyl-meth~~lene]-6-cyano-2-indolinone 3-Z-[1-(4-{4-methyl-piperazin-1-!~l-carbonylmethyl)-anilino)-1-phenyl-7.29 methylene]-6-c:yano-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-8.0 anilino)-1-phenyl-methl~lene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(dimethylamino-metf ylcarbonyl)-N-methyl-amino)-anilino)-8.1 1-phenyl-methylen~:]-6-fluoro-2-indolinone 3-Z-[1-(4-(dimethylamino-methyl)-anilino)-1-phenyl-methylene]-6-fluoro-8.2 2-in~iolinone 3-Z-[1-(4-(N-(2-d imethylamino-ett- yl)-N-acetyl-amino)-anilino)-1-phenyl-8.3 methylene]-6-i luoro-2-indolinone 3-Z-[1-(4-(N-tert.butoxycarbonyl-~~thylamino-methyl)-anilino)-1-phenyl-methylene]-6- luoro-2-indolinone 3-Z-[1-(4-(1-methyl-imidazol-2~ y1)-anilino)-1-phenyl-methylene]-6-8.5 fluoro-a'.-indolinone 3-Z-[1-(4-(N-(2-dimethylaminc~-ethyl)-N-propylsulphonyl-amino)-8.6 anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(4-methyl-piperazin-1-yl-carbonyl)-anilino)-1-phenyl-8.7 methylene]-6-iiuoro-2-indolinone 3-Z-[1-(4-(N-(3-dimethylamino~ propyl)-N-acetyl-amino)-anilino)-1-8.8 phenyl-methylene ~-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-8.9 .

anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(pyrrolidin-1-yl-methyl)-~~nilino)-1-phenyl-methylene]-6-fluoro-8.10 2-in~iolinone 3-Z-[1-(4-(N-(N-(2-d imethylamino-ethyl)-N-methyl-amino-8.11 methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-~-indolinone 3-Z-[1-(4-((4-methyl-piperazi ~-1-yl)-methyl)-anilino)-1-phenyl-8.12 methylene]-6-lluoro-2-indolinone 3-Z-[1-(4-(N-((2-dimethylamino-ethyl)-carbonyl)-N-methyl-amino)-8.13 anilino)-1-phenyl-meth~~lene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(2-d imethylamino-eti ~yl)-N-methyl-amino-methyl)-anilino)-8.14 1-phenyl-methylen~:]-6-fluoro-2-indolinone 3-Z-[1-(4-(piperid in-1-yl-methyl)-< <nil ino)-1-phenyl-methylene]-6-fluoro-8.15 2-in~iolinone 3-Z-[1-(4-(N-tert. butoxycarbon yl-methylamino-methyl)-anilino)-1-8.16 phenyl-methylene ~-6-fluoro-2-indolinone 3-Z-[1-(4-(N-methyl-N-methylsulphonyl-amino)-anilino)-1-phenyl-8.17 methylene]-6-iluoro-2-indolinone 3-Z-[1-(4-methylsulphonyl-aniliiio)-1-phenyl-methylene]-6-fluoro-2-8.18 indolinone 3-Z-[1-(4-(N-methyl-N-acetyl-arr ino)-anilino)-1-phenyl-methylene]-6-8.19 fluoro-~'.-indolinone 8.20 3-Z-(1-anilino-1-phenyl-methylen)-6-tluoro-2-indolinone 3-Z-[1-(4-(N-(dimethylamino-cart~onylmethyl)-N-methylsulphonyl-ami-8.21 no)-anilino)-1-phenyl-mev hylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(dirnethylaminomethyl)- anilino)-1-(4-iod-phenyl)-methylene]-9.0 6-fluoro-2-indolinone 3-Z-[1-(4-(dimethylaminome rhyl)-anilino)-1-(3-fluoro-phenyl )-9.1 methylene]-6-i luoro-2-indolinone 3-Z-[1-(4-(N-(3-d imethylamino-p ropyl)-N-acetyl-amino)-anilino)-1-(3-9.2 fluoro-phenyl)-methyl;neJ-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-9.3 anilino)-1-(3-fluoro-phenyl)-rnethylene]-6-fluoro-2-indolinone 3-Z-[1-{4-(dimethylaminomethyl i-anilino)-1-{4-(2-acetylamino-ethyl)-9.4 phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-(4-(2-9.5 acetylamino-ethyl)-phenyl)-rnethylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-9.6 anilino)-1-(4-(2-acetylamino-etiyl)-phenyl)-methylene]-6-fluoro-2-ind ~linone 3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-(3,4,5-trifluoro-phenyl)-9.7 methylene]-6-iluoro-2-indolinone 3-Z-[1-(4-(N-(3-d imethylamino- propyl)-N-acetyl-amino)-an ilino)-1-9.8 (3,4,5-trifluoro-phenyl)-mE thylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-9.9 anilino)-1-(3,4,5-trifluoro-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-(4-methoxycarbonylmethyl-9.10 phenyl)-methylenE~]-6-fluoro-2-indolinone 3-Z-[1-(4-(dimethylaminomethyl)~~anilino)-1-(3-iod-phenyl)-methylene]-9.11 6-fluoro~ 2-indolinone 3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-(3-methoxycarbonylmethyl-9.12 phenyl)-methylenE~]-6-fluoro-2-indolinone 3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-(3-(N-tert.butoxycarbonyl-9.13 aminomethyl)-phenyl)-mE thylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-9.14 anilino)-1-(4-methoxycarbonylmethyl-phenyl)-methylene]-6-fluoro-2-indelinone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-9.15 anilino)-1-(4-methoxycarbonylmethyl-phenyl)-methylene]-6-fluoro-2-ind ~linone 3-Z-[1-(4-(dimethylaminomethyl I-anilino)-1-(3-cyanomethyl-phenyl)-9.16 methylene]-6-iluoro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-9.17 anilino)-1-(4-(N-tert.butoxycarbor yl-aminomethyl)-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-(4-(N-tert.butoxycarbonyl-9.18 aminomethyl)-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(dimethylaminomethyl)-;~nilino)-1-(3-(N-tert.butoxycarbonyl-2-9.19 amino-ethyl)-phenyl)-mei hylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-acetyl-N-methyl-amii ~o)-anilino)-1-(4-(2-methoxycarbonyl-9.20 ethyl)-phenyl)-methyl:ne]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-9.21 anilino)-1-(4-(2-methoxycarbonyl~ ethyl)-phenyl)-methylene]-6-fluoro-ind ~linone 3-Z-[1-(4-(N-(2-dimethylaminc-ethyl)-N-methylsulphonyl-amino)-9.22 anilino)-1-(4-methoxycarbonylmethyl-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(3-d imethylamino-propyl)-N-acetyl-amino)-anilino)-1-(4-(2-9.23 methoxycarbonyl-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-tert.butoxycarbonyl- ~nethylamino-methyl)-anilino)-1-(4-(2-9.24 methoxycarbonyl-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(4-methyl-piperazi n-1-yl-carbonyl)-anilino)-1-(4-(2-9.25 methoxycarbonyl-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-( 1-methyl-imidazol-2-y I)-anilino)-1-(4-(2-methoxycarbonyl-9.26 ethyl)-phenyl)-methyl~~ne]-6-fluoro-2-indolinone 3-Z-[1-(4-methylsulphonyl-anilii ~0)-1-(4-(2-methoxycarbonyl-ethyl)-9.27 phenyl)-methylenE ]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-9.28 anilino)-1-(3-methoxycarbonylmethyl-phenyl)-methylene]-6-fluoro-2-ind ~linone 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-9.29 anilino)-1-(3-methoxycarbonylmethyl-phenyl)-methylene]-6-fluoro-2-ind ~linone 3-Z-[1-(4-(4-methyl-pipera:'in-1-yl-carbonyl)-anil ino)-1-(3-9.30 methoxycarbonylmethyl-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(dimethylamino-meth ylcarbonyl)-N-methyl-amino)-anilino)-9.31 1-(3-methoxycarbonylmethyl-phe nyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(3-d imethylamino-p ropyl )-N-acetyl-amino)-anil ino)-1-(3-9.32 methoxycarbonylmethyl-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-~ ahyl)-N-acetyl-amino)-anil ino)-1-(3-9.33 methoxycarbonylmethyl-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-dimethylamino-bu~:ylcarbonyl)-N-methyl-amino)-anilino)-9.34 1-(3-methoxycarbonylmethyl-phenyl)-methylene]-6-fluoro-2-indolinone 9?

3-Z-[1-anilino-1-(4-methoxycarbonylmethyl-phenyl)-methylene]-6-9.35 fluoro-~'.-indolinone 3-Z-[1-(4-(1-methyl-imidazol-2-yl)~ ~anilino)-1-(4-methoxycarbonylmethyl-9.36 phenyl)-methylenE~]-6-fluoro-2-indolinone 3-Z-[1-(4-(4-methyl-pipera; yin-1-yl-carbonyl)-anilino)-1-(4-9.37 methoxycarbonylmethyl-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(dimethylamino-cart>onylmethyl)-N-methylsulphonyl-ami-9.38 no)-anilino)-1-(4-methoxycarborn~lmethyl-phenyl)-methylene]-6-fluoro-2-irniolinone 3-Z-[1-(4-(N-(dimethylamino-metf ylcarbonyl)-N-methyl-amino)-anilino)-9.39 1-(4-methoxycarbonylmethyl-phe nyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-methyl-N-; acetyl-amino)-anilino)-1-(4-9.40 methoxycarbonylmethyl-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-etY~ylcarbonyl)-N-methyl-amino)-anilino)-9.41 1-(4-methoxycarbonylmethyl-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-methylsulphonyl-anilino)-1-(4-methoxycarbonylmethyl-9.42 phenyl)-methylene ]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(3-dimethylamino -propylcarbonyl)-N-methyl-amino)-9.43 anilino)-1-(4-methoxycarbonylm~thyl-phenyl)-methylene]-6-fluoro-2-ind ~linone 3-Z-[1-(4-(N-(3-d imethylami no-p ropyl )-N-acetyl-amino)-an il ino)-1-(4-9.44 methoxycarbonylmethyl-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-anilino-1-(3-methoxycar ~onylmethyl-phenyl)-methylene]-6-9.45 fluoro-c-indolinone 3-Z-[1-(4-methylsulphonyl-anilino)-1-(3-methoxycarbonylmethyl-9.46 phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-( 1-methyl-imidazol-2-yl)- anilino)-1-(3-methoxycarbonylmethyl-9.47 phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-j1-(4-(N-(dimethylamino-carl~onylmethyl)-N-methylsulphonyl-ami-9.48 no)-anilino)-1-(3-methoxycarbonylmethyl-phenyl)-methylene]-6-fluoro-2-in lolinone 3-Z-[1-(4-(N-(3-dimethylamino-propylcarbonyl)-N-methyl-amino)-9.49 anilino)-1-(3-methoxycarbonylmethyl-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-ettiylcarbonyl)-N-methyl-amino)-anilino)-9.50 1-(3-methoxycarbonylmethyl-phe nyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-9.51 anilino)-1-(3-(2-methoxycarbonyl~~ethyl}-phenyl)-methylene]-6-fluoro-ind ~linone 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-9.52 anilino)-1-(3-(2-methoxycarbonyl~~ethyl)-phenyl)-methylene]-6-fluoro-ind alinone 3-Z-[1-(4-(N-(dimethylamino-metl- ylcarbonyl)-N-methyl-amino)-anilino)-9.53 1-(3-(2-methoxycarbonyl-eths~l)-phenyl)-methylene]-6-fluoro-2-ind ~linone 3-Z-[1-(4-(N-(3-dimethylamino-prc ~pyl)-N-acetyl-amino)-anilino)-1-(3-(2-9.54 methoxycarbonyl-ethyl)-pheny )-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-9.55 anilino)-1-(3-(N-tent.butoxycarboryl-aminomethyl)-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-methyl-N-acetyl-ami no)-anilino)-1-(3-acetylaminomethyl-9.56 phenyl)-methylene~-6-chloro-2-indolinone 3-Z-[1-(4-(N-(3-d imethylamino-p ropyl)-N-acetyl-amino)-an ilino)-1-(3-9.57 acetylaminomethyl-phenyl)-r~ethylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-9.58 anilino)-1-(3-acetylaminomethyl-phenyl)-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-{dimethylamino-metf,ylcarbonyl)-N-methyl-amino)-anilino)-9.59 1-(3-acetylaminomethyl-pheny )-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(2-d imethylamino-ethyl)-anilino)-1-(4-(2-methoxycarbonyl-9.60 ethyl)-phenyl)-methyl~~ne]-6-fluoro-2-indolinone 3-Z-[1-(4-{N-(2-dimethylamino-etr ~ylcarbonyl)-N-methyl-amino)-anilino)-9.61 1-(4-(2-methoxycarbonyl-eth~~l)-phenyl)-methylene]-6-fluoro-2-ind ~linone 3-Z-[1-(4-(N-(dimethylamino-mett- ylcarbonyl)-N-methyl-amino)-anilino)-9.62 1-(4-(2-methoxycarbonyl-eths~l)-phenyl)-methylene]-6-fluoro-2-ind ~linone 3-Z-[1-(4-(2-dimethylamino-eth yi)-anilino)-1-(3-(2-ethoxycarbonyl-9.63 ethyl)-phenyl)-methyi~;ne]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-et hyl )-N-acetyl-amino)-anilino)-1-(4-(2-9.64 methoxycarbonyl-ethyl)-pheny )-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(3-dimethylamino~~propylcarbonyl)-N-methyl-amino)-9.65 anilino)-1-(3-(2-ethoxycarbonyl-Ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-dimethylamino-but ylcarbonyl)-N-methyl-amino)-anilino)-9.66 1-(3-(2-ethoxycarbonyl-ethyl)-phe nyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(1-methyl-imidazol-2-yl)-anilino)-1-(3-(2-ethoxycarbonyl-9.67 ethyl)-phenyl)-methylE~ne]-6-fluoro-2-indolinone 3-Z-[1-{4-(N-(4-dimethylamino-buiylcarbonyl)-N-methyl-amino)-anilino)-9.68 1-(4-(2-methoxycarbonyl-eth~~I)-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-anilino-1-(4-(2-methoxyc< <rbonyl-ethyl )-phenyl )-methylene]-6-9.69 fluoro-2-indolinone 3-Z-[1-(4-(pyrrolid in-1-yl-methyl )-anilino)-1-(4-(2-methoxycarbonyl-9.70 ethyl)-phenyl)-methylf:ne]-6-fluoro-2-indolinone 3-Z-[1-(4-(diethylaminomethyl)-ar ilino)-1-(4-(2-methoxycarbonyl-ethyl)-9.71 phenyl)-methylenE ]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-tert. butoxycarbor iyl-amino-methyl)-anilino)-1-(4-(2-9.72 methoxycarbonyl-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(2-dimethylamino-ethyl) anilino)-1-(3-methoxycarbonylmethyl-9.73 phenyl)-methylene ]-6-fluoro-2-indolinone 3-Z-[1-(4-(2-dimethylamino-ethyl) an ilino)-1-(4-methoxycarbonylmethyl-9.74 phenyl)-methylene ]-6-fluoro-2-indolinone 3-Z-[1-(4-(dimethylaminomethyl)-;~nilino)-1-(3-(2-ethoxycarbonyl-ethyl)-9.75 phenyl)-methylene ]-6-fluoro-2-indolinone 3-Z-[1-(4-(2-dimethylamino-ethy 1)-anilino)-1-(4-(2-methoxycarbonyl-9.76 ethyl)-phenyl)-methylf:ne]-6-chloro-2-indolinone 3-Z-[1-(4-(1-methyl-imidazol-2-yl)-an ilino)-1-(4-(2-ethoxycarbonyl-9.77 ethyl)-phenyl)-methylE:ne]-6-chloro-2-indolinone 3-Z-[1-(4-dimethylaminomethyl-ar~ilino)-1-(4-(2-methoxycarbonyl-ethyl)-9.78 phenyl)-methylene~-6-chloro-2-indolinone 3-Z-[1-(4-d imethylaminomethyl-a nilino)-1-(4-(2-ethoxycarbonyl-ethyl )-9.79 phenyl)-methylene)-6-fluoro-2-indolinone 3-Z-[1-(4-((4-methyl-pipera~ in-1-yl)-methyl)-anilino)-1-(3-(2-9.80 methoxycarbonyl-ethyl)-pheny )-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(imidazol-1-yl-methyl I-anilino)-1-(3-(2-methoxycarbonyl-9.81 ethyl)-phenyl)-methyl:ne]-6-fluoro-2-indolinone 3-Z-[1-(4-((4-methyl-pipera~ in-1-yl )-methyl)-anilino)-1-(4-(2-9.82 methoxycarbonyl-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(imidazol-1-yl-methyl I-anilino)-1-(4-(2-methoxycarbonyl-9.83 ethyl)-phenyl)-methyl:ne]-fi-fluoro-2-indolinone 3-Z-[1-(4-(N-(2-d imethylamino-etf ~yl)-N-methyl-aminomethyl)-anilino)-1-9.84 (4-(2-methoxycarbonyl-ethyl)-phE nyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-etl-yl)-N-methyl-aminomethyl)-anilino)-1-9.85 (3-(2-ethoxycarbonyl-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(pyrrolidin-1-yl-methyl )-anilino)-1-(4-(2-methoxycarbonyl-9.86 ethyl)-phenyl)-methylE~ne]-6-chloro-2-indolinone 3-Z-[1-anilino-1-(3-(2-ethoxyca~ ~bonyl-ethyl)-phenyl)-methylene]-6-9.87 fluoro-~ -indolinone 3-Z-[1-(4-(N-tert. butoxycarbor ~yl-amino-methyl)-anilino)-1-(3-(2-9.88 ethoxycarbonyl-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-tert.butoxycarbonyl-methylamino-methyl)-anilino)-1-(3-(2-9.89 ethoxycarbonyl-ethyl)-phenyl;-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethyl-aililino)-1-(3-methoxycarbonylmethoxy-9.90 phenyl)-methylenE ]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethyl-aililino)-1-(4-methoxycarbonylmethoxy-9.91 phenyl)-methylene ]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethyl-ar~ilino)-1-(3-(2-ethoxycarbonyl-ethoxy)-9.92 phenyl)-methylenE ]-6-fluoro-2-indolinone 3-Z-[1-(4-(pyrrolid in-1-yl-methy )-anilino)-1-(4-(2-methoxycarbonyl-9.93 ethyl)-phenyl)-methylE:ne]-6-bromo-2-indolinone 3-Z-[1-{4-(dimethylaminomethy )-anilino)-1-{4-(2-methoxycarbonyl-9.94 ethyl)-phenyl)-methylE:ne]-6-bromo-2-indolinone 3-Z-[1-(4-(diethylaminomethyl)-ar ilino)-1-(4-(2-methoxycarbonyl-ethyl)-9.95 phenyl)-methylene~-6-bromo-2-indolinone 3-Z-[1-(3-dimethylaminomethyl-ariilino)-1-(4-(2-methoxycarbonyl-ethyl)-9.96 phenyl)-methylenE~]-6-fluoro-2-indolinone 3-Z-[1-(3-dimethylaminomethyl-~ nilino)-1-(3-(2-ethoxycarbonyl-ethyl)-9.97 phenyl)-methylenE;]-6-fluoro-2-indolinone 3-Z-[1-(3-dimethylaminomethyl-anilino)-1-(4-(2-methoxycarbonyl-ethyl)-9.98 phenyl)-methylene ]-6-chloro-2-indolinone 3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-(3,4-dimethoxy-phenyl)-10.0 methylene]-6-c:yano-2-indolinone 3-Z-[1-(4-(N-methyl-N-methyl ~ulphonyl-amino)-anilino)-1-(3-(2-11.0 methoxycarbonyl-vinyl)-phenyl )-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(dimethylaminomethy )-anilino)-1-(4-(2-methoxycarbonyl-11.1 vinyl)-phenyl)-methylE~ne]-6-chloro-2-indolinone 3-Z-[1-(4-(d imethylaminomethy I)-anilino)-1-(4-(2-carbamoyl-vinyl )-11.2 phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(dimethylaminomethy )-anilino)-1-(4-(2-methoxycarbonyl-11.3 vinyl)-phenyl)-methyl:ne]-6-fluoro-2-indolinone 3-Z-[1-(4-(dimethylaminomethy )-anilino)-1-(3-(2-methoxycarbonyl-11.4 vinyl)-phenyl)-methyl;ne]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethyl-ar ~ilino)-1-(3-(2-methoxycarbonyl-ethyl )-12.0 phenyl)-methyleneJ-6-chloro-2-indolinone 3-Z-[1-(4-(N-methyl-N-methyl ~ulphonyl-amino)-anilino)-1-(3-(2-12.1 methoxycarbonyl-ethyl)-phenyl )-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-dimethylaminomethy I-anilino)-1-(4-(2-carbamoyl-ethyl)-12.2 phenyl)-methylenE ]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethyl-ariilino)-1-(4-(2-methoxycarbonyl-ethyl)-12.3 phenyl)-methylenE ]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethyl-ariilino)-1-(3-(2-methoxycarbonyl-ethyl)-12.4 phenyl)-methylenE~]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethyl-ariilino)-1-(4-amino-phenyl)-methylene]-13.0 6-chloro~~2-indolinone 3-Z-[1-(4-(N-((2-dimethylaminc -ethyl)-carbonyl)-N-methyl-amino)-13.1 anilino)-1-(4-amino-phenyl)-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-' -yl-methylcarbonyl)-N-methyl-amino)-13.2 anilino)-1-(4-amino-phenyl)-inethylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(2-d imethylamino-c;thyl)-N-acetyl-amino)-an ilino)-1-(4-13.3 amino-phenyl)-methyl:ne]-6-chloro-2-indolinone 3-Z-[1-(4-(4-methyl-piperazin- I -yl-carbonyl)-anilino)-1-(4-amino-13.4 phenyl)-methylene ~-6-chloro-2-indolinone 3-Z-[1-(4-dimethylaminomethyl~~anilino)-1-(4-aminomethyl-phenyl)-14.0 methylene]-6-c;hloro-2-indolinone 3-Z-[1-(4-(N-((4-methyl-pipera~:in-1-yl)-methylcarbonyl)-N-methyl-15.0 amino)-anilino)-1-(4-aminometnyl-phenyl)-methylene]-6-chloro-2-ind ~linone 3-Z-[1-(4-(N-((4-methyl-pipera~:in-1-yl)-methylcarbonyl)-N-methyl-16.0 amino)-anilino)-1-(4-hydroxy-phenyl)-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-((2-d imethylamino-ethyl )-carbonyl)-N-methyl-amino)-16.1 anilino)-1-(4-hydroxy-phenyl) methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(2-d imethylamino-~;thyl)-N-acetyl-amino)-anilino)-1-(4-16.2 hydroxy-phenyl)-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(3-d imethylamino-p ropyl)-N-acetyl-amino)-anil inn)-1-(4-16.3 hydroxy-phenyl)-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-dimethylaminometfiyl-anilino)-1-(4-hydroxy-phenyl)-16.4 methylene]-6-c:hloro-2-indolinone 3-Z-[1-(4-ethylaminomethyl-anili no)-1-phenyl-methylene]-6-chloro-2-17.0 indolinone-trifluoroacetate 3-Z-[1-(4-methylamino-methyl-an lino)-1-phenyl-methylene]-6-chloro-2-17.1 indolinone 3-Z-(1-(4-(N-(2-piperazin-1-yl-eth ylcarbonyl)-N-methyl-amino)-anilino)-17.2 1-phenyl-methylent;]-6-chloro-2-indolinone 3-Z-[1-(4-(piperazin-1-yl-methyl )-anilino)-1-phenyl-methylene]-6-chloro-17.3 2-in~lolinone 3-Z-[1-(4-(piperazin-1-yl-carboi ~yl)-anilino)-1-phenyl-methylene]-6-17.4 chloro-;?-indolinone 3-Z-[1-(4-(amino-methyl)-anilin ~)-1-phenyl-methylene]-6-chloro-2-17.5 ind ~linone 3-Z-[1-(4-(N-(piperazin-1-yl-mE;thylcarbonyl)-N-isopropyl-amino)-17.6 anilino)-1-phenyl-methy lene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(piperazin-1-yl-meth,rlcarbonyl)-N-methyl-amino)-anilino)-17.7 1-phenyl-methylenE:]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(N-(3-amino-propyl)-N-methyl)-amino-methyl)-anilino)-1-17.8 phenyl-methylene:-6-chloro-2-indolinone 3-Z-[1-(4-(methylamino-methyl)~~anilino)-1-(4-(2-oxo-pyrrolidin-1-yl)-17.9 phenyl)-methylene~-6-chloro-2-indolinone 3-Z-[1-(4-(ethylamino-methyl)-ani ino)-1-phenyl-methylene]-6-bromo-2-17.10 ind ~linone 3-Z-[1-(4-(methylamino-methyl)-anilino)-1-phenyl-methylene]-6-bromo-17.11 2-in~iolinone 3-Z-[1-(4-(ethylamino-methyl)-ani lino)-1-phenyl-methylene]-6-cyano-2-17.12 indolinone 3-Z-[1-(4-(piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-17.13 phenyl-methylene;i,-6-cyano-2-indolinone 3-Z-[1-(4-(ethylamino-methyl)-an lino)-1-phenyl-methylene]-6-fluoro-2-17.14 indolinone 3-Z-[1-(4-(methylamino-methyl)-anilino)-1-phenyl-methylene]-6-fluoro-17.15 2-in~lolinone 3-Z-[1-(4-(dimethylaminomethyl )-anilino)-1-(3-aminomethyl-phenyl)-17.16 methylene]-6- ~luoro-2-indolinone 3-Z-[1-(4-(dimethylaminomethyl)~ anilino)-1-(3-(2-amino-ethyl)-phenyl)-17.17 methylene]-6- 7uoro-2-indolinone 3-Z-[1-(4-(d imethylaminomethyl )-anilino)-1-(4-aminomethyl-phenyl)-17.18 methylene]-6-Fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-~' -yl-methylcarbonyl)-N-methyl-amino)-17.19 anilino)-1-(4-aminomethyl-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(methylamino-methyl)-a nilino)-1-(4-(2-carboxy-ethyl)-phenyl)-17.20 methylene]-6-'luoro-2-indolinone 3-Z-[1-(4-(methylamino-methyl)-anilino)-1-(4-(2-methylcarbamoyl-17.21 ethyl)-phenyl)-methylne]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-~ -yl-methylcarbonyl)-N-methyl-amino)-17.22 anilino)-1-(3-aminomethyl-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(amino-methyl)-anilir o)-1-(4-(2-methoxycarbonyl-ethyl)-17.23 phenyl)-methylenE ]-6-fluoro-2-indolinone 3-Z-[1-(4-(amino-methyl)-anilino)-1-(3-(2-ethoxycarbonyl-ethyl)-phenyl)-17.24 methylene]-6-i~luoro-2-indolinone 3-Z-[1-(4-(methylamino-methyl)-aniiino)-1-(3-(2-ethoxycarbonyl-ethyl)-17.25 phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-aminomethylcarbon~rl-N-methyl-amino)-anilino)-1-phenyl-18.0 methylene]-6-c:hloro-2-indolinone 19.0 3-Z-[1-(4-carboxy-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-carboxymethyl-anilino)-1-phenyl-methylene]-6-chloro-2-19.1 ind~linone 3-Z-[1-(3-carboxymethyl-aniline ~)-1-phenyl-methylene]-6-chloro-2-19.2 ind ~linone 19.3 3-Z-[1-(3-carboxy-anilino)-1-phenyl-methyleneJ-6-chloro-2-indolinone 3-Z-[1-(4-dimethylaminomethyl-aoilino)-1-(3-(2-carboxy-ethyl)-phenyl)-20.0 methylene]-6-c;hloro-2-indolinone 3-Z-[1-(4-d imethylaminomethyl-ao ilino)-1-(4-(2-carboxy-ethyl)-phenyl)-20.1 methylene]-6-iluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethyl-;~nilino)-1-(3-carboxymethyl-phenyl)-20.2 methylene]-6-iluoro-2-indolinone lOb 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-20.3 methylene]-6-'luoro-2-indolinone 3-Z-[1-(4-d imethylaminomethyl- ~nilino)-1-(4-carboxymethyl-phenyl)-20.4 methylene]-6- ~uoro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-20.5 anilino)-1-(4-carboxymethyl-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-20.6 anilino)-1-(4-carboxymethyl-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-(1-(4-(N-methyl-N-acetyl-an lino)-anilino)-1-(4-(2-carboxy-ethyl)-20.7 phenyl)-methylenE ]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-20.8 anilino)-1-(4-(2-carboxy-ethyl)-phc;nyl )-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-20.9 anilino)-1-(4-(2-carboxy-ethyl)-phEnyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(3-dimethylamino-prc~pyl)-N-acetyl-amino)-anilino)-1-(4-(2-20.10 carboxy-ethyl)-phenyl)-me~thylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-tert. butoxycarbonyl-i nethylamino-methyl)-an ilino)-1-(4-(2-20.11 carboxy-ethyl)-phenyl)-mE~thylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(4-methyl-piperazin-1-srl-carbonyl)-anilino)-1-(4-(2-carboxy-20.12 ethyl)-phenyl)-methylne]-6-fluoro-2-indolinone 3-Z-[1-(4-(1-methyl-imidazol-2 -yl)-anilino)-1-(4-(2-carboxy-ethyl)-20.13 phenyl)-methylene ]-6-fluora-2-indolinone 3-Z-[1-(4-methylsulphonyl-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-20.14 methylene]-6-lluoro-2-indolinone 3-Z-[1-(4-(4-methyl-pipera:~in-1-yl-carbonyl)-an ilino)-1-(3-20.15 carboxymethyl-phenyl)-mE;thylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-20.16 anilino)-1-(3-carboxymethyl-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(dimethylamino-metl~ylcarbonyl)-N-methyl-amino)-anilino)-20.17 1-(3-carboxymethyl-phenyl)- methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-dimethylamino-bu tylcarbonyl)-N-methyl-amino)-anilino)-20.18 1-(3-carboxymethyl-phenyl)- methylene]-6-fluoro-2-indolinone 3-Z-[1-anilino-1-(3-carboxymethyl-phenyl)-methylene]-6-fluoro-2-20.19 indolinone 3-Z-[1-(4-methylsulphonyl-anilino)-1-(3-carboxymethyl-phenyl)-20.20 methylene]-6-r7uoro-2-indolinone 3-Z-[1-(4-( 1-methyl-imidazol-2-yl; -anilino)-1-(3-carboxymethyl-phenyl )-20.21 methylene]-6- luoro-2-indolinone 3-Z-[1-(4-(N-(dimethylamino-carl~onylmethyl)-N-methylsulphonyl-ami-20.22 no)-anilino)-1-(3-carboxymetl5yl-phenyl)-methylene]-6-fluoro-2-indofinone 3-Z-[1-anilino-1-(4-carboxyme :hyl-phenyl)-methylene]-6-fluoro-2-20.23 indolinone 3-Z-[1-(4-( 1-methyl-imidazol-2-yl;-anifino)-1-(4-carboxymethyl-phenyl)-20.24 methylene]-6-iluoro-2-indolinone 3-Z-[1-(4-(N-(3-dimethylamino-propylcarbonyl)-N-methyl-amino)-20.25 anilino)-1-(4-carboxymethyl-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(dimethylamino-metf- ylcarbonyl)-N-methyl-amino)-anilino)-20.26 1-(4-carboxymethyl-phenyl )-~methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(4-methyl-pipera;'in-1-yl-carbonyl)-anilino)-1-(4-20.27 carboxymethyl-phenyl)-mfahylene]-6-fluoro-2-indolinone 3-Z-[1-(4-methylsulphonyl-ani lino)-1-(4-carboxymethyl-phenyl)-20.28 methylene]-6-iluoro-2-indolinone 3-Z-[1-(4-(N-methyl-N-acetyl-amino)-anilino)-1-(4-carboxymethyl-20.29 phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(dimethylamino-carbonylmethyl)-N-methylsulphonyl-ami-20.30 no)-anilino)-1-(4-carboxymet~yl-phenyl)-methylene]-6-fluoro-2-inc olinone 3-Z-[1-(4-(N-(2-dimethylamino-etl~ylcarbonyl)-N-methyl-amino)-anilino)-20.31 1-(4-carboxymethyl-phenyl) methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(3-dimethylaminc-propylcarbonyl)-N-methyl-amino)-20.32 anilino)-1-(4-carboxymethyl-phe~~yl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-' I -yl-methylcarbonyl)-N-methyl-amino)-20.33 anilino)-1-(3-(2-carboxy-ethyl)-ph~nyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylaminc-ethyl)-N-methylsulphonyl-amino)-20.34 anilino)-1-(3-carboxymethyl-phe ~yl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylaminc-ethyl)-N-methylsulphonyl-amino)-20.35 anilino)-1-(3-(2-carboxy-ethyl)-phi:nyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(dimethylamino-metf'nylcarbonyl)-N-methyl-amino)-anilino)-20.36 1-(3-(2-carboxy-ethyl)-phenyl >-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-(3-(2-20.37 carboxy-ethyl)-phenyl)-mE~thylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(dimethylamino-metf~ylcarbonyl)-N-methyl-amino)-anilino)-20.38 1-(4-(2-carboxy-ethyl)-phenyl;,-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(2-dimethylamino-ett iyl)-an ilino)-1-(4-(2-carboxy-ethyl)-20.39 phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-etr ylcarbonyl)-N-methyl-amino)-anilino)-20.40 1-(4-(2-carboxy-ethyl)-phenyl;-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(2-dimethylamino-ett iyl)-anilino)-1-(3-(2-carboxy-ethyl)-20.41 phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-(4-(2-20.42 carboxy-ethyl)-phenyl)-mE~thylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(3-dimethylamino ~propylcarbonyl)-N-methyl-amino)-20.43 anilino)-1-(3-(2-carboxy-ethyl)-phEnyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-dimethylamino-butylcarbonyl)-N-methyl-amino)-anilino)-20.44 1-(3-(2-carboxy-ethyl)-phenyl )-methylene]-6-fluoro-2-indofinone 3-Z-[1-(4-(1-methyl-imidazol ~-yl)-anilino)-1-(3-(2-carboxy-ethyl)-20.45 phenyl)-methylenf;]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-dimethylamino-butylcarbonyl)-N-methyl-amino)-anilino)-20.46 1-(4-(2-carboxy-ethyl)-phenyl )-methylene]-6-fluoro-2-indolinone 3-Z-[1-an ilino-1-(4-(2-carboxy-E ~thyl)-phenyl)-methylene]-6-fluoro-2-20.47 indolinone 3-Z-[1-(4-(pyrrolidin-1-yl-methyl)-unilino)-1-(4-(2-carboxy-ethyl)-phenyl)-20.48 methylene]-6-~luoro-2-indolinone 3-Z-[1-(4-(diethylaminomethyl)-a~ iilino)-1-(4-(2-carboxy-ethyl)-phenyl)-20.49 methylene]-6- luoro-2-indolinone 3-Z-[1-(4-aminomethyl-anilirn~)-1-(4-(2-carboxy-ethyl)-phenyl)-20.50 methylene]-6- 'luoro-2-indolinone 3-Z-[1-(4-(2-dimethylamino-ethyl;-anilino)-1-(3-carboxymethyl-phenyl)-20.51 methylene]-6-l~uoro-2-indolinone 3-Z-[1-(4-(2-dimethylamino-ethyl;-anilino)-1-(4-carboxymethyl-phenyl)-20.52 methylene]-6-t~luoro-2-indolinone 3-Z-[1-(4-(2-dimethylamino-etl iyl)-anilino)-1-(4-(2-carboxy-ethyl)-20.53 phenyl)-methylene~-6-chloro-2-indolinone 3-Z-[1-(4-(1-methyl-imidazol-2 -yi)-anilino)-1-(4-(2-carboxy-ethyl)-20.54 phenyl)-methylene~-6-chloro-2-indolinone 3-Z-[1-(4-d imethylaminomethyl-aoilino)-1-(4-(2-carboxy-ethyl)-phenyl)-20.55 methylene]-6-r:hloro-2-indolinone 3-Z-[1-(4-((4-methyl-piperazin-1 ~ yl)-methyl)-anilino)-1-(3-(2-carboxy-20.56 ethyl)-phenyl)-methylnne]-6-fluoro-2-indolinone 3-Z-[1-(4-(imidazol-1-yl-methyl)-a iilino)-1-(3-(2-carboxy-ethyl)-phenyl)-20.57 methylene]-6-iluoro-2-indolinone 3-Z-[1-(4-(N-(2-d imethylamino-etloyl)-N-methyl-aminomethyl)-anilino)-1-20.58 (3-(2-carboxy-ethyl)-phenyl) -methyleneJ-6-fluoro-2-indolinone 3-Z-[1-(4-((4-methyl-piperazin-1-yl)-methyl)-anilino)-1-(4-(2-carboxy-20.59 ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(imidazol-1-yl-methyl)-~ nilino)-1-(4-(2-carboxy-ethyl)-phenyl)-20.60 methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(pyrrolidin-1-yl-methyl)-alnilino)-1-(4-(2-carboxy-ethyl)-phenyl)-20.61 methylene]-6-~~hloro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methyl-aminomethyl)-anilino)-1-20.62 (4-(2-carboxy-ethyl)-phenyl) methyleneJ-6-fluoro-2-indolinone 3-Z-[1-anilino-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-20.63 indolinone 3-Z-[1-(4-aminomethyl-aniline)-1-(3-(2-carboxy-ethyl)-phenyl)-20.64 methylene]-6- ~uoro-2-indolinone 3-Z-[1-(4-methylaminomethyl-an ilino)-1-(3-(2-carboxy-ethyl)-phenyl)-20.65 methylene]-6= 'luoro-2-indofinone 3-Z-[1-(4-dimethylaminomethyl-a nilino)-1-(3-carboxymethoxy-phenyl)-20.66 methylene]-6-tluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(4-carboxymethoxy-phenyl)-20.67 methylene]-6-i luoro-2-indolinone 3-Z-[1-(4-(pyrrolidin-1-yl-methyl)-~ nilino)-1-{4-(2-carboxy-ethyl)-phenyl)-10.68 methylene]-6-k~romo-2-indolinone 3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-(4-(2-carboxy-ethyl)-10.69 phenyl)-methylene~-6-bromo-2-indolinone 3-Z-[1-(4-(diethylaminomethy l)-anilino)-1-(4-(2-carboxy-ethyl)-10.70 methylene]-6-kpromo-2-indolinone 3-Z-[1-(3-dimethylaminomethyl-aoilino)-1-(4-(2-carboxy-ethyl)-phenyl)-20.71 methylene]-6-lluoro-2-indolinone 3-Z-[1-(3-dimethylaminomethyl-a nilino)-1-(3-(2-carboxy-ethyl)-phenyl)-20.72 methylene]-6-fluoro-2-indolinone 3-Z-[1-(3-dimethylaminomethyl-a nilino)-1-(4-(2-carboxy-ethyl)-phenyl )-20.73 methylene]-6-:,hloro-2-indolinone 3-Z-[1-(4-dimethylaminometh~ ~I-anilino)-1-(3-(2-carbamoyl-ethyl)-21.0 phenyl)-methylenE~]-6-chloro-2-indolinone 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(3-(2-methylcarbamoyl-ethyl)-21.1 phenyl)-methylenE]-6-chloro-2-indolinone 3-Z-[1-(4-d imethylaminomethyl-ai lilino)-1-(4-(2-methylcarbamoyl-ethyl)-21.2 phenyl)-methylenE~]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethyl-a iilino)-1-(3-dimethylcarbamoylmethyl-21.3 phenyl)-methylenE~]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethy I-anilino)-1-(3-(2-carbamoyl-ethyl)-21.4 phenyl)-methylenE,]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethyl-ariilino)-1-(3-(2-methylcarbamoyl-ethyl)-21.5 phenyl)-methylenE ]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(3-(2-dimethylcarbamoyl-21.6 ethyl)-phenyl)-methyl~:ne]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethyl-ai ~ilino)-1-(3-carbamoylmethyl-phenyl)-21.7 methylene]-6-i luoro-2-indolinone 3-Z-[1-(4-dimethylaminomethyl-a nilino)-1-(3-methylcarbamoylmethyl-21.8 phenyl)-methylene ]-6-fluoro-2-indolinone 3-Z-[1-(4-d imethylaminomethyl-aioilino)-1-(4-carbamoylmethyl-phenyl)-21.9 methylene]-6-lluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(4-(2-dimethylcarbamoyl-21.10 ethyl)-phenyl)-methyl;ne]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(4-(2-(4-methyl-piperazin-1-21.11 yl-carbonyl)-ethyl)-phenyl)-niethylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-21.12 anilino)-1-(4-carbamoylmethyl-phEnyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-21.13 anilino)-1-(4-carbamoylmethyl-phEnyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethyl-aililino)-1-(4-dimethylcarbamoylmethyl-21.14 phenyl)-methylene ]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethyl-~ nilino)-1-(4-methylcarbamoylmethyl-21.15 phenyl)-methylene ]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-21.16 anilino)-1-(4-methylcarbamoylmethyl-phenyl)-methylene]-6-fluoro-2-ind ~linone 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-21.17 anilino)-1-(4-dimethylcarbamoyln~ethyl-phenyl)-methylene]-6-fluoro-2-ind ~linone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-21.18 anilino)-1-(4-methylcarbamoylmethyl-phenyl)-methylene]-6-fluoro-2-ind ~linone 3-Z-[1-(4-(N-methyl-N-acetyl-ami~ io)-anilino)-1-(4-(2-methylcarbamoyl-21.19 ethyl)-phenyl)-methylne]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-21.20 anilino)-1-(4-(2-methylcarbamoyl~~ethyl)-phenyl)-methylene]-6-fluoro-ind olinone 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-21.21 anilino)-1-(4-(2-methylcarbamoyl~~ethyl)-phenyl)-methylene]-6-fluoro-indalinone 3-Z-[1-(4-(N-tert.butoxycarbonyl-i nethylamino-methyl)-anilino)-1-(4-(2-21.22 methylcarbamoyl-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-( 1-methyl-imidazol-2-~'I)-anilino)-1-(4-(2-methylcarbamoyl-21.23 ethyl)-phenyl)-methylne]-6-fluoro-2-indolinone 3-Z-[1-(4-methylsulphonyl-anilino)-1-{4-(2-methylcarbamoyl-ethyl)-21.24 phenyl)-methylen~]-6-fluoro-2-indolinone 3-Z-[1-(4-(4-methyl-piperaz~n-1-yl-carbonyl)-anilino)-1-(4-(2-21.25 methylcarbamoyl-ethyl)-phen~~l)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(4-methyl-piperazin-1-yl-carbonyl)-anilino)-1-(3-21.26 methylcarbamoylmethyl-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-'I-yl-methylcarbonyl)-N-methyl-amino)-21.27 anilino)-1-(3-methylcarbamoylrr ethyl-phenyl)-methylene]-6-fluoro-2-inc olinone 3-Z-[1-(4-(4-methyl-piperazin-1-yl -methyl)-anilino)-1-phenyl-methylene]-22.0 6-chloro-1,3-di hydro-indol-2-thion 3-Z-[1-(4-(N-acetylaminomethyl~;arbonyl-N-methyl-amino)-anilino)-1-23.0 phenyl-methyleneJ-6-chloro-2-indolinone 3-Z-[1-(4-(N-(2-dimethylamino-~ahyl)-N-acetyl-amino)-anilino)-1-(4-23.1 acetylamino-phenyl)-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(dimethylamino-methylcarbonyl)-N-methyl-amino)-anilino)-23.2 1-(4-acetylamino-phenyl)-rr ethylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-23.3 anilino)-1-(4-acetylamino-phen~~l)-methylene]-6-chloro-2-indolinone 3-Z-(1-(4-(piperazin-1-yl-carbonyl)-anilino)-1-(4-acetylamino-phenyl)-23.4 methylene]-6-c;hloro-2-indolinone 3-Z-[1-(4-dimethylaminomethyi-anilino)-1-(4-acetylamino-phenyl)-23.5 methylene]-6-c:hloro-2-indolinone 3-Z-[1-(4-dimethylaminometh~~l-anilino)-1-(4-acetylaminomethyl-23.6 phenyl)-methylene~-6-chioro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-23.7 anilino)-1-(4-acetylaminometryl-phenyl)-methylene]-6-chloro-2-ind ~linone 3-Z-[1-(4-d imethylaminomethyl-anilino)-1-(4-benzoylamino-phenyl)-23.8 methylene]-6-~;hloro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-' -yl-methylcarbonyl)-N-methyl-amino)-23.9 anilino)-1-(4-benzoylaminomelhyl-phenyl)-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(3-acetylaminomethyl-23.10 phenyl)-methylenE~]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(3-propionylaminomethyl-23.11 phenyl)-methylenE ]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(3-benzoylaminomethyl-23.12 phenyl)-methylenE ]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethyl-aoilino)-1-(3-phenylacetylaminomethyl-23.13 phenyl)-methylenE]-6-fluoro-2-indolinone 3-Z-[1-(4-d imethylaminomethyl~ ~anilino)-1-(3-(2-acetylamino-ethyl)-23.14 phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethyl-~~nilino)-1-(3-(2-benzoylamino-ethyl)-23.15 phenyl)-methylene ]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(3-(2-propionylamino-ethyl)-23.16 phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(3-(2-phenylacetylamino-23.17 ethyl)-phenyl)-methylne]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminometh~rl-anilino)-1-(4-acetylaminomethyl-23.18 phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(4-propionylaminomethyl-23.19 phenyl)-methylene ]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethyl-aioilino)-1-(4-phenylacetylaminomethyl-23.20 phenyl)-methylene ]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-'1-yl-methylcarbonyl)-N-methyl-amino)-23.21 anilino)-1-(4-acetylaminometloyl-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-' -yl-methylcarbonyl)-N-methyl-amino)-23.22 anilino)-1-(4-propionylaminomE~thyl-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-' -yl-methylcarbonyl)-N-methyl-amino)-23.23 anilino)-1-(4-phenylacetylaminor~ethyl-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-23.24 anilino)-1-(3-cyclopropylcarbonylaminomethyl-phenyl)-methylene]-6-fluoro-a'.-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-23.25 aniiino)-1-(3-cyclobutylcarbonyl~minomethyl-phenyl)-methylene]-6-fluoro-~-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-23.26 anilino)-1-(3-(pyridin-2-yl-carbonylaminomethyl)-phenyl)-methylene]-fluoro-~-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-23.27 anilino)-1-(3-cyclohexylcarbonylaminomethyl-phenyl)-methylene]-6-fluoro ~-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-23.28 anilino)-1-(3-(pyridin-3-yl-carbonylaminomethyl}-phenyl)-methylene]-fluoro-~ -indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-23.29 anilino)-1-(3-isobutyrylaminomEthyl-phenyl)-methylene]-6-fluoro-2-ind ~linone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-23.30 anilino)-1-(3-(3-methylbutyryl-~minomethyl-phenyl)-methylene]-6-fluoro-~-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin- I-yl-methylcarbonyl)-N-methyl-amino)-23.31 anilino)-1-(3-cyclohexylmetllylcarbonylaminomethyl-phenyl)-methylene]-6-Fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-'I-yl-methylcarbonyl)-N-methyl-amino)-23.32 anilino)-1-(3-methoxyacetylamincmethyl-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-' I -yl-methylcarbonyl)-N-methyl-amino)-23.33 anilino)-1-(3-(2-methoxybenzoyl~~aminomethyl)-phenyl)-methylene]-6-fluoro-:!-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-' -yl-methylcarbonyl)-N-methyl-amino)-23.34 anilino)-1-(3-tert.butylacetylaminomethyl-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-' -yl-methylcarbonyl)-N-methyl-amino)-23.35 anilino)-1-(3-(2-thiophen-carbony laminomethyl)-phenyl)-methylene]-6-fluoro-a'.-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-23.36 anilino)-1-(3-pivaloylaminomeihyl-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-23.37 anilino)-1-(3-(2-furoylaminomethyl)-phenyl)-methylene]-6-fluoro-2-ind ~linone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-23.38 anilino)-1-(3-acetylaminomettiyl-phenyl)-methylene]-6-fluoro-2-ind ~linone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-23.39 anilino)-1-(3-propionylaminomEthyl-phenyl)-methylene]-6-fluoro-2-ind ~linone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-y1-methylcarbonyl)-N-methyl-amino)-23.40 anilino)-1-(3-benzoylaminomeihyl-phenyl)-methylene]-6-fluoro-2-ind ~linone 3-Z-[1-(4-(N-(4-methyl-piperazin- I-yl-methylcarbonyl)-N-methyl-amino)-23.41 anilino)-1-(3-phenylacetylaminornethyl-phenyl)-methylene]-6-fluoro-2-inc olinone 3-Z-[1-(4-dimethylar ninomethyl-anilino)-1-(3-23.42 cyclopropylcarbonylaminomei hyl-phenyl)-methylene]-6-fluoro-2-ind olinone 3-Z-[1-(4-dimethylarninomethyl-anilino)-1-(3-23.43 cyclobutylcarbonylaminometl~yl-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminom ethyl-anilino)-1-(3-(pyridin-2-yl-23.44 carbonylaminomethyl)-phenyl )-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylarninomethyf-anilino)-1-(3-23.45 cyclohexylcarbonylaminometl~yl-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminom~ahyl-anilino)-1-(3-(pyridin-3-yl-23.46 carbonylaminomethyl)-phenyl )-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(3-isobutyrylaminomethyl-23.47 phenyl)-methylenE ]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomettryl-anilino)-1-(3-(3-methylbutyryl-23.48 aminomethyl-phenyl)-me :hylene]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylar iinomethyl-anilino)-1-(3-23.49 cyclohexylmethylcarbonylaminor~ethyl-phenyl)-methylene]-f-fluoro-2-ind ~linone 3-Z-[1-(4-dimethylan iinomethyl-anilino)-1-(3-23.50 methoxyacetylaminomethyl-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-d imethylaminomethy I-anilino)-1-(3-(2-methoxybenzoyl-23.51 aminomethyl)-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylan~inomethyl-anilino)-1-(3-23.52 tert.butylacetylaminomethyl-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomrthyl-anilino)-1-(3-(2-thiophen-23.53 carbonylaminomethyl)-phenyl )-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(3-pivaloylaminomethyl-23.54 phenyl)-methylenE ]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(3-(2-furoylaminomethyl)-23.55 phenyl)-methylenE ]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminom~ahyl-anilino)-1-(3-(pyridin-4-yl-23.56 carbonylaminomethyl)-phenyl I-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylariinomethyl-anilino)-1-(4-24.0 phenylsulphonylaminomethyl-phenyl)-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-24.1 anilino)-1-(4-methylsulphonylaminomethyl-phenyl)-methylene]-6-chloro-2-in~iolinone 3-Z-[1-(4-dimethylar~inomethyl-anilino)-1-(4-24.2 methylsulphonylaminomethyl-phenyl)-methylene]-6-chloro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-24.3 anilino)-1-(4-phenylsulphonylaminomethyl-phenyl)-methylene]-6-chloro-2-imiolinone 3-Z-[1-(4-dimethylan~inomethyl-anilino)-1-(3-24.4 methylsulphonylaminomethyl-phe nyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylar~inomethyl-anilino)-1-(3-24.5 ethylsulphonylaminomethyl-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylariinomethyl-anilino)-1-(3-24.6 phenylsulphonylaminomethyl-phE nyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(3-(2-ethylsulphonylamino-24.7 ethyl)-phenyl)-methyl:ne]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylariinomethyl-anilino)-1-(4-24.8 methylsulphonylaminomethyl-phE nyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylarninomethyl-anilino)-1-(4-24.9 ethylsulphonylaminomethyl-phenyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-dimethylarninomethyl-anilino)-1-(4-24.10 benzylsulphonylaminomethyl-phE~nyl)-methylene]-6-fluoro-2-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-' -yl-methylcarbonyl)-N-methyl-amino)-24.11 anilino)-1-(4-methylsulphonylami~iomethyl-phenyl)-methylene]-6-fluoro-2-in ~olinone 3-Z-[1-(4-(N-(4-methyl-piperazin-' -yl-methylcarbonyl)-N-methyl-amino)-24.12 anilino)-1-(4-ethylsulphonylaminomethyl-phenyl)-methylene]-6-fluoro-indolinone 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-24.13 anilino)-1-(4-benzylsulphonylamirnomethyl-phenyl)-methylene]-6-fluoro-2-in~~olinone 3-Z-f 1-(4-trimethylammoniumm~ahyl-anilino)-1-(4-(2-carboxy-ethyl)-25.0 phenyl)-methylenel-6-fluoro-2-indolinone-iodide 3-Z-f 1-(4-trimethylammoniumm~ahyl-anilino)-1-(3-(2-carboxy-ethyl)-25.1 phenyl)-methylenel-6-fluoro-2-indolinone-iodide 3-Z-f 1-(4-auanidinomethyl-anili no)-1-(4-(2-carboxy-ethyl)-phenyl)-26.0 methylenel-6-iluoro-2-indolinone 3-Z-f 1-(4-auanidinomethyl-anili no)-1-(3-(2-carboxv-ethyl)-phenyl ~

26.1 methylenel-6-lluoro-2-indolinone Abbreviations used:
HOBt= 1-hydroxy-1H-benzotriazole TBTU = O-benzotriazol-1-yl-N,N,N',N'=:etramethyluronium-tetrafluoroborate Preparation of the starting compounds:
Example I:
dimethyl 2-(4-fluoro-2-nitroahenyl)-malonat~;
185 g of potassium-tert-butoxide are added to a solution of 188 ml of dimethyl malonate in 970 ml of N-methylpyrrolidone, while cooling with ice, and the mixture is stirred for 2 hours. 150 ml of 2,5-~lifluoronitrobenzene are added dropwise to the resulting suspension over a period of 30 minutes and then stirred for 6 hours at 85 °C. The mixture is ~~oured onto 4 litres of ice water and 250 ml of concentrated hydrochloric ac d and extracted with 2 litres of ethyl acetate. The organic phase is dried with sodium sulphate and evaporated down. The oily residue is stirreC twice with water and then taken up in 600 ml ethyl acetate. The solution is dried with sodium sulphate and evaporated to dryness. The crystallised crude product is recrystallised from 600 ml ethyl acetatelhexane = 2:8 and dried.
Yield: 222 g (59 % of theory) Rf value: 0.40 (silica gel, cyclohexanelethyl acetate = 5:1 ) C11H1oFNOs Mass spectrum: mlz = 270 [M-H]-The following compounds are prepared analogously to Example I:
(1.1 ) diethyl 2-(4-bromo-2-nitrophenyi)-malooate from 2,5-dibromonitrobenzene and diethyl n~alonate Rf value: 0.40 (silica gel, petroleum ether/ef~iyl acetate = 5:1 ) C13H14grNOg Mass spectrum: m!z = 3591361 [M]+
(1.2) dimethyl 2-(4-cyano-2-nitrophenyl)-malonate from 4-chloro-3-nitro-benzonitrile and dimetl~yl malonate Rf value: 0.50 (silica gel, methylene chloridelmethanol = 50:1 ) ClzH1oN20s Mass spectrum: mlz = 277 [M-H]~

Example II:
methyl 4-cyano-2-nitroahenylacetate 14.2 g dimethyl 2-(4-cyano-2-nitrophenyl)-rr~alonate (educt 1.2) are dissolved in 200 ml dimethylsulphoxide and 4.5 g lithium chloride and 1.0 ml of water is added. The solution is stirred for 3.5 hours pit 100 °C, then combined with 300 ml ice water and left to stand for 12 hours. 'l~he precipitate formed is suction filtered, taken up in methylene chloride and washed with water. The organic phase is dried over sodium sulphate, conce ~trated in the rotary evaporator and dried.
Yield: 7.7 g (68 % of theory) Rf value: 0.40 (silica gel, methylene chloridE~lmethanol) = 50:1 C10HSN2~4 Mass spectrum: m/z = 219 [M-HJ
Example III:
4-fluoro-2-nitrophenylacetic acid 50.0 g of dimethyl 2-(4-fluoro-2-nitrophenyl) ~malonate (educt I) are stirred in 400 ml of 6 molar hydrochloric acid for 20 h~~urs at 100 °C, then combined with 400 ml of water and cooled to 0 °C. The: precipitate formed is suction filtered, washed with water and 100 ml petroleum ether and dried.
Yield: 34.5 g (94 % of theory) Rf value: 0.30 (silica gel, cyclohexane/ethyl acetate) = 5:2 CsH6FN04 Mass spectrum: mlz = 154 [M-COO-H]-Example IV:
6-fluoro-2-indolinone 119 g 4-fluoro-2-nitrophenylacetic acid (educt III) are hydrogenated in 600 ml acetic acid with the addition of 20 g palladium on activated charcoal (10%) under 50 psi of hydrogen pressure. The cat~~lyst is suction filtered and the solvent is distilled off. The crude product is extracted with 500 ml petroleum ether, suction filtered, washed with water arid dried.
Yield: 82.5 g (91 % of theory) Rf value: 0.30 {silica gel, petroleum etherleihyl acetate = 1:1 ) Mass spectrum: mlz = 150 [M-H]' The following compounds are prepared analogously to Example IV:
(IV.1 ) 6-bromo-2-indolinone from diethyl 2-(4-bromo-2-nitrophenyl)-malcnate (educt 1.1) with Raney nickel as hydrogenation catalyst Rf value: 0.45 (silica gel, petroleum ether/et~yl acetate = 1:1 ) C8H6BrN0 Mass spectrum: mlz = 2101212 [M-H]' (IV.2) 6-cyano-2-indolinone from methyl 4-cyano-2-nitrophenylacetate (educt II) with palladiumlcalcium carbonate as hydrogenation catalyst Rf value: 0.45 (silica gel, methylene chloridE~lmethanol = 9:1 ) Mass spectrum: mlz = 157 [M-H]' Example V:
1-acetyl-6-fluoro-2-indolinone 82.5 g 6-fluoro-2-indolinone (educt IV) are stirred in 180 ml acetic anhydride for 3 hours at 130 °C. After cooling to ambiE nt temperature the precipitate is suction filtered, washed with 100 ml of petrc leum ether and dried.
Yield: 64.8 g (61 % of theory) Rf value: 0.75 (silica gel, petroleum etherletloyl acetate = 1:1 ) C~oH8FN02 Mass spectrum: m/z = 192 [M-H]' The following compounds are prepared an~~logously to Example V:
(V.1) 1-acetyl-6-chloro-2-indolinone from 6-chloro-2-indolinone and acetic anhydride R, value: 0.55 (silica gel, petroleum etherleihyl acetate = 2:3) C~~H~oCIN06 Mass spectrum: mlz = 2081210 [M-H]-(V.2) 1-acetyl-6-bromo-2-indolinone from 6-bromo-2-indolinone (educt IV.1 ) and acetic anhydride Rf value: 0.60 (silica gel, petroleum ether/ethyl acetate = 2:1 ) C,oH8BrN02 Mass spectrum: mlz = 2531255 [M]+
(V.3) 1-acetyl-6-cyano-2-indolinone from 6-cyano-2-indolinone (educt IV.2) and acetic anhydride Rf value: 0.60 (silica gel, methylene chloridE~lmethanol = 50:1 ) C~~H8Nz02 Mass spectrum: mlz = 199 [M-H]' Example VI:
1-acetyl-5-nitro-6-chloro-2-indolinone 2.75 g 1-acetyl-6-chloro-2-indolinone (educt V.1 ) are placed in 40 ml concentrated sulphuric acid and at -10°C 1.05 g of ammonium nitrate are added. The mixture is stirred for 1.5 hours at ambient temperature. After this time the mixture is poured onto ice water and stirred for a further 20 minutes.
The solution is neutralised with concentrated ammonia, the precipitate formed is suction filtered and washed with a little ethanol and ether.
Yield: 2.80 g (84 % of theory) C~oH~CIN20a Mass spectrum: mlz = 254 [M]+

Example VII:
1-acetyl-3-(1-hyd roxy-1-(3-iodo-phenyl)-mei hylenel-6-chloro-2-indolinone 10.5 g 1-acetyl-6-chloro-2-indolinone (educe V.1 ), 13.6 g 3-iodobenzoic acid and 17.7 g TBTU are placed in 100 ml of diinethylformamide, 35 ml triethylamine are added and the mixture is ~ tirred for 12 hours at ambient temperature. After this time the solvent is eliminated, the residue is combined with water, suction filtered and washed with a little water, methanol and ether and dried in vacuo at 100°C.
Yield: 12.9 g (59 % of theory) Rf value: 0.80 (silica gel, methylene chloridelmethanol = 9:1 ) C~7H~~CIIIVC3 Mass spectrum: mlz = 4381440 [M-H]-The following compounds are prepared analogously to Example VII:
(V11.1 ) 1-acetyl-3-[1-hydroxy-1-(4-methoxyc;~rbonylmethyl-phenyl)-methylene)-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (educt V) and methyl (4-carboxyphenyl)-acetate (prepared according to Tetrahedron 1997, 53, 7335-7340) (VI1.2) 1-acetyl-3-[1-hydroxy-1-(4-chloro-phEnyl)-methylene]-6-chloro-2-indolinone from 1-acetyl-6-chloro-2-indolinone (educt ~'.1 ) and 4-chloro-benzoic,acid (VI1.3) 1-acetyl-3-[1-hydroxy-1-(4-benzyloxy~phenyl)-methylene]-6-chloro-2-indolinone from 1-acetyl-6-chloro-2-indolinone (educt ~'.1 ) and 4-benzyloxy-benzoic acid (V11.4) 1-acetyl-3-[1-hydroxy-1-(3,4-dimetho:~y-phenyl)-methylene]-6-chloro-2-indolinone from 1-acetyl-6-chloro-2-indolinone (educt ~'.1 ) and 3,4-dimethoxy-benzoic acid (V11.5) 1-acetyl-3-[1-hydroxy-1-(3,4-dimethoxy-phenyl)-methylene]-6-cyano-2-indolinone from 1-acetyl-6-cyano-2-indolinone (educt \~.3) and 3,4-dimethoxy-benzoic acid (VI1.6) 1-acetyl-3-[1-hydroxy-1-(3-vitro-4-hydroxy-phenyl)-methylene]-6-chloro-2-indolinone from 1-acetyl-6-chloro-2-indolinone (educt \~.1 ) and 3-vitro-4-hydroxy-benzoic acid (V11.7) 1-acetyl-3-[1-hydroxy-1-(3-fluoro-phenyl)-methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (educt V) and 3-fluoro-benzoic acid (V11.8) 1-acetyl-3-[1-hydroxy-1-(4-(2-acetyla~ino-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone from 1-acetyl-f-fluoro-2-indolinone (educt V) and 4-(2-acetylamino-ethyl)-benzoic acid (prepared according to J. Am. Chem. Soc. 1943, 65, 2377) (Vll.9) 1-acetyl-3-[1-hydroxy-1-(3,4,5-triouor~-phenyl)-methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (educt V) and 3,4,5-trifluoro-benzoic acid (V11.10) 1-acetyl-3-[1-hydroxy-1-(3-methoxy~;arbonylmethyl-phenyl)-methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (educt V) and (3-carboxyphenyl)-acetate methyl (prepared analogously to Tetrahedrc n 1997, 53, 7335-7340) (VI1.11) 1-acetyl-3-[1-hydroxy-1-(3-(N-tert.b~itoxycarbonyl-aminomethyl)-phenyl)-methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (educt V~ and 3-(N-tert.butoxycarbonyl-aminomethyl)-benzoic acid (prepared acconling to Tetrahedron 1997, 53, 7335-7340) (V11.12) 1-acetyl-3-[1-hydroxy-1-(3-cyanomEahyl-phenyl)-methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (educt V) and (3-carboxy-phenyl)-acetonitrile (prepared according to J. Prakt. Chem. 1998, 340, 367-374) (V11.13) 1-acetyl-3-[1-hydroxy-1-(4-(N-tert.butoxycarbonyl-aminomethyl)-phenyl)-methylene)-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (educt V) and 4-(N-tert.butoxycarbonyl-aminomethyl)-benzoic acid (prepared according to Bioorg. Med. Chem. Lett 2000, 70, 553-557) (V11.14) 1-acetyl-3-[1-hydroxy-1-(4-iodo-phenyl)-methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (educt V ) and 4-iodo-benzoic acid (V11.15) 1-acetyl-3-[1-hydroxy-1-(4-iodo-phenyl)-methylene]-6-chloro-2-indolinone from 1-acetyl-6-chloro-2-indolinone (educt ~'.1 ) and 4-iodo-benzoic acid (V11.16) 1-acetyl-3-[1-hydroxy-1-(3-iodo-phenyl)-methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (educt V) and 3-iodo-benzoic acid (V11.17) 1-acetyl-3-[1-hydroxy-1-(4-(2-methcxycarbonylethyl)-phenyl)-methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (educt V) and 4-(2-methoxycarbonylethyl)-benzoic acid (prepared analogously to Tetrahedron 1997, 53, 7335-7340) (V11.18) 1-acetyl-3-[1-hydroxy-1-(3-(2-methoxycarbonylethyl)-phenyl)-methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (educt V) and 3-(2-methoxycarbonylethyl)-benzoic acid (prepared analogously to Tetrahedron 199?, 53, 7335-7340) (V11.19) 1-acetyl-3-[1-hydroxy-1-(3-(N-tert.b.itoxycarbonyl-2-aminoethyl)-phenyl)-methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (educt ~) and 3-(N-tert.butoxycarbonyl-2-aminoethyl)-benzoic acid (prepared analog«usly to Bioorg. Med. Chem. Lett 2000, 10, 553-557) (V11.20) 1-acetyl-3-[1-hydroxy-1-(4-(N-tert.butoxycarbonyl-2-aminoethyl)-phenyl)-methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (eduet V) and 4-(N-tert.butoxycarbonyl-2-aminoethyl)-benzoic acid (prepared analogously to Bioorg. Med. Chem. Lett 2000, ?0, 553-557) (V11.21 ) 1-acetyl-3-[1-hydroxy-1-(4-acE~tylamino-3-nitro-phenyl)-methylene]-6-chloro-2-indolinone from 1-acetyl-6-chloro-2-indolinone (educt \'.1 ) and 3-acetylamino-4-nitro-benzoic acid (V11.22) 1-acetyl-3-[1-hydroxy-1-(4-(im dazol-1-yl-methyl)-phenyl)-methylene]-6-chloro-2-indolinone from 1-acetyl-6-chloro-2-indolinone (educt ~'.1 ) and 4-(imidazol-1-yl-methyl)-benzoic acid (prepared according to J. Med Chem. 1987, 30, 1342-1347) (V11.23) 1-acetyl-3-[1-hydroxy-1-(4-{2-oxo-pyrrolidin-1-yl)-phenyl)-methylene]-6-chloro-2-indolinone from 1-acetyl-6-chloro-2-indolinone (educt ~'.1 ) and 4-(2-oxo-pyrrolidin-1-yl)-benzoic acid (prepared according to J. Med Chem. 1999, 42, 2332-2343) (V11.24) 1-acetyl-3-[1-hydroxy-1-(4-nitro-phenyl)-methylene]-6-chloro-2-indolinone from 1-acetyl-6-chloro-2-indolinone (educt ~'.1 ) and 4-nitro-benzoic acid (VI1.25) 1-acetyl-3-[1-hydroxy-1-(4-cyano-phenyl)-methylene]-6-chloro-2-indolinone from 1-acetyl-6-chloro-2-indolinone (educt ~'.1 ) and 4-cyano-benzoic acid (V11.26) 1-acetyl-3-[1-hydroxy-1-(3-ac~tylaminomethyl-phenyl)-methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (educt ~') and 3-acetylaminomethyl-benzoic acid (prepared according to J. Med. Chem. 1997, 40, 4030-4.052) (VI1.27) 1-acetyl-3-[1-hydroxy-1-(3-(2-ethox~carbonylethyl)-phenyl)-methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (educt V) and 3-(2-ethoxycarbonylethyl)-benzoic acid (prepared analogously to Tetr~~hedron 1997, 53, 7335-7340) (V11.28) 1-acetyl-3-[1-hydroxy-1-(4-(2-methc~xycarbonylethyl)-phenyl)-methylene]-6-chloro-2-indolinone from 1-acetyl-6-chloro-2-indolinone (educt \~.1 ) and 4-(2-methoxycarbonylethyl)-benzoic acid (prepared analogously to Tetrahedron 1997, 53, 7335-7340) (V11.29) 1-acetyl-3-[1-hydroxy-1-(4-(2-ethoxycarbonylethyl)-phenyl)-methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (educt V) and 4-(2-ethoxycarbonylethyl)-benzoic acid (prepared analogously to Tetr~~hedron 1997, 53, 7335-7340) (V11.30) 1-acetyl-3-[1-hydroxy-1-(3-methoxy~:arbonylmethyloxy-phenyl)-methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (educt V) and 3-methoxycarbonyl-methyloxy-benzoic acid (for preparation see Tetrahedron Letters 1998, 39, 8563-8566) (VI1.31 ) 1-acetyl-3-[1-hydroxy-1-(4-methoxy;arbonylmethyloxy-phenyl)-methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (educt V) and 4-methoxycarbonyl-methyloxy-benzoic acid (prepared analogously to Tetrahedron Letters 1998, 39, 8563-8566) (V11.32) 1-acetyl-3-[1-hydroxy-1-(3-(2-ethoxvcarbonyl-ethyloxy)-phenyl)-methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (educt V~ and 3-(2-ethoxycarbonyl-ethyloxy)-benzoic acid (for preparation see I~CT Int. Appl. W09620173, 60) (V11.33) 1-acetyl-3-[1-hydroxy-1-(4-(2-ethox~~carbonyl-ethyloxy)-phenyl)-methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (educt V) and 4-(2-ethoxycarbonyl-ethyloxy)-benzoic acid (for preparation see I~CT Int. Appl. W09620173, 58) Example VIII:
1-acet I-3- 1-methox -1- 3-iodo- hen I -methylenel-6-chloro-2-indolinone 2.36 g of trimethyloxonium tetrafluoroborate are added batchwise to a solution of 3.52 g of 1-acetyl-3-[1-hydroxy-1-(3-iodo-phenyl)-methylene]-6-chloro-2-indolinone (educt VII) and 2.72 ml of ethyldiisopropylamine in 80 ml dichloromethane and the mixture is stirred f~~r one hour at ambient temperature. Then another 1.4 ml ethyldiisopropylamine and 1.2 g trimethyloxonium tetrafluoroborate are added and the mixture is stirred for a further two hours at ambient temperature. T ien it is extracted with water, the organic phase is dried over magnesium sul f~hate and evaporated to dryness.
The residue is recrystallised from ether and dried in vacuo at 80 °C.
Yield: 2.40 g (66 % of theory) Rf value: 0.60 (silica gel, petroleum etherldi~;hloromethanelethyl acetate =
5:4:1 ) Mass spectrum: mlz = 4381440 [M-H]-M.p. 185 - 187 °C
The following compounds are prepared ana ogously to Example VIII:
(V111.1 ) 1-acetyl-3-[1-methoxy-1-(4-mE thoxycarbonylmethyl-phenyl)-methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(4-methoxycarbonylmethyl-phenyl)-methylene]-6-fluoro-2-indolinone (educt VI1.1 ) (V111.2) 1-acetyl-3-[1-methoxy-1-(4-chloro-phenyl)-methylene]-6-chloro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(4-chloro-phenyl)-methylene]-6-chloro-2-indolinone (educt V11.2) (V111.3) 1-acetyl-3-[1-methoxy-1-(4-benzyloxy-phenyl)-methylene]-6-chloro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(4-benzyloxy-~~henyl)-methylene]-6-chloro-2-indolinone (educt V11.3) (V111.4) 1-acetyl-3-[1-methoxy-1-(3,4-climethoxy-phenyl)-methylene]-6-chloro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(3,4-dimethoxy-phenyl)-methylene]-6-chloro-2-indolinone (educt V11.4) (VI11.5) 1-acetyl-3-[1-methoxy-1-(3,4-climethoxy-phenyl)-methylene]-6-cyano-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(3,4-dimethox~~-phenyl)-methylene]-6-cyano-2-indolinone (educt V11.5) (V111.6) 1-acetyl-3-[1-methoxy-1-(3-nitno-4-hydroxy-phenyl)-methylene]-6-chloro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(3-nitro-4-hydr~~xy-phenyl)-methylene]-6-chloro-2-indolinone (educt VI1.6) (V111.7) 1-acetyl-3-[1-methoxy-1-(3-fluoro-phenyl)-methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(3-fluoro-phernil)-methylerre]-6-fluoro-2-indolinone (educt V11.7) (V111.8) 1-acetyl-3-[1-methoxy-1-(4-(2-acetylamino-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(4-(2-acetylamino-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (educt V11.8) (V111.9) 1-acetyl-3-[1-methoxy-1-(3,4,~-trifluoro-phenyl)-methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(3,4,5-trifluoro-phenyl)-methylene]-6-fluoro-2-indolinone (educt VI1.9) (V111.10) 1-acetyl-3-[1-methoxy-1-(3-mEthoxycarbonylmethyl-phenyl)-methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(3-methoxycar~onylmethyl-phenyl)-methylene]-6-fluoro-2-indolinone (educt V11.10) (V111.11) 1-acetyl-3-[1-methoxy-1-(3-(N~tert.butoxycarbonyl-aminomethyl)-phenyl)-methylene]-6-fluoro-c-indolinone from 1-acetyl-3-[1-hydroxy-1-(3-(N-tert.buto;cycarbonyl-aminomethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (educt VI1.11 ) (V111.12) 1-acetyl-3-[1-methoxy-1-(3-cy~~nomethyl-phenyl)-methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(3-cyanometh~~l-phenyl)-methylene]-6-fluoro-2-indolinone (educt V11.12) (V111.13) 1-acetyl-3-[1-methoxy-1-(4-(N~~tert.butoxycarbonyl-aminomethyl)-phenyl)-methylene]-6-fluoro-~ -indolinone from 1-acetyl-3-[1-hydroxy-1-(4-(N-tert.buto:<ycarbonyl-aminomethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (educt V11.13) (V111.14) 1-acetyl-3-[1-methoxy-1-(4-ioco-phenyl)-methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(4-iodo-phenyl)-methyleneJ-6-fluoro-2-indolinone (educt V11.14) (V111.15) 1-acetyl-3-[1-methoxy-1-(4-iocio-phenyl)-methylene]-6-chloro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(4-iodo-pheny )-methylene]-6-chloro-2-indolinone (educt VI1.15) (V111.16) 1-acetyl-3-[1-methoxy-1-(3-ioclo-phenyl)-methylene)-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(3-iodo-phenyl)-methylene]-6-fluoro-2-indolinone (educt V11.16) (V111.17) 1-acetyl-3-[1-methoxy-1-(3-(2-methoxycarbonylethyl)-phenyl)-methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(3-(2-methoxy;arbonylethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (educt V11.17) (VI11.18) 1-acetyl-3-[1-methoxy-1-(4-(2-methoxycarbonylethyl)-phenyl)-methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(4-(2-methoxy~;arbonylethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (educt VI1.18) (V111.19) 1-acetyl-3-[1-methoxy-1-(4-(N~tert.butoxycarbonyl-2-aminoethyl)-phenyl)-methylene]-6-fluoro-2-ii~dolinone from 1-acetyl-3-[1-hydroxy-1-(4-(N-tert.buto;cycarbonyi-2-aminoethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (educt VII.:?0) (VI11.20) 1-acetyl-3-[1-methoxy-1-(3-(N-tert.butoxycarbonyl-2-aminoethyl)-phenyl)-methylene]-6-fluoro-2-iodolinone from 1-acetyl-3-[1-hydroxy-1-(3-(N-tert.buto;cycarbonyl-2-aminoethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (educt VI1.19) (V111.21) 1-acetyl-3-[1-methoxy-1-(3-ac~;tylaminomethyl-phenyl)-methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(3-acetylamincmethyl-phenyl)-methylene]-6-fluoro-2-indolinone (educt VI1.26) (V111.22) 1-acetyl-3-[1-methoxy-1-(3-(2-ethoxycarbonylethyl)-phenyl)-methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(3-(2-ethoxycarbonylethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (educt VI1.27) (V111.23) 1-acetyl-3-[1-methoxy-1-(4-(2-methoxycarbonylethyl)-phenyl)-methylene]-6-chloro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(4-(2-methoxy~;arbonylethyl)-phenyl)-methylene]-6-chloro-2-indolinone (educt V11.28) (V111.24) 1-acetyl-3-[1-methoxy-1-(4-(2-ethoxycarbonylethyl)-phenyl)-methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(4-(2-ethoxycarbonylethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (educt VI1.29) (V111.25) 1-acetyl-3-[1-methoxy-1-(4-mE~thoxycarbonylmethyloxy-phenyl)-methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(4-methoxycar5onylmethyloxy-phenyl)-methylene]-6-fluoro-2-indolinone (educt VII. 30) (V111.26) 1-acetyl-3-[1-methoxy-1-(3-mE~thoxycarbonylmethyloxy-phenyl)-methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(3-methoxycarbonylmethyloxy-phenyl)-methylene]-6-fluoro-2-indolinone (educt VI I. 31 ) (V111.27) 1-acetyl-3-[1-methoxy-1-(3-(2-ethoxycarbonyl-ethyloxy)-phenyl)-methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(3-(2-ethoxycarbonyl-ethyloxy)-phenyl)-methylene]-6-fluoro-2-indolinone (educt V11.32) (V111.28) 1-acetyl-3-[1-methoxy-1-(4-(2~~ethoxycarbonyl-ethyloxy)-phenyl)-methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(4-(2-ethoxycarbonyl-ethyloxy)-phenyl)-methylene]-6-fluoro-2-indolinone (educt V11.33) Example IX:
1-acetyl-3-f 1-ethoxy-1-phenyl-methylenel-6 ~chloro-2-indolinone A solution of 41.9 g 1-acetyl-6-chloro-2-indc~linone (educt V.1 ) and 136 ml triethyl orthobenzoate in 150 ml acetic anhydride is stirred for six hours at 120°C. After cooling the mixture is evaporated down by half, the crystals precipitated are suction filtered and dried at 100 °C in vacuo.
Yield: 38.0 g (56 % of theory) Rf value: 0.60 (silica gel, petroleum etherldi ;hloromethanelethyl acetate =
5:4:1 ) C~sH~6CIN03 Mass spectrum: mlz = 3421344 [M+H]+
M.p. 185 - 187 °C
The following compounds are prepared analogously to Example IX:
(1X.1 ) 1-acetyl-3-[1-ethoxy-1-phenyl-methylE:ne]-6-bromo-2-indolinone from 1-acetyl-6-bromo-2-indolinone (educt \i.2) (1X.2) 1-acetyl-3-[1-ethoxy-1-phenyl-methylE:ne]-6-cyano-2-indolinone from 1-acetyl-6-cyano-2-indolinone (educt V'.3) (1X.3) 1-acetyl-3-[1-ethoxy-1-phenyl-methylE:ne]-6-fluoro-2-indolinone from 1-acetyl-fi-fluoro-2-indolinone (educt V) (1X.4) 1-acetyl-3-[1-ethoxy-1-phenyl-methylE:ne]-5-vitro-6-chloro-2-indolinone from 1-acetyl-5-vitro-6-chloro-2-indolinone (educt VI) Example X:
1-acetyl-3-f 1-chloro-1-(4-acetylamino-3-nitro-phenyl)met~ilenel-2-indolinone A suspension of 11.4 g of 1-acetyl-3-(1-hydroxy-1-(4-acetylamino-3-nitro--phenyl)methylene)-2-indolinone (educt VI I.~'.1 ) and 9.37 g of phosphorus pentachloride in 200 ml dioxane is stirred fc r 4 hours at 100 °C.
After the addition of a further 2.0 g of phosphorus pentachloride the mixture is stirred for a further 3 hours at 100 °C. Then the so vent is distilled off, the residue is stirred with 100 ml of ethyl acetate, suction filtered, washed with ethyl acetate and dried at 60 °C.
Yield: 6.40 g (53 % of theory) Rf value: 0.70 (silica gel, dichloromethane/sthyl acetate = 9:1 ) C19H14CIN3~5 Mass spectrum: mlz = 3981400 [M-H]~
The following compounds are prepared analogously to Example X:
(X.1 ) 1-acetyl-3-[1-chloro-1-(4-(imidazol-1-yl-methyl)-phenyl)-methylene]-6-chloro-2-indolinone from 1-acetyl-3-[1-hydroxy-1-(4-(imidazol-1-yl-methyl)-phenyl)-methylene]-6-chloro-2-indolinone (educt V11.22) (X.2) 1-acetyl-3-[1-chloro-1-(4-(2-oxo-pyrrol din-1-yl)-phenyl)-methylene]-6-chloro-2-indolinone from 1-acetyl-3-[1-chloro-1-(4-(2-oxo-pyrrofilin-1-yl)-methyl)-phenyl)-methylene]-6-chloro-2-indolinone (educt VII 23) (X.3) 1-acetyl-3-[1-chloro-1-(4-nitro-phenyl)-methylene]-6-chloro-2-indolinone from 1-acetyl-3-[1-chloro-1-(4-nitro-methyl)-phenyl)-methylene]-6-chloro-2-indolinone (educt VI1.24) (X.4) 1-acetyl-3-[1-chloro-1-(4-cyano-pheny )-methylene]-6-chloro-2-indolinone from 1-acetyl-3-[1-chloro-1-(4-cyano-methyl)-phenyl)-methylene]-6-chloro-2-indolinone (educt VI1.25) Example XI:
N-(2-dimethylamino-ethyl)-4-nitro-benzamic a 1.25 ml N,N-dimethylaminoethylamine are dissolved with 3 ml triethylamine in 20 ml methylene chloride and cooled to 0°C. Then 2 g of 4-nitrobenzoic acid chloride are added batchwise and the mixture is stirred for 5 minutes in the cold and for 20 minutes at ambient temperature. Finally, the precipitate is removed by suction filtering and the organic phase is washed with water, dried over sodium sulphate and concentratE~d in the rotary evaporator.
Yield: 1.8 g (70 % of theory) Rf value: 0.78 (silica gel, methylene chloridE;lmethanol = 9:1 ) C11H15N3~3 Mass spectrum: m/z = 238 [M+H]+
The following compounds are prepared analogously to Example XI:
(XI.1 ) N-(2-dimethylamino-ethyl)-N-methyl-4-vitro-benzamide (XI.2) N-(3-dimethylamino-propyl)-4-vitro-bE nzamide (X1.3) N-(3-dimethylamino-propyl)-N-methyl~~4-nitra-benzamide (XI.4) N-(2-dimethylamino-ethyl)-N-ethyl-4-vitro-benzamide.
(XI.S) N-(2-(tert-butyloxycarbonyl-methylam no-ethyl)-N-methyl-4-nitro-benzamide (X1.6) N,N-bis-(2-diethylamino-ethyl)-4-nitro~~benzamide (X1.7) N-(2-tert-butyloxycarbonyl-amino-eth~~l)-4-vitro-benzamide (X1.8) N-(2-dimethylamino-ethyl)-3-nitro-ber~zamide (X1.9) N-(2-dimethylamino-ethyl)-N-methyl-;~-nitro-benzamide (X1.10) N-(3-dimethylamino-propyl)-3-nitro-t~enzamide (X1.11 ) N-(3-dimethylamino-propyl)-N-methyl-3-nitro-benzamide (X1.12) 2-N-(dimethylamino-methyl)-carbamoyl-5-nitro-furan (X1.13) 4-(4-methyl-piperazin-1-yl-carbonyl)~~nitrobenzene (X1.14) 4-(piperidin-1-yl-carbonyl)-nitrobenzene (X1.15) N-cyclohexyl-N-methyl-4-nitro-benz~imide (X1.16) N-isopropyl-4-nitro-benzamide (X1.17) 4-(2,3,4,5-tetrahydro-1(H)-benzo[d]~zepin-3-yl-carbonyl)-nitrobenzene (X1.18) 4-(4-hydroxy-piperidin-1-yl-carbonyl;-nitrobenzene (X1.19) 4-(4-tert-butyloxycarbonyl-piperazin-1-yl-carbonyl)-nitrobenzene (X1.20) 4-(4-tert-butyloxycarbonyl-[1,4]diazepan-1-yl-carbonyl)-nitrobenzene (X1.21 ) 4-(N-(3-dimethylamino-propyl)-N-methyl-carbamoylmethyl)-nitrobenzene (X1.22) 4-(N-(2-dimethylamino-ethyl)-N-methyl-carbamoylmethyl)-nitrobenzene (X1.23) 4-[(4-methyl-piperazin-1-yl)-carbony methyl]-nitrobenzene Example XII:
2-amino-5-(4-methyl-piperazin-1-yl-carbonv! - ridine 3.00 g 6-amino-nicotinic acid are dissolved n 30 ml of dimethylformamide and 4.05 g of N,N-carbonyldiimidazole are added. The mixture is briefly heated to 70°C and then stirred for a further hour at a rbient temperature. After this time 4.85 ml of N-methylpiperazine are added arid the mixture is stirred for 12 hours at ambient temperature. The solvent is eliminated and the residue is purified through a silica gel column with mei hylene chloridelethanollammonia 7:1:0.1 as eluant.
Yield: 4.1 g (86 % of theory) Rf value: 0.60 (silica gel, methylene chloridE~lethanollammonia = 5:1:0.1 ) C11H1sNa0 Mass spectrum: mlz = 221 [M+H]+
The following compounds are prepared analogously to Example XII:
(X11.1 ) 4-nitro-1-methyl-2-[(2-dimethylamino~~ethyl)-N-methyl-carbamoyl]-pyrrole (X11.2) 4-nitro-1-methyl-2-[(4-methyl-piperazin-1-yl)-carbonyl]-pyrrole Example XIII:
4-(dimethylamino-ethoxy)-nitrobenzene 5.2 g p-nitrophenol are dissolved in 200 ml ;acetone and 7.2 g 2-chloro-N,N-dimethylethylamin-hydrochlori 1e and 11 g potassium carbonate are added. The mixture is stirred for 12 hou -s at reflux temperature. After cooling the salts are filtered off, the filtrate i:; evaporated down and the residue is taken up in methylene chloride. The organic phase is washed with water, dried over sodium sulphate and finally the solvent is eliminated.
Yield: 4.1 g (53% of theory) Rf value: 0.45 (silica gel, methylene chloridE~lmethanol = 9:1 ) elOH 14N2~3 Mass spectrum: mlz = 211 [M+H]+
Example XIV:
4-~N-((4-methyl-piperazin-1-yl)-aminocarbooyll-N-methyl-amino'-nitrobenzene 11.6 ml of phosgene solution in toluene (20%) are dissolved in 20 ml of tetrahydrofuran and 3.0 g of N-methyl-4-nitroaniline and 2.8 ml triethylamine in 30 ml of tetrahydrofuran are added dropvrise at 0 °C. The mixture is stirred for 0.5 hours at 0 °C and for a further hour pit ambient temperature.
Then it is cooled again to 0°C, 5.4 ml of 1-amino-4-m~ahyl-piperazine in 10 ml of tetrahydrofuran are added and the mixture is stirred for 2 hours at ambient temperature. After this time the solvent is eliminated, the residue is taken up in ethyl acetate and extracted with water. Tl~e organic phase is dried over sodium sulphate and finally the solvent is rE moved. The residue is purified through an aluminium oxide column (activit~~ 2-3) with methylene chloride/ethanol 40:1 as eluant.
Yield: 3.3 g (56% of theory) Rf value: 0.30 (aluminium oxide, methylene chloride/ethanol = 40:1 ) M.p. 170-172 °C
C13H19N5~3 Mass spectrum: mlz = 294 [M+H]+
The following compounds are prepared analogously to Example XIV:
(XIV.1 ) 4-{N-[(1-methyl-piperidin-4-yl)-aminocarbonyl]-N-methyl-amino}-nitrobenzene (XIV.2) 4-{N-((4-methyl-piperazin-1-yl)-carbonyl]-N-methyl-amino}-nitrobenzene (XIV.3) 4-{N-[N-(3-dimethylamino-propyl)-arninocarbonyl]-N-methyl-amino}-nitrobenzene (XIV.4) 4-[N-(pyridin-4-yl-methylaminocarbcnyl)-N-methyl-amino]-nitrobenzene (XIV.S) 4-{N-[(1-methyl-piperidin-4-oxy)-carbonyl]-N-methyl-amino}-nitrobenzene Example XV:
The syntheses of the following compounds ire already described in International Application WO 01127081:
(XV.1 ) 4-[(2,6-dimethyl-piperidin-1-yl)-meth~~l]-aniline (XV.2) N-(2-dimethylamino-ethyl)-N-methyl ulphonyl-p-phenylenediamine (XV.3) 3-(dimethylaminomethyl)-aniline (XV.4) 4-(dimethylaminomethyl)-aniline (XV.S) 4-(2-dimethylamino-ethyl)-aniline (XV.6) 4-[N-(2-dimethylamino-ethyl)-N-acets~l-amino]-aniline (XV.7) 4-[N-(3-dimethylamino-propyl)-N-acetyl-amino]-aniline (XV.B) 4-[N-(2-dimethylamino-ethyl)-N-benzoyl-amino]-aniline (XV.9) 4-[N-(2-dimethylamino-ethyl)-N-prop onyl-amino]-aniline (XV.10) 4-[N-(2-dimethylamino-ethyl)-N-butyryl-amino]-aniline (XV.11 ) 4-[N-(2-dimethylamino-ethyl)-N-isot~utyryl-amino]-aniline (XV.12) 4-(N-tert.butoxycarbonyl-aminomethyl)-aniline (XV.13) 4-(N-ethyl-N-tert.butoxycarbonyl-ar~inomethyl)-aniline (XV.14) 4-[N-(4-chlorophenyl-methyl~N-teri.butoxycarbonyl-aminomethyl]-aniline (XV.15) 4-(N-cyclohexyl-N-tert.butoxycarbo ~yl-aminomethyl)-aniline (XV.16) 4-(N-isopropyl-N-tert.butoxycarbony~l-aminomethyl)-aniline (XV.17) 4-(N-propyl-N-tert.butoxycarbonyl-aminomethyl)-aniline (XV.18) 4-(N-methyl-N-tert.butoxycarbonyl-s~minomethyl)-aniline (XV.19) 4-(N-butyl-N-tert.butoxycarbonyl-an~inomethyl)-aniline (XV.20) 4-(N-methoxycarbonyl-methyl-N-tert.butoxycarbonyl-aminomethyl)-aniline (XV.21 ) 4-(N-benzyl-N-tert.butoxycarbonyl-aminomethyl)-aniline (XV.22) 4-(pyrrolidin-1-yl-methyl)-aniline (XV.23) 4-(morpholin-4-yl-methyl)-aniline (XV.24) 4-(hexamethyieneiminomethyl)-anil'ne (XV.25) 4-(4-hydroxy-piperidin-1-yl-methyl)-aniline (XV.26) 4-(4-methoxy-piperidin-1-yl-methyl)~aniline (XV.27) 4-(4-methyl-piperidin-1-yl-methyl)-aniline (XV.28) 4-(4-ethyl-piperidin-1-yl-methyl)-aniline (XV.29) 4-(4-isopropyl-piperidin-1-yl-methyl I-aniline (XV.30) 4-(4-phenyl-piperidin-1-yl-methyl)-aniline (XV.31 ) 4-(4-benzyl-piperidin-1-yl-methyl)-aniline (XV.32) 4-(4-ethoxycarbonyl-piperidin-1-yl-rnethyl)-aniline (XV.33) 4-(N,N-dipropyl-aminomethyl)-aniline (XV.34) 4-(4-tert.butoxycarbonyl-piperazin-' -yl-methyl)-aniline (XV.35) 4-(2-morpholin-4-yl-ethyl)-aniline (XV.36) 4-(2-pyrrolidin-1-yl-ethyl)-aniline (XV.37) 4-(2-piperidin-1-yl-ethyl)-aniline (XV.38) 4-(N-propyl-N-benzyl-aminomethyl)-aniline (XV.39) 4-[N-(n-hexyl)-N-methyl-aminometl-yl]-aniline (XV.40) 4-[N-methyl-N-(4-chlorbenzyl)-aminomethyl]-aniline (XV.41 ) 4-[N-methyl-N-(4-brombenzyl)-amir,omethyl]-aniline (XV.42) 4-[N-methyl-N-(4-methylbenzyl)-aminomethyl]-aniline (XV.43) 4-[N-methyl-N-(4-fluorbenzyl)-aminomethyl]-aniline (XV.44) 4-[N-methyl-N-(3-chlorbenzyl)-aminomethyl]-aniline (XV.45) 4-[N-methyl-N-(3,4-dimethoxybenz~il)-aminomethyl]-aniline (XV.46) 4-[N-methyl-N-(4-methoxybenzyl)-~ minomethyl]-aniline (XV.47) 4-(N-2,2,2-trifluorethyl-N-benzyi-arr~inomethyl)-aniline (XV.48) 4-[N-2,2,2-trifluorethyl-N-(4-chlorbenzyl)-aminomethyl]-aniline (XV.49) 4-(thiomorpholin-4-yl-methyl)-aniline (XV.50) 4-(1-oxo-thiomorpholin-4-yl-methyl)-aniline (XV.51) 4-(1,1-dioxo-thiomorpholin-4-yl-melhyl)-aniline (XV.52) 4-(azetidin-1-yl-methyl)-aniline (XV.53) 4-(3,4-dihydropyrrolidin-1-yl-methyll-aniline (XV.54) 4-(3,4-dihydropiperidin-1-yl-methyl)-aniline (XV.55) 4-(2-methoxycarbonyl-pyrrolidin-1-yl-methyl)-aniline (XV.56) 4-(3,5-dimethyl-piperidin-1-yl-methyl)-aniline (XV.57) 4-(4-phenyl-piperazin-1-yl-methyl)-~miline (XV.58) 4-(4-phenyl-4-hydroxy-piperidin-1-yl-methyl)-aniline (XV.59) 4-[N-(3,4,5-trimethoxy-benzyl)-N-m~ahy!-aminomethyl]-aniline (XV.60) 4-[N-(3,4-dimethoxy-benzyl)-N-ethyl-aminomethyl]-aniline (XV.61 ) 4-(N-benzyl-N-ethyl-aminomethyl)-aniline (XV.62) 4-[N-(2,6-dichlorobenzyl)-N-methyl aminomethyl]-aniline (XV.63) 4-[N-(4-trifluoromethylbenzyl)-N-mE~thyl-aminomethyl]-aniline (XV.64) 4-(N-benzyl-N-isopropyl-aminometl~yl)-aniline (XV.65) 4-(N-benzyl-N-tert.butyl-aminometryl)-aniline (XV.66) 4-(diethylamino-methyl)-aniline (XV.67) 4-(2-diethylamino-ethyl)-aniline (XV.68) 4-(N,N-diisopropyl-aminomethyl)-aniline (XV.69) 4-(N,N-diisobutyl-aminomethyl)-aniline (XV.70) 4-(2,3,4,5-tetrahydro-benzo(d)azepin-3-yl-methyl)-aniline (XV.71 ) 4-(2,3-dihydro-isoindol-2-yl-methyl)aniline (XV.72) 4-(6,7-dimethoxy-1,2,3,4-tetrahydrc-isoquinolin-2-yl-methyl)-aniline (XV.73) 4-(1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl)-aniline (XV.74) 4-[N-(2-hydroxy-ethyl)-N-benzyl-arr inomethyl]-aniline (XV.75) 4-[N-(1-ethyl-pentyl)-N-(pyridin-2-yl~~methyl)-aminomethyl]-aniline (XV.76) 4-(piperidin-1-yl-methyl)-3-nitro-aniline (XV.77) 4-(piperidin-1-yl-methyl)-3-amino-aniline (XV.78) 4-(N-benzyl-N-methyl-aminomethyl I-aniline (XV.79) 4-(N-ethyl-N-methyl-aminomethyl)-~~niline (XV.80) 4-(N-phenethyl-N-methyl-aminome~:hyl)-aniline (XV.81 ) 4-[N-(3,4-dihydroxy-phenethyl)-N-nlethyl-aminomethyl]-aniline (XV.82) 4-[N-(3,4,5-trimethoxy-phenethyl)-~l-methyl-aminomethyl]-aniline (XV.83) 4-[N-(3,4-dimethoxy-phenethyl)-N-rnethyl-aminomethyl]-aniline (XV.84) 4-[N-(3,4-dimethoxy-benzyl)-N-met iyi-aminomethyl]-aniline (XV.85) 4-[N-(4-chloro-benzyl)-N-methyl-an~~inomethyl]-aniline (XV.86) 4-[N-(4-bromo-benzyl)-N-methyl-aminomethyl]-aniline (XV.87) 4-[N-(4-fluoro-benzyl)-N-methyl-amdnomethyl]-aniline (XV.88) 4-[N-(4-methyl-benzyl)-N-methyl-an~inomethyl]-aniline (XV.89) 4-[N-(4-nitro-phenethyl)-N-methyl-aminomethyl]-aniline (XV.90) 4-(N-phenethyl-N-benzyl-aminomethyl)-aniline (XV.91 ) 4-(N-phenethyl-N-cyclohexyl-amino methyl)-aniline (XV.92) 4-[N-(2-(pyridin-2-yl)-ethyl)-N-methyl-aminomethyl]-aniline (XV.93) 4-[N-(2-(pyridin-4-yl)-ethyl)-N-meth~~l-aminomethyl]-aniline (XV.94) 4-[N-(pyridin-4-yl-methyl)-N-methyl-aminomethyl]-aniline (XV.95) 4-(N,N-dibenzylaminomethyl)-aniline (XV.96) 4-[N-(4-nitro-benzyl)-N-propyl-aminomethyl]-aniline (XV.97) 4-[N-benzyl-N-(3-cyano-propyl)-aminomethyl]-aniline (XV.98) 4-(N-benzyl-N-allyl-aminomethyl)-aniline (XV.99) 4-[N-benzyl-N-(2,2,2-trifluorethyl)-aminomethyl]-aniline (XV.100) 4-[(benzo(1,3)dioxol-5-yl-methyl)-methyl-aminomethyl]-aniline (XV.101 ) 4-(7-chloro-2,3,4,5-tetrahydro-benzo(d)azepin-3-yl-methyl)-aniline (XV.102) 4-(7,8-dichloro-2,3,4,5-tetrahydro-benzo(d)azepin-3-yl-methyl)-aniline (XV.103) 4-(7-methoxy-2,3,4,5-tetrahydro-benzo(d)azepin-3-yl-methyl)-aniline (XV.104) 4-(7-methyl-2,3,4,5-tetrahydro-berizo(d)azepin-3-yl-methyl)-aniline (XV.105) 4-(7,8-dimethoxy-2,3,4,5-tetrahydno-benzo(d)azepin-3-yl-methyl)-aniline (XV.106) 4-(6,7-dichloro-1,2,3,4-tetrahydro-~soquinolin-2-yl-methyl)-aniline (XV.107) 4-(6,7-dimethyl-1,2,3,4-tetrahydro~~isoquinolin-2-yl-methyl)-aniline (XV.108) 4-(6-chloro-1,2,3,4-tetrahydro-isoc~uinolin-2-yl-methyl)-aniline (XV.109) 4-(7-chloro-1,2,3,4-tetrahydro-isocauinolin-2-yl-methyl)-aniline (XV.110) 4-(6-methoxy-1,2,3,4-tetrahydro-i~ oquinolin-2-yl-methyl)-aniline (XV.111 ) 4-(7-methoxy-1,2,3,4-tetrahydro-i: oquinolin-2-yl-methyl)-aniline (XV.112) 4-(2,3,4,5-tetrahydro-azepino(4,5-b)pyrazin-3-yl-methyl)-aniline (XV.113) 4-(7-amino-2,3,4,5-tetrahydro-azepino(4,5-b)pyrazin-3-yl-methyl)-aniline (XV.114) 4-(2-amino-5,6,7,8-tetrahydro-azepino(4,5-d)thiazol-6-yl-methyl)-aniline (XV.115) 4-(5,6,7,8-tetrahydro-azepino(4,5-d)thiazol-6-yl-methyl)-aniline (XV.116) 4-(4-methyl-piperazin-1-yl)-aniline (XV.117) 4-[N-(2-dimethylamino-ethyl)-N-m~ahyl-amino]-aniline (XV.118) 4-[N-(3-dimethylamino-propyl)-N-methyl-amino]-aniline (XV.119) N-(3-dimethylamino-propyl)-N-mei hylsulphonyl-p-phenylenediamine (XV.120) 4-[(N-dimethylaminocarbonylmethyl-N-methylsulphonyl)-amino]-aniline (XV.121) N-(4-aminophenyl)-N-methyl-methanesulphonamide (XV.122) 4-(imidazol-4-yl)-aniline (XV.123) 4-(tetrazol-5-yl)-aniline (XV.124) 3-[N-(2-dimethylamino-ethyl)-N-propionyl-amino]-aniline (XV.125) N-(dimethylamino-methylcarbonyl;~-N-methyl-p-phenylenediamine (XV.126) N-[(2-dimethylamino-ethyl)-carbonyl]-N-methyl-p-phenylenediamine (XV.127) N-dimethylaminocarbonylmethyl-hl-acetyl-p-phenylenediamine (XV.128) N-methylaminocarbonylmethyl-N-nethylsulphonyl-p-phenylenediamine (XV.129) N-aminocarbonylmethyl-N-methyl:>ulphonyl-p-phenylenediamine (XV.130) 4-(imidazolidin-2,4-dion-5-yliden-riethyl)-aniline (XV.131 ) 4-(imidazolidin-2,4-dion-5-yl-meth,rl)-aniline (XV.132) 4-(2-oxo-pyrrolidin-1-yl-methyl)-ariline (XV.133) N-cyanomethyl-N-methylsulphonyl-p-phenylenediamine (XV.134) 4-[2-(imidazol-4-yl)-ethyl]-aniline (XV.135) 4-[(4-methyl-piperazin-1-yl)-methyl]-aniline (XV.136) 4-[N-(2-(N-benzyl-N-methyl-amine )-ethyl)-N-methylsulphonyl-amino]-aniline (XV.137) 4-[N-(3-(N-benzyl-N-methyl-amine)-propyl)-N-methylsulphonyl-amino]-aniline (XV.138) N-cyclohexyl-p-phenylenediamine (XV.139) 4-(pyridin-4-yl-methyl)-aniline (XV.140) 4-(imidazol-1-yl-methyl)-aniline (XV.141 ) 4-benzyl-aniline (XV.142) N-(3-trifluoracetylamino-propyl)-N-methylsulphonyl-p-phenylenediamine (XV.143) tert. butyl 4-amino-phenylacetate (XV.144) 4-(imidazol-2-yl)-aniline (XV.145) 4-(1-methyl-imidazol-2-yl)-aniline (XV.146) 4-(1-ethyl-imidazol-2-yl)-aniline (XV.147) 4-(1-benzyl-imidazol-2-yl)-aniline (XV.148) 4-[N-(2-dimethylamino-ethyl)-N-m~ahylsulphonyl-amino]-3-amino-aniline (XV.149) 4-[N-(2-dimethylamino-ethyl)-N-m~ahylsulphonyl-amino]-3-chloro-aniline (XV.150) 4-[N-(2-dimethylamino-ethyl)-N-acetyl-amino]-3-amino-aniline (XV.151 ) 4-[N-(2-dimethylamino-ethyl)-N-acetyl-amino]-3-bromo-aniline (XV.152) 4-[2-(4-hydroxy-piperidin-1-yl)-ethyl-amino]-aniline (XV.153) N-(2-dimethylamino-ethyl)-N-ethylsulphonyl-p-phenylenediamine (XV.154) N-(2-dimethylamino-ethyl)-N-prop~~lsulphonyl-p-phenylenediamine (XV.155) N-(2-dimethylamino-ethyl)-N-isopropylsulphonyl-p-phenylenediamine (XV.156) N-(2-dimethylamino-ethyl)-N-butylsulphonyl-p-phenylenediamine (XV.157) N-(2-dimethylamino-ethyl)-N-benzylsulphonyl-p-phenylenediamine (XV.158) N-(2-dimethylamino-ethyl)-N-pher~ylsulphonyl-p-phenylenediamine (XV.159) 4-((3-hydroxy-pyrrolidin-1-yl)-methyl)-aniline (XV.160) 4-[N-(2-dimethylamino-ethyl)-N-(furan-2-carbonyl)-amino]-aniline (XV.161) 4-[N-(2-dimethylamino-ethyl)-N-(2-methoxy-benzoyl)-amino]-aniline (XV.162) 4-[N-(2-dimethylamino-ethyl)-N-(p,rridine-3-carbonyl)-amino]-aniline (XV.163) 4-[N-(2-dimethylamino-ethyl)-N-(p ienyl-acetyl)-amino]-aniline (XV.164) N-(piperidin-1-yl-methylcarbonyl)-I~-methyl-p-phenylenediamine (XV.165) N-(morpholin-4-yl-methylcarbonyl)-N-methyl-p-phenylenediamine (XV.166) N-[(4-benzyl-piperazin-1-yl)-methylcarbonyl]-N-methyl-p-phenylenediamine (XV.167) N-(pyrrolidin-1-yl-methylcarbonyl)-N-methyl-p-phenylenediamine (XV.168) 4-(5-methyl-imidazol-4-yl)-aniline (XV.169) N-[(2-dimethylamino-ethyl)-carbonyl]-N-isopropyl-p-phenylenediamine (XV.170) N-[(2-dimethylamino-ethyl)-carbonyl]-N-benzyl-p-phenylenediamine (XV.171 ) N-(N-aminocarbonylmethyl-N-methyl-amino)-methylcarbonyl)-N-methyl-p-phenylenediamine (XV.172) N-[(N-benzyl-N-methyl-amino)-me~:hylcarbonyl]-N-methyl-p-phenylenediamine (XV.173) N-[di-(2-methoxyethyl)-amino-meihylcarbonyl]-N-methyl-p-phenylenediamine (XV.174) N-[(2-(4-tert.butoxycarbonyl-piper,~zin-1-yl)-ethyl)-carbonyl]-N-methyl-p-phenylenediamine (XV.175) N-[(2-(piperidin-1-yl)-ethyl)-carboryl]-N-methyl-p-phenylenediamine (XV.176) N-[(2-(N-benzyl-N-methyl-ami ~o)-ethyl)-carbonyl]-N-methyl-p-phenylenediamine (XV.177) N-(dimethylaminomethylcarbonyl)~~N-isopropyl-p-phenylenediamine (XV.178) N-(piperidin-1-yl-methylcarbonyl)-I~-isopropyl-p-phenylenediamine (XV.179) N-[(4-tent.butoxycarbonyl-piperazio-1-yl)-methylcarbonyl]-N-isopropyl-p-phenylenediamine {XV.180) N-[(N-benzyl-N-methyl-amino)-methylcarbonyl]-N-benzyl-p-phenylenediamine (XV.181 ) N-(dimethylaminomethylcarbonyl)~ N-benzyl-p-phenylenediamine (XV.182) N-(piperidin-1-yl-methylcarbonyl)-IJ-benzyl-p-phenylenediamine (XV.183) 4-(1,2,4-triazol-1-yl-methyl)-anilinE~
(XV.184) 4-(1,2,3-triazol-2-yl-methyl)-anilinE
(XV.185) 4-(1,2,3-triazoi-1-yl-methyl)-anilinE
(XV.186) 4-[(N-ethoxycarbonylmethyl-N-methyl-amino)-methyl]-aniline (XV.187) 4-[(N-aminocarbonylmethyl-N-methyl-amino)-methyl]-aniline (XV.188) 4-(azetidin-1-yl-methyl)-aniline (XV.189) 4-[(di-(2-methoxy-ethyl)-amino)-methyl]-aniline {XV.190) 4-[(N-(2-(2-methoxy-ethoxy)-ethyl,~-N-methyl-amino)-methyl]-aniline (XV.191 ) 4-[N-(N-tert.butoxycarbonyl-3-ami ~o-propyl)-N-methyl-aminomethyl]-aniline (XV.192) 4-[(N-(methylcarbamoyl-methyl)-N-methyl-amino)-methyl]-aniline (XV.193) 4-[(N-(dimethylcarbamoyl-methyl) N-methyl-amino)-methyl]-aniline (XV.194) 4-[(N-propyl-N-methyl-amino)-methyl]-aniline (XV.195) 4-[(N-(2-dimethylamino-ethyl)-N-rr,ethyl-amino)-methyl]-aniline (XV.196) 4-[(N-(3-dimethylamino-propyl)-N-methyl-amino)-methyl]-aniline (XV.197) 4-[(N-(2-methoxy-ethyl)-N-methyl-amino)-methyl]-aniline (XV.198) 4-[(N-(2-hydroxy-ethyl)-N-methyl-amino)-methyl]-aniline (XV.199) 4-[(N-{dioxolan-2-yl-methyl)-N-me~:hyl-amino)-methyl]-aniline (XV.200) 4-(3-oxo-piperazin-1-yl-methyl)-aniline (XV.201 ) N-[di-(2-hydroxyethyl)-amino-metP~ylcarbonyl]-N-methyl-p-phenylenediamine (XV.202) N-[(N-(2-methoxyethyl)-N-methyl-amino)-methylcarbonyl]-N-methyl-p-phenylenediamine (XV.203) N-[(N-(2-dimethylamino-ethyl)-N-methyl-amino)-methylcarbonyl]-N-methyl-p-phenylenediamine (XV.204) N-((4-methyl-piperazin-1-yl)-meth~ilcarbonyl]-N-methyl-p-phenylenediamine (XV.205) N-[(imidazol-1-yl)-methylcarbonyl]-N-methyl-p-phenylenediamine (XV.206) N-[(phthalimido-2-yl)-methylcarbo iyl]-N-methyl-p-phenylenediamine (XV.207) 4-(piperidin-1-yl-methyl)-aniline The following compounds are prepared analogously to Example XV:
(XV.208) N-(dimethylcarbamoylmethyl)-p-pl~enylenediamine (XV.209) di-(2-hydroxyethyl)-aminomethyl-~ niline (XV.210) 4-[N-(2-dimethylamino-ethyl)-N-(rr~ethoxyacetyl)-amino]-aniline (XV.211 ) 4-[N-(2-dimethylamino-ethyl)-N-(3 4-dimethoxy-benzoyl)-amino]-aniline (XV.212) 4-[N-(2-(N-benzyl-N-methyl-amino)-ethyl)-N-propionyl-amino]-aniline (XV.213) 4-[N-(2-dimethylamino-ethyl)-N-(p ~ridine-4-carbonyl)-amino]-aniline (XV.214) 4-[N-(2-(N-benzyl-N-methyl-amino)-ethyl)-N-acetyl-amino]-aniline (XV.215) N-(dimethylaminomethylcarbonyl)~~N-methyl-3-methoxy-p-phenylenediamine (XV.216) N-(dimethylaminomethylcarbonyl)-N-methyl-3-cyano-p-phenylenediamine (XV.217) 3-(pyridin-4-yl-methyl)-aniline (XV.218) 4-amino-N-(2-dimethylamino-ethy )-benzamide (XV.219) 4-amino-N-(2-dimethylamino-ethy )-N-methyl-benzamide (XV.220) 4-amino-N-(3-dimethylamino-propyl)-benzamide (XV.221 ) 4-amino-N-(3-dimethylamino-propyl)-N-methyl-benzamide (XV.222) 4-amino-N-(2-dimethylamino-ethyl )-N-ethyl-benzamide (XV.223) 4-amino-N-(2-(tert-butyloxycarbonyl-methylamino-ethyl)-N-ethyl-benzamide (XV.224) 4-amino-N,N-bis-(2-diethylamino-f~thyl)-benzamide (XV.225) 4-amino-N-(2-tert-butyloxycarbon~~l-amino-ethyl)-benzamide.
(XV.226) 3-amino-N-(2-dimethylamino-ethyl)-benzamide (XV.227) 3-amino-N-(2-dimethylamino-ethyl)-N-methyl-benzamide (XV.228) 3-amino-N-(3-dimethylamino-propyl)-benzamide (XV.229) 3-amino-N-(3-dimethylamino-propyl)-N-methyl-benzamide (XV.230) 5-amino-2-N-(dimethylamino-methyl)-carbamoyl-furan (XV.231 ) 4-(4-methyl-piperazin-1-yl-carbons~l)-aniline (XV.232) 4-(piperidin-1-yl-carbonyl)-aniline (XV.233) 4-amino-N-cyclohexyl-N-methyl-b~:nzamide (XV.234) 4-amino-N-isopropyl-benzamide (XV.235) 4-(2,3,4,5-tetrahydro-1 (H)-benzo[ci]azepin-3-yl-carbonyl)-aniline (XV.236) 4-(4-hydroxy-piperidin-1-yl-carbonyl)-aniline (XV.237) 4-(4-tert-butyloxycarbonyl-piperaz n-1-yl-carbonyl)-aniline (XV.238) 4-(4-tert-butyloxycarbonyl-[1,4]dia?epan-1-yl-carbonyl)-aniline (XV.239) 4-amino-1-methyl-2-[N-(2-dimethylamino-ethyl)-N-methyl-carbamoyl]-pyrroie (XV.240) 4-amino-1-methyl-2-[(4-methyl-piperazin-1-yl)-carbonyl]-pyrrole (XV.241 ) N-(2-dimethylamino-ethyl)-N-acet~~l-2,5-diamino-pyridine (XV.242) 4-(1-(2-dimethylamino-ethyl)-imidazol-2-yl)-aniline (XV.243) N-[(2-(4-methyl-piperazin-1-yl)-ethyl)-carbonyl]-N-methyl-p-phenylenediamine (XV.244) N-[(2-dimethylamino-ethyl)-carboryl]-N-methyl-p-phenylenediamine (XV.245) trans-N-dimethylaminomethylcarbonyl-N'-(tert.-butoxycarbonyl)-cyclohexyl-1,4-diamine (XV.246) 4-(2-dimethylamino-ethoxy)-anilint;
(XV.247) 4-[(4-dimethylamino-piperidin-1-yly-methyl]-aniline (XV.248) N-[(4-tert.butoxycarbonyl-piperazi i-1-yl)-methylcarbonyl]-N-methyl-p-phenylenediamine (XV.249) N-hydroxymethylcarbonyl-N-meth yl-p-phenylenediamine (XV.250) 4-[N-(N-tert.butoxycarbonyl-3-ami iopropyl)-N-methyl-aminomethyl]-aniline (XV.251 ) N-[(4-methyl-homopiperazin-1-yl)-methylcarbonyl]-N-methyl-p-phenylenediamine (XV.252) N-[(4-ethyl-piperazin-1-yl)-methylcarbonyl]-N-methyl-p-phenylenediamine (XV.253) N-[(4-methyl-piperazin-1-yl)-meth~~lcarbonyl]-p-phenylenediamine (XV.254) N-[(1-methyl-piperidin-4-yl)-methy carbonyl]-N-methyl-p-phenylenediamine (XV.255) 4-(N-(3-dimethylamino-propyl)-N-rnethyl-carbamoylmethyl)-aniline (XV.256) 4-(N-(2-dimethylamino-ethyl)-N-m~ahyl-carbamoylmethyl)-aniline (XV.257) 4-[(4-methyl-piperazin-1-yl)-carboilylmethyl]-aniline (XV.258) N-(4-dimethylaminobutylcarbonyl)~~N-methyl-p-phenylenediamine (XV.259) N-dimethylaminomethylcarbonyl-f~l'-(tert.-butoxycarbonyl)-2,3-dimethyl-p-phenylenediamine (XV.260) N-[(4-methyl-piperazin-1-yl)-methylcarbonyl]-N'-(tert.-butoxycarbonyl)-2,3-dimethyl-p-phenylened famine (XV.261 ) N-[(4-methyl-piperazin-1-yl)-aminocarbonyl]-N-methyl-p-phenylenediamine (XV.262) N-[(4-methyl-piperazin-1-yl)-methsrlcarbonylJ-N-methyl-m-phenylenediamine (XV.263) N-[(4-methyl-piperazin-1-yl)-methvlcarbonyl]-m-phenylenediamine (XV.264) N-dimethylaminomethylcarbonyl-~I-methyl-m-phenylenediamine (XV.265) N-[(1-methyl-piperidin-4-yl)-amino:,arbonyl]-N-methyl-p-phenylenediamine (XV.266) N-[(3-dimethylamino-propyl)-carbonyl]-N-methyl-p-phenylenediamine (XV.267) N-[(4-methyl-piperazin-1-yl)-carbonyl]-N-methyl-p-phenylenediamine (XV.268) N-[N-(3-dimethylamino-propyl)-arr inocarbonyl]-N-methyl-p-phenylenediamine (XV.269) N-(pyridin-4-yl-methylaminocarborryl)-N-methyl-p-phenylenediamine (XV.270) N-(1-methyl-piperidin-4-oxy-carbo iyl)-N-methyl-p-phenylenediamine Example XVI:
traps-N-dimethylaminomethylcarbonvl-cyclc hexyl-1,4-diamine-trifluor0acetate 400 mg of traps-N-dimethylaminomethylcarl~onyl-N'-(tert.-butoxycarbonyl)-cyclohexyl-1,4-diamine (educt XV.245) are nissolved in 12 ml methylene chloride and 5.0 ml of trifluoroacetic acid ar~~ added. The mixture is stirred for 0.5 hours at ambient temperature, evaporated down, combined with toluene and concentrated again in the rotary evaporator.
Yield: 420 mg (100% of theory), C10H21 N3~
Mass spectrum: mlz = 200 [M+H]+
The following compounds are prepared analogously to Example XVI:
(XV1.1 ) N-dimethylaminomethylcarbonyl-2,;:-dimethyl-p-phenylenediamine (XVI.2) N-[(4-methyl-piperazin-1-yl)-methylcarbonyl]-2,3-dimethyl-p-phenylenediamine Example XVII:
cis-N-dimethylaminomethylcarbonyl-N-metf yl-cyclohexyl-1,4-diamin-trifl a o ro a cetate 5.0 g of N-dimethylaminomethylcarbonyl-N-methyl-p-phenylenediamine (educt XV.125) are dissolved in 250 ml glacial acei.ic acid and 500 mg of Nishimura catalyst (Rh(III)-IPt(IV)-oxide) are added. The mixture is hydrogenated for 9 hours at ambient temperature under 50 psi, evaporated down, combined with water and then neutralised with sodium hyd rogen carbonate solution. After evaporation the residue is taken up in meth~~lene chloride, filtered, dried over sodium sulphate and finally the solvent is el Iminated.
Yield: 1.5 g (29% of theory), x%11 H23N3~
Mass spectrum: mlz = 213 [M]+
Example XVIII:
N-acetyl-4-(2-diethylamino-ethyl-sulphonyl~ aniline 9.0 g of 4-acetamido-phenylsulphinic acid are dissolved in 10 ml of water and 45 ml of 1 N sodium hydroxide solution and a.47 g of 2-chlorotriethylamine hydrochloride are added. The mixture is stirred for 5 hours at reflux temperature. After cooling, sodium hydroxide solution is added until an alkaline reaction is obtained, the mixture is extracted with ethyl acetate, dried over magnesium sulphate and finally the solvent is eliminated.
Yield: 9.85 g (73% of theory), C14H22N2~3S
Mass spectrum: mlz = 298 [M]+
Example XIX:
4-(2-diethylamino-ethyl-sulphonyl)-aniline 9.85 g of N-acetyl-4-(2-diethylamino-ethyl-s.ilphonyl)-aniline (educt XVII) are dissolved in 25 ml of ethanol and 100 ml of 3N hydrochloric acid are added.
The mixture is stirred for 1 hour at reflux temperature. After cooling it is neutralised, extracted three times with methylene chloride, dried over magnesium sulphate and finally the solvent is eliminated.
Yield: 5.75 g (68% of theory), C12H2oN2~2s Mass spectrum: mlz = 257 [M+H]+
Example XX:
3-Z-f 1-(4-(dimethylcarbamoylmethylamino)-snilino)-1-phenyl-methylenel-6-chloro-2-indolinone 6.0 g of 1-acetyl-3-(1-ethoxy-1-phenylmethylen)-6-chloro-2-indolinone (educt IX) and 3.9 g of N-(dimethylcarbamoylmeths~l)-p-phenylenediamine (educt XV.208) are dissolved in 50 ml of dimethylformamide and stirred for 4.5 hours at 120°C. After cooling water is added, the precipitate formed is suction filtered and washed with methanol. The product is purified through a silica gel column with methylene chloridelmethanol (' 00:1 ) as eluant and finally recrystallised from ether.
Yield: 4.4 g (49% of theory), M.p. 208-211 °C
C27H25CIN4~3 Mass spectrum: mlz = 487/489 [M-H]-Example XXI:
3-Z-f1-(4-(N (dimethyl-carbamoyl-methyl)-l~-(2-bromo-ethyl-carbonyl)-amino)-anilino)-1-phenyl-methylenel-6-chloro-2-indolinone 500 mg of 3-Z-[1-(4-(dimethylcarbamoylmeihylamino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (educt Xx) and 430 mg sodium hydrogen carbonate are placed in 10 ml of methylene chloride and 190 mg of 3-bromopropionic acid chloride are slowly added. The mixture is stirred for 1 hour at ambient temperature. Then it is filtered and the filtrate is evaporated down. The precipitate formed is recrystallisE:d from methanol.
Yield: 270 mg (42 % of theory) Rf value: 0.50 (silica gel, methylene chloridElmethanol = 9:1 ) C30H28BrCIN4~4 Mass spectrum: mlz = 62116231625 [M-H]-The following compound is prepared analoc ously to Example XXI:
(XX1.1 ) 3-Z-[1-(4-(N-(dimethyl-carbamoyl-methyl)-N-(bromo-acetyl)-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone from 3-Z-[1-(4-(dimethylcarbamoylmethylarriino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (educt XX) and bromc~acetylchloride Preparation of the end compounds:
Example 1.0 3-Z-f1-(4-(N-(2-dimethylamino-ethyl)-N-mete IYSUlphonvl-amino)-anilino)-1-phenyl-methylenel-6-chloro-2-indolinone 0.3 g of 1-acetyl-3-(1-ethoxy-1-phenylmethylen)-6-chloro-2-indolinone (educt IX) and 0.5 g of N-(2-dimethylamino-ethyl)-fJ-methylsulphonyl-p-phenylenediamine (educt XV.2) are dissolv~:d in 20 ml of dimethylformamide and stirred for 3 hours at 120°C. After cooling 0.8 ml of piperidine are added and the mixture is stirred for a further hour art ambient temperature. The solvent is eliminated and the residue is puri~~ied through a silica gel column with methylene chloridelmethanol (15:1 ) as eluant.
Yield: 0.2 g (40% of theory), Rf value: 0.5 (silica gel, methylene chloridelmethanol = 9:1 ) M.p. 237-239 °C
C26H2~CIN403S
Mass spectrum: mlz = 511/513 [M+H]+
The following compounds of general formul;~ I-1 are prepared analogously to Example 1.0 \ /
-N
H
\~O
CI N
H
(I-1 ) Exam R4 Ra, empirical mass m.p. Rf edgy ct ple formula spectrum[C] value*

R4, -N(Me)-(CO)-CH2-X~'. 4611463 237- 0 1.1 I CzsH25CIN4O2 .

NMe2 125 (M+H]+ 239 (A) R' 4 4171419 266- 0.50 ~

1.2 I -COOEt - C24H~gCIN2O3 [M-H]' 268 (B) Ra ~ -N(S02Me)-(CH2)-X~~~ 5231525 0.50 1.3 I C H CIN404S 254 (CO)-NMe2 12 [M-H]~ (C) ~

Ra XV. 452/454 276- 0.50 ~

1.4 I -N(S02Me)-CH3 C2sH2oCINs03S

[ 1 (~) R4' 308 1.5 I ~ -N(COMe)-CH3 - C24H2oCIN3O2 ~ (decom M (C) H
( ]

p.) R' -N(S02Et)-(CH2)2-X~ 5231525 0.50 .

1.6 I C27H2sCIN403S 220 , NMe2 15 [M-H]~ (C) R4, -N(COEt)-(CH2)r 4871489 0.50 1.7 . XV C2aH29CIN402 144 . NMe2 (M-H]~ (C) R4, ~ -N(S02Me)-(CH2)3-X~ 524/526 0.50 ~

1.8 I C2~H29CIN403S 214 NMe2 11 [M] (A) R' -N(CO-nPr)-(CH2)2- 5011503 0.50 1.9 I XV.10 C29H3~CIN402 218 NMe2 [M-H]- (A) R' -N(CO-iPr)-(CH2)2- 5011503 0.50 1.10 I XV.11 C29H3~CIN402 239 NMe2 [M-H]- (A) R4, -N(COMe)-(CH2)2- 4751477 0.50 1.11 I ~ XV C2,H2~CIN402 170 NMe2 [M+Hl+ (A) Ra -N(COPh)-(CH2)r 5 O

1.12 I ~ XV C32H29CIN4O2 M+H 9 215 NMe2 [ ] ( ) Ra ~ -N(CO-Bn)-(CH2)2-X~~~ 5511553 0.50 1.13 I C33H31CIN4O2 233 NMe2 16 [M+H]+ (A) Ra ~ -N[CO-(3-pyridyl)]-X~v 5381540 0.50 1.14 I C31H28CIN5O2 134 (CH2)2-NMe2 16 [M+H]+ (A) ?

Ra ~ -N[CO-(2-furanyl)]-X~v 5271529 0.50 1.15 I C30H27CIN4O3 236 (CH2)2-NMe2 16') [M+H]+ (A) R4' -N[CO-(2-Me0-X~ 567/569 0.50 .

1.16 I ~ phenyl)]-(CH~)2- C33H31CIN4O3 + 148 16 [M+H] (A) ~

NMe2 R4.
-N(SOZ-nPr)- X~ 5371539 0.50 ~ .

1.17 I C28H3~CINd03S 222 (CH2)2-NMe2 15~f [M-H]~ (C) R4.
~ -N(S02-iPr)-(CH2)2-X~ 5 0 . 9 O
l 1.18 I C2aH3~CIN40aSM 167 C
H

NMe2 150 [ ] ( ) R4.
~ -N(S02Bn)-(CHz)2- 5 0 /

1.19 I C32H3~CiN403SM 132 C
H

NMe2 15T [ ] ( ) ~N X~'. 5901592 0.50 ~ N
~
~

1.20 I Me.N~ C35H34CINgO2 235 '' '- -~
' ..~, o 160 [M-H] (A) X~'. 501 /503 0.50 \ N
J

1.21 / Me, ~ C2gH27CIN4O3 259 ' 16 [M-H]- (A) R4, 1 Me X~'. C 501 /503235 0.50 22 / ~ ~N~ H
CIN
O

. . 29 -.N o 164 + (A) [M+H]

~ R4 N a X~I~ 535/537 0.50 /

1.23 Me. C2sH2sCIN505S 181 ~

~.N o 17Z [M-H]' (A) R4, 40405 0.50 1.24 / ~ -CH2-NMe2 XV C24H22CIN30 207 [ ] (A) R4' Me 1.25 XV C2 470/472 226 0.50 / ~ -N~ 1 H
CIN

,~ 9 [M-H]- (A) Me 3o R4, Me XV 492/494 0 ~ . 50 1.26 / .~N,." C2sHaoCIN3O3 140 .
' ' o 19~) [M+H]+ (A) ~-oMe R4, N=N X~ 450/452 0 ~ . 50 1.27 / .~N,> C24H~$CIN50 230 .
+

18 [M+Na] (A) p Ra' OH
N 4621464 0.50 1.28 / ~ 2o CZSH2sCIN303 228 a ~~ ''"oH , [M-H] (A) N~ XV. 427/429 290 0.50 1 / ~ ~ N CIN
29 0 d H
C

. , ~ 4 ( z5 ecom '9 16 [M+H]+ (A) R4.
Et 502/504 0.50 'N

1.30 ~ ~ fiotBu XV.13 CZ9H3oCIN303 201 -~

o [ M-H]' (A) Ra 1 ~%'~ X~'. 4271429 0.50 31 ~ ~

. N C25H19CIN4O 279 Me 14 [ M+H]+ (A) ~

Ra r"o 4461448 0.50 1.32 ~ N~ XV.;?3C2sH2aCIN302 245 +

[M+Hl (A) Ra 502/504 0.50 ~

1.33 ~ -CH2-(NBnMe) XV.78 C3oH2sCIN30 168 [ ] (A) M+Na Ra 1 -N~ 4301432 0.50 34 ~ ~

. .~ XV.;?2C2sH2aCIN30 + 226 [M+H] (A) R4.
~N.Me X~ 459/461 228- 0.40 .

1.35 ~, ,~NJ CZ~H2~CIN40 13 [M+H] 230 (D) i R4.
-N(S02-nBu)- X~ 553/555 0.70 .

1.36 ~ C2sHssCIN403S 185 (CH2)2-NMe2 15p [M+H]+ (A) R4.
-N(CO-CH2-OMe)- X~ 505/507 0.40 .

1.37 ~ C2aH29CIN403 174 , (CH2)2-NMe2 21 [M+H]+ (A) ~) R4' -N[CO-(3,4-XV 5971599 0.50 ~ .

1.38 ~ dimethoxy-phenyl)]- CsaHssCINaOa 174 211 [M+H]+ (A) (CHZ)2-NMe2 Ra Me XV 434/436 0.30 ~ .

1.39 ~ yN.~ C2sH2aCIN302 + 208 193 [M+H] (A) OH

1.40 I R4 -N(COEt)-(CH2)2- X~~~ C34HssCiNaO2 5651567 158 0.80 (NBnMe) 212 [M+H]+ (A) R4, -N[CO-(4-pyridyl)]- X~°. 5381540 0.25 1.41 I C3~ H28CIN5OZ 199 (CH2)2-NMe2 213 [M+H]+ (A) R~ O
X~'. 5611563 0.50 1.42 I ' Me~N~' 0 20~ C32H2sCIN4O4 [M-H]_ 274 (A) R4 Me 488/490 171- 0.50 1.43 I ~ ,~ o otBu XV.18 C28H28CIN3O3 [M_H]- 173 (A) R4~ ~N~Me XV. 515/517 265- 0.50 1.44 I \ Me. ~~J 20,1 C29HsoCIN502 [M]+ 269 (E) -N O
R, OH
XV. 521 /523 259- 0.20 1.45 I ~ Me.N~N''''oH 2O1 CzaH2sCIN4O4 [M+H]+ 260 (F) ..~. o Ra rv~ XV. 4871489 229- 0.25 1.46 I ~ Me. ~ CZgH27CINqO2 0 16 T [M+H]+ 230 (F) R4' Me X~r . 5181520 167- 0.10 1.47 I \ Me. ~N~NMe C29H32CiNgO2 20 3 [M+H]+ 169 (F) X~ ~ C27H22CIN5O2 4841486 288- 0.25 I Me.
1.48 , ,,N~ 20 ~ [M+H]+ 289 (F) R4, O ~N~Me X~ ~ 473/475 0.25 1.49 I ~.~NJ 231 C27H2eCIN402 [M+H]+ 274 (F) Me.
4 ~

1 I R .,N X~'. 614/616 0.25 50 N'>

. ~ C H CIN O _ 134 .- 174 [M-H] (A) ~-OtBu R' -N(COMe)-(CHZ)2-X~'. 5511553 0 1.51 I , C33H31CIN4O2 195 .

(NBnMe) 214 [M+H]+ (A) Ra 0 545/547 0.25 I ~ N~

1.52 ~ XV.34 C3~H33CIN4O3 225 otBu +

[M+H] (A) Ra I v oMe _N(Me)-(CO)-CH2-X~'. 4911493 238- 0.30 1.53 C2~H2~CIN403 NMe2 21 [M+H]+ 241 (A) ~

I ~ R4' 4021404 0.25 1.54 ~ -CH2-NMe2 XV C24H22CIN30 193 , [M-H] (A) ~ R4 XV. 438/440 0.45 1.55 - -CH2-(4-pyridyl) Cz'H2oCIN30 243 21 [M+H]+ (A) T

R4, ~ o ~N-Me 473/475 0.45 1.56 I ,N ,,~''N,J XI C2sH2aCIN502 + 265 I

[M+H]

H N~
3851387 328- 0.40 1.57 I ~ - - C22H~5CIN40 [M-H]- 330 (F) R4, I ' N -N(COMe)-(CH2)2-X~ 4761478 176- 0.60 ~

1.58 C H CIN O
2s Zs 5 2 NMe2 241 [M+H]+ 177 (H) R4.

-NH-(CO)-CH2- 4531455 0.40 ' 1.59 X~ C25H29CIN402 n. d.
I

NMe2 IM+H]+ (A) R4, -N(Me)-(CO)-CH2- 4671469 257- 0.20 1.60 XVII C2sHa~CIN402 NMe2 [M+H]+ 260 (F) R4, ~N-Me ~'~' 476/478 296- 0.55 M

1.61 ~ I C2sH2sCIN502 +

24~ M+H 299 I
[ ] ( ) Me R -CO-NMe-(CH2)2- X~'. 478/480 230- 0.30 ~

1.62 ~ I C2sH2sCIN502 NMe2 23a [M+H]+ 232 (K) R' -N(COMe)-(CH2)3- 4891491 0.20 ~

1.63 ~ XV C28H29CIN402 187 NMe2 [M+H]+ (A) Ra 510/512 154- 0.40 1.64 ~ ~ -S02-(CH2)2-NEt2XI;C C2~HZaCIN303S

[M+H]+ 159 (F) R4~ N~ XV 4841486 211- 0.20 ~ ~ '''~ .

1 N CzaH2sCIN50 . ~NMe2 24 [M+H]+ 216 (L) ?

R' o N XV CIN 4581460 270 0.20 ~ ~ . 0 C
H

1.66 3 +

2~
2~

[M+H] (A) XV. 5591561 255- 0.20 R4, ~

1.67 ~ N N C311"i31CIN4O4+
'' otBu 23 [M+H] 256 (A) 'v 'J 7 Ra ~ XV. 4861488 0.20 ~

1 ~ o CZSH2aCIN302 164 . 23 + (A) 3 [M+H]

Ra -N(Me)-(CO)- XV. 4751477 219- 0.20 69 ~ C2~H2~CIN402 . (CH2)2-NMe2 12 [M+H]+ 221 (A) i R' -CH2-NMe-(CH2)2-X1,'. 4611463 0.25 1.70 I C2~H29CIN40 151 ' NMe2 195 [M+H]+ (A) R4' Me,N /I X~'. 528!520 204- 0.25 , ' 1.71 I ~ ~. CsoHs2CINs02 ~~

243 [M-H]_ 208 (A) ~e R' XV'. 5321534 212- 0.25 1.72 I ~ -O-(CH2)2-NMe2 C2sH2aCIN3Oz 3 [ 1 () R' 1 ~, XV'. C2sH3~CIN40 485/487 198 0.25 73 I ~ N~NMez . ,'~ 24l [M-H]_ (A) R4 417/419 0.25 1.74 - -CH2-COOMe - C24H~gCIN2O3 192 [M-H]_ (A) I ~ R4' 403/405 1.75 - -COOMe - C23H~7CIN2O3 209 n.
d.

[M-H]_ R4.
4161418 0.25 1.76 I ~ -(CH2)2-NMe2 XV C25HZaCIN30 217 [M-H]_ (A) R4~ H 4741476 0.25 ~ ' 1.77 i otau XV.12 C2~H2sCIN303 203 ~~

o [M-H]_ (A) Ra ~ -N(iPr)-(CO)-CH2-X~ 4871489 0.25 ~

1.78 I C2aH29CIN4O2 216 ' NMe2 17 [M-H]- (A) R4 ~~

Me ~ XV 628/630 0.25 I ~ otBu . O 164 Me~ CIN
H
C

1.79 N~ 5 4o s5 17'a [M-H]_ (A) mo R' /

1.80 I ~ -CH2-NEt2 XV.'36C2sH2sCIN30 M 244 .
H

[ ] (A) Ra, X~'. 4301432 0.25 ~

1.81 I -CH2-(NMePr) C2sH2sCIN30 188 19 [M-H]~ (A) 4~
1 I R ~N a X~I~ C H CIN O 443/445 295 0.25 . 26 25 4 11 [M-H]_ ( ) ~

Ra, X~'. 473/475 0 \ 25 1.83 I ~vN~ C2~H2~CIN402 148 .

NMe 21 M-H _ A
z a [ ] ( ) Ra, ~N~ X~v 602/604 0 1.84 I oteu CsaHssCIN504 + 199 .
Me.
~

N 243 M+H A
o [ ] () Ra ~ -N(Me)-(CO)-CH2-XV. 432/434 0.25 1.85 I C2aH20CIN303 250 OH 24 [M-H]- (A) a Ra, ~ -N(Me)-(CH2)2- ~ . 445/447 1.86 I C2sH27CIN40 238 n.
d.

NMe2 11 [M-H]-T

R' ~a N a N ~ ' 545/547 0.25 1.87 I otBu Cs~H35CIN4O3 _ 148 ~~ '~

O 25') [M-H] (A) Ra, N~Me XV. 5281530 0.25 I \ N

1.88 ~--i C301"~32CIN5O2 223 Me, ~ -.. N o 251 [M-H] (A) R' -N(Me)-(CO)-CH2-XV. 486/488 226- 0.40 1.89 I C27HZaCIN5O2 NMe2 213 [M+H]+ 228 (A) R4~ ~N~Et X1~'. 5281530 255- 0.35 1.90 ~ ~ Me. ~N'-~ C3oH32CIN5O2 ..N o 252 [M-H]' 257 (F) R4 N~Me X~,'. 515/517 280- 0.30 1.91 ~ ~ nne. ~ C3pH31CINqO2 ..N o 254 [M+H] 283 (M) R4~ ~N~Me X~'. 502/504 251- 0.45 1.92 ~ ~ H-~N'~ 253 C2aH2aCIN502 M+H + 255 A
N o [ ] ( ) R4 o X~~. 503/505 215- 0.30 1.93 ~ ~ '~N-~., C29H31CIN4O2 H3C N(CH3)2 25 ~ [M+H]+ 224 {F) R4 ~o X~ ~ 4891491 150- 0.40 1.94 ~ ~ ~~~'~,,-N(cH3)z 253 CZSH2sCIN402 [M+H]+ 158 (A) R~ O
XV. 487/489 244- 0.40 1.95 ~ ~ '~~~~ C2sH27CINa0z N,cH 25 T [M+H] 248 (A) R , N(CH3)z ' XV. 5031505 216- 0.80 1.96 ~ ~ Me.N 253 C2sH3~CIN402 [M H]+ 218 (N) ,'~' o +
Ra cH3 -NH-(CO)-CH2- 475/477 246- 0.50 1.97 ~ GH NMe2 XV1.1 CZ~H27CIN402 [M+H]+ 250 (F) RQ
~ CH3 N N'Me 530/532 271- 0.50 1.g8 H~ J XVI.2 C3oH32CIN5O2 -.N o [M+H]+ 275 (F) R4~ ~N-Me XV. 517/519 250- 0.50 1.99 ~ ~ Me. ~'NJ 261 C28H29C~N602 M+H 253 D
-. N o [ 1+ ( ) Ra' 1.100I ~ -CH2-COOEt - C25H2~CIN203 166 .

[M+Hl (A) Ra~ ~N~Me XV'. 516/518 265- 0.35 ~

1.101I Me. ~ C29H3oCIN502 ~. N o 26 [M+H]+ 270 (O) Ra' N(CH3)2 1.102 X~'. C 4891491 238- 0.35 I ~ Me H
~ CIN
O

. ~ 28 +
~.N o 26~ 29 [M+H] 242 (F) Me Ra N

I
~ XV'. 502/504 290- 0.50 , 1.103 N CZaH2eCINs02 Me~N-~ 26l [M+H]+ 293 (A) o R , (CH3)2 a ~ XV 504/506 192- 0.60 .

1.104I ~ Me C2sHsoCIN502 ~

.N 26 [M+H]+ 195 (O) ~. O

N
R' I ' a '' XV 510/512 222- 0.60 \ .

1.105I C2sH24CIN502 Me.N~ 26 [M+H]+ 223 (A) a Ra~ N~Me X~ 517/519 237- 0.30 ~ .

1.106I ~ Me. ~ C29H29CIN4O3 +
~.N o 27') [M+H] 240 (A) *Eluant mixtures:
(A): silica gel, methylene chloridelmethanol 9:1 (B): silica gel, toluenelethyl acetate 9:1 (C): silica gel, methylene chloridelmethanol 10:1 (D): silica gel, methylene chloridelmethanol 5:1 (E): silica gel, methylene chloridelmethanoliammonia 5:1:0.01 (F): silica gel, methylene chloride/methanollammonia 9:1:0.1 (G): silica gel, methylene chloridelethanol 5 1 (H): silica gel, methylene chloridelmethanol~'ammonia 10:1:0.1 (I): silica gel, methylene chloridelethanol 15:1 (K): silica gel, methylene chloridelethanollammonia 20:1:0.1 (L): silica gel, methylene chloride/ethanol 1():1 (M): silica gel, methylene chloridelmethanollammonia 9:1:0.01 (N): aluminium oxide, methylene chloridelethanol 30:1 (O): aluminium oxide, methylene chlorideleihanol 20:1 Example 2.0 3-Z-f 1-(4-(N-(2-dimethylamino-ethyl )-N-metloylsulphonyl-amino)-anilino)-1-phenyl-methylenel-6-chloro-5-nitro-2-indolir one 0.4 g of 1-acetyl-3-(1-ethoxy-1-phenylmethylen)-6-chloro-5-nitro-2-indolinone (educt 1X.4) and 0.3 g of N-(2-dimethylamin ~-ethyl)-N-methylsulphonyl-p-phenylenediamine (educt XV.2) are dissolvE;d in 5 ml of dimethylformamide and stirred at 80°C for 4 hours. After cooling, 1.0 ml piperidine is added and the mixture is stirred for a further 3 hours at ambient temperature. The solvent is eliminated and the residue is purified through a silica gel column with methylene chloridelmethanol (9:1 ) as eluan ~.
Yield: 0.4 g (79% of theory), Rf value: 0.5 (silica gel, methylene chloridelmethanol = 9:1 ) M.p. 224 °C
C2sH2sCIN505S
Mass spectrum: mlz = 5561558 [M+H]+
The following compounds of general formul,~ I-2 are prepared analogously to Example 2.0:
R4.
(I v i~
.,N
O ~ / /':O
CI 'N
(I-2) mass m.p.
ExampleR4' educt empirical Rfvalue*
formula spectrumo [ C]

-N(Me)-(CO)- 5061508 2.1 x'125 C261-124CIN504 266 0.50 (A) CH2-NMe2 [M+H]+

2.2 -CH2-NMe2 XV.4 C241-I21CIN403 260 0.50 (A) [M-H]--N(COMe)- 5201522 2.3 XV.6 C271-126CIN504 226 0.50 (A) (CH2)2-NMe2 [M H

*Eluant mixture:
(A): silica gel, methylene chloridelmethanol 9:1 Example 3.0 3-Z-f 1-(4-(N-(dimethyl-carbamoyl-methyl)-N-(2-ayrrolid in-1-yl-ethyl-carbonyl )-amino)-anilino)-1-phenyl-methylenel-6-chloro-2-indolinone 0.3 g of 3-Z-[1-(4-(N-(dimethyl-carbamoyl-methyl)-N-(2-bromo-ethyl-carbonyl)-amino)-anilino)-1-phenyl-methylene]-6-chloio-2-indolinone (educt XXI) and 0.1 ml of pyrrolidine are dissolved in 6 ml of dimethylformamide and stirred for 1.5 hours at ambient temperature. After cooling, 1.1 ml of 1 N sodium hydroxide solution are added and the mixture is stirred for another hour at ambient temperature. Water is added, the precipitate formed is suction filtered and purified through a silica gel column with a gradient of methylene chloride and methanollammonia as eluant.
Yield: 0.1 g (57% of theory), Rf value: 0.20 (silica gel, methylene chloridE~lmethanollammonia = 9:1:0.1 ) M.p. 224-226 °C
C32H~CIN5O3 Mass spectrum: mlz = 5701572 [M-H]~
The following compounds of general formul;~ I-3 are prepared analogously to Example 3.0:

R4.
," \
\ /
/ ~I
CI ~N
H (I-3) ExampleR4' educt empirical mass m~p~ Rf value*
formula spectrum[C]

Me N N~ 556/558 115-3.1 z ~N~ XXI.1 C3~1-I32CIN5O3 0.30 (A) o ~.~, o [M-H]' 117 N Mez 546/548 Me2 ~

3.2 o N XXI C3p~I32CIN5O3+ 226 0.25(A) M+H
[ ]

Me2N NMe2 532/534 276-3.3 o N~ XXI.1 C29f-l3oCIN5O3 0.25 + (A) [ M+H] 279 *Eluant mixture:
(A): silica gel, methylene chloridelmethanoliammonia 9:1:0.1 Example 4.0 3-Z-f 1-(4-(N-methyl-N-methylsulphonvl-amii lo)-anilino)-1-(3-iodo-ahenvl)-methylenel-6-chloro-2-indolinone 0.9 g of 1-acetyl-3-(1-methoxy-1-(3-iodo-ph~:nyl)-methylene)-6-chloro-2-indolinone (educt VIII) and 0.5 g of N-methyl-N-methylsulphonyl-p-phenylenediamine (educt XV.121 ) are dissc Ived in 10 ml of dimethylformamide and stirred at 120°C for 3 hours. After cooling, 1.5 ml of piperidine are added and the mixture is stirred for another hour at ambient temperature. Water is added, the precipitatE~ obtained is suction filtered, washed with a little water, methanol and etr er and finally dried in vacuo at 100°C.
Yield: 0.9 g (74% of theory), Rf value: 0.6 (silica gel, methylene chloridelmethanol = 9:1 ) M.p. 292-294 °C
C231~19CIIN3O3S
Mass spectrum: mlz = 5781580 [M-H]-The following compounds of general formul;~ I-4 are prepared analogously to Example 4.0 4~

H
=O
CI ~ H (I-4) Exam- mass m.p. Rf R3 R4' educ~s empirical formula ple spectrum[C] value*

VIII 529/531 238- 0.30 4.1 I ' -CH2-NMe2 C24H2~CIIN30 , , XV.~f [M+H]+ 240 (A) .

' -N(Me)-(CO)- VI I 4951497 277- 0.20 I.
?

4.2 I C2sH2aC12N402 ~

, CH2-NMe2 XV.1;?5 [M+H]+ 279 (B) ' -N(COMe)- VIII.? 5071509 241- 0.10 4.3 ~ C2~H26CI2N402 (CH2)2-NMe2 XV.B [M-H]- 243 (B) CI I JN~Me VIII. 548/550 266- 0.10 Z

4.4 ~ Me. ~ C29H29CI2N502 , N o ~ M-H - 268 B
w~. XV.2 [ ] ( ) )4 ' -N(COMe)- V111.2 5211523 241- 0 4.5 I -- C2eH2sCI2N40z .
.

,, CH -NMe XV, [M-H] 242 (B) ( 2)3 z T

VI11.2 4381440 243- 0.10 4.6 I ~ -CH2-NMe2 C24H21C12N30 , , XV.~~. [M+H] 244 (B) -Bno VI11.3 510/512 224- 0.30 I

4.7 ~ -CH2-NMe2 C31H2aCIN3O2 , , XV.~~. [M+H]+ 226 (B) Bno I -N(Me)-(CO)- VII 567/569 269- 0.10 ' I.

4.8 C33H31CIN4O3 CH2-NMe2 XV.1;?5 [M+H]+ 271 (B) ' ~N'Me VIII. 622/624 247- 0.20 Bno 3 4.9 I Me, ~ C36H3sCINsO3 +
I

wN o XV.2~)4 [M+H] 248 B
() Bno I -N(COMe)- VIII.3 581/583 207- 0.10 ' 4.10 C H CIN O

(CH2)2-NMe2 XV.Ij [M+H]+ 209 (B) Bno ' -N(COMe)- VI11.3 595/597 223- 0.10 4.11 ~ C35H35CIN4O3 (CH2)3-NMe2 XV.~~ [M+H]+ 224 (B) Me0 oMe -N(COMe)- VI11.1 533/535 128- 0.75 4.12 I ' C2sH31CINa0a ' , (CH2)2-NMe2 XV.~i [M-H]- 130 (C) OMe ~' -Me Meo N~ VIII.~1 574/576 208- 0.65 ' 4.13 l Me. C31H34CIN5O4 ~

o XV.2i)4 [ 1 ( ) w~.

Me0 oMe -N(SO2Me)- VIII. 569/571 198- 0.75 ~

4.14 I ' C2sH31CIN4O5S

. , (CH2)2-NMe2 XV.;? [M-H]- 200 (C) Me0 oMe VII 462/464 239- 0.70 I.
~

4.15 I ' -CH2-NMe2 C2sH2sCIN3O3 . , M_H - 240 C
. XV.~~ [ 1 ( ) Meo oMe o Me VIII. 533/535 147- 0 ~ 70 4.16 I ' .,~-N,_, C2sH31CIN4O4 .

, , NMe2 XV.219 [M-H]- 149 (C) O-N OH VIII. 4651467 e30 0.15 ~

4.17 -CH2-NMe2 C H CIN p d 24 21 4 4 ( COm XV.~t + (D) [M+H]

. p.) *Eluant mixtures:
(A): silica gel, methylene chloridelmethanol 9:1 (B): silica gel, methylene chloridelethanol 11):1 (C): silica gel, methylene chloride/methanol 4:1 (D): silica gel, methylene chloride/methanol~acetic acid 9:1:0.1 Example 5.0 3-Z-(1-(4-(N-(dimethylamino-methylcarbony )-N-methyl-amino)-anilino)-1-(4-(imidazol-1-yl-methyl)-phenyl)-methylenel-6-chloro-2-indolinone 0.7 g of 1-acetyl-3-(1-chloro-1-(4-(imidazol-'I-yl-methyl)-phenyl)-methylene)-chloro-2-indolinone (educt X.1 ), 0.4 g of N-( ~imethylamino-methylcarbonyl)-N-methyl-p-phenylenediamine (educt XV.125) and 1.2 ml of triethylamine are dissolved in 10 ml of dimethylformamide arn1 stirred for 15 hours at 60°C.
After cooling, 10 ml of methanol and 2 ml concentrated ammonia are added and the mixture is stirred for a further three yours at ambient temperature.
Water is added and the mixture is extracted with ethyl acetate. The organic phase is washed three times with water, dri~:d over sodium sulphate and concentrated in the rotary evaporator. The residue is purified through a silica gel column with methylene chloridelmetharr~llammonia 10:1:0.1 as eluant.
Yield: 0.1 g (5% of theory), Rf value: not determined M.p. 268-269 °C
CsoH2sCIN602 Mass spectrum: mlz = 5411543 [M+H]+

The following compounds of general formul;~ I -5 are prepared analogously to Example 5.0:
(I-5) Exam- mass m.p. Rf R3 R4' educ~s empirical formula ple spectrum[C] value*

N
I
<

N -N(COMe)- X'1 5551557 258-5.1 C H CIN O n.
31 31 6 2 d.

' (CHZ)2-NMe2 XV.~i + 259 I [M+H]

N
~~
~

N ~N-Me X.1 594/596 5.2 Me. ~ C33H34CIN7O2 227 n.
d.

I ' ~ ~ N o XV.2~ _ )4 [M-H]

N
, I
<

N -N(COMe)- X'1 5671569 239- 0.20 5.3 C H CIN p I ' (CH2)3-NMe2 XV.~~ [M-H]_ 240 (A) X.2 5111513 228- 0.30 N~

. I ' .~ C3oHzsCIN4O2 -XV.~ [M-H] 238 (B) -N(Me)-(CO)- X~2 5421544 304- 0.30 5.5 I ' C3oH3oCIN5O3 CH2-NMe2 XV.1;?5 [M-H]- 311 (B) 4~

R
/ -N
H
\=O
CI N
H

O

X.2 485/487 266- 0.30 5.6 ~ \ -CH2-NMe2 C28H2~CIN402 XV.~t [M-H]- 267 (B) ~ X'2 N~Me 556/558 277- 0.40 o 5.7 ~ \ ,,~-N,J G3~H30CIN5O3 +

XV.2;31 [M+H] 280 (B) -N(COMe)- X~2 5701572 0.10 5.8 ~ \ Cs2HsaCIN5O3 n. d.

(CH2)s-NMe2 XV.~~ _ (B) [M-Hl -S02-(CH2)2- X~2 5911593 0.40 5.9 ~ \ C3lf"~33CIN4O4S n. d.

NEt2 Xlx _ (B) [M-H]

X.2 501 /503246- 0.35 5.10 ~ \ -CH2-NEtMe C29H29CIN402 XV.79 [M+H]+ 249 (C) X.2 573/575 227- 0 5.11 ~ \ ~~ h-otBu C32H3sCIN4O4 .
-, - o XV.18 [M+H]+ 231 (D) o, +,o-HzN ~ -N(Me)-(CO)- X 5211523 254- 0.40 5.12 ~ \ C2sH25CIN6O4 , , CH2-NMe2 XV.1;?5 [M+H]+ 256 (B) o, +,o-HZN ~ -N(S02Me)- X 5711573 218- 0.50 5.13 ~ \ C2sH2~CIN605S

, , (CH2)2-NMe2 XV.;~ [M+H]+ 220 (B) o, +,o-HzN N N~ X 4881490 170 0.30 14 \

. ~ .~ C2sH24CIN5O3 ' ~,~ [M-H] (decomp.)(B) o +~-X

531 /533190- 0.30 HZN N Me 5.15 ~ \ ~~- J C27H2sCIN6O4 XV.2:31 [M-H]- 195 (E) Q + -N ~

HZN -N(COMe)- X 533/535 248- 0.30 5.16 I ~ C2~H27CIN604 , , (CH2)2-NMe2 XV.~~ [M-H]~ 250 (F) o, +~-HzN N -N(COMe)- X 5471549 168- 0.30 5.17 I ~ C28H29~!INgO4 ' , (CH2)3-NMe2 XV, [M-H]- 170 (G) ~

:N X.3 4471449 290- 0.30 5.18 I ~ -CH2-NMe2 C24H2~CIN4O3 XV.-t [M-H]- 292 (H) -N(COMe)- X~3 5181520 243- 0.35 5.19 I v C27H25CIN5O4 (CH2)2-NMe2 XV,,3 [M-H]- 244 (I) ~N'Me X.3 559/561 265- 0.25 5.20 I ~ Me. ~ C29H29CIN604 - wN XV.2i)1 [M-H]- 266 (I) ~ ~ -N(Me)-(CO)- X~3 5061508 0.35 5.21 ~ C2sH2aCIN5O4 290 CH2-NMe2 XV.1;?5 [M+H]+ (I) X.3 5181520 297- 0.40 N N~Me 5.22 I v ~~- J C271...124CIN5O4 +

XV.2;31 [M+H] 298 (I) Nc X.4 427/429 0.10 I

5.23 ~ -CH2-NMe2 C25H2~CIN40 n. d.

, , XV.~t _ (K) [M-H]

*Eluant mixtures:
(A): silica gel, methylene chloridelmethanol~ammonia 10:1:0.1 (B): silica gel, methylene chloride/methanol~ammonia 9:1:0.1 (C): silica gel, ethyl acetatelmethanollammc~nia 7:3:0.1 (D): silica gel, ethyl acetatelammonia 10:1 (E): silica gel, ethyl acetatelmethanollammc nia 8:2:0.2 (F): silica gel, ethyl acetatelmethanollammcnia 8.5:1.5:0.15 (G): silica gel, methylene chloridelmethanol'ammonia 8.5:1.5:0.15 (H): silica gel, methylene chloride/ethanol 5 1 (I): silica gel, methylene chloride/ethanollanimonia 20:1:0.1 (K): silica gel, methylene chloride/methanol 9:1 Example 6.0 3-Z-f1-(4-(N-(2-dimethylamino-ethyl)-N metlwlsulahonyl-amino)-anilino)-1-Qhenyl-methylenel-6-bromo-2-indolinone 1.0 g of 1-acetyl-3-(1-ethoxy-1-phenylmethylen)-6-bromo-2-indolinone (educt 1X.1 ) and 0.7 g of N-(2-dimethylamino-ethyl;-N-methylsulphonyl-p-phenylenediamine (educt XV.2) are dissolvf:d in 4 ml of dimethylformamide and stirred for 2 hours at 120°C. After cooling a little methanol is added and the precipitate formed is suction filtered. Th~:n the residue is suspended in a little ethanol, 3.3 ml of 1 N sodium hydroxide: solution are added and the mixture is stirred for another hour at ambiert temperature. After this time water is added, the precipitate is suction filt~:red and washed with water, methanol and ether.
Yield: 0.7 g (50% of theory), Rf value: 0.35 (silica gel, methylene chloridE~lmethanol = 9:1 ) M.p. 204-205 °C
C26H27BrN403s Mass spectrum: mlz = 5551557 [M]+
The following compounds of general formul;~ I-6 are prepared analogously to Example 6.0:
Ra \ /
-N
/ H
~O
N (I-6) H

Exam- mass m.p. Rr R4 R4' educt empirical formula ple spectrum[C] value*

R4, -N(Me)-{CO)-CH2- 5051507 253- 0.35 6.1 I XV.1:?5C26HZSBrN402 NMe2 [M+H]+ 256 (A) R' 4481450 236- 0.20 6.2 I ~ -CH2-NMe2 XV.~E C24H22BrN30 [M+H]+ 238 (A) Ra ~ -N(COMe)-(CH2)2- 5171519 0.25 6.3 I XV.Ii C2~H2~BrN402 147 NMe2 [M-H]- (A) IV 4111413 0.20 6.4 ~ _ - C2~H22BrN30 358 [M]+ (A) R4 Et 5461548 186- 0.60 ~

6.5 I otBu XV.13 C29H3oBrN30s -~

o [M-H]- 188 (A) Ra ~~ 469/471 302- 0.50 I

6.6 ~ N XV.1~t5C25H~9BrN40 Me [M-H]' 304 (A) R' -N(S02Bn)- 6291631 131- 0.25 6.7 I XV.1;)7C32H3tBrN4O3S

, (CH2)2-NMe2 [M-H]- 134 (A) R4, -N(S02nPr)- 5811583 228- 0.25 6.8 I ~ XV.1:~3CZgH3~BrN4O3S

{CH2)2-NMe2 [M-H]- 230 (A) Ra y O ~N-Me 515/517 268- 0.25 6.9 I , ,,~-N,J XV.2:31C2~Hz5BrN402 -[M-H] 270 (A) R' -N(COMe)-(CH2)s- 5311533 0.25 6.10 I , XV. C28H29BrN402 138 T

NMe2 [M-H]~ (A) R4, ~N~Me 560/562 276- 0.40 NJ

6.11 I ~ Me. ~ XV.2i)4C29H3oBrN502 +

~.N o [M+H] 278 (A) R4, 6 N~ 4741476 243- 0.50 12 I ~

. .~ XV.~ C26H24BrN30 2 +

[M+H] 247 (B) 6.13 I , Me.N~ NMez XV.2~)3C29H32BrN502 + 178 .

'v. o [M+Hl (C) Ra ~N.Me 503/505 0.70 6.14 I ,,~N,J XV.1;35C2~H27BrN40 + 247 ' [M+H] (D) R4, ~ -N(Me)-(CO)- 5191521 0.30 6.15 I XV.1;?6C2~H2~BrN402 229 (CH2)2-NMe2 [M+H]+ (D) R' -CH2-NMe-(CH2)2- 5051507 0.20 6.16 I XV.1~a5C2~H29BrN40 160 NMe2 [M+H]+ (D) R< Me 532/534 212- 0.55 ~

6.17 I ~~ o otBu XV.18 C28H28BrN303 [M-H]' 215 (E) {A): silica gel, methylene chloridelmethanol 9:1 (B): silica gel, methylene chloridelmethanol~ammonia 9:1:0.01 (C): aluminium oxide, methylene chloridelmethanol 9:1 (D): silica gel, methylene chloridelmethanol,'ammonia 5:1:0.1 (E): silica gel, methylene chloridelmethanol~ammonia 9:1:0.1 Example 7.0 3-Z-f 1-(4-(N-(2-d imethylamino-ethyl)-N-metl ~Isulphonyl-amino)-anilino)-1-phenyl-methylenel-6-cyano-2-indolinone 67 mg of 1-acetyl-3-(1-ethoxy-1-phenylmethylen)-6-cyano-2-indolinone (educt IX.2) and 60 mg of N-(2-dimethylamino-ethyl)-N-methylsulphonyl-p-phenylenediamine (educt XV.2) are dissolvE:d in 5 ml of dimethylformamide and stirred for 1.5 hours at 80°C. After cooling, 2 ml concentrated ammonia solution are added and the mixture is stirrec for a further 10 minutes at ambient temperature. After this time water i:~ added, the precipitate is suction filtered, dissolved again in methylene chlori~ielmethanol and dried over sodium sulphate. After removal of the solve it the residue is washed with ether and dried at 80°C.
Yield: 28 mg (26% of theory), Rf value: 0.15 (silica gel, methylene chloridE~lmethanol = 9:1 ) M.p. 270 °C
C27H27N5~3S
Mass spectrum: mlz = 501 [M]+
The following compounds of general formul;~ I-7 are prepared analogously to Example 7.0:
/ Ra \ /
/~H
~O
NC ~H (I-7) Exam- mass m.p. Rr R4 R4' educ;t empirical formula ple spectrum[C] value*

Ra -N(Me)-(CO)-CH2- 452 263- 0.10 7.1 ~ XV.125 C27H25N502 NMe2 [M+H]+ 266 (A) R' 4 393 267- 0.60 ~

7.2 ~ -CH2-NMe2 XV.~~ C25HZZNaO

[M-H]- 269 (B) R4, -N(COMe)-(CH2)2- 464 277- 0.40 7.3 ~' XV.~i Cz8H2~N502 NMe2 [M-H]- 280 (A) Ra 4141416 338- 0.30 ~

7.4 ~ -Br - C22H~aBrN30 [M-H]- 340 (A) R4, Et 493 201- 0.55 ~

7.5 ~ ~~ o otBu XV.13 C3oHaoNaOs [M-H]- 204 (A) R4, 7.6 N~ XV.2~)7C2aH2sNa0 433 259 0.25 ~ ~

M-H - A
[ ] () R' 423 256- 0.50 7.7 ~ ~ -O-(CH2)2-NMe2 XV.2~~6C2sH2aNaO2 [M-H]- 258 (B) R4, 7 o H XV C 450 258- 0.20 8 ~ ~ ~ 2 I8 H
~N~'' N

. ' . 27 NMe2 M-H - 260 B
[ ] () R' 0 ~N~Me 462 328- 0.75 7.9 ~ , XV.2:31C28H25N5O2 ~-N,J

, [M-H]- 329 (B) R' -N(COMe)-(CH2)s- 478 7.10 ~ XV.~~ C29~"~29N5~2 262 n.
d.

. NMe2 [M-H]-R4, ~N-Me 507 305- 0.15 \ NJ

7.11 ~ Me. ~ XV.2~)4C3oHsoNs02 +

~.N o [M+H] 307 (A) R' 4 421 0.10 7 -N~
12 I ~

. ,~ XV.~2 C2~H24N40 248 +

[M+H] (A) 7 I R4 Me. ~N~~ 509 218- 0.40 2~)3 H
N

. . 3o N~ NMe2 32 +
s ,' [M+H] 220 (C) Ra 7 o N XV C 466 247- 0.10 14 I ~ 2;?0 H
N

. , ., . 2a ~ 27 +
NMe 5 z z [M+H] 249 (B) R4, o N a 466 208- 0 7.15 I , 'v' ~- XV.219 C28H2~N502 .

NMe [M+H]+ 210 (B) z R4, o Me 480 264- 0 7.16 I ~ w~"N'~NMe XV.2;?1C29H29N5O2 + .

z [M+H] 267 (B) R4.
~ -N(Me)-(CO)- 466 015 7.17 I XV.1;?6C28H2~N502 274 (CH2)2-NMe2 + (A) [M+H]

N N~ 593 251- 0 7.18 I , otBu XV.2~~8C~H36N604 + .
Me.
~ J

N M+H 254 A
, ~.~, o [ ] ( ) I ~ R4' 393 0.35 7.19 ~ -CHZ-NMe2 XV.:3 C25H22Na0 232 , [M-H] (A) I ~ R4' o Me 466 188- 0.40 7 ~ vN' 2;?7 C

N

. ' . 28 ~ 2~
s , NMe + +
[M H] 191 (C) R4, ~0 494 0.30 \ NJ

7.21 I Me. ~ XV.1ii5C29H27N503 301 N +

.. L M+Hl (A) o Ra, 7.22 ~ \ Me, ~N'--~N'Me XV.2:~1 C3~H32N602 250 n. d.
,, N o [M-HJ_ Ra ~N~Et 519 0.45 7.23 ~ \ Me. ~NJ XV.2:52 C3~H32N602 276 ..N o IM_HJ_ (B) R , ~N~Me 7.24 ~ , a Me.N~NJ XV.2ii2 C3oH3oN602 507 199 0.50 'v. o [M+Hl+ (B) ~ Ra' -N(Me)-(CO)-CH2- 452 0.50 7.25 ~ NMe2 XV.2~i4 C2~H25N502 [M+H]+ 199 (B) ~ R , HIV-Me 7.26 ~ - a 'N~N'J XV.2~i3 C2sHzsNs02 493 + 196 0.30 o [M+H] (A) Ra~ 0 494 0.45 7.27 ~ ~ v~ -~~N~oH3~2 XV.2;i5 C3oH3~N5O2 [M+H]+ 201 C
() Ra~ ~0 480 0.25 7.28 ~ ~ v~ -~.N~cH3~2 XV.2;i6 C2sH2sNs02 [M+H]+ 206 C

Ra~ O
478 0.30 7.29 ~ ~ ~~~N~ XV.2:i7 C2sH2~N502 + 256 (C) ~'~'cH3 [M+Hl (A): silica gel, methylene chloridelmethanol 9:1 (B): silica gel, methylene chloride/methanol 4:1 (C): silica gel, methylene chloride/methanol~'ammonia 9:1:0.1 Example 8.0 3-Z-f 1-(4-(N-(2-dimethylamino-ethyl)-N-metlwlsulphonyl-amino)-anilino)-1-phenyl-methylenel-6-fluoro-2-indolinone 325 mg of 1-acetyl-3-(1-ethoxy-1-phenylme:hylen)-6-fluoro-2-indolinone (educt IX.3) and 310 mg N-(2-dimethylamino-ethyl)-N-methylsulphonyl-p-phenylenediamine (educt XV.2) are dissolvE:d in 2 ml of dimethylformamide and stirred for 4 hours at 120°C. After cooling methanol and water are added, the mixture is extracted with ethyl acetate a id the organic phase is concentrated in the rotary evaporator. The residue obtained is purified through a silica gel column with methylene chloridel Methanol 9:1 as eluant. The product is suspended in a little ethanol to el urinate the acetyl group, 1.3 ml of 1 N sodium hydroxide solution are added arid the mixture is stirred for another hour at ambient temperature. After this time water is added, the precipitate is suction filtered and washed with water, methanol and ether. The residue is dried in vacuo at 100°C.
Yield: 0.3 g (61 % of theory), Rf value: 0.25 (silica gel, methylene chloridE~lmethanollammonia = 9:1:0.1 ) M.p. 259-261 °C
CzsHz7FNa0aS
Mass spectrum: m/z = 493 [M-H]-The following compounds of general formul;~ I-8 are prepared analogously to Example 8.0:
Ra -N
H
=O
(I-8) F

Exam- mass m.p. Rr R4 R4' educt empirical formula ple spectrum[C] value*

R' -N(Me)-(CO)-CH2- 445 0.25 8.1 I XV.1;?5C26H25FNaO2 226 , NMe2 [M+H]+ (A) R4.
386 229- 0.35 8.2 I ~ -CH2-NMe2 XV.'~ C24H22FNs0 [M-H]' 232 (A) -N(COMe)-(CH2)2- 459 225- 0.25 8.3 I XV.~i C2~H27FN402 NMe2 [M+H]+ 227 (A) R4 Et 486 0.50 ~

8.4 I otBu XV.13 C2sHsoFNsOs 182 ,~

o [M-H]_ Ra 8 I ~ ~~ XV C 411 050 ~ 1 H
f5 FN

. N . 25 290 ' ~9 Me + (C) [M+H]

Ra ' -N(S02nPr)- 521 0.35 8.6 I ~.1:i4 CZ$H3~FN403S 227 (CH2)z-NMe2 [M-H]- (A) R' r'' 457 0.35 ~ o -Me 8.7 I ~-NJ XV.2:31C2~H25FNa02 + 118 . [M+H] (A) R' -N(COMe)-(CH2)s- 473 0.25 8.8 I XV.'~ C28H29FN4O2 214 NMe2 [M+H]+ (A) R4 ~N Me 500 0.30 ~ NJ

8.9 I Me. ~ XV.2~)4C29H3oFN502 + 230 wN o [M+H] (A) Ra 8 -N~ 414 0.25 ~ ~

. .~ XV.~2 C26HzaFNsO + 220 [M+H] A
() 8.11 ~ Me. ~ XV.2~)3C29H32FN5p2 - 150 .
'~
NMe2 [M-H]

RQ
~N.Me 443 0.15 8.12 ~ ,,~-NJ XV.1.35C2~H2~FN40 198 +

[M+H] (A) R' -N(Me)-(CO)- 459 0.40 8.13 ~ XV.1;?6C2~H2~FN402 201 (CH2)2-NMe2 [M+H]+ (A) R' -CH2-NMe-(CH2)2- 445 0.30 8.14 ~ XV.1!a5C2~HZ9FN40 141 NMe2 [M+H]+ (A) R' 8.15 , XV.2i)7C2~H26FN30 426 223 0.60 ~ ~ ~N~

, [M-H]- (A) R4~ Me 474 0.55 N

8.16 ~ ~ ~oteu XV.18 C2aH2sFNaOa 168 ~~

o +
[M+Hl Ra 438 295- 0.60 ~

8.17 ~ -NMe-S02Me XV.1;?1C23H2oFN303S

[M+H]+ 300 (A) Ra 409 255- 0.50 ~

8.18 ~ -S02Me - C22H~7FN203S

[M+H]+ 260 (A) Ra 402 310- 0.45 8.19 ~ ~ -N(COMe)-CH3 - C2aH2oFNs02 [M+H] 315 (A) I \ 331 299- 0.60 8.20 - - C2~H~5FN20 [M+H]+ 305 (A) R' -N(S02Me)-(CH2)- 509 270- 0.50 8.21 I XV.1;?0C26H2sFNa0aS

(CO)-NMe2 [M+H]+ 274 (E) (A): silica gel, methylene chloridelmethanollammonia 9:1:0.1 (B): silica gel, methylene chloridelmethanollammonia 10:1:0.1 (C): silica gel, methylene chloridelmethanol 9:1 (D): silica gel, methylene chloridelmethanol~ammonia 7:1:0.1 (E): aluminium oxide, methylene chloridelm~ahanol 19:1 Example 9.0 3-Z-f 1-(4-(dimethylaminomethyl)-anilino)-1-14-iodo-ahenyl)-methylenel-6-fluoro-2-indolinone 3.5 g of 1-acetyl-3-(1-methoxy-1-(4-iodo-ph~;nyl)-methylene)-6-fluoro-2-indolinone (educt V111.14) and 1.6 g of 4-(dirnethylaminomethyl)-aniline (educt XV.4) are dissolved in 30 ml of dimethylforniamide and stirred for 2 hours at 120°C. After cooling the solvent is eliminated, the residue is taken up in 30 ml of methanol and 2 spatula tips of sodium m~;thoxide are added. After a yellow precipitate has formed the solvent is remov~;d by suction filtering, the residue is washed with a little methanol and ether aid finally dried in vacuo at 100°C.
Yield: 1.9 g (46% of theory), Rf value: 0.3 (silica gel, methylene chloridelmethanol = 9:1 ) M.p. 243-246 °C
C24H2~ FI N30 Mass spectrum: mlz = 514 [M+H]+
The following compounds of general formul ~ I-9a are prepared analogously to Example 9.0:

R4.
/ \

-N
H
~~ O
R2 / H (I_9a) Exa em ~irical m.p, Rr Exam-R3 R4' educts mass spectrum mple formula [C] value*ple V I 404 225- 0.20 I I
.7 9.1 -F I ' -CH2-NMe2 C24H2~F2N3O

, , X V.4 [M-H]- 227 (A) .

-N(COMe)- V111.7 491 160- 0.20 9.2 -F I ' C2sH2sF2NaO2 , , (CH2)3-NMe2 xV.7 [M+H] 163 (A) ~N-Me ' J V 111.7 518 218- 0.40 Me.

9.3 -F I N C2gH29F2N5~2 '' +
~

, ' ~' X'.204 [M+H] 220 (A) .

H3C~0 V I 471 106- 0.25 I I
.8 9.4 -F -CH2-NMe2 C28H29FN402 I ' X V.4 [M-H]- 110 (A) H3C~0 -N(COMe)- V111.8 558 194- 0.25 9.5 -F Ca2HssFN54s I ' (CHZ)s-NMe2 ~V.7 [M+H]+ 196 (A) H3CN o N N-Me J V I 583 238- 0.25 9 F Me- I I
6 .8 . - N C33H37FN6~3 ,~
o I ' ~' X~ .204 [M-H]- 240 (A) F F V I 440 267- 0.35 I I
.9 9.7 -F I ' -CHZ-NMe2 C24H~9F4N30 ' , M-H - 269 A
F XV.4 [ ] ( ) -N(COMe)- V111.9 527 210- 0.15 9.8 -F I ' C2gH26F4N4~2 ' , (CHZ)a-NMe2 xV.7 [M+H]+ 212 (A) ~N-Me ' J V I 554 216- 0.20 Me. I I
.9 9.9 -F I N C29H2~FaNsO2 , , o X'.204 [M+H]+ 218 (A) 0 oMe V111.1 460 173- 0.30 9.10-F ' -CH2-NMe2 C2~HZ6FN303 I - . XV.4 [M+H]+ 176 (A) V111.16 514 198- 0.30 9.11-F I ' -CH2-NMe2 C24HZ~FIN30 ' , ~V.4 [M+H] 200 (B) VI11.10 458 195- 0.25 oMe 9.12-F ' -CH2_NMe2 C27H2sFNsOs I ~ V.4 [M-H]' 198 (A) - , tBuO o V111.11 517 230- 0.30 9.13-F -CH2-NMe2 C3pH33FN4O3 ' +
I , , ~ V.4 [M+H] 240 (A) o OMe V I 567 188- 0.40 -N(S02Me)- I I
.1 9.14-F ' C2gH3~ FN4O5S

I. . (CHz)2-NMe2 ~:V.2 [M+H]+ 189 (A) O OMe ~ ~Me V 111 Me, ~ . 572 200- 0.35 F

9.15- ~ N C321"134FN5~4 +

XV.204 [M+H] 203 (C) cN V111.12 427 130- 0.25 9.16-F I ~ -CH2-NMe2 C2sH2sFNa0 ', ' X V.4 [M+H]+ 135 (A) OtBu ~''N.Me '~ N

HN Me. ~ V111.13 629 215- 0.35 o J

9.17-F v wN o CssHa~FNs4a +

~ Xy.204 [ ] ( ) M+H 220 A

OtBu '~

HN V111.13 517 186- 0.35 O

9.18-F ~ -CH2-NMe2 C3pH33FNa03 ~ +
X V.4 [M+H] 190 (A) OtBu O~

NH
VI11.20 531 0.40 9.19-F -CH2-NMe2 C3~H35FN4O3 n.
b.

v XV.4 + (A) [M+HJ

OMe V111.18 488 166- 0.40 9.20-F -NMe-(COMB) C28H2sFN30a / ~ - M+H 170 A
[ ]+ ( ) OMe r~N.Me -N,J V111.18 586 176- 0.30 1 F Me.

9.2 - N C33H3gFN504 +

X'.204 [M+H] 180 (A) OMe -N(S02Me)- VI11.18 581 195- 0.45 9.22-F CsoHsaFNaOsS

(CH2)2-NMe2 xV.2 [M+H]+ 198 (A) OMe o -N(COMe)- VI1.18 559 100- 0.50 9.23 -F C32H35FN4~4 I ~ (CH2)3-NMe2 XV.7 [M+H]+ 104 (A) OMe o Me V I I I .18 558 132- 0.80 9.24 -F ~ ,~N~otBu C32H34FN305 I o Xv,18 [M-H]- 137 (D) .
OMe 0 0 ~N,Me VI11.18 543 234- 0.60 9.25 -F ~ .,~N,..J C31H31FN4~4 I X'.231 [M+H]+ 236 (A) OMe o N7 V111.18 497 110- 0.40 9.26 -F ~ ~%~tv C29f"~25FN4~3 I Me X'.145 [M+H]+ 115 (A) OMe o V I I I .18 495 130- 0.60 9.27 -F I ~ -S02Me - C26H2aFN20sS M+H 137 A
[ 1+ ( ) oMe Me. ~ J .Me V111.10 572 0.60 9.28 -F ~ N C32H34FN504 189 I - . ~~~~ o X\.'.204 [M+Hl+ (B) -N(SOZMe)- V111.10 56? 0.60 9.29 -F I ~ oMe C291"131FN4~5S n. b.
(CH2)2-NMe2 ~:V.2 [M+H]+ (B) OMe O ~N-Me V111.10 529 201- 0.60 9.30 -F I ~ .,~'-N,J C30H29FN4~4 X\x.231 [M+H]+ 203 (B) -N(Me)-(CO)- V 11.10 517 0.60 9.31 -F ~ OMe C29H29FN404 126 I CHZ-NMe2 Xv.125 [M+H]+ (B) O

-N(COMe)- V111.10 531 0.50 OMe 9.32-F ~ C30H31FN4~4 179 , (CH2}2-NMe2 XV.6 [M+H]+

-N(COMe)- V111.10 545 0.20 oMe 9.33-F ~ C31H33FN4~4 123 (CH2)s-NMe2 XV.7 [M+H]+

-N(Me)-(CO)-VI11.10 559 0.20 OMe 9.34-F ~ C32H35FN4~4 201 , (CH2)a-NMe2 XV.258 IM+H]+

0 oMe V111.1 403 198- 0.80 9.35-F ~ -H C24H~9FN203 ~ _ [M+H]+ 206 (A) O OMe N 1 V I 483 223- 0.75 ~ I I
.1 9.36-F v ~%~N C2aH28FN40s ~ Me X V'.145 [M+H] 226 (A) 0 oMe V111.1 O ~N-Me 529 215- 0.30 9.37-F ~ v .,~-N,J CsoH2sFN40a +

- . X'.231 [M+H] 220 (A) 0 oMe -N(S02Me)- V111 . 581 227- 0.65 9.38-F ~ (CH2)-(CO)- C29HZ9FN4O6S

- . X'.120 [M+H]+ 230 (A) NMe2 O OMe V111.1 -N(Me)-(CO)- 517 128- 0.45 9.39-F ~ C29H29FN404 , CH2-NMe2 X~~.125 [M+H]+ 130 (A) O OMe -N(COMe)- V 111.1 474 218- 0.40 9.40-F v C27H24FN3~4 ~ CH3 - [M H 223 + ( ) + ] A

o OMe _N(Me)-(CO)-V111.1 531 192- 0.40 9.41-F ~ C30H31FN4~4 ~ (CH2)2-NMe2 XV.126 [M+H]+ 194 (A) .

o OMe V' 11.1 481 205- 0.65 9.42-F v -S02Me C25H21FN20sS

~ _ [M+H]+ 214 (A) .

o OMe V 11.1 -N(Me)-(CO)- 545 190- 0.15 43 -F v C31 H33FN4~4 . ~ (CH2)3-NMe2 XV .266 [M+H]+ 193 (A) .

0 oMe V111.1 -N(COMe)- 545 184- 0.50 44 -F v C31 H33FN4~4 . ~ (CH2)3-NMe2 XV.7 [M+H] 188 (A) .

VI 11.10 403 0.70 oM

9 -F e -H C24H19FN203 114 45 ~

. / - [M+H]+
,. .

O

V111.10 481 0.60 oM

46 -F e -S02Me C25H2~ FN205S 129 9 ~

. ~ - [M+H]+
,- , oMe N~ V111.10 483 0.60 ~%'~ FN 125 O
C
H

9.47-F ~ N 4 2g ~ Me X\x.145 + (B) ,- . [M+H]

o -N(S02Me)-V 11.10 581 0.60 oM

9.48-F e (C1..12)_(CO)- C29H29FN406S 163 ~

/ X~~.120 LM+H] ( .- .

NMe2 -N(Me)-(CO)-V111.10 545 0.10 oMe 49 -F ~ C31H33FN4O4 101 . ~ (CH2)a-NMe2 X/.266 [M+Hl+ ( O

-N(Me)-(CO)-VI11.10 531 0.20 oMe 9 -F ~ C3pE'131 161 50 FN4~4 . I (CHZ)2-NMe2 XV.126 [M+H]+ (B) Meo o N~Me Me. ~ VI 1.17 586 181- 0.20 ~ ~
H
FN
C

9.51-F . 4 I ~ , M+H 183 B
XV .204 [ ] ( ) Me0 0 -N(S02Me)- VI1.17 581 158- 0.35 52 -F C30H33FN4~5S

. (Chi2)2-NMe2xV.2 [M+H]+ 160 (B) Me0 0 -N(Me)-(CO)-V111.17 531 0.40 53 -F CsoHs~FNaOa n.
9 b.

. I ~ CH2_NMe2 X\,'.125 [M+H]+ (B) Me0 0 -N(COMe)- V111.17 559 0.50 54 -F C32H35FN4~4 n.
9 b.

. (CH2)3-NMe2 ~V.7 + ( [M+Hl tBuO o ~'' .Me Me, ~N J VI 11.11 629 0.35 FN b ~
1"1 C

9.55-F . 41 + n.
N o 6 .

~ , X\x.204 [M+H] (A) I

o~-CHs HN -NMe-(CO)- V 11.21 473 122- 0.50 9 -F C27H25FNa0a . I ~ CH3 _ [M+H]+ 126 (F) o~-CHs HN -N(COMe)- V111.21 544 80- 0.25 9 -F W '31H34FN5~3 . ~ CH2)s-NMe2 CV.7 [M+H] 83 (A) I ( ,, .

O~-CHs HN -N(S02Me)- V111.21 566 190- 0.30 9.58 -F C2sHa2FNsOaS

I ' (CH2)2-NMe2 ~V.2 [M+Hl+ 195 (A) O~-CHs HN -N(Me)-(CO)-VI11.21 516 238- 0.30 9.59 -F C2sHsoFNsOs I ' CH2-NMe2 X,'.125 [M+Hl+ 241 (G) OMe V111.18 488 205- 0.55 9.60 -F -(CH2)2-NMe2 C29H3oFN3O3 ' XV.5 [M+H]+ 208 (G) I
.- .

OMe -N(Me)-(CO)-V111.18 543 196- 0.20 9.61 -F C31 H31 FN4~4 I ' (CH2)2-NMe2 Xy.12g [M-H]- 202 (A) OMe -N(Me)-(CO)-V111.18 531 177- 0.30 62 -F C30H31FN4~4 . I ' CH2-NMe2 XV.125 [M+H]+ 182 (A) Et0 O

V111.22 500 100- 0.35 9.63 -F -(CH2)2-NMe2 C3pH32FN3O3 ' XV.5 [M-H]- 105 (B) I

OMe -N(COMe)- VI11.18 545 167- 0.40 9 -F C311"133FIV4~4 . I ' (CH2)2-NMe2 XV.6 [M+H]+ 169 (A) Et0 O

-N(Me}-(CO)-VI11.22 571 0.35 9.65 -F CasHs~FNaOa n.d.

I ' (CH2)s-NMe2 X'.266 _ (A) [M-Hl Et0 O

-N(Me)-(CO)-V111.22 585 0.40 9.66-F C34H39FN4~4 I1.CI.

(CH2)a-NMe2 XV.258 _ (A) [M-hi]

Et0 V111.22 511 95- 0.25 '~

9.67-F C3oH2~FNa0a ~ ~ Me X~ .145 [M+H]+ 105 (B) OMe -N(Me)-(CO)-VI11.18 573 173- 0.20 9.68-F C331"~37FN4~4 (CH2)a-NMe2 X'.258 [M+H]+ 175 (A) OMe V111.18 417 168- 0.65 9.69-F -H C25H2~ FN203 / ~ - M+H 174 A
[ ]+ ( ) OMe V I 500 168- 0.40 N~ I I C
.18 H
FN
~

9.70-F ~ .~ 30 30 +

X'J.22 [M+H] 173 (B) OMe o VI11.18 502 0.45 9.71-F -CH2-NEt2 C3oH32FN303 n.d.

X'J.66 [M+H]+ (B) OMe H V111.18 544 0.30 N

9.72-F fiotBu C311"132FN305 n.Cl.
~~

~ X'J.12 [M-H]- (G) V111.10 472 165- 0.25 oMe 9.73-F ~ _(CH2)2-NMe2 C28H28FN303 ~ ~;V.S [M-H]- 170 (B) O OMe V111.1 472 193- 0.25 9.74-F I v -(CH2)rNMe2 C28H2aFN303 XV.5 [M-H]- 197 (B) Et0 O

V111.22 488 48- 0.45 9.75-F -CHZ-NMe2 C29H3oFN3O3 XV.4 [M+H]+ 52 (B) OMe V111.23 504/506 156- 0.30 9.76-CI -(CH2)2-NMe2 C29H3oCIN3O3 ~ XV.5 [M+H]+ 160 (H) I

OMe N~ V111.23 513/515 0.40 77 CI ~%~ C

CIN
O

. - N 29 110 ~ Me X'.145 + (H) I [M+H]

OMe V111.23 4901492 173- 0.70 9.78-CI -CH2-NMe2 CZ8H28CIN3O3 ~ XV.4 [M+H]+ 175 (I) I

OEt V111.24 488 158- 0.35 9.79-F -CH2-NMe2 C2gH30FN3~3 ~ XV.4 [M+H]+ 161 (B) I

Me0 O

rN~Me V111.17 529 147- 0.50 9.80-F ~ .,~N.J C31H33FN4C3 +

I X\'.135 [M+H] 150 (I) MeO O

,_N V111.17 497 182- 0.60 9.81-F ~ .,~N,J C29H25FN403 +

I X\'.140 [M+H] 185 (K) OMe o V111.18 ~N~Me 529 0.35 9.82-F . ~!31H33FN4~3 184 ~N,J

~ , X'.135 + ( [M+H]

OMe O
V111.18 497 0.45 9.83-F \ ,'~ J ~!29H25FN4~3 233 +

X'.140 [M+H] ( OMe -CH2-NMe- V111.18 531 0.40 9.84-F C3~H35FN4~3 120 ~ v CH2)2-NMe2 X'.195 M+H + ~ ) ( [ ]

Et0 O

-CH2-NMe- V111.22 545 0.40 9.85-F C32H3~FNa03 n.d.

(CH2)2-NMe2 X'.195 [M+Hl+ ( OMe o V111.23 5161518 195- 0.30 9 CI N~ CIN

h"1 . - ~ .~ 3O3 30 +

X'J.22 [M+H] 197 (H) Et0 O

V111.22 431 156- 0.80 9.87-F -H C26H23FN203 / ~ - [M+H]+ 160 (M) Et0 O

H V111.22 560 0.50 N

9.88-F h-otBu C32H34FN3~5 n.d.
~~

~ o X'J.12 + ( [M+Hl Et0 O

Me V111.22 574 0 9.89-F ~ ,~N~--otBu C33H3fiFN3~5+ n.d. .

o X'J.18 [M+Hl O) Me0 O
~

o VI 476 0.25 11.25 9.90-F -CH2-NMe2 C2~H26FN304 129 xV.4 [M+H]+ (B) OMe VI

. 476 0.25 9.91-F o ~ -CH2-NMe2 C27H2sFN3Ua + 155 XV.4 [M+H] (B) OEt O

V I 504 0.20 I
I
.27 9.92-F o -CH2-NMe2 C28H28FN304 n.d.

X'/.4 [M+H]+ (B) OMe V111.18 9 B N~ ~ 5601562 230- 0.45 C
H
B

. r .~ 3 +

r X'.22 [M+H] 235 (B) OMe V111.18 5341536 178- 0.35 9.94-Br -CH2-NMe2 C28H2$BrN303 / ~ 1 M+H 180 B
X !.4 [ ]+ ( ) OMe V111.18 562/564 173- 0.40 9.95-Br -CH2-NEt2 C3pH32BrN3O3 X'.66 [M+H]+ 176 (B) *Eluant mixtures:
(A): silica gel, methylene chloride/methanol,'ammonia 9:1:0.1 (B): silica gel, methylene chloridelmethanol 9:1 (C): silica gel, methylene chloridelmethanol'ammonia 8:1:0.1 (D): silica gel, methylene chloridelmethanol~ammonia 10:1:0.1 (E): silica gel, methylene chloridelmethanol,'ammonia 5:1:0.01 (F): silica gel, ethyl acetatelmethanollammc~nia = 9:1:0.1 (G): aluminium oxide, methylene chloridelrr ethanol = 19:1 (H): silica gel, methylene chloridelmethanoLammonia 9:1:0.01 (I): silica gel, methylene chloridelmethanol ;~:1 (K): aluminium oxide, methylene chloridelet ianol = 20:1 (L): silica gel, petroleum etherlethyl acetate 1:1 The following compounds of general formul;~ I-9b are prepared analogously to Example 9.0:

R4.
R
N
H
O
R2 -~ H (I_9b) Exa mass mp. R,-RZ R3 R4' ecluctsempirical formula mple spectrum[C] value*

OMe o V111.18 474 176- 0.40 9.96-F -CH2-NMe2 C2aH28FN303 ~ ~ V.3 [M+H]+ 179 (A) Et0 O

VI11.22 486 0.45 9.97-F -CH2-NMe2 C29H3oFN303 n.d.

~ ~ V.3 _ (B) [M-Hl OMe o V111.23 4901492 163- 0.40 9.98-CI -CH2-NMe2 C2aH28CIN303 ~ ~.V.3 [M+H]+ 165 (A) *eluant mixtures:
(A): silica gel, methylene chloridelmethanol 9:1 (B): silica gel, methylene chloridelmethanol;'ammonia 9:1:0.1 Example 10.0 3-Z-f 1-(4-(dimethylaminomethyl)-anilino)-1-13,4-dimethoxy-phenyl)-methylenel-6-cyano-2-indolinone 130 mg of 1-acetyl-3-(1-methoxy-1-(3,4-dimethoxy-phenyl)-methylene)-6-cyano-2-indolinone (educt VI11.5) and 58 me of 4-(dimethylaminomethyl)-aniline (educt XV.4) are dissolved in 5 ml of dimethylformamide and stirred for 2 hours at 80°C. After cooling the solvent is eliminated and the residue is purified through a silica gel column with mei hylene chloridelmethanol 9:1 as eluant.
Yield: 21 mg (12% of theory), Rf value: 0.35 (silica gel, methylene chloridE~/methanol = 9:1 ) M.p. 265 °C
C27H2sN4~a Example 11.0 3-Z-f 1-(4-(N-methyl-N-methylsulphonyl-amigo)-anilino)-1-(3-(2-methoxycarbonyl-vinyl)-phenyl)-methylenel~ 6-chloro-2-indolinone 580 mg of 3-Z-[1-(4-(N-methyl-N-methylsul~~honyl-amino)-anilino)-1-(3-iodo-phenyl)-methylene]-6-chloro-2-indolinone (E~duct 4.0) and 140 ml methyl acrylate are dissolved in 20 ml acetonitrile and 11 ml of dimethylformamide and 11 mg of palladium(II)-acetate, 2 ml of i riethylamine and 30 mg of tri-ortho-tolyl-phosphine are added. The soluti~~n is stirred for 10 hours at 90°C
under nitrogen as protective gas. After cooling it is filtered through Celite, the solvent is eliminated and the residue is puri ~ied through a silica gel column with methylene chloridelmethanol 20:1 as eluant.
Yield: 450 mg (84% of theory), Rf value: 0.30 (silica gel, toluenelethyl acet~~te = 1:1 ) M.p. 228-232 °C

Mass spectrum: mlz = 5371539 [M]+

The following compounds of general formul;~ I-11 are prepared analogously to Example 11.0:
R4, ~H
y) H (1_11 ) Exam- mass m.p. Rr R2 R3 R4' educt empirical formula ple spectrum[C] value*

O OMe 4861488 150- 0.50 11.1 -CI -CH2-NMe2 4.'I C28H26CIN303 / \ ~M-H 155 A
- () ]

N HZ

455 269- 0.20 ~

11.2 -F -CH2-NMe2 9.i) C2~H25FNa02 I ~ ~M-H]' 270 (B) OMe 470 205- 0.65 ~

11.3 -F -CH2-NMe2 9.t) C2sH2sFNs4s / ~ M-H - 208 A
f l ( ) O OMe 472 138- 0.45 11.4 -F -CH2-NMe2 4.1 G28H26FN303 I \ [M+H~+ 140 (A) *Eluant mixtures:
(A): silica gel, methylene chloridelmethanol 5:1 (B): silica gel, methylene chloridelmethanol'ammonia 9:1:0.01 Example 12.0 3-Z-f 1-(4-dimethylaminomethyl-anilino)-1-(3-(2-methoxycarbonyl-ethyl)-phenyl)-methylenel-6-chloro-2-indolinone 1.0 g of 3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-(3-(2-methoxycarbonyl-vinyl)-phenyl)-methylene]-6-chloro-2-indolin one (educt 11.1 ) are dissolved in 100 ml of methanol and 200 mg of 10% palladium/charcoal is added as catalyst. Then the mixture is hydrogenated for 6 hours at ambient temperature under 50 psi of hydrogen pressure. After thE: reaction has ended the catalyst is filtered off, the solvent is eliminated and tl~e residue is dried in vacuo at 100°C.
Yield: 900 mg (90% of theory), Rf value: 0.40 (silica gel, methylene chloridE~lmethanol = 9:1 ) M.p. 160 °C
C2sH2sCIN303 Mass spectrum: mlz = 4901492 [M+H]+
The following compounds of general formul;~ I-12 are prepared analogously to Example 12.0:
R4, .H
-O
RZ / H (1_12) Exam- mass m.p. Rr Rz R3 R4' edu~t empirical formula p p [ value le s ectrum~~

O OMe -N(Me)- 5381540 148- 0.50 12.1 -CI 11.0 C27H26CIN305S

I ~ S02Me [M-H]- 150 (A) NHz 459 0.70 12.2 -F -CH2-NMe2 11.2 C2~H2~FN402 150 [M+H]+ (B) OMe 474 0.35 12.3 -F -CH2-NMe2 11.3 C28H28FN303 140 / ~ (M+H]+ (A) O OMe 474 140- 0.30 12.4 -F -CH2-NMe2 11.4 C28H28FN303 / \ (M H 142 A
() *Eluant mixtures:
(A): silica gel, methylene chloridelmethanol 9:1 (B): silica gel, methylene chloridelmethanol, ammonia 5:1:0.01 Example 13.0 3-Z-f 1-(4-dimethylaminomethyl-anilino)-1-(4-amino-ahenyl)-methylenel-6-chloro-2-indolinone 130 mg of 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(4-nitro-phenyl)-methylene]-6-chloro-2-indolinone (educt 5.18) are dissolved in 20 ml of ethanol and 20 ml of ethyl acetate and 100 mg of Raney nickel are added as catalyst. Then the mixture is hydrogenated for 20 hours at ambient temperature. After the end of the reaction ttie catalyst is filtered off, the ' solvent is eliminated, the residue is washed with a little diisopropylether and purified through a silica gel column with mel hylene chloridelethanollammonia 30:1:0.1 as eluant. The product is washed vrith a little diisopropylether and dried in vacuo.
Yield: 80 mg (66% of theory), Rf value: 0.60 (silica gel, methylene chloridE~lethanollammonia = 20:1:0.1 ) M.p. 263-264 °C
C2aH2sCIN40 Mass spectrum: mlz = 4191421 [M+H]+
The following compounds of general formul~~ I-13 are prepared analogously to Example 13.0 Ra \ /
/ -N
H
~=O
CI ~ H (I-13) Exam- mass m.p. Rf R4 R4' edu empirical ~t formula ple spectrum[C] value*

R4.
-N(Me)-(CO)-CH2- 4761478 275- 0.10 13.1 I 5.21 CZ6H2sCIN502 NMe2 [M+H]+ 276 (A) R4~ ~N~Me 5291531 268- 0.15 ~ N
J

13.2 I Me 5.20 C29H3~CIN602 ~
' ~N [M-H]- 269 (A) Ra ~ -N(CO 4 0.25 (CH2)2 13.3 I NMe 5.19 C27H2aCIN502 M+H 2 270 2 [ ] (A) R' 13.4 ~ ~N~Me 4881490 279- 0.30 ,,~-N,J 5.22 C27H2sCIN502 [M+H]+ 280 (A) *Eluant mixtures:
(A): silica gel, methylene chloridelethanollainmonia 20:1:0.1 Example 14.0 3-Z-f 1-(4-dimethylaminomethyl-anilino)-1-(4-aminomethyl-phenyl)-methylenel-6-chloro-2-indolinone 900 mg of 3-Z-[1-(4-dimethylaminomethyl-a~ilino)-1-(4-cyano-phenyl)-methylene]-6-chloro-2-indolinone (educt 5.23) are dissolved in 20 ml of methylene chloride, 30 ml of methanolic ammonia are added and 200 mg of Raney nickel are added as catalyst. Then tr a mixture is hydrogenated for 2 hours 15 minutes at ambient temperature and under 50 psi hydrogen pressure. After the end of the reaction the catalyst is filtered off, the solvent is eliminated and the residue is washed with a little methanol and diethyl ether.
To liberate the base the residue is taken up in 1 N sodium hydroxide solution and extracted four times with methylene chl ~ridelmethanol 9:1. The combined organic phases are washed with water and dried over sodium sulphate. The product is washed with a little diethyl ether ~~nd dried in vacuo.
Yield: 680 mg (75% of theory), Rf value: 0.60 (silica gel, methylene chloridE~lmethanollammonia = 9:1:0.1 ) M.p. 211-214 °C
C25H25CI N4~
Mass spectrum: mlz = 4331435 [M+H]+

Example 15.0 3-Z-11-(4-(N-((4-methyl-piperazin-1-yl)-meth ylcarbonyl)-N-methyl-amino)-anilino)-1-(4-aminomethyl-phenyl)-methylenel-6-chloro-2-indolinone 1.39 g of 1-acetyl-3-Z-[1-(4-(N-((4-methyl-pi~erazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-(4-cyano-phenyl)-rnethylene]-6-chloro-2-indolinone are dissolved in 20 ml methylene chloride, ~ 0 ml of methanolic ammonia are added and 200 mg Raney nickel are added as catalyst. Then the mixture is hydrogenated for 2 hours at ambient tempe ~ature under 50 psi hydrogen pressure. After the end of the reaction the catalyst is filtered off, the solvent is eliminated and the residue is washed with a little methanol and diethyl ether.
To liberate the base the residue is taken up in 1 N sodium hydroxide solution and extracted four times with methylene chl ~ridelmethanol 9:1. The combined organic phases are washed with water and dried over sodium sulphate. The product is purified through a silica gel colurr~~n with a gradient of methylene chloride and methylene chloridelmethanollammonia 8:1:0,1 as eluant. The product is washed with a little diethyl ether rind dried in vacuo.
Yield: 700 mg (54% of theory), Rf value: 0.15 (silica gel, methylene chloridE~/methanollammonia = 9:1:0.1 ) M.p. 232-235 °C
C301"'133CIN6~2 Mass spectrum: mlz = 5441546 [M]+
Example 16.0 3-Z-f 1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-(4-hydroxy-phenyl)-methylenel-6-;,hloro-2-indolinone 100 mg of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-(4-benzyloxy-phenyl)-metliylene]-6-chloro-2-indolinone (educt 4.9) are dissolved in 2 ml trifluoroacE tic acid and stirred for 5 hours at 50°C. After the end of the reaction the solvE nt is eliminated. To liberate the base the residue is taken up in water and ccmcentrated ammonia is added until an alkaline reaction is obtained. The precipitate formed is suction filtered, washed with water and at 100°C dried.

' Yield: 10 mg (12% of theory), Rf value: 0.30 (silica gel, methylene chloridE~lmethanol = 4:1 ) M.p. 174-176 °C
C2gH30~!IN5O3 Mass spectrum: mlz = 5321534 [M+H]+
The following compounds of general formul;~ I-16 are prepared analogously to Example 16.0:
HO
Ra \ /
-N
H
\~O
CI ~~ H (I-16) Exam- mass m.p. Rf R4 R4' eductempirical formula ple spectrum[C] value*

R' -N(Me)-(CO)-CH2- 4771479 239- 0.50 16.1 ~ 4..3 CZ6HZSCIN403 , NMe2 [M+H]+ 241 (A) Ra -N(COMe)-(CH2)2- 4911493 249- 0.40 16.2 ~ 4.10 C27H2~CIN403 NMe2 [M+H]+ 251 (A) Ra -N(COMe)-(CH2)3- 5031505 169- 0.30 16.3 ~ 4.11 C28H29CIN403 , NMe2 [M-H]- 170 (A) R' 4181420 215- 0.05 16.4 ~ ~ -CHZ-NMez 4. C24H22CIN302 ~

[M-H]' 217 (B) *Eluant mixtures:
(A): silica gel, methylene chloridelmethanol 4:1 (A): silica gel, methylene chloridelethanol 11):1 Examale 17.0 3-Z-f1-(4-ethylaminomethyl-anilino)-1-phern~l-methylenel-6-chloro-2-indolinone-trifluoroacetate 180 mg of 3-Z-[1-(4-(N-tert.butoxycarbonyl-~ahylaminomethyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (e~iuct 1.30) are dissolved in 5 ml methylene chloride and 0.5 ml of trifluoroac~aic acid are added. The mixture is stirred for 10 hours at ambient temperature. After this time the solvent is largely eliminated and the precipitate formed is suction filtered.
Yield: 110 mg (60% of theory), Rf value: 0.20 (silica gel, methylene chloridE~lmethanol = 9:1 ) M.p. 260 °C
Cz4H2zCIN30 Mass spectrum: mlz = 4021404 [M-H]-The following compounds of general formul;~ I-17 are prepared analogously to Example 17.0 R4.

H
=O
Rz ~ H (1_17) Exam- mass m.p. Rr R2 R3 R4' eruct empirical formula ple spectrum[C] value*

I ~ 3881390 0.15 17.1 -CI ~ -CH2-NHMe 1.43 C23H2oCIN30 250 - [M-H]~ (A) I Me.N~ 514/516 0.25 ~

17.2 -CI . ~' ~'> 1.50 C29HsoCIN502 224 .

,, M-H - A
[ ] ( ) I ~ ~-'' N H 443/445 0.25 17.3 -CI ~ ,,~N,._~ 1.52 C26H2sCIN40 240 -[M-H] (A) I ' ~ ~NH 457/459 0.25 17.4 -CI ~ , 1.67 C26H2sCIN402 289 ~-N,J

, M-H - A
[ ] () I ~ 3741376 0.70 17.5 -CI ~ -CH2-NH2 1.77 C22H~aCIN30 265 _ (B) [M-H]

I ~ Me ~NH 528/530 0.70 17.6 -CI ~ Me--~ 1.79 C3oH32CIN5O2 164 ~

N _ (B) , o [M-Hl I ~ ~NH 500/502 0.70 17.7 -CI ~ H3c 1,84 C28H28CIN502 172 ~

~ [M_H]_ (B) o I ~ Me NHZ 447/449 0.70 17 CI ~ N~ 1 C 221 CIN

. - . ~ . 26 +
LM+H] (B) ~o 473/475 240- 0.25 17.9 -CI I ; -CH2-NHMe 5 11 C2~H25CIN402 , , [M+H] 244 (C) I ~ 446/448 274- 0.10 17.10-Br ~ -CH2-NHEt E .5 C24H22BrN30 [M-H]- 276 (A) I ~ 4561458 252- 0.40 17.11-Br ~ -CH2-NHMe 617 C23H2oBrN30 [M+Na]+ 255 (C) I 393 0.25 17.12-CN \ -CH2-NHEt 7.5 C25H22N40 249 , , [M-H]- (A) -I ' N NH 491 0.15 J

17.13-CN , , H3C 7.18 C29H2aN602 146 ~

~ [M_Hl_ (A) o I ' 386 285- 0.40 17.14-F , . -CH2-NHEt 8.4 C24H22FNs0 [M-H]- 288 (D) O

17.15-F \ -CH2-NHMe 8.16 C23H2oFN30 M H 251 C
.

, _ () [ 1 NHz 415 168- 0.25 17.16-F I ' -CH2-NMe2 9.13 C25H2sFNa0 [M-H]- 175 (C) NHz 431 155- 0.45 17.17-F ' -CH2-NMe2 9.19 C26H27FNa0 I. . [M+H]+ 160 (E) N HZ

417 203- 0.25 17.18-F I ' -CH2-NMe2 9.18 C25HZSFNaO

- - [M+H]+ 207 (C) NHz ~'NMe 529 170- 0.15 NJ

17.19-F / ' H3C~~ 9.17 C3oH33FN6C)2+

[M+H] 175 (C) ,.

OH

O

446 245- 0.20 17.20-F I ' -CH2-NHMe 2C.11 C26H24FN303 [M+H]+ 251 (F) O

459 239- 0.30 17.21-F I ' -CH2-NHMe 21.22 C26H24FN303 [M+H] 243 (C) NHZ ~NMe 529 17.22-F \ H3~~ 9.55 C3oH33FN602 n. n.
I + d. d.

,~' o [M+H]

OMe O

444 158- 0.25 17.23-F I ~ -CH2-NH2 9.72 C26H24FN303 - . [M-H]' 163 (C) Et0 O

460 205- 0.30 17.24-F -CH2-NH2 9.88 C27H26FN303 [M+H]+ 210 (D) Et0 O

474 148- 0.30 17.25-F -CH2-NHMe 9.89 C28H2SFN303 I ~ [M+H]+ 150 (D) *Eluant mixtures:
(A): silica gel, methylene chloridelmethanol 9:1 (B): silica gel, methylene chloridelmethanol 10:1 (C): silica gel, methylene chloridelmethanol~'ammonia 9:1:0.1 (D): silica gel, methylene chloridelmethanoL'ammonia 9:1:0.01 (E): silica gel, methylene chloride/methanol~ammonia 8:2:0.2 (F): Reversed phase RPB, methanollsaline solution (5%) = 3:2 Example 18.0 3-Z-f 1-(4-(N-aminomethylcarbonyl-N-methy -amino)-anilino)-1-phenyl-methylenel-6-chloro-2-indolinone 600 mg of 3-Z-[1-(4-(N-(phthalimido-2-yl-mEahylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-ind ~linone (educt 1.42) are dissolved in 30 ml of ethanol and 500 mg of hydrazinE: hydrate (80%) are added. The mixture is stirred for 4 hours at 50°C. After ~;ooling 20 ml methylene chloride are added and the precipitate formed is suction filtered. The filtrate is concentrated by evaporation and purified th ~ough a silica gel column with methylene chloridelmethanollammonia 10:1:0.1 as eluant.
Yield: 100 mg (22% of theory), Rf value: 0.40 (silica gel, methylene chloridE~lmethanollammonia = 9:1:0.1 ) M.p. 204-206 °C
C24H2~CIN402 Mass spectrum: mlz = 4321434 [M]+
Example 19.0 3-Z-f 1-(4-carboxy-anilino)-1-phenyl-methyle nel-6-chloro-2-indolinone 450 mg of 3-Z-[1-(4-ethoxycarbonyl-anilino)~1-phenyl-methylene]-6-chloro-2-indolinone (educt 1.2) are dissolved in 10 ml of ethanol and 2 ml of 1 N
sodium hydroxide solution are added. The mixture i:~ stirred for 3 hours at 80°C. After cooling, 2 ml of 1 N hydrochloric acid are added and the mixture is stirred for half an hour at ambient temperature. The precipitate formed is suction filtered and washed with ethanol and diethyl ether.
Yield: 320 mg (76% of theory), Rf value: 0.40 (silica gel, methylene chloridelethanol = 9:1 ) M.p. 333-334 °C (decomposition) C22H~5CIN2O3 Mass spectrum: mlz = 389/391 [M-H]-The following compounds of general formul;~ I-19 are prepared analogously to Example 19.0 Ra \ /
-N
H
~O
CI ~ H (I-19) Exam- mass m.p. Rf R4 R4' edu empirical ~t formula ple spectrum[C] value*

Ra 4031405 0.25 ~

19.1 ~ -CH2-COOH 1.1()0C23H~7CIN203 277 [M-H]~ (A) ~ R4' 4031405 0.15 19.2 ~ -CH2-COOH 1.74 C23H~7GIN203 209 , [M-H] (A) ~ R4' 3891391 0.25 19.3 ~ -COOH 1.75 C22H~5CIN203 321 , [M-HJ (A) *Eluant mixtures:
(A): silica gel, methylene chloridelmethanol 9:1 Example 20.0 3-Z-f 1-(4-d imethvlaminomethvl-anilino)-1-(3-(2-carboxv-ethyl)-phenvl)-methylenel-6-chloro-2-indolinone 900 mg of 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(3-(2-methoxycarbonyl-ethyl)-phenyl)-methylene]-6-chloro-2-indolirone (educt 12.0) are dissolved in ml of ethanol and 5 ml of 1 N sodium hydroxide solution are added. The mixture is stirred for 5 hours at ambient temperature. After cooling, 5 ml of hydrochloric acid are added. The precipitatE: formed is suction filtered and washed with water.
Yield: 830 mg (95% of theory), Rf value: 0.50 (Reversed phase RP8, meth;~nollsaline solution (5%) = 4:1 ) M.p. 210-215 °C

Mass spectrum: mlz = 4761478 [M+HJ+

The following compounds of general formul;~ I-20a are prepared analogously to Example 20.0 4~

H
~ ,~= o R2 '~ H (I-20a) Exam- mass m.p. Rr RZ R3 R4' ec empirical uct formula ple spectrum[C] value*

OH

0 460 0.65 20.1 -F -CH2-NMe2 1:?.3 G27H26FN303 250 [M+H]+ (A) OH

444 278- 0.10 20.2 -F ~ -CH2-NMe2 9.12 C26H24FN303 ~ [M-H]- 282 (B) O OH

458 198- 0.20 20.3 -F -CH2-NMe2 1;?.4 C2~H2sFNa0a / \ [M-H 200 C
- () ]

O OH

444 212- 0.30 20.4 -F ~ -CH2-NMe2 910 C26H24FN34a ~ [M-H]~ 216 (D) a off J Me H ~ 558 260- 0.20 3~ C
C

20.5 -F ~ v 0 915 3~H3zFN5 +
~4 [M+H] 263 (D) O OH

-N(S02Me)- 553 246- 0.30 20.6 -F ' 9.14 C28H29FN405S
I

(CH2)2-NMe2 . [M+H]+ 249 (D) OH

-NMe-(CO)- 474 286- 0.60 20.7 -F 9.20 C27HZaFNsOa I ' CH3 [M+H]+ 290 (E) OH
Me H ~' J 570 215- 0.20 20.8 -F ~ 9.21 Cs2HsaFNsOa I ' M-H - 222 D
[ ] () OH

-N(S02Me)- 567 160- 0.20 20.9 -F 9.22 C2gH31FN405S

I ' (CH2)2-NMe2 [M+H]+ 165 (D) OH

-N(COMe)- 545 153- 0.15 20.10-F 9.23 C3~ H33FN40a I ' (CH2)3-NMe2 [M+H]+ 158 (D) OH

Me 546 215- 0.60 20.11-F otBu 9.24 C3~H32FN305 ~~

I ' o M+H 219 E
[ ]+ ( ) OH

O O r'~'N-Me 529 179- 0.25 20.12-F ' ,,~-N,J 9 25 C3oH2sFNa0a +

I M+H 186 E
[ ] ( ) OH

N~ 483 264- 0.65 20 F ~%~ 9 26 C

FN

. - 2$

I ' Me M+H 267 E

OH

481 146- 0.70 20.14-F -S02Me 9.27 C25H2~ FN205S

/ ~ [M+H]+ 155 (E) OH

r'N.Me 515 0.70 20.15-F ~ ~ ,,~-NJ 9.30 C29H2~FN404 + 251 [M+H] (E) OH
~NMe O H ~ 558 0.10 2 F 3~

0.16 - ~ 9.28 C3~H32FN504 234 ~ ' [M+H] (E) OH

-N(Me)-(CO)- 503 0.60 20.17-F v 9.31 C28H2~FN40a 203 ~ CH2_NMe2 [M+H]+ (E) OH

-N(Me)-(CO)- 545 20.18-F 9.34 C3~H33FN404 251 n.
b.

(CH2)4-NMe2 [M+H]+

OH

387 0.60 20.19-F ~ -H 9.45 C23H~7FN203 130 ~ [M-H]~ (E) OH

467 0.55 20.20-F ~ -S02Me 9.46 C24H~9FN205S 139 ~ [M+H]+ (E) OH

20 F ~~ 9 47 C 469 1 035 21 ~ H
FN

. - ~ N 4 57 2~
z~

~ Me + (E) [M+H]

off -N(S02Me)-567 0.55 20.22-F ~ (CH2)-(CO)- 9 48 C28H27FN406S 183 ~ [M+H]+ (E) ' , ' NMe2 O OH

389 237- 0.10 20.23-F ~ -H 9.35 C23H~~FN203 [M+H]+ 240 (D) O OH
20 F ~%~ 9 C 469 259- 0.15 . - ~ . 2~H2~FN403 Me M +H 265 D
- . [ ]+ ( ) O OH

-N(COMe)- 531 274- 0.15 20.25-F ~ 9.44 C3oH3~FNaOa ~ (CH2)3-NMe2 [M+H] 278 (D) .

O OH

-N(Me)-(CO)- 503 258- 0.20 20.26-F ~ 9.39 C28H2~FN404 CH2-NMe2 [M+H]+ 264 (D) O OH

p ~N-Me 515 279- 0.15 20.27-F ~ v .,~-N,J 9.37 C29H2~FNa04 +

[M+H] 282 (D) O OH

467 260- 0.35 20.28-F ~ -S02Me 9.42 C24H~9FN205S

[M+H]+ 266 (F) O OH

-N(COMe)- 460 290- 0.30 20.29-F v 9.40 C26H22FNsOa ~ CH3 [M+H]+ 294 (F) off -N(S02Me)-567 238- 0.30 20.30-F ~ CH2-(CO)- 9 38 C28H27FN406S

~ [M+H] 242 (F) .

NMe2 O OH

-N(Me)-(CO)- 517 250- 0.35 20.31-F ~ 9 41 C29H29FN404 (CH2)2-NMe2 [M+H]+ 255 (F) O OH

-N(Me)-(CO)- 531 184- 0.25 20.32-F ' 9.43 C3oH3~FNaOa I

(CH2)3-NMe2 [M+H]+ 190 (F) O OH
~NMe H ~ 572 170- 0.40 3~

20.33-F 1v 9.51 C32HsaFNsOa ~

I M_H - 175 C
' '' [ ] ( ) OH

-N(S02Me)- 553 0.60 20.34-F 9.29 C28H29FN405S 180 I ~ , (CH2)2-NMe2 [M+H]+ (C) O OH

-N(S02Me)- 567 196- 0.30 20.35-F 9.52 C29H3~FN405S

I ' (CH2)2-NMe2 [M+H]+ 199 (C) O OH

-N(Me)-(CO)- 517 0.20 20.36-F 9.53 C29H29FN40a 150 I ' CH2-NMe2 [M+H]+ (C) O OH

-N(COMe)- 545 206- 0.30 20.37-F 9.54 C3~ H33FN40a I ' (CH2)s-NMe2 [M+H]+ 210 (A) OH

-N(Me)-(CO)- 517 231- 0.60 20.38-F 9.62 C29H29FN40a CH2-NMe2 [M+H]+ 236 (A) OH

474 218- 0.50 20.39-F -(CH2)2-NMe29 60 C2sH28FNs03 I M+H 222 A
' [ ]+ ( ) OH

-N(Me)-(CO)- 531 215- 0.50 20.40-F 9.61 C3oH3~FNaOa I ' (CH2)2-NMe2 [M+H]+ 218 (A) O OH

474 172- 0.15 20.41-F -(CH2)2-NMe29.63 C2aH28FN303 I [M H 177 G
+ ]+ ( ) OH

-N(COMe)- 531 230- 0.50 20.42-F 9.64 C3oH3~FNaOa I ' (CH2)2-NMe2 [M+H]+ 234 (A) O OH

-N(Me)-(CO)- 545 170- 0.30 20.43-F 9.65 C3~H33FN40a I ' (CH2)a-NMe2 [M+H]+ 175 (E) O OH

-N(Me)-(CO)- 559 142- 0.10 20.44-F 9.66 C32Hs5FNa0a I ' (CH2)a-NMe2 [M+H]+ 146 (G) O OH

N7 483 262- 0.20 ~
~

20.45-F % 9.67 C28H23FN403 N

/ ' Me [ M+H]+ 269 (E) OH

-N(Me)-(CO)- 559 234- 0.30 20.46-F 9 68 C32HssFNaOa I ' (CH2)a-NMez [M+H]+ 236 (A) OH

403 231- 0.20 20.47-F -H 9 69 C2aH19FN203 I ' M+H 233 A
[ ]+ ( ) OH

486 205- 0.10 20 F N~ 9 . - .~ . C29H28FN303 / ~ M+H 210 E
[ ]+ ( ) OH

488 145- 0.15 20.49-F -CH2-NEt2 9.71 C2shiaoFNsCs r ~ M+H 150 E
[ ]+ ( ) OH

430 280- 0.05 20.50-F -CH2-NH2 17.23 C25H22FN303 I ~ M-H - 285 H
[ 1 () OH

460 273- 0.15 20.51-F ~ -(CH2)2-NMe29.73 C2~H26FN303 ~ [M+H]+ 276 (E) O OH

460 230- 0.05 20.52-F ~ ~ -(CH2)2-NMe29.74 C2,H26FN303 [M+H]+ 235 (E) OH

490/492 255- 0.50 20.53-CI -(CH2)2-NMe29.76 C28H28CIN303 / ~ M+H 258 A
[ ]+ ( ) OH

4991501 296- 0.50 20 CI ~%~ 9 77 H

CIN

. - 2a 2s / ~ Me M +H 300 A
() OH

4761478 228- 0.50 20.55-CI -CH2-NMe2 9 78 C27H26CIN303 / ~ M+H 230 A
[ 1+ ( ) O OH

r"'N.Me 515 210- 0.40 20.56-F N,J 9.80 C3pH31FN403 +

I M+H 215 A
[ ] ( ) O OH

483 240- 0.50 20.57-F .,~N.~ 9.81 C28H23FN403 I \ [M+H 245 () A

O OH

-C H 2-N 517 0.30 M e-20.58-F 9.85 C3oH33FNa03 n.d.

I ~ (CH2)2-NMe2 [M+H]+ (I) OH

O r''N-Me 515 0.35 20.59-F , 9.82 C3oH3~FNa43 275 ~-NJ

I ~ , M+H A
[ ]+ ( ) OH

O
483 0.55 20.60-F ,J 9.83 C2aH2sFNa0a 280 [M+H]+ (A) OH

5021504 260- 0.50 20 CI N~ 9 86 H

C

. - .~ 2a s I ~ M+H 266 A
[ ]+ ( ) OH

-CH2-NMe- 517 0.05 20.62-F 9 84 C3oH33FNa03 n.d.

(CH2)z-NMe2 [M+H]+ (E) HO O

403 110- 0.60 20.63-F -H 9 8? C2aH~9FN203 I M+H 112 K
[ ]+ ( ) HO O

432 260- 0.60 20.64-F -CH2-NH2 17.24 C25H22FNaOa . [M+H]+ 263 (A) HO O

446 265- 0.60 20.65-F -CH2-NHMe 17.25 C26H24FN303 [M+H]+ 270 (A) HO O

O

20.66-F ~ -CH2-NMe2 9.90 C26H24FNs4a M 250 M
H

/ + () [ 1 OH
O

20.67-F ~ -CH2-NMe2 9.91 C26H24FN304 M 247 M
~ H +

/ [ 1 () OH

5461548 290- 0.30 20 B N~ 9 C

B
N

. r .~ . 29 - 2a r / [M+H]+ 293 (E) OH

520/522 243- 0.25 20.69-Br -CH2-NMe2 9.94 C2~H26BrN303 / ~ [M+H]+ 246 (E) OH

5481550 252- 0.35 20.70-Br -CH2-NEt2 9.95 C29HsoBrN34$

I M+H 255 E
[ ]+ ( ) *Eluant mixtures:
(A): Reversed phase RPB, methanollsaline solution(5%) = 4:1 (B): silica gel, methylene chloridelmethanol = 8:2 (C): silica gel, methylene chloridelmethanol = 5:1 (D): Reversed phase RPB, methanollsaline solution(5%) = 3:2 (E): silica gel, methylene chloridelmethanol = 9:1 (F): Reversed phase RPB, methanollsaline ~olution(5%) = 7:3 (G): silica gel, methylene chloridelmethanol lammonia = 9:1:0,1 (H): aluminium oxide, methylene chloridelm~thanol = 19:1 (I): Reversed Phase RPB, methanoll saline solution (5%) = 4:2 (K): silica gel, petroleum etherlethyl acetate = 1:1 (M): silica gel, methylene chloridelmethanol = 4:1 The following compounds of general formul;~ I-20b are prepared analogously to Example 20.0:
R4.

H
O
R2 '~ ~ (I-20b) Exam- mass m.p. Rf RZ R3 R4' ec empirical uct formula ple spectrum[C] value*

OH

460 0.20 20.71 -F -CH2-NMe2 9 96 C2~H26FN303 150 / ~ ~M+Hl+ (A) O OH

460 105- 0.30 20.72 -F -CH2-NMe2 9 97 C2~H26FN303 / (M H 109 B
+ J+ ( ) OH

4761478 230- 0.50 20.73 -CI -CH2-NMe2 9 98 C2~H26CIN30s / ~ M+H 235 C
f ]+ ( ) ~'Eluant mixtures:

(A): silica gel, methylene chloridelmethanol = 5:1 (B): silica gel, methylene chloridelmethanol = 9:1 (C): Reversed Phase RPB, methanollsaline solution (5%) = 4:1 Examale 21.0 3-Z-f 1-(4-dimethylaminomethyl-anilino)-1-(3-(2-carbamoyl-ethyl)-ahenyl)-methylenel-6-chloro-2-indolinone 480 mg of 3-Z-[1-(4-dimethylaminomethyl-a~ilino)-1-(3-(2-carboxyethyl)-phenyl)-methylene]-6-chloro-2-indolinone (educt 20.0), 350 mg TBTU, 150 mg HOBt and 420 ml triethylamine are dissolved in 10 ml of dimethylformamide and 620 mg of N-hydroxysuccinimide-ammonium salt are added. The mixture is stirred for 20 hours at ambient temperature. After the solvent has been eliminated the residue is suspended in a little ethyl acetate and water, filtered off and washed with water. The residue is purified through an aluminium oxide column (activity 2-3) with methylene chlorid~:lethanol 20:1 as eluant. The product is recrystallised from diethyl ether and dried in vacuo at 100°C.
Yield: 370 mg (78% of theory), Rf value: 0.40 (aluminium oxide, methylene chloridelethanol = 20:1 ) M.p. 222-225 °C
C2~H2~CIN402 Mass spectrum: mlz = 4751477 [M+H]+
The following compounds of general formul ~ I-21 are prepared analogously to Example 21.0 R4.
-N
H
=O
R (I-21 ) Exam- mass m.p. Rr RZ R3 R4' ec empirical uct formula ple spectrum[C] value*

21).0 4891491 223- 0.50 21.1 -CI -CH2-NMe2 CZ8H29CIN4O2 / \ 225 A
:'* + ]+ ( ) [M H

21).1 473 148- 0.40 21.2 -F -CH2-NMe2 C28H29FN402 / M+H 150 B
'* [ ]+ ( ) NMez 21).2 473 98- 0.30 21.3 -F -CH2-NMe2 C28H29FN402 *** [M+H]+ 103 (C) NHZ

459 223- 0.50 21.4 -F -CH2-NMe2 21).3 C2~Hz~FN402 , [M H 225 A

NHMe 2~).3 473 210- 0.70 21.5 -F -CH2-NMe2 CZ$H29FN402 / \ [M H 213 A
~'* + ]+ ( ) NMez 2i).3 487 213- 0.80 21.6 -F -CH2-NMe2 C2gH3~FN4O2 *** [M+H]+ 215 (A) N HZ

443 115- 0.25 21.7 -F ~ -CH2-NMe2 2~).2 C2sH25FN402 ~ [M-H]' 120 (C) NHMe 2().2 457 222- 0.25 21.8 -F ~ -CH2-NMe2 C27H2~FN402 I ,.* [M-H]- 225 (C) NHZ

443 143- 0.40 21.9 -F I ~ -CH2-NMe2 21).4 C26H2sFNa02 [M-H]- 146 (D) N Mez 21).1 487 198- 0.60 21.10-F -CH2-NMe2 C2gH31FN4~2 I ~ *k* [M+H]+ 200 (B) Me N

21).1 542 0.60 21.11-F -CH2-NMe2 C32HssFNs02 175 *,.** [M+H]* (g) NHZ ~NMe H ~ 557 150- 0.40 21.12-F I v ~ 21).5 C3~H33FN603 +

[M+H] 156 (E) ,.

NHZ

-N(S02Me)- 552 197- 0.50 21.13-F v 2~).6 C28H3oFN504S

I , , (CH2)rNMe2 [M+H]+ 199 (D) NMe2 2i).4 473 147- 0.35 21.14-F ~ -CH2-NMe2 C28H29FN4O2 I ~** [M+H]+ 152 (D) .

NHMe 2~).4 459 208- 0.35 21.15-F ~ -CH2-NMe2 C2~H27FN402 I ~* [M+H]+ 214 (D) .

p NHMe -N(S02Me)- 2l).6 566 218- 0.70 21.16-F I ' C29H32FN5O4S

(CH2)2-NMe2 ''* [M+H]+ 222 (F) p NMez -N(S02Me)- 21).6 580 199- 0.40 21.17-F ' C30H34FN5~4S
I

,. . (CH2)2-NMe2 *k* (M+H]+ 205 (C) NHMe ~ Me H ~ 2~),5 571 155- 0.20 21.18-F I ' ~ o C32f"~35FN6~3+

,.* [M+H] 160 (C) ,.

-N(Me)-(CO)-211.7 487 137- 0.50 21.19-F C28H27FN403 I ' CH3 "* [M+H]+ 145 (C) ~NMe p H ~ 2~~,$ 585 211- 0.40 3 "' 21.20-F ~v C33~ +
~37FN6~3 I ' ..* M+H 219 C
[ 1 () -N(S02Me)- 2i).9 578 192- 0.50 21.21-F C30H34FN504S

I ' (CH2)2-NMe2 ~'* [M-H]- 200 (C) o Me 2C 559 180- 0.50 N .11 21.22-F ~-otBu C32H35FN404 ,~ +

I ' p t* [M+H] 187 (C) N~ 2C~:13 496 262- 0.40 21.23-F '~ C29H2sFN502 I Me M+H 266 C
' ~* [ ]+ ( ) 20.14 494 180- 0.60 21.24-F -S02Me C26HzaFN3O4S

/ M+H 188 C
''* [ ]+ ( ) p O r''N.Me 20.12 542 226- 0.50 21.25-F .,~'-N,,J * C31H32FN5~3 +

/ M+H 230 ' [ ] (C) NHMe J Me o H ~ 20.16 571 0.10 3~

21.26-F ~ ~!32H35FN6~3 213 o +

~ :.* [M+H] (G) NHMe p p r''N.Me 20.15 528 0.40 ~

. ~ ~ ,,~ ;.* 30 [M+H]+ (G) , 5 *Eluant mixtures:
(A): silica gel, methylene chloridelmethanol~ammonia = 5:1:0.01 (B): aluminium oxide, methylene chlorideletianol = 20:1 (C): silica gel, methylene chloride/methanol,'ammonia = 9:1:0.1 (D): silica gel, methylene chloridelmethanol,'ammonia = 6:1:0.1 (E): silica gel, methylene chloride/methanoLammonia = 5:1:0.1 (F): silica gel, methylene chloridelmethanoliammonia = 7:1:0.1 (G): silica gel, methylene chloridelmethanol = 9:1 ** with methylammonium chloride as base Equivalent *** with dimethylammonium chloride as base equivalent **** with piperidine hydrochloride as base a ~uivalent Example 22.0 3-Z-f 1-(4-(4-methyl-piperazin-1-yl-methyl)-a ~ilino)-1-phenyl-methylenel-6-chloro-1,3-dihydro-indol-2-thione 460 mg of 3-Z-[1-(4-(4-methyl-piperazin-1-y-methyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (educt 1.35) are dissolved in 5 ml of pyridine and 220 mg of phosphorus pentasulphide are added. The mixture is stirred for 2 hours at 120°C. After cooling it is diluted vrith water and 0.5 ml of concentrated ammonia is added. The preci~~itate formed is suction filtered and purified through a silica gel column with mes.hylene chloridelmethanol 9:1 as eluant. The product is recrystallised from petroleum ether and dried in vacuo at 100°C.
Yield: 300 mg (63% of theory), R, value: 0.50 (silica gel, methylene chloridE~lmethanol = 9:1 ) M.p. 250-252 °C
C2~H2~CIN4S
Mass spectrum: mlz = 475/477 [M+H]+
Example 23.0 3-Z-f 1-(4-(N-acetylaminomethylcarbonyl-N-i nethyl-amino)-anilino)-1-phenyl-methylenel-6-chloro-2-indolinone 61 mg of 3-Z-[1-(4-(N-aminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (e~iuct 18.0) are dissolved in 3 ml acetic acid and 0.1 ml acetic anhydride are added. The mixture is stirred for 1.5 hours at ambient temperature. After this time the solvent is eliminated, the residue is suspended in a little water and suction filtered. The product is dried in vacuo at 100°C.
Yield: 60 mg (90% of theory), Rf value: 0.50 (silica gel, methylene chloridE:lmethanol = 9:1 ) M.p. 291-292 °C
C26H23CIN4~3 Mass spectrum: mlz = 4971499 [M+Na]+

The following compounds of general formul;~ I-23 are prepared analogously to Example 23.0:
R4.
-N
H
=O
(I-23) Exam- mass m.p. Rr R~ R3 R4' ec empirical uct formula ple spectrum[C] value*

o~-CHs HN -N(COMe)- 530/532 187- 0.15 23.1 -CI ~ ~ 1:3.3 C29H3oCIN503 (CHz)2-NMe2 [M-H]- 188 (A) C~-CHs HN -N(Me)-(CO)- 5181520 249- 0.15 23.2 -CI ~ ~ 1:3.1 C28H28CIN503 CH2_NMe2 [M+H]+ 250 (A) CH3 ~NCH3 H3 ~ 571 /573168- 0.10 1.

23.3 -CI ~ v ~ 0 3.2 C3~H33CIN6O3 [M_H]- 170 (A) C~-CH3 HN O ~N-CH 5281530 0.15 23.4 -CI ~ ~ ,,~-N,J 3 1.3.4 C29H2sCIN503- 160 [M-H] (A) O

N 4591461 158- 0.25 23.5 -CI ~ ~ -CH2-NMe2 13.0 C26H2sCIN402 [M-H]- 159 (A) HN'~~ 4731475 219- 0.30 23.6 -CI I ~ -CH2-NMe2 1~G.0 C2~H2~CIN402 [M-H]- 220 (B) HN'~°3 H3 ~NCH3 5851587 252- 0.25 23.7 -CI I ~ ~v~ 1!).O C32H35CIN6C3 M_H ~ 255 B
C ] ( ) I
5351537 238 0.45 23.8 -CI HN o -CH2-NMe2 14.0 C32H2sCIN402 I ~ [M-H]- (dec.) (B) I~
HN H3 ~ JNCH3 '_ 647/649 282- 0.40 23.9 -CI o ~ 0 1.).O C3,H37CIN6O3 I ~ (M-H]- 284 (B) °~,-CH3 HN 457 245- 0.40 23.10 -F I \ -CH2-NMe2 17.16 C27H2~FN402 [M_H]- 250 (C) °~ Et HN 471 212- 0.35 23.11 -F I ~ -CH2-NMe2 17.16 C28H29FN402 (M-H - 214 D
1 () HN 519 237- 0.40 23.12 -F I \ -CH2-NMe2 17 .16 C32H29FN402 (M-H - 240 D
1 () I \
533 187- 0.30 23.13 -F HN -CH2-NMe2 17.16 C33H3~FNa02 \ [M-H]' 190 (D) I
~ Hs NH
471 234- 0.30 23.14 -F -CH2-NMe2 17.17 CZ$H29FN402 I \ [M-H]' 237 (D) I\
NH 533 144- 0.45 23.15 -F -CH2-NMe2 17.17 C33H3~FN402 [M-H]' 150 (C) I\
Et C~NH
485 235- 0.25 23.16 -F -CH2-NMe2 17.17 C29H3~FN402 I \ [M-H]' 237 (D) \ I
NH
547 217- 0.30 23.17 -F I \ -CH2-NMe2 17.17 C34H33FN402 [ ] 220 D
M-H ' ( ) ,.

HN'~0 457 112- 0.25 23.18 -F I \ -CH2-NMe2 17.18 C2~H2~FN402 [M-H]' 120 (D) Et HN"~C 586 176- 0.30 23.19 -F -CH2-NMe2 17'.18 C28HZ9FN402 I ~ , [M+H]+ 180 (D) \ I

535 80- 0.35 23.20-F HN o -CH2-NMe2 17.18 G33H3~FN402 +

I \ [M+H] 85 (D) HN"~ ~NCH3 p H3C, 569 230- 0.35 23 F ~

. - \ , 17.19 C32H35FN603 N

I , [ M-H]- 235 (D) Et "~ J oH3 HN H3~ ~ 583 205- 0.30 . - \ ,,N o 17.19 C33H37FN603 I [ M-H]- 210 (D) \I
NCH

HN 3 645 217- 0.35 F H3~ ~ ~

23.23- o ,,N o 17.19 C3sH39FN603 -[M-H] 220 (D) I\

o~
~NCH

HN 3 597 209- 0.30 H ~

23.24-F ~v o 17.22 C34H3~FNs03 +

I \ [M+H] 212 D
() CH

J 611 190- 0.30 ~

23.25-F ~v 7.22 C35H39FN6O3 +

\ M+H 193 D
I [ ] ( ) INCH

HN H ~ ~NJ 3 634 160- 0.30 23.26-F 3 N 17.22 C36H3sFN~03 +

I \ M+H 163 D
[ ] ( ) O
~ ~NCH

H NJ 639 223- 0.30 H3~ ~

23.27-F , 17.22 C3~H43FN603 N

I \ , ( [M+H]+ 227 D) N
~ I INCH

HN ~N.J 3 634 170- 0.25 H

23.28-F 3~N 17.22 C36H3sFIV~03 \ ( [M+H]+ 175 D) I

N~cH cH3 3 H 599 194- 0.20 N~

23.29-F 3 17.22 C34H39FN6O3 ~v~

\ M+H + 196 D
I [ ] ( ) Hs CHs O
~ ~NCH

HN 3 613 197- 0.70 H3~ ~

23.30-F N 17.22 C35H41FN603 +
, I \ , M+H 200 E
,, f ] () cH

3 653 130- 0.75 ~N~
H

23.31-F N 3~v~ 17.22 C38H45FIVsC3[M+H~+ 135 (E) OMe ~ cH

H H3 ~ J 601 155- 0.60 ~

23.32- lv 17.22 C33H3~FIVs44 F

\ M+H 159 E
'~' [ ] ( ) Me0 _ ~ I ~NCH3 HN Hs~~ ' 663 168- 0.35 23.33_F 17 C38H39FN604 +
.22 [M+H] 172 (C) ,. .

C(CH3)s ~p ~NCH

H H 627 85- 0.35 ~

23.34-F 3~N- 17.22 C3sHa3FNs03 ~
p I v ~~ [M+H]+ 90 (C) s ~NCH

H C 639 170- 0.25 ~

23.35-F ,;N 17.22 C35HssFNs4aS

\ M+H + 175 C
I [ ] ( ) ~CH3~3C~o HN ~ CH

H ~ 613 242- 0.30 23.36-F I v ~v o 17.22 C35Ha~ FIVs03+

[M+H] 245 (C) ,.

~NCH

H 623 155- 0.65 3~
~

23.37-F N 17.22 C35H3sFIVsOa+

\ M+H 160 F
I [ 1 () p CH

H 3 571 190- 0.60 H3C1 ~ ~

23.38-F N 17.22 C32HasFIVs03+
o I [M H 195 F
+ ] ( ) Et ~NCH

H 585 203- 0.65 ~
3~

23.39-F N 17.22 C33H37FN603 ~~

I ~ ~~ [M+H] 209 (E) p N NCH3 633 145- 0.60 HN H3~

23.40-F N 17.22 C3~H37FIVs(~3 ~~ +
o I ~ ~~ [M+H] 150 (F) I \

NCH

o H ~ ~ 647 148- 0.65 23.41-F HN 3~N 17.22 C38H39FN603 o [M+H]+ 151 (F) I \

o~

HN 485 216- 0.35 23.42-F -CH2-NMe2 17.16 C29H29FN402 I \ [M+H]'' 220 (D) HN 499 214- 0.35 23.43-F -CH2-NMe2 17.16 C3oH3~FN4~2 I \ [M+H]+ 217 (D) O N
\ /

HN 522 205- 0.35 23.44-F -CH2-NMe2 17.16 C3~H28FN502 I \ [M+H]+ 210 (D) ~

H 527 235- 0.35 23.45-F -CH2-NMe2 17.16 C32H35FN402 I \ [M+H]+ 237 (D) o \ I

HN 520 135- 0.20 23.46-F -CHZ-NMe2 17.16 C3~H28FN502 I \ [M-H]- 140 (D) O CHs ~~H

H 487 210- 0.20 23.47-F 3 -CH2-NMe2 17.16 C29H3~FN402 I \ [M+H]+ 215 (D) H3~CHs O
HN 501 202- 0.25 23.48 -F I -CH2-NMe2 17.16 C3oH33FNa(~2 M+H 206 [ ]+ (D) 23.49 -F HN -CHZ-NMe2 17.16 C33H3~FN4p2 541 198- 0.35 I \ [M+H]+ 203 (D) O'' OMe HN~ 489 173- 0.35 23.50 -F I \ -CH2-NMe2 17.16 C28H29FN403 [M+H]+ 177 (D) Me0 o ~ I
549 202- 0.50 23.51 -F HN\ -CH2-NMe2 17.16 C33H3~FNa03 [M-H]- 207 (C) I
C~~"~3~3 HN 513 203- 0.45 23.52 -F -CH2-NMe2 17.16 C3~H35FNa02 I v [M-H]- 209 (C) o s~
HN 527 245- 0.35 23.53 -F / \ -CH2-NMe2 17.16 C3oH27FN402S [M+H]+ 250 (C) ~CH3~3C'l%O
HN
501 248- 0.45 23.54 -F ~ v -CH2-NMe2 17.16 C3oH33FN4~2 . [M+H] 252 (C) HN 511 216- 0.30 23.55-F -CH2-NMe2 17.16 C3oH27FN403 [M+H]+ 219 (C) O ~ IV

HN 522 167- 0.20 23.56-F -CH2-NMe2 17.16 C3~H28FN502 I \ M+H 170 D
[ ]+ ( ) *Eluant mixtures:
(A): silica gel, methylene chloridelethanollainmonia = 20:1:0.01 (B): silica gel, methylene chloridelmethanoliammonia = 9:1:0.01 (C): aluminium oxide, methylene chloridelm~thanol = 19:1 (D): silica gel, methylene chloridelmethanol~ ammonia = 9:1:0.1 (E): silica gel, methylene chloridelmethanoliammonia = 8:2:0.2 (F): aluminium oxide, methylene chloridelm~ahanol = 9:1 The following were alternatively used as ac~rlating agents:
benzoylchloride, propionylchloride, phenyla~;etylchloride, cyclopropanecarbonylchloride, cyclobutane~;arbonylchloride, pyridin-2-yl-carbonylchloride, pyridin-3-yl-carbonylchlori 1e, pyridin-4-yl-carbonylchloride, cyclohexylcarbonylchloride, isobutyrylchlori~ie, 3-methylbutyrylchloride, cyclohexylmethylcarbonylchloride, methoxy ~cetylchloride, 2-methoxy-benzoylchloride, tert.-butylacetylchloride, th ophen-2-carbonylchloride, pivaloylchloride, 2-furoyl-chloride.
Example 24.0 3-Z-f 1-(4-dimethylaminomethyl-anilino)-1-(4-phenylsulphonylaminomethyl-phenyl)-methylenel-6-chloro-2-indolinone 100 mg of 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(4-aminomethyl-phenyl)-methylene]-6-chloro-2-indolinone (educt 14 0) are dissolved in 5 ml methylene chloride and at 0 °C 5 ml of pyridine and 45 pl of benzenesulphonylchloride are added. The mixture is stirred for 10 minutes at 0 °C and then for 2 hours at ambient temperature. After this time the :~olvent is eliminated, the residue is suspended in 1 N sodium hydroxide solution, suction filtered and washed with a little water. The product is dried at 100°C.
Yield: 87 mg (66% of theory), Rf value: 0.30 (silica gel, methylene chloridE~lmethanollammonia = 9:1:0.1 ) M.p. 170 °C (decomp.) C3~ H29CIN4O3S
Mass spectrum: m/z = 5731575 [M+H]+
The following compounds of general formul~~ I-24 are prepared analogously to Example 24.0:
R4, l~

N
H
~N~ (I-24) H
Exam- mass m.p. Rr R2 R3 R4' ec empirical ple uct formula spectrum[C] value*

HN- oo J ~H3 H3 1 !i.0 6211623 260- 0.20 ~

24.1 -CI ~ ~v C3~H35CIN6O4S

~ .,* [M-H]- 263 (A) HN'S~O 11.0 511/513 0.35 ~

24.2 -CI -CH2-NMe2 C26H27CIN403S n.
v d.

I .~* [M+H]+ (A) I \

,' N NCH

HN'S~O H 683/685 248- 0.35 ~ 'J

24.3 -CI o s 1'.i.0C36H3~CIN604S
~?v ~
o I \ ~~ [M-H]' 251 (A) O=S-CH3 HN 17.16 495 170- 0.30 24.4 -F -CH2-NMe2 C26H2~FN403S

I \ '~* [M+H]+ 180 (B) O:S-Et HIV 17.16 509 200- 0.40 24.5 -F -CH2-NMe2 C26H27FN4~3S

I *k* [M H 204 C
\ + () +]

os I

v HIV 557 125- 0.30 24.6 -F -CH2-NMe2 17.16 C3~Hz9FN403S

I \ M+H 130 B
[ ]+ ~ ) O
Et , Q .S,N
H

17.17 521 100- 0.35 24.7 -F -CH2-NMe2 C2gH3~FN4O3S

I \ *k* [M_H 110 B
' () HN'S~O 17.18 493 80- 0.35 24.8 -F -CH2-NMe2 C26H27FN403S

I ;,* [M-H]' 85 (B) Et HN'S=O 17.18 507 90- 0.40 24.9 -F -CH2-NMe2 C2~H29FN403S

I *** [M-H]' 100 (B) 17 571 115- 0.35 HN~ .18 o 24.10-F o -CH2-NMe2 C32H31FN4~3~'J

\ *"** [M+H] 120 (B) o cH

HN~ o H3 J 17.19 605 205- 0.25 11 ~

. - \ ~v C3~H35FN604S

~ :.* [M-H]- 210 (B) ,. , Et HN~S~O ~NCH3 17.19 619 212- 0.25 24 F O Hs~
12 ~

. _ N C32H37FN604S
*

I k* M-H]~ 215 (B) [

\I
~NCH3 N

H ~ 17.19 683 115- 0.35 HN' ,J
a 3 24.13-F o ~ ~ C371"139FN6~4S
*~~** [M+H] 120 B

\ ( ) *Eluant mixtures:
(A): silica gel, methylene chloridelmethanohammonia = 9:1:0.01 (B): silica gel, methylene chloridelmethanohammonia = 9:1:0.1 (C): aluminium oxide, methylene chloridelm~thanol = 19:1 ** with methanesulphonylchloride as sulphonating agent *** with ethanesulphonylchloride as sulphor ating agent **** with a-toluenesulphonylchloride as sulphonating agent Example 25.0 3-Z-f 1-(4-Trimethylammoniummethyl-anilinc ~)-1-(4-(2-carboxy-ethyl)-ahenyl)-methylenel-6-fluoro-2-indolinone-iodide 200 mg of 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (e~luct 20.1 ) are dissolved in 40 ml of acetone and 250 ml of methyl iodide are added. The mixture is stirred for 20 hours at ambient temperature. After this time the precipitated residue is suction filtered. The product is dried at 80°t~ in vacuo.
Yield: 200 mg (83% of theory), R~-value: 0.50 (Reversed Phase RPB, meth;~nollsaline solution (5°!°) = 4:1 ) Mp. 210 °C
C2gH2gFN3031 Mass spectrum: mlz = 474 [M+H]+
The following compound of general formula I-25 is prepared analogously to Example 25.0:
R 4, R~_-N
H
O
R2 ~ H~ (I-25) Exam- mass m.p. Rr R2 R3 R4' ec uct empirical formula ple spectrum [°C] value*
O OH
Me 474 0.50 25.1 -F N~Me i- 2~).3 C28H2gFN3031 150 I '' ~~- Me [M+H]+ (A) *eluant mixtures:
(A): Reversed Phase RPB, methanol/saline solution (5%) = 4:1 Example 26.0 3-Z-(1-(4-Guanidinomethyl-anilino)-1-(4-(2-c;arboxy-ethyl)-phenyl)-methylenel-6-fluoro-2-indolinone-iodide 170 mg of 3-Z-(1-(4-aminomethyl-anilino)-1 ~ (4-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (educt 20.:50) are dissolved in 20 ml tetrahydrofuran and 390 mg of 3,5-dimethyl ~yrazole-1-carboxylic acid amidine nitrate and 330 ml of diethylisopropylamine are added. The mixture is refluxed for 10 hours with stirring. After this time the solvent is evaporated down, water is added and the residue precipitated is suction filtered. The product is dried at 80°C.
Yield: 150 mg (81 % of theory), R~-value: 0.40 (silica gel, methylene chloridE~/methanollacetic acid = 5:1:0.1 ) Mp. 290 °C
C26H24FN5~3 Mass spectrum: mlz = 474 [M+H]+
The following compound of general formula I-26 is prepared analogously to Example 26.0:
R 4, -- N
H
w v ,~O
R2 ''~ H (I_26) Exam- mass m.p. Rr R2 R3 R4' ec empirical uct formula ple spectrum[C] value*

O OH

H 474 0.70 26.1 -F ~~HN NHz 20.64 C26H2aFNs4s 305 , [M+H]+ (A) *eluant mixtures:
(A): Reversed Phase RPB, methanollsaline solution (5%) = 4:1 Example 27.0 3-Z-f 1-(4-(N-(4-methyl-piperazin-1-yl-methy carbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylenel-6-chloro-2-indolinone x ethanesulphonic acid a) 3-Z-f1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylenel-6-chloro-2-indolinone 10.25 g of 1-acetyl-3-(1-ethoxy-1-phenylme:hylen)-6-chloro-2-indolinone (educt IX) and 8.6 g of N-[(4-methyl-piperazin-1-yl)-methylcarbonyl]-N-methyl-p-phenylenediamine (educt XV.204) are dissolved in 100 ml of dimethylformamide and stirred for 4 hours at 120°C. After cooling, 20 ml of 6 N sodium hydroxide solution are added and the mixture is stirred for another hour at ambient temperature. Water is addEd, the precipitate formed is suction filtered and washed with a little water and 2)0 ml of ethanol. The residue is dissolved in methylene chloride, extracted vrith water and dried over sodium sulphate. After the solvent has been eliminated the substance is again washed with a little methanol and dried in v,~cuo at 100 °C.
Yield: 15.48 g (74% of theory), Rf value: 0.50 (silica gel, methylene chloridE~lmethanollammonia 5:1:0.01 ) IR spectrum: 1645 cm'' M.p. 265-269 °C
C2gH3pCIN5~2 Mass spectrum: m/z = 5151517 [M]+
Elemental analysis: calculated: C 67.49 H 5.86 CI 6.87 N 13.57 found: C 67.42 H 5.83 CI 6.97 N 13.59 b) 3-Z-f1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylenel-6-chloro-2-indolinone x ethanesulphonic acid 1.5 g of 3-Z-[1-(4-(N-(4-methyl-piperazin-1-~~I-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-chloi~o-2-indolinone are placed in 22.5 ml of methanol, the mixture is heated to 50°C and 0.25 ml of ethanesulphonic acid in 0.14 g water are added dropwise. Tree mixture is slowly cooled to ambient temperature, lastly by means of an ice bath to 0°C. The precipitate formed is suction filtered and washed with ~ little tert.butylmethylether. The residue is dried in vacuo at 40°C.
Yield: 1.7 g (93% of theory), IR spectrum: 1655 cm~' M.p. 307 °C
C29H30CIN502 X C2Hg03~J
Mass spectrum: mlz = 5161518 [M+H]+
Example 28 Dry ampoule containing 75 ma of active suk~stance aer 10 ml Composition:
Active substance 75.0 mg Mannitol 50.0 mg water for injections ad 10.0 ml Preparation:
Active substance and mannitol are dissolved in water. After packaging, the solution is freeze-dried. To produce the solution ready for use, the product is dissolved in water for injections.

Example 29 Dry ampoule containing 35 ma of active suk~stance per 2 ml Composition:
Active substance 35.0 mg Mannitol 100.0 mg water for injections ad 2.0 ml Preparation:
Active substance and mannitol are dissolved in water. After packaging, the solution is freeze-dried.
To produce the solution ready for use, the ~ roduct is dissolved in water for injections.
Example 30 Tablet containing 50 mg of active substancE:
Composition:
(1 ) Active substance 50.0 mg (2) Lactose 98.0 mg (3) Maize starch 50.0 mg (4) Polyvinylpyrrolidone 15.0 mg (5) Magnesium stearate 2.0 ma 215.0 mg Preparation:
(1 ), (2) and (3) are mixed together and grar elated with an aqueous solution of (4). (5) is added to the dried granulated mai~ erial. From this mixture tablets are pressed, biplanar, faceted on both sides and with a dividing notch on one side.
Diameter of the tablets: 9 mm.

Example 31 Tablet containing 350 ma of active substance Composition:
(1 ) Active substance350.0 mg (2) Lactose 136.0 mg (3) Maize starch 80.0 mg (4) Polyvinylpyrrolidone30.0 mg (5) Magnesium stearate4.0 ma 600.0 mg Preparation (1 ), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dried granulated material. From this mixture tablets are pressed, biplanar, faceted on both side: and with a dividing notch on one side.
Diameter of the tablets: 12 mm.
Example 32 Capsules containing 50 ma of active substance Composition:
(1 ) Active substance50.0 mg (2) Dried maize starch58.0 mg (3) Powdered lactose 50.0 mg (4) Magnesium stearate2.0 ma 160.0 mg Preparation:
(1 ) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing.

' This powder mixture is packed into size 3 herd gelatine capsules in a capsule filling machine.
Example 33 Capsules containing 350 ma of active substance Composition:
(1 ) Active substance350.0 mg (2) Dried maize starch46.0 mg (3) Powdered lactose 30.0 mg (4) Magnesium stearate4.0 ma 430.0 mg Preparation:
(1 ) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing.
This powder mixture is packed into size 0 h;~rd gelatine capsules in a capsule filling machine.
Example 34 Suppositories containing 100 ma of active substance 1 suppository contains:
Active substance 100.0 mg Polyethyleneglycol (M.W. 1500) 600.0 mg Polyethyleneglycol (M.W. 6000) 460.0 mg Polyethylenesorbitan monostearate 840.0 ma 2000.0 mg Preparation:
The polyethyleneglycol is melted together ~n~ith polyethylene sorbitan monostearate. At 40°C the ground active s~ibstance is homogeneously dispersed in the melt. It is cooled to 38°C ~ nd poured into slightly chilled suppository moulds.
The following compounds may be prepared analogously to the foregoing Examples:
(1 ) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-carbamoyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (2) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-ethyl-carbamoyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (3) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-methyl-carbamoyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (4) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-carbamoyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (5) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-ethyl-carbamoyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (6) 3-Z-[1-(3-(N-(2-dimethylamino-ethyl)~~N-methyl-carbamoyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (7) 3-Z-[1-(3-(N-(2-dimethylamino-ethyl)~~carbamoyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolino (8) 3-Z-[1-(3-(N-(2-dimethylamino-ethyl)~~N-ethyl-carbamoyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolino (9) 3-Z-[1-(3-(N-(3-dimethylamino-propy )-N-methyl-carbamoyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (10) 3-Z-[1-(3-(N-(3-dimethylamino-propyl)-carbamoyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (11 ) 3-Z-[1-(3-(N-(3-dimethylamino-propyi)-N-ethyl-carbamoyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (12) 3-Z-[1-(3-(N-(4-methyl-piperazin-1-yl- methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-i idolinone (13) 3-Z-[1-(3-(N-(dimethylamino-methylc~~rbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinor a (14) 3-Z-[1-(4-methylsulphonyl-anilino)-1-,phenyl-methylene]-6-chloro-2-indolinone (15) 3-Z-[1-anilino-1-phenyl-methylene]-Ei-chloro-2-indolinone (16) 3-Z-[1-(4-nitro-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (17) 3-Z-[1-(4-fluoro-anilino)-1-phenyl-mf~thylene]-6-chloro-2-indolinone (18) 3-Z-[1-(4-chloro-anilino)-1-phenyl-m~ahylene]-6-chloro-2-indolinone (19) 3-Z-[1-(4-bromo-anilino)-1-phenyl-msthylene]-6-chloro-2-indolinone (20) 3-Z-[1-(4-iodo-anilino)-1-phenyl-metl~ylene]-6-chloro-2-indolinone (21 ) 3-Z-[1-(4-cyano-anilino)-1-phenyl-mEahylene]-6-chloro-2-indolinone (22) 3-Z-[1-(4-methoxy-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (23) 3-Z-[1-(4-ethoxy-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (24) 3-Z-[1-(4-trifluoromethyl-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (25) 3-Z-[1-(4-methylmercapto-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (26) 3-Z-[1-(4-(isopropylaminomethyl)-an~lino)-1-phenyl-methylene]-6-chloro-2-indolinone (27) 3-Z-[1-(4-(anilinomethyl)-anilino)-1-p~enyl-methyfene]-6-chloro-2-indolinone (28) 3-Z-[1-(4-(isobutylaminomethyl)-anilioo)-1-phenyl-methylene]-6-chloro-2-indolinone (29) 3-Z-[1-(4-(cyclohexylaminomethyl)-a~iilino)-1-phenyl-methylene]-6-chloro-2-indolinone (30) 3-Z-[1-(4-(benzylaminomethyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (31) 3-Z-[1-(4-((N-isopropyl-N-methyl-amine)-methyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (32) 3-Z-[1-(4-((N-ethyl-N-propyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (33) 3-Z-[1-(4-((N-ethyl-N-isopropyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (34) 3-Z-[1-(4-(dipropylaminomethyl)-anili ~o)-1-phenyl-methylene]-6-chloro-2-indolinone (35) 3-Z-[1-(4-(diisopropylaminomethyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (36) 3-Z-[1-(4-((N-benzyl-N-ethyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (37) 3-Z-[1-(4-(dibenzylaminomethyl)-ani ino)-1-phenyl-methylene]-6-chloro-2-indolinone (38) 3-Z-[1-(4-(3,6-dihydro-2H-pyridine-1 ~y1-methyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (39) 3-Z-[1-(4-(3,5-dimethyl-piperidin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (40) 3-Z-[1-(4-(azepan-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (41 ) 3-Z-[1-(4-(2-amino-ethyl)-anilino)-1-~~henyl-methylene]-6-chloro-2-indolinone (42) 3-Z-[1-(4-(2-methylamino-ethyl)-anili io)-1-phenyl-methylene]-6-chloro-2-indolinone (43) 3-Z-[1-(4-(2-ethylamino-ethyl)-aniline )-1-phenyl-methylene]-6-chloro-2-indolinone (44) 3-Z-[1-(4-(2-diethylamino-ethyl)-anilii~o)-1-phenyl-methylene]-6-chloro-2-indolinone (45) -Z-[1-(4-(2-piperidin-1-yl-ethyl)-anilirn~)-1-phenyl-methylene]-6-chloro-indolinone (46) 3-Z-[1-(4-(2-acetylamino-ethyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (47) 3-Z-[1-(4-(3-amino-propyl)-anilino)-1 ~ phenyl-methylene]-6-chloro-2-indolinone (48) 3-Z-[1-(4-(3-dimethylamino-propyl)-a~ilino)-1-phenyl-methylene]-6-chloro-2-indolinone (49) 3-Z-[1-(4-(N-ethylaminomethylcarbor~yl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinorn:
(50) 3-Z-[1-(4-(N-diethylaminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinorn~
(51) 3-Z-[1-(4-(N-dipropylaminomethylcarbcnyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinon~:
(52) 3-Z-[1-(4-(N-((N-ethyl-N-methyl-amino)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-c:hloro-2-indolinone (53) 3-Z-[1-(4-(N-((N-ethyl-N-propyl-amino)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-chloro ~'.-indolinone (54) 3-Z-[1-(4-(N-((N-methyl-N-propyl-amino)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (55) 3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-ethyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (56) 3-Z-[1-(4-(N-dimethylaminomethylcarb~nyl-N-propyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (57) 3-Z-[1-(4-(N-dimethylaminomethylcarbonyl-N-butyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (58) 3-Z-[1-(4-(N-(2-amino-ethylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (59) 3-Z-[1-(4-(N-(2-diethylamino-ethylcarbc>nyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinon a (60) 3-Z-[1-(4-(N-acetyl-N-(2-aminoethyl)~~amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (61) -Z-[1-(4-(N-acetyl-N-(2-methylamino~ethyl)-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (62) 3-Z-[1-(4-(N-acetyl-N-(3-amino-propel)-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (63) 3-Z-[1-(4-(N-acetyl-N-(3-methylaminc>-propyl)-amino)-anilino)-1-phenyf-methylene]-6-chloro-2-indolinone (64) 3-Z-[1-(4-(N-acetyl-N-(2-piperidin-1-yl-ethyl)-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (65) 3-Z-[1-(4-(N-acetyl-N-(aminocarbonylmethyl)-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (66) 3-Z-[1-(4-(N-acetyl-N-(piperidin-1-yl-c:arbonylmethyl)-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinon~:
(67) 3-Z-[1-(4-(N-(2-ethylamino-ethyl)-N-r~ethylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinorn:
(68) 3-Z-[1-(4-(N-(2-diethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinc~ne (69) 3-Z-[1-(4-(N-(2-pyrrolidin-1-yl-ethyl)-PJ-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolincme (70) 3-Z-[1-(4-(N-(2-piperidin-1-yl-ethyl)-f~-methylsulphony!-amino)-anilino)-1-phenyl-methyiene]-6-chloro-2-indolinone (71) 3-Z-[1-(4-(N-(2-piperazin-1-yl-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolirn~ne (72) 3-Z-[1-(4-(N-(2-(4-morpholin-1-yl)-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-a'-indolinone (73) 3-Z-[1-(4-(2-diethylamino-ethoxy)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (74) 3-Z-[1-(4-(3-dimethylamino-propoxy)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (75) 3-Z-[1-(4((N-phenethyl-N-methyl-am no)-methyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indofinone (76) 3-Z-[1-(4-carbamoylmethyl-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (77) 3-Z-[1-(4-methylcarbamoylmethyl-anilino)-1-phenyl-methyleneJ-6-chloro-2-indolinone (78) 3-Z-[1-(4-dimethylcarbamoylmethyl-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (79) 3-Z-[1-(4-tetrazol-5-yl-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (80) 3-Z-[1-(4-((2-methoxy-ethyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (81 ) 3-Z-[1-(4-(di-(2-methoxy-ethyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (82) 3-Z-[1-(4-((N-tert.butoxycarbonyl-2-amino-ethyl)-amino-methyl)-anilino)-1-phenyl-methyleneJ-6-chloro-2-indolinone (83) 3-Z-[1-(4-((N-tert.butoxycarbonyl-3-a wino-propyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (84) 3-Z-[1-(4-((2-amino-ethyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (85) 3-Z-[1-(4-((3-amino-propyl)-amino-m~ahyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (86) 3-Z-[1-(4-((2-acetylamino-ethyl)-amigo-methyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (87) 3-Z-[1-(4-((3-acetylamino-propyl)-arr~ino-methyl)-anilino)-1-phenyi-methylene]-6-chloro-2-indolinone (88) 3-Z-[1-(4-((2-methylsulphonylamino-ethyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (89) 3-Z-[1-(4-((3-methylsulphonylamino-~ropyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (90) 3-Z-[1-(4-(N-(2-amino-ethyl)-N-methyl-amino-methyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (91 ) 3-Z-[1-(4-(N-(2-methylamino-ethyl)-1~1-methyl-amino-methyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (92) 3-Z-[1-(4-(N-(2-acetylamino-ethyl)-N~~methyl-amino-methyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinon a (93) 3-Z-(1-(4-(N-(2-methylsulphonylamino-ethyl)-N-methyl-amino-methyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (94) 3-Z-[1-(4-(carbamoylmethyl-amino-methyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (95) 3-Z-[1-(4-(dimethylcarbamoyl-methyl-amino-methyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (96) 3-Z-[1-(4-(methylcarbamoyl-methyl-amino-methyl)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (97) 3-Z-[1-(4-(N-(pyridin-4-yl-methylcarbcynyl)-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (98) 3-Z-[1-(4-(N-(4-propyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-2 -indolinone (99) 3-Z-[1-(4-(N-(4-butyl-piperazin-1-yl-rr~ethylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (100) 3-Z-[1-(4-(N-(4-isopropyl-piperazin-l~~yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-c;hloro-2-indolinone (101 ) 3-Z-[1-(4-(N-(4-(2-hydroxy-ethyl)-pipf:razin-1-yl-methylcarbonyl)-N
methyl-amino)-anilino)-1-phenyl-methyl:ne]-6-chloro-2-indolinone (102) 3-Z-[1-(4-(N-(4-(2-methoxy-ethyl)-piperazin-1-yl-methylcarbonyl)-N
methyl-amino)-anilino)-1-phenyl-methyl;ne]-6-chloro-2-indolinone (103) 3-Z-[1-(4-(N-(4-(2-ethoxy-ethylrpiperazin-1-yl-methylcarbonyl)-N
methyl-amino)-anilino)-1-phenyl-methyl:ne]-6-chloro-2-indolinone (104) 3-Z-[1-(4-(N-(4-(2-amino-ethyl)-pipenazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methyl ene]-6-chloro-2-indolinone (105) 3-Z-[1-(4-(N-(4-(2-dimethylamino-etr~yl)-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-metl~ylene]-6-chloro-2-indolinone (106) 3-Z-[1-(4-(N-(4-(2-phenyl-piperazin-"-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-:,hloro-2-indolinone (107) 3-Z-[1-(4-(N-(4-(5-methyl-2,5-diaza-t~icyclo[2.2.1]-hept-2-yl)-methylcarbonyl)-N-methyl-amino)-aniliro)-1-phenyl-methylene]-6-chloro-2-indolinone (108) 3-Z-[1-(4-(N-(homopiperazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (109) 3-Z-[1-(4-(N-(3,4,5-trimethyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-~;hloro-2-indolinone (110) 3-Z-[1-(4-(N-(2,4,6-trimethyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-~;hloro-2-indolinone (111 ) 3-Z-[1-(4-(N-(trans-2,4,5-trimethyl-pil>erazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methyl:ne]-6-chloro-2-indolinone (112) 3-Z-[1-(4-(N-(cis-2,4,5-trimethyl-pipei~azin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methyl:ne]-6-chloro-2-indolinone (113) 3-Z-[1-(4-(N-(2,4-dimethyl-piperazin-t-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-c;hloro-2-indolinone (114) 3-Z-[1-(4-(N-(3,4-dimethyl-piperazin-t-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene)-6-c:hloro-2-indolinone (115) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl~~methylcarbonyl)-N-ethyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-2 -indolinone (116) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yf~~methylcarbonyl)-N-propyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-2 -indolinone (117) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl~ methylcarbonyl)-N-isopropyl-amino)-anilino)-1-phenyl-methylene]-6-c;hloro-2-indolinone (118) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl~ methylcarbonyl)-N-butyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-2 -indolinone (119) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl~ methylcarbonyl)-N-phenyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (120) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-benzyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-a-indolinone (121 ) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-aminocarbonylmethyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (122) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-dimethylaminocarbonylmethyl-amino)-a nilino)-1-phenyl-methylene]-6-chloro-2-indolinone (123) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-3-bromo-anilino)-1-phenyl-methylene]-E.-chloro-2-indolinone (124) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-3-chloro-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (125) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-3-fluoro-anilino)-1-phenyl-methylene]-6~ chloro-2-indolinone (126) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-3-methyl-anilino)-1-phenyl-methylene]-f.-chloro-2-indolinone (127) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-3-methoxy-anilino)-1-phenyl-methylene:'-6-chloro-2-indolinone (128) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl ~methylcarbonyl)-N-methyl-amino)-3-hydroxy-anilino)-1-phenyl-methylene]~~6-chloro-2-indolinone (129) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl~~methylcarbonyl)-N-methyl-amino)-3-cyano-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (130) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl~~methylcarbonyl)-N-methyl-amino)-3-trifluormethyl-anilino)-1-phenyl-methy ene]-6-chloro-2-indolinone (131 ) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl«methylcarbonyl)-N-methyl-amino)-3-aminocarbonyl-anilino)-1-phenyl-metr~ylene]-6-chloro-2-indolinone (132) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl~~methylcarbonyl)-N-methyl-amino)-3-amino-an ilino)-1-phenyl-methylene]-6 -chloro-2-indolinone (133) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl~~methylcarbonyl)-N-methyl-amino)-3-nitro-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (134) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yi~~methylcarbonyi)-N-methyl-amino)-3-acetylamino-anilino)-1-phenyl-methylf:ne]-6-chloro-2-indolinone (135) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methy!carbonyl)-N-methyl-amino)-3-methylsulphonylamino-anilino)-1-phe ~yl-methylene]-6-chloro-2-indolinone (136) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methy!carbonyl)-N-methyl-amino)-3,5-dibromo-anilino)-1-phenyl-methyler a]-6-chloro-2-indolinone (137) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methy!carbonyl)-N-methyl-amino)-3,5-dichloro-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (138) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methy!carbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-5-nitro-6-c hloro-2-indolinone (139) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methy!carbonyl)-N-methyl-amino)-(pyridin-3-yl-amino))-1-phenyl-methyler a]-6-chloro-2-indolinone (140) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methy!carbonyl)-N-methyl-amino)-(pyridin-2-yl-amino))-1-phenyl-methylen a]-6-chloro-2-indolinone (141) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-amino)-3-bromo-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (142) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methy!carbonyl)-amino)-3-chloro-anilino)-1-phenyl-methylene]-6-chioro-2-indolinone (143) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl ~methy!carbonyl)-amino)-3-fluoro-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (144) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl~~methy!carbonyl)-amino)-3-methyl-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (145) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl~~methylcarbonyl)-amino)-3-methoxy-anilino)-1-phenyl-methylene]-E -chloro-2-indolinone (146) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl~~methylcarbonyl)-amino)-3-hydroxy-anilino)-1-phenyl-methylene]-6~~chloro-2-indolinone (147) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl~~methy!carbonyl)-amino)-3-cyano-anilino)-1-phenyl-methylene]-6-chloro-2 -indolinone (148) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl~~methylcarbonyl)-amino)-3-trifluormethyl-anilino)-1-phenyl-methyleoe]-6-chloro-2-indolinone (149) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl~~methylcarbonyl)-amino)-3 aminocarbonyl-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (150) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl~~methy!carbonyl)-amino)-3-amino anilino)-1-phenyl-methylene]-6-chloro-2 -indolinone (151) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-amino)-3-nitro-anilino)-1-phenyl-methylene]-6-chloro-~'-indolinone (152) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-amino)-3-acetylamino-anilino)-1-phenyl-methyler a]-6-chloro-2-indolinone (153) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-amino)-3 methylsulphonylamino-anilino)-1-pheny I-methyleneJ-6-chloro-2-indolinone (154) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-amino)-3,5-dibromo-anilino)-1-phenyl-methylene]-Ir-chloro-2-indolinone (155) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-amino)-3,5-dichloro-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone (156) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-(4-(2-oxo-oxazolidin-3-yl)-phE nyl)-methylene]-6-chloro-2-indolinone (157) 3-Z-[1-(4-(N-(dimethylamino-methylcarbonyl)-N-methyl-amino)-anilino) 1-(4-(2-oxo-oxazolidin-3-yl)-phenyl)-me :hylene]-6-chloro-2-indolinone (158) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)~~N-acetyl-amino)-anilino)-1-(4-(2-oxo-oxazolidin-3-yl)-phenyl)-methylene]-6-chloro-2-indolinone (159) 3-Z-[1-(4-(N-(3-dimethylamino-propy )-N-acetyl-amino)-anilino)-1-(4-(2-oxo-oxazolidin-3-yl)-phenyl)-methylene]-6-chloro-2-indolinone (160) 3-Z-[1-(4-(dimethylamino-methyl)-anilino)-1-(4-(2-oxo-oxazolidin-3-yl)-phenyl)-methylene]-6-chloro-2-indolinor~e (161 ) 3-Z-[1-(4-ethylaminomethyl-anilino)-~ -(4-(2-oxo-oxazolidin-3-yl)-phenyl)-methylene]-6-chloro-2-indolinor~e (162) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl~~methylcarbonyl)-N-methyl-amino)-anil ino)-1-(4-(2-oxo-oxazolid in-3-yl)-phe nyl)-methylene]-6-chloro-2-indolinone (163) 3-Z-[1-(4-(4-methyl-piperazin-1-yl-carbonyl)-anilino)-1-(4-methoxycarbonylamino-phenyl)-methylE~ne]-6-chloro-2-indolinone (164) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-(4-methoxycarbonylamino-ph~ ~nyl)-methyleneJ-6-chloro-2-indolinone (165) 3-Z-[1-(4-(N-(dimethylamino-methylc ~rbonyl)-N-methyl-amino)-anilino) 1-(4- methoxycarbonylamino-phenyl)-m~thylene]-6-chloro-2-indolinone (166) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-(4-methoxycarbonylamino-phenyl)-methyl:ne]-6-chloro-2-indolinone (167) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-(4 methoxycarbonylamino-phenyl)-methyl:ne]-6-chloro-2-indolinone (168) 3-Z-[1-(4-(dimethylamino-methyl)-anilino)-1-(4-methoxycarbonylamino-phenyl)-methylene]-6-chloro-2-indolino«e (169) 3-Z-[1-(4-ethylaminomethyl-anilino)-'I-(4-methoxycarbonylamino-phenyl)-methylene]-6-chloro-2-indolinone (170) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-(4-methoxycarbonylamino-phenyl)-methylene]-6-chloro-2-indolinone (171) 3-Z-[1-(4-(4-methyl-piperazin-1-yl-carbonyl)-anilino)-1-(4-methoxycarbonylamino-phenyl)-methylE;ne]-6-chloro-2-indolinone (172) 3-Z-[1-(4-(N-(pyridin-4-yl-methylcarb~myl)-amino)-anilino)-1-phenyl-methylene]-6-cyano-2-indolinone (173) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)~~N-methylsulphonyl-amino)-anilino)-1-(4-(2-oxo-pyrrolidine-2-yl)-phe:nyl)-methylene]-6-cyano-2-indolinone (174) 3-Z-[1-(4-(N-(dimethylamino-methylc~rbonyl)-N-methyl-amino)-anilino) 1-(4- (2-oxo-pyrrolidine-2-yl)-phenyl)-mE~thylene]-6-cyano-2-indolinone (175) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)~N-acetyl-amino)-anilino)-1-(4-(2-oxo-pyrrolidine-2-yl)-phenyl)-methylene:I-6-cyano-2-indolinone (176) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-(4-(2-oxo-pyrrol id ine-2-yl )-phe ny1)-methylene: -6-cyano-2-i ndol inone (177) 3-Z-[1-(4-(dimethylamino-methyl)-anilino)-1-(4-(2-oxo-pyrrolidine-2-yl)-phenyl)-methylene]-6-cyano-2-indolinore (178) 3-Z-[1-(4-ethylaminomethyl-anilino)-1-(4-(2-oxo-pyrrolidine-2-yl)-phenyl)-methyleneJ-6-cyano-2-indolinor a (179) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl~ methylcarbonyl)-N-methyl-amino)-anilino)-1-(4-(2-oxo-pyrrolidine-2-yl)-phE~nyl)-methylene]-6-cyano-2-indolinone (180) 3-Z-[1-(4-(4-methyl-piperazin-1-yl-carbonyl)-anilino)-1-(4-(2-oxo-pyrrolidine-2-yl)-phenyl)-methylene]-6-c,rano-2-indolinone (181 ) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-(3,4-dimethoxy-phenyl)-meth ~lene]-6-cyano-2-indolinone (182) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-ethylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinc ne (183) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-propionyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinonE;
(184) 3-Z-[1-(4-(N-(3-dimethylaminopropyly-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-~indolinone (185) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)~~N-butyryl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinonE:
(186) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)~~N-isobutyryl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinonE:
(187) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)~~N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone (188) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)~~N-benzoyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indoiinonE:
(189) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl) N-phenylacetyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinonE~
(190) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-(pyrid-3-yl-carbonyl)-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone (191) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-(furan-2-yl-carbonyl)-amino)-aniiino)-1-phenyl-methylene]-6-fluoro-2-indolinone (192) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-(2-methoxy-benzoyl)-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone (193) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-isopropylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone (194) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-benzylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone (195) 3-Z-[1-(4-(N-(4-benzyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone (196) 3-Z-[1-(4-(N-(piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolino ~e (197) 3-Z-[1-(4-(N-(morpholin-4-yl-methylc~~rbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolino ~e (198) 3-Z-[1-(4-(N-(piperidin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinon~:
(199) 3-Z-[1-(4-(N-(benzylmethylamino-mE~thylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2 ~indolinone (200) 3-Z-[1-(4-(N-(methylamino-methylcai~bonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinont:
(201) 3-Z-[1-(4-((2,6-dimethyl-piperidin-1-yl)-methyl)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone (202) 3-Z-[1-(4-((N-(2-(2-methoxy-ethoxy)-ethyl)-N-methyl-amino)-methyl)-anilino)-1-phenyl-methylene]-6-fluoro-2- indolinone (203) 3-Z-[1-(4-(triazol-1-yl-methyl)-anilino;~-1-phenyl-methylene]-6-fluoro-2-indolinone (204) 3-Z-[1-(4-(di-(2-hydroxy-ethyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone (205) 3-Z-[1-(4-(5-methyl-imidazol-4-yl)-an lino)-1-phenyl-methylene]-6-fluoro-2-indolinone (206) 3-Z-[1-(4-(morpholin-4-yl-methyl)-ani ino)-1-phenyl-methylene]-6-fluoro-2-indolinone (207) 3-Z-[1-(4-(N-benzyl-N-methyl-amino-methyl)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone (208) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-butylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolino ne (209) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)~N-methoxyacetyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolino ne (210) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)~N-(3,4-dimethoxy-benzoyl)-amino)-anilino)-1-phenyl-methylene]-6-tluoro-2-indolinone (211) 3-Z-[1-(4-(N-(2-hydroxy-ethyl)-N-met~yl-amino-methyl)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinonE~
(212) 3-Z-[1-(4-(N-(2-benzylmethylamino-ethyl)-N-propionyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolino ~e (213) 3-Z-[1-(4-(N-(2-methylamino-ethyl)-N-propionyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinonE
(214) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-(pyrid-4-yl-carbonyl)-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone (215) 3-Z-[1-(4-(N-(phthalimido-2-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2 -indolinone (216) 3-Z-[1-(4-(N-aminomethylcarbonyl-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone (217) 3-Z-[1-(4-(N-tent.butoxycarbonyl-methylamino-methyl)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinonc;
(218) 3-Z-[1-(4-(N-(di-(2-hydroxy-ethyl)-an-ino-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-l~uoro-2-indolinone (219) 3-Z-[1-(4-(N-(pyrrolidin-1-yl-methylc~rbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone (220) 3-Z-[1-(4-(N-(imidazol-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinonE~
(221) 3-Z-[1-(4-(N-(2-(4-tent.butoxycarbonyl-piperazin-1-yl)-ethylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methyl:ne]-6-fluoro-2-indolinone (222) 3-Z-[1-(4-(N-(2-(piperazin-1-yl)-ethylc:arbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2- indolinone (223) 3-Z-(1-(4-(N-(2-benzylmethylamino-ethyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinonE~
(224) 3-Z-[1-(4-(N-(2-methylamino-ethyl)-N-acetyl-amino)-anilino)-1-pheny!-methylene]-6-fluoro-2-indolinone (225) 3-Z-[1-(4-((4-tert.butoxycarbonyl-pipE~razin-1-yl)-methyl)-anilino)-1-phenyl-methylene]-6-fluoro-2-indoiinonE~
(226) 3-Z-[1-(4-(piperazin-1-yl-methyl)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone (227) 3-Z-[1-(4-(N-(dimethylamino-methylc~rbonyl)-N-methyl-amino)-3-methoxy-anilino)-1-phenyl-methylene]-E-fluoro-2-indolinone (228) 3-Z-[1-(3-(dimethylamino-methyl)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone (229) 3-Z-[1-(4-(4-methyl-piperazin-1-yl-carbonyl)-pyridin-2-yl-amino)-1-phenyl-methylene]-6-fluoro-2-indolinonE
(230) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-(pyridin-3-yl-amino))-1-phenyl-methylene]-6-fluoro-2~~indolinone (231 ) 3-Z-[1-(4-(4-methyl-piperazin-1-yl-carbonyl)-3-methyl-pyrrol-3-yl-amino)-1-phenyl-methylene]-6-fluoro-2-i ndolinone (232) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)~N-methyl-carbamoyl)-3-methyl-pyrrol-3-yl-amino)-1-phenyl-methylene]~ 6-fluoro-2-indolinone (233) 3-Z-[1-(4-(2-diethylamino-ethyl-sulphonyl)-anilino)-1-phenyl-methyleneJ-6-fluoro-2-indolinone (234) 3-Z-[1-(4-(1-(2-dimethylamino-ethyl)-imidazol-2-yl)-anilino)-1-phenyl-methyleneJ-6-fluoro-2-indolinone (235) 3-Z-[1-(4-(piperidin-1-yl-carbonyl)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone (236) 3-Z-[1-(4-(4-tert.butoxycarbonyl-pipe-azin-1-yl-carbonyl)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinonE:
(237) 3-Z-[1-(4-(piperazin-1-yl-carbonyl)-ar~ilino)-1-phenyl-methyleneJ-6-fluoro-2-indolinone (238) 3-Z-[1-(4-(N-cyclohexyl-N-methyl-carbamoyl)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone (239) 3-Z-[1-(4-(N-(2-(4-methyl-piperazin-1-yl)-ethyl-carbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone (240) 3-Z-[1-(4-(2-dimethylamino-ethoxy)-~nilino)-1-phenyl-methyieneJ-6-fluoro-2-indolinone (241 ) 3-Z-[1-(4-((4-dimethylamino-piperidin-1-yl)-methyl)-anilino)-1-phenyl-methyleneJ-6-fluoro-2-indolinone (242) 3-Z-[1-(4-(2-dimethylamino-ethyl)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone (243) 3-Z-[1-(4-(N-tert.butoxycarbonyl-amino-methyl)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone (244) 3-Z-[1-(4-aminomethyl-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone (245) 3-Z-[1-(4-(N-(dimethylamino-methylc~rbonyl)-N-isopropyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone (246) 3-Z-[1-(4-(N-(4-tert.butoxycarbonyl-p perazin-1-yl-methylcarbonyl)-N
isopropyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone (247) 3-Z-[1-(4-(N-(piperazin-1-yl-methylcarbonyl)-N-isopropyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone (248) 3-Z-[1-(4-(diethylamino-methyl)-aniliro)-1-phenyl-methyleneJ-6-fluoro-2-indolinone (249) 3-Z-[1-(4-(N-propyl-N-methyl-amino-methyl)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone {250) 3-Z-[1-{4-{4-methyl-piperazin-1-yl)-aoilino)-1-phenyl-methylene]-6-fluoro-2-indolinone (251 ) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl) ~N-methyl-carbamoyl)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinonE:
(252) 3-Z-[1-(4-(N-(4-tert.butoxycarbonyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methyl one]-6-fluoro-2-indolinone (253) 3-Z-[1-(4-(N-(piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone (254) 3-Z-[1-(4-(N-(hydroxy-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinonE~
(255) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl) N-methyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinonE~
(256) 3-Z-[1-(4-(N-(N-(tert.butoxycarbonyl-;3-amino-propyl)-N-methyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone (257) 3-Z-[1-{4-(N-(N-(3-amino-propyl)-N-methyl)-amino-methyl)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinonE~
(258) 3-Z-[1-(4-(N-(4-methyl-homopiperazio-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-f luoro-2-indolinone (259) 3-Z-[1-(4-(N-(dimethylamino-methylc ~rbonyl)-N-methyl-amino)-3-cyano-anilina)-1-phenyl-methylene]-6-flnoro-2-indolinone (260) 3-Z-[1-(4-(N-(4-ethyl-piperazin-1-yl-rr ethylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone (261 ) 3-Z-(1-(4-(N-(1-methyl-piperidin-4-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone (262) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl~~methylcarbonyl)-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolino ~e (263) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-methyl-carbamoylmethyl)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone (264) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methyl-carbamoylmethyl)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone (265) 3-Z-[1-(4-(4-methyl-piperazin-1-yl-canbonylmethyl)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone (266) 3-Z-[1-(4-(N-(4-dimethylamino-butyl-carbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2 -indolinone (267) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-aminocarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2~~indolinone (268) 3-Z-[1-(4-(N-(1-methyl-piperidin-4-yl-aminocarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methyfene]-6-fluoro-2~~indolinone (269) 3-Z-[1-(4-(N-(3-dimethylamino-propyl-carbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2~~indolinone (270) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-carbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2- indolinone (271 ) 3-Z-[1-(4-(N-(N-(3-dimethylamino-prc~pyl)-aminocarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-lluoro-2-indolinone (272) 3-Z-[1-(4-(N-(pyridin-4-yl-methylamirocarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2- indolinone (273) 3-Z-[1-(4-(N-(1-methyl-piperidin-4-oxy-carbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2- indolinone (274) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-(4-(2-oxo-oxazolidin-3-yl)-phe nyl)-methylene]-6-fluoro-2-indolinone (275) 3-Z-[1-(4-(N-(dimethylamino-methylc~rbonyl)-N-methyl-amino)-anilino) 1-(4-(2-oxo-oxazolidin-3-yl)-phenyl)-mei hylene]-6-fluoro-2-indolinone (276) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-(4-(2-oxo-oxazolidin-3-yl)-phenyl)-methylene]-6-fluoro-2-indolinone (277) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-(4-(2-oxo-oxazolidin-3-yl)-phenyl)-methylene]-6-fluoro-2-indolinone (278) 3-Z-[1-(4-(dimethylamino-methyl)-anilino)-1-(4-(2-oxo-oxazolidin-3-yl)-phenyl)-methylene]-6-fluoro-2-indolinon (279) 3-Z-[1-(4-ethylaminomethyl-anilino)-1-(4-(2-oxo-axazolidin-3-yi)-phenyl)-methylene]-6-fluoro-2-indolinon (280) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl~ methylcarbonyl)-N-methyl-amino)-anilino)-1-(4-(2-oxo-oxazolidin-3-yl)-phenyl)-methylene]-6-fluoro-2-indolinone (281 ) 3-Z-[1-(4-(4-methyl-piperazin-1-yl-carbonyl)-anilino)-1-(4-methoxycarbonylamino-phenyl)-methylE~ne]-6-fluoro-2-indolinone (282) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)~N-methylsulphonyl-amino)-anilino)-1-(4-methoxycarbonylamino-phenyl)-methylene]-6-fluoro-2-indolinone (283) 3-Z-[1-(4-(N-(dimethylamino-methylcarbonyl)-N-methyl-amino)-anilino) 1-(4- methoxycarbonylamino-phenyl)-methylene]-6-fluoro-2-indolinone (284) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)~N-acetyl-amino)-anilino)-1-(4-methoxycarbonylamino-phenyl)-methylE;ne]-6-fluoro-2-indolinone (285) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-(4-methoxycarbonylamino-phenyl)-methylE;ne]-6-fluoro-2-indolinone (286) 3-Z-[1-(4-(dimethylamino-methyl)-an lino)-1-(4-methoxycarbonylamino-phenyl)-methylene]-6-fluoro-2-indolinone (287) 3-Z-[1-(4-ethylaminomethyl-anilino)-' -(4-methoxycarbonylamino-phenyl)-methylene]-6-fluoro-2-indolinone (288) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl ~methylcarbonyl)-amino)-N-methyl-anilino)-1-(4-methoxycarbonylamino-ph enyl)-methylene]-6-fluoro-2-indolinone (289) 3-Z-[1-(4-(4-methyl-piperazin-1-yl-ca ~bonyl)-anilino)-1-(4-methoxycarbonylamino-phenyl)-methylE:ne]-6-fluoro-2-indolinone (290) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)~~N-methylsulphonyl-amino)-anilino)-1-(4-(2-oxo-pyrrolidine-2-yl)-phE:nyl)-methylene]-6-fluoro-2-indoiinone (291 ) 3-Z-[1-(4-(N-(dimethylamino-methylc~rbonyl)-N-methyl-amino)-anilino) 1-(4-(2-oxo-pyrrolidine-2-yl)-phenyl)-methylene]-6-fluoro-2-indolinone (292) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl) N-acetyl-amino)-anilino)-1-(4-(2-oxo-pyrrolidine-2-yl)-phenyl)-methylene I-6-fluoro-2-indolinone (293) 3-Z-[1-(4-(N-(3-dimethylamino-propy~)-N-acetyl-amino)-anilino)-1-(4-(2-oxo-pyrrolidine-2-yl)-phenyl)-methylene;~-6-fluoro-2-indolinone (294) 3-Z-[1-(4-(dimethylamino-methyl)-anilino)-1-(4-(2-oxo-pyrrolidine-2-yl)-phenyl)-methylene]-6-fluoro-2-indolinon a (295) 3-Z-[1-(4-ethylaminomethyl-anilino)-~~ -(4-(2-oxo-pyrrolidine-2-yl)-phenyl)-methylene]-6-fluoro-2-indolinon a (296) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl~~methylcarbonyl)-N-methyl-amino)-anilino)-1-(4-(2-oxo-pyrrolidine-2-yl)-phE:nyl )-methylene]-6-fluoro-2-indolinone (297) 3-Z-[1-(4-(4-methyl-piperazin-1-yl-carbonyl)-anilino)-1-(4-(2-oxo-pyrrolidine-2-yl)-phenyl)-methylene]-6-fil uoro-2-indolinone (298) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)~N-methylsulphonyl-amino)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-rnethylene]-6-chloro-2-indolinone (299) 3-Z-[1-(4-(N-(dimethylamino-methylcarbonyl)-N-methyl-amino)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methyler~e]-6-chloro-2-indolinone (300) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)~~N-acetyl-amino)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-ch laro-2-indolinone (301 ) 3-Z-[1-(4-(N-(2-methylamino-ethyl)-~-acetyl-amino)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-ch loro-2-indolinone (302) 3-Z-[1-(4-(N-(3-dimethylamino-propy )-N-acetyl-amino)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-ch oro-2-indolinone (303) 3-Z-[1-(4-(N-(3-methylamino-propyl)-N-acetyl-amino)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-ch oro-2-indolinone (304) (305) 3-Z-[1-(4-(3-dimethylamino-propyl)-a~ilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinor~e (306) 3-Z-[1-(4-ethylaminomethyl-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinone (307) 3-Z-[1-(4-methylaminomethyl-anilino;-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-chioro-2-indolinone (308) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl~~methylcarbonyl)-N-methyl-amino) anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-riethylene]-6-chloro-2-indolinone (309) 3-Z-[1-(4-(4-methyl-piperazin-1-yl-carbonyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-inclolinone (310) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-methylsulphonyl-amino)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-r ethylene]-6-chloro-2-indolinone (311) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-propylsulphonyl-amino)-an ilino)-1-(4-(2-carboxy-ethyl)-phenyl)-r iethylene]-6-chloro-2-indol inone (312) 3-Z-[1-(4-aminomethyl-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinone (313) (314) 3-Z-[1-(3-(methylamino-methyl)-anilir~o)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinone (315) 3-Z-[1-(3-(2-dimethylamino-ethyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinone (316) 3-Z-[1-(3-(3-dimethylamino-propyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinorre (317) (318) 3-Z-[1-(4-(N-(dimethylamino-carbony lmethyl)-N-methylsulphonyl-ami-no)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinone (319) 3-Z-[1-(4-(N-methyl-N-methylsulphor~yl-amino)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-in~iolinone (320) 3-Z-[1-(4-(N-methyl-N-acetyl-amino)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinorie (321 ) (322) 3-Z-[1-(4-(N-(N-(2-dimethylamino-etr~yl)-N-methyl-amino-methylcarbonyl)-N-methyl-amino)-anilin o)-1-(4-(2-carboxy-ethyl )-phenyl)-methylene]-6-chloro-2-indolinone (323) 3-Z-[1-(4-(2-diethylamino-ethyl-sulphonyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-inclolinone (324) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl-~;arbonyl)-N-methyl-amino)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-r~ethylene]-6-chloro-2-indolinone (325) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)~N-methyl-amino-methyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methyler a]-6-chloro-2-indolinone (326) 3-Z-[1-(4-(2-dimethylamino-ethoxy)-~nilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinor a (327) 3-Z-[1-(4-(N-(4-dimethylamino-butyl-~;arbonyl)-N-methyl-amino)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-r~ethylene]-6-chloro-2-indolinone (328) 3-Z-[1-(4-(N-(3-dimethylamino-propyl-carbonyl)-N-methyl-amino)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-riethylene]-6-chloro-2-indolinone (329) 3-Z-[1-(4-(methylethylamino-methyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinor a (330) 3-Z-[1-(4-(methylpropylamino-methyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinor a (331 ) 3-Z-[1-(4-(methylbenzylamino-methy )-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinor a (332) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methyl-amino-methyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl-methylen ~]-6-chloro-2-indolinone (333) 3-Z-[1-(4-(piperidin-1-yl-methyl)-anili ~0)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinone (334) 3-Z-[1-(4-(azetidin-1-yl-methyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinone (335) 3-Z-[1-(4-((4-methyl-piperazin-1-yl)-methyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-in~iolinone (336) 3-Z-[1-(4-(piperazin-1-yl-methyl)-anil no)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinorie (337) 3-Z-[1-(4-(morpholin-4-yl-methyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinorie (338) 3-Z-[1-(4-(thiomorpholin-4-yl-methyl)~anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinor~e (339) 3-Z-[1-(4-(imidazol-1-yl-methyl)-anilir~o)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinone (340) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl) N-methylsulphonyl-amino)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-r~ethylene]-6-chloro-2-indolinone (341) 3-Z-[1-(4-(N-(dimethylamino-methylc~rbonyl)-N-methyl-amino)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methyler a]-6-chloro-2-indolinone (342) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl) N-acetyl-amino)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-ch oro-2-indolinone (343) 3-Z-[1-(4-(N-(2-methylamino-ethyl)-N-acetyl-amino)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-ch oro-2-indolinone (344) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-ch oro-2-indolinone (345) 3-Z-[1-(4-(N-(3-methylamino-propyl)-N-acetyl-amino)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-ch' oro-2-indolinone (346) 3-Z-[1-(4-(3-dimethylamino-propyl)-a iilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinor a (347) 3-Z-[1-(4-ethylaminomethyl-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinone (348) 3-Z-[1-(4-methylaminomethyl-anilino;-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinone (349) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-rnethylene]-6-chloro-2-indolinone (350) 3-Z-[1-(4-(4-methyl-piperazin-1-yl-carbonyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-irnlolinone (351 ) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-methylsulphonyl-amino)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-rnethylene]-6-chloro-2-indolinone (352) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl) ~N-propylsulphonyl-amino)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-rnethylene]-6-chloro-2-indolinone (353) 3-Z-[1-(4-aminomethyl-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinone (354) 3-Z-[1-(3-(dimethylamino-methyl)-an'~fino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-chioro-2-indolinor~e (355) 3-Z-[1-(3-(methylamino-methyl)-anilirro)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinone (356) 3-Z-[1-(3-(2-dimethylamino-ethyl)-an lino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinor~e (357) 3-Z-[1-(3-(3-dimethylamino-propyl)-a~ilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinor~e (358) 3-Z-[1-(4-(2-dimethylamino-ethyl)-an lino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinor~e (359) 3-Z-[1-(4-(N-(dimethylamino-carbonylmethyl)-N-methylsulphonyl-ami-no)-anilino)-1-(3-(2-carboxy-ethyl)-phen yl)-methylene]-6-chloro-2-indolinone (360) 3-Z-[1-(4-(N-methyl-N-methylsulphoryl-amino)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-inclolinone (361) 3-Z-[1-(4-(N-methyl-N-acetyl-amino)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinor a (362) 3-Z-[1-(4-(1-methyl-imidazol-2-yl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinor a (363) 3-Z-[1-(4-(N-(N-(2-dimethylamino-ethyl)-N-methyl-amino-methylcarbonyl)-N-methyl-amino)-anilin ~)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinone (364) 3-Z-[1-(4-(2-diethylamino-ethyl-sulph~nyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-inclolinone (365) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl-;,arbonyl)-N-methyl-amino)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-rnethylene]-6-chloro-2-indolinone (366) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methyl-amino-methyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylerie]-6-chloro-2-indolinone (367) 3-Z-[1-(4-(2-dimethylamino-ethoxy)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinorre (368) 3-Z-[1-(4-(N-(4-dimethylamino-butyl-;arbonyl)-N-methyl-amino)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-rnethylene]-6-chloro-2-indolinone (369) 3-Z-[1-(4-(N-(3-dimethylamino-propy-carbonyl)-N-methyl-amino)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-rnethylene]-6-chloro-2-indolinone (370) 3-Z-[1-(4-(methylethylamino-methyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinorie (371) 3-Z-[1-(4-(methylpropyiamino-methyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinorie (372) 3-Z-[1-(4-(methylbenzylamino-methy )-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinor~e (373) 3-Z-[1-(4-(diethylamino-methyl)-anilir~o)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinone (374) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methyl-amino-methyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl-methylen~;)-6-chloro-2-indolinone (375) 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilirro)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinone (376) 3-Z-[1-(4-(pyrrolidin-1-yi-methyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinor a (377) 3-Z-[1-(4-(azetidin-1-yl-methyl)-aniline)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinone (378) 3-Z-[1-(4-((4-methyl-piperazin-1-yl)-methyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-inclolinone (379) 3-Z-[1-(4-(piperazin-1-yl-methyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinor a (380) 3-Z-[1-(4-(morpholin-4-yl-methyl)-ani ino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinor a (381) 3-Z-[1-(4-(thiomorpholin-4-yl-methyl)~~anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinor a (382) 3-Z-[1-(4-(imidazol-1-yl-methyl)-anilioo)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinone (383) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-(4-carboxymethyl-phenyl)-methylene]-6-chloro-2-indolinone (384) 3-Z-[1-(4-(N-(dimethylamino-methylcarbonyl)-N-methyl-amino)-anilino)-1-(4-carboxymethyl-phenyl)-methylene]-6-chloro-2-indolinone (385) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)~~N-acetyl-amino)-anilino)-1-(4-carboxymethyl-phenyl)-methylene]-6-cr loro-2-indolinone (386) 3-Z-[1-(4-(N-(2-methylamino-ethyl)-~-acetyl-amino)-anilino)-1-(4-carboxymethyl-phenyl)-methylene]-6-cl- loro-2-indolinone (387) 3-Z-[1-(4-(N-(3-dimethylamino-propy )-N-acetyl-amino)-anilino)-1-(4-carboxymethyl-phenyl)-methylene]-6-ch loro-2-indolinone (388) 3-Z-[1-(4-(N-(3-methylamino-propyl)-N-acetyl-amino)-anilino)-1-(4-carboxymethyl-phenyl)-methylene]-6-chloro-2-indolinone (389) 3-Z-[1-(4-(dimethylamino-methyl)-anilino)-1-(4-carboxymethyl-phenyl)-methylene]-6-chloro-2-indolinone (390) 3-Z-[1-(4-(3-dimethylamino-propyl)-a~ilino)-1-(4-carboxymethyl-phenyl)-methylene]-6-chloro-2-indolinor~e (391 ) 3-Z-[1-(4-ethylaminomethyl-anilino)-1-(4-carboxymethyl-phenyl)-methylene]-6-chloro-2-indolinone (392) 3-Z-[1-(4-methylaminomethyl-anilino;-1-(4-carboxymethyl-phenyl)-methylene]-6-chloro-2-indolinone (393) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl~~methylcarbonyl)-N-methyl-amino) anilino)-1-(4-carboxymethyl-phenyl)-me :hylene]-6-chloro-2-indolinone (394) 3-Z-[1-(4-(4-methyl-piperazin-1-yl-carbonyl)-anilino)-1-(4-carboxymethyl-phenyl)-methylene]-6-chloro-2-indolinone (395) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-methylsulphonyl-amino)-anilino)-1-(4-carboxymethyl-phenyl)-me:hylene]-6-chloro-2-indolinone (396) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-propylsulphonyl-amino)-anilino)-1-(4-carboxymethyl-phenyl)-me :hylene]-6-chloro-2-indolinone (397) 3-Z-[1-(4-aminomethyl-anilino)-1-(4-carboxymethyl-phenyl)-methylene]-6-chloro-2-indolinone (398) 3-Z-[1-(3-(dimethylamino-methyl)-anilino)-1-(4-carboxymethyl-phenyl)-methylene]-6-chloro-2-indolinone (399) 3-Z-[1-(3-(methylamino-methyl)-anili~io)-1-(4-carboxymethyl-phenyl)-methylene]-6-chloro-2-indolinone (400) 3-Z-[1-(3-(2-dimethylamino-ethyl)-anilino)-1-(4-carboxymethyl-phenyl)-methylene]-6-chloro-2-indolinone (401) 3-Z-[1-(3-(3-dimethylamino-propyl)-anilino)-1-(4-carboxymethyl-phenyl)-methylene]-6-chloro-2-indolinone (402) 3-Z-[1-(4-(2-dimethylamino-ethyl)-anilino)-1-(4-carboxymethyl-phenyl)-methylene]-6-chloro-2-indolinone (403) 3-Z-[1-(4-(N-(dimethylamino-carbonylmethyl)-N-methylsulphonyl-ami-no)-anilino)-1-(4-carboxymethyl-phenyl;-methylene]-6-chloro-2-indolinone (404) 3-Z-[1-(4-(N-methyl-N-methylsulphor~yl-amino)-anilino)-1-(4-carboxymethyl-phenyl)-methylene]-6-cl- loro-2-indolinone (405) 3-Z-[1-(4-(N-methyl-N-acetyl-amino)-anilino)-1-(4-carboxymethyl-phenyl)-methylene]-6-chloro-2-indolinor~e (406) 3-Z-[1-(4-(1-methyl-imidazol-2-yl)-an lino)-1-(4-carboxymethyl-phenyl)-methylene]-6-chloro-2-indolinone (407) 3-Z-[1-(4-(N-(N-(2-dimethylamino-etryl)-N-methyl-amino-methylcarbonyl)-N-methyl-amino)-anilin ~)-1-(4-carboxymethyl-phenyl)-methylene]-6-chloro-2-indolinone (408) 3-Z-[1-(4-(2-diethylamino-ethyl-sulph~nyl)-anilino)-1-(4-carboxymethyl-phenyl)-methylene]-6-chloro-2-indolinor~e (409) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl-~;arbonyl)-N-methyl-amino)-an ilino)-1-(4-carboxymethyl-phenyl)-me :hylene]-6-chloro-2-indolinone (410) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methyl-amino-methyl)-anilino)-1-(4-carboxymethyl-phenyl)-methylene]~~6-chloro-2-indolinone (411 ) 3-Z-[1-(4-(2-dimethylamino-ethoxy)-~ nilino)-1-(4-carboxymethyl-phenyl)-methylene]-6-chloro-2-indolinor a (412) 3-Z-[1-(4-(N-(4-dimethylamino-butyl-~;arbonyl)-N-methyl-amino)-anilino)-1-(4-carboxymethyl-phenyl)-me :hylene]-6-chloro-2-indolinone (413) 3-Z-(1-(4-(N-(3-dimethylamino-propyl-carbonyl)-N-methyl-amino)-anilino)-1-(4-carboxymethyl-phenyl)-me :hylene]-6-chloro-2-indolinone (414) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-(3-carboxymethyl-phenyl)-me':hylene]-6-chloro-2-indolinone (415) 3-Z-[1-(4-(N-(dimethylamino-methylcarbonyl)-N-methyl-amino)-anilino)-1-(3-carboxymethyl-phenyl)-methylene]-6-chloro-2-indolinone (416) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-(3-carboxymethyl-phenyl)-methylene]-6-chloro-2-indolinone (417) 3-Z-[1-(4-(N-(2-methylamino-ethyl)-f~l-acetyl-amino)-anilino)-1-(3-carboxymethyl-phenyl)-methylene]-6-cr~loro-2-indolinone (418) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-(3-carboxymethyl-phenyl)-methylene]-6-cl- loro-2-indolinone (419) 3-Z-[1-(4-(N-(3-methylamino-propyl)-N-acetyl-amino)-anilino)-1-(3-carboxymethyl-phenyl)-methylene]-6-cl- loro-2-indolinone (420) 3-Z-[1-(4-(dimethylamino-methyl)-an.lino)-1-(3-carboxymethyl-phenyl)-methylene]-6-chloro-2-indolinone (421 ) 3-Z-[1-(4-(3-dimethylamino-propyl)-anilino)-1-(3-carboxymethyl-phenyl)-methylene]-6-chloro-2-indolinorie (422) 3-Z-[1-(4-ethylaminomethyl-anilino)-' -(3-carboxymethyl-phenyl)-methylene]-6-chloro-2-indolinone (423) 3-Z-[1-(4-methylaminomethyi-anilinoy-1-(3-carboxymethyl-phenyl)-methylene]-6-chloro-2-indolinone (424) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl~~methylcarbonyl)-N-methyl-amino) anilino)-1-(3-carboxymethyl-phenyl)-methylene]-6-chloro-2-indolinone (425) 3-Z-[1-(4-(4-methyl-piperazin-1-yl-cavbonyl)-anilino)-1-(3 carboxymethyl-phenyl)-methylene]-6-ch loro-2-indolinone (426) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-methylsulphonyl-amino)-anilino)-1-(3-carboxymethyl-phenyl)-me rhylene]-6-chloro-2-indolinone (427) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-propylsulphonyl-amino)-anilino)-1-(3-carboxymethyl-phenyl)-me thylene]-6-chloro-2-indolinone (428) 3-Z-[1-(4-aminomethyl-anilino)-1-(3-carboxymethyl-phenyl)-methylene]
6-chloro-2-indolinone (429) 3-Z-[1-(3-(dimethylamino-methyl)-anilino)-1-(3-carboxymethyl-phenyl)-methylene]-6-chloro-2-indolinone (430) 3-Z-[1-(3-(methylamino-methyl)-anilirio)-1-(3-carboxymethyl-phenyl)-methylene]-6-chloro-2-indolinone (431) 3-Z-[1-(3-(2-dimethylamino-ethyl)-anilino)-1-(3-carboxymethyl-phenyl)-methylene]-6-chloro-2-indolinone (432) 3-Z-[1-(3-(3-dimethylamino-propyl)-anilino)-1-(3-carboxymethyl-phenyl)-methylene)-6-chloro-2-indolinooe (433) 3-Z-[1-(4-(2-dimethylamino-ethyl)-anilino)-1-(3-carboxymethyl-phenyl)-methylene]-6-chloro-2-indolinone (434) 3-Z-[1-(4-(N-(dimethylamino-carbonylmethyl)-N-methylsulphonyl-ami-no)-anilino)-1-(3-carboxymethyl-phenyl;-methylene]-6-chloro-2-indolinone (435) 3-Z-[1-(4-(N-methyl-N-methylsulphoriyl-amino)-anilino)-1-(3-carboxymethyl-phenyl)-methylene]-6-cr loro-2-indolinone (436) 3-Z-[1-(4-(N-methyl-N-acetyl-amino)-anilino)-1-(3-carboxymethyl-phenyl)-methylene]-6-chloro-2-indolinorie (437) 3-Z-[1-(4-(1-methyl-imidazol-2-yl)-an lino)-1-(3-carboxymethyl-phenyl)-methylene]-6-chloro-2-indolinone (438) 3-Z-[1-(4-(N-(N-(2-dimethylamino-etr~yl)-N-methyl-amino-methylcarbonyl)-N-methyl-amino)-anilino)-1-(3-carboxymethyl-phenyl)-methylene]-6-chloro-2-indolinone (439) 3-Z-[1-(4-(2-diethylamino-ethyl-sulphonyl)-anifino)-1-(3-carboxymethyl-phenyl)-methylene]-6-chloro-2-indolinor~e (440) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl-~;arbonyl)-N-methyl-amino)-anilino)-1-(3-carboxymethyl-phenyl)-me rhylene]-6-chloro-2-indolinone (441 ) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl) N-methyl-amino-methyl)-anilino)-1-(3-carboxymethyl-phenyl)-methylene] ~6-chloro-2-indolinone (442) 3-Z-[1-(4-(2-dimethylamino-ethoxy)-~ nilino)-1-(3-carboxymethyl-phenyl)-methylene]-6-chloro-2-indolinor~e (443) 3-Z-[1-(4-(N-(4-dimethylamino-butyl-~;arbonyl)-N-methyl-amino)-anilino)-1-(3-carboxymethyl-phenyl)-me rhylene]-6-chloro-2-indolinone (444) 3-Z-[1-(4-(N-(3-dimethylamino-propyl-carbonyl)-N-methyl-amino)-anilino)-1-(3-carboxymethyl-phenyl)-me rhylene]-6-chloro-2-indolinone (445) (446) (447) 3-Z-[1-(4-(N-(2-methylamino-ethyl)-N-acetyl-amino)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (448) 3-Z-[1-(4-(N-(3-methylamino-propyl)-N-acetyl-amino)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (449) 3-Z-[1-(4-(3-dimethylamino-propyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinor a (450) 3-Z-[1-(4-ethylaminomethyl-anilino)-'I-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (451 ) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-methylsulphonyl-amino)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-rnethylene]-6-fluoro-2-indolinone (452) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl) ~N-propylsulphonyl-amino)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-rnethylene]-6-fluoro-2-indolinone (453) (454) (455) 3-Z-[1-(3-(methylamino-methyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (456) 3-Z-[1-(3-(2-dimethylamino-ethyl)-an lino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (457) 3-Z-[1-(3-(3-dimethylamino-propyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinon a (458) (459) 3-Z-[1-(4-(N-(dimethylamino-carbonylmethyl)-N-methylsulphonyl-ami-no)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (460) 3-Z-[1-(4-(N-methyl-N-methylsulphoryl-amino)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (461 ) 3-Z-[1-(4-(N-(N-(2-dimethylamino-eti-yl)-N-methyl-amino-methylcarbonyl)-N-methyl-amino)-anilin ~)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (462) 3-Z-[1-(4-(2-diethylamino-ethyl-sulphnnyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (463) (464) (465) 3-Z-[1-(4-(2-dimethylamino-ethoxy)-sniiino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinon (466) (467) 3-Z-[1-(4-(N-(3-dimethylamino-propyl-carbonyl)-N-methyl-amino)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-riethylene]-6-fluoro-2-indolinone (468) 3-Z-[1-(4-(methylethylamino-methyl)..anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinore (469) 3-Z-[1-(4-(methylpropylamino-methy )-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinon a (470) 3-Z-[1-(4-(methylbenzylamino-methyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (471 ) 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilioo)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (472) 3-Z-[1-(4-(azetidin-1-yl-methyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (473) 3-Z-[1-(4-(piperazin-1-yl-methyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (474) 3-Z-[1-(4-(morpholin-4-yl-methyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinon a (475) 3-Z-[1-(4-(thiomorpholin-4-yl-methyl)~.anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinon a (476) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)~N-acetyl-amino)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (477) 3-Z-[1-(4-(N-{2-methylamino-ethyl)-N-acetyl-amino)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (478) 3-Z-[1-(4-(N-(3-methylamino-propyl)-N-acetyl-amino)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (479) 3-Z-[1-(4-(3-dimethylamino-propyl)-a iilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinon (480) 3-Z-[1-(4-ethylaminomethyl-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (481 ) (482) 3-Z-[1-(4-(4-methyl-piperazin-1-yl-carbonyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (483) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-methylsulphonyl-amino)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-riethylene]-6-fluoro-2-indolinone (484) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-propylsulphonyl-amino)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-riethylene]-6-fluoro-2-indolinone (485) (486) (487) 3-Z-[1-(3-(methylamino-methyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (488) 3-Z-[1-(3-(2-dimethylamino-ethyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinon (489) 3-Z-[1-(3-(3-dimethylamino-propyi)-a~ilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinon (490) (491 ) 3-Z-[1-(4-(N-(dimethylamino-carbonylmethyl)-N-methylsulphonyl-ami-no)-anilino)-1-(3-(2-carboxy-ethyl)-phen yl)-methylene]-6-fluoro-2-indolinone (492) 3-Z-[1-(4-(N-methyl-N-methylsulphoryl-amino)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (493) 3-Z-[1-(4-(N-methyl-N-acetyl-amino)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinon (494) (495) 3-Z-[1-(4-(N-(N-(2-dimethylamino-ethyl)-N-methyl-amino-methylcarbonyl)-N-methyl-amino)-anilin ~)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (496) 3-Z-[1-(4-(2-diethylamino-ethyl-sulph~nyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (497) 3-Z-[1-(4-(N-(2-dimethyfamino-ethyl-c;arbonyl)-N-methyl-amino)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-riethylene]-6-fluoro-2-indolinone (498) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methyl-amino-methyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (499) 3-Z-[1-(4-(2-dimethylamino-ethoxy)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinon s (500) (501 ) (502) 3-Z-[1-(4-(methylethylamino-methyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinon s (503) 3-Z-[1-(4-(methylpropylamino-methyl-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinon (504) 3-Z-[1-(4-(methylbenzylamino-methyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinon a (505) 3-Z-[1-(4-(diethylamino-methyl)-anilir~o)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (506) 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilioo)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (507) 3-Z-[1-(4-(pyrrolidin-1-yl-methyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methyleneJ-6-fluoro-2-indolinon a (508) 3-Z-[1-(4-(azetidin-1-yl-methyl)-aniline)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (509) 3-Z-[1-(4-(piperazin-1-yl-methyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinon (510) 3-Z-[1-(4-(morpholin-4-y1-methyl)-ani ino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinon (511 ) 3-Z-[1-(4-(thiomorpholin-4-yl-methyl)~~anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinon (512) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-(4-carboxymethyl-phenyl)-methylene]-6-fluoro-2-indolinone (513) 3-Z-[1-(4-(N-(2-methylamino-ethyl)-N-acetyl-amino)-anilino)-1-(4-carboxymethyl-phenyl)-methylene)-6-fluoro-2-indolinone (514) 3-Z-[1-(4-(N-(3-methylamino-propyl)-N-acetyl-amino)-anilino)-1-(4-carboxymethyl-phenyl)-methylene]-6-fluoro-2-indolinone (515) 3-Z-[1-(4-(3-dimethylamino-propyl)-a ~ilino)-1-(4-carboxymethyl-phenyl)-methylene]-6-fluoro-2-indolinon (516) 3-Z-[1-(4-ethylaminomethyl-anilino)-1-(4-carboxymethyl-phenyl)-methylene]-6-fluoro-2-indolinone (517) 3-Z-[1-(4-methylaminomethyl-anilino;-1-(4-carboxymethyl-phenyl)-methylene]-6-fluoro-2-indolinone (518) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-methylsulphonyl-amino)-an ilino)-1-(4-carboxymethyl-phenyl)-me rhylene]-6-fluoro-2-indolinone (519) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-propylsulphonyl-amino)-anilino)-1-(4-carboxymethyl-phenyl)-merhyfeneJ-6-fluoro-2-indolinone (520) 3-Z-[1-(4-aminomethyl-anilino)-1-(4-carboxymethyl-phenyl)-methyleneJ-6-fluoro-2-indolinone (521 ) 3-Z-[1-(3-(dimethylamino-methyl)-an lino)-1-(4-carboxymethyl-phenyl)-methylene]-6-fluoro-2-indolinone (522) 3-Z-[1-(3-(methylamino-methyl)-anilioo)-1-(4-carboxymethyl-phenyl)-methylene]-6-fluoro-2-indolinone (523) 3-Z-[1-(3-(2-dimethylamino-ethyl)-anllino)-1-(4-carboxymethyl-phenyl)-methylene]-6-fluoro-2-indolinone (524) 3-Z-[1-(3-(3-dimethylamino-propyl)-anilino)-1-(4-carboxymethyl-phenyl)-methylene]-6-fluoro-2-indolinone (525) (526) 3-Z-[1-(4-(N-methyl-N-methylsulphor~yl-amino)-anilino)-1-(4-carboxymethyl-phenyl)-methylene]-6-fl~ oro-2-indolinone (527) 3-Z-[1-(4-(N-(N-(2-dimethylamino-ethyl)-N-methyl-amino methylcarbonyl)-N-methyl-amino)-anilin ~)-1-(4-carboxymethyl-phenyl)-methylene]-6-fluoro-2-indolinone (528) 3-Z-[1-(4-(2-diethylamino-ethyl-sulphonyl)-anilino)-1-(4-carboxymethyl-phenyl)-methylene]-6-fluoro-2-indolinone (529) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methyl-amino-methyl)-anilino)-1-(4-carboxymethyl-phenyl)-methylene] -6-fluoro-2-indolinone (530) 3-Z-[1-(4-(2-dimethylamino-ethoxy)-~nilino)-1-(4-carboxymethyl-phenyl)-methylene]-6-fluoro-2-indolinon a (531 ) 3-Z-[1-(4-(N-(4-dimethylamino-butyl-~;arbonyl)-N-methyl-amino)-anilino)-1-(4-carboxymethyl-phenyl)-me rhylene]-6-fluoro-2-indolinone (532) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-(3-carboxymethyl-phenyl)-methylene]-6-fluoro-2-indolinone (533) 3-Z-[1-(4-(N-(2-methylamino-ethyl)-N-acetyl-amino)-anilino)-1-(3-carboxymethyl-phenyl)-methylene]-6-fluoro-2-indolinone (534) 3-Z-[1-(4-(N-(3-dimethylamino-propyi)-N-acetyl-amino)-anilino)-1-(3-carboxymethyl-phenyl)-methylene]-6-fluoro-2-indolinone (535) 3-Z-[1-(4-(N-(3-methylamino-propyl)-N-acetyl-amino)-anilino)-1-(3-carboxymethyl-phenyl)-methylene]-6-fluoro-2-indolinone (536) 3-Z-[1-(4-(3-dimethylamino-propyl)-a iilino)-1-(3-carboxymethyl-phenyl)-methylene]-6-fluoro-2-indolinon s (537) 3-Z-[1-(4-ethylaminomethyl-anilino)-1-(3-carboxymethyl-phenyl)-methylene]-6-fluoro-2-indolinone (538) 3-Z-[1-(4-methylaminomethyl-anilino~-1-(3-carboxymethyl-phenyl)-methylene]-6-fluoro-2-indolinone (539) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-methylsulphonyl-amino)-anilino)-1-(3-carboxymethyl-phenyl)-methylene]-6-fluoro-2-indolinone (540) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl) ~N-propylsulphonyl-amino)-anilino)-1-(3-carboxymethyl-phenyl)-methylene]-6-fluoro-2-indolinone (541 ) 3-Z-[1-(4-aminomethyl-anilino)-1-(3-c;arboxymethyl-phenyl)-methylene]-6-fluoro-2-indolinone (542) 3-Z-[1-(3-(dimethylamino-methyl)-anllino)-1-(3-carboxymethyl-phenyl)-methylene]-6-fluoro-2-indolinone (543) 3-Z-[1-(3-(methylamino-methyl)-anilirro)-1-(3-carboxymethyl-phenyl)-methylene]-6-fluoro-2-indolinone (544) 3-Z-(1-(3-(2-dimethylamino-ethyl)-an lino)-1-(3-carboxymethyl-phenyl)-methylene]-6-fluoro-2-indolinone (545) 3-Z-[1-(3-(3-dimethylamino-propyl)-a~ilino)-1-(3-carboxymethyl-phenyl)-methylene]-6-fluoro-2-indolinon a (546) (547) 3-Z-[1-(4-(N-methyl-N-methylsulphoryl-amino)-anilino)-1-(3-carboxymethyl-phenyl)-methylene]-6-fluoro-2-indolinone (548) 3-Z-[1-(4-(N-methyl-N-acetyl-amino)-anilino)-1-(3-carboxymethyl-phenyl)-methylene]-6-fluoro-2-indolinon (549) 3-Z-[1-(4-(N-(N-(2-dimethylamino-eti-yl)-N-methyl-amino-methylcarbonyl)-N-methyl-amino)-anilin ~)-1-(3-carboxymethyl-phenyl)-methylene]-6-fluoro-2-indolinone (550) 3-Z-[1-(4-(2-diethylamino-ethyl-sulph~nyl)-anilino)-1-(3-carboxymethyl-phenyl~methylene]-6-fluoro-2-indolinon (551) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl-~;arbonyl)-N-methyl-amino)-anilino)-1-(3-carboxymethyl-phenyl)-me :hylene]-6-fluoro-2-indolinone (552) 3-Z-(1-(4-(N-(2-dimethylamino-ethyl) N-methyl-amino-methyl)-anilino)-1-(3-carboxymethyl-phenyl)-methylene]~~6-fluoro-2-indolinone (553) 3-Z-[1-(4-(2-dimethylamino-ethoxy)-~nilino)-1-(3-carboxymethyl-phenyl)-methylene]-6-fluoro-2-indolinon s (554) 3-Z-[1-(4-(N-(3-dimethylamino-propyl-carbonyl)-N-methyl-amino)-anilino)-1-(3-carboxymethyl-phenyl)-me ~hylene]-6-fluoro-2-indolinone (555) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl}~N-methylsulphonyl-amino)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-rnethylene]-6-bromo-2-indolinone (556) 3-Z-[1-(4-(N-(dimethylamino-methylcarbonyl)-N-methyl-amino)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methyler ~e]-6-bromo-2-indolinone (557) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)~~N-acetyl-amino)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinone (558) 3-Z-[1-(4-(N-(2-methylamino-ethyl)-~-acetyl-amino)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinone (559) 3-Z-[1-(4-(N-(3-dimethylamino-propy )-N-acetyl-amino)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-br«mo-2-indolinone (560) 3-Z-[1-(4-(N-(3-methylamino-propyl)-N-acetyl-amino)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinone (561) 3-Z-[1-(4-(3-dimethylamino-propyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinooe (562) 3-Z-[1-(4-ethylaminomethyl-anilino)-' -(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinone (563) 3-Z-[1-(4-methylaminomethyl-anilino:~-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinone (564) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl~~methylcarbonyl)-N-methyl-amino)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-r~ethylene]-6-bromo-2-indolinone (565) 3-Z-[1-(4-(4-methyl-piperazin-1-yl-cavbonyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-in~iolinone (566) 3-Z-[1-(4-(N-(3-dimethylamino-propyi)-N-methylsulphonyl-amino)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-r~ethylene]-6-bromo-2-indolinone (567) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl) N-propylsulphonyl-amino)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-r~ethylene]-6-bromo-2-indolinone (568) 3-Z-[1-(4-aminomethyl-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinone (569) 3-Z-[1-(3-(dimethylamino-methyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinorre (570) 3-Z-[1-(3-(methylamino-methyl)-anilirio)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinone (571) 3-Z-[1-(3-(2-dimethylamino-ethyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinorre (572) 3-Z-[1-(3-(3-dimethylamino-propyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolino~oe (573) 3-Z-[1-(4-(2-dimethylamino-ethyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinooe (574) 3-Z-[1-(4-(N-(dimethylamino-carbonylmethyl)-N-methylsulphonyl-ami-no)-anilino)-1-(4-(2-carboxy-ethyl)-pher yl)-methylene]-6-bromo-2-indolinone (575) 3-Z-[1-(4-(N-methyl-N-methylsulphoriyl-amino)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-in jolinone (576) 3-Z-[1-(4-(N-methyl-N-acetyl-amino)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinoi~e (577) 3-Z-[1-(4-(1-methyl-imidazol-2-yl)-an lino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinooe (578) 3-Z-[1-(4-(N-(N-(2-dimethylamino-ethyl)-N-methyl-amino-methylcarbonyl)-N-methyl-amino)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinone (579) 3-Z-[1-(4-(2-diethylamino-ethyl-sulphonyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-irnlolinone (580) 3-Z-(1-(4-(N-(2-dimethylamino-ethyl-~;arbonyl)-N-methyl-amino)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-r~ethylene]-6-bromo-2-indolinone (581 ) 3-Z-(1-(4-(N-(2-dimethylamino-ethyl) N-methyl-amino-methyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methyler a]-6-bromo-2-indolinone (582) 3-Z-[1-(4-(2-dimethylamino-ethoxy)-~ nilino)-1-(4-(2-carboxy-ethyl) phenyl)-methylene]-6-bromo-2-indolinoi~e (583) 3-Z-[1-(4-(N-(4-dimethylamino-butyl-~;arbonyl)-N-methyl-amino)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-r~ethylene]-6-bromo-2-indolinone (584) 3-Z-[1-(4-(N-(3-dimethylamino-propy~~-carbonyl)-N-methyl-amino)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-r ethylene]-6-bromo-2-indol inone (585) 3-Z-[1-(4-(methylethylamino-methyl)-anilino)-1-(4-(2-carboxy-ethyf)-phenyl)-methylene]-6-bromo-2-indolinone (586) 3-Z-[1-(4-(methylpropylamino-methyl-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinoi~e (587) 3-Z-[1-(4-(methylbenzylamino-methy )-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinone (588) 3-Z-(1-(4-(N-(2-dimethylamino-ethyl)~~N-methyl-amino-methyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl-methylen~:]-6-bromo-2-indolinone {589) 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilioo)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinone (590) 3-Z-[1-(4-(azetidin-1-yl-methyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinone (591) 3-Z-[1-(4-((4-methyl-piperazin-1-yl)-methyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-irnlolinone (592) 3-Z-[1-(4-(piperazin-1-yl-methyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinone (593) 3-Z-[1-(4-(morpholin-4-yl-methyl)-ani ino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinotie (594) 3-Z-[1-(4-(thiomorpholin-4-yl-methyl)~~anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinoi~e (595) 3-Z-[1-(4-(imidazol-1-yl-methyl)-anilir~o)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinone (596) 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinone (597) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)~N-methylsulphonyl-amino)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-r ethylene]-6-bromo-2-indolinone (598) 3-Z-[1-(4-{N-{dimethylamino-methylc~rbonyl)-N-methyl-amino)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methyler a]-6-bromo-2-indolinone (599) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinone (600) 3-Z-[1-(4-(N-(2-methylamino-ethyl)-N-acetyl-amino)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-brc>mo-2-indolinone (601 ) 3-Z-[1-(4-(N-(3-dimethylamino-propy )-N-acetyl-amino)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-brc~mo-2-indolinone (602) 3-Z-[1-(4-(N-(3-methylamino-propyl)-N-acetyl-amino)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-brc~mo-2-indolinone (603) 3-Z-[1-(4-(3-dimethylamino-propyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinoi~e (604) 3-Z-[1-(4-ethylaminomethyl-anilino)-' -(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinone (605) 3-Z-[1-(4-methylaminomethyl-anilino i-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinone (606) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino) anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-rnethylene]-6-bromo-2-indolinone (607) 3-Z-[1-(4-(4-methyl-piperazin-1-yl-ca~bonyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-in~lolinone (608) 3-Z-[1-(4-(N-(3-dimethylamino-propy )-N-methylsulphonyl-amino)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-rnethylene]-6-bromo-2-indolinone (609) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)~~N-propylsulphonyl-amino)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-rnethylene]-6-bromo-2-indolinone (610) 3-Z-[1-(4-aminomethyl-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinone (611 ) 3-Z-[1-(3-(dimethylamino-methyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinoile (612) 3-Z-[1-(3-(methylamino-methyl)-anilirro)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinone (613) 3-Z-[1-(3-(2-dimethylamino-ethyl)-an lino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinooe (614) 3-Z-[1-(3-(3-dimethylamino-propyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinoile (615) 3-Z-[1-(4-(2-dimethylamino-ethyl)-an lino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinoile (616) 3-Z-[1-(4-(N-(dimethylamino-carbonylmethyl)-N-methylsulphonyl-ami-no)-anilino)-1-(3-(2-carboxy-ethyl)-phen yl)-methylene]-6-bromo-2-indolinone (617) 3-Z-[1-(4-(N-methyl-N-methylsulphor~yl-amino)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-in lolinone (618) 3-Z-[1-(4-(N-methyl-N-acetyl-amino)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinooe (619) 3-Z-(1-(4-(1-methyl-imidazol-2-yl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinoiie (620) 3-Z-[1-(4-(N-(N-(2-dimethylamino-ethyl)-N-methyl-amino-methylcarbonyl)-N-methyl-amino)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinone (621 ) 3-Z-[1-(4-(2-diethylamino-ethyl-sulphonyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-in lolinone (622) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl-~:arbonyl)-N-methyl-amino)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-rnethylene]-6-bromo-2-indolinone (623) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl) N-methyl-amino-methyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methyler a]-6-bromo-2-indolinone (624) 3-Z-[1-(4-(2-dimethylamino-ethoxy)-~ nilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinor~e (625) 3-Z-[1-(4-(N-(4-dimethylamino-butyl-~;arbonyl) -N-methyl-amino)-aniiino)-1-(3-(2-carboxy-ethyl)-phenyl)-r ethylene]-6-bromo-2-indol inone (626) 3-Z-[1-(4-(N-(3-dimethylamino-propy~-carbonyl)-N-methyl-amino)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-r~ethylene]-6-bromo-2-indolinone (627) 3-Z-[1-(4-(methylethylamino-methyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinorre (628) 3-Z-[1-(4-(methylpropylamino-methyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinorre (629) 3-Z-(1-(4-(methylbenzylamino-methy )-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinorie (630) 3-Z-[1-(4-(diethylamino-methyl)-anilir~o)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinone (631) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methyl-amino-methyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl-methylenE;]-6-bromo-2-indolinone (632) 3-Z-[1-(4-(piperidin-1-yl-methyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinone (633) 3-Z-[1-(4-(pyrrolidin-1-yl-methyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinorie (634) 3-Z-[1-(4-(azetidin-1-yl-methyl)-aniline)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinone (635) 3-Z-[1-(4-((4-methyl-piperazin-1-yl)-methyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-in~iolinone (636) 3-Z-[1-(4-(piperazin-1-yl-methyl)-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinorre (637) 3-Z-[1-(4-(morpholin-4-yl-methyl)-ani ino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinor~e (638) 3-Z-[1-(4-(thiomorpholin-4.-yl-methyl)~~anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinoi~e (639) 3-Z-[1-(4-(imidazol-1-yl-methyl)-anilir~o)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinone (640) 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(4-carboxymethylamino-phenyl)-methylene]-6-fluoro-2-indolinon a (641 ) 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(3-carboxymethylamino-phenyl)-methylene]-6-fluoro-2-indolinon a (642) 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(4-(N-methyl-carboxymethylamino)-phenyl)-methylene]-6-fluoro-2-indolinone (643) 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(3-(N-rnethyl-carboxymethylamino)-phenyl)-methylene]-6-fluoro-2-indolinone (644) 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(4-carboxymethoxy-phenyl)-methylene]-6-chloro-2-indolinone (645) 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(3-carboxymethoxy-phenyl)-methylene]-6-chloro-2-indolinone (646) 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(4-carboxymethylamino-phenyl)-methylene]-6-chloro-2-indolinor~e (647) 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(3-carboxymethylamino-phenyl)-methylene]-6-chloro-2-indolinor~e (648) 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(4-(N-methyl-carboxymethylamino)-phenyl)-methylene]-6-chloro-2-indolinone (649) 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(3-(N-methyl-carboxymethylamino)-phenyl)-methylene]-6-chloro-2-indolinone (650) 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(4-carboxymethoxy-phenyl)-methylene]-6-bromo-2-indolinone (651 ) 3-Z-[1-(4-dimethylaminomethyl-aniliro)-1-(3-carboxymethoxy-phenyl)-methylene]-6-bromo-2-indolinone (652) 3-Z-[1-(4-dimethylaminomethyl-aniliro)-1-(4-carboxymethylamino-phenyl)-methylene]-6-bromo-2-indolinoi~e (653) 3-Z-[1-(4-dimethylaminomethyl-aniliro)-1-(3-carboxymethylamino-phenyl)-methylene]-6-bromo-2-indolino~ie (654) 3-Z-[1-(4-dimethylaminomethyl-aniliro)-1-(4-(N-methyl-carboxymethylamino)-phenyl)-methyler a]-6-bromo-2-indolinone (655) 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(3-(N-methyl-carboxymethylamino)-phenyl)-methylen a]-6-bromo-2-indolinone In the above Tables Me denotes methyl, Et denotes ethyl, Pr denotes propyl, nPr denotes n-propyl, iPr denotes isopropyl, nBu denotes n-butyl, tBu denotes tert.-butyl and Bn denotes benzyl.

Claims (19)

Claims
1. Compounds of general formula wherein X denotes an oxygen or sulphur atom, R1 denotes a hydrogen atom, a C1-4-alkoxy-carbonyl, C1-3-alkyl-carbonyl, aminomethyl, C1-3-alkylaminomethyl, di-(C1-3-alkyl)-aminomethyl or a 5- to 7-membered cycloalkyleneiminomethyl group R2 denotes a fluorine, chlorine or bromine atom or a cyano group, R3 denotes a phenyl or naphthyl group or a phenyl or naphthyl group mono- or disubstituted by a fluorine, chlorine, bromine or iodine atom, by a trifluoromethyl, C1-3-alkyl or C1-3-alkoxy group, while in the case of disubstitution the substituents may be identical or different and the abovementioned unsubstituted as well as the mono- and disubstituted phenyl and naphthyl groups may additionally be substituted by a fluorine, chlorine, bromine or iodine atom, by a C1-3-alkyl, C1-4-alkoxy, C1-4-alkoxy-carbonyl, C1-4-alkoxy-carbonyl-C1-3-alkoxy, C1-4-alkyloxy-carbonylamino, C1-4-alkoxy-carbonyl-C1-3-alkylamino, C1-4-alkoxy-carbonyl-C1-3-alkyl-N-(C1-3-alkyl)-amino, aminocarbonyl-, C1-3-alkylamino-carbonyl, di-(C1-3-alkyl)-amino-carbonyl, benzyloxy, carboxy, carboxy-C1-3-alkoxy, carboxy-C1-3-alkylamino, carboxy-C1-3-alkyl-N-(C1-4-alkyl)-amino, cyano, trifluoromethyl, nitro, amino, C4-7-cycloalkylamino, C1-3-alkyl-carbonyl-amino, N-(C1-3-alkyl)-N-(C1-3-alkyl-carbonyl)-amino, phenyl-carbonylamino, N-(C1-3-alkyl)-N-(phenyl-carbonyl)-amino, benzyl-carbonylamino, N-(C1-3-alkyl)-N-(benzyl-carbonyl)-amino, hydroxy, C1-3-alkylsulphonylamino, N-(C1-3-alkyl)-C1-3-alkylsulphonylamino, phenylsulphonylamino, N-(C1-3-alkyl)-phenylsulphonylamino, phenyl-C1-3-alkyl-sulphonylamino, N-(C1-3-alkyl)-N-(phenyl-C1-3-alkyl-sulphonyl)-amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group, by a C1-3- or C4-6-alkyl group which is substituted by a hydroxy, cyano, carboxy, C1-4-alkoxy, C1-4-alkoxy-carbonyl, aminocarbonyl, (C1-3-alkyl-amino)-carbonyl, di-(C1-3-alkyl)-aminocarbonyl, amino, C1-3-alkylamino, [di-(C1-3-alkyl)-amino], N-(C1-4-alkoxy-carbonyl)-amino, N-(C1-4-alkoxy-carbonyl)-N-(C1-3-alkyl)-amino, phenylamino, diphenylamino, N-phenyl-N-(C1-3-alkyl)-amino, benzylamino, dibenzylamino, N-benzyl-N-(C1-3-alkyl)-amino, heteroarylamino, N-heteroaryl-N-(C1-3-alkyl)-amino, C1-4-alkyl-sulphonylamino, N-(C1-3-alkyl)-C1-4-alkylsulphonylamino, phenyl-sulphonylamino, N-(C1-3-alkyl)-phenylsulphonylamino, phenyl-C1-3-alkyl-sulphonylamino, N-(C1-3-alkyl)-N-(phenyl-C1-3-alkyl-sulphonyl)-amino, benzylcarbonylamino, N-(C1-3-alkyl)-N-(benzylcarbonyl)-amino, phenylcarbonylamino, N-(C1-3-alkyl)-N-(phenylcarbonyl)-amino, 4-(C1-3-alkyl)-piperazin-1-yl-carbonyl, (C1-6-alkyl-carbonyl)-amino, N-(C1-3-alkyl)-N-(C1-6-alkyl-carbonyl)-amino,C3-7-cycloalkyl-carbonyl)-amino, N-(C1-3-alkyl)-N-(C3-7-cycloalkyl-carbonyl)-amino, (C3-7-cycloalkyl-C1-3-alkyl-carbonyl)-amino, N-(C1-3-alkyl)-N-(C3-7-cycloalkyl-C1-3-alkyl-carbonyl)-amino, (C1-4-alkoxy-C1-3-alkyl-carbonyl)-amino, N-(C1-3-alkyl)-N-(C1-4-alkoxy-C1-3-alkyl-carbonyl)-amino, (heteroaryl-carbonyl)-amino, N-(C1-3-alkyl)-N-(heteroaryl-carbonyl)-amino, (C3-7-cycloalkyl-sulphonyl)-amino, N-(C1-3-alkyl)-N-(C3-7-cycloalkyl-sulphonyl)-amino, (C3-7-cycloalkyl-C1-3-alkyl-sulphonyl)-amino, N-(C1-3-alkyl)-N-(C3-7-cycloalkyl-C1-3-alkyl-sulphonyl)-amino, (C1-4-alkoxy-C1-3-alkyl-sulphonyl)-amino, N-(C1-3-alkyl)-N-(C1-4-alkoxy-C1-3-alkyl-sulphonyl)-amino, (heteroaryl-sulphonyl)-amino, N-(C1-3-alkyl)-N-(heteroaryl-sulphonyl)-amino, tetrazolyl or heteroaryl group, by a carboxy-C2-3-alkenyl, aminocarbonyl-C2-3-alkenyl, (C1-3-alkyl-amino)-carbonyl-C2-3-alkenyl, di-(C1-3-alkyl)-amino-carbonyl-C2-3-alkenyl or C1-4-alkoxy-carbonyl-C2-3-alkenyl group, by a heteroaryl group or by a cycloalkyleneimino or cycloalkyleneimino-C1-3-alkyl group with in each case 5 to 7 ring members, wherein in each case a methylene group linked to the imino group is replaced by a carbonyl or sulphonyl group or the two methylene groups linked to the imino group are each replaced by a carbonyl group or a -CH2-CH2- group linked to the imino group is replaced by the group -O-CO-, while the carbonyl group of the -O-CO- group is linked to the imino group and a phenyl ring may be used to the 5- to 7-membered cycloalkyleneimino group via two adjacent carbon atoms, or by a cycloalkyleneimino, cycloalkyleneiminocarbonyl, cycloalkyleneiminosulphonyl, cycloalkyleneimino-C1-3-alkyl, cycloalkyleneiminocarbonyl-C1-3-alkyl or cycloalkyleneiminosulphonyl-C1-3-alkyl group with 4 to 7 ring members in each case, while in each case the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be substituted by a carboxy, C1-3-alkoxy-carbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, phenyl-C1-3-alkylamino or N-(C1-3-alkyl)-phenyl-C1-3-alkylamino group or may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, -NH, -N(C1-3-alkyl), -N(phenyl), -N(C1-3-alkyl-carbonyl) or -N(benzoyl)- group, while the substituents may be identical or different, R4 denotes a benzopyrazolyl group, a C3-7-cycloalkyl group which may be substituted by a N-[di-(C1-3-alkyl)-amino-C1-3-alkyl-carbonyl]-amino or N-[di-(C1-3-alkyl)-amino-C1-3-alkyl-carbonyl]-N-C1-3-alkyl-amino group, while the methylene group in the 4 position of a 6- or 7-membered cycloalkyl group may be substituted by an amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group or replaced by a -NH or -N(C1-3-alkyl) group, or a phenyl, naphthyl or heteroaryl group substituted by the group R9 which may additionally be mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C1-5-alkyl, trifluoromethyl, hydroxy, C1-4-alkoxy, benzyloxy, carboxy, C1-4-alkoxy-carbonyl, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, acetylamino, C1-3-alkyl-sulphonylamino, aminocarbonyl, C1-3-alkyl-aminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, aminosulphonyl, C1-3-alkyl-aminosulphonyl, di-(C1-3-alkyl)-aminosulphonyl, nitro or cyano groups, while the substituents may be identical or different and wherein R9 denotes a hydrogen, fluorine, chlorine, bromine or iodine atom, a cyano, nitro, amino, C1-5-alkyl, C3-7-cycloalkyl, trifluoromethyl, phenyl, tetrazolyl or heteroaryl group, a C1-3-alkyl-sulphonyl, amino-C1-3-alkyl-sulphonyl, (C1-3-alkylamino)-C1-3-alkyl-sulphonyl or di-(C1-3-alkyl)-amino-C1-3-alkylsulphonyl group, a C1-4-alkoxy group, a .omega.-C1-3-alkoxy-C2-3-alkoxy, phenyl-C1-3-alkoxy, .omega.-amino-C2-3-alkoxy, .omega.-(C1-3-alkylamino)-C2-3-alkoxy, .omega.-[di-(C1-3-alkyl)-amino]-C2-3-alkoxy, .omega.-(phenyl-C1-3-alkylamino)-C2-3-alkoxy, .omega.-[N-(C1-3-alkyl)-phenyl-C1-3-alkylamino]-C2-3-alkoxy, .omega.-(C5-7-cycloalkyleneimino)-C2-3-alkoxy or C1-3-alkylmercapto group, a carboxy or C1-4-alkoxy-carbonyl group, aminocarbonyl, C1-4-alkyl-amino-carbonyl, N-(C1-5-alkyl)-C1-3-alkylaminocarbonyl, C3-7-cycloalkyl-amino-carbonyl, N-(C1-5-alkyl)-C3-7-cycloalkylaminocarbonyl, (phenyl-C1-3-alkyl)-amino-carbonyl, N-(C1-3-alkyl)-phenyl-C1-3-alkylamino-carbonyl group, a C1-3-alkylaminocarbonyl or N-(C1-3-alkyl)-(C1-3-alkylaminocarbonyl group, wherein one or two alkyl moieties are substituted independently of one another by a nitro, cyano, carbamoyl, N-(C1-3-alkyl)-carbamoyl, di-N-(C1-3-alkyl)-carbamoyl, carboxy or C1-4-alkoxy-carbonyl group or in the 2 or 3 position by an amino, (C1-3-alkyl)-amino, di-C1-3-alkyl)-amino, (C1-4-alkoxy-carbonyl)-amino, N-(C1-4-alkoxy-carbonyl)-N-(C1-3-alkyl)-amino, piperazino, N-(C1-3-alkyl)-piperazino, a 4- to 7-membered cycloalkyleneimino group, a hydroxy or methoxy group, a 4- to 7-membered cycloalkyleneiminocarbonyl group wherein the cycloalkylene moiety may be fused to a phenyl ring via two adjacent ring atoms or may be bridged to a methylene or ethylene group via two non-adjacent ring atoms or one or two hydrogen atoms in each case may be replaced by a C1-3-alkyl group and/or in each case the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneiminocarbonyl group may be substituted by a carboxy, C1-4-alkoxy-carbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, di-(C1-3-alkyl)-amino-C1-3-alkyl, di-(C1-3-alkyl)-amino, phenyl-C1-3-alkylamino or N-(C1-3-alkyl)-phenyl-C1-3-alkylamino group, a hydroxy or methoxy group or replaced by an oxygen or sulphur atorn, by a sulphinyl, sulphonyl or -NH
group or by a nitrogen atom, the by a C1-3-alkyl, phenyl, C1-3-alkyl-carbonyl, C1-4-alkoxy-carbonyl, di-(C1-3-alkyl)-amino-C1-3-alkyl, .omega.-hydroxy-C2-3-alkyl or benzoyl group, a 4- to 7-membered cycloalkyleneimino group wherein a methylene group linked to the imino group by a carbonyl or sulphonyl group may be replaced or the cycloalkylene moiety may be fused to a phenyl ring or one or two hydrogen atoms in each case may be replaced by a C1-3-alkyl group and/or in each case the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be substituted by a carboxy, C1-4-alkoxy-carbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, phenyl-C1-3-alkylamino or N-(C1-3-alkyl)-phenyl-C1-3-alkylamino group or replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, -NH, -N(C1-3-alkyl), -N(phenyl), -N(C1-3-alkyl-carbonyl) or -N(benzoyl) group, a C1-4-alkyl group substituted by the group R10, where R10 denotes a C3-7-cycloalkyl group, while the methylene group in the ~ position of a 6- or 7-membered cycloalkyl group may be substituted by an amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group or replaced by a -NH or -N(C1-3-alkyl) group or in a 5- to 7-membered cycloalkyl group a -(CH2)2 group may be replaced by a -CO-NH group, a -(CH2)3 group may be replaced by a -NH-CO-NH or -CO-NH-CO group or a -(CH2)4 group may be replaced by a -NH-CO-NH-CO group, while in each case a hydrogen atom bonded to a nitrogen atom may be replaced by a C1-3-alkyl group, a phenyl, triazolyl or heteroaryl group, a hydroxy or C1-4-alkoxy group, an amino, C1-7-alkylamino, di-(C1-7-alkyl)-amino, phenylamino, N phenyl-N-(C1-3-alkyl)-amino, N-(phenyl-C1-3-alkyl)-amino, N-(C1-3-alkyl)-N-(phenyl-C1-3-alkyl)-amino or di-(phenyl-C1-3-alkyl)-amino group, a .omega.-hydroxy-C2-3-alkyl-amino, N-(C1-3-alkyl)-(.omega.-hydroxy-C2-3-alkyl)-amino, di-(.omega.-hydroxy-C2-3-alkyl)-amino or di-(.omega.-(C1-3-alkoxy)-C2-3-alkyl)-amino-group, a C1-3-alkyl-carbonylamino-C2-3-alkyl-amino or C1-3-alkyl-carbonyl-amino-C2-3-alkyl-N-(C1-3-alkyl)-amino group, a C1-4-alkyloxy-carbonyl-amino, N-(C1-4-alkyloxy-carbonyl)-N-(C1-3-alkyl)-amino or N-{.omega.-(N-(C1-4-alkoxy-carbonyl)-amino]-(C1-4-alkyl)}-N-(C1-3-alkyl)-amino group, a C1-3-alkylsulphonylamino, N-(C1-3-alkyl)-C1-3-alkylsulphonylamino, C1-3-alkylsulphonylamino-C2-3-alkyl-amino or C1-3-alkylsulphonyl-amino-C2-3-alkyl-N-(C1-3-alkyl)-amino group, a hydroxycarbonyl-C1-3-alkylamino or N-(C1-3-alkyl)-hydroxycarbonyl-C1-3-alkyl-amino group, an N-(.omega.-amino-C2-3-alkyl)-N-(C1-3-alky)-amino, N-(.omega.-C1-3-alkylamino-C2-3-alkyl)-N-(C1-3-alkyl)-amino, N-[.omega.-di-(C1-3-alkyl)-amino-C2-3-alkyl)-N-(C1-3-alkyl)-amino, N-(C1-C1-3-alkoxy-C1-3-alkoxy-C1-3-alkyl)-amino or N-(.omega.-C1-3-alkoxy-C2-3-alkoxy-C1-3-alkyl)-N-(C1-3-alkyl)-amino group, a guanidino group wherein one or two hydrogen atoms may each be replaced by a C1-3-alkyl group, a C4-7-cycloalkylamino, C4-7-cycloalkyl-C1-3-alkylamino or C4-7-cyclo-alkenylamino group wherein position 1 of the ring does not participate in the double bond and the abovementioned groups may each additionally be substituted at the aminonitrogen atom by a C5-7-cycloalkyl, C2-4-alkenyl or C1-4-alkyl group may, a 4- to 7-membered cycloalkyleneimino group wherein the cycloalkylene moiety may be fused with a phenyl group or with an oxazolo, imidazolo, thiazolo, pyridino, pyrazino or pyrimidino group optionally substituted by a fluorine, chlorine, bromine or iodine atom or by a nitro, C1-3-alkyl, C1-3-alkoxy or amino group and/or one or two hydrogen atoms may each be replaced by a C1-3-alkyl, C1-4-alkoxy-carbonyl, amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group C5-7-cycloalkyl or phenyl group and/or the methylene group in position 3 of a 5-membered cycloalkyleneimino group may be substituted by a hydroxy, hydroxy-C1-3-alkyl, C1-4-alkoxy or C1-3-alkoxy-C1-3-alkyl group, in each case the methylene group in position 3 or 4 of a 6- or 7-membered cycloalkyleneimino group may be substituted by a hydroxy, hydroxy-C1-3-alkyl, C1-4-alkoxy, C1-4-alkoxy-C1-3-alkyl, carboxy, C1-4-alkoxy-carbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, C1-3-alkylamino, di-(C1-3-alkyl)-amino, N-(phenyl-C1-3-alkyl)-amino or N-(C1-3-alkyl)-N-(phenyl-C1-3-alkyl)-amino group or may be replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, -NH, -N(C1-3-alkyl-), -N(phenyl), -N(phenyl-C1-3-alkyl-), -N(C1-3-alkyl-carbonyl-), -N(C1-4-hydroxy-carbonyl-), -N(C1-4-alkoxy-carbonyl-), -N(benzoyl-) or -N(phenyl-C1-3-alkyl-carbonyl-) group, while a methylene group linked to an imino-nitrogen atom of the cycloalkyleneimino group may be replaced by a carbonyl or sulphonyl group or in a 5- to 7 membered monocyclic cyclo-alkyleneimino group or a cyclcoalkyleneimino group fused to a phenyl group the two methylene groups linked to the imino-nitrogen atom may each be replaced by a carbonyl group, and all the dialkylamino groups contained in the group R10 may also be present in quaternised form, for example as the N-methyl-(N,N-dialkyl)-ammonium group, the counter-ion preferably being selected from among the iodide, chloride, bromide, methylsulphonate, para-toluenesulphonate, or trifluoroacetate, or R9 denotes a C1-4-alkyl group which is substituted by a carboxy, C1-4-alk-oxy-carbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, N-[amino-C1-3-alkyl]-aminocarbonyl, N-[(C1-3-alkyl)-amino-C1-3-alkyl]-aminocarbonyl, N-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-aminocarbonyl, N-[amino-C1-3-alkyl]-N-(C1-3-alkyl)-aminocarbonyl, N-[(C1-3-alkyl)-amino-C1-3-alkyl]-N-(C1-3-alkyl)-aminocarbonyl, N-(C3-7-cycloalkyl)-N-(C1-3-alkyl)-amino or N-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-N-(C1-3-alkyl)-aminocarbonyl group or by a 4- to 7-membered cycloalkyleneiminocarbonyl group, while in the abovementioned cycloalkyleneimino groups one or two hydrogen atoms may each be replaced by a C1-3-alkyl, carboxy, C1-4-alkoxy-carbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl or di-(C1-3-alkyl)-aminocarbonyl group or one or two hydrogen atoms, which are bonded to a carbon atom not adjacent to the imino group, may be replaced by an amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, phenyl-C1-3-alkylamino or N-(C1-3-alkyl)-phenyl-C1-3-alkylamino group and/or the methylene group in the 4 position of a 6- or 7-membered cyclo-alkyleneimino group may be replaced by one of the groups -S, -SO, -SO2, -NH, -N(C1-3-alkyl), -N(phenyl), -N(C1-3-alkyl-carbonyl), -N(C1-4-alkoxy-carbonyl), -N(benzoyl) or -O-, an N-(C1-3-alkyl)-C1-3-alkyl-carbonyl-amino group which is additionally substituted in the alkyl moiety by a carboxy or C1-4-alkoxy-carbonyl group, or a group of formula wherein R7 denotes a hydrogen atom, a C1-4-alkyl or C3-7-cycloalkyl group, a C1-3-alkyl group terminally substituted by a phenyl, heteroaryl, trifluoromethyl, aminocarbonyl, C1-4-alkylamino-carbonyl, di-(C1-4-alkyl)-amino-carbonyl, C1-3-alkyl-carbonyl, C1-3-alkyl-sulphonylamino, N-(C1-3-alkyl)-C1-3-alkyl-sulphonylamino, C1-3-alkyl-aminosulphonyl or di-(C1-3-alkyl)-aminosulphonyl group, a C2-3-alkyl group terminally substituted by a hydroxy or C1-3-alkoxy group, a C1-4-alkyl-carbonyl, benzylcarbonyl, heteroarylcarbonyl, heteroaryl-C1-3-alkyl-carbonyl, cycloalkyleneimino-C1-3-alkyl-carbonyl with 5 to 7 ring atoms in the cycloalkyleneimino moiety, C1-3-alkoxy-C1-3-alkyl-carbonyl, amino-C1-3-alkylcarbonyl, (C1-3-alkyl)-amino-C1-3-alkyl-carbonyl, di-(C1-3-alkyl)-amino-carbonyl-C1-3-alkyl, C1-4-alkylsulphonyl, phenylsulphonyl, heteroarylsulphonyl, heteroaryl-C1-3-alkyl-sulphonyl or benzyl-sulphonyl group or a phenylcarbonyl group optionally substituted in the phenyl moiety by one or two methoxy groups and R8 denotes a C1-3-alkyl, di-(C1-3-alkyl)-amino-C1-3-alkyl-amino-carbonyl or 1-(C1-3-alkyl)-piperidin-4-yl-aminocarbonyl group, a C1-4-alkyl-carbonyl group terminally substituted by a (.omega.-alkoxy-C2-3-alkyl)-amino, C1-3-alkyl-carbonyl-amino or N-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-N-(C1-3-alkyl)-amino group or a C2-4-alkyl, carbonyl, C1-4-alkyl-carbonyl or carbonyl-C1-3-alkyl group terminally substituted by one of the groups described under R10, while R10 additionally also denotes a C5-7-cycloalkyloxy group wherein the methylene group may be substituted in the 4 position by a -NH or-N(C1-3-alkyl)- group, a 5- to 7-membered cycloalkyleneimino-amino group, while the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be substituted by a carboxy, C1-3-alkoxycarbonyl, aminocarbonyl, C1-3-alkylaminocarbonyl, di-(C1-3-alkyl)-aminocarbonyl, phenyl-C1-3-alkylamino or N-(C1-3-alkyl)-phenyl-C1-3-alkylamino group or replaced by an oxygen or sulphur atom, by a sulphinyl, sulphonyl, -NH, -N(C1-3-alkyl), -N(phenyl), -N(C1-3-alkyl-carbonyl) or-N(benzoyl)- group, or may denote an N-(heteroaryl-C1-3-alkyl)-amino group, R5 denotes a hydrogen atom or a C1-3-alkyl group and R6 denotes a hydrogen atom or a nitro group, while the unsubstituted, mono- or disubstituted phenyl groups contained in the above definitions, whether singly bonded or fused on, may additionally be substituted by one or two fluorine, chlorine, bromine or iodine atoms or by one or two C1-5-alkyl, C1-4-alkoxy, benzyloxy, carboxy, cyano, C1-4-alkoxy-carbonyl, aminocarbonyl, C1-4-alkylamino-carbonyl, di-(C1-4-alkyl)-amino-carbonyl, aminosulphonyl, C1-3-alkyl-aminosulphonyl, di-(C1-3-alkyl)-aminosulphonyl, trifluoromethyl, nitro, amino, hydroxy, C1-3-alkylsulphonylamino, C1-3-alkylamino or di-(C1-3-alkyl)-amino groups, while the substituents may be identical or different, the abovementioned alkyl groups including straight-chain and branched alkyl groups, wherein additionally one to 3 hydrogen atoms may be replaced by fluorine atoms, while, unless otherwise stated, the expression a heteroaryl group refers to a monocyclic 5- or 6-membered heteroaryl group optionally substituted in the carbon skeleton by a C1-3-alkyl group, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C1-3-alkyl or phenyl-C1-3-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted key a C1-3-alkyl, amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl, di-(C1-3-alkyl)-amino-C1-3-alkyl or phenyl-C1-3-alkyl group or an oxygen or sulphur atom and additionally contains a nitrogen atom or an imino group optionally substituted key a C1-3-alkyl or phenyl-C1-3-alkyl group and two nitrogen atoms, and moreover a phenyl ring may be fused to the abovementioned monocyclic heterocyclic groups via two adjacent carbon atoms and the bonding takes place via a nitrogen atom or via a carbon atom of the heterocyclic moiety or a fused-on phenyl ring, and additionally any carboxy, amino or imino group present may be substituted by a group which can be cleaved in vivo, or may be present in the form of a prodrug group, e.g. in the form of s group which may be converted in vivo into a carboxy group or in the form of a group which may be converted in vivo into an imino or amino group, the tautomers, enantiomers, diastereomers, mixtures thereof and the salts thereof, with the exception of the compounds (Z)-3-[1-(4-piperidinomethyl-phenylamino)-' -phenyl-methylidene]-6-chloro-2-indolinone and (Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-6-bromo-2-indolinone.
2. Compounds of general formula (I) according to claim 1 wherein X denotes an oxygen or sulphur atom, R1 denotes a hydrogen atom, a C1-4-alkoxy-carbonyl, C1-3-alkyl-carbonyl, aminomethyl, C1-3-alkylaminomethyl, di-(C1-3-alkyl)-aminomethyl or a 5- to 7-membered cycloalkyleneiminomethyl group, R2 denotes a fluorine, chlorine or bromine atom or a cyano group, R3 denotes a phenyl or naphthyl group or a phenyl or naphthyl group mono- or disubstituted by a fluorine, chlorine, bromine or iodine atom, by a trifluoromethyl, C1-3-alkyl or C1-3-alkoxy group, while in the case of disubstitution the substituents may be identical or different and the abovementioned unsubstituted as well as the mono- and disubstituted phenyl and naphthyl groups may additionally be substituted by a fluorine, chlorine, bromine or iodine atom, by a C1-3-alkyl, C1-4-alkoxy, benzyloxy, carboxy, cyano, trifluoromethyl, nitro, amino, C1-3-alkyl-carbonyl-amino, C1-4-alkyloxy-carbonylamino, N-(C1-3-alkyl)-N-(C1-3-alkyl-carbonyl)-amino, phenyl-carbonylamino, N-(C1-3-alkyl)-N-(phenyl-carbonyl)-amino, benzyl-carbonylamino, N-(C1-3-alkyl)-N-(benzyl-carbonyl)-amino, hydroxy, C1-3-alkylsulphonylamino, N-(C1-3-alkyl)-N-(C1-3-alkylsulphonyl)-amino, phenylsulphonylamino, N-(C1-3-alkyl)-N-(phenylsulphonyl)-amino, benzylsulphonylamino, N-(C1-3-alkyl)-N-(benzylsulphonyl)-amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group, by a hydroxy-C1-3-alkyl, cyano-C1-3-alkyl, carboxy-C1-3-alkyl, C1-4-alkoxy-C1-3-alkyl, amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl, [di-(C1-3-alkyl)-amino]-C1-3-alkyl, benzylamino-C1-3-alkyl, dibenzylamino-C1-3-alkyl, N-benzyl-N-(C1-3-alkyl)-amino-C1-3-alkyl, benzylcarbonylamino-C1-3-alkyl, N-(C1-3-alkyl)-N-(benzylcarbonyl)-amino-C1-3-alkyl, phenylcarbonylamino-C1-3-alkyl, N-(C1-3-alkyl)-N-(phenylcarbonyl)-amino-C1-3-alkyl, phenylamino-C1-3-alkyl, diphenylamino-C1-3-alkyl, N-phenyl-N-(C1-3-alkyl)-amino-C1-3-alky , heteroarylamino-C1-3-alkyl, N-heteroaryl-N-(C1-3-alkyl)-amino-C1-3-alkyl, C1-4-alkyl-sulphonylamino-C1-3-alkyl, N-(C1-3-alkyl)-N-(C1-4-alkyl-sulphonyl)-amino-C1-3-alkyl, phenyl-sulphonylamino-C1-3-alkyl, N-(C1-3-alkyl)-N-(phenyl-sulphonyl)-amino-C1-3-alkyl, benzyl-sulphonylamino-C1-3-alkyl, N-(C1-3-alkyl)-N-(benzyl-sulphonyl)-amino-C1-3-alkyl, C1-4-alkoxy-carbonyl-C1-3-alkyl, N-(C1-4-alkoxy-carbonyl)-amino-C1-3-alkyl, N-(C1-3-alkyl)-N-(C1-4-alkoxy-carbonyl)-amino-C1-3-alkyl, aminocarbonyl-C1-3-alkyl, (C1-3-alkylamino)-carbonyl-C1-3-alkyl, di-(C1-3-alkyl)-aminocarbonyl-C1-3-alkyl, (C1-6-alkyl-carbonyl)-amino-C1-3-alkyl, N-(C1-3-alkyl)-N-(C1-6-alkyl-carbonyl)-amino-C1-3-alkyl, (C3-7-cycloalkyl-carbonyl)-amino-C1-3-alkyl, N-(C1-3-alkyl)-N-(C3-7-cycloalkyl-carbonyl)-amino-C1-3-alkyl, (C3-7-cycloalkyl-C1-3-alkyl-carbonyl)-amino-C1-3-alkyl, N-(C1-3-alkyl)-N-(C3-7-cycloalkyl-C1-3-alkyl-carbonyl)-amino-C1-3-alkyl, (C1-4-alkoxy-C1-3-alkyl-carbonyl)-amino-C1-3-alkyl, N-(C1-3-alkyl)-N-(C1-4-alkoxy-C1-3-alkyl-carbonyl)-amino-C1-3-alkyl, (heteroaryl-carbonyl)-amino-C1-3-alkyl, N-(C1-3-alkyl)-N-(heteroaryl-carbonyl)-amino-C1-3-alkyl, 4-(C1-3-alkyl)-piperazin-1-yl-carbonyl-(C1-3-alkyl), tetrazolyl-C1-3-alkyl or heteroaryl-C1-3-alkyl group, by a carboxy-C2-3-alkenyl, aminocarbonyl-C2-3-alkenyl, (C1-3-alkyl-amino)-carbonyl-C2-3-alkenyl, di-(C1-3-alkylamino)-carbonyl-C2-3-alkenyl or C1-4-alkoxy-carbonyl-C2-3-alkenyl group or by a cycloalkyleneimino or cycloaklyleneimino-C1-3-alkyl group each with 5 to 7 ring members, wherein in each case one or two methylene groups adjacent to the nitrogen atom may be replaced by a carbonyl or sulphonyl group or a -CH2-CH2- group linked to the imino group may be replaced by the group -O-CO-, while the carbonyl group of the -O-CO- group is linked to the imino group, while the substituents may be identical or different, R4 denotes a benzopyrazolyl or 1-(C1-3-alky )-piperidin-4-yl group, a cyclohexyl group which is substituted by a N-[di-(C1-3-alkyl)-amino-C1-3-alkyl-carbonyl]-amino or N-[di-(C1-3-alkyl)-amino-C1-3-alkyl-carbonyl]-N-C1-3-alkyl-amino group, or a phenyl, furyl, pyrrolyl, pyridinyl or naphthyl group, each of which is substituted in the carbon skeleton by a fluorine, chlorine, bromine or iocine atom, by a C1-3-alkyl, C1-4-alkoxy, cyano, nitro, carboxy or trifluoromethyl group, by a .omega.-amino-C2-3-alkoxy, .omega.-[(C1-3-alkyl)-amino]-C2-3-alkoxy, .omega.-[di-(C1-3-alkyl)-amino]-C2-3-alkoxy, C1-3-alkyl-sulphonyl, (C1-3-alkyl)-amino-C1-3-alkyl-sulphonyl, amino-C1-3-alkyl-sulphonyl, di-(C1-3-alkyl)-amino-C1-3-alkyl-sulphonyl, 4-(C1-3-alkyl)-piperazino or heteroaryl group, by a C1-3-alkyl group which is terminally substituted by a carboxy, C1-4-alkoxy-carbonyl, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, N-(C1-3-alkyl)-N-(.omega.-amino-C2-3-alkyl)-amino, N-benzyl-N-(C1-3-alkyl)-amino, N-[.omega.-(di-(C1-3-alkyl)-amino)-C2-3-alkyl]-N-(C1-3-alkyl)-amino, N-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-N-(C1-3-alkyl)-amino-carbonyl, N-(.omega.-hydroxy-C2-3-alkyl)-N-(C1-3-alkyl)-amino, di-(.omega.-hydroxy-C2-3-alkyl)-amino, N-(.omega.-C1-3-alkoxy-C2-3-alkoxy-C1-3-alkyl)-N-(C1-3-alkyl)-amino, N-(C1-4-alkoxy-carbonyl)-amino, N-(C1-4-alkoxy-carbonyl)-N-(C1-3-alkyl)-amino, N-{.omega.-[N-(C1-4-alkoxy-carbonyl)-amino]-(C1-4-alkyl))-N-(C1-3-alkyl)-amino, heteroaryl, triazolyl or by a 5- to 7-membered cycloalkyleneimino or cycloalkyleneiminocarbonyl group, while in the abovementioned cycloalkyleneimino groups one or two hydrogen atoms may each be replaced by a C1-3-alkyl, C1-4-alkoxy-carbonyl, amino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group and/or the methylene group in the 4 position of a 6- or 7-membered cycloalkyleneimino group may be replaced by one of the groups -NH, -N(C1-3-alkyl), -N(C1-4-alkoxy-carbonyl) or -O-, by a carbonyl group which is substituted by a C1-3-alkoxy, N-[amino-C1-3-alkyl]-amino, N-[(C1-3-alkyl)-amino-C1-3-alkyl]-amino, N-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-amino, N-[amino-C1-3-alkyl]-N-(C1-3-alkyl)-amino, N-[(C1-3-alkyl)-amino-C1-3-alkyl]-N-(C1-3-alkyl)-amino, N-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-N-(C1-3-alkyl)-amino, N-(C3-7-cycloalkyl)-N-(C1-3-alkyl)-amino or 5- to 7-membered cycloalkyleneimino group, while the methylene group in the 4 position of a 6- or 7-membered cycloalkylene group may be replaced by a -NH, -N(C1-3-alkyl) or -N(C1-4-alkyloxy-carbonyl)-group, or by a group of formula wherein R7 denotes a hydrogen atom or a C1-4-alkyl, C1-4-alkyl-carbonyl, benzylcarbonyl, heteroarylcarbonyl, cycloalkyleneimino-C1-3-alkyl-carbonyl with 5 to 7 ring atoms in the cycloalkyleneimino moiety, C1-3-alkoxy-C1-3-alkyl-carbonyl, amino-C1-3-alkyl-carbonyl, (C1-3-alkyl)-amino-C1-3-alkyl-carbonyl, di-(C1-3-alkyl)-amino-carbonyl-C1-3-alkyl, C1-4-alkylsulphonyl, phenylsulphonyl, heteroarylsulphonyl or benzylsulphonyl group or a phenylcarbonyl group optionally substituted in the phenyl moiety by one or two methoxy groups and R8 denotes a C1-3-alkyl group, a C2-4-alkyl group terminally substituted by an amino, (C1-3-alkyl)-amino, di-(C1-3-alkyl)-amino or N-benzyl-N-(C1-3-alkyl)-amino group, an amino-carbonyl-C1-3-alkyl, (C1-3-alkyl)-amino-carbonyl-C1-3-alkyl or di-(C1-3-alkyl)-amino-carbonyl-C1-3-alkyl group, a di-(C1-3-alkyl)-amino-C1-3-alkyl-amino-carbonyl, 4-(C1-3-alkyl)-piperazin-1-yl-carbonyl, 4-(C1-3-alkyl)-piperazin-1-yl-aminocarbonyl, 1-(C1-3-alkyl)-piperidin-4-yl-aminocarbonyl, 1-(C1-3-alkyl)-piperidin-4-yl-oxy-carbonyl or (pyridinyl-C1-3-alkyl)-aminocarbonyl group or a C1-4-alkyl-carbonyl group terminally substituted by a hydroxy, C1-4-alkyloxy, amino, (C1-3-alkyl)-amino, di-(C1-3-alkyl)-amino, (.omega.-hydroxy-C2-3-alkyl)-amino, di-(.omega.-hydroxy-C2-3-alkyl)-amino, (.omega.-alkoxy-C2-3-alkyl)-amino, di-(.omega.-alkoxy-C2-3-alkyl)-amino, C1-3-alkyl-carbonyl-amino, N-benzyl-N-(C1-3-alkyl)-amino, N-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-N-(C1-3-alkyl)-amino, 1-(C1-3-alkyl)-piperidin-4-yl or heteroaryl group or by a 5- to 7-membered cycloalkyleneimino group, while the cycloalkylene group may be substituted by a C1-3-alkyl group and/or one or two methylene groups linked to the imino group may be replaced by a carbonyl group and/or the methylene group in the 4 position of a 6- or 7-membered cycloalkylimino group may be replaced by an -NH, -N(C1-3-alkyl), -N(benzyl), -N(C1-4-alkoxy-carbonyl) or -O- and/or a phenyl ring may be fused via two adjacent carbon atoms of the cycloalkyleneimino group, while a 2- or 3-linked pyrrolyl group may additionally be substituted at the nitrogen atom by a C1-3-alkyl group, R5 denotes a hydrogen atom or a C1-3-alkyl group and R6 denotes a hydrogen atom or a nitro group, while the unsubstituted, mono- or disubstituted phenyl groups contained in the above definitions may additionally be substituted by a fluorine, chlorine, bromine or iodine atom or by a C1-3-alkyl, C1-3-alkoxy, benzyloxy, carboxy, cyano, trifluoromethyl, nitro, amino, hydroxy, C1-3-alkylsulphonylamino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group or by two methyl groups, the abovementioned alkyl groups including straight-chain and branched alkyl groups, wherein additionally one to 3 hydrogen atoms may be replaced by fluorine atoms, while, unless otherwise stated, the express on a heteroaryl group refers to a monocyclic 5- or 6-membered heteroaryl group optionally substituted in the carbon skeleton by a C1-3-alkyl group, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C1-3-alkyl or phenyl-C1-3-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted try a C1-3-alkyl, amino-C1-3-alkyl, [(C1-3-alkyl)-amino]-C1-3-alkyl, [di-(C1-3-alkyl)-amino]-C1-3-alkyl or phenyl-C1-3-alkyl group or an oxygen or sulphur atom and additionally contains a nitrogen atom or an imino group optionally substituted by a C1-3-alkyl or phenyl-C1-3-alkyl group and two nitrogen atoms, and moreover a phenyl ring may be fused to the abovementioned monocyclic heterocyclic groups via two adjacent carbon atoms and the bonding takes place via a nitrogen atom or via a carbon atom of the heterocyclic moiety or a fused-on phenyl ring, and additionally any carboxy, amino or imino group present may be substituted by a group which can be cleaved in vivo, the tautomers, enantiomers, diastereomers, mixtures thereof and the salts thereof, with the exception of the compounds (Z)-3-[1-(4-piperidinomethyl-phenylamino)- -phenyl-methylidene)-6-chloro-2-indolinone and (Z)-3-[1-(4-piperidinomethyl-phenylamino)- -phenyl-methylidene]-6-bromo-2-indolinone.
3. Compounds of general formula (I) according to claim 1 wherein X denotes an oxygen or sulphur atom, R1 denotes a hydrogen atom, a C1-4-alkoxy-carbonyl, C1-3-alkyl-carbonyl, aminomethyl, C1-3-alkylaminomethyl, di-(C1-3-alkyl)-aminomethyl or a 5- to 7-membered cycloalkyleneiminomethyl group, R2 denotes a fluorine, chlorine or bromine atom or a cyano group, R3 denotes a phenyl or naphthyl group or a phenyl or naphthyl group mono- or disubstituted by a fluorine, chlorine, bromine or iodine atom, by a trifluoromethyl, C1-3-alkyl or C1-3-alkoxy group, while in the case of disubstitution the substituents may be identical or different and the abovementioned unsubstituted as well as the mono- and disubstituted phenyl and naphthyl groups may additionally be substituted by a fluorine, chlorine, bromine or ioc ine atom, by a C1-3-alkyl, C1-4-alkoxy, benzyloxy, carboxy, cyano, trifluoromethyl, nitro, amino, C1-3-alkyl-carbonyl-amino, C1-4-alkyloxy-carbonylamino, hydroxy, C1-3-alkylsulphonylamino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group, by a hydroxy-C1-3-alkyl, cyano-C1-3-alkyl, carboxy-C1-3-alkyl, C1-4-alkoxy-C1-3-alkyl, amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl, [di-(C1-3-alkyl)-amino]-C1-3-alkyl, benzylamino-C1-3-alkyl, dibenzylamino-C1-3-alkyl, N-benzyl-N-(C1-3-alkyl)-amino-n1-3-alkyl, benzylcarbonylamino-C1-3-alkyl, phenylcarbonylamino-C1-3-alkyl, phenylamino-C1-3-alkyl, diphenylamino-C1-3-alkyl, N-phenyl-N-(C1-3-alkyl)-amino-C1-3-alkyl, heteroarylamino-C1-3-alkyl, N-heteroaryl-N-(C1-3-alkyl)-amino-C1-3-alkyl, C1-4-alkyl-sulphonylamino-C1-3-alkyl, phenyl-sulphonylamino-C1-3-alkyl, benzyl-sulphonylamino-C1-3-alkyl, C1-4-alkoxy-carbonyl-C1-3-alkyl, N-(C1-4-alkoxy-carbonyl)-amino-C1-3-alkyl, aminocarbonyl-C1-3-alkyl, (C1-3-alkylamino)-carbonyl-C1-3-alkyl, di-(C1-3-alkyl)-aminocarbonyl-C1-3-alkyl, (C1-6-alkyl-carbonyl)-amino-C1-3-alkyl, N-(C1-3-alkyl)-N-(C1-6-alkyl-carbonyl)-amino-C1-3-alkyl, (C3-7-cycloalkyl-carbonyl)-amino-C1-3-alkyl, N-(C1-3-alkyl)-N-(C3-7-cycloalkyl-carbonyl)-amino-C1-3-alkyl, (C3-7-cycloalkyl-C1-3-alkyl-carbonyl)-amino-C1-3-alkyl, N-(C1-3-alkyl)-N-(C3-7-cycloalkyl-C1-3-alkyl-carbonyl)-amino-C1-3-alkyl, (C1-4-alkoxy-C1-3-alkyl-carbonyl)-amino-C1-3-alkyl, N-(C1-3-alkyl)-N-(C1-4-alkoxy-C1-3-alkyl-carbonyl)-amino-C1-3-alkyl, (heteroaryl-carbonyl)-amino-C1-3-alkyl, N-(C1-3-alkyl)-N-(heteroaryl-carbonyl)-amino-C1-3-alkyl, 4-(C1-3-alkyl)-piperazin-1-yl-carbonyl-(C1-3-alkyl), tetrazolyl-C1-3-alkyl or imidazoyl-C1-3-alkyl group, by a carboxy-C2-3-alkenyl, aminocarbonyl-C2-3-alkenyl or C1-4-alkoxy-carbonyl-C2-3-alkenyl group or by a 5- to 7-membered cycloalkyleneimino group wherein one or two methylene groups adjacent to the nitrogen atom may be replaced by a carbonyl group or a -CH2-CH2- group linked to the imino group may be replaced by the group -O-CO-, while the carbonyl group of the -O-CO-group is linked to the imino group, while the substituents may be identical or different, R4 denotes a benzopyrazolyl or 1-(C1-3-alkyl)-piperidin-4-yl group, a cyclohexyl group which is substituted by n N-[di-(C1-3-alkyl)-amino-C1-3-alkyl-carbonyl]-amino or N-[di-(C1-3-alkyl)-amino-C1-3-alkyl-carbonyl]-N-(C1-3-alkyl)-amino group, or a phenyl, furyl, pyrrolyl, pyridinyl or naphthyl group each of which may be substituted in the carbon skeleton by a fluorine, chlorine, bromine or iodine atom, by a C1-3-alkyl, C1-3-alkoxy, cyano, nitro, carboxy or trifluoromethyl group, by a w-[di-(C1-3-alkyl)-amino]-C2-3-alkoxy, C1-3-alkyl-sulphonyl, di-(C1-3-alkyl)-amino-C1-3-alkyl-sulphonyl, 4-(C1-3-alkyl)-piperazino, imidazolyl, C1-3-alkyl-imidazolyl or [di-(C1-3-alkyl)-amino]-C1-3-alkyl-imidazolyl group, by a C1-3-alkyl group which is terminally substituted by a carboxy, C1-4-alkoxy-carbonyl, amino, C1-3-alkylam no, di-(C1-3-alkyl)-amino, N-(C1-3-alkyl)-N-(.omega.-amino-C2-3-alkyl)-amino, N-benzyl-N-(C1-3-alkyl)-amino, N-[.omega.-(di-(C1-3-alkyl)-amino)-C2-3-alkyl]-N-(C1-3-alkyl)-amino, N-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-N-(C1-3-alkyl) amino-carbonyl, N-(.omega.-hydroxy-C2-3-alkyl)-N-(C1-3-alkyl)-amino, di-(.omega.-hydroxy-C2-3-alkyl)-amino, N-(.omega.-C1-3-alkoxy-C2-3-alkoxy-C1-3-alkyl) N-(C1-3-alkyl)-amino, N-(C1-4-alkoxy-carbonyl)-amino, N-(C1-4-alkoxy-carbonyl)-N-(C1-3-alkyl)-amino, N-{.omega.-[N-(C1-4-alkoxy-carbonyl)-amino]-(C1-4-alkyl)}-N-(C1-3-alkyl)-amino, pyridinyl, triazolyl, pyrrolidino, piperidino, di-(C1-3-alkyl)-piperidino, [di-(C1-3-alkyl)-amino]-piperidino, piperazino, morpholino, (C1-3-alkyl)-piperazino, (C1-3-alkyl)-piperazin-1-yl carbonyl or 4-(C1-4-alkoxy-carbonyl)-piperazino group, by a carbonyl group which is substituted by a C1-4-alkoxy, N-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-amino, N-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-N-(C1-3-alkyl)-amino, N-(C3-7-cycloalkyl)-N-(C1-3-alkyl)-amino, piperidino, piperazino, 4-(C1-4-alkyloxy-carbonyl)-piperazino or 4-(C1-3-alkyl)-piperazino group, or by a group of formula wherein R7 denotes a hydrogen atom or a C1-3-alkyl, C1-3-alkyl-carbonyl, benzylcarbonyl, pyridinylcarbonyl, furanylcarbonyl, pyrrolidino-C1-3-alkyl-carbonyl, C1-3-alkoxy-C1-3-alkyl-carbonyl, di-(C1-3-alkyl)-amino-carbonyl-C1-3-alkyl, C1-4-alkylsulphonyl or benzylsulphonyl group or a phenylcarbonyl group optionally substituted in the phenyl moiety by one or two methoxy groups and R8 denotes a C1-3-alkyl, di-(C1-3-alkyl)-amino-C1-4-alkyl-amino-carbonyl or di-(C1-3-alkyl)-amino-carbonyl-C1-3-alkyl group, a C2-3-alkyl group terminally substituted by a di-(C1-3-alkyl)-amino or N-benzyl-N-(C1-3-alkyl)-amino group, a 4-(C1-3-alkyl)-piperazin-1-yl-carbonyl, 4-(C1-3-alkyl)-piperazin-1-yl-aminocarbonyl, 1-(C1-3-alkyl)-piperidin-4-yl-aminocarbonyl, 1-(C1-3-alkyl)-piperidin-4-yl-oxy-carbonyl or (pyridinyl-C1-3-alkyl)-aminocarbonyl group or a C1-4-alkyl-carbonyl group terminally substituted by a hydroxy, amino, di-(C1-3-alkyl)-amino, di-(.omega.-hydroxy-C2-3-alkyl)-amino, C1-3-alkyl-carbonyl-amino, N-benzyl-N-(C1-3-alkyl)-amino, N-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-N-(C1-3-alkyl)-amino, imidazolyl, piperazino, 4-(C1-3-alkyl)-piperazin-1-yl, 4-benzyl-piperazin-1-yl, 4-(C1-4-alkoxy-carbonyl)-piperazin-1-yl, 4-(C1-3-alkyl)-homo-piperazin-1-yl, morpholino, pyrrolidino, piperidino, 1-(C1-3-alkyl)-piperidin-4-yl, 4-(C1-3-alkyl)-piperidin-1-yl or phthalimido group, while a 2- or 3-linked pyrrolyl group may additionally be substituted at the nitrogen atom by a C1-3-alkyl group, R5 denotes a hydrogen atom or a C1-3-alkyl group and R6 denotes a hydrogen atom or a nitro group, while the unsubstituted, mono- or disubstituted phenyl groups contained in the above definitions may additionally be substituted by a fluorine, chlorine, bromine or iodine atom or by a C1-3-alkyl, C1-3-alkoxy, benzyloxy, carboxy, cyano, trifluoromethyl, nitro, amino, hydroxy, C1-3-alkylsulphonylamino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group or by two methyl groups, the abovementioned alkyl groups including straight-chain and branched alkyl groups, wherein additionally one to 3 hydrogen atoms may be replaced by fluorine atoms, while, unless otherwise stated, the expression a heteroaryl group refers to a monocyclic 5- or 6-membered heteroaryl group optionally substituted in the carbon skeleton by a C1-3-alkyl group, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C1-3-alkyl or phenyl-C1-3-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C1-3-alkyl or phenyl-C1-3-alkyl group or an oxygen or sulphur atom a id additionally a nitrogen atom or an imino group optionally substituted by a C1-3-alkyl or phenyl-C1-3-alkyl group and two nitrogen atoms, and moreover a phenyl ring may be fused to the abovementioned monocyclic heterocyclic groups via two adjacent carbon atoms and the bonding takes place via a nitrogen atom or via a carbon atom of the heterocyclic moiety or a fused-on phenyl ring, and additionally any carboxy, amino or imino group present may be substituted by a group which can be cleaved in vivo, the tautomers, enantiomers, diastereomers mixtures thereof and the salts thereof, with the exception of the compounds (Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-6-chloro-2-indolinone and (Z)-3-[1-(4-piperidinomethyl-phenylamino)-1-phenyl-methylidene]-6-bromo-2-indolinone.
4. Compounds of general formula I according to claim 1, wherein R1, R2, R3, R5, R6 and X are defined as in claim 3 and R4 denotes a benzopyrazolyl or 1-(C1-3-alky )-piperidin-4-yl group, a cyclohexyl group which is substituted by an N-[di-(C1-3-alkyl)-amino-C1-3-alkyl-carbonyl]-amino or N-[di-(C1-3-alkyl)-amino-C1-3-alkyl-carbonyl]-N-C1-3-alkyl-amino group, or a phenyl, furyl, pyrrolyl, pyridinyl or naphthyl group, each of which may be substituted in the carbon skeleton by a fluorine, chlorine, bromine or iodine atom, by a C1-3-alkyl, C1-3-alkoxy, cyano, nitro, carboxy or trifluoromethyl group, by a .omega.-[di-(C1-3-alkyl)-amino]-C2-3-alkoxy, C1-3-alkyl-sulphonyl, di-(C1-alkyl)-amino-C1-3-alkyl-sulphonyl, 4-(C1-3-alkyl)-piperazino, imidazolyl, C1-3-alkyl-imidazolyl or [di-(C1-3-alkyl)-amino]-C1-3-alkyl-imidazolyl group, by a carbonyl group which is substituted by a C1-4-alkoxy, N-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-amino, N [di-(C1-3-alkyl)-amino-C1-3-alkyl]-N-C1-3-alkyl-amino, N-(C3-7-cycloalkyl)-N-(C1-3-alkyl)-amino, piperidino, piperazino, 4-(C1-4-alkyloxy-carbonyl;-piperazino or 4-(C1-3-alkyl)-piperazino group, or by a group of formula wherein R7 denotes a hydrogen atom or a C1-3-alkyl, C1-3-alkyl-carbonyl, benzylcarbonyl, pyridinylcarbonyl, furanylcarbonyl, pyrrolidino-C1-3-alkyl-carbonyl, C1-3-alkoxy-C1-3-alkyl-carbonyl, di-(C1-3-alkyl)-amino-carbonyl-C1-3-alkyl, C1-~-alkylsulphonyl or benzylsulphonyl group or a phenylcarbonyl group optionally substituted in the phenyl moiety by one or two methoxy groups and R8 denotes a C1-3-alkyl, di-(C1-3-alkyl)-amino-C1-3-alkyl-amino-carbonyl or di-(C1-3-alkyl)-amino-carbonyl-C1-3-alkyl group, a C2-3-alkyl group terminally substituted by a di-(C1-3-alkyl)-amino or N-benzyl-N-(C1-3-alkyl)-amino group, a 4-(C1-3-alkyl)-piperazin-1-yl-carbonyl, 4-(C1-3-alkyl)-piperazin-1-yl-aminocarbonyl, 1-(C1-3-alkyl)-piperidin-4-yl-aminocarbonyl, 1-(C1-3-alkyl)-piperidin-4-yl-oxy-carbonyl or (pyridinyl-C1-3-alkyl)-aminocarbonyl group or a C1-4-alkyl-carbonyl group terminally substituted by a hydroxy, amino, di-(C1-3-alkyl)-amino, d-(.omega.-hydroxy-C2-3-alkyl)-amino, C1-3-alkyl-carbonyl-amino, N-benzyl-N-(C1-3-alkyl)-amino, N-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-N-(C1-3-alkyl)-amino, imidazolyl, piperazino, 4-(C1-3-alkyl)-piperazin-1-yl, 4-benzyl-piperazin-1-yl, 4-(C1-4-alkoxy-carbonyl)-piperazin-1-yl, 4-(C1-3-alkyl)-homo-piperazin-1-yl, morpholino, pyrrolidino, piperidino, 1-(C1-3-alkyl)-piperidin-4-yl, 4-(C1-3-alkyl)-piperidin-1-yl or phthalimido group, while a 2- or 3-linked pyrrolyl group may additionally be substituted at the nitrogen atom by a C1-3-alkyl group, while the unsubstituted, mono- or disubstituted phenyl groups contained in the above definitions may additionally be substituted by a fluorine, chlorine, bromine or iodine atom or by a C1-3-alkyl, C1-3-alkoxy, benzyloxy, carboxy, cyano, trifluoromethyl, nitro, amino, hydroxy, C1-3-alkylsulphonylamino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group or by two methyl groups, the abovementioned alkyl groups including straight-chain and branched alkyl groups, wherein additionally one to 3 hydrogen atoms may be replaced by fluorine atoms, while, unless otherwise stated, the express on a heteroaryl group refers to a monocyclic 5- or 6-membered heteroaryl group optionally substituted in the carbon skeleton by a C1-3-alkyl group, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C1-3-alkyl or phenyl-C1-3-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C1-3-alkyl or phenyl-C1-3-alkyl group or an oxygen or sulphur atom aid additionally a nitrogen atom or an imino group optionally substituted by a C1-3-alkyl or phenyl-C1-3-alkyl group and two nitrogen atoms, and moreover a phenyl ring may be fused to the abovementioned monocyclic heterocyclic groups via two adjacent carbon atoms and the bonding takes place via a nitrogen atom or via a carbon atom of the heterocyclic moiety or a fused-on phenyl ring, and additionally any carboxy, amino or imino group present may be substituted by a group which can be cleaved in vivo, the tautomers, enantiomers, diastereomers. mixtures thereof and the salts thereof.
5. Compounds of general formula I according to claim 3, wherein R1, R2, R4, R5, R6 and X are defined as in c aim 3 and R3 denotes a phenyl or naphthyl group or a phenyl or naphthyl group mono- or disubstituted by a fluorine, chlorine, bromine or iodine atom, by a trifluoromethyl, C1-3-alkyl or C1-3-alkoxy group, while in the case of disubstitution the substituents may be identical or different and the abovementioned unsubstituted as well as the mono- and disubstituted phenyl and naphthyl groups may additionally be substituted by a fluorine, chlorine, bromine or iodine atom, by a C1-3-alkyl, C1-4-alkoxy, benzyloxy, carboxy, cyano, trifluoromethyl, nitro, amino, C1-3-alkyl-carbonyl-amino, C1-4-alkyloxy-carbonylamino, hydroxy, C1-3-alkylsulphonylamino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group, by a hydroxy-C1-3-alkyl, cyano-C1-3-alkyl, carboxy-C1-3-alkyl, C1-4-alkoxy-C1-3-alkyl, amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl, [di-(C1-3-alkyl)-amino]-C1-3-alkyl, benzylamino-C1-3-alkyl, dibenzylamino-C1-3-alkyl, N-benzyl-N-(C1-3-alkyl)-amino-(C1-3-alkyl, benzylcarbonylamino-C1-3-alkyl, phenylcarbonylamino-C1-3-alkyl, phenylamino-C1-3-alkyl, diphenylamino-C1-3-alkyl, N-phenyl-N-(C1-3-alkyl)-amino-C1-3-alkyl, heteroarylamino-C1-3-alkyl, N-heteroaryl-N-(C1-3-alkyl)-amino-C1-3-alkyl, C1-4-alkyl-sulphonylamino-C1-3-alkyl, phenyl-sulphonylamino-C1-3-alkyl, benzyl-sulphonylamino-C1-3-alkyl, C1-4-alkoxy-carbonyl-C1-3-alkyl, N-(C1-4-alkoxy-carbonyl)-amino-C1-3-alkyl, aminocarbonyl-C1-3-alkyl, (C1-3-alkylamino)-carbonyl-C1-3-alkyl, di-(C1-3-alkyl)-aminocarbonyl-C1-3-alkyl, (C1-6-alkyl-carbonyl)-amino-C1-3-alkyl N-(C1-3-alkyl)-N-(C1-6-alkyl-carbonyl)-amino-C1-3-alkyl, (C3-7-cycloalkyl-carbonyl)-amino-C1-3-alkyl, N-(C1-3-alkyl)-N-(C3-7-cycloalkyl-carbonyl)-amino-C1-3-alkyl, (C3-7-cycloalkyl-C1-3-alkyl-carbonyl)-amino C1-3-alkyl, N-(C1-3-alkyl)-N-(C3-7-cycloalkyl-C1-3-alkyl-carbonyl)-amino-C1-3-alkyl, (C1-4-alkoxy-C1-3-alkyl-carbonyl)-amino-C1-3-alkyl, N-(C1-3-al kyl)-N-(C1-4-alkoxy-C1-3-alkyl-carbonyl)-amino-C1-3-alkyl, (heteroaryl-carbonyl)-amino-C1-3-alkyl, N-(C1-3-alkyl)-N-(heteroaryl-carbonyl)-amino-C1-3-alkyl, 4-(C1-3-alkyl)-piperazin-1-yl-carbonyl-(C1-3-alkyl), tetrazolyl-C1-3-alkyl or imidazoyl-C1-3-alkyl group, by a carboxy-C2-3-alkenyl, aminocarbonyl-C2-3-alkenyl or C1-4-alkoxy-carbonyl-C2-3-alkenyl group or by a 5- to 7-membered cycloalkylene imino group wherein one or two methylene groups adjacent to the nitrogen atom may be replaced by a carbonyl group or a -CH2-CH2- grout linked to the imino group may be replaced by the group -O-CO-, while the carbonyl group of the -O-CO- group is linked to the imino group, while the substituents may be identical or different, and the unsubstituted, mono- or disubstituted phenyl groups contained in the above definitions may additionally be substituted by a fluorine, chlorine, bromine or iodine atom or by a C1-3-alkyl, C1-3-alkoxy, benzyloxy, carboxy, cyano, trifluoromethyl, nitro, amino, hydroxy, C1-3-alkylsulphonylamino, C1-3-alkylamino or di-(C1-3-alkyl)-amino group or by two methyl groups, the abovementioned alkyl groups including straight-chain and branched alkyl groups, wherein additionally one to 3 hydrogen atoms may be replaced by fluorine atoms, while, unless otherwise stated, the expression a heteroaryl group refers to a monocyclic 5- or 6-membered heteroaryl group optionally substituted in the carbon skeleton by a C1-3-alkyl group, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C1-3-alkyl or phenyl-C1-3-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted try a C1-3-alkyl or phenyl-C1-3-alkyl group or an oxygen or sulphur atom and additionally a nitrogen atom or an imino group optionally substituted try a C1-3-alkyl or phenyl-C1-3-alkyl group and two nitrogen atoms, and moreover a phenyl ring may be fused to the abovementioned monocyclic heterocyclic groups via two adjacent carbon atoms and the bonding takes place via a nitrogen atom or via a carbon atom of the heterocyclic moiety or a fused-on phenyl ring, and additionally any carboxy, amino or imino group present may be substituted by a group which can be cleaved in vivo, the tautomers, enantiomers, diastereomers, mixtures thereof and the salts thereof.
6. Compounds of general formula I according to claim 1, wherein X denotes an oxygen or sulphur atom, R1 denotes a hydrogen atom, a C1-4-alkoxy-carbonyl, C1-3-alkyl-carbonyl, aminomethyl, C1-3-alkylaminomethyl, di-(C1-3-alkyl)-aminomethyl or a 5- to 7-membered cycloalkyleneiminomethyl group.
R2 denotes a fluorine, chlorine or bromine atom or a cyano group, R3 denotes a phenyl or naphthyl group or a phenyl or naphthyl group mono- or distributed by a fluorine, chlorine, bromine or iodine atom, by a trifluoromethyl, C1-3-alkyl or C1-3-alkoxy group, while in the case of disubstitution the substituents may be identical or different and the abovementioned unsubstituted as well as the mono- and disubstituted phenyl and naphthyl groups may additionally be substituted by a C1-3-alkyl-carbonyl-amino, C1-4-alkyloxy-carbonylamino, benzyloxy or hydroxy group, by a hydroxy-C1-3-alkyl, carboxy-C1-3-alkyl, C1-4-alkoxy-C1-3-alkyl, cyano-C1-3-alkyl, benzylamino-C1-3-alkyl, dibenzylamino-C1-3-alkyl, N-benzyl-N-(C1-3-alkyl)-amino-C1-3-alkyl, C1-4-alkoxy-C1-3-alkyl-carbonylamino-C1-3-alkyl, C3-7-cycloalkyl-carbonylamino-C1-3-alkyl, C3-7-cycloalkyl-C1-3-alkyl-carbonylamino-C1-3-alkyl, benzylcarbonylamino-C1-3-alkyl, phenylcarbonylamino-C1-3-alkyl, heteroaryl-carbonylamino-C1-3-alkyl, phenylamino-C1-3-alkyl, diphenylamino-C1-3-alkyl, N-phenyl-N-(C1-3-alkyl)-amino-C1-3-alkyl, heteroarylamino-C1-3-alkyl, N-heteroaryl-N-(C1-3-alkyl)-amino-C1-3-alkyl, C1-4-alkyl-sulphonylamino-C1-3-alkyl, phenyl-sulphonylamino-C1-3-alkyl, benzyl-sulphonylamino-C1-3-alkyl, C1-4-alkoxy-carbonyl-C1-3-alkyl, N-(C1-4-alkoxy-carbonyl)-amino-C1-3-alkyl, aminocarbonyl-C1-3-alkyl, (C1-3-alkylamino)-carbonyl-C1-3-alkyl, di-(C1-3-alkyl)-aminocarbonyl-C1-3-alkyl, 4-(C1-3-alkyl)-piperazin-1-yl-carbonyl-(C1-3-alkyl) or tetrazolyl-C1-3-alkyl group, by an aminocarbonyl-C2-3-alkenyl or C1-4-alkoxy-carbonyl-C2-3-alkenyl group or by a 5- to 7-membered cycloalkyleneimino groups, wherein one or two methylene groups adjacent to the nitrogen atom may be replaced by a carbonyl group or a -CH2-CH2- group linked to the imino group may be replaced by the group -O-CO-, while the carbonyl group of the -O-CO- group is linked to the imino group, while the substituents may be identical or different, R4 denotes a benzopyrazolyl or 1-(C1-3-alkyl)-piperidin-4-yl group, a cyclohexyl group which is substituted by a N-[di-(C1-3-alkyl)-amino-C1-3-alkyl-carbonyl]-amino or N-[di-(C1-3-alkyl)-amino-C1-3-alkyl-carbonyl]-N-(C1-3-alkyl)-amino group, or a phenyl, pyridinyl or naphthyl group or a pyrrolyl group optionally substituted at the nitrogen by a C1-3-alkyl group, each of which may be substituted by a fluorine, chlorine, bromine or iodine atom, by a C1-3-alkyl, C1-3-alkoxy, cyano, nitro, carboxy or trifluoromethyl group, by a .omega.-[di-(C1-3-alkyl)-amino]-C2-3-alkoxy, C1-3-alkyl-sulphonyl, di-(C1-alkyl)-amino-C1-3-alkyl-sulphonyl, 4-(C1-3-alkyl)-piperazino, imidazolyl, C1-3-alkylimidazolyl or [di-(C1-3-alkyl)-amino]-C1-3-alkyl-imidazolyl group, by a C1-3-alkyl group which is terminally substituted by a carboxy, C1-3-alkoxy-carbonyl, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, N-(C1-3-alkyl)-N-(.omega.-amino-C2-3-alkyl)-amino, N-benzyl-N-(C1-3-alkyl)-amino, N-[.omega.-(di-(C1-3-alkyl)-amino)-C2-3-alkyl]-N-(C1-3-alkyl)-amino, N-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-N-(C1-3-alkyl)-amino-carbonyl, N-(.omega.-hydroxy-C2-3-alkyl)-N-(C1-3-alkyl)-amino, di-(.omega.-hydroxy-C2-3-alkyl)-amino, N-(.omega.-C1-3-alkoxy-C2-3-alkoxy-C1-3-alkyl)-N-(C1-3-alkyl)-amino, N-(C1-4-alkoxy-carbonyl)-amino, N-(C1-4-alkoxy-carbonyl)-N-(C1-3-alkyl)-amino, N-{.omega.-[N-(C1-4-alkoxy-carbonyl)-amino]-(C1-3-alkyl)}-N-(C1-3-alkyl)-amino, pyridinyl, triazolyl, pyrrolidino, piperidino, di-(C1-3-alkyl)-piperidino, [di-(C1-3-alkyl)-amino]-piperidino, piperazino, morpholino, (C1-3-alkyl)-piperazino, 4-(C1-3-alkyl)-piperazino-carbonyl or 4-(C1-4-alkoxy-carbonyl)-piperazino group, by a carbonyl group which is substituted by a C1-3-alkoxy, N-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-amino, N-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-N-(C1-3-alkyl)-amino, N-(C3-7-cycloalkyl-N-(C1-3-alkyl)-amino, piperidino, piperazino, 4-(C1-4-alkyloxy-carbonyl)-piperazino or (C1-3-alkyl)-piperazino group, or by a group of formula wherein R7 denotes a hydrogen atom, a C1-3-alkyl, C1-3-alkyl-carbonyl, benzylcarbonyl, pyridinylcarbonyl, furanylcarbonyl, pyrrolidino-C1-3-alkyl-carbonyl, C1-3-alkoxy-C1-3-alkyl-carbonyl, di-(C1-3-alkyl)-amino-carbonyl-C1-3-alkyl, C1-4-alkylsulphonyl or benzylsulphonyl group or a phenylcarbonyl group optionally substituted in the phenyl moiety by one or two methoxy groups and R8 denotes a C1-3-alkyl, .omega.-[di-(C1-3-alkyl)-amino]-C2-3-alkyl, di-(C1-3-alkyl)-amino-carbonyl-C1 3-alkyl, di-(C1-3-alkyl)-amino-C1-3-alkyl-amino-carbonyl or .omega.-[N-benzyl-N-(C1-3-alkyl)-amino]-C2-3-alkyl group or a 4-(C1-3-alkyl)-piperazin-1-yl-carbonyl, 4-(C1-3-alkyl)-piperazin-1-yl-aminocarbonyl, 1-(C1-3-alkyl)-piperidin-4-yl-aminocarbonyl, 1-(C1-3-alkyl)-piperidin-4-yl-oxy-carbonyl or (pyridinyl-C1-3-alkyl)-aminocarbonyl group or a C1-3-alkyl-carbonyl group terminally substituted by a hydroxy, amino, di-(C1-3-alkyl)-amino, d -(.omega.-hydroxy-C2-3-alkyl)-amino, C1-3-alkyl-carbonyl-amino, N-benzyl-N-(C1-3-alkyl)-amino, N-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-.LAMBDA.-(C1-3-alkyl)-amino, imidazolyl, piperazino, 4-(C1-3-alkyl)-piperazin-1-yl, 4-benzyl-piperazin-1-yl, 4-(C1-4-alkoxy-carbonyl)-piperazin-1-yl, 4-(C1-3-alkyl)-homopiperazin-1-yl, morpholino, pyrrolidino, piperidino-, 1-(C1-3-alkyl)-piperidin-4-yl, 4-(C1-3-alkyl)-piperidin-1-yl or phthalimido group, R5 denotes a hydrogen atom or a C1-3-alkyl group and R6 denotes a hydrogen atom or a nitro group, while the unsubstituted, mono- or disubstituted phenyl groups contained in the above definitions may additionally be substituted by a cyano or a methoxy group or by two methyl groups, and the abovementioned alkyl groups include straight-chain and branched alkyl groups, wherein additionally one to 3 hydrogen atoms may be replaced by fluorine atoms, while, unless otherwise stated, the expression a heteroaryl group refers to a monocyclic 5- or 6-membered heteroaryl group optionally substituted in the carbon skeleton by a C1-3-alkyl group, wherein the 6-membered heteroaryl group contains one, two or three nitrogen atoms and the 5-membered heteroaryl group contains an imino group optionally substituted by a C1-3-alkyl or phenyl-C1-3-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C1-3-alkyl, amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl, di-(C1-3-alkyl)-amino-C1-3-alkyl or phenyl-C1-3-alkyl group or an oxygen or sulphur atom and additionally a nitrogen atom or an imino group optionally substituted by a C1-3-alkyl or phenyl-C1-3-alkyl group and two nitrogen atoms, and moreover a phenyl ring may be fused to the abovementioned monocyclic heterocyclic groups via two adjacent carbon atoms and the bonding takes place via a nitrogen atom or via a carbon atom of the heterocyclic moiety or a fused-on phenyl ring, and additionally any carboxy, amino or imino group present may be substituted by a group which can be cleaved in vivo, the tautomers, enantiomers, diastereomers mixtures thereof and the salts thereof.
7. ~Compounds of general formula I according to claim 1, wherein X denotes an oxygen atom, R1 denotes a hydrogen atom, R2 denotes a fluorine, chlorine or bromine atom or a cyano group, R3 denotes a phenyl group or a phenyl group monosubstituted by a fluorine, chlorine, bromine or iodine atom or by a C1-3alkoxy group, while the abovementioned unsubstituted and monosubstituted phenyl groups may additionally be substituted in the 3 or 4-position by a fluorine, chlorine or bromine atom, by a C1-3-alkoxy or C1-2-alkyl-carbonyl-amino group, by a carboxy-C1-3-alkyl, C1-4-alkoxy-carbonyl-C1-3-alkyl, aminocarbonyl-C1-3-alkyl, (C1-2-alkylamino)-carbonyl-C1-3-alkyl, di-(C1-2-alkyl)-amino-carbonyl-C1-3-alkyl, (C1-2-alkyl-carbonyl)-amino-C1-3-alkyl or (phenyl-carbonyl)-amino-C1-3-alkyl group, while the substituents may be identical or different, R4 denotes a phenyl group which is substituted by a C1-3-alkyl group terminally substituted by a di-(C1-2-alkyl)-amino group or by a group of formula wherein R7 denotes a C1-2-alkyl, C1-2-alkyl-carbonyl, di-(C1-2-alkyl)-amino-carbonyl-C1-3-alkyl or C1-3-alkylsulphonyl group and R8 denotes a C1-3-alkyl or .omega.-[di-(C1-2-alkyl)-amino]-C2-3-alkyl group or a C1-3-alkyl-carbonyl group terminally substituted by a di-(C1-2-alkyl)-amino, piperazino or 4-(C1-3-alkyl)-piperazin-1-yl group, R5 denotes a hydrogen atom and R6 denotes a hydrogen atom, while the abovementioned alkyl groups include straight-chain and branched alkyl groups, wherein additionally one to 3 hydrogen atoms may be replaced by fluorine atoms, while additionally any carboxy, amino or imino group present may be substituted by a group which can be cleaved in vivo, the tautomers, enantiomers, diastereomers mixtures thereof and the salts thereof.
8. Compounds of general formula I according to claim 1, wherein X, R1, R2, R3, R5 and R6 are defined as in claim 7 and R4 denotes a phenyl group which is substituted by a group of formula wherein R7 denotes a C1-2-alkyl, C1-2-alkyl-carbonyl, di-(C1-2-alkyl)-amino-carbonyl-C1-3-alkyl or C1-3-alkylsulphonyl group and R8 denotes a C1-3-alkyl or .omega.-[d -(C1-2-alkyl)-amino]-C2-3-alkyl group or a C1-3-alkyl-carbonyl group terminally substituted by a di-(C1-2-alkyl)-amino, piperazino or 4-(C1-3-alkyl)-piperazin-1-yl group, the abovementioned alkyl groups including straight-chain and branched alkyl groups, wherein additionally one to 3 hydrogen atoms may be replaced by fluorine atoms, while additionally any carboxy, amino or imino group present may be substituted by a group which can be cleaved in vivo, the tautomers, enantiomers, diastereomers, mixtures thereof and the salts thereof.
9. ~Compounds of general formula I according to claim 1, wherein X, R1, R2, R4, R5 and R6 are defined as in claim 7 and R3 denotes a phenyl group or a phenyl group monosubstituted by a fluorine, chlorine or bromine atom or by a C1-3-alkoxy group, while the abovementioned unsubstituted and monosubstituted phenyl groups are additionally substituted in the 3- or 4-position by a fluorine, chlorine or bromine atom, by a C1-3-alkoxy or C1-2-alkyl-carbonyl-amino group or by a carboxy-C1-3-alkyl, C1-3-alkoxy-carbonyl-C1-3-alkyl, aminocarbonyl-C1-3-alkyl, (C1-2-alkylamino)-carbonyl C1-3-alkyl, di-(C1-2-alkyl)-amino-carbonyl-C1-3-alkyl, (C1-2-alkyl-carboy yl)-amino-C1-3-alkyl or (phenyl-carbonyl)-amino-C1-3-alkyl group, while the substituents may be identical or different, the abovementioned alkyl groups including straight-chain and branched alkyl groups, wherein additionally one to 3 hydrogen atoms may be replaced by fluorine atoms, while additionally any carboxy, amino or imino group present may be substituted by a group which can be cleaved in vivo, the tautomers, enantiomers, diastereomers, mixtures thereof and the salts thereof.
10. Compounds of general formula I according to claim 1, wherein X denotes an oxygen atom, R1 denotes a hydrogen atom, R2 denotes a bromine atom, R3 denotes a phenyl group, R4 denotes a 1-(C1-3-alkyl)-piperidin-4-yl group or a phenyl group which is substituted in the 4-position by a C1-3-alkyl group terminally substituted by a C1-3-alkylamino, di-(C1-3-alkyl)-amino, N-[.omega.-(di-(C1-3-alky)-amino)-C2-3-alkyl]-N-(C1-3-alkyl)-amino or N-(C1-4-alkyloxy-carbonyl)-N-(C1-3-alkyl)-amino group,~

by a 1-(C1-3-alkyl)-imidazol-2-yl or 4-(C1-3-alkyl)-piperazin-1-yl-carbonyl group or by a group of formula wherein R7 denotes a C1-3-alkyl, C1-3-alkyl-carbonyl, C1-3-alkyl-sulphonyl or benzylsulphonyl group and R8 denotes a .omega.-[di-(C1-3-alkyl)-amino]-C2-3-alkyl, .omega.-[di-(C1-3-alkyl)-amino]-C1-4-alkyl-carbonyl, .omega.-[4-(C1-3-alkyl)-piperazin-1-yl]-C1-3-alkyl-carbonyl or .omega.-N-[di-(C1-3-alkyl)-amino-C2-3-alkyl]-N-(C1-3-alkyl)-amino}-C1-3-alkyl-carbonyl group, R5 denotes a hydrogen atom and R6 denotes a hydrogen atom, the abovementioned alkyl groups including straight-chain and branched alkyl groups, wherein additionally one to 3 hydrogen atoms may be replaced by fluorine atoms, the tautomers, enantiomers, diastereomers mixtures thereof and the salts thereof.
11. Compounds of general formula I according to claim 1, wherein X denotes an oxygen atom, R1 denotes a hydrogen atom, R2 denotes a fluorine atom, R3 denotes a phenyl group which is optionally substituted in the 3- or 4-position by a fluorine or iodine atom or by a cyano-C1-3-alkyl, amino-C1-3-alkyl, C1-3-alkylamino-C1-3-alkyl, C1-5-alkyl-carbonylamino-C1-3-alkyl, C1-4-alkyloxy-carbonyl-amino-C1-3-alkyl, C1-4-alkyloxy-C1-3-alkyl-carbonyl-amino-C1-3-alkyl, C3-7-cycloalkyl-carbonyl-amino-C1-3-alkyl, C3-7-cycloalkyl-C1-3-alkyl-carbonyl-amino-C1-3-alkyl, N-(phenyl-carbonyl)-amino-C1-3-alkyl, N-(benzyl-carbonyl)-amino-C1-3-alkyl, heteroaryl-carbonyl-amino-C1-3-alkyl, N-(C1-3-alkylsulphonyl)-amino-C1-3-alkyl, N-(phenylsulphonyl)-amine-C1-3-alkyl, N-(benzylsulphonyl)-amino-C1-3-alkyl, carboxy-C1-3-alkyl, C1-4-alkoxy-carbonyl-C1-3-alkyl, aminocarbonyl-C1-3-alkyl, C1-3-alkylaminocarbonyl-C1-3-alkyl, di-(C1-3-alkyl)-aminocarbonyl-C1-3-alkyl, 4-(C1-3-alkyl)-piperazin-1-yl-carbonyl-C1-3-alkyl, 2-(aminocarbonyl)-C2-3-alkenyl or 2-(C1-3-alkyloxy-carbonyl)-C2-3-alkenyl group, or a phenyl group trisubstituted in the 3-, 4- and 5-position by fluorine atoms, R4 denotes a phenyl group which may be substituted in the 4-position by a C1-3-alkyl group terminally substituted by a pyrrolidin-1-yl, piperidin-1-yl, 4-(C1-3-alkyl)-piperazin-1-yl, C1-3-alkylamino, di-(C1-3-alkyl)-amino, N-[di-(C1-3-alkyl)-amino-C2-3-alkyl]-N-(C1-3-alkyl)-amino or N-(C1-4alkyloxy-carbonyl)-N-(C1-3-alkyl)-amino group, by a C1-3-alkyl-sulphonyl, 1-(C1-3-alkyl)-imidazol-2-yl or 4-(C1-3-alkyl)-piperazin-1-yl-carbonyl group or by a group of formula wherein R7 denotes a C1-3-alkyl, C1-3-alkyl-carbonyl, C1-3-alkyl-sulphonyl or benzylsulphonyl group and~

R8 denotes a C1-3-alkyl, .omega.-[di-(C1-3-alkyl)-amino]-C2-3-alkyl, .omega.-[di-(C1-3-alkyl)-amino]-C1-3-alkyl-carbonyl, di-(C1-3-alkyl)-amino-carbonyl-C1-3-alkyl, .omega.-[4-(C1-3-alkyl)-piperazin-1-yl]-C1-3-alkyl-carbonyl or .omega.-{N-[di-(C1-3-alkyl)-amino-C2-3-alkyl]-N-(C1-3-alkyl)-amino}-C1-3-alkyl-carbonyl group, R5 denotes a hydrogen atom and R6 denotes a hydrogen atom, while the term heteroaryl group denotes a pyridinyl, furyl or thienyl group, and unsubstituted or monosubstituted phenyl groups contained in the abovementioned definitions may additionally be substituted by a methoxy group and the abovementioned alkyl groups include straight-chain and branched alkyl groups, wherein additionally one to 3 hydrogen atoms may be replaced by fluorine atoms, while additionally any carboxy, amino or imino group present may be substituted by a group which can be cleaved in vivo, the tautomers, enantiomers, diastereomers, mixtures thereof and the salts thereof.
12. Compounds of general formula I according to claim 1, wherein X denotes an oxygen atom, R1 denotes a hydrogen atom, R2 denotes a cyano group, R3 denotes a phenyl group optionally substituted by one or two methoxy groups, R4 denotes a phenyl group which is substituted in the 3- or 4-position by a bromine atom, by a C1-3-alkyl group terminally substituted by a pyrrolidin-1-yl, piperidin-1-yl, 4-(C1-3-alkyl)-piperazin 1-yl-carbonyl, C1-3-alkylamino, di-(C1-3-alkyl)-amino, N-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-N-(C1-3-alkyl)-aminocarbonyl or N-(C1-4-alkyloxy-carbonyl)-N-(C1-3-alkyl)-amino group, by a .omega.-di-(C1-3-alkyl)-amino-C2-3-alkoxy, N-(di-(C1-3-alkyl)-amino-C2-3-alkyl)-amino-carbonyl, N-[di-(C1-3-alkyl)-amino-C2-3-alkyl]-N-(C1-3-alkyl)-amino-carbonyl or 4-(C1-3-alkyl)-piperazin-1-yl-carbonyl group or by a group of formula wherein R7 denotes a hydrogen atom car a C1-3-alkyl, C1-3-alkyl-carbonyl or C1-3-alkylsulphonyl group and R8 denotes a .omega.-[di-(C1-3-alkyl) amino]-(C2-3-alkyl), .omega.-[di-(C1-3-alkyl)-amino]-C1-3-alkyl-carbonyl, .omega.-(piperazin-1-yl)-C1-3-alkyl-carbonyl, .omega.-[4-(C1-3-alkyl)-piperazin-1-yl]-C1-3-alkyl-carbonyl, .omega.
[4-(C1-4-alkyloxy-carbonyl)-piperazin-1-yl]-C1-3-alkyl-carbonyl, .omega.-[4-(C1-3-alkyl)-homopiperazin-1-yl]-C1-3-alkyl-carbonyl, .omega.-morpholino-C1-3-alkyl-carbonyl or .omega.-{N-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-N-(C1-3-alkyl)-amino}-C1-3-alkyl-carbonyl group, R5 denotes a hydrogen atom and R6 denotes a hydrogen atom, the abovementioned alkyl groups including straight-chain and branched alkyl groups, wherein additionally one to 3 hydrogen atoms may be replaced by fluorine atoms, while additionally any carboxy, amino or imino group present may be substituted by a group which can be cleaved in vivo, their stereoisomers and their salts.
13. Compounds of general formula I according to claim 1, wherein X denotes an oxygen or sulphur atom, R1 denotes a hydrogen atom, R2 denotes a chlorine atom, R3 denotes a phenyl group which is optionally monosubstituted in the 3- or 4-position by a chlorine or iodine atom, by a cyano, hydroxy, benzyloxy, amino or nitro group or by an aminomethyl, acetylamino, phenylcarbonylamino-C1-3-alkyl, C1-3-alkylsulphonylamino-C1-3-alkyl, phenylsulphonylamino-C1-3-alkyl, acetylaminomethyl, imidazol-1-yl-methyl, 2-oxo-pyrrolidin-1-yl, 2-carboxy-ethyl, 2-methoxycarbonyl-ethyl, 2-aminocarbonyl-ethyl, 2-(methylaminocarbonyl)-ethyl or 2-methoxycarbonyl-ethenyl group, or a 3-hydroxy-4-nitro-phenyl, 4-amino-3-nitrophenyl or 3,4-dimethoxyphenyl group, R4 denotes a 5-(4-methyl-piperazin-1-yl-carbonyl)-pyridin-2-yl, 2-[N-acetyl-N-(.omega.-dimethylamino-C23-alkyl)-amino]-pyridine-5-yl, benzo-pyrazol-6-yl, 1-methyl-2-(4-methyl-piperazin-1-yl-carbonyl)-pyrrol-4-yl, 2-(N-dimethylamino-ethyl-N-methyl-aminocarbonyl)-pyrrol-4-yl, -methyl-2-(N dimethylamino-ethyl-N-methyl-aminocarbonyl)-pyrrol-4-yl, 4-(N-dimethylamino-methylcarbonylamino)-cyclohexyl or 4-[(N-dimethylamino-methylcarbonyl)-N-methyl-amino]cyclohexyl group or a phenyl group which is substituted in the 3-position by a carboxy, carboxy-C1-3-alkyl, C1-4alkoxy-carbonyl, C1-4-alkoxy-carbonyl-C1-3-alkyl, dimethylamino-C1-3-alkyl or pyridin-4-yl-C1-3-alkyl group or is substituted in the 4-position by a carboxy, .omega.-[di-(C1-3-alkyl)-amino]-C2-3-alkoxy, ethoxycarbonyl, piperidin-1-yl-carbonyl, 4 -(C1-4-alkyloxy-carbonyl)-piperazin-1-yl-carbonyl, N-(C3-7-cycloalkyl)-N-(C1-3-alkyl)-amino-carbonyl or N-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-N-(C1-3-alkyl)-aminocarbonyl group, by a [di-(C1-3-alkyl)-amino]-C1-3-alkylsulphonyl group, by a C1-3-alkyl group terminally substituted by a carboxy, C1-4-alkyloxy-carbonyl, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, N-benzyl-N-(C1-3-alkyl)-amino, N-(2-hydroxyethyl)-N-(C1-3-alkyl)-amino, Di-(2-hydroxy-ethyl)-amino, triazolyl, N-(methoxyethoxyethyl)-N-(C1-3-alkyl)-amino, N-(amino-C1-3-alkyl)-N-(C1-3-alkyl)-amino, N-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-N-(C1-3-alkyl)-amino, N-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-N-(C1-3-alkyl)-amino-carbonyl, N-(C1-4-alkyloxy-carbonyl-amino-C1-3-alkyl)-N-(C1-3-alkyl)-amino, N-(C1-4-alkyloxy-carbonyl)-amino or N-(C1-4-alkyloxy-carbonyl)-N-(C1-3-alkyl)-amino group, by a 1-methyl-imidazol-2-yl, 5-methyl-1H-imidazol-4-yl, 1-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-imidazol-2-yl, 4-methyl-piperazin-1-yl, piperazinylcarbonyl or 4-methyl-piperazin-1-yl-carbonyl group or by a group of formula wherein R7 denotes a hydrogen atom or a C1-3-alkyl, C1-3-alkyl-carbonyl, di-(C1-3-alkyl)-amino-carbonyl-C1-3-alkyl, benzylcarbonyl, pyridinylcarbonyl, furanylcarbonyl, methoxymethylcarbonyl, C1-4-alkylsulphonyl or benzylsulphonyl group or a phenylcarbonyl group optionally substituted in the phenyl moiety by one or two methoxy groups and R8 denotes a C1-3-alkyl, .omega.-[di-C1-3-alkyl)-amino]-C2-3-alkyl, .omega.-[N-benzyl-N-(C1-3-alkyl)-amino]-C2-3-alkyl, N-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-amino-carbonyl, (pyridinyl-C1-3-alkyl)-amino-carbonyl, 1-(C1-3-alkyl)-piperidin-4-yl-amino-carbonyl-,1-(C1-3-alkyl)-piperidin-4-yl-oxy-carbonyl, 4-(C1-3-alkyl)-piperazin-1-yl-amino-carbonyl, 4-(C1-3-alkyl)-piperazin-1-yl-carbonyl or di-(C1-3-alkyl)-aminocarbonyl-C1-3-alkyl group or a C1-4-alkyl-carbonyl group terminally substituted by a hydroxy, amino, di-(C1-3-alkyl)-amino, N-benzyl-N-(C1-3-alkyl)-amino, di-(2-hydroxyethyl)-amino, acetylamino, N-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-N-(C1-3-alkyl)-amino, imidazol-1-yl, piperazin-1-yl, 4-(C1-3-alkyl)-piperazin-1-yl, 4-benzyl-piperazin-1-yl, 4-(C1-4-alkyloxy-carbonyl)-piperazin-1-yl, 4-(C1-3-alkyl)-homopiperazin-1-yl, morpholin-4-yl, pyrrolidin-1-yl, piperidin-1-yl, 1-(C1-3-alkyl)-piperidin-4-yl or phthalimido group, R5 denotes a hydrogen atom and R6 denotes a hydrogen atom or a nitro group, while the unsubstituted or monosubstituted phenyl groups mentioned in the above definitions may additionally be substituted by a methoxy or a cyano group or by two methyl groups, the abovementioned alkyl groups including straight-chain and branched alkyl groups, wherein additionally one to 3 hydrogen atoms may be replaced by fluorine atoms, while additionally any carboxy, amino or imino group present may be substituted by a group which can be cleaved in vivo, the tautomers, enantiomers, diastereomers mixtures thereof and the salts thereof.
14. The following compounds of general formula I:

(a) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone, (b) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone, (c) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone, (d) 3-Z-[1-(4-(N-(4-ethyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone, (e) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-(3,4-dimethoxy-phenyl)-methylene]-6-chloro-2-indolinone, (f) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-(3,4-dimethoxy-phenyl)-methylene]-6-chloro-2-indolinone, (g) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-bromo-2-indolinone, (h) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-bromo-2-indolinone, (i) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-cyano-2-indolinone, (j) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-cyano-2-indolinone, (k) 3-Z-[1-(4-(N-(4-ethyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-cyano-2-indolinone, (l) 3-Z-[1-(4-(N-(dimethylamino-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone, (m) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone, (n) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-fluoro-2-indolinone, (o) 3-Z-[1-(4-(dimethylaminomethyl)-anilino]-1-(3-fluoro-phenyl)-methylene]-6-fluoro-2-indolinone, (p) 3-Z-[1-(4-(N-(3-dimethylamino-propyl)-N-acetyl-amino)-anilino)-1-(3-fluoro-phenyl)-methylene]-6-fluoro-2-indolinone, (q) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-(3-fluoro-phenyl)-methylene]-6-fluoro-2-indolinone, (r) 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(4-(2-carbamoyl-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone, (s) 3-Z-[1-(4-(N-(piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-chloro-2-indolinone, (t) 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinone, (u) 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone, (v) 3-Z-[1-(4-dimethylaminomethyl-anilino)-~-(3-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone, (w) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-(4-carboxymethyl-phenyl)-methylene]-6-fluoro-2-indolinone, (x) 3-Z-[1-(4-dimethylaminomethyl-anilino)-~-(4-(2-methylcarbamoyl-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone, (y) 3-Z-[1-(4-dimethylaminomethyl-anilino)-~-(3-(2-carbamoyl-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone, (z) 3-Z-[1-(4-dimethylaminomethyl-anilino)-~-(3-(2-dimethylcarbamoyl-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone, (aa) 3-Z-[1-(4-(N-(2-dimethylamino-ethyl)-N-methylsulphonyl-amino)-anilino)-1-(4-dimethylcarbamoylmethyl-phenyl)-methylene]-6-fluoro-2-indolinone, (ab) 3-Z-[1-(4-(N-methyl-N-acetyl-amino)-anilino)-~-(4-(2-methylcarbamoyl-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone, (ac) 3-Z-[1-(4-(N-(4-methyl-piperazin-1-yl-methylcarbonyl)-N-methyl-amino)-anilino)-1-(4-acetylamino-phenyl)-methylene]-6-chloro-2-indolinone, (ad) 3-Z-[1-(4-dimethylaminomethyl-anilino]-1-(4-acetylaminomethyl-phenyl)-methylene]-6-chloro-2-indoiinone, (ae) 3-Z-[1-(4-dimethylaminomethyl-anilino]-1-(3-acetylaminomethyl-phenyl)-methylene]-6-fluoro-2-indolinone, (af) 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(3-benzoylaminomethyl-phenyl)-methylene]-6-fluoro-2-indolinone and (ag) 3-Z-[1-(4-dimethylaminomethyl-anilino)-1-(3-(2-acetylamino-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (ah) 3-Z-[1-(4-(N-(2-dimethylamino-ethylcarbonyl)-N-methyl-amino)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone, (ai) 3-Z-[1-(4-(pyrrolidin-1-yl-methyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone and (aj) 3-Z-(1-(4-dimethylaminomethyl-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinone (ak) 3-Z-[1-(4-diethylaminomethyl-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-fluoro-2-indolinone (al) 3-Z-[1-(4-(2-dimethylamino-ethyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinone (am) 3-Z-[1-(4-{pyrrolidin-1-yl-methyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-chloro-2-indolinone (an) 3-Z-[1-(4-(pyrrolidin-1-yl-methyl)-aniline)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinone (ap) 3-Z-[1-(4-(dimethylaminomethyl)-anilino)-1-(4-(2-carboxy-ethyl)-phenyl)-methylene]-6-bromo-2-indolinone (ao) 3-Z-[1-(4-(diethylaminomethyl)-anilino)-1-(4-(2-carboxy-ethyl)-methylene]-6-bromo-2-indolinone while additionally any carboxy, amino or imino group present may be substituted by a group which can be cleaved in vivo, and the salts thereof.
15. Physiologically acceptable salts of the compounds according to claims 1 to 14.
16. Pharmaceutical compositions containing a compound of general formula I
according to at least one of claims 1 to 14, or a physiologically acceptable salt according to claim 15 optionally together with one or more inert carriers and/or diluents.
17. Use of a compound of general formula I according to at least one of claims 1 to 14, or a physiologically acceptable salt according to claim 15, for preparing a pharmaceutical composition which is suitable for treating excessive or anomalous cell proliferation.
18. Process for preparing a pharmaceutical composition according to claim 16, characterised in that a compound of general formula I according to at least one of claims 1 to 14, or a physiologically acceptable salt according to claim 15, is incorporated by a non-chemical method in one or more inert carriers and/or diluents.
19. Process for preparing the compounds a cording to claims 1 to 15, characterised in that a. a compound of general formula wherein the groups Z1 and R3 may optionally change positions, X, R2, R3 and R6 are defined as in claim 1, R1' has the meanings given for R~ hereinbe ore or denotes a protective group for the nitrogen atom of the lactam group, while R1 may also denote a bond to a solid phase, optionally formed via a spacer, and Z1 denotes a halogen atom, a hydroxy, alkoxy or aryl-alkoxy group, e.g. a chlorine or bromine atom, a methoxy, ethoxy or benzyloxy group, is reacted with an amine of general formula wherein R4 and R5 are as hereinbefore defined, and if necessary any protective group used for the nitrogen atom of the lactam group is subsequently cleaved or any protective group used is subsequently cleaved from a solid phase, b. in order to prepare a compound of general formula I wherein R4 contains the group R8, where R8 denotes a C1-4-alkyl-carbonyl group terminally substituted by a hydroxy, C1-3-alkyoxyl group, amino, (C1-3-alkyl)-amino, di-(C1-3-alkyl)-amino, (.omega.-hydroxy-C2-3-alkyl)-amino, di-(.omega.-hydroxy-349~

C2-3-alkyl)-amino, (.omega.-alkoxy-C2-3-alkyl)-amino, di-(.omega.-alkoxy-C2-3-alkyl)-amino, C1-3-alkyl-carbonyl-amino, N-benzyl-N-C1-3-alkyl-amino, N-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-N-C1-3-alkyl-amino, 1-(C1-3-alkyl)-piperidin-4-yl- group or by a 5- to 7-membered cycloalkyleneimino group, while the cycloalkylene group may be substituted by a C1-3-alkyl group and/or one or two methylene groups linked to the imino group may be replaced by a carbonyl group and/or the methylene group in the 4 position of a 6- or 7-~
membered cycloalkylimino group may be replaced by an -NH, -N(C1-3-alkyl), -NI benzyl), -N(C1-4-alkoxy-carbonyl) or -O- and/or a phenyl ring may be fused on via two adjacent carbon atoms of the cycloalkyleneimino group:

a compound of general formula wherein R2, R3, R5, R6, R7 and X are defined as in claim 1, R1' has the meanings given for R1 hereinbefore or denotes a protective group for the nitrogen atom of the lactam group, while R1' may also denote a bond to a solid phase optionally formed via a spacer, n denotes the number 1, 2, 3 or 4 and Z2 denotes a leaving group, for example a halogen atom or an alkyl or arylsulphonyloxy group such as the chlorin, bromine or iodine atom or the methylsulphonyloxy, ethylsulphonyloxy, .rho.-toluenesulphonyloxy, or trifluoromethanesulphonyloxy group, is reacted with a hydroxide base such as sodium or potassium hydroxide or a compound of general formula H-R8' (VIII) wherein R8~ denotes a C1-3-alkyloxy, amino, (C1-3-alkyl)-amino, di-(C1-3-alkyl)-amino, (.omega.-hydroxy-C2-3-alkyl)-amino, di-(.omega.-hydroxy-C2-3-alkyl)-amino, (.omega.-alkoxy-C2-3-alcyl)-amino, di-(.omega.-alkoxy-C2-3-alkyl)-amino, C1-3-alkyl-carbonyl-amino, N-benzyl-N-C1-3-alkyl-amino, N-[di-(C1-3-alkyl)-amino-C1-3-alkyl]-N-C1-3-alkyl-amino or a 5- to 7-membered cycloalkylerieimino group, while the cycloalkylene group may be substituted by a C1-3-alkyl group and/or one or two methylene groups linked to the imino group may be replaced by a carbonyl group and/or the methylene group in the 4 position of a 6- or 7-membered cycloalkylim no group may be replaced by a -NH, -N(C1-3-alkyl), -N(benzyl), -N(C1-4-alkoxy-carbonyl) or -O- and/or a phenyl ring may be fused on via two adjacent carbon atoms of the cycloalkyleneimino group, and if necessary any protective group used for the nitrogen atom of the lactam group is subsequently cleaved or any protective group used is subsequently cleaved from a solid phase, c. in order to prepare a compound of general formula I wherein R3 denotes a phenyl or naphthyl group substituted by a carboxy-C2-3-alkenyl, amino-carbonyl-C2-3-alkenyl, (C1-3-alkylamino)-carbonyl-C2-3-alkenyl, di-(C1-3-alkyl-amino)-carbonyl-C2-3-alkenyl or C1-4-alkoxy-carbonyl-C2_3-alkenyl group, a compound of general formula wherein R2, R4, R5, R6 and X are defined as in claim 1, R1' has the meanings given for R1 hereinbeiore or denotes a protective group for the nitrogen atom of the lactam group, while R1' may also denote a bond to a solid phase optionally formed via a spacer, and Z3 denotes a leaving group, for example a halogen atom or an alkyl or arylsulphonyloxy group such as the chlorine, bromine or iodine atom or the methylsulphonyloxy, ethylsulphonyloxy, p-toluenesulphonyloxy or trifluoromethanesulphonyloxy group, is reacted with an alkene of general formula wherein R3' denotes an amino, (C1-3-alkylamino), di-(C1-3-alkylamino) or C1-4-alkoxy-group and n is the number 0 or 1, d. in order to prepare a compound of general formula I wherein R3 denotes a phenyl or naphthyl group substituted by a carboxy-C1-3-alkyl, C1-4-alkoxy-carbonyl-C1-3-alkyl, aminocarbonyl-C1-3-alkyl, (C1-3-alkylamino)-carbonyl-C1-3-alkyl, di-(C1-3-alkyl)-aminocarbonyl-C1-3-alkyl or 4-(C1-3-alkyl)-piperazin-1-yl-carbonyl-(C1-3-alkyl) group, a compound of general formula wherein R2, R4, R5, R6 and X are defined as in claim 1, R1' has the meanings given for R1 hereinbeiore or denotes a protective group for the nitrogen atom of the lactam group, while R1' may also denote a bond to a solid phase optionally formed via a spacer, A denotes a C2-3-alkenyl group and R3 denotes a hydroxy, C1-4-alkoxy, amino, (C1-3-alkylamino), di-(C1-3-alkyl)-amino or 4-(C1-3-alkyl)-piperazin-1-yl group, is hydrogenated and subsequently any protective group which may be used for the nitrogen atom of the lactam group is cleaved or is cleaved from a solid phase as described in process (a) described hereinbefore, and then an alkoxycarbonyl group is optionally converted by hydrolysis into a corresponding carboxy compound, or an amino or alkylamino group is converted by reductive alkylation into a corresponding alkylamino or dialkylamino compound, or a dialkylamino group is converted by alkylation into a corresponding trialkylammonium compound, or an amino or alkylamino group is converted by acylation or sulphonation into a corresponding acyl or sulphonyl compound, or a carboxy group is converted by esterification or amidation into a corresponding ester or aminocarbonyl compound, or a cycloalkyleneimino group wherein a methylene group is replaced by a sulphur atom is converted by oxidation into a corresponding sulphinyl or sulphonyl compound, or a nitro group is converted by reduction into a corresponding amino compound, or a cyano group is converted by reduction into a corresponding aminomethyl compound, or an arylalkyloxy group is converted using acid into a corresponding hydroxy compound, or an alkoxycarbonyl group is converted by saponification into a corresponding carboxy compound, or a phenyl group substituted by an amino, alkylamino, aminoalkyl or N-alkyl-amino group is converted by reaction with a corresponding cyanate, iso-cyanate or carbamoylhalide into a corresponding urea compound of general formula I, or a carbonyl group is converted by reaction with phosphorus pentasulphide into a corresponding thiocarbonyl compound, or a phenyl group substituted by an amino, alkylamino, aminoalkyl or N-alkyl-amino group is converted by reaction with a corresponding compound which transfers the amidino group or by reaction with a corresponding nitrite into a corresponding guanidino compound of general formula I.
CA002493721A 2002-07-23 2003-07-22 Indoline derivatives substituted in position 6, production and use thereof as medicaments Abandoned CA2493721A1 (en)

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