NZ538337A

NZ538337A - Indolinone derivatives substituted in position 6, production and use thereof as medicaments for treating abnormal cell proliferation

Info

Publication number: NZ538337A
Application number: NZ538337A
Authority: NZ
Inventors: Gerald Juergen Roth; Armin Heckel; Joerg Kley; Thorsten Lehmann-Lintz; Frank Hilberg; Ulrike Tontsch-Grunt; Meel Jacobus C A Van
Original assignee: Boehringer Ingelheim Pharma
Priority date: 2002-07-23
Filing date: 2003-07-22
Publication date: 2007-02-23

Abstract

Disclosed herein are indoline or indolinone derivatives substituted in position 6 of general formula (I), wherein R1 to R6 and X are as defined in the specification, the tautomers, enantiomers thereof, the mixtures and salts thereof, especially physiologically compatible salts which have valuable pharmaceutical properties, especially an inhibiting effect on various receptor tyrosine kinases and on the proliferation of endothelial cells and various tumor cells, medicaments containing these compounds, the use thereof and a method for the production thereof.

Description

New Zealand Paient Spedficaiion for Paient Number 538337 wo 2004/009547 1 pct/ep2003/007961 81674pct.211 538337 Indolinone derivatives substituted in position 6, production and use thereof as medicaments The present invention relates to indolinone derivatives, substituted in the 6-position, of the formula to their tautomers, enantiomers, diastereomers, their mixtures and their salts, in particular their physiologically acceptable salts, which have useful pharmacological properties, to medicaments comprising these compounds, to their use and to 15 processes for their preparation.

| The above compounds of the formula I have useful pharmacological properties, in particular an inhibiting effect on various kinases, especially on receptor tyrosine kinases, such as VEGFR1, VEGFR2, VEGFR3, PDGFRoc, PDGFR0, FGFR1, 20 FGFR3, EGFR, HER2, c-Kit, IGF1R and HGFR, Flt-3, and on the proliferation of cultivated human cells, in particular that of endothelial cells, for example in angiogenesis, but also on the proliferation of other cells, in particular tumour cells.

Accordingly, the present invention provides the above compounds of the formula I, which have useful pharmacological properties, medicaments comprising these pharmacologically active compounds, their use and processes for their preparation. 2 Moreover, the present invention provides the physiologically acceptable salts of the compounds according to the invention, medicaments comprising these compounds which in addition, if appropriate, contain one or more inert carrier materials and/or diluents, and their use for preparing a medicament suitable in particular for treating 5 excessive or anormal cell proliferations.

The present invention furthermore provides processes for preparing this medicament, characterized in particular in that the compounds according to the invention or their physiologically acceptable salts are incorporated into one or more inert carrier 10 materials and/or diluents.

In the above formula I, X is an oxygen atom, R1 is a hydrogen atom, R2 is a fluorine, chlorine or bromine atom or a cyano group, R3 is a phenyl group or a phenyl group which is monosubstituted by a fluorine, chlorine, bromine or iodine atom or by a Ci-3-alkoxy group, where the abovementioned unsubstituted and the monosubstituted phenyl groups may additionally be substituted in the 3- or 4-position by a fluorine, chlorine or bromine atom, by a cyano group, by a Ci-3-alkoxy or C-i-2-alkyl-carbonyl-amino group, by a cyano-Ci-3-alkyl, carboxy-C-i-3-alkyl, carboxy-C-M-alkoxy, carboxy-Ci-3-alkylamino, carboxy-Ci-3-alkyl-N-(Ci-3-alkyl)-amino, C-M-alkoxy-carbonyl-Ci-3-alkyl, Ci-4-alkoxy-carbonyl-Ci-3-alkoxy, Ci-4-alkoxy- carbonyl-Ci-3-alkylamino, CM-alkoxy-carbonyl-Ci.3-alkyl-N-(Ci-3-alkyl)-amino, amino-Ci-3-alkyl, aminocarbonyl-Ci-3-alkyl, (Ci-2-alkylamino)-carbonyl-Ci-3-alkyl, di-(Ci-2-alkyl)-aminocarbonyl-Ci.3-alkyl, (Ci.2-alkyl-carbonyl)-amino-Ci-3-alkyl, (Ci-4-alkoxy-carbonyl)-amino-Ci-3-alkyl, (C3. 6-alkyl-carbonyl)-amino-Ci-3-alkyl, (phenyl-carbonyl)-amino-Ci-3-alkyl, (C3-6-cycloalkyl-carbonyl)-amino-Ci-3-alkyl, (C3-6-cycloalkyl-Ci-3-alkyl-carbonyl)-amino-Ci-3-alkyl, (thiophen-2-yl-carbonyl)-amino-Ci-3-alkyl, (furan-2-yl-carbonyl)-amino-Ci-3-alkyl, (phenyl-Ci-3-alkyl-carbonyl)-amino-Ci-3-alkyl, (2-(Ci-4-alkoxy)-benzoyl-carbonyl)-amino-Ci-3-alkyl, (pyridin-2-yl-carbonyl)-amino-Ci.3-alkyl, (pyridin-3-yl-carbonyl)-amino-Ci-3-alkyl-, (pyridin-4-yl-carbonyl)-amino-Ci-3-alkyl- or C-i-3-alkyl-piperazin-1 -yl-carbonyl-Ci-3-alkyl group, by a carboxy-C2-3-alkenyl, aminocarbonyl-C2-3-alkenyl, (C-i-3-alkyl-amino)-carbonyl-C2-3-alkenyl, di-(Ci_3-alkyl)-amino-carbonyl-C2-3-alkenyl or Ci-4-alkoxy-carbonyl-C2-3-alkenyl group, where the substituents may be identical or different, R4 is a phenyl group or a phenyl group which is monosubstituted by a Ci-3-alkyl group which is terminally substituted by an amino, guanidino, mono- or di-(Ci-2-alkyl)-amino-, N-[o-di-(Ci-3-alkyl)-amino-C2-3-alkyl]-N-(Ci-3-alkyl)-amino, N-methyl-(C3-4-alkyl)-amino, N-(Ci-3-alkyl)-N-benzylamino, N-(Ci^-alkoxycarbonyl)-amino, N-(Cm-alkoxycarbonyl)-Ci-4-alkylamino, 4-(Ci-3-alkyl)-piperazin-1 -yl, imidazol-1-yl, pyrrolidin-1 -yl, azetidin-1-yl, morpholin-4-yl, piperazin-1-yl, thiomorpholin-4-yl group, by a di-(Ci-3-alkyl)-amino-(Ci-3-alkyl)-sulphonyl, 2-[di-(Ci-3-alkyl)-amino]-ethoxy, 4-(Ci.3-alkyl)-piperazin-1 -yl-carbonyl, {co-[di-(Ci-3-alkyl)-amino]-(C2-3-alkyl)}-N-(Ci.3-alkyl)-amino-carbonyl, 1-(Ci-3-alkyl)imidazol-2-yl, (Ci-3-alkyl)-sulphonyl group, or by a group of the formula W -N V7 in which R7 is a Ci-2-alkyl, Ci-2-alkyl-carbonyl, di-(Ci-2-alkyl)-amino-carbonyl-Ci.3-alkyl or Ci-3-alkylsulphonyl group and R8 is Ci-3-alkyl, Q-[di-(Ci-2-alkyl)-amino]-C2-3-alkyl, ©-[mono-(Ci-2-alkyl)-amino]-C2-3-alkyl group, or a (Ci-3-alkyl)-carbonyl, (C4-6-alkyl)-carbonyl or carbonyl-(Ci-3-alkyl) group which is terminally substituted by a di-(Ci-2-alkyl)-amino, piperazin-1-yl or 4-(C-i-3-alkyl)-piperazin-1-yl group, where all dialkylamino groups present in the radical R4 may also be present in quaternized form, for example as an N-methyl-(N,N-dialkyl)-ammonium group, where the counterion is preferably selected from the group consisting of iodide, chloride, bromide, methylsulphonate, para-toluenesulphonate and trifluoroacetate, R5 is a hydrogen atom and R6 is a hydrogen atom, where the abovementioned alkyl groups include linear and branched alkyl groups in which additionally one to 3 hydrogen atoms may be replaced by fluorine atoms, where additionally a carboxyl, amino or imino group present may be substituted by an in vivo cleavable radical or may be present in the form of a prodrug radical, for example in the form of a group which can be converted in vivo into a carboxyl group or in the form of a group which can be converted in vivo into an imino or amino group, their tautomers, enantiomers, diastereomers, their mixtures and their salts.

Particularly preferred compounds of the above formula I are those compounds in which X, R1, R5 and R6 are as defined under I. and: II.i. R2 and R4 are as defined under I. and R3 is a phenyl group or a phenyl group which is monosubstituted by a fluorine, chlorine, bromine or iodine atom or by a Ci-3-alkoxy group, where the abovementioned unsubstituted and the monosubstituted phenyl groups may additionally be substituted in the 3- or 4-position by a fluorine, chlorine or bromine atom, by a cyano group, by a Ci-3-alkoxy or Ci-2-alkyl-carbonyl-amino group, by a cyano-Ci-3-alkyl, carboxy-Ci-3-alkyl, carboxy-Ci-4-alkoxy, carboxy-Ci-3-alkylamino, carboxy-Ci-3-alkyl-N-(Ci-3-alkyl)-amino, Ci-4-alkoxy-carbonyl-Ci-3-alkyl, Ci-4-alkoxy-carbonyl-Ci-3-alkoxy, C-M-alkoxy-carbonyl-Ci-3-alkylamino, C-i-4-alkoxy-carbonyl-Ci-3-alkyl-N-(C-i-3-alkyl)-amino, amino-C-i-3-alkyl, aminocarbonyl-Ci^-alkyl, (Ci-2-alkylamino)-carbonyl-Ci-3-alkyl, di-(Ci-2-alkyl)-aminocarbonyl-Ci-3-alkyl, (Ci-2-alkyl-carbonyl)-amino-Ci-3-alkyl, (Cm-alkoxy-carbonyl)-amino-Ci-3-alkyl, (C3-6-alkyl-carbonyl)-amino-Ci-3-alkyl, (phenyl-carbonyl)-amino-C-i-3-alkyl, 6 (C3-6-cycloalkyl-carbonyl)-amino-Ci-3-alkyl, (C3-6-cycloalkyl-Ci-3-alkyl-carbonyl)-amino-Ci-3-alkyl, (phenyl-carbonyl)-amino-Ci-3-alkyl, (thiophen-2-yl-carbonyl)-amino-Ci-3-alkyl, (furan-2-yl-carbonyl)-amino-Ci-3-alkyl, (phenyl-Ci-3-alkyl-carbonyl)-amino-Ci-3-alkyl, (2-(Ci-4-5 a I koxy)-benzoyl-carbonyl )-ami no-Ci .3-alkyl, (pyrid i n-2-yl -ca rbonyl )- amino-Ci-3-alkyl, (pyridin-3-yl-carbonyl)-amino-Ci-3-alkyl, (pyridin-4-yl-carbonyl)-amino-Ci-3-alkyl or Ci-3-alkyl-piperazin-1 -yl-carbonyl-Ci-3-alkyl group, by a carboxy-C2-3-alkenyl, aminocarbonyl-C2-3-alkenyl-, (Ci-3-alkyl- amino)-carbonyl-C2-3-alkenyl-, di-(Ci-3-alkyl)-amino-carbonyl-C2-3-alkenyl or Ci^-alkoxy-carbonyl-C2-3-alkenyl group, where the substituents may be identical or different; II.ii. R2 and R4 are as defined under I. and R3 is a phenyl group which is substituted by a Ci-2-alkyl-carbonyl-amino group, by a carboxy-Ci-3-alkyl, carboxy-C-M-alkoxy, C1.4-alkoxy-carbonyl-C1.3-alkyl, Ci-4-alkoxy-carbonyl-Ci-3-alkoxy, aminocarbonyl-Ci-3-alkyl, (C1-2-25 alkylamino)-carbonyl-Ci-3-alkyl, di-(Ci-2-alkyl)-aminocarbonyl-Ci.3-alkyl, (Ci-2-alkyl-carbonyl)-amino-Ci-3-alkyl, (Ci-4-alkoxy-carbonyl)-amino-Ci-3-alkyl, (phenyl-carbonyl)-amino-Ci-3-alkyl, (C3-6-cycloalkyl-carbonyl)-amino-Ci-3-alkyl, (C3-6-cycloalkyl-Ci-3-alkyl-carbonyl)-amino-Ci-3-alkyl, (thiophen-2-yl-carbonyl)-amino-Ci-3-alkyl, (furan-2-yl-carbonyl)-amino-30 Ci-3-alkyl, (phenyl-Ci.3-alkyl-carbonyl)-amino-Ci-3-alkyl, (2-(Ci^- alkoxy)-benzoyl-carbonyl)-amino-Ci-3-alkyl, (pyridin-2-yl-carbonyl)-amino-Ci-3-alkyl, (pyridin-3-yl-carbonyl)-amino-Ci-3-alkyl, (pyridin-4-yl- carbonyl)-amino-Ci-3-alkyl or Ci-3-alkyl-piperazin-1 -yl-carbonyl-Ci-3-alkyl group, by an aminocarbonyl-C2-3-alkenyl, (Ci-3-alkylamino)-carbonyl-C2-3-alkenyl, di-(Ci.3-alkyl)-amino-carbonyl-C2.3-alkenyl or Ci-4-alkoxy-carbonyl-C2.3-alkenyl group; ll.iii. R2 and R4 are as defined under Land R3 is a phenyl group substituted by a carboxy-C-i-3-alkyl or C-M-alkoxy-carbonyl-Ci-3-alkyl group; II.iv. R3 and R4 are as defined under I. and R2 is a fluorine or chlorine atom; ll.v. R2 and R3 are as defined under I. and R4 is a phenyl group or a phenyl group which is monosubstituted by a C-i-3-alkyl group which is terminally substituted by an amino, guanidino, mono- or di-(Ci.2-alkyl)-amino-, N-[ro-di-(Ci-3-alkyl)-amino-C2. 3-alkyl]-N-(Ci-3-alkyl)-amino, N-methyl-(C3-4-alkyl)-amino, N-(Ci-3-alkyl)-N-benzylamino, N-(Ci^-alkoxycarbonyl)-amino, N-(Ci^-alkoxycarbonyl)-Ci-4-alkylamino, 4-(Ci-3-alkyl)-piperazin-1 -yl, imidazol-1 -yl, pyrrolidin-1-yl, azetidin-1-yl, morpholin-4-yl, piperazin-1-yl, thiomorpholin-4-yl group, by a di-(Ci-3-alkyl)-amino-(Ci-3-alkyl)-sulphonyl, 2-[di-(Ci-3-alkyl)-amino]-ethoxy, 4-(Ci.3-alkyl)-piperazin-1 -yl-carbonyl, {©-[di-(Ci-3-alkyl)-amino]- 8 (C2-3-alkyl)}-N-(Ci-3-alkyl)-amino-carbonyl, 1-(Ci-3-alkyl)imidazol-2-yl, (Ci.3-alkyl)-sulphonyl group, or by a group of the formula in which R7 is a Ci-2-alkyl, Ci-2-alkyl-carbonyl, di-(Ci-2-alkyl)-amino-carbonyl-Ci-3-alkyl or Ci-3-alkylsulphonyl group and R8 is Ci-3-alkyl, co-[di-(Ci.2-alkyl)-amino]-C2-3-alkyl, ©-[mono-(Ci-2-alkyl)-amino]-C2-3-alkyl group, or a (Ci-3-alkyl)-carbonyl, (C4-6-alkyl)-carbonyl or carbonyl-(Ci-3-alkyl) group which is terminally substituted by a di-(Ci-2-alkyl)-amino, piperazin-1-yl or 4-(Ci.3-alkyl)-piperazin-1-yl group, where all dialkylamino groups present in the radical R4 may also be present in quaternized form, for example as an N-methyl-(N,N-dialkyl)-ammonium group, where the counterion is preferably selected from the group consisting of iodide, chloride, bromide, methylsulphonate, para-toluenesulphonate and trifluoroacetate.

Subgroups of particularly preferred compounds of the above formula I which are to be mentioned in particular are those in which: / -N \ R8 R7 Ill.i. X, R1, R2, R5 and R6 are as defined under I., R3 is as defined under II.i. and R4 is as defined under ll.v.; 9 lll.ii. lll.iii.

Ill.iv.

A further preferred group of compounds of the above formula I are those in which X is an oxygen atom, R1 is a hydrogen atom, R2 is a fluorine, chlorine or bromine atom or a cyano group, R3 is a phenyl group or a phenyl group which is monosubstituted by a fluorine, chlorine, bromine or iodine atom or by a Ci-3-alkoxy group, where the abovementioned unsubstituted and the monosubstituted phenyl groups may additionally be substituted in the 3- or 4-position by a fluorine, chlorine or bromine atom, by a Ci-3-alkoxy or Ci-2-alkyl-carbonyl-amino group, by a carboxy-Ci-3-alkyl, aminocarbonyl-Ci-3-alkyl, (C-i-2-alkylamino)-carbonyl-C-i-3-alkyl, di-(Ci-2-alkyl)-aminocarbonyl-Ci-3-alkyl, (Ci-2-alkyl-carbonyl)-amino-Ci-3-alkyl or (phenyl-carbonyl)-amino-C-i-3-alkyl group, X, R1, R2, R5 and R6 are as defined under I., R3 is as defined under II.ii. and R4 is as defined under ll.v.; X, R1, R2, R5 and R6 are as defined under I., R3 is as defined under ll.iii. and R4 is as defined under ll.v.; X, R1, R5 and R6 are as defined under I., R2 is as defined under ll.iv., R3 is as defined under ll.i., II.ii. or ll.iii. and R4 is as defined under ll.v. where the substituents may be identical or different, R4 is a phenyl group which is substituted by a Ci-3-alkyl group terminally substituted by a di-(Ci-2-alkyl)-amino group, or by a group of the formula in which R7 is a C-i-2-alkyl, C-i-2-alkyl-carbonyl, di-(Ci-2-alkyl)-amino-carbonyl-Ci_3-alkyl or Ci-3-alkylsulphonyl group and R8 is a Ci-3-alkyl or ©-[di-(Ci.2-alkyl)-amino]-C2-3-alkyl group, or a Ci-3-alkyl-carbonyl group terminally substituted by a di-(Ci-2-alkyl)-amino, piperazino or 4-(Ci.3-alkyl)-piperazin-1-yl group, R5 is a hydrogen atom and R6 is a hydrogen atom, where the abovementioned alkyl groups include linear and branched alkyl groups in which additionally one to 3 hydrogen atoms may be replaced by fluorine atoms, where additionally a carboxyl, amino or imino group present may be substituted by an in vivo cleavable radical, / —N \ R8 R 7 11 their tautomers, enantiomers, diastereomers, their mixtures and their salts. The following compounds of the formula I are particularly preferred: (a) 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (b) 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (c) 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (d) 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (e) 3-Z-[1 -(4-(N-(2-dimethylaminoethy!)-N-methy!sulphonylamino)ani!ino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (f) 3-Z-[1 -(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 40 (g) 3-Z-[1 -(4-(1 -methylimidazol-2-yl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (h) 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (i) 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-30 carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone G) 3-Z-[1 -(4-(pyrrolidin-1 -ylmethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (k) 3-Z-[1 -(4-(diethylaminomethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (I) 3-Z-[1 -(4-(2-dimethylaminoethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (m) 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (n) 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-45 chloro-2-indolinone 12 (o) 3-Z-[1-(4-(pyrrolidin-1 -ylmethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (p) 3-Z-[1 -(4-(dimethylaminomethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-5 6-bromo-2-indolinone (q) 3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)-methylene]-6-bromo-2-indolinone where additionally a carboxyl, amino or imino group present may be substituted by an in vivo cleavable radical or may be present in the form of a prodrug radical, for example in the form of a group which can be converted in vivo into a carboxyl group or in the form of a group which can be converted in vivo into an imino or amino and their salts.

A group which can be converted in vivo into a carboxyl group is to be understood as meaning, for example, a hydroxymethyl group, a carboxyl group which is esterified 20 with an alcohol in which the alcoholic moiety is preferably a Ci-6-alkanol, a phenyl-Ci-3-alkanol, a C3-9-cycloalkanol, where a Cs-s-cycloalkanol may additionally be substitituted by one or two Ci-3-alkyl groups, a Cs-s-cycloalkanol in which one methylene group in the 3- or 4-position is replaced by an oxygen atom or by an imino group optionally substituted by a Ci^-alkyl, phenyl-Ci-3-alkyl, phenyl-Ci.3-alkoxy-4)^5 carbonyl or Ci-6-alkyl-carbonyl group and in which the cycloalkanol moiety may additionally be substituted by one or two Ci-3-alkyl groups, a C4-7-cycloalkenol, a C3-5-alkenol, a phenyl-C3-5-alkenol, a C3-5-alkynol or a phenyl-C3-5-alkynol, with the proviso that no bond to the oxygen atom originates from a carbon atom which carries a double or triple bond, a C3-8-cycloalkyl-Ci-3-alkanol, a bicycloalkanol having a total of 30 8 to 10 carbon atoms which may additionally be substituted in the bicycloalkyl moiety by one or two C-i-3-alkyl groups, a 1,3-dihydro-3-oxo-1-isobenzofuranol or an alcohol of the formula Ra-C0-0-(RbCRc)-0H, 13 in which Ra is a Ci-s-alkyl, C5-7-cycloalkyl, phenyl or phenyl-Ci-3-alkyl group, Rb is a hydrogen atom, a Ci.3-alkyl, Cs-7-cycloalkyl or phenyl group, and Rc is a hydrogen atom or a Ci-3-alkyl group, and a radical cleavable in vivo from an imino or amino group is to be understood as meaning, for example, a hydroxyl group, an acyl group, such as the benzoyl or 10 pyridinoyl group, or a Ci-i6-alkylcarbonyl group, such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a Ci-16-alkoxy-carbonyl group, such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, 15 undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, a phenyl-Ci-6-alkoxy-carbonyl group, such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a Ci.3-alkylsulphonyl-Ci-4-alkoxy-carbonyl, C1.3-alkoxy-C2-4-alkoxy-C2^-alkoxy-carbonyl or RaC0-0-(RbCRc)-0-C0- group, in which Ra is a Ci-s-alkyl, C5-7-cycloalkyl, phenyl or phenyl-Ci-3-alkyl group, Rb is a hydrogen atom, a Ci.3-alkyl, C5-7-cycloalkyl or phenyl group and Rc is a hydrogen atom, a Ci.3-alkyl or RaC0-0-(RbCRc)-0- group, in which Ra 25 to Rc are as defined above, and additionally, for an amino group, the phthalimido group, where the ester radicals mentioned above can also be used as a group which can be converted in vivo into a carboxyl group.

Preferred prodrug radicals for a carboxyl group are a Ci-6-alkoxy-carbonyl group, such as the methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl 14 or cyclohexyloxycarbonyl group, or a phenyl-Ci_3-alkoxy-carbonyl group, such as the benzyloxycarbonyl group, and, for an imino or amino group, a C-i-g-alkoxy-carbonyl group, such as the methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxy-carbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl, cyclohexyloxycarbonyl, n-heptyloxycarbonyl, n-octyloxycarbonyl or n-nonyloxycarbonyl group, a phenyl-C^-alkoxy-carbonyl group, such as the benzyloxycarbonyl group, a phenylcarbonyl group optionally substituted by a Ci_3-alkyl group, such as the benzoyl or 4-ethyl-benzoyl group, a pyridinoyl group, such as the nicotinoyl group, a C1.3-alkylsulphonyl-n-C2.3-alkoxy-carbonyl or Ci.3-alkoxy-C2-3-alkoxy-Ci-4-alkoxy-carbonyl group, such as the 2-methylsulphonylethoxycarbonyl or 2-(2-ethoxy)-ethoxycarbonyl group.

According to the invention, the novel compounds are obtained, for example, by the following processes, which are known in principle from the literature: a. reaction of a compound of the formula in which the radicals Z1 and R3 may, if appropriate, change their positions, X, R2, R3 and R6 are as defined at the outset, R1' has the meanings mentioned at the outset for R1 or is a protective group for the nitrogen atom of the lactam group, where R1 may also, if appropriate, represent a bond, formed via a spacer, to a solid phase, and Z1 is a halogen atom, a hydroxyl, alkoxy or arylalkoxy group, for example a chlorine or bromine atom, a methoxy, ethoxy or benzyloxy group, Z! (V), with an amine of the formula R4\ / R5 N I H (VI), in which R4 and R5 are defined as mentioned at the outset, and, if required, the product is subsequently cleaved from a protective group used for the nitrogen atom of the lactam group or from a solid phase. ^ 0 Suitable protective groups for the nitrogen atom of the lactam group are, for example, an acetyl, benzoyl, ethoxycarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl group and suitable solid phases are a resin, such as a 4-(2',4'-dimethoxyphenylaminomethyl)-15 phenoxy resin, where the attachment is expediently via the amino group, or a p-benzyloxybenzyl alcohol resin, where the attachment is expediently via a spacer, such as a 2,5-dimethoxy-4-hydroxybenzyl derivative.

The reaction is expediently carried out in a solvent, such as dimethylformamide, ^.0 toluene, acetonitrile, tetrahydrofuran, dimethyl sulphoxide, methylene chloride or a mixture thereof, if appropriate in the presence of an inert base, such as triethylamine, N-ethyldiisopropylamine or sodium bicarbonate, at temperatures between 20 and 175°C, where any protective groups used may be simultaneously removed owing to transamidation.

If, in a compound of the formula V, Z1 is a halogen atom, the reaction is preferably carried out in the presence of an inert base at temperatures between 20 and 120°C.

If, in a compound of the formula V, Z1 is a hydroxyl, alkoxy or arylalkoxy group, the 30 reaction is preferably carried out at temperatures between 20 and 200°C. 16 The subsequent removal of a protective group used, which may be required, if appropriate, is expediently carried out either hydrolytically in an aqueous or alcoholic solvent, for example in methanol/water, ethanol/water, isopropanol/water, tetrahydrofuran/water, dioxane/water, dimethylformamide/water, methanol or ethanol, 5 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, 10 butylamine, dimethylamine or piperidine, in a 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.

Cleavage from a solid phase employed is preferably carried out using trifluoroacetic acid and water at temperatures between 0 and 35°C, preferably at room temperature. b. To prepare a compound of the formula I in which R3 is a phenyl or naphthyl group substituted by a carboxy-C2-3-alkenyl, aminocarbonyl-C2-3-alkenyl, (Ci-3-alkylamino)-20 carbonyl-C2-3-alkenyl, di-(Ci-3-alkylamino)-carbonyl-C2-3-alkenyl or Ci-4-alkoxy-carbonyl-C2-3-alkenyl group, reaction of a compound of the formula in which 17 R2, R4, R5, R6 and X are as defined at the outset, R1' has the meanings mentioned at the outset for R1 or is a protective group for the nitrogen atom of the lactam group, where R1, may also, if appropriate, represent a bond, formed via a spacer, to a solid phase, and 5 Z3 is a leaving group, for example a halogen atom or an alkyl- or arylsulphonyloxy group, such as a chlorine, bromine or iodine atom or a methylsulphonyloxy, ethylsulphonyloxy, p-toluenesulphonyloxy or trifluoromethanesulphonyloxy group, with an alkene of the formula O (X), in which R3' is an amino, (Ci-3-alkylamino), di-(Ci-3-alkylamino) or Ci-4-alkoxy group and n is the number 0 or 1.

The reaction is expediently carried out with palladium catalysis, using, for example, palladium(ll) acetate, palladium(ll) chloride, bis(triphenylphosphine)palladium(ll) acetate, bis(triphenylphosphine)palladium(ll) chloride, palladium/carbon, bis-[1,2-^20 bis(diphenylphosphino)ethane]palladium(0), dichloro-(1,2-bis(diphenylphosphino)-ethane)palladium(ll), tetrakistriphenylphosphinepalladium(O), tris(dibenzylidene-acetone)dipalladium(O), 1,1 '-bis(diphenylphosphino)ferrocenedichloropalladium(ll) or tris(dibenzylideneacetone)dipalladium(0)/chloroform adduct, in the presence of a base, such as triethylamine, diisopropylethylamine, lithium carbonate, potassium 25 carbonate, sodium carbonate, caesium carbonate, and a ligand, such as triphenylphosphine, tri-ortho-tolylphosphine or tri-(tert-butyl)phosphine, in solvents such as acetonitrile, N-methylpyrrolidinone, dioxane or dimethylformamide and mixtures thereof. 18 The cleavage of a protective group used for the nitrogen atoms of the lactam group or from a solid phase, which may be required, if appropriate, is carried out as described above under process (a). c. To prepare a compound of the formula I in which R3 is a phenyl or naphthyl group substituted by m w15 in which R2, R4, R5, R6 and X are as defined at the outset, R1' has the meanings mentioned at the outset for R1 or is a protective group for the nitrogen atom of the lactam group, where R1, may also, if appropriate, represent a bond, formed via a spacer, to a solid phase, A is a C2-3-alkenyl group and R3 is a hydroxyl, Ci-4-alkoxy, amino, (Ci-3-alkylamino) or di-(C-i-3-alkyl)amino group. a carboxy-Ci-3-alkyl, C1 -4 -a I koxy-ca rbon y I -C1.3-a I ky I, aminocarbonyl-Ci-3-alkyl, (Ci-3-alkylamino)-carbonyl-Ci-3-alkyl or di-(Ci-3-alkyl)-aminocarbonyl-Ci-3-alkyl group, hydrogenation of a compound of the formula The hydrogenation is preferably carried out using catalytic hydrogenation with 25 hydrogen in the presence of a catalyst, such as palladium/carbon or platinum, in a 19 solvent, such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, if appropriate with addition of an acid, such as hydrochloric acid, at temperatures between 0 and 50°C, but preferably at room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 5 bar.

The cleavage of a protective group used for the nitrogen atom of the lactam group or from a solid phase, which may be required, if appropriate, is carried out as described under process (a).

| If, according to the invention, a compound of the formula I is obtained which contains an alkoxycarbonyl group, this can be converted by hydrolysis into a corresponding carboxyl compound, or if a compound of the formula I is obtained which contains an amino or alkylamino group, this can be converted by reduction alkylation into a corresponding alkylamino or dialkylamino compound, or if a compound of the formula I is obtained which contains a dialkylamino group, this 20 can be converted by alkylation into a corresponding trialkylammonium compound, or ^ if a compound of the formula I is obtained which contains an amino or alkylamino group, this can be converted by acylation or sulphonation into a corresponding acyl or sulphonyl compound, respectively, or if a compound of the formula I is obtained which contains a carboxyl group, this can be converted by esterification or amidation into a corresponding ester or aminocarbonyl compound, respectively, or if a compound of the formula I is obtained which contains a nitro group, this can be converted by reduction into a corresponding amino compound, or if a compound of the formula I is obtained which contains a cyano group, this can be converted by reduction into a corresponding aminomethyl compound, or if a compound of the formula I is obtained which contains an arylalkyloxy group, this 5 can be converted with acid into a corresponding hydroxyl compound, or if a compound of the formula I is obtained which contains an alkoxycarbonyl group, this can be converted by hydrolysis into a corresponding carboxyl compound, or if a compound of the formula I is obtained in which R4 is a phenyl group substituted ^ by an amino, alkylamino, aminoalkyl or N-alkylamino group, this can then be converted by reaction with a corresponding cyanate, isocyanate or carbamoyl halide into a corresponding urea compound of the formula I, or if a compound of the formula I is obtained in which R4 is a phenyl group substituted by an amino, alkylamino, aminoalkyl or N-alkylamino group, this can subsequently be converted by reaction with a corresponding amidino-group-transferring compound or by reaction with a corresponding nitrile into a corresponding guanidino compound of the formula I.

The subsequent hydrolysis is preferably carried out in an aqueous solvent, for ^ example in water, methanol/water, ethanol/water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid, such as trifluoroacetic acid, hydrochloric acid or sulphuric acid, or in the presence of an alkali 25 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 preferably carried out in a suitable solvent, 30 such as methanol, methanol/water, methanol/water/ammonia, ethanol, ether, tetrahydrofuran, dioxane or dimethylformamide, if appropriate with addition of an acid, such as hydrochloric acid, in the presence of catalytically activated hydrogen, for example of hydrogen in the presence of Raney nickel, platinum or 21 palladium/carbon, 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, dichloromethane, acetone or acetonitrile, in the presence of alkylating agents, such as alkyl iodides, alkyl bromides, alkyl chlorides, methanesulphonic acid alkyl esters, para-toluenesulphonic acid alkyl esters or alkyl 10 trifluoroacetates, at temperatures between 0 and 100°C, preferably at temperatures between 20 and 60°C.

The subsequent acylation or sulphonylation is expediently carried out using the corresponding free acid or a corresponding reactive compound, such as its 15 anhydride, ester, imidazolide or halide, preferably in a solvent, such as methylene chloride, diethyl ether, tetrahydrofuran, toluene, dioxane, acetonitrile, dimethyl sulphoxide or dimethylformamide, if appropriate in the presence of an inorganic or a tertiary organic base, at temperatures between -20 and 200°C, preferably at temperatures between 20°C and the boiling point of the solvent used. The reaction 20 with the free acid can, if appropriate, be carried out in the presence of an agent which activates the acid or of a dehydrating agent, for example in the presence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, 25 N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N'-dicyclohexyl-carbodiimide/1-hydroxybenzotriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, 2-(1 H-benzotriazol-1 -yl)-1,1,3,3-tetramethyluronium tetrafluoroborate/1 -hydroxybenzotriazole, N,N'-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, and, if 30 appropriate, with addition of a base, such as pyridine, 4-dimethylaminopyridine, N-methylmorpholine or triethylamine, expediently at temperatures between 0 and 150°C, preferably at temperatures between 0 and 100°C. The reaction with a corresponding reactive compound can, if appropriate, be carried out in the presence 22 of a tertiary organic base, such as triethylamine, N-ethyl-diisopropylamine, N-methylmorpholine or pyridine, or, if an anhydride is used, in the presence of the corresponding acids, at temperatures between 0 and 150°C, preferably at temperatures between 50 and 100°C.

The subsequent esterification or amidation is expediently carried out by reacting a reactive corresponding carboxylic acid derivative with an appropriate alcohol or amine, as described above.

The esterification or amidation is preferably carried out in a solvent, such as | methylene chloride, diethyl ether, tetrahydrofuran, toluene, dioxane, acetonitrile, dimethyl sulphoxide or dimethylformamide, if appropriate in the presence of an inorganic or a tertiary organic base, preferably at temperatures between 20°C and the boiling point of the solvent used. Here, the reaction with a corresponding acid is 15 preferably carried out in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N'-dicyclohexylcarbodi-20 imide/1 -hydroxybenzotriazole, 2-(1 H-benzotriazol-1 -yl)-1,1,3,3-tetramethyluronium- tetrafluoroborate, 2-(1 H-benzotriazol-1 -yl)-1,1,3,3-tetramethyluronium | tetrafluoroborate/1 -hydroxybenzotriazole, N,N'-carbonyldiimidazole or triphenyl- phosphine/carbon tetrachloride, and, if appropriate, with addition of a base, such as pyridine, 4-dimethylaminopyridine, N-methylmorpholine or triethylamine, expediently 25 at temperatures between 0 and 150°C, preferably at temperatures between 0 and 100°C, and the acylation with a corresponding reactive compound, such as its anhydride, ester, imidazolide or halide, is, if appropriate, carried out in the presence of a tertiary organic base, such triethylamine, N-ethyldiisopropylamine or N-methylmorpholine, at temperatures between 0 and 150°C, preferably at 30 temperatures between 50 and 100°C.

The subsequent reduction of a nitro group is preferably carried out hydrogenolytically, for example with hydrogen in the presence of a catalyst, such as 23 palladium/carbon or Raney nickel, in a solvent, such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, if appropriate with addition of an acid, such as hydrochloric acid or glacial acetic acid, at temperatures between 0 and 50°C, but preferably at room temperature, and at a 5 hydrogen pressure of from 1 to 7 bar, but preferably from 3 to 5 bar.

The subsequent hydrogenation of a cyano group is preferably carried out hydrogenolytically, for example using hydrogen in the presence of a catalyst, such as palladium/carbon or Raney nickel, in a solvent, such as methanol, ethanol, ethyl 10 acetate, methylene chloride, dimethylformamide, dimethylformamide/acetone or ^ glacial acetic acid, if appropriate with addition of an acid, such as hydrochloric acid or glacial acetic acid, at temperatures between 0 and 50°C, but preferably at room temperature, and at a hydrogen pressure of from 1 to 7 bar, but preferably of from 3 to 5 bar.

The subsequent preparation of a corresponding guanidino compound of the formula I is expediently carried out by reaction with an amidino-group-transferring compound, such as 3,5-dimethylpyrazole-1-carboxamidine, preferably in a solvent, such as dimethylformamide, and, if appropriate, in the presence of a tertiary organic base, 20 such as triethylamine, at temperatures between 0 and 50°C, preferably at room temperature.

In the reactions described above, any reactive groups present, such as carboxyl, hydroxyl, amino, alkylamino or imino groups, can be protected during the reaction by 25 customary protective groups which are removed again after the reaction.

A protective radical for a carboxyl group is, for example, the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group, and a protective group for a hydroxyl, amino, alkylamino or imino group is, for example, the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group, and, for the amino group, additionally the phthalyl group. 24 The subsequent removal of a protective radical used is, if appropriate, carried out, for example, hydrolytically in an aqueous solvent, for example in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an 5 acid, such as trifluoroacetic acid, hydrochloric acid or sulphuric 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 benzyloxycarbonyl radical is removed, for ^ example, hydrogenolytically, for example using hydrogen in the presence of a catalyst, such as palladium/carbon, in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, if appropriate with addition of an acid, such as hydrochloric acid or glacial acetic acid, 15 at temperatures between 0 and 50°C, but preferably at room temperature, and at a hydrogen pressure of from 1 to 7 bar, but preferably of from 3 to 5 bar.

A methoxybenzyl group can also be removed in the presence of an oxidizing agent, such as cerium(IV) ammonium nitrate, in a solvent, such as methylene chloride, 20 acetonitrile or acetonitrile/water, at temperatures between 0 and 50°C, but preferably at room temperature.

However, a 2,4-dimethoxybenzyl radical is preferably removed in trifluoroacetic acid in the presence of anisole.

A tert-butyl or tert-butyloxycarbonyl radical is preferably removed by treatment with an acid, such as trifluoroacetic acid or hydrochloric acid, using, if appropriate, a solvent, such as methylene chloride, dioxane, ethyl acetate or ether.

A phthalyl radical is preferably removed in the presence of hydrazine or a primary amine, such as methylamine, ethylamine or n-butylamine, in a solvent, such as methanol, ethanol, isopropanol, toluene/water or dioxane, at temperatures between 20 and 50°C.

Furthermore, chiral compounds of the formula I obtained can be separated into their enantiomers and/or diastereomers.

Thus, for example, compounds of the formula I obtained which occur as racemates can be separated by methods known per se (see Allinger N. L. and Eliel E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) into their enantiomers, and compounds of the formula I having at least 2 asymmetric carbon atoms can, owing to their physicochemical differences, be separated by methods known per se, 10 for example by chromatography and/or fractional crystallization, into their | diastereomers, which, if they are obtained in racemic form, can then be separated into the enantiomers as mentioned above.

The separation of enantiomers is preferably carried out by column separation on 15 chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance which forms salts or derivatives, such as, for example, esters or amides, with the racemic compound, in particular acids and their activated derivatives or alcohols, and separating the mixture of diastereomeric salts or derivatives obtained in this manner, for example owing to different solubilities, 20 whereupon the free enantiomers can be released from the pure diastereomeric salts or derivatives by action of suitable agents. Particularly common optically active acids | are, for example, the D and L forms of tartaric acid, 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. A suitable 25 optically active alcohol is, for example, (+)- or (-)-menthol, and a suitable optically active acyl radical in amides is, for example, the (+)- or (-)-menthyloxycarbonyl radical.

Furthermore, the compounds of the formula I obtained can be converted into their 30 salts, in particular, for pharmaceutical use, into their physiologically acceptable salts, with inorganic or organic acids. Acids suitable for this purpose are, for example, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, maleic acid, methanesulphonic acid, 26 ethanesulphonic acid, para-toiuenesuiphonic acid, phenylsulphonic acid or L-(+)-mandelicacid.

Moreover, the resulting novel compounds of the formula I can, if they contain a 5 carboxyl group, then, if desired, be converted into their salts with inorganic or organic bases, in particular, for pharmaceutical use, into their physiologically acceptable salts. Bases suitable for this purpose are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

Also suitable, for compounds of the formula I which contain 2 or more acidic or basic ^ groups, are salts with 2 or more inorganic or organic bases or acids (disalts etc.).

Some of the compounds of the general formulae V to XI used as starting materials are known from the literature or can be obtained by processes known from the 15 literature or can be obtained by the processes described above and in the examples. Compounds of the general formula IX, for example, are described in the German patent application 198 44 003.

As already mentioned at the outset, the novel compounds of the formula (I) have 20 useful pharmacological properties, in particular in inhibiting action on various kinases, especially on receptor tyrosine kinases, such as VEGFR1, VEGFR2, VEGFR3, ^ PDGFRa, PDGFRp, FGFR1, FGFR3, EGFR, HER2, c-Kit, IGF1R and HGFR, Flt-3, and on the proliferation of cultivated human cells, in particular that of endothelial cells, for example in angiogenesis, but also on the proliferation of other cells, in 25 particular of tumour cells.

The biological properties of the novel compounds were examined by the following standard methods: Human umbilical cord endothelial cells (HUVEC) were cultivated in IMDM (Gibco BRL), supplemented with 10% foetal bovine serum (FBS) (Sigma), 50 pM IJ-mercaptoethanol (Fluka), standard antibiotics, 15 pg/ml of endothelial cell growth factor (ECGS, Collaborative Biomedical Products) and 100 pg/ml of heparin (Sigma) 27 on gelatin-coated culture bottles (0.2 % gelatin, Sigma) at 37°C, 5% C02, in an atmosphere saturated with water.

To examine the inhibitory activity of the compounds according to the invention, the 5 cells were "starved" for 16 hours, i.e. kept in culture medium without growth factors (ECGS + heparin). Using trypsin/EDTA, the cells were detached from the culture bottles and washed once with serum-containing medium. 2.5 x 103 cells were then seeded in each well.

The proliferation of the cells was stimulated using 5 ng/ml of VEGF165 (vascular | endothelial growth factor; H. Weich, GBF Brunswick) and 10 pg/ml of heparin. Per plate, as control value, in each case 6 wells were not stimulated.

The compounds according to the invention were dissolved in 100% dimethyl 15 sulphoxide and, in triplicate, added to the cultures in different dilutions, the maximum dimethyl sulphoxide concentration being 0.3%.

The cells were incubated at 37°C for 76 hours, and 3H-thymidine (0.1 |j Ci/well, Amersham) was then added for a further 16 hours to determine DNA synthesis. The 20 radioactively labelled cells were then immobilized on filter mats and the incorporated radioactivity was determined in a p counter. To determine the inhibitory activity of the ) compounds according to the invention, the mean value for 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 in percent of the control (HUVEC without inhibitor), and the concentration of active compound at which the proliferation of the cells is inhibited by 50% (IC50) was derived therefrom.

The compounds of the formula I according to the invention have an IC50 between 50 |jM and 1 nM. 28 Owing to their inhibitory action on the proliferation of cells, in particular of endothelian cells and of tumour cells, the compounds of the formula I are suitable for treating diseases in which the proliferation of cells, in particular that of endothelial cells, plays a role.

Thus, for example, the proliferation of endothelial cells and the related neovascularization is a decisive step in tumour progression (Folkman J. et al., Nature 339. 58-61, (1989); Hanahan D. and Folkman J., Cell 86, 353-365, (1996)). Furthermore, the proliferation of endothelial cells is also of importance in 10 haemangiomes, in metastasization, in rheumatoid arthritis, in psoriasis and in ocular ^ neovascularization (Folkman J., Nature Med. 1, 27-31, (1995); Carmeliet P & Rakeh J., Nature 407. 249-257, (2000)). The therapeutic benefit of inhibitors of endothelial cell proliferation in the animal model was shown, 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 15 Natl Acad Sci USA 93, 2002-2007, (1996)).

Thus, the compounds of the formula I, their tautomers, their stereoisomers or their physiologically acceptable salts are suitable, for example, for treating tumours (for example squamous epithelium carcinoma, astrocytoma, Kaposi sarcoma, 20 glioblastoma, lung cancer, cancer of the bladder, neck carcinoma, oesophagus carcinoma, melanoma, ovarial carcinoma, prostate carcinoma, breast cancer, small-^ cell lung carcinoma, glioma, colorectal carcinoma, pancreas carcinoma, urogenital cancer and gastrointestinal carcinoma, and also haematological cancers, such as, for example, multiple myeloma and acute myelotic leukaemia), psoriasis, arthritis (for 25 example rheumatoid arthritis), haemangioma, angiofibroma, disorders of the eye (for example diabetic retinopathy), neovascular glaucoma, disorders of the kidneys (for example glomerulonephritis), diabetic nephropathy, malignant nephrosclerosis, thrombic microangiopathic syndromes, transplantation rejections and glomerulopathy, fibrotic disorders (for example cirrhosis of the liver), mesangial-cell-30 proliferative disorders, atherosclerosis, injuries of the nerve tissue and for inhibiting the reocclusion of vessels after balloon catheter treatment, in vessel prosthetics or after implantation of mechanical devices for keeping vessels open (for example stents) or other disorders in which cell proliferation or angiogenesis play a role. 29 Owing to their biological properties, the compounds according to the invention can be used alone or in combination with other pharmacologically active compounds, for example in tumour therapy in monotherapy or in combination with other antitumor therapeutics, for example in combination with topoisomerase inhibitors (for example etoposide), mitosis inhibitors (for example vinblastine, Taxol), compounds which interact with nucleic acids (for example cisplatin, cyclophosphamide, adriamycin), hormone antagonists (for example tamoxifen), steroids and analogues thereof (for example dexamethasone), inhibitors of metabolic processes (for example 5-FU etc.), cytokines (for example interferons), kinase inhibitors (for example EGFR kinase inhibitoren, such as, for example, Iressa; Gleevec), allosterically acting receptor tyrosine kinase inhibitors, antibodies (for example Herceptin), COX-2 inhibitors or else in combination with radiotherapy, etc. These combinations can be administered either simultaneously or sequentially.

The invention is illustrated in more detail by the examples below: Example Name 1.0 3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(3-iodophenyl)-methylene]-6-chloro-2-indolinone 1.1 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1 -(3-iodophenyl)methylene]-6- chloro-2-indolinone 1.2 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-chlorophenyl)methylene]-6-chloro-2-indolinone 1.3 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(4-chlorophenyl)methylene]-6-chloro-2-indolinone 1.4 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-chlorophenyl)methylene]-6-chloro-2- indolinone 1.5 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-chlorophenyl)methylene]-6-chloro-2-indolinone 1.6 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1 -(4-chlorophenyl)methylene]- 6-chloro-2-indolinone 1.7 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(3,4-dimethoxyphenyl)methylene]-6-chloro-2-indolinone 1.8 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1-(3,4-dimethoxyphenyl)methylene]-6-chloro-2- indolinone 1.9 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(3,4-dimethoxyphenyl)methylene]-6-chloro-2-indolinone 1.10 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1 -(3,4-dimethoxyphenyl)-methylene]-6-chloro-2-indolinone 31 1.11 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylcarbamoyl)anilino)-1-(3,4-dimethoxyphenyl)methylene]-6-chloro-2-indolinone 2.0 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1 -(4-cyanophenyl)-methylene]- 6-chloro-2-indolinone 3.0 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1 -(4-iodophenyl)methylene]-6- fluoro-2-indolinone 3.1 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1 -(3-fluorophenyl)methylene]- 6-fluoro-2-indolinone 3.2 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamirio)anilino)-1-(3-fluorophenyl)methylene]-6-fluoro-2-indolinone 3.3 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-fluorophenyl)methylene]-6-fluoro-2- indolinone 3.4 3-Z-[1 -(4-(dimethylaminomethyl)anilino)-1 -(4-(2-acetylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.5 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-(2-acetylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.6 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-acetylaminoethyl)phenyl)methylene]-6- fluoro-2-indolinone 3.7 3-Z-[1 -(4-(dimethylaminomethyl)anilino)-1 -(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.8 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1 -(3-iodophenyl)methylene]-6- fluoro-2-indolinone 3.9 3-Z-[1 -(4-(dimethylaminomethyl)anilino)-1 -(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.10 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1 -(3-(N-tert-butoxycarbonyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 32 3.11 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.12 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6- fluoro-2-indolinone 3.13 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1 -(3-cyanomethylphenyl)-methylene]-6-fluoro-2-indolinone 3.14 3-Z-[1 -(4-(N-(4-methylpiperaziri-1 -ylmethylca rbonyl )-N- methylamino)anilino)-1-(4-(N-tert-butoxycarbonyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.15 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1 -(4-(N-tert-butoxycarbonyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.16 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1 -(3-(N-tert-butoxycarbonyl-2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.17 3-Z-[1 -(4-(N-Acetyl-N-methylamino)anilino)-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.18 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]- 6-fluoro-2-indolinone 3.19 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.20 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.21 3-Z-[1-(4-(N-tert-butoxycarbonylmethylaminomethyl)anilino)-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.22 3-Z-[1 -(4-(4-methyl pi perazin-1 -yl-carbonyl)anilino)-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 33 3.23 3-Z-[1 -(4-(1 -methylimidazol-2-yl)anilino)-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.24 3-Z-[1 -(4-methylsulphonylanilino)-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.25 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6- fluoro-2-indolinone 3.26 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(3-methoxycarbonylmethylpheriyl)methylene]-6-fluoro-2-indolinone 3.27 3-Z-[1-(4-(4-methylpiperazin-1 -yl-carbonyl)anilino)-1 -(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.28 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.29 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.30 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.31 3-Z-[1-(4-(N-(4-dimethylamino-butylcarbonyl)-N-methylamino)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.32 3-Z-[1-Anilino-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro- 2-indolinone 3.33 3-Z-[1 -(4-(1 -methylimidazol-2-yl)anilino)-1 -(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.34 3-Z-[1 -(4-(4-methylpiperazin-1 -ylcarbonyl)anilino)-1 -(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.35 3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-methylsulphonylamino)anilino)-1-(4-methoxycarbonylmethylphenyl)-methylene]-6-fluoro-2-indolinone 34 3.36 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.37 3-Z-[1 -(4-(N-methyl-N-acetylamino)anilino)-1 -(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.38 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.39 3-Z-[1 -(4-methylsulphonylanilino)-1 -(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.40 3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.41 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.42 3-Z-[1-Anilino-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro- 2-indolinone 3.43 3-Z-[1-(4-methylsulphonylanilino)-1-(3-methoxycarbonylmethylphenyl)-methylene]-6-fluoro-2-indolinone 3.44 3-Z-[1 -(4-(1 -methylimidazol-2-yl)anilino)-1 -(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.45 3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-methylsulphonylamino)anilino)-1-(3-methoxycarbonylmethylphenyl)-methylene]-6-fluoro-2-indolinone 3.46 3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.47 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.48 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]- 6-fluoro-2-indolinone 3.49 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.50 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.51 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.52 3-Z-[1 -(4-(N-(4-methylpiperaziri-1 -ylmethylcarbonyl)-N- methylamino)anilino)-1-(3-(N-tert-butoxycarbonyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.53 3-Z-[1 -(4-(N-methyl-N-acetylamino)anilino)-1 -(3-acetylaminomethylphenyl)methylene]-6-chloro-2-indolinone 3.54 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(3-acetylaminomethylphenyl)methylene]-6-chloro-2-indolinone 3.55 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(3-acetylaminomethylphenyl)methylene]-6-chloro-2-indolinone 3.56 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-acetylaminomethylphenyl)methylene]-6-chloro-2-indolinone 3.57 3-Z-[1 -(4-(2-dimethylaminoethyl)anilino)-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.58 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.59 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.60 3-Z-[1 -(4-(2-dimethylaminoethyl)anilino)-1 -(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.61 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 36 3.62 3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.63 3-Z-[1-(4-(N-(4-dimethylaminobutylca rbonyl )-N-methylamino)anilino)-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.64 3-Z-[1 -(4-(1 -methylimidazol-2-yl)anilino)-1 -(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.65 3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.66 3-Z-[1anilino-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro- 2-indolinone 3.67 3-Z-[1 -(4-(pyrrolidin-1 -ylmethyl)anilino)-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.68 3-Z-[1 -(4-(diethylaminomethyl )anilino)-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.69 3-Z-[1 -(4-(N-tert-butoxycarbonylaminomethyl)anilino)-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.70 3-Z-[1 -(4-(2-dimethylaminoethyl)anilino)-1 -(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.71 3-Z-[1 -(4-(2-dimethylaminoethyl)anilino)-1 -(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.72 3-Z-[1 -(4-(dimethylaminomethyl)anilino)-1 -(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.73 3-Z-[1 -(4-(2-dimethylaminoethyl)anilino)-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone 3.74 3-Z-[1 -(4-(1 -methylimidazol-2-yl)anilino)-1 -(4-(2-ethoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone 3.75 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone 37 3.76 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.77 3-Z-[1 -(4-((4-methylpiperazin-1 -yl)methyl)anilino)-1 -(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.78 3-Z-[1 -(4-(imidazol-1 -ylmethyl)anilino)-1 -(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.79 3-Z-[1 -(4-((4-methylpiperazin-1 -yl)methyl)anilino)-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.80 3-Z-[1 -(4-(imidazol-1 -ylmethyl)anilino)-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.81 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.82 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.83 3-Z-[1 -(4-(pyrrolidin-1 -ylmethyl)anilino)-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone 3.84 3-Z-[1anilino-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2- indolinone 3.85 3-Z-[1 -(4-(N-tert-butoxycarbonylaminomethyl)anilino)-1 -(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.86 3-Z-[1-(4-(N-tert-butoxycarbonylmethylaminomethyl)anilino)-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.87 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-methoxycarbonylmethoxy-phenyl)methylene]-6-fluoro-2-indolinone 3.88 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-methoxycarbonylmethoxy-phenyl)methylene]-6-fluoro-2-indolinone 3.89 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2-ethoxycarbonyl-ethoxy)phenyl)methylene]-6-fluoro-2-indolinone 38 3.90 3-Z-[1 -(4-(pyrrolidin-1 -ylmethyl)anilino)-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-bromo-2-indolinone 3.91 3-Z-[1 -(4-(dimethylaminomethyl)anilino)-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-bromo-2-indolinone 3.92 3-Z-[1 -(4-(diethylaminomethyl )anilino)-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-bromo-2-indolinone 3.93 3-Z-[1 -(3-dimethylaminomethylanilino)-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.94 3-Z-[1 -(3-dimethylaminomethylanilino)-1 -(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.95 3-Z-[1 -(3-dimethylaminomethylanilino)-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone 4.0 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1 -(3,4-dimethoxyphenyl)-methylene]-6-cyano-2-indolinone .0 3-Z-[1 -(4-(N-methyl-N-methylsulphonylamino)anilino)-1 -(3-(2-methoxycarbonylvinyl)phenyl)methylene]-6-chloro-2-indolinone .1 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1 -(4-(2-methoxycarbonyl-vinyl)phenyl)methylene]-6-chloro-2-indolinone .2 3-Z-[1 -(4-(dimethylaminomethyl)anilino)-1 -(4-(2-carbamoyl-vinyl)phenyl)methylene]-6-fluoro-2-indolinone .3 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1 -(4-(2-methoxycarbonyl-vinyl)phenyl)methylene]-6-fluoro-2-indolinone .4 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1 -(3-(2-methoxycarbonyl-vinyl)phenyl)methylene]-6-fluoro-2-indolinone 6.0 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone 6.1 3-Z-[1 -(4-(N-methyl-N-methylsulphonylamino)anilino)-1 -(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone 39 6.2 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-(2-carbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 6.3 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 6.4 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 7.0 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-aminomethylphenyl)-methylene]-6-chloro-2-indolinone 8.0 3-Z-[1 -(4-(N-((4-methylpiperazin-1 -yl)methylcarbonyl)-N-methylamino)anilino)-1-(4-aminomethylphenyl)methylene]-6-chloro-2- indolinone 9.0 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1 -(3-aminomethylphenyl)-methylene]-6-fluoro-2-indolinone 9.1 3-Z-[1 -(4-(dimethylaminomethyl)anilino)-1 -(3-(2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 9.2 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1 -(4-aminomethylphenyl)-methylene]-6-fluoro-2-indolinone 9.3 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -yimethyica rbonyl )-N-methylamino)anilino)-1-(4-aminomethylphenyl)methylene]-6-fluoro-2- indolinone 9.4 3-Z-[1 -(4-(methylaminomethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 9.5 3-Z-[1 -(4-(methylaminomethyl)anilino)-1 -(4-(2-methylcarbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 9.6 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-aminomethylphenyl)methylene]-6-fluoro-2- indolinone 40 9.7 3-Z-[1 -(4-(aminomethyl)anilino)-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 9.8 3-Z-[1 -(4-(aminomethyl)anilino)-1 -(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 9.9 3-Z-[1 -(4-(methylaminomethyl)anilino)-1 -(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone .0 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone .1 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone .2 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carboxymethylphenyl)-methylene]-6-fluoro-2-indolirione .3 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone .4 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethylphenyl)-methylene]-6-fluoro-2-indolinone .5 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -yimethyica rbonyl)-N-methylamino)anilino)-1-(4-carboxymethylphenyl)methylene]-6-fluoro-2- indolinone .6 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone .7 3-Z-[1 -(4-(N-methyl-N-acetylamino)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone .8 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro- 2-indolinone .9 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 41 .10 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone .11 3-Z-[1-(4-(N-tert-butoxycarbonylmethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone .12 3-Z-[1 -(4-(4-methylpiperazin-1 -ylcarbonyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone .13 3-Z-[1 -(4-(1 -methylimidazol-2-yl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone .14 3-Z-[1 -(4-methylsulphonylanilino)-1 -(4-(2-carboxyethyl)phenyl)methylerie]-6-fluoro-2-indolinone .15 3-Z-[1 -(4-(4-methylpiperazin-1 -ylca rbonyl )anilino)-1 -(3-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone .16 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-carboxymethylphenyl )methylene]-6-fluoro-2- indolinone .17 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone .18 3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1-(3-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone .19 3-Z-[1-Anilino-1-(3-carboxymethylphenyl)-methylene]-6-fluoro-2- indolinone .20 3-Z-[1 -(4-methylsulphonylanilino)-1 -(3-carboxymethylphenyl )-methylene]-6-fluoro-2-indolinone .21 3-Z-[1 -(4-(1 -methylimidazol-2-yl)anilino)-1 -(3-carboxymethylphenyl)-methylene]-6-fluoro-2-indolinone .22 3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-methylsulphonylamino)anilino)-1-(3-carboxymethylphenyl)-methylene]- 6-fluoro-2-indolinone 42 .23 3-Z-[1 anilino-1 -(4-carboxymethylphenyl)methylene]-6-fluoro-2- indolinone .24 3-Z-[1 -(4-(1 -methylimidazol-2-yl)anilino)-1 -(4-carboxymethylphenyl)-methylene]-6-fluoro-2-indolinone .25 3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone .26 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone .27 3-Z-[1-(4-(4-methylpiperazin-1 -yl-carbonyl)anilino)-1 -(4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone .28 3-Z-[1 -(4-methylsulphonylanilino)-1 -(4-carboxymethylphenyl)-methylene]-6-fluoro-2-indolinone .29 3-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(4-carboxymethylphenyl)-methylene]-6-fluoro-2-indolinone .30 3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-methylsulphonylamino)anilino)-1-(4-carboxymethylphenyl)methylene]- 6-fluoro-2-indolinone .31 3-Z-[1-(4-(N-(2-dimethylaminoethylca rbonyl )-N-methylamino)anilino)-1-(4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone .32 3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone .33 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro- 2-indolinone .34 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(3-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone .35 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 43 .36 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone .37 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone .38 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)pheriyl)methylene]-6-fluoro-2-indolinone .39 3-Z-[1 -(4-(2-dimethylaminoethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone .40 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone .41 3-Z-[1 -(4-(2-dimethylaminoethyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone .42 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolirione .43 3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone .44 3-Z-[1-(4-(N-(4-dimethylamino-butylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone .45 3-Z-[1 -(4-(1 -methylimidazol-2-yl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone .46 3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone .47 3-Z-[1ariilino-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2- indolinone .48 3-Z-[1 -(4-(pyrrolidin-1 -ylmethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone .49 3-Z-[1 -(4-(diethylaminomethyl )anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 44 .50 3-Z-[1-(4-aminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]- 6-fluoro-2-indolinone .51 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(3-carboxymethylphenyl)-methylene]-6-fluoro-2-indolinone .52 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-carboxymethylphenyl)-methylene]-6-fluoro-2-indolinone .53 3-Z-[1 -(4-(2-dimethylaminoethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone .54 3-Z-[1 -(4-(1 -methylimidazol-2-yl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone .55 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone .56 3-Z-[1 -(4-((4-methylpiperazin-1 -yl)methyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone .57 3-Z-[1 -(4-(imidazol-1 -ylmethyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone .58 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone .59 3-Z-[1 -(4-((4-methylpiperazin-1 -yl)methyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone .60 3-Z-[1 -(4-(imidazol-1 -ylmethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone .61 3-Z-[1 -(4-(pyrrolidin-1 -ylmethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone .62 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone .63 3-Z-[1 anilino-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2- indolinone 45 .64 3-Z-[1-(4-aminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]- 6-fluoro-2-indolinone .65 3-Z-[1 -(4-methylaminomethylanilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone .66 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carboxymethoxy-phenyl)-methylene]-6-fluoro-2-indolinone .67 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-carboxymethoxy-phenyl)phenyl)methylene]-6-fluoro-2-indolinone .68 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone .69 3-Z-[1 -(4-(dimethylaminomethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone .70 3-Z-[1 -(4-(diethylaminomethyl )anilino)-1 -(4-(2-carboxyethyl)-methylene]-6-bromo-2-indolinone .71 3-Z-[1 -(3-dimethylaminomethylanilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone .72 3-Z-[1 -(3-dimethylaminomethylanilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone .73 3-Z-[1 -(3-dimethylaminomethylanilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 11.0 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2-carbamoyl-ethyl)phenyl)methylene]-6-chloro-2-indolinone 11.1 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-methylcarbamoyl-ethyl)phenyl)methylene]-6-chloro-2-indolinone 11.2 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-methylcarbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.3 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-dimethylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 46 11.4 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2-carbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.5 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-methylcarbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.6 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-dimethylcarbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.7 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carbamoylmethylphenyl)-methylene]-6-fluoro-2-indolinone 11.8 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-methylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 11.9 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carbamoylmethylphenyl)-methylene]-6-fluoro-2-indolinone 11.10 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-dimethylcarbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.11 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-(2-(4-methylpiperazin-1 -yl-carbonyl)ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.12 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-carbamoylmethylphenyl)methylene]-6-fluoro- 2-indolinone 11.13 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-carbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 11.14 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-dimethylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 11.15 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-methylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 11.16 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-methylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 47 11.17 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-dimethylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 11.18 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-methylcarbamoylmethylphenyl)methylene]-6- fluoro-2-indolinone 11.19 3-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(4-(2-methylcarbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.20 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -yimethyica rbonyl)-N-methylamino)anilino)-1-(4-(2-methylcarbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.21 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-methylcarbamoylethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.22 3-Z-[1-(4-(N-tert-butoxycarbonylmethylaminomethyl)anilino)-1-(4-(2-methylcarbamoylethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.23 3-Z-[1 -(4-(1 -methylimidazol-2-yl)anilino)-1 -(4-(2-methylcarbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.24 3-Z-[1 -(4-methylsulphonylanilino)-1 -(4-(2-methylcarbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.25 3-Z-[1 -(4-(4-methylpiperazin-1 -ylcarbonyl)anilino)-1 -(4-(2-methylcarbamoylethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.26 3-Z-[1 -(4-(4-methylpiperazin-1 -ylcarbonyl)anilino)-1 -(3-methylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 11.27 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-methylcarbamoylmethylphenyl)methylene]-6- fluoro-2-indolinone 12.0 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-acetylaminomethylphenyl)-methylene]-6-chloro-2-indolinone 48 12.1 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-acetylaminomethylphenyl)methylene]-6- chloro-2-indolinone 12.2 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-benzoylaminophenyl)-methylene]-6-chloro-2-indolinone 12.3 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -yimethyica rbonyl)-N-methylamino)anilino)-1-(4-benzoylaminomethylphenyl)methylene]-6- chloro-2-indolinone 12.4 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-acetylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 12.5 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-propionylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.6 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-benzoylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.7 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-phenylacetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.8 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2-acetylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.9 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2-benzoylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.10 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2-propionylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.11 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2-phenylacetylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.12 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-acetylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 12.13 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-propionylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 49 12.14 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-phenylacetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.15 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-acetylaminomethylphenyl)methylene]-6- fluoro-2-indolinone 12.16 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -yimethyica rbonyl)-N-methylamino)anilino)-1-(4-propionylaminomethylphenyl)methylene]-6- fluoro-2-indolinone 12.17 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -yimethyica rbonyl)-N-methylamino)anilino)-1-(4-phenylacetylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 12.18 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-cyclopropylcarbonylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 12.19 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-cyclobutylcarbonylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 12.20 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-(pyridin-2-yl-carbonylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.21 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-cyclohexylcarbonylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 12.22 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -yimethyica rbonyl)-N-methylamino)anilino)-1-(3-(pyridin-3-yl-carbonylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.23 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-isobutyrylaminomethylphenyl)methylene]-6- fluoro-2-indolinone 50 12.24 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -yimethyica rbonyl)-N-methylamino)anilino)-1-(3-(3-methylbutyrylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 12.25 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1 -(3-cyclohexylmethylcarbonylaminomethylphenyl)methylene]-6-fluoro-2- indolinone 12.26 3-Z-[1 -(4-(N-(4-methylpiperaziri-1 -yimethyica rbonyl)-N-methylamino)anilino)-1-(3-methoxyacetylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 12.27 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N- methylamino)anilino)-1-(3-(2-methoxybenzoyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.28 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-tert-butylacetylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 12.29 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-thiophen-carbonylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.30 3-Z-[1 -(4-(N-(4-methyl pi perazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-pivaloylaminomethylphenyl)methylene]-6- fluoro-2-indolinone 12.31 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-furoylaminomethyl)phenyl)methylene]-6- fluoro-2-indolinone 12.32 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -yimethyica rbonyl)-N-methylamino)anilino)-1-(3-acetylaminomethylphenyl)methylene]-6- fluoro-2-indolinone 51 12.33 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-propionylaminomethylphenyl)methylene]-6- fluoro-2-indolinone 12.34 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-benzoylaminomethylphenyl)methylene]-6- fluoro-2-indolinone 12.35 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-phenylacetylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 12.36 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-cyclopropylcarbonylaminomethylphenyl)methylene]-6-fluoro-2- indolinone 12.37 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-cyclobutylcarbonylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.38 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(pyridin-2-yl-carbonylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.39 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-cyclohexylcarbonylaminomethylphenyl)methylene]-6-fluoro-2- indolinone 12.40 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(pyridin-3-yI -carbonylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.41 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-isobutyrylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.42 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(3-methylbutyryl-aminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.43 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-cyclohexylmethylcarbonylaminomethylphenyl)methylene]-6-fluoro-2- indolinone 52 12.44 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-methoxyacetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.45 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2-methoxybenzoyl-aminomethyl)phenyl)methylene]-6-fluoro-2-iridolinone 12.46 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-tert-butylacetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.47 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2-thiophenecarbonylaminomethyl)phenyl)methylene]-6-fluoro-2- indolinone 12.48 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-pivaloylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.49 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2-furoylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.50 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(pyridin-4-yI -carbonylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 13.0 3-Z-[1 -(4-trimethylammoniummethylanilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone iodide 13.1 3-Z-[1 -(4-trimethylammoniummethylanilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone iodide 14.0 3-Z-[1 -(4-guanidinomethylanilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 14.1 3-Z-[1 -(4-guanidinomethylanilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone Abbreviations used: 53 HOBt = 1 -hydroxy-1 H-benzotriazole 5 TBTU = 0-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate Preparation of the starting materials: 10 Example I: Dimethyl 2-(4-fluoro-2-nitrophenvl)malonate With ice-cooling, 185 g of potassium ferf-butoxide are added to a solution of 188 ml of dimethyl malonate in 970 ml of N-methylpyrrolidone, and the mixture is stirred for 15 2 hours. Over a period of 30 minutes, 150 ml of 2,5-difluoronitrobenzene are added dropwise to the resulting slurry, and the mixture is then stirred at 85°C for 6 hours. The mixture is poured into 4 liters of ice-water and 250 ml of concentrated hydrochloric acid and extracted with 2 liters of ethyl acatate. The organic phase is dried with sodium sulphate and concentrated. The oily residue is triturated twice with 20 water and then taken up in 600 ml of ethyl acetate. The solution is dried with sodium sulphate and concentrated to dryness. The resulting crude product is recrystallized ) from 600 ml of ethyl acetate/hexane = 2:8 and dried.

Yield: 222 g (59% of theory) Rf value: 0.40 (silica gel, cyclohexane/ethyl acetate = 5:1) CnHioFNOe Mass spectrum: m/z = 270 [M-H]" The following compounds are prepared analogously to Example I: (1.1) Diethyl 2-(4-bromo-2-nitrophenyl)malonate from 2,5-dibromonitrobenzene and diethyl malonate Rf value: 0.40 (silica gel, petroleum ether/ethyl acetate = 5:1) Ci3Hi4BrN06 54 Mass spectrum: m/z = 359/361 [M]+ (I.2) Dimethyl 2-(4-cyano-2-nitrophenyl)malonate from 4-chloro-3-nitrobenzonitrile and dimethyl malonate 5 Rf value: 0.50 (silica gel, methylene chloride/methanol = 50:1) C12H10N2O6 Mass spectrum: m/z = 277 [M-H]" Example II: ^ Methyl 4-cvano-2-nitrophenvlacetate 14.2 g of dimethyl 2-(4-cyano-2-nitrophenyl)malonate (starting material 1.2) are dissolved in 200 ml of dimethyl sulphoxide, and 4.5 g of lithium chloride and 1.0 ml of water are added. The solution is stirred at 100°C for 3.5 hours, 300 ml of ice-water 15 are then added and the mixture is allowed to stand for 12 hours. The resulting precipitate is filtered off with suction, taken up in methylene chloride and washed with water. The organic phase is dried over sodium sulphate, concentrated using a rotary evaporator and dried.

Yield: 7.7 g (68% of theory) Rf value: 0.40 (silica gel, methylene chloride/methanol) = 50:1 C10H8N2O4 | Mass spectrum: m/z = 219 [M-H]" Example III: 4-Fluoro-2-nitrophenvlacetic acid At 100°C, 50.0 g of dimethyl 2-(4-fluoro-2-nitrophenyl)malonate (starting material I) are stirred in 400 ml of 6 molar hydrochloric acid for 20 hours, 400 ml of water are then added and the mixture is cooled to 0°C. The resulting precipitate is filtered off 30 with suction, washed with water and 100 ml of petroleum ether and dried.

Yield: 34.5 g (94% of theory) Rf value: 0.30 (silica gel, cyclohexane/ethyl acetate) = 5:2 C8H6FN04 55 Mass spectrum: m/z = 154 [M-COO-H]" Example IV: 6-Fluoro-2-indolinone With addition of 20 g of palladium on activated carbon (10%), 119 g of 4-fluoro-2-nitrophenylacetic acid (starting material III) are hydrogenated in 600 ml of acetic acid under a hydrogen pressure of 50 psi. The catalyst is filtered off with suction and the 10 solvent is distilled off. The crude product is triturated with 500 ml of petroleum ether, filtered off with suction, washed with water and dried.

Yield: 82.5 g (91 % of theory) Rf value: 0.30 (silica gel, petroleum ether/ethyl acetate = 1:1) C8H6FNO Mass spectrum: m/z = 150 [M-H]" The following compounds are prepared analogously to Example IV: (IV.1) 6-Bromo-2-indolinone 20 from diethyl 2-(4-bromo-2-nitrophenyl)malonate (starting material 1.1) using Raney nickel as hydrogenation catalyst Rf value: 0.45 (silica gel, petroleum ether/ethyl acetate = 1:1) C8H6BrNO Mass spectrum: m/z = 210/212 [M-H]" (IV.2) 6-Cyano-2-indolinone from methyl 4-cyano-2-nitrophenylacetate (starting material II) using palladium/calcium carbonate as hydrogenation catalyst Rf value: 0.45 (silica gel, methylene chloride/methanol = 9:1) C9H6N20 Mass spectrum: m/z = 157 [M-H]" 56 Example V: 1 -acetyl-6-fluoro-2-indolinone At 130°C, 82.5 g of 6-fluoro-2-indolinone (starting material IV) are stirred in 180 ml 5 acetic anhydride for 3 hours. After cooling to room temperature, the precipitate is filtered off with suction, washed with 100 ml of petroleum ether and dried.

Yield: 64.8 g (61 % of theory) Rf value: 0.75 (silica gel, petroleum ether/ethyl acetate = 1:1) C10H8FNO2 10 Mass spectrum: m/z = 192 [M-H]" The following compounds are prepared analogously to Example V: (V.1) 1-acetyl-6-chloro-2-indolinone 15 from 6-chloro-2-indolinone and acetic anhydride Rf value: 0.55 (silica gel, petroleum ether/ethyl acetate = 2:3) CnHioCINOe Mass spectrum: m/z = 208/210 [M-H]" (V.2) 1-acetyl-6-bromo-2-indolinone from 6-bromo-2-indolinone (starting material IV. 1) and acetic anhydride | Rf value: 0.60 (silica gel, petroleum ether/ethyl acetate = 2:1) CioHsBrNC^ Mass spectrum: m/z = 253/255 [M]+ (V.3) 1 -acetyl-6-cyano-2-indolinone from 6-cyano-2-indolinone (starting material IV.2) and acetic anhydride Rf value: 0.60 (silica gel, methylene chloride/methanol = 50:1) C11H8N2O2 30 Mass spectrum: m/z = 199 [M-H]" 57 Example VI: 1-acetvl-3-ri-hvdroxv-1-(3-iodophenvl)methvlenel-6-chloro-2-indolinone 10.5 g of 1-acetyl-6-chloro-2-indolinone (starting material V.1), 13.6 g of 3-iodobenzoic acid and 17.7 g of TBTU are initially charged in 100 ml of dimethylformamide, 35 ml of triethylamine are added and the mixture is stirred at room temperature for 12 hours. After this time, the solvent is removed under reduced pressure, water is added to the residue and the residue is filtered off with suction, washed with a little water, methanol and ether and dried at 100°C under reduced 10 pressure.

^ Yield: 12.9 g (59 % of theory) Rf value: 0.80 (silica gel, methylene chloride/methanol = 9:1) C17H11CIINO3 Mass spectrum: m/z = 438/440 [M-H]" The following compounds are prepared analogously to Example VI: (VI. 1) 1-acetyl-3-[1-hydroxy-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro- 2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and methyl (4-carboxyphenyl)acetate (preparation according to Tetrahedron 1997, 53, 7335-) 7340) (VI.2) 1-acetyl-3-[1-hydroxy-1-(4-chlorophenyl)methylene]-6-chloro-2-indolinone 25 from 1 -acetyl-6-chloro-2-indolinone (starting material V.1) and 4-chlorobenzoic acid (VI .3) 1-acetyl-3-[1-hydroxy-1-(3,4-dimethoxyphenyl)methylene]-6-chloro-2-indolinone from 1-acetyl-6-chloro-2-indolinone (starting material V.1) and 3,4-dimethoxybenzoic 30 acid (VI.4) 1 -acetyl-3-[1-hydroxy-1 -(3,4-dimethoxyphenyl)methylene]-6-cyano-2-indolinone 58 from 1-acetyl-6-cyano-2-indolinone (starting material V.3) and 3,4-dimethoxybenzoic acid (VI.5) 1-acetyl-3-[1-hydroxy-1-(3-fluorophenyl)methylene]-6-fluoro-2-indolinone 5 from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-fluorobenzoic acid (VI.6) 1 -acetyl-3-[1 -hydroxy-1 -(4-(2-acetylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 4-(2-acetylaminoethyl)-10 benzoic acid (preparation according to J. Am. Chem. Soc. 1943, 65, 2377) (VI.7) 1 -acetyl-3-[1 -hydroxy-1 -(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and methyl 15 (3-carboxyphenyl)acetate (preparation analogously to Tetrahedron 1997, 53, 7335-7340) (VI.8) 1 -acetyl-3-[1 -hydroxy-1 -(3-(N-tert-butoxycarbonylaminomethyl)phenyl)-methylene]-6-fluoro-2-indolinone 20 from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-(N-tert-butoxycarbonyl- aminomethyl)benzoic acid (preparation according to Tetrahedron 1997, 53, 7335-| 7340) (VI.9) 1 -acetyl-3-[1 -hydroxy-1 -(3-cyanomethylphenyl)methylene]-6-fluoro-2-25 indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and (3-carboxyphenyl)-acetonitrile (preparation according to J. Prakt. Chem. 1998, 340, 367-374) (VI. 10) 1-acetyl-3-[1-hydroxy-1-(4-(N-tert-butoxycarbonylaminomethyl)phenyl)-30 methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 4-(N-tert-butoxycarbonyl-aminomethyl)benzoic acid (preparation according to Bioorg. Med. Chem. Lett 2000, 10, 553-557) 59 (Vl.11) 1-acetyl-3-[1-hydroxy-1-(4-iodophenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 4-iodobenzoic acid (VI. 12) 1-acetyl-3-[1-hydroxy-1-(4-iodophenyl)methylene]-6-chloro-2-indolinone from 1-acetyl-6-chloro-2-indolinone (starting material V.1) and 4-iodobenzoic acid (VI.13) 1-acetyl-3-[1-hydroxy-1-(3-iodophenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-iodobenzoic acid (VI.14) 1-acetyl-3-[1 -hydroxy-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 4-(2-methoxycarbonylethyl)benzoic acid (preparation analogously to Tetrahedron 1997, 15 53,7335-7340) (VI.15) 1-acetyl-3-[1-hydroxy-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-(2-20 methoxycarbonylethyl)benzoic acid (preparation analogously to Tetrahedron 1997, 53, 7335-7340) (VI. 16) 1-acetyl-3-[1-hydroxy-1 -(3-(N-tert-butoxycarbonyl-2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 25 from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-(N-tert-butoxycarbonyl-2-aminoethyl)benzoic acid (preparation analogously to Bioorg. Med. Chem. Lett 2000, 10, 553-557) (VI. 17) 1-acetyl-3-[1-hydroxy-1-(4-(N-tert-butoxycarbonyl-2-30 aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 4-(N-tert-butoxycarbonyl-2-aminoethyl)benzoic acid (preparation analogously to Bioorg. Med. Chem. Lett 2000, 10, 553-557) 60 (VI. 18) 1 -acetyl-3-[1 -hydroxy-1 -(4-cyanophenyl)methylene]-6-chloro-2-indolinone from 1-acetyl-6-chloro-2-indolinone (starting material V.1) and 4-cyanobenzoic acid (VI. 19) 1 -acetyl-3-[1-hydroxy-1 -(3-acetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-acetylaminomethyl-benzoic acid (prepared according to J. Med. Chem. 1997, 40, 4030-4052) | (VI.20) 1-acetyl-3-[1 -hydroxy-1 -(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-(2-ethoxycarbonylethyl)benzoic acid (preparation analogously to Tetrahedron 1997, 53, 15 7335-7340) (VI .21) 1-acetyl-3-[1 -hydroxy-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone from 1-acetyl-6-chloro-2-indolinone (starting material V.1) and 4-(2-20 methoxycarbonylethyl)benzoic acid (preparation analogously to Tetrahedron 1997, 53, 7335-7340) ^ (VI.22) 1-acetyl-3-[1 -hydroxy-1 -(4-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro- 2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 4-(2- ethoxycarbonylethyl)benzoic acid (preparation analogously to Tetrahedron 1997, 53, 7335-7340) (VI.23) 1-acetyl-3-[1-hydroxy-1-(3-methoxycarbonylmethyloxy-phenyl)methylene]-6-30 fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-methoxycarbonylmethyloxybenzoic acid (preparation see Tetrahedron Letters 1998, 39, 8563-8566) 61 (VI.24) 1-acetyl-3-[1 -hydroxy-1 -(4-methoxycarbonylmethyloxyphenyl)methylene]-6-fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 5 4-methoxycarbonylmethyloxybenzoic acid (preparation analogously to Tetrahedron Letters 1998, 39, 8563-8566) (VI .25) 1 -acetyl-3-[1 -hydroxy-1 -(3-(2-ethoxycarbonylethyloxy)phenyl)methylene]-6-fluoro-2-indolinone 10 from 1 -acetyl-6-fluoro-2-indolinone (starting material V) and 3-(2- ethoxycarbonylethyloxy)benzoic acid (preparation see PCT Int. Appl. W09620173, 60) (VI.26) 1-acetyl-3-[1-hydroxy-1-(4-(2-ethoxycarbonylethyloxy)phenyl)methylene]-6-15 fluoro-2-indolinone from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 4-(2-ethoxycarbonylethyloxy)benzoic acid (preparation see PCT Int. Appl. W09620173, 58) (VI.27) 1-acetyl-3-[1 -hydroxy-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-bromo-2-indolinone from 1-acetyl-6-bromo-2-indolinone (starting material V.2) and 4-(2-methoxycarbonylethyl)-benzoic acid (preparation analogously to Tetrahedron 1997, 53, 7335-7340) Example VII: 1-acetvl-3-M-methoxv-1-(3-iodophenvl)methvlenel-6-chloro-2-indolinone 30 A little at a time, 2.36 g of trimethyloxonium tetrafluoroborate are added to a solution of 3.52 g of 1-acetyl-3-[1-hydroxy-1-(3-iodophenyl)methylene]-6-chloro-2-indolinone (starting material VI) and 2.72 ml of ethyldiisopropylamine in 80 ml of dichloromethane, and the mixture is stirred at room temperature for one hour. 62 Another 1.4 ml of ethyldiisopropylamine and 1.2 g of trimethyloxonium tetrafluoroborate are added, and the mixture is stirred at room temperature for another two hours. The mixture is then extracted with water and the organic phase is dried over magnesium sulphate and evaporated to dryness. The residue is 5 recrystallized from ether and dried at 80°C under reduced pressure.

Yield: 2.40 g (66 % of theory) Rf value: 0.60 (silica gel, petroleum ether/dichloromethane/ethyl acetate = 5:4:1) C18H13CIINO3 Mass spectrum: m/z = 438/440 [M-H]" m.p. 185- 187 °C The following compounds are prepared analogously to Example VII: (VI 1.1) 1-acetyl-3-[1-methoxy-1-(4-methoxycarbonylmethylphenyl)methylene]-6-15 fluoro-2-indolinone from 1 -acetyl-3-[1 -hydroxy-1 -(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone (starting material VI.1) (VII.2) 1-acetyl-3-[1-methoxy-1-(4-chlorophenyl)methylene]-6-chloro-2-indolinone 20 from 1 -acetyl-3-[1 -hydroxy-1 -(4-chlorophenyl)methylene]-6-chloro-2-indolinone (starting material VI.2) i (VII.3) 1-acetyl-3-[1-methoxy-1-(3,4-dimethoxyphenyl)methylene]-6-chloro-2-indolinone from 1 -acetyl-3-[1 -hydroxy-1 -(3,4-dimethoxyphenyl)methylene]-6-chloro-2-indolinone (starting material VI.3) (VI 1.4) 1 -acetyl-3-[1-methoxy-1 -(3,4-dimethoxyphenyl)methylene]-6-cyano-2-indolinone from 1 -acetyl-3-[1 -hydroxy-1 -(3,4-dimethoxyphenyl)-methylene]-6-cyano-2-indolinone (starting material VI.4) (VI 1.5) 1 -acetyl-3-[1-methoxy-1 -(3-fluorophenyl)methylene]-6-fluoro-2-indolinone 63 from 1 -acetyl-3-[1 -hydroxy-1 -(3-fluorophenyl)methylene]-6-fluoro-2-indolinone (starting material VI.5) (VII.6) 1-acetyl-3-[1-methoxy-1-(4-(2-acetylaminoethyl)phenyl)methylene]-6-fluoro-2-5 indolinone from 1 -acetyl-3-[1 -hydroxy-1 -(4-(2-acetylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI.6) (VII.7) 1 -acetyl-3-[1 -methoxy-1 -(3-methoxycarbonylmethylphenyl)methylene]-6-10 fluoro-2-indolinone from 1 -acetyl-3-[1-hydroxy-1 -(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone (starting material VI.7) (VII.8) 1-acetyl-3-[1-methoxy-1-(3-(N-tert-butoxycarbonylaminomethyl)phenyl)-15 methylene]-6-fluoro-2-indolinone from 1 -acetyl-3-[1 -hydroxy-1 -(3-(N-tert-butoxycarbonyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI.8) (VI 1.9) 1-acetyl-3-[1-methoxy-1-(3-cyanomethylphenyl)methylene]-6-fluoro-2-20 indolinone from 1 -acetyl-3-[1 -hydroxy-1 -(3-cyanomethylphenyl)methylene]-6-fluoro-2-indolinone ^ (starting material VI.9) (VI 1.10) 1 -acetyl-3-[1 -methoxy-1 -(4-(N-tert-butoxycarbonyl-25 aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone from 1 -acetyl-3-[1 -hydroxy-1 -(4-(N-tert-butoxycarbonyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI.10) (Vll.11) 1-acetyl-3-[1-methoxy-1-(4-iodophenyl)methylene]-6-fluoro-2-indolinone from 1 -acetyl-3-[1 -hydroxy-1 -(4-iodophenyl)methylene]-6-fluoro-2-indolinone (starting material Vl.11) 64 (VII. 12) 1 -acetyl-3-[1 -methoxy-1 -(4-iodophenyl)methylene]-6-chloro-2-indolinone from 1 -acetyl-3-[1 -hydroxy-1 -(4-iodophenyl)methylene]-6-chloro-2-indolinone (starting material VI.12) (VII.13) 1-acetyl-3-[1-methoxy-1-(3-iodophenyl)methylene]-6-fluoro-2-indolinone from 1 -acetyl-3-[1 -hydroxy-1 -(3-iodophenyl)methylene]-6-fluoro-2-indolinone (starting material VI. 13) (VII. 14) 1 -acetyl-3-[1 -methoxy-1 -(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone from 1 -acetyl-3-[1 -hydroxy-1 -(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI. 14) (VII.15) 1-acetyl-3-[1 -methoxy-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone from 1 -acetyl-3-[1 -hydroxy-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI.15) (VII.16) 1-acetyl-3-[1-methoxy-1-(4-(N-tert-butoxycarbonyl-2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone from 1 -acetyl-3-[1 -hydroxy-1 -(4-(N-tert-butoxycarbonyl-2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI.17) (VII.17) 1-acetyl-3-[1-methoxy-1-(3-(N-tert-butoxycarbonyl-2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone from 1 -acetyl-3-[1 -hydroxy-1 -(3-(N-tert-butoxycarbonyl-2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI.16) (VI 1.18) 1 -acetyl-3-[1 -methoxy-1 -(3-acetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone from 1 -acetyl-3-[1 -hydroxy-1 -(3-acetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone (starting material VI.19) 65 (VII.19) 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-2-5 indolinone (starting material VI.20) (VI 1.20) 1 -acetyl-3-[1 -methoxy-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone from 1 -acetyl-3-[1 -hydroxy-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-10 2-indolinone (starting material VI.21) (VII.21) 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-2-15 indolinone (starting material VI.22) (VII.22) 1 -acetyl-3-[1 -methoxy-1 -(4-methoxycarbonylmethyloxyphenyl)-methylene]-6-fluoro-2-indolinone from 1-acetyl-3-[1 -hydroxy-1 -(4-methoxycarbonylmethyloxyphenyl)methylene]-6-20 fluoro-2-indolinone (starting material VI.23) (VI 1.23) 1 -acetyl-3-[1 -methoxy-1 -(3-methoxycarbonylmethyloxyphenyl)-methylene]-6-fluoro-2-indolinone from 1 -acetyl-3-[1 -hydroxy-1 -(3-methoxycarbonylmethyloxyphenyl)methylene]-6-25 fluoro-2-indolinone (starting material VI.24) (VI 1.24) 1 -acetyl-3-[1 -methoxy-1 -(3-(2-ethoxycarbonylethyloxy)phenyl)methylene]-6-fluoro-2-indolinone from 1 -acetyl-3-[1 -hydroxy-1 -(3-(2-ethoxycarbonylethyloxy)phenyl)methylene]-6-30 fluoro-2-indolinone (starting material VI.25) (VI 1.25) 1 -acetyl-3-[1 -methoxy-1 -(4-(2-ethoxycarbonylethyloxy)phenyl)methylene]-6-fluoro-2-indolinone 66 from 1 -acetyl-3-[1 -hydroxy-1 -(4-(2-ethoxycarbonylethyloxy)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI.26) (VI 1.26) 1 -acetyl-3-[1 -methoxy-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-bromo-2-indolinone from 1 -acetyl-3-[1 -hydroxy-1 -(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-bromo-2-indolinone (starting material VI.27) Example VIII: 1 -Acetvl-3-f1 -chloro-1 -(4-cvanophenvl)methvlene1-6-chloro-2-indolinone A suspension of 7.0 g of 1-acetyl-3-[1 -hydroxy-1 -(4-cyanophenyl)methylene]-6-chloro-2-indolinone (starting material VI.18) and 6.39 g of phosphorus pentachloride in 150 ml of dioxane is stirred at 100°C for 6 hours. After addition of a further 1.0 g of 15 phosphorus pentachloride, the mixture is stirred at 110°C for another 4 hours. The solvent is then distilled off and the residue is washed with ethyl acetate.

Yield: 4.5 g (61 % of theory) Rf value: 0.70 (silica gel, methylene chloride/methanol = 50:1) C18H10CI2N2O2 Example IX: The syntheses of the following compounds have already been described in the international application WO 01/27081: (IX.1) 4-(diethylaminomethyl)aniline (IX.2) N-(2-dimethylaminoethyl)-N-methylsulphonyl-p-phenylenediamine 30 (IX.3) 3-(dimethylaminomethyl)aniline (IX.4) 4-(dimethylaminomethyl)aniline 67 (IX.5) 4-(2-dimethylaminoethyl)aniline (IX.6) 4-[N-(2-dimethylaminoethyl)-N-acetylamino]aniline 5 (IX.7) 4-[N-(3-dimethylaminopropyl)-N-acetylamino]aniline (IX.8) 4-[(N-dimethylaminocarbonylmethyl-N-methylsulphonyl)amino]anilirie (IX.9) N-(4-aminophenyl)-N-methylmethanesulphonamide (IX.10) N-(dimethylaminomethylcarbonyl)-N-methyl-p-phenylenediamine (IX. 11) N-[(2-dimethylaminoethyl)carbonyl]-N-methyl-p-phenylenediamine 15 (IX. 12) 4-(N-tert-butoxycarbonylaminomethyl)aniline (IX. 13) 4-(N-ethyl-N-tert-butoxycarbonylaminomethyl)aniline (IX.14) 4-[(4-methylpiperazin-1-yl)methyl]aniline (IX.15) 4-(imidazol-1 -ylmethyl)aniline (IX. 16) 4-(1 -methylimidazol-2-yl)aniline 25 (IX.17) 4-[(N-(2-dimethylaminoethyl)-N-methylamino)methyl]aniline (IX.18) 4-(N-methyl-N-tert-butoxycarbonylaminomethyl)aniline (IX.19) N-[(4-methylpiperazin-1 -yl)methylcarbonyl]-N-methyl-p-phenylenediamine (IX.20) 4-(4-tert-butoxycarbonylpiperazin-1 -ylmethyl)aniline (IX.21) 4-(thiomorpholin-4-ylmethyl)aniline 68 (IX.22) 4-(pyrrolidin-1 -ylmethyl)aniline (IX.23) 4-(morpholin-4-yl-methyl)aniline (IX.24) 4-(N-benzyl-N-methylaminomethyl)aniline (IX.25) 4-(N-ethyl-N-methy!aminomethyl)aniline 10 (IX.26) 4-[N-(2-dimethylaminoethyl)-N-methylamino]aniline (IX.27) 4-[(N-propyl-N-methylamino)methyl]aniline The following compounds are prepared analogously to Example IX: (IX.28) 4-[N-(2-(N-benzyl-N-methylamino)ethyl)-N-acetylamino]aniline (IX.29) 4-amino-N-(2-dimethylaminoethyl)-N-methylbenzamide 20 (IX.30) 4-(4-methylpiperazin-1-ylcarbonyl)aniline I (IX.31) 4-(2-dimethylaminoethoxy)aniline (IX.32) N-(4-dimethylaminobutylcarbonyl)-N-methyl-p-phenylenediamine (IX.33) N-[(3-dimethylaminopropyl)carbonyl]-N-methyl-p-phenylenediamine 69 Preparation of the end products: Example 1.0 3-Z-M-(4-(N-Methvl-N-methvlsulphonvlamino)anilino)-1-(3-iodophenvl)methvlene1-6-chloro-2-indolinone 0.9 g of 1-acetyl-3-(1 -methoxy-1 -(3-iodophenyl)methylene)-6-chloro-2-indolinone (starting material VII) and 0.5 g of N-methyl-N-methylsulphonyl-p-phenylenediamine (starting material IX.9) are dissolved in 10 ml of dimethylformamide and stirred at 10 120°C for 3 hours. After cooling, 1.5 ml of piperidine are added and the mixture is stirred at room temperature for another hour. Water is added and the resulting precipitate is filtered off with suction, washed with a little water, methanol and ether and finally dried under reduced pressure at 100°C.

Yield: 0.9 g (74% of theory), Rf value: 0.6 (silica gel, methylene chloride/methanol = 9:1) m.p. 292-294 °C C23H19CIIN3O3S Mass spectrum: m/z = 578/580 [M-H]" The following compounds of the formula 1-1 are prepared analogously to Example 1.0: (1-1) 70 Ex-ampl e R3 R4' Starting materials Empirical formula Mass spectrum m.p.

[°C] Rf value* 1.1 <4 -CH2-NMe2 vii ix.4 c24h21ciin3o 529/531 [M+H]+ 238-240 0.30 (A) 1.2 -N(Me)-(CO)-CH2-NMe2 vii.2 ix.10 c26h24ci2n4o2 495/497 [M+H]+ 277-279 0.20 (B) 1.3 Clx Qc -N(COMe)-(CH2)2-NMe2 vii.2 ix.6 c27h26ci2n4o2 507/509 [M-H]" 241-243 0.10 (B) 1.4 Ck Qc pn-Me Me. f ^ wn O vii.2 ix.19 c29h2gci2n502 548/550 [m-h]- 266-268 0.10 (B) 1.5 CL Qc -N(COMe)-(CH2)3-NMe2 vii.2 ix.7 c28h28ci2n4o2 521/523 [M-H]' 241-242 0.10 (B) 1.6 CL Qc -CH2-NMe2 vii.2 ix.4 c24H2ici2n30 438/440 [M+H]+ 243-244 0.10 (B) 1.7 OMe MeO j -N(COMe)-(CH2)2-NMe2 vii.3 ix.6 c29h31cin4o4 533/535 [M-H]" 128-130 0.75 (C) 1.8 MeO ?Me pN-Me Me. f ^ wN o vii.3 ix.19 c3iH34CINS04 574/576 [m-h]- 208-210 0.65 (C) 1.9 MeO ,OMe -N(S02Me)-(CH2)2-NMe2 vii.3 ix.2 c28H3I ci n4oss 569/571 [M-H]- 198-200 0.75 (C) 1.10 ^ OMe MeO j A -CH2-NMe2 vii.3 ix.4 c26h26cin3o3 462/464 [M-H]" 239-240 0.70 (c) 71 MeO ?Me 0 jye VII.3 533/535 147- 0.70 1.11 rs C29H31CIN4O4 [M-H]- 149 (C) NMe2 IX.29 *Eluent mixtures: (A): silica gel, methylene chloride/methanol 9:1 (B): silica gel, methylene chloride/ethanol 10:1 (C): silica gel, methylene chloride/methanol 4:1 Example 2.0 3-Z-f1-(4-(Dimethvlaminomethvl)anilino)-1-(4-cvanophenvl)methvlenel-6-chloro-2-indolinone 1.07 g of 1-acetyl-3-[1-chloro-1-(4-cyanophenyl)methylene]-6-chloro-2-indolinone (starting material VII) and 0.54 g of 4-(dimethylaminomethyl)aniline (starting material IX.4) are dissolved in 10 ml of dimethylformamide and stirred at 80°C for 3 hours. 15 After cooling, 1 ml of 6N aqueous sodium hydroxide is added, and the mixture is stirred at room temperature for 30 minutes. Water is added and the mixture is extracted three times with methylene chloride. The combined organic phases are washed twice with water, dried over sodium sulphate and concentrated using a rotary evaporator, and the product is recrystallized from diethyl ether.

Yield: 0.92 g (72% of theory), Rf value: 0.1 (silica gel, methylene chloride/methanol = 9:1) C25H21CIN4O Mass spectrum: m/z = 427/429 [M-H]-25 Example 3.0 3-Z-[1-(4-(dimethvlaminomethvl)anilino)-1 -(4-iodophenvl)methylene1-6-fluoro-2-indolinone 3.5 g of 1-acetyl-3-(1-methoxy-1-(4-iodophenyl)methylene)-6-fluoro-2-indolinone 30 (starting material VII.11) and 1.6 g of 4-(dimethylaminomethyl)aniline (starting 72 material IX.4) are dissolved in 30 ml of dimethylformamide and stirred at 120°C for 2 hours. After cooling, the solvent is removed under reduced pressure, the residue is taken up in 30 ml of methanol and 2 spatula tips of sodium methoxide are added. Once a yellow precipitate has formed, this is filtered off with suction from the solvent 5 and the residue is washed with a little methanol and ether and finally dried under reduced pressure at 100°C.

Yield: 1.9 g (46% of theory), Rf value: 0.3 (silica gel, methylene chloride/methanol = 9:1) m.p. 243-246 °C 10 C24H21FIN3O Mass spectrum: m/z = 514 [M+H]+ The following compounds of the formula l-3a are prepared analogously to Example 3.0: Ex-amp le R2 R3 R4' Starting materials Empirical formula Mass spectrum m.p. [°C] Rf value* f U VII.5 404 225- 0.20 3.1 -F Cl -CH2-NMe2 C24H21F2N3O 227 H- IX.4 [M-H]" (A) 3.2 -F 4 -N(COMe)-(CH2)3-NMe2 VII.5 IX.7 C28H28F 2N402 491 [M+H]+ 160-163 0.20 (A) 73 3.3 -F 4 pN'Me Me. /* -Po VII.5 IX.19 C2gH2gF2Ns02 518 [M+H]+ 218-220 0.40 (A) 3.4 -F H3CrO N 4 -CH2-NMe2 VII.6 IX.4 C28H2gFN402 471 [M-H]- 106-110 0.25 (A) 3.5 -F H3C^0 N h -N(COMe)-(CH2)3-NMe2 VII.6 IX.7 C32H36FNS03 558 [M+H]+ 194-196 0.25 (A) 3.6 -F H3CrO N h pN-Me Me. f ^ -Po VII.6 IX.19 C33H37FN6O3 583 [M-H]- 238-240 0.25 (A) 3.7 -F °y-OMe -CH2-NMe2 VII.1 IX.4 C27H26FN303 460 [M+H]+ 173-176 0.30 (A) 3.8 -F 4 -CH2-NMe2 VII.13 IX.4 C24H2iFIN30 514 [M+H]+ 198-200 0.30 (B) 3.9 -F o -CH2-NMe2 VII.7 IX.4 C27H26FN303 458 [M-H]' 195-198 0.25 (A) 3.10 -F tBuO n r° ,-NH 4 -CH2-NMe2 VII.8 IX.4 C3OH33FN403 517 [M+H]+ 230-240 0.30 (A) 74 3.11 -f -N(S02Me)-(CH2)2-NMe2 VII.1 IX.2 c29h3ifn405s 567 [M+H]+ 188-189 0.40 (A) 3.12 -f °^-OMe P M-Me Me. f ^ -;N O VII.1 IX.19 c32h34fnS04 572 [M+H]+ 200-203 0.35 (c) 3.13 -f ,-CN 4 -CH2-NMe2 VII.9 IX.4 c26H23fn4o 427 [M+H]+ 130-135 0.25 (A) 3.14 -f OtBu p N-Me Me. f ^ N~s- -/ o VII.10 IX.19 c35h41fn604 629 [M+H]+ 215-220 0.35 (A) 3.15 -f OtBu HN^ $ -CH2-NMe2 VII.10 IX.4 C30H33FN4O3 517 [M+H]+ 186-190 0.35 (A) 3.16 -f OtBu U NH i -CH2-NMe2 VII.17 IX.4 C31H35FN403 531 [M+H]+ n.d. 0.40 (A) 3.17 -f OMe \ -NMe-(COMe) VII.15 c28h26fn304 488 [M+H]+ 166-170 0.40 (A) 3.18 -f OMe \ pN.Me Me. _T ^ -;N O VII.15 IX.19 C33H36FN504 586 [M+H]+ 176-180 0.30 (A) 75 3.19 -F OMe \ -N(S02Me)-(CH2)2-NMe2 VII.15 IX.2 C30H33FN4O5S 581 [M+H]+ 195-198 0.45 (A) 3.20 -F OMe -N(COMe)-(CH2)3-NMe2 VII.15 IX.7 C32H35FN404 559 [M+H]+ 100-104 0.50 (A) 3.21 -F OMe \ Me °tBu " o VII.15 IX.18 C32H34FN305 558 [M-H]" 132-137 0.80 (D) 3.22 -F OMe J, 'N-Me -rN^ VII.15 IX.30 C31H31FN4O4 543 [M+H]+ 234-236 0.60 (A) 3.23 -F OMe Me VII.15 IX.16 C29H25FN403 497 [M+Hf 110-115 0.40 (A) 3.24 -F OMe -S02Me VII.15 C26H23FN205S 495 [M+H]+ 130-137 0.60 (A) 3.25 -F O ^OMe P N-Me Me. f ^ wN o VII.7 IX.19 C32H34FNS04 572 [M+H]+ 189 0.60 (B) 3.26 -F o ^OMe -N(S02Me)-(CH2)2-NMe2 VII.7 IX.2 CMH31FN4O5S 567 [M+Hf n.d. 0.60 (B) 76 3.27 -F 0 ^°Me o 0 o / VII.7 IX.30 C3oH2gFN404 529 [M+H]+ 201-203 0.60 (B) 3.28 -F o ^OMe -N(Me)-(CO)-CH2-NMe2 VII.7 IX.10 C29H2gFN404 517 [M+H]+ 126 0.60 (B) 3.29 -F o ^OMe -N(COMe)-(CH2)2-NMe2 VII.7 IX.6 C30H31FN4O4 531 [M+H]+ 179 0.50 (B) 3.30 -F o ^OMe -N(COMe)-(CH2)3-NMe2 VII.7 IX.7 C31H33FN404 545 [M+H]+ 123 0.20 (B) 3.31 -F o ^OMe -N(Me)-(CO)-(CH2)4-NMe2 VII.7 IX.32 C32H3SFN404 559 [M+H]+ 201 0.20 (B) 3.32 -F °^OMe -H VII.1 C24Hi9FN203 403 [M+H]+ 198-206 0.80 (A) 3.33 -F °^OMe ■J? Me VII.1 IX.16 C28H23FN403 483 [M+H]+ 223-226 0.75 (A) 3.34 -F °y-OMe Q< 0^N3NMe VII.1 IX.30 C3oH2gFN404 529 [M+H]+ 215-220 0.30 (A) 3.35 -F CVoMe -N(S02Me)-(CH2)-(CO)-NMe2 VII.1 IX.8 C2gH29FN406S 581 [M+H]+ 227-230 0.65 (A) 77 3.36 -F °^-OMe a -N(Me)-(CO)-CH2-NMe2 vii.1 ix.10 c2gh2gfn404 517 [M+H]+ 128-130 0.45 (A) 3.37 -F °|-OMe -N(COMe)-CH3 vii.1 C27H24FN304 474 [M+H]+ 218-223 0.40 (A) 3.38 -F °|-OMe -N(Me)-(CO)-(CH2)2-NMe2 vii.1 ix.11 C30H31FN4O4 531 [M+H]+ 192-194 0.40 (A) 3.39 -F -S02Me vii.1 c25h2ifn205s 481 [M+H]+ 205-214 0.65 (A) 3.40 -F °^OMe -N(Me)-(CO)-(CH2)3-NMe2 vii.1 ix.33 C3iH33FN404 545 [M+H]+ 190-193 0.15 (A) 3.41 -F °y~OMe -N(COMe)-(CH2)3-NMe2 vii.1 ix.7 C3IH33FN404 545 [M+H]+ 184-188 0.50 (A) 3.42 -f O ^OMe -h vii.7 c24h19fn2o3 403 [M+H]+ 114 0.70 (B) 3.43 -f o ^OMe -S02Me vii.7 C25H2iFN205S 481 [M+H]+ 129 0.60 (B) 3.44 -f o ■>$ Me vii.7 ix.16 c28h23fn4o3 483 [M+H]+ 125 0.60 (B) 78 3.45 -F o ^°Me -N(S02Me)-(CH2)-(CO)-NMe2 VII.7 IX.8 C2gH29FN406S 581 [M+H]+ 163 0.60 (B) 3.46 -F o ^OMe -N(Me)-(CO)-(CH2)3-NMe2 VII.7 IX.33 C31H33FN4O4 545 [M+H]+ 101 0.10 (B) 3.47 -F o ^OMe -N(Me)-(CO)-(CH2)2-NMe2 VII.7 IX.11 C30H31FN4O4 531 [M+H]+ 161 0.20 (B) 3.48 -F p N-Me Me. f ^ -Fo VII.14 IX.19 C30H31FN4O4 586 [M+H]+ 181-183 0.20 (B) 3.49 -F MeO q -N(S02Me)-(CH2)2-NMe2 VII.14 IX.2 C30H33FN4O5S 581 [M+H]+ 158-160 0.35 (B) 3.50 -F MeO q dx -N(Me)-(CO)-CH2-NMe2 VII.14 IX.10 C30H31FN4O4 531 [M+H]+ n.d. 0.40 (B) 3.51 -F MeO q -N(COMe)-(CH2)3-NMe2 VII.14 IX.7 C32H35FN404 559 [M+H]+ n.d. 0.50 (E) 3.52 -F tBu°ro .-NH 4 P N-Me r-N J Me. j ^ w o VII.8 IX.19 C35H41FN6O4 629 [M+H]+ n.d. 0.35 (A) 79 3.53 -F °rCH3 HN 4 -NMe-(CO)- ch3 VII.26 c27h25fn403 473 [M+H]+ 122-126 0.50 (F) 3.54 -F VCH3 HN <4 -N(COMe)-(CH2)3-NMe2 VII.26 IX.7 C31H34FN5O3 544 [M+H]+ 80-83 0.25 (A) 3.55 -F VCH3 HN 4 -N(S02Me)-(CH2)2-NMe2 VII.18 IX.2 c2gh32fn504s 566 [M+H]+ 190-195 0.30 (A) 3.56 -F VCH3 HN 4 -N(Me)-(CO)-CH2-NMe2 VII.18 IX.10 cmh30fn5o3 516 [M+H]+ 238-241 0.30 (g) 3.57 -F OMe \ -(CH2)2-NMe2 VII.15 IX.5 C29H3oFN303 488 [M+H]+ 205-208 0.55 (G) 3.58 -F OMe \ -N(Me)-(CO)-(CH2)2-NMe2 VII.15 IX.11 C31H31FN404 543 [M-H]" 196-202 0.20 (a) 3.59 -F OMe \ -N(Me)-(CO)-CH2-NMe2 VII.15 IX.10 C30H31FN4O4 531 [M+H]+ 177-182 0.30 (a) 3.60 -F Etoro (X -(CH2)2-NMe2 VII.19 IX.5 c3oh32fn303 500 [M-H]- 100-105 0.35 (b) 80 3.61 -F OMe \ -N(COMe)-(CH2)2-NMe2 VII.15 IX.6 C31H33FN4O4 545 [M+H]+ 167-169 0.40 (a) 3.62 -F Etoro o -N(Me)-(CO)-(CH2)3-NMe2 VII.19 IX.33 C33H37FN4O4 571 [M-H]' n.d. 0.35 (a) 3.63 -F ^O -N(Me)-(CO)-(CH2)4-NMe2 VII.19 IX.32 C34H39FN4O4 585 [M-H]" n.d. 0.40 (a) 3.64 -F ^o ■J? Me VII.19 IX.16 C3OH27FN403 511 [M+H]+ 95-105 0.25 (b) 3.65 -F OMe -N(Me)-(CO)-(CH2)4-NMe2 VII.15 IX.32 C33H37FN4O4 573 [M+H]+ 173-175 0.20 (a) 3.66 -F OMe -H VII.15 c25h21fn2o3 417 [M+H]+ 168-174 0.65 (a) 3.67 -F OMe *0 VII.15 IX.22 C30H30FN3O3 500 [M+H]+ 168-173 0.40 (b) 3.68 -F OMe -CH2-NEt2 VII.15 IX.1 c3oh32fn303 502 [M+H]+ n.d. 0.45 (b) 81 3.69 -f OMe H -yTNy-otBu " o VII.15 IX.12 C31H32FN3O5 544 [M-H]" n.d. 0.30 (G) 3.70 -f O ^OMe -(CH2)2-NMe2 VII.7 IX.5 c28h28fn303 472 [M-H]- 165-170 0.25 (b) 3.71 -f °^-OMe q< -(CH2)2-NMe2 VII.1 IX.5 c28h28fn303 472 [M-H]' 193-197 0.25 (b) 3.72 -f ^O -CH2-NMe2 VII.19 IX.4 C29H30FN3O3 488 [M+H]+ 48- 52 0.45 (b) 3.73 -CI OMe \ -(CH2)2-NMe2 VII.20 IX.5 C29H30CIN3O3 504/506 [M+H]+ 156-160 0.30 (h) 3.74 -CI OMe ■J? Me VII.20 IX.16 C29H25CIN403 513/515 [M+H]+ 110 0.40 (h) 3.75 -CI OMe \ -CH2-NMe2 VII.20 IX.4 C28H28CIN3O3 490/492 [M+H]+ 173-175 0.70 (i) 3.76 -f OEt -CH2-NMe2 VII.21 IX.4 C29H30FN3O3 488 [M+H]+ 158-161 0.35 (b) 82 3.77 -F S~~^ N"Me vii.14 ix.14 C31H33FN4O3 529 [M+H]+ 147-150 0.50 (I) 3.78 -F /=N vii.14 ix.15 cmh25fn4o3 497 [M+H]+ 182-185 0.60 (K) 3.79 -F OMe <D 0 vii.15 ix.14 C31H33FN4O3 529 [M+H]+ 184 0.35 (B) 3.80 -F OMe /=N vii.15 ix.15 C29H25FN403 497 [M+H]+ 233 0.45 (B) 3.81 -F OMe \ -CH2-NMe-(CH2)2-NMe2 vii.15 ix.17 C31H35FN403 531 [M+H]+ 120 0.40 (B) 3.82 -F -CH2-NMe-(CH2)2-NMe2 vii.19 ix.17 c32h37fn403 545 [M+H]+ n.d. 0.40 (K) 3.83 -ci OMe .fP vii.20 ix.22 C30H30CIN3O3 516/518 [M+H]+ 195-197 0.30 (H) 3.84 -F -h vii.19 c26h23fn2o3 431 [M+H]+ 156-160 0.80 (M) 83 3.85 -F H <VotBu O VII.19 IX.12 C32H34FNs05 560 [M+H]+ n.d. 0.50 (L) 3.86 -F Me ' O VII.19 IX.18 C33H36FN3O5 574 [M+H]+ n.d. 0.60 (L) 3.87 -F MeO T O^ <4 -CH2-NMe2 VII.22 IX.4 C27H26FN304 476 [M+H]+ 129 0.25 (B) 3.88 -F OMe °*S O q.

-CH2-NMe2 VII.23 IX.4 C27H26FN304 476 [M+H]+ 155 0.25 (B) 3.89 -F OEt O 4 -CH2-NMe2 VI 1.24 IX.4 CMH30FN3O4 504 [M+Hf n.d. 0.20 (B) 3.90 -Br OMe \ VII.26 IX.22 C3oH3oBrN303 560/562 [M+H]+ 230-235 0.45 (B) 3.91 -Br OMe \ -CH2-NMe2 VII.26 IX.4 C28H28BrN303 534/536 [M+H]+ 178-180 0.35 (B) 3.92 -Br OMe -CH2-NEt2 VII.26 IX.1 C3oH32BrN303 562/564 [M+H]+ 173-176 0.40 (B) 84 *Eluent mixtures: (A): silica gel, methylene chloride/methanol/ammonia 9:1:0.1 (B): silica gel, methylene chloride/methanol 9:1 (C): silica gel, methylene chloride/methanol/ammonia 8:1:0.1 5 (D): silica gel, methylene chloride/methanol/ammonia 10:1:0.1 (E): silica gel, methylene chloride/methanol/ammonia 5:1:0.01 (F): silica gel, ethyl acetate/methanol/ammonia = 9:1:0,1 (G): alumina, methylene chloride/methanol = 19:1 (H): silica gel, methylene chloride/methanol/ammonia 9:1:0.01 10 (I): silica gel, methylene chloride/methanol 5:1 (K): alumina, methylene chloride/ethanol = 20:1 (L): silica gel, petroleum ether/ethyl acetate 1:1 (M): silica gel, petroleum ether/ethyl acetate 1:2 The following compounds of the formula l-3b are prepared analogously to Example 3.0: (l-3b) Ex-amp le R2 R3 R4' Starting materials Empirical formula Mass spectrum m.p. [°C] Rf value* OMe 3.93 -F -CH2-NMe2 VII.15 IX.3 C28H28FN3O3 474 [M+H]+ 176-179 0.40 (A) 85 3.94 -F Etoro Q> -CH2-NMe2 VII.19 IX.3 C29H30FN3O3 486 [M-H]" n.d. 0.45 (B) 3.95 -CI OMe -CH2-NMe2 VII.20 IX.3 C28H28CI NS03 490/492 [M+H]+ 163-165 0.40 (A) *Eluent mixtures: (A): silica gel, methylene chloride/methanol 9:1 (B): silica gel, methylene chloride/methanol/ammonia 9:1:0.1 Example 4.0 3-Z-ri-(4-(Dimethvlaminomethvl)anilino)-1-(3.4-dimethoxyphenvl)methvlenel-6-10 cvano-2-indolinone 130 mg of 1-acetyl-3-(1-methoxy-1-(3,4-dimethoxyphenyl)methylene)-6-cyano-2-indolinone (starting material VII.4) and 58 mg of 4-(dimethylaminomethyl)aniline (starting material IX.4) are dissolved in 5 ml of dimethylformamide and stirred at 80°C for 2 hours. After cooling, the solvent is removed under reduced pressure and the H5 residue is purified on a silica gel column using the mobile phase methylene chloride/methanol 9:1.

Yield: 21 mg (12% of theory), Rf value: 0.35 (silica gel, methylene chloride/methanol = 9:1) m.p. 265 °C 20 C27H26N4O3 86 Example 5.0 3-Z-M-(4-(N-Methvl-N-methvlsulphonvlamino)anilino)-1-(3-(2-methoxvcarbonvl-vinvl)phenvl)methvlene1-6-chloro-2-indolinone 5 580 mg of 3-Z-[1 -(4-(N-methyl-N-methylsulphonylamino)anilino)-1 -(3-iodophenyl)-methylene]-6-chloro-2-indolinone (starting material 1.0) and 140 ml of methyl acrylate are dissolved in 20 ml of acetonitrile and 11 ml of dimethylformamide, and 11 mg of palladium(ll) acetate, 2 ml of triethylamine and 30 mg of tri-ortho-tolylphosphine are added. Under nitrogen as protective gas, the solution is stirred at 90°C for 10 hours. 10 After cooling, the solution is filtered through Celite, the solvent is removed under reduced pressure and the residue is purified on a silica gel column using the mobile phase methylene chloride/methanol 20:1.

Yield: 450 mg (84% of theory), Rf value: 0.30 (silica gel, toluene/ethyl acetate = 1:1) m.p. 228-232 °C C27H24CIN3O5S Mass spectrum: m/z = 537/539 [M]+ The following compounds of the formula I-5 are prepared analogously to Example 20 5.0: (I-5) 87 Ex-ampl e R2 R3 R4' Starting materials Empirical formula Mass spectrum m.p. [°C] Rr value* .1 -ci °^-OMe Ci.

-CH2-NMe2 1.1 c2sh26ciN3O3 486/488 [M-H]" 150-155 0.50 (a) .2 -f nh2 o.

-CH2-NMe2 3.0 c27h25fn4o2 455 [M-H]" 269-270 0.20 (b) .3 -f OMe o< xx -CH2-NMe2 3.0 c28h26fn303 470 [M-H]- 205-208 0.65 (a) .4 -f °^-OMe (X -CH2-NMe2 1.1 c28h26fn303 472 [M+H]+ 138-140 0.45 (a) *Eluent mixtures: (A): silica gel, methylene chloride/methanol 5:1 (B): silica gel, methylene chloride/methanol/ammonia 9:1:0.01 Example 6.0 3-Z-M-(4-Dimethvlaminomethvlanilino)-1 -(3-(2-methoxvcarbonvlethvl)phenvl)methvlene1-6-chloro-2-indolinone 1.0 g of 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-(2-methoxycarbonyl-vinyl)phenyl)methylene]-6-chloro-2-indolinone (starting material 5.1) is dissolved in 100 ml of methanol, and 200 mg of 10 per cent palladium/carbon as catalyst are added. The mixture is then hydrogenated at room temperature and a hydrogen 88 pressure of 50 psi for 6 hours. After the reaction has ended, the catalyst is filtered off, the solvent is removed under reduced pressure and the residue is dried under reduced pressure at 100°C.

Yield: 900 mg (90% of theory), Rf value: 0.40 (silica gel, methylene chloride/methanol = 9:1) m.p. 160 °C C28H28CIN3O3 Mass spectrum: m/z = 490/492 [M+H]+ The following compounds of the formula I-6 are prepared analogously to Example ^ 6.0: R4- Example R2 R3 R4' Starting materials Empirical formula Mass spectrum m.p. [°C] Rf value* °y-OMe ( -N(Me)- 538/540 148- 0.50 6.1 -CI ) .0 C27H26CIN3O5S O S02Me [M-H]' 150 (A) 89 6.2 -f NH2 ra -CH2-NMe2 .2 C27H27FN402 459 [M+H]+ 150 0.70 (B) 6.3 -f OMe \ -CH2-NMe2 .3 C28H28FN303 474 [M+H]+ 140 0.35 (A) 6.4 -f 0-b-OMe Cl -CH2-NMe2 .4 c28h28fn3o3 474 [M+H]+ 140-142 0.30 (A) *Eluent mixtures: (A): silica gel, methylene chloride/methanol 9:1 (B): silica gel, methylene chloride/methanol/ammonia 5:1:0.01 Example 7.0 3-Z-[1-(4-Dimethylaminomethylanilino)-1 -(4-aminomethvlphenvl)methylene1-6-chloro-.10 2-indolinone 900 mg of 3-Z-[1-(4-dimethylaminomethylanilino)-1 -(4-cyanophenyl)methylene]-6-chloro-2-indolinone (starting material 2.0) are dissolved in 20 ml of methylene chloride and 30 ml of methanolic ammonia and, as catalyst, 200 mg of Raney nickel are added. The mixture is then hydrogenated at room temperature and a hydrogen 15 pressure of 50 psi for 2 hours and 15 minutes. After the reaction has ended, the catalyst is filtered off, the solvent is removed under reduced pressure and the residue is washed with a little methanol and diethyl ether. To liberate the base, the residue is taken up in 1N aqueous sodium hydroxide solution and extracted four times with methylene chloride/methanol 9:1. The combined organic phases are washed with 20 water and dried over sodium sulphate. The product is washed with a little diethyl ether and dried under reduced pressure. 90 Yield: 680 mg (75% of theory), Rf value: 0.60 (silica gel, methylene chloride/methanol/ammonia = 9:1:0.1) m.p. 211-214 °C C25H25CIN4O 5 Mass spectrum: m/z = 433/435 [M+H]+ Example 8.0 3-Z-H-(4-(N-((4-Methvlpiperazin-1-vl)methvlcarbonvl)-N-methvlamino)anilino)-1-(4-aminomethvlphenvl)methvlene1-6-chloro-2-indolinone 1.39 g of 1-acetyl-3-Z-[1-(4-(N-((4-methylpiperazin-1-yl)methylcarbonyl)-N-methylamino)anilino)-1-(4-cyanophenyl)methylene]-6-chloro-2-indolinone are dissolved in 20 ml of methylene chloride and 30 ml of methanolic ammonia and, as catalyst, 200 mg of Raney nickel are added. The mixture is then hydrogenated at room temperature at a hydrogen pressure of 50 psi for 2 hours. After the reaction has ended, the catalyst is filtered, the solvent is removed under reduced pressure and the residue is washed with a little methanol and diethyl ether. To liberate the base, the residue is taken up in 1N aqueous sodium hydroxide solution and extracted four times with methylene chloride/methanol 9:1. The combined organic phases are washed with water and dried over sodium sulphate. The product is purified on a silica gel column using, as mobile phase, a gradient of methylene chloride and methylene chloride/methanol/ammonia 8:1:0.1. The product is washed with a little diethyl ether and dried under reduced pressure.

Yield: 700 mg (54% of theory), Rf value: 0.15 (silica gel, methylene chloride/methanol/ammonia = 9:1:0.1) m.p. 232-235 °C C30H33CIN6O2 Mass spectrum: m/z = 544/546 [M]+ 91 Example 9.0 3-Z-M-(4-(Dimethvlaminomethvl)anilino)-1-(3-aminomethvlphenyl)methvlenel-6-fluoro-2-indolinone 2.72 g of 3-Z-[1 -(4-(dimethylaminomethyl)anilino)-1 -(3-(N-tert-butoxycarbonyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material 3.10) are dissolved in 50 ml of methylene chloride, and 10 ml of trifluoroacetic acid are added. The mixture is stirred at room temperature for 3 hours. After this time, most of the solvent is removed under reduced pressure and the residue is taken up in ethyl acetate and washed twice with 1N aqueous sodium hydroxide solution. The organic phase is dried over sodium sulphate, the solvent is removed using a rotary evaporator and the residue is purified on a silica gel column using the mobile phase methylene chloride/methanol/ammonia 9:1:0.1. The product is washed with a little diethyl ether and dried under reduced pressure.

Yield: 1.77 g (81 % of theory), Rf value: 0.25 (silica gel, methylene chloride/methanol/ammonia 9:1:0.1) m.p. 168-175 °C C25H25FN4O Mass spectrum: m/z = 415 [M-H]" The following compounds of the formula I-9 are prepared analogously to Example 9.0: N 92 Example R2 R3 R4' Starting materials Empirical formula Mass spectrum m.p. [°C] Rf value* 9.1 -F -CH2-NMe2 3.16 c26h27fn4o 431 [M+H]+ 155-160 0.45 (C) 9.2 -F NH, b.

-CH2-NMe2 3.15 C25H25FN40 417 [M+H]+ 203-207 0.25 (A) 9.3 -F % • P NMe •-/ o 3.14 c3oh33fn602 529 [M+H]+ 170-175 0.15 (A) 9.4 -F OH -CH2-NHMe .11 C26H24FN303 446 [M+H]+ 245-251 0.20 (D) 9.5 -F NHCH, -CH2-NHMe 11.22 c26h24fn303 459 [M+H]+ 239-243 0.30 (A) 9.6 -F r nh2 4 ■ P NMe O 3.52 C3oH33FN602 529 [M+H]+ n.d. n.d. 9.7 -F OMe -ch2-nh2 3.69 c26h24fn3o3 444 [M-H]' 158-163 0.25 (A) 93 9.8 -F -CH2-NH2 3.85 C27H26FN3O3 460 [M+H]+ 205-210 0.30 (B) 9.9 -F Etoro O -CH2-NHMe 3.86 C28H28FN3O3 474 [M+H]+ 148-150 0.30 (B) *Eluent mixtures: (A): silica gel, methylene chloride/methanol/ammonia 9:1:0.1 (B): silica gel, methylene chloride/methanol/ammonia 9:1:0.01 5 (C): silica gel, methylene chloride/methanol/ammonia 8:2:0.2 (D): Reversed phase RP8, methanol/sodium chloride solution(5%) = 3:2 Example 10.0 3-Z-[1-(4-Dimethvlaminomethvlanilino)-1 -(3-(2-carboxvethvl)phenvl)methvlenel-6-chloro-2-indolinone 900 mg of 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2- methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone (starting material 6.0) are dissolved in 10 ml of ethanol, and 5 ml of 1N aqueous sodium hydroxide solution are added. The mixture is stirred at room temperature for 5 hours. After cooling, 5 ml of 1N hydrochloric acid are added. The resulting precipitate is filtered off with suction and washed with water.

Yield: 830 mg (95% of theory), Rf value: 0.50 (reversed phase RP8, methanol/sodium chloride solution (5%) = 4:1) 20 m.p. 210-215 °C C27H26CIN3O3 Mass spectrum: m/z = 476/478 [M+H]+ 94 The following compounds of the formula 1-1 Oa are prepared analogously to Example 10.0: (1-1 Oa) Example R2 R3 R4' Starting materials Empirical formula Mass spectrum m.p.

[°C] Rf value* .1 -F OH -CH2-NMe2 6.3 C27H26FN303 460 [M+H]+ 250 0.65 (A) .2 -F OH o< o -CH2-NMe2 3.9 C26H24FN303 444 [M-H]' 278-282 0.10 (B) .3 -F °^OH dx -CH2-NMe2 6.4 C27H26FN303 458 [M-H]" 198-200 0.20 (C) .4 -F °^-OH -CH2-NMe2 3.7 C26H24FN303 444 [M-H]- 212-216 0.30 (D) 95 .5 -F °f-OH h • P NMe Vo 3.12 C3IH32FNS04 558 [M+H]+ 260-263 0.20 (D) .6 -F °^-OH q -N(S02Me)-(CH2)2-NMe2 3.11 C28H2gFN405S 553 [M+H]+ 246-249 0.30 (D) .7 -F OH -NMe-(CO)- ch3 3.17 C27H24FN304 474 [M+H]+ 286-290 0.60 (E) .8 -F OH ra KP NMe Vo 3.18 C32H34FN504 570 [M-H]" 215-222 0.20 (D) .9 -F OH -N(S02Me)-(CH2)2-NMe2 3.19 C2gH3iFN405S 567 [M+H]+ 160-165 0.20 (D) .10 -F OH -N(COMe)-(CH2)3-NMe2 3.20 C3iH33FN404 545 [M+H]+ 153-158 0.15 (D) .11 -F OH \ Me -yf^y-OtBu ' O 3.21 C3iH32FN305 546 [M+H]+ 215-219 0.60 (E) .12 -F OH o 0 cd 3.22 C3oH2gFN404 529 [M+H]+ 179-186 0.25 (E) 96 .13 -f OH -p Me 3.23 c28h23fn403 483 [M+H]+ 264-267 0.65 (E) .14 -f OH -S02Me 3.24 c25h21fn2o5s 481 [M+H]+ 146-155 0.70 (E) .15 -f OH 3.27 c2gh27fn404 515 [M+H]+ 251 0.70 (E) .16 -f OH .p NMe W o 3.25 C31H32FN5O4 558 [M+H]+ 234 0.10 (E) .17 -f OH (X -N(Me)-(CO)-CH2-NMe2 3.28 c28h27fn404 503 [M+H]+ 203 0.60 (E) .18 -f OH -N(Me)-(CO)-(CH2)4-NMe2 3.31 C31H33FN4O4 545 [M+H]+ 251 n.d. .19 -f OH -H 3.42 C23H17FN203 387 [M-H]" 130 0.60 (E) .20 -f OH dx -S02Me 3.43 c24higfn205s 467 [M+H]+ 139 0.55 (E) 97 .21 -F OH 0< (S Me 3.44 C27H2IFN403 469 [M+H]+ 157 0.35 (E) .22 -F OH -N(S02Me)-(CH2)-(CO)-NMe2 3.45 C2sH27FN406S 567 [M+H]+ 183 0.55 (E) .23 -F °|-OH -H 3.32 C23Hi7FN203 389 [M+H]+ 237-240 0.10 (D) .24 -F °^-OH Me 3.33 c27h21fn4o3 469 [M+H]+ 259-265 0.15 (D) .25 -F °^-OH -N(COMe)-(CH2)3-NMe2 3.41 C3oH3iFN404 531 [M+H]+ 274-278 0.15 (D) .26 -F °^-OH -N(Me)-(CO)-CH2-NMe2 3.36 c28h27fn4o4 503 [M+H]+ 258-264 0.20 (D) .27 -F °y-OH vOMe 3.34 C2gH27FN404 515 [M+Hf 279-282 0.15 (D) .28 -F °^OH -S02Me 3.39 C24HigFN205S 467 [M+H]+ 260-266 0.35 (F) .29 -F °y-OH -N(COMe)- ch3 3.37 c26h22fn3o4 460 [M+H]+ 290-294 0.30 (F) 98 .30 -F °y-OH -N(S02Me)-CH2-(CO)-NMe2 3.35 C28H27FN40eS 567 [M+H]+ 238-242 0.30 (F) .31 -F °*-OH q -N(Me)-(CO)-(CH2)2-NMe2 3.38 C29H2gFN404 517 [M+H]+ 250-255 0.35 (F) .32 -F °|-OH q -N(Me)-(CO)-(CH2)3-NMe2 3.40 C30H31FN4O4 531 [M+H]+ 184-190 0.25 (F) .33 -F °y-OH (S NMe ■-/ o 3.48 C32H34FN504 572 [M-H]' 170-175 0.40 (C) .34 -F OH o< (A -N(S02Me)-(CH2)2-NMe2 3.26 C28H2gFN405S 553 [M+H]+ 180 0.60 (C) .35 -F °^OH Q -N(S02Me)-(CH2)2-NMe2 3.49 CMH31FN405S 567 [M+H]+ 196-199 0.30 (C) .36 -F °^OH Q> -N(Me)-(CO)-CH2-NMe2 3.50 C29H2gFN404 517 [M+H]+ 150 0.20 (C) .37 -F °^OH dx -N(COMe)-(CH2)3-NMe2 3.51 C31H33FN404 545 [M+H]+ 206-210 0.30 (A) 99 .38 -F OH -N(Me)-(CO)-CH2-NMe2 3.59 C2gH2gFN404 517 [M+H]+ 231-236 0.60 (A) .39 -F OH -(CH2)2-NMe2 3.57 C28H28FN303 474 [M+Hf 218-222 0.50 (A) .40 -F OH -N(Me)-(CO)-(CH2)2-NMe2 3.58 C30H31FN4O4 531 [M+H]+ 215-218 0.50 (A) .41 -F °^-OH Q -(CH2)2-NMe2 3.60 C28H28FN303 474 [M+H]+ 172-177 0.15 (G) .42 -F OH \ -N(COMe)-(CH2)2-NMe2 3.61 C30H31FN4O4 531 [M+H]+ 230-234 0.50 (A) .43 -F °^-OH w -N(Me)-(CO)-(CH2)3-NMe2 3.62 C31H33FN4O4 545 [M+H]+ 170-175 0.30 (E) .44 -F <VoH Qj -N(Me)-(CO)-(CH2)4-NMe2 3.63 C32H35FN404 559 [M+H]+ 142-146 0.10 (G) .45 -F °j-OH A ■£> Me 3.64 C28H23FN403 483 [M+H]+ 262-269 0.20 (E) 100 .46 -F OH -N(Me)-(CO)-(CH2)4-NMe2 3.65 C32H35FN4O4 559 [M+H]+ 234-236 0.30 (A) .47 -F OH \ -H 3.66 C24H19FN2O3 403 [M+H]+ 231-233 0.20 (A) .48 -F OH 3.67 C29H28FN3O3 486 [M+H]+ 205-210 0.10 (E) .49 -F OH -CH2-NEt2 3.68 C29H30FN3O3 488 [M+H]+ 145-150 0.15 (E) .50 -F OH \ -CH2-NH2 9.7 C25H22FN3O3 430 [M-H]" 280-285 0.05 (H) .51 -F OH % -(CH2)2-NMe2 3.70 C27H26FN3O3 460 [M+H]+ 273-276 0.15 (E) .52 -F °-b-OH q -(CH2)2-NMe2 3.71 C27H26FN3O3 460 [M+H]+ 230-235 0.05 (E) .53 -CI OH \ -(CH2)2-NMe2 3.73 C28H28CIN3O3 490/492 [M+H]+ 255-258 0.50 (A) 101 .54 -CI OH Me 3.74 C2sH23CI N4O3 499/501 [M+H]+ 296-300 0.50 (a) .55 -CI OH -CH2-NMe2 3.75 C27H2gCI N3O3 476/478 [M+H]+ 228-230 0.50 (a) .56 -F °^-OH (u r^N-Me 3.77 C30H31FN4O3 515 [M+H]+ 210-215 0.40 (a) .57 -F °^OH Q.

/=N 3.78 C28H23FN403 483 [M+H]+ 240-245 0.50 (a) .58 -F °y-OH (S -CH2-NMe-(CH2)2-NMe2 3.82 C30H33FN4O3 517 [M+H]+ n.d. 0.30 (i) .59 -F OH m n_Me 3.79 C30H31FN4O3 515 [M+H]+ 275 0.35 (a) .60 -F OH \ /=N 3.80 C28H23FN403 483 [M+H]+ 280 0.55 (a) .61 -CI OH .yrO 3.83 c29H28cin303 502/504 [M+H]+ 260-266 0.50 (a) 102 .62 -F OH \ -CH2-NMe-(CH2)2-NMe2 3.81 C30H33FN4O3 517 [M+H]+ n.d. 0.05 (E) .63 -F HOro o -H 3.84 C24H19FN2O3 403 [M+H]+ 110-112 0.60 (K) .64 -F ^o -CH2-NH2 9.8 C25H22FN3O3 432 [M+H]+ 260-263 0.60 (A) .65 -F ^0 -CH2-NHMe 9.9 C26H24FN3O3 446 [M+H]+ 265-270 0.60 (A) .66 -F HO n T o^ 4 -CH2-NMe2 3.87 C26H24FN3O4 462 [M+H]+ 250 0.10 (M) .67 -F OH °*s O -CH2-NMe2 3.88 C26H24FN3O4 462 [M+H]+ 247 0.15 (M) .68 -Br OH 3.90 C29H28BrN303 546/548 [M+H]+ 290-293 0.30 (E) .69 -Br OH \ -CH2-NMe2 3.91 C27H26BrN303 520/522 [M+H]+ 243-246 0.25 (E) 103 OH J .70 -Br X -CH2-NEt2 3.92 C29H3oBrN303 548/550 [M+H]+ 252-255 0.35 (E) *Eluent mixtures: (A): reversed phase RP8, methanol/sodium chloride solution (5%) = 4:1 (B): silica gel, methylene chloride/methanol = 8:2 > (C): silica gel, methylene chloride/methanol = 5:1 (D): reversed phase RP8, methanol/sodium chloride solution (5%) = 3:2 (E): silica gel, methylene chloride/methanol = 9:1 (F): reversed phase RP8, methanol/sodium chloride solution (5%) = 7:3 (G): silica gel, methylene chloride/methanol/ammonia = 9:1:0.1 10 (H): alumina, methylene chloride/methanol = 19:1 (I): reversed phase RP8, methanol/sodium chloride solution (5%) = 4:2 (K): silica gel, petroleum ether/ethyl acetate = 1:1 (M): silica gel, methylene chloride/methanol = 4:1 The following compounds of the formula 1-1 Ob are prepared analogously to Example 10.0: (1-10b) 104 Example R2 R3 R4' Starting materials Empirical formula Mass spectrum m.p. [°C] Rr value* .71 -F OH -CH2-NMe2 3.93 C27H26FN303 460 [M+H]+ 150 0.20 (A) .72 -F °^OH o -CH2-NMe2 3.94 C27H26FN303 460 [M+H]+ 105-109 0.30 (B) .73 -CI OH -CH2-NMe2 3.95 C27H26CIN3O3 476/478 [M+H]+ 230-235 0.50 (C) *Eluent mixtures: (A): silica gel, methylene chloride/methanol = 5:1 (B): silica gel, methylene chloride/methanol = 9:1 (C): reversed phase RP8, methanol/sodium chloride solution (5%) = 4:1 Example 11.0 3-Z-M-(4-Dimethvlaminomethvlanilino)-1-(3-(2-carbamovlethvl)phenvl)methvlene1-6-chloro-2-indolinone 480 mg of 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (starting material 10.0), 350 mg of TBTU, 150 mg of HOBt and 420 ml of triethylamine are dissolved in 10 ml 15 of dimethylformamide, and 620 mg of N-hydroxysuccinimide ammonium salt are added. The mixture is stirred at room temperature for 20 hours. After removal of the solvent under reduced pressure, the residue is suspended in a little ethyl acetate and 105 water, filtered off and washed with water. The residue is purified on an alumina column (activity 2-3) using the mobile phase methylene chloride/ethanol 20:1. The product is recrystallized from diethyl ether and dried under reduced pressure at 100°C.

Yield: 370 mg (78% of theory), Rf value: 0.40 (alumina, methylene chloride/ethanol = 20:1) m.p. 222-225 °C C27H27CIN4O2 Mass spectrum: m/z = 475/477 [M+H]+ The following compounds of the formula 1-11 are prepared analogously to Example 11.0: R4- Example R2 R3 R4' Starting materials Empirical formula Mass spectrum m.p. [°C] Rf value* 0*-NHCH3 ( .0 489/491 223- 0.50 11.1 -CI ) -CH2-NMe2 C28H29CIN4O2 rS ** [M+Hf 225 (A) ■ 106 11.2 -f NHCH, -CH2-NMe2 .1 ** c28h29fn4o2 473 [M+H]+ 148-150 0.40 (b) 11.3 -f NMe2 (u -CH2-NMe2 .2 *** c28h29fn4o2 473 [M+H]+ 98-103 0.30 (c) 11.4 -f °^NH2 QJ -CH2-NMe2 .3 c27h27fn4o2 459 [M+H]+ 223-225 0.50 (a) 11.5 -f °^-NHMe 4 -CH2-NMe2 .3 ** c28h29fn4o2 473 [M+H]+ 210-213 0.70 (A) 11.6 -f °|-NMe2 Q -CH2-NMe2 .3 icicle C29h3ifn402 487 [M+H]+ 213-215 0.80 (A) 11.7 -f CM *>/ -CH2-NMe2 .2 c26h25fn4o2 443 [M-H]" 115-120 0.25 (c) 11.8 -f NHMe oA Q -CH2-NMe2 .2 ** c27h27fn4o2 457 [M-H]" 222-225 0.25 (c) 11.9 -f -CH2-NMe2 .4 c26h25fn4o2 443 [M-H]" 143-146 0.40 (D) 107 11.10 -f NMe2 \ -CH2-NMe2 .1 c2gh3ifn402 487 [M+H]+ 198-200 0.60 (B) 11.11 -f Me 6 N -CH2-NMe2 .1 **** c32h36fn5o2 542 [M+H]+ 175 0.60 (B) 11.12 -f NMe ■-/ o .5 c31h33fn6o3 557 [M+H]+ 150-156 0.40 (E) 11.13 -f -N(S02Me)-(CH2)2-NMe2 .6 c28h3ofn504s 552 [M+H]+ 197-199 0.50 (D) 11.14 -f Cy-NMe2 a -CH2-NMe2 .4 *** c28H29fn4o2 473 [M+H]+ 147-152 0.35 (D) 11.15 -f °|-NHMe q- -CH2-NMe2 .4 ** c27H27fn4o2 459 [M+H]+ 208-214 0.35 (D) 11.16 -f °y-NHMe -N(S02Me)-(CH2)2-NMe2 .6 ** cmh32fn504s 566 [M+H]+ 218-222 0.70 (F) 11.17 -f °^-NMe2 Q< -N(S02Me)-(CH2)2-NMe2 .6 *** c30h34fn5o4s 580 [M+H]+ 199-205 0.40 (C) 108 11.18 -F °<b-NHMe .P NMe H^o .5 ** C32H35FNe03 571 [M+Hf 155-160 0.20 (C) 11.19 -F NHCH, -N(Me)-(CO)-CH3 .7 ** C28H27FN403 487 [M+H]+ 137-145 0.50 (C) 11.20 -F NHCH, \ ■ P NMe •-/ o .8 ** C33H37FN6O3 585 [M+H]+ 211-219 0.40 (C) 11.21 -F NHCH, \ -N(S02Me)-(CH2)2-NMe2 .9 ** c30h34fn5o4s 578 [M-H]- 192-200 0.50 (C) 11.22 -F NHCH, Me -yf^y-OtBu " o .11 ** C32H3sFN404 559 [M+H]+ 180-187 0.50 (C) 11.23 -F NHCH, Me .13 ** C2gH26FN502 496 [M+H]+ 262-266 0.40 (C) 11.24 -F NHCH, \ -S02Me .14 ** C26H24FN304S 494 [M+H]+ 180-188 0.60 (C) 11.25 -F NHCH, vCN'Me .12 ** C3IH32FN503 542 [M+H]+ 226-230 0.50 (C) 109 11.26 -F NHMe 03S dx ■ P NMe .16 ** C32H35FN6O3 571 [M+H]+ 213 0.10 (G) 11.27 -F NHMe VNCT" .15 ** C30H30FN5O3 528 [M+H]+ 245 0.40 (G) *Eluent mixtures: (A): silica gel, methylene chloride/methanol/ammonia = 5:1:0.01 ^ (B): alumina, methylene chloride/ethanol = 20:1 5 (C): silica gel, methylene chloride/methanol/ammonia = 9:1:0.1 (D): silica gel, methylene chloride/methanol/ammonia = 6:1:0.1 (E): silica gel, methylene chloride/methanol/ammonia = 5:1:0.1 (F): silica gel, methylene chloride/methanol/ammonia = 7:1:0.1 (G): silica gel, methylene chloride/methanol = 9:1 ** using methylammonium chloride as base equivalent *** using dimethylammonium chloride as base equivalent **** using piperidine hydrochloride as base equivalent Example 12.0 3-Z-f1-(4-Dimethvlaminomethvlanilino)-1 -(4-acetvlaminomethvlphenvl)methvlenel-6-chloro-2-indolinone 100 mg of 3-Z-[1-(4-dimethylaminomethylanilino)-1 -(4-aminomethylphenyl)-20 methylene]-6-chloro-2-indolinone (starting material 7.0) are dissolved in 5 ml of methylene chloride and 5 ml of pyridine, and 20 jjl of acetyl chloride are added at 0°C. The mixture is stirred at 0°C for 10 minutes and at room temperature for a further 4 hours. Another 20 |jl of acetyl chloride are then added, and the mixture is stirred at room temperature for 12 hours. After this time, the solvent is removed 110 under reduced pressure and the residue is taken up in methylene chloride and washed with water. The aqueous phase is extracted twice with methylene chloride and the combined organic phases are dried over sodium sulphate. The solvent is removed using a rotary evaporator and the residue is washed with ether.

Yield: 51 mg (47% of theory), Rf value: 0.30 (silica gel, methylene chloride/methanol/ammonia = 9:1:0.01) m.p. 219-220 °C C27H27CIN4O2 Mass spectrum: m/z = 473/475 [M-H]" The following compounds of the formula 1-12 are prepared analogously to Example 12.0: R4' Example R2 R3 R4' Starting materials Empirical formula Mass spectrum m.p. [°C] Rr value* 12.1 -CI CH, HN^n KP NCH, Vo 8.0 C32H35CIN6O3 585/587 [M-H]" 252-255 0.25 (B) 111 12.2 -CI J? -CH2-NMe2 7.0 C32H2gCI N402 535/537 [M-H]" 238 (de-comp.) 0.45 (b) 12.3 -CI 9 ■ P NCH, ■-/ o 8.0 C37H37CIN603 647/649 [M-H]" 282-284 0.40 (b) 12.4 -F °rCH3 HN 4 -CH2-NMe2 9.0 C27H27FN402 457 [M-H]- 245-250 0.40 (C) 12.5 -F °^-Et HN 4 -CH2-NMe2 9.0 C28H29FN402 471 [M-H]' 212-214 0.35 (d) 12.6 -F °rO HN 4 -CH2-NMe2 9.0 C32H29FN402 519 [M-H]- 237-240 0.40 (d) 12.7 -F HN 4 -CH2-NMe2 9.0 C33H3iFN402 533 [M-H]- 187-190 0.30 (d) 12.8 -F CH, O^ U NH 4 -CH2-NMe2 9.1 c28h29fn4o2 471 [M-H]" 234-237 0.30 (d) 112 12.9 -F 0 NH i -CH2-NMe2 9.1 c33h31 fn4o2 533 [M-H]" 144-150 0.45 (C) 12.10 -F Et u NH -CH2-NMe2 9.1 c29h31fn4o2 485 [M-H]- 235-237 0.25 (D) 12.11 -F jcO u NH i -CH2-NMe2 9.1 c34h33fn4o2 547 [M-H]- 217-220 0.30 (D) 12.12 -F CH, HN-^0 -CH2-NMe2 9.2 c27h27fn4o2 457 [M-H]- 112-120 0.25 (D) 12.13 -F Et HN"V, -CH2-NMe2 9.2 C28H29FN4O2 586 [M+H]+ 176-180 0.30 (D) 12.14 -F % -CH2-NMe2 9.2 c33h31fn4o2 535 [M+H]+ 80-85 0.35 (D) 12.15 -F CH, HN-^0 ■ P NCH, -V o 9.3 C32H35FN6O3 569 [M-H]- 230-235 0.35 (D) 113 12.16 -F Et HN"^n CO I o % d*? CO I 9.3 C33H37FN6O3 583 [M-H]" 205-210 0.30 (D) 12.17 -F S0 ■ P NCH, Vo 9.3 C38H39FN6O3 645 [M-H]- 217-220 0.35 (D) 12.18 -F HN 4 O 9.6 C34H37FNe03 597 [M+H]+ 209-212 0.30 (D) 12.19 -F vo HN 4 .p NCH, H>c^ ^ •-/ o 9.6 C35H39FN6O3 611 [M+H]+ 190-193 0.30 (D) 12.20 -F VO HN 4 -P NCH, --/ o 9.6 C36H36FN7O3 634 [M+H]+ 160-163 0.30 (D) 12.21 -F °rO HN 4 ■ P NCH, ■-/ o 9.6 C37H43FN6O3 639 [M+H]+ 223-227 0.30 (D) 12.22 -F ^ N VO HN 4 CO I o CO X 9.6 C36H36FN7O3 634 [M+H]+ 170-175 0.25 (D) 114 12.23 -F r. CH3 v HN CH3 4 NCH, w O 9.6 C34H39FN6O3 599 [M+H]+ 194-196 0.20 (D) 12.24 -F H3CY-CH3 "J HN <4 .p NCH, H'°^ ^ ■-/ o 9.6 C35H41FN6O3 613 [M+H]+ 197-200 0.70 (E) 12.25 -F HN 4 NCH, Vo" 9.6 C38H45FN6O3 653 [M+H]+ 130-135 0.75 (E) 12.26 -F _ OMe V HN 4 CO I o o^' CO X 9.6 C33H37FN6O4 601 [M+H]+ 155-159 0.60 (E) 12.27 -F MeO VO HN 4 .p NCH, w. 0 9.6 C38H39FN6O4 663 [M+H]+ 168-172 0.35 (C) 12.28 -F P~Yf CO .p NCH, w O 9.6 C36H43FN6O3 627 [M+H]+ 0 00 0.35 (C) 12.29 -F VO HN 4 .p NCH, H'c^^ w 0 9.6 C35H35FN6O3S 639 [M+H]+ 170-175 0.25 (C) 115 12.30 -F i^zhCrO HN 4 -P NCH- w o 9.6 C35H41FN6O3 613 [M+H]+ 242-245 0.30 (C) 12.31 -F HN 4 I o o^' CO I 9.6 C35H35FN6O4 623 [M+Hf 155-160 0.65 (F) 12.32 -F VCH3 HN 4 .p NCH, o 9.6 C32H35FNe03 571 [M+H]+ 190-195 0.60 (F) 12.33 -F o ct -^-Et HN 4 -P NCH, Vo 9.6 C33H37FN6O3 585 [M+H]+ 203-209 0.65 (E) 12.34 -F HN 4 rONCHs •-/ 0 9.6 C37H37FN6O3 633 [M+H]+ 145-150 0.60 (F) 12.35 -F o r° HN 4 CO I o % Oft CO X 9.6 C38H39FN6O3 647 [M+H]+ 148-151 0.65 (F) 12.36 -F HN 4 -CH2-NMe2 9.0 C29H29FN402 485 [M+H]+ 216-220 0.35 (D) 116 12.37 -F VO HN 4 -CH2-NMe2 9.0 C3oH3iFN402 499 [M+H]+ 214-217 0.35 (D) 12.38 -F vO HN 4 -CH2-NMe2 9.0 C3IH28FN502 522 [M+H]+ 205-210 0.35 (D) 12.39 -F °rO HN 4 -CH2-NMe2 9.0 C32H35FN402 527 [M+H]+ 235-237 0.35 (D) 12.40 -F « N vO HN 4 -CH2-NMe2 9.0 C3iH28FN502 520 [M-H]' 135-140 0.20 (D) 12.41 -F r» CH3 3 HN CH3 4 -CH2-NMe2 9.0 C29H3iFN402 487 [M+H]+ 210-215 0.20 (D) 12.42 -F H3Cy-CH3 HN 4 -CH2-NMe2 9.0 C3oH33FN402 501 [M+Hf 202-206 0.25 (D) 12.43 -F HN 4 -CH2-NMe2 9.0 C33H37FN402 541 [M+H]+ 198-203 0.35 (D) 117 12.44 -F _ OMe V HN 4 -CH2-NMe2 9.0 c28h2gfn403 489 [M+H]+ 173-177 0.35 (D) 12.45 -F MeO vO HN 4 -CH2-NMe2 9.0 C33H31FN4O3 549 [M-H]' 202-207 0.50 (C) 12.46 -F C(CH3)3 >° HN 4 -CH2-NMe2 9.0 C3IH35FN402 513 [M-H]' 203-209 0.45 (C) 12.47 -F vO HN 4 -CH2-NMe2 9.0 C3oH27FN402S 527 [M+H]+ 245-250 0.35 (C) 12.48 -F (CH3)3Cro HN 4 -CH2-NMe2 9.0 c3c)h33fn402 501 [M+H]+ 248-252 0.45 (C) 12.49 -F HN 4 -CH2-NMe2 9.0 c3oh27fn403 511 [M+H]+ 216-219 0.30 (C) 12.50 -F vO HN 4 -CH2-NMe2 9.0 C3iH28FN502 522 [M+H]+ 167-170 0.20 (D) *Eluent mixtures: 118 (A): silica gel, methylene chloride/ethanol/ammonia = 20:1:0.01 (B): silica gel, methylene chloride/methanol/ammonia = 9:1:0.01 (C): alumina, methylene chloride/methanol = 19:1 (D): silica gel, methylene chloride/methanol/ammonia = 9:1:0.1 5 (E): silica gel, methylene chloride/methanol/ammonia = 8:2:0.2 (F): alumina, methylene chloride/methanol = 9:1 Alternatively, the following acylating agents were used: benzoyl chloride, propionyl chloride, phenylacetyl chloride, cyclopropanecarbonyl 10 chloride, cyclobutanecarbonyl chloride, pyridin-2-ylcarbonyl chloride, pyridin-3-^ ylcarbonyl chloride, pyridin-4-ylcarbonyl chloride, cyclohexylcarbonyl chloride, isobutyryl chloride, 3-methylbutyryl chloride, cyclohexylmethylcarbonyl chloride, methoxyacetyl chloride, 2-methoxybenzoyl chloride, tert-butylacetyl chloride, thiophene-2-carbonyl chloride, pivaloyl chloride, 2-furoyl chloride Example 13.0 3-Z-[1-(4-Trimethvlammoniummethvlanilino)-1-(4-(2-carboxvethvl)phenyl)methvlenel-20 6-fluoro-2-indolinone iodide 200 mg of 3-Z-[1-(4-dimethylaminomethylanilino)-1 -(4-(2-^ carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material 10.1) are dissolved in 40 ml of acetone, and 250 ml of methyl iodide are added. The mixture is stirred at room temperature for 20 hours. After this time, the resulting residue is 25 filtered off with suction. The product is dried at 80°C under reduced pressure.

Yield: 200 mg (83% of theory), Rf value: 0.50 (reversed phase RP8, methanol/sodium chloride solution (5%) = 4:1) m.p. 210 °C C28H29FN3O3I 30 Mass spectrum: m/z = 474 [M+H]+ 119 The following compound of the formula 1-13 is prepared analogously to Example 13.0: (1-13) •5 Example R2 R3 R4' Starting materials Empirical formula Mass spectrum m.p.

[°C] Rf value* X O o 13.1 -F Q\ Me .J?* Me .3 C28H29FN3O3I 474 [M+H]+ 150 0.50 (A) *Eluent mixture: (A): reversed phase RP8, methanol/sodium chloride solution (5%) = 4:1 10 Example 14.0 3-Z-f1-(4-Guanidinomethvlanilino)-1-(4-(2-carboxvethvl)phenvl)methvlenel-6-fluoro-2-indolinone iodide 170 mg of 3-Z-[1 -(4-aminomethylanilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material 10.50) are dissolved in 20 ml of tetrahydrofuran, and 390 mg of 3,5-dimethylpyrazole-1-carboxamidine nitrate and 330 ml of diethylisopropylamine are added. The mixture is stirred under reflux for 10 hours. 120 After this time, the solvent is concentrated, water is added and the resulting residue is filtered off with suction. The product is dried at 80°C.

Yield: 150 mg (81% of theory), Rf value: 0.40 (silica gel, methylene chloride/methanol/acetic acid = 5:1:0.1) m.p. 290 °C C26H24FN5O3 Mass spectrum: m/z = 474 [M+H]+ The following compound of the formula 1-14 is prepared analogously to Example 14.0: (1-14) Example R2 R3 R4' Starting materials Empirical formula Mass spectrum m.p. [°C] Rf value* X 0 0 14.1 -F 4 <VH* HN .64 C26H24FN5O3 474 [M+Hf 305 0.70 (A) *Eluent mixture: (A): reversed phase RP8, methanol/sodium chloride solution (5%) = 4:1 Example 15 121 Dry vial with 75 mg of active compound per 10 ml Composition: Active compound 75.0 mg Mannitol 50.0 mg Water for injection ad 10.0 ml Preparation: Active compound and mannitol were dissolved in water. After filling, the product is freeze-dried. The ready-to-use solution is obtained by dissolving the product in water for injection.

Example 16 Dry vial with 35 mg of active compound per 2 ml Composition: Active compound 35,0 mg Mannitol 100,0 mg Water for injection ad 2.0 ml Preparation: Active compound and mannitol were dissolved in water. After filling, the product is freeze-dried. The ready-to-use solution is obtained by dissolving the product in water 30 for injection. 122 Example 17 Tablet with 50 mg of active compound 5 Composition: (1) Active compound 50.0 mg (2) Lactose 98.0 mg (3) Maize starch 50.0 mg (4) Polyvinylpyrrolidone .0 mg (5) Magnesium stearate 2.0 mq 215.0 mg Preparation: (1), (2) and (3) are mixed and granulated using an aqueous solution of (4). (5) is added to the dried granules. From this mixture, biplanar tablets having a facet on both sides and being partially scored on one side are pressed.

Diameter of the tablets: 9 mm.

Example 18 Tablet with 350 mg of active compound Composition: (1) Active compound 350.0 mg (2) Lactose 136.0 mg (3) Maize starch 80.0 mg (4) Polyvinylpyrrolidone .0 mg (5) Magnesium stearate 4,0 ma 600.0 mg 123 Preparation: (1), (2) and (3) are mixed and granulated using an aqueous solution of (4). (5) is added to the dried granules. From this mixture, biplanar tablets having a facet on both sides and being partially scored on one side are pressed.

Diameter of the tablets: 12 mm.

Example 19 Capsules with 50 mg of active compound Composition: (1) Active compound 50.0 mg (2) Maize starch, dried 58.0 mg 15 (3) Lactose, powdered 50.0 mg (4) Magnesium stearate 2.0 mg 160.0 mg Preparation: (1) is ground with (3). This ground material is, with vigorous mixing, added to the mixture of (2) and (4).

This powder mixture is, in a capsule filling machine, filled into hard gelatin capsules size 3.

Example 20 Capsules with 350 mg of active compound Composition: (1) Active compound 350.0 mg (2) Maize starch, dried 46.0 mg (3) Lactose, powdered 30.0 mg (4) Magnesium stearate 4.0 mg 430.0 mg 124 Preparation: (1) is ground with (3). This ground material is, with vigorous mixing, added to the mixture of (2) and (4).

This powder mixture is, in a capsule filling machine, filled into hard gelatin capsules size 0.

Example 21 Suppositories with 100 mg of active compound 1 suppository contains: Active compound 100.0 mg Polyethylene glycol (MW 1500) 600.0 mg Polyethylene glycol (MW 6000) 460.0 mg Polyethylene sorbitan monostearate 840.0 mg 2 000.0 mg Preparation: The polyethylene glycol is melted together with polyethylene sorbitan monostearate. At 40°C, the ground active substance is homogeneously dispersed in the melt. The melt is cooled to 38°C and poured into slightly pre-cooled suppository moulds.

Analogously to the examples above, it is possible to prepare the following compounds: (1) 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (2) 3-Z-[1 -(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 125 3) 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 4) 3-Z-[1 -(4-(N-(2-methylaminoethyl)-N-acetylamino)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone ) 3-Z-[1 -(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 6) 3-Z-[1 -(4-(N-(3-methylaminopropyl)-N-acetylamino)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 7) 3-Z-[1 -(4-(3-dimethylaminopropyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 8) 3-Z-[1 -(4-ethylaminomethylanilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 9) 3-Z-[1 -(4-methylaminomethylanilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone ) 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 11) 3-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 12) 3-Z-[1 -(4-(N-(3-dimethylaminopropyl)-N-methylsulphonylamino)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 13) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-propylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 14) 3-Z-[1-(4-aminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone ) 3-Z-[1 -(3-(methylaminomethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 16) 3-Z-[1 -(3-(2-dimethylaminoethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 17) 3-Z-[1-(3-(3-dimethylaminopropyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 18) 3-Z-[1 -(4-(N-(dimethylamino-carbonylmethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 126 (19) 3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (20) 3-Z-[1 -(4-(N-methyl-N-acetylamino)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (21) 3-Z-[1-(4-(N-(N-(2-dimethylaminoethyl)-N-methylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (22) 3-Z-[1 -(4-(2-diethylaminoethylsulphonyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 10 (23) 3-Z-[1 -(4-(N-(2-dimethylaminoethyl-carbonyl)-N-methylamino)anilino)-1 -(4-(2-^ carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (24) 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (25) 3-Z-[1-(4-(2-dimethylaminoethoxy)anilino)-1-(4-(2-15 carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (26) 3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (27) 3-Z-[1 -(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (28) 3-Z-[1-(4-(methylethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone ^ (29) 3-Z-[1-(4-(methylpropylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (30) 3-Z-[1 -(4-(methylbenzylaminomethyl)anilino)-1 -(4-(2-25 carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (31) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenylmethylene]-6-chloro-2-indolinone (32) 3-Z-[1-(4-(azetidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (33) 3-Z-[1 -(4-((4-methylpiperazin-1 -yl)methyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (34) 3-Z-[1 -(4-(piperazin-1 -ylmethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 127 (35) 3-Z-[1 -(4-(morpholin-4-ylmethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (36) 3-Z-[1 -(4-(thiomorpholin-4-ylmethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (37) 3-Z-[1 -(4-(imidazol-1 -ylmethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (38) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (39) 3-Z-[1 -(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (40) 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (41) 3-Z-[1 -(4-(N-(2-methylaminoethyl)-N-acetylamino)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (42) 3-Z-[1 -(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (43) 3-Z-[1 -(4-(N-(3-methylaminopropyl)-N-acetylamino)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (44) 3-Z-[1 -(4-(3-dimethylaminopropyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (45) 3-Z-[1 -(4-ethylaminomethylanilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (46) 3-Z-[1-(4-methylaminomethylanilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (47) 3-Z-[1-(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (48) 3-Z-[1 -(4-(4-methylpiperazin-1 -ylcarbonyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (49) 3-Z-[1 -(4-(N-(3-dimethylaminopropyl)-N-methylsulphonylamino)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (50) 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-propylsulphonylamino)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 128 (51) 3-Z-[1-(4-aminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (52) 3-Z-[1-(3-(dimethylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (53) 3-Z-[1-(3-(methylaminomethyl)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (54) 3-Z-[1 -(3-(2-dimethylaminoethyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (55) 3-Z-[1-(3-(3-dimethylaminopropyl)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone £ (56) 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (57) 3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 15 (58) 3-Z-[1 -(4-(N-methyl-N-methylsulphonylamino)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (59) 3-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (60) 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(3-(2-20 carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (61) 3-Z-[1 -(4-(N-(N-(2-dimethylaminoethyl)-N-methylaminomethylcarbonyl)-N-^ methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methy!ene]-6-chloro-2- indolinone (62) 3-Z-[1 -(4-(2-diethylaminoethylsulphonyl)anilino)-1 -(3-(2-25 carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (63) 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (64) 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (65) 3-Z-[1-(4-(2-dimethylaminoethoxy)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (66) 3-Z-[1 -(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 129 (67) 3-Z-[1 -(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (68) 3-Z-[1 -(4-(methylethylaminomethyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (69) 3-Z-[1-(4-(methylpropylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (70) 3-Z-[1 -(4-(methylbenzylaminomethyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (71) 3-Z-[1 -(4-(diethylaminomethyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]- 6-chloro-2-indolinone ^ (72) 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1 -(3-(2-carboxyethyl)phenylmethylene]-6-chloro-2-indolinone (73) 3-Z-[1 -(4-(pyrrolidin-1 -ylmethyl)anilino)-1 -(3-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (74) 3-Z-[1 -(4-(azetidin-1 -ylmethyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (75) 3-Z-[1 -(4-((4-methylpiperazin-1 -yl)methyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (76) 3-Z-[1-(4-(piperazin-1-ylmethyl)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone ^ (77) 3-Z-[1-(4-(morpholin-4-ylmethyl)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (78) 3-Z-[1 -(4-(thiomorpholin-4-ylmethyl)anilino)-1 -(3-(2- carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (79) 3-Z-[1 -(4-(imidazol-1 -ylmethyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (80) 3-Z-[1-(4-(N-(2-methylaminoethyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (81) 3-Z-[1 -(4-(N-(3-methylaminopropyl)-N-acetylamino)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (82) 3-Z-[1 -(4-(3-dimethylaminopropyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 130 (83) 3-Z-[1 -(4-ethylaminomethylanilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (84) 3-Z-[1 -(4-(N-(3-dimethylaminopropyl)-N-methylsulphonylamino)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (85) 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-propylsulphonylamino)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (86) 3-Z-[1 -(3-(methylaminomethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (87) 3-Z-[1 -(3-(2-dimethylaminoethyl)anilino)-1 -(4-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone ^ (88) 3-Z-[1-(3-(3-dimethylaminopropyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (89) 3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 15 (90) 3-Z-[1 -(4-(N-methyl-N-methylsulphonylamino)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (91) 3-Z-[1 -(4-(N-(N-(2-dimethylaminoethyl)-N-methylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (92) 3-Z-[1 -(4-(2-diethylaminoethylsulphonyl)anilino)-1 -(4-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone ^ (93) 3-Z-[1-(4-(2-dimethylaminoethoxy)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (94) 3-Z-[1 -(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1 -(4-(2-25 carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (95) 3-Z-[1 -(4-(methylethylaminomethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (96) 3-Z-[1 -(4-(methylpropylaminomethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (97) 3-Z-[1-(4-(methylbenzylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 131 (98) 3-Z-[1 -(4-(azetidin-1 -ylmethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (99) 3-Z-[1 -(4-(piperazin-1 -ylmethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (100) 3-Z-[1-(4-(morpholin-4-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (101) 3-Z-[1 -(4-(thiomorpholin-4-ylmethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (102) 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1 -(3-(2-10 carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 0 (103) 3-Z-[1 -(4-(N-(2-methylaminoethyl)-N-acetylamino)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (104) 3-Z-[1 -(4-(N-(3-methylaminopropyl)-N-acetylamino)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 15 (105) 3-Z-[1-(4-(3-dimethylaminopropyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (106) 3-Z-[1-(4-ethylaminomethylanilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (107) 3-Z-[1 -(4-(4-methylpiperazin-1 -ylcarbonyl)anilino)-1 -(3-(2-20 carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (108) 3-Z-[1 -(4-(N-(3-dimethylaminopropyl)-N-methylsulphonylamino)anilino)-1 -(3-^ (2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (109) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-propylsulphonylamino)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (110) 3-Z-[1-(3-(methylaminomethyl)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (111) 3-Z-[1 -(3-(2-dimethylaminoethyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (112) 3-Z-[1-(3-(3-dimethylaminopropyl)anilino)-1-(3-(2-30 carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (113) 3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 132 114) 3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 115) 3-Z-[1 -(4-(N-methyl-N-acetylamino)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 116) 3-Z-[1-(4-(N-(N-(2-dimethylaminoethyl)-N-methylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 117) 3-Z-[1 -(4-(2-diethylaminoethylsulphonyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 118) 3-Z-[1 -(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 119) 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 120) 3-Z-[1 -(4-(2-dimethylaminoethoxy)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 121) 3-Z-[1 -(4-(methylethylaminomethyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 122) 3-Z-[1 -(4-(methylpropylaminomethyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 123) 3-Z-[1 -(4-(methylbenzylaminomethyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 124) 3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 125) 3-Z-[1 -(4-(pyrrolidin-1 -ylmethyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 126) 3-Z-[1 -(4-(azetidin-1 -ylmethyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 127) 3-Z-[1 -(4-(piperazin-1 -ylmethyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 128) 3-Z-[1 -(4-(morpholin-4-ylmethyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 133 129) 3-Z-[1 -(4-(thiomorpholin-4-ylmethyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 130) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 131) 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 132) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 133) 3-Z-[1 -(4-(N-(2-methylaminoethyl)-N-acetylamino)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 134) 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 135) 3-Z-[1 -(4-(N-(3-methylaminopropyl)-N-acetylamino)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 136) 3-Z-[1 -(4-(3-dimethylaminopropyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 137) 3-Z-[1 -(4-ethylaminomethylanilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 138) 3-Z-[1 -(4-methylaminomethylanilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 139) 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 140) 3-Z-[1 -(4-(4-methylpiperazin-1 -ylcarbonyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 141) 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 142) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-propylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 143) 3-Z-[1-(4-aminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 144) 3-Z-[1 -(3-(dimethylaminomethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 134 145) 3-Z-[1-(3-(methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 146) 3-Z-[1-(3-(2-dimethylaminoethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 147) 3-Z-[1-(3-(3-dimethylaminopropyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 148) 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 149) 3-Z-[1 -(4-(N-(dimethylaminocarbonylmethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 150) 3-Z-[1 -(4-(N-methyl-N-methylsulphonylamino)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 151) 3-Z-[1 -(4-(N-methyl-N-acetylamino)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 152) 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 153) 3-Z-[1 -(4-(N-(N-(2-dimethylaminoethyl)-N-methylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 154) 3-Z-[1 -(4-(2-diethylaminoethylsulphonyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 155) 3-Z-[1 -(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 156) 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 157) 3-Z-[1 -(4-(2-dimethylaminoethoxy)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 158) 3-Z-[1 -(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 159) 3-Z-[1 -(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 160) 3-Z-[1 -(4-(methylethylaminomethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 135 (161) 3-Z-[1 -(4-(methylpropylaminomethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (162) 3-Z-[1 -(4-(methylbenzylaminomethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (163) 3-Z-[1 -(4-(diethylaminomethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (164) 3-Z-[1-(4-(N-(2-dirriethyiarriinoethyi)-N-rriethyiaminorrieihyi)aniiino)-1-(4-(2-carboxyethyl)-phenylmethylene]-6-bromo-2-indolinone (165) 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-^ carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (166) 3-Z-[1-(4-(azetidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (167) 3-Z-[1 -(4-((4-methylpiperazin-1 -yl)methyl)anilino)-1 -(4-(2-15 carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (168) 3-Z-[1 -(4-(piperazin-1 -ylmethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (169) 3-Z-[1 -(4-(morpholin-4-ylmethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (170) 3-Z-[1-(4-(thiomorpholin-4-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone ^ (171) 3-Z-[1 -(4-(imidazol-1 -ylmethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (172) 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (173) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (174) 3-Z-[1 -(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (175) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (176) 3-Z-[1 -(4-(N-(2-methylaminoethyl)-N-acetylamino)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 136 177) 3-Z-[1 -(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 178) 3-Z-[1 -(4-(N-(3-methylaminopropyl)-N-acetylamino)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 179) 3-Z-[1 -(4-(3-dimethylaminopropyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 180) 3-Z-J1 -(4-eihyiaminomeihyianiiino)-1 -(3-(2-carboxyeihyi)phenyi)meihyiene]-6-bromo-2-indolinone 181) 3-Z-[1-(4-methylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 182) 3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-methylamino)anilino)-1 (3-(2-carboxyethyl)pheriyl)methylene]-6-bromo-2-indolinone 183) 3-Z-[1 -(4-(4-methylpiperazin-1 -ylcarbonyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 184) 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 185) 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-propylsulphonylamino)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 186) 3-Z-[1 -(4-aminomethylanilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 187) 3-Z-[1 -(3-(dimethylaminomethyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 188) 3-Z-[1 -(3-(methylaminomethyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 189) 3-Z-[1 -(3-(2-dimethylaminoethyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 190) 3-Z-[1 -(3-(3-dimethylaminopropyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 191) 3-Z-[1 -(4-(2-dimethylaminoethyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 192) 3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-methylsulphonylamino)anilino) 1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 137 (193) 3-Z-[1 -(4-(N-methyl-N-methylsulphonylamino)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (194) 3-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (195) 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone / a r\r\\ r\ ^ t a /a /k i /k i /r\ _i: j. _ . i • il..i\ l i j.i_ . .i • n_. .i __i_ »\ k i (i »o) o-z_-[ i -(H-(iN-(iN-(^-uirneinyiaminueiriyi)-iN-meinyiaminomeinyicarDonyi)-i\i-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (197) 3-Z-[1 -(4-(2-diethylaminoethylsulphonyl)anilino)-1 -(3-(2-^ carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (198) 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (199) 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1 -(3-(2-15 carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (200) 3-Z-[1-(4-(2-dimethylaminoethoxy)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (201) 3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (202) 3-Z-[1 -(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (203) 3-Z-[1-(4-(methylethylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (204) 3-Z-[1 -(4-(methylpropylaminomethyl)anilino)-1 -(3-(2-25 carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (205) 3-Z-[1 -(4-(methylbenzylaminomethyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (206) 3-Z-[1 -(4-(diethylaminomethyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (207) 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1 -(3-(2-carboxyethyl)phenylmethylene]-6-bromo-2-indolinone 138 (208) 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (209) 3-Z-[1 -(4-(azetidin-1 -ylmethyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (210) 3-Z-[1 -(4-((4-methylpiperazin-1 -yl)methyl)anilino)-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (211) 3-Z-[1-(4-(piperazin-1-yimethyi)aniiino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (212) 3-Z-[1-(4-(morpholin-4-ylmethyl)anilino)-1-(3-(2- carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone ^ (213) 3-Z-[1-(4-(thiomorpholin-4-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (214) 3-Z-[1-(4-(imidazol-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 15 (215) 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-carboxymethylaminophenyl)-methylene]-6-fluoro-2-indolinone (216) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carboxymethylamino-phenyl)-methylene]-6-fluoro-2-indolinone (217) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(N-methyl- carboxymethylamino)phenyl)methylene]-6-fluoro-2-indolinone (218) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(N-methyl-^ carboxymethylamino)phenyl)methylene]-6-fluoro-2-indolinone (219) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethoxyphenyl)-methylene]-6-chloro-2-indolinone (220) 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-carboxymethoxyphenyl)-methylene]-6-chloro-2-indolinone (221) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethylaminophenyl)-methylene]-6-chloro-2-indolinone (222) 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-carboxymethylaminophenyl)-30 methylene]-6-chloro-2-indolinone (223) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(N-methyl-carboxymethylamino)phenyl)methylene]-6-chloro-2-indolinone

Claims

139 (224) 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(N-methyl-carboxymethylamino)phenyl)methylene]-6-chloro-2-indolinone (225) 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-carboxymethoxyphenyl)-methylene]-6-bromo-2-indolinone 5 (226) 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-carboxymethoxyphenyl)-methylene]-6-bromo-2-indolinone (227) 3-Z-[1 -(4-dimethyiaminomethyianiiino)-1 -(4-carboxymeihyiaminophenyi)-methylene]-6-bromo-2-indolinone (228) 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-carboxymethylaminophenyl)-10 methylene]-6-bromo-2-indolinone (229) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(N-methyl-carboxymethylamino)phenyl)methylene]-6-bromo-2-indolinone (230) 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(N-methyl-carboxymethylamino)phenyl)methylene]-6-bromo-2-indolinone 15 In the tables above, Me is methyl, Et is ethyl, 20 Pr is propyl, nPr is n-propyl, • iPr is isopropyl, nBu is n-butyl, tBu is tert-butyl and 25 Bn is benzyl. 140 What is claimed is 1. A compound of general formula in which X is an oxygen atom, R1 is a hydrogen atom, R2 is a fluorine, chlorine or bromine atom or a cyano group, R3 is a phenyl group which is substituted by a Ci-2-alkyl-carbonyl-amino group, by a carboxy-Ci-3-alkyl, carboxy-C-M-alkoxy, C^-alkoxy-carbonyl-Ci-3-alkyl, Ci-4-alkoxy-carbonyl-C-i-3-alkoxy, aminocarbonyl-Ci-3-alkyl, (Ci.2-alkylamino)-carbonyl-Ci.3-alkyl, di-(Ci.2-alkyl)-aminocarbonyl-Ci.3-alkyl, (Ci_2-alkyl-carbonyl)-amino-Ci-3-alkyl, (Ci^-alkoxy-carbonyl)-amino-Ci.3-alkyl, (phenyl-carbonyl)-amino-Ci-3-alkyl, (C3-6-cycloalkyl-carbonyl)-amino-Ci-3-alkyl, (C3.6-cycloalkyl-Ci-3-alkyl-carbonyl)-amino-Ci-3-alkyl, (thiophen-2-yl-carbonyl)-amino-Ci-3-alkyl, (furan^-yl-carbonyO-amino-C^s-alkyl, (phenyl-Ci-3-alkyl-carbonyl)-amino-Ci-3-alkyl, (2-(Ci^-alkoxy)-benzoyl-carbonyl)-amino-C1.3-alkyl, (pyridin-2-yl-carbonyl)-amino-Ci.3-alkyl, (pyridin-3-yl-carbonyl)-amino- intellectual property office of n.z. 18 DEC 2006 DPrcit/cn 141 Ci-3-alkyl, (pyridin-4-yl-carbonyl)-amino-C-i-3-alkyl or Ci_3-alkyl-piperazin-1-yl-carbonyl-Ci-3-alkyl group, by an aminocarbonyl-C2-3-alkenyl, (Ci-3-alkylamino)-carbonyl-C2-3-alkenyl, di-(Ci.3-alkyl)-amino-carbonyl-C2-3-alkenyl or Ci^-alkoxy-carbonyl-C2-3-alkenyl group, R4 is a phenyl group or a phenyl group which is monosubstituted by a Ci-3-alkyl group which is terminally substituted by an amino, guanidino, mono- or di-(Ci.2-alkyl)-amino-, N-[ra-di-(Ci_3-alkyl)-amino-C2-3-alkyl]-N-(Ci-3-alkyl)-amino, N-methyl-(C3^-alkyl)-amino, N-(Ci-3-alkyl)-N-benzylamino, N-(Ci^-alkoxycarbonyl)-amino, N^C-M-alkoxycarbonyO-C^-alkylamino, 4-(Ci-3-alkyl)-piperazin-1-yl, imidazol-1-yl, pyrrolidin-1 -yl, azetidin-1-yl, morpholin-4-yl, piperazin-1-yl, thiomorpholin-4-yl group, by a di-(Ci-3-alkyl)-amino-(Ci.3-alkyl)-sulphonyl, 2-[di-(Ci.3-alkyl)-amino]-ethoxy, 4-(Ci-3-alkyl)-piperazin-1 -yl-carbonyl, {a)-[di-(C1.3-alkyl)-amino]-(C2-3-alkyl)}-N-(Ci-3-alkyl)-amino-carbonyl, 1 -(Ci.3-alkyl)imidazol-2-yl, (Ci-3-alkyl)-sulphonyl group, or by a group of the formula /R8 —N ^R7 in which R7 is a Ci_2-alkyl, Ci_2-alkyl-carbonyl, di-(Ci.2-alkyl)-amino-carbonyl-Ci-3-alkyl or Ci.3-alkylsulphonyl group and R8 is Ci.3-alkyl, ©-[di-(Ci-2-alkyl)-amino]-C2-3-alkyl, co-[mono-(Ci-2-alkyl)-amino]-C2-3-alkyI group, or intellectual property office of n.z.

1 8 DEC 2006 142 a (Ci-3-alkyl)-carbonyl, (C4-6-alkyl)-carbonyl or carbonyl-(Ci_3-alkyl) group which is terminally substituted by a di-(Ci-2-alkyl)-amino, piperazin-1-yl or 4-(Ci.3-alkyl)-piperazin-1-yl group, where all dialkylamino groups present in the radical R4 may also be present in quaternized form where the counterion is selected from the group consisting of iodide, chloride, bromide, methylsulphonate, para-toluenesulphonate and trifluoroacetate, R5 is a hydrogen atom and R6 is a hydrogen atom, where the abovementioned alkyl groups include linear and branched alkyl groups in which additionally one to 3 hydrogen atoms may be replaced by fluorine atoms, where additionally a carboxyl, amino or imino group present may be substituted by an in vivo cleavable radical or may be present in the form of a group which can be converted in vivo into a carboxyl group or in the form of a group which can be converted in vivo into an imino or amino group, and a tautomer, enantiomer, diastereomer, mixture thereof and salt thereof.

2. A compound of general formula I according to Claim 1 in which the dialkylamino group present in the radical R4 in quaternized form is an N-methyl-(N,N-dialkyl)-ammonium group.

3. A compound of general formula I according to Claim 1 in which X, R1, R2, R4, R5 and R6 are as defined in Claim 1 and intellectual property office of n.z. 1 8 DEC 2006 d e? er i w tr r> 143 R3 is a phenyl group substituted by a carboxy-Ci_3-alkyl or Ci-4-alkoxy-carbonyl-C-i_3 alkyl group.

4. A compound of general formula I according to any one of Claims 1 to 3, in which X, R1, R3, R4, R5 and R6 are as defined in any one of Claims 1 to 3 and R2 is a fluorine or chlorine atom.

5. The following compounds of general formula I according to Claim 1: (a) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6 chloro-2-indolinone (b) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (c) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (d) 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (e) 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (f) 3-Z-[1 -(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (g) 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (h) 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (i) 3-Z-[1 -(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (j) 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone (k) 3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 144 (I) 3-Z-[1 -(4-(2-dimethylaminoethyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (m) 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (n) 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone (o) 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (p) 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone (q) 3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)-methylene]-6-bromo-2-indolinone and a salt thereof.

6. A physiologically acceptable salt of a compound according to any one of Claims 1 to 5.

7. A medicament, comprising a compound of general formula I according to any one of Claims 1 to 5 or a physiologically acceptable salt according to Claim 6, if appropriate in addition to one or more inert carrier materials and/or diluents.

8. The use of a compound of general formula I according to any one of Claims 1 to 5 or of a physiologically acceptable salt according to Claim 6 for preparing a medicament suitable for treating excessive or abnormal cell proliferation.

9. A process for preparing a medicament according to Claim 7, wherein, by a non-chemical route, a compound of the formula I according to any one of Claims 1 to 5 or a physiologically acceptable salt according to Claim 6 is incorporated into one or more inert carrier materials and/or diluents.

10. A process for preparing the compounds according to any one of Claims 1 to 5, wherein intellectual property office of n.z. 18 DEC 2006 145 a. a compound of the formula k' X R3 \ (v), in which the radicals Z1 and R3 may, if appropriate, change their positions, X, R2, R3 and R6 are as defined in Claim 1, R1' has the meanings mentioned at the outset for R1 or is a protective group for the nitrogen atom of the lactam group, where R1 may also, if appropriate, represent a bond, formed via a spacer, to a solid phase, and Z1 is a halogen atom, a hydroxyl, alkoxy or arylalkoxy group, is reacted with an amine of general formula in which R4 and R5 are defined as mentioned at the outset, and, if required, the product is subsequently cleaved from a protective group used for the nitrogen atom of the lactam group or from a solid phase, b. for preparing a compound of the formula I in which R3 is a phenyl or naphthyl group substituted by a carboxy-C2-3-alkenyl, aminocarbonyl-C2-3-alkenyl, (Ci-3-alkyl-amino)-carbonyl-C2.3-alkenyl, di-(Ci.3-alkylamino)-carbonyl-C2-3-alkenyl or C1-4-alkoxy-carbonyl-C2-3-alkenyl group, a compound of the formula (vi), intellectual property office of n.z. 1 8 DEC 2006 received 146 k' \ (IX), in which R2, R4, R5, R6 and X are as defined in Claim 1, R1' has the meanings mentioned at the outset for R1 or is a protective group for the nitrogen atom of the lactam group, where R1, may also, if appropriate, represent a bond, formed via a spacer, to a solid phase, and Z3 is a leaving group, is reacted with an alkene of general formula in which R3' is an amino, (Ci-3-alkylamino), di-(Ci-3-alkylamino) or Ci-4-alkoxy group and n is the number 0 or 1, c. to prepare a compound of the formula I, in which R3 is a phenyl or naphthyl group substituted by a carboxy-Ci_3-alkyl, Ci^-alkoxy-carbonyl-Ci_3-alkyl, aminocarbonyl-Ci-3-alkyl, (Ci-3-alkylamino)-carbonyl-Ci-3-alkyl or di-(Ci.3-alkyl)aminocarbonyl-Ci-3-alkyl group, a compound of general formula O (X), intellectual property office of n.z. 18 DEC 2006 R E" r PI v F n 147 in which R2, R4, R5, R6 and X are as defined in claim 1, R1' has the meanings mentioned at the outset for R1 or is a protective group for the nitrogen atom of the lactam group, where R1, may also, if appropriate, represent a bond, formed via a spacer, to a solid phase, A is a C2-3-alkenyl group and R3 is a hydroxyl, Ci-4-alkoxy, amino, (Ci.3-alkylamino) or di-(Ci.3-alkyl)amino group, is hydrogenated and the product is subsequently cleaved from any protective groups used for the nitrogen atom of the lactam group or from a solid phase, as described above under process (a), and an alkoxycarbonyl group is, if appropriate, subsequently converted by hydrolysis into a corresponding carboxyl 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, respectively, or intellectual property office of n.z. 18 DEC 2006 RPPdurr* 148 a carboxyl group is converted by esterification or amidation into a corresponding ester or aminocarbonyl compound, respectively, 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 with an acid into a corresponding hydroxyl compound, or an alkoxycarbonyl group is converted by hydrolysis into a corresponding carboxyl compound, or a phenyl group substituted by an amino, alkylamino, aminoalkyl or N-alkyl-amino group is converted by reaction with an appropriate amidino-group-transferring compound or by reaction with an appropriate nitrile into a corresponding guanidine compound of general formula I.

11. The process according to Claim 10, wherein Z1 is a chlorine or bromine atom, a methoxy, ethoxy or benzyloxy group.

12. The process according to Claim 10 or 11, wherein Z3 is a halogen atom or an alkyl- or arylsulphonyloxy group.

13. The process according to Claim 12, wherein Z3 is a chlorine, bromine or iodine atom or a methylsulphonyloxy, ethylsulphonyloxy, p-toluenesulphonyloxy or trifluoromethanesulphonyloxy group.

14. The following compound of general formula I according to Claim 1: 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone. intellectual property office of n.z. 18 DEC 2006 149

15. 1 -acetyl-6-fluoro-2-indolinone.

16. A compound of general formula I as defined in Claim 1 substantially as herein described with reference to any one or more of the Examples, including the analogous compounds on pages 124 to 139.

17. A compound of general formula I according to any one of Claims 1 to 6 substantially as herein described.

18. A medicament according to claim 7 in which the compound of general formula I or the physiologically acceptable salt thereof is substantially as herein described with reference to any one or more of Examples.

19. A medicament according to Claim 7 substantially as herein described with reference to any one or more of Examples 15 to 21.

20. A medicament according to Claim 7 substantially as herein described.

21. The use according to Claim 8 in which the compound of general formula I or the physiocogically acceptable salt thereof is substantially as herein described with reference to any one or more of Examples.

22. The use according to Claim 8 in which the medicament is substantially as herein described with reference to any one or more of Examples 15 to 21.

23. The use according to Claim 8 substantially as herein described.

24. A process according to Claim 9 substantially as herein described with reference to any one or more of Examples 15 to 21.

25. A process according to Claim 9 substantially as herein described.

26. A process according to Claim 10, substantially as herein described with reference to any one or more of the Examples 1 to 14, including the analogous compounds on pages 124 to 139.

27. A process according to any one of Claims 10 to 13, substantially as herein described. END OF CLAIMS intellectual property office of n.z. 1 8 DEC 2006 O I™*" r* i i f