INDOLINONE DERIVATIVES, SUBSTITUTED IN THE 6-POSITION, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS

DERIVES D'INDOLINONE SUBSTITUES EN POSITION 6, LEUR PREPARATION ET LEUR UTILISATION COMME MEDICAMENTS

English Abstract

The present invention relates to indolinone derivatives,
substituted in the 6-position, of the formula

(see formula I)
in which

X is oxygen; R1, R5 and R6 are hydrogen; R2 is halo or cyano;
and R3 and R4 are optionally substituted phenyl, to their
tautomers, enantiomers, diastereomers, to their mixtures and
to their salts, in particular their physiologically
acceptable salts, which have useful pharmacological
properties, in particular in inhibiting action on various
receptor tyrosine kinases and on the proliferation of
endothelial cells and various tumour cells, to medicaments
comprising these compounds, to their use and to processes
for their preparation.

French Abstract

L'invention concerne des dérivés d'indolinone substitués en position 6, de formule générale (I), dans laquelle R¿1? à R¿6? et X ont la définition mentionnée dans la revendication (1), leurs tautomères, énantiomères, diastéréomères, leurs mélanges et leurs sels, notamment leurs sels physiologiquement acceptables, qui présentent des propriétés pharmacologiques intéressantes, notamment un effet inhibiteur sur différents récepteurs à tyrosine kinase, et sur la prolifération de cellules endothéliales et de différentes cellules tumorales. L'invention concerne également des médicaments contenant lesdits composés, l'utilisation de ces derniers et des procédés pour la préparation desdits composés.

Claims

140
CLAIMS:

1. A compound of the formula
Image
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 C1-2-alkyl-carbonyl-amino group,

by a carboxy-C1-3-alkyl, carboxy-C1-4-alkoxy,
C1-4-alkoxy-carbonyl-C1-3-alkyl, C1-4-alkoxy-carbonyl-
C1-3-alkoxy, aminocarbonyl-C1-3-alkyl, (C1-2-alkylamino)-
carbonyl-C1-3-alkyl, di-(C1-2-alkyl)-aminocarbonyl-C1-3-alkyl,
(C1-2-alkyl-carbonyl)-amino-C1-3-alkyl, (C1-4-alkoxy-carbonyl)-
amino-C1-3-alkyl, (phenyl-carbonyl)-amino-C1-3-alkyl,
(C3-6-cycloalkyl-carbonyl)-amino-C1-3-alkyl, (C3-6-cycloalkyl-
C1-3-alkyl-carbonyl)-amino-C1-3-alkyl, (thiophen-2-yl-
carbonyl)-amino-C1-3-alkyl, (furan-2-yl-carbonyl)-amino-
C1-3-alkyl, (phenyl-C1-3-alkyl-carbonyl)-amino-C1-3-alkyl,
(2-(C1-9-alkoxy)-benzoyl-carbonyl)-amino-C1-3-alkyl,


141
(pyridin-2-yl-carbonyl)-amino-C1-3-alkyl, (pyridin-3-yl-
carbonyl)-amino-C1-3-alkyl, (pyridin-4-yl-carbonyl)-amino-
C1-3-alkyl or C1-3-alkyl-piperazin-1-yl-carbonyl-C1-3-alkyl
group, or

by an aminocarbonyl-C2-3-alkenyl, (C1-3-alkylamino)-
carbonyl-C2-3-alkenyl, di- (C1-3-alkyl)-amino-carbonyl-
C2-3-alkenyl or C1-4-alkoxy-carbonyl-C2-3-alkenyl group,

where the substituents may be identical or
different,

R4 is a phenyl group or a phenyl group which is
monosubstituted

by a C1-3-alkyl group which is terminally
substituted by an amino, guanidino, mono- or di-(C1-2-alkyl)-
amino-, N-[.omega.-di-(C1-3-alkyl)-amino-C2-3-alkyl]-N-(C1-3-alkyl)-
amino, N-methyl-(C3-4-alkyl)-amino, N-(C1-3-alkyl)-
N-benzylamino, N-(C1-4-alkoxycarbonyl)-amino,
N-(C1-4-alkoxycarbonyl)-C1-4-alkylamino, 4-(C1-3-alkyl)-
piperazin-1-yl, imidazol-1-yl, pyrrolidin-1-yl,
azetidin-1-yl, morpholin-4-yl, piperazin-1-yl, or
thiomorpholin-4-yl group,

by a di-(C1-3-alkyl)-amino-(C1-3-alkyl)-sulphonyl,
2-[di-(C1-3-alkyl)-amino]-ethoxy, 4-(C1-3-alkyl)-piperazin-
1-yl-carbonyl, {.omega.-[di-(C1-3-alkyl)-amino]-(C2-3-alkyl)}-
N-(C1-3-alkyl)-amino-carbonyl, 1-(C1-3-alkyl)imidazol-2-yl, or
(C1-3-alkyl)-sulphonyl group, or

by a group of the formula
Image


142
in which

R7 is a C1-2-alkyl, C1-2-alkyl-carbonyl,
di-(C1-2-alkyl)-amino-carbonyl-C1-3-alkyl or
C1-3-alkylsulphonyl group and

R8 is C1-3-alkyl, .omega.-[di-(C1-2-alkyl)-amino]-
C2-3-alkyl, .omega.-[mono-(C1-2-alkyl)-amino]-C2-3-alkyl group, or
a (C1-3-alkyl)-carbonyl, (C4-6-alkyl)-carbonyl or

carbonyl-(C1-3-alkyl) group which is terminally substituted
by a di-(C1-2-alkyl)-amino, piperazin-1-yl or 4-(C1-3-alkyl)-
piperazin-1-yl group,

where all dialkylamino groups present in the
radical R4 may also be present in quaternized form,

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,

or a tautomer, enantiomer, or diastereomer
thereof, or a mixture thereof, or a salt thereof.

2. A compound according to claim 1 wherein the
dialkyl amino groups present in the radical R4 are an
N-methyl-(N,N-dialkyl)-ammonium group.

3. A compound according to claim 2, wherein the
counterion for the N-methyl-(N,N-dialkyl)-ammonium group is
selected from the group consisting of iodide, chloride,
bromide, methylsulphonate, para-toluenesulphonate and
trifluoroacetate.


143
4. A compound of the formula I according to claim 1
in which

X, R1, R2, R4, R5 and R6 are as defined in claim 1
and

R3 is a phenyl group substituted by a carboxy-
C1-3-alkyl or C1-4-alkoxy-carbonyl-C1-3-alkyl group.

5. A compound of the formula I according to any one
of claims 1 to 4, 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.
6. A compound:

(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;


144
(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;

(l) 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;
or


145
(q) 3-Z-[1-(4-(diethylaminomethyl)anilino)-

1-(4-(2-carboxyethyl)-methylene]-6-bromo-2-indolinone;
or a salt of any one of compounds (a) to (q).

7. A compound: 3-Z-[1-(4-dimethylaminomethylanilino)-
1-(4-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-
2-indolinone or a salt thereof.

8. 1-acetyl-6-fluoro-2-indolinone or a salt thereof.
9. A physiologically acceptable salt of a compound as
defined in any one of claims 1 to 7.

10. A medicament, comprising a compound as defined in
any one of claims 1 to 7 or a physiologically acceptable
salt as defined in claim 9, and one or more components
selected from inert carrier materials and diluents.

11. The use of a compound as defined in any one of
claims 1 to 7 or of a physiologically acceptable salt as
defined in claim 9 in preparing a medicament for treating
excessive or abnormal cell proliferation.

12. A process for preparing a medicament as defined in
claim 10, wherein, by a non-chemical route, a compound as
defined in any one of claims 1 to 7 or a physiologically
acceptable salt as defined in claim 9 is incorporated into
one or more components selected from inert carrier materials
and diluents.

13. A process for preparing a compound of the
formula (I) as defined in claim 1, wherein:

a. a compound of the formula


146
Image
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 meaning defined in claim 1 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 the formula
Image
in which

R4 and R5 are defined as in claim 1,

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,


147
b. for preparing a compound of the formula I in

which R3 is a phenyl group substituted by an aminocarbonyl-
C2-3-alkenyl, (C1-3-alkyl-amino) -carbonyl-C2-3-alkenyl,

di-(C1-3-alkylamino)-carbonyl-C2-3-alkenyl or C1-4-alkoxy-
carbonyl-C2-3-alkenyl group,

a compound of the formula
Image
in which

R2, R4, R5, R6 and X are as defined in claim 1,

R1' has the meaning defined in claim 1 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
the formula

Image
in which

R3 is an amino, (C1-3-alkylamino),
di-(C1-3-alkylamino) or C1-4-alkoxy group and


148
n is the number 0 or 1,

c. to prepare a compound of the formula I, in
which R3 is a phenyl group substituted by a carboxy-
C1-3-alkyl, C1-4-alkoxy-carbonyl-C1-3-alkyl, (C1-2-alkylamino)-
carbonyl-C1-3-alkyl or di-(C1-2-alkyl)aminocarbonyl-C1-3-alkyl
group,

a compound of the formula

Image
in which

R2, R4, R5, R6 and X are as defined in claim 1,

R1' has the meaning defined in claim 1 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 C1-4-alkoxy, amino, (C1-3-alkylamino) or
di-(C1-3-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,


149
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

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 the formula I.


150
14. The process according to claim 13, wherein, in the
compound of formula (V), Z1 is a chlorine or bromine atom, or
a methoxy, ethoxy or benzyloxy group.

15. The process according to claim 13, wherein, in the
compound of formula (IX), the leaving group Z3 is a halogen
atom or an alkyl- or arylsulphonyloxy group.

16. The process according to claim 15, wherein Z3 is a
halogen atom and the halogen atom is selected from chlorine,
bromine and iodine.

17. The process according to claim 15, wherein Z3 is an
alkyl- or arylsulphonyloxy group and the alkyl- or
arylsulphonyloxy group is selected from a
methylsulphonyloxy, ethylsulphonyloxy, p-toluenesulphonyloxy
and trifluoromethanesulphonyloxy group.

Description

Boehringer Ingelheim Pharma GmbH & Co. KG 1-1504
foreign filing text
Indolinone derivatives, substituted in the 6-position, their preparation and
their use as medicaments

The present invention relates to indolinone derivatives, substituted in the 6-
position,
of the formula

R4
R3
N
R6 \ R5
X

R2 N
R1 (I),

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
processes for their preparation.

The above compounds of the formula I have useful pharmacological properties,
in
particular an inhibition action on various kinases, especially on receptor
tyrosine
kinases, such as VEGFR1, VEGFR2, VEGFR3, PDGFRa, PDGFRI3, FGFR1,
FGFR3, EGFR, HER2, c-Kit, IGF1 R 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.
CA 02493436 2005-01-21


CA 02493436 2005-01-21
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
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
materials and/or diluents.

1. In the above formula I,
X is an oxygen atom,
R' 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 C1_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 C1_3-alkoxy or C1_2-alkyl-carbonyl-amino group,
by a cyano-C1.3-alkyl, carboxy-C1.3-alkyl, carboxy-Cl.4-alkoxy, carboxy-
C1_3-alkylamino, carboxy-C1.3-alkyl-N-(C1_3-alkyl)-amino, C1.4-alkoxy-
carbonyl-C1.3-alkyl, C1_4-alkoxy-carbonyl-C1_3-alkoxy, C1.4-alkoxy-


CA 02493436 2005-01-21

3
carbonyl-C1_3-alkylamino, C1_4-alkoxy-carbonyl-C1_3-alkyl-N-(C1_3-alkyl)-
amino, amino-C1_3-alkyl, aminocarbonyl-C1.3-alkyl, (C1.2-alkylamino)-
carbonyl-C1.3-alkyl, di-(C1.2-alkyl)-aminocarbonyl-C1.3-alkyl, (C1.2-alkyl-
carbonyl)-amino-C1_3-alkyl, (C1_4-alkoxy-carbonyl)-amino-C1.3-alkyl, (C3-
6-alkyl-carbonyl)-amino-C1_3-alkyl, (phenyl-carbonyl)-amino-C1_3-alkyl,
(C3.6-cycloalkyl-carbonyl)-amino-C1_3-alkyl, (C3_6-cycloalkyl-C1_3-alkyl-
carbonyl)-amino-C1_3-alkyl, (thiophen-2-yl-carbonyl)-amino-C1_3-alkyl,
(furan-2-yl-carbonyl)-amino-C1.3-alkyl, (phenyl-C1.3-alkyl-carbonyl)-
amino-C1.3-alkyl, (2-(C1_4-alkoxy)-benzoyl-carbonyl)-amino-C1.3-alkyl,
(pyridin-2-yl-carbonyl)-amino-C1.3-alkyl, (pyridin-3-yl-carbonyl)-amino-
C1_3-alkyl-, (pyridin-4-yl-carbonyl)-amino-C1_3-alkyl- or C1_3-alkyl-
piperazin-1-yi-carbonyl-C1.3-alkyl group,

by a carboxy-C2_3-alkenyl, aminocarbonyl-C2.3-alkenyl, (C1.3-alkyl-
amino)-carbonyl-C2_3-alkenyl, di-(C1.3-alkyl)-amino-carbonyl-C2_3-alkenyl
or C1_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 C1_3-alkyl group which is terminally substituted by an amino,
guanidino, mono- or di-(C1_2-alkyl)-amino-, N-[w-di-(C1_3-alkyl)-amino-C2_
3-alkyl]-N-(C1.3-alkyl)-amino, N-methyl-(C3.4-alkyl)-amino, N-(C1_3-
alkyl)-N-benzylamino, N-(C1.4-alkoxycarbonyl)-amino, N-(C1.4-
alkoxycarbonyl)-C1.4-alkylamino, 4-(C1.3-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-(C1_3-alkyl)-amino-(C1.3-alkyl)-sulphonyl, 2-[di-(C1_3-alkyl)-amino]-
ethoxy, 4-(C1.3-alkyl)-piperazin-1-yl-carbonyl, {co-[di-(C1_3-alkyl)-amino]-
(C2_3-alkyl)}-N-(C1.3-alkyl)-amino-carbonyl, 1-(C1_3-alkyl)imidazol-2-yl,
(C1.3-alkyl)-sulphonyl group, or


CA 02493436 2005-01-21
4
by a group of the formula
R8
R7
in which
R7 is a C1.2-alkyl, C1_2-alkyl-carbonyl, di-(C1.2-alkyl)-amino-
carbonyl-C1.3-alkyl or C1.3-alkylsulphonyl group and

R8 is C1.3-alkyl, w-[di-(C1_2-alkyl)-amino]-C2_3-alkyl, co-[mono-(C1_2-
alkyl)-amino]-C2_3-alkyl group, or

a (C1_3-alkyl)-carbonyl, (C4_6-alkyl)-carbonyl or carbonyl-(C1.3-
alkyl) group which is terminally substituted by a di-(C1_2-alkyl)-
amino, piperazin-1-yl or 4-(C1.3-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-toluenesuI phonate 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


CA 02493436 2005-01-21
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,

5 their tautomers, enantiomers, diastereomers, their mixtures and their salts.

II. Particularly preferred compounds of the above formula I are those
compounds
in which X, R1, R5 and R6 are as defined under I. and:
I1.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 C1_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 C1.3-alkoxy or C1.2-alkyl-carbonyl-amino group,

by a cyano-C1_3-alkyl, carboxy-C1_3-alkyl, carboxy-C1.4-alkoxy, carboxy-
C1.3-alkylamino, carboxy-C1_3-alkyl-N-(C1.3-alkyl)-amino, C1_4-alkoxy-
carbonyl-Cl.3-alkyl, C1.4-alkoxy-carbonyl-C1_3-alkoxy, C1-4-alkoxy-
carbonyl-C1_3-alkylamino, C1_4-alkoxy-carbonyl-C1.3-alkyl-N-(C1_3-alkyl)-
amino, amino-C1.3-alkyl, aminocarbonyl-C1_3-alkyl, (C1.2-alkylamino)-
carbonyl-C1_3-alkyl, di-(C1.2-alkyl)-aminocarbonyl-C1_3-alkyl, (C1_2-alkyl-
carbonyl)-amino-C1.3-alkyl, (C1.4-alkoxy-carbonyl)-amino-C1_3-alkyl, (C3_
6-alkyl-carbonyl)-amino-C1.3-alkyl, (phenyl-carbonyl)-amino-C1_3-alkyl,
(C3.6-cycloalkyl-carbonyl)-amino-C1.3-alkyl, (C3_6-cycloalkyl-C1_3-alkyl-
carbonyl)-amino-C1.3-alkyl, (thiophen-2-yl-carbonyl)-amino-C1.3-alkyl,


CA 02493436 2005-01-21

6
(furan-2-yl-carbonyl)-amino-C1.3-alkyl, (phenyl-C13-alkyl-carbonyl)-
amino-C1_3-alkyl, (2-(C1.4-alkoxy)-benzoyl-carbonyl)-amino-C1.3-alkyl,
(pyridin-2-yl-carbonyl)-amino-Cl.3-alkyl, (pyridin-3-yl-carbonyl)-amino-
C1.3-alkyl, (pyridin-4-yl-carbonyl)-amino-C1.3-alkyl or C1.3-alkyl-piperazin-
1-yi-carbonyl-C1.3-alkyl group,

by a carboxy-C2.3-alkenyl, aminocarbonyl-C2.3-alkenyl-, (C1.3-alkyl-
amino)-carbonyl-C2.3-alkenyl-, di-(C1.3-alkyl)-amino-carbonyl-C2_3-
alkenyl or C1.4-alkoxy-carbonyl-C2.3-alkenyl group,
where the substituents may be identical or different;
Il.ii. R2 and R4 are as defined under I. and
R3 is a phenyl group which is substituted

by a C1.2-alkyl-carbonyl-amino group,

by a carboxy-Cl.3-alkyl, carboxy-C1.4-alkoxy, C1.4-alkoxy-carbonyl-C1.3-
alkyl, C1_4-alkoxy-carbonyl-C1 3-alkoxy, aminocarbonyl-Cl.3-alkyl, (C1-2-
alkylamino)-carbonyl-Cl.3-alkyl, di-(C1.2-alkyl)-aminocarbonyl-C1 3-alkyl,
(C1.2-alkyl-carbonyl)-amino-C1 3-alkyl, (C1-4-alkoxy-carbonyl)-amino-C1.3-
alkyl, (phenyl-carbonyl)-amino-C13-alkyl, (C8.6-cycloalkyl-carbonyl)-
amino-C1_3-alkyl, (C3.6-cycloalkyl-C1.3-alkyl-carbonyl)-amino-C1.3-alkyl,
(thiophen-2-yl-carbonyl)-amino-C1.3-alkyl, (furan-2-yl-carbonyl)-amino-
C1.3-alkyl, (phenyl-C1.3-alkyl-carbonyl)-amino-C1.3-alkyl, (2-(C14-
alkoxy)-benzoyl-carbonyl)-amino-Cl.3-alkyl, (pyridin-2-yl-carbonyl)-
amino-Cl.3-alkyl, (pyridin-3-yl-carbonyl)-amino-Cl.3-alkyl, (pyridin-4-yl-
carbonyl)-amino-C1.3-alkyl or C1.3-alkyl-piperazin-1-yl-carbonyl-Cl.3-alkyl
group,


CA 02493436 2005-01-21
7
by an aminocarbonyl-C2_3-alkenyl, (C1_3-alkylamino)-carbonyl-C2_3-
alkenyl, di-(C1.3-alkyl)-amino-carbonyl-C2_3-alkenyl or C1-4-alkoxy-
carbonyl-C2_3-alkenyl group;

ll.iii. R2 and R4 are as defined under I. and

R3 is a phenyl group substituted by a carboxy-C1.3-alkyl or C1_4-alkoxy-
carbonyl-C1.3-alkyl group;

11. 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 C1.3-alkyl group which is terminally substituted by an amino,
guanidino, mono- or di-(C1.2-alkyl)-amino-, N-[o -di-(C1.3-alkyl)-amino-C2_
3-alkyl]-N-(C1.3-alkyl)-amino, N-methyl-(C3.4-alkyl)-amino, N-(C1_3-
alkyl)-N-benzylamino, N-(C1.4-alkoxycarbonyl)-amino, N-(C1_4-
alkoxycarbonyl)-C1.4-alkylamino, 4-(C1_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-(C1.3-alkyl)-amino-(C1.3-alkyl)-sulphonyl, 2-[di-(C1.3-alkyl)-amino]-
ethoxy, 4-(C1.3-alkyl)-piperazin-1-yl-carbonyl, {c -[di-(C1_3-alkyl)-amino]-
(C2_3-alkyl)}-N-(C1_3-alkyl)-amino-carbonyl, 1-(C1_3-alkyl)imidazol-2-yl,
(C1.3-alkyl)-sulphonyl group, or

by a group of the formula


CA 02493436 2005-01-21
8

R8
R7
in which

R7 is a C1.2-alkyl, C1.2-alkyl-carbonyl, di-(C1.2-alkyl)-amino-
carbonyl-C1_3-alkyl or C,_3-alkylsulphonyl group and

R8 is C1.3-alkyl, co-[di-(C1.2-alkyl)-amino]-C2.3-alkyl, co-[mono-(C1.2-
alkyl)-amino]-C2.3-alkyl group, or

a (C1.3-alkyl)-carbonyl, (C4.6-alkyl)-carbonyl or carbonyl-(C1.3-
alkyl) group which is terminally substituted by a di-(C1.2-alkyl)-
amino, piperazin-1 -yl or 4-(C1_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, methylsuIphonate, para-toluenesuI phonate and
trifluoroacetate.

Ill. Subgroups of particularly preferred compounds of the above formula I
which
are to be mentioned in particular are those in which:

Ill.i. X, R', R2, R5 and R6 are as defined under I., R3 is as defined
under ILl. and R4 is as defined under ll.v.;

Ill.ii. X, R', R2, R5 and R6 are as defined under I., R3 is as defined
under ll.ii. and R4 is as defined under ll.v.;


CA 02493436 2005-01-21
9
Ill.iii. X, R', R2, R5 and R6 are as defined under I., R3 is as defined
under Il.iii. and R4 is as defined under II.v.;

Ill.iv. X, R', R5 and R6 are as defined under I., R2 is as defined under
ll.iv., R3 is as defined under II.i., ll.ii. or ll.iii. and R4 is as defined
under Il.v.

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 C1_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 C1.3-alkoxy or C1_2-alkyl-carbonyl-amino group,

by a carboxy-C1_3-alkyl, aminocarbonyl-C1_3-alkyl, (C1.2-alkylamino)-carbonyl-
C1_3-alkyl, di-(C1.2-alkyl)-aminocarbonyl-C1.3-alkyl, (C1.2-alkyl-carbonyl)-
amino-
C1.3-alkyl or (phenyl-carbonyl)-amino-C1.3-alkyl group,
where the substituents may be identical or different,
R4 is a phenyl group which is substituted


CA 02493436 2005-01-21
by a C1.3-alkyl group terminally substituted by a di-(C1_2-alkyl)-amino group,
or
by a group of the formula
R8
-N
5 R7
in which

R7 is a C1_2-alkyl, C1.2-alkyl-carbonyl, di-(C1_2-alkyl)-amino-carbonyl-C1_3-
alkyl or C1.3-alkylsulphonyl group and
R8 is a C1.3-alkyl or co-[di-(C1_2-alkyl)-amino]-C2.3-alkyl group, or

a C1.3-alkyl-carbonyl group terminally substituted by a di-(C1_2-alkyl)-
amino, piperazino or 4-(C1.3-alkyl)-piperazin-1-yl group,

R5 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,

their tautomers, enantiomers, diastereomers, their mixtures and their salts.
The following compounds of the formula I are particularly preferred:


CA 02493436 2005-01-21
11
(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
Q) 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-
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


CA 02493436 2005-01-21

12
(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
group,

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
with an alcohol in which the alcoholic moiety is preferably a C1_6-alkanol, a
phenyl-
C1.3-alkanol, a C3_9-cycloalkanol, where a C5_8-cycloalkanol may additionally
be
substitituted by one or two C1_3-alkyl groups, a C5_8-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 C1.3-alkyl, phenyl-C1.3-alkyl, phenyl-C1_3-
alkoxy-
carbonyl or C1.6-alkyl-carbonyl group and in which the cycloalkanol moiety may
additionally be substituted by one or two C1_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-C1.3-alkanol, a bicycloalkanol having
a total of
8 to 10 carbon atoms which may additionally be substituted in the bicycloalkyl
moiety
by one or two C1_3-alkyl groups, a 1,3-dihydro-3-oxo-1-isobenzofuranol or an
alcohol
of the formula

Ra-CO-O-(RbCRc)-OH,
in which
Ra is a C1.8-alkyl, C5_7-cycloalkyl, phenyl or phenyl-C1.3-alkyl group,

Rb is a hydrogen atom, a C1.3-alkyl, C5.7-cycloalkyl or phenyl group, and


CA 02493436 2005-01-21
13
Rc is a hydrogen atom or a C,_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
pyridinoyl group, or a C1_16-alkylcarbonyl group, such as the formyl, acetyl,
propionyl,
butanoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a C1_16-
alkoxy-
carbonyl group, such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,
isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl,
hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl,
undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, a phenyl-

C1_6-alkoxy-carbonyl group, such as the benzyloxycarbonyl,
phenylethoxycarbonyl or
phenylpropoxycarbonyl group, a C1.3-alkylsulphonyl-C1_4-alkoxy-carbonyl, C1.3-
alkoxy-C2-4-alkoxy-C2_4-alkoxy-carbonyl or RaCO-O-(RbCRc)-O-CO- group, in
which
Ra is a C1_8-alkyl, C5_7-cycloalkyl, phenyl or phenyl-C1.3-alkyl group,

Rb is a hydrogen atom, a C1_3-alkyl, C5_7-cycloalkyl or phenyl group and

Rc is a hydrogen atom, a C1_3-alkyl or RaCO-O-(RbCRc)-O- group, in which Ra
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 C1.6-alkoxy-carbonyl
group,
such as the methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl,
isopropyloxycarbonyl, n-butyloxycarbonyl, n-pentyloxycarbonyl, n-
hexyloxycarbonyl
or cyclohexyloxycarbonyl group, or a phenyl-C1_3-alkoxy-carbonyl group, such
as the
benzyloxycarbonyl group, and,


CA 02493436 2005-01-21
14
for an imino or amino group, a C,_9-alkoxy-carbonyl group, such as the methoxy-

carbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-
butyloxy-
carbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl, cyclohexyloxycarbonyl,
n-heptyloxycarbonyl, n-octyloxycarbonyl or n-nonyloxycarbonyl group, a phenyl-
C1.3-
alkoxy-carbonyl group, such as the benzyloxycarbonyl group, a phenylcarbonyl
group
optionally substituted by a C1.3-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 C1.3-alkoxy-C2_3-alkoxy-C1.4-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
Z1
R3
R6 X
N
R2
R1 (V)
in which
the radicals Z' and R3 may, if appropriate, change their positions,
X, R2, R3 and R6 are as defined at the outset,
R" 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 Z' is a halogen atom, a hydroxyl, alkoxy or arylalkoxy group, for example
a
chlorine or bromine atom, a methoxy, ethoxy or benzyloxy group,

with an amine of the formula


CA 02493436 2005-01-21

R4R5
I
H (VI),
in which
R4 and R5 are defined as mentioned at the outset,
5 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.

Suitable protective groups for the nitrogen atom of the lactam group are, for
example,
an acetyl, benzoyl, ethoxycarbonyl, tert-butyloxycarbonyl or benzyloxycarbonyl
group
10 and

suitable solid phases are a resin, such as a 4-(2',4'-
dimethoxyphenylaminomethyl)-
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,
15 such as a 2,5-dimethoxy-4-hydroxybenzyl derivative.

The reaction is expediently carried out in a solvent, such as
dimethylformamide,
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, Z' 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, Z' is a hydroxyl, alkoxy or arylalkoxy
group, the
reaction is preferably carried out at temperatures between 20 and 200 C.

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


CA 02493436 2005-01-21

16
solvent, for example in methanol/water, ethanol/water, isopropanol/water,
tetra hyd rofu ra n/wate r, dioxane/water, dimethylformamide/water, methanol
or ethanol,
in the presence of an alkali metal base, such as lithium hydroxide, sodium
hydroxide
or potassium hydroxide, at temperatures between 0 and 100 C, preferably at
temperatures between 10 and 50 C,

or, advantageously, by transamidation with an organic base, such as ammonia,
butylamine, dimethylamine or piperidine, in 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, (C,.3-
alkylamino)-
carbonyl-C2.3-alkenyl, di-(C,.3-alkylamino)-carbonyl-C2_3-alkenyl or C1.4-
alkoxy-
carbonyl-C2_3-alkenyl group,
reaction of a compound of the formula
Z3
R4
N
R5
R6 X
N
R

R" (IX),
in which
R2, R4, R5, R6 and X are as defined at the outset,


CA 02493436 2005-01-21

17
R" has the meanings mentioned at the outset for R1 or is a protective group
for the
nitrogen atom of the lactam group, where R'' may also, if appropriate,
represent a
bond, formed via a spacer, to a solid phase, and
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
R3, n \
(X),
in which
R3" is an amino, (C1_3-alkylamino), di-(C1.3-alkylamino) or C1-4-alkoxy group
and
n is the number 0 or 1.

The reaction is expediently carried out with palladium catalysis, using, for
example,
palladium(II) acetate, palladium(II) chloride,
bis(triphenylphosphine)palladium(ll)
acetate, bis(triphenylphosphine)palladium(II) chloride, palladium/carbon, bis-
[1,2-
bis(diphenylphosphino)ethane]palladium(0), dichloro-(1,2-
bis(diphenylphosphino)-
ethane)palladium(II), tetrakistriphenylphosphinepaIladium(0),
tris(dibenzylidene-
acetone)dipalladium(0), 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
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.

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).


CA 02493436 2005-01-21

18
c. To prepare a compound of the formula I in which R3 is a phenyl or naphthyl
group
substituted by

a carboxy-C1.3-alkyl, C1.4-alkoxy-carbonyl-C1.3-alkyl, aminocarbonyl-C1.3-
alkyl,
(C1.3-alkylamino)-carbonyl-C1.3-alkyl or di-(C1_3-alkyl)-aminocarbonyl-C1.3-
alkyl
group,

hydrogenation of a compound of the formula
R3, YO
A
R4
N
R5
R6 X
N
R

R1 (XI),
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, C1_4-alkoxy, amino, (C1_3-alkylamino) or di-(C1.3-
alkyl)amino group.
The hydrogenation is preferably carried out using catalytic hydrogenation with
hydrogen in the presence of a catalyst, such as palladium/carbon or platinum,
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, at temperatures between 0 and 50 C, but
preferably


CA 02493436 2005-01-21
19
at room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably
3 to
bar.

The cleavage of a protective group used for the nitrogen atom of the lactam
group or
5 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
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 suiphonation 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


CA 02493436 2005-01-21
if a compound of the formula I is obtained which contains an arylalkyloxy
group, this
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,
5 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
10 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
15 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,
20 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
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,
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
palladium/carbon, or in the presence of a metal hydride, such as sodium
borohydride,
lithium borohydride, sodium cyanoborohydride or lithium aluminium hydride, at


CA 02493436 2005-01-21

21
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
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
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
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,
trimethylchIorosilane,
phosphorus trichioride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide,
N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N'-dicyclohexyl-
carbodiimide/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 triphenylphosphine/carbon tetrachloride, and, if
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
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


CA 02493436 2005-01-21

22
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
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-
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-hydroxybenzotriazo le, 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
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
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
palladium/carbon or Raney nickel, in a solvent, such as methanol, ethanol,
ethyl
acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid,
if


CA 02493436 2005-01-21

23
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 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
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,
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
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, trifiuoroacetyl, benzoyl, ethoxycarbonyl, tert-butoxycarbonyl,
benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group, and,
for
the amino group, additionally the phthalyl group.


CA 02493436 2005-01-21

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
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,
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,
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.


CA 02493436 2005-01-21

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
5 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,
for example by chromatography and/or fractional crystallization, into their
10 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
chiral phases or by recrystallization from an optically active solvent or by
reaction
15 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,
whereupon the free enantiomers can be released from the pure diastereomeric
salts
20 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, camphorsuIphonic acid, glutamic
acid,
N-acetylglutamic acid, aspartic acid, N-acetylaspartic acid or quinic acid. A
suitable
optically active alcohol is, for example, (+)- or (-)-menthol, and a suitable
optically
25 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
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,


CA 02493436 2005-01-21

26
ethanesulphonic acid, para-toluenesulphonic acid, phenylsulphonic acid or L-
(+)-
mandelic acid.

Moreover, the resulting novel compounds of the formula I can, if they contain
a
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
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
useful pharmacological properties, in particular in inhibiting action on
various kinases,
especially on receptor tyrosine kinases, such as VEGFR1, VEGFR2, VEGFR3,
PDGFR X, PDGFR3, FGFR1, FGFR3, EGFR, HER2, c-Kit, IGF1 R and HGFR, Fit-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 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
R-mercaptoethanol (Fluka), standard antibiotics, 15 pg/ml of endothelial cell
growth


CA 02493436 2005-01-21

27
factor (ECGS, Collaborative Biomedical Products) and 100 pg/ml of heparin
(Sigma)
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
cells were "starved" for 16 hours, i.e. kept in culture medium without growth
factors
(EGGS + 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
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 p
Ci/well,
Amersham) was then added for a further 16 hours to determine DNA synthesis.
The
radioactively labelled cells were then immobilized on filter mats and the
incorporated
radioactivity was determined in a R 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 pM and 1 nM.


CA 02493436 2005-01-21

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
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 at. (O'Reilly M.S. et al., Cell 88, 277-285, (1997); Parangi S. et
al., Proc
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,
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
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-
proliferative disorders, atherosclerosis, injuries of the nerve tissue and for
inhibiting
the reocciusion of vessels after balloon catheter treatment, in vessel
prosthetics or


CA 02493436 2005-01-21
29
after implantation of mechanical devices for keeping vessels open (for example
stents) or other disorders in which cell proliferation or angiogenesis play a
role.
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.


CA 02493436 2005-01-21

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
3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-
1.4 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-ch loro-2-indolinone

1.7 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1 -(3,4-
d imethoxyphenyl)methylene]-6-chloro-2-indolinone

3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-
1.8 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


CA 02493436 2005-01-21
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-acetylamino)anilino)-1-(3-
fluorophenyl)methylene]-6-fluoro-2-indolinone
3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-
3.3 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-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-
3.6 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


CA 02493436 2005-01-21

32
3.11 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-
1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone
3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-
3.12 methylamino)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-
fluoro-2-indolinone
3.13 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-cyanomethyiphenyl)-
methylene]-6-fluoro-2-indolinone
3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-
3.14 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-tent-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-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-
3.18 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-methylpiperazin-1-yl-carbonyl )anilino)-1-(4-(2-
methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone


CA 02493436 2005-01-21
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-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-
3.25 methylamino)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-
fluoro-2-indolinone
3.26 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-
1-(3-methoxycarbonylmethylphenyl)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-[l -(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-
(3-methoxycarbonylmethyl phenyl)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-Z-[1-Anilino-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-
3.32
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-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-
3.35 methylsulphonylamino)anilino)-1-(4-methoxycarbonylmethyiphenyl)-
methylene]-6-fluoro-2-indolinone


CA 02493436 2005-01-21
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-methyiamino)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-Z-[l-(4-(N-(dimethylaminocarbonylmethyl)-N-
3.45 methylsulphonylamino)anilino)-1-(3-methoxycarbonylmethylphenyl)-
methyiene]-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-methoxycarbonylmethyl phenyl)methylene]-6-fluoro-2-indolinone
3-Z-[1-(4-(N-(4-methylpiperazin-l -ylmethylcarbo,nyl)-N-
3.48 methylamino)anilino)-1-(3-(2-methoxycarbonylethyl)phenyi)methylene]-
6-fluoro-2-indolinone


CA 02493436 2005-01-21
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-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-
3.52 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


CA 02493436 2005-01-21
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-dimethylaminobutylcarbonyl)-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-[1 anilino-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
------ ------ -


CA 02493436 2005-01-21
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-[1 anilino-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-dimethylaminomethylan iii no)-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


CA 02493436 2005-01-21
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)anihlino)-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

5.0 3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(3-(2-
methoxycarbonylvinyi)phenyl)methylene]-6-chloro-2-indolinone
5.1 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(2-methoxycarbonyl-
vinyl)phenyl)methylene]-6-chloro-2-indolinone
5.2 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(2-carbamoyl-
vinyl)phenyl)methylene]-6-fluoro-2-indolinone

5.3 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(2-methoxycarbonyl-
vinyl)phenyl)methylene]-6-fluoro-2-indolinone
5.4 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)phenyi)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
------- - ------


CA 02493436 2005-01-21
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-aminomethyiphenyl)-
methylene]-6-chloro-2-indolinone

3-Z-[1-(4-(N-((4-methylpiperazin-1-yl)methylcarbonyl)-N-
8.0 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

3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-
9.3 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
3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-
9.6 methylamino)anilino)-1-(3-aminomethylphenyl)methylene]-6-fluoro-2-
indolinone


CA 02493436 2005-01-21
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
10.0 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone

10.1 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
10.2 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-carboxymethylphenyl)-
methylene]-6-fluoro-2-indolinone
10.3 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone

10.4 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethyl phenyl)-
methylene]-6-fluoro-2-indolinone
3-Z-[1-(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-
10.5 methylamino)anilino)-1-(4-carboxymethylphenyl)methylene]-6-fluoro-2-
indolinone
10.6 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-
1-(4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone
10.7 3-Z-[1 -(4-(N-methyl-N-acetylamino)an ilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-
10.8 methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-
2-indolinone
10.9 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-
1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone


CA 02493436 2005-01-21
41
10.10 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone

10.11 3-Z-[1-(4-(N-tert-butoxycarbonylmethylaminomethyl)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
10.12 3-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
10.13 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone

10.14 3-Z-[1-(4-methylsulphonylanilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
10.15 3-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(3-
carboxymethylphenyl)methylene]-6-fluoro-2-indolinone
3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-
10.16 methylamino)anilino)-1-(3-carboxymethylphenyl)methylene]-6-fluoro-2-
indolinone
10.17 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-
(3-carboxymethylphenyl)methylene]-6-fluoro-2-i ndoli none

10.18 3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1-
(3-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone
10.19 3-Z-[1-Anilino-1-(3-carboxymethylphenyl)-methylene]-6-fluoro-2-
indolinone
10.20 3-Z-[1-(4-methylsulphonylanilino)-1-(3-carboxymethyiphenyl)-
methylene]-6-fluoro-2-indolinone

10.21 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(3-carboxymethylphenyl)-
methylene]-6-fluoro-2-indolinone
3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-
10.22 methylsulphonylamino)anilino)-1-(3-carboxymethylphenyl)-methylene]-
6-fluoro-2-indolinone


CA 02493436 2005-01-21

42
3-Z-[1 anilino-1-(4-carboxymethylphenyl)methylene]-6-fluoro-2-
10.23
indolinone
10.24 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-carboxymethylphenyl)-
methylene]-6-fluoro-2-indolinone

10.25 3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-
1-(4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone
10.26 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-
(4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone
10.27 3-Z-[1-(4-(4-methylpiperazin-1-yl-carbonyl)anilino)-1-(4-
carboxymethylphenyl)methylene]-6-fluoro-2-indolinone

10.28 3-Z-[1-(4-methylsulphonylanilino)-1-(4-carboxymethylphenyl)-
methylene]-6-fluoro-2-indolinone
10.29 3-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(4-carboxymethylphenyl)-
methylene]-6-fluoro-2-indolinone
3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-
10.30 methylsulphonylamino)anilino)-1-(4-carboxymethylphenyl)methylene]-
6-fluoro-2-indolinone
10.31 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-
(4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone

10.32 3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-
1-(4-carboxymethylphenyl )methylene]-6-fluoro-2-indol i none
3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-
10.33 methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-
2-indolinone
10.34 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-
1-(3-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone
10.35 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-
1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indoli none


CA 02493436 2005-01-21

43
3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-
10.36
(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
10.37 3-Z-[1 -(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1 -(3-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone

10.38 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-
(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
10.39 3-Z-[1 -(4-(2-dimethylaminoethyl)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
10.40 3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-
(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone

10.41 3-Z-[1 -(4-(2-dimethylaminoethyl)anilino)-1 -(3-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
10.42 3-Z-[1 -(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1 -(4-(2-
ca rboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone

10.43 3-Z-[1 -(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-
1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
10.44 3-Z-[1 -(4-(N-(4-dimethylamino-butylcarbonyl)-N-methylamino)anilino)-
1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
10.45 3-Z-[1 -(4-(1 -methylimidazol-2-yl)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone

10.46 3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1-
(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
10.47 3-Z-[1 anilino-1-(4-(2-carboxyethyl)phenyl)methyl en e]-6-fl u o ro-2-
indolinone
10.48 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone

10.49 3-Z-[1 -(4-(diethylaminomethyl)anilino)-1 -(4-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone


CA 02493436 2005-01-21

44
3-Z-[1-(4-aminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-
10.50
6-fluoro-2-indolinone
10.51 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(3-carboxymethylphenyl)-
methylene]-6-fluoro-2-indolinone

10.52 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-carboxymethylphenyl)-
methylene]-6-fluoro-2-indolinone
10.53 3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone
3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2-
10.54
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone
10.55 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone

10.56 3-Z-[1-(4-((4-methylpiperazin-1-yl)methyl)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
10.57 3-Z-[1-(4-(imidazol-1-ylmethyl )anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
10.58 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-
(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone

10.59 3-Z-[1-(4-((4-methylpiperazin-1-yl)methyl)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
10.60 3-Z-[1-(4-(imidazol-1-ylmethyl)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
10.61 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone

10.62 3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-
(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
10.63 3-Z-[1 anilino-1 -(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-
indolinone


CA 02493436 2005-01-21
3-Z-[1-(4-aminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-
10.64
6-fluoro-2-indolinone
10.65 3-Z-[1-(4-methylaminomethylanilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone

10.66 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-carboxymethoxy-phenyl)-
methylene]-6-fluoro-2-indolinone
10.67 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(4-carboxymethoxy-
phenyl)phenyl)methylene]-6-fluoro-2-indolinone
10.68 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone

10.69 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
10.70 3-Z-[1 -(4-(diethylaminomethyl)anilino)-1 -(4-(2-carboxyethyl)-
methylene]-6-bromo-2-indolinone
10.71 3-Z-[1 -(3-dimethylaminomethylanilino)-1 -(4-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone

10.72 3-Z-[1 -(3-dimethylaminomethylanilino)-1 -(3-(2-
ca rboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
3-Z-[1 -(3-dimethylaminomethylanilino)-1 -(4-(2-
10.73
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-methyl carbamoyl-
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


CA 02493436 2005-01-21
46
11.4 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(2-carbamoyl-
ethyl)p henyl)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-carbamoylmethyiphenyl)-
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
3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-
11.12 methylamino)anilino)-1-(4-carbamoylm ethyl phenyl)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-
methylca rbamoylmethylphenyl)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


CA 02493436 2005-01-21
47
3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-
11.17
1-(4-dimethylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone
3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-
11.18 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

3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-
11.20 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
3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-
11.27 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


CA 02493436 2005-01-21
48
3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-
12.1 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
3-Z-[1-(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-
12.3 methylamino)anilino)-1-(4-benzoylaminomethylphenyl)methylene]-6-
chloro-2-indolinone
12.4 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-acetylaminomethylphenyl)-
methyl ene]-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


CA 02493436 2005-01-21

49
3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-
12.14
phenylacetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone
3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-
12.15 methylamino)anilino)-1-(4-acetylaminomethylphenyl)methylene]-6-
fluoro-2-indolinone
3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-
12.16 methylamino)anilino)-1-(4-propionylaminomethylphenyl)methylene]-6-
fluoro-2-indolinone
3-Z-[1-(4-(N-(4-methylpiperazin-l-ylmethyl carbonyl)-N-
12.17 methylamino)anilino)-1-(4-phenylacetylaminomethylphenyl)-
methylene]-6-fluoro-2-indolinone
3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-
12.18 methylamino)anilino)-1-(3-cyclopropylcarbonylaminomethylphenyl)-
methylene]-6-fluoro-2-indolinone
3-Z-[1-(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-
12.19 methylamino)anilino)-1-(3-cyclobutylcarbonylaminomethylphenyl)-
methylene]-6-fluoro-2-indolinone
3-Z-[1-(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-
12.20 methylamino)anilino)-1-(3-(pyridin-2-yl-
carbonylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone
3-Z-[1-(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-
12.21 methylamino)anilino)-1-(3-cyclohexylcarbonylaminomethylphenyl)-
methylene]-6-fluoro-2-indolinone
3-Z-[1-(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-
12.22 methylamino)anilino)-1-(3-(pyridin-3-yl-
carbonylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone
3-Z-[1-(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-
12.23 methylamino)anilino)-1-(3-isobutyrylaminomethylphenyl)methylene]-6-
fluoro-2-indolinone


CA 02493436 2005-01-21

3-Z-[1-(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-
12.24 methylamino)anilino)-1-(3-(3-methylbutyrylaminomethylphenyl)-
methylene]-6-fluoro-2-indolinone
3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-
12.25 methylamino)anilino)-1-(3-
cyclohexylmethylcarbonylaminomethylphenyl)methylene]-6-fluoro-2-
indolinone
3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-
12.26 methylamino)anilino)-1-(3-methoxyacetylaminomethylphenyl)-
methylene]-6-fluoro-2-indolinone
3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-
12.27 methylamino)anilino)-1-(3-(2-methoxybenzoyl-
aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone
3-Z-[1-(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-
12.28 methylamino)anilino)-1-(3-tert-butylacetylaminomethylphenyl)-
methylene]-6-fluoro-2-indolinone
3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-
12.29 methylamino)anilino)-1-(3-(2-thiophen-
carbonylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone
3-Z-[1-(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-
12.30 methylamino)anilino)-1-(3-pivaloylaminomethylphenyl)methylene]-6-
fluoro-2-indolinone
3-Z-[1 -(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-
12.31 methylamino)anilino)-1-(3-(2-furoylaminomethyl)phenyl)methylene]-6-
fluoro-2-indolinone
3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-
12.32 methylamino)anilino)-1-(3-acetylaminomethylphenyl)methylene]-6-
fluoro-2-indolinone


CA 02493436 2005-01-21

51
3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-
12.33 methylamino)anilino)-1-(3-propionylaminomethylphenyl)methylene]-6-
fluoro-2-indoli none

3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-
12.34 methylamino)anilino)-1-(3-benzoylaminomethylphenyl)methylene]-6-
fluoro-2-indolinone
3-Z-[1 -(4-(N-(4-methylpiperazin-1 -ylmethylcarbonyl)-N-
12.35 methylamino)anilino)-1-(3-phenylacetylaminomethylphenyl)-
methylene]-6-fluoro-2-indolinone
3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-
12.36 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

3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-
12.39 cyclohexylcarbonylaminomethylphenyl)methylene]-6-fluoro-2-
indolinone

12.40 3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-(pyridin-3-yl-
carbonyla minomethyl)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-methyl butyryl-
aminomethylphenyl)methylene]-6-fluoro-2-indolinone

3-Z-[1 -(4-dimethylaminomethylanilino)-1 -(3-
12.43 cyclohexylmethylcarbonylaminomethylphenyl)methylene]-6-fluoro-2-
indolinone


CA 02493436 2005-01-21

52
3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-
12.44
methoxyacetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone
12.45 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-methoxybenzoyl-
aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone

12.46 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-tert-
butylacetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone
3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-
12.47 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-yl-
carbonyl aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone
13.0 3-Z-[1-(4-trimethylammon iummethylanilino)-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


CA 02493436 2005-01-21

53
Abbreviations used:

HOBt = 1-hydroxy-1 H-benzotriazole

TBTU = O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate
Preparation of the starting materials:

Example I:

Dimethyl 2-(4-fluoro-2-nitropheny)malonate
With ice-cooling, 185 g of potassium tert-butoxide are added to a solution of
188 ml
of dimethyl malonate in 970 ml of N-methylpyrrolidone, and the mixture is
stirred for
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
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)
C11H1oFN06
Mass spectrum: m/z = 270 [M-H]-

The following compounds are prepared analogously to Example I:
(1.1) Diethyl 2-(4-bromo-2-nitrophenyl)maIonate
from 2,5-dibromonitrobenzene and diethyl malonate
Rf value: 0.40 (silica gel, petroleum ether/ethyl acetate = 5:1)
C13H14BrNO6


CA 02493436 2005-01-21

54
Mass spectrum: m/z = 359/361 [M]+

(1.2) Dimethyl 2-(4-cyano-2-nitrophenyl)malonate
from 4-chloro-3-nitrobenzonitrile and dimethyl malonate
Rf value: 0.50 (silica gel, methylene chloride/methanol = 50:1)
C12H1oN2O6
Mass spectrum: m/z = 277 [M-H]-
Example II:
Methyl 4-cyano-2-nitrophenylacetate
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
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
C1oH8N2O4
Mass spectrum: m/z = 219 [M-H]-
Example III:
4-Fluoro-2-nitrophenylacetic 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
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
C8H6FNO4


CA 02493436 2005-01-21

Mass spectrum: m/z = 154 [M-COO-H]-

Example IV:
5
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
15 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]-Example V:


CA 02493436 2005-01-21

56
1 -acetyl-6-fluoro-2-indoli none
At 130 C, 82.5 g of 6-fluoro-2-indolinone (starting material IV) are stirred
in 180 ml
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
Mass spectrum: m/z = 192 [M-H]-
The following compounds are prepared analogously to Example V:
(V.1) 1-acetyl-6-chloro-2-indolinone
from 6-chloro-2-indolinone and acetic anhydride
Rf value: 0.55 (silica gel, petroleum ether/ethyl acetate = 2:3)
C11H10CINO6
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)
C10H8BrNO2
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)
C11H8N202
Mass spectrum: m/z = 199 [M-H]-
Example VI:

1-acetyl-3-[1-hydroxy-1 -(3-iodoghenyl)methylenel-6-chloro-2-indolinone


CA 02493436 2005-01-21

57
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
pressure.
Yield: 12.9 g (59 % of theory)
Rf value: 0.80 (silica gel, methylene chloride/methanol = 9:1)
C1H11CIINO3
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 -hyd roxy- 1 -(4-chlorophenyl) methylene]-6-ch loro-2- i
ndoli none
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
acid

(VI.4) 1-acetyl-3-[1-hydroxy-1-(3,4-dimethoxyphenyl)methylene]-6-cyano-2-
indolinone
from 1-acetyl-6-cyano-2-indolinone (starting material V.3) and 3,4-
dimethoxybenzoic
acid


CA 02493436 2005-01-21
58
(VI.5) 1-acetyl-3-[1-hydroxy-1-(3-fluorophenyl)methylene]-6-fluoro-2-
indolinone
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)-
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
(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
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-
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)-
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)

(VI.11) 1 -acetyl-3-[1 -hydroxy-1 -(4- iodoph enyl)methyle ne]-6-fl uoro-2-i
ndol i none
from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 4-iodobenzoic
acid


CA 02493436 2005-01-21

59
(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,
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-
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
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. Left
2000, 10, 553-557)
(VI.17) 1-acetyl-3-[1-hydroxy-1-(4-(N-tert-butoxycarbonyl-2-
aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone
from 1 -acetyl-6-fl uoro-2-i ndoli none (starting material V) and 4-(N-tert-
butoxycarbonyl-
2-aminoethyl)benzoic acid (preparation analogously to Bioorg. Med. Chem. Lett
2000, 10, 553-557)

(VI.18) 1 -acetyl-3-[1 -hydroxy-1 -(4-cyanophenyl)methylene]-6-chloro-2-
indolinone


CA 02493436 2005-01-21

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
5 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
10 from 1-acetyl-6-fluoro-2-indolinone (starting material V) and 3-(2-
ethoxycarbonylethyl)benzoic acid (preparation analogously to Tetrahedron 1997,
53,
7335-7340)

(VI.21) 1-acetyl-3-[1-hydroxy-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-

15 chloro-2-indolinone
from 1-acetyl-6-chloro-2-indolinone (starting material V.1) and 4-(2-
methoxycarbonylethyl)benzoic acid (preparation analogously to Tetrahedron
1997,
53, 7335-7340)

20 (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-
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)

(VI.24) 1-acetyl-3-[1-hydroxy-1-(4-methoxycarbonylmethyloxyphenyl)methylene]-6-

fluoro-2-indolinone


CA 02493436 2005-01-21

61
from 1-acetyl-6-fluoro-2-indolinone (starting material V) and
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
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-
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-acetyl-3-[1-methoxy-1-(3-iodophenyl)methylenel-6-chloro-2-indolinone
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.
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


CA 02493436 2005-01-21

62
dried over magnesium sulphate and evaporated to dryness. The residue is
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 I.1) 1-acetyl-3-[1-methoxy-1-(4-methoxycarbonylmethylphenyl)methylene]-6-
fluoro-2-indolinone
from 1-acetyl-3-[1-hydroxy-1-(4-methoxycarbonylmethylphenyl)methylene]-6-
fluoro-2-
indolinone (starting material VI.1)
(VI I.2) 1-acetyl-3-[1-methoxy-1-(4-chlorophenyl)methylene]-6-chloro-2-
indolinone
from 1-acetyl-3-[1-hydroxy-1-(4-chlorophenyl)methylene]-6-chloro-2-indolinone
(starting material VI.2)

(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-
indoli none
(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)

(VII.5) 1 -acetyl-3-[1 -methoxy- 1 -(3-fl uoro phenyl)m ethylene]-6-fl uoro-2-
i nd ol i none
from 1-acetyl-3-[1-hydroxy-1-(3-fluorophenyl)methylene]-6-fluoro-2-indolinone
(starting material V1.5)


CA 02493436 2005-01-21

63 (VI 1.6)1-acetyl-3-[1-methoxy-1-(4-(2-acetylaminoethyl)phenyl)methylene]-6-
fluoro-2-
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-
fluoro-2-indoli none
from 1-acetyl-3-[1-hydroxy-l -(3-methoxycarbonylmethylphenyl)methylene]-6-
fluoro-2-
indolinone (starting material V1.7)
1:0
(VII .8)1-acetyl-3-[1-methoxy-1-(3-(N-tert-butoxycarbonylaminomethyl)phenyl)-
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)
(VII.9)1-acetyl-3-[1-methoxy-1-(3-cyanomethylphenyl)methylene]-6-fluoro-2-
indolinone
from 1-acetyl-3-[1-hydroxy-1-(3-cyanomethylphenyl)methylene]-6-fluoro-2-
indolinone
(starting material VI.9)
(VII.10) 1-acetyl-3-[1-methoxy-1-(4-(N-tert-butoxycarbonyl-
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)
(VII.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 VI.11)

(VI I.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)


= CA 02493436 2005-01-21
64
(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)
(VI I.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-
ami n oethyl)phenyl)m ethyle ne]-6-fl uoro-2-i ndol in one
from 1-acetyl-3-[1-hydroxy-1-(3-(N-tert-butoxycarbonyl-2-
aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone (starting material VI.16)
(VI I.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)
(VII.19) 1-acetyl-3-[1-methoxy-1-(3-(2-ethoxycarbonylethyl)phenyl)methyl ene]-
6-fluoro-2-indolinone


CA 02493436 2005-01-21

from 1-acetyl-3-[1-hydroxy-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-
fluoro-2-
indolinone (starting material VI.20)

(VI 1.20) 1 -acetyl-3-[1 -methoxy-1 -(4-(2-
methoxycarbonylethyl)phenyl)methylene]-
5 6-chloro-2-indolinone
from 1-acetyl-3-[1-hydroxy-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-
chloro-
2-indolinone (starting material VI.21)

(VI I.21) 1-acetyl-3-[1-methoxy-1-(4-(2-ethoxycarbonylethyl)phenyl)methylene]-
10 6-fluoro-2-indolinone
from 1-acetyl-3-[1-hydroxy-1-(4-(2-ethoxycarbonylethyl)phenyl)methylene]-6-
fluoro-2-
indolinone (starting material Vl.22)

(VI I.22) 1-acetyl-3-[1-methoxy-1-(4-methoxycarbonylmethyloxyphenyl)-
15 methylene]-6-fluoro-2-indolinone
from 1-acetyl-3-[1-hydroxy-1-(4-methoxycarbonylmethyloxyphenyl)methylene]-6-
fluoro-2-indolinone (starting material VI.23)

(VII.23) 1-acetyl-3-[1-methoxy-1-(3-methoxycarbonylmethyloxyphenyl)-
20 methylene]-6-fluoro-2-indolinone
from 1-acetyl-3-[1-hydroxy-1-(3-methoxycarbonylmethyloxyphenyl)methylene]-6-
fluoro-2-indolinone (starting material VI.24)

(VI I.24) 1 -acetyl-3-[1 -methoxy-1 -(3-(2-
25 ethoxycarbonylethyloxy)phenyl)methylene]-6-fluoro-2-indolinone
from 1-acetyl-3-[1-hydroxy-1-(3-(2-ethoxycarbonylethyloxy)phenyl)methylene]-6-
fluoro-2-indolinone (starting material VI.25)

(VI I.25) 1 -acetyl-3-[1 -methoxy-1 -(4-(2-
30 ethoxycarbonylethyloxy)phenyl)methylene]-6-fluoro-2-indolinone
from 1-acetyl-3-[1-hydroxy-1-(4-(2-ethoxycarbonylethyloxy)phenyl)methylene]-6-
fluoro-2-indolinone (starting material VI.26)


CA 02493436 2005-01-21
66
(VI I.26) 1-acetyl-3-[1-methoxy-1-(4-(2-methoxycarbonylethyl)phenyl)methyl
ene]-
6-bromo-2-indoli none
from 1-acetyl-3-[1-hydroxy-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-
bromo-2-indolinone (starting material VI.27)
Example VIII:

1-Acetyl-3-[1-chloro-1-(4-cyanophenyl methyl enel-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
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)
C15H10CI2N2O2

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
(IX.3) 3-(dimethylaminomethyl)aniline

(IX.4) 4-(dimethylaminomethyl)aniline
(IX.5) 4-(2-dimethylaminoethyl)aniline

(IX.6) 4-[N-(2-dimethylaminoethyl)-N-acetylamino]aniline


CA 02493436 2005-01-21

67
(IX.7) 4-[N-(3-dimethylaminopropyl)-N-acetylamino]aniline

(IX.8) 4-[(N-dimethylaminocarbonylmethyl-N-methylsulphonyl)amino]aniline
(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
(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

(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
(IX.22) 4-(pyrrolidin-1-ylmethyl)aniline


CA 02493436 2005-01-21

68
(IX.23) 4-(morpholin-4-yl-methyl)aniline

(1X.24) 4-(N-benzyl-N-methylaminomethyl)aniline
(1X.25) 4-(N-ethyl-N-methylaminomethyl)aniline

(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

(IX.30) 4-(4-methylpiperazin-1-ylcarbonyl)aniline
(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


CA 02493436 2005-01-21
69
Preparation of the end products:

Example 1.0

3-Z-[1 -(4-(N-Methyl-N-methylsulphonylamino)anilino)-1-(3-
iodophenyl)methylenel-6-
chloro-2-indolinone
0.9 g of 1-acetyl-3-(1-methoxy-1-(3-iodophenyl)methyl ene)-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
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
C23H 19CI I N3O3S
Mass spectrum: m/z = 578/580 [M-H]-

The following compounds of the formula I-1 are prepared analogously to
Example 1.0:

41
R3

H

O
C 1 H (I-1 )


CA 02493436 2005-01-21
Ex- Starting Rf
Empirical Mass M.P. amp/ R3 R4' materi-
formula spectrum [ C] value*
e als

VII 529/531 238- 0.30
-CH2-NMe2 C24H21CIIN3O
IX.4 [M+H]+ 240 (A)
Cl -N(Me)-(CO)- VII.2 495/497 277- 0.20
1.2 C26H24C12N402
CH2-NMe2 IX.10 [M+H]+ 279 (B)
Cl -N(COMe)- Vll.2 C27H26C12N4O2 507/509 241- 0.10
1.3 CH2)2-NMe2 IX.6 [M-H]" 243 (B)

CI T"N-Me VII.2 548/550 266- 0.10
1.4 Me,N-~-NJ C29H29C12N502
"i, 0 IX.19 [M-H]- 268 (B)
ci -N(COMe)- VII.2 521/523 241- 0.10
1.5 C28H28C12N4O2
(CH2)3-NMe2 IX.7 [M-H]- 242 (B)
ci VIl.2 438/440 243- 0.10
1.6 -CH2-NMe2 C24H21C12N3O
IX.4 [M+H]+ 244 (B)
Meo OMe -N(COMe)- VII.3 533/535 128- 0.75
1.7 I ` C29H31CIN4O4
(CH2)2-NMe2 IX.6 [M-H]- 130 (C)
MeO OMe r--"N-Me VII.3 574/576 208- 0.65
1.8 Ox Me,N~ C31H34CIN5O4
"1, o IX.19 [M-H]" 210 (C)
MeO OMe -N(S02Me)- VII.3 569/571 198- 0.75
1.9 C2aH31 CIN4O5S
(CH2)2-NMe2 IX.2 [M-H]" 200 (C)
Meo oMe VII.3 462/464 239- 0.70
1.10 Ox, -CH2-NMe2 C26H26CIN3O3
IX.4 [M-H]" 240 (C)


CA 02493436 2005-01-21
71
Meo oMe o Me VII.3 533/535 147- 0.70
C29H31CIN4O4
1.11 NMe2 IX 29 [M-H]" 149 (C)
*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-[1-(4-(Dimethylaminomethyl)anilino)-l-(4-cyanophenvl)methvlenel-6-chloro-2-

indolinone
1.07 g of 1 -acetyl-3- [1 -ch loro- 1 -(4-cyanophe nyl) methylene]-6-ch loro-2-
i ndol i none
(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.
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-HI-
Example 3.0

3-Z-[1-(4- dimethylaminomethyl)anilino)-1-(4-iodophenyl)methvlenel-6-fluoro-2-
indolinone


CA 02493436 2005-01-21

72
3.5 g of 1-acetyl-3-(1-meth oxy-1-(4-iodophenyl)methylene)-6-fluoro-2-
indolinone
(starting material V11.11) and 1.6 g of 4-(dimethylaminomethyl)aniline
(starting
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
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
C24H21FIN3O
Mass spectrum: m/z = 514 [M+H]+

The following compounds of the formula I-3a are prepared analogously to
Example
3.0:

R4'
R3

H
O
R2 N (I-3a)
H
Ex- Starting
Empirical Mass m. p. Rf
amp R2 R3 R4' materi-
formula spectrum [ C] value*
le als

F V11.5 404 225- 0.20
3.1 -F / -CH2-NMe2 C24H21F2N3O
IX.4 [M-H]" 227 (A)


= CA 02493436 2005-01-21
73
F -N(COMe)- NITS 491 160- 0.20
3.2 -F C23H28F2N402
(CH2)3-NMe2 IX.7 [M+H]+ 163 (A)
F Me
NN j VII.5 518 218- 0.40
3.3 -F Me,N C29H29F2N502 IX.19 [M+H]+ 220 (A)

H3
Cr0
N VII.6 471 106- 0.25
2
3.4 -F -CH2-NMe2 C28H29FN402
/ IX.4 [M-Hl- 110 (A)
H3Cr0
N -N(COMe)- VII.6 558 194- 0.25
3.5 -F C32H36FN503
/ (CH2)3-NMe2 IX.7 [M+H]+ 196 (A)
H3cN JN Me VII.6 583 238- 0.25
3.6 -F Me~NO C33H37FN603
/ 1X.19 [M-Hl- 240 (A)
F. OMe VII.1 460 173- 0.30
3.7 -F -CH2-NMe2 C27H26FN303
IX.4 [M+H]+ 176 (A)
VII.13 514 198- 0.30
3.8 -F -CH2-NMe2 C24H21FIN30
IX.4 [M+H]+ 200 (B)
0
VII.7 458 195- 0.25
3.9 -F OMe -CH2-NMe2 C27H26FN303
IX.4 [M-H]" 198 (A)
tBuO 0
NH V11.8 517 230- 0.30
3.10 -F -CH2-NMe2 C30H33FN403
IX.4 [M+H]+ 240 (A)


CA 02493436 2005-01-21
74
3.11 -F oMe V11.1 C29H31FN405S 567 188- 0.40
405S
(CH2)2-NMe2 IX.2 [M+H]+ 189 (A)
0 OMe Me J Me VI1.1 572 200- 0.35
3.12 -F N 0 C32H34FN504 +
IX.19 [M+H] 203 (C)
3.13 -F CN -CH2-NMe2 V11.9 C26H23FN40 427 130- 0.25
I
IX.4 [M+H]+ 135 (A)
OtBu r''`N-Me
HN'~0 Me. ~N VII.10 629 215- 0.35
3.14 -F N C35H41 FN604
0 IX.19 [M+H]+ 220 (A)
OtBu
HN'~0 VII.10 517 186- 0.35
3.15 -F -CH2-NMe2 C30H33FN403 +
IX.4 [M+H] 190 (A)
OtBu

NH V11.17 531 0.40
3.16 -F -CH2-NMe2 C31H35FN403 + n.d.

OMe
o VII.15 488 166- 0.40
3.17 -F / -NMe-(COMe) - C28H26FN304 [M+H]+ 170 (A)
OMe N-Me
VI1.15 586 176- 0.30
3.18 -F Me~N 0 C33H36FN504 +
IX.19 [M+H] 180 (A)
lux,


CA 02493436 2005-01-21
OMe
o -N(SO2Me)- VII.15 581 195- 0.45
3.19 -F C30H33FN405S
(CH2)2-NMe2 IX.2 [M+H]+ 198 (A)
OMe
o -N(COMe)- VII.15 559 100- 0.50
3.20 -F C32H35FN404
(CH2)3-NMe2 IX.7 [M+H]+ 104 (A)
OMe
o Me VII.15 558 132- 0.80
3.21 -F r 0tBu C32H34FN305
/ 0 IX.18 [M-Hl- 137 (D)
OMe
0 0 rN-Me VII.15 543 234- 0.60
3.22 -FIX.30 C31H31FN404 LM+Hl+ 236 (A)
OMe
0 NI VII.15 497 110- 0.40
3.23 -F N C29H25FN403
Me IX.16 [M+H]+ 115 (A)
lox

OMe
0 VII.15 495 130- 0.60
3.24 -F -SO2Me C26H23FN205S
[M+H]+ 137 (A)
NMe
3OMe Me. N V11.7 572 189 0.60
3.25 -F N 0 C32H34FN504 +
IX.19 [M+H] (B)
0
OMe -N(SO2Me)- VII.7 567 0.60
3.26 -F C29H31FN405S
(CH2)2-NMe2 IX.2 [ M+H ]+ n.d. (B)


CA 02493436 2005-01-21
76
0
oMe or'N-Me V11.7 529 201- 0.60
3.27 -F N. C3oH29FN404
IX.30 [M+HJ+ 203 (B)
0
3.28 -F OMe -N(Me)-(CO)- VII.7 C29H29FN404 517 126 0.60
CH2-NMe2 IX.10 [M+HI+ (B)
0
3.29 -F OMe -N(COMe)- VII.7 C30H31FN404 531 179 0.50
(CH2)2-NMe2 IX.6 [M+H]+ (B)
0
3.30 -F OMe -N(COMe)- VII.7 C31H33FN404 545 123 0.20
(CH2)3-NMe2 IX.7 [M+H]+ (B)
0
3.31 -F OMe -N(Me)-(CO)- VII.7 C32H35FN404 559 201 0.20
(CH2)4-NMe2 IX.32 [M+H]+ (B)
3.32 -F O OMe -H V11.1 C24H19FN203 403 198- 0.80
_ [M+H]+ 206 (A)
0 ,e N-3 V11.1 483 223- 0.75
3.33 -F N C28H23FN403
Me IX.16 [M+H]+ 226 (A)
O OMe
0 N-Me VI1.1 529 215- 0.30
3.34 -F N\---/ C3oH29FN404
IX.30 [M+H]+ 220 (A)
0 oMe -N(S02Me)- V11.1
581 227- 0.65
3.35 -F (CH2)-(CO)- C29H29FN406S
= IX.8 [M+H)+ 230 (A)
NMe2


CA 02493436 2005-01-21
77

oMe -N(Me)-(CO)- VII-1 517 128- 0.45
3.36 -F C29H29FN4O4
CH2-NMe2 IX.10 [M+H]+ 130 (A)
OMe
-N(COMe)- VII.1 474 218- 0.40
3.37 -F C27H24FN304
CH3 _ [M+H]+ 223 (A)
oMe -N(Me)-(CO)- V11.1 531 192- 0.40
3.38 -F C30H31FN404
(CH2)2-NMe2 IX.11 [M+H]+ 194 (A)
0 OMe V11.1
481 205- 0.65
3.39 -F -SO2Me C25H21FN205S
~. _ [M+H]+ 214 (A)
OMe -N(Me)-(CO)- VI1.1 545 190- 0.15
3.40 -F C31H33FN404
(CH2)3-NMe2 IX.33 [M+H]+ 193 (A)
3.41 -F 0 oMe V11.1 C31H33FN404 545 184- 0.50
4
(CH2)3-NMe2 IX.7 [M+H]+ 188 (A)
0
V11.7 403 0.70
3.42 -F OMe -H C24H19FN203 [M+H]+ 114 (B)
0
VII.7 481 0.60
3.43 -F OMe _S02Me C25H21FN205S [M+H]+ 129 (B)
0
OMe N-3 V11.7 483 0.60
3.44 -F N C28H23FN403 125
Me IX.16 [M+H]+ (B)


CA 02493436 2005-01-21
78
o -N(SO2Me)-
VI I.7 581 0.60
3.45 -F oMe (CH2)-(CO)- C29H29FN406S 163
IX.8 [M+H] (B)
NMe2

0
3.46 -F OMe -N(Me)-(CO)- VII.7 C31H33FN404 545 101 0.10
r
(CH2)3-NMe2 IX.33 [M+H]+ (B)
0
3.47 -F oMe -N(Me)-(CO)- VII.7 C30H31FN404 531 161 0.20
(CH2)2-NMe2 IX.11 [M+H]+ (B)
Me0
O Me Me VII.14 586 181- 0.20
3.48 -F N O C30H31 FN404
IX. 19 [M+H]+ 183 (B)
MeO O
3.49 -F -N(SO2Me)- VII.14 C30H33FN405S 581 158- 0.35
I ` (CH2)2-NMe2 IX.2 [M+H]+ 160 (B)
MeO f O
3.50 -F -N(Me)-(CO)- VII.14 C30H31FN404 531 0.40
` CH2-NMe2 IX.10 [M+H]+ n.d. (B)
MeO O
3.51 -F -N(COMe)- VII.14 C32H35FN404 559 0.50
` (CH2)3-NMe2 IX.7 [M+H]+ n.d. (E)
tBuO
o Me, Me
H VI1.8 629 0.35
3.52 -F N-41 C35H41FN604 + n.d.
0 IX=19 [M+H] (A)


CA 02493436 2005-01-21

79
O~-CH3
HN -NMe-(CO)- VI1.26 473 122- 0.50
3.53 -F CH3 - C27H25FN403 [M+H]+ 126 (F)
O.--CH3
HN -N(COMe)- VII.26 544 80- 0.25
3.54 -F CH2 3-NMe2 C31H34FN503
( ) IX.7 [M+H]+ 83 (A)
O~-CH3
HN -N(S02Me)- VII.18 566 190- 0.30
3.55 -F C29H32FN504S
(CH2)2-NMe2 IX.2 [M+H]+ 195 (A)
O~-CH3
3.56 -F HN -N(Me)-(CO)- VII.18 C29H30FN503 516 238- 0.30
CH2-NMe2 IX.10 [M+H]+ 241 (G)
OMe
VII.15 488 205- 0.55
3.57 -F -(CH2)2-NMe2 C29H3oFN303
IX.5 [M+H]+ 208 (G)
OMe
-N(Me)-(CO)- VII.15 543 196- 0.20
3.58 -F C31H31FN404
` (CH2)2-NMe2 IX.11 [M-H]" 202 (A)
OMe
-N(Me)-(CO)- VII.15 531 177- 0.30
3.59 -F C30H31FN404
` CH2-NMe2 IX.10 [M+H]+ 182 (A)
EtO O
VI1.19 500 100- 0.35
3.60 -F -(CH2)2-NMe2 C3oH32FN303 M-H " 105 (B)
[ ] )


CA 02493436 2005-01-21
OMe
O -N(COMe)- VII.15 C31H33FN404 545 167- 0.40
3.61 -F (CH2)2-NMe2 IX.6 [M+H]+ 169 (A)
EtO O
3.62 -F -N(Me)-(CO)- VII-19
C33H37FN404 571 n.d. 0.35
I (CH2)3-NMe2 IX.33 [M-H]" (A)
EtO O

3.63 -F -N(Me)-(CO)- VII-19 C34H39FN404 585 n.d. 0.40
(CH2)4-NMe2 IX.32 [M-H]" (A)
EtO O
N3 VII.19 511 95- 0.25
3.64 - F C3oH27FN403
Me IX.16 [M+H]+ 105 (B)
OMe
3.65 O -N(Me)-(CO)- VII.15 573 173- 0.20
-F C33H37FN404
I (CH2)4-NMe2 IX.32 [M+H]+ 175 (A)
OMe
o VII.15 417 168- 0.65
3.66 -F -H C25H21 FN203
- [M+H]+ 174 (A)
OMe
o VII.15 500 168- 0.40
3.67 -F rN~ C30H30FN303
IX.22 [M+H]+ 173 (B)
OMe
o VII.15 502 0.45
-CH2-NEt2 C3oH32FN303 + n.d.
3.68 -F
lox


CA 02493436 2005-01-21

81
OMe
0 H V11.15 544 0.30
3.69 -F N1rotBu C31H32FN305 n.d.
o IX.12 [M-H] (G)
0
OMe VII.7 472 165- 0.25
3.70 -F -(CH2)2-NMe2 C28H28FN303
IX.5 [M-Hl- 170 (B)
O OMe
VII.1 472 193- 0.25
3.71 -F -(CH2)2-NMe2 C28H28FN303
IX.5 [M-H]" 197 (B)
EtO O
V11.19 488 48- 0.45
3.72 -F -CH2-NMe2 C29H30FN303
IX.4 [M+H]+ 52 (B)
OMe
o VII.20 504/506 156- 0.30
3.73 -Cl -(CH2)2-NMe2 C29H30CIN303
IX.5 [M+H]+ 160 (H)
OMe
O N VII.20 513/515 0.40
3.74 -Cl N C29H25CIN403
[M+H]+ 110
(H)
Me IX.16

OMe
O VII.20 490/492 173- 0.70
3.75 -Cl -CH2-NMe2 C28H28CIN303
IX.4 [M+H]+ 175 (I)
,lax,

OEt
o VII.21 488 158- 0.35
3.76 -F -CH2-NMe2 C29H30FN303
IX.4 [M+H]+ 161 (B)


CA 02493436 2005-01-21

82
MeO O
r--",N-Me VII.14 529 147- 0.50
3.77 -F rN,J C31H33FN403
IX.14 [M+H]+ 150 (1)
MeO O
N VII.14 497 182- 0.60
3.78 -F ,rNJ C29H25FN403
IX.15 [M+H] 185 (K)
OMe
0 r--\N-Me VII.15 529 0.35
3.79 -F N,.J C31 H33FN403 + 184 IX. 14 OMe

O N VII.15 497 0.45
3.80 -F C29H25FN403 233
IX.15 [M+H]+ (B)
OMe

3.81 -F -CH2-NMe- VII.15 C31H35FN403 531 120 0.40
a (CH2)2-NMe2 IX.17 [M+H]+ (B)
EtO O
3.82 -F -CH2-NMe- VII.19 C32H37FN403 545 0.40
(CH2)2-NMe2 IX.17 [M+H]+ n.d. (K)
OMe
o VII.20 516/518 195- 0.30
3.83 -Cl rN0 C30H30CIN303
IX.22 [M+H]+ 197 (H)
EtO O
VII.19 431 156- 0.80
3.84 -F -H C26H23FN203
[M+H]+ 160 (M)


CA 02493436 2005-01-21

83
EtO O
H V11.19 560 0.50
3.85 -F r-NrOtBu C32H34FN305 n.d.
o IX.12 [M+H]+ (~)
EtO O
Me VII.19 574 0.60
3.86 -F i o otBu C33H36FN305 n.d.

MeO O
of VII.22 476 0.25
3.87 -F -CH2-NMe2 C27H26FN304 + 129

OMe
o VII.23 476 0.25
3.88 -F O -CH2-NMe2 C27H26FN304 + 155

OEt
3.89 -F O O -CH2-NMe2 V11.24 C29H3oFN304 504 0.20
IX.4 [M+H]+ n.d. (B)
OMe
o VII.26 560/562 230- 0.45
3.90 -Br rN C30H30BrN3O3 +
IX.22 [NI+H] 235 (B)
lux

OMe
o V11.26 534/536 178- 0.35
3.91 -Br -CH2-NMe2 C28H28BrN3O3
IX.4 [M+H]+ 180 (B)
OMe
o VII.26 562/564 173- 0.40
3.92 -Br -CH2-NEt2 C30H32BrN3O3
IX.1 [M+H]+ 176 (B)
lux


CA 02493436 2005-01-21

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
(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
(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 I-3b are prepared analogously to
Example
3.0:

R4'
R3

H
O
R2 N (I-3b)
H
Ex- Starting Rf
Empirical Mass m. p.
amp R2 R3 R4' materi- formula spectrum [ C] value
le als
OMe
o V11.15 474 176- 0.40
3.93 -F -CH2-NMe2 C28H28FN303
IX.3 [M+H]+ 179 (A)


CA 02493436 2005-01-21
VI1.19 486 0.45
EtO 6:0
3.94 -F -CH2-NMe2 C29H30FN303 n.d.
IX.3 [M-H]" (B)
OMe
o VII.20 490/492 163- 0.40
3.95 -Cl -CH2-NMe2 C28H28CIN303
IX.3 [M+H]+ 165 (A)
lux

*Eluent mixtures:
(A): silica gel, methylene chloride/methanol 9:1
(B): silica gel, methylene chloride/methanol/ammonia 9:1:0.1
5

Example 4.0
3-Z-[1-(4-(Dimethylaminomethyl)anilino)-1-(3,4-dimethoxyphenyl)methylene]-6-
10 cyano-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
15 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 C27H26N403

Example 5.0


CA 02493436 2010-09-23
25771-993

86
3-Z-[1-(4-(N-Methyl-N-methylsulphonylamino)anilino)-1-(3-(2-methoxycarbonyl-
vinyl)phen rI methylenel-6-chloro-2-indolinone
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(II) 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.
TM
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 1-5 are prepared analogously to Example
5.0:

R4'
R3

H
O
R N (1-5)

Start-
Ex-
ampi R 2 R3 R4' ing Empirical Mass m.p. Rr
mate- formula spectrum [ C] value*
e
rials I I I I


CA 02493436 2005-01-21
87
O OMe
486/488 150- 0.50
5.1 -Cl -CH2-NMe2 1.1 C28H26CIN303
/ " [M-H]- 155 (A)
NHZ
0 455 269- 0.20
5.2 -F -CH2-NMe2 3.0 C27H25FN402
I [M-H] 270 (B)
OMe

5.3 -F la CH2-NMe2 3.0 C28H26FN303 470 205- 0.65
[M-H]' 208 (A)
O OMe
472 138- 0.45
5.4 -F -CH2-NMe2 1.1 C28H26FN303 [M+H]+ 140 (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-[1-(4-Dimethylaminomethylanilino) 1-(3-(2-
methoxycarbonylethyl)phenyl)methylenel-6-chloro-2-indolinone
1.0 g of 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-(2-methoxycarbonyl-
vinyl)phenyl)methylene]-6-chloro-2-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
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),


CA 02493436 2005-01-21
88

Rf value: 0.40 (silica gel, methylene chloride/methanol = 9:1)
m.p. 160 C

C28H28C1 N303
Mass spectrum: m/z = 490/492 [M+H]+
The following compounds of the formula 1-6 are prepared analogously to Example
6.0:

R41
R3

H
O
R2 N (1-6)


Start-
Ex-
ing Empirical Mass m.p. Rf
am- R2 R3 R4`
pie mate- formula spectrum [ C] value*
rials

O OMe

6.1 -Cl -N(Me)- 5.0 C27H26C1N305S 538/540 148- 0.50
l S02Me [M-H]" 150 (A)
NHZ
0 459 0.70
6.2 -F -CH2-NMe2 5.2 C27H27FN402 [M+H]+ 150 (B)
OMe
0 474 0.35
6.3 -F -CH2-NMe2 5.3 C28H28FN303 [M+H]+ 140 (A)


CA 02493436 2005-01-21

89
O OMe
474 140- 0.30
6.4 -F -CH2-NMe2 5.4 C28H28FN303 [M+H]+ 142 (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-Dimethylaminomethlaanilino)-1-(4-aminomethylphenyl)methylene]-6-
chloro-
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
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 1 N 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 washed with a little
diethyl
ether and dried under reduced pressure.
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
C25H25CIN40
Mass spectrum: m/z = 433/435 [M+H]+
Example 8.0


CA 02493436 2005-01-21

3-Z-[1 -4-(N-((4-Methylpiperazin-1-yl)methylcarbonyl)-N-methylamino)anilino)-1-
(4-
aminomethylPhenyl)methvlenel-6-chloro-2-indolinone
1.39 g of 1-acetyl-3-Z-[1-(4-(N-((4-methylpiperazin-1-yl)methylcarbonyl)-N-
5 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
10 residue is washed with a little methanol and diethyl ether. To liberate the
base, the
residue is taken up in 1 N 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
15 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
20 C30H33CIN602
Mass spectrum: m/z = 544/546 [M]+
Example 9.0
3-Z-[1 -(4-(Dimethylaminomethvl)anilino)-I -(3-aminomethIy Shen l 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 1 N aqueous sodium hydroxide solution. The
organic


CA 02493436 2005-01-21
91
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
C25H25FN40
Mass spectrum: m/z = 415 [M-H]-
The following compounds of the formula 1-9 are prepared analogously to Example
9.0:
R4'
R3

H
O
R2 N (1-9)

Start-
Ex-
ing Empirical Mass m.p. Rf
am- R2 R3 R4`
ple mate- formula spectrum [ C] valu'
rials
NHZ
431 155- 0.45
9.1 -F -CH2-NMe2 3.16 C26H27FN40 [M+H]+ 160 (C)
NHZ
417 203- 0.25
9.2 -F -CH2-NMe2 3.15 C25H25FN40 [M+H]+ 207 (A)


CA 02493436 2005-01-21

92
NH2 r--'NMe 529 170- 0.15
9.3 -F H3CNr N`J 3.14 C30H33FN602 M+H + 175 (A)
OH
O
446 245- 0.20
9.4 -F \ -CH2-NHMe 10.11 C26H24FN303
[M+H]+ 251 (D)
NHCH3
0
459 239- 0.30
9.5 -F -CH2-NHMe 11.22 C26H24FN303 +
[M+H] 243 (A)
NH2 f--\NMe 529
9.6 -F H 3 c 'r N J 3.52 C30H33FN602 n.d. n.d.
" o [M+H]
+
OMe
0
444 158- 0.25
9.7 -F -CH2-NH2 3.69 C26H24FN303
[M-H]" 163 (A)
EtO 4
60 205- 0.30
9.8 -F E$:T -CH2-NH2 3.85 C27H26FN303 [M+H]+ 210 (B)
EtO 4
74 148- 0.30
-CH2-NHMe 3.86 C28H28FN303 [M+H]+ 150 (B)
9.9 -F 6:0

*Eluent mixtures:
(A): silica gel, methylene chloride/methanol/ammonia 9:1:0.1
(B): silica gel, methylene chloride/methanol/ammonia 9:1:0.01
(C): silica gel, methylene chloride/methanol/ammonia 8:2:0.2


CA 02493436 2005-01-21

93
(D): Reversed phase RP8, methanol/sodium chloride solution(5%) = 3:2
Example 10.0
3-Z-f1-(4-Dimethylaminomethylanilino)-1-(3-(2-carbo yethyl)phenyl)methylenel-6-

chloro-2-indoli none
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 1 N aqueous sodium hydroxide
solution
are added. The mixture is stirred at room temperature for 5 hours. After
cooling, 5 ml
of I N 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)
m.p. 210-215 C

C27H26CIN3O3
Mass spectrum: m/z = 476/478 [M+H]+
The following compounds of the formula 1-1 Oa are prepared analogously to
Example
10.0:

41
R3

H
O
R2 N (I-10a)
H


CA 02493436 2005-01-21
94
Start-
Ex- Rf
ing Empirical Mass m.p.
am- R2 R3 R4'
mate- formula spectrum ['Cl value*
pie
rials
OH
460 0.65
10.1 -F / \ -CH2-NMe2 6.3 C27H26FN303 [M+H]+ 250 (A)
OH
O 444 278- 0.10
10.2 -F -CH2-NMe2 3.9 C26H24FN303 M-H - 282 (B)
[ ] O OH

458 198- 0.20
10.3 -F r -CH2-NMe2 6.4 C27H26FN303 [M-H]' 200 (C)
O OH
444 212- 0.30
10.4 -F -CH2-NMe2 3.7 C26H24FN303
[M-H]- 216 (D)
0 OH ~NMe 558 260- 0.20
10.5 -F H3CN 0 3.12 C311-13, FN504
[M+H]+ 263 (D)
0
OH
10.6 -F -N(SO2Me)- 3.11 C28H29FN405S 553 246- 0.30
(CH2)2-NMe2 [M+H]+ 249 (D)
OH
O -NMe-(CO)- 3.17 474 286- 0.60
10.7 -F CH3 C27H24FN304 []+ 290 (E)
M+H


CA 02493436 2005-01-21

OH
O H3O ~NMe 570 215- 0.20
10.8 -F N o 3.18 C32H34FN504 [M-Hl- 222 O
D
OH

10.9 -F -N(SO2Me)- 3.19 C29H31FN405S 567 160- 0.20
1 ` (CH2)2-NMe2 [M+H]+ 165 (D)
OH

10.10 -F -N(COMe)- 3.20 C31H33FN404 545 153- 0.15
` (CH2)3-NMe2 [M+H]+ 158 (D)
OH
o Me 546 215- 0.60
10.11 -F / ' o OtBu 3.21 C31H32FN305 [M+H]+ 219 (E)
OH
O 0 rN-Me 529 179- 0.25
10.12 -F 3.22 C3oH29FN404 [M H 186 (E)
OH
o N-3 483 264- 0.65
10.13 -F >'Me 3.23 C28H23FN403 M+H 267 (E)
[]+ OH

0 481 146- 0.70
10.14 -F / -SO2Me 3.24 C25H21FN205S [M+H]+ 155 E
O
OH
O 0 r'N-Me 515 0.70
10.15 -F N 3.27 C29H27FN404 251


CA 02493436 2005-01-21

96
OH
O H3G ~NMe 558 0.10
10.16 -F N 3.25 C31H32FN504 [M+H]+ 234 (E)
OH
-N(Me)-(CO)- 503 0.60
10.17 -F 3.28 C28H27FN404 203
CH2-NMe2 [M+H]+ (E)
OH
-N(Me)-(CO)- 545
10.18 -F 3.31 C31H33FN404 + 251 n.d.
(CH2)4-NMe2 [M+H]
OH
O 387 0.60
10.19 -F -H 3.42 C23H17FN203 [M-H]_ 130 (E)
OH
467 0.55
10.20 -F -SO2Me 3.43 C24H19FN205S [M+H]+ 139 (E)
OH
O N1 469 0.35
10.21 -F ~N 3.44 C27H21FN403 157
Me [M+H]+ (E)
O OH _N(SO2Me)-
567 0.55
10.22 -F (CH2)-(CO)- 3.45 C28H27FN406S [M+H]+ 183 (E)
NMe2

OH
389 237- 0.10
10.23 -F -H 3.32 C23H17FN203
[M+H]+ 240 (D)
0 OH
NI 469 259- 0.15
10.24 -F N~ 3.33 C27H21FN403
Me [M+H]+ 265 (D)


CA 02493436 2005-01-21
97
-N(COMe)- 3.41 C30H31FNaO4 531 274- 0.15
10.25 -F
(CH2)3-NMe2 [M+H]+ 278 (D)
0
~H -N(Me)-(CO)- 3.36 C28H27FN404 503 258- 0.20
10.26 -F
CH2-NMe2 [M+H]+ 264 (D)
0 OH
515 279- 0.15
10.27 -F / O ~N Me 3.34 C29H27FN404
[M+H]+ 282 (D)
O OH
467 260- 0.35
10.28 -F -SO2Me 3.39 C24H19FN205S
[M+H]+ 266 (F)
-N(COMe)- 3.37 C26H22FN304 460 290- 0.30
10.29 -F OH
CH3 [M+H]+ 294 (F)
OH -N(S02Me)-
567 238- 0.30
10.30 -F CH2-(CO)- 3.35 C28H27FN406S
[M+H]+ 242 (F)
NMe2

0
~H -N(Me)-(CO)-
3.38 C29H29FN404 517 250- 0.35
10.31 -F
(CH2)2-NMe2 [M+H]+ 255 (F)
0
~H -N(Me)-(CO)- 3.40 C30H31FN404 531 184- 0.25
10.32 -F
(CH2)3-NMe2 [M+H]+ 190 (F)
O OH
NM
H C ~e 572 170- 0.40
10.33 -F 3 'N 3.48 C32H34FN504
'1, 0 [M-H]' 175 (C)


CA 02493436 2005-01-21

98
OH
-N(SO2Me)- 553 0.60
10.34 -F 3.26 C28H29FN405S 180
(CH2)2-NMe2 [M+H] (C)
O OH

10.35 -F -N(SO2Me)- 3.49 C29H31FN405S 567 196- 0.30
1 (CH2)2-NMe2 [M+H]+ 199 (C)
O OH
c -N(Me)-(CO)- 517 0.20
10.36 -F 3.50 C29H29FN404 + 150
CH2-NMe2 [M+H] (C)
O OH
10.37 -F -N(COMe)- 3.51 C31H33FN404 545 206- 0.30
(CH2)3-NMe2 [M+H]+ 210 (A)
OH

10.38 -F 0 -N(Me)-(CO)- 3.59 C29H29FN404 517 231- 0.60
1 ` CH2-NMe2 [M+H]+ 236 (A)
OH
474 218- 0.50
10.39 -F -(CH2)2-NMe2 3.57 C28H28FN303
[M+H]+ 222 (A)
OH

10.40 -F 0-N(Me)-(CO)- 3.58 C30H31FN404 531 215- 0.50
` (CH2)2-NMe2 [M+H]+ 218 (A)
O OH
474 172- 0.15
10.41 -F -(CH2)2-NMe2 3.60 C28H28FN303 [M+H]+ 177 (G)


CA 02493436 2005-01-21
99
OH

10.42 -F 0 -N(COMe)- 3.61 C30H31 FN404 531 230- 0.50
` (CH2)2-NMe2 [M+H]+ 234 (A)
0 OH
-N(Me)-(CO)- 3.62 C 545 170- 0.30
10.43 -F (CH2)3-NMe2 31 H33FNa0a [M+H]+ 175 (E)
0 OH

10.44 -F -N(Me)-(CO)- 3.63 C32H35FN404 559 142- 0.10
(CH2)4-NMe2 [M+H]+ 146 (G)
0 OH
N 483 262- 0.20
10.45 -F xkN 3.64 C28H23FN403
Me [M+H]+ 269 (E)
OH

10.46 -F 0 -N(Me)-(CO)- 3.65 C32H35FN404 559 234- 0.30
lux (CH2)4-NMe2 [M+H]+ 236 (A)
OH
0 403 231- 0.20
10.47 -F / -H 3.66 C24H19FN203 M+H 233 (A)
OH
0 486 205- 0.10
10.48 -F NO 3.67 C29H28FN303 M+H 210 (E)
[ ]+ OH

0 488 145- 0.15
10.49 -F -CH2-NEt2 3.68 C29H30FN303 M+H 150 E


CA 02493436 2005-01-21
100
OH
0 430 280- 0.05
10.50 -F -CH2-NH2 9.7 C25H22FN303
/ [M-H] 285 (H)
OH
O 460 273- 0.15
10.51 -F / -(CH2)2-NMe2 3.70 C27H26FN303 [M+H]+ 276 (E)
O OH
460 230- 0.05
10.52 -F -(CH2)2-NMe2 3.71 C27H26FN303
[M+H]+ 235 (E)
OH
0 490/492 255- 0.50
10.53 -Cl / -(CH2)2-NMe2 3.73 C28H28CIN303 [M H 258 A
+ ]+ ( )
OH
e N-3 499/501 296- 0.50
10.54 -Cl / Me 3.74 C28H23CIN403 M H 300 (A)
` [ +]+ OH

O 476/478 228- 0.50
10.55 -Cl / -CH2-NMe2 3.75 C27H26CIN303 [M H 230 A
+ ]+ ( )
lx,

O OH
r--",N-Me 515 210- 0.40
10.56 -F N,--j 3.77 C30H31 FN403
/ [M+H]+ 215 (A)
O OH
N 483 240- 0.50
10.57 -F ~NJ 3.78 C28H23FN403
/ [M+H]+ 245 (A)


CA 02493436 2005-01-21
101
O OH
c -CH2-NMe- 517 0.30
10.58 -F 3.82 C30H33FN403 n.d.
I (CH2)2-NMe2 [M+H]+ (I)
OH
r--,N-Me 515 0.35
NJ 3.79 C30H31FN4O3 275
10.59 -F r

lox
OH
N 483 0.55
10.60 -F r N.~ 3.80 C28H23FN403 280

OH
502/504 260- 0.50
10.61 -Cl NO 3.83 C29H28CIN303 M+H 266 (A)
[ ]+ OH

-CH2-NMe- 517 0.05
10.62 -F 3.81 C30H33FNa03 n.d.
(CH2)2-NMe2 [M+H]+ (E)

HO 4
03 110- 0.60
-H 3.84 C24H19FN203 M+H 112 (K)
10.63 -F aIrO

[ l+ HO 4

32 260- 0.60
-CH2-NH2 9.8 C25H22FN303 M+H 263 (A)
10.64 -F 6:rO

[ l+ HO c5:rO 446 265- 0.60
10.65 -F -CH2-NHMe 9.9 C26H24FN303 M+H 270 (A)
[ l+


CA 02493436 2005-01-21
102
HO O
462 0.10
250 (M)
10.66 -F -CH2-NMe2 3.87 C26H24FN304 [M+H]+ (M)

462 0.15
10.67 -F O -CH2-NMe2 3.88 C26H24FN304 247

OH
546/548 290- 0.30
10.68 -Br / N0 3.90 C29H28BrN3O3 M+H 293 (E)
[ ]+ OH

520/522 243- 0.25
10.69 -Br / -CH2-NMe2 3.91 C27H26BrN3O3 M+H 246 (E)
[ ]+ OH

548/550 252- 0.35
10.70 -Br / -CH2-NEt2 3.92 C29H30BrN3O3 [M+H]+ 255 (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
(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


CA 02493436 2005-01-21
103
The following compounds of the formula I-1 Ob are prepared analogously to
Example
10.0:

R41
R3

H
O
R2 H (I-1Ob)

Start-
Ex-
am- R 2 R3 R 4` ing Empirical Mass m.p. Rt-
pie mate- formula spectrum [ C] value*
rials
OH
0 460 0.20
10.71 -F / -CH2-NMe2 3.93 C27H26FN303 [M+H]+ 150 (A)
O OH
460 105- 0.30
10.72 -F -CH2-NMe2 3.94 C27H26FN303 [M+H]+ 109 (B)
OH
0 476/478 230- 0.50
10.73 -CI / -CH2-NMe2 3.95 C27H26CIN303 M+H 235 (C)
[ ]+ *Eluent mixtures:

(A): silica gel, methylene chloride/methanol = 5:1
(B): silica gel, methylene chloride/methanol = 9:1


CA 02493436 2005-01-21
104
(C): reversed phase RP8, methanol/sodium chloride solution (5%) = 4:1
Example 11.0
3-Z-[1-(4-Dimethylaminomethylanilino)-1-(3-(2-carbamovlethyl phenyl)methylene]-
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
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
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 I-11 are prepared analogously to
Example
11.0:


CA 02493436 2005-01-21
105

R41
R3

H
O
R2 H (I-11)

Start-
Ex-
ing Empirical Mass m.p. Rf
am- R2 R3 R4'
pie mate- formula spectrum [ C] value*
rials
o NHCH3
10.0 489/491 223- 0.50
11.1 -Cl -CH2-NMe2 C28H29CIN4O2
/ ** [M+H]+ 225 (A)
NHCH3
0 10.1 473 148- 0.40
11.2 -F -CH2-NMe2 C28H29FN402 M+H 150 (B)
NMe2
0 10.2 473 98- 0.30
11.3 -F -CH2-NMe2 C28H29FN402 / _ *** [M+H]+ 103 (C)

o NH2
459 223- 0.50
11.4 -F -CH2-NMe2 10.3 C27H27FN402 / \ [M+H]+ 225 (A)


CA 02493436 2005-01-21
106
0 NHMe
10.3 473 210- 0.70
11.5 -F -CH2-NMe2 C28H29FN402 [M+H]+ 213 (A)
** O NMez

10.3 487 213- 0.80
11.6 -F / -CH2-NMe2 *** C29H31FN402 [M+H]+ 215 (A)
NH2
0 443 115- 0.25
11.7 -F -CH2-NMe2 10.2 C26H25FN402
[M-Hl- 120 (C)
NHMe
0 10.2 457 222- 0.25
11.8 -F -CH2-NMe2 ** C27H27FN402 [M-H]' 225 (C)
0 NHz
443 143- 0.40
11.9 -F / -CH2-NMe2 10.4 C26H25FN402
[M-H]' 146 (D)
NMe2
0 10.1 487 198- 0.60
11.10 -F / -CH2-NMe2 *** C29H31FN402 M+H + 200 (B)
[ l Me

N 10.1 542 0.60
11.11 -F 0 -CH2-NMe2 C32H36FN502 175
**** [M+H]+ (B)
0 NH2
N
Me 557 150- 0.40
11.12 -F H3C'N 10.5 C31H33FN603 0 [M+H]+ 156 (E)


CA 02493436 2005-01-21
107
0 NH2
11.13 -F -N(SO2Me)- 10.6 C28H30FN5O4S 552 197- 0.50
(CH2)2-NMe2 [M+H]+ 199 (D)
11.14 -F NMe2 -CH2-NMe2 10.4 C28H29FN402 473 147- 0.35
*** [M+H]+ 152 (D)
0 NHMe
10.4 459 208- 0.35
11.15 -F -CH2-NMe2 C27H27FN402 ** [M+H]+ 214 (D)

0 NHMe
11.16 -F -N(S02Me)- 10.6 C29H32FN504S 566 218- 0.70
(CH2)2-NMe2 ** [M+H]+ 222 (F)
1 1 . 1 7 -F 0 ,e2
-N(S02Me)- 10.6 C30H34FN5O4S 580 199- 0.40
(CH2)2-NMe2 *** [M+H]+ 205 (C)
0 NHMe H3C ~NMe 10.5 571 155- 0.20
11.18 -F TN C32H35FN603
0 ** [M+H]+ 160 (C)
NHCH3
0
-N(Me)-(CO)- 10.7 C28H27FN403 487 137- 0.50
11.19 -F
CH3 ** [M+H]+ 145 (C)
NHCH3
0 ~NMe 10.8 585 211- 0.40
11.20 -F H3 0 ** C33H37FN603 M+H + 219
[ ] (C)
NHCH3 0 11.21 -F -N(S02Me)- 10.9 C30H34FN5O4S 578 192- 0.50
/ (CH2)2-NMe2 ** [M-H]" 200 (C)


CA 02493436 2005-01-21
108
NHCH3
o Me 10.11 559 180- 0.50
N
11.22 -F / r o
oteu C32H35FN404 M+H 187 (C)
NHCH3
o N-3 10.13 496 262- 0.40
11.23 -F / >'NN e C29H26FN502
M+H 266 (C)
** [ ]+ NHCH3

0 10.14 494 180- 0.60
11.24 -F / -SO2Me C26H24FN304S M+H 188 (C)
NHCH3
0 0 ''N-Me 10.12 542 226- 0.50
11.25 -F N,--j C31H32FN503 M+H 230 (C)
NHMe
o H JMe 10.16 571 0.10
11.26 -F 3clv o ** C32H35FN603 213
[M+H] (G)
NHMe
0 0 r'N-Me 10.15 528 0.40
11.27 -F N,J C30H30FN5O3 245
*Eluent mixtures:
(A): silica gel, methylene chloride/methanol/ammonia = 5:1:0.01
(B): alumina, methylene chloride/ethanol = 20:1
(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


CA 02493436 2005-01-21
109
** using methylammonium chloride as base equivalent
**' using dimethylammonium chloride as base equivalent
**** using piperidine hydrochloride as base equivalent

Example 12.0

3-Z-[1- 4-Dimethylaminomethylanilino)-1-(4-acetylaminomethylphenyl)methylenel-
6-
chloro-2-indoli none
100 mg of 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-aminomethylphenyl)-
methylene]-6-chloro-2-indolinone (starting material 7.0) are dissolved in 5 ml
of
methylene chloride and 5 ml of pyridine, and 20 pi 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 pI of acetyl chloride are then added, and the
mixture is
stirred at room temperature for 12 hours. After this time, the solvent is
removed
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:


CA 02493436 2005-01-21
110

R41
3

H
0
R2 N (1-12)

Start-
Ex-
ing Empirical Mass m.p. Rf-
am- R2 R3 Ra,
mate- formula spectrum [ C] value*
pie
rials
HN'~~3 H3JNCH3 585/587 252- 0.25
12.1 -Cl J 8.0 C32H35CIN6O3 M-H " 255 (B)
r~
535/537 238 0.45
12.2 -CI HN 0 -CH2-NMe2 7.0 C32H29CIN4O2 (de_
comp.)

2 ~NJ CH3 647/649 282- 0.40
12.3 -CI HN H3v o 8.0 C37H37CIN6O3
[M-H]" 284 (B)
0.1-CH3
HN 457 245- 0.40
12.4 -F -CH2-NMe2 9.0 C27H27FN402 [M-H]" 250 (C)


CA 02493436 2005-01-21
111
0~- Et
HN 471 212- 0.35
12.5 -F -CH2-NMe2 9.0 C28H29FN402
[M-H]" 214 (D)
o /
HN 519 237- 0.40
12.6 -F -CH2-NMe2 9.0 C32H29FN402
[M-H] 240 (D)
0 533 187- 0.30
12.7 -F HN -CH2-NMe2 9.0 C33H31FN402
[M-H]" 190 (D)
C H3
NH
471 234- 0.30
12.8 -F -CH2-NMe2 9.1 C28H29FN402
/ \ [M-H]" 237 (D)
0 533 144- 0.45
12.9 -F NH -CH2-NMe2 9.1 C33H31FN402
[M-H]" 150 (C)
Et
o NH
485 235- 0.25
12.10 -F -CH2-NMe2 9.1 C29H31FN402
/ \ [M-H]" 237 (D)


CA 02493436 2005-01-21
112
NH
547 217- 0.30
12.11 -F -CH2-NMe2 9.1 C34H33FN402 [M-H]" 220 (D)
CH3
HN40 457 112- 0.25
12.12 -F -CH2-NMe2 9.2 C27H27FN402 M-H " 120 (D)
Et
HN4 0 586 176- 0.30
12.13 -F -CH2-NMe2 9.2 C28H29FN4O2 [M+H]+ 180 (D)
535 80- 0.35
12.14 -F HN 0 -CH2-NMe2 9.2 C33H31 FN4O2

4 H3 rNCH3
HN 0 H 1-NJ 569 230- 0.35
12.15 -F 3c1v 0 9.3 C32H35FN603 [M-H]" 235 O
D
Et
HN 40 H3~NCH3 583 205- 0.30
12.16 -F ev o 9.3 C33H37FN603 M-H " 210 (D)
[ J ~NCH3 645 217- 0.35

12.17 -F HN 0 H3v 0 9.3 C38H39FN603 [M-H]" 220 (D)


CA 02493436 2005-01-21
113
H N`J CH3 597 209- 0.30
0o
12.18 -F 3-j= 9.6 C34H37FN603 M+H 212 (D)
a H ~CH611 190- 0.30
12.19 F 3 9.6 C35H39FN603 M+H 193 (D)
o
NCH,
12.20 -F 9.6 C36H36FN703
[M+H]+ 163 (D)
0 ~-o J
HN H3 CH3 639 223- 0.30
12.21 -Fv 9.6 C37H43FN603
[M+H]+ 227 (D)
N
o \NCH3
HN H -N 634 170- 0.25
12.22 -F 3 v C36H36FN703
o 9.6
[M+H]+ 175 (D)
0,7 CH3
HN CH3 H3 CH3 599 194- 0.20
12.23 -F \ 9.6 C34H39FN603 M+H + 196 (D)
H3CH3 ow

HN H~NCH3 613 197- 0.70
12.24 -F 3 v o 9.6 C35H41 FN6O3
[M+H]+ 200 (E)


CA 02493436 2005-01-21
114
_N.J CH3 653 130- 0.75
12.25 -F HN H3 0 9.6 C38H45FN603
[M+H]+ 135 (E)
O OMe
H N H3 J CH3 601 155- 0.60
12.26 -F v 9.6 C33H37FN604 M+H + 159 (E)
[ ] MeO

o / ~NCH3 663 168- 0.35
12.27 -F H3clv 9.6 C38H39FN604
[M+H]+ 172 (C)
C(CH3)3

1~ r--"NCH 627 85- 0.35
12.28 -F HN H3C1v-~ 9.6 C36H43FN603
[M+H]+ 90 (C)
s
HN H ~NCH3 639 170- 0.25
12.29 -F 3 9.6 C35H35FN603S M+H + 175 (C)
(CH3)3C`7~--

HN rN J CH3 613 242- 0.30
12.30 -F H3"'N 9.6 C35H41 FN603 [M+H]+ 245 (C)
0
HN H ( ~NCH3 623 155- 0.65
12.31 -F 30'N- 9.6 C35H35FN604 [M+H]+ 160 O
F


CA 02493436 2005-01-21
115
0 CH3
HN H ~NCH3 571 190- 0.60
12.32 -F 3C 9.6 C32H35FN603
[M+H]+ 195 (F)
0
Et
HN H JNCH3 585 203- 0.65
12.33 -F 3 9.6 C33H37FN603 o [M+H]+ 209 (E)

HN O H3 J CH3 633 145- 0.60
12.34 -Fvo 9.6 C37H37FN603
[M+H]+ 150 (F)
o H3 CNCH3 647 148- 0.65
12.35 -F HNe1v o 9.6 C38H39FN603 [M+H]+ 151 (F)
o~
HN 485 216- 0.35
12.36 -F -CH2-NMe2 9.0 C29H29FN402 M+H 220 (D)
0
HN 499 214- 0.35
12.37 -F -CH2-NMe2 9.0 C3oH31FN402 M+H 217 (D)
0 N
HN 522 205- 0.35
12.38 -F -CH2-NMe2 9.0 C31H28FN502
[M+H]+ 210 (D)


CA 02493436 2005-01-21
116
0 ~-o
HN 527 235- 0.35
12.39 -F -CH2-NMe2 9.0 C32H35FN402 [M+H]+ 237 (D)
o
HN 520 135- 0.20
12.40 -F -CH2-NMe2 9.0 C31H28FN502
[M-H]" 140 (D)
0 CH3
H N H3 487 210- 0.20
12.41 -F -CH2-NMe2 9.0 C29H31FN402
D
[M+H] 215 O
H3CCH3
O
HN 501 202- 0.25
12.42 -F -CH2-NMe2 9.0 C30H33FN402 [M+H]+ 206 (D)

541 198- 0.35
12.43 -F HN -CH2-NMe2 9.0 C33H37FN402
[M+H]+ 203 (D)
O OMe
H N 489 173- 0.35
12.44 -F -CH2-NMe2 9.0 C28H29FN403
[M+H]+ 177 (D)
MeO
O 0
12.45 -F HN -CH2-NMe2 9.0 C33H31FN403 549 202- 0.50
[M-H]" 207 (C)


CA 02493436 2005-01-21
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O
12.46 -F HN -CH2-NMe2 9.0 C31H35FN402 513 203- 0.45
[M-H]" 209 (C)
o s
HN 527 245- 0.35
12.47 -F -CH2-NMe2 9.0 C30H27FN402S M+H 250 (C)
[ ] (CH3>3Cro

HN
501 248- 0.45
12.48 -F -CH2-NMe2 9.0 C30H33FN402
[M+H]+ 252 (C)
o 1
HN 511 216- 0.30
12.49 -F -CH2-NMe2 9.0 C3oH27FN403 M+H 219 (C)
[ l+ O CN

HN 522 167- 0.20
12.50 -F -CH2-NMe2 9.0 C31H28FN502 [M+H] 170 (D)
*Eluent mixtures:
(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
(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:


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benzoyl chloride, propionyl chloride, phenylacetyl chloride,
cyclopropanecarbonyl
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-Trimethylammoniummethylanilino)-1-(4-(2-
carboxyethyl)phenyl)methylenel-
6-fluoro-2-indoli none 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
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
C28H29FN3031
Mass spectrum: m/z = 474 [M+H]+

The following compound of the formula 1-13 is prepared analogously to Example
13.0:


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R4'
3

H
O
H (1-13)
R

Start-
Ex-
ing Empirical Mass m.p. Rf
am- R2 R3 R4'
mate- formula spectrum [ C] value*
ple
rials
O OH
Me 474 0.50
13.1 -F N= Me 10.3 C28H29FN3031 150
/ "Me [M+H]+ (A)
*Eluent mixture:
(A): reversed phase RP8, methanol/sodium chloride solution (5%) = 4:1
Example 14.0

3-Z-[1-(4-Guanidinomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylenel-6-
fluoro-2-
indolinone iodide
170 mg of 3-Z-[1-(4-aminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-
6-
fluoro-2-indoli none (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.
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),


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Rf value: 0.40 (silica gel, methylene chloride/methanol/acetic acid = 5:1:0.1)
m.p. 290 C
C26H24FN503
Mass spectrum: m/z = 474 [M+H]+
The following compound of the formula 1-14 is prepared analogously to Example
14.0:
R4.
3

H
O
R H (1-14)


Start-
Ex-
ing Empirical Mass m.p. Rf
am- R2 R3 R4`
pie mate- formula spectrum [ C] value*
rials
O OH
H
14.1 -F {HN NH2 10.64 C26H24FN503 M+H + 305 0.70
[ ] (A)
*Eluent mixture:
(A): reversed phase RP8, methanol/sodium chloride solution (5%) = 4:1
Example 15


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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
for injection.

Example 17


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Tablet with 50 mg of active compound

Composition:
(1) Active compound 50.0 mg
(2) Lactose 98.0 mg
(3) Maize starch 50.0 mg
(4) Polyvinylpyrrolidone 15.0 mg
(5) Magnesium stearate 2.0 ma
215.0 mg
Preparation:
(1), (2) and (3) are mixed 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 30.0 mg
(5) Magnesium stearate 4,0 ma
600.0 mg
Preparation:


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(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
(3) Lactose, powdered 50.0 mg
(4) Magnesium stearate 2.0 ma
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


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430.0 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 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


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(2) 3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone
(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
(5) 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
(10) 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
(15) 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


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(18) 3-Z-[1-(4-(N-(dimethylamino-carbonylmethyl)-N-
methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-
2-indolinone
(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
(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-
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-
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-l-ylmethyl)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-
6-chloro-2-indolinone


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(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
(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-ca rboxyethyl)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


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(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
(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
(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-
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)methylene]-6-chloro-2-
indolinone
(62) 3-Z-[1-(4-(2-diethylaminoethylsulphonyl)anilino)-1-(3-(2-
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


CA 02493436 2005-01-21
129
(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
(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


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130
(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
(83) 3-Z-[1-(4-ethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-
6-
fl uoro-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
(90) 3-Z-[l-(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-
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


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(97) 3-Z-[1-(4-(methylbenzylaminomethyl)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone

(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-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
(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
(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-
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-
carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone


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(113) 3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-
methylsulphonylamino)anilino)-
1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone
(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


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(128) 3-Z-[1-(4-(morpholin-4-ylmethyl)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-fIuoro-2-indolinone
(129) 3-Z-[1-(4-(thiomorpholin-4-ylmethyl)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-fIuoro-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


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(144) 3-Z-[1-(3-(dimethylaminomethyl)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(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


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(160) 3-Z-[1-(4-(methylethylaminomethyl)anilino)-1-(4-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(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-dimethylaminoethyl)-N-methylaminomethyl)anilino)-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-l-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-
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-l-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


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(176) 3-Z-[1-(4-(N-(2-methylaminoethyl)-N-acetylamino)anilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(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-[1-(4-ethylaminomethylanilino)-1-(3-(2-
carboxyethyl)phenyl)methylene]-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)phenyl)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


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(192) 3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-
methylsulphonylamino)anilino)-
1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone
(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
(196) 3-Z-[1-(4-(N-(N-(2-dimethylaminoethyl)-N-methylaminomethylcarbonyl)-N-
methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methyl ene]-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-

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-
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


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(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-ylmethyl)anilino)-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
(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)-
methylene]-6-chloro-2-indolinone
(223) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(N-methyl-
carboxymethylamino)phenyl)methylene]-6-chloro-2-indolinone


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(224) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(N-methyl-
carboxymethylamino)phenyl)methylene]-6-chloro-2-indolinone
(225) 3-Z-[1-(4-d imethylaminomethylanilino)-1-(4-carboxymethoxyphenyl)-
methylene]-6-bromo-2-indolinone
(226) 3-Z-[1-(4-d imethylaminomethylanilino)-1-(3-carboxymethoxyphenyl)-
methylene]-6-bromo-2-indolinone
(227) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethylaminophenyl)-
methylene]-6-bromo-2-indolinone
(228) 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carboxymethylaminophenyl)-
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
In the tables above,
Me is methyl,
Et is ethyl,
Pr is propyl,
nPr is n-propyl,
Pr is isopropyl,
nBu is n-butyl,
tBu is tert-butyl and
Bn is benzyl.

Representative Drawing