UA79625C2 - Indolinon derivatives substituted in the position 6 - Google Patents

Abstract

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

Description

Description of the invention

The present invention relates to new substituted indolinone derivatives of general formula 3Y in position 6

M e /, Mr x ah 70 vg x

E of their tautomers, enantiomers, diastereomers, their mixtures and their salts, primarily their physiologically compatible salts, which have valuable pharmacological properties, medicinal products containing these compounds, their use and the method of their preparation. 12 The above-mentioned compounds of the general formula I have valuable pharmacological properties, primarily an inhibitory effect on various kinases, mainly receptor tyrosine kinases, such as MESEKI, MESEK2, MESEKZ, ROOBKK z,

ROSEKVD, EOEKI, ESEKZ, ESEK, NEK, s-Kii, ISETK, NOBK and RII-Z, as well as on the proliferation of cultured human cells, primarily endothelial cells, for example during angiogenesis (development of blood vessels), and on the proliferation of other cells, primarily tumor cells.

Accordingly, the object of this invention is the compounds of the general formula I presented above, which have valuable pharmacological properties, as well as medicinal products containing these pharmacologically active compounds, the use of these compounds and the method of their preparation.

The object of this invention is, in addition, physiologically compatible salts of the compounds proposed in the invention, medicinal products containing these compounds, which additionally optionally contain one or more inert carriers and/or diluents, as well as the use of similar compounds for obtaining a medicinal product suitable primarily for the treatment of excessive or abnormal cell proliferation.

The object of this invention is further methods of obtaining medicinal products, which differ primarily in that the compounds proposed in the invention or their physiologically compatible salts are combined with one or more inert carriers and/or diluents. y 3o Y. In the above general formula | with

X means an oxygen atom, so

B" means a hydrogen atom,

B2 means a fluorine, chlorine or bromine atom or a cyano group, me)

BZ means a phenyl group or a phenyl group monosubstituted by a fluorine, chlorine, bromine or iodine atom, or a C-C-C-Alkoxy group - a phenyl group, while the specified unsubstituted as well as monosubstituted phenyl groups can additionally be substituted in position C or by 4 identical or different substituents selected from the group, which includes a fluorine atom, a chlorine atom, a bromine atom, a cyano group, a C.i.sub.6-alkyloxy group, a C.--Soalkylcarbonylamino group, a cyano-C.i-S.sub.alkyl group, a carboxy-C. carboxy-C.-Salkylamino group, 70 carboxy-C4-Salkyl-M-(C-Salkyl)amino group, C-Slalkoxycarbonyl-C 1-Salkyl, - with C.-C.alkoxycarbonyl-C 1-Salkoxy group, C4-C. Alkoxycarbonyl-C -Salkylamino group, C.-C.Alkoxycarbonyl-C 1-Salkyl-M-(C4-Salkyl) amino group, amino-C.-Salkyl, aminocarbonyl-C.-Salkyl, "» (C4-Soalkylamino)carbonyl -C 1-Salkyl, di(Ci-Soalkyl)aminocarbonyl-C /-Salkyl, (C4-Soalkylcarbonyl)amino-C 1-Salkyl, (C4-C,Alkoxycarbonyl)amino-C 1-Salkyl, («C3-Salkylcarbonyl )amino-C 1-Szalkyl, (phenylcarbonyl)am ino-C.-Salkyl, - (C3-Secycloalkylcarbonyl)amino-C 4-Salkyl, (C3-Cocycloalkyl-C -Salkylcarbonyl)amino-C 4-Salkyl, (phenylcarbonyl)amino-C -Salkyl, (thiophene-2- ylcarbonyl)amino-C 4-Salkyl, (furan-2-ylcarbonyl)amino-C. )amino-C /-Szalkyl,

Ge») (pyridin-2-ylcarbonyl)amino-C 4-Salkyl, (pyridin-3-ylcarbonyl)amino-C.4-Salkyl, (pyridin-4-ylcarbonyl)amino-C.i-Salkyl, S.i - Szalkylpiperazine-1-ylcarbonyl-C.-- Szalkyl, carboxy-Co-Szalkenyl, o aminocarbonyl-Szalkenyl, (C4-Szalkylamino)carbonyl-S 5-Szalkenyl, di(S.4-Szalkyl)aminocarbonyl-S 5 -Czalkenyl and C.-C.Alkoxycarbonyl-Co-Szalkenyl,

IN? means a phenyl group or a phenyl group monosubstituted by a terminally substituted amino group, a guanidino group, a mono- or di(C.sub.1-Salkyl)amino group, M-I(F-di(C.sub.-Salkyl)amino-C»-Salkyl -M -A(C4-C alkyl)amino group, M-methyl-(C3-C alkyl)amino group, M-(C4-C alkyl)-M-benzylamino group, o M-(C4-C alkoxycarbonyl)amino group, M-(C .4-C,Alkoxycarbonyl)-C 1-C,alkylamino group, 4-(C,4-Salkyl)piperazin-1-yl, imidazol-1-yl, pyrrolidin-1-yl, azetidin-1-yl, morpholin- 4-yl, co-piperazin-1-yl, thiomorpholin-4-yl C.-Salkyl group or monosubstituted di(C.4-Salkyl)amino-(C.4-Salkyl)usulfonyl, 2-|IdyY(C.- C-alkyl)amino|ethoxy group, 6o 4-(C-C-C-alkyl)piperazin-1-ylcarbonyl, /o-Idy(C-4-C-alkyl)amino|-(C-C-C-alkyl))-M-(C-4- C-alkyl)aminocarbonyl, 1-86.-Calkyl)imidazol-2-yl, (C--Calkyl)usulfonyl or a group of the formula /- -M

M? b5 " in which

B'/ represents C 1-Soalkyl, C 1-Soalkylcarbonyl, di(C 1-Soalkyl)aminocarbonyl-C 1-Salkyl or

S.-Salkylsulfonyl and

BZ is C 4-Salkyl, o-Idi(C-4-Soalkyl)amino|-Co-Salkyl, o-(mono(C.-Soalkyl)amino|-Co-Salkyl. or o substituted in the terminal position di( C4-Soalkyl)amino group, piperazin-1-yl or 4-(C4-Salkyl)piperazin-1-yl (C.--Salkyl)carbonyl, (C.-Salkyl)ucarbonyl or carbonyl(C.--Salkyl) group , while all the dialkylamino groups present in the KE" residue can also be represented in a quaternized form, for example, in the form of an M-methyl-(M,M-dialkyl)ammonium group, where the counterion is preferably selected from iodide, 70 chloride, bromide, methyl sulfonate, para -toluenesulfonate and trifluoroacetate, 25 means a hydrogen atom and 25 means a hydrogen atom, while the above alkyl groups mean linear and branched alkyl groups, in which from one to three hydrogen atoms can additionally be replaced by fluorine atom(s) , and in addition, the present carboxy-, amino-, or imino group can be replaced by a residue that is cleaved by ip mimo, accordingly, it can be presented in the form of prolicars of a residue, for example in the form of a group that is converted immediately into a carboxy group, or in the form of a group that is converted immediately into an imino or amino group, while to the compounds of the formula I| also include their tautomers, enantiomers, diastereomers, their mixtures and their salts. 20 I. Particularly preferred compounds of the above general formula I include compounds in which X, B", K9 and 2? have the values specified above in point I and in which further

Pi. 82 and 27 have the values indicated above in item I, and

BZ means a phenyl group or a phenyl group monosubstituted by a fluorine, chlorine, bromine or iodine atom or a CpCalkoxy group, while the indicated unsubstituted and also monosubstituted phenyl groups can additionally be "E 25 substituted in position C or 4 identical or different substituents selected from the group, which includes a fluorine atom, a chlorine atom, a bromine atom, a cyano group, a C.i.sub.6-alkyloxy group, a C.--Soalkylcarbonylamino group, a cyano-C.i-S.sub.alkyl group, a carboxy-C. carboxy-C-C-C alkylamino group, carboxy-C-C-C alkyl-M-(C-C alkyl)amino group, C-C-Alkoxycarbonyl-C 1-C alkyl,

C.-C.Alkoxycarbonyl-C 1-Calkoxy group, C4-C.Alkoxycarbonyl-C-C-Alkylamino group, iv) 30 C.i-C.Alkoxycarbonyl-C 1-Calkyl-M-(C4-Calkyl)amino group, amino-C .-Salkyl, aminocarbonyl-C.-Salkyl, sc (C4-Soalkylamino)carbonyl-C 1-Salkyl, di-(C4-Soalkyl)aminocarbonyl-C 4-Salkyl, (C4-Soalkylcarbonyl)amino-C 1-Salkyl, (C4-C,Alkoxycarbonyl)amino-C1-Salkyl, (C3-Salkylcarbonyl)amino-C1-Salkyl, (phenylcarbonyl)amino-C1-Salkyl, (C3-Ce-cycloalkylcarbonyl)amino-C and FU -Salkyl, (C3-Sbcycloalkyl-C | -Salkylcarbonyl)amino-C and -Salkyl, (phenylcarbonyl)amino-C--Salkyl, 35 (thiophen-2-ylcarbonyl)amino-C 4-Salkyl, (furan-2- ylcarbonyl)amino-C.4-Salkyl, - (phenyl-C.4-Salkylcarbonyl)amino-C 4-Salkyl, (2-(C4-C,Alkoxy)benzoylcarbonyl)amino-C /-Salkyl, (pyridine-2 -ylcarbonyl)amino-C 4-Salkyl, (pyridin-3-ylcarbonyl)amino-C. Szalkyl, carboxy-C.--Szalkenyl, "aminocarbonyl-Co-Szalkenyl, (C4-Szalkyamino)carbo nil-C 5-Czalkenyl, 40 di-(C4-Czalkyl)aminocarbonyl-C»-Czalkenyl and C-C, alkoxycarbonyl-Co-Szalkenyl, - with N.i. B2 and B? have the values specified above in point I, and z" VZ means a phenyl group substituted by | C.-Salkylcarbonylamino group, carboxy-C.-Salkyl, carboxy-C,-C.alkoxy group, C.--Slalkoxycarbonyl-C 1-Salkyl, C.4-Slalkoxycarbonyl-C 1-Salkoxy group, aminocarbonyl-C.4-Salkyl , (C--Soalkylamino)carbonyl-C -Salkyl, di-(C--Soalkyl)aminocarbonyl-C /-C4-C3 395 alkyl, (C4-Soalkylcarbonyl)amino-C 1-Salkyl, (C4-C.Alkoxycarbonyl )amino-C 1-C alkyl, (phenylcarbonyl)amino-C 4-C alkyl, (C 3-Cocycloalkylcarbonyl)amino-C 4-C alkyl, (se) (C 3-Seccycloalkyl-C,-C alkylcarbonyl)amino-C 4-C alkyl, (phenylcarbonyl)amino-C.4-Salkyl, (thiophen-2-ylcarbonyl)amino-C.4-Salkyl, (furan-2-ylcarbonyl)amino-C--Salkyl,

Ф (phenyl-C,4-C alkylcarbonyl)amino-C 4-C alkyl, (2-(C 4-C,alkoxy)benzoylcarbonyl)amino-C 4-C alkyl, co 50 (pyridin-2-ylcarbonyl)amino-C 4- Szalkyl, (pyridin-3-ylcarbonyl)amino-C.4-Szalkyl, (pyridin-4-ylcarbonyl)amino-C 4-Szalkyl, C-Szalkylpiperazin-1-ylcarbonyl-C 1-Szalkyl, sl y y . : . and aminocarbonyl-C-C-Salkenyl, (C4-Salkylamino)carbonyl-C 5-Salkenyl, di-(C1-Salkyl)aminocarbonyl-C»-Salkenyl or C,-C,Alkoxycarbonyl-C»-Salkenyl,

N.iiii. B2 and 27 have the values indicated above in item I, a

BZ means a phenyl group substituted by carboxy-C.--C alkyl or C.-C.-Alkoxycarbonyl-C 1-C alkyl. or chlorine,

P.u. 82 and 23 have the values indicated above in point I, but what about B? means a phenyl group or a phenyl group monosubstituted with a terminally substituted amino group, a guanidino group, a mono- or di-(C 1 -C 3 alkyl)amino group, M-(o-di-(C 4 -C 3 alkyl)amino-Co-C 3 alkyl -M- (C4-C alkyl)amino group, M-methyl-(C3-C alkyl)amino group, IM-(C41-C alkyl)-M-benzylamino group,

M-(C4-C.Alkoxycarbonyl)amino group, M-(C.4-C,Alkoxycarbonyl)-C1-C,Alkylamino group, 4-(C.4-C.Alkyl)piperazin-1-yl, imidazol-1-yl , pyrrolidin-1-yl, azetidin-1-yl, morpholin-4-yl, diperazin-1-yl, thiomorpholin-4-yl C.-Salkyl group or monosubstituted di-(C4-Salkyl)amino-(C 1 -Salkyl)usulfonyl, 2-|di-(C4-Salkyl)amino|)ethoxy group, 4-(C4-Salkyl)piperazin-1-ylcarbonyl, io-Idi-(C4-Salkyl)amino|-(Co-Salkyl) )-Mm-(C,4-Salkyl)aminocarbonyl, 1-86,-Salkyl)imidazol-2-yl, (C--Salkyl)usulfonyl or a group of the formula /k

And in which 70 V'/ is C 4-Soalkyl, C 1-C 1-Soalkylcarbonyl, di-(C--Soalkylaminocarbonyl-C-S-alkyl or C 4-C 3 alkylsulfonyl and

BZ is C 4-Salkyl, F-Idi-(C4-Soalkyl)amino|-Co-Salkyl, F-Imono-(C.4-Soalkyl)amino|-Co-Salkyl. or substituted in the terminal position with a di-(C4-Soalkyl)amino group, piperazin-1-yl or 4-(C4-Salkyl)piperazin-1-yl (C.--Salkyl)carbonyl, (C.-Salkyl)ucarbonyl or carbonyl -(C4i-Szalkyl 75 Group, while all dialkylamino groups present in the KE" residue can also be represented in a quaternized form, for example in the form of an M-methyl-(M,M-dialkyl)ammonium group, where the counterion is preferably selected from iodide, chloride , bromide, methylsulfonate, para-toluenesulfonate and trifluoroacetate.

IP Among the particularly preferred compounds of the above general formula I, a subgroup of compounds in which:

I. X, B", 82, 25 and 5 have the values indicated above in point I, KZ has the values indicated above in point II., and B? has the values indicated above in point II.M,

IN.i. X, B", 2, VZ and K9 have the values indicated above in paragraph |, KZ has the values indicated above in paragraph II., and K7 has the values indicated above in paragraph II.M, p. 29 IN. X, B", B, 25 and B? have the values indicated above in point I, KE? has the above mentioned in p.I. values, and BC" has (9 values specified above in p.II.M,

N.M. Х, В", V and KE? have the values indicated above in point I, EK? has the values indicated above in point II., KZ has the values indicated above in point II, P.ii or II. , and 27 has the values indicated above in item II.M.

X means an oxygen atom, p

"B" means a hydrogen atom, Ge

K means a fluorine, chlorine or bromine atom or a cyano group,

BZ means a phenyl group or a phenyl group monosubstituted by a fluorine, chlorine, bromine or iodine atom or a C-C-C 35 carboxy group, while the specified unsubstituted and monosubstituted phenyl groups can additionally be substituted in the C position or by 4 identical or different substituents selected from groups that include a fluorine atom, a chlorine atom, a bromine atom, a C.i-Salkoxy group, a C.-Soalkylcarbonylamino group, a carboxy-C.-Salkyl, an aminocarbonyl-C -Salkyl, (C4-Soalkylamino)carbonyl-C 1-Salkyl, di -(C4-Soalkyl)aminocarbonyl-C 4-Szalkyl, "(C4-Soalkylcarbonyl)amino-C 1-Szalkyl and (phenylcarbonyl)amino-C.-Szalkyl, 40 B" means a phenyl group substituted by substituted in the terminal position di- (C.4-Soalkyl)uamino group - with a C.-Alkyl group or a group of the formula x" /t -M chd 45! - in which co B'/ represents C 1-Soalkyl, C.-Soalkylcarbonyl, di-(C --Soalkyl)uaminocarbonyl-S.-Szalkyl or

S.-Salkylsulfonyl, a

Me. BZ is C 4-Salkyl or o-Idi-(C 1-Salkyl)amino|-C-Salkyl or substituted in the terminal position by 20 di-(C 1-Salkyl)amino group, piperazine group or 4-(C 4-Salkyl) piperazin-1-yl C-Salkylcarbonyl group, sp 25 means a hydrogen atom and means a hydrogen atom, while the above alkyl groups mean linear and branched alkyl groups in which from one to three hydrogen atoms can additionally be replaced by an atom (-y) fluorine, and in addition, the present carboxy-, amino- or imino group can be replaced by a residue that is cleaved by mimo, their tautomers, (F) enantiomers, diastereomers, their mixtures and their salts. The following compounds of the general formula I are most preferred: g (a). 3-2-(/1--4-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-b-chloro-2-indolinone, (6). 3-2-(/1--4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene-b-fluoro-2-indolinone, in (c) 3-2-(/1--4 -dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-b-fluoro-2-indolinone, (9 3-27-(11-(4-(M-(4-methylpiperazin-1-ylmethylcarbonyl )-M-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6-fluoro-2-indolinone, (d) and 3-27-(11--4-(-«M -(2-dimethylaminoethyl)-M-methylsulfonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene-b-fluoro-2-indolinone,

(e) 3-27-(11--4-(-M-(3-dimethylaminopropyl)-M-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene-b-fluoro-2- indolinone, bu 3-2-(1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-b-fluoro-2-indolinone, ( h) 3-27-11--4-(-«M-(dimethylaminomethylcarbonyl)-M-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6b-fluoro-2-indolinone , (y) 70 3-27-(11--4-(-«M-(2-dimethylaminoethylcarbonyl)-M-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene-b-fluoro -2-indolinone, (QU 3-2-(11-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-b-fluoro-2-indolinone , (lu). 3-2-(1-(4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene-b-fluoro-2-indolinone, (m). 3-2 -(1-(4--2-dimethylaminoethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-b-chloro-2-indolinone, (n). 3-2-(11-- 4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-b-chloro-2-indolinone, (0). 3-2-(1-(4-(pyrrolidin-1-ylmethyl)anilino) )-1-(4-(2-carboxyethyl)phenyl)methylene|-6b-chloro-2-indolinone, (n). 3-2-11-(4-(n irolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|)-6-bromo-2-indolinone, (p). 3-2-(11--4-(dimethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6-bromo-2-indolinone (c). 3-2-(/1-(4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)methylene-6-bromo-2-indolinone, while, in addition, carboxy-, amino- or the imino group can be replaced by a residue that is cleaved by ip mimo, respectively, can be represented as a prodrug residue, for example, in the form of a group that is converted by ip mimo into a carboxy group, or in the form of a group that is converted by ip mimo into an imino- or amino group, as well as their salt

By a group that is immediately converted into a carboxy group, we mean, for example, a hydroxymethyl c o group or an alcohol-esterified carboxy group, in which the alcohol moiety is preferably

C-Svalkanol, phenyl-C-S-alkanol, C3-Socycloalkanol, while C5-Svacycloalkanol can additionally be i) substituted by one or two C-and-Salkyl groups, C5-Svacycloalkanol, in which the methylene group in position C or 4 is replaced on an oxygen atom or on an imino group optionally substituted by C.-Salkyl, phenyl-C.-Salkyl, phenyl-C.-Salkyloxycarbonyl or C.-Salkylcarbonyl, and the cycloalkanol fragment can additionally be substituted by one or two C.- By alkyl groups, C,-C7cycloalkenol, C3-Svalkenol, phenyl-C3-Svalkenol, C3-Svalquinol or phenyl-C3-Svalquinol, provided that the carbon atom bearing a double or triple bond is not bonded to the oxygen atom , C c3z-Ci-Scycloalkyl-Ci-Salkanol, bicycloalkanol, which "o contains a total of 8 to 10 carbon atoms and which in the bicycloalkyl fragment can be additionally substituted by one or two C.i-Salkyl groups, 1,3-dihydro-3- oxo-1-isobenzfuranol or an alcohol of the formula me) kA.-COo-0o--KbStg)-OH, in which

Ka means C1-C6alkyl, C5-C6cycloalkyl, phenyl or phenyl-C6-C6alkyl,

KE means a hydrogen atom, C1-C6 alkyl, C1-C6 cycloalkyl or phenyl and

Es means a hydrogen atom or C-Salkyl, "and by a residue that is cleaved away from an imino- or amino group, it is meant, for example, a c-hydroxy group, an acyl group such as benzoyl or pyridinoyl, or a C 4-Sialkylcarbonyl group , such as formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl, an allyloxycarbonyl group, ;" C.-Sivalkoxycarbonyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl,

Ooctyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or -I hexadecyloxycarbonyl, phenyl-C.4-C-C-alkyloxycarbonyl group such as benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl, /C-C-C-alkylsulfonyl-C-C-1-alkoxycarbonyl group, and C-C-C-C-alkyloxycarbonyl -Co-alkoxy-Co-alkoxycarbonyl group or group KaCO-O-(КАСКо)-ОО-СО, in which Ka means

He» C.-Salkyl, C--Ccycloalkyl, phenyl or phenyl-C.-Salkyl, Ku means a hydrogen atom, C.4-Salkyl, C.S-Ccycloalkyl or phenyl and Ko means a hydrogen atom, C.i-Salkyl or a group КАСО-О-(КБСК)-О, in which Ka-Ко have the values indicated above, and in the case of a residue that is cleaved away from the amino group, the sp phthalimido group is additionally meant, while the above-mentioned ester residues can also be used as a group that turns into a carboxy group. Preferred prodrug residues, in the form of which the carboxy group can be represented, are C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1-C1. --Csalkoxycarbonyl group, such as benzyloxycarbonyl, and (F, prodrug residues, in the form of which an imino- or amino group can be represented, is ka C.-Ssalkoxycarbonyl group, such as methoxycarbonyl, ethoxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl . benzoyl or 4-ethylbenzoyl, a pyridinoyl group such as nicotinoyl,

C.4-C alkylsulfonyl-n-C.sub.6-C.sub.alkoxycarbonyl group or C.-C.sub.6-C.sub.6-C.sub.4-C.sub.alkoxy-C.sub.4-C;alkylsulfonyl group such as 2-methylsulfonylethoxycarbonyl or 2-(2-ethoxy)ethoxycarbonyl. 65 New compounds are obtained according to the invention, for example, by methods known in principle from the literature.

a) In this variant, the compound of the general formula and in ve X ng M. ks in which the residues 77 and KZ may optionally change positions, X, B 2, KZ and K9 have the values specified above 70, K" has the values specified above for В! value or means a protecting group for the nitrogen atom of the lactam group, while В" may also represent an optional spacer bond with the solid phase, and 7 ! means a halogen atom, a hydroxy-, alkoxy-, or aryl-alkoxy group, for example, a chlorine or bromine atom, a methoxy-, ethoxy-, or benzyloxy group, subjected to interaction with an amine of the general formula

When in

And nom in which B and B? have the above values, and then, if necessary, cleave off the protecting group that was used for the nitrogen atom of the lactam group or the compound thus obtained from the solid phase.

As an example of a protecting group for the nitrogen atom of the lactam group, an acetyl, benzoyl, ethoxycarbonyl, tert-butyloxycarbonyl, or benzyloxycarbonyl group can be mentioned, and as an example of a solid phase, a resin such as 4-(2'4-dimethoxyphenylaminomethyl)phenoxy resin can be mentioned, a connection with which is preferably formed by an amino group, or a resin that is p-benzyloxybenzyl alcohol, the connection with which is preferably formed by an intermediate member, such as a 2,5-dimethoxy-4-hydroxybenzyl derivative. with

The interaction described above is preferably carried out in a solvent such as dimethylformamide, toluene, o acetonitrile, tetrahydrofuran, dimethylsulfoxide, methylene chloride or mixtures thereof, optionally in the presence of an inert base such as triethylamine, M-ethyldiisopropylamine or sodium bicarbonate, at a temperature of 20 to 1759C, while as a result of peramidation, cleavage of the used protective group may occur at the same time. at

If in the compound of the general formula M 7" means a halogen atom, then in this case the interaction of CM is preferably carried out in the presence of an inert base at a temperature from 20 to 12026.

If in the compound of the general formula M 7" means a hydroxy-, alkyl- or aryl-alkyl group, then in this case the interaction is preferably carried out at a temperature from 20 to 20096. (is)

Necessary under certain conditions, the subsequent cleavage of the used protective group is expediently carried out either hydrolytically in an aqueous or alcoholic solvent, for example in methanol/water, ethanol/water, isopropanol/water, tetrahydrofuran/water, dioxane/water, dimethylformamide/water, methanol or ethanol , in the presence of an alkali metal hydroxide, such as lithium hydroxide, sodium hydroxide or potassium hydroxide, at a temperature of from 0 to 1009C, preferably from 10 to 502C, or, most preferably, by transamidation under

WITH the help of 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 amount of the amine used, at a temperature of 0 to 1002C, preferably from 10 to 5020. "» Separate the obtained compound from the used solid phase preferably with the help of trifluoroacetic acid and water at a temperature from 0 to 352C, preferably at room temperature. b) In this variant, to obtain a compound of the general formula !, in which BK Z means substituted -i carboxy- C.-C.alkenyl, aminocarbonyl-Co-Salkenyl, (C4-Salkylamino)carbonyl-C o-Salkenyl, o di(C1-Salkylamino)carbonyl-Co-Salkenyl or /C.i-C.Alkoxycarbonyl-Co-Salkenyl phenyl or naphthyl group, compound of the general formula (22) 73 we KI p

M sl / "dv nya in M o y (o, with which B2, B", ER, 5 | X have the values indicated above, EK! has the values indicated above for KE or means a protecting group for the nitrogen atom of the lactam group, when this BC may also represent an optional bond formed by the spacer with the solid phase, and 73 means a group that is removed, for example a halogen atom or an alkyl or arylsulfonyloxy group, in particular a chlorine, bromine or iodine atom or a methylsulfonyloxy-, ethylsulfonyloxy-, p -toluenesulfonyloxy- or trifluoromethanesulfonyloxy group, are subjected to interaction with an alkene of the general formula b5 c) vt" 0.53 , o, o, in which K" means amino-, (C4-Calkylamino)-, di(C-C-Calkylamino)- or cyclylamino -C.alkoxy group, and n means a number

O or 1.

It is advisable to carry out a similar interaction during palladium catalysis using, for example, palladium acetate), palladium chloride), bis(triphenylphosphine)palladium acetate!), 70 bis(triphenylphosphine)palladium(II) chloride, palladium on activated carbon, bis1,2-bis (diphenylphosphino)ethane|palladium(0), dichloro(1,2-bisidiphenylphosphino)ethane)palladium), tetrakistriphenylphosphinepalladium(O), tris(dibenzylideneacetone)dipalladium(0), 1,1-bis(diphetylphosphino)ferrocenedichloropalladium) or tris adduct (dibenzylideneacetone)dipalladium(0) and chloroform, in the presence of a base such as triethylamine, diisopropylethylamine, lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, and a ligand such as triphenylphosphine, tri-ortho-tolylphosphine, or tri(tert-butyl )phosphine, in solvents such as acetonitrile,

M-methylpyrrolidinone, dioxane or dimethylformamide and their mixtures.

The process of subsequent cleavage of the used protective group for the nitrogen atom of the lactam group or the resulting compound from the solid phase is similar to that described above for option (a), which is necessary under certain conditions. c) In this variant, to obtain a compound of the general formula !, in which BK Z means substituted by 2o carboxy-C.-C. S-alkylamino)carbonyl-C 1-Salkyl or di(C-Salkyl)aminocarbonyl-C /-Salkyl a phenyl or naphthyl group, a compound of the general formula

KK) t o

My ECO n

In le cm so, (Ce) in which 22, 87, 25, B and X have the values indicated above, B" has the values indicated above for B or means b" a protecting group for the nitrogen atom of the lactam group, while B! can also represent a bond with the solid phase optionally formed by a spacer, A means C»o-Salkenyl and VU means hydroxy-, C-C-Alkoxy-, N-amino-, (Ci-Salkylamino)- or di-( S.-Szalkyl) amino group, subjected to hydrogenation.

Such hydrogenation is conveniently carried out by catalytic hydrogenation with hydrogen in the presence of a catalyst such as palladium on carbon or platinum in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, optionally with the addition of an acid such as as hydrochloric acid, at a temperature from 0 to 50 °C, preferably, however, at room temperature, and at a hydrogen pressure of 1 to 7 bar, preferably, however, from 3 to 5 bar. c» The process of the necessary, under certain conditions, subsequent removal of the used protective group for the nitrogen atom of the lactam group or the resulting compound from the solid phase is similar to that described above for option (a).

If, according to the invention, a compound of the general formula I is obtained, which contains an alkoxycarbonyl group, 49 then this compound can be converted by hydrolysis into the corresponding carboxy compound, or the compound is obtained

If the general formula !, which contains an amino or alkylamino group, then such a compound can be translated by

Te) hydroalkylation into the corresponding alkylamino or dialkylamino compound, or a compound of the general formula I containing a dialkylamino group is obtained, then this compound can be converted by alkylation into the corresponding

For a trialkylammonium compound, or a compound of the general formula I is obtained, which contains an amino or alkylamino group, if this compound can be converted by acylation or sulfonylation into a corresponding acyl or sulfonyl compound, or a compound of the general formula I is obtained, which contains a carboxy group, then such a compound sl can be converted by esterification or amidation into the corresponding ester or the corresponding aminocarbonyl compound, or a compound of the general formula I containing a nitro group is obtained, then this compound can be converted by reduction into the corresponding amino compound, or a compound of the general formula I, 22 containing a cyano group is obtained, then this compound can be converted by reduction into the corresponding aminomethyl

F! compound, or a compound of the general formula I is obtained, which contains an arylalkyloxy group, then such a compound can be converted by treatment with an acid into the corresponding hydroxy compound, or a compound of the general formula I is obtained, which contains an alkoxycarbonyl group, then this compound can be converted by saponification into the corresponding carboxy compound, or obtain a compound of the general formula I, in which K is a phenyl group substituted by an amino group, because an alkylamino group, an aminoalkyl group, or an aminoalkyl group, then this compound can be converted by subsequent interaction with the appropriate cyanate, isocyanate, or carbamoyl halide into a corresponding urea compound of the general formula I, or a compound is obtained of the general formula I, in which B" represents a phenyl group substituted by an amino group, an alkylamino group, an aminoalkyl group, or an aminoalkyl group, then this compound can be converted by subsequent reaction with a corresponding compound that transfers an amidino group, or by reaction with a corresponding nitrile into a corresponding guanidino compound according to of the general formula I.

The subsequent hydrolysis is preferably carried out in an aqueous solvent, such as water, methanol/water, ethanol/water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid, or in the presence alkali metal hydroxide, such as lithium hydroxide, sodium hydroxide or potassium hydroxide, at a temperature from 0 to 1002C, preferably from 10 to 5096.

The subsequent hydroalkylation is preferably carried out in a solvent suitable for this purpose, such as methanol, methanol/water, methanol/water/ammonia, ethanol, ether, tetrahydrofuran, dioxane or dimethylformamide, optionally with the addition of an acid such as hydrochloric acid, in the presence catalytically activated hydrogen, 70 for example hydrogen in the presence of Raney nickel, platinum or palladium on carbon, or in the presence of a metal hydride such as sodium borohydride, lithium borohydride, sodium cyanoborohydride or lithium aluminum hydride, at a temperature from

О to 1002С, mostly from 20 to 8020.

The subsequent alkylation is preferably carried out in a solvent suitable for this purpose, such as a simple ether, tetrahydrofuran, dioxane, dichloromethane, acetone or acetonitrile, in the presence of alkylating agents, such as 75 alkyl iodides, alkyl bromides, alkyl chlorides, ethers of alkylmethanesulfonic acids, ethers of alkyl-ly/odg --osluolsulfonic acids or alkyltrifluoroacetates, at a temperature from 0 to 1002C, preferably from 20 to 6020.

The subsequent acylation or sulfonylation is preferably carried out using a suitable free acid or a suitable reactive compound, such as its anhydride, ether, imidazolide or halide, preferably in a solvent such as methylene chloride, diethyl ether, tetrahydrofuran, toluene, dioxane, acetonitrile, dimethylsulfoxide or dimethylformamide, optionally in the presence of an inorganic or tertiary organic base at a temperature from -20 to 2009C, preferably from 209C to the boiling point of the solvent used. Interaction with free acid, if necessary, can be carried out in the presence of an acid activator or a dehydrating agent, for example, in the presence of isobutyl ether of chloroformic EM 259 acid, tetraethyl ether of orthocarbonic acid, trimethyl ether of orthoacetic acid, Ge) 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, M,M'-dicyclohexylcarbodiimide, M,M'-dicyclohexylcarbodiimide/M-hydroxysuccinimide,

M,M'-dicyclohexylcarbodiimide/1-hydroxybenzotriazole, 2-(1-Hbenzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, 2-(1H-benzotriazol-1-yl)-1,1 tetrafluoroborate ,3,3 Cheo, -tetramethyluronium/1-hydroxybenzotriazole, M,M'-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, and if necessary with the addition of a base such as pyridine, 4-dimethylaminopyridine, M-methylmorpholine or triethylamine, preferably at temperature from 0 to 1502C, preferably from 0 to 1002. Interaction with the corresponding reactive compound can, if necessary, be carried out in the presence of a tertiary organic base, such as triethylamine, M-ethyldiisopropylamine, M-methylmorpholine or pyridine, or using an anhydride in

From the presence of the appropriate acid at a temperature from 0 to 1502C, preferably from 50 to 10020. -

Subsequent esterification or subsequent amidation is conveniently carried out by reacting the appropriate reactive carboxylic acid derivative with the appropriate alcohol or amine as described above.

Etherification or amidation is preferably carried out in a solvent such as methylene chloride, diethyl ether, tetrahydrofuran, toluene, dioxane, acetonitrile, dimethylsulfoxide or dimethylformamide, optionally in the presence of an inorganic or tertiary organic base, preferably at a temperature from 202C to the boiling point of the used solvent At the same time, the interaction with the corresponding acid is preferably carried out in the presence of a dehydrating agent, for example, in the presence of isobutyl ether of chloroformic acid, tetraethyl ether of orthocarbonic acid, trimethyl ether of orthoacetic acid, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide , -I 45 M,M'-dicyclohexylcarbodiimide, M,M'-dicyclohexylcarbodiimide/M-hydroxysuccinimide,

M,M'-dicyclohexylcarbodiimide/1-hydroxybenzotriazole, tetrafluoroborate (Ce) 2-(1-Hbenzotriazol-1-yl)-1,1,3,3-tetramethyluronium, tetrafluoroborate 2-(1H-benzotriazol-1-yl)- 1,1,3,3-tetramethyluronium/1-hydroxybenzotriazole, M,M'-carbonyldiimidazole or

Ф triphenylphosphine/carbon tetrachloride, and if necessary with the addition of a base such as pyridine, ko 50 4-dimethylaminopyridine, M-methylmorpholine or triethylamine, preferably at a temperature from 0 to 1509С, sp preferably from 0 to 10092С, and acylation is preferably carried out by interaction with a suitable reactive compound, such as the anhydride, ether, imidazolide or halide of the specified acid, optionally in the presence of a tertiary organic base, such as triethylamine, M-ethyldiisopropylamine, 5M-methylmorpholine or pyridine, at a temperature of from 0 to 1502C, preferably from 50 to 10020.

The subsequent reduction of the nitro group is preferably carried out by hydrogenolysis, for example, under the action of hydrogen in (F) in the presence of a catalyst such as palladium on carbon or Raney nickel in a solvent such as methanol,

GI ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone, or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid or glacial acetic acid, at a temperature of 0 to 50 2C, preferably, however, at room temperature, and at hydrogen pressure from 1 to 7 bar, preferably, however, from 3 to 5 bar.

Subsequent hydrogenation of the cyano group is preferably carried out by hydrogenolysis, for example, under the action of hydrogen in the presence of a catalyst such as palladium on carbon or Raney nickel in a solvent such as methanol, ethanol, ethyl acetate, methylene chloride, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, optionally necessarily with the addition of an acid, such as hydrochloric acid or glacial acetic acid, at a water temperature of 65 to 502C, preferably, however, at room temperature, and at a hydrogen pressure of from 1 to 7 bar, preferably, however, from

From to 5 bar.

The following process of obtaining the corresponding guanidino compound of the general formula | preferably by reacting with a compound which transfers the amidino group, such as 3,5-dimethylpyrazole-1-carboxylic acid amidine, preferably in a solvent such as dimethylformamide, and optionally in the presence of a tertiary organic base such as triethylamine, at a temperature from 0 up to 502C, preferably at room temperature.

When carrying out the reactions described above, the reactive groups present under certain conditions, such as carboxy-, hydroxy-, amino-, alkylamino-, or imino groups, can be protected for the duration of the reaction with ordinary protective groups and removed again after the reaction is completed.

As an example of a protective group for a carboxy group, we can name a trimethylsilyl, metal, ethyl, 7/0 tert-butyl, benzyl or tetrahydropyranyl group, as an example of a protective group for a hydroxy-, amino-, alkylamino- or imino group, we can name an acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl , tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group, and for the amino group - an additional phthalic group.

If necessary, subsequent cleavage of the protecting group used can be carried out, for example, by hydrolysis in an aqueous solvent, such as water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid, or in the presence of an alkali metal hydroxide, such as lithium hydroxide, potassium hydroxide or sodium hydroxide, at a temperature of from 0 to 1002C, preferably from 10 to 5020.

However, cleavage of the benzyl, methoxybenzyl or benzyloxycarbonyl group is carried out, for example, by hydrogenolysis, in particular under the action of hydrogen in the presence of a catalyst such as palladium on carbon, in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid , optionally with the addition of an acid, such as hydrochloric acid or glacial acetic acid, at a temperature of from 0 to 502C, but preferably at room temperature, and at a hydrogen pressure of from 1 to 7 bar, more preferably from 3 to 5 bar. si

The methoxybenzyl group can also be cleaved in the presence of an oxidant such as cerium ammonium nitrate (IM) or in a solvent such as methylene chloride, acetonitrile or acetonitrile/water at a temperature of 0 to 502C, preferably, however, at room temperature. The 2,4-dimethoxybenzyl group is preferably, however, cleaved in trifluoroacetic acid in the presence of anisole. IF) tert-Butyl or tert-butyloxycarbonyl group is preferably cleaved by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane, ethyl acetate or ether. (Se)

The phthalyl group is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, P ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxane at a temperature of 20 to 50260. -

In addition, chiral compounds of the general formula | can be divided into their enantiomers and/or diastereomers.

So, for example, the obtained compounds of the general formula I, which are formed in the form of racemates, can be "separated by known methods | see AIPShpdeg M.I. and EEEpe! E.Y., "Torisv ip e (egeospetivigh", t.b., ed. MMieu Ipiegesiepse, 1971) into their optical antipodes, and compounds of the general formula I with at least 2 asymmetric carbon atoms can be separated on the basis of differences in their physical - chemical properties according to known methods, for example, chromatography and/or fractional crystallization, into their diastereomers, which, when they are formed in racemic form, can then be separated, as described above, into enantiomers.

Separation into enantiomers is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by interaction with an optically active substance that - forms salts or derivatives with a racemic compound, such as esters or amides, primarily with acids and their activated derivatives or alcohols, and separating the resulting mixture of diastereomeric salts or derivatives, for example, based on differences in their solubility, while free antipodes can be released from pure diastereomeric salts or (o) derivatives by the influence of a suitable agent for this purpose. As an example of the 50 optically active acids that are most often used for this purpose, we can name O- and | -forms of tartaric acid, dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, M-acetylglutamic acid, aspartic acid, M-acetylaspartic acid or quinic acid. An example of an optically active alcohol is (y)- or (-)U-menthol, and an example of an optically active acyl fragment in amides is (y)- or (-)-menthyloxycarbonyl residue. 22 In addition, compounds of formula | can be converted into their salts, primarily into those suitable for

Gee! physiologically compatible salts with inorganic or organic acids for pharmaceutical use. Examples of acids suitable for this purpose include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, para-toluenesulfonic acid. , 60 phenylsulfonic acid or I -(-)-mandelic acid.

In addition, new compounds of formula I obtained in this way, if they contain a carboxy group, can be converted into their salts with inorganic or organic bases, first of all, into their physiologically acceptable salts suitable for pharmaceutical use. Examples of suitable bases for this purpose include sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and b5 triethanolamine.

Compounds of the general formula I, which contain two or more acidic or basic groups, can also be presented in the form of salts with two or more inorganic or organic bases or acids (in the form of so-called double salts, etc.).

The compounds of the general formulas M-XI used as starting products are partially known from the literature, or they are obtained by methods known from the literature, or they can be obtained by the methods described above and in the following examples. So, for example, compounds of general formula IX are described in (application OE 19844003).

As already mentioned above, new compounds of the general formula | have valuable pharmacological properties, primarily an inhibitory effect on various kinases, mainly on receptor tyrosine kinases, such as MESEK1, MESEK2,

MESEKZ, ROSEKOo, ROSOEKD, EOEKT, EOEKZ, ESEK, NEK, c-Kii, ISETK, NOBK and RI-Z, as well as on the proliferation of 7/0 Cultured human cells, primarily endothelial cells, for example during angiogenesis, and on the proliferation of other cells , primarily tumor cells.

The biological properties of the new compounds were studied by the standard method described below.

Human umbilical cord endothelial cells (NOMES) were cultured in IMOM medium (Birso VKI company), supplemented with 1075 fetal calf serum (FCS) (Zidta company), 50 μM Dr-mercaptoethanol (75 Rika company), standard antibiotics, endothelial cell growth factor at a concentration of 15 μg /ml (ЕСО5, SopParogaime Viotedis! Rhodysiv company) and heparin at a concentration of 100 µg/ml (Zidt company), in gelatin-coated culture cups (0.295 gelatin, Zidt company) at a temperature of 372C and a CO content of 595" in an atmosphere saturated with water vapor .

To study the inhibitory activity of the compounds proposed in the invention, the cells were maintained for 16 hours on a "starvation diet", that is, in a culture medium without growth factors (ESOZ nheparins).

Next, the cells were detached from the culture plates using trypsin/EDTC and washed once in medium containing serum. After that, the cells were seeded on tablets in the amount of 2.5x103 cells per well.

Cell proliferation was stimulated with the help of MESRE-65 (vascular endothelial growth factor ("umazsiag epaoipeiia! dgouli Tasiog), N. MUvisi, OVE Vgaipzspmed) at a concentration of Bbng/ml and heparin u.i SI at a concentration of 1Okg/ml. 6 wells of each tablet used as a control without stimulating the cells contained in them.

The compounds proposed in the invention were dissolved in 100956 dimethyl sulfoxide and added to cell cultures in different dilutions in three replicates, while the maximum concentration of dimethyl sulfoxide was 0.395. Io)

The cells were incubated for 7 hours at 372C, after which ZN-thymidine (0.1 μCi/well, Ategzpat company) was added for the next 16 hours to detect DNA synthesis. Then radioactively labeled cells were immobilized on filter cloths and bound (embedded) radioactivity was determined using a D-radiation counter. To determine the inhibitory activity of the compounds proposed in the invention, obtained for not He"! the average value of stimulated cells was subtracted from the average value obtained for stimulated cells

With a cell factor (in the presence or absence of the compounds proposed in the invention). -

Relative cell proliferation was calculated as a percentage of the control (NOMES-cells without inhibitor) and the concentration of the active substance at which 5095 inhibition of cell proliferation (ISvo) is achieved was determined. "

The value of IS»5o in the compounds of the general formula I| proposed in the invention is from 5O0mMm to 1nM. - 70 Compounds of the general formula I! due to their inhibitory effect on the proliferation of cells, primarily endothelial and tumor cells, they are suitable for the treatment of diseases in which cell proliferation plays a certain role,

From" primarily endothelial cells.

So, for example, the proliferation of endothelial cells and the associated formation of new vessels are decisive factors in the progression of tumors (BoYKtap .. et al., Maishge 339, 1989, pp. 58-61; Napayap 0. and RoiKktap /, sei 86 , 1996, pp. 353-365). In addition, the proliferation of endothelial cells is of particular importance in hemangiomas, metastasis, rheumatic arthritis, psoriasis, and the formation of new eye vessels (Se) (BoiYiktap .), Mayte May. 1, 1995, pp. 27-31; Sagpteiyiyi R. and Kakeypi .., Mayte 407, 2000, pp. 249-257).

The therapeutic efficacy of inhibitors of endothelial cell proliferation was confirmed by modeling

Fo on animals, for example, |O'i«eiShu, etc. as well as Ragapdi and others. (SOi«eiShu M.5. et al., Se 88, 1997, ka 20 p. 277-285; Raghapadi 5. et al., Rgos. May). Asai. si. OBA 93, 1996, p. 2002-2007)|.

Accordingly, the compounds of the general formula I, their tautomers, their stereoisomers or their physiologically acceptable salts are suitable, for example, for the treatment of tumors (in particular, squamous cell carcinoma, astrocytoma, sarcoma

Kaposi's, glioblastoma, lung cancer, bladder cancer, occipital and cervical cancer, esophageal cancer, melanoma, ovarian cancer, prostate cancer, breast cancer, small cell lung cancer, glioma, colon cancer, pancreatic cancer, genitourinary cancer and gastrointestinal cancer

HF) tract, as well as blood cancers (such as multiple myeloma and acute myeloid leukemia), psoriasis, arthritis (for example, rheumatoid arthritis), hemangioma, angiofibroma, eye diseases (for example, diabetic retinopathy), neovascular glaucoma, kidney diseases (for example, glomerulonephritis ), diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, transplant rejection 60 and glomerulopathy, fibrous diseases (for example, cirrhosis of the liver), associated with the proliferation of mesangial cells, diseases, arteriosclerosis, lesions of nervous tissue and to inhibit re-occlusion of vessels after treatment with balloon catheter, during vascular prosthetics or after use, respectively, the introduction of mechanical devices to maintain vascular patency (for example, stents) or other diseases in which cell proliferation or angiogenesis play a role. because the compounds proposed in the invention, due to their biological properties, can be used individually or in combination with other pharmacologically active compounds, for example, for the therapeutic treatment of tumors in monotherapy or in combination with other antitumor therapeutic agents, for example, in combination with topoisomerase inhibitors (for example, etoposide), with antimitotic agents (for example, vinblastine, taxol), with compounds that interact with nucleic acids (for example, cis-platinum, cyclophosphamide, adriamycin), with hormone antagonists (for example, tamoxifen), with steroids and their analogues (for example, dexamethasone), with inhibitors of metabolic processes (for example, 5-RSh, etc.), with cytokines (for example, interferons), with inhibitors of kinases (for example, ESEK-kinase inhibitors, such as Iressa, SiIemes), with inhibitors of receptor tyrosine kinase, which have an allosteric effect, with /o antibodies ( for example Herceptin), with COX-2 inhibitors, or in combination with radiation therapy, etc. In such combinations, the active substances can be administered either simultaneously or sequentially, respectively, the active substances can be used in combination with non-pharmacological types of therapy simultaneously or sequentially.

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That's how I saw it in the bedroom

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From the 13th nkarboshchii Erokeiy Ilyan o OA. -іВ Oz nON; I'm 0 in Der ONd, I'm sure I'm the aunt of a Venetian! вн келий ех M, vezh i яю У зак зер

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And Lyushok is vinified and the hair dryer is thrown into the air

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Had (aminomethylvniya yav i t SHY!

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ЯБЯй 8-20 methloylerazin-1 iyacarbonianinnemi i

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F then sp then 60 bo

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ПЯ55 135 spi sktdeya mete i Ko pivna

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And OCHE-apetianami poets tk kant izn prastipeninb" and yannia kirboksya "I a. ME TYLANINO. (about sl d ikdishch y: reni aet ale Oto "V inlo SHY (g) tenis b-yugore indolinoya: va 72 sl ko 60 b5

Lyrics -- payi yin ya

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Te zh banty rennometinenii b. fluorine onivscholinone o. ! at

EYE VIP metuotiverazny and nkrboni ani

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Be (Vch LA dimethyl stynaminaminomeneninovya 00000000 janiya Kolni lamas TNK UMetiLev "ke YAN "y E

Id vk vvi ik Indovina,

To the cross, the poets of today's science -

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And what's new NOV: HER.

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The following abbreviations are used in the following examples: Ge)

HOBT 1-hydroxy-1H-benzotriazole

TBTU tetrafluoroborate O-benzotriazol-1-yl-M,M,M',M'-tetramethyluronium -

Preparation of starting compounds

Example

Dimethyl ether of 2-(4-fluoro-2-nitrophenyl)malonic acid « du To a solution of 188 ml of dimethyl ether of malonic acid in 9/00 ml of M-methylpyrrolidone while cooling with ice, add 185 g of potassium tert-butylate and then the mixture is stirred for 2 hours. 150 ml of 2,5-difluoronitrobenzene is added dropwise to the resulting thick suspension over 30 minutes and then stirred for 1 hour at 8520. After that, the mixture is poured into a mixture of 4 liters of water with ice and 250 ml of concentrated hydrochloric acid and extracted with 2 liters of ethyl acetate. The organic phase is dried over sodium sulfate and concentrated. The oily residue is extracted twice by stirring with water and then dissolved in bbOml of ethyl acetate. The resulting solution is dried over sodium sulfate and concentrated to dryness. The crystallized crude product is recrystallized from bObOml of a mixture of ethyl acetate/hexane in a ratio of 2:8 and dried. se) Yield: 222g (59965 from theory).

Fu Value K,: 0.40 (silica gel, cyclohexane/ethyl acetate in a ratio of 5:1). co Mass spectrum: t/2 - 270 |M-NO. c Analogously to example I, the following compounds are obtained: (1.1) 2-(4-bromo-2-nitrophenyl)malonic acid diethyl ether: the specified compound is obtained from 2,5-dibromonitrobenzene and malonic acid diethyl ether, Ku value 0.40 (silica gel , petroleum ether/ethyl acetate in a ratio of 5:1),

S.13N.AVHMO v, iF) mass spectrum: t/2 - 359/361 |MI"; co (1.2) dimethyl ether of 2-(4-cyano-2-nitrophenyl)malonic acid: the specified compound is obtained from 4- chloro-3-nitrobenzonitrile and dimethyl ether of malonic acid, in the value of K,: 0.50 (silica gel, methylene chloride/methanol in the ratio 50:1),

C12NioM2Ov, mass spectrum: t/2 - 277 |M-NO.

Example II

Methyl ether of 4-cyano-2-nitrophenylacetic acid 65 14.27 dimethyl ether of 2-(4-cyano-2-nitrophenyl)umalonic acid (educt I.2) is dissolved in 200 ml of dimethyl sulfoxide and 4.5 g of lithium chloride and 1.0 ml of water Then the solution is stirred for 3.5 hours at

1009, after which it is mixed with 300 ml of a mixture of water and ice and left to stand for 12 hours. The sediment that has fallen out is separated by vacuum filtration, dissolved in methylene chloride and washed with water. The organic phase is dried over sodium sulfate, evaporated on a rotary evaporator and dried.

Output: 7.7g (6895 from theory).

K value: 0.40 (silica gel, methylene chloride/methanol in a ratio of 50:1).

Mass spectrum: t/2 - 219 |M-NO.

Example PI 70 4-fluoro-2-nitrophenylacetic acid 50.0 g of dimethyl ether of 2-(4-fluoro-2-nitrophenyl)malonic acid (educt I) is stirred for 20 hours at 1002 in 400 ml of b-molar hydrochloric acid, after which it is mixed with 400 ml of water and cool to 092C. The precipitate that has fallen is separated by vacuum filtration, washed with water and 100 ml of petroleum ether and dried.

Yield: 34.5g (94905 from theory).

K value: 0.30 (silica gel, cyclohexane/ethyl acetate in a ratio of 5:2).

SaNeEMO,.

Mass spectrum: t/2 - 154 |IM-SOO-NI.

Example IM b-fluoro-2-indolinone 119g of 4-fluoro-2-nitrophenylacetic acid (Educt II) is hydrogenated in bbOml of acetic acid with the addition of 20g of palladium on activated carbon (10956) at a hydrogen pressure of B5Olbs/sq.in. After that, the catalyst is separated by vacuum filtration and the solvent is distilled off. The crude product is extracted by mixing with

B5O0Oml of petroleum ether, separated by vacuum filtration, washed with water and dried.

Yield: 82.5g (91905 from theory). with

Value of K. 0.30 (silica gel, petroleum ether/ethyl acetate in a ratio of 1:1). at

SanNeEMO.

Mass spectrum: pt/2 -150 IM-NO.

Similarly to example IM, the following compounds are obtained: (IM.1) 6-bromo-2-indolinone: this specified compound is obtained from the diethyl ether of 2-(4-bromo-2-nitrophenyl)malonic acid (educt 11) in DS in the presence of Raney nickel as a hydrogenation catalyst, the value of K,: 0.45 (silica gel, petroleum ether/ethyl acetate in the ratio 1:1), ix,

SanevVgMo, Ge) mass spectrum: t/2 - 210/212 IM-NO; (IM.2) 6-cyano-2-indolinone: - the indicated compound is obtained from the methyl ether of 4-piano-2-nitrophenylacetic acid (educt II) in the presence of palladium on calcium carbonate as a hydrogenation catalyst, the value of K,: 0.45 ( silica gel, methylene chloride/methanol in a ratio of 9:1), "

SenNiemM.oo, then mass spectrum: t/2 -157 IM-NG. a c Example M: c» 1-acetyl-6b-fluoro-2-indolinone 82.5 g of b-fluoro-2-indolinone (educt IM) is stirred at 13092C in 180 ml of acetic anhydride for 10 hours. 415 After cooling to room temperature, the precipitate is separated by vacuum filtration, washed with 100 ml -1 of petroleum ether and dried.

Output: 64.8g (61905 from theory). is), Value of K. 0.75 (silica gel, petroleum ether/ethyl acetate in a ratio of 1:1). because SioNaEMO".

Mass spectrum: p/z: -192 IM-NO. similarly to example M, the following compounds are obtained: c (M.1) 1-acetyl-6b-chloro-2-indolinone: the indicated compound is obtained from b-chloro-2-indolinone and acetic anhydride, Ku value 0.55 (silica gel, petroleum ether/ethyl acetate in a ratio of 2:3),

C14NioSIMO in, mass spectrum: t/2 - 208/210 IM-NO; iF) (M.2) 1-acetyl-6-bromo-2-indolinone: the specified compound is obtained from b-bromo-2-indolinone (educt IM. 1) and acetic anhydride, Ku value 0.60 (silica gel, petroleum ether/ethyl acetate in a ratio of 2:1), in StoNaHgMo", mass spectrum: t/2 - 253/255 |MI"; (M.3) 1-acetyl-6b-cyano-2-indolinone: the specified compound is obtained from of 6b-cyano-2-indolinone (educt IM.2) and acetic anhydride, K value: 0.60 (silica gel, methylene chloride/methanol in a ratio of 50:1), 65 С14НаМ2О», mass spectrum: t/2 -199 IM-LEG.

Example MI 1-acetyl-3-(1-hydroxy-1-I(3-iodophenyl)methylene-b-chloro-2-indolinone 10.5 g. 1-acetyl-b-chloro-2-indolinone (educt M.1 ), 13.6 g of 3-iodobenzoic acid and 17.7 g of TBTU are added to 100 ml of dimethylformamide, after which 35 ml of triethylamine is added and the mixture is stirred for 12 hours at room temperature. After this period of time, the solvent is distilled off, the residue is mixed with water, and subjected to vacuum filtration , washed with a small amount of water, methanol and ether and dried under vacuum at 10026.

Yield: 12.9g (59906 from theory). 70 K value: 0.80 (silica gel, methylene chloride/methanol in a ratio of 9:1).

C47 We carry it with.

Mass spectrum: p/2 - 438/440 |M-NO.

Analogously to the MI example, the following compounds are obtained: (MI.1) 1-acetyl-3-/1-hydroxy-1-(4-methoxycarbonylmethylphenyl)methylene|i-b-fluoro-2-indolinone: the specified compound is obtained from 1-acetyl -b-fluoro-2-indolinone (educt M) and methyl ether (4-carboxyphenyl)acetic acid (the method of preparation of which is described in Teigapedgop, 53, 1997, pp. 7335-73401; (MI.2). 1-acetyl- 3-P1-hydroxy-1-(4-chlorophenyl)methylene|-b-chloro-2-indolinone: this compound is obtained from 1-acetyl-b-chloro-2-indolinone (educt M.1) and 4-chlorobenzoic acid ; (MI.3). 1-acetyl-3-(1-hydroxy-1-(3,4-dimethoxyphenyl)methylene|-b-chloro-2-indolinone: the specified compound is obtained from 1-acetyl-b-chloro- of 2-indolinone (educt M.1) and 3,4-dimethoxybenzoic acid; (MI.4). 1-acetyl-3-(1-hydroxy-1-(3,4-dimethoxyphenyl)methylene|)-6-cyano -2-indolinone: the indicated compound is obtained from 1-acetyl-b-cyano-2-indolinone (educt M.3) and 3,4-dimethoxybenzoic acid; (MI.5). 1-acetyl-3-P1-hydroxy- 1-(3-fluorophenyl)methylene|-6-fluoro-2-indolinone: this compound is obtained from 1-acetyl-b-fluoro- 2-indolinone (educt M) and 3-fluorobenzoic acid; Ge (MI.6). 1-acetyl-3-(1-hydroxy-1-(4--2-acetylaminoethyl)phenyl)methylene|-b-fluoro-2-indolinone: this compound is obtained from 1-acetyl-b-fluoro-2-indolinone (educt M) and 4-(2-acetylaminoethyl)benzoic acid, the preparation method of which is described in .). At. Spent boss, 65, 1943, p. 2377|; (MI.7). 1-acetyl-3-/1-hydroxy-1-(3-methoxycarbonylmethylphenyl)methylene-b-fluoro-2-indolinone: this compound is obtained from 1-acetyl-b-fluoro-2-indolinone (educt M) and -methyl (3-carboxyphenyl)acetic acid ester | the method of obtaining which is similar to that described in Teigapedgop, 53, 1997, pp. 7335-7340); sch (MI.8). 1-acetyl-3-|/1-hydroxy-1-(3-(M-tert-butoxycarbonylaminomethyl)phenyl)methylene-b-fluoro-2-indolinone: (Ce) this compound is obtained from 1-acetyl-6-fluoro -2-indolinone (educt M) and 3-(M-tert-butoxycarbonylaminomethyl)benzoic acid | the method of obtaining which is described in Teigapeagop, 53, F 1997, p. 7335-7340); - (MI.9). 1-acetyl-3-P1-hydroxy-1-(3-cyanomethylphenyl)methylene|-b-fluoro-2-indolinone: the specified compound is obtained from 1-acetyl-b-fluoro-2-indolinone (educt M) and (Z -carboxyphenyl)acetonitrile, the preparation method of which is described in .). Rgaki Spet., 340, 1998, pp. 367-3741|; " (MI.10). 1-acetyl-3-|/1-hydroxy-1-(4-(M-tert-butoxycarbonylaminomethyl)phenyl)methylene-b-fluoro-2-indolinone: the indicated compound is obtained Kk) 1-acetyl-b-fluoro-2 -indolinone (educt M) and -c 4-(M-tert-butoxycarbonylaminomethyl)benzoic acid, the method of preparation of which is described in Viogd. Honey. Spent Hek, 10, 2000, pp. 553-557; ," (MI.11). 1-acetyl-3-(1-hydroxy-1-(4-iodophenyl)methylene|)-b-fluoro-2-indolinone: the specified compound is obtained from 1-acetyl-b-fluoro-2-indolinone (educt M) and 4-iodobenzoic acid; (MI.12). 1-acetyl-3-(/1-hydroxy-1-(4-iodophenyl)methylene|-6b-chloro-2-indolinone: - And the specified compound is obtained from 1-acetyl-b-chloro-2-indolinone (educt M 1) and 4-iodobenzoic acid; (MI.13). 1-acetyl-3-(1-hydroxy-1-(3-iodophenyl)methylene|)-b-fluoro-2-indolinone: the indicated compound obtained from 1-acetyl-b-fluoro-2-indolinone (educt M) and 3-iodobenzoic acid; (e) (MI.14). 1-acetyl-3-(1-hydroxy-1-(4-(- 2-methoxycarbonylethyl)phenyl)methylene|-b-fluoro-2-indolinone: the specified compound is obtained from 1-acetyl-b-fluoro-2-indolinone (educt M) and 4--2-methoxycarbonylethyl)benzoic acid | production method which is described in Teigapeagop, 53, 1997, pp. 7335-7340); sl (MI.15). 1-acetyl-3-(1-hydroxy-1-(3--2-methoxycarbonylethyl)phenyl)methylene|-b-fluoro-2-indolinone: the specified compound is obtained from 1-acetyl-b-fluoro-2-indolinone ( educt M) and 3-(2-methoxycarbonylethyl)benzoic acid, the method of preparation of which is similar to that described in Teigapeagop, 53, 1997, pp. 7335-73401; (MI.16). 1-acetyl-3-/1-hydroxy-1-(3-(M-tert-butoxycarbonyl-2-aminoethyl)phenyl)methylene|-b-fluoro-2-indolinone: this compound is obtained from 1-acetyl-6- fluoro-2-indolinone (educt M) and

IF) 3-(M-tert-butoxycarbonyl-2-aminoethyl)benzoic acid, the method of preparation of which is described in Visogd. Honey. Spent ime) Hack, 10, 2000, pp. 553-557|; (MI.17). 1-acetyl-3-/1-hydroxy-1-(4-(M-tert-butoxycarbonyl-2-aminoethyl)phenyl)methylene|-b-fluoro-2-indolinone: 60 the specified compound is obtained from 1-acetyl-6 -fluoro-2-indolinone (educt M) and 4-(M-tert-butoxycarbonyl-2-aminoethyl)benzoic acid | the method of preparation of which is similar to that described in

Visogd. Honey. Spent And hey. 10, 2000, pp. 553-557; (MI.18). 1-acetyl-3-P1-hydroxy-1-(4-cyanophenyl)methylene|-b-chloro-2-indolinone: the indicated compound is obtained from 1-acetyl-b-chloro-2-indolinone (educt M. 1) and 4-cyanobenzoic acid; 65 (MI.19). 1-acetyl-3-|(1-hydroxy-1-(3-acetylaminomethylphenyl)methylene|-b-fluoro-2-indolinone: this compound is obtained from 1-acetyl-b-fluoro-2-indolinone (educt M) and Z-acetylaminomethylbenzoic acid

(obtained according to U. Med. Spet., 40, 1997, p. 4030-40521; (MI.20). 1-acetyl-3-(1-hydroxy-1. -(3-(2-ethoxycarbonylethyl)phenyl) )methylene|)-b-fluoro-2-indolinone: the indicated compound is obtained from 1-acetyl-b-fluoro-2-indolinone (educt M) and 3-(2-ethoxycarbonylethyl)benzoic

ACID, the method of obtaining which is similar to that described in Teigapeadgop, 53, 1997, pp. 7335-7340); (MI.21). 1-acetyl-3-/1-hydroxy-1-(4--2-methoxycarbonylethyl)phenyl)methylene|-b-chloro-2-indolinone: the specified compound is obtained from 1-acetyl-b-chloro-2-indolinone ( educt M.1) and 4-(2-methoxycarbonylethyl)benzoic acid, the method of obtaining which is similar to that described in Teigapeagop, 53, 1997, pp. 7335-73401; (MI.22). 1-acetyl-3-|/1-hydroxy-1-(4-(2-ethoxycarbonylethyl)phenyl)methylene|-b-fluoro-2-indolinone: 70 the specified compound is obtained from 1-acetyl-b-fluoro-2- indolinone (educt M) and 4-(2-ethoxycarbonylethyl)benzoic acid, the method of preparation of which is similar to that described in Teigapeagop, 53, 1997, pp. 7335-73401; (MI.23). 1-acetyl-3-(1-hydroxy-1-(3-methoxycarbonylmethyloxyphenyl)methylene|-b-fluoro-2-indolinone: the indicated compound is obtained from 1-acetyl-b-fluoro-2-indolinone (educt M) and C -Methoxycarbonylmethyloxybenzoic acid, the method of preparation of which is described in Teigapeagop I eChCegv, 39, 1998, pp. 8563-8566); (MI.24). 1-acetyl-3-(1-hydroxy-1-(4-methoxycarbonylmethyloxyphenyl)methylene|-b-fluoro-2-indolinone: the specified compound is obtained from 1-acetyl-b-fluoro-2-indolinone (educt M) and 4 -Methoxycarbonylmethyloxybenzoic acid, the method of obtaining which is similar to that described in Teigapeagop I eChCegz, 39, 1998, pp. 8563-8566); (MI.25). 1-acetyl-3-|/1-hydroxy-1-(3-(2-ethoxycarbonylethyloxy)phenyl)methylene-b-fluoro-2-indolinone: the specified compound is obtained from 1-acetyl-6-fluoro-2-indolinone ( educt M) and 3-(2-ethoxycarbonylethyloxy)benzoic acid, the preparation method of which is described in UUO 96/20173, p.b601; (MI.26). 1-acetyl-3-|/1-hydroxy-1-(4-(2-ethoxycarbonylethyloxy)phenyl)methylene-b-fluoro-2-indolinone: the specified compound is obtained from 1-acetyl-6-fluoro-2-indolinone ( educt M) and 4-(2-ethoxycarbonylethyloxy)benzoic acid (the method of its preparation is described in UUO 96/20173, p.581; (MI.27). 1-acetyl-3-(1-hydroxy-1-(4- (-2-methoxycarbonylethyl)phenyl)methylene|-6-bromo-2-indolinone: the specified compound is obtained from 1-acetyl-b6-bromo-2-indolinone (educt M.2) and 4--2-methoxycarbonylethyl)benzoin acid, the method of obtaining which is similar to that described in Teigapeagop, 53, 1997, pp. 7335-7340). (8)

Example MY 1-acetyl-3-(1-methoxy-1-(3-iodophenyl)methylene|-b-chloro-2-indolinone

A solution of 3.52 g of 1-acetyl-3-(1-hydroxy-1-(3-iodophenyl)methylene|-b-chloro-2-indolinone (MI educt) and 2.72 ml of isoethyldiisopropylamine in 8 VO ml of dichloromethane is mixed in portions with 2 ,3bg of trimethyloxonium tetrafluoroborate and stir for an hour at room temperature. After that, 1.4 ml of ethyldiisopropylamine and 1.2 g of trimethyloxonium tetrafluoroborate are again added and stirred for the next two hours at room temperature. Then it is extracted with water, the organic phase is dried over magnesium sulfate and concentrated to dryness.

The residue is recrystallized from ether and dried in a vacuum at 8020. me)

Yield: 2.40g (66905 from theory). Cha

Value of K. 0.60 (silica gel, petroleum ether/dichloromethane/ethyl acetate in the ratio 5:4:1).

SivNizZSIMO with.

Mass spectrum: p/2 - 438/440 |M-NO. "

Ill 185-18726.

Similarly to the example of MI! the following compounds are obtained: - c (MI.1). 1-acetyl-3-(/1-methoxy-1-(4-methoxycarbonylmethylphenyl)methylene|-b-fluoro-2-indolinone: and the indicated compound is obtained Kk! ,» 1-acetyl-3-(1-hydroxy-1 -(4-methoxycarbonylmethylphenyl)methylene|-b-fluoro-2-indolinone (Educt MI.1); (MII.2). 1-Acetyl-3-(1-methoxy-1-(4-chlorophenyl)methylene|) |-b-chloro-2-indolinone: the specified compound is obtained from 1-acetyl-3-|1-hydroxy-1-(4-chlorophenyl)methylene)|-b-chloro-2-indolinone (educt MI.2); - and (MII.3). 1-acetyl-3-|/1-methoxy-1-(3,4-dimethoxyphenyl)methylene|-b-chloro-2-indolinone: the specified compound is obtained from 1-acetyl-3 -/P-hydroxy-1-(3,4-dimethoxyphenyl)methylene|-b-chloro-2-indolinone (MI.3 educt); (o) (MII.4). 1-acetyl-3-(/1 -methoxy-1-(3,4-dimethoxyphenyl)methylene|-6-cyano-2-indolinone: 7 50 this compound is obtained from 1-acetyl-3-|1-hydroxy-1-(3,4-dimethoxyphenyl)methylene |-6-cyano-2-indolinone (educt MI.4); cl (MII.5). 1-acetyl-3-/1-methoxy-1-(3-fluorophenyl)methylene|-b-fluoro-2- indolinone: the specified compound is obtained from 1-acetyl-3-|1-hydroxy-1-(33-fluorophenyl)methylene)|-b-fluoro-2-indolinone (educt

MI.5); (MII.6). 1-acetyl-3-(/1-methoxy-1-(4--2-acetylaminoethyl)phenyl)methylene|-b-fluoro-2-indolinone: the specified compound is obtained Kk! 1-acetyl-3-(1-hydroxy-1-(4--2-acetylaminoethyl)phenyl)methylene|-b-fluoro-2-indolinone (educt MI.6); name) (MII.7). 1-acetyl-3-(1-methoxy-1-(3-methoxycarbonylmethylphenyl)methylene|)|-b-fluoro-2-indolinone: the specified compound is obtained Kk! bo /1-acetyl-3-(/1-hydroxy-1-(3-methoxycarbonylmethylphenyl)methylene|-b-fluoro-2-indolinone (educt MI.7); (MII.8). 1-acetyl-3- (/1-Methoxy-1-(3-(N-tert-butoxycarbonylaminomethyl)phenyl)methylene|-b-fluoro-2-indolinone: the specified compound is obtained Kk! 1-acetyl-3-(1-hydroxy-1-( 3-(M-tert-butoxycarbonylaminomethyl)phenyl)methylene|-b-fluoro-2-indolinone (educt MI.8); (MII.9). 1-acetyl-3-/1-methoxy-1-(3- cyanomethylphenyl)methylene|-b-fluoro-2-indolinone: this compound is obtained from 1-acetyl-3-/1-hydroxy-1-(3-cyanomethylphenyl)methylene|-b-fluoro-2-indolinone (educt MI. 9);

(MII.10). 1-acetyl-3-(/1-methoxy-1-(4-(M-tert-butoxycarbonylaminomethyl)phenyl)methylene-b-fluoro-2-indolinone: the specified compound is obtained Kk! 1-acetyl-3-(1- hydroxy-1-(4-(M-tert-butoxycarbonylaminomethyl)phenyl)methylene|-b-fluoro-2-indolinone (educt 85 ML); (MII.11). 1-acetyl-3-(1-methoxy-1 -(4-iodophenyl)methylene|-b-fluoro-2-indolinone: the indicated compound is obtained from 1-acetyl-3-/1-hydroxy-1-(4-iodophenyl)methylene1|-b-fluoro-2-indolinone ( educt

MI.11); (MII.12). 1-acetyl-3-(/1-methoxy-1-(4-iodophenyl)methylene|-b-chloro-2-indolinone: 70 the specified compound is obtained from 1-acetyl-3-(1-hydroxy-1-(4 -iodophenyl)methylene|-b-chloro-2-indolinone (educt

MI.12); (MII.13). 1-acetyl-3-(1-methoxy-1-(3-iodophenyl)methylene|-b-fluoro-2-indolinone: this compound is obtained from 1-acetyl-3-(1-hydroxy-1-(3-iodophenyl) )methylene1|-b-fluoro-2-indolinone (educt

MI.13); (MI.14)3. 1-Acetyl-3-(/1-methoxy-1-(3-(2-methoxycarbonylethyl)phenyl)methylene-b-fluoro-2-indolinone: the specified compound is obtained from Kk! 1-acetyl-3-(1-hydroxy- 1-(3-(2-methoxycarbonylethyl)phenyl)methylene|-b-fluoro-2-indolinone (educt MI.14); (MI.15). 1-acetyl-3-(/1-methoxy-1-( 4-(2-Methoxycarbonylethyl)phenyl)methylene-b-fluoro-2-indolinone: the specified compound is obtained from 1-acetyl-3-(1-hydroxy-1-(4-(-2-methoxycarbonylethyl)phenyl)methylene| -b-fluoro-2-indolinone (educt MI.15); (MII.16). 1-acetyl-3-(/1-methoxy-1-(4-(M-tert-butoxycarbonyl-2-aminoethyl)phenyl) )methylene|-b-fluoro-2-indolinone: the specified compound is obtained from Kk! 1-acetyl-3-(1-hydroxy-1-(4-(N-tert-butoxycarbonyl-2-aminoethyl)phenyl)methylene|-b -fluoro-2-indolinone (educt

MI.17); with (MII.17). 1-acetyl-3-(/1-methoxy-1-(3-(N-tert-butoxycarbonyl-2-aminoethyl)phenyl)methylene|-b-fluoro-2-indolinone: the indicated compound is obtained by Kk!i) 1- acetyl-3-(1-hydroxy-1-(3-(M-tert-butoxycarbonyl-2-aminoethyl)phenyl)methylene|-b-fluoro-2-indolinone (educt

MI.16); (MII.18). 1-Acetyl-3-(/1-methoxy-1-(3-acetylaminomethylphenyl)methylene|-b-fluoro-2-indolinone: using this compound, Kk! 1-acetyl-3-11-hydroxy-1-( 3-acetylaminomethylphenyl)methylene|-b-fluoro-2-indolinone (educt MI.19); c (MII.19). 1-acetyl-3-(/1-methoxy-1-(3-(2-ethoxycarbonylethyl) phenyl)methylene|-b-fluoro-2-indolinone: This compound is obtained by Kk! 1-acetyl-3-(1-hydroxy-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene|-b-fluoro-2 -indolinone (educt MI.20); me) (MII.20). 1-acetyl-3-(1-methoxy-1-(4-(-2-methoxycarbonylethyl)phenyl)methylene|-b-chloro-2- indolinone: the indicated compound is obtained from 1-acetyl-3-(1-hydroxy-1-(4-(-2-methoxycarbonylethyl)phenyl)methylene|-b-chloro-2-indolinone (educt MI.21); (MII.21). 1-Acetyl-3-(/1-methoxy-1-(4-(2-ethoxycarbonylethyl)phenyl)methylene|-b-fluoro-2-indolinone: the indicated compound is obtained by Kk! « 1-acetyl -3-(1-hydroxy-1-(4-(2-ethoxycarbonylethyl)phenyl)methylene|-b-fluoro-2-shdolinone (educt MI.22); with c (MII.22). 1-acetyl-3 -(/1-methoxy-1-(4-methoxycarbonylmethyloxyphenyl)methylene|)|-b-fluoro-2-indolinone :

And the specified compound is obtained Kk! and?" 1-acetyl-3-(1-hydroxy-1-(4-methoxycarbonylmethyloxyphenyl)methylene|i-b-fluoro-2-indolinone (educt MI.23); (MII.23). 1-acetyl-3-(/ 1-Methoxy-1-(3-methoxycarbonylmethyloxyphenyl)methylene|)|-b-fluoro-2-indolinone: the specified compound is obtained from Kk!-I 1-acetyl-3-(1-hydroxy-1-(3-methoxycarbonylmethyloxyphenyl)methylene |i-b-fluoro-2-indolinone (educt MI.24); (MII.24). 1-acetyl-3-(1-methoxy-1-(3-(2-ethoxycarbonylethyloxy)phenyl)methylene|-b -fluoro-2-indolinone: and, the specified compound is obtained Kk!

He» 1-acetyl-3-(1-hydroxy-1-(3-(2-ethoxycarbonylethyloxy)phenyl)methylene|-b-fluoro-2-indolinone (educt MI.25); (MII.25). 1- acetyl-3-(1-methoxy-1-(4-(2-ethoxycarbonylethyloxy)phenyl)methylene|-b-fluoro-2-indolinone: from the specified compound, Kk! sp 1-acetyl-3-(1-hydroxy- 1-(4-(2-ethoxycarbonylethyloxy)phenyl)methylene|-b-fluoro-2-indolinone (educt MI.26); (MII.26). 1-acetyl-3-(/1-methoxy-1-( 4-(-2-Methoxycarbonylethyl)phenyl)methylene-β6-bromo-2-indolinone: the indicated compound is obtained from 1-acetyl-3-(1-hydroxy-1-(4--2-methoxycarbonylethyl)phenyl)methylene| -6-bromo-2-indolinone (MI.27 educt).

An example of MIA

F) 1-acetyl-3-|(1-chloro-1-(4-cyanophenyl)methylene|-b-chloro-2-indolinone suspension 7.0 g of 1-acetyl-3-(1-chloro-1-( 4-cyanomethyl)phenyl)methylene|-b-chloro-2-indolinone (educt MI.18) and 6.39 g of phosphorus pentachloride in 150 ml of dioxane are stirred for two hours at 10020. After the addition of an additional 1.0 g of phosphorus pentachloride, they are stirred for the next 4 hours at 110 °C. Finally, the solvent is distilled off and the residue is washed with ethyl acetate.

Output: 4.5g (6195 from theory).

Value of K,: 0.70 (silica gel, methylene chloride/methanol in a ratio of 50:1).

SiovNioSiBM2O". 65 Example IH

Methods of synthesis of the compounds listed below are already described in (MUO 01/270811:

(IX.1) 4-(diethylaminomethyl)aniline, (IX.2) M-(2-dimethylaminoethyl)-M-methylsulfonyl-p-phenylenediamine, (IX.3) 3--dimethylaminomethyl)aniline, (IX.4) 4--(dimethylaminomethyl)aniline, (IX.5) 4--2-dimethylaminoethyl)aniline, (IX.6) 4-IM-(2-dimethylaminoethyl)-M-acetylamino|aniline, (IX.7). 4-IM-(3-dimethylaminopropyl)-M-acetylamino|aniline, (IX.8). 4-(M-dimethylaminocarbonylmethyl-M-methylsulfonyl)amino|aniline, 70 (IX.9) M-(4-aminophenyl)-M-methylmethanesulfonamide, (IX.10) M-(dimethylaminomethylcarbonyl)-M-methyl-p- phenylenediamine, (IX.11). hCh-(K2-dimethylaminoethyl)-carbonyl|-M-methyl-p-phenylenediamine, (IX.12) 4-(M-tert-butoxycarbonylaminomethyl)aniline, (IX.13). 4-(M-ethyl-M-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-(M-(2-dimethylaminoethyl)-M-methylamino)methylaniline, (IX.18) 4-(«М -methyl-M-tert-butoxycarbonylaminomethyl)aniline, (IX.19). M-K4-methylpiperazin-1-yl)umethylcarbonyl|-M-methyl-p-phenylenediamine, (IX.20) 4-(4-tert-butoxycarbonylpiperazin-1-ylmethyl)aniline, (IX.21) 4-(thiomorpholine -4-ylmethyl)aniline, (IX.22) 4-(pyrrolidin-1-ylmethyl)aniline, (IX.23) 4-(morpholin-4-ylmethyl)aniline, (IX.24) 4-(M- benzyl-M-methylaminomethyl)aniline, (IX.25) 4-("M-ethyl-M-methylaminomethyl)uaniline, and) (IX.26) 4-("M-(2-dimethylaminoethyl)-M-methylamino| aniline, (IX.27) 4-(M-propyl-M-methylamino)methylaniline.

Similarly to example IX, the following compounds are obtained: ю зо (IX.28). 4-IM-(2-(M-benzyl-M-methylamino)ethyl)-M-acetylamino|aniline, (IX.29) 4-amino-M-(2-dimethylaminoethyl)-M-methylbenzamide, c (IX. 30) 4-(4-methylpiperazin-1-ylcarbonyl)aniline, Ge (IX.31) 4--2-dimethylaminoethoxy)aniline, (IX.32). M-(4-dimethylaminobutylcarbonyl)-M-methyl-p-phenylenediamine, me) (IX.33). M-(3-dimethylaminopropyl)carbonyl)|-M-methyl-p-phenylenediamine. uh-

Preparation of final compounds

Example 1.0 3-2-11-(4--(M-methyl-M-methylsulfonylamino)anilino)-1-(3-iodophenyl)methylene|-6b-chloro-2-indolinone and 1-acetyl-3-(1 -methoxy-1-(3-iodophenyl)methylene)-6b-chloro-2-indolinone (MI educt) and O.5 g

M-methyl-M-methylsulfonyl-p-phenylenediamine (educt IX.9) is dissolved in 10 ml of dimethylformamide and stirred for 1 hour at 1202С. After cooling, 1.5 ml of piperidine is added to the reaction mixture and stirred for an hour at room temperature. Next, water is added, the precipitate that has fallen out is separated by vacuum filtration, washed with a small amount of water, methanol and ether, and finally dried in vacuum at 10090.

Yield: 0.9g (7495 from theory). -I Value of K,: 0.6 (silica gel, methylene chloride/methanol in a ratio of 9:1). ill 292-29496. i-o SozNioSiIIM5055. (o) Mass spectrum: pt/2 - 578/580 |M-NO. 7 50 Similarly to example 1.0, the following compounds of the general formula 1-1 are obtained: sl

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Example 2.0 where 3-2-(I1--4-(dimethylaminomethyl)anilino)-1-(4-cyanophenyl)methylene|-b-chloro-2-indolinone 1.07g 1-acetyl-3-(1-chloro- 1-(4-cyanophenyl)methylene|-b-chloro-2-indolinone (educt MI) and 0.54 g of 60 4-(dimethylaminomethyl)aniline (educt IX.4) are dissolved in 10 ml of dimethylformamide and stirred for 2 hours at 802C. After After cooling, ml of sodium hydroxide solution was added to the reaction mixture and stirred for 30 min at room temperature.After that, water was added and extracted three times with methylene chloride.

The combined organic phases are washed twice with water, dried over sodium sulfate, evaporated on a rotary evaporator, and the product is recrystallized from diethyl ether. because Output: 0.92g (7290 from theory).

Value of K,: 0.1 (silica gel, methylene chloride/methanol in a ratio of 9:1).

SoBNi SIM, O.

Mass spectrum: p/2 - 427/429 |M-NO.

Example 3.0 3-27-11--4--dimethylaminomethyl)anilino)-1-(4-iodophenyl)methylene|-b-fluoro-2-indolinone

3.5 g of 1-acetyl-3-(1-methoxy-1-(4-iodophenyl)methylene)-6-fluoro-2-indolinone (educt MI.11) and 1.6 g of 4-(dimethylaminomethyl)aniline (educt IX .4) dissolve in ZOml of dimethylformamide and stir for 2 hours at 12020. After cooling, the solvent is distilled off, and the residue is dissolved in ZOml of methanol and sodium methylate is added twice on the tip of a 70 spatula. After the formation of a yellow precipitate, it is separated from the solvent by vacuum filtration, the residue is washed with a small amount of methanol and ether, and finally dried in a vacuum at 10090.

Yield: 1.9g (4695 from theory).

Ku value: 0.3 (silica gel, methylene chloride/methanol in a ratio of 9:1).

Idle 243-246260.

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(G): aluminum oxide, methylene chloride/methanol in the ratio 19:1, (3): silica gel, methylene chloride/methanol/ammonia in the ratio 9:1:0.01, (I): silica gel, methylene chloride/methanol in the ratio 5: 1, (K): aluminum oxide, methylene chloride/ethanol in a ratio of 20:1, (L): silica gel, petroleum ether/ethyl acetate in a ratio of 1:1, (M): silica gel, petroleum ether/ethyl acetate in a ratio of 1:2.

Similarly to example 3.0, the following compounds of the general formula 1-36 are obtained:

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Ch ee ev She: ! S Shchi E : ; Ge) ; i i i i, I t / I Ko ; Y 1 her C, E her ; | | ! | Solvent systems: (A): silica gel, methylene chloride/methanol in a 9:1 ratio, "(B): silica gel, methylene chloride/methanol/ammonia in a 9:1:0.1 ratio.

Example 4.0 - with 3-2-(I1--4-(dimethylaminomethyl)anilino)-1-(3,4-dimethoxyphenyl)methylene|-6-cyano-2-indolinone" with 130 mg of 1-acetyl-3-(1 -methoxy-1-(3,4-dimethoxyphenyl)methylene)-6-cyano-2-indolinone (educt MIII.4) and 58 mg of 4-(dimethylaminomethyl)aniline (educt IX.4) are dissolved in 5 ml of dimethylformamide and stirred for 2 hours at 809C. After cooling, the solvent is distilled off and the residue is purified on a silica gel column using a mixture of methylene chloride/methanol in the ratio of 9:1 as an eluent. -and Output: 21mg (1295 from theory). c Value of K,: 0.35 (silica gel, methylene chloride/methanol in a ratio of 9:1).

Ill. 26596.

Me C27NovMaOz. of 50 Example 5.0 3-27-(1--4-(-MI-methyl-M-methylsulfonylamino)anilino)-1-(3-(2-methoxycarbonylvinyl)phenyl)methylene-b-chloro-2-yn sl dolinone 5 mg of 3-2-(1-(4-((M-methyl-M-methylsulfonylamino)anilino)-1-(3-iodophenyl)methylene|-b-chloro-2-indolinone (educt 1.0) and 14b0ml of methyl of acrylic acid ether is dissolved in 20 ml of acetonitrile and 11 ml of dimethylformamide, and 11 mg of palladium(I) acetate, 2 ml of triethylamine and 30 mg of tri-ortho-tolylphosphine are added to the mixture. The solution is stirred for 1 hour at 902 in a nitrogen atmosphere as a protective gas. After cooling, it is filtered through Celite. , the solvent is distilled off and the residue is purified on a silica gel column using a mixture of methylene chloride/methanol in the ratio of 20:1 as an eluent.

Output: 45Ω (84595 from theory). 60 K value: 0.30 (silica gel, toluene/ethyl acetate in a 1:1 ratio). ill. 228-23296.

С27НодСИМа5О55.

Mass spectrum: t/2 - 537/539 | MI.

Similarly to example 5.0, the following compounds of the general formula 1-5 are obtained: b5 and

IN SH5)

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"Solvent systems: (A): silica gel, methylene chloride/methanol in a ratio of 5:1, (B): silica gel, methylene chloride/ methanol/ammonia in the ratio 9:1:0.01.

Example 6.0 3-27-(1--4-dimethylaminomethylanilino)-1-(3-(-2-methoxycarbonylethyl)phenyl)methylene|-b-chloro-2-indolinone - with 1.0 g "from 3-2-11 --4--(dimethylaminomethyl)anilino)-1-(3-(2-methoxycarbonylvinyl)phenyl)methylene|-6b-chloro-2-indolinone (educt 5.1) is dissolved in 100 ml of methanol and 200 mg of 1090 palladium is added to charcoal as a catalyst. Hydrogenation is then carried out for two hours at room temperature and a hydrogen pressure of 5Opsig. After the reaction is complete, the catalyst is filtered off, the solvent is distilled off, and the residue is dried in vacuo at 10090. -i Yield: 30Omg (9095 from theory). c Value Ku, 0.40 (silica gel, methylene chloride/methanol in a ratio of 9:1).

Ill. 16026. (22) SovNovSIMzOz. ma 70 Mass spectrum: t/2 - 490/492 MANI". sp Similarly to example 6.0, the following compounds of the general formula 1-6 are obtained:

F) ime) 60 b5 vaye c

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E Shk Pn i i z I T i schu, NM ' ChMT I ; r ki she I! more

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And her drinking I t her: yati t--- I st shk: petottnt bed Ж vidkt naisiЖ Pe tzhtjnya-neyaenih "fena: penya and b

Solvent systems: (A): silica gel, methylene chloride/methanol in a ratio of 9:1, (B): silica gel, methylene chloride/methanol/ammonia in a ratio of 5:1:0.01.

Example 7.0 « 3-2-(I1--4-dimethylaminomethylanilino)-1-(4-aminomethylphenyl)methylene|)-b-chloro-2-indolinone 40 900 mg 3-2-(I1--4-dimethylaminomethylanilino)-1 -(4-cyanophenyl)methylene|-b-chloro-2-indolinone (educt 2.0) C is dissolved in 20 ml of methylene chloride, after which 30 ml of methanolic ammonia is added, and then 200 mg of Raney nickel "" as a catalyst. Next, hydrogenation is carried out for 2 h 15 min at at room temperature and a hydrogen pressure of B5Olbs/sq.in. " After completion of the reaction, the catalyst is filtered off, the solvent is distilled off, and the residue is washed with a small amount of methanol and diethyl ether. To isolate the base, the residue is dissolved in In. sodium chloride solution 45 g and extracted four times with a mixture of methylene chloride/methanol in a ratio of 9:11. The combined organic phases are washed with water and dried over sodium sulfate. The product is washed with a small amount of diethyl

Ge) of ether and dried in a vacuum.

Output: b8Omg (7595 from theory). me) Value of K,: 0.60 (silica gel, methylene chloride/methanol/ammonia in the ratio 9:1:0.1).

GI 50 Il 211-21426.

SoBNoBSIMO. sl Mass spectrum: t/2 - 433/435 MANI".

Example 8.0 3-2-(11-(4-(MI-(4-methylpiperazin-1-yl)umethylcarbonyl)-M-methylamino)anilino)-1-(4-aminomethylphenyl)methylene-b-chloro-2-indolinone

HF) 1.39 g t 1-acetyl-3-2-(1-(4-(M-(4-methylpiperazin-1-yl)umethylcarbonyl)-M-methylamino)anilino)-1-(4-cyanophenyl)methylene |-6-chloro-2-indolinone is dissolved in 20 ml of methylene chloride, after which 30 ml of methanolic ammonia is added, and then 200 mg of Raney nickel as a catalyst. Next, it is hydrogenated for 2 hours at room temperature and a hydrogen pressure of 60 BO pounds/sq.in. After completion of the reaction, the catalyst is filtered off, the solvent is distilled off, and the residue is washed with a small amount of methanol and diethyl ether. To isolate the base, the residue is dissolved in a solution of In. of sodium hydroxide and extracted four times with a mixture of methylene chloride/methanol in a ratio of 9:1.

The combined organic phases are washed with water and dried over sodium sulfate. The product is purified on a silica gel column using a gradient of methylene chloride and a mixture of methylene chloride/methanol/ammonia in the ratio of 65 VA:0.1 as an eluent. The product is washed with a small amount of diethyl ether and dried in a vacuum.

Output: 7OOmg (5495 from theory).

K value: 0.15 (silica gel, methylene chloride/methanol/ammonia in the ratio 9:1:0.1). ill. 232-23596.

Mass spectrum: t/2 - 544/546 MI".

Example 9.0 3-2-(I1--4-(dimethylaminomethyl)anilino)-1-(3-aminomethylphenyl)methylene|-6-fluoro-2-indolinone 2.12g 70... 3-27-(/1- (4--(Dimethylaminomethyl)anilino)-1-(3-(M-tert-butoxycarbonylaminomethyl)phenyl)methylene|)-b-fluoro-2-indolinone (educt 3.10) is dissolved in 5 Oml of methylene chloride and 1 Oml of trifluoroacetic acid is added. The mixture is stirred for hours at room temperature. After this period of time, the solvent is almost completely distilled off, the residue is dissolved in ethyl acetate and washed twice with 1N. sodium hydroxide solution.

The organic phase is dried over sodium sulfate, the solvent is evaporated on a rotary evaporator and the residue 75 is purified on a silica gel column using a mixture of methylene chloride/methanol/ammonia in the ratio 9:1:0.1 as an eluent. The product is washed with a small amount of diethyl ether and dried in a vacuum.

Yield: 1.77g (81905 from theory).

K value: 0.25 (silica gel, methylene chloride/methanol/ammonia in the ratio 9:1:0.1). ill 168-17596. 20 SoBNoBEM, O.

Mass spectrum: t/2 - 415 |M-NO.

Similarly to example 9.0, the following compounds of the general formula 1-9 are obtained: this is AK s i (Z o 30 sa - cm de 9)

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And PO, more And more Yi shi she s o t she. ren vo) i ! more: 1 part "Solvent systems: (A): silica gel, methylene chloride/methanol/ammonia in the ratio 9:1:0.1, (B): silica gel, methylene chloride/methanol/ammonia in the ratio 9:1:0 ,01, (B): silica gel, methylene chloride/methanol/ammonia in a ratio of 8:2:0.2, (D): reverse phase KR8, methanol/common salt solution (595th) in a ratio of 3:2.

Example 10.0 mg 3-27-(1--4-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-b-chloro-2-indolinone 9b0Omg 3-2-(1--4-dimethylaminomethylanilino) )-1-(3-(2-methoxycarbonylethyl)phenyl)methylene-b-chloro-2-indolinone and) (educt 6.0) is dissolved in 1 ml of ethanol and 5 ml of other sodium hydroxide solution. The mixture is stirred for 5 hours at room temperature. After cooling, add 5 ml of 1n. hydrochloric acid. The sediment that has fallen out is separated by vacuum filtration and then washed with water. Output: 83 Ohms (9595 from theory).

Ku value 0.50 (inverted phase of CRZ, methanol/common salt solution (595th) in a ratio of 4:1). with

Ill 210-21596. "at

C27NovSIMazOz.

Mass spectrum: t/2 - 476/478 MANI. F

Similarly to example 10.0, the following compounds of the general formula 1-10a are obtained:

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Tb7y IT ENUMVE 555 baNoVIb. o mno od There are 7 y ; Solvent systems: (A): reverse phase KRV8, methanol/common salt solution (595th) in a ratio of 41, (B): silica gel, methylene chloride/methanol in a ratio of 8:2, (B): silica gel, methylene chloride/methanol in a ratio of 5:1, (D): reversed phase KR8, methanol/common salt solution (595th) in a ratio of 3:2, (D): silica gel, methylene chloride/methanol in a ratio of 9:1, (E): reverse phase KRB8, methanol/common salt solution (595th) in a ratio of 7:3, (G): silica gel, methylene chloride/methanol/ammonia in a ratio of 9:1:0.1, (8) ( 3): aluminum oxide, methylene chloride/methanol in a ratio of 19:1, (I): reversed phase of KRZ, methanol/common salt solution (595th) in a ratio of 4:2, (K): silica gel, petroleum ether/ethyl acetate in 1-1 ratio, solvent (M): silica gel, methylene chloride/methanol in a 4:1 ratio.

Analogously to example 10.0, the following compounds of the general formula 1-106р are obtained: с (Се) ше ил- л Шко зей и: ж Я

I Janv from - : ve Kelovu 5 | and Iii fboryuunh | and to them VN. VE OKO rbN.- 95 Nim; BOM OO ONA and OO Me; | : With and shk is, And! live still chic ' | ! Oh! shi Z; so what ! with and ! in Me; ; Y and VE: ZI!

I and N. . K. i E I | H : 7 Solvent systems: (A): silica gel, methylene chloride/methanol in a ratio of 5:1, (B): silica gel, methylene chloride/methanol in a ratio of 9:1, (B): reverse phase KRB8, methanol/common salt solution ( 595th) in a ratio of 4:1. because Example 11.0

3-27-(1--4-dimethylaminomethylanilino)-1-(3-(2-carbamoylethyl)phenyl)methylene|-b-chloro-2-indolinone 480 mg /3-2-(I1-4-dimethylaminomethylanilino)-1 -(3-(2-carboxyethyl)phenyl)methylene)-b-chloro-2-indolinone (educt 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 the ammonium salt of M-hydroxysuccinimide is added. The mixture is stirred for 20 hours at room temperature. After distilling off the solvent, the residue is suspended in a small amount of ethyl acetate and water, filtered and then washed with water. Next, the residue is purified on a column packed with aluminum oxide (activity 2-3) using a mixture of methylene chloride/ethanol in the ratio of 20:11 as an eluent. The product is recrystallized from diethyl ether and dried under vacuum at 10090.

Output: Z7Omg (7895 from theory).

Value of K,: 0.40 (aluminum oxide, methylene chloride/ethanol in a ratio of 20:1). idl 222-22596.

C27H2; SIMA:O".

Mass spectrum: t/2 - 475/477 MANI.

Similarly to example 11.0, the following compounds of the general formula 1-11 are obtained: - "Ж cyst, and

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Ge) Example 12.0 3-2-(I1--4-dimethylaminomethylanilino)-1-(4-acetylaminomethylphenyl)methylene|-b-chloro-2-indolinone

Me, 100 mg of 3-2-(1--4-dimethylaminomethylanilino)-1-(4-aminomethylphenyl)methylene|)-b-chloro-2-indolinone (educt 7.0) is dissolved in 5 ml of methylene chloride and 5 ml of pyridine and at 0С add 20 μl of acetyl chloride. The mixture is stirred first for 1 hour at 02C, and then for the next 4 hours at room temperature. After that, another 20 μl of acetyl chloride is added and the mixture is stirred for 12 hours at room temperature. After this period of time, the solvent is distilled off and the residue is dissolved 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 sulfate. 22 After that, the solvent is evaporated on a rotary evaporator and the residue is washed with ether.

GF) Yield: 51mg (4795 from theory).

K value: 0.30 (silica gel, silica gel, methylene chloride/methanol/ammonia in the ratio 9:1:0.01). name) ill 219-22096. 60 Mass spectrum: p/2 - 473/475 |M-NO.

Similarly to example 12.0, the following compounds of the general formula 1-12 are obtained: b5 ke

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In other variants, the following acylating agents were used: benzoyl chloride, propionyl chloride, phenylacetyl chloride, cyclopropane carbonyl chloride, cyclobutane carbonyl chloride, pyridin-2-yl carbonyl chloride, pyridin-3-yl carbonyl chloride, pyridin-4-yl carbonyl chloride, cyclohexyl carbonyl 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. ise)

Example 13.0 Gee! 3-27-(1--4-trimethylammoniummethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-b6-fluoro-2-indolinone iodide

Dissolve 200 mg of 3-2-(1--4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-b-fluoro-2-indolinone (educt 10.1) in 40 ml of acetone and add 250 ml methyl iodide. The mixture is stirred for 20 hours at room temperature. After this period of time has passed, the sediment that has fallen out is separated by vacuum filtration. The product is dried in a vacuum at 8020.

Output: 200Ω (8395 from theory). WITH

Value of K. 0.50 (inverted phase of CRZ, methanol/common salt solution (595th) in a ratio of 4:1). with SovNozEMzOzi. z» Mass spectrum: t/2 - 474 MANI.

Similarly to example 13.0, the following compound of the general formula 1-13 is obtained: where

F E U sl S -o

I. Y | ME 1 Y | ; I am 60; BUT. ! ! and; her and I! b 7 Solvent system: (A): reverse phase KRB8, methanol/common salt solution (595th) in a ratio of 4:1. 65 Example 14.0 3-2-(1-(4-guanidinomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6-fluoro-2-indolinone iodide

17mg of 3-7-(/1-(4-aminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene-b-fluoro-2-indolinone (educt 10.50) is dissolved in 2 ml of tetrahydrofuran and 39mg of amidine nitrate is added 3,5-dimethylpyrazole-1-carboxylic acid and

ZZOml of diethylisopropylamine. The mixture is stirred for 1 hour under reflux.

After this period of time, the solvent is removed, water is added, and the sediment that has fallen out is separated by vacuum filtration. The product is dried at 8026.

Output: 15 Ohms (8195 from theory).

K value: 0.40 (silica gel, methylene chloride/methanol/acetic acid in a ratio of 5:1:0.1).

Idl 29096. 170 SovNo4EM5O»z.

Mass spectrum: t/2 - 474 MANI".

Similarly to example 14.0, the following compound of the general formula 1-14 is obtained:

In the same

DV

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Example 15 b

Ampoules with a dry preparation containing 75 mg of the active ingredient per 1 ml

Zo Composition: - active substance 75.0 mg mannitol 500 mg « water for injections up to 10.Oml - s Preparation: "z The active substance and mannitol are dissolved in water. After packing, the solution is subjected to lyophilization. The solution ready for use is obtained by dissolving the dry composition in water for injections.

Example 16

Ampoules with a dry preparation containing 35 mg of the active substance per 2 ml -| Composition: is, active substance Z5, Omg (is) mannitol 100, Omg water for injections up to 2, Oml with 50 s.

The active substance and mannitol are dissolved in water. After packaging, the solution is subjected to lyophilization. The ready-to-use solution is obtained by dissolving the dry composition in water for injections. 5B Example 17

A tablet with 5 mg of active substance (F; Composition: ime) (1) active substance 50 mg 60 (2) lactose 98 mg (3) corn starch 50 mg (4) polyvinylpyrrolidone 5 mg (5) magnesium stearate 2, 0mg 215, Omega 65 Obtaining:

Ingredient (1) is mixed with ingredients (2) and (3) and the mixture is granulated using an aqueous solution of ingredient (4). Add ingredient (5) to the dried granulate. From this mixture, two-flat tablets with a two-sided facet and a one-sided notch are pressed.

Tablet diameter: 9 mm.

Example 18

A tablet with 35 mg of the active substance

Composition: (1) active substance Z50, Omg (2) lactose 136, Omg (3) corn starch 80, Omg (4) polyvinylpyrrolidone ZO, Omg (5) magnesium stearate 4 Omg, 600 OMG

Obtaining:

Ingredient (1) is mixed with ingredients (2) and (3) and the mixture is granulated using an aqueous solution of ingredient (4). Add ingredient (5) to the dried granulate. From this mixture, two-flat tablets with a two-sided facet and a one-sided notch are pressed. 720 Tablet diameter: 12 mm.

Example 19

Capsules with 5mg of active ingredient

Ingredients: (1) active substance 50.Omg Ge) (2) corn starch, dried 58.Omg (3) lactose, powder 50.Omg (4) magnesium stearate 2.0mg 160.Omg

Obtaining:

Ingredient (1) is ground together with ingredient (3). A mixture of ingredients (2) and (4) is added to this mixture obtained by rubbing with intensive stirring. Finally, this powder mixture is packed in a machine d for filling capsules into hard gelatin detachable capsules of size 3.

Example 20 -

Capsules with 35 mg of active substance

Composition: (1) active substance Z50, Omg h (2) corn starch, dried 46, Omg h s (3) lactose, powdered ZO, Omg h (4) magnesium stearate 4, Omg h?

AZO, Omg

Preparation: - Ingredient (1) is ground together with ingredient (3). A mixture of ingredients (2) and (4) is added to this mixture obtained by rubbing with intense mixing. At the end, this powder mixture is packaged in a machine for filling capsules into hard gelatin detachable capsules of size 0. (o) Example 21 7 50 Suppositories with 100 mg of active substance

Composition of 1 suppository: 1 ml of active substance 100.Omg polyethylene glycol (MM 1500) 600.Omg 556 polyethylene glycol (MM 6000) Or Omg polyethylene sorbitan monostearate /840.Omg

IF) 2000, Omg name)

Preparation: polyethylene glycol is melted together with polyethylene sorbitan monostearate. At 40 9C, the crushed active ingredient is homogeneously dispersed in the resulting molten mass. After that, the molten mass is cooled to 382 and poured into slightly cooled forms for suppositories.

Similarly to the above examples, the following compounds can also be obtained: (in 65 3-27-(/1-(4--M-(2-dimethylaminoethyl)-M-methylsulfonylamino)anilino)-1-(4-(2-carboxyethyl )phenyl)methylene|-6b-chloro-2-indolinone,

3-27-11--4--M-(dimethylaminomethylcarbonyl)-M-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6b-chloro-2-yn dolinone, I C 3 -27-(11--4-(-M-(2-dimethylaminoethyl)-M-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6b-chloro-2-indolino n, (4) 3-2-11-(4-(M-(2-methylaminoethyl)-M-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-b-chloro-2-indolinone , (5) about 3-2-11-(4-(«M-(3-dimethylaminopropyl)-M-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-b-chloro- 2-indolinone, (6) 3-27-(11--4-(M-(3-methylaminopropyl)-M-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|)| -b-chloro-2-indolino n, 9 (7). 3-2-11-(4--3-dimethylaminopropyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6b-chloro-2-indolinone, (8). 3-2-(1-(4-ethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene|)-b-chloro-2-indolinone, (9). 3-2-(/1-(4-methylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6b-chloro-2-indolinone, (10) 3-27-(11-(4- (M-(4-methylpiperazin-1-ylmethylcarbonyl)-M-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6-chloro-2-indolinone, (11). 3-2 -(1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|)-b-chloro-2-indolinone, (12) 3-27- (11--4-(-M-(3-dimethylaminopropyl)-M-methylsulfonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6b-chloro ch -2-indolinone, (13) o 3-27-(1--4--M-(2-dimethylaminoethyl)-M-propylsulfonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene-b-chloro-2-Indolinone, ( 143. 3-2-(11-(4-aminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6b-chloro-2-indolinone, yzo (153. 3-2-1-( 3-(methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-b-chloro-2-indolinone, (16). 3-2-/11-(3-(-2-dimethylaminoethyl) )anilino)-1-(4-(2-carboxyethyl)phenyl)methylene-b-chloro-2-indolinone, c (17). 3-2-(1-(3--3-dimethylaminopropyl)anilino)-1 -(4-(2-carboxyethyl)phenyl)methylene|i-b-chloro-2 -indolinone, Ge (18) 3-2-11--4--H-(dimethylaminocarbonylmethyl)-M-methylsulfonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene-ime) b-chloro- 2-indolinone, i- (19) 3-27-(1--4--"M-methyl-M-methylsulfonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-b-chloro -2-indolinone, (20). 3-2-11-(4-(-(M-methyl-M-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|)-6b-chloro-2-indolinone, « (21 ) 3-27-(11-(4-(-M-(M-(2-dimethylaminoethyl)-M-methylaminomethylcarbonyl)-M-methylamino)anilino)-1-(4-(2-carboxyethyl)f with c enyl (22). )-6b-chloro-2-indolinone, "" (23) 3-M-(1--4-(-«M-(2-dimethylaminoethylcarbonyl)-M-methylamino)anilino)-1-(4-(2 -carboxyethyl)phenyl)methylene-b-chloro-2-indolinone, - (24) 3-27-(11--4-(-M-(2-dimethylaminoethyl)-M-methylaminomethyl)anilino)-1-( 4-(2-carboxyethyl)phenyl)methylene-b-chloro-2-indse)olinone,

Ge" (25). 3-2-(/1-(4--2-dimethylaminoethoxy)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-b-chloro-2-indolinone, (26) 20 3-27 -(11--4-(-M-(4-dimethylaminobutylcarbonyl)-M-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6b-chloro-2-sp indolinone, (27 ) 3-27-(11--4--M-(3-dimethylaminopropylcarbonyl)-M-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6b-chloro-2-Indolinone, (28). 3-2-(11-(4-(methylethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6b-chloro-2-indolinone,

F) (29). 3-2-(/1-(4-(methylpropylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-b-chloro-2-indolinone, ka (30). 3-2-( 11-(4-(methylbenzylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|i-b-chloro-2-indolinone, (31) in 3-27-(11--4-( -"M-(2-dimethylaminoethyl)-M-methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenylmethylene|-6b-chloro-2-indolinone, (32). 3-2-(1- (4-(azetidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|)-b-chloro-2-indolinone, (33). 3-2-(1-(4 -(4-methylpiperazin-1-yl)methyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|)-b-chloro-2-indolinone, (34). 3-2-11-( 4-(piperazin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-b-chloro-2-indolinone, 65 (35). 3-2-(1-(4- (morpholin-4-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-b-chloro-2-indolinone, (36). 3-2-(1-(4-(thiomorpholin- 4-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-b-chloro-2-indolinone,

(37). 3-2-(1-(4-(imidazol-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|)-6b-chloro-2-indolinone, 3-27-(11 --4-(-«M-(2-dimethylaminoethyl)-M-methylsulfonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene-b-chloro-2-Indolinone, (39) 3-27 -11--4--M-(dimethylaminomethylcarbonyl)-M-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-6b-chloro-2-yn dolinone, (40) 70 3- 27-(11--4-(-M-(2-dimethylaminoethyl)-M-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-6b-chloro-2-indolino n, ( 41) 3-27-(11--4-(M-(2-methylaminoethyl)-M-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-6b-chloro-2-indolinone , (42) 3-27-11-(4-(-M-(3-dimethylaminopropyl)-M-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene-b-chloro-2- indolinone, (43) 3-27-(11--4-(M-(3-methylaminopropyl)-M-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|)|-b -chloro-2-indolino n, (44). 3-7-(1-(4-(3-dimethylaminopropyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|i-b-chloro-2-indolinone, (45). 3-2- (/1-(4-ethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene|)-b-chloro-2-indolinone, (46). 3-2-(/1--4-methylaminomethylanilino )-1-(3-(2-carboxyethyl)phenyl)methylene|-b-chloro-2-indolinone, (47) 3-27-(11-(4-(M-(4-methylpiperazin-1-ylmethylcarbonyl) -M-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-6- chloro-2-indolinone, (48). 3-2-(1-(4-(4-methylpiperazine) -1-ylcarbonyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|)-b-chloro-2-indolinone, i) (49) 3-27-(11--4-(-М -(3-dimethylaminopropyl)-M-methylsulfonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-6b-chloro-2-indolinone, yzo (50) 3-27-(1-- 4--M-(2-dimethylaminoethyl)-M-propylsulfonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene-b-chloro-2c-Indolinone, Ge (51). 3-2-(1-(4-aminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-6b-chloro-2-indolinone, (52). 3-2-1-(3-- dimethylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|)-b-chloro-2-indolinone, me) (53). 3-2-[11-(3-(methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-b-chloro-2-indolinone, i- (54). 3-2-(11-(3--2-dimethylaminoethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene-b-chloro-2-indolinone, (55). 3-2-(1-(3--3-dimethylaminopropyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|i-b-chloro-2-indolinone, (56). 3-2-(11-(4--2-dimethylaminoethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene-b-chloro-2-indolinone, « (57) 3-2-11- -4-(-"M-(dimethylaminocarbonylmethyl)-M-methylsulfonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene-z b-chloro-2-indolinone, - (58) and?" 3-27-(1--4--«M-methyl-M-methylsulfonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-b-chloro-2-indolinone, (59). 3-2-(11-(4-(-(M-methyl-M-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|)-6b-chloro-2-indolinone, (60 ). 61) 3-27-(11-(4-(-M-(M-(2-dimethylaminoethyl)-M-methylaminomethylcarbonyl)-M-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl) )methylene|-6b-chloro-2-indolinone,

Ge" (62). 3-2-(/1-(4--2-diethylaminoethylsulfonyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|)-6b-chloro-2-indolinone, (63) 20 3- 27-(11--4-(-M-(2-dimethylaminoethylcarbonyl)-M-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene-b-chloro-2-y sp ndolinone, ( 64) 3-27-(11--4-(-M-(2-dimethylaminoethyl)-M-methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene-b-chloro-2-inde olinone, (65). 3-2-(/1-(4--2-dimethylaminoethoxy)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-b-chloro-2-indolinone, o (66) ka 3-2 -11-(4-(4-(4-dimethylaminobutylcarbonyl)-M-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-b-chloro-2-indolinone, in (67) 3 -2-11-(4-(«M-(3-dimethylaminopropylcarbonyl)-M-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-b-chloro-2-Indolinone, (68 ). 3-2-(11-(4-(methylethylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-6b-chloro-2-indolinone, (69). 3-2-(/1 -(4-(methylpropylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-b-chloro-2-indolinone, 65 (70). 3-2-(11-(4-(methylbenzylaminomethyl) )anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|i-b-chloro-2-indolinone, (72)

3-27-(11--4-(-«M-(2-dimethylaminoethyl)-M-methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenylmethylene|-6b-chloro-2-indolinone,

(73). 3-2-(1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene-b-chloro-2-indolinone,

(74). 3-2-(11-(4-(azetidin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|)-b-chloro-2-indolinone,

(75). 3-2-(1-(4-(4-methylpiperazin-1-yl)methyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|)-b-chloro-2-indolinone,

(76). 3-2-11-(4-(piperazin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-b-chloro-2-indolinone,

(77). 3-2-(1-(4-(morpholin-4-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-b-chloro-2-indolinone,

(78). 3-2-(1-(4-(thiomorpholin-4-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-b-chloro-2-indolinone,

70 (79). 3-2-(1-(4-(imidazol-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|)-6b-chloro-2-indolinone,

(80) 3-27-(1--4-(-M-(2-methylaminoethyl)-M-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6b-fluoro-2 -indolinone,

(81) 3-27-11--4-(H-(3-methylaminopropyl)-M-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene-b-fluoro-2-indolino n ,

9 (82). 3-2-(11-(4-(3-dimethylaminopropyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-b-fluoro-2-indolinone,

(83). 3-2-(/1-(4-ethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene|)-b-fluoro-2-indolinone,

(84) 3-27-(11--4-(-M-(3-dimethylaminopropyl)-M-methylsulfonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-b-fluoro

-2-indolinone,

(85) 3-27-(1--4-(-M-(2-dimethylaminoethyl)-M-propylsulfonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene-b-fluoro-2- indolinone,

(86). 3-2-(I1-(3-(methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene-b-fluoro-2-indolinone,

(87). 3-2-(I1-(3--2-dimethylaminoethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-b-fluoro-2-indolinone,

(88). 3-2-(1-(3-(3-dimethylaminopropyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-b-fluoro-2-indolinone, and)

(89) 3-2-11--4-(-"M-(dimethylaminocarbonylmethyl)-M-methylsulfonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene-b-fluoro-2-indolinone, (90) 3-2-(1-(4--M-methyl-M-methylsulfonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-b-fluoro-2-indolinone, with

(91) 3-27-(11-(4-(-M-(M-(2-dimethylaminoethyl)-M-methylaminomethylcarbonyl)-M-methylamino)anilino)-1-(4-(2-carboxyethyl)f enyl)methylene|-b-fluoro-2-indolinone, me)

(92). 3-2-(1-(4--2-diethylaminoethylsulfonyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-b-fluoro-2-indolinone, i-

(93). 3-2-(I1-(4--2-dimethylaminoethoxy)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene-b-fluoro-2-indolinone,

(94) 3-27-(11--4-(-M-(3-dimethylaminopropylcarbonyl)-M-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6b-fluoro- 2 -indolinone, "

(95). 3-2-(11-4-(methylethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene-b-fluoro-2-indolinone, from c (96). 3-2-(11-«(4-(methylpropylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|)|-b-fluoro-2-indolinone, . (97). (98) 2-(1-(4--azetidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-b-fluoro-2-indolinone, (99). 3-2-( I1-(4-(piperazin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene-b-fluoro-2-indolinone, (100). 3-2-(11-(4 -(morpholin-4-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-b-fluoro-2-indolinone, -I (101). 3-2-11-(4-( thiomorpholin-4-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-b-fluoro-2-indolinone, (102) ik 3-27-(11--4-(-«М -(2-dimethylaminoethyl)-M-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-6b-fluoro-2-indolino (22) H, (103) and 3-27-( 1--4-(-M-(2-methylaminoethyl)-M-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-6b-fluoro-2-indolinone, c (104) 3 -27-(11-(4-(M-(3-methylaminopropyl)-M-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene-b-fluoro-2-indolino n, (105 ). 3-2-(1-4-(3-dimethylaminopropyl)anilino)-1-(3-(2-carboxyethyl)uphenyl)methylene|-b-fluoro-2-indol non, (106). 3-2-(1-(4-ethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-b-fluoro-2-indolinone, iF) (107) ka 3-2-(1-( 4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-b-fluoro-2-indolinone, (108) in 3-2-H1-(4- (m-(3-dimethylaminopropyl)-M-methylsulfonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene-6-fluoro-2-indolinone,

(109) 3-27-(1--4-(-M-(2-dimethylaminoethyl)-M-propylsulfonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene-b-fluoro-2- indolinone,

65 (110). 3-2-(11-(3-"methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-b-fluoro-2-indolinone,

(111). 3-2-11-(3--2-dimethylaminoethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene-b-fluoro-2-indolinone,

(112). 3-2-(11--3-(3-dimethylaminopropyl)anilino)-1-(3-(2-carboxyethyl)uphenyl)methylene|-b-fluoro-2-indolinone,

3-2-11--4-(M-(dimethylaminocarbonylmethyl)-M-methylsulfonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene-

/ 8-fluoro-2-indolinone,

(114) 3-27-(11--4-(-«M-methyl-M-methylsulfonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene-b-fluoro-2-indolinone,

(1153. 3-2-(11-(4--(M-methyl-M-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methyleneI-b-fluoro-2-indolinone,

(116)

70 3-27-(11-(4-(-M-(M-(2-dimethylaminoethyl)-M-methylaminomethylcarbonyl)-M-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene |-b-fluoro-2-indolinone,

(117). 3-2-(1-(4--2-diethylaminoethylsulfonyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-6b-fluoro-2-indolinone,

(118) 3-27-11--4-(-H-(2-dimethylaminoethylcarbonyl)-M-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene-b-fluoro-2-i ndolinone,

(119) 3-27-(11--4-(-«M-(2-dimethylaminoethyl)-M-methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene-b-fluoro-2 -ind olinone,

(120). 3-2-(1-(4--2-dimethylaminoethoxy)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-b-fluoro-2-indolinone,

(121). 3-2-(11-(4--"methylethylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-b-fluoro-2-indolinone,

(122). 3-2-(11--4-(methylpropylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|)|-b-fluoro-2-indolinone,

(123). 3-2-(1-(4--"methylbenzylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-b-fluoro-2-indolinone,

(124). 3-2-(1-(4-(diethylaminomethyl)anilino)-1-(3 -(2-carboxyethyl)phenyl)methylene|)-b-fluoro-2-indolinone,

(125). 3-2-(1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-b-fluoro-2-indolinone, sc

(126). 3-2-(1-(4-(azetidin-1-ylmethyl)anilino)-1-(3 -(2-carboxyethyl)phenyl)methylene|-b-fluoro-2-indolinone,

(127). 3-2-(11-(4-(piperazin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-b-fluoro-2-indolinone, and)

(128). 3-2-11-(4-(morpholin-4-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-b-fluoro-2-indolinone,

(129). 3-2-(11-(4-(thiomorpholin-4-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-b-fluoro-2-indolinone,

(130) yuzo 3-27-(11--4-(-«M-(2-dimethylaminoethyl)-M-methylsulfonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene-6-bromo -2 - Indolinon, p

(131) "o 3-2-11--4--"M-(dimethylaminomethylcarbonyl)-M-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|)-b-bromo-2 -i ndolinon, Me

(132) and - 3-2-11-44-(M-(2-dimethylaminoethyl)-M-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6-bromo-2- indolino n, (133) 3-27-(1--4-(-M-(2-methylaminoethyl)-M-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|)|- 6-bromo-2-indolinone, « from (38) 2 s 3-27-(11--4-(-M-(3-dimethylaminopropyl)-M-acetylamino)anilino)-1-(4-(2- carboxyethyl)phenyl)methylene-6-bromo-2-indolinone, :z" (135) 3-27-(1--4-(M-(3-methylaminopropyl)-M-acetylamino)anilino)-1-( 4-(2-carboxyethyl)phenyl)methylene)|-6-bromo-2-indolino n, -I shchi (136). 3-2-(11-(4-(3-dimethylaminopropyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6-bromo-2-indolinone, (137). 3-2-( /1-(4-ethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6-bromo-2-indolinone, and, (138). 3-2-(1-(4-methylaminomethylanilino) -1-(4-(2-carboxyethylphenyl)methylene|-6-bromo-2-indolinone, b (139) 500 3-7-114(4-(«M-(4-methyltperazin-1-ylmethylcarbonyl)-M -methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene)-6-6 derom-2-indolinone, c (140) 3-27-(1-(4-(4-methylpiperazine- 1-ylcarbonyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene I-6-bromo-2-indolinone, (141) in C-2-I1-(4-(M-(3-dimethylaminopropyl) -M-methylsulfonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene)-6-bromo-2-indolinone, iF) (142) ka 3-2-11--4-(H-( 2-dimethylaminoethyl)-M-propylsulfonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6-bromo-2-indolinone, in (143). 3-2-(/1-(4 -aminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene|)-6-bromo-2-indolinone,

(144). 3-27-(1-(3-(dimethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6-bromo-2-indolinone,

(145). 3-2-11-(3-"methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6-bromo-2-indolinone,

(146). 3-2-(14(3-2-dimethylaminoethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene-6-bromo-2-indolinone,

(147). 3-2-(1--3-(3-dimethylaminopropyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene-6-bromo-2-indolinone,

65 (148). 3-2-11-(4--2-dimethylaminoethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6-bromo-2-indolinone,

(149)

3-2-11--4-(-"M-(dimethylaminocarbonylmethyl)-M-methylsulfonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene-b-bromo-2-indolinone, (150) 3-27-(1--4-(-«M-methyl-M-methylsulfonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|i|-6-bromo-2-indolinone, ( 151). 3-2-(1-(4--(M-methyl-M-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene)|-6b-bromo-2-indolinone, (1523). 3-2-(1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|)|-6-bromo-2-indolinone , (153) 3-27-(11-(4-(-M-(M-(2-dimethylaminoethyl)-M-methylaminomethylcarbonyl)-M-methylamino)anilino)-1-(4-(2-carboxyethyl)f 70 enyl)methylene-b6-bromo-2-indolinone, (154). 3-2-(1-(4--2-diethylaminoethylsulfonyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|- 6-bromo-2-indolinone, (155) 3-27-(11-(4-(MI-(2-dimethylaminoethylcarbonyl)-M-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene |)-6-bromo-2- indolinone, (156) 3-27-(11--4-(-M-(2-dimethylaminoethyl)-M-methylaminomethyl)anilino)-1-(4-(2-carboxyethyl) )phenyl)methylene-6-bromo-2-indolinone, (157). 3-2-(/ 1-(4--2-dimethylaminoethoxy)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6-bromo-2-indolinone, (158) 3-27-(11--4-( -"M-(4-dimethylaminobutylcarbonyl)-M-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6-bromo-2-indolinone, (159) 3-27-(11- -4-(-M-(3-dimethylaminopropylcarbonyl)-M-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6-bromo-2-Indolinone, sc (160). 3-2-(11-4-(methylethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6-bromo-2-indolinone, (161). 3-2-(I1-(4-(methylpropylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6-bromo-2-indolinone, i) (162). 3-2-(1-(4--"methylbenzylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|i|-6-bromo-2-indolinone, (163). 3-2- (/1-(4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6-bromo-2-indolinone, (164) yzo 3-27-(11--4 --M-(2-dimethylaminoethyl)-M-methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenylmethylene|-6-bromo-2-indolinone, c (165). 3-2-11- (4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene)-6-bromo-2-indolinone, Ge (166). 3-2-(1-(4 --azetidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6-bromo-2-indolinone, (167). 3-2-(1-(4-( 4-methylpiperazin-1-yl)methyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|i|-6-bromo-2-indolinone, me) (168). 3-2-(1 -(4-(piperazin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6-bromo-2-indolinone, i- (169). 3-2-(11- (4-(morpholin-4-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6-bromo-2-indolinone, (170). 3-2-11-(4-( thiomorpholin-4-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene)-6-bromo-2-indolinone, (171). 3-2-11-(4-(imidazo 1-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6-bromo-2-indolinone, (172). 3-M-(1-4-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene)|-6-bromo-2-indolinone, « i TZ) 2 s 3-27-(11-- 4-(-"M-(2-dimethylaminoethyl)-M-methylsulfonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene-6-bromo-2-Indolinone, :z" (179 3-27 -11--4--«M-(dimethylaminomethylcarbonyl)-M-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-6-bromo-2-indolinone, -I (175) so 3-27-(11--4-(-«M-(2-dimethylaminoethyl)-M-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-6-bromo-2- indolino n, b (176) more 5o 0 Z-7-140(4-(M-(2-methylaminoethyl)-Mm-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|)- 6b-bromo-2-indolinone, (177) sp 3-27-(11--4-(-M-(3-dimethylaminopropyl)-M-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl )methylene-6-bromo-2-indolinone, (178) 3-27-(1--4-(M-(3-methylaminopropyl)-M-acetylamino)anilino)-1-(3-(2-carboxyethyl) )phenyl)methylene)|-6-bromo-2-indolino n,

F) (179). 3-2-(11-(4-(3-dimethylaminopropyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-6-bromo-2-indolinone, ka (180). 3-2- (/1-(4-ethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene|)-6-bromo-2-indolinone, (181). 3-2-11 -(4-methylaminomethylanilino)- 1-(3-(2-carboxyethyl)phenyl)methylene|-6-bromo-2-indolinone, 60 (182) 3-27-(11-(4-(M-(4-methylpiperazin-1-ylmethylcarbonyl)- M-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-6-bromo-2-indolinone, (183) 3-27-(1-(4-(4-methylpiperazine-1- ylcarbonyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methyleneI-6-bromo-2-indolinone, 65 (184) 3-27-(11--4--M-(3-dimethylaminopropyl)- M-methylsulfonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-6-bromo

-2-indolinone, 3-27-(1--4-(-M-(2-dimethylaminoethyl)-M-propylsulfonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene-6-bromo- 2-indolinone, (186). 3-2-(1-(4-aminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene)-6-bromo-2-indolinone, (187). 3-2-11-(3--dimethylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-6-bromo-2-indolinone, (188). 3-2-(1-(3 -«methylaminomethyl)anilino)-1-(3 -(2-carboxyethyl)phenyl)methylene|-6-bromo-2-indolinone, (189). 3-2-(I1-(3--2-dimethylaminoethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|)|-6-bromo-2-indolinone, 70 (190). 3-2-(1-(3-(3-dimethylaminopropyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-6-bromo-2-indolinone, (191). 3-2-( I1-(4--2-dimethylaminoethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|)|-6-bromo-2-indolinone, (192) 3-2-11--4- (-"M-(dimethylaminocarbonylmethyl)-M-methylsulfonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene-b-bromo-2-indolinone, (193) 3-27-(1--4 -(-«M-methyl-M-methylsulfonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|i|-6-bromo-2-indolinone, (194). 3-2-(1 -(4--(M-methyl-M-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene)|-6b-bromo-2-indolinone, (195). 3-2-( 1-(4-(1-methylimidazol-2-yl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|)|-6-bromo-2-indolinone, (196) 3-27-( 11-(4-(-M-(M-(2-dimethylaminoethyl)-M-methylaminomethylcarbonyl)-M-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene-b6-bromo-2 -indolinone, (197). 3-2-(1-(4--2-diethylaminoethylsulfonyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-6-bromo-2-indolinone, (198 ) 3-27-(11--4-(-M-(2-dimethylaminoethylcarbonyl)-M-methylamino)ani lino)-1-(3-(2-carboxyethyl)phenyl)methylene-6-bromo-2-indolinone, (99) and) 3-27-(11--4-(-M-(2-dimethylaminoethyl) )-M-methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene-6-bromo-2-indolinone, (200). 3-2-(I1-(4--2-dimethylaminoethoxy)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-6-bromo-2-indolinone, yuzo (201) 3-27- (11--4-(-"M-(4-dimethylaminobutylcarbonyl)-M-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-6-bromo-2-s indolinone, Ge ( 202) 3-27-(11--4-(-M-(3-dimethylaminopropylcarbonyl)-M-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-6-bromo-2 me ) -Indolinone, i- (203). 3-2-(I1-4-(methylethylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-6-bromo-2-indolinone, (204 ). 3-2-(I1-4-(methylpropylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-6-bromo-2-indolinone, (205). 3-2-(1 -(4--"methylbenzylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|i|-6-bromo-2-indolinone, (206). 3-2-(/1-(4-(diethylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-6-bromo-2-indolinone, « zo (FO) 2 s 3-27 -(11--4--M-(2-dimethylaminoethyl)-M-methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenylmethylene|-6-bromo-2-indolinone, ;" (208) 3-2-(1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene)-6-bromo-2-indolinone, (209). 3- 2-(1-(4--azetidin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-6-bromo-2-indolinone, (210). 3-2-( 1-(4-((4-methylpiperazin-1-yl)methyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|i|-6-bromo-2-indolinone, -I (211) 3-2-(1-(4-(piperazin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene)|-6b-bromo-2-indolinone, (2123. 3- 2-11-"(4-(morpholin-4-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-6-bromo-2-indolinone, ik (213). 3-2- 11-(4-(thiomorpholin-4-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene)-6-bromo-2-indolinone,

Ge" (214). 3-2-11-(4-(imidazol-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-6-bromo-2-indolinone, (215). 3-2-(/1--4-dimethylaminomethylanilino)-1-(4-carboxymethylaminophenyl)methylene-b-fluoro-2-indolinone, yu (216). 3-2-(/1--4-dimethylaminomethylanilino)-1-(3-carboxymethylaminophenyl)methylene-b-fluoro-2-indolinone, c (217) 3-27-(1--4-dimethylaminomethylanilino)-1- (4-"M-methylcarboxymethylamino)phenyl)methylene|-b-fluoro-2-indolinone, (218) 3-27-(1--4-dimethylaminomethylanilino)-1-(3-(M-methylcarboxymethylamino)phenyl)methylene |-b-fluoro-2-indolinone, (219). 3-2-(I1-4-dimethylaminomethylanilino)-1-(4-carboxymethoxyphenyl)methylene|-6b-chloro-2-indolinone,

F) (220). 3-2-(/1-4-dimethylaminomethylanilino)-1-(3-carboxymethoxyphenyl)methylene|-6b-chloro-2-indolinone, ka (221). 3-2-(11--4-dimethylaminomethylanilino)-1-(4-carboxymethylaminophenyl)methylene|-b-chloro-2-indolinone, (222). 3-2-(I1--4-dimethylaminomethylanilino)-1-(3-carboxymethylaminophenyl)methylene|-b-chloro-2-indolinone, 60 (223) 3-27-(11--4-dimethylaminomethylanilino)-1- (4-((M-methylcarboxymethylamino)phenyl)methylene|-b-chloro-2-indolinone, (224) 3-27-(11--4-dimethylaminomethylanilino)-1-(3-(M-methylcarboxymethylamino)phenyl) methylene|-b-chloro-2-indolinone, (225). 3-2-(/1--4-dimethylaminomethylanilino)-1-(4-carboxymethoxyphenyl)methylene|i-6-bromo-2-indolinone, 65 ( 226). 3-2-(/1--4-dimethylaminomethylanilino)-1-(3-carboxymethoxyphenyl)methylene|i-6-bromo-2-indolinone, (227). 3-2-(I1--4- dimethylaminomethylanilino)-1-(4-carboxymethylaminophenyl)methylene|-6-bromo-2-indolinone,

(228). 3-2-(1--4-dimethylaminomethylanilino)-1-(3-carboxymethylaminophenyl)methylene|-6-bromo-2-indolinone, 3-27-(1--4-dimethylaminomethylanilino)-1-(4-" M-methylcarboxymethylamino)phenyl)methylene|-6-bromo-2-indolinone and (230) 3-27-(11--4-dimethylaminomethylanilino)-1-(3-(M-methylcarboxymethylamino)phenyl)methylene|-6- bromo-2-indolinone.

The abbreviations used in the above tables have the following meanings:

Me methyl, 70 E ethyl,

Pg propyl, pPg n-propyl,

Irg isopropyl, pVy n-butyl,

You eat tert-butyl her

Vp benzyl.

Claims (1)

The formula of the invention 1. Compounds of the general formula with ОО) ух о ШЧ РЕ : с | | "n5 i) гехи ой Зо in which c X means an oxygen atom, "со B" means a hydrogen atom, B2 means a fluorine, chlorine or bromine atom or a cyano group, and BZ means a phenyl group or monosubstituted by a fluorine, chlorine, bromine or iodine atom or a C-Salkoxy group and a phenyl group, while the specified unsubstituted as well as monosubstituted phenyl groups can additionally be substituted in position C or 4 by identical or different substituents selected from the group that includes a fluorine atom, a chlorine atom, a bromine atom, a cyano group, C.i-Salkoxy group, C.--Soalkylcarbonylamino group, cyano-C.i-Salkyl, " carboxy-C-Salkyl, carboxy-C4-C, alkoxy group, carboxy-C4-Salkylamino group, carboxy-C4-Salkyl-M-( C4-Salkyl)amino group, C-C.Alkoxycarbonyl-C-Salkyl, - with C.-C.Alkoxycarbonyl-C 1-C-Alkoxy group, C4-C.Alkoxycarbonyl-C-C-Alkylamino group, and C.-C.Alkoxycarbonyl-C 1-Salkyl-M-(C4-Salkyl) amino group, amino-C.-Salkyl, aminocarbonyl-C.-Salkyl, (C4-Soalkylamino)carbonyl-C 1-Salkyl, di(C--Soalkyl)aminocarbonyl-C -Salkyl, (C4-Soalkylcarbonyl)amino-C 1-Salkyl, (C4-C,Alkoxycarbonyl)amino-C 1-Salkyl, (C3-Salkylcarbonyl)amino-C 4-Salkyl , (phenylcarbonyl)amino-C4-Salkyl, -and (C3-Svocycloalkylcarbonyl)amino-C /-Salkyl, (C3-Cscycloalkyl-C-Salkylcarbonyl)amino-C 4-Salkyl, co (phenylcarbonyl)amino-C -Salkyl, (thiophene-2-ylcarbonyl)amino-C-Salkyl, (furan-2-ylcarbonyl)amino-C-Salkyl, (phenyl-C.4-Salkylcarbonyl)amino-C 4-Salkyl, (2-(C4-C ,Alkoxy)benzoylcarbonyl)amino-C /-Salkyl, (o) (pyridin-2-ylcarbonyl)amino-C 4-Salkyl, (pyridin-3-ylcarbonyl)amino-S.-Salkyl, t 50 (pyridin-4- ylcarbonyl)amino-C.i-Salkyl, C.4-Salkylpiperazine-1-ylcarbonyl-C.-Salkyl, carboxy-Co-Salkenyl, aminocarbonyl-Co-Salkenyl, (C.4-Salkylamino)carbonyl-C»-Salkenyl . Il, V? means a phenyl group or a phenyl group monosubstituted by a terminally substituted amino group, a guanidino group, a mono- or di(C 1 -C 1 -Soalkyl)amino group, 29 MA a -di(C--Salkyl)amino-Co-Salkyl|-M-(C. 4-Salkyl)amino group, M-methyl-(C3-C.alkyl)amino group, Ge! M-(C4-Calkyl)-M-benzylamino group, M-(C4-C, alkoxycarbonyl) amino group, M-(C4-C.Alkoxycarbonyl)-C 1-C, alkylamino group, 4-(C4-Calkyl) piperazine-1 -yl, imidazol-1-yl, co-pyrrolidin-1-yl, azetidin-1-yl, morpholin-4-yl, piperazin-1-yl, thiomorpholin-4-yl, C. and C. alkyl group or monosubstituted di( C.--Calkyl)amino-(C.4-Calkyl)sulfonyl, 2-Di(C4-Calkyl)amino|ethoxy group, because 4-(C4-Calkyl)piperazin-1-ylcarbonyl, 4F -Id( (C.4-Calkyl)amino|-(C»-Calkyl))-M-(C4-Calkyl)aminocarbonyl, 1-86.-Calkyl)imidazol-2-yl, (C-Calkyl)usulfonyl or a group of the formula Z, still b5 about E" in which B'/ represents C 1-Soalkyl, C 1-Soalkylcarbonyl, di(C 4-Soalkyl)aminocarbonyl-C 1-Salkyl or C-Alkylsulfonyl, and BZ is C 4-Salkyl, 5-Idi(C-Soalkyl)amino|-Co-Salkyl, 2-Imono(C-Soalkyl)amino|-Co-Salkyl. or substituted in the terminal position by a di(C4i-Soalkyl)amino group, piperazin-1-yl or 4-(C4-Salkyl)piperazin-1-yl (C.--Salkyl)carbonyl, (C.-Salkyl)ucarbonyl or carbonyl ( C.--Alkyl) group, while all dialkylamino groups present in the KE" residue can also be represented in a quaternized 70 form, for example in the form of an M-methyl-(M,M-dialkyl)ammonium group, where the counterion is preferably selected from iodide, chloride, bromide, methylsulfonate, para-toluenesulfonate and trifluoroacetate, BE? means a hydrogen atom, and means a hydrogen atom, while the above alkyl groups mean linear and branched alkyl groups, in which from one to three hydrogen atoms can additionally be replaced by a fluorine atom(s), and in addition, the carboxy-, amino-, or imino group present may be replaced by a residue that is cleaved by ip mimo, respectively, may be represented as a prodrug residue, for example, as a group that is converted by ip mimo into a carboxy group, or as a group , which is transformed immediately into an imino or amino group, their tautomers, enantiomers, diastereomers, their mixtures and their salts. 720 2. Compounds of the general formula I according to claim 1, in which X, EK", 2, B", 25 and E5 have the values specified in claim 1, and KZ means a phenyl group substituted by a C.-Soalkylcarbonylamino group, carboxy-C.- -Salkyl, carboxy-C.-C, alkoxy group, C.i-C; alkoxycarbonyl-C.-C.alkyl, C.i-C; alkoxycarbonyl-C-C-alkyloxy group, aminocarbonyl-C /-Salkyl, (C4-Soalkylamino)carbonyl -C 1-Salkyl, sc 25 di(C--Soalkyl)aminocarbonyl-C 1-Salkyl, (C4-Soalkylcarbonyl)amino-C /-Salkyl, (C4-C.Alkoxycarbonyl)amino-C 1-Salkyl, (phenylcarbonyl )amino-C.4-Calkyl, (o) (C3-C-cycloalkylcarbonyl)amino-C 4-Calkyl, (C3-C-cycloalkyl-C4-Calkylcarbonyl)amino-C/-Calkyl, (phenylcarbonyl)amino-C 4-Salkyl, (thiophen-2-ylcarbonyl)amino-C. -(C4-C.Alkoxy)benzoylcarbonyl)amino-C 4-C alkyl, (pyridin-2-ylcarbonyl)amino-C.-C alkyl, (pyridin-3-ylcarbonyl)amino-C 4-C alkyl, (pyridin-4- ylcarbonyl)amino-C.4-Szal kilom, p C.-Salkylpiperazine-1-ylcarbonyl-C 4-Salky, aminocarbonyl-C-Salkenyl, "co (C4-Salkylamino)carbonyl-C 5-Salkenyl, di(Ci-Salkyl)aminocarbonyl-C 5-Salkenyl or C.-C.Alkoxycarbonyl-Co-Szalkenyl. (22) 3. Compounds of the general formula I according to claim 1, in which X, B", B2, B", 25 and KZ have the values specified in claim 1, and BZ means a phenyl group substituted by carboxy-C.--Szalkyl or C. -C,Alkoxycarbonyl-C -Szalkylom. 4. Compounds of the general formula I according to any of claims 1-3, in which Х, К1, 3, в, Ви and 5 have the values indicated in claims 1-3, and КЕ? means a fluorine or chlorine atom. " 5. Compounds of the general formula I according to claim 1, selected from the group that includes (and). 3-2-(/1--4-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene|-b-chloro-2-indolinone, - c (6). 3-2-(/1--4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene-b-fluoro-2-indolinone, "from (c). 3-2-(I1-4 -dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene|)|-b-fluoro-2-indolinone, " (9 3-2-(1-(4-(M-(4-methylpiperazine- 1-ylmethylcarbonyl)-M-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6-fluoro-2-indolinone, - (d) so 3-2-11-(4-( "M-(2-dimethylaminoethyl)-M-methylsulfonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6-fluoro-2-indolinone, (o) (e) t 50 0 3- 7-11--4--M-(3-dimethylaminopropyl)-M-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|)|-b-fluoro-2-indolinone, sl OK). 3-2-(1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-b-fluoro-2-indolinone, (c) 3- 27-11--4-(-«M-(dimethylaminomethylcarbonyl)-M-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6b-fluoro-2-y HnDOLlinOn, o (y ) 3-27-(11--4-(-«M-(2-dimethylaminoethylcarbonyl)-M-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene-b-fluoro-2-y name) ndolinone, (ju. 3-2-(1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene-b-fluoro-2-indolinone, 60 (lu). 3-2-(1-(4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene-b-fluoro-2-indolinone, (m). 3-2-(1-(4--2-dimethylaminoethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-b-chloro-2-indolinone, (N). 3-2-(11--4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-b-chloro-2-indolinone, (0). 3-2-(1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6b-chloro-2-indolinone, (n). 3-2-11-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|)-6-bromo-2-indolinone, 65 (p). 3-2-/11-"(4-(dimethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene|-6-bromo-2-indolinone, (with). 3-2-(1-4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)methylene|-6-bromo-2-indolinone, (t) 3-2-(11-(4-(dimethylaminomethylanilino)-1-(4-(2-ethoxycarbonylethyl)phenyl)methylene|-b-fluoro-2-indolinone, and also their salts. 6. The compound according to any one of claims 1-5, which differs in that it is a physiologically compatible salt. Official bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2007, M 10, 10.07.2007. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. s o IS) sch (Se) (22) m. shi s ;" -I se) (22) with 50 sl F) ime) 60 b5