SK6462002A3 - 6-position substituted indoline, production and use thereof as a medicament - Google Patents

Abstract

The invention relates to a 6-substituted indoline of formula (I), wherein R1 to R5 and X are as defined in claim 1, isomers and salts of said compound, in particular physiologically compatible salts of said compound having pharmacologically important characteristics, in particular inhibiting action on different receptor-tyrosine kinases and cyclin/CDK complexes in addition to inhibiting the proliferation of endothelial cells and different tumor cells. The invention also relates to medicaments containing said compounds, the use of said compounds and a method for the production thereof.

Description

6-substituted indolinones, process for their preparation, pharmaceutical composition containing them and their use

Technical field

The invention relates to the 6-substituted indolinones of their tautomers, diastereomers, enantiomers, mixtures and salts thereof, in particular physiologically acceptable salts having valuable properties, processes for their preparation and their use.

BACKGROUND OF THE INVENTION

Compounds of formula I

R ³

wherein R ¹ represents a hydrogen atom or a prodrug group have valuable pharmacological properties, particularly an inhibiting effect on various kinases, especially on receptor kinases such as VEGFR2, PDGFR, PDGFR, FGFR1, FGFR3, EGFR, HER2, IGF1R and HGFR and complex to cyclin dependent kinases (CDKs) such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9 with their specific cyclins (A, B1, B2, C, D1, D2, D3, E, F, G1, G2, H, I and K) and on viral cyclins (see Mengtao L. in J. Virology 71 (3), 1984-1991 (1977)), on proliferatively cultured human cells, especially endothelial cells, for example in angiogenesis, but also for the proliferation of other cells, especially tumor cells.

Other compounds of formula (I) above wherein R ^{@ 1 is} not hydrogen or a precursor group are valuable intermediates for the preparation of the above compounds.

• · β · · ·

2. Summary of the Invention

The present invention provides compounds of the formula I wherein R ¹ is hydrogen or a prodrug having valuable pharmacological properties; The invention further encompasses pharmaceutical compositions comprising said pharmacologically active compounds, their use and methods for their preparation.

In the above general formula

X is an oxygen or sulfur atom,

R ¹ represents a hydrogen atom or a precursor group such as a C 1-4 alkoxycarbonyl group or a C 2-4 alkanoyl group,

R ² is carboxy, a linear or branched Ci-6-alkoxycarbonyl, C4-7-cycloalkoxy-carbonyl or aryloxycarbonyl group, a linear or branched Ci-6-alkoxycarbonyl group which is the terminal alkyl-substituted phenyl, heteroaryl, carboxy, Ci-3-alkoxy-carbonyl, aminocarbonyl, Ci-3-alkylamino-carbonyl or di- (Ci_3-alkyl) -aminokarbonylovou group, a linear or branched C ₂ -6 alkoxy-carbonyl group which is substituted in the terminal alkyl moiety by a chlorine atom or by a hydroxy-, C 1-3 -alkoxy-, amino-, C 1-3 -alkylamino- or di- (C 1-3 -alkyl) -amino-, aminocarbonyl or methylaminocarbonyl group , an ethylaminocarbonyl group optionally at the 2-position of the ethyl group substituted with a hydroxy- or C 1-3 -alkoxy- group, or unless R ⁴ is an aminosulfonylphenyl group or W- (C 1-5) -alkyl) -C 1-3 alkylaminocarbonyl, R ² is also di- (C 1-2 -alkyl) aminocarbonyl,

R ³ represents hydrogen, C 1-6 -alkyl, C 3-7 -cycloalkyl, trifluoromethyl or heteroaryl, phenyl or naphthyl, phenyl or naphthyl mono- or disubstituted with fluorine, chlorine, bromine or iodine, trifluoromethyl -, C 1-3 alkyl- or C 1-3 -alkoxy-, wherein in the case of disubstitution the substituents may be

The same or different and wherein said unsubstituted as well as mono- and disubstituted phenyl or naphthyl groups may additionally be substituted by hydroxy-, hydroxy-C1-8. _3- alkyl- or C 1-3 -alkoxy-C 1-3 -alkyl-, cyano-, carboxy-, carboxy-C 1-3 -alkyl-, C 1-3 -alkoxycarbonyl-, aminocarbonyl-, C _1-3 -alkylamino-carbonyl- or di-C 1-6 -alkyl-aminocarbonyl, nitro-, amino-, C 1-3 -alkylamino-, di- (C 1-3 -alkyl) amino or amino-C 1-3 -alkyl, C 1-6 -alkyl; _3- alkylcarbonylamino-, N-C 1-6 -alkyl-C 1-6 -alkylcarbonylamino-, C 1-6 -alkylcarbonylamino- _3- alkylcarbonylamino-C 1-3 -alkyl-, N - (C 1-3 -alkyl) -C 1. _3- alkylcarbonylaminoC 1-3 -alkyl-, C 1-3 -alkylsulfonylamino-, C 1-3 -alkylsulfonylamino-; _3- alkylsulfonylamino-C 1-3 -alkyl, N - (C 1-6 -alkyl-C 1-6 -alkylsulfonylamino-C 1-8 -alkyl- or aryl-C 1-3 alkylsulfonylamino-, cycloalkylamino-, cycloalkyleneimino-, cycloalkyleneiminocarbonyl-, cycloalkylenimino-C 1-6 -alkyl; 3-alkyl-, cycloalkyleneiminocarbonyl-C 1-3 -alkyl or cycloalkyleneiminosulfonyl-C 1-3 -alkyl each having 4 to 7 ring members, wherein the methylene group at the 4-position of the six- or seven-membered cycloalkyleneimino group may be replaced by an oxygen or sulfur atom, a sulfinyl group -, sulfonyl-, -NH- or -N (C _1-3 -alkyl) -, or may be substituted by heteroaryl or heteroaryl-C _1-3 alkyl,

R ⁴ is C _{3. A 7-} cycloalkyl group, wherein the methylene group at the 4-position of the six- or seven-membered cycloalkyl group may be replaced by amino-, C 1-3 -alkylamino- or di- (C 1-3 -alkyl) -amino-, or may be replaced by -NH- or -A / (C _1-3 -alkyl) -, or is a phenyl group substituted by R ⁶ , wherein the phenyl group may additionally be mono- or di- substituted by a fluorine, chlorine, bromine or iodine atom, a C 1-5 group -alkyl-, trifluoromethyl-, hydroxy-, C 1-6 alkyl; _3- alkoxy-, carboxy-, C 1-6 alkyl; _3- alkoxycarbonyl-, amino-, acetylamino-, C 1-6 -alkylsulfonyl-amino-, aminocarbonyl-, C 1-6 -alkyl-; _3- alkyl-aminocarbonyl-, di- (C 1-3 -alkyl) -aminocarbonyl-, amino-

Sulfonyl-, Ci. _3- alkyl-aminosulfonyl-, di-C 1-6 -alkyl-aminosulfonyl-, nitro- or cyano-, wherein the substituents may be the same or different and wherein

R ⁶ is H, fluorine, chlorine, bromine, iodine, cyano, nitro, amino, Ci-5-alkyl, _C3-.7 cycloalkyl, trifluoromethyl, phenyl, tetrazolyl or heteroaryl group, , a group of formula

about.

wherein the hydrogen atoms bonded to the nitrogen atom may be replaced independently of one another by Ci. _3- alkyl,

A C 1-3 -alkoxy group; _3- alkoxy-Ci. _3- alkoxy, phenyl-C 1-3 -alkoxy, amino-C ₂ . ₃ -alkoxy, Ci.3-amino-3-C ₂ alkoxy, di _{(first 3} alkyl) amino-C 2-3 alkoxy, phenyl-Ci-3-alkylamino-C2-3 N - (C _1-3 -alkyl) -phenyl-C 1-6 alkoxy; ₃ -alkylamino-C 2-3 alkoxy, C ^ -cykloalkylénimino-C _2-3 alkoxy group or a C. _3- alkylmercapto-, carboxy, C 1-4 -alkoxycarbonyl, aminocarbonyl, C 1-3 alkylamino-carbonyl, N - (C _1-5 -alkyl) -C 1-3 -alkylaminocarbonyl, phenyl-C _1-3 -alkylaminocarbonyl N - (C 1-3 -alkyl) -phenyl- C 1. _3- alkylaminocarbonyl, piperazinocarbonyl or N - (C _1-3 -alkyl) piperazinocarbonyl,

Ci. _3- alkylaminocarbonyl or N - (C 1-5 -alkyl) -C 1. _{A 3-} alkylaminocarbonyl group in which the alkyl moiety is substituted by a carboxyl group or a C 1-3 alkoxycarbonyl group, or in the 2 or 3 position by di- (C _1-3 -alkyl) amino-, piperazino-, N - (C _1-3) -alkyl) -piperazino- or 4- to 7-membered cycloalkyleneimine group,

C ₃ . _{A 7-} cycloalkyl-carbonyl group, wherein the methylene group at the 4-position of the 6- or 7-membered cycloalkyl moiety may be substituted by an amino-, C _1-3 -alkyl group

-5amino- or di- (C _1-3 -alkyl) -amino-, or replaced by -NH- or - V (C _1-3 -alkyl) -, an up to 7-membered cycloalkyleneimine group to which an methylene-bound methylene group can be replaced by a carbonyl group or a sulfonyl group, the cycloalkylene moiety of which may be fused to the phenyl ring, or one or two hydrogen atoms may be replaced by C 1-6 alkyl; _{The 3-} alkyl group and / or the methylene group at the 4-position of the six or seven membered cycloalkyleneimine group may be substituted with a carboxyl group, C 1-6 alkyl. _3- alkoxycarbonyl, aminocarbonyl, Ci. _3- alkylaminocarbonyl, di- (C _1-3 -alkyl) aminocarbonyl, phenyl-C 1-6 -alkylaminocarbonyl; ₃ -alkylamino groups and / or N- (C _{first 3} -alkyl) phenyl-C-i_ ₃ -alkylamino group, or may be replaced by O or S, sulfinyl, sulfonyl, -NH-, - / V (C _1-3 -alkyl) -, N - (phenyl) -, - N (C _1-3 -alkylcarbonyl) - or - N (benzoyl) C 1-4 -alkyl substituted with R ⁷ , wherein:

R ⁷ is C ₃ . _{A 7-} cycloalkyl group, wherein the methylene group at the 4-position of the six or seven membered cycloalkyl group may be substituted with an amino group, C 1-6 -cycloalkyl; _{A 3-} alkylamino group, a di- (C _1-3 -alkyl) -amino group, or replaced by an -NH- group or a - N (C _1-3 -alkyl) - group, in a 5-7 membered cycloalkyl group the group may be - (CH ₂ ) ₂ replaced by -CO-NH-, - (CH ₂ ) ₃ - by -NH-CO-NH or -CO-NH-CO-, or - (CH ₂ ) ₄ - may be replaced by -NH-CO -NH-CO-, wherein the hydrogen atom bonded to the nitrogen atom may be replaced by C 1-6. _{A 3-} alkyl group, an aryl or heteroaryl group, a hydroxy- or C 1-6 -alkyl group; ₃ -alkoxy-, · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

6-amino-, C 1-6 -alkyl; _7- alkylamino-, di- (C _1-7 -alkyl) -amino-, phenylamino-, N-phenylC _1-3 -alkylamino-, phenyl-C 1-6 -alkylamino-; _3- alkyl-amino-, N - (C 1-3 -alkyl) -phenyl- C _1-3 -alkyl- amino or di- (phenyl-C 1-3 -alkyl) -amino-, a-hydroxy-C ₂ - group - 3-alkyl-amino, / V- (Ci. ₃ alkyl) -CO-C _{2-hydroxy-3-alkylamino,} di- (o-hydroxy-C _{2. 3-alkyl)} amino, di " (O (C ₃ -alkoxy) -C _{second 3} alkyl) -aminoalebo / N- (dioxolan-2-yl) -C-3-alkyl-amino group, Ci.3-alkylcarbonylamino-C ₂ - 3-alkyl-annino- or C-3-alkylcarbonylamino-C ₂ .3-alkyl / N (Ci-3-alkyl) amino, a C-3-alkylsulfonylamino, A / - (3-C alkyl) -C-3-alkyl-sulfonylamino, C1.3alkylsulfonylamino _2-C 3-alkyl-amino or C. _3-C alkylsulfonylamino _{second 3-} alkyl- N - (C 1-3 -alkyl) -amino-, hydroxycarbonyl-C 1-3 -alkylamino- or N-C 1-6 -alkyl-hydroxycarbonyl-C 1-3 -alkylamino-, guanidine, in which one or two hydrogen atoms may each be replaced by a C 1-6 -alkyl group, a group of the formula

- N (R ⁸ ) - CO - (CH ₂ ) _n - R ⁹ (II) wherein

R ⁸ is hydrogen or C 1-3 -alkyl, n is 0, 1, 2, or 3,

R ⁹ represents amino-, C 1-4 -alkylamino-, di- (C 1-4 -alkyl) -amino-, phenyl-amino-, N - (C 1-4 -alkyl) -phenylamino-, benzylamino-, N - (CM -alkyl) benzylamino- or C 1-4 -alkoxy-, 4- to 7-membered cycloalkyleneimine group, wherein the methylene group at the 4-position of a 6-membered or 7-membered cycloalkylenimine group may in each case be replaced by an oxygen or sulfur atom, a sulfinyl-, sulfonyl-, -NH- , - N - (C 1-3 alkyl) -, - N - (phenyl) -, - N - (C _1-3 -alkylcarbonyl) - or N - (benzoyl) -, or when n is 1, 2, or 3 may also be a hydrogen atom, a group of the formula: · · · · · · · · · · · · · · · · · · · · · · · · ···· ·· ·· ·· ··· ·· ····

7-N (R ¹⁰⁾ - (CH ₂₎ m - (CO) _O - R @ ¹¹ (III) wherein

R ¹⁰ represents a hydrogen atom, a C 1-3 -alkyl group, a C 1-3 -alkylcarbonyl group, an arylcarbonyl group, a phenyl-C 1-3 -alkylcarbonyl group, a C 1-3 -alkylsulfonyl group, an arylsulfonyl group or a phenyl-C 1-6 alkyl group. ₃ -alkylsulfonyl, m is 1, 2, 3 or 4, o is 1 or, when m is 2, 3 or 4, also 0 and R ¹¹ is amino-, C 1-4 -alkylamino-, di - (C 1-4 -alkyl) -amino-, phenyl-amino-, N- (C 1-4 -alkyl) -phenylamino-, benzylamino-, N- (C 1-4 -alkyl) benzylamino-, C 1-4 -alkoxy- or a C 1-3 -group -alkoxy-C 1-3 -alkoxy-, optionally with C 1-6 -alkyl; _{A 3-} alkyl- in the 1-position substituted by a di (C 1-4 -alkyl) -amino-C 1-3 -alkylamino- or 4- to 7-membered cycloalkyleneimine group, wherein the cycloalkylene moiety may be fused to a phenyl ring, or a methylene group at the 4-position in the 7-membered cycloalkyleneimine group may in each case be replaced by an oxygen or sulfur atom, a sulfinyl-, sulfonyl-, -NH-, - / V (C _1-3 -alkyl) -, - N (phenyl) -, -A / - (C 1-3 alkyl) or N (benzoyl) -, a C 4-7 -cycloalkylamino-, a C 4-7 -cycloalkyl-C 1-3 -alkylamino- or a C 4-7 -cycloalkenylamino- group in which the 1-position of the ring does not participate in the double bond and wherein said groups may be additionally substituted at the amino nitrogen atom by C 5-7-cycloalkyl, _C2 ^ -alkenyl, or CM-alkyl, 4 to 7 membered cykloalkylénimínovú group, the cycloalkylene moiety may be fused with a phenyl group or a oxazolo-, imidazolo-, thiazolo-, pyridino-, pyrazino- or a pyrimidino-, optionally substituted with a fluorine, chlorine, bromine or iodine atom, a nitro- group, a C 1-6 -alkyl-, a C 1-3 alkoxy or an amino group, and · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Wherein one or two hydrogen atoms may be replaced by a C-1.3 alkyl group, a C-7-cycloalkyl group or a phenyl group, and / or whose methylene group at the 3-position of a five-membered cycloalkyleneimine group may be substituted by hydroxy, hydroxy-C 1. C ₃ alkyl; _{A 3-} alkoxy- or C 1-3 -alkoxy-C 1-3 alkyl group in which the methylene group at the 3- or 4-position of the 6-membered or 7-membered cycloalkyleneimine group may be substituted with a hydroxy group, the hydroxy-C 1-6 alkyl group; _{A 3-} alkyl group, a C 1-3 alkoxy group or a C 1-6 alkyl group; _3- alkoxy-C _1-3 alkyl, carboxy-, C 1-4 -alkoxycarbonyl-, aminocarbonyl-, C _1-3 -alkylaminocarbonyl-, di (C _1-3 -alkyl) -aminocarbonyl-, phenyl-C 1-6 -alkyl; _3- alkylamino- or N - (C _1-3 -alkyl) phenyl-C _1-3 -alkylamino-, or said methylene group may be replaced by an oxygen or sulfur atom, a sulfinyl-, sulfonyl-, -NH-, - (VH) - group; -alkyl) -, - N - (phenyl) -, - N (phenyl-C _1-3 -alkyl) -, - N (C _1-3 -alkylcarbonyl) -, - N (C 1-4 -hydroxycarbonyl) -, - N - (C 1-4 -alkoxycarbonyl) -, - N - (benzoyl) - or N - (phenyl-C _1-3 -alkylcarbonyl) -, wherein the methylene group attached to the imine nitrogen atom of the cycloalkylenimine group can be replaced by a carbonyl group or a sulfonyl group, or in a 5- to 7-membered monocyclic or phenyl-fused cycloalkylenimine group, both methylene groups bound by an imine nitrogen atom may be replaced by a carbonyl group, or R ⁶ represents a C 1-6 alkyl group which is substituted by carboxy-,

C _1-3 -alkoxycarbonyl-, aminocarbonyl-, Ci. ₃ alkylaminocarbonyl or di (C ₃ alkyl) aminocarbonyl or a 4 to 7 membered group cykloalkyléniminokarbonylovou, A / - (C _{first 3} -alkyl) -C 2-4-alkanoylamino which is alkyl substituted by carboxy addition or C 1-6 alkyl. _3- alkoxycarbonyl, formula ·· ···· · ·

-9-N (R ¹² ) -CO- (CH ₂ ) _p -R ¹³ (IV) wherein

R ¹² is H, Cl-6 alkyl or C 3. _7- cycloalkyl, or terminal C 1-4 alkyl substituted by phenyl, heteroaryl, trifluoromethyl, hydroxy, C 1-3 alkoxy, aminocarbonyl, C 1-4 -alkylaminocarbonyl, di (C 1-4 -alkyl) amino- carbonyl, C 1-3 -alkylcarbonyl, C 1-6 -alkylsulfonylamino, N - (C _1-3 -alkyl) -C 1-3 -alkylsulfonylamino, C 1-3 -alkylaminosulfonyl or di- (C 1-3- ₎ alkyl) amino-sulfonyl and p is 0, 1, 2, or 3 a

R ¹³ has the same meaning as R ⁷ , or when p is

1,2 or 3, R ¹³ can be a hydrogen atom, a group of the formula

-N (R ⁴⁾ - _(CH2), - (CO) _r - R ¹⁵ (V) wherein

R ¹⁴ is hydrogen, C 1-4 -alkyl, C 1-3 -alkylcarbonyl, arylcarbonyl, phenyl-C 1-6 -alkyl; _3- alkyl-carbonyl, heteroarylcarbonyl, heteroaryl-C 1-3 -alkylcarbonyl, C 1-4 -alkylsulfonyl, aryl-sulfonyl, phenyl-C _1-3 -alkylsulfonyl, heteroaryl-sulfonyl or heteroaryl-C 1. 3alkylsulfonyl, q is 1, 2, 3 or 4, r is 1, or when q is 2, 3 or 4, r is also 0 and

R ¹⁵ has the same meaning as R ⁷ , as defined above,

-N (R ¹⁶⁾ -SO ₂ -R ¹⁷ (VI) · · · · · ·

-10 in which

R ¹⁶ represents a hydrogen atom or a terminal C 1-6 alkyl group optionally substituted by cyano-, trifluoromethylcarbonylamino- or N - (C 1-3 alkyl) trifluoromethylcarbonylamino- and

R ¹⁷ is C _1-3 -alkyl, amino substituted by di- (C _1-3 -alkyl) -amino-C 1-3 -alkylcarbonyla or di- (C 1-3 -alkyl) -amino-C 1-6 -alkyl; _3- alkyl-sulfonyl- and di- (C 1-3 -alkyl) -aminocarbonyl-C 1-3 -alkyl, or N - (C 1-3 -alkyl) - C 1-5 -alkylsulfonylamino- or N - (C 1-6 -alkyl) (3-alkyl) phenylsulfonylamino- in which the alkyl moiety is additionally substituted by cyano or carboxy-, wherein all of the R ⁶ moieties mentioned containing single bonded or fused phenyl groups may be mono- or di-substituted by a fluorine, chlorine, bromine or iodine atom, Ci. _5- alkyl-, trifluoromethyl-, hydroxy-, C 1-3 -alkoxy-, carboxy-, C 1-3 -alkoxycarbonyl-, aminocarbonyl-, C 1-4 alkylamino-carbonyl-, di- (C 1-4 -alkyl) -amino-carbonyl-, aminosulfonyl -, C 1-3 alkyl-aminosulfonyl-, di- (C _1-3 -alkyl) -aminosulfonyl-, C 1-3 -alkylsulfonylamino-, nitro- or cyano-, wherein the substituents may be the same or different, or two adjacent hydrogen atoms the phenyl group may be replaced by methylenedioxy-, and

R ⁵ represents a hydrogen atom or a C 1-3 -alkyl group, the term "aryl" means a mono- or di-substituted phenyl or naphthyl group optionally substituted by a fluorine, chlorine, bromine or iodine atom, cyano-, trifluoromethyl-, nitro-, carboxy-, aminocarbonyl-, C 1-3 -alkyl or C 1-3 -alkoxy- and the term heteroaryl means a monocyclic five- or six-membered heteroaryl group, optionally substituted by a C 1-3 -alkyl group in the carbon moiety, said six-membered heteroaryl group comprising one, two or three nitrogen atoms; and ·· ···· · ·

The 11-membered heteroaryl group contains an imino group, an oxygen atom or a sulfur atom, optionally substituted with a C 1-3 -alkyl or a phenyl-C 1. ₃ -alkyl, or a group optionally comprising a C-3-alkyl or by phenyl-C. _{A 3-} alkylsubstituted amino group or an oxygen or sulfur atom, and in addition a nitrogen atom, or optionally contains a C 1-3 -alkyl or phenyl-C 1-3 -alkyl group substituted by an imino group and two nitrogen atoms, in addition to said monocyclic heterocyclic groups via two adjacent carbon atoms of the fused phenyl ring and the bond occurs via a nitrogen atom or through the carbon atom of the heterocyclic moiety or the fused phenyl ring, the hydrogen atoms in the above alkyl and alkoxy groups or the alkyl moieties of the groups I above may be partially or totally replaced by fluorine atoms , said saturated alkyl and alkoxy moieties of predetermined groups containing more than 2 carbon atoms include, unless otherwise indicated, their branched isomers, for example, the isopropyl, tert-butyl and isobutyl groups, and wherein the hydrogen atom of the aforementioned carbox or a saturated N-heterocyclic group, such as a piperidine group, may additionally be replaced by a residue which is cleavable in vivo.

In vivo deprotected amino or amino means, for example, hydroxy, acyl, such as benzoyl or pyridinoyl, or C 1-6 -alkanoyl, such as formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl a group, allyloxycarbonyl-, C _1-6 -alkoxycarbonyl- such as methoxycarbonyl-, ethoxycarbonyl-, propoxycarbonyl-, isopropoxycarbonyl-, butoxycarbonyl-, tert -butoxycarbonyl-, pentoxycarbonyl-, hexyloxycarbonyl-, octyloxycarbonyl-, octyloxy -, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxykarbonyl-, phenylethoxycarbonyl or phenylpropoxycarbonyl group, _{Ci.3-alkylsulfonyl-C2} -4 -alkoxycarbonyl • ·

-12, C 1-3 -alkoxy-C 2-4 -alkoxy-C 2-4 -alkoxycarbonyl or R _e CO-O- (R _f CR _g ) -O-CO-, in which

R _e represents a C 1-6 -alkyl group, a C 3-7 -cycloalkyl group, a phenyl or a phenyl-C 1-3 -alkyl group,

Rf represents a hydrogen atom; ₃ alkyl group, a C ₅ _7 cycloalkyl or phenyl, and

R 8 represents a hydrogen atom, C 1-6. _{A 3-} alkyl group or an R _e CO-O (R _f CR g) -O-CO- group in which R _e to R _g are as defined above, furthermore an amino group can be considered a phthalimido group, wherein the above ester residues can be used as described above carboxyl group in vivo convertible groups.

A remarkable subset of compounds of formula I are those in which

X, R ¹ and R ³ to R ⁵ are as defined above and

R ² is unbranched or branched. _6- alkoxycarbonyl, C4-7-cycloalkoxycarbonyl or aryloxycarbonyl, straight or branched C1-6-alkoxycarbonyl which is substituted in the alkyl terminus by phenyl-, heteroaryl-, carboxy-, C1-3alkoxycarbonyl-, C1-3alkoxycarbonyl-, C1-3alkoxycarbonyl- 3-alkylaminocarbonyl or di (C ₁ _ ₃ alkyl) aminocarbonyl, straight or branched C 2-6 alkoxy-carbonyl group which is substituted in the alkyl end group by a chlorine or a hydroxy, C1.3alkoxy-, amino -, C 1-3 -alkylamino- or di- (C 1-3 -alkyl) -amino-, their tautomers, diastereomers, enantiomers, mixtures thereof and salts thereof.

A second remarkable subgroup of compounds of formula I are those in which

X, R ¹ and R ³ to R ⁵ are as defined above and

R ² represents aminocarbonyl or methylaminocarbonyl group, an ethylaminocarbonyl group optionally in the 2-ethyl group substituted by hydroxy or C 3 alkoxy, or, when R ⁴ does not represent-aminosulfonyl-phenyl group, or / \ / - (C 5 -alkyl) -C 1-3 alkylaminocarbonyl-phenyl, R ² may also be a di (C 1. ₂ alkyl) -aminokarbonylovú group, • • · ·

13 their tautomers, diastereomers, enantiomers, mixtures thereof and salts thereof.

A third notable subgroup of compounds of formula I are those in which:

X, R ¹ to R ³ and R ⁵ are as defined above and

R ⁴ represents R ⁷ - (C 1-4 -alkyl) -phenyl in which

R ⁷ is amino-, C ₁ . _7- alkylamino-, di- (C 1-7 -alkyl) -amino-, phenylamino-, N -phenyl-C 1-3 -alkyl-amino-, phenyl-C 1-3 -alkyl-amino-, N- ( C _1-3 -alkyl) -phenylC 1-3 -alkylamino- or di- (phenyl-C 1-3 -alkyl) -amino-, or represents a phenyl group substituted with a group of the formula

-N (R ¹² ) - CO - (CH ₂ ) _p - R ¹³ (IV) wherein R ¹² , p and R ¹³ are as defined above, their tautomers, diastereomers, enantiomers, mixtures thereof and salts thereof.

Preferred compounds of formula I are those in which

R ¹ and R ³ are as defined above, and

X is an oxygen atom,

R ² is a carboxyl group, unbranched or branched C 1-6; _{A 6-} alkoxy-carbonyl group, a C5-y-cycloalkoxycarbonyl group or a phenoxycarbonyl group, a straight or branched C1-3-alkoxycarbonyl group which is substituted in the terminal alkyl moiety by a phenyl-, heteroaryl-, carboxy-, C1-3- alkoxycarbonyl-, aminocarbonyl-, C1-6alkoxycarbonyl; ₃ alkylaminocarbonyl or di (C | .3 alkyl) -aminokarbonylovou, straight or branched C ₂ .3-alkoxy-carbonyl which is substituted with an alkyl end portion with chloro, hydroxy, Ci. _3- alkoxy-, amino-, C 1-6 -alkyl; _3- alkylamino- or di- (C _1-3 -alkyl) -amino-, aminocarbonyl or methylaminocarbonyl, ethylaminocarbonyl optionally in the 2-position of the ethyl group substituted with hydroxy- or C 1-6 -alkyl; _3- alkoxy- or, if R ^{4 is} not an aminosulfonyl-phenyl- or N - (C 1-5 -alkyl) -C 1-3 -alkylaminocarbonyl-phenyl- group, R ² may also be di (C 1-2 -alkyl) -aminocarbonyl group,

R ⁴ represents a C 3-7 cycloalkyl group, e 9 9

99

99

99

999999

-14 wherein the methylene group at the 4-position of a six or seven membered cycloalkyl group may be replaced by amino-, C 1-3 -alkylamino- or di- (C 1-3 -alkyl) -amino-, or may be replaced by -NH- or -A- Or (R ⁶⁾ -substituted phenyl which may additionally be mono- or di-substituted by fluorine, chlorine or bromine, C 1-3 -alkyl-, trifluoromethyl-, hydroxy-, C 1-3 -alkoxy-, carboxy-, Ci. _3- alkoxycarbonyl-, amino-, acetylamino-, aminocarbonyl-, C 1-3 -alkyl-aminocarbonyl-, di- (C _1-3 -alkyl) -aminocarbonyl-, nitro- or cyano-, wherein the substituents may be the same or different and while

R ⁶ is H, fluorine, chlorine, bromine, iodine, cyano, nitro, amino, Cys-alkyl, _C3-.7 cycloalkyl, trifluoromethyl, phenyl, tetrazolyl or heteroaryl group, of formula

wherein the hydrogen atom bonded to the nitrogen atom may be replaced by a C _1-3 alkyl group, a C 1-3 -alkoxy-, amino-C 2-3 -alkoxy-, C _1-3 -alkylamino-, C 2-3 -alkoxy-, di - (C ₃ alkyl) amino-C _2-3-alkoxy, phenyl-C. ₃ -alkylamino-C 2-3 alkoxy, A / - (C ₃ -alkyl) phenyl-C ₃ -alkylamino-C 2-3 alkoxy, pyrrolidino-C2-3-alkoxy, piperidino-C 2-3 alkoxy, - or a C 1-3 -alkylmercapto-, a carboxy-, a C 1-4 -alkoxycarbonyl-, an aminocarbonyl-, a C 1-6 -carbonyl group. _3- alkyl-amino-carbonyl-, phenyl-C 1-6 alkyl; _3- alkylamino-carbonyl- or N - (C 1-3 -alkyl) -phenyl- Ci. ₃ -alkylamino-carbonyl, C ₃ .7-cycloalkyl-carbonyl, wherein the methylene group in the 4-position six or seven membered cycloalkyl can be replaced by -NH- or -A / (Ci-3 alkyl) -, and 7-membered a cycloalkyleneimine group in which the group has a cyclic alkyleneimine group in which it is

-15, the imino-bound methylene group may be replaced by a carbonyl- or sulfonyl- group, or one or two hydrogen atoms may each be replaced by a C 1-6 -alkyl group and / or the methylene group at the 4-position of a six or seven-membered cycloalkyleneimine group may be substituted by a carboxyl group , C- |. ₃ alkoxycarbonyl, aminocarbonyl, C 1-6 alkyl; _3- alkylaminocarbonyl, di- (C _1-3 -alkyl) -aminocarbonyl, phenylC 1-3 -alkylamino or N - (C _1-3 -alkyl) -phenyl-C 1-6 -alkylaminocarbonyl; _{A 3-} alkylamino group, or may be replaced by an oxygen or sulfur atom, a sulfinyl-, sulfonyl-, -NH- or -A / (C _1-3 -alkyl) - group, a terminal C 1-6 alkyl group, substituted with R ⁷ , wherein:

R ⁷ represents a C 3-7 -cycloalkyl group, wherein the methylene group at the 4-position of the 6 or 7 membered cycloalkyl group may be replaced by -NH or -N (C _1-3 -alkyl) -, or in the 5- to 7-membered cycloalkyl group may be replaced by - ( CH 2) 2 -CO-NH-, - (CH ₂ ) ₃ -NH-CO-NH-, or - (CH 2) 4 -NH-CO-NHCO-, wherein the hydrogen atom is attached to the atom The nitrogen may always be replaced by C-. _3- alkyl, phenyl or heteroaryl, hydroxy- or C 1-6 -alkyl; _3- alkoxy-, amino-, C _1-6 -alkylamino-, di- (C _1-6 -alkyl) -amino-, phenylamino-, N -phenylC 1-6 -alkylamino-, phenyl-C 1-6 -alkyloxy- _3- alkylamino- N - (C 1-3 -alkyl) -phenyl-C 1-6 -alkylamino-; ₃ -alkylaminoalebo di- (phenyl-Ci. ₃ alkyl) amino group, a hydroxy-C ₂ _3-alkylamino-, A / - _{(C1. 3} alkyl) -O-C2-3-hydroxy alkylamino, di- _{(o-hydroxy-C2} 3-alkyl) amino, di (o (C ₃ alkoxy) C _2-3 alkyl) -aminoalebo A / - (2-dioxolan yl) -C. _3- alkyl-amino-, -, -, -, -, -, -, -, -, -, -, - ··············································

C1-3-alkylcarbonylamino-C2-3-alkyl-amino- or C1-3-alkyl; _3- alkylcarbonylamino-C 2-3 -alkyl- N - (C 1-3 -alkyl) -amino-, C 1-3 -alkylsulfonylamino-, N 2 - (C 1-3 -alkyl) - C 1-3 -alkyl- sulfonylamino, C1.3alkylsulfonylamino-C 2-3 alkyl amino or C ₃ -C alkylsulfonylamino _{second 3-} alkyl- N - (C 1-3 -alkyl) -amino-, hydroxycarbonyl-C 1-3 -alkylamino- or N - (C _1-3 -alkyl) -hydroxycarbonyl-C 1-3 -alkylamino - a guanidine group in which one hydrogen atom may be replaced by a C 1-3 alkyl group, a group of the formula

- N (R ⁸ ) - CO - (CH ₂ ) _n - R ⁹ (II) wherein

R ⁸ represents a hydrogen atom or a C 1-3 -alkyl group, n represents a number of 0,1,2, or 3,

R ⁹ is amino-, C 1-6 alkyl; _3- alkylamino-, di- (C _1-3 -alkyl) -amino-, phenylamino-, benzylamino- or C 1-4 -alkoxy-, a 5- to 7-membered cycloalkylene-imine group, wherein the methylene group at the 4-position is a 6-membered or 7-membered piperidine the group may be replaced by an oxygen or sulfur atom, a group -NH-, -A / (C 1-3 -alkyl) -, -A / (phenyl) -, - N (C 1-3 -alkylcarbonyl) - or - / In (benzoyl) -, or when n is 1, 2 or 3, R ⁹ may also be hydrogen, a group of the formula

-N (R ¹⁰ ) - (CH ₂ ) _m - (CO) n - R (III) wherein

R ¹⁰ represents a hydrogen atom, a C 1-3 -alkyl group, a C 1-3 -alkylcarbonyl group, a C _1-3 -alkylasulfonyl group, m is 1, 2 or 3, o is 1 or, when m is 2 or 3, also Number 0 and · · · · ···································· · · «·· ·· ·· ··· ·· ····

-17R ¹¹ is an amino, Ci-3-alkylamino, di- (Ci.3 alkyl) amino, or a C-3-alkoxy-Ci-3-alkoxy, or a 5- to 7-membered a cycloalkylene-imine group, wherein the methylene group at the 4-position of the piperidine group may be replaced by an oxygen or sulfur atom, -NH-, - / V (C _1-3 -alkyl) -, - / V (phenyl) -, - / V ( C _1-3 -alkylcarbonyl) - or-N- (benzoyl) -, a C 4-7 -cycloalkylamino- or C 4-7 -cycloalkenylamino- group in which the 1-position of the ring does not participate in a double bond, up to a 7-membered cycloalkyleneimine group in which the cycloalkylene moiety may be fused to a phenyl group or, one or two hydrogen atoms may each be replaced by a C 1-3 alkyl group, and / or the methylene group at the 3-position of the pyrrolidine group may be substituted by hydroxy, C 1-3 -alkoxy-, methylene group the 4-position of the 6-membered or 7-membered cycloalkyleneimine group may be substituted with a hydroxy group , hydroxy-C 1-3 -alkyl, C 1-6 -alkyl; _3- alkoxy-, carboxy-, C 1-3 -alkoxycarbonyl-, aminocarbonyl-, C 1-3 -alkylaminocarbonyl, di- (C 1-3 -alkyl) aminocarbonyl-, phenyl-C 1-3 -alkylamino- or N - (C 1-6 -alkyloxy) 3-alkyl) -phenyl-C 1-3 -alkylamino-, or said methylene group may be replaced by an oxygen or sulfur atom, a sulfinyl-, a sulfonyl-, -NH-, - N - (C 1-3 -alkyl) -, N - (phenyl) -, N - (phenyl-C _1-3 -alkyl) -, - N - (C 1-3 -alkylcarbonyl) -, -N (C 1-4 -hydroxycarbonyl) -, N - (C 1-4) -alkoxycarbonyl) -, - N - (benzoyl) - or - N - (phenyl-C 1-3 -alkylcarbonyl) wherein the methylene group attached to the imine nitrogen atom of the cycloalkylenimine group may be replaced by a carbonyl group or a sulfonyl group, or in a five membered up to 6-membered monocyclic or phenyl-fused cycloalkylenimine • • • ·

• · ···············

The 18-moieties of the two methylene groups bonded to the imine nitrogen atom may each be replaced by a carbonyl group, or R ⁶ represents a C 1-6 alkyl group which is substituted at the terminal portion by a carboxy-, C 1-6 -alkyl group. _{A 3-} alkoxycarbonyl-, aminocarbonyl-, C 1-3 -alkylaminocarbonyl- or di- (C 1-3 -alkyl) aminocarbonyl- or a 4-7 membered cycloalkyleneiminocarbonyl group of the formula

-N (R ¹² ) -CO- (CH ₂ ) _p -R ¹³ (IV) wherein

R ¹² is hydrogen, C 1-3 -alkyl or C 3-8 -cycloalkyl, phenyl-C 1-3 -alkyl or heteroaryl-C 1-3 -alkyl and p is 0, 1, 2 or 3; and

R ¹³ has the same meaning as R ⁷ , or when p is

1,2 or 3, R ¹³ can also be a hydrogen atom, a group of the formula

-N (R ¹⁴ ) - (CH ₂ ) _q - (CO) _r - R ¹⁵ (V) wherein

R ¹⁴ represents hydrogen, C 1-4 -alkyl, C 1-3 -alkylcarbonyl, phenylcarbonyl, phenyl-C _1-3 -alkylcarbonyl, heteroarylcarbonyl, heteroaryl-C 1. _3- alkylcarbonyl, C 1-4 -alkylsulfonyl, phenylsulfonyl, phenyl-C 1-3 -alkylsulfonyl, heteroarylsulfonyl or heteroaryl-C 1. _{3 is an} alkylsulfonyl group, q is 1, 2, 3 or 4, r is 1, or when q is 2, 3 or 4, r is also 0 and

R ¹⁵ has the same meaning as R ⁷ , as defined above,

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

-19-N (R ¹⁶⁾ -SO ₂ - R ¹⁷ (VI) in which

R ¹⁶ is H or a terminal CM-alkyl optionally substituted by cyano, trifluoromethyl-carbonyl-amino or N- (C ^ ₃ alkyl), trifluoromethyl-carbonyl-amino and R ¹⁷ is C 3 alkyl group, amino substituted by di- (C _1-3 -alkyl) amino-C ₁ . ₃ karbonylalebo alkyl-di- (Cl. ₃ alkyl) amino-C ₁ _ ₃ alkyl-sulfonyl group and a di- (Ci. ₃ alkyl) aminocarbonyl-Ci-3-alkyl, wherein all of R ^The aforementioned radicals containing single-bonded or fused phenyl groups may be mono- or di-substituted by a fluorine, chlorine or bromine atom, a C _1-3 -alkyl-, trifluoromethyl-, hydroxy-, C 1-3 -alkoxy-, carboxy-, C 1-6 -alkyl-, C _1-3 -alkyl-, C _1-3 -alkyl-, C 1-3- _3- alkoxycarbonyl-, aminocarbonyl-, C 1-3 alkylamino-carbonyl-, aminosulfonyl-, C 1-8 -alkyl-aminosulfonyl-, nitro- or cyano-, wherein the substituents may be the same or different, or two adjacent hydrogen atoms of the phenyl group may be replaced by methylenedioxy-, a

R ⁵ represents a hydrogen atom or C 1-6 alkyl; _{A 3-} alkyl group, said heteroaryl group optionally being a C _1-3 alkyl-substituted pyridinyl-, pyrazinyl-, pyrimidinyl-, pyridazinyl-, pyrrolyl-, furyl-, thienyl-, oxazolyl-, thiazolyl-, pyrazolyl-, imidazolyl- or triazolyl- in which one hydrogen atom bonded to the nitrogen atom can be replaced by C 1-7. _3- alkyl or phenyl-C 1-6 alkyl. ₃ -alkyl, and the five-membered, at least one NH-containing heteroaryl groups are linked through carbon or nitrogen, in the above groups can be hydrogen bonded to the nitrogen atom, is replaced with the in vivo leaving group, in particular acetyl or t in the above-mentioned groups containing carboxyl groups, the carboxyl groups may be substituted in vivo by a leaving group, for example in the form of a tert-butoxycarbonyl group, hydrogen atoms in the above alkyl and alkoxy groups, or in the alkyl moieties above. of the specified groups of formula I may be wholly or partially replaced by fluorine atoms and the above-mentioned radicals containing saturated alkyl or alkoxy moieties containing more than two carbon atoms may be branched or unbranched unless otherwise stated, their tautomous diastereomers, enantiomers, mixtures and salts thereof.

A notable subset of preferred compounds of Formula I are those in which

X, R ¹ and R ³ to R ⁵ are as defined above and

^R2 is a linear or branched Ci-6 alkoxy-carbonyl, C5-7cykloalkoxykarbonylovú group or a phenoxycarbonyl group, a straight or branched Ci.3-alkoxy-carbonyl group which is in the terminal alkyl group substituted with phenyl, carboxyl, C -3-alkoxycarbonyl-, aminocarbonyl-, C 1-3 -alkylaminocarbonyl- or di-C 1-6 -alkyl-4-aminocarbonyl-, straight or branched C 2-3 -alkoxycarbonyl which is substituted in the terminal alkyl moiety by hydroxy-, C 1-3 -alkoxy-, amino-, C 1-3 -alkylamino- or di- (C _1-3 -alkyl) -amino-, tautomers, diastereomers, enantiomers, mixtures and salts thereof.

A second very remarkable subset of preferred compounds of formula I are those in which

X, R ¹ and R ³ to R ⁵ are as defined above and

^R2 is an aminocarbonyl or methylaminocarbonyl group, an ethylaminocarbonyl group which may optionally be substituted at the 2-position of the ethyl group or a hydroxy group Ci.3-alkoxy, wherein when R ⁴ is not phenyl-aminosulfonyl and / or N (C 5 alkyl) -C 1-3 -alkylaminocarbonyl-phenyl, then R ² may also mean di- (C 1-2 -alkyl) -aminocarbonyl, their tautomers, diastereomers, enantiomers, mixtures and salts thereof.

• · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··· «e ····

A third very remarkable subset of preferred compounds of Formula I are those in which

X, R ¹ to R ³ and R ⁵ are as defined above and

R ⁴ represents R ⁷ - (n-C 1-6 -alkyl) -phenyl in which

R ⁷ is amino-, C 1-6 -alkylamino-, di- (C _1-6 -alkyl) -amino-, phenylamino-, N -phenyl-C _1-3 -alkyl-amino-, phenyl-C _1-3 -alkyl- amino-, N - (C _1-3 -alkyl) phenyl phenyl. _3- alkylamino- or di- (phenyl-C _1-3 -alkyl) -amino-, or a phenyl group which is substituted with a group of formula IV

- N (R ¹² ) - CO - (CH ₂ ) _p - R ¹³ (IV) wherein R ¹² , p and R ¹³ are as defined above, their tautomers, diastereomers, enantiomers, mixtures thereof and salts thereof.

Highly preferred compounds of formula I are those in which

X is an oxygen atom,

R ¹ represents a hydrogen atom,

R ² represents a carboxyl group, a straight or branched C 1-4 alkoxycarbonyl group or a phenoxycarbonyl group, a straight or branched C _1-3 -alkoxycarbonyl group which is substituted in the terminal alkyl part by phenyl, carboxyl, C 1-6 -alkyloxycarbonyl; _3- alkoxycarbonyl, aminocarbonyl, C-. _{A 3-} alkylaminocarbonyl or di- (C _1-3 -alkyl) aminocarbonyl group, a straight or branched C _2-3 -alkoxycarbonyl group, which is substituted in the terminal alkyl moiety by a hydroxy-, C- | _3- alkoxy-, amino-, C 1-6 -alkyl; ₃ alkylamino- or di- (C _1-3 -alkyl) -amino-, aminocarbonyl or methylaminocarbonyl, an ethylaminocarbonyl group which may be optionally substituted at the 2-position in the ethyl group by a hydroxy- or C 1-8 -alkoxy- group, provided that R ^{4 is} not aminosulfonylphenyl or N - (C 1-5 -alkyl) -C 1-3 -alkylaminocarbonylphenyl, then R ² may also be a di- (C 1-2 -alkyl) aminocarbonyl group, · · · · · · · · · · · · · · · · · · · · · · · · · ·

-22R ³ represents a C 1-6 alkyl or phenyl group which may be substituted by a fluorine, chlorine or bromine atom, a trifluoromethyl-, C 1-3 alkyl-, hydroxy- or C 1-6 -alkyl group. ₃ -alkoxy-,

R ⁴ represents a C 5-6 -cycloalkyl group, wherein the methylene group at the 4-position of the cyclohexyl group may be substituted with an amino-, C 1-6 -alkyl group. _3- alkylamino- or di- (C 1-3 -alkyl) amino-, or replaced by -NH- or-N- (C 1-3 -alkyl) -, phenyl, phenyl disubstituted by C _1-3 -alkyl-, C1 3alkoxy- or nitro-, wherein the substituents may be the same or different, or a phenyl group substituted by R ⁶ , wherein said phenyl may be additionally substituted by a fluorine, chlorine or bromine atom, or an amino- or nitro- group, wherein R ⁶ represents an atom fluorine, chlorine or bromine,

A C 1-3 -alkyl, a C 1-3 -alkoxy, a nitro, an amino or a C 1 -cycloalkyl group attached via a carbon atom to a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a triazolyl group or a tetrazolyl group, said heteroaromatic groups being a carbon skeleton substituted with a C 1-6 alkyl group; _{The 3-} alkyl group or one hydrogen atom bonded to the nitrogen atom can be replaced by a C 1-3 -alkyl group or a phenyl-C _1-3 -alkyl group, a group of the formula

carboxy-, C 1-4 -alkoxycarbonyl-, phenyl-C _1-3 -alkyl-amino-carbonyl- or C 5-7 -cycloalkyl-carbonyl-, a 5- or 6-membered cycloalkyleneimine group, wherein: 4 · 4 4 4 · «4« «« «« «4 4 4 4 4 4 4 4 4 4 4« «

-23metylénová group at position 4 of the piperidine group can be replaced by oxygen, S, NH or a group of N / (Ci_3alkyl) -, straight-chain, Ci.3-alkyl group in the end portion substituted by R ^7, wherein

R ⁷ is C ₅ .7-cycloalkyl, wherein the five or six membered cycloalkyl group may be - (CH 2) 2 group is replaced by -CO-NH-, - (CH 2) 3 can be replaced by NH-CO The -NH-α group - (CH 2) 4 - may be replaced by -NH-CO-NH-CO-, wherein each hydrogen atom bonded to the nitrogen atom may be replaced by a C 1-3 -alkyl group, a phenyl or a pyridinyl group, or via a pyrrole, pyrazolyl, imidazolyl or triazolyl group, wherein said heteroaryl groups may be substituted in the carbon skeleton by a C 1-3 alkyl group, or the hydrogen bonded to the nitrogen atom may be replaced by a C 1-6 carbon atom or a nitrogen atom. _{A 3-} alkyl group, a hydroxy- or a C 1-3 -alkoxy group, an amino- group, a C 1-6 alkyl group, a C 1-6 alkyl group, a C 1-6 alkyl group, a C 1-6 alkyl group, or a C 1-6 alkyl group; _6- alkylamino-, di-C 1-6 -alkyl-4-amino-, phenylamino-, N -phenyl-3-alkyl-amino-, phenyl-C 1-6 -alkylamino-; ₃ -alkylamino and / or N (C ₃ -alkyl) phenyl-C ₃ -alkylamino, CO-hydroxy-C ₂ .3-alkyl-amino, A / - (Ci-3-alkyl) - a hydroxy-C 2-3 alkylamino, di- _{(o-hydroxy-C2} -3 alkyl) amino or di- (ro- (C | .3 alkoxy) _2-C 3-alkyl ) amino-, C1-3-alkylcarbonylamino-C2-3-alkyl-amino- or C1-3-alkylcarbonylamino- C2-3-alkyl- N - (C1-3-alkyl) amino, C1-3-alkylsulfonylamino -, N - (C 1-3 -alkyl) - C 1. ₃ -alkylsulfonylamino-, C1-3alkyl-sulfonyl-C 2-3 alkylamino, or C 3-C 2-3 alkylsulfonylamino--alkyl / - (C ₃ alkyl) amino group, a hydroxycarbonyl-C-3 alkyl-amino- or N - (C 1-3 -alkyl) hydroxy-carbonyl-CT-3-alkyl-amino-, -, -, -, -, -, - • · · · · · # # # # # # # # # # # # # # é é é é é é é é é é é

A -24guanidine group in which hydrogen may be replaced by a C _1-3 -alkyl- group of the formula

- N (R ⁸ ) - CO - (CH ₂ ) _n - R ⁹ (II) wherein

R ⁸ is hydrogen or C 1-6 -alkyl, n is 0, 1, 2, or 3,

R ⁹ is amino-, C 1-6 alkyl; _3- alkylamino-, di- (C _1-3 -alkyl) -amino or C 1-4 -alkoxy-, 5- to 7-membered cycloalkyleneimine group, wherein the methylene group at the 4-position of the piperidine group may be replaced by -NH-, -A / ( C _1-3 -alkyl) - or - N (C _1-3 -alkylcarbonyl) -, or when n is 1, 2, or 3 may also be hydrogen, a group of the formula

-N (R ^m ) - (CH ₂ ) _m - (CO) n -R "(III) wherein

R ¹⁰ represents a hydrogen atom or a C 1-6 alkyl group, m is 1, 2, 3 or 4, o is 1 or, when m is 2, 3 or 4, also 0 and

R ¹¹ represents amino-, C 1-6 alkyl; _3- alkylamino-, di- (C _1-3 -alkyl) -amino-, C 1-4 -alkoxy- or methoxy-C 1-6 -alkyl; _{A 3-} alkoxy-, or 5- or 6-membered cycloalkyleneimine group, wherein the methylene group at the 4-position of the piperidine group may in each case be replaced by -NH-, -A / (C _1-3 -alkyl) -, or - V (C 1-6 alkyl) -; ₃ -alkylcarbonyl) -, azetidino-, pyrrolidino-, piperidino-, 2,6-dimethyl-piperidino-, 3,5-dimethyl-piperidino- or azepino-, wherein the methylene group at the 3-position of the pyrrolidine group may be substituted hydroxy,

-25 ······························ * the methylene group at the 4-position of the piperidine group may be substituted by hydroxy, hydroxy-C 1-3 -alkyl- or C 1-3 alkoxy-, or said methylene group may be replaced by an oxygen or sulfur atom, a sulfinyl-, sulfonyl-, NH-, - N - (C 1-3 -alkyl) -, N - (C 1-3 -alkylcarbonyl) -, - N - (benzoyl) - or - N - (phenyl-C 1-3 -alkylcarbonyl) -, wherein the methylene bonded to the imine nitrogen atom of the pyrrolidine, piperidine or piperazine group may be replaced by a carbonyl group, or R ⁶ represents a straight-chain C 1-3 -alkyl group whose terminal part is substituted by a carboxyl group or a C 1-3 -alkoxycarbonyl group -, a group of the formula

-N (R ¹² ) -CO- (CH ₂ ) _p -R ¹³ (IV) wherein

R ¹² is hydrogen, C 1-3 -alkyl or phenyl-C 1-6 -alkyl; ₃ alkyl group, p is 0,1 or 2 and

R ¹³ is amino-, C 1-4 -alkylamino-, di- (C 1-4 -alkyl) -amino-, benzylamino-, N-C 1-6 -alkyl-benzylamino, C 1-3 -alkoxy-C 1-3 -alkylamino-, N- (C ~ ^ alkyli-cis-alkoxy-cis-alkyl-amino, di (2-methoxyethyl) amino, di- (co-hydroxy ₂ -3alkyl) amino or aminocarbonyl-methyl N - (methyl) -amino-, optionally bonded via a nitrogen atom, optionally substituted with a C 1-5 alkyl group, a pyrrolyl group, a pyrazolyl group or an imidazolyl group, a pyrrolidino-, piperidino-, morpholino-, thiomorpholino- or piperazine-group which is optionally in the 4-position substituted by C 1-3 -alkyl-, phenyl-C 1-3 -alkyl-, C _1-3 -alkylcarbonyl- or C _1-4 -alkoxycarbonyl- when n is 1 or 2, R ¹² it may also be a hydrogen atom, a group of the formula <RTIgt;</RTI><RTIgt; · · · C · C · * * * * *

-26-N (R ¹⁴ ) - (CH ₂ ), - (CO), - R ¹⁵ (V) in which

R ¹⁴ represents a hydrogen atom, a C 1-4 -alkyl group, a C 1-3 -alkylcarbonyl group, a phenylcarbonyl group, a phenyl-C 1-3 -alkylcarbonyl group, a furylcarbonyl group, a pyridinylcarbonyl group, a furyl-C 1-5 -alkylcarbonyl group, pyridinyl-C 1-6 alkyl. _3- alkylcarbonyl, C 1-4 -alkylsulfonyl, phenylsulfonyl or phenyl-C _1-3 -alkylsulfonyl, q is 1, 2 or 3, r is 1, or when q is 2 or 3, r is also a number 0 a

R ¹⁵ represents amino-, C 1-4 -alkylamino-, di- (C 1-4 alkyl) -amino-, phenylamino-, N - (C _1-4 alkyl) -phenylamino-, benzylamino- or N - (C 1-4 -alkyl) -benzylamino-, or a group of the formula

-N (R ¹⁶ ) -SO ₂ -R ¹⁷ (VI) wherein

R ¹⁶ represents a hydrogen atom or a terminal C 1-3 -alkyl group optionally substituted by cyano-, trifluoromethyl-carbonyl-amino- or N - (C _1-3 -alkyl) -trifluoromethyl-carbonyl-amino- and

R ¹⁷ represents a C 1-3 -alkyl group, wherein all the R ⁶ moieties containing single bonded or fused phenyl groups mentioned above may be substituted by a fluorine, chlorine or bromine atom, methyl, trifluoromethyl, methoxy, nitro or kayno- and

R ⁵ represents a hydrogen atom, wherein in the abovementioned radicals the hydrogen atom bound to the nitrogen atom may be replaced by an acetyl or tert-butoxycarbonyl group, the carboxyl groups in the abovementioned radicals may also be in the form of tert-butoxycarbonyl precursor groups;

Saturated alkyl or alkoxy moieties containing more than two carbon atoms may be unbranched or branched, unless otherwise specified, their tautomers, diastereomers, enantiomers, mixtures and salts thereof, unless otherwise stated.

A particularly notable subset of the highly preferred compounds of formula I are those in which

X, R ¹ , R ³ , and R ⁵ are as defined above,

R ² represents a straight or branched C 1-4 alkoxycarbonyl or a phenoxycarbonyl group, a straight or branched C 1-3 alkoxycarbonyl group which may be substituted in the terminal alkyl moiety by phenyl-, carboxy-, C _1-3 -alkoxycarbonyl-, aminocarbonyl-, C 1-6 -alkoxycarbonyl- . _3- alkylaminocarbonyl- or di- (C 1-3 -alkyl) aminocarbonyl-, or a straight or branched C 2-3 alkoxycarbonyl group which is substituted in the terminal alkyl moiety by a hydroxy-, C 1-3 -alkoxy-, amino group -, C 1-3 -alkylamino- or di- (C _1-3 -alkyl) -amino-,

R ⁴ represents R ⁷ - (n-C 1-3 -alkyl) -phenyl in which

R ⁷ is amino-, C 1-6 alkyl; _6- alkylamino-, di- (C 1-4 -alkyl) -amino-, ωhydroxy-C ₂ . _{3-alkyl-amino,} / V- (Ci. ₃ alkyl) -O-hydroxy-C ₂ .3-alkyl-amino, di (C _{rohydroxy-2. 3-alkyl)} amino group or a di or a phenyl group substituted with a group of formula IV

N (R ¹² ) - CO - (CH ₂ ) _p - R ¹³ (IV) wherein

R ¹² , p and R ¹³ are as defined above, their tautomers, diastereomers, enantiomers, mixtures thereof and salts thereof.

A second, particularly remarkable subset of the highly preferred compounds are those in which

X, R ¹ , R ³ , and R ⁵ are as defined above,

R ² represents an aminocarbonyl or methylaminocarbonyl group, an ethylaminocarbonyl group optionally in the 2-position of the ethyl-substituted group; · Hydroxy- or C 1-4 -alkoxy- group, or if: R ^{4 is} not an aminosulfonylphenyl or N - (C 1-5 -alkyl) -C 1-3 -alkylaminocarbonyl R ² is also a di- (C 1-2 -alkyl) aminocarbonyl group,

R ⁴ represents R ⁷ - (n-C _1-3 -alkyl) -phenyl in which

R ⁷ is amino-, C 1-6 alkyl; ₆ -alkylamino, di- (Ci_4-alkyl) amino, C ₂ ωhydroxy-.3-alkyl-amino, / V- (Ci-3-alkyl) -új-hydroxy-C ₂ .3-alkyl- amino, di (C _{cohydroxy-second 3-alkyl)} amino group or a di (o- (Ci.3 alkoxy) -C _{second 3-alkyl)} amino, or represents phenyl which is substituted with a group of formula IV

-N (R ¹² ) -CO- (CH ₂ ) _p -R ¹³ (IV) wherein

R ¹² , p and R ¹³ are as defined above, their tautomers, diastereomers, enantiomers, mixtures thereof and salts thereof.

The most preferred compounds of formula I are those in which

X is an oxygen atom,

R ¹ and R ⁵ are each a hydrogen atom,

R ² is methoxycarbonyl, ethoxycarbonyl or aminocarbonyl,

R ³ represents a phenyl group,

R ^{4 is a} phenyl group which is monosubstituted with R ⁶ , wherein

R ⁶ represents a N-methyl-imidazol-2-yl group, a straight or branched C 1-3 alkyl group, the terminal part of which is substituted by C 1-4 -alkylamino-, di- (C 1-4 -alkyl) -amino-, piperidino or group 2 6-dimethyl-piperidino-, a group of formula IV

-N (R ¹² ) -CO- (CH ₂ ) _p -R ¹³ (IV) wherein

R ¹² is C 1-6. _3- alkyl, p is the number 1 or 2 and p is 1 or 2 and p is 1 or 2 and p is 1 or 2 and • · · · · · · · · · · ···

-29R ¹³ represents a di- (C 1-3 -alkyl) amino group or a group of formula V

-N (R ¹⁴ ) - (CH ₂ ) _q - (CO) _r -R ¹⁵ (V) wherein

R ¹⁴ is C 1-6. _3- alkylcarbonyl or C 1-6 alkyl; _{The 3-} alkylsulfonyl group q is 1, 2 or 3, r is 1, or, if q is 2 or 3, r can be 0 and

R ¹⁵ represents a di- (C _1-3 -alkyl) amino group, said radicals containing saturated alkyl moieties having more than two carbon atoms may be unbranched or branched, unless otherwise stated, their tautomers, diastereomers, enantiomers, mixtures and salts.

A particularly notable subset of the most preferred compounds of formula I are those in which

X, R ¹ , R ³ and R ⁵ are as defined above,

^R2 is metoxykarbonyloá or ethoxycarbonyl, and

R ⁴ represents a C 1 -C 6 -alkyl-amino-C 1-6 alkylphenyl group or a phenyl group substituted with a group of formula IV

-N (R ¹² ) -CO- (CH ₂ ) _p -R ¹³ (IV) wherein

R ¹² , p and R ¹³ are as defined above, their tautomers, diastereomers, enantiomers, mixtures thereof and salts thereof.

Particularly noteworthy compounds of formula I include:

(a) 3-Z- [1- (4- (piperidin-1-ylmethyl) anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (b) 3-Z - [(1- (4- (piperidin-1-yl-methyl) -anilino) -1-phenyl-methylene] -6-carbamoyl-2-indolinone,

(C) 3-Z- [1- (4- (piperidin-1-ylmethyl) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (d) 13-Z- [1- (4- (dimethylaminomethyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (e) 3-Z- [1- (4 - ((2,6- dimethyl-piperidin-1-yl) -methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (f) 3-Z- [1- (4 - (N - (2- dimethylamino-ethyl) - (N-acetyl-amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (g) 3-Z- [1- (4 - (N - (3-dimethylamino) (propyl) - N -acetyl-amino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (h) 3-Z- [1- (4 - (N - (2-dimethylamino- ethyl) - (N-methylsulfonyl-amino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (i) 3-Z- [1- (4- (dimethylaminomethyl) anilino) -1-phenyl] (j) 3-Z- [1- (4- (N-acetyl- N -dimethylaminocarbonylmethylamino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-methylene] -6-methoxycarbonyl-2-indolinone -indolinone, (k) 3-Z- [1- (4-ethylaminomethyl-anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (1) 3-Z- [1- (4- ( 1 -me (imidazol-2-yl) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (m) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl-N-methyl-amino) -anilino) -1-Phenylmethylene] -6-methoxycarbonyl-2-indolinone, (n) 3-Z- [1- (4- (N - (2-dimethylamino-ethyl) - N -methylsulfonylamino) -anilino) -1-Phenylmethylene] -6-methoxycarbonyl-2-indolinone, (o) 3-Z- [1- (4 - (N - (3-dimethylamino-propyl) - N -methylsulfonylamino) -anilino) - 1-Phenylmethylene] -6-methoxycarbonyl-2-indolinone, (p) 3-Z- [1- (4- (N-dimethylaminocarbonylmethyl- N -methylsulfonylamino) -anilino) -1-phenylmethylene] -6- methoxycarbonyl-2-indolinone, (q) 3-Z- [1- (4 - (N - ((2-dimethylamino-ethyl) -carbonyl) - N -methylamino) -anilino) -1-phenylmethylene] 6-Methoxycarbonyl-2-indolinone, (R) 3-Z- [1- (4 - (N - (2-dimethylamino-ethyl) - N -acetyl-amino) -anilino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone and ··· ········ · · · · · · · · · · · · · · · · · · · · · · · · (S) 3-Z- [1- (4-methylaminomethy)] 1-anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, their tautomers, mixtures thereof and salts thereof.

Another sub-group of compounds of formula I include those in which:

X is an oxygen or sulfur atom,

R ¹ represents a hydrogen atom or a precursor group such as a C 1-4 alkoxycarbonyl group or a C 2-4 alkanoyl group,

R ² represents a carboxyl group, a straight or branched C 1-6 -alkoxycarbonyl group, a C 5-7 -cycloalkoxycarbonyl group or a phenyl-C 1-3 -alkoxycarbonyl group, an aminocarbonyl group or a C 1-2 alkylaminocarbonyl group or, unless R ⁴ represents an aminosulfonylphenyl group N- (Ci. ₆ alkyl) -Ci.3-alkylaminocarbonyl-phenyl group, and also di _(C1 .2 alkyl) -aminokarbonylovú group,

R ³ represents a hydrogen atom, a C 1-8 -alkyl group, a C 3-7 -cycloalkyl group, a trifluoromethyl group or a heteroaryl group, a phenyl or naphthyl group, a phenyl or naphthyl group mono- or disubstituted with a fluorine, chlorine, bromine or iodine atom, trifluoromethyl -, C _1-3 alkyl- or C 1-3 -alkoxy-, wherein in the case of disubstitution the substituents may be the same or different and wherein said unsubstituted as well as mono- and disubstituted phenyl or naphthyl groups may additionally be substituted by hydroxy-, hydroxy- C 1-3 -alkyl- or C 1-6 -alkoxy-C 1-6 -alkyl-, cyano-, carboxy-, carboxy-C 1-6 -alkyl; _3- alkyl-, C 1-5 -alkoxycarbonyl-, aminocarbonyl-, C 1-6 -alkyl- _3- alkylaminocarbonyl- or di- (C _1-3 -alkyl) -aminocarbonyl, nitro-, amino-, C 1-6 -alkylamino; _3- alkylamino-, di- (C _1-3 -alkyl) -amino or amino-C 1-6 -alkyl; C ₃ alkyl; ₃ -alkylcarbonylamino-, N - (C 1-6 -alkyl) - C 1-6 -alkylcarbonylamino-, C 1-3 -alkylcarbonylamino-C 1-3 -alkyl-, N - (C _1-3 -alkyl) -C 1-3- alkylcarbonylaminoC 1-3 -alkyl-, C 1-5 -alkylsulfonylamino-, C 1-3 -alkylsulfonylamino-C 1-3 -alkyl, N ··· ··· · · · · · · · · · · · • · · · · · ·

-32 (C 1-3 -alkyl) -C 1-3 -alkylsulfonylamino-C 1-3 -alkyl- or aryl-C 1-3 -alkylsulfonylamino-, cycloalkylamino-, cycloalkyleneimino-, cycloalkyleneimino-carbonyl-, cycloalkyleneimino-C 1-3 -alkyl-, cycloalkylene-imino-carbonyl- alkyl or cycloalkyleneimino-sulfonyl-C 1-3 -alkyl having in each case 4 to 7 ring members, wherein the methylene group in the 4-position of the 6 or 7-membered cycloalkyleneimino group may be replaced by an oxygen or sulfur atom, a sulfinyl-, sulfonyl-, -NH- or - / V (C _1-3 -alkyl) -, or may be substituted with a heteroaryl group or a heteroaryl-C 1-3 alkyl group,

R ⁴ is C ₃ -7-cycloalkyl group wherein a methylene group in the 4-position six or seven membered cycloalkyl group may be substituted by amino, or a group C1.3alkylamino- di (Ci.3 alkyl) amino group or a substituted NH- or - N - (C _1-3 -alkyl) -, or represents a phenyl group substituted by R ⁶ , wherein the phenyl group may additionally be substituted by a fluorine, chlorine, bromine or iodine atom, a C 1-5 -alkyl-, trifluoromethyl- , C- |. _3- alkoxy-, carboxy-, C 1-6 alkyl; _3- alkoxycarbonyl-, aminosulfonyl-, nitro- or cyano-, wherein

R ⁶ is H, fluorine, chlorine, bromine, iodine, cyano, nitro, amino, Ci-5-alkyl, _C3-.7 cycloalkyl, trifluoromethyl, phenyl, tetrazolyl or heteroaryl group, .

Ci-3 alkoxy group optionally substituted by 1 to 3 fluoro, Ci-3-alkoxy-3-alkoxy, phenyl-C 3 alkoxy group, _amino-C2 -3 alkoxy group, C ₁ _3-alkylamino- 3-C ₂ alkoxy, di (Ci-3-alkyl) amino-C ₂ .3alkoxylovú group, a phenyl-C. ₃ -alkylamino-C 2-3 alkoxy, A / - (C ₃ -alkyl) phenyl-C ₃ -alkylamino-C _2-3-alkoxy, C5-7-cykloalkylénimino-C 2-3 alkoxy or a group Ci. _3- alkylmercapto-, carboxy, C 1-4 -alkoxycarbonyl, aminocarbonyl, C 1-3 alkylaminocarbonyl, N - (C _1-5 -alkyl) -C 1-3 -alkylaminocarbonyl, phenyl-C 1-3 -alkylamino- carbonyl group, N - (C 1-3 -alkyl) -phenyl-C 1-3 -alkylamino · · · · · · · · · · · ·························································

-33carbonyl, piperazinocarbonyl or N - (C 1-3 -alkyl) piperazinocarbonyl,

A C 1-3 -alkylaminocarbonyl or a N- (C 1-5 -alkyl) -C 1-3 -alkylaminocarbonyl group in which the alkyl moiety is substituted by a carboxyl group or a C _1-3 alkoxycarbonyl group, or in the 2 or 3 position by a di- (C _1-3 ) group -alkyl) amino-, piperazino-, N - (C 1-3 -alkyl) -piperazino- or 4- to 7-membered cycloalkyleneimine, up to 7-membered cycloalkyleneimine, the methylene-bound methylene group may be replaced by a carbonyl or sulfonyl group group wherein a cycloalkylene moiety may be fused to a phenyl ring, or one or two hydrogen atoms may be replaced by Ci-3-alkyl group and / or a methylene group at the 4 cykloalkylénimínovej six or seven membered group is optionally substituted by carboxy, C ₃ - alkoxycarbonyl, aminocarbonyl, C 1-3 -alkylaminocarbonyl, di- (C _1-3 -alkyl) -amino carbonyl, phenyl-C 1-3 alkylamino or N - (C 1-3 -alkyl) -phenyl-C 1-3 alkylamino, or may be replaced by oxygen or sulfur, sulfinyl-, sulfonyl-, -NH-, - / The (C. _3- alkyl) -, N- (phenyl) -, - N (C _1-3 -carbonyl) - or -N (benzoyl) -, C 1-4 -alkyl, which may be substituted by hydroxy- or C 1-3 -alkoxy-, amino-, C 1-7 -alkylamino-, di- (C _1-7 -alkyl) -amino-, di- (C 1 -C ₆ -alkyl) amino-C 2-3 -alkylamino-, tri- V, / V, / V- (Ci <r -alkyl) amino-C _{2-3-alkylamino,} phenylamino, A / -phenyl-Ci-3-alkyl-amino, phenyl-Ci-3-alkylamino, N - (C 1-3 -alkyl) -phenyl-C 1-3 -alkylamino- or di- (phenyl-C 1-3 -alkyl) -amino-, C _1-3 -alkylcarbonylamino-, N - (C _1-3 -alkyl) -C 1 -. 3-alkylcarbobylamino-, C 1-3 -alkoxycarbonyl-C 1-3 -alkylamino- or N - (C 1-3 -alkyl) -C 1. ₃ -Alkoxycarbonyl-1-3-alkylamino-, · ····

-34C 1-4 -cycloalkylamino-, C 4-7 -cycloalkyl-C 1-3 -alkylamino- or C 4-7 -cycloalkenylamino- in which the 1-position of the ring does not participate in the double bond and wherein said groups may be additionally substituted on the amino nitrogen atom Ci_3-alkyl groups and hydrogen atoms may be partially or fully substituted by fluorine and may be substituted by _C-5 _7 cycloalkyl, C 2-4 alkyl, up to 7 membered cykloalkyléniminovou group, wherein the methylene group attached to imnoskupinu it may be replaced by a carbonyl group or a sulfonyl group, the cycloalkylene moiety may be condensed with a phenyl group or optionally with a fluorine, chlorine, bromine or iodine atom, a nitro-, C 1-3 -alkyl-, C 1-3 -alkoxy- or amino-substituted group oxazolo-. imidazolo-, thiazolo-, pyridino-, pyrazino- or pyrimidino-, one or two hydrogen atoms may be replaced by a C _1-3 -alkyl group, a C 1-4 -cycloalkyl group or a phenyl group, the methylene group at the 4-position of a six-membered or seven-membered cycloalkyleneimine group may be substituted by hydroxy, carboxy-, C 1-6 -alkoxycarbonyl-, aminocarbonyl-, C 1-3 -alkylamino-carbonyl, di- (C 1-3 -alkyl) aminocarbonyl-, phenyl-C 1-3 -alkylamino- or N- (C _1-3 -alkyl) -phenyl-C 1-3 -alkylamino-, or said methylene group may be replaced by an oxygen or sulfur atom, sulfinyl-, sulfonyl-, -NH-, - N (C _1-3 -alkyl) -, -N (phenyl) -, - N (C _1-3 -alkylcarbonyl) -, or - N (benzoyl) -, carboxy-, C _{1 -} . _3- alkoxycarbonyl-, aminocarbonyl-, C-. _3- alkylaminocarbonyl- or di- (C _1-3 -alkyl) aminocarbonyl-, or substituted by a 4-7 membered cycloalkyleneimine group, an amino-, pyrrolidino-, piperidino-, morpholino-, benzoylamino- or N - (C _1-3 alkyl) group -benzoylamino-, a N- (C _1-3 -alkyl) -C 2-4 -alkanoylamino- group which is additionally substituted in the alkyl moiety by a carboxyl group or a C 1-6 -benzoylamino- group; _{A 3-} alkoxycarbonyl group, a group of the formula II, B, B, H, H, H; B β B B B t BB · φ φ φ φ φ φ φ φ φ φ φ

-35- N (R ⁸ ) -CO- (CH ₂ ) _n -R ⁹ (H) wherein

R ⁸ is hydrogen or C 1-3 -alkyl, n is 0, 1, 2, or 3,

R ⁹ represents amino-, C 1-4 -alkylamino-, phenylamino-, alkyl) -phenylamino-, benzylamino-, N - (C 1-4 -alkyl) -benzylamino- or di (C 1-4 -alkyl) -amino-; - a 7-membered cycloalkyleneimine group, wherein the methylene group at the 4-position of a 6-membered or 7-membered cycloalkylenimine group can always be replaced by an oxygen or sulfur atom, a sulfinyl-, sulfonyl-, -NH-, -A / (C _1-3 alkyl) - group, N - (phenyl) -, - N - (C _1-3 -alkylcarbonyl) - or - N - (benzoyl) -, or when n is 1, 2, or 3 may also be hydrogen, a group of formula III

-N (R 10) - (CH ₂ ) n -, - (CO) _o -R ¹ '(III) wherein

R ¹⁰ is H, C. ₃ alkyl group, a Ci_3-alkylcarbonyl, arylcarbonyl, phenyl-C ₁ _3-alkylcarbonyl, C ^ s-alkylsulfonyl group, an arylsulfonyl group or a phenyl-C | .3-alkylsulfonyl, m is 1, 2,3 or 4, and is 0 or 1; and

R ¹¹ represents amino-, C 1-4 -alkylamino-, phenylamino-, N- (C 1-4 alkyl) -phenylamino-, benzylamino-, N - (C 1-4 -alkyl) -benzylamino- or di (C 1-4 -alkyl) an amino-, 4- to 7-membered cycloalkyleneimine group, wherein the cycloalkylene moiety may be fused to the phenyl ring, or the methylene group at the 4-position of a six- or seven-membered cycloalkyleneimine group may be replaced by an oxygen or sulfur atom, sulfinyl-, sulfonyl- -NH-, - / V (Ci-3 ······························ ··· · · ·······························

-36alkyl) -, - N - (phenyl) -, - N - (C 1-3 -alkylcarbonyl) - or - N - (benzoyl) -, C 1-3 -alkoxy- or in the 1-position optionally C- | A di-(C 1-6 -alkyl) -amino-C 1-3 -alkylamino- group or a N- (C 1-3 -alkyl) -C 1-5 -alkylsulfonylamino- or a N- (C 1-3) -substituted by a 3-alkyl-substituted group. -alkyl) -phenylsulfonylamino- in which the alkyl moiety is additionally substituted by a cyano or carboxyl group, wherein all of the R ⁶ moieties mentioned containing single bonded or fused phenyl groups may be mono- or di-substituted by a fluorine, chlorine, bromine or iodine atom, C 1-5 -alkyl-, trifluoromethyl-, C 1-3 -alkoxy-, carboxy-, C 1-3 -alkoxycarbonyl-, aminosulfonyl-, nitro- or cyano-, wherein the substituents may be the same or different, or two adjacent hydrogen atoms of the phenyl group may be replaced by methylenedioxy-, and

R ⁵ represents a hydrogen atom or C 1-6 alkyl; _3- alkyl, wherein the term "aryl" refers to an optionally mono- or di-substituted phenyl or naphthyl group, substituted by a fluorine, chlorine, bromine or iodine atom, a trifluoromethyl-, C 1-3 -alkyl- or C 1-3 -alkoxy- group and heteroaryl refers to a monocyclic 5- or 6-membered heteroaryl group optionally substituted by a C 1-3 -alkyl group, said six-membered heteroaryl group containing one, two or three nitrogen atoms and a five-membered heteroaryl group containing an imino group, an oxygen atom or a sulfur atom optionally substituted with C 1-6 -3-alkyl, or optionally contains a C 1-3 -alkyl-substituted amino group and an oxygen or sulfur atom, or optionally contains a C 1-3 -alkyl-substituted amino group and two nitrogen atoms, and in addition may be monocyclic to said heterocyclic groups via two adjacent carbon atoms the fused phenyl ring, the above-mentioned saturated alkyl and alkoxy moieties of the predetermined groups containing more than 2 carbon atoms include, unless otherwise indicated, their branched isomers, for example, isopropyl, tert-butyl and isobutyl groups, and wherein said the carboxyl, amino and imino groups may be substituted with a residue which is cleavable in vivo, their isomers and their salts.

The novel compounds of the invention can be prepared, for example, by the following essentially known literature:

a) converting a compound of formula VII

R ³

(VII) in which

X and R ³ are as defined above,

R ² 'is defined as R ² mentioned in the beginning,

R ¹⁸ represents a hydrogen atom or a nitrogen protecting group of the lactam group, wherein one of the radicals R ² 'and R ¹⁸ can optionally form a solid-phase bond via a spacer and the other of the radicals mentioned above, and

Z ¹ represents a halogen atom, a hydroxy, alkoxy or arylalkoxy, e.g., Cl or Br, methoxy, ethoxy, or benzyloxy, with an amine of the formula VIII

(VIII) in which:

R ⁴ and R ⁵ are specified above, ·· ····

If desired, subsequent cleavage of the used nitrogen protecting group of the lactam group or cleavage from the solid phase.

A suitable nitrogen protecting group of the lactam group is, for example, an acetyl group, a benzoyl group, an ethoxycarbonyl group, a tert-butyloxycarbonyl group or a benzyloxycarbonyl group and a suitable solid phase is a resin such as 4- (2 ', 4'-dimethoxyphenylaminomethyl) phenoxy resin. it occurs via an amino group or a p-benzyloxybenzyl alcohol resin, the bond conveniently being via an intermediate such as 2,5-dimethoxy-4-hydroxybenzyl derivative.

The conversion is conveniently carried out in a solvent environment such as dimethylformamide, toluene, acetonitrile, tetrahydrofuran, dimethylsulfoxide, methylene chloride, or mixtures thereof, optionally in the presence of an inert base such as triethylamine, N-ethyl diisopropylamine or sodium bicarbonate at temperatures between 20 ° C. and 175 ° C, wherein the protecting group used can be cleaved simultaneously as a result of amidation.

When Z ¹ in the compound of formula VII is a halogen atom, then said conversion is preferably carried out in the presence of an inert base at temperatures between 20 and 120 ° C.

When Z ¹ in the compound of formula VII is a hydroxyl group, an alkoxy group or an arylalkoxy group, then said conversion is preferably carried out at temperatures between 20 and 200 ° C.

The optional subsequent subsequent cleavage of the protecting group used is conveniently carried out or 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. an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C, or is preferably carried out by amidation with an organic base such as ammonia, butylamine, dimethylamine or piperidine in a solvent environment such as methanol, ethanol, dimethylformamide and mixtures thereof, or in excess of the amine used at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

The cleavage of the solid phase used is preferably carried out with trifluoroacetic acid and water at temperatures between 0 and 35 ° C, preferably at room temperature.

b) Preparation of compound of formula I, wherein R ² other than the carboxyl group is designated as the beginning, resulting in a conversion of IX

(IX) in which

R ¹ and R ³ to R ⁵ are as defined above, or a reactive derivative thereof with a compound of formula X

H - R ¹⁹ (X) in which

R ¹⁹ represents C 1-6 -alkanol, C 4-6 -cycloalkanol or an aromatic alcohol,

C 1-6 -alkanol, which in the terminal alkyl moiety is substituted by phenyl, heteroaryl, carboxyl, C 1-6 -alkanol; ₃ -alkoxycarbonyl, aminocarbonyl, C 1-3 -alkylaminocarbonyl or di- (C _1-3 -alkyl) aminocarbonyl,

C 1-6 -alkanol substituted in the terminal alkyl moiety with a chlorine atom or a hydroxy-, C 1-6 -alkyl group. _3- alkoxy-, amino-, C 1-6 -alkyl; _3- alkylamino- or di- (C _1-3 -alkyl) amino-, amino, or methylamino, ethylamino or di- (C 1-2 -alkyl) amino, which may optionally be substituted in the 2-position of the ethyl group by hydroxy or C 1-6 alkyl; ₃ -alkoxy-.

· 9 • 9 9 9 999 999 9 · · · 9 9 9 9 9 999 9 999 999 9 999 999 999 999 999 ·· ··· ·· ····

The esterification or amidation is preferably carried out in a solvent environment 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 temperatures between 20 ° C and reflux temperature. the solvent used. The conversion is carried out with the appropriate acid, preferably in the presence of a water-removing agent, for example in the presence of isobutyl chloroformate, tetraethyl carbonate, methyl orthoacetic acid, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, phosphorochlorosilicon, phosphorochlorite N, N -dicyclohexylcarbodiimide, N, N -dicyclohexylcarbodiimide, N-hydroxysuccinimide, N, N-dicyclohexylcarbodiimide, 1-hydroxy-benzotriazole, 2- (1H-benzotriazol-1-yl) -

1,1,3,3-tetramethyluronium tetrafluoroborate, 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate / 1-hydroxybenzotriazole, N, N-carbonyldiimidazole or triphenylphosphine % of carbon tetrachloride and optionally with an addition of a base such as pyridine, 4-dimethylaminopyridine, N-methylmorpholine or triethylamine, suitably at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 100 ° C, and acylation is carried out with the appropriate reactive compound such as anhydride, ester, imidazolide or halide optionally in the presence of a tertiary organic base such as triethylamine, N-ethyldiisopropylamine or N-methylmorpholine at temperatures between 0 and 150 ° C, preferably at temperatures between 50 and 100 ° C.

c) Preparation of a compound of formula I wherein R ⁴ is C 1-4 alkyl substituted with R ⁷ wherein

R ⁷ is amino-, C 1-7 -alkylamino-, di- (C 1-7 -alkyl) -amino-, phenylamino-, N -phenyl-C 1-4 -alkyl-amino-, phenyl-C 1-7 -alkyl-amino -, N- (C _1-3 -alkyl) phenyl-C 1-6 alkyl; _3- alkylamino- or di- (phenyl-C _1-3 -alkyl) -amino-, α-hydroxy-C ₂ . ₃ -alkylamino, N- (C ₃ -alkyl) -O-C _2-hydroxy-3 -alkylamino, di- (hydroxy-ro-C _{second 3-alkyl)} amino, di (CO- (C ₃ -alkoxy) -C ₂ 3-alkyl) -aminoalebo / N- (dioxolan-2-yl) -C. _3- alkyl-amino-; _{3-alkylcarbonylamino} C _{2nd 3-} alkyl-amino- or C 1-6 alkyl; ₃ -alkylkarbonyla no I-C _{2nd 3-a} I kyl-A / - _(3-al C 1 alkyl) -amino innovators, • · · · ·

· · · · · · · · · · · · · · · · · · · · ·

99 ·· ··· ·····

-41 C1-3-alkylsulfonylamino-, N - (C1-3-alkyl) - C1-3-alkylsulfonylamino-, C1-3-alkylsulfonylamino-C2-3-alkylamino- or C1-3-alkylsulfonylamino-C _2,3 -alkyl- N - (C _1-3 -alkyl) -amino-, a group of formula III

-N (R °) - (CH _{2) m} - (CO) _a R ¹¹ (III) wherein

R ¹⁰ represents a hydrogen atom, a C 1-6 alkyl group, a C 1-6 alkyl group or a C 1-6 alkyl group; _3- alkylcarbonyl, arylcarbonyl, phenyl-C 1-3 -alkylcarbonyl, C 1-3 -alkylsulfonyl, arylsulfonyl or phenyl-C 1-3 -alkylsulfonyl, m is 1, 2, 3 or 4, o is 1 and

R ¹¹ represents amino-, C 1-4 -alkylamino-, di- (C 1-4 -alkyl) -amino-, phenylamino-, N- (C 1-4 -alkyl) -phenylamino-, benzylamino-, N - (C 1-4-) alkyl) benzylamino-, C 1-3 -alkoxy- or C 1-3 -alkoxy-C 1-3 -alkoxy-, optionally C _1-3 -alkyl- substituted di- (C 1-4 -alkyl) amino-C _1-3 -alkylamino- or a 4- to 7-membered cycloalkyleneimine group, wherein the cycloalkylene moiety may be fused to the phenyl ring, or the methylene group at the 4-position of a 6-membered or 7-membered cycloalkyleneimine group may be replaced by an oxygen or sulfur atom; sulfinyl-, sulfonyl-, -NH- -, - (C 1-6 -alkyl) -, - N - (phenyl) -, - N - (C _1-3 -alkylcarbonyl) - or -N (benzoyl) -, a C 4-7 -cycloalkylamino- group, C 4-7 cycloalkyl-Ci-3-alkylamino or C4-7cykloalkenylamino-, wherein the position of the ring 1 not involved in the double bond, and wherein said radicals may be additionally substituted at the amino nitrogen atom by C-7-cycloalkyl, _C2 _4-olefins 1- or C _1-4 -alkyl-, or a 4-7 membered cycloalkyleneimine group, the cycloalkylene moiety of which may be fused with a phenyl group or with an oxazolo-, imidazolo-, thiazolo-, pyridino-,

-42-pyrazino- or pyrimidino-, optionally substituted with a fluorine, chlorine, bromine or iodine atom, a nitro-, a C 1-3 -alkyl-, a C 1-3 alkoxy or an amino group and in which one or two hydrogen atoms may be replaced by a C 1-3 alkyl group, _7 _{C5-cycloalkyl} or phenyl, and / or wherein a methylene group in position 3 of five cykloalkylénimínovej group may be substituted by hydroxy, hydroxy-C-i_ ₃ -alkyl, C. _{A 3-} alkoxy- or C 1-3 -alkoxy-C 1-3 alkyl group in which the methylene group at the 3- or 4-position of a 6-membered or 7-membered cycloalkyleneimine group may be substituted with a hydroxy group, hydroxy-C 1-6 -alkyl. _{A 3-} alkyl group, a C 1-3 alkoxy- group, a C 1-6 alkyl group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 1-6 alkyl group, a C 1-6 _3- alkoxy-Ci. _3- alkyl, carboxyl, C 1-4 -alkoxycarbonyl-, aminocarbonyl-, C 1-3 -alkylaminocarbonyl-, di- (C _1-3 -alkyl) aminocarbonyl-, phenyl-C 1-6 -alkyl; _3- alkylamino- or N - (C _1-3 -alkyl) -phenyl-C 1-6 alkyl; _{The 3-} alkylamino-, or said methylene group may be replaced by an oxygen or sulfur atom, a sulfinyl-, sulfonyl-, -NH-, - (V (C _1-3 -alkyl) -, -A / (phenyl) -, -) group. N (phenyl-C _1-3 -alkyl) -, - N - (C _1-3 -alkylcarbonyl) -, - N - (C 1-4 -alkoxycarbonyl) -, -A / (benzoyl) - or -A (phenyl-C 1-3 -alkylcarbonyl) -, wherein the methylene group which is bonded to the imine nitrogen atom of the cycloalkyleneimine group may be replaced by a carbonyl group or a sulfonyl group, or in a 5- to 7-membered monocyclic or phenyl group fused cycloalkyleneimine group both the methylene groups bonded by an imine nitrogen atom may be replaced by carbonyl groups by conversion of a compound of formula XI. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

in which

R ¹ , R ⁵ and X are defined as above,

R ² 'has the same meaning as R ² above,

R ¹⁸ represents a hydrogen atom or a nitrogen protecting group of the lactam group, wherein one of the radicals R ² and R ¹⁸ can optionally form a solid phase bond via the Spacer and the other of said radicals as defined above, and A represents C 1-4; an alkyl group; and

Z ² is an exchangeable group, for example an alkyl or arylsulfonyloxy group such as methylsulfonyloxy, ethylsulfonyloxy, p-toluenesulfonyloxy or trifluoromethanesulfonyloxy, with an amine of formula XII

H - R ⁷ '(XII) wherein

R ⁷ 'has the same meaning as R ^{7 above} and, if desired, subsequent cleavage of the protecting group used from the nitrogen atom of the lactam group or from the solid phase.

The conversion is conveniently carried out in a solvent environment such as methylene chloride, tetrahydrofuran, 1,4-dioxane, toluene, acetonitrile, dimethylsulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone or mixtures thereof, optionally with the addition of water as a co-solvent and / or with an addition. an inert auxiliary base, for example sodium bicarbonate, pyridine, 2,4,6-trimethylpyridine, quinoline, triethylamine, N-ethyldiisopropylamine, N-ethyl-dicyclohexylamine, • ······························································

1,4-diazobicyclo [2.2.2] octane or 1,8-diazobicyclo [5.4.0] -undec-7-ene, at temperatures between -50 and +100 ° C, preferably at temperatures between -10 and + 50 ° C, whereby the protective group used can be simultaneously cleaved off as a result of the amidation.

Any desired cleavage of the used nitrogen protecting group of the lactam group or cleavage from the solid phase is carried out as described in a.

If the compound of formula I of the present invention contains an alkoxycarbonyl group, it may be converted to the corresponding carboxyl compound by hydrolysis, or if the compound of formula I of the present invention contains an amino or alkylamino group, the compound may be converted to the corresponding alkylamino- or reductive alkylation. a dialkylamino compound or, if the compound of formula I of the present invention contains an amino or alkylamino group, the compound may be converted by acylation or sulfonation to the corresponding acyl or sulfonyl compound, or if the compound of formula I of the present invention contains a carboxyl group, by esterification or amidation to convert to the corresponding ester or aminocarbonyl compound, or if the compound of formula I contains a cycloalkyleneimine group in which one methylene group is replaced a sulfur atom, this may be converted by oxidation into a corresponding sulfinyl or sulfonyl compound, or the compound of formula I of the present invention, the nitro group, this may be converted by reduction into a corresponding amino compound, or a compound of formula I of the invention wherein R ⁴ is the group an amino-, alkylamino-, aminoalkyl- or N-alkyl-amino- substituted phenyl group, may subsequently be converted into the corresponding urea compound of formula I or the compound of formula I of the present invention by conversion with the appropriate cyanate, isocyanate or carbamoyl halide. R ⁴ represents an amino-, alkylamino-, aminoalkyl- or N -alkyl-amino- substituted phenyl group, possibly followed by conversion with the appropriate amidino group. ·· · · · ··· · · ··· · · ····

-45 by converting a group or by conversion with the corresponding nitrile to the corresponding guanidine compound of formula I.

The subsequent hydrolysis is preferably carried out in an aqueous solvent environment, for example 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; in the presence of an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C.

Subsequent reductive alkylation is preferably carried out in a suitable solvent such as methanol, methanol / water, methanol / water / ammonia, ethanol, ether, tetrahydrofuran, dioxane or dimethylformamide, optionally with an acid addition such as hydrochloric acid in the presence of active hydrogen, for example hydrogen in the presence. 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 temperatures between 0 and 100 ° C, preferably between 20 and 80 ° C.

Subsequent acylation or sulfonation is conveniently carried out with the appropriate free acid or the corresponding reactive compound such as the anhydride, ester, imidazolide or halide of the appropriate acid, preferably in a solvent environment such as methylene chloride, diethyl ether, tetrahydrofuran, toluene, dioxane, acetonitrile, dimethylsulfoxide or dimethylformamide oxide. in the presence of an inorganic or tertiary organic base at temperatures between -20 and 200 ° C, preferably at temperatures between 20 ° C and the boiling point of the solvent used. The conversion with the free acid may be carried out in the presence of an acid activating agent or in the presence of a water-withdrawing agent, for example in the presence of isobutyl chloroformate, tetraethyl carbonate, methyl orthoacetic acid, 2,2-dimethoxypropane, tetramethoxysilane, phosphorous chloride, phosphorous, N, N-dicyclohexylcarbodiimide, N, N '- dicyclohexylcarbodiimide (N -hydroxysuccinimide), N, N-dicyclohexylcarbodiimide / 1-hydroxybenztriazole, 2 (1H-benzotriazol-1-yl) -1,1 , 3,3-tetramethyluronium tetrafluoroborate, 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate / 1-hydroxybenztriazole, Ν, Ν ¹ carbonyldiimidazole or triphenylphosphine % of carbon tetrachloride and optionally with an addition of a base such as pyridine, 4-dimethylaminopyridine, N-methylmorpholine or triethylamine, suitably at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 1 Deň: 22 ° C. Conversion with the appropriate reactive compound can be carried out in the presence of a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine, N-methylmorpholine or pyridine, or using an anhydride in the presence of the appropriate acid at temperatures between 0 and 150 ° C, preferably at temperatures between 50 and 100 ° C.

Subsequent esterification or amidation is conveniently accomplished by conversion of the corresponding reactive carboxylic acid derivative with the appropriate alcohol or amine, as previously described.

The subsequent oxidation of the sulfur atom is preferably carried out in a solvent or solvent mixture, for example water, water / pyridine, acetone, methylene chloride, acetic acid, acetic acid / acetic anhydride, dilute sulfuric acid or trifluoroacetic acid, depending on the oxidizing agent used. -80 and 100 ° C.

The preparation of the corresponding sulfinyl compound of the formula I is carried out by oxidation with an equivalent of the oxidizing agent used, for example hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or formic acid at 0 ° C to 20 ° C, or acetone at 0 to 60 ° C, with peroxyacid such as is permetic acid in glacial acetic acid or trifluoroacetic acid at 0 to 50 ° C, or with m-chloroperbenzoic acid in methylene chloride, chloroform or dioxane at -20 to 80 ° C, with potassium periodate in aqueous methanol or ethanol at -15 to 80 ° C 25 ° C, bromine in glacial acetic acid or aqueous acetic acid in the presence of a weak base such as sodium acetate, with N-bromosuccinimide in ethanol, with tert-butyl hypochlorite in methanol at -80 to -30 ° C, with iodobenzodichloride in aqueous pyridine at 0 to 50 ° C, with nitric acid in glacial acetic acid at 0 to 20 ° C, chromic acid in glacial acid seline acetic acid or acetone at 0 to 20 ° C and with sulfuryl chloride in methylene chloride at -70 ° C, and the thioether-chlorine complex thus obtained is conveniently hydrolyzed in aqueous ethanol.

The preparation of the corresponding sulfonyl compound of the formula I is carried out by oxidation starting from the corresponding sulfinyl compound, suitably with one or more equivalents of the oxidizing agent used or starting from the corresponding mercapto compound, conveniently by reaction with two or more equivalents of the oxidizing agent used, for example hydrogen peroxide in ice.

-47 acetic acid / acetic anhydride, in trifluoroacetic acid or formic acid at 20 to 100 ° C or in acetone at 0 to 60 ° C, with a peroxyacid such as permetic acid or m-chloroperbenzoic acid in glacial acetic acid, in trifluoroacetic acid, methylene chloride or chloroform at temperatures between 0 and 60 ° C, with nitric acid in glacial acetic acid at 0 to 20 ° C, with chromic acid, sodium periodate or potassium permanganate in acetic acid, water / sulfuric acid or acetone at 0 to 60 ° C Deň: 18 ° C.

Subsequent reduction of the nitro group is preferably carried out hydrogenolytically, for example with hydrogen in the presence of a catalyst such as palladium on carbon or Raney nickel in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid, optionally with an acid addition such as hydrochloric acid or glacial acetic acid, at temperatures between 0 and 50 ° C, preferably at room temperature and at a hydrogen pressure of about 1 to 7 bar, but preferably from 0.3 to 5 MPa ( from 3 to 5 bars).

The subsequent preparation of the corresponding urea compound of the formula I is conveniently carried out by treatment with an inorganic cyanate or the corresponding isocyanate or carbamoyl chloride, preferably in a solvent such as dimethylformamide and optionally in the presence of a tertiary organic base such as triethylamine at temperatures between 0 and 50 ° C. rooms.

The subsequent preparation of the corresponding guanidine compound of the formula I is conveniently carried out by conversion with a compound which carries an amidino- group such as 3,5-dimethylpyrazole-1-carboxyamidine, preferably in a solvent environment such as dimethylformamide and optionally in the presence of a tertiary organic base such as triethylamine at temperatures between 0 and 50 ° C, preferably at room temperature.

In the above-described conversions, optional reactive groups such as carboxy, hydroxy, amino, alkylamino or imino- can be protected during the conversion by conventional protecting groups which can be cleaved again after the conversion.

Protecting groups for the carboxyl group include, for example, trimethylsilyl-, methyl-, ethyl-, tert-butyl-, benzyl- or tetrahydropyranyl- and hydroxy-, amino-, alkylamino-protecting groups. or imino- are suitable, for example, acetyl-, trifluoroacetyl-, benzoyl-, ethoxycarbonyl-, tert-butoxycarbonyl-, benzyloxycarbonyl-, benzyl-, methoxybenzyl- or 2,4-dimethoxybenzyl- groups, and in addition to the phthalyl group to protect the amino group.

Optional subsequent cleavage of the protecting group used may be carried out, for example, 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 or sulfuric acid, or in the presence of an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide, at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C.

Cleavage of the benzyl-, methoxybenzyl- or benzyloxycarbonyl radical can also be carried out by hydrogenolysis, for example with 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. by adding an acid such as hydrochloric acid or glacial acetic acid at temperatures between 0 and 50 ° C, but preferably at room temperature, and under a hydrogen pressure of about 1 to 7 bar, preferably 0.3 to 7 bar. 0.5 MPa (3 to 5 bar).

Cleavage of the methoxybenzyl group can also be carried out in the presence of an oxidizing agent such as ammonium cerium nitrate in a solvent environment such as methylene chloride, acetonitrile or acetonitrile / water at temperatures between 0 and 50 ° C, preferably at room temperature.

The cleavage of the 2,4-dimethoxybenzyl moiety can preferably be carried out in trifluoroacetic acid in the presence of anisole.

The cleavage of the tert-butyl or tert-butyloxycarbonyl moiety can preferably be carried out with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane, ethyl acetate or ether.

The cleavage of the phthalyl residue may preferably be carried out in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent environment such as methanol, ethanol, isopropanol, toluene / water or dioxane at temperatures between 20 and 50 ° C.

-49 ·· ·············

The prepared chiral compounds of formula I may be further subdivided into their enantiomers and / or diastereomers.

For example, the racemate compound of formula I prepared can be resolved into optical antipodes by methods generally known per se (see: Allinger N.L. and Eliel E.L. in Topics in Stereochemistry, Vol. 6. Wiley Interscience, 1871); compounds of the formula I having at least 2 asymmetric carbon atoms can be separated into their diastereomers by methods known per se, for example by chromatography and / or fractional crystallization, because of their different physico-chemical properties; when obtained in racemic form, they can be further resolved into their enantiomers as described above.

The enantiomeric resolution may advantageously be carried out by separation on a chiral phase column, or by recrystallization from an optically active solvent, or by conversion with a substance which forms optically active salts or derivatives with the racemic compound, in particular with acids or their activated derivatives or with alcohols, diastereomeric salts or derivatives, for example because of their different solubility, and free antipodes can be released from the pure diastereomeric salts or derivatives by treatment with suitable agents. Particularly useful are the optically active acids, for example, the D- and L-forms of tartaric acid, dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, N-acetylglutamic acid, aspartic acid, VV -acetylaspartic acid or choline acid. Suitable optically active alcohols include, for example, (+) or (-) menthol, and as the optically active acyl residue in amides, for example, (+) or (-) methyloxycarbonyl is suitable.

The prepared compounds of the formula I can be further converted into salts, in particular for pharmaceutical use, into physiologically acceptable salts with inorganic or organic acids. Suitable are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, maleic acid or methanesulfonic acid.

In addition, the novel compounds of formula (I), if they contain a carboxyl group, can then be converted into their inorganic salts, or

• · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Organic bases, in particular for pharmaceutical use for physiologically acceptable salts. Suitable bases are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

The starting materials of the formulas VII to XII are either known from the literature or can be prepared in the literature by the methods described, since they can be prepared by the methods described in the description or in the Examples. For example, compounds of formula (IX) are described in German patent application 198 24 922.5. Further, compounds of formula XI are available from compounds of formula I wherein R ⁴ in the alkyl moiety is a hydroxy substituted C 1-4 -alkyl-phenyl group, for example by conversion with alkyl or arylsulfonyl chlorides.

It has already been mentioned that the novel compounds of formula I, wherein ^R1 is a hydrogen atom or a prodrug group have valuable pharmacological properties, particularly inhibitory effects on various kinases, especially receptor tyrosine kinases such as VEGFR2, PDGFR, PDGFR, FGFR1, FGFR3, EGFR , HER2, IGF1R and HGFR as well as cyclin dependent kinases (CDKs) such as CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8 and CDK9 with their specific cyclins (A, B1, B2 , C, D1, D2, D3, E, F, G1, G2, H, I and K) and on viral cyclins, on proliferatively cultured human cells, especially endothelial cells, for example in angiogenesis, but also on the proliferation of other cells , especially tumor cells.

The biological properties of the novel compounds were tested using the following standard procedures.

Human umbilical cord endothelial cells (Humane Nabelschnur Endothelzellen, HUVEC) were cultured in IMDM medium (Gibco BRL) supplemented with 10% fetal bovine serum (FBS, Sigma), 50 μΜ β-mercaptoethanol (Fluka), standard antibiotic, 15 pg. ml @ ¹ endothelial growth factor / ECGS, Collaborative Biomedical Products) and 100 pg.mľ ¹ heparin (Sigma) on gelatin-coated culture flasks (0.2% strength gelatine, Sigma) at 37 ° C in a 5% CO _2, and saturated with water vapor.

To monitor the inhibitory potency of the compounds of this invention, cells were starved for 16 hours, i.e., maintained in a culture medium free of the culture medium. ··· ··· ···· · ·· ··· ···························································

-51 growth factors (ECGS + heparin). Cells were detached from the culture flasks with trypsin / EDTA and washed once in serum. They were then seeded at a density of ^2.5 x 10 ³ cells per well.

Cell proliferation was stimulated by 5 ng.ml ₆ 5 ¹ VEGF (vascular endothelial growth factor; H. Weich, GBF Braunschweig) and 10 pg.mľ ¹ heparin. There were six unstimulated wells per control in each culture plate.

The compounds of this invention were dispersed in 100% dimethylsulfoxide and various dilutions were prepared for triplicate assays, with a maximum dimethylsulfoxide concentration of 0.3%.

The cells were incubated for 76 hours at 37 ° C, then ³ H-thymidine (0.1 µl Ci / well, Amersham) was added for an additional 16 hours to determine DNA synthesis. The radiolabeled cells were then immobilized on the filter tissue and the incorporated radioactivity was determined using a β-counter. Mean values of unstimulated cells that were subtracted from the mean values of stimulated cells (in the presence and absence of compounds of the invention) were used to determine the inhibitory effect of the compounds of the invention.

The relative proliferation in percent of control (HUVEC without inhibitor) was calculated and the effective concentration was deduced to reduce cell proliferation to 50% (IC 50).

By way of example, test results of the following compounds (a) to (s) of the general formula I are given:

(a) 3-Z- [1- (4- (piperidin-1-yl-methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (b) 3-Z - [(1- (4- (piperidin-1-ylmethyl) -anilino) -1-phenyl-methylene] -6-carbamoyl-2-indolinone, (c) 3-Z- [1- (4- (piperidine- 1-yl-methyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (d) 3-Z- [1- (4- (dimethylaminomethyl) -anilino) -1-phenyl-methylene] - 6-ethoxycarbonyl-2-indolinone, (e) 3-Z- [1- (4 - ((2,6-dimethyl-piperidin-1-yl) -methyl) -anilino) -1-phenyl-methylene] - 6-ethoxycarbonyl-2-indolinone, 6-ethoxycarbonyl-2-indolinone, 6-ethoxycarbonyl-2-indolinone, 6-ethoxycarbonyl-2-indolinone, (F) 3-Z- [1- (4- (N - (2-dimethylamino-ethyl) - N -acetyl-amino) -anilino) -1-phenyl-methylene] -6- ethoxycarbonyl-2-indolinone, (g) 3-Z- [1- (4 - (N - (3-dimethylamino-propyl) - N -acetyl-amino) -anilino) -1-phenyl-methylene] -6 - ethoxycarbonyl-2-indolinone, (h) 3-Z- [1- (4- (N - (2-dimethylamino-ethyl) - N -methylsulfonylamino) -anilino) -1-phenylmethylene] - 6-ethoxycarbonyl-2-indolinone, (i) 3-Z- [1- ( 4- (dimethylaminomethyl) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (j) 3-Z- [1- (4- (N-acetyl- N -dimethylaminocarbonylmethyl-amino)) (anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (k) 3-Z- [1- (4-ethylaminomethyl-anilino) -1-phenylmethylene] -6-methoxycarbonyl-2- (1) 3-Z- [1- (4- (1-methyl-imidazol-2-yl) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (m) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl- N -methylamino) anilino) -1-phenylmethylene] -

6-methoxycarbonyl-2-indolinone, (n) 3-Z- [1- (4 - (N - (2-dimethylaminoethyl) - N -methylsulfonylamino) anilino) -1-phenylmethylene] -

6-methoxycarbonyl-2-indolinone, (o) 3-Z- [1- (4- (N - (3-dimethylamino-propyl) - N -methylsulfonyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (p) 3-Z- [1- (4- (N-dimethylaminocarbonylmethyl-N-methylsulfonylamino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl- 2-indolinone, (q) 3-Z- [1- (4 - (N - ((2-dimethylamino-ethyl) -carbonyl) - N -methyl-amino) -anilino) -1-phenyl-methylene] 6-Methoxycarbonyl-2-indolinone, (R) 3-Z- [1- (4 - (N - (2-dimethylamino-ethyl) - N -acetyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone and (s) 3-Z- [1- (4-methylaminomethyl-anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone.

The following table contains the determined values:

compound IC ₅₀ [μΜ] (A) 0.04 (B) 0.35 (C) 0.01 (D) 0.02 (Θ) 0.05 (F) 0.01 (G) 0,003 (H) 0.01 (I) 0.03 (J) 0.02 (A) 0.03 (I) 0.1 (M) 0.02 (N) 0.02 (about) 0.01 (P) 0.02 (Q) 0.02 (L) 0.01 (with) 0.04

Because of their inhibitory effects on cell proliferation, in particular on the proliferation of endothelial cells and tumor cells, said compounds of formula I are useful in the treatment of diseases associated with the proliferation of cells, especially endothelial cells.

For example, endothelial cell proliferation and associated neovascularization is one of the critical steps in cancer development (Folkman J. et al., Nature 339. 58-61 (1989); Hanahan D. and Folkman J., Cell 86, 353-365 (1996). )). Furthermore, endothelial cell proliferation is also important in hemangiomas, metastasis, rheumatoid arthritis, psoriasis, and ocular neovascularization (Folkman J., Nature Med. 1, 27-31 (1995)). Therapeutic Need for Inhibitors

· · · · · · ··· · · · • · • · • · • • · • · • · • · • · · · · • · • • · · · · 4 · · • • · · • • · • • · • • · • · · · · > · · · · · · ····

endothelial cell proliferation has been demonstrated in an animal model as disclosed, for example, by O'Reilly et al. and Parangi et al. (O'Reilly MS et al., Cell 88, 277-285 (1997); Parangi S. et al., Proc. Natl. Ac. Sci USA 93, 2002-2007 (1996)).

The compounds of the formula I, their tautomers, stereoisomers or their physiologically tolerable salts are therefore suitable, for example, for the treatment of tumors (e.g., epithelial cell carcinoma, astrocytoma, Kaposi's sarcoma, glioblastoma, lung cancer, respiratory cancer , prostate cancer, breast cancer, polycellular lung cancer, glioma, colorectal tumors, urogenital cancers such as polymyeloma), psoriasis, arthritis (e.g., rheumatoid arthritis), hemangioma, abgiofibroma, eye diseases (e.g., diabetic retinopathy) glomerulonephritis), diabetic nephropathy, malignant nephrosclerosis, microangiopathic thrombic syndrome, transplant rejection and glomerulopathy, fibrotic diseases (e.g. liver cirrhosis), proliferative mesangiab cell diseases, arteriosclerosis nerve tissue damage, and for suppressing vascular reocclusion after balloon catheter treatment, vascular prosthesis, or mechanical vessel opening devices (e.g., stents), or other diseases characterized by cell proliferation or angiogenesis.

Because of their biological properties, the compounds of the invention can be used alone or in combination with other pharmacologically active substances, for example in tumor therapy as monotherapy or in combination with other anti-cancer drugs, for example in combination with topoisomerase inhibitors (e.g. Etoposide), mitosis inhibitors (e.g. Vinblastine, Taxol), compounds that interact with nucleic acids (e.g. cis-Platin, Cyclophosphamide, Adriamycin), hormone antagonists (e.g. Tamoxifen), inhibitors of metabolic processes (e.g. 5-FU and others) , cytokines (e.g., interferons), kinase inhibitors, antibodies, or also in combination with radiation therapy and the like. Said combinations may be used simultaneously or sequentially.

For pharmaceutical use, the compounds of this invention are generally used in warm-blooded animals, particularly humans, in doses of 0.01 to 100 mg.kg ^-1 body weight. ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

-55hmotnosti, preferably 0.1 to 20 mg.kg ^"1 of body weight. The compounds of the invention are generally formulated for administration with one or more conventional inert carriers and / or diluents, for example, corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, water, tartaric acid, water, water. / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, stearyl alcohol, carboxymethylcellulose or fat-containing substances such as hardened fat, or with suitable mixtures thereof to form a conventional galenic preparation such as tablets, dragees, capsules, powders injectable solutions, ampoules, suspensions, solutions, sprays or drops.

Abbreviations used:

FMOC = 9-fluorenylmethoxycarbonyl HOBt = 1-hydroxy-1H-benzotriazole TBTU = O-benzotriazol-1-yl- N, N, N, N, N-tetramethyluronium tetrafluoroborate DBU = 1,8-diazobicyclo [5.4.0 ] IDEC-7-ene.

The invention is illustrated by the following examples.

DETAILED DESCRIPTION OF THE INVENTION

Preparation of the starting compounds

Preparation 1 using solid phase

Rink resin (MBHA resin, Novabiochem) (2.0 g) was swelled in 30 ml of dimethylformamide. Then 40 mL of 30% piperidine in dimethylformamide was added and the mixture was shaken for 7 minutes until the FMOC protecting group was cleaved. The resin was then washed several times with dimethylformamide. Then 0.4 g of 2-indolinine-6-carboxylic acid (prepared similarly to Langenbeck et al., Justus Liebigs Ann. Chem. 499. 201-208 (1932)), 297 mg HOBt, 706 mg TBTU and 0, 9 ml of N-ethyl-diisopropylamine in 30 ml of dimethylformamide and the reaction mixture was shaken for one hour. The solution was then separated from the resin by suction and the resin was washed five times with 30 ml of dimethylformamide and two times with 30 ml.

9 • 9

-56metylénchloridu. It was dried by flushing with nitrogen. The product yield was 1.9 g of saturated resin.

Preparation 2 using solid phase

1.9 g of the prepared resin were stirred with 6 ml of acetic anhydride and 6 ml of triethyl orthobenzoate at 110 ° C for 3 hours. The reaction mixture was then allowed to cool, the resin was washed with dimethylformamide and then with methylene chloride. Yield: 1.9 g wet resin.

Similar to Preparation 2, the following saturated resins were prepared:

(1) a resin saturated with 3-Z- (1-ethoxy-methylene) -6-carbamoyl-2-indolinone; prepared from the resin prepared in Example I by conversion with triethyl orthoformate, (2) a resin saturated with 3-Z- (1-methoxy-1-methyl-methylene) -6-carbamoyl-2-indolinone; prepared from the resin prepared in Example I by conversion with trimethyl orthoacetate; (3) a resin saturated with 3-Z- (1-methoxy-1-ethyl-methylene) -6-carbamoyl-2-indolinone; prepared from the resin prepared in Example I by conversion with trimethyl orthopropionate; (4) a resin saturated with 3-Z- (1-methoxy-1-propylmethylene) -6-carbamoyl-2-indolinone; it was prepared from the resin prepared in Example I by conversion with trimethyl orthobutyrate.

Preparation of N - (4-Nitrophenyl) - N -methyl-methanesulfonamide

3.0 g of N-methyl-4-nitroaniline was dissolved in 20 ml of pyridine and 2.4 g of methanesulfonic acid chloride was added dropwise at room temperature. The reaction mixture was stirred at room temperature for 12 hours. The mixture was then poured into water and the precipitate formed was filtered off and dried in vacuo at 50 ° C. Yield: 4.0 g (87% of theory);

Rf value: 0.5 (silica gel, ethyl acetate / toluene = 7: 3). Mp 107-108 ° C.

·································································································· • · · ························

Preparation of N - (2-Dimethylamino-ethyl) - N -methylsulfonyl-4-nitroaniline

38.9 g of N-methylsulfonyl-4-nitroaniline were dissolved in 2.0 liters of acetone, 51.9 g of 1-chloro-2-dimethylaminoethane, 77.4 g of potassium carbonate and 5.0 g of sodium iodide were added. and the mixture was stirred together at 50 ° C for 4 days, after which an additional 25.9 g of 1-chloro-2-dimethylaminoethane, 49.8 g of potassium carbonate and 5.0 g of sodium iodide in 500 ml of acetone were added after 12 hours. and after 36 hours an additional 26.0 g of 1-chloro-2-dimethylaminoethane, 50.0 g of potassium carbonate and 5.0 iodide in 100 ml of acetone were added. After this time, the batch was filtered and the filtrate was concentrated. The residue was stirred in ether, filtered with suction and dried at 40 ° C. Yield: 25.3 g (49% of theory);

Rf value: 0.5 (silica gel, methylene chloride / methanol / ammonia = 9: 1: 0.1). C11H17N3O4S

ESI-MS: m / z = 288 [M + H] +.

Similar to Preparation 4, the following compounds were prepared:

(1) 4- [N- (3-dimethylamino-propyl) - N -methylsulfonylamino] -nitrobenzene (2) N-carboxymethyl- N -methylsulfonyl-4-nitroaniline (3) N -cyanomethyl - N -methylsulfonyl-p-phenylenediamine (4) 4- [N - (2- (N-benzyl-N-methyl-amino) -ethyl) - N -methylsulfonyl-amine-nitrobenzene (5) 4 - [N- (3-phthalimido-2-yl-propyl) - N -methylsulfonylamino] - nitrobenzene (6) 4- [N - (3- (N-benzyl-N-methyl-amino) ) propyl) - / \ / - methylsulphonyl-amino] -nitrobenzene.

Preparation of N - (Dimethylaminocarbonyl-methyl) - N -methylsulfonyl-4-nitro-aniline

7.0 g of N-carboxymethyl- N -methylsulfonyl-4-nitroaniline, 2.5 g of dimethylaminohydrochloride, 8.1 g of TBTU and 3.9 g of HOBT were dissolved in 125 ml of dimethylformamide and 17 at 0 ° C were added. 6 ml of N-ethyldiisopropylamine. The reaction mixture was stirred at room temperature for 4 hours, diluted with 1 liter of water and the precipitate formed was collected.

-58odsávaním. After washing with water ethanol and ether, the residue was dried at 70 ° C under vacuum.

Yield: 5.3 g (69% of theory);

Rf value: 0.40 (silica gel, methylene chloride / methanol = 9: 1), C11H15N3O5S

ESI-MS: m / z = 300 [M-H] -.

Similar to Preparation 5, the following compounds were prepared:

(1) 4 - [(N-dimethylaminocarbonylmethyl) amino] nitrobenzene, prepared by the reaction of 4- (N-carboxymethyl-amino) -nitrobenzene and dimethylamine hydrochloride, (2) 4- (N-methylaminocarbonylmethyl- N -methylsulfonylamino) -nitrobenzene, prepared by the reaction of N-carboxymethyl- N -methylsulfonyl-4-nitroaniline and methylamine hydrochloride, (3) 4 - [N - (methylcarbamoyl-methyl) - N -methylamino) methyl] nitrobenzene, prepared by reaction 4 - [(N-carboxymethyl- N -methyl-amino) -methyl] -nitrobenzene and methylamine hydrochloride, (4) 4 - [N - (dimethylcarbamoyl-methyl) - N -methyl-amino) -methyl] nitrobenzene , prepared by the reaction of 4 - [(N-carboxymethyl- N -methyl-amino) -methyl] -nitrobenzene and dimethylamine hydrochloride.

Preparation 6 4- [N- (2-Dimethylamino-ethyl) - N-acetylamino] methyl] nitrobenzene

3.6 g of 4- (2-dimethylamino-ethylamino) nitrobenzene (according to Gabbay et al., J. Am. Chem. Soc. 91, 5136 (1969)) was dissolved in 50 ml of methylene chloride and 5.0 ml of triethylamine was added. Acetyl chloride (1.3 mL) was then slowly added dropwise to this mixture at room temperature and the mixture was stirred at room temperature for 2 hours. Then, triethylamine (5.0 mL) and acetyl chloride (1.3 mL) were added again and the reaction mixture was heated at reflux for an additional two hours. The solvent was then removed, the residue was triturated with ethyl acetate and the organic phase was washed twice with water. After drying over anhydrous magnesium sulfate, the solvent was removed and the residue was dried in vacuo.

································ ··················································

-59The product yield was 2.0 g (45% of theory),

Rf value: 0.55 (silica gel, methylene chloride / methanol / ammonia = 9: 1: 0.1),

C12H17N3O3

ESI-MS: m / z = 252 [M + H] &lt; ^{+ &gt};.

As in Preparation 6, the following compounds were prepared:

(1) 4- [N - (3-dimethylamino-propyl) - N -acetyl-amino] -nitrobenzene, prepared by the reaction of 4- (3-dimethylamino-propylamino) -nitrobenzene (according to Gabbay et al., J. Am. Chem. Soc., 91, 5136 (1969)) and acetyl chloride, (2) 4- [N - (2-dimethylamino-ethyl) - N -propionyl-amino] -nitrobenzene, prepared by the reaction of 4- (2-dimethylamino) (3) 4- [N-acetyl-N - (dimethylaminocarbonylmethyl) amino] nitrobenzene, prepared by the reaction of 4 - [N - (dimethylaminocarbonylmethyl) amino] nitrobenzene and acetyl chloride, ( 4) 4- [N - (2-dimethylamino-ethyl) - N -butyrylamino-nitrobenzene, prepared by the reaction of 4- (2-dimethylamino-ethylamino) -nitrobenzene and butyryl chloride, (S) 4 - [N - (2-dimethylamino-ethyl) - N -isobutyryl-amino] nitrobenzene, prepared by reaction

4- (2-dimethylamino-ethylamino) -nitrobenzene and isobutyryl chloride, (6) 4- [N- (2-dimethylamino-ethyl) - N -benzoylamino] -nitrobenzene, prepared by reaction of 4- (2-dimethylamino-ethylamino) ) -nitrobenzene and benzoyl chloride, (7) 4- [N- (2-dimethylamino-ethyl) - N -acetyl-amino] -1,3-dinitrobenzene, prepared by the reaction of 4- (2-dimethylamino-ethyl-amino) - 1,3-dinitrobenzene and acetyl chloride, (8) 4- [N - (2-dimethylamino-ethyl) - N - (furan-2-carbonyl) amino] nitrobenzene, prepared by reaction of 4- (2-dimethylamino-ethylamino) (9) 4- [N - (2-dimethylamino-ethyl) - N - (2-methoxy-benzoyl) -amino] -nitrobenzene, prepared by reaction of 4- (2-) -nitrobenzene and furan-2-carbonyl chloride; (10) 4- [N - (2-dimethylamino-ethyl) - N - (pyridine-3-carbonyl) amino] nitrobenzene, prepared by reaction of 4- (dimethylamino-ethylamino) -nitrobenzene and 2-methoxy-benzoyl chloride; 2-dimethylamino-ethylamino) -nitrobenzene and nicotinic acid chloride, (11) 4- [N - (2-dimethylamino-ethyl) - N - (phenylacetyl) amino] nitrobenzene, prepared by reaction of 4- (2) dimethylamino-ethylamino) (12) 4- [N - (2-dimethylamino-ethyl) - N -acetyl-amino] -3-bromo-nitrobenzene, prepared by the reaction of 4 - [N - (2-dimethylamino-ethyl) -nitrobenzene and phenylacetyl chloride; ) -amino] -3-bromo-nitrobenzene and acetyl chloride, · · · · · · · · · · · · · · · (13) N-acryloyl-N-methyl-4-nitro-aniline, prepared by the reaction of 4-methylamino-nitrobenzene and acrylic acid chloride, (14) N-acryloyl-N-isopropyl-4- nitro-aniline, prepared by reaction of 4-isopropylaminonitrobenzene and acrylic acid chloride, (15) N-acryloyl- N -benzyl-4-nitro-aniline, prepared by reaction of 4-benzylamino-nitrobenzene and acrylic acid chloride, (16) / V - bromoacetyl-N-methyl-4-nitroaniline, prepared by reaction of 4-methylamino-nitrobenzene and bromoacetyl chloride, (17) N-bromoacetyl- N -isopropyl-4-nitroaniline, prepared by reaction of 4-isopropylaminonitrobenzene and bromoacetyl chloride, (18) N -Bromoacetyl- N -benzyl-4-nitroaniline, prepared by reaction for 4-benzylaminonitrobenzene and bromoacetyl chloride,

Preparation 7

A / - (dimethylaminomethylcarbonyl) - / V-methyl-4-nitroaniline

To 1.8 g of dimethylamine hydrochloride and 5.5 g of potassium carbonate in 80 ml of acetone was added 4.2 g of N-bromoacetyl-N-methyl-4-nitroaniline at room temperature in three portions. The reaction mixture was stirred at room temperature for 12 hours, then filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed twice with water, dried over anhydrous sodium sulfate and finally evaporated in a rotary evaporator.

Yield: 2.8 g (79% of theory), Rf value: 0.5 (silica gel, methylene chloride / methanol = 7: 3), m.p. 121-122 ° C.

As in Preparation 7, the following compounds were prepared:

(1) N - (piperidin-1-ylmethylcarbonyl) - N -methyl-4-nitroaniline, (2) N - (morpholin-4-ylmethylcarbonyl) - N -methyl-4-nitroaniline, (3) N - [(4-benzyl-piperazin-1-yl) -methylcarbonyl] - N -methyl-4-nitroaniline, (4) N - (pyrrolidin-1-ylmethylcarbonyl) - N - methyl-4-nitroaniline, (5) N - [(N-aminocarbonylmethyl- N -methyl-amino) -methylcarbonyl] - N -methyl-4-nitroaniline, ··········· · ································································ (6) N - [(N -benzyl- N -methyl-amino) -methylcarbonyl] - N -methyl-4-nitroaniline, (7) N / - [di- (2-methoxyethyl) amino-methylcarbonyl] - N -methyl-4-nitroaniline, (8) N - (dimethylaminomethylcarbonyl) - N -isopropyl-4-nitroaniline, (9) N - ( piperidin-1-ylmethylcarbonyl) -N-isopropyl-4-nitroaniline, (10) N - [(4-tert-butoxycarbonylpiperazin-1-yl) methylcarbonyl] -N-isopropyl-4-nitroaniline (11) N - [(N-benzyl- N -methyl-amino) -methylcarbonyl] - N -benzyl-4-nitroaniline, (12) N - (d) imethylaminomethylcarbonyl) - N -benzyl-4-nitroaniline, (13) N - (piperidin-1-ylmethylcarbonyl) - N -benzyl-4-nitroaniline, (14) N - [di- (2-hydroxyethyl) (1-amino-methylcarbonyl) - N -methyl-4-nitroaniline, (15) N - [N - (2-methoxyethyl) - N -methyl-amino) -methylcarbonyl) - N -methyl-4- (16) N - [(N - (2-dimethylamino-ethyl) - N -methylamino) methylcarbonyl] - N -methyl-4-nitroaniline, (17) N - [(4-methyl- piperazin-1-yl) methylcarbonyl] -N-methyl-4-nitroaniline, (18) N - [(imidazol-1-yl) methylcarbonyl] - N -methyl-4-nitroaniline, (19) / V - [(phthalimido-2-yl) methylcarbonyl] - / V-methyl-4-nitroaniline.

Preparation of N - [(2-Dimethylaminoethyl) carbonyl] -N-benzyl-4-nitroaniline

0.5 g of dimethylamine hydrochloride, 1.1 ml of triethylamine and 1.2 g of N -acroyl- N -benzyl-4-nitroaniline were dissolved in 50 ml of methanol. The solution was stirred at room temperature for 24 hours. The reaction mixture was then concentrated, and the residue was purified on an alumina column (2-3 activity) using methylene chloride and ethanol (50: 1) as eluent.

Yield: 1.4 g (98% of theory); Rf value: 0.8 (alumina, methylene chloride / ethanol = 20: 1); mp 73 DEG C .;

Similar to Preparation 8, the following compounds were prepared:

(1) N - [(2-dimethylamino-ethyl) -carbonyl] - N -isopropyl-4-nitroaniline, prepared by the reaction of N-acryloyl- N -isopropyl-4-nitroaniline and dimethylamine hydrochloride, (2) A) - [(2-dimethylamino-ethyl) -carbonyl] - N -methyl-4-nitroaniline, prepared by the reaction of Nakryloyl-N-methyl-4-nitroaniline and dimethylamine hydrochloride, (3) N - [(2- (4-tert-butoxycarbonyl-piperazin-1-yl) -ethyl) 1-carbonyl] - N -methyl-4-nitroaniline, prepared by the reaction of N -acryloyl- N -methyl-4-nitroaniline and N-tert-butoxycarbonylpiperazine, (4) N - [(2- (piperidine-1)) -yl) -ethyl) -carbonyl] -N-methyl-4-nitroaniline, prepared by the reaction of Nakryloyl- N -methyl-4-nitroaniline and piperidine, (S) N - [(2 - (N-benzyl- (N-methyl-amino) -ethyl) -carbonyl] - N -methyl-4-nitroaniline, prepared by the reaction of N-acryloyl- N -methyl-4-nitroaniline and N -benzyl- N -methyl- amine.

Preparation 9 4- (4-Methyl-piperazin-1-yl) -nitrobenzene

A mixture of 4-chloro-1-nitrobenzene (31.5 g) and 1-methylpiperazine (44.4 ml) was stirred at 90 ° C for 18 hours. The mixture was then poured into ice water and the precipitate formed was collected by suction filtration. The collected fraction was washed with water and recrystallized from ethanol / water (1: 1). The product was dried under vacuum at 75 ° C. Yield: 44.0 g (99% of theory),

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 10: 1), m.p. 108-112 ° C.

As in Preparation 9, the following compounds were prepared:

(1) N - (2-dimethylaminoethyl) - N -methyl-4-nitroaniline, prepared by the reaction of 1-fluoro-4-nitrobenzene and 1-dimethylamino-2-methylaminoethane, (2) N - (3-dimethylaminopropyl) - N -methyl-4-nitroaniline, prepared by the reaction of 1-fluoro-4-nitrobenzene and 1-dimethylamino-3-methylamino-propane, (3) 4- (N-carboxymethyl-amino) -nitrobenzene, prepared by the reaction of 1-fluoro- 4-nitrobenzene and glycine, (4) N -cyclohexyl-p-phenylenediamine, prepared by the reaction of 1-fluoro-4-nitrobenzene and cyclohexylamine, (S) 6 - [N - (2-dimethylamino-ethyl) -] - -methylsulfonylamino] -3-phthalimido-2-yl-nitrobenzene, prepared by the reaction of 2-nitro-4-phthalimido-2-yl-fluorobenene, N - (2-dimethylamino-ethyl) methanesulfonamide and sodium hydride as a base; (6) 6 - [N - (2-dimethylamino-ethyl) - N -methylsulfonyl-amino] -1,3- dinitrobenzene, prepared by the reaction of 2,4-dinitro-chlorobenzene, N- (2-dimethylamino-ethyl) -methanesulfonamide and sodium hydride as the base, (7) 4- [N- (2-dimethylamino-ethyl) - N -methylsulfonylamino] -3-chloronitrobenzene, prepared by reaction of 2-fluoro-5-nitro-chlorobenzene, N - (2-dimethylamino-ethyl) -methanesulfonamide and sodium hydride as a base, (8) 4- (2-dimethylamino-ethylamino) -1,3-dinitrobenzene, prepared by the reaction of 1-chloro-2,

4-dinitro-benzene and N, N -dimethylethylenediamine, (9) 4- [N - (2-dimethylamino-ethyl) - N - (ethylsulfonyl) amino] nitrobenzene, prepared by reaction of 1-fluoro-4- nitro-benzene, N- (2-dimethylamino-ethyl) -ethanesulfonamide and sodium hydride as the base, (10) 4- [N - (2-dimethylamino-ethyl) - N - (propylsulfonyl) -amino] - nitrobenzene, prepared by the reaction of 1-fluoro-4-nitro-benzene, N- (2-dimethylamino-ethyl) -propanesulfonamide and sodium hydride as a base, (11) 4- [N - (2-dimethylamino-ethyl) -] N - (butylsulfonyl) -amino] -nitrobenzene, prepared by the reaction of 1-fluoro-4-nitro-benzene, N - (2-dimethylamino-ethyl) -butanesulfonamide and sodium hydride hydride as the base, (12) 4 - [/ v] - (2-dimethylamino-ethyl) - N - (benzylsulfonyl) -amino] -nitrobenzene, prepared by the reaction of 1-fluoro-4-nitro-benzene, N - (2-dimethylaminoethyl) -phenylmethanesulfonamide and sodium hydride as a base, ( 13) 4- [N- (2-dimethylamino-ethyl) - N - (phenylsulfonyl) -amino] -nitrobenzene, prepared by the reaction of 1-fluoro-4-nitro-benzene, N - (2-dimethylamino-ethyl) (14) 4- [N- (2-dimethylamino-ethyl) - N - (isopropylsulfonyl) amino] nitrobenzene, prepared by the reaction of 1-fluoro-4-nitro-benzene N - (2-dimethylamino-ethyl) -isopropylsulfonamide and sodium hydride as a base, (15) 4 - [N - (2-dimethylamino-ethyl) -amino] -3-bromo-nitrobenzene, prepared by the reaction of 2-bromo (16) 4-isopropylamino-nitrobenzene, prepared by the reaction of 1-fluoro-4-nitrobenzene and isopropylamine, (17) 4-benzylamino-nitrobenzene , prepared by reacting 1-fluoro-4-nitrobenzene and benzylamine.

• · ·

-64Preparing 10

4- (imidazol-4-yl) -1-nitrobenzene

9.5 g of 2-phenylimidazole were cautiously dissolved in 50 ml of concentrated sulfuric acid and 5.8 g of ammonium nitrate was added to this solution at 0 ° C. After stirring at 0 ° C for 60 minutes, the mixture was poured into ice water, basified with aqueous ammonia solution and the precipitate formed was collected by suction filtration and recrystallized from ethanol.

Yield: 8.0 g (64% of theory), Rf value of the product: 0.6 (silica gel, ethyl acetate / ethanol = 10: 1),

C 9 H 7 N 3 O 2 Mass spectrum: m / z = 189 [M] ⁺ .

As in Preparation 10, the following compounds were prepared:

(1) 4- (imidazol-2-yl) -nitrobenzene, prepared by reaction from 4- (imidazol-2-yl) -benzene, (2) 4- (5-methyl-imidazol-4-yl) -nitrobenzene, prepared by reaction from 4-methyl-5-phenylimidazole (J. Heterocyclic. Chem. 1983, 20, 1277-1281).

Preparation 11

4- (2- (imidazol-4-yl) -ethylene) -nitrobenzene

1.5 g of 4-nitrobenzaldehyde and 7.45 g of (N-trityl-imidazol-4-ylmethyl) -triphenylphosphonium chloride were dissolved in 75 ml of tetrahydrofuran and 3 ml of DBU were added dropwise to the solution at room temperature. The reaction mixture was stirred at room temperature for 120 minutes and then poured into water, and the precipitate was collected by suction filtration. The product was slurried in 25 ml of dilute hydrochloric acid (I want 1 mol.dm &^lt; ^{3 &gt;} ) and refluxed for 4 hours. The solution was then neutralized with ammonia solution, extracted with ethyl acetate, and the organic phase was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was purified on a silica gel column using 10: 1 methylene chloride / methanol as eluent.

• ·

-65 Yield: 1.0 g (47% of th.)

Rf value of the product: 0.6 (silica gel, ethyl acetate / ethanol =

10: 1), mp 185-188 ° C.

Preparation 12

4- (piperidin-1-yl-methyl) nitrobenzene

40.0 g of 4-nitrobenzyl bromide was dissolved in 500 ml of methylene chloride, 51.5 ml of triethylamine was added, and 18.3 ml of piperidine was carefully added dropwise. After the exothermic reaction was completed, the reaction mixture was refluxed for an additional 30 minutes. After cooling, it was washed with water and the organic phase was dried over anhydrous sodium sulfate and finally evaporated.

Yield: 36.3 g (89% of theory),

Rf value of the product: 0.6 (silica gel, methylene chloride / methanol = 9: 1), C12H16N2O2

Mass spectrum: m / z = 221 [M] &lt; ^{+ &gt};.

Similar to Preparation 12, the following compounds were prepared:

(1) 4 - [(2,6-dimethyl-piperidin-1-yl) -methyl] -nitrobenzene, (2) 3- (N, N -dimethylaminomethyl) -nitrobenzene, (3) 4- ( N, N -dimethylaminomethyl) -nitrobenzene, (4) 4- (2-dimethylamino-ethyl) -nitrobenzene, (S) 4- (2-diethylamino-ethyl) -nitrobenzene (6) 4- (diethylamino-) methyl) -nitrobenzene, (7) 4- (N-benzyl- N -methyl-aminomethyl) -nitrobenzene, (8) 4- (N-ethyl- N -methyl-aminomethyl) -nitrobenzene, (9) 4 - [N- (n-hexyl) - N -methyl-aminomethyl) nitrobenzene, (10) 4- (thiomorpholin-4-ylmethyl) -nitrobenzene, (11) 4 - [(4-methyl- (12) 4- (imidazol-1-yl-methyl) -nitrobenzene, (13) 4- [2- (4-hydroxy-piperidin-1-yl) -ethyl] - (piperazin-1-yl) -methyl] -nitrobenzene amino] nitrobenzene.

-66 ·········································· (14) 4 - [(3-Hydroxy-pyrrolidin-1-yl) -methyl] -nitrobenzene, ( 15) 4- (1,2,4-triazol-1-yl-methyl) -nitrobenzene, (16) 4- (1,2,3-triazol-2-yl-methyl) -nitrobenzene, (17) 4- (1,2,3-triazol-1-yl-methyl) -nitrobenzene, (18) 4 - [(N-ethoxycarbonyl-methyl- N -methyl-amino) -methyl] nitrobenzene, (19) 4- [ (N-aminocarbonyl-methyl- N -methyl-amino) -methyl] -nitiobenzene, (20) 4- (azetidin-1-yl-methyl) -nitrobenzene, (21) 4 - [(di- (2- (22) 4 - [N - (N-tert-butoxycarbonyl-3-amino-propyl) - N -methylaminomethyl] -nitrobenzene, (23) 4- [(N-propyl- N -methyl-amino) -methyl] -nitrobenzene, (24) 4 - [(N - (2-dimethylamino-ethyl) - N -methyl-amino) -methyl] -nitrobenzene (25) 4 - [(N - (3-dimethylamino-propyl) - N -methyl-amino) -methyl] -nitrobenzene, (26) 4 - [(N - (2-methoxy-ethyl) - N -methyl-amino) -methyl] -nitrobenzene, (2 S) 4 - [(N - (2-h) (28-methyl-N-methyl-N-methyl-amino) -methyl] -nitrobenzene, (28) 4 - [(N - (dioxol-2-yl-methyl) - N -methyl-amino]) (29) 4- (3-oxo-piperazin-1-ylmethyl) -nitrobenzene.

Preparation 13

4 - [(/ V-carboxymethyl-A / -methyl-amino) -methyl] -nitrobenzene

7.33 g of 4 - [(N -ethoxycarbonyl-methyl- N -methyl-amino) -methyl] -nitrobenzene were dissolved in 140 ml of ethanol, 34.0 ml of sodium hydroxide solution (ον ₃ οη = 1 mol) was added ³ ) and the mixture was stirred at room temperature for half an hour. The reaction mixture was then neutralized with dilute hydrochloric acid (c _H 1 = 1 mol.dm ³ ), the solvent was removed, the residue was stirred in methylene chloride and extracted with water. The aqueous phase was concentrated and the residue was recrystallized from methylene chloride.

Yield: 5.43 g (84% of theory),

Rf value of product: 0.4 (silica gel, methylene chloride / methanol = 2: 1),

C10H12N2O4

Mass spectrum: m / z = 223 [M] &lt; ^{+ &gt};.

······································ • · ·························

-67Preparation 14

4 - (/ V-ethyl-aminomethyl) -nitrobenzene

6.0 g of 4-nitrobenzyl bromide was dissolved in 25 ml of ethanol, the solution was mixed with ml of a 10% ethanol solution of ethylamine, and the reaction mixture was refluxed for 2 hours. Then the solution was rotovapped, the residue was stirred in methylene chloride and washed with dilute sodium hydroxide solution. Finally, the organic phase was evaporated.

Yield: 2.3 g (46% of theory),

Rf value of product: 0.2 (silica gel, methylene chloride / methanol = 9: 1),

C9H12N2O2

Mass Spectrum: m / z = 179 [M-H] '.

Similar to Preparation 14, the following compounds were prepared:

(1) 4- [N- (4-chlorobenzyl) -aminomethyl] -nitrobenzene, (2) 4- (N -cyclohexyl-aminomethyl) -nitrobenzene, (3) 4- (N-isopropyl-aminomethyl) -nitrobenzene, (4) 4- (N-propyl-aminomethyl) -nitrobenzene, (5) 4- (N-methyl-aminomethyl) -nitrobenzene, (6) 4- (N-butyl-aminomethyl) -nitrobenzene (7) 4- (N-methoxycarbonyl-methyl-aminomethyl) -nitrobenzene, (8) 4- (N-benzyl-aminomethyl) -nitrobenzene, (9) 4- (aminomethyl) -nitrobenzene, (10) 4 - (pyrrolidin-1-yl-methyl) -nitrobenzene, (11) 4- (morpholin-4-ylmethyl) -nitrobenzene, (12) 4- (hexamethyleniminomethyl) -nitrobenzene, (13) 4- ( 4-hydroxy-piperidin-1-yl-methyl) -nitrobenzene, (14) 4- (4-methoxy-piperidin-1-yl-methyl) -nitrobenzene, (15) 4- (4-methyl-piperidine-1- (16) 4- (4-ethyl-piperidin-1-ylmethyl) -nitrobenzene, (17) 4- (4-isopropyl-piperidin-1-ylmethyl) -nitrobenzene, ( 18) 4- (4-phenyl-piperidin-1-yl-methyl) -nitrobenzene, (19) 4- (4-benzyl-piperidin-1-yl-methyl) -nitrobenzene, (20) 4- (4-ethoxycarbonyl) -piperidin-1-yl-methyl) -nitrobenzene, (21) 4- (V, Vd) (22) 4- (4-tert-butoxycarbonyl-piperazin-1-ylmethyl) -nitrobenzene, (23) 4- (2-morpholin-4-yl-ethyl) -nitrobenzene, ( 24) 4- (2-pyrrolidin-1-yl-ethyl) -nitrobenzene, (25) 4- (2-piperidin-1-yl-ethyl) -nitrobenzene, (26) 4- (N-ethyl) - N -benzyl-aminomethyl) nitrobenzene, (27) 4- (N-propyl-N-benzyl-aminomethyl) nitrobenzene, (28) 4- [N-methyl-N - (4-chlorobenzyl) (29) 4 - [N-methyl- N - (4-bromobenzyl) -aminomethyl] -nitrobenzene; (30) 4 - [N -methyl- N - (4-fluorobenzyl) -aminomethyl] -nitrobenzene; (31) 4- [N-methyl-N- (4-methylbenzyl) -aminomethyl] -nitrobenzene, (32) 4- [N-methyl- N - (3-chlorobenzyl) -aminomethyl] -nitrobenzene; (33) 4- [N-methyl- N - (3,4-dimethoxybenzyl) -aminomethyl] -nitrobenzene; (34) 4 - [N -methyl- N - (4) -aminomethyl] -nitrobenzene; (35) 4- () / -2,2,2-trifluoroethyl-1H-benzylaminomethyl) nitrobenzene, (36) 4- [Λ / -2,2,2-methoxybenzyl) aminomethyl] nitrobenzene; (37) 4- (thiomorpholin-4-ylmethyl) -nitrobenzene, (38) 4- (azet) -trifluoroethyl- N - (4-chlorobenzyl) aminomethyl] nitrobenzene idion-1-yl-methyl) -nitrobenzene, (39) 4- (3,4-dihydropyrrolidin-1-yl-methyl) -nitrobenzene, (40) 4- (3,4-dihydropiperidin-1-yl) (41) 4- (2-methoxycarbonyl-pyrrolidin-1-yl-methyl) -nitrobenzene, (42) 4- (3,5-dimethyl-piperidin-1-yl-methyl) -nitrobenzene, (43) 4- (4-phenyl-piperazin-1-yl-methyl) -nitrobenzene, (44) 4- (4-phenyl-4-hydroxy-piperidin-1-yl-methyl) -nitrobenzene, (45) 4 - [N - (3,4,5-trimethoxybenzyl) - N -methyl-aminomethyl] nitrobenzene, (46) 4 - [N - (3,4-dimethoxybenzyl) - N -ethyl-aminomethyl] - nitrobenzene, (47) 4- [N - ((2,6-dichlorobenzyl) - N -methyl) aminomethyl] nitrobenzene, (48) 4- [N - (4-trifluoromethylbenzyl) - N] - methyl) -aminomethyl] -nitrobenzene, (49) 4- (N-benzyl-N-isopropyl-aminomethyl) -nitrobenzene, (50) 4- (N-benzyl-N-tert-butyl-aminomethyl) - nitrobenzene,

· · · · · · ···· • · • · • • • · • • • • • • · • • • · • • · · · • · • • • «· · • · • • • · • • • · • • • • • · • · · • · • · • · · • · ····

(51) 4- (N, N-isopropyl-aminomethyl) -nitrobenzene, (52) 4- (N, N -diisobutyl-aminomethyl) -nitrobenzene, (53) 4- (2,3,4,5-tetrahydro) -benzo (d) azepin-3-yl-methyl) -nitrobenzene, (54) 4- (2,3-dihydro-isoindol-2-ylmethyl) -nitrobenzene, (55) 4- (6,7-dimethoxy) -1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl) -nitrobenzene, (56) 4- ( _1,2,3,4 -tetrahydro-isoquinolin-2-yl-methyl) -nitrobenzene, (57) 4- (N - (2-hydroxyethyl) - N -benzyl-aminomethyl] -nitiobenzene, (58) 4 - [N - (1-ethylpentyl) - N - (pyridin-2-yl-) - methyl) aminomethyl] -nitrobenzene, (59) 4- (piperidin-1-yl-methyl) -1,3-dinitrobenzene, (60) 4- (N-phenethyl-N-methyl-aminomethyl) nitrobenzene, (61) 4- [N - (3,4-dihydroxy-phenethyl) - N -methyl-aminomethyl] -nitrobenzene ₁ (62) 4 - [N - (3? 5-trimethoxy-phenethyl) - N -methyl (63) 4- [N- (3,4-dimethoxy-phenethyl) -N-methyl-aminomethyl] -nitrobenzene, (64) 4- [N - (3,4-dimethoxy-benzyl) -aminomethyl] nitrobenzene; N - N -methyl-aminomethyl] -nitrobenzene, (65) 4- [N - (4-chloro-benzyl) - N -methyl-aminomethyl] -nitrobenzene, (66) 4- [N - (4) bromo-benzyl) - / V-methyl-amine (67) 4 - [N - (4-fluoro-benzyl) - N -methyl-aminomethyl] -nitrobenzene, (68) 4- [N - (4-methyl-benzyl) - N-methyl-aminomethyl] -nitrobenzene, (69) 4- [N- (4-nitro-phenethyl) -N-methyl-aminomethyl] -nitrobenzene, (70) 4- (N-phenethyl- N -benzyl) (71) 4- (N-phenethyl-N-cyclohexyl-aminomethyl) -nitrobenzene, (72) 4- [N - (2- (pyridin-2-yl) ethyl) -A N-methyl-aminomethyl] -nitrobenzene, (73) 4- [N - (2- (pyridin-4-yl) -ethyl) - N -methyl-aminomethyl] -nitrobenzene, (74) 4 - [N - (pyridin-4-yl-methyl) - N -methyl-aminomethyl] -nitrobenzene, (75) 4- (N, N-dibenzyl-aminomethyl) -nitrobenzene, (76) 4 - [N - ( 4-nitro-phenethyl) - N -propyl-aminomethyl] -nitrobenzene, (77) 4- (N-benzyl- N - (3-cyano-propyl) -aminomethyl) -nitrobenzene, (78) 4- ( N -benzyl- N -allyl-aminomethyl) nitrobenzene, (79) 4- [N -benzyl-N- (2,2,2-trifluoroethyl) aminomethyl] nitrobenzene, (80) 4- [] N- (2-benzo (1,3) dioxol-5-ylmethyl) -N-methyl-aminomethyl] nitrobenzene, (81) 4- (7-chloro-2,3,4,5-tetrahydro- benzo (d) azepin-3-ylmethyl) nitrobenzene, (82) 4- (7.8 -dichloro-2,3,4,5-tetrahydro-benzo (d) azepin-3-yl-methyl) -nitrobenzene, · 9 · · · ·

9 9 9 9 9 999 9 9 9 (83) 4- (7-Methoxy-2,3,4,5-tetrahydro-benzo (d) azepin-3-ylmethyl) -nitrobenzene, (84) 4- ( 7-methyl-2,3,4,5-tetrahydro-benzo (d) azepin-3-ylmethyl) -nitrobenzene, (85) 4- (7,8-dimethoxy-2,3,4,5-tetrahydro -benzo (d) azepin-3-yl-methyl) -nitrobenzene, (86) 4- (6,7-dichloro-1,2,3,4-tetrahydro-isoquinolin-2-ylmethyl) -nitrobenzene, ( 87) 4- (6,7-dimethyl-1,2,3,4-tetrahydro-isoquinolin-2-ylmethyl) -nitrobenzene, (88) 4- (6-chloro-1,2,3,4- tetrahydro-isoquinolin-2-ylmethyl) nitrobenzene, (89) 4- (7-chloro-1,2,3,4-tetrahydro-isoquinolin-2-ylmethyl) nitrobenzene, (90) 4- (6-) methoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl) nitrobenzene, (91) 4- (7-methoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl) nitrobenzene, (92) 4 - [(2,3,4,5-tetrahydro-azepino (4,5-b) pyrazin-3-yl) methyl] nitrobenzene, (93) 4 - [(7-amino-2) , 3,4,5-tetrahydro-azepino (4,5-b) pyrazin-3-yl) -methyl] -nitrobenzene, (94) 4 - [(2-amino-5,6,7,8-tetrahydro-azepino ( 4,5-d) thiazol-6-ylmethyl-nitrobenzene, (95) 4 - [(5,6,7,8-tetrahydro-azepino) 5-d) Thiazol-6-yl) methyl] nitrobenzene;

Preparation 15

4- (1,1-Dioxo-thiomorpholin-4-yl-methyl) -nitrobenzene

6.0 g of 4- (thiomorpholin-4-ylmethyl) nitrobenzene was dissolved in 100 ml of methylene chloride and 10.3 g of meta-chloroperbenzoic acid was slowly added to the solution. After stirring for another 3 hours at room temperature, the precipitate formed was collected on a filter.

Yield: 6.2 g (91% of theory),

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 1: 1), C11H14N2O4S

Mass spectrum: m / z = 270 [M] &lt; ^{+ &gt};.

Similar to Preparation 15, the following compound was prepared:

(1) 4- (1-Oxo-thiomorpholin-4-ylmethyl) -nitrobenzene.

Preparation 16

4 - [N- (3-Amino-propyl) - N -methylsulfonyl-amino] -nitrobenzene ··· ··········· · · · · · E · · · · · e · e · • · • · • · · · · · ♦ · ♦ ·

9.5 g of 4- [N - (3-phthalimido-2-yl-propyl) - N -methylsulfonyl-amino] -nitrobenzene were dissolved in 200 ml of ethanol, 11.5 ml of hydrazine hydrate were added and the reaction mixture was stirred for 1 hour. The mixture was stirred at 50 ° C for 5 hours. After cooling, the residue was concentrated, water was added and the solution was extracted with methylene chloride. The organic phase was dried, concentrated and purified on a silica gel column (using methylene chloride / methanol / ammonia = 9: 1: 0.1 as eluent).

Yield: 2.5 g (39% of theory),

Rf value of product: 0.2 (silica gel, methylene chloride / methanol = 9: 1), C10H15N3O4S

Mass spectrum: m / z = 272 [M-H] -.

Similar to Preparation 16, a compound was prepared:

(1) 6 - [N - (2-dimethylaminoethyl) - N -methylsulfonylamino] -3-amino-nitrobenzene, prepared from 6 - [N - (2-dimethylaminoethyl) - N -methylsulfonylamino] -3 phthalimido-2-yl-nitrobenzene.

Preparation 17

4- (1-methyl-imidazol-2-yl) nitrobenzene

7.5 g of 4- (imidazol-2-yl) -nitrobenzene were dissolved in 50 ml of dimethylsulfoxide and 5.0 g of potassium tert-butylate were added at 0 ° C. After stirring at room temperature for one hour, 2.6 ml of methyl iodide was added dropwise and the mixture was stirred at room temperature for one hour. It was then poured into ice water and the precipitate formed was filtered off with suction, washed with water and dried.

Yield: 6.1 g (76% of theory), Rf value of product: 0.6 (silica gel, methylene chloride / methanol = 10: 1), mp 186-187 ° C.

Similar to Preparation 17, the following compounds were prepared:

(1) 4- (1-ethyl-imidazol-2-yl) -nitrobenzene, prepared by the reaction of 4- (imidazol-2-yl) -nitrobenzene and ethyliodide, (2) 4- (1-benzyl-imidazole-2- yl) -nitrobenzene, prepared by reaction from 4- (imidazol-2-yl) nitrobenzene and benzyl bromide.

9 9 9 9 9 9 9 9 9 9 9 9 999 999 9

9

99 99 999

9

9999

Preparation 18 4 - [(N - (2- (2-Methoxy-ethoxy) -ethyl) - N -methyl-amino) -methyl] nitrobenzene

5.0 g of 4-methylaminomethylnitrobenzene were dissolved in 30 ml of dimethylformamide and 4.6 g of 2- (2-methoxy-ethoxy) -ethyl chloride were added. After stirring at 100 ° C for six hours, the solvent was removed and the residue was triturated in ethyl acetate. The organic phase was washed with water and dried over anhydrous sodium sulfate. After removal of the solvent, the residue was purified on an alumina column (2-3 activity) using toluene and ethyl acetate (5: 1) as eluent.

Yield: 2.3 g (29% of theory),

Rf value of product: 0.5 (alumina, toluene / ethyl acetate = 5: 1), C13H20N2O4

ESI-MS: m / z = 267 [M-H] &lt; + &gt;

Preparation 19

4 - (/ V-ethyl- / V-t-butoxycarbonyl-aminomethyl) -nitrobenzene

2.2 g of 4- (ethylaminomethyl) nitrobenzene were dissolved in 50 ml of ethyl acetate, 2.6 g of di-tert-butyl dicarbonate (tert-butoxycarbonylanhydride) were added, and the mixture was stirred at room temperature for 30 minutes. Then the solution was washed with water and concentrated.

Yield: 3.4 g, Rf value of the product: 0.3 (silica gel, methylene chloride / methanol = 50: 1), m.p. 85 ° C.

As in Preparation 19, the following compounds were prepared:

(1) 4- [N- (4-chlorophenylmethyl) -N-tert-butoxycarbonyl-aminomethyl] nitrobenzene, (2) 4- (N-tert-butoxycarbonyl-aminomethyl) nitrobenzene, (3) 4- (N-cyclohexyl- N -t-butoxycarbonyl-aminomethyl) nitrobenzene, (4) 4- (N-isopropyl- N -t-butoxycarbonyl-aminomethyl) nitrobenzene, (5) 4 - (/ -) V-methyl- / V-t-butoxycarbonyl-aminomethyl) nitrobenzene,

(6) 4- (N-propyl- N - tert -butoxycarbonyl-aminomethyl) -nitrobenzene, (7) 4- (N -butyl- N - tert -butoxycarbonyl-aminomethyl) -nitrobenzene, (8) 4 - (N-methoxycarbonyl-methyl-N-tert-butoxycarbonyl-aminomethyl) -nitrobenzene, (9) 4- (N-benzyl-N-tert-butoxycarbonyl-aminomethyl) -nitiobenzene, (10) 4- N - (3-Trifluoroacetylaminopropyl) - N -methylsulfonylamino] nitrobenzene, prepared by reaction from 4 - [N - (3-amino-propyl) - N -methylsulfonylamino] -nitrobenzene and trifluoroacetic anhydride, ( 11) 4 - [(4-tert-butoxycarbonyl-piperazin-1-yl) -methyl] -nitrobenzene.

Preparation 20

4- (Piperidin-1-yl-methyl) -aniline

37.0 g of 4- (piperidin-1-ylmethyl) -nitrobenzene were dissolved in 300 ml of methanol, and 8.0 g of Raney nickel were added. The batch was hydrogenated under a pressure of about 3 bar of hydrogen at room temperature for 85 minutes. The catalyst was then filtered off and the filtrate was evaporated.

Yield: 24.0 g (75% of theory),

Rf value of product: 0.4 (silica gel; methylene chloride / methanol = 9: 1), C12H18N2

ESI-MS: m / z = 191 [M + H] &lt; ^{+ &gt};.

Similar to Preparation 20, the following compounds were prepared:

(1) 4 - [(2,6-dimethyl-piperidin-1-yl) -methyl] -aniline, (2) N- (2-dimethylamino-ethyl) - N -methylsulfonyl-p-phenylenediamine, ( (3) 3- (dimethylaminomethyl) -aniline, (4) 4- (dimethylaminomethyl) -aniline, (5) 4- (2-dimethylamino-ethyl) -aniline, (6) 4- [N - (2-dimethylamino- (7) 4- [N - (3-dimethylamino-propyl) - N -acetyl-amino] -aniline, (8) 4 - [N - (ethyl) ethyl] - N -acetyl-amino] -aniline; (2-dimethylamino-ethyl) - N -benzoyl-amino] -aniline, (9) 4- [N - (2-dimethylamino-ethyl) - N -propionyl-amino] -aniline, (10) 4 - [N- (2-dimethylamino-ethyl) - N -butyrylamino] -aniline; (11) 4 - [N - (2-dimethylamino-ethyl) - N -isobutyryl-amino] (12) 4- (N-tert-butoxycarbonyl-aminomethyl) -aniline, (13) 4- (N-ethyl- N-tert-butoxycarbonyl-aminomethyl) -aniline, (14) 4- N- (4-chlorophenylmethyl) -N-tert-butoxycarbonylaminomethyl] -aniline, (15) 4- (N-cyclohexyl- N-tert-butoxycarbonylaminomethyl) -aniline, (16) 4- ( N -isopropyl- N -tert-butoxycarbonyl-aminomethyl) -aniline, (17) 4- (N -propyl- N -tert-butoxycarbonyl-aminomethyl) -aniline, (18) 4- (N -methyl) - / V-te tert-butoxycarbonyl-aminomethyl) -aniline, (19) 4- (N-butyl- N-tert-butoxycarbonyl-aminomethyl) -aniline, (20) 4- (N-methoxycarbonyl-methyl-) N-tert- butoxycarbonylaminomethyl) -aniline, (21) 4- (N-benzyl- N -t-butoxycarbonyl-aminomethyl) -aniline, (22) 4- (pyrrolidin-1-ylmethyl) -aniline, (23) 4- (morpholin-4-yl-methyl) -aniline, (24) 4- (hexamethyleneiminomethyl) -aniline, (25) 4- (4-hydroxy-piperidin-1-yl-methyl) -aniline, (26) 4- ( 4-Methoxy-piperidin-1-yl-methyl-aniline, (27) 4- (4-methyl-piperidin-1-yl-methyl) -aniline, (28) 4- (4-ethyl-piperidine) -1-yl-methyl) -aniline, (29) 4- (4-isopropyl-piperidin-1-yl-methyl) -aniline, (30) 4- (4-phenyl-piperidin-1-yl-methyl) - aniline, (31) 4- (4-benzyl-piperidin-1-yl-methyl) -aniline, (32) 4- (4-ethoxycarbonyl-piperidin-1-yl-methyl) -aniline, (33) 4 - (N, N-dipropyl-aminomethyl) -aniline, (34) 4- (4-tert-butoxycarbonyl-piperazin-1-yl-methyl) -aniline, (35) 4- (2-morpholine-4- (36) 4- (2-pyrrolidin-1-yl-ethyl) -aniline, (37) 4- (2-piperidin-1-yl-ethyl) -anil n, (38) 4- (N-propyl- N -benzyl-aminomethyl) -aniline, (39) 4 - (N - (n -hexyl) - N -methyl-aminomethyl] -aniline, (40) ) 4- [N-methyl-N- (4-chlorobenzyl) -aminomethyl] -aniline, (41) 4 - [N-methyl- N - (4-bromobenzyl) -aminomethyl] -aniline, (42) ) 4- [N-Methyl- N - (4-methylbenzyl) aminomethyl] -aniline,

(43) 4- [N-methyl- N - (4-fluorobenzyl) -aminomethyl] -aniline, (44) 4 - [N -methyl- N - (3-chlorobenzyl) -aminomethyl] -aniline, (45) 4- [N-methyl- N - (3,4-dimethoxybenzyl) -aminomethyl] -aniline, (46) 4 - [N -methyl- N - (4-methoxybenzyl) -aminomethyl] -aniline (47) 4- (N-2 ₁ 2,2-trifluoroethyl- N -benzylaminomethyl) aniline, (48) 4 - [N -2,2,2-trifluoroethyl- N - (4) (49) 4- (thiomorpholin-4-ylmethyl) -aniline, (50) 4- (1-oxo-thiomorpholin-4-ylmethyl) -aniline, (51) 4- (1,1-dioxo-thiomorpholin-4-yl-methyl) -aniline, (52) 4- (azetidin-1-yl-methyl) -aniline, (53) 4- (3,4-d) (54) 4- (3,4-dihydropiperidin-1-ylmethyl) -aniline, (55) 4- (2-methoxycarbonyl-pyrrolidin-1-yl) -hydropyrrolidin-1-yl-methyl) -aniline; yl] -methyl) -aniline, (56) 4- (3,5-dimethyl-piperidin-1-yl-methyl) -aniline, (57) 4- (4-phenyl-piperazin-1-yl-methyl) - aniline, (58) 4- (4-phenyl-4-hydroxy-piperidin-1-yl-methyl) -aniline, (59) 4- [N - (3? 5-trimethoxy-benzyl) - N -methyl-aminomethyl aniline, (60) 4- [N - (3,4-dimethoxy-benzyl) - N -ethyl-aminomethyl] - aniline, (61) 4- (N-benzyl-N-ethyl-aminomethyl) -aniline, (62) 4 - [N - (2,6-dichlorobenzyl) - N -methyl-aminomethyl] -aniline, ( 63) 4- [N- (4-trifluoromethylbenzyl) - N -methyl-aminomethyl] -aniline, (64) 4- (N-benzyl- N -isopropyl-aminomethyl) -aniline, (65) 4- (N-benzyl- N -t-butyl-aminomethyl) -aniline, (66) 4- (diethylamino-methyl) -aniline, (67) 4- (2-diethylamino-ethyl) -aniline, (68) 4 - (N, N -diisopropyl-aminomethyl) -aniline, (69) 4- (N, N-diisobutyl-aminomethyl) -aniline, (70) 4- (2,3,4,5-tetrahydro- benzo (d) azepin-3-yl-methyl) -aniline, (71) 4- (2,3-dihydro-isoindol-2-ylmethyl) -aniline, (72) 4- (6,7-dimethoxy- 1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl) -aniline, (73) 4- (1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl) -aniline, (74) 4 - [N - (2-hydroxy-ethyl) - N -benzyl-aminomethyl] -aniline, (75) 4- [N - (1-ethyl-pentyl) -A] - (pyridin-2-yl-methyl) -aminomethyl] -aniline, (76) 4- (piperidin-1-ylmethyl) -3-nitro-aniline, (77) 4- (piperidine) -1-ylmethyl) -3-amino-aniline, (78) 4- (N-benzyl- N -methyl-aminomethyl) - aniline, (79) 4- (N-ethyl- N -methyl-aminomethyl) -aniline, (80) 4- (N-phenethyl- N -methyl-aminomethyl) -aniline, (81) 4- [ N - (3,4-dihydroxy-phenethyl) - N -methyl-aminomethyl] -aniline, (82) 4- [N - (3? 5-trimethoxy-phenethyl) -N-methyl-aminomethyl] -aniline, ( 83) 4- [N - (3,4-dimethoxy-phenethyl) - N -methyl-aminomethyl] -aniline, (84) 4- [N - (3,4-dimethoxy-benzyl) - N -methyl (85) 4 - [N - (4-chloro-benzyl) - N -methyl-aminomethyl] -aniline, (86) 4 - [N - (4-bromo-benzyl) - N-methyl-aminomethyl] -aniline, (87) 4 - [N - (4-fluoro-benzyl) - N -methyl-aminomethyl] -aniline, (88) 4 - [N - (4-methyl) (89) 4 - [N - (4-nitro-phenethyl) - N -methyl-aminomethyl] -aniline, (90) 4 - (N -benzyl) - N -methyl-aminomethyl] -aniline; phenethyl- N -benzyl-aminomethyl) -aniline, (91) 4- (N -phenethyl- N -cyclohexyl-aminomethyl) -aniline, (92) 4 - [N - (2- (pyridine-2-) (93) 4- [N - (2- (pyridin-4-yl) ethyl) - N -methyl-aminomethyl] -aniline, (93) 94) 4- [N - (pyridin-4-ylmethyl) - N -methyl-aminomethyl] -aniline, (95) 4- (N, N -dibenzylaminomethyl) -aniline, (96) 4 - [N - (4-nitro-benzyl) - N -propyl-aminomethyl] -aniline, (97) 4 - [N-benzyl-N- (3-cyano-propyl) -aminomethyl] -aniline, ( 98) 4- (N-benzyl- N -allyl-aminomethyl) -aniline, (99) 4 - [N -benzyl- N - (2,2,2-trifluoroethyl) -aminomethyl] -aniline, ( 100) 4 - [(benzo (1,3) dioxol-5-ylmethyl) -methyl-aminomethyl] -aniline, (101) 4- (7-chloro-2,3,4,5-tetrahydro-benzo ( (d) azepin-3-yl-methyl) -aniline, (102) 4- (7,8-dichloro-2,3,4,5-tetrahydro-benzo (d) azepin-3-yl-methyl) -aniline, (103) 4- (7-methoxy-2,3,4,5-tetrahydro-benzo (d) azepin-3-ylmethyl) -aniline, (104) 4- (7-methyl-2,3,4) , 5-tetrahydro-benzo (d) azepin-3-yl-methyl) -aniline, (105) 4- (7,8-dimethoxy-2,3,4,5-tetrahydro-benzo (d) azepin-3- (106) 4- (6,7-dichloro-1,2,3,4-tetrahydro-isoquinolin-2-ylmethyl) -aniline,

(107) 4- (6,7-dimethyl-1,2,3,4-tetrahydro-isoquinolin-2-ylmethyl) -aniline, (108) 4- (6-chloro-1,2,3,4) -tetrahydro-isoquinolin-2-yl-methyl) -aniline, (109) 4- (7-chloro-1,2,3,4-tetrahydro-isoquinolin-2-ylmethyl) -aniline, (110) 4- (6-methoxy-1,2,3,4-tetrahydro-isoquinolin-2-yl-methyl) -aniline, (111) 4- (7-methoxy-1,2,3,4-tetrahydro-isoquinoline-2- (112) 4- (2,3,4,5-tetrahydro-azepino (4,5-b) pyrazin-3-ylmethyl) -aniline, (113) 4- (7-) amino-2,3,4,5-tetrahydro-azepino (4,5-b) pyrazin-3-ylmethyl) -aniline, (114) 4- (2-amino-5,6,7,8-tetrahydro) -azepino (4,5-d) thiazol-6-ylmethyl) -aniline, (115) 4- (5,6,7,8-tetrahydro-azepino (4,5-d) thiazol-6-yl) (116) 4- (4-methyl-piperazin-1-yl) -aniline, (117) 4- [N- (2-dimethylamino-ethyl) - N -methyl-amino] -aniline (118) 4- [N - (3-dimethylamino-propyl) - N -methyl-amino] -aniline, (119) N - (3-dimethylamino-propyl) - N -methylsulfonyl-p-phenylenediamine (120) 4 - [(N-dimethylaminocarbonyl-methyl- N -methylsulfonyl) -amino] -aniline, (121) N - (4-aminophenyl) - N -methyl-me (122) 4- (imidazol-4-yl) -aniline, (123) 4- (tetrazol-5-yl) -aniline, (124) 4- [N - (2-dimethylamino-ethyl) -] N-propionyl-amino] -aniline, (125) N - (dimethylaminomethylcarbonyl) -N-methyl-p-phenylenediamine, (126) N - [(2-dimethylamino-ethyl) -carbonyl] - N -methyl- p-phenylenediamine, (127) 4- (N -acetyl- N - (dimethylaminocarbonyl-methyl) -amino) -aniline, (128) N -methylaminocarbonyl-methyl- N -methylsulfonyl-p-phenylenediamine, (129) N-aminocarbonyl-methyl-N-methylsulfonyl-p-phenylenediamine, (130) 4- (imidazolidin-2,4-dione-5-ylidene-methyl) -aniline, (131) 4- (imidazolidin-2, 4-Dione-5-yl-methyl) -aniline, (132) 4- (2-oxo-pyrrolidin-1-yl-methyl) -aniline, (133) N -cyanomethyl- N -methylsulfonyl-p-phenylenediamine (134) 4- [2- (imidazol-4-yl) -ethyl] -aniline, (135) 4 - [(4-methyl-piperazin-1-yl) -methyl] -aniline, (136) 4 - [N- (2 - (N-benzyl- N -methyl-amino) -ethyl) - N -methylsulfonylamino] -aniline, (137) 4- [N - (3 - (N -) (benzyl- (N-methyl-amino) -propyl) - N -methylsulfonyl-amino] -aniline, (138) N-cyclohexyl-p-phenylenediamine, · 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 139 (139 ) 4- (pyridin-4-yl-methyl) -aniline, (140) 4- (imidazol-1-yl-methyl) -aniline, (141) 4-benzyl-aniline, (142) AF (3-trifluoroacetylamino) (143) 4-amino-phenylacetic acid tert-butyl ester, (144) 4- (imidazol-2-yl) -aniline, (145) 4- (1-methyl-propyl) -N-methylsulfonyl-p-phenylenediamine; -imidazol-2-yl) -aniline, (146) 4- (1-ethyl-imidazol-2-yl) -aniline, (147) 4- (1-benzyl-imidazol-2-yl) -aniline, (148) 14 - [N - (2-dimethylamino-ethyl) - N -methylsulfonyl-amino-3-amino-aniline, (149) 4 - [N - (2-dimethylamino-ethyl) - N -methylsulfonyl- amino] -3-chloro-aniline, (150) 4- [N - (2-dimethylamino-ethyl) - N -acetyl-amino] -3-amino-aniline, (151) 4 - [N - ( 2-dimethylamino-ethyl) -N-acetyl-amino] -3-bromo-aniline, (152) 4- [2- (4-hydroxy-piperidin-1-yl) -ethylamino] -aniline, ( 153) N- (2-dimethylamino-ethyl) - N -ethylsulfonyl-p-phenylenediamine, (154) N - (2-dimethylamino-ethyl) - N -pipylsulfonyl-p-phenylene ndiamine, (155) N- (2-dimethylamino-ethyl) - N -isopropylsulfonyl-p-phenylenediamine, (156) N- (2-dimethylamino-ethyl) - N -butylsulfonyl-p-phenylenediamine, (157) N - (2-dimethylamino-ethyl) - N -benzylsulfonyl-p-phenylenediamine, (158) N - (2-dimethylamino-ethyl) - N -phenylsulfonyl-p-phenylenediamine, (159) 4 - ((3-hydroxy-pyrrolidin-1-yl) -methyl) -aniline, (160) 4- [N - (2-dimethylamino-ethyl) - N - (furan-2-carbonyl) -amino] - aniline, (161) 4- [N - (2-dimethylamino-ethyl) - N - (2-methoxy-benzoyl) -amino] -aniline, (162) 4 - [N - (2-dimethylamino-ethyl) N - (N- (pyridine-3-carbonyl) -amino) -aniline, (163) 4- [N - (2-dimethylamino-ethyl) - N - (phenyl-acetyl) -amino] -aniline, ( 164) N - (piperidin-1-ylmethylcarbonyl) - N -methyl-p-phenylenediamine, (165) N - (morpholin-4-ylmethylcarbonyl) - N -methyl-p-phenylenediamine, ( 166) N - [(4-benzyl-piperazin-1-yl) -methylcarbonyl] -N-methyl-p-phenylenediamine, (167) N - (pyrrolidin-1-ylmethylcarbonyl) - N -methyl -p-phenylenediamine, (168) 4- (5-methyl-imidazol-4-yl) -aniline, (169) N - [(2-dimethylamino-ethyl) -carbonyl] - [Vi] (170) N - [(2-dimethylamino-ethyl) -carbonyl] -N-benzyl-p-phenylenediamine; (171) N - (N-aminocarbonyl-methyl- N -methylamino) methylcarbonyl) - N -methyl-p-phenylenediamine, (172) N - [( (N-benzyl- N -methyl-amino) -methylcarbonyl] - N -methyl-p-phenylenediamine, (173) N - [di- (2-methoxyethyl) amino-methylcarbonyl) - N -methyl- p-phenylenediamine, (174) N - [(2- (4-tert-butoxycarbonylpiperazin-1-yl) ethyl) carbonyl] - N -methyl-p-phenylenediamine, (175) N - [2] - (piperidin-1-yl) -ethyl) -carbonyl] - N -methyl-p-phenylenediamine, (176) N - [(2- (N-benzyl- N -methyl-amino) -ethyl) -carbonyl] - N -methyl-p-phenylenediamine, (177) N - (dimethylaminomethylcarbonyl) - N -isopropyl-p-phenylenediamine, (178) N - (piperidin-1-ylmethylcarbonyl) - N) -isopropyl-p-phenylenediamine, (179) N - [(4-tert-butoxycarbonylpiperazin-1-yl) methylcarbonyl] - N -isopropyl-p-phenylenediamine, (180) N - [(N -benzyl-N-methyl-amino) -methylcarbonyl] - N -benzyl-p-phenylenediamine, (181) N - (dimethylaminomethylcarbonyl) - N -benzyl-p-phenylenediamine, (182) N - (piperidine- 1-ylmethylcarbonyl) -N-benzyl-p-phenylenediamine, (183) 4- (1,2) , 4-triazol-1-yl-methyl-aniline, (184) 4- (1,2,3-triazol-2-yl-methyl) -aniline, (185) 4- (1,2,3-triazole- 1-yl-methyl) -aniline, (186) 4 - [(N-ethoxycarbonyl-methyl- N -methylamino) -methyl] aniline, (187) 4 - [(N-aminocarbonyl-methyl- N-methyl-amino) -methyl] -aniline, (188) 4- (azetidin-1-yl-methyl) -aniline, (189) 4 - [(di- (2-methoxy-ethyl) -amino) (methyl) -aniline, (190) 4 - [(N - (2- (2-methoxy-ethoxy) -ethyl) - N -methyl-amino) -methyl] -aniline, (191) 4- [ N - (N-tert-butoxycarbonyl-3-amino-propyl) - N -methylaminomethyl] -aniline, (192) 4 - [(N - (methylcarbamoyl-methyl) - N -methyl-amino) - methyl] -aniline, (193) 4 - [(N - (dimethylcarbamoyl-methyl) - N -methyl-amino) -methyl] -aniline, (194) 4 - [(N-propyl- N -methyl) (195) 4 - [(N - (2-dimethylamino-ethyl) - N -methyl-amino) -methyl] -aniline, (196) 4 - [(N - (3-dimethylamino-propyl) - N -methyl-amino) -methyl] -aniline, (197) 4 - [(N - (2-methoxy-ethyl) - N -methyl-amino) -methyl] - aniline, (198) 4 - [(N - (2-hydroxy-ethyl) - N -methyl-amino) -methyl] -aniline, (199) 4 - [(N - (dioxolan-2-yl) - methyl) -N-methyl-amino) -methyl l] -aniline,. ··.: · * · f; ···; ...........; (200) 4- (3-oxo-piperazin-1-ylmethyl) -aniline, (201) N- [di- (2- N-methyl-p-phenylenediamine, (202) N - [(N - (2-methoxyethyl) - N -methyl-amino) -methylcarbonyl] - N -methyl- p-phenylenediamine, (203) N - [(N - (2-dimethylamino-ethyl) - N -methyl-amino) -methylcarbonyl] - N -methyl-p-phenylenediamine, (204) N - [ (4-Methyl-piperazin-1-yl) -methylcarbonyl] - N -methyl-p-phenylenediamine, (205) N - [(imidazol-1-yl) -methylcarbonyl] - N -methyl-p-phenylenediamine (206) N - [(phthalimido-2-yl) -methylcarbonyl] -N-methyl-p-phenylenediamine.

Preparation 21 4- (4-Hydroxymethyl-piperidin-1-yl-methyl-amino) -aniline

1.1 g of 4- (4-ethoxycarbonyl-piperidin-1-yl-methyl-amino) -aniline was dispersed in 15 ml of tetrahydrofuran. 175 mg of boron hydride were added at room temperature and the mixture was stirred for 24 hours. Then an additional 175 mg of lithium borohydride was added and the reaction stirred for an additional 7.5 hours. This was followed by the addition of 15 ml of water and stirring for 10 minutes. The mixture was then extracted 3 times with 15 ml of ethyl acetate each time. The combined organic layers were washed with water and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated. The residue was purified on a silica gel column using methylene chloride / methanol / ammonia (4: 1: 0.01) as eluent.

Yield: 200 mg (27% of theory). Product value: 0.4 (silica gel, methylene chloride / methanol / ammonia = 4: 1: 0.01), m.p. 157 ° C.

Preparation 22

4-Ethoxycarbonylmethyl-3-nitro-benzoic acid methyl ester

54.3 g of methyl 3-nitrobenzoate were dissolved in 100 ml of dimethylformamide with 29.0 g of methyl chloroacetate. At -10 ° C, the prepared solution was added dropwise to a solution of 78.5 g of potassium tert-butylate in 500 ml.

-81 dimethylformamide. The reaction mixture was stirred for 10 minutes and then poured into a solution of 350 mL concentrated hydrochloric acid in 2 L ice water. The solution was stirred for 0.5 h, the precipitate formed was collected on a suction filter and washed with water. The product was recrystallized from methanol and dried under vacuum at 40 ° C.

Yield: 48.3 g (51% of theory),

Rf value of product: 0.7 (silica gel, petroleum ether / ethyl acetate = 1: 1), m.p. 65-73 ° C.

Similar to Preparation 22, the following compound was prepared:

(1) 4-Methoxycarbonyl-methyl-3-nitrobenzoic acid ethyl ester, prepared by reaction from 4-ethyl-thioxycarbonyl-methyl-3-nitrobenzoic acid 4-ethyl ester.

Preparation 23

2-Indolinone-6-carboxylic acid methyl ester

48.3 g of 4-ethoxycarbonylmethyl-3-nitro-benzoic acid methyl ester was dissolved in 800 ml of concentrated acetic acid, 500 g of palladium on carbon (10%) were added, and the solution was hydrogenated with hydrogen under a pressure of approximately 0 for 2.5 hours. 35 MPa (50 psi). After completion of the hydrogenation, the catalyst was filtered off, the filtrate was evaporated, the residue was taken up in 150 ml of tert-butyl methyl ether, filtered and dried in vacuo at 100 ° C.

Yield: 28.6 g (98% of theory),

Rf value: 0.4 (silica gel, methylene chloride / methanol = 10: 1), mp 208-211 ° C.

Similar to Preparation 23, the following compound was prepared:

(1) 2-indolinone-6-carboxylic acid ethyl ester, prepared by reaction from ethyl 4-methoxycarbonylmethyl-3-nitro-benzoate.

·· ···· · ·

-82Preparation 24

-Acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-ethyloxycarbonyl-2-indolinone

15.0 g of 2-indolinone-6-carboxylic acid ethyl ester, 49.6 ml of triethyl orthobenzoate and 150 ml of acetic anhydride were stirred at 110 ° C for 4 hours. The solvent was then removed, the residue was recrystallized from petroleum ether and dried under vacuum at 50 ° C.

Yield: 16.9 g (61% of theory),

Rf value of product: 0.5 (silica gel, petroleum ether / methylene chloride / ethyl acetate = 5: 4: 1), mp 98-100 [deg.] C., C22H21NO5.

Similar to Preparation 24, the following compounds were prepared:

(1) 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone, prepared by reaction from 2-indolinone-6-carboxylic acid methyl ester, triethyl orthobenzoate and acetic anhydride, (2) 1-Acetyl-3- (1-ethoxy-1-ethylmethylene) -6-ethoxycarbonyl-2-indolinone, prepared by reaction from 2-indolinone-6-carboxylic acid ethyl ester, orthopropionic acid triethyl ester and acetic anhydride.

Preparation of final compounds

Example 1

3-Z- [1- (4- (piperidin-1-yl-methyl) anilino) -1-phenyl-methylene] -6-carbamoyl-2-indolinóntrifluóracetát

300 mg of the prepared resin was dispersed in 3 ml of dimethylformamide and, after addition of 0.2 g of 4- (piperidin-1-ylmethyl) -aniline, the reaction mixture was shaken for 22 hours at 70 ° C. This was followed by filtration, washing the resin several times with methylene chloride, methanol and dimethylformamide. 1 ml of methanolic ammonia solution was then added for two hours to remove the acetyl group. After ·· · · ·· • ·· · · · ··· ! í.

•. . ·· ·· · · · ·!. ·

·..· ..· with.·.:..

After further washing, 4 ml of 10% trifluoroacetic acid in methylene chloride was added over 60 minutes, the resin was separated and the solution was concentrated.

Yield: 69 mg,

Rf value of product: 0.1 (silica gel, methylene chloride / methanol = 9: 1), C28H28N4O2

Mass spectrum: m / z = 452 [M] &lt; ^{+ &gt};.

As in Example 1, the following compounds were prepared:

(1) 3-Z- (1-anilino-1-phenyl-methylene) -6-carbamoyl-2-indolinone, prepared from a resin prepared similar to Example II and from aniline, C22H17N3O2, mass spectrum: m / z = 355 [M] ⁺ , (2) 3-Z- [1- (4-dimethylaminomethyl-anilino) -1-phenyl-methylene] -6-carbamoyl-2-indolinone trifluoroacetate, prepared from a resin prepared similar to Preparation 2 az 4-dimethylaminomethyl-aniline, C25H24N4O2, mass spectrum: m / z = 412 [M] ⁺ , (3) 3-Z- [1- (4- (2-diethylamino-ethyl) -anilino) - 1-phenylmethylene] -6-carbamoyl-2-indolinone trifluoroacetate, from the resin, similar to Preparation 2 and 4- (2-diethylamino-ethyl) -aniline,

C28H3ON4O2, mass spectrum: m / z = 454 [M] &lt; ^{+ &gt};, (4) 3-Z- [1- (4- (morpholin-4-ylmethyl) -anilino) -1-phenylmethylene] -6- carbamoyl-2-indolinone trifluoroacetate, the compound was prepared from a resin prepared similar to Preparation 2 and from 4 (morpholin-4-ylmethyl) -aniline, Rf value of the product: 0.50 (silica gel, methylene chloride / methanol = 4) (1) C27H26N4O3, mass spectrum: m / z = 454 [M] &lt; ^{+ &gt}; ) -1-phenyl-methylene] -6-carbamoyl-

2-indolinone trifluoroacetate, the compound was prepared from a resin prepared similar to Preparation 2 and from 4- (1-oxo-thiomorpholin-4-ylmethyl) -aniline,

Rf value of the product: 0.30 (silica gel, methylene chloride / methanol = 9: 1) C27H26N4O3S, mass spectrum: m / z = 486 [M] ⁺ , (6) 3-Z- [1- (4- ( 1,1-dioxo-thiomorpholin-4-yl-methyl) -aniline) -1-phenyl-methylene] -6-carbamoyl-

2-indolinone trifluoroacetate, prepared by reaction from a resin prepared similar to Preparation 2 and 4- (1,1-dioxothiomorpholin-4-ylmethyl) -aniline,

Product value: 0.30 (silica gel, methylene chloride / methanol = 9: 1),

C27H26N4O4S, Mass Spectrum: m / z = 502 [M] ⁺ , (7) 3-Z- [1- (4- (benzylaminomethyl) anilino) -1-phenylmethylene] -6-carbamoyl-2-indolinone trifluoroacetate, from the resin, similar to Preparation 2 and 4- [N - (phenylmethyl) - N - tert -butoxycarbonylaminomethyl] aniline,

Product value: 0.40 (silica gel, methylene chloride / methanol = 4: 1), C30H26N4O2, mass spectrum: m / z = 474 [M] ⁺ , (8) 3-Z- [1- (4- (aminomethyl) (amino) -1-phenylmethylene] -6-carbamoyl-2-indolinone trifluoroacetate, prepared from a resin prepared similar to Preparation 2 and from 4- (tert -butoxycarbonylaminomethyl) aniline,

Product value: 0.10 (silica gel, methylene chloride / methanol = 4: 1),

C 23 H 20 N 4 O 2, mass spectrum: m / z = 384 [M] ⁺ ,

(9) 3- Ζ- [1- (4- (2,6-dimethylpiperidin-1-ylmethyl) -anilino) -1-phenylmethylene] -6-carbamoyl-

2-indolinone trifluoroacetate, the compound was prepared from a resin prepared similar to Preparation 2 and from 4- (2,6-dimethylpiperidin-1-ylmethyl) -aniline,

Rf value of product: 0.45 (silica gel, methylene chloride / methanol = 4: 1),

C 3 H 32 N 4 O 2, mass spectrum: m / z = 480 [M] ⁺ , (10) 3-Z- [1- (4- (pyrrolidin-1-ylmethyl) anilino) -1-phenylmethylene] -6-carbamoyl-2 -indolinone trifluoroacetate, the compound was prepared from a resin prepared similar to Preparation 2 and from 4 (pyrrolidin-1-ylmethyl) -aniline, Rf value of the product: 0.15 (silica gel, methylene chloride / methanol = 4: 1) , C27H26N4O2, mass spectrum: m / z = 438 [M] ⁺ , (11) 3-Z- [1- (3- (dimethylaminomethyl) anilino) -1-phenylmethylene] -6-carbamoyl-2-indolinone trifluoroacetate, the compound was prepared from a resin prepared similar to Preparation 2 and from 3dimethylaminomethyl-aniline,

Product value: 0.23 (silica gel, methylene chloride / methanol = 4: 1), C25H24N4O2, mass spectrum: m / z = 412 [M] ⁺ , (12) 3-Z- [1- (3 - (/ N-methyl- N -ethyl-aminomethyl) -anilino) -1-phenylmethylene] -6-carbamoyl-2-indolinone trifluoroacetate, from a resin prepared similar to Preparation 2 and 3- (N-methyl- N -) - ethyl-aminomethyl) aniline,

Rf value of product: 0.23 (silica gel, methylene chloride / methanol = 4: 1),

C26H26N4O2, mass spectrum: m / z = 426 [M] &lt; ^{+ &gt};, (13) 3-Z- [1- (3- (methylaminomethyl) anilino) -1-phenylmethylene] -6-carbamoyl- 2-indolinone trifluoroacetate, the compound was prepared from a resin prepared similar to Preparation 2 and from 4- (N-tert-butoxycarbonyl- N -methyl-aminomethyl) -aniline,

Rf value of the product: 0.06 (silica gel, methylene chloride / methanol = 4: 1), C24H22N4O2, mass spectrum: m / z = 399 [M + H] ⁺ , (14) 3-Z- [1- ( 3-hydroxymethyl-anilino) -1-phenyl-methylene] -6-carbamoyl-2-indolinone, prepared from a resin prepared similar to Preparation 2 and from 3-aminobenzyl alcohol,

Rf value of product: 0.7 (silica gel, methylene chloride / methanol = 4: 1) C23H19N3O3, mass spectrum: m / z = 385 [M] ⁺ , (15) 3-Z- [1- (4- ( methoxycarbonylmethylaminomethyl) anilino) -1-phenylmethylene] -6-carbamoyl-2-indolinone trifluoroacetate, prepared from a resin prepared similar to Preparation 2 and from 4- (N-methoxycarbonylmethyl) - N-tert-butoxycarbonyl- aminomethyl) aniline,

Rf value of product: 0.40 (silica gel, methylene chloride / methanol = 9: 1) C26H24N4O4, mass spectrum: m / z = 457 [M + H] ⁺ , (16) 3-Z- [1- (4) - (N-methylsulfonyl- N - (dimethylaminocarbonyl-methyl) -amino) -anilino) -1-phenylmethylene] -6-carbamoyl-2-indolinone, prepared from a resin prepared similar to Preparation 2 and from 4 - (N-methylsulfonyl- N - (dimethylaminocarbonylmethyl) amino) aniline,

Rf value of product: 0.40 (silica gel, methylene chloride / methanol = 9: 1) C27H27N5O5S, mass spectrum: m / z = 533 [M] ⁺ , · · ····

...... 1 (3) 3-Z- [1- (4- (N-acetylaminomethyl) anilino) -1-phenylmethylene] 6-carbamoyl-2-indolinone prepared from the resin prepared as in Preparation 2 and 4- (N-acetyl-aminomethyl) -aniline _Rf Rf value of the product: 0.70 (silica gel, methylene chloride / methanol = 4: 1) C 25 H 22 N 4 O 3, mass spectrum: m / z = 426 [M] ⁺ , (18) 3-Z- [1- (3,4-dimethoxy-anilino) -1-phenyl-methylene] -6-carbamoyl- 2-indolinone, the compound was prepared from a resin prepared similar to Preparation 2 and from 3,4-dimethoxy-aniline,

Rf value of product: 0.40 (silica gel, methylene chloride / methanol = 9: 1), C24H21N3O4, mass spectrum: m / z = 415 [M] ⁺ , (19) 3-Z- [1- (4-) (morpholin-4-yl) anilino) -1-phenylmethylene] -6-carbamoyl-2-indolinone trifluoroacetate, prepared from a resin prepared similar to Preparation 2 and from 4-morpholin-4-yl-aniline,

Rf value of product: 0.20 (silica gel, methylene chloride / methanol = 9: 1) C26H24N4O3, mass spectrum: m / z = 440 [M] ⁺ , (20) 3-Z-1- (4-acetylamino-) anilino) -1-phenyl-methylene] -6-carbamoyl-2-indolinone, the compound was prepared from a resin prepared similar to Preparation 2 and from 4-acetylamino-aniline,

Rf value of product: 0.25 (silica gel, methylene chloride / methanol = 9: 1) C24H20N4O3, mass spectrum: m / z = 412 [M] ⁺ , (21) 3-Z- [1- (4-amino) -anilino) -1-phenylmethylene] -6-carbamoyl-2-indolinone, the compound was prepared from a resin prepared similar to Preparation 2 and from 4-amino aniline,

-88Rf-value: 0.40 (silica gel, methylene chloride / methanol = 9: 1) C22H18N4O2, mass spectrum: m / z = 370 [M] ⁺ , (22) 3-Z- [1- (4-) (N-methyl-N-acetylaminoanilino) -1-phenylmethylene] -6-carbamoyl-2-indolinone, prepared from a resin prepared similar to Preparation 2 and from 4- (N-methyl- N -acetyl-amino) aniline,

C25H22N4O3, mass spectrum: m / z = 426 [M] &lt; ^{+ &gt};, (23) 3-Z- [1- (4-ethoxycarbonyl-anilino) -1-phenyl-methylene] -6-carbamoyl-2-indolinone; prepared from a resin prepared similar to Preparation 2 and from ethyl 4-aminobenzoate,

C25H21N3O4, mass spectrum: m / z = 427 [M] &lt; ^{+ &gt};, (24) 3-Z- [1- (4-carboxy-anilino) -1-phenyl-methylene] -6-carbamoyl-2-indolinone; prepared from a resin prepared similar to Preparation 2 and from an acid

4-amino-benzoic acid,

Rf value of the product: 0.11 (silica gel, methylene chloride / methanol = 9: 1), C23H17N3O4, mass spectrum: m / z = 398 (MH) -, (25) 3-Z- [1- (4-) benzylcarbamoyl-anilino) -1-phenylmethylene] -6-carbamoyl-2-indolinone, prepared from a resin prepared similar to Preparation 2 and from 4-aminobenzoic acid benzylamide,

Rf value of the product: 0.21 (silica gel, methylene chloride / methanol = 9: 1) C30H24N4O3, mass spectrum: m / z = 488 [M] ⁺ , (26) 3-Z- [1- (cyclohexylamino) -1-phenyl-methylene] -6-carbamoyl-2-indolinone, the compound was prepared from a resin prepared similar to Preparation 2 and cyclohexylamine,

Rf value of product: 0.60 (silica gel, methylene chloride / methanol = 9: 1),

C22H23N3O2, mass spectrum: m / z = 361 [M] ⁺ , (2 S) 3-Z- [1- (4-amino-cyclohexylamino) -1-phenyl-methylene] -6-carbamoyl-2-indolinone- trifluoroacetate, the compound was prepared from a resin prepared similar to Preparation 2 and from 4-amino-cyclohexylamine,

C22H24N4O2, mass spectrum: m / z = 376 [M] &lt; ^{+ &gt};, (28) 3-Z- [1- (N-methyl-piperidin-4-ylamino) -1-phenyl-methylene] -6-carbamoyl -2-indolinone trifluoroacetate, the compound was prepared from a resin prepared similar to Preparation 2 and from 4-amino-1-methyl-piperidine,

Rf value of the product: 0.15 (silica gel, methylene chloride / methanol = 4: 1)

C22H24N4O2, mass spectrum: m / z = 376 [M] ⁺ , (29) 3-Z- [1- (4- (piperidin-1-ylmethyl) amino) -1-methylmethylene] -6 -carbamoyl-2-indolinone-trifluoroacetate, the compound was prepared from a resin prepared similar to Preparation 2 (2) and from 4 (piperidin-1-ylmethyl) -aniline,

Rf value of the product: 0.30 (silica gel, methylene chloride / methanol = 4: 1),

C23H26N4O2, mass spectrum: m / z = 390 [M] &lt; + &gt;, (30) 3-Z- [1- (3-dimethylaminomethyl-anilino) -1-methyl-methylene] -6-carbamoyl-2-indolinone trifluoroacetate, ·· ··

The compound was prepared from a resin prepared similar to Preparation 2 (2) and from 3dimethylaminomethyl-aniline,

Rf value of product: 0.51 (silica gel, methylene chloride / methanol = 4: 1), C2OH22N4O2, mass spectrum: m / z = 351 [M + H] ⁺ , (31) 3-Z- [1- ( 4 - (/ V-methyl- / V-benzylamino-methyl) anilino) -1-methyl-methylene] -6-carbamoyl-

2-indolinone trifluoroacetate, the compound was prepared from a resin prepared similar to Preparation 2 (2) and from 4- (N-methyl- N -benzyl-aminomethyl) -aniline,

Rf value of the product: 0.73 (silica gel, methylene chloride / methanol = 4: 1) C26H26N4O2, mass spectrum: m / z = 426 [M] &lt; ^{+ &gt};, (32) 3-Z- [1- (4- ( N-methylsulfonyl- N - (2-dimethylaminoethyl) amino) anilino) -1-methylmethylene] -6-carbamoyl-2-indolinone trifluoroacetate, prepared from a resin prepared similar to Preparation 2 (2) and from 4- (/ Vmetylsulfonyl- / N- (2-dimethylamino-ethyl) amino) -aniline,

C22H27N5O4S, mass spectrum: m / z = 458 [M + H] &lt; ^{+ &gt};, (33) 3-Z- [1- (4-chloro-anilino) -1-methyl-methylene] -6-carbamoyl-2-indolinone, the compound was prepared from a resin prepared similar to Preparation 2 (2) and from 4-chloro-aniline,

Rf value of the product: 0, 10 (silica gel, methylene chloride / methanol = 9: 1), C ₁₇ H ₁₄ CIN ₃ 0 _2, MS: m / z = 327/329 [M] ^+, (34) 3 -Z- [1- (3-Chloro-amino) -1-methyl-methylene] -6-carbamoyl-2-indolinone, prepared from a resin prepared similar to Preparation 2 (2) and from 3-chloro-aniline , • 9 • · · · · · · ·

-91 Rf value of the product: 0.11 (silica gel, methylene chloride / methanol = 9: 1), C ₁₇ H ₁₄ CIN ₃ 0 ₂ , mass spectrum: m / z = 327/329 [M] ⁺ , (35 13-Z- [1- (4-Methoxycarbonyl-anilino) -1-methyl-methylene] -6-carbamoyl-2-indolinone, prepared from a resin prepared similar to Preparation 2 (2) and from methyl 4- amino-benzoic acid,

Rf value of the product: 0.11 (silica gel, methylene chloride / methanol = 9: 1), CigHi7N ₃ O4, MS: m / z = 351 [M] ^+, (36) 3-Z- [1- ( 4-carboxy-anilino) -1-methyl-methylene] -6-carbamoyl-2-indolinone, prepared from a resin prepared similar to Preparation 2 (2) and from 4-amino-benzoic acid,

C ₂₈ H ₁₅ N ₃ O ₄ , mass spectrum: m / z = 336 [MH] -, (37) 3-Z- [1- (4-methyl-3-nitro-anilino) -1-methyl-methylene] (6-carbamoyl-2-indolinone, the compound was prepared from a resin prepared similar to Preparation 2 (2) and from 4-methyl-3-nitroaniline,

Rf value of the product: 0.82 (silica gel, methylene chloride / methanol = 4: 1),

C ₁₈ H ₂₆ N ₄ O, mass spectrum: m / z = 352 [M] ⁺ , (38) 3-Z- [1- (4- (piperidin-1-ylmethyl) -anilino) -1 -propylmethylene] -6-carbamoyl-2-indolinone trifluoroacetate, from a resin prepared similarly to Preparation 2 (4) and 4- (piperidin-1-ylmethyl) -aniline, Rf value of the product: 0.37 (gel) silica, methylene chloride / methanol = 4: 1), ₂ C 5 H ₃ oN ₂ 0 _4, MS: m / z = 418 [m] +,

· · · · · · ···· · · · · • · • • • • · • 9 • • • · • • · · · • • 9 • • ··· · • • • • · e 9 * • • • · • • • • · · «· · · · · · · · ····

(39) 3-Z- [1- (3-dimethylaminomethyl-anilino) -1-propylmethylene] -6-carbamoyl-2-indolinone trifluoroacetate, from a resin prepared similar to Preparation 2 (4) and 3-dimethylaminomethyl-aniline, Rf - product value: 0.42 (silica gel, methylene chloride / methanol = 4: 1), C22H26N4O2, mass spectrum: m / z = 378 [M] ⁺ , (40) 3-Z- [1- (4- ( N-methyl- N -benzylaminomethyl) anilino-1-propylmethylene] -6-carbamoyl-

2-indolinone trifluoroacetate, from a resin prepared similar to Preparation 2 (4) and 4- [N-methyl- N -benzyl] aminomethyl] aniline,

Rf value of product: 0.81 (silica gel, methylene chloride / methanol = 4: 1), C28H30N4O2, mass spectrum: m / z = 454 [M] ⁺ , (41) 3-Z- [1- (4-) (N-methylsulfonyl- N - (2-dimethylaminoethyl) amino) anilino) -1-propylmethylene] -6-carbamoyl-2-indolinone trifluoroacetate, from a resin prepared similar to Preparation 2 (4) and 4 - [/ In-methylsulfonyl-A / - (2dimetylamino-ethyl) amino) -aniline,

Rf value of product: 0.59 (silica gel, methylene chloride / methanol = 4: 1), C24H31N5O4S, mass spectrum: m / z = 486 [M + H] ⁺ , (42) 3-Z- [1 - ( 4-chloro-anilino) -1-propylmethylene] -6-carbamoyl-2-indolinone, from a resin prepared similar to Preparation 2 (4) and 4-chloro-aniline,

Rf value of product: 0.17 (silica gel, methylene chloride / methanol = 9: 1), C19H18ClN3O2, mass spectrum: m / z = 355/357 [M] ⁺ , (43) 3-Z- [1- ( 3-chloro-anilino) -1-propyl-methylene] -6-carbamoyl-2-indolinone, from a resin prepared similar to Preparation 2 (4) and 3-chloro-aniline,

Rf value of product: 0.12 (silica gel, methylene chloride / methanol = 9: 1), ····················· · ····················································

-93C19H18CIN3O2, mass spectrum: m / z = 355/357 [M] ⁺ , (44) 3-Z- [1- (4-methoxycarbonyl-anilino) -1-propylmethylene] -6-carbamoyl-2-indolinone , from a resin prepared similar to Preparation 2 (4) and 4-aminobenzoic acid methyl ester,

Rf value of product: 0.8 (silica gel, methylene chloride / methanol = 4: 1), C21H21N3O4, mass spectrum: m / z = 379 [M] ⁺ , (45) 3-Z- [1- (4-) carboxy-anilino) -1-propyl-methylene] -6-carbamoyl-2-indolinone, from a resin prepared similar to Preparation 2 (4) and from 4-aminobenzoic acid, C20H19N3O4, mass spectrum: m / z = 364 [ MH] ⁺ , (46) 3-Z- [1- (4-methyl-3-nitro-anilino) -1-propylmethylene] -6-carbamoyl-2-indolinone, from a resin prepared similar to Preparation 2 ( 4) az 4-methyl-3-nitroaniline, Rf value of the product: 0.86 (silica gel, methylene chloride / methanol = 4: 1), C20H20N4O4, mass spectrum: m / z = 380 [M] ⁺ .

Example 2

3-Z- [1- (3- (piperidin-1-yl-methyl) anilino) -1-phenyl-methylene] -6-carbamoyl-2-indolinóntrifluóracetát

2.0 g of 3-Aminobenzyl alcohol in 20 ml of diphenylformamide similar to Example 1, together with 2.0 g of resin prepared similar to Preparation 2, were shaken at 70 ° C for 22 hours. The solvent was then removed by suction and the resin was washed several times with dimethylformamide and methylene chloride. The saturated resin (200 mg) was then dispersed in 2 ml of methylene chloride and after addition of 0.2 ml of methanesulfonic acid chloride and 0.1 ml of triethylamine the mixture was allowed to stand at room temperature for 2 hours. The resin was then washed several times with methylene chloride,

9 ···································································

-94 was dispersed in 2 ml of methylene chloride and 0.2 ml of piperidine was added. After one hour, the resin was washed with methylene chloride and dimethylformamide and then worked up as in Example 1.

Yield: 15 mg,

Rf value of the product: 0.30 (silica gel, methylene chloride / methanol = 4: 1),

C28H28N4O2.

Mass spectrum: m / z = 452 [M] &lt; ^{+ &gt};.

The following compounds were prepared as in Example 2:

(1) 3-Z- [1- (3- (diethylaminomethyl) anilino) -1-phenylmethylene] -6-carbamoyl-2-indolinone trifluoroacetate, prepared from a resin prepared similar to Preparation 2 and from diethylamine,

Rf value of product: 0.80 (silica gel, methylene chloride / methanol = 4: 1),

C27H28N4O2, mass spectrum: m / z = 440 [M] &lt; + &gt;, (2) 3-Z- [1- (3- (benzylaminomethyl) anilino) -1-phenylmethylene] -6-carbamoyl-2-indolinone trifluoroacetate, the compound was prepared from a resin prepared similar to Preparation 2 and from benzylamine,

Rf value of product: 0.80 (silica gel, methylene chloride / methanol = 4.Ί),

C 30 H 26 N 4 O 2, mass spectrum: m / z = 474 [M] +, (3) 3-Z- [1- (3- (N-methyl- N -benzylaminomethyl) anilino) -1-phenylmethylene ] -6-carbamoyl-

2-indolinone trifluoroacetate, the compound was prepared from a resin prepared similar to Preparation 2 and from N-methylbenzylamine,

Rf value of product: 0.80 (silica gel, methylene chloride / methanol = 4: 1),

C31H28N4O2, mass spectrum: m / z = 488 [M] &lt; ^{+ &gt};, (4) 3-Z- [1- (3- (butylaminomethyl) amino) -1-phenylmethylene] -6-carbamoyl-2 -indolinone trifluoroacetate, the compound was prepared from a resin prepared similar to Preparation 2 and from butylamine,

Rf value of the product: 0.40 (silica gel, methylene chloride / methanol = 4: 1), C27H28N4O2, mass spectrum: m / z = 440 [M] ⁺ , (S) 3-Z- [1- (3-) (aminomethyl) -anilino) -1-phenylmethylene] -6-carbamoyl-2-indolinone trifluoroacetate, prepared from a resin prepared similar to Preparation 2 and from ammonia,

C23H20N4O2, mass spectrum: m / z = 385 [M + H] ⁺ , (6) 3-Z- [1- (3- (N - (3-dimethylarninopropyl) - N -methylaminomethyl) anilino) -1- phenylmethylene] -6-carbamoyl-2-indolinone trifluoroacetate, prepared from a resin prepared similar to Preparation 2 and from 1-dimethylamino-3-methylaminopropane,

Rf value of the product: 0.67 (silica gel, methylene chloride / methanol = 4: 1), C29H33N5O, mass spectrum: m / z = 484 [M + H] ⁺ , (7) 3-Z- [1 - ( 3- (N - (2-dimethylaminoethyl) - N -methyl-aminomethyl) -anilino) -1-phenylmethylene] 6-carbamoyl-2-indolinone trifluoroacetate, prepared from a resin prepared similar to Preparation 2 and 1-dimethylamino-2-methylaminoethane,

Rf value of product: 0.40 (silica gel, methylene chloride / methanol = 4: 1), C28H31N5O2, mass spectrum: m / z = 470 [M + H] ⁺ .

·· ··· «• ·

Example 96

3-Z- [1- (4- (piperidin-1-yl-methyl) anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone

1.5 g of 1-Acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-ethoxycarbonyl-2-indolinone and 1.1 g of 4- (piperidin-1-ylmethyl) -aniline were dissolved in 15 ml of dimethylformamide and the solution was stirred at 100 ° C for 45 minutes. After cooling, 5.0 mL of piperidine was added and the reaction mixture was stirred at room temperature for an additional three hours. After removal of the solvent, the residue was purified on an alumina column (oxide activity 2-3) using methylene chloride and ethanol (100: 3) as eluent.

Yield: 1.1 g (58% of theory), Rf value of product: 0.5 (aluminum oxide, methylene chloride / ethanol = 100: 3) C30H31N3O3, mass spectrum: m / z = 481 [M] ⁺ .

As in Example 3, the following compounds were prepared:

(1) 3-Z- [1- (4-bromo-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenyl- methylene) -6-ethoxycarbonyl-2-indolinone and 4-bromoaniline,

Rf value of product: 0.4 (silica gel, toluene / ethyl acetate = 5: 1),

C ₂₄ H 19 BrN ₂ O ₃ , mass spectrum: m / z = 462/464 [M] ⁺ , (2) 3- Z- [1- (3- (dimethylaminomethyl) anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-ethoxycarbonyl-2-indolinone and 3- (dimethylaminomethyl) -aniline,

Rf value of product: 0.5 (alumina, methylene chloride / ethanol = 30: 1),

C27H27N3O3.

ESI-MS: m / z = 442 [M + H] &lt; ^{+ &gt};

• · «3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 - (4- (dimethylaminomethyl) anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-ethoxycarbonyl- 2-indolinone and 4- (dimethylaminomethyl) aniline,

Rf value of product: 0.7 (alumina, ethyl acetate / ethanol = 20: 1),

C27H27N3O3.

ESI-MS: m / z = 442 [M + H] ⁺ , (4) 3-Z- [1- (4 - [(2,6-dimethyl-piperidin-1-yl) -methyl] -anil (i) -1-Phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-ethoxycarbonyl-2-indolinone and 4- [ (2,6-dimethyl-piperidin-1-yl) methyl] -aniline,

Rf value of the product: 0.6 (silica gel, methylene chloride / ethanol = 5: 1),

C 32 H 35 N 3 O 3, mass spectrum: m / z = 509 [M] ⁺ , (S) 3-Z- [1- (4- (2-dimethylamino-ethyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl- 2-indolinone prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-ethoxycarbonyl-2-indolinone and 4- (2-dimethylamino-ethyl) -aniline,

Rf value of product: 0.2 (silica gel, methylene chloride / ethanol = 5: 1),

C 28 H 29 N 3 O 3, mass spectrum: m / z = 44 [M] ⁺ , (6) 3-Z- [1- (4 - (N - (2-dimethylamino-ethyl) - N -acetyl-amino) -anilino) 1-Phenylmethylene] -6-ethoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-ethoxycarbonyl-2-indolinone and 4- (A) / - (2-dimethylamino-ethyl) - / V-acetyl-amino) -aniline,

Rf value of the product: 0.4 (alumina, methylene chloride / ethanol = 20: 1),

C30H32N4O4, mass spectrum: m / z = 512 [M] < ^{+ &gt};,^&gt;········ · 7 7 7 7 (7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 7 4-tert-Butyloxycarbonyl-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-ethoxycarbonyl-2- indolinone and 4-tert-butyloxycarbonyl-aniline,

Rf value of the product: 0.4 (alumina, methylene chloride / ethanol = 40: 1),

C29H28N2O5, mass spectrum: m / z = 484 [M] &lt; ^{+ &gt};, (8) 3-Z- [1- (4- (N- (3-dimethylamino-propyl) - N -acetyl-amino) -anilino) 1-Phenylmethylene] -6-ethoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-ethoxycarbonyl-2-indolinone and 4 - (N -) - (3-dimethylaminopropyl) - / V-acetyl-amino) -aniline,

Rf value of product: 0.2 (alumina, methylene chloride / ethanol = 40: 1),

C31H34N4O4, mass spectrum: m / z = 526 [M] &lt; ^{+ &gt};, (9) 3-Z- [1- (4 - (N - (2-dimethylaminoethyl) - N -methylsulfonylamino) anilino) -1-phenylmethylene ] -

6-ethoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-ethoxycarbonyl-2-indolinone and N - (2-dimethylamino-ethyl) - N, methylsulphonyl-p-phenylenediamine,

Rf value of the product: 0.3 (alumina, methylene chloride / ethanol = 40: 1),

C29H32N4O5S, mass spectrum: m / z = 548 [M] &lt; ^{+ &gt};, (10) 3-Z- [1- (4- (4-methyl-piperazin-1-yl) -amino) -1-phenyl-methylene 6-ethoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-ethoxycarbonyl-

2-indolinone and 4- (4-methyl-piperazin-1-yl) -aniline,

Rf value of product: 0.3 (alumina, ethyl acetate),

C29H30N4O3.

ESI-MS: m / z = 483 [M + H] &lt; ^{+ &gt};, M + H &lt; ^{+ &gt}; · · · · · · · T · 9 t 11 t 11 11 11 11 11 11 11 11 11 11 11 11 11 11 (11) 3-Z- [1- (4 - (/ V- ( 2-dimethylamino-ethyl) - (N-methyl-amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenyl- methylene) -6-ethoxycarbonyl-2-indolinone and 4 - (N- (2-dimethylamino-ethyl) - N -methylamino ₎ -aniline ₎

Rf value of product: 0.5 (alumina, methylene chloride / ethanol = 20: 1),

C29H32N4O3.

ESI-MS: m / z = 485 [M + H] +, (12) 3-Z- [1- (4 - (N - (3-dimethylamino-propyl) - N -methyl] -amino) -anilino ) -1-phenyl-methylene] -

6-ethoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-ethoxycarbonyl-2-indolinone and 4- (N - (3-dimethylamino-propyl) - / V-methyl-amino) -aniline,

Rf value of product: 0.5 (alumina, ethyl acetate),

C30H34N4O3.

ESI-MS: m / z = 499 [M + H] &lt; ^{+ &gt};, (13) 3-Z- [1- (4- (N-methyl-acetylamino) -anilino) -1-phenyl-methylene] -6 -ethoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-ethoxycarbonyl-2-indolinone and 4-amino- N -methyl-acetanilide,

Rf value of the product: 0.3 (silica gel, methylene chloride / ethanol = 15: 1),

C27H25N3O3, mass spectrum: m / z = 455 [M] ⁺ , (14) 3-Z- [1- (4- (N-methylmethylsulfonylamino) anilino) -1-phenylmethylene] -6-ethoxycarbonyl-

2-indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-ethoxycarbonyl-2-indolinone and N - (4-aminophenyl) - N -methyl-methanesulfonamide,

Rf value of product: 0.8 (alumina, ethyl acetate),

C26H25N3O5S, mass spectrum: m / z = 491 [M] &lt; ^{+ &gt};

-100- (15) 3-Z- [1- (4 - (N - (3-dimethylaminopropyl) - N -methylsulphonylamino) -anilino) -1-phenyl- methylene] -6-ethoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-ethoxycarbonyl-2-indolinone and N - (3-dimethylamino-propyl) - / V-methylsulfonyl-p-phenylenediamine,

Rf value of the product: 0.6 (silica gel, methylene chloride / ethanol / ammonia = 5: 2: 0.01),

C30H34N4O5S.

ESI-MS: m / z = 563 [M + H] ⁺ , (16) 3- Z - [1- (4- (N-dimethylaminocarbonylmethyl- N -methylsulfonylamino) anilino) -1-phenylmethylene] 6-ethoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-ethoxycarbonyl-2-indolinone and 4- (N-dimethylaminocarbonylmethyl) -N- methylsulfonyl) amino) aniline,

Product value: 0.6 (silica gel, methylene chloride / ethanol = 10: 1), C29H30N4O6S,

ESI-MS: m / z = 561 [MH] +, (17) 3- Z- [1- (4- (imidazol-4-yl) anilino) -1-phenylmethylene] -6-ethoxycarbonyl- 2-indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-ethoxycarbonyl-2-indolinone and 4- (imidazol-4-yl) -aniline,

Product value: 0.5 (silica gel, methylene chloride / ethanol / ammonia = 10: 1: 0.01),

C27H22N4O3, mass spectrum: m / z = 450 [M] &lt; ^{+ &gt};, (18) 3-Z- [1- (4- (tetrazol-5-yl) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl- 2-indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-ethoxycarbonyl-2-indolinone and 4- (tetrazol-5-yl) -aniline,

Product value: 0.5 (silica gel, methylene chloride / ethanol = 5: 1),

C25H20N6O3 »

ESI-MS: m / z = 451 [MH] &lt; + &gt;, &lt; tb &gt; ______________________________________ &lt; tb &gt; ♦ ♦ · ♦ · ♦ · · · · · · · · · · · · ·

-101- (19) 3-Z- [1- (4- (N-benzyl- N -methylaminomethyl) anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, prepared by reaction 1- acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-ethoxycarbonyl-2-indolinone and 4- (N-benzyl-N-methyl-aminomethyl) -aniline,

Rf value of the product: 0.4 (silica gel, methylene chloride / ethanol = 10: 1),

C33H31N3O3.

ESI-MS: m / z = 516 [MH] -, (20) 3-Z- [1- (4 - (N - (2-dimethylamino-ethyl) - N -propionyl-amino) -aniline) -1-phenyl-methylene] -

6-ethoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-ethoxycarbonyl-2-indolinone and 4 - [- N - (2-dimethylamino-ethyl) - / \ / - propionyl-amino] -aniline,

Rf value of product: 0.2 (silica gel, methylene chloride / ethanol = 5: 1),

C31H34N4O4.

ESI-MS: m / z = 525 [MH] -, (21) 3-Z- [1- (4- (pyrrolidin-1-ylmethyl) -anilino) -1-phenyl-methylene] -6- ethoxycarbonyl-2-indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-ethoxycarbonyl-2-indolinone and 4- (pyrrolidin-1-ylmethyl) -aniline,

Product value: 0.1 (silica gel, methylene chloride / ethanol = 5: 1),

C29H29N3O3.

ESI-MS: m / z = 466 [MH] +, (22) 3-Z- [1- (4- (N-methyl-N-phenethylaminomethyl) anilino) -1-phenylmethylene] - 6-ethoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-ethoxycarbonyl-2-indolinone and 4- (N-phenethyl- N -methyl-aminomethyl) ) aniline,

Rf value of the product: 0.4 (silica gel, methylene chloride / ethanol = 10: 1),

C34H33N3O3.

ESI-MS: m / z = 530 [M-H] -

-102- (2S) 3- Ζ- [1- (4- (N-dimethylaminomethylcarbonyl-N-methylamino) anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, prepared by reaction of 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-ethoxycarbonyl-2-indolinone and N-dimethylaminomethylcarbonyl- N -methyl-p-phenylenediamine,

Rf value of product: 0.1 (silica gel, methylene chloride / ethanol = 10: 1), C29H30N4O4,

ESI-MS: m / z = 497 [MH] -, (24) 3-Z- [1- (4 - (N - (2-dimethylaminoethyl) - N -ethylsulfonylamino) anilino) -1-phenyl- methylene] 6-ethoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-ethoxycarbonyl-2-indolinone and N - (2-dimethylamino-ethyl) -] \ / - ethylsulfonyl-p-phenylenediamine,

Product value: 0.6 (silica gel, methylene chloride / ethanol = 5: 1), C30H34N4O5S,

ESI-MS: m / z = 561 [MH] -, (25) 3-Z- [1- (4- (N-tert-butoxycarbonyl- N -ethyl-aminomethyl) anilino) -1- phenyl-methylene] 6-ethoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-ethoxycarbonyl-2-indolinone and 4- (N-tert-butoxycarbonyl- A / -ethylaminomethyl) -aniline,

Product value: 0.5 (silica gel, methylene chloride / methanol = 10: 1),

C32H35N3O5.

ESI-MS: m / z = 540 [MH] -, (26) 3-Z- [1- (4- (piperidin-1-ylmethyl) anilino) -1-ethylmethylene] -6-ethoxycarbonyl-2-indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-ethyl-methylene) -6-ethoxycarbonyl-2-indolinone and 4- (piperidin-1-ylmethyl) -aniline,

Rf value of product: 0.9 (silica gel, methylene chloride / ethanol = 5: 1),

C26H31N3O3.

ESI-Mass Spectrum: m / z = 432 [MH] &lt; - &gt;, &quot; H &quot; · · · Φ · · · · · · · · ·

- 103 - (27) 3- Ζ- [1- (4- (N - (2-dimethylaminoethyl) - N -methylsulfonylamino) anilino) -1-ethylmethylene] -6-ethoxycarbonyl-2-indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-ethyl-methylene) -6-ethoxycarbonyl-2-indolinone and N - (2-dimethylamino-ethyl) - N -methylsulfonyl-p-phenylenediamine,

Product value: 0.3 (silica gel, methylene chloride / ethanol = 5: 1),

C25H32N4O5S.

ESI-MS: m / z = 499 [MH] -, (28) 3-Z- [1- (4- (dimethylaminomethyl) anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4- (dimethylaminomethyl) aniline,

Product value: 0.6 (silica gel, methylene chloride / methanol = 5: 1),

C26H25N3O3.

ESI-MS: m / z = 428 [M + H] ⁺ , (29) 3-Z- [1- (4 - [(2,6-dimethyl-piperidin-1-yl) -methyl] - anilino-1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and 4 - [(2,6-dimethyl-piperidin-1-yl) -methyl] -aniline,

Product value: 0.5 (reverse phase RP 8, methanol / 5% aqueous sodium chloride = 4: 1),

C31H33N3O3.

ESI-MS: m / z = 496 [M + H] +, (30) 3-Z- [1- (4 - (N - (2-dimethylamino-ethyl) -N-methylsulfonylamino) anilino) -1-phenylmethylene 6-Methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and N - (2-dimethylaminoethyl) -. \ / - methylsulfonyl-p-phenylenediamine,

Product value: 0.6 (silica gel, methylene chloride / methanol = 5: 1),

C28H30N4O5S.

ESI-MS: m / z = 533 [M-H] &lt; + &gt;, 9,999

-104- (31) 3- [1- (4- (N - (3-dimethylamino-propyl) - N -methylsulfonyl-amino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2- indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and N - (3-dimethylamino-propyl) - N -methylsulfonyl-p-phenylenediamine,

Rf value of product: 0.5 (alumina, methylene chloride / methanol = 30: 1),

C29H32N4O5S.

ESI-MS: m / z = 547 [MH] -, (32) 3-Z- [1- (4- (N-dimethylaminocarbonyl-methyl- N -methylsulfonyl-amino) -anilino) -1-phenyl- methylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4 - ((N-dimethylaminocarbonyl-methyl) / V-methylsulfonyl) amino) aniline,

Rf value of product: 0.5 (alumina, methylene chloride / methanol = 20: 1),

C28H28N4O6S.

ESI-MS: m / z = 547 [MH] -, (33) 3-Z- [1- (4- (N-acetyl- N -dimethylaminocarbonyl-methylamino) -anilino) -1-phenylmethylene 6-Methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4 - ((N-acetyl-N) - dimethylaminocarbonylmethyl) -amino) -aniline,

Rf value of the product: 0.6 (silica gel, methylene chloride / methanol = 10: 1), C29H28N4O5,

ESI-MS: m / z = 511 [MH] -, (34) 3-Z- [1- (4- (N-dimethylaminocarbonyl-methyl-amino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl -2-indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and 4 - ((N-dimethylaminocarbonyl-methyl) -amino) -aniline,

Product value: 0.6 (alumina, methylene chloride / methanol = 30: 1), C27H26N4O4.

ESI-MS: m / z = 469 [MH] &lt; - &gt;, &lt; tb &gt; &lt; - &gt; · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 105 - (35) 3-Z- [1- (4- (N - (3-dimethylamino-propyl) -N-acetyl-amino) -a-ilino) -1 - phenyl-methylene] -

6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and N - (3-dimethylamino-propyl) - N - acetyl-p-phenylenediamine,

Rf value of product: 0.5 (alumina, methylene chloride / methanol = 20: 1),

C30H32N4O4.

ESI-MS: m / z = 511 [MH] -, (36) 3-Z- [1- (4- (N-methylaminocarbonyl-methyl- N -methylsulfonylamino) -anilino) -1-phenyl-methylene 6-Methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and N -methylaminocarbonylmethyl- N -methylsulfonyl- p-phenylenediamine,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 10: 1),

C27H26N4O6S.

ESI-MS: m / z = 533 [MH] -, (37) 3-Z- [1- (4 - ((imidazolidin-2,4-dione-5-ylidene) methyl) anilino) -1-phenylmethylene 6-Methoxycarbonyl-2-indolinone prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4 - ((imidazolidine-2,4-) dione-5-ylidene) methyl) aniline,

Rf value of the product: 0.4 (silica gel, methylene chloride / methanol = 10: 1),

C27H20N4O5.

ESI-MS: m / z = 479 [MH] -, (38) 3-Z- [1- (4 - (N - ((2-dimethylamino-ethyl) -carbonyl) - N -methyl-) - amino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and N, N- ((2-dimethylamino-ethyl) carbonyl) - / V-methyl-p-phenylenediamine,

Rf value of product: 0.5 (alumina, methylene chloride / methanol = 20: 1),

C29H30N4O4.

ESI-MS: m / z = 497 [M-H] -,

-106- (39) 3-N- [1- (4- (N-tert-butoxycarbonylaminomethyl) anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by reaction of 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and 4- (N-tert-butoxycarbonylaminomethyl) aniline,

Rf value of the product: 0.3 (alumina, methylene chloride / methanol = 20: 1),

C29H29N3O5.

ESI-MS: m / z = 498 [MH] -, (40) 3-Z- [1- (4- (2-oxopyrrolidin-1-ylmethyl) anilino) -1-phenylmethylene] -6-methoxycarbonyl -

2-indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4- (2-oxo-pyrrolidin-1-ylmethyl) aniline,

Rf value of the product: 0.3 (silica gel, methylene chloride / methanol = 20: 1),

C28H25N3O4.

ESI-MS: m / z = 466 [MH] -, (41) 3-Z- [1- (4- (N-aminocarbonyl- N -methylsulfonyl-amino) -anilino) -1-phenyl-methylene ] -6-methoxycarbonyl-2-indolinone, prepared from 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and N-aminocarbonylmethyl-N-methylsulfonyl-p-phenylenediamine,

Rf value of product: 0.7 (silica gel, methylene chloride / methanol = 5: 1), C26H24N4O6S,

ESI-MS: m / z = 519 [MH] -, (42) 3-Z- [1- (4- (thiomorpholin-4-ylmethyl) -anilino) -1-phenyl-methylene] -6- methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and 4- (thiomorpholin-4-ylmethyl) -aniline,

Rf value of product: 0.4 (silica gel, methylene chloride / methanol = 15: 1), C28H27N3O3S,

ESI-MS: m / z = 484 [MH] &lt; - &gt;, &lt; tb &gt; ______________________________________ &lt; tb &gt; ···················································

- 107 - (43) 3- Ζ- [1- (4- (1,1-dioxo-thiomorpholin-4-ylmethyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2- indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4- (1,1-dioxo-thiomorpholin-4-ylmethyl) -aniline,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 10: 1),

C28H27N3O5S.

ESI-MS: m / z = 516 [MH] -, (45) 3-Z- [1- (4- (N-tert-butoxycarbonyl-ethylaminomethyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl -2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4- (N-ethyl-N-tert-butoxycarbonylaminomethyl) aniline,

Rf value of the product: 0.6 (silica gel, methylene chloride / methanol = 10: 1),

C31H33N3 O5,

ESI-MS: m / z = 526 [M-H] -,

3-Z- [1- (4- (N-benzyl-N-methyl-aminomethyl) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by reaction of 1-acetyl- 3- (1-ethoxy-1-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and 4- (N-benzyl- N -methyl-aminomethyl) aniline,

Product value: 0.5 (silica gel, methylene chloride / methanol = 10: 1),

C32H29N3O3.

ESI-MS: m / z = 502 [MH] -, (47) 3-Z- [1- (4- (1-oxo-thiomorpholin-4-ylmethyl) -anilino) -1-phenyl-methylene 6-Methoxycarbonyl-2-indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4- (1-oxo-thiomorpholine-4) yl-methyl) -aniline,

Product value: 0.7 (silica gel, methylene chloride / methanol = 10: 1),

C ₂ 8H27N3O4S,

ESI-MS: m / z = 500 [MH] &lt; - &gt;, &lt; - &gt; · · · · · · · · · · · · · · · · · · · · · · · · ·

-108- (48) 3-Z- [1- (4- (2- (imidazol-4-yl) -ethyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-methoxycarbonyl-2-indolinone, and 4- (2- (imidazol-4-yl) -ethyl) -aniline,

Product value: 0.4 (silica gel, methylene chloride / methanol = 5: 1),

C28H24N4O3.

ESI-MS: m / z = 463 [MH] -, (49) 3-Z- [1- (4- (morpholin-4-ylmethyl) -anilino) -1-phenyl-methylene] -6- methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and 4- (morpholin-4-ylmethyl) -aniline,

Product value: 0.5 (silica gel, methylene chloride / methanol = 10: 1),

C28H27N3O4.

ESI-MS: m / z = 468 [MH] -, (50) 3-Z- [1- (4- (4-methylpiperazin-1-yl) methyl) anilino) -1-phenylmethylene] -6-methoxycarbone nyl-2-indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and 4 - ((4-methyl-piperazin-1-yl) - methyl) aniline,

Product value: 0.4 (silica gel, methylene chloride / methanol 5: 1),

C29H30N4O3.

ESI-MS: m / z = 481 [MH], (51) 3-Z- [1- (4 - ((2 - (N-benzyl- N -methyl-amino) -ethyl) -) -. (methylsulfonyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-methoxycarbonyl-2- indolinone and 4 - (N - (2 - (N -benzyl-N -methyl-amino) -ethyl) - N -methylsulfonyl-amino) -aniline,

Product value: 0.7 (silica gel, methylene chloride / methanol = 10: 1),

C34H34N4O5S.

ESI-MS: m / z = 609 [MH] &lt; + &gt;, &lt; tb &gt; ______________________________________ &lt; tb &gt; • · ··· ♦ ·· ···· · ·· ···················

-109- (52) 3- Ζ- [1- (4-cyclohexylaminoanilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) ) -6-methoxycarbonyl-2-indolinone and N-cyclohexyl-p-phenylenediamine,

Rf value of product: 0.8 (silica gel, methylene chloride / methanol = 10: 1),

C29H28N2O3.

ESI-MS: m / z = 451 [MH] +, (53) 3- Z- [1- (4- (pyridin-4-ylmethyl) -anilino) -1-phenylmethylene] -6- methoxycarbonyl-2-indolinone prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and 4- (pyridin-4-ylmethyl) -aniline,

Rf value of the product: 0.6 (silica gel, methylene chloride / methanol / ammonia =

5: 1: 0.01).

C ₂ 9H ₂ 3N ₃ O 3,

ESI-MS: m / z = 460 [MH] -, (54) 3-Z- [1- (4- (imidazol-1-ylmethyl) -anilino) -1-phenyl-methylene] -6 -methoxycarbonyl-2-indolinone prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and 4- (imidazol-1-ylmethyl) -aniline,

Rf value of product: 0.4 (silica gel, methylene chloride / methanol / ammonia =

10: 1: 0.01).

C27H22N4O3.

ESI-MS: m / z = 449 [MH] -, (55) 3 -Z- [1- (4- (imidazol-1-ylmethyl) -anilino) -1-phenyl-methylene] -6- methoxycarbonyl-2-indolinone prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and 4- (imidazol-1-ylmethyl) -aniline,

Rf value of product: 0.4 (silica gel, methylene chloride / methanol / ammonia =

10: 1: 0.01), ·································· · ··· ·· ····

-110C27H22N4O3.

ESI-MS: m / z = 449 [MH] -, (56) 3-Z- [1- (N-methyl-piperidin-4-ylamino) -1-phenyl-methylene] -6-methoxycarbonyl -2-indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and 4-amino-1-methyl-piperidine,

Rf value of product: 0.3 (silica gel, methylene chloride / methanol = 5: 1),

C23H25N3O3.

ESI-MS: m / z = 390 [MH] -, (57) 3-Z- [1- (4- (imidazol-4-ylmethyl) -anilino) -1-phenyl-methylene] -6- methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and 4- (imidazol-4-ylmethyl) -aniline,

Rf value of product: 0.2 (silica gel, methylene chloride / methanol = 5: 1),

C27H22N4O3.

ESI-MS: m / z = 449 [MH] -, (58) 3-Z- [1- (4 - ((4-hydroxy-piperidin-1-yl) -methyl) -anilino) -1-phenyl -methylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4 - ((4-hydroxy- piperidin-1-yl) methyl) aniline,

Rf value of the product: 0.1 (silica gel, methylene chloride / methanol = 10: 1),

C29H29N3O3.

ESI-MS: m / z = 482 [MH] -, (59) 3-Z- [1- (4 - ((4-methoxy-piperidin-1-yl) -methyl) -anilino) -1 -phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4 - ((4-methoxy- piperidin-1-yl) methyl) aniline,

Rf value of the product: 0.4 (silica gel, methylene chloride / methanol = 10: 1), · · · · · · · · · · · _β · ·························································

-111 C30H31N3O4,

ESI-MS: m / z = 496 [MH] -, (60) 3-Z- [1- (4-benzyl-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, prepared by reaction 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and 4-benzyl-aniline,

Rf value of the product: 0.6 (silica gel, methylene chloride / methanol = 10: 1),

C30H24N2O3, mp .: 224 ° C.

(61) 3-N- [1- (4- (N - (3-trifluoroacetylaminopropyl) - N -methylsulfonylamino) anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by reaction 1 - acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and N - (3-trifluoroacetylamino-propyl) - N -methylsulfonyl-p-phenylenediamine,

Rf value of product: 0.5 (alumina, methylene chloride / methanol = 20: 1),

C29H27F3N4O6S.

ESI-MS: m / z = 615 [M-H] -, (62) 3-Z- [1- (4-tert-butoxycarbonyl-methyl-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-

2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4-aminophenylacetic acid tert-butyl ester,

Rf value of product: 0.5 (alumina, ethyl acetate),

C30H30N2O5.

ESI-MS: m / z = 497 [MH] -, (63) 3-Z- [1- (4-tert-butoxycarbonyl-anilino) -1-ethyl-methylene] -6-ethoxycarbonyl-2-indolinone, prepared by reaction 1-acetyl-3- (1-ethoxy-1-ethyl-methylene) -6-ethoxycarbonyl-2-indolinone and 4-tert-butoxycarbonyl-aniline,

Rf value of the product: 0.4 (alumina, methylene chloride / ethanol = 20: 1),

C25H29N2O5 ·

· · · · · · ···· • • • · • · • • · • · T • · · · • • ··· · • • 9 · • • • • • • · · · · · · ·

9 · 9 · 9 · 9 · 9

-112ESI-mass spectrum: m / z = 435 [MH] -, (64) 3-Z- [1- (4- (4-tert-butoxycarbonyl-piperazin-1-ylmethyl) -anilino) -1- phenyl-methylene-6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and 4- (4-tert-butoxycarbonyl-piperazine-1) yl-methyl) -aniline,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 10: 1), C33H36N4O5,

ESI-MS: m / z = 567 [MH] -, (65) 3-Z- [1- (4- (1-methyl-inidazol-2-yl) -anilino) -1-phenyl-methylene] - 6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and 4- (1-methyl-imidazol-2-yl) -aniline,

Rf value of the product: 0.6 (silica gel, methylene chloride / methanol = 5: 1), C27H22N4O3,

ESI-MS: m / z = 449 [MH] -, (66) 3-Z- [1- (4- (N - (2-dimethylaminoethyl) - N -methylsulfonylamino) -3-nitroanilino) -1 -phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 6- (N - (2-dimethylamino) (ethyl-N-methylsulfonyl-amino) -3-amino-nitrobenzene, Rf value of the product: 0.6 (silica gel, methylene chloride / methanol = 5: 1), C28H29N5O7S,

ESI-MS: m / z = 578 [MH] -, (67) 3-Z- [1- (4 - (N - (2-dimethylamino-ethyl) - N -methylsulfonylamino) -3- amino-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4- ( / V- (2-dimethylamino-ethyl) - / V-methylsulfonyl-amino) -3-amino-aniline,

Rf value of product: 0.5 (alumina, methylene chloride / methanol = 20: 1),

C28H31N5O5S, · ············

β) · v · v v v t t t t t t t t t t t e t e e t e e t e e e

-113ESI-mass spectrum: m / z = 548 [MH] -, (68) 3-Z- [1- (4 - ((3- (N-benzyl- N -methylamino) -propyl) - N) methyl-sulphonyl-amino) anilino) -

1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4 - (N - ( 3 - (/ V-benzyl- / V-methyl-amino) propyl) - / V-methylsulphonyl-amino) -aniline,

Rf value of the product: 0.6 (silica gel, methylene chloride / methanol = 10: 1),

C35H36N4O5S.

ESI-MS: m / z = 623 [MH] -, (69) 3- Z - [1- (4 - (N - (2-dimethylaminoethyl) - N -methylsulfonylamino) -3-chloroanilino) -1 -phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4- (N - (2-dimethylamino) ethyl) - / V-methylsulfonyl-amino) -3-chloro-aniline,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 10: 1),

C28H29CIN4O5S.

ESI-MS: m / z = 567/569 [MH] -, (70) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl- N -methylamino) anilino) -1-phenylmethylene 6-Methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and N-dimethylaminomethylcarbonyl- N -methyl-p- phenylenediamine,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 9: 1),

C28H28N4O4.

ESI-MS: m / z = 483 [MH] -, (71) 3-Z- [1- (4 - (N - (2-dimethylamino-ethyl) - N -acetyl-amino) -anilino) 1-Phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4 - (N - (2 dimethylamino-ethyl) - / \ / - acetyl-amino) -aniline,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 9: 1),

C29H30N4O4

-114ESI-mass spectrum: m / z = 497 [MH] -, (72) 3-Z- [1- (4 - (N - (2-dimethylamino-ethyl) - N -propionyl-amino) -anilino) -1-Phenylmethylene] -

6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4- (N - (2-dimethylamino-ethyl) - A / propionyl-amino) -aniline,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 9: 1), C30H32N4O4,

ESI-MS: m / z = 511 [MH] -, (73) 3-Z- [1- (4 - (N - (2-dimethylamino-ethyl) - N -butyrylamino) -anilino) 1-Phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4 - (N - (2 dimethylamino-ethyl) - / V-butyryl-amino) -aniline,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 8: 1), C31H34N4O4,

ESI-MS: m / z = 525 [MH] -, (74) 3-Z- [1- (4 - (N - (2-dimethylamino-ethyl) - N -isobutyryl-amino) anilino)) 1-Phenylmethylene] 6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4 - (N - ( 2-dimethylamino-ethyl) -N-isobutyryl-amino) -aniline,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 9: 1), C32H34N4O4,

ESI-MS: m / z = 525 [MH] -, (75) 3-Z- [1- (4 - (N - (2-dimethylamino-ethyl) - N -benzoyl-amino) -anilino) 1-Phenylmethylene] 6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4 - (N - ( 2-dimethylamino-ethyl) - / V-benzoyl-amino) -aniline,

Product value: 0.5 (silica gel, methylene chloride / methanol = 9: 1),

C34H32N4O4, ······················· · · · * ·. ·......

- 115ESI-mass spectrum: m / z = 559 [MH] -, (76) 3-Z- [1- (4 - (N - (2-dimethylamino-ethyl) - N -acetyl-amino) -3] -amino-anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4 - (/ V- (2-dimethylamino-ethyl) - / V-acetyl-amino) -3-amino-aniline,

Rf value of product: 0.5 (alumina, methylene chloride / methanol = 20: 1),

C29H31N5O4.

ESI-MS: m / z = 512 [MH] -, (77) 3-Z- [1- (4- (4-hydroxymethylpiperidin-1-ylmethyl) amino) -1-phenylmethylene] -6 -methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4- (4-hydroxymethyl-piperidin-1-yl-) methyl-amino) -aniline,

Rf value of product: 0.3 (silica gel, methylene chloride / methanol = 5: 1),

C30H31N3O4.

ESI-MS: m / z = 496 [MH] -, (78) 3-Z- [1- (4- (2- (4-hydroxy-piperidin-1-yl) -ethyl) -anilino) -1 -phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4- (2- ( 4-hydroxy-piperidin-1-yl) -ethyl-amino) -aniline,

Rf value of the product: 0.3 (silica gel, methylene chloride / methanol = 5: 1),

C30H31N3O4.

ESI-MS: m / z = 496 [MH] -, (79) 3-Z- [1- (4 - (N - (2-dimethylamino-ethyl) - N -propylsulfonylamino) -anilino) -1 -phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and N - (2-dimethylamino-ethyl) - / \ / - propylsulfonyl-p-phenylenediamine,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 9: 1),

C30H34N2O5S, ························· · · · · · · · · · · · · · · · · · · · · · · · ·

-116ESI-mass spectrum: m / z = 561 [MH] -, (80) 3-Z- [1- (4 - (N - (2-dimethylaminoethyl) - N -butylsulfonylamino) anilino) -1-phenyl methylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and N- (2-dimethylamino-ethyl) N / n-butylsulfonyl-p-phenylenediamine,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 9: 1),

C31H36N4O5S.

ESI-MS: m / z = 575 [MH] -, (81) 3-Z- [1- (4 - (N - (2-dimethylamino-ethyl) - N -phenylsulfonyl-amino) -anilino) 1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and N - (2- dimethylamino-ethyl) - / V-phenylsulfonyl-p-phenylenediamine,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 9: 1),

C33H32N4O5S.

ESI-MS: m / z = 595 [MH] -, (82) 3-Z- [1- (4 - (N - (2-dimethylamino-ethyl) - N -benzylsulfonylamino) -anilino) -1 -phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and N - (2-dimethylamino- ethyl) - / V-benzylsulfonyl-p-phenylenediamine,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 9: 1),

C34H34N4O5S.

ESI-MS: m / z = 609 [MH] -, (83) 3-Z- [1- (4 - (N - (2-dimethylaminoethyl) - N -ethylsulfonylamino) anilino) -1-phenyl- methylene] 6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and N - (2-dimethylamino-ethyl) - A / N-ethyl-sulfonyl-p-phenylenediamine,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 9: 1),

C29H32N4O5S, e ····················· ·· ·· ·· ·· ··· ·· ····

-117 ESI-mass spectrum: m / z = 547 [MH] -, (84) 3-Z- [1- (4 - ((imidazolidin-2,4-dione-5-yl) -methyl) -anilino) - 1-Phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4 - ((imidazolidine) 2,4-dione-5-yl) methyl) aniline,

Rf value of the product: 0.6 (silica gel, methylene chloride / methanol = 5: 1),

C27H22N4O5.

ESI-MS: m / z = 481 [MH] -, (85) 3-Z- [1- (4 - ((3-hydroxy-pyrrolidin-1-yl) -methyl) -anilino) - 1-Phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4 - ((3 -hydroxy-pyrrolidin-1-yl) -methyl) -aniline,

Rf value: 0.1 (silica gel, methylene chloride / methanol = 10: 1),

C28H27N3O4.

ESI-MS: m / z = 468 [MH] -, (86) 3- Z- [1- (4- (cyclohexylmethyl) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2- indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4- (cyclohexylmethyl) aniline (Eur. J. Med. Chem. Chim. Ther., 27, 537-544 (1992)).

Rf value of the product: 0.6 (silica gel, methylene chloride / methanol = 10: 1),

C30H30N2O3.

ESI-MS: m / z = 465 [MH] -, (87) 3-Z- [1- (4- (cyclohexylcarbonyl) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and 4- (cyclohexylcarbonyl) -aniline, · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ····

-118 Product value: 0,5 (silica gel, methylene chloride / methanol = 10: 1),

C30H28N2O4.

ESI-MS: m / z = 479 [MH] -, (88) 3-Z- [1- (4-diethylaminomethyl-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, prepared by reaction 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and 4- (diethylamino-methyl) -aniline,

Product value: 0.4 (silica gel, methylene chloride / methanol = 10: 1),

C28H29N3O3.

ESI-MS: m / z = 454 [MH] -, (89) 3-Z- [1- (4 - (N - (n-hexyl) - N -methyl-aminomethyl) anilino) -1 -phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4 - (N -) - (n-hexyl) - / V-methyl-amino-methyl) aniline,

Product value: 0.6 (silica gel, methylene chloride / methanol = 10: 1),

C31H35N3O3.

ESI-MS: m / z = 496 [MH] -, (90) 3-Z- [1- (4 - (N - (2-dimethylamino-ethyl)) - N - (furan-2-carbonyl) (amino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4- (N - (2-dimethylamino-ethyl) - N - (furan-2-carbonyl) -amino) -aniline,

Product value: 0.5 (silica gel, methylene chloride / methanol = 9: 1),

C32H30N4O5.

ESI-MS: m / z = 549 [MH] -, (91) 3- Z - [1- (4 - (N - (2-dimethylaminoethyl) - N - (2-methoxybenzoyl)) - amino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4- ( N - (2-dimethylamino-ethyl) - N - (2-methoxy-benzoyl) -amino) -aniline, ·············· ·· in · · · · ···· · ·· • · ··· · · · · · · ·· ·· ·"· ···· ·· ·· · ··· ·· ····

-119Rf-value of the product: 0.5 (silica gel, methylene chloride / methanol = 9: 1),

C35H34N4O5.

ESI-MS: m / z = 589 [MH] -, (92) 3-Z- [1- (4- (N - (2-dimethylaminoethyl) - N - (pyridine-3-carbonyl)) amino) anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4- (/ V- (2-dimethylamino-ethyl) - / V- (pyridin-3-carbonyl) amino) aniline,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 9: 1),

C33H31N5O4.

ESI-MS: m / z = 560 [MH] -, (93) 3-Z- [1- (4 - (N - (2-dimethylamino-ethyl)) - N - (phenyl-acetyl) - amino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4 - (/ \ / - (2-dimethylamino-ethyl) - / \ / - (phenylacetyl) amino) -aniline,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 9: 1),

C35H34N4O4.

ESI-MS: m / z = 573 [MH] -, (94) 3-Z- [1- (4- (N-ethyl- N -methylaminomethyl) anilino) -1-phenylmethylene] -6-methoxycarbone nyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4- (N-ethyl- N -methyl-aminomethyl) aniline,

Rf value of the product: 0.3 (silica gel, methylene chloride / methanol = 10: 1),

C27H27N3O3.

ESI-MS: m / z = 440 [MH] -, (95) 3- Z- [1- (4- (imidazol-2-yl) anilino) -1-phenylmethylene] -6-methoxycarbonyl- 2-indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4- (imidazol-2-yl) -aniline,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 10: 1), ··· ···

-120C26H20N4O3.

ESI-MS: m / z = 435 [MH] +, (96) 3- Z- [1- (4- (1-ethyl-imidazol-2-yl) -anilino) -1-phenyl-methylene] - 6-methoxycarbonyl-2-indolinone prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and 4- (1-ethyl-imidazol-2-yl) -aniline,

Product value: 0.4 (silica gel, methylene chloride / methanol = 10: 1), C28H24N4O3,

ESI-MS: m / z = 463 [MH] -, (97) 3- Z- [1- (4- (1-benzyl-imidazol-2-yl) -anilino) -1-phenyl-methylene] -6 -methoxycarbonyl-2-indolinone prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and 4- (1-benzyl-imidazol-2-yl) -aniline,

Rf value of the product: 0.3 (silica gel, methylene chloride / methanol = 20: 1),

C33H26N4O3.

ESI-MS: m / z = 525 [MH] -, (98) 3-Z- [1- (4 - (N - (2-dimethylamino-ethyl) - N -isopropylsulfonyl-amino) -anilino) -1-Phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and N - (2-dimethylamino) ethyl) - / V-isopropylsulfonyl-p-phenylenediamine,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 9: 1),

C30H34N4O5S.

ESI-MS: m / z = 561 [MH] -, (99) 3-Z- [1- (4 - (N - (piperidin-1-ylmethylcarbonyl) - N -methylamino) -anilino -1-Phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and N - (piperidine) (1-ylmethylcarbonyl) -N-methyl-p-phenylenediamine,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 9: 1),

-121 -

C31H32N4O4.

ESI-MS: m / z = 523 [MH] -, (100) 3-Z- [1- (4 - (N - (morpholin-4-ylmethylcarbonyl) - N -methylamino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone, and N - (morpholine-4) yl-methylcarbonyl) - / V-methyl-p-phenylenediamine,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 9: 1), C30H30N4O5,

ESI-MS: m / z = 525 [MH] -, (101) 3-Z- [1- (4 - (N - ((4-benzyl-piperazin-1-yl) -methylcarbonyl) - N) (methyl-amino) -anilino) 1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and N - ((4-benzyl-piperazin-1-yl) -methylcarbonyl) - N -methyl-p-phenylenediamine, Rf product value: 0.5 (silica gel, methylene chloride / methanol = 9: 1) , C37H37N5O4,

ESI-MS: m / z = 614 [MH] -, (102) 3-Z- [1- (4 - (N - (pyrrolidin-1-ylmethylcarbonyl) - N -methylamino) -anilino) 1-Phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and N - (pyrrolidin-1- yl-methylcarbonyl) - / \ / - methyl-p-phenylenediamine,

Product value: 0.5 (silica gel, methylene chloride / methanol = 9: 1), C30H30N4O4,

ESI-MS: m / z = 509 [MH] -, (103) 3-Z- [1- (4- (N - (2-dimethylamino-ethyl) - N -acetyl-amino) -3- bromo-anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4 - (/ N- (2-dimethylamino-ethyl) - / V-acetyl-amino) -3-bromo-aniline,

Product value: 0.6 (silica gel, methylene chloride / methanol = 5: 1), ················ · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

-122 θ2θΗ29ΒΓΝ4θ4,

ESI-MS: m / z = 575/577 [MH] -, (104) 3-Z- [1- (4- (5-methyl-imidazol-4-yl) -anilino) -1-phenyl-methylene 6-Methoxycarbonyl-2-indolinone prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4- (5-methyl-imidazol-4-yl) ) aniline,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol / ammonia =

10: 1: 0,01), θ27Η22Ν4θ3,

ESI-MS: m / z = 449 [MH] -, (105) 3-Z- [1- (4 - (N - ((2-dimethylaminoethyl) carbonyl) - N -isopropylamino) anilino) -1 -phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and N - ((2-dimethylamino) ethyl) carbonyl) - / \ / - isopropyl-p-phenylenediamine,

Rf value of the product: 0.1 (silica gel, methylene chloride / methanol = 10: 1),

C31H34N4O4.

ESI-MS: m / z = 525 [MH] -, (106) 3-Z- [1- (4 - (N - ((2-dimethylamino-ethyl) -carbonyl) - N -benzylamino) (Anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and N, - ((2-dimethylamino-ethyl) carbonyl) - / V-benzyl-p-phenylenediamine,

Rf value of the product: 0.1 (silica gel, methylene chloride / methanol = 10: 1),

C31H34N4O4.

ESI-MS: m / z = 525 [MH] -, (107) 3-Z- [1- (4- (N-butyl-N-tert-butoxycarbonylaminomethyl) anilino) -1-phenylmethylene] -6- methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4- (N-butyl- N-tert-butoxycarbonylaminomethyl) - aniline, ···························· ·························· ···

-123 Rf value of the product: 0.5 (silica gel, methylene chloride / methanol = 9: 1),

C33H37N3O5.

ESI-MS: m / z = 554 [MH] -, (108) 3-Z- [1- (4 - (N - ((N-aminocarbonyl-methyl- N -methyl-amino)) methylcarbonyl) (N-methyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) -6- methoxycarbonyl-2-indolinone and N - (N-aminocarbonyl-methyl- N -methylamino) methylcarbonyl) - N -methyl-p-phenylenediamine,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 9: 1),

C29H29N5O5.

ESI-MS: m / z = 526 [MH] -, (109) 3-Z- [1- (4 - (N - ((N-benzyl- N -methyl-amino) -methylcarbonyl) -) A / -methyl-amino) anilino) -

1-Phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and N - ((R) -benzyl- / V-methyl-amino) -methylcarbonyl) - / \ / - methyl-p-phenylenediamine,

Product value: 0.5 (silica gel, methylene chloride / methanol = 9: 1),

C34H32N4O4.

ESI-MS: m / z = 559 [MH] -, (110) 3-Z- [1- (4 - (N - (di- (2-methoxyethyl) amino) methylcarbonyl) -] - methyl-amino) anilino) -

1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and N - (di- ( 2-methoxyethyl) aminomethylcarbonyl-N-methyl-p-phenylenediamine, Product Value: 0.5 (silica gel, methylene chloride / methanol = 9: 1),

C32H36N4O4.

ESI-MS: m / z = 571 [MH] -, (111) 3-Z- [1- (4 - (N - ((2- (4-tert-butoxycarbonyl-piperazin-1-yl))) ethyl) carbonyl) -N / -methyl-amino) anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone,

-124 prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and N - ((2- (4-tert-butoxycarbonyl-piperazin-1-yl)) ethyl) carbonyl) - / \ / - methyl-p-phenylenediamine,

Rf value of product: 0.8 (silica gel, methylene chloride / methanol = 5: 1), C36H41N5O6,

ESI-MS: m / z = 638 [MH] +, (112) 3- Z- [1- (4 - (N - ((2- (piperidin-1-yl) ethyl) carbonyl) -) (N-Methylamino) -amino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2- indolinone and N - ((2- (piperidin-1-yl) ethyl) carbonyl) - N -methyl-p-phenylenediamine,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 5: 1), C32H34N4O4,

ESI-MS: m / z = 537 [MH] -, (113) 3-Z- [1- (4 - (N - ((2 - (N-benzyl - N - methylamino) ethyl)) carbonyl) -N-methylamino) anilino) 1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl- 2-indolinone and N - ((2- (N-benzyl-N-methyl-amino) -ethyl) -carbonyl) - N -methyl-p-phenylenediamine _I Rf value of the product: 0.4 ( silica gel, methylene chloride / methanol = 10: 1), C35H34N4O4,

ESI-MS: m / z = 573 [MH] -, (114) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl- N -isopropylamino) -anilino) -1-phenylmethylene] - 6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and N - (dimethylaminomethylcarbonyl) - N -isopropyl-p- phenylenediamine,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 9: 1), C30H32N4O4,

ESI-MS: m / z = 511 [MH] &lt; + &gt;, ·················· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

-125- (115) 3- [1- (4- (N - (piperidin-1-ylmethylcarbonyl) - N -isopropylamino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl- 2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and N - (piperidin-1-ylmethylcarbonyl) - N -isopropyl p-phenylenediamine,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 9: 1),

C33H36N4O4.

ESI-MS: m / z = 551 [MH] -, (116) 3-Z- [1- (4- (N - ((4-tert-butoxycarbonylpiperazin-1-yl) methylcarbonyl) -) N-isopropyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-methoxycarbonyl -2-indolinone and N - ((4-tert-butoxycarbonylpiperazin-1-yl) methylcarbonyl) - N -isopropyl-p-phenylenediamine,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 9: 1),

C37H43N5O6.

ESI-MS: m / z = 652 [MH] -, (117) 3-Z- [1- (4 - (N - ((N-benzyl- N -methylamino) methylcarbonyl) - N -) - benzylamino) anilino) -

1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and N - ((A) -benzyl- / V-methyl-amino) -methylcarbonyl) - / V-benzyl-p-phenylenediamine,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 9: 1),

C40H36N4O4.

ESI-MS: m / z = 635 [MH] -, (118) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl-N-benzylamino) -anilino) -1-phenylmethylene 6-Methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and N - (dimethylaminomethylcarbonyl) - N -benzyl- p-phenylenediamine,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 9: 1),

C34H32N4O4.

ESI-MS: m / z = 559 [MH] &lt; + &gt;, &lt; tb &gt; ______________________________________ &lt; tb &gt; ·····················································

-126- (119) 3-Z- [1- (4 - (N - (piperidin-1-ylmethylcarbonyl) - N -benzylamino) -anilino) -1-phenylmethylene] -6- methoxycarbonyl-2-indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4- (5-methyl-imidazol-4-yl) -aniline,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 9: 1),

C37H36N4O4.

ESI-MS: m / z = 599 [MH] -, (120) 3-Z- [1- (4- (1,2,4-triazol-2-ylmethyl) -anilino) -1-phenyl methylene] -6-methoxycarbonyl-

2-indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and 4- (1,2,4-triazol-1-ylmethyl) - aniline

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 10: 1),

C26H21N5O3.

ESI-MS: m / z = 450 [MH] -, (121) 3- Z- [1- (4- (1,2,3-triazol-2-ylmethyl) -anilino) -1-phenyl methylene] -6-methoxycarbonyl-

2-indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4- (1,2,3-triazol-2-ylmethyl) - aniline

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 20: 1),

C26H21N5O3.

ESI-MS: m / z = 450 (122) 3-Z- [1- (4- (1,2,3-triazol-1-ylmethyl) -anilino) -1-phenyl-methylene 6-Methoxycarbonyl-2-indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4- (1,2,3-triazol-1-yl) methyl) aniline,

Rf value of product: 0.4 (silica gel, methylene chloride / methanol = 9: 1),

C26H21N5O3.

ESI-MS: m / z = 450 [M-H] '

-127- ·· ········································ (123) 3-Z- [1- (4 - ((N-aminocarbonyl-methyl-N)]) (methyl-amino) -methyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-methoxycarbonyl -2-indolinone and 4 - ((N-aminocarbonyl-methyl- N -methyl-amino) -methyl) -aniline,

Product value: 0.5 (silica gel, methylene chloride / methanol = 9: 1),

C27H26N4O4.

ESI-MS: m / z = 469 [MH] -, (124) 3-Z- [1- (4 - ((di- (2-methoxy-ethyl) amino) methyl) anilino) -1- phenyl-methylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4 - ((di- ( 2-methoxy-ethyl) amino) methyl) aniline,

Product value: 0.5 (silica gel, methylene chloride / methanol = 9: 1),

C30H33N3O5.

ESI-MS: m / z = 514 [MH] -, (125) 3-Z- [1- (4- (pyrrolidin-1-yl) -methyl) -anilino) -1-phenyl -methylene] -6-methoxycarbonyl-2-indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4- (pyrrolidin-1-ylmethyl) ) aniline,

Product value: 0.5 (silica gel, methylene chloride / methanol = 9: 1),

C28H27N3O3.

ESI-MS: m / z = 452 [MH] -, (126) 3-Z- [1- (4 - ((di- (2-hydroxyethyl) amino) methyl) anilino) -1-phenylmethylene 6-Methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4 - ((di- (2-hydroxyethyl)) ) amino) methyl) aniline,

Product value: 0.5 (silica gel, methylene chloride / methanol = 9: 1),

C28H29N3O5.

ESI-MS: m / z = 486 [MH] &lt; + &gt;, &lt; tb &gt; ______________________________________ &lt; tb &gt; • · · ♦ · · · · · · · · · · · · · · · · ·

-128- (127) 3- [1- (4 - ((N -ethoxycarbonyl-methyl-N-methyl-amino) -methyl) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2- indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4 - ((N-ethoxycarbonyl-methyl- N -methyl-amino) -methyl) ) aniline,

Rf value of product: 0.5 (alumina, methylene chloride / ethanol = 40: 1),

C29H29N3O5.

ESI-MS: m / z = 498 [MH] -, (128) 3-Z- [1- (4- (azetidin-1-ylmethyl) -anilino) -1-phenylmethylene] -6 -methoxycarbonyl-2-indolinone prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4- (azetidin-1-ylmethyl) -aniline,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol / ammonia =

9: 1: 0.5,

C27H25N3O3.

ESI-MS: m / z = 438 [MH] -, (129) 3-Z- [1- (4- (N-propyl- N - tert -butoxycarbonylaminomethyl) anilino) -1-phenylmethylene] 6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4- (N-propyl- N -tert- butoxycarbonylamino) aniline,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 9: 1),

C32H35N3O5.

ESI-MS: m / z = 540 [MH] -, (130) 3-Z- [1- (4 ((N - (2- (2-methoxy-ethoxy) ethyl)) - N -methylamino (methyl) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4 - (/ V- (2- (2-methoxy-ethoxy) ethyl) - / V-methyl-amino) methyl) aniline,

Rf value of product: 0.4 (silica gel, methylene chloride / methanol = 9: 1),

C30H33N3O5.

ESI-MS: m / z = 514 [M-H] '

-129- (131) 3- [1- (4 - ((N - (tert-butoxycarbonyl-3-amino-propyl) -N-methylamino) methyl) anilino) -1-phenyl- methylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4 - (N - (N-tert) -butoxycarbonyl-3-amino-propyl) - N -methyl-aminomethyl) -aniline, Rf product value: 0.5 (silica gel, methylene chloride / methanol = 9: 1), C33H38N4O5,

ESI-MS: m / z = 571 [MH] -, (132) 3-Z- [1- (4 - ((N - (methylcarbamoyl-methyl) - N -methyl-amino) -methyl)) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4- ( (/ N- (methylcarbamoyl-methyl) -N- / methyl-amino) methyl) aniline,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 9: 1), C28H28N4O4,

ESI-MS: m / z = 483 [MH] -, (133) 3-Z- [1- (4 - ((N - (dimethylcarbamoyl-methyl) - N -methyl-amino) methyl)) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4 - ((A N - (dimethylcarbamoyl-methyl) - (N -methyl-amino) -methyl) -aniline, Rf product value: 0.3 (silica gel, methylene chloride / methanol = 10: 1),

C29H30N4O4.

ESI-MS: m / z = 497 [MH] -, (134) 3-Z- [1- (4-methyl-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, prepared by reaction 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and 4-methyl-aniline,

Rf value of product: 0.4 (silica gel, methylene chloride / methanol = 9: 1),

C24H20N2O3.

ESI-MS: m / z = 383 [M-H] &lt; + &gt;

-130 - (135) 3-Z- [1- (4 - ((N-propyl- N -methyl-amino) -methyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2- indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and 4 - ((N-propyl- N -methyl-amino) -methyl) - aniline

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 9: 1),

C28H29N3O3.

ESI-MS: m / z = 454 [MH] -, (136) 3-Z- [1- (4 - ((N - (2-hydroxy-ethyl) - N -methylamino) -methyl) 1-Acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4 - ((1-ethoxycarbonyl) -6-methoxycarbonyl-2-indolinone) N- (2-hydroxy-ethyl) - / \ / - methyl-amino) methyl) aniline,

Rf value of product: 0.5 (alumina, methylene chloride / ethanol = 40: 1),

C27H27N3O4.

ESI-MS: m / z = 456 [MH] -, (137) 3-Z- [1- (4 - ((N - (2-dimethylamino-ethyl) - N -methylamino) -methyl) (Anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4 - (( / V- (2-dimethylamino-ethyl) -N- / methyl-amino) methyl) aniline,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 9: 1), C29H32N4O3,

ESI-MS: m / z = 483 [MH] -, (138) 3-Z- [1- (4 - ((N- (3-dimethylamino-propyl) - N -methylamino)) - methyl) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4- ( (A / - (3-dimethylaminopropyl) - / V-methyl-amino) methyl) aniline,

Product value: 0.5 (silica gel, methylene chloride / methanol = 9: 1), C30H34N4O3,

ESI-MS: m / z = 497 [M-H] &lt; - &gt;

9 9 9 ··· 9 9 9 · ···· 9 9 9 9 9 9 9 · 9 999 e 9 · 9 · 9 ·· 0 9 9 0 0 90 • 9 99 99 999 99 9999

-131- (139) 3- [1- (4- (3-oxo-piperazin-1-ylmethyl) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2- indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4- (3-oxo-piperazin-1-ylmethyl) -aniline,

Rf value of the product: 0.46 (silica gel, methylene chloride / methanol = 9: 1),

C28H26N4O4.

ESI-MS: m / z = 481 [M-H] -.

Example 4

3-Z- [1- (4-carboxy-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone

485 mg of 3-Z- [1- (4-tert-butoxycarbonyl-anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone was dissolved in 15 ml of methylene chloride and 6.0 ml of trifluoroacetic acid was added. The reaction mixture was stirred at room temperature for 2 hours.

The solvent was then removed and the residue was recrystallized from ether.

Yield: 375 mg (87% of theory),

Rf value of the product: 0.3 (silica gel, methylene chloride / methanol = 10: 1)

C 25 H 20 N 2 O 5, mass spectrum: m / z = 428 [M] ⁺ .

As in Example 4, the following compounds were prepared:

(1) 3-Z- [1- (4-Aminomethyl-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, prepared from 3-Z- [1- (4 - (N - tert-butyl)] (butoxycarbonyl-aminomethyl) -anilino) -1-phenylmethylene] 6-methoxycarbonyl-2-indolinone,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol / ammonia =

5: 1: 0.01).

C24H21N3O3.

ESI-MS: m / z = 398 [MH] -, (2) 3-Z- [1- (4-ethylaminomethyl-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, prepared from 3-Z- [1- (4- (N-tert-butoxycarbonyl-ethylaminomethyl) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, • Φ ·· ·· ······ · ··· ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··· ·· ····

-132 Rf value of product: 0.4 (silica gel, methylene chloride / methanol / ammonia =

10: 1: 0.01).

C26H25N3O3.

ESI-MS: m / z = 426 [MH] -, (3) 3-Z- [1- (4-carboxymethyl-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, prepared from 3-Z- [1- (4-tert-butoxycarbonyl-methyl-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone,

Product value: 0.1 (aluminum oxide, methylene chloride / ethanol / ammonia = 5: 1: 0.01),

C26H22N2O5.

ESI-MS: m / z = 441 [MH] ^- , (4) 3-Z- [1- (4-carboxy-anilino) -1-ethyl-methylene] -6-ethoxycarbonyl-2-indolinone, prepared from 3-Z- [1- (4-tert-butoxycarbonyl-anilino) -1-ethyl-methylene] -6-ethoxycarbonyl-2-indolinone,

Rf value of the product: 0.1 (alumina, methylene chloride / ethanol = 20: 1),

C21H20N2O5.

ESI-MS: m / z = 379 [MH] -, (S) 3-Z- [1- (4- (piperazin-1-ylmethyl) -anilino) -1-phenyl-methylene] -6- methoxycarbonyl-2-indolinone, prepared from 3-Z- [1- (4- (4-tert-butoxycarbonyl-piperazin-1-ylmethyl) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone,

Rf value of product: 0.1 (silica gel, methylene chloride / methanol / ammonia =

10: 1: 0.01).

C28H28N4O3.

ESI-MS: m / z = 469 [M + H] ⁺ , (6) 3-Z- [1- (4-butylaminomethylanilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared from 3- N- [1- (4- (N-butyl-N-tert-butoxycarbonyl-aminomethyl) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 9: 1),

· · · · · · ···· · · • • • · • • • • • • · • • • · • • · · · • • • • • · · · • · • • • · • • • • • • • • • • • · · · · 9 · · · · • · ····

- 133 C28H29N3O3

ESI-MS: m / z = 454 [MH] -, (7) 3-Z- [1- (4-ethylaminomethyl-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, prepared from 3-Z- [1- (4 - (/ V-tert-butoxycarbonyl- / V-ethylaminomethyl) anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone,

Rf value of the product: 0.3 (silica gel, methylene chloride / methanol / ammonia = 10: 1: 0.01),

C27H27N3O3.

ESI-MS: m / z = 442 [M + H] ⁺ , (8) 3-Z- [1- (4-ethylaminomethyl-anilino) -1-phenyl-methylene] -6-carbamoyl-2-indolinone, prepared from 3-Z- [1- (4- (N-tert-butoxycarbonyl-ethylaminomethyl) -anilino) -1-phenylmethylene] -6-carbamoyl-2-indolinone,

Rf value of product: 0.2 (silica gel, methylene chloride / methanol / ammonia = 5: 1: 0.01),

C25H24N4O2.

ESI-MS: m / z = 411 [MH] -, (9) 3-Z- [1- (4 - (N - (piperazin-1-ylmethylcarbonyl) - N -isopropylamino) - anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared from 3-N- [1- (4 - (N - ((4-tert-butoxycarbonylpiperazin-1-yl) methylcarbonyl) -) -. (isopropyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, Rf product value: 0.35 (silica gel, methylene chloride / methanol = 9: 1), C32H35N5O4,

ESI-MS: m / z = 552 [MH] -, (10) 3-Z- [1- (4- (N - ((2- (piperazin-1-yl) ethyl) -carbonyl)) - (N-methyl-amino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared from 3-Z- [1- (4 - (N - ((2- (4-tert-butoxycarbonylpiperazine) (1-yl) -ethyl) -carbonyl) -N-methyl-amino) -anilino) -phenyl-methylene] -6-methoxycarbonyl-2-indolinone;

-134Product Value: 0,4 (silica gel, methylene chloride / methanol / ammonia = 5: 1: 0,01),

C31H33N5O4.

ESI-MS: m / z = 540 [M + H] &lt; ^{+ &gt};, (11) 3-Z- [1- (4- (N-propyl-aminomethyl) -anilino) -1-phenyl-methylene] -6 -methoxycarbonyl-2-indolinone, prepared from 3-N- [1- (4- (N-propyl- N-tert-butoxycarbonylaminomethyl) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone,

Rf value of the product: 0.35 (silica gel, methylene chloride / methanol = 9: 1),

C27H27N3O3.

ESI-MS: m / z = 440 [MH] -, (12) 3-Z- [1- (4 - (N - (3-amino-propyl) - N -methylamino) methyl) (Anilino) -1-phenylmethylene] 6-methoxycarbonyl-2-indolinone, prepared from 3-Z- [1- (4 - ((N - (tert-butoxycarbonyl-3-aminopropyl) - N -methyl) amino) methyl) anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone,

Rf value of the product: 0.35 (silica gel, methylene chloride / methanol = 9: 1), C28H30N4O3,

ESI-MS: m / z = 471 [M + H] &lt; ^{+ &gt};.

Example 5

3-Z- [1- (4-methylaminomethyl-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone

100 mg of 3-Z- [1- (4- (N-benzyl-N-methyl-aminomethyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone was dissolved in 20 ml of ethanol. 0.2 ml of hydrochloric acid (i = 1 mol.dm &^lt; ^{3 &gt;} ) was added and the reaction mixture was hydrogenated at room temperature under 50 psi of hydrogen for 70 minutes. After hydrogenation, the mixture was filtered and the filtrate was evaporated in a rotary evaporator. The residue was dried under vacuum at 100 ° C.

Yield: 50 mg (53% of theory), · φ φ · · · · · · · · · · 53 53 53 53 53 53 53 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

- 135 Rf value of the product: 0,3 (silica gel, methylene chloride / ethanol / ammonia =

5: 1: 0.01).

C26H25N3O3.

ESI-MS: m / z = 426 [M-H] -.

As in Example 5, the following compounds were prepared:

(1) 3-Z- [1- (4-methylaminomethylanilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared from 3-Z- [1- (4- (N-benzyl- N -) - methyl-aminomethyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone,

Rf value of product: 0.2 (silica gel, methylene chloride / methanol / ammonia =

10: 1: 0, 01)

C25H23N3O3.

ESI-MS: m / z = 412 [MH] -, (2) 3-Z- [1- (4- (N - (2-methylaminoethyl) - N -methylsulfonylamino) -anilino) -1 phenyl-methylene] -

6-methoxycarbonyl-2-indolinone, prepared from 3-Z- [1- (4 - ((2- (N-benzyl- N -methylamino) ethyl) - N -methylsulfonylamino) anilino ) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone,

Product value: 0.3 (silica gel, methylene chloride / methanol / ammonia =

10: 1: 0, 01)

C27H28N4O5S.

ESI-MS: m / z = 519 [MH] -, (3) 3-Z- [1- (4 - (N - (2-amino-ethyl) - N -methylsulfonyl-amino) -anilino) ) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, prepared from 3-Z- [1- (4- (N-cyanomethyl- N -methylsulfonyl-amino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone,

Product value: 0.5 (silica gel, methylene chloride / methanol / ammonia =

5: 1: 0.01).

C26H26N4O5S.

ESI-MS: m / z = 505 [MH] &lt; + &gt;,&lt; tb &gt; ______________________________________ &lt; tb &gt; ···· · ··· · ·. · · · · · · · · · · · · · · · · · · · · · · ¹

-136- (4) 3-Z- [1- (4 - (N- (3-methylamino-propyl) - N -methylsulfonyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl- 2-indolinone, prepared from 3-Z- [1- (4 - (N - (3- (N-benzyl- N -methyl-amino) -propyl) - N -methylsulfonylamino) -anilino) -1 phenyl-methylene] -6-methoxycarbonyl-2-indolinone,

Rf value of product: 0.3 (silica gel, methylene chloride / methanol / ammonia =

5: 1: 0.01).

C28H30N4O5S.

ESI-MS: m / z = 533 [MH] -, (S) 3-Z- [1- (4 - (N - (piperazin-1-ylmethylcarbonyl) - N -methylamino) anilino) - 1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone prepared from 3-Z- [1- (4 - (N - ((4-benzyl-piperazin-1-yl) methylcarbonyl) - N -methyl- amino) anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2indolinónu,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 9: 1),

C30H31N5O4.

ESI-MS: m / z = 524 [MH] -, (6) 3-Z- [1- (4 - (N - (methylamino-methylcarbonyl) - N -methylamino) anilino) -1-phenyl- methylene] -

6-methoxycarbonyl-2-indolinone, prepared from 3-Z- [1- (4 - (N - ((N-benzyl- N -methylamino) methylcarbonyl) - N -methylamino) anilino) -1 phenyl-methylene] -6-methoxycarbonyl-2-indolinone,

Rf value of the product: 0.3 (silica gel, methylene chloride / methanol = 9: 1),

C27H26N4O4.

ESI-MS: m / z = 469 [MH] -, (7) 3-Z- [1- (4- (N - ((2-methylamino-ethyl) -carbonyl) - N -methyl) - amino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared from 3-N- [1- (4 - (N - ((2 - (N-benzyl-N-methylamino)) ethyl) carbonyl) - / V-methyl-amino) anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone,

Rf value of product: 0.3 (silica gel, methylene chloride / methanol / ammonia =

5: 1: 0.01).

C28H28N4O4, •

-137-

ESI-MS: m / z = 483 (M-H) ’.

Example 6

3-Z- [1- (4-ureidomethyl-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone

300 mg of 3-Z- [1- (4-aminomethyl-anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone was dissolved in 15 ml of methanol and 200 ml of triethylamine was added. Then 400 mg of potassium cyanate in 5 ml of water was added. After stirring at room temperature for two days, the reaction mixture was rotary evaporated, the residue was stirred in methylene chloride and washed once with water and once with saturated aqueous sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and evaporated. The residue was dried at 100 ° C under vacuum.

Yield: 100 mg (21% of theory), Rf value of product: 0.7 (silica gel, methylene chloride / methanol = 5: 1), C25H22N4O4,

ESI-MS: m / z = 441 [M-H] &lt; + &gt;.

Example 7

3-Z- [1- (4-guanidinomethyl-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-indolinone

300 mg of 3-Z- [1- (4-aminomethyl-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone was dissolved in 5 ml of dimethylformamide and 300 ml of triethylamine was added. Then 700 mg of 3,5-dimethylpyrazole-1-carboxylic acid amidine in 5 ml of dimethylformamide was added. After stirring at room temperature for one day, the reaction mixture was evaporated in a rotary evaporator. The residue was dried at 100 ° C under vacuum.

Yield: 200 mg (87% of theory),

Rf value of product: 0.1 (reverse phase RP8, methanol / 5% sodium chloride solution = 6: 4),

C25H23N5O3.

Mass spectrum: m / z = 441 [M] &lt; ^{+ &gt};.

· · · · · · · · · · · · · · · · · · · · · · · · · · · ··· _Α . * * ··· ·· · ··· · · ·, / .. · * ·· * ··· * * ·· * ····

-138 Example 8

3-Z- [1- (4-acetylamino-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone

100 mg of 3-Z- [1- (4-aminomethylanilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone was dissolved in 5 ml of glacial acetic acid, 0.1 ml of acetic anhydride was added and the mixture was The mixture was stirred at room temperature for 10 minutes. The reaction mixture was then poured into a saturated aqueous sodium carbonate solution and extracted four times with methylene chloride. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and evaporated. The residue was dried at 100 ° C under vacuum.

Yield: 20 mg (23% of theory), Rf value of product: 0.4 (silica gel, methylene chloride / methanol = 10: 1), C26H23N3O4,

ESI-MS: m / z = 440 (M-H) ’.

As in Example 8, the following compounds were prepared:

(1) 3-Z- [1- (4- (N-methylsulfonylaminomethyl) anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by the reaction of 3-Z- [1- (4-aminomethylanilino) -1 - phenylmethylene] -6-methoxycarbonyl-2-indolinone and methanesulfonyl chloride / triethylamine,

Product value: 0.7 (silica gel, methylene chloride / methanol = 5: 1), C25H23N3O5S,

ESI-MS: m / z = 476 [MH] -, (2) 3-Z- [1- (4- (4-benzoyl-piperazin-1-ylmethyl) -anilino) -1-phenyl-methylene 6-Methoxycarbonyl-2-indolinone prepared by the reaction of 3-Z- [1- (4- (piperazin-1-ylmethyl) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone and benzoyl chloride,

Product value: 0.7 (silica gel, methylene chloride / methanol = 10: 1) C35H32N4O4,

ESI-MS: m / z = 571 [M-H] &lt; - &gt;, &lt; - &gt;

-139- (3) 3-Z- [1- (4 - ((N - (3-acetylamino-propyl) - N -methyl-amino) -methyl) -anilino) -1-phenyl-methylene] - 6-methoxycarbonyl-2-indolinone, prepared from 3-Z- [1- (4 - ((N - (3-amino-propyl) - N -methyl-amino) -methyl) -anilino) -1-phenylmethylene ] -6-methoxycarbonyl-2-indolinone,

Rf value of product: 0.3 (silica gel, methylene chloride / methanol = 9: 1), C30H32N4O4,

ESI-MS: m / z = 511 [M-H] &lt; + &gt;

Example 9

3-Z- [1- (4- (piperidin-1-yl-methyl) anilino) -1-phenyl-methylene] -6-carboxy-2-indolinone

0.8 g of 3-Z- [1- (4- (piperidin-1-ylmethyl) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone was dissolved in 30 ml of ethanol, 8 , 3 ml of a solution of sodium hydroxide (1 Wet = ^{"2 3),} and the mixture was stirred at 80 ° C. After cooling, the mixture was neutralized with dilute hydrochloric acid (8.3 mL, C = C _H 1 Wet ^'3). The precipitate formed was collected by suction filtration, washed with water, ethanol and ether and dried at 100 ° C under vacuum.

Yield: 0.7 g (89% of theory), Rf value of product: 0.2 (silica gel, methylene chloride / methanol = 5: 2), C26H27N3O3,

Mass Spectrum: m / z = 453 [M] &lt; ^{+ &gt};.

The following compounds were prepared as in Example 9:

(1) 3-Z- [1- (4-bromo-anilino) -1-phenyl-methylene] -6-carboxy-2-indolinone, prepared from 3-Z- [1- (4-bromo-anilino) - 1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, Rf value of the product: 0.4 (silica gel, toluene / ethyl acetate = 5: 1),

C22H18BrN2O3, ESI mass spectrum: m / z = 435/437 [M + H] ⁺ , (2) 3-Z- [1- (3- (dimethylaminomethyl) anilino) -1-phenylmethylene] -6- carboxy-2-indolinone, prepared from 3-Z- [1- (3- (dimethylaminomethyl) anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, 9 ··· ············································ ·

-140Rf-value of the product: 0.7 (reverse phase RP8, methanol / 5% sodium chloride = 4: 1),

C25H23N3O3.

ESI-MS: m / z = 414 [M + H] ⁺ , (3) 3-Z- [1- (4- (dimethylaminomethyl) anilino) -1-phenylmethylene] -6-carboxy-2- indolinone, prepared from 3-Z- [1- (4- (dimethylaminomethyl) anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone,

Product value: 0.7 (reverse phase RP8, methanol / 5% aqueous sodium chloride solution = 4: 1),

C25H23N3O3.

ESI-MS: m / z = 412 [MH] -, (4) 3-Z- [1- (4 - [(2,6-dimethyl-piperidin-1-yl) -methyl] -anilino) -1 phenyl-methylene] -6-carboxy-

2-indolinone, prepared from 3-Z- [1- (4 - [(2,6-dimethyl-piperidin-1-yl) -methyl] -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl- 2-indolinone,

Product value: 0.6 (reverse phase RP8, methanol / 5% aqueous sodium chloride = 4: 1),

C30H31N3O3.

ESI-MS: m / z = 482 [M + H] ⁺ , (S) 3-Z- [1- (4- (1-methyl-imidazol-2-yl) -anilino) -1-phenyl-methylene 6-Carboxy-2-indolinone, prepared from 3-Z- [1- (4- (1-methyl-imidazol-2-yl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2- indolinone,

Product value: 0.6 (reverse phase RP8, methanol / 5% aqueous sodium chloride = 4: 1),

C26H20N4O3.

ESI-MS: m / z = 435 [M-H] -, (6) 3-Z- [1- (4- (N-acetyl- N -dimethylaminocarbonylmethylamino) anilino) -1-phenylmethylene] -

6-carboxy-2-indolinone, • ··· e ························

-141 prepared from 3-Z- [1- (4- (N-acetyl- N -dimethylaminocarbonyl-methyl-amino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone,

Product value: 0.3 (silica gel, methylene chloride / methanol = 10: 1),

C28H26N4O5.

ESI-MS: m / z = 497 [MH] -, (7) 3-Z- [1- (4-ethylaminomethyl-anilino) -1-phenyl-methylene] -6-carboxy-2-indolinone, prepared from 3-Z- [1- (4-ethylaminomethyl-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2indolinónu,

Product value: 0.6 (reverse phase RP8, methanol / 5% aqueous sodium chloride = 4: 1),

C25H23N3O3.

ESI-MS: m / z = 412 [M-H] -, (8) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl- N -methylamino) anilino) -1-phenylmethylene] -

6-carboxy-2-indolinone, prepared from 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl - N -methylamino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone .

Product value: 0.6 (reverse phase RP8, methanol / 5% aqueous sodium chloride = 4: 1),

C27H26N4O4.

ESI-MS: m / z = 469 [MH] ^- , (9) 3-Z- [1- (4- (N-tert-butoxycarbonyl-ethylaminomethyl) -anilino) -1-phenyl-methylene] -6 - carboxy-2-indolinone, prepared from 3-Z- [1- (4- (N-tert-butoxycarbonyl-ethylaminomethyl) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone,

Product value: 0.4 (silica gel, methylene chloride / methanol = 10: 1),

C30H31N3O5.

ESI-MS: m / z = 512 [M-H] -,

-142 ····································· (10) 3-Z- [1- (4 - ((N-carboxymethyl- N -methyl-amino) -methyl) -anilino) -1-phenyl-methylene] - 6-methoxycarbonyl-2-indolinone, prepared from 3-Z- [1- (4 - ((N -ethoxycarbonylmethyl- N -methylamino) methyl) -anilino) -1-phenylmethylene] -6-methoxycarbonyl 2-indolinone,

Rf value of product: 0.4 (silica gel, methylene chloride / methanol = 6: 1), C27H25N3O5,

ESI-MS: m / z = 470 [M-H] -.

Example 10

3-Z- [1- (4- (piperidin-1-yl-methyl) anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2indolinón

0.9 g of 3-Z- [1- (4- (piperidin-1-ylmethyl) -anilino) -1-phenylmethylene] -6-carboxy-2-indolinone was stirred in 35 ml of dimethylformamide and 0.80 g was added. 4 g of carbonyldiimidazole. The mixture was stirred at room temperature for 14 hours. Then 20 ml of methanol were added and the mixture was again stirred at 50 ° C for 3 hours. The solvent was removed and the residue was purified on a silica gel column using methylene chloride / methanol as eluent.

Yield: 0.5 g (49% of theory), Rf value of product: 0.5 (alumina, methylene chloride / methanol = 30: 1), C29H29N3O3,

ESI-MS: m / z = 468 [M + H] &lt; ^{+ &gt};.

As in Example 10, the following compounds were prepared:

(1) 3-Z- [1- (4- (Piperidin-1-yl-methyl) -anilino) -1-phenyl-methylene] -6-benzyloxycarbonyl-2-indolinone, prepared by reaction of 1-phenyl-methylene] - 6-carboxy-2-indolinone and benzyl alcohol, Rf value of the product: 0.6 (alumina, methylene chloride / methanol = 30: 1)

C35H33N3O3, mass spectrum: m / z = 543 [M] &lt; + &gt;, &lt; tb &gt; &lt; tb &gt; ··· · · · ♦ ··· · · · · · · ·

143- (2) 3-Z- [1- (4- (piperidin-1-ylmethyl) -anilino) -1-phenylmethylene] -6-isopropyloxycarbonyl-

2-indolinone, prepared by reacting 3-Z- [1- (4- (piperidin-1-ylmethyl) and nilino) -1-phenylmethylene] -6-carboxy-2-indolinone and isopropanol,

Product value: 0.4 (alumina, methylene chloride / isopropanol = 30: 1),

C31H33N3O3, mass spectrum: 95 [M] ⁺ , (3) 3-Z- [1- (4- (piperidin-1-ylmethyl) -anilino) -1-phenylmethylene] -6-propyloxycarbonyl -2-indolinone, prepared by reacting 3-Z- [1- (4- (piperidin-1-ylmethyl) -anilino) -1-phenylmethylene] -6-carboxy-2-indolinone and n-propanol,

Product value: 0.7 (silica gel, methylene chloride / methanol = 5: 1),

C31H33N3O3, mass spectrum: m / z = 495 [M] &lt; ^{+ &gt};, (4) 3-Z- [1- (4- (piperidin-1-ylmethyl) -anilino) -1-phenylmethylene] -6- butyloxycarbonyl-2-indolinone, prepared by the reaction of 3-Z- [1- (4- (piperidin-1-ylmethyl) -anilino) -1-phenyl-methylene] -6-carboxy-2-indolinone and n-butanol,

Product value: 0.5 (silica gel, methylene chloride / methanol = 10: 1),

C32H35N3O3, mass spectrum: m / z = 509 [M] ⁺ , (S) 3-Z- [1- (4-bromo-anilino) -1-phenyl-methylene] -6-carbamoyl-2-indolinone, prepared by reaction 3-Z- [1- (4-bromo-anilino) -1-phenyl-methylene] -6-carboxy-2-indolinone and ammonia,

Product value: 0.5 (silica gel, methylene chloride / methanol = 10: 1),

022Ηΐ6θΓΝ2θ3, mass spectrum: m / z = 432/434 [M-H] ’, ·· ···· ··

-144- (6) 3-Z- [1- (4- (piperidin-1-ylmethyl) anilino) -1-phenylmethylene] -6-ethylcarbamoyl-2-indolinone, prepared by reaction of 3-Z- [1- ( 4- (piperidin-1-yl-methyl) -anilino) -1-phenyl-methylene] -6-carboxy-2-indolinone and ethylamine gas,

Product value: 0.6 (silica gel, methylene chloride / methanol = 5: 1), C30H32N4O2, mass spectrum: m / z = 480 [M] ⁺ , (7) 3-Z- [1- (4- (dimethylaminomethyl) (Anilino) -1-phenylmethylene] -6 - [(2-methyloxyethoxy) carbonyl] -2-indolinone prepared by the reaction of 3-Z- [1- (4- (dimethylaminomethyl) anilino) -1 -phenyl-methylene] -6-carboxy-2-indolinone and methyl glycol,

Product value: 0.8 (silica gel, methylene chloride / methanol = 4: 1), C25H23N3O3

ESI-MS: m / z = 470 [MH] -, (8) 3-Z- [1- (4- (dimethylaminomethyl) anilino) -1-phenylmethylene] -6 - [(2-dimethylaminoethoxy) carbonyl -2-indolinone, prepared by reacting 3-Z- [1- (4- (dimethylaminomethyl) anilino) -1-phenylmethylene] -6-carboxy-2-indolinone and 2-dimethylaminoethanol,

Product value: 0.5 (silica gel, methylene chloride / methanol = 5: 2), C29H32N4O3,

ESI-MS: m / z = 483 [MH] -, (9) 3-Z- [1- (4- (dimethylaminomethyl) anilino) -1-phenylmethylene] -6 - [(2- / N-tert- butoxycarbonyl-amino-ethoxy) carbonyl] -2-indolinone, prepared by the reaction of 3-Z- [1- (4- (dimethylaminomethyl) anilino) -1-phenylmethylene] -6-carboxy-2-indolinone and 2- N, N tert-butoxycarbonyl-amino-ethanol,

Product value: 0.8 (silica gel, methylene chloride / methanol = 5: 2), C32H36N4O5,

ESI-MS: m / z = 412 [M-H] ’, 9 99 99, 9 9, 9 9, 9 9

999999 · 9 9 9 9 9

9,999,999 • 9,999,999,999,999,999

145- (10) 3-Z- [1- (4- (dimethylaminomethyl) anilino) -1-phenylmethylene] -6 - [(2,2,2-trifluoroethoxy) carbonyl] -2-indolinone prepared by the reaction of 3-Z- [1- (4- (dimethylaminomethyl) -anilino) -1-phenylmethylene] -6-carboxy-2-indolinone, and 2,2,2-trifluoroethanol,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 5: 1), C27H24F3N3O3,

ESI-MS: m / z = 494 [M-H] -,

Example 11

3-Z- [1- (4- (piperidin-1-yl-methyl) anilino) -1-phenyl-methylene] -6-carbamoyl-2-indolinone

0.9 g of 3-Z- [1- (4- (piperidin-1-ylmethyl) -anilino) -1-phenyl-methylene] -6-carboxy-2-indolinone, 0.8 g, was stirred in 25 ml of dimethylformamide. TBTU and 0.4 g HOBT and 1.0 ml triethylamine was added. The mixture was stirred at room temperature for 15 minutes. Ammonia gas (15 minutes) was then added at 10-15 ° C and the mixture was then stirred at room temperature for 1.5 hours. The precipitate formed was collected on a suction filter, washed with water, ethanol and ether and dried at 100 ° C under vacuum.

Yield: 0.6 g (64% of theory),

Rf value of the product: 0.4 (reverse phase RP8, methanol / 5% aqueous sodium chloride solution = 6: 4),

C 28 H 28 N 4 O 2, ESI mass spectrum: m / z = 453 [M + H] ⁺ .

As in Example 11, the following compounds were prepared:

(1) 3-Z- [1- (4- (piperidin-1-yl-methyl) -anilino) -1-phenyl-methylene] -6-dimethylcarbamoyl-2-indolinone, prepared by the reaction of 3-Z- [1- (4) - (piperidin-1-ylmethyl) -anilino) -1-phenylmethylene] -6-carboxy-2-indolinone and dimethylamine hydrochloride / diisopropylethylamine,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol = 5: 1), C30H32N4O2,

ESI-MS: m / z = 481 [M + H] &lt; ^{+ &gt};

-146- (2) 3-Z- [1- (4- (piperidin-1-yl-methyl) -anilino) -1-phenyl-methylene] -6 - (N-ethyl- N -methyl-carbamoyl) ) -2-indolinone prepared by the reaction of 3-Z- [1- (4- (piperidin-1-ylmethyl) anilino) -1-phenylmethylene] -6-carboxy-2-indolinone and N-ethyl- N -methylamine .

Rf value of product: 0.5 (alumina, methylene chloride / ethanol = 20: 1),

C31H34N4O2.

ESI-MS: m / z = 495 [M + H] ⁺ , (3) 3-Z- [1- (4- (piperidin-1-ylmethyl) -anilino) -1-phenylmethylene] - 6-methylcarbamoyl-2-indolinone, prepared by the reaction of 3-Z- [1- (4- (piperidin-1-ylmethyl) -anilino) -1-phenylmethylene] -6-carboxy-2-indolinone and methylamine hydrochloride / diisopropylethylamine,

Rf value of the product: 0.3 (alumina, methylene chloride / ethanol = 20: 1),

C29H30N4O2.

ESI-MS: m / z = 467 [M + H] ⁺ , (4) 3-Z- [1- (3- (dimethylaminomethyl) anilino) -1-phenylmethylene] -6-methylcarbamoyl-2-indolinone, prepared by reacting 3-Z- [1- (3- (dimethylaminomethyl) anilino) -1-phenylmethylene] -6-carboxyl-2-indolinone and methylamine hydrochloride / triethylamine,

Rf value of the product: 0.3 (silica gel, methylene chloride / ethanol = 2: 1),

C26H26N4O2, mass spectrum: m / z = 426 [M] ⁺ , (S) 3-Z- [1- (4- (piperidin-1-ylmethyl) -anilino) -1-phenyl-methylene] -6- (2-hydroxyethylcarbamoyl) -2-indolinone, prepared by the reaction of 3-Z- [1- (4- (piperidin-1-ylmethyl) -anilino) -1-phenylmethylene] -6-carboxy-2-indolinone and ethanolamine / diisopropylethylamine

Rf value of product: 0.5 (alumina, methylene chloride / methanol = 20: 1),

C30H32N4O3.

ESI-MS: m / z = 495 [M-H] -,

-147- (6) 3-Z- [1- (4- (piperidin-1-ylmethyl) -anilino) -1-phenyl-methylene] -6-diethylcarbamoyl-2-indolinone, prepared by reaction of 3-Z- [1] - (4- (piperidin-1-ylmethyl) -anilino) -1-phenylmethylene] -6-carboxy-2-indolinone and diethylamine hydrochloride / diisopropylethylamine,

Rf value of the product: 0.8 (alumina, methylene chloride / methanol = 10: 1),

C32H36N4O2.

ESI-MS: m / z = 509 [M + H] ⁺ , (7) 3-Z- [1- (4- (N-tert-butoxycarbonyl-ethylaminomethyl) -anilino) -1-phenyl-methylene] -6-carbamoyl-2-indolinone, prepared from 3-Z- [1- (4- (N-tert-butoxycarbonylethylaminomethyl) anilino) -1-phenylmethylene] -6-carboxy-2-indolinone,

Rf value of the product: 0.3 (silica gel, toluene / ethyl acetate / ethanol = 4: 2: 1),

C30H32N4O4.

ESI-MS: m / z = 511 [M-H] - (8) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl- N -methylamino) anilino) -1-phenylmethylene] -

6-carbamoyl-2-indolinone, prepared from 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl- N -methylamino) -anilino) -1-phenylmethylene] -6-carboxy-2-indolinone,

Rf value of product: 0.5 (silica gel, methylene chloride / methanol / ammonia = 5: 1: 0.01),

C27H27N5O3.

ESI-MS: m / z = 468 [M-H] &lt; + &gt;

Example 12

3-Z- [1- (4- (N-Dimethylaminomethylcarbonyl- N -methylamino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, citric acid salt

To a solution of 3.25 g of citric acid monohydrate in 50 ml of methanol was added 5.0 g of 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl- N -methyl-148)] at room temperature. ♦ ♦ · · • · · «« «« «« «« «« «« «« «« «« « Amino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone. The solution was then concentrated, the residue washed with ether and recrystallized from ethyl acetate.

Yield: 6.3 g (90% of theory),

Rf value of the product: 0.6 (silica gel, methylene chloride / methanol / ammonia =

5: 1: 0.01), mp 198 ° C,

C28H28N4O5 x ΟρΗβΟχ,

ESI-MS: m / z = 483 [M-H] -, analysis: calculated C, 60.34; H, 5.37; N, 8.28;

calculated C 59.98%, H 5.25%, 8.13% N.

As in Example 12, the following compound was prepared:

(1) 3-Z- [1- (4- (dimethylaminomethyl) anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone x methanesulfonic acid prepared by the reaction of 3-Z- [1- (4- (dimethylaminomethyl) (-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone and methanesulfonic acid,

Rf value of the product: 0.6 (silica gel, methylene chloride / methanol / ammonia =

5: 1: 0.01), mp: 275 ° C,

C26H25N3O2 X CH4O3S

ESI-MS: m / z = 426 [M-H] -, Analysis: Calculated: C, 61.92; H, 5.59; N, 8.03; S, 6.12;

calculated C 61.43%, H 5.87%, N 7.85%, S 5.39%.

As in the above examples, the following compounds can be prepared:

(1) 3-Z- (1-anilino-1-phenyl-methylene) -6-ethoxycarbonyl-2-indolinone, (2) 3-Z- [1- (4-nitroanilino) -1-phenyl] -methylene] -6-ethoxycarbonyl-2-indolinone, (3) 3-Z- [1- (4-fluoro-amino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (4) 3- Z- [1- (4-chloro-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (S) 3-Z- [1- (4-iodo-anilino) -1-phenyl- methylene] -6-ethoxycarbonyl-2-indolinone,

-149 · · ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** (6) 3-Z- [1- (4-cyano-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (7) 3-Z- [1- (4-methoxy-anilino) ) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (8) 3-Z- [1- (4-ethoxy-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (9) 3-Z- [1- (4-trifluoromethylamino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (10) 3-Z- (1- (4-) methyl-anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (11) 3-Z- [1- (4-methylmercapto-anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2 (12) 3-Z- [1- (4-aminomethyl-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (13) 3-Z- [1- (4- ( isopropylaminomethyl) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (14) 3-Z- [1- (4- (anilinomethyl) anilino) -1-phenylmethylene] -6- ethoxycarbonyl-2-indolinone, (15) 3-Z- [1- (4- (propylaminomethyl) anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (16) 3-Z- [1- (4- (Butylaminomethyl) anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (17) 3-Z- [1- (4- (isobutylaminomethyl) anilino) -1-phenylmethylene (18) 3-Z- [1- (4- (cyclohexylaminomethyl) anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (19) 3- Z- [1- (4- (benzylaminomethyl) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (20) 3-Z- [1- (4 - ((N-ethyl- (N-methyl-amino) -methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (21) 3-Z- [1- (4 - ((N-methyl) (N-propyl-amino) -methyl) -anilino) -1-phenyl-methylene] -5-ethoxycarbonyl-2-indolinone, (22) 3-Z- [1- (4 - ((N - isopropyl-N-methyl-amino) -methyl) -anilino) -1-phenyl-methylene] -5-ethoxycarbonyl-2-indolinone, (23) 3-Z- [1- (4 - ((A) (ethyl-N-propyl-amino) -methyl) -anilino) -1-phenyl-methylene] -5-ethoxycarbonyl-2-indolinone, (24) 3-Z- [1- (4 - ((A) (-ethyl- N -isopropyl-amino) -methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (2S) 3-Z- [1- (4- (dipropylaminomethyl) ) anilino) -1-phenyl-methylene] -6-ethoxycarbonyl l-2-indolinone, ·· ····

-150- (2S) 3-Z- [1- (4- (diisopropylaminomethyl) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (27) 3-Z- [1- (4- ( (N-benzyl- N -ethyl-amino) -methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (28) 3-Z- [1- (4- (dibenzylaminomethyl) (-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (2 S) 3-Z- [1- (4- (3,6-dihydro-2H-pyridin-1-ylmethyl) -anilino) ) 1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (30) 3-Z- [1- (4- (3,5-dimethyl-piperidin-1-ylmethyl-anilino) 1-phenyl- methylene] -5-ethoxycarbonyl-2-indolinone, (31) 3-Z- [1- (4- (azepan-1-ylmethyl) -amino) -1-phenylmethylene] -6-ethoxycarbonyl- (32) 3-Z- [1- (4- (piperazin-1-ylmethyl) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (33) 3-Z- [1] - (4- (morpholin-4-yl-methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (3S) 3-Z- [1- (4- (thiomorpholin-4-yl) - methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (3 S) 3-Z- [1- (4- (1-oxo-thiomorpholin-4-ylmethyl) -anilino) -1 phenyl-methylene] -6-ethoxycarbonyl-2- (36) 3-Z- [1- (4- (1,1-dioxo-thiomorpholin-4-ylmethyl) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, ( 37) 3-Z- [1- (4- (acetylamino-methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (38) 3-Z- [1- (4- (2- amino-ethyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (39) 3-Z- [1- (4- (2-methylamino-ethyl) -anilino) -1-phenyl -methylene] -6-ethoxycarbonyl-2-indolinone, (40) 3-Z- [1- (4- (2-ethylamino-ethyl) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (41) 3-Z- [1- (4- (2-diethylamino-ethyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, 4 «9 · 9 9 · 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 ·

-151- (42) 3-Z- [1- (4- (2-piperidin-1-yl-ethyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (43) 3 -Z- [1- (4- (2-Acetylamino-ethyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (44) 3-Z- [1- (4- (3) (amino-propyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (45) 3-Z- [1- (4- (3-dimethylamino-propyl) -anilino) -1- phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (46) 3-Z- [1- (4- (N-aminomethylcarbonyl-N-methyl-amino) -anilino) -1-phenyl-methylene] - 6-ethoxycarbonyl-2-indolinone, (47) 3- Z - [1- (4- (N -methylaminomethylcarbonyl- N -methylamino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2 (48) 3-Z- [1- (4- (N-ethylaminomethylcarbonyl- N -methylamino) -anilino) -1-phenylmethylene] -

6-ethoxycarbonyl-2-indolinone, (49) 3-Z- [1- (4- (N-diethylaminomethylcarbonyl-N-methylamino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2- (50) 3-N- [1- (4 - (N - (piperidin-1-ylmethylcarbonyl) - N -methylamino) anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2 (51) 3-Z- [1- (4- (N - (morpholin-4-ylmethylcarbonyl) - N -methylamino) -anilino) -1-phenylmethylene] -6- ethoxycarbonyl-2-indolinone, (52) 3- Z - [1- (4 - (N - (piperazin-1-ylmethylcarbonyl) - N -methylamino] anilino) -1-phenylmethylene] -6 -ethoxycarbonyl-2-indolinone, (53) 3-Z- [1- (4 - (N - (2-amino-ethylcarbonyl) - N -methyl-amino) -anilino) -1-phenyl-methylene] - 6-ethoxycarbonyl-2-indolinone, (54) 3 -Z- [1- (4 - (N - (2-methylamino-ethylcarbonyl) - N -methyl-amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (55) 3-Z- [1- (4- (N - (2-diethylamino-ethylcarbonyl) - N -methylamino) -anilino) -1-phenylmethylene ] -6-ethoxycarbonyl-2-indolinone, (56) 3-Z- [1- (4- (N -acetyl- N - (2-aminoethyl) amino) anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (57 13-Z- [1- (4- (N-acetyl- N - (2-methylamino-ethyl) -amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indol ίη.

-152- (58) 3-Z- [1- (4- (N-acetyl- N - (2-methylamino-propyl) -amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2- (59) 3-Z- [1- (4 - (N-acetyl- N - (2-piperidin-1-yl-ethyl) -amino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl -2-indolinone, (60) 3-Z- [1- (4- (N-acetyl-N- (aminocarbonylmethyl) amino) anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone (61) 3-Z- [1- (4- (N -acetyl- N - (dimethylaminocarbonylmethyl) amino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (62) 13-Z- [1- (4- (N-acetyl-N- (piperidin-1-ylcarbonylmethyl) amino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone (63) 3-Z- [1- (4 - (N-methyl- N - (aminocarbonyl) amino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (64) 3 -Z- [1- (4 - (N-methyl- N - (methylaminocarbonyl) amino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (65) 3-Z- [1] - (4- (N-methyl- N - (dimethylaminocarbonyl) amino) -anilino) -1-phenylmethylene] 6-ethoxycarbonyl-2-indolinone, (66) 3-Z- [1- (4- (N-methyl- N - (piperidin-1-yl-carbones) (1) -amino) -anilino) -1-phenyl-methylene] 6-ethoxycarbonyl-2-indolinone, (67) 3-Z- [1- (4- (N - (2-aminoethyl)) - N -methylsulfonyl] (amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (68) 3-Z- [1- (4- (N- (2-methylamino-ethyl) - N -methylsulfonyl-amino) (-anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (69) 3-Z- [1- (4- (N - (2-ethylamino-ethyl) - N -methylsulfonylamino)) -anilino) -1-phenyl-methylene] 6-ethoxycarbonyl-2-indolinone, (70) 3-Z- [1- (4- (N - (2-diethylamino-ethyl) - N -methylsulfonyl-amino)) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (71) 3-Z- [1- (4 - (N - (2-pyrrolidin-1-yl-ethyl)) - N -methylsulfonylamino (-anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (72) 3-Z- [1- (4- (N- (2-piperidin-1-yl-ethyl)) - N -methylsulfonyl (amino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (73) 3-Z- [1- (4- (N- (2-piperazin-1-yl-ethyl)) -] N-methylsulfonyl-amino) -amino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone;

-153- (74) 3-Z- [1- (4 - (N - (2- (morpholin-4-yl) -ethyl) - N -methylsulfonylamino) anilino) -1-phenylmethylene] -6- ethoxycarbonyl-2-indolinone, (75) 3-Z- [1- (4- (N - (aminocarbonylmethyl) - N -methylsulfonylamino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2 (76) 3-Z- [1- (4 - (N - (methylaminocarbonylmethyl) - N -methylsulfonylamino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone (77) 3-Z- [1- (4 - (N - (ethylaminocarbonylmethyl) - N -methylsulfonyl-amino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (78) ) 3-N- [1- (4- (N - (N - (2-dimethylamino-ethyl) - N -methyl-amino) -carbonyl-methyl) - N -methylsulfonyl-amino) -anilino -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (79) 3-Z- [1- (4 - (N - (diethylaminocarbonyl-methyl) - N -methylsulfonyl-amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (80) 3-Z- [1- (4 - (N - (pyrrolidin-1-yl-carbonylmethyl) - N -) - methylsulfonyl-amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (81) 3-Z- [1- (4 - (N - (piperidin-1-yl-carbonyl-methyl)) N / -metylsul (82-Phenyl-amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (82) 3-Z- [1- (4 - (N - (piperazin-1-yl-carbonyl-methyl)) - (N-methylsulfonyl-amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (83) 3-Z- [1- (4 - (N - ((morpholin-4-yl)) (carbonylmethyl) - N -methylsulfonyl-amino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (84) 3-Z- [1- (4- (2-dimethylamino-ethoxy) (-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (85) 3-Z- [1- (4- (3-dimethylamino-propoxy) -anilino) -1-phenyl-methylene] -6 -ethoxycarbonyl-2-indolinone, (86) 3-Z- [1- (4- (aminocarbonylmethyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (87) 3-Z- [1- (4- (2-Aminocarbonyl-ethyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (88) 3-Z- [1- (4- (pyridin-2-yl) -anilino)) -1-Phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (89) 3-Z- [1- (4- (pyridin-3-yl) anilino) -1-phenylmethylene] -6-ethoxycarbonyl -2-indolinone (90) 3-Z- [1- (4- (pyridin-4-yl) anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone _I ···· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ····

-154- (91) 3-Z- [1- (4- (N-acetyl- N -methylamino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (92) 13-Z- [1- (4- (N-ethylcarbonyl- N - (dimethylaminocarbonylmethyl) amino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (93) 3- Z- [1- (carbamoyl-methyl-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (94) 3-Z- [1- (4-dimethylcarbamoyl-methyl-anilino) -1 - phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (95) 3-Z- [1- (4- (piperidin-1-ylmethyl) -anilino) -methylene] -6-ethoxycarbonyl-2-indolinone, (96) 3-Z- [1- (4- (piperidin-1-yl-methyl) -anilino) -propylidene] -6-ethoxycarbonyl-2-indolinone, (97) 3-Z- [1- (4- (piperidin-1-yl-methyl) -anilino) -butylidene] -6-ethoxycarbonyl-2-indolinone, (98) 3-Z- [1- (4- (N - (3-dimethylaminopropyl)) -N (acetyl-amino) -anilino) -methylene] -6-ethoxycarbonyl-2-indolinone, (99) 3-Z- [1- (4- (N - (3-dimethylamino-propyl) - N -) -) acetyl-amino) -anilino) -ethylidene] -6-ethoxycarbonyl-2-indolinone, (100) 3-Z- [1- (4- (N - (3-dimethylamino-propyl) - N -acetyl) amino) anilino) -propylid en] -6-ethoxycarbonyl-2-indolinone, (101) 3-Z- [1- (4 - (N - (3-dimethylamino-propyl) - N -acetyl-amino) -anilino) -butylidene] - 6-ethoxycarbonyl-2-indolinone, (102) 3-Z- [1- (4 - (N - (2-dimethylamino-ethyl) - N -methylsulfonyl-amino) -anilino) -methylene] -6-ethoxycarbonyl -2-indolinone, (103) 3-Z- [1- (4- (N - (2-dimethylamino-ethyl) - N -methylsulfonyl-amino) -anilino) -propylidene] -

6-ethoxycarbonyl-2-indolinone, (104) 3-Z- [1- (4 - (N - (2-dimethylamino-ethyl) - N -methylsulfonylamino) -anilino) -butylidene] -

6-ethoxycarbonyl-2-indolinone, (105) 3-Z- [1- (4-tetrazol-5-yl-anilino) -methylene] -6-ethoxycarbonyl-2-indolinone, (106) 3-Z- [1] - (4-Tetrazol-5-yl-anilino) -ethylidene] -6-ethoxycarbonyl-2-indolinone, (107) 3-Z- [1- (4-tetrazol-5-yl-anilino) -propylidene] -6 -ethoxycarbonyl-2-indolinone, (108) 3-Z- [1- (4-tetrazol-5-yl-anilino) -butylidene] -6-ethoxycarbonyl-2-indolinone, (109) 3-Z- [1- (4-carboxy-anilino) -methylene] -6-ethoxycarbonyl-2-indolinone, (110) 3-Z- [1- (4-carboxy-anilino) -propylidene] -6-ethoxycarbonyl-2-indolinone, (111) 13-Z- [1- (4-carboxy-anilino) -butylidene] -6-ethoxycarbonyl-2-indolinone,

• ·

-155- (112) 3- [1- (4- (N - (3-dimethylamino-propionyl) - N -dimethylaminocarbonylmethyl-anilino) anilino) -1-phenyl-methylene] -6-ethoxycarbonyl- 2-indolinone, (113) 3-Z- [1- (4- (N - (4-dimethylamino-butyryl) - N -dimethylaminocarbonyl-methylamino) anilino) -1-phenyl-methylene] -6- ethoxycarbonyl-2-indolinone, (114) 3-N- [1- (4- (N-dimethylaminocarbonyl-methyl- N - (2-dimethylamino-ethylsulfonyl) amino) -anilino) -1-phenyl-methylene] - 6-ethoxycarbonyl-2-indolinone, (115) 3-Z- [1- (4- (N-dimethylaminocarbonyl-methyl- N - (3-dimethylaminopropyl-sulfonyl) amino) -anilino) -1-phenyl-methylene ] -6-ethoxycarbonyl-2-indolinone, (116) 3-Z- [1- (4 - ((2-hydroxy-ethyl) -amino-methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl -2-indolinone, (117) 3-Z- [1- (4 - ((2-methoxy-ethyl) -amino-methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (118) 3-Z- [1- (4 - ((2-dimethylamino-ethyl) -amino-methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (119) 3-Z- [1- (4 - ((3-dimethylamino-propyl) -methyl-amino) anilino) -1-phenyl-methylene] -6etoxykarbonyl-2-indoline (120) 3-Z- [1- (4 - ((N-tert-butoxycarbonyl-2-amino-ethyl) -aminomethyl) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl- (121) 3-Z- [1- (4 - ((N-tert-butoxycarbonyl-3-amino-propyl) -aminomethyl) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl -2-indolinone, (122) 3-Z- [1- (4 - ((2-amino-ethyl) -amino-methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (123) 3-Z- [1- (4 - ((3-amino-propyl) -amino-methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (124) 3- Z- [1- (4 - ((2-acetylamino-ethyl) -amino-methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (125) 3-Z- [1- (4) - ((3-acetylamino-propyl) -amino-methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (126) 3-Z- [1- (4 - ((2- methylsulfonylamino-ethyl) -amino-methyl) -anilino) -1-phenyl-methylene] 6-ethoxycarbonyl-2-indolinone, (127) 3-Z- [1- (4 - ((3-methylsulfonylamino-propyl) -amino) methyl) anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone,

-156- (128) 3-N- [1- (4 - (N - (N - tert -butoxycarbonyl-2-amino-ethyl) - N -methyl-aminomethyl) anilino) -1-phenyl -methylene] -6-ethoxycarbonyl-2-indolinone, (129) 3-Z- [1- (4 - (N - (2-amino-ethyl) - N -methyl-amino-methyl) -anilino) - 1-Phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (130) 3-Z- [1- (4 - (N - (2-acetylamino-ethyl) - N -methyl-amino-methyl) -anilino) -1-Phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (131) 3-Z- [1- (4 - (N - (2-methylsulfonylamino-ethyl) - N -methyl-aminomethyl) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (132) 3-Z- [1- (4- (carboxymethyl-amino-methyl) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl- 2-indolinone, (133) 3-Z- [1- (4- (ethoxycarbonyl-methyl-amino-methyl) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (134) 3- Z- [1- (4- (carbamoyl-methyl-amino-methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (135) 3-Z- [1- (4- ( dimethylcarbamoyl-methyl-amino-methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (136) 3-Z- [1- (4- (methylcarbamoyl-methyl-amino-methyl) -anilino) -1 -fen (137) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl- N -methyl-amino) -3-amino-anilino) -1-phenyl-methylene] - (1-methyl-ethylene) -6-methoxycarbonyl-2-indolinone 6-ethoxycarbonyl-2-indolinone, (138) 3- [1- (4- (N-dimethylaminomethylcarbonyl- N -methylamino) -3-nitroanilino) -1-phenylmethylene] -6-ethoxycarbonyl -2-indolinone, (139) 3- [1- (4- (N-dimethylaminomethylcarbonyl- N -methylamino) -3-acetylaminoanilino) -1-phenylmethylene] -6-ethoxycarbonyl-2- (140) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl- N -methylamino) -3-methylsulfonylamino-anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone (141) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl- N -methyl-amino) -3-cyano-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, ( 142) 3-N- [1- (4- (N-dimethylaminomethylcarbonyl- N -methylamino) -3-hydroxy-anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (143) 3 Z- [1- (4 - (/ V-dimetylaminometylkarbonyl- / V-methyl-amino) -3-methoxy-anilino) -1fenyl-methylene] -6-ethoxycarbonyl-2-indolinone,

- 157 - (144) 3-N- [1- (4- (N-dimethylaminomethylcarbonyl-N-methylamino) -3-ethoxycarbonylanilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, ( 145) 3-N- [1- (4- (N-dimethylaminomethylcarbonyl- N -methyl-amino) -3-carboxy-anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (146) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl- N -methylamino) -3-carbamoyl-anilino) -

1-Phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (147) 3- Z- [1- (4- (N-dimethylaminomethylcarbonyl- N -methylamino) -3-chloroanilino) -1-phenyl -methylene] -6-ethoxycarbonyl-2-indolinone, (148) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl-N-methylamino) -3-fluoro-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (149) 3- Z41- (4- (N-dimethylaminomethylcarbonyl- N -methylamino) -3-bromoanilino) -1-phenylmethylene] -6-ethoxycarbonyl-2 (150) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl- N -methylamino) -3-methyl-anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (151) 3-N- [1- (4- (N-dimethylaminomethylcarbonyl- N -methylamino) -3-trifluoromethylanilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (152) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl- N -methylamino) -3,5-dibromoanilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (153) 3-Z - [1- (4- (N-dimethylaminomethylcarbonyl- N -methylamino) -3,5-dichloroanilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (154) 3-Z- [1- (4- (dimethylaminomethyl) -3-amino-aniline o) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (155) 3-Z- [1- (4- (dimethylaminomethyl) -3-nitroanilino) -1-phenylmethylene] -6-ethoxycarbonyl-

2-indolinone, (156) 3-Z- [1- (4- (dimethylaminomethyl) -3-acetylamino-anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (157) 3-Z- [1- (4- (dimethylaminomethyl) -3- (methylsulfonylamino) anilino) -1-phenylmethylene] 6-ethoxycarbonyl-2-indolinone, (158) 3-Z- [1- (4- (dimethylaminomethyl) -3] (cyano-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (159) 3-Z- [1- (4- (dimethylaminomethyl) -3-hydroxy-anilino) -1-phenyl-methylene -6-ethoxycarbonyl-2-indolinone, • · ··· ·

-158- (160) 3-Z- [1- (4- (dimethylaminomethyl) -3-methoxy-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (161) 3-Z- [ 1- (4- (dimethylaminomethyl) -3- (ethoxycarbonyl) anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (162) 3-Z- [1- (4- (dimethylaminomethyl) -3- carboxy-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (163) 3-Z- [1- (4- (dimethylaminomethyl) -3-carbamoyl-anilino) -1-phenyl-methylene] 6-ethoxycarbonyl-2-indolinone, (164) 3-Z- [1- (4- (dimethylaminomethyl) -3-chloroanilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (165) 13-Z- [1- (4- (dimethylaminomethyl) -3-fluoro-anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (166) 3-Z- [1- (4- (dimethylaminomethyl) -3-bromo-anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (167) 3-Z- [1- (4- (dimethylaminomethyl) -3-methyl-anilino) -1-Phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (168) 3-Z- [1- (4- (dimethylaminomethyl) -3-trifluoromethyl-anilino) -1-phenylmethylene] -6- ethoxycarbonyl-2-indolinone, (169) 3-Z- [1- (4- (dimethylaminomethyl) -3,5-dibromo) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (170) 3-Z- [1- (4- (dimethylaminomethyl) -3,5-dichloro-anilino) -1-phenyl-methylene ] -6-ethoxycarbonyl-2-indolinone, (171) 3-Z- [1- (4 - (N - ((4-methyl-piperazin-1-yl) -methylcarbonyl) - N -methyl-amino)] -anilino) 1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (172) 3-Z- [1- (4 - (N - (imidazo-1-ylmethylcarbonyl) - N -methyl- amino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (173) 3-Z- [1- (4- (N - (phthalimido-2-ylmethylcarbonyl) -N-methyl) (amino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (174) 3-Z- [1- (4- (N-aminomethylcarbonyl- N -methylamino) -anilino) - 1-Phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (175) 3-Z- [1- (4- (N-acetylaminomethylcarbonyl- N -methylamino) anilino) -1-phenylmethylene] -6- ethoxycarbonyl-2-indolinone, · · 2 ind «« «« «« «« «« «« «« «« «« «« • · · · ·····················

159- (176) 3-Z- [1- (4- (N-methylsulfonylaminomethylcarbonyl- N -methylamino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (177) 3-Z - [1- (4 - (N - ((N - (2-methoxyethyl) - N -methylamino) methylcarbonyl) - N -methylamino) -anilino) -1-phenylmethylene] -6- ethoxycarbonyl-2-indolinone, (178) 3-Z- [1- (4- (N - ((N - (2-dimethylaminoethyl) - N -methyl-amino) -methylcarbonyl) - N -methylamino) - anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (179) 3-Z- [1- (4 - (N - ((di- (2-hydroxyethyl) amino) methylcarbonyl)) (N-Methylamino) anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (180) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl) -N-methyl] (amino) -anilino) -methylene] -6-ethoxycarbonyl-2-indolinone, (181) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl- N -methylamino) -anilino) -ethylidene] -6-ethoxycarbonyl -2-indolinone, (182) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl- N -methyl-amino) -anilino) -propylidene] 6-ethoxycarbonyl-2-indolinone, (183) 3 -Z- [1- (4- (N-dimethylaminomethylcarbonyl- N -methyl-amino) -anilino) -butylidene] -6-ethoxycarbonyl-2 -indolinone, (184) 3-Z- [1- (4- (dimethylaminomethyl) -anilino) -methylene] -6-ethoxycarbonyl-2-indolinone, (185) 3-Z- [1- (4- (dimethylaminomethyl)) -anilino) -ethylidene] -6-ethoxycarbonyl-2-indolinone, (186) 3-Z- [1- (4- (dimethylaminomethyl) -anilino) -propylidene] -6-ethoxycarbonyl-2-indolinone, (187) 3-Z - [1- (4- (dimethylaminomethyl) -anilino) -butylidene] -6-ethoxycarbonyl-2-indolinone, (188) 3-Z- [1- (4- (N-dimethylaminocarbonyl-methylamino) -anilino] -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (189) 3-Z- [1- (4 - (N - (3-dimethylamino-propyl) - N -acetyl-amino) anilino) - 1-phenyl-methylene] 6-ethoxycarbonyl-2-indolinone, (190) 3-Z- [1- (4 - ((imidazolidin-2,4-dione-5-ylidene) -methyl) -anilino) -1- phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (191) 3-Z- [1- (4- (N - ((2-dimethylamino-ethyl) -carbonyl) - N -methyl-amino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (192) 3-Z- [1- (4- (N-tert-butoxycarbonylaminomethyl) anilino) -1-phenylmethylene] -6-ethoxycarbonyl- 2-indolinone, ·· ····

-160 - (193) 3-N- [1- (4- (2-oxo-pyrrolidin-1-ylmethyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (194 13-Z- [1- (4- (N-aminocarbonyl-methyl- N -methylsulfonylamino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (195) 3-Z- [1- (4- (N -cyanomethyl-N-methylsulfonyl-amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (196) 3-Z- [1- (4- ( 2- (imidazol-4-yl) -ethyl) -anilino-1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (197) 3-Z- [1- (4 - ((2- (N-benzyl- N -methyl-amino) -ethyl) - N -methylsulfonyl-amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (198) 3-Z- [ 1- (4-Cyclohexylamino-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (199) 3-Z- [1- (4- (imidazol-1-ylmethyl) -anilino) -1 -phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (200) 3-Z- [1- (4- (imidazol-1-ylmethyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl -2-indolinone, (201) 3-Z- [1- (N-methyl-piperidin-4-ylamino) -1-phenyl-methylene-6-ethoxycarbonyl-2-indolinone, (202) 3-Z- [1- (4- (imidazol-4-yl-m (203) 3-Z- [1- (4 - ((4-hydroxy-piperidin-1-yl) methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone Ino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (204) 3-Z- [1- (4 - ((4-methoxy-piperidin-1-yl) -methyl) -anilino) - 1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (205) 3-Z- [1- (4-benzyl-anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (206) 13-Z- [1- (4- (N - (3-trifluoroacetylamino-propyl) - N -methylsulfonylamino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, ( 207) 3-Z- [1- (4- (4-tert-butoxycarbonyl-piperazin-1-ylmethyl) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (208) 3-Z - [1- (4- (1-Methyl-imidazol-2-yl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, · * · * * * * * * * * * * * · * * ♦♦ ♦♦ ♦♦ ♦♦ ♦♦

-161- (209) 3- [1- (4- (1-methyl-imidazol-2-yl) -ailino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (210) 3 -Z- [1- (4 - (N - (2-dimethylamino-ethyl) - N -methylsulfonylamino) -3-amino-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, ( 211) 3-Z- [1- (4 - ((3- (N-benzyl- N -methyl-amino) -propyl) - N -methylsulfonylamino) -anilino) -1-phenyl-methylene] 6-ethoxycarbonyl-2-indolinone, (212) 3-Z- [1- (4 - (N - (2-dimethylamino-ethyl) - N -acetyl-amino) -anilino) -1-phenyl-methylene 6-Ethoxycarbonyl-2-indolinone, (213) 3-Z- [1- (4- (N- (2-dimethylamino-ethyl) - N -butyrylamino) -anilino) -1-phenyl- methylene] -

6-ethoxycarbonyl-2-indolinone, (214) 3-Z- [1- (4 - (N - (2-dimethylamino-ethyl) - N -isobutyryl-amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (215) 3-Z- [1- (4 - (N - (2-dimethylamino-ethyl) - N -benzoylamino) -anilino) -1-phenylmethylene ] -

6-ethoxycarbonyl-2-indolinone, (216) 3-Z- [1- (4- (N - (2-dimethylamino-ethyl) - N -acetyl-amino) -3-amino-anilino) -1- phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (217) 3-Z- [1- (4- (4-hydroxymethyl-piperidin-1-ylmethyl) -anilino) -1-phenyl-methylene] - 6-ethoxycarbonyl-2-indolinone, (218) 3-Z- [1- (4- (2- (4-hydroxy-piperidin-1-yl) -ethyl) -anilino) -1-phenyl-methylene] -6 -ethoxycarbonyl-2-indolinone, (219) 3-Z- [1- (4 - (N - (2-dimethylamino-ethyl) - N -propylsulfonyl-amino) -anilino) -1-phenyl-methylene 6-ethoxycarbonyl-2-indolinone, (220) 3- Z - [1- (4 - (N - (2-dimethylamino-ethyl) - N -butylsulfonylamino) -anilino) -1-phenyl- methylene] -6-ethoxycarbonyl-2-indolinone, (221) 3-Z- [1- (4 - (N - (2-dimethylamino-ethyl) - N -phenylsulfonylamino) -anilino) -1-Phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (222) 3-Z- [1- (4- (N - (2-dimethylamino-ethyl) - N -benzylsulfonylamino) - (223) 3-Z- [1- (4 - ((imidazolidin-2,4-dione-5-yl) methyl) ananino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone -1-Phenylmethylene] -6-ethoxycarbonyl-2-indoline n, (224) 3-Z- [1- (4 - ((3-hydroxy-pyrrolidin-1-yl) -methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone; · ·· ······ • •• 9 9999999

9 9 9 f 9 ··· 9 ··

9,999,999,999,999

9 99 9999

99 99 999 99 999

-162- (225) 3-Z- [1- (4- (cyclohexylmethyl) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (226) 3-Z- [1- (4- (cyclohexyl-carbonyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (227) 3- Z- [1- (4-diethylaminomethyl-anilino) -1-phenyl-methylene ] -6-ethoxycarbonyl-2-indolinone, (228) 3-Z- [1- (4 - (N - (n-hexyl) - N -methyl-aminomethyl) -anilino) -1-phenyl-methylene] 6-ethoxycarbonyl-2-indolinone, (229) 3- [1- (4- (N - (2-dimethylamino-ethyl) - N - (furan-2-carbonyl) amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (230) 3-Z- [1- (4- (N- (2-dimethylamino-ethyl) - N - (2-methoxy-benzoyl)) (amino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (231) 3-Z- [1- (4 - (N - (2-dimethylaminoethyl)) - N - (pyridine-3-carbonyl) -amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (232) 3-Z- [1- (4 - (N - (2-dimethylamino) (ethyl) - N - (phenyl-acetyl) -amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (233) 3-Z- [1- (4- (imidazole- 2-yl) -anilino-1-phenyl-methylene] -6-ethoxycarbonyl-2- (234) 3-Z- [1- (4- (1-ethyl-imidazol-2-yl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (235) 3- Z- [1- (4- (1-Benzyl-imidazol-2-yl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (236) 3-Z- [1- (4) - (N- (2-dimethylamino-ethyl) - N -isopropylsulfonyl-amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (237) 3-Z- [1 - ( 4- (N - ((4-benzyl-piperazin-1-yl) -methylcarbonyl) - N -methyl-amino) -anilino) -

1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (238) 3-Z- [1- (4 - (N - (pyrrolidin-1-ylmethylcarbonyl) - N -methylamino) - anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (239) 3-Z- [1- (4- (N - (2-dimethylamino-ethyl) - N -acetyl-amino)) -3-Bromo-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (240) 3-Z- [1- (4- (5-methyl-imidazol-4-yl) -anilino)] -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone;

-163- (241) 3-N- [1- (4- (N - ((2-dimethylamino-ethyl) -carbonyl) - N -isopropyl-amino) -anilino) -1-phenyl-methylene] -6- ethoxycarbonyl-2-indolinone, (242) 3-Z- [1- (4 - (N - ((2-dimethylamino-ethyl) -carbonyl) - N -benzyl-amino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (243) 3-Z- [1- (4- (N-butyl-N-tert-butoxycarbonyl-aminomethyl) anilino) -1-phenylmethylene] -6-ethoxycarbonyl- 2-indolinone, (244) 3-N- [1- (4- (AF ((N-aminocarbonyl-methyl-N-methyl-amino) -methylcarbonyl) - N -methyl-amino) -anilino) - 1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (245) 3-Z- [1- (4 - (N - ((N-benzyl- N -methyl-amino) -methylcarbonyl) -) (N-methyl-amino) anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (246) 3-Z- [1- (4 - (N - (di- (2-methoxyethyl)) (amino-methylcarbonyl) - N -methyl-amino) -anilino) 1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (247) 3-Z- [1- (4 - (N - (( 2- (4-tert-butoxycarbonyl-piperazin-1-yl) -ethyl) -carbonyl- N -methylamino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (248) 3 Z- [1- (4 - (/ V - ((2- (piperidin-1-yl) -ethyl yl) -carbonyl- (N-methyl-amino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (249) 3-Z- [1- (4 - (N - ((2) - (N-benzyl- (N-methyl-amino) -ethyl) -carbonyl) - N -methyl-amino) anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (250) 3 -Z- [1- (4- (N-dimethylaminomethylcarbonyl- N -isopropylamino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (251) 3-Z- [1 - ( 4- (N - (piperidin-1-ylmethylcarbonyl) - N -isopropylamino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (252) 3-Z- [ 1- (4- (N - (4-tert-butoxycarbonyl-piperazin-1-yl) -methylcarbonyl) - N -isopropyl-amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2- indolinone, (253) 3-Z- [1- (4 - (N - ((N-benzyl-N-methyl-amino) -methylcarbonyl) - N -benzylamino) anilino) -1- phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (254) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl- N -benzylamino) -anilino) -1-phenylmethylene] -6- ethoxycarbonyl-2-indolinone, (255) 3-Z- [1- (4- (N - (piperidin-1-ylmethylcarbonyl) - N -benzylamino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl (256) 3-Z- [1- (4- (1,2,4-triazol-2-ylmethyl) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone , ·················································· · • · ·························

-164- (257) 3- [1- (4- (1,2,3-triazol-2-ylmethyl) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (258) 3-Z- [1- (4- (1,2,3-triazol-1-yl-methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (259) 3-N- [1- (4 - ((N-aminocarbonyl-methyl- N -methyl-amino) -methyl) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, ( 260) 3-Z- [1- (4 - ((di- (2-methoxy-ethyl) -amino) -methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (261) 3-Z- [1- (4 - ((di- (2-hydroxy-ethyl) -amino) -methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone (262) 3-Z- [1- (4 - ((N-ethoxycarbonyl-methyl- N -methyl-amino) -methyl) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2- (263) 3-Z- [1- (4- (azetidin-1-ylmethyl) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (264) 3-Z- [1- (4- (N-propyl- N - tert -butoxycarbonyl-aminomethyl) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (265) 3-Z- [1- (4 - ((N - (2- (2-methoxy-ethoxy) -ethyl) - N -methyl-amino) -methyl) -anilino) -1-phenyl- methylene] -6-ethoxycarbonyl-2-indolinone, (266) 3-Z- [1- (4 - ((N - (tert -butoxycarbonyl-3-amino-propyl) - N -methyl-amino) -) methyl-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (267) 3-Z- [1- (4 - ((N - (methylcarbamoylmethyl) - N -methyl- amino) -methyl) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (268) 3-Z- [1- (4 - ((N - (dimethylcarbamoyl-methyl) - N) -) (methyl-amino) -methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (269) 3-Z- [1- (4 - ((N-propyl-N) -) methyl-amino) -methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (270) 3-Z- [1- (4 - ((N - (2-dimethylamino) (ethyl) - (N-methyl-amino) -methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (271) 3-Z- [1- (4 - ((R) - (3-dimethylamino-propyl) - N -methyl-amino) -methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (272) 3-Z- [1- (4 - ((/ V- (2-methoxy-ethyl) - / V-methyl-amino) methyl) anilino) -1-phenyl-methylene] -

6-ethoxycarbonyl-2-indolinone,

-165 ······················································· (273) 3-Z- [1- (4 - ((/ V ~ (2-hydroxy-ethyl))) (N-methyl-amino) -methyl) -amino-1-phenyl-methylene] -

6-ethoxycarbonyl-2-indolinone, (274) 3- [1- (4 - ((N - (dioxolan-2-ylmethyl) - N -methylamino) methyl) -anilino) - 1-Phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (275) 3-Z- [1- (4- (3-oxo-piperazin-1-ylmethyl) -anilino) -1-phenyl- methylene] -6-ethoxycarbonyl-2-indolinone, (276) 3-Z- [1- (4 - (N - (piperazin-1-ylmethylcarbonyl) - N -isopropyl-amino) -anilino) -1 - phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (277) 3-Z- [1- (4 - (N - ((2- (piperazin-1-yl) ethyl) -carbonyl)) -] N-methyl-amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (278) 3-Z- [1- (4 - ((N - (3-amino-propyl)) (N-methyl-amino) -methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (279) 3-Z- [1- (4 - (N - (3- methylamino-propyl) - (N-methylsulfonylamino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (280) 3-Z- [1- (4-ureidomethyl-anilino) -1 -phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (281) 3-Z- [1- (4-guanidinomethyl-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (282) 3-Z- [1- (4- (N-methylsulfonyl-aminomethyl) -an (283) 3-Z- [1- (4- (4-benzoyl-piperazin-1-ylmethyl) -anilino) -1- (amino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (284) 3-Z- [1- (4 - ((N - (3-acetylamino-propyl) - N -methyl-amino) -methyl) - anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (285) 3-Z- [1- (4 - ((N- (3-methylsulfonylamino-propyl) - N -methyl-amino)) - methyl) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (286) 3-Z- [1- (4 - ((N-carboxymethyl-N-methylamino) methyl)) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (287) 3-Z- (1-anilino-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone, (288) 3 -Z- [1- (4-Nitro-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (289) 3-Z- [1- (4-fluoro-anilino) -1-phenyl -methylene] -6-methoxycarbonyl-2-indolinone, (290) 3- Z- [1- (4-chloro-anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (291) 3- Z- [1- (4-Bromo-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, ··········· ··· • t · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

-166- (292) 3-Z- [1- (4-iodo-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (293) 3-Z- [1- (4- cyano-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (294) 3- Z- [1- (4-carboxy-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone (295) 3-Z- [1- (4-methoxy-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (296) 3-Z- [1- (4-ethoxy-anilino) ) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (297) 3-Z- [1- (4-trifluoromethyl-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (298) 3-Z- [1- (4-methylmercapto-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (299) 3-Z- [1- (4- (isopropylaminomethyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (300) 3-Z- [1- (4- (anilinomethyl) anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (301) 13-Z- [1- (4- (isobutylaminomethyl) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (302) 3-Z- [1- (4- (cyclohexylaminomethyl) -anilino)] -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (303) 3-Z- [1- (4- (benzyla) (methyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (304) 3-Z- [1- (4 - ((N-methyl- N -propyl-amino) -methyl) -) - (anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (305) 3-Z- [1- (4 - ((N-isopropyl- N -methyl-amino) -methyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (306) 3-Z- [1- (4 - ((N-ethyl- N -propyl-amino) -methyl) -anilino) -1 -phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (307) 3-Z- [1- (4 - ((N-ethyl-1H-isopropyl-amino) -methyl) -anilino) -1 -phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (308) 3- Z- [1- (4- (dipropylaminomethyl) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (309) 3- Z- [1- (4- (diisopropylaminomethyl) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (310) 3-Z- [1- (4 - ((N-benzyl-) -ethyl-amino) -methyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone,

-167- (311) 3-Z- [1- (4- (dibenzylaminomethyl) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (312) 3-Z- [1- (4- ( 3,6-Dihydro-2 H -pyridin-1-ylmethyl-anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (313) 3-Z- [1- (4- (3) (5-Dimethyl-piperidin-1-ylmethyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (314) 3-Z- [1- (4- (azepan-1-) (methyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (315) 3-Z- [1- (4- (2-aminoethyl) anilino) -1-phenylmethylene] -6-methoxycarbonyl -2-indolinone, (316) 3-Z- [1- (4- (2-methylamino-ethyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (317) 3-Z- [ 1- (4- (2-ethylamino-ethyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (318) 3- Z- [1- (4- (2-dimethylamino-ethyl)) - anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (319) 3-Z- [1- (4- (2-diethylamino-ethyl) -anilino) -1-phenylmethylene] -6-methoxycarbonyl -2-indolinone, (320) 3-Z- [1- (4- (2-piperidin-1-yl-ethyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (321) 3-Z - [1- (4- (2- acetylamino-ethyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (322) 3-Z- [1- (4- (3-amino-propyl) -anilino) -1-phenyl-methylene -6-Methoxycarbonyl-2-indolinone, (323) 3-Z- [1- (4- (3-dimethylamino-propyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (324) 3- N- [1- (4- (N-aminomethylcarbonyl- N -methyl-amino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (325) 3-Z- [1- (4) - (N -ethylaminomethylcarbonyl- N -methyl-amino) -anilino) -1-phenylmethylene] 6-methoxycarbonyl-2-indolinone, (326) 3-Z- [1- (4 - (N-diethylaminomethylcarbonyl) - (N-methyl-amino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone,

• t ···· · · · · • • • • «· • • · · · • • • • · • • · • • • · • • • • · · · · · · · ····

-168- (327) 3- [1- (4- (N-dipropylaminomethylcarbonyl- N -methyl-amino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (328) 3 Z- [1- (4 - (/ V - ((N-ethyl- / V-methyl-amino) -methylcarbonyl) - / V-methyl-amino) anilino) -1-phenyl-methylene] -6-methoxycarbonyl -2-indolinone, (329) 3-Z- [1- (4 - (N - ((N-ethyl- N -propyl-amino) -methylcarbonyl) - N -methyl-amino) -anilino) 1 -phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (330) 3-Z- [1- (4- (N - ((N-methyl- N -propyl-amino) -methylcarbonyl) - N) - methyl-amino) anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (331) 3- Z- [1- (4- (N-dimethylaminomethylcarbonyl-N-ethyl-amino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (332) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl- N -propyl-amino) -anilino) -1-phenylmethylene] - 6-Methoxycarbonyl-2-indolinone, (333) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl- N -butylamino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone (334) 3- [1- (4 - (N - (2-amino-ethylcarbonyl) -N-methyl-amino) -anilino) -1-phenyl-methylene] 6-methoxycarbonyl-2-indole (335) 3-Z- [1- (4 - (N - (2-diethylamino-ethylcarbonyl) - N -methyl-amino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone (336) 3-Z- [1- (4- (N-acetyl-N- (2-aminoethyl) amino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (337) 3-Z- [1- (4- (N-acetyl- N - (2-methylamino-ethyl) -amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, ( 338) 3-N- [1- (4- (N-acetyl- N - (3-methylamino-propyl) -amino) -anilino) -1-phenyl-methylene] 6-methoxycarbonyl-2-indolinone, ( 339) 3-N- [1- (4 - (N-acetyl- N - (2-piperidin-1-yl-ethyl) -amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2- (340) 3-N- [1- (4- (N-acetyl- N - (aminocarbonylmethyl) amino) anilino) -1-phenylmethylene] 6-methoxycarbonyl-2-indolinone, (341) 3-N- [1- (4- (N-acetyl- N - (piperidin-1-ylcarbonylmethyl) amino) anilino) -1-phenylmethylene] -6-methoxycarbonyl-2 -indolinone, (342) 3-Z- [1- (4- (N-methyl- N - (aminocarbonyl) amino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, • · · · · · · · · · · · Φ φ • · · · · · · · · · ···· φ • φ φ φ φ φ φφ · · · · · · · · Φ ······

- 169- (343) 3- [4- (N - (N-methyl-N - (methylaminocarbonyl) amino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, ( 344) 3-Ζ- [1- (4 - (N-methyl-N- (dimethylaminocarbonyl) amino) -anilino) -1-phenylmethylene] -

6-Methoxycarbonyl-2-indolinone, (345) 3- [1- (4- (N-methyl- N - (piperidin-1-ylcarbonyl) amino) -anilino) -1-phenyl- methylene] -

6-methoxycarbonyl-2-indolinone, (346) 3- [1- (4 - (N - (2-ethylaminoethyl) - N -methylsulfonylamino) anilino) -1-phenylmethylene] -

6-methoxycarbonyl-2-indolinone, (347) 3-Z- [1- (4 - (N - (2-diethylamino-ethyl) - N -methylsulfonylamino) -anilino) -1-phenylmethylene] 6-Methoxycarbonyl-2-indolinone, (348) 3- [1- (4- (N - (2-pyrrolidin-1-yl-ethyl) - N -methylsulfonyl-amino) -anilino) -1 -phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (349) 3-Z- [1- (4 - (N - (2-piperidin-1-yl-ethyl) - N -methylsulfonylamino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (350) 3-Z- [1- (4- (N - (2-piperazin-1-yl-ethyl) - N -methylsulfonylamino)] (-anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (351) 3-Z- [1- (4 - (N - (2- (4-morpholin-1-yl)) - ethyl) - N -methylsulfonyl-amino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (352) 3-Z- [1- (4- (N - (ethylaminocarbonyl-methyl) (N-methylsulfonyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (353) 3-Z- [1- (4 - (N - (diethylaminocarbonyl-methyl)) (N-methylsulfonyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (354) 3-Z- [1- (4- (N - (pyrrolidin-1-yl) carbonyl-methyl) - / V-methylsulfonyl nyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (355) 3-Z- [1- (4 - (N - (piperidin-1-yl-carbonyl-methyl) (N-methylsulfonyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (356) 3-Z- [1- (4- (N - (piperazine-1-)) yl-carbonyl-methyl-N-methylsulfonyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (357) 3- Z- [1- (4- (N- ( (morpholin-4-yl) -carbonyl-methyl) -N-methylsulfonyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (358) 3-Z- [1- (4 - (2-dimethylamino-ethoxy) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, ·· ····

-170- (359) 3-Z- [1- (4- (3-dimethylamino-propoxy) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (360) 3-Z- [ 1- (4- (aminocarbonyl-methyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (361) 3- Z- [1- (4- (2-aminocarbonyl-ethyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (362) 3-Z- [1- (4- (pyridin-2-yl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2 (363) 3-Z- [1- (4- (pyridin-3-yl) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, ( 364) 3-Z- [1- (4 ((N-phenethyl- N -methylamino) methyl) anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (365) 3-Z - [1- (4- (N-acetyl- N -methyl-amino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (366) 3-Z- [1 - ( 4- (N-ethylcarbonyl-N- (dimethylaminocarbonyl-methyl) -amino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (367) 3-Z- [1- (4- (N-methyl- N -methylsulfonyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (368) 3-Z- [1- (4-carboxymethylanilino) -1- phenylmethyl n] -6-methoxycarbonyl-2-indolinone, (369) 3-Z- [1- (4-carbamoyl-methyl-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (370) 3-Z - [1- (4-Dimethylcarbamoyl-methyl-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (371) 3-Z- [1- (4-tetrazol-5-yl-anilino) -1 -phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (372) 3-Z- [1- (4- (piperidin-1-ylmethyl) -anilino) -methylene] -6-methoxycarbonyl- 2-indolinone, (373) 3-Z- [1- (4- (piperidin-1-ylmethyl) -anilino) -ethylidene] -6-methoxycarbonyl-2-indolinone, (374) 3-Z- [1- (4- (piperidin-1-yl-methyl) -anilino) -propylidene] -6-methoxycarbonyl-2-indolinone, (375) 3-Z- [1- (4- (piperidin-1-yl-methyl) -anilino) -butylidene] -6-methoxycarbonyl-2-indolinone, (376) 3-Z- (1- (4- (N - (3-dimethylamino-propyl) - N -acetyl-amino) -anilino) -methylene) -6-methoxycarbonyl-2 -indolinone, f ··· ··················· ·· ····

-171- (377) 3-Z- [1- (4 - (N- (3-dimethylamino-propyl) - N -acetyl-amino) -anilino) -ethylidene] -6-methoxycarbonyl-2-indolinone, (378) 3-N- [1- (4- (N - (3-dimethylamino-propyl) - N -acetyl-amino) -anilino) -propylidene] -6-methoxycarbonyl-2-indolinone, (379) 13-Z- [1- (4- (N - (3-dimethylamino-propyl) - N -acetyl-amino) -anilino) -butylidene] -6-methoxycarbonyl-2-indolinone, (380) 3- N- [1- (4- (N- (2-dimethylamino-ethyl) - N -methylsulfonylamino) -anilino) -methylene] -6-methoxycarbonyl-2-indolinone, (381) 3-Z- [1- (4- (N - (2-dimethylamino-ethyl) - N -methylsulfonylamino) -anilino) -ethylidene] -6-methoxycarbonyl-2-indolinone, (382) 3-Z- [1- (4- (A) / - (2-dimethylamino-ethyl) - / V-methylsulfonylamino) anilino) propylidene] -

6-methoxycarbonyl-2-indolinone, (383) 3- [1- (4 - (N - (2-dimethylamino-ethyl) - N -methylsulfonylamino) -anilino) -butylidene] -6-methoxycarbonyl-2 -indolinone, (384) 3-Z- [1- (4-tetrazol-5-yl-anilino) -methylene] -6-methoxycarbonyl-2-indolinone, (385) 3-Z- [1- (4-tetrazole) (5-yl-anilino) -ethylidene] -6-methoxycarbonyl-2-indolinone, (386) 3-Z- [1- (4-tetrazol-5-yl-anilino) -propylidene] -6-methoxycarbonyl-2- (387) 3-Z- [1- (4-tetrazol-5-yl-anilino) -butylidene] -6-methoxycarbonyl-2-indolinone, (388) 3-Z- [1- (4-carboxy- anilino) -methylene] -6-methoxycarbonyl-2-indolinone, (389) 3-Z- [1- (4-carboxy-anilino) ethylidene] -6-methoxycarbonyl-2-indolinone, (390) 3-Z- [1- (4-carboxy-anilino) -propylidene] -6-methoxycarbonyl-2-indolinone, (391) 3-Z- [1- (4-carboxy-anilino) -butylidene] -6-methoxycarbonyl-2-indolinone (392) 3-Z- [1- (4- (N-benzyl- N -methylaminomethyl) -anilino) -1-methylmethylene] -6-methoxycarbonyl-2-indolinone, (393) 3 -Z- [1- (4- (2,3,4,5-tetrahydro-benzo (d) azepin-3-ylmethyl) -anilino) -1-methylmethylene] -6-methoxycarbonyl-2-ind (394) 3-Z- [1- (4 - ((benzo (1,3) dioxol-5-ylmethyl) methyl-aminomethyl) anilino) -1-methylmethylene] -6-methoxycarbonyl -2-indolinone, (395) 3-N- [1- (4- (N-phenethyl-N-methyl-aminomethyl) -anilino) -1-methyl-methylene] -6-methoxycarbonyl-2- indolinone, (396) 3-N- [1- (4- (N - (3,4-dimethoxy-benzyl) - N -methyl-aminomethyl) -anilino) -1-methylmethylene] -6-methoxycarbonyl-2 -indolinone, ············

172- (397) 3- [1- (4 - (N- (4-chloro-benzyl) -N-methyl-amino-methyl) -anilino) -1-methyl-methylene] 6-methoxycarbonyl- 2-indolinone, (398) 3-Z- [1- (4- (N - (4-methylbenzyl) - N -methyl-amino-methyl) -anilino) -1-methyl-methylene] -

6-methoxycarbonyl-2-indolinone, (399) 3-Z- [1- (4 - (N - (4-fluoro-benzyl) - N -methyl-amino-methyl) -anilino) -1-methyl- methylene] -

6-methoxycarbonyl-2-indolinone, (400) 3- Z - [1- (4 - (N - (4-bromo-benzyl) - N -methyl-amino-methyl) -anilino) -1-methyl- methylene] 6-methoxycarbonyl-2-indolinone, (401) 3-Z- [1- (4 - (N - (3-dimethylamino-propionyl) - N -dimethylaminocarbonylmethylamino) anilino) -1-phenyl-methylene 6-Methoxycarbonyl-2-indolinone, (402) 3-Z- [1- (4- (N - (4-dimethylamino-butyryl) - N -dimethylaminocarbonylmethylamino) anilino) -1-phenyl-methylene 6-Methoxycarbonyl-2-indolinone, (403) 3- [1- (4- (N-dimethylaminocarbonylmethyl) - N - (2-dimethylaminoethylsulfonyl) amino) anilino) -1-phenyl- methylene] -6-methoxycarbonyl-2-indolinone, (404) 3-Z- [1- (4- (N-dimethylaminocarbonylmethyl-N- (3-dimethylamino-propylsulfonyl) amino) -anilino) -1-phenyl- methylene] -6-methoxycarbonyl-2-indolinone, (405) 3-Z- [1- (4 - ((2-hydroxy-ethyl) amino-methyl) -anilino) -1-phenyl-methylene] -6- methoxycarbonyl-2-indolinone, (406) 3-Z- [1- (4 - ((2-methoxy-ethyl) -amino-methyl) -anilino) phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (407) 13-Z- [1- (4 - ((2-dimethylamino-ethyl) -amino-methyl) -anilino) -1-phenyl 1-methylene] -6-methoxycarbonyl-2-indolinone, (408) 3-Z- [1- (4 - ((3-dimethylamino-propyl) amino-methyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl- 2-indolinone, (409) 3-Z- [1- (4 - ((N-tert-butoxycarbonyl-2-amino-ethyl) -aminomethyl) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2- (410) 3-N- [1- (4 - ((N-tert-butoxycarbonyl-3-amino-propyl) -aminomethyl) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (411) 3-N- [1- (4 - ((2-amino-ethyl) -amino-methyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (412) 3- Z- [1- (4 - ((3-Amino-propyl) -amino-methyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, 9 9 9 99 9 • 9 999 9 9 9 9 9 9 9 999 999 9 9 9 9 9 9 9 9 9 9 9

· 99 99 999 999999

- 173- (413) 3-N- [1- (4 - ((2-acetylaminoethyl) amino-methyl) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (414) 3- Z- [1- (4 - ((3-Acetylamino-propyl) amino-methyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (415) 3-Z- [1- (4 - ((2-methanesulfonylamino-ethyl) -methyl-amino) anilino) -1-phenyl-methylene] -

6-methoxycarbonyl-2-indolinone, (416) 3-Z- [1- (4 - ((3-methylsulfonylamino-propyl) amino-methyl) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone (417) 3- [1- (4- (N - (N-tert-butoxycarbonyl-2-amino-ethyl) - N -methylamino-methyl) anilino) -1-phenyl- methylene] -6-methoxycarbonyl-2-indolinone, (418) 3-Z- [1- (4- (N- (2-amino-ethyl) -N-methyl-amino-methyl) -anilino) -1-phenyl -methylene] -6-methoxycarbonyl-2-indolinone, (419) 3-Z- [1- (4 - (N - (2-acetylamino-ethyl) - N -methyl-amino-methyl) -anilino) - 1-Phenylmethylene] -6-methoxycarbonyl-2-indolinone, (420) 3-Z- [1- (4 - (N - (2-methylsulfonylamino-ethyl) - N -methyl-amino-methyl) - anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (421) 3-Z- [1- (4- (carboxymethyl-amino-methyl) -anilino) -1-phenyl-methylene] -6 -methoxycarbonyl-2-indolinone, (422) 3-Z- [1- (4- (ethoxycarbonyl-methyl-amino-methyl) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (423) 3 -Z- [1- (4- (carbamoyl-methyl-amino-methyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (424) 3-Z- [1- (4- (ester dimethyl arbamoyl-methyl-amino-methyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (425) 3-Z- [1- (4- (methylcarbamoyl-methyl-amino-methyl) - anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (426) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl- N -methylamino) -3-amino-anilino) -1 - phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (427) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl-N-methylamino) -3-nitro-anilino) -1 - phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (428) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl-N-methylamino) -3-acetylaminoanilino) -1-phenylmethylene ] -6-methoxycarbonyl-2-indolinone, • ·· »

(429) 3-N- [1- (4- (N-dimethylaminomethylcarbonyl- N -methyl-amino) -3-methylsulfonylamino-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, ( 430) 3-N- [1- (4- (N-dimethylaminomethylcarbonyl- N -methylamino) -3-cyano-anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (431) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl- N -methylamino) -3-hydroxy-anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (432) 3- N- [1- (4- (N-dimethylaminomethylcarbonyl- N -methyl-amino) -3-methoxy-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (433) 3-Z- [ 1- (4- (N-dimethylaminomethylcarbonyl- N -methylamino) -3-ethoxycarbonylanilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (434) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl- N -methylamino) -3-carboxy-anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone ₁ (435) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl- N -methyl-amino) -3-carbamoyl-anilino) 1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (436) 3-Z- [1- (4 - (/ -) - In-dimethylamino-methylcarbonyl-A / -methyl-amino) -3-chloro- anilino) -1 phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (437) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl-N-methylamino) -3-fluoro-anilino) -1 - phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (438) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl- N -methylamino) -3-bromoanilino) -1-phenylmethylene 6-Methoxycarbonyl-2-indolinone, (439) 3- [1- (4- (N-dimethylaminomethylcarbonyl- N -methyl-amino) -3-methyl-anilino) -1-phenyl-methylene] - 6-methoxycarbonyl-2-indolinone, (440) 3- [1- (4- (N-dimethylaminomethylcarbonyl- N -methylamino) -3-trifluoromethylanilino) -1-phenylmethylene] -6-methoxycarbonyl -2-indolinone, (441) 3- [1- (4- (N-dimethylaminomethylcarbonyl-N-methylamino) -3,5-dibromo-anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone (442) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl- N -methylamino) -3,5-dichloroanilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone (443) 3-Z- [1- (4- (dimethylaminomethyl) -3-amino-anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (444) 3-Z- [1- (4- (dimethylaminomethyl) -3-nitro-aniline o) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone;

-175- (445) 3-Z- [1- (4- (dimethylaminomethyl) -3-acetylamino-anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (446) 3-Z- [1- (4- (dimethylaminomethyl) -3-methylsulfonylamino-anilino) -1-phenylmethylene] 6-methoxycarbonyl-2-indolinone, (447) 3-Z- [1- (4- (dimethylaminomethyl) -3-cyano-anilino) -1-Phenylmethylene] -6-methoxycarbonyl-2-indolinone, (448) 3-Z- [1- (4- (dimethylaminomethyl) -3-hydroxy-anilino) -1-phenylmethylene] -6- methoxycarbonyl-2-indolinone, (449) 3-Z- [1- (4- (dimethylaminomethyl) -3-methoxy-anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (450) 3- Z- [1- (4- (dimethylaminomethyl) -3-ethoxycarbonylanilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (451) 3-Z- [1- (4- (dimethylaminomethyl) -3-carboxy) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (452) 3-Z- [1- (4- (dimethylaminomethyl) -3-carbamoylanilino) -1-phenyl-methylene] -6- methoxycarbonyl-2-indolinone, (453) 3-Z- [1- (4- (dimethylaminomethyl) -3-chloro-anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (454) 3- Z - [1- (4- (dimethyl) aminomethyl) -3-fluoro-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (455) 3-Z- [1- (4- (dimethylaminomethyl) -3-bromo-anilino) -1 -phenylmethylene] -6-methoxycarbonyl-2-indolinone, (456) 3-Z- [1- (4- (dimethylaminomethyl) -3-methyl-anilino) -1-phenylmethylene] -6-methoxycarbonyl-2 -indolinone, (457) 3-Z- [1- (4- (dimethylaminomethyl) -3-trifluoromethyl-anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (458) 3-Z- [1- (4-Dimethylaminomethyl-3,5-dibromo-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (459) 3-Z- [1- (4- (dimethylaminomethyl) -3,5- dichloro-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (460) 3-Z- [1- (4- (dimethylaminomethyl) anilino) -1-phenyl-methylene] -6- [ (2-Hydroxy-ethoxy) carbonyl] -2-indolinone, · · ·, · · · · · · · · · · · · · · · · · · · · · · ···· · ·· ·· ·· ··· ·· ····

-176- (461) 3-Z- [1- (4- (dimethylaminomethyl) -anilino) -1-phenylmethylene] -6 - [(ethoxycarbonylmethoxy) carbonyl] -2-indolinone, (462) 3 -Z- [1- (4- (dimethylaminomethyl) -anilino) -1-phenylmethylene] -6 - [(carboxymethoxy) carbonyl] -2-indolinone, (463) 3-Z- [1 - ( 4- (dimethylaminomethyl) anilino) -1-phenylmethylene] -6 - [(carbamoylmethoxy) carbonyl] -2-indolinone, (464) 3-Z- [1- (4 - (N-dimethylaminomethylcarbonyl) - (N-methyl-amino) -anilino) -1-phenylmethylene] -6 - [(2-hydroxy-ethoxy) -carbonyl] -2-indolinone, (465) 3-Z- [1- (4 - (V) (dimethylaminomethylcarbonyl- N -methyl-amino) -anilino) -1-phenylmethylene] -6 - [(ethoxycarbonylmethoxy) carbonyl] -2-indolinone, (466) 3-Z- [1- (4- ( (N-dimethylaminomethylcarbonyl- N -methyl-amino) -anilino) -1-phenylmethylene] -6 - [(carboxymethoxy) carbonyl] -2-indolinone, (467) 3-Z- [1 - ( 4- (N-dimethylaminomethylcarbonyl- N -methylamino) -anilino) -1-phenylmethylene] -6 - [(carbamoylmethoxy) carbonyl] -2-indolinone, (468) 3-Z- [ 1- (4- (N-dimethylaminomethylcarbonyl- N -methylamino) -anilino) -1-phenylmethylene] -6 - [(2-methoxyethoxy) y) -carbonyl] -2-indolinone, (469) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl- N -methyl-amino) -anilino) -1-phenyl-methylene] -6- [ (2-dimethylaminoethoxy) carbonyl] -2-indolinone, (470) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl-n-methylamino) -anilino) -1-phenylmethylene] -6 - [(2- (N-tert-butoxycarbonyl-amino) -ethoxy) -carbonyl] -2-indolinone, (471) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl) - N -methyl- amino) -anilino) -1-phenylmethylene] -6 - [(2-aminoethoxy) carbonyl] -2-indolinone, (472) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl-)] - N-methyl-amino) -anilino) -1-phenylmethylene] -6 - [(2,2,2-trifluoroethoxy) carbonyl] -2-indolinone, (473) 3-Z- [1- (4- (/ V - ((4-methyl-piperazin-1-yl) -methylcarbonyl) - / V-methyl-amino) anilino) -

1-Phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (474) 3-Z- [1- (4 - (N - (imidazo-1-ylmethylcarbonyl) - N -methyl-amino) - anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (475) 3-Z- [1- (4 - (N - (phthalimido-2-ylmethylcarbonyl) - N -methylamino)) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (476) 3-Z- [1- (4- (N-aminomethylcarbonyl- N -methylamino) -anilino) -1 -phenyl-methylene] -6-methoxycarbonyl-2-indolinone, · · · · · β β β β β β β β · · · ··· ··· ···· · ·· ·· ·· ··· ·· ····

-177- (477) 3- [4- (N - (N-acetylaminomethylcarbonyl- N -methylamino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (478) 13-Z- [1- (4- (N-methylsulfonylaminomethylcarbonyl- N -methyl-amino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (479) 3-Z- [1- (4 - (/ V - ((/ V- (2-methoxy-ethyl) - / V-methyl-amino) methylcarbonyl) - / V-methyl-amino) anilino) -1-phenyl-methylene] -6-methoxycarbonyl- 2-indolinone, (480) 3-Z 41 - (4 - (N - ((N - (2-dimethylaminoethyl) - N -methyl-amino) -methylcarbonyl) - N -methylamino) -anilino) -1 -phenylmethylene] -6-methoxycarbonyl-2-indolinone, (481) 3-Z- [1- (4- (N - ((di- (2-hydroxyethyl) amino) methylcarbonyl) -N) - (amino-amino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (482) 3- Z- [1- (4-tert-butoxycarbonyl-methyl-anilino) -1-phenyl-methylene 6-Methoxy-carbonyl-2-indolinone, (483) 3- [1- (4- (N-dimethylaminomethylcarbonyl- N -methyl-amino) -anilino) -methylene] -6-methoxycarbonyl-2 -indolinone, (484) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl-N-methyl-amino) -anilino) -ethylidene] -6-methoxycarbone nyl-2-indolinone, (485) 3-N- [1- (4- (N-dimethylaminomethylcarbonyl- N -methyl-amino) -anilino) -propylidene] -

6-methoxycarbonyl-2-indolinone, (486) 3- [1- (4- (N-dimethylaminomethylcarbonyl-N-methyl-amino) -anilino) -butylidene] -6-methoxycarbonyl-2-indolinone, ( 487) 3-Z- [1- (4- (dimethylaminomethyl) anilino) -methylene] -6-methoxycarbonyl-2-indolinone, (488) 3-Z- [1- (4- (dimethylaminomethyl) anilino) - ethylidene] -6-methoxycarbonyl-2-indolinone, (489) 3-Z- [1- (4- (dimethylaminomethyl) anilino) propylidene] -6-methoxycarbonyl-2-indolinone, (490) 3-Z- [ 1- (4- (dimethylaminomethyl) anilino) butylidene] -6-methoxycarbonyl-2-indolinone, (491) 3-Z- [1- (4-tert-butyloxycarbonyl-anilino) -1-phenyl-methylene] -6- Methoxycarbonyl-2-indolinone, (492) 3-Z- [1- (4- (N - (2-dimethylamino-ethyl) - N -methyl-amino) -anilino) -1-phenyl-methylene] - 6-methoxycarbonyl-2-indolinone, (493) 3-Z- [1- (4- (N - (3-dimethylamino-propyl) - N -methyl-amino) -anilino) -1-phenyl-methylene] -

6-Methoxycarbonyl-2-indolinone, 999 9 9 9 9 9 9 9 · ·· 99,999,999,999

-178- (494) 3-Z- [1- (4- (N-methyl-acetylamino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (495) 3-Z- [1- (4- (imidazol-4-yl) anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (496) 3-Z- [1- (4 - ((V) - (dioxolan-2-yl-methyl) - N -methyl-amino) -methyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (497) 3-Z- [1- (4- (N-benzyl- N -methyl-amino-methyl) -anilino) -1-methyl-methylene] -6-carbamoyl-2-indolinone, (498) 3-Z- [1- (4- (2,3,4,5-tetrahydro-benzo (d) azepin-3-ylmethyl) -anilino) -1-methyl-methylene] -6-carbamoyl-2-indolinone, (499) 3-Z- [ 1- (4 - ((benzo (1,3) dioxol-5-yl-methyl) -methyl-aminomethyl) -anilino) -1-methyl-methylene] -6-carbamoyl-2-indolinone, (500) 3- N- [1- (4- (N-phenethyl- N -methyl-amino-methyl) -anilino) -1-methylmethylene] -6-carbamoyl-2-indolinone, (501) 3-Z- [ 1- (4- (N - (3,4-dimethoxy-benzyl) - N -methyl-aminomethyl) -anilino) -1-methyl-methylene] -6-carbamoyl-2-indolinone, (502) 3- Z- [1- (4 - (/ V- (4-chloro-benzyl) - / V-methyl-amino-methyl) anilino) -1-methyl-metylénj-

6-carbamoyl-2-indolinone, (503) 3- Z - [1- (4 - (N - (4-methyl-benzyl) - N -methyl-amino-methyl) -anilino) -1-methyl- methylene] -

6-carbamoyl-2-indolinone, (504) 3- Z - [1- (4 - (N - (4-fluoro-benzyl) - N -methyl-amino-methyl) -anilino) -1-methyl- methylene] -

6-carbamoyl-2-indolinone, (505) 3-Z- [1- (4- (N- (4-bromo-benzyl) - N -methyl-amino-methyl) -anilino) -1-methyl- metylénj-

6-carbamoyl-2-indolinone, (506) 3-Z- [1- (4 - ((N - (2-methoxy-ethyl) - N -methyl-amino) -methyl) -anilino) -1- phenyl-metylénj-

6-methoxycarbonyl-2-indolinone, (507) 3-Z- [1- (4- (dimethylaminomethyl) anilino) -1-phenylmethylene] -6 - [(2-aminoethoxy) carbonyl] -2 -indolinone, (508) 3-Z- [1- (4 - ((N - (3-methylsulfonylamino-propyl) - N -methylamino) -methyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone.

Example 13

Dry ampoules with 75 mg of active substance per 10 ml. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··· ·· ····

-179-

Ingredients: active substance 75.0 mg mannitol 50.0 mg water for injections up to 10.0 ml

Preparation: The active substance and mannitol were dissolved in water, freeze-dried after filling the ampoules. Dissolution to a solution suitable for use is carried out with water for injection purposes.

Example 14

Dry ampoules with 35 mg of active substance per 2 ml

Ingredients: active substance 35.0 mg mannitol 100.0 mg water for injections up to 2.0 ml

Preparation: The active substance and mannitol were dissolved in water, freeze-dried after filling the ampoules. Dissolution to a solution suitable for use is carried out with water for injection purposes.

Example 15

Tablets containing 50 mg of the active substance

Ingredients: (1) active substance 50.0 mg (2) milk sugar 98.0 mg (3) corn starch 50.0 mg (4) polyvinylpyrrolidone 15.0 mg (5) magnesium stearate 2.0 mq total 215.0 mg

mm.

Preparation: Components (1), (2) and (3) are mixed and granulated with an aqueous solution of component (4). The dried granulate is mixed with component (5). Biplanar tablets with bilateral facet and one-sided score are compressed from this mixture. Tablet Diameter 9 ·· ····

-180-

Example 16 Tablets with 350 mg of the active substance Ingredients: (1) active substance 350.0 mg (2) milk sugar 136.0 mg (3) corn starch 80.0 mg (4) polyvinylpyrrolidone 30.0 mg (5) magnesium stearate 4.0 mq together 600.0 mg

Preparation: Components (1), (2) and (3) are mixed and granulated with an aqueous solution of component (4). The dried granulate is mixed with component (5). Biplanar tablets with bilateral facet and one-sided score are compressed from this mixture. Tablet diameter 12 mm.

Example 17

Capsules containing 50 mg of the active substance

(1) active substance 50.0 mg (2) dried corn starch 58.0 mg (3) powdered milk sugar 50.0 mg (4) magnesium stearate 2,0 mu together 160.0 mg

Preparation: component (1) is rubbed together with component (2). A mixture of components (2) and (4) is added to the comminuted mixture with vigorous stirring. The powder mixture is filled into hard gelatin size 3 capsules in a capsule filler.

Example 18

Capsules with 350 mg of the active substance

Ingredients: (1) active substance 350.0 mg (2) dried corn starch 46.0 mg

-181 - (3) powdered milk sugar 30.0 mg (4) magnesium stearate 4.0 mg total 430.0 mg

Preparation: component (1) is rubbed together with component (2). A mixture of components (2) and (4) is added to the comminuted mixture with vigorous stirring. The powder mixture is filled into hard gelatin size 0 capsules in a capsule filler.

Example 19

Suppositories containing 100 mg of active substance

1 suppository contains: active substance 100.0 mg polyethylene glycol (mw 1500) 600.0 mg polyethylene glycol (mol. wt. 6000) 460.0 mg Polyethylene sorbitan monostearate 840.0 mq total 2000.0 mg

Preparation: The polyethylene glycols are melted together with the polyethylene sorbitan monostearate. The active ingredient is dispersed homogeneously into the melt at 40 ° C. Cool to 38 ° C and pour into pre-chilled suppository molds.

Claims (10)

1. The indolinones substituted in the 6-position of the general formula I (D in which: X is an oxygen or sulfur atom, R ¹ represents a hydrogen atom or a precursor group, R ² is carboxy, a linear or branched Ci-6-alkoxycarbonyl, C4-7-cycloalkoxy-carbonyl or aryloxycarbonyl group, a linear or branched Ci-6-alkoxycarbonyl group which is the terminal alkyl-substituted phenyl, heteroaryl, carboxyl, C 1-6 alkyl; _{A 3} -alkoxycarbonyl group, an aminocarbonyl group, a C 1-3 alkylaminocarbonyl group or a di- (C _1-3 -alkyl) aminocarbonyl group, a linear or branched C 2-6-3 alkoxycarbonyl group which is in the terminal alkyl portion substituted with a chlorine atom or a hydroxy-, β-3-alkoxy-, amino-, C 1-6 -alkyl group. _3- alkylamino- or di- (C _1-3 -alkyl) -amino, aminocarbonyl or methylaminocarbonyl, ethylaminocarbonyl optionally in the 2-position of the ethyl group substituted by hydroxy- or C 1-3 -alkoxy-, or as long as R ^{4 is} not aminosulphonyl-phenyl or /V-(Ci-5-alkyl)-Ci.3alkylaminokarbonylovú group, ^R2 is also a di (C ₁ _ ₂ alkyl) aminocarbonyl, R ³ is hydrogen, C. ₆ -alkyl, C ₃ -7-cycloalkyl, trifluoromethyl or heteroaryl group, • ···· ·· · -183phenyl or naphthyl, phenyl or naphthyl mono- or disubstituted by fluorine, chlorine, bromine or iodine, trifluoromethyl-, C 1-3 -alkyl- or C 1-3 -alkoxy-, in which case the substituents may be the same or different in the case of disubstitution, and wherein said unsubstituted as well as mono- and disubstituted phenyl or naphthyl groups may additionally be substituted by hydroxy-, hydroxy-C 1-6. _3- alkyl- or C 1-6 alkyl; _3- alkoxy-Ci. _3- alkyl-, cyano-, carboxy-, carboxy-C 1-3 -alkyl-; _3- alkoxycarbonyl-, aminocarbonyl-, C-. _3- alkylaminocarbonyl- or di- (C _1-3 -alkyl) -aminocarbonyl, nitro-, amino-, C 1-6 -alkylamino; _3- alkylamino-, di-C 1-6 -alkyl-amino or amino-C 1-6 -alkyl; C ₃ alkyl; ₃ alkylcarbonylamino, / N _(C1-.3 alkyl) -C _{first 3-} alkylcarbonylamino-, C 1-3 -alkylcarbonylamino-C 1-3 -alkyl-, N - (C _1-3 -alkyl) -C 1-3 -alkylcarbonylamino-3-alkyl-, C 1-6 -alkylcarbonylamino-C 1-3 -alkyl-; ₃ -alkylsulfonylamino-, alkylsulfonylamino-Cys-Cys-alkyl, N (C _{first 3} alkyl) -Ci.3-alkylsulfonylamino-Ci-3-alkyl or aryl-C i_ ₃ -alkylsulfonylamino-, cycloalkylamino group , cycloalkylenimino-, cycloalkylenimino-carbonyl-, cycloalkylenimino-C 1. _3- alkyl-, cycloalkyleneiminocarbonyl-C 1-3 -alkyl or cycloalkyleneiminosulfonyl-C 1-3 -alkyl having in each case 4 to 7 ring members, the methylene group in the 4-position of the 6-membered or 7-membered cycloalkyleneimino group can be replaced by an oxygen or sulfur atom, , sulfonyl-, -NH- or -N- (C _1-3 -alkyl), or may be substituted by heteroaryl or heteroaryl-C 1-6 alkyl. ₃ alkyl, R ⁴ is C 3. _{A 7-} cycloalkyl group, wherein the methylene group at the 4-position of the six- or seven-membered cycloalkyl group may be replaced by amino-, C 1-3 -alkylamino- or di- (C 1-3 -alkyl) -amino-, or may be replaced by -NH- .or - / W (C ₁ _ ₃ alkyl) -, · · · · · * -184or is phenyl substituted with R ⁶ , wherein the phenyl may be mono- or di-substituted by fluorine, chlorine, bromine or iodine, with C 1-4 -alkyl-, trifluoromethyl-, hydroxy- C1-3-alkoxy-, carboxy-, C1-3-alkoxybonyl-, amino-, acetylamino-, C1-3alkoxy-, C1-3alkoxy-, C1-3alkoxy-, acetylamino- ₃ -alkylsulfonyl-amino-, aminocarbonyl-, C 1-3 -yl-aminocarbonyl-, di- (C 1-3 -alkyl) -aminocarbonyl-, aminosulfonyl-, C 1-3 -alkylaminesulfonyl-; di- (C _1-3 -alkyl) -aminosulfonyl-, nitro- or cyano-, wherein the substituents are the same or different and wherein R ⁶ represents a hydrogen, fluorine, chlorine, bromine or iodine atom, a cyano-, nitro-amino group -, C 1-5 -alkyl-, C ₃ . _7- cycloalkyl-, trifluoromethyl-, phenyl-, tetrazolyl- or heterocyclyl, a group of the formula in which the hydrogen atoms attached to the nitrogen atom can be replaced independently of one another by a C 1-3 -alkyl group, A C 1-3 -alkoxy group; ₃ -alkoxy-Ci.3-alkoxy, phenyl-C ^ alkoxy group, _amino-C2 -3 alkoxy group, a C 3 -alkylamino-C _{2nd 3} -alkoxy, di (Ci-3-alkyl) amino-C _2-3-alkoxy, phenyl-C. ₃ -alkylamino-C _2-.3 alkoxy, /V-(Ci.3-alkyi)-fenyl-Ci.3-alkylamino-C _2-.3 alkoxy, C on _C-2 cykloalkylénimino-3- an alkoxy group or a C 1-3 -alkylmercapto-, carboxyl group, a C 1-6 alkyl group; _4- alkoxycarbonyl, aminocarbonyl, C 1-3 -alkylaminocarbonyl, N - (C _1-5 -alkyl) -C 1-3 -alkylaminocarbonyl, phenyl-C 1-3 -alkylaminocarbonyl, N - ( C _1-3 -alkyl) phenyl-C 1-3 -alkylaminocarbonyl, piperazinocarbonyl or N - (C 1-3 -alkyl) piperazinocarbonyl, C 1-3 -alkylaminocarbonyl or N - (C 1-6 -alkyl) -C 1-6 -alkylaminocarbonyl in which the alkyl moiety is substituted by a carboxyl or C 1-3 alkoxycarbonyl group, or in the 2 or 3 position by a di- (C 1-3 -alkyl) group ··· ·· ·········································· ······· ·· ·· ·· ··· ·· ···· -185amino-, piperazino-, N- (C1-4-alkyl) -piperazino- or 4- to 7-membered cycloalkyleneimine, C3-7-cycloalkylcarbonyl, wherein the methylene group at the 4-position of the 6-membered or 7-membered cycloalkyl amino moiety may be substituted -, C 1-3 -alkylamino- or di- (C 1-3 -alkyl) -amino-, or replaced by -NH- or -A / (C 1-3 -alkyl) -, A 4 to 7 membered cycloalkyleneimine group whose methylene-bound methylene group may be replaced by a carbonyl group or a sulfonyl group whose cycloalkylene moiety may be fused to a phenyl ring, or one or two hydrogen atoms may be replaced by a C 1-3 -alkyl group and / or the methylene group at the 4-position of a six or seven membered cycloalkyleneimine group may be substituted by carboxyl, C 1-3 -alkoxycarbonyl, aminocarbonyl, C _1-3 -alkylaminocarbonyl, di- (C 1-3 -alkyl) aminocarbonyl, phenyl-C 1-3 -alkylamino or N - (C 1-3 -alkyl) -phenyl-C 1-3 -alkylamino, or may be replaced by an oxygen or sulfur atom, sulfinyl-, sulfonyl-, -NH-, - N (C 1-3 -alkyl) -, - N (phenyl) -, - N (C 1-3 -alkylcarbonyl) - or - N (benzoyl) C 1-4 -alkyl substituted with R ⁷ , wherein: R ⁷ represents a C 3-7 -cycloalkyl group, wherein the methylene group at the 4-position of a six- or seven-membered cycloalkyl group may be substituted by amino, C 1-3 -alkylamino, di- (C 1-3 -alkyl) -amino, or replaced by - NH- or - N (C 1-3 -alkyl) -, in a 5-7 membered cycloalkyl group, one - (CH 2) 2 - group may be replaced by -CO-NH-, - (CH 2) 3 - group -NH -CO-NH- or -CO-NH-CO-, or - (CH 2) 4 may be replaced by -NH-CO-NH-CO- with a hydrogen atom - 186 bonded to the nitrogen atom may be replaced by C 1-6. _{A 3-} alkyl group, an aryl or heteroaryl group, a hydroxy- or C 1-6 -alkyl group; _3- alkoxy-, amino-, C 1-6 -alkyl; _7- alkylamino-, di- (C 1-7 -alkyl) -amino-, phenylamino-, N -phenyl-C 1-3 -alkyl-amino-, phenyl-C 1-6 -alkyl-; _3- alkyl-amino-, N - (C _1-3 -alkyl) -phenyl-C 1-6 alkyl; _{3-alkyl-aminoalebo} di- (phenyl-Ci. ₃ alkyl) amino group, a _{hydroxy-C2. 3} -alkylamino, A / - _{(C1. 3} alkyl) o-hydroxy-C2. ₃ -alkylamino, di- (o-hydroxy-C _{second 3-alkyl)} amino, di (O- (C ₁ _ ₃ -alkoxy) -C _2-3 -alkyl) -aminoalebo / N ( dioxolan-2-yl) -C. _{3-alkyl-amino,} alkylcarbonylamino group, C ₃ -C _2-3 -alkyl-amino or C. ₃ alkylcarbonylamino-C _2-3 alkyl- / N _{(C1. 3} alkyl) amino, C ^ -alkylsulfonylamino-, / V- (Ci. ₃ alkyl) -C ₃ alkyl- sulfonylamino-, C- | ₃ alkylsulfonylamino-C2-alkyl _3-amino or C. ₃ alkylsulfonylamino-C2 _3-alkyl / N (Cl. ₃ alkyl) amino group, a hydroxycarbonyl-C-3-alkylamino and / or N (Cl. ₃ alkyl) -hydroxy-carbonylalkyl C. _{A 3-} alkyl-amino-, guanidine group in which one or two hydrogen atoms may each be replaced by C 1-6 alkyl; _3- alkyl, a group of formula - N (R ⁸ ) - CO - (CH ₂ ) _n - R ⁹ (H) wherein R ⁸ represents a hydrogen atom or C 1-6 alkyl; _3- alkyl, n is 0,1,2, or 3, R ⁹ is amino-, C 1-4 -alkylamino-, di- (C 1-4 -alkyl) -amino-, phenyl-amino-, N - (C 1-4 -alkyl) -phenylamino-, benzylamino-, N - ( (C 1-4 -alkyl) benzylamino- or C 1-4 -alkoxy-, 4- to 7-membered cycloalkyleneimine group, wherein the methylene group at the 4-position of a 6-membered or 7-membered cycloalkylenimine group may be replaced by an oxygen or sulfur atom, a sulfinyl-, sulfonyl- NH, N / (C |. _3-187 ···· • · e · • · · · • · · · • · · · · · · · ···· »·» · · • Alkyl) -, - / V (phenyl) - - - - - - - - - - - - - - - - , - N - (C _1-3 -alkylcarbonyl) - or - N - (benzoyl) -, or when n is 1, 2, or 3 may also be hydrogen, a group of the formula -N ^{(R 0)} - _{(CH2) m} - (CO) _a R ¹¹ (III) wherein R ¹⁰ represents hydrogen, C 1-3 -alkyl, C 1-3 -alkylcarbonyl, arylcarbonyl, phenyl-C 1-3 -alkylcarbonyl, C 1-6 -alkyl; _{A 3-} alkylsulfonyl group, an arylsulfonyl group or a phenyl-C 1-6 alkyl group; ₃ -alkylsulfonyl, m is 1, 2, 3 or 4, o is 1, or, when m is 2, 3 or 4, o can also be 0 and R ¹¹ represents amino-, C 1-4 -alkylamino-, di-C 1-6 -alkyl-4-amino-, phenyl-amino-, N - (C 1-6 -alkyl) -phenylamino-, benzylamino-, N- (C 1-6 -alkyl) benzylamino -, C _1-4 -alkoxy- or C 1-3 -alkoxy-C _1-3 -alkoxy-, optionally substituted by a C 1-3 -alkyl- in the 1-position substituted by a di (C 1-4 -alkyl) -amino-C _1-3 -alkylamino- or 4 a 7-membered cycloalkyleneimine group, wherein the cycloalkylene moiety may be fused to the phenyl ring, or the methylene group at the 4-position of a six or seven membered cycloalkyleneimine group may be replaced by an oxygen or sulfur atom, a sulfinyl-, sulfonyl-, -NH-, -A group / (C ₃ alkyl) -, - / V (phenyl) -, - / V (C ₃ alkylcarbonyl) - or - / V (benzoyl) -, C ₄ .7-cycloalkylamino, C ₄ -7 cycloalkyl-C 1-3 -alkylamino- or C 4-7 cycloalkenylamino- in which the ring position 1 does not participate in the double bond and wherein said groups may additionally be substituted on the amino nitrogen atom by a C 1-4 -cycloalkyl-, C 2-4 -alkenyl- or C 1-4 -alkyl-, a 4-7 membered cycloalkylenimine group, Which cycloalkylene moiety may be condensed with a phenyl group or with an oxazolo-, imidazolo-, thiazolo-, pyridino-, pyrazino- or pyrimidino- group, optionally substituted by a fluorine, chlorine, bromine or iodine atom, a nitro- group, a C 1-3 group -alkyl-, C 1-3 alkoxy or amino, and / or whose one or two hydrogen atoms may be replaced by a C 1-3 alkyl, C 3-7 -cycloalkyl or phenyl group, and / or wherein the methylene group at the 3-position of the five-membered cycloalkyleneimine group may be substituted with hydroxy, hydroxy-C 1-3 alkyl, C 1-3 -alkoxy- or C 1-3 -alkoxy-C 1-3 alkyl, wherein the methylene group at the 3- or 4-position of the six- or seven-membered cycloalkyleneimine group may be substituted with hydroxy, hydroxy- C 1-3 -alkyl, C 1-3 -alkoxy- or C 1-3 -alkoxy-C 1-3 -alkyl, carboxyl, C 1-4 -alkoxycarbones 1-, aminocarbonyl-, C 1-6 alkyl; _3- alkylaminocarbonyl-, di- (C 1-3 -alkyl) -aminocarbonyl-, phenyl-C 1-3 -alkylamino or N - (C 1-3 -alkyl) -phenyl- C 1-3 -alkylamino-, or said methylene group may be replaced oxygen or sulfur atom, sulfinyl-, sulfonyl-, -NH-, N - (C 1-3 -alkyl) -, N - (phenyl) -, N - (phenyl-C 1-3 -alkyl) -, - N (C _1-3 -alkylcarbonyl) -, N - (C 1-4 -hydroxycarbonyl) -, - N (C 1-4 -alkoxycarbonyl) -, - N - (benzoyl) - or -A / (phenyl-C _1-3 - wherein the methylene group bonded to the imino nitrogen of the cycloalkylenimine group may be replaced by a carbonyl group or a sulfonyl group, or in the 5- to 7-membered monocyclic or phenyl-fused cycloalkyleneimine group, both methylene imines may be bonded, replaced by a carbonyl group, -189or R ⁶ is C 1-6 -alkyl which is substituted by carboxyl, C 1-3 -alkoxycarbonyl, aminocarbonyl, C 1-3 alkylaminocarbonyl or di- (C 1-3 -alkyl) aminocarbonyl or 4-7 membered cycloalkyleneiminocarbonyl, a (C 1 -C 3 -alkyl) - C 2-4 -alkanoylamino- group which is additionally substituted by an alkyl group or a C 1-3 -alkoxycarbonyl group, of the formula -N (R ¹² ) -CO- (CH ₂ ) _p -R ¹³ (IV) wherein R ¹² is H, C ₆ alkyl, or C _3-7 cycloalkyl group, or a terminal-Ci.3 alkyl, substituted phenyl, heteroaryl, trifluoromethyl, hydroxy, C1.3alkoxyskupinou, aminocarbonyl, alkylamino-CM -carbonyl, di- (C 1-4 -alkyl) aminocarbonyl, C 1-6 -carbonyl; _3- alkyl-carbonyl, C _3-6 -alkylsulfonyl-amino, N - (C 1-3 -alkyl) -C 1. ₃ -alkylsulfonylamino, C 1-3 -alkyl aminosulfonyl or di- (C 1-3 -alkyl) aminosulfonyl and p is 0, 1, 2, or 3; and R ¹³ has the same meaning as R ⁷ , or when p is 1, 2 or 3, R ¹³ may be a hydrogen atom, a group of the formula -N (R ¹⁴ ) - (CH ₂ ), - (CO), - R ¹⁵ (V) wherein R ¹⁴ represents a hydrogen atom, a C 1-3 -alkyl group, a C 1-3 -alkylcarbonyl group, an arylcarbonyl group, a phenyl-C _1-3 -alkylcarbonyl group, a heteroarylcarbonyl group, a heteroaryl-C 1-3 -alkylcarbonyl group, a C 1-4 alkylsulfonyl group, an arylsulfonyl group, phenyl-C _1-3 -alkyl- · · alkyl------------------ ·· ·· ···· -190sulfonyl, heteroarylsulfonyl or heteroaryl-C 1. _{3 is an} alkylsulfonyl group, q is 1, 2, 3 or 4, r is 1, or when q is 2, 3 or 4, r is also 0 and R ¹⁵ has the same meaning as R ⁷ , as defined above, -N (R ¹⁶ ) -SO ₂ -R ¹⁷ (VI) wherein R ¹⁶ represents a hydrogen atom or a terminal C 1-4 alkyl group optionally substituted by cyano-, trifluoromethyl-carbonyl-amino- or N - (C 1-3 alkyl) -trifluoromethyl-carbonyl-amino- and R ¹⁷ represents a C 1-3 -alkyl group, amino substituted with di- (C 1-3 -alkyl) amino-C 1-6 alkyl; _3- alkyl-carbonylamino or di- (C 1-3 -alkyl) amino-C 1-6 alkyl; _3- alkyl-sulfonyl- and di- (C _1-3 -alkyl) -aminocarbonyl-C 1-3 -alkyl-, or a 4- (C 1-8 -alkyl-C 5-6 -alkylsulfonylamino- or N - (C 1-3 -alkyl) group ) -phenylsulfonylamino- in which the alkyl moiety is additionally substituted by cyano or carboxy-, wherein all of the radicals mentioned for R ⁶ containing single-bonded or fused phenyl groups may be mono- or di-substituted by fluorine, chlorine, bromine or iodine, C - _5- alkyl-, trifluoromethyl-, hydroxy-, C _1-3 -alkoxy-, carboxy-, η 3 -alkoxycarbonyl-, aminocarbonyl-, C-malkylamino-carbonyl-, di- (C 1-4) alkyl) amino-carbonyl, aminosulfonyl, aminosulfonyl-C1-3alkyl, di _{(C1. 3} alkyl) aminosulfonyl-, Cl. ₃ alkyl-sulfonylamino, nitro or cyano, the substituents can be the same or different, or two adjacent hydrogen atoms of the phenyl group may be replaced by a methylenedioxy- group, and R ⁵ represents a hydrogen atom or C 1-6 alkyl; _{A 3-} alkyl group; -191 wherein the term aryl refers to a mono- or di-substituted phenyl or naphthyl group, optionally substituted by a fluorine, chlorine, bromine or iodine atom, a cyano-, trifluoromethyl-, nitro-, carboxy-, aminocarbonyl-, C 1-3 -alkyl or C 1-3 -alkoxy and the term heteroaryl refers to a monocyclic five- or six-membered heteroaryl group optionally substituted by a C 1-3 -alkyl group in the carbon moiety, wherein said six-membered heteroaryl group contains one, two or three nitrogen atoms and the five-membered heteroaryl group contains imino, oxygen or sulfur, optionally substituted with C 1-6 alkyl; _{A 3-} alkyl or phenyl-C 1-4 -alkyl group, or optionally contains a C 1-3 -alkyl- group or a phenyl-C 1-3 -alkyl-substituted amino group or an oxygen or sulfur atom and in addition a nitrogen atom, or optionally contains a C 1-3 -alkyl or phenyl group -C 1-3 alkyl substituted amino and two nitrogen atoms, and in addition, the phenyl ring may be fused to said monocyclic heterocyclic groups via two adjacent carbon atoms and a bond occurs through the nitrogen atom or through the carbon atom of the heterocyclic moiety or the fused phenyl ring, atoms the hydrogen in the above-mentioned alkyl and alkoxy groups or in the alkyl portions of the above-defined groups of formula I may be partially or totally replaced by fluorine atoms, and the hydrogen atom of said carboxyl group or hydrogen atom bonded to the nitrogen atom may be replaced in vivo by a leaving group; T automomers, diastereomers, enantiomers, mixtures thereof and salts thereof. 2. The indolinone of formula I according to claim 1, wherein R ¹ and R ^{2 3} are as defined above, and X is an oxygen atom, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, 4, and 4 · · · · 4 · · ♦ · 99 · 44 99 99 44 44 44 44 44 99 -192 R ² is a carboxyl group, a straight or branched C 1-6 -alkoxycarbonyl group, a C 1-6 -cycloalkoxycarbonyl group or a phenoxycarbonyl group, a straight or branched C 1-3 -alkoxycarbonyl group which is substituted by a phenyl- , heteroaryl-, carboxy-, C 1-3 -alkoxycarbonyl-, aminocarbonyl-, C 1-3 -alkylaminocarbonyl- or di- (C 1-3 -alkyl) aminocarbonyl, a linear or branched C 2-3 -alkoxycarbonyl group which: is substituted in the alkyl terminal part by a chlorine atom, a hydroxy-, C 1-6 -alkyl group. ₃ -alkoxy, amino, C ₁ _ ₃ -alkylamino or di- (C. _3-alkyl) amino, aminocarbonyl or methylaminocarbonyl group, ethylaminocarbonyl group optionally in the 2-ethyl group substituted with a hydroxy or C 3 -alkoxy- or, if R ^{4 is} not an aminosulfonyl-phenyl- or N - (C _1-5 -alkyl) -C 1-3 -alkylaminocarbonyl-phenyl- group, R ² may also be di (C 1-2 -alkyl) ) -aminocarbonyl, R ⁴ represents a C 3-7 -cycloalkyl group, wherein the methylene group at the 4-position of a six or seven membered cycloalkyl group may be replaced by an amino-, C 1-3 -alkylamino- or di- (C 1-3 -alkyl) group ) amino, or can be replaced by -NH- or - / \ Z (C ₃ alkyl) -, or a group ^{R6-substituted} phenyl group which may be additionally mono- or di-substituted by F, Cl, Br, Ci. _3- alkyl-, trifluoromethyl-, hydroxy-, ω-3-alkoxy-, carboxy-, C 1-3 -alkoxycarbonyl-, amino-, acetylamino-, aminocarbonyl-, C 1-3 -alkyl-aminocarbonyl-, di- (C 1-3) -alkyl) aminocarbonyl-, nitro or cyano, the substituents may be the same or different, and wherein R ⁶ is H, fluorine, chlorine, bromine, iodine, cyano, nitro, amino, C-5- alkyl, _C3 7-cycloalkyl, trifluoromethyl, phenyl, tetrazolyl or heteroaryl group of formula ---- CH · · «« «« «« «· · · · • -193 in which a hydrogen atom bonded to the nitrogen atom may be replaced C1.3alkylovou group, alkoxy group-Ci.3, _{amino-C2-3-alkoxy,} C. ₃ -alkylamino, C _2-3 -alkoxy, di (C ₃ alkyl) amino-C _{2nd 3} alkoxy-, phenyl-C 3 -alkylamino-C _{2nd 3} -alkoxy, / V- (Ci. ₃ alkyl) _{phenyl-Cl-3alkylamino-2} C-.3 alkoxy, pyrrolidin-3-C ₂ alkoxy, C _{2-piperidino-3-alkoxy} or C1.3alkylmerkapto-, carboxyl, CM-alkoxycarbonyl, aminocarbonyl, Ci-3-alkylamino-carbonyl, phenyl-Ci-3-alkylamino-carbonyl, or A / - (C ₁ _3-alkyl) -phenyl C ₁ _ ₃ alkylamino-carbonyl, C ₃ -7-cycloalkyl-carbonyl, wherein the methylene group in the 4-position six or seven membered cycloalkyl can be replaced by -NH- or - / V (C-I_3 alkyl) -. A 4 to 7 membered cycloalkyleneimine group in which the imine-bound methylene group can be replaced by a carbonyl or sulfonyl group, or one or two hydrogen atoms can each be replaced by a C 1-3 -alkyl group and / or a methylene group at the 4-position of a 6 or 7-membered cycloalkylene the group may be substituted with a carboxyl group, a C 1-3 -alkoxycarbonyl group, an aminocarbonyl group, a C _1-3 -alkylaminocarbonyl group, a di- (C _1-3 -alkyl) aminocarbonyl group, a phenyl-C 1-6 -alkylamino group or a N - (C _1-3 ) group alkyl) -phenyl-C. _{A 3-} alkylamino group, or may be replaced by an oxygen or sulfur atom, a sulfinyl-, sulfonyl-, -NH- or - N (C _1-3 -alkyl) -, terminal C 1-4 alkyl group substituted with R ⁷ , wherein R ^{7 is} substituted with R ⁷ represents a C 5-7 -cycloalkyl group, wherein the methylene group at the 4-position of a six-membered or seven-membered cycloalkyl group may be replaced by -NH or - / V (C _1-3 -alkyl) -, or a 5- to 7-membered cycloalkyl group may be replaced - (CH ₂ ) 2 -CO-NH-, group - (CH ₂ ) ₃ -194 ···· · · · · ··· · ··· · ··· · -NH-CO-NH-, or - (CH 2) 4 - -NH-CO-NHCO-, the hydrogen atom bonded to the nitrogen atom can always be replaced C 1-3 -alkyl, phenyl or heteroaryl, hydroxy- or C 1-8 -alkoxy-, amino-, C 1-6 -alkylamino-, di- (C 1-6 -alkyl) -amino-, phenylamino-, -phenyl-C 1-3 -alkyl-amino-, phenyl-C 1-6 -alkyl-amino-; ₃ -alkylamino, / V- (Ci-3-alkyl) -phenyl-Ci-3-alkylaminoalebo di- (phenyl-C | .3 alkyl) amino group, a hydroxy-C ₂ -3 alkyl-amino, N- (Ci_3-alkyl) -R _C-2 hydroxy-3-alkylamino, di- (ro-hydroxy-C ₂ .3-alkyl) amino, di (O- (C ₍ 1-3-alkoxy) -C 2-3 -alkyl) amino or N - (dioxolane- ₂ -yl) - C 1-3 -alkyl-amino-, a C ₁ -C 3 -alkyl-amino group; _{3-alkylcarbonylamino} C 2-3 alkyl amino or C 3 -alkylcarbonyl like amino-C 2-3 alkyl-, and I / N _(C1-.3 alkyl, and I) I-a mono-, a C 3-alkylsulfonylamino, A / - (Ci-3-alkyl) -C-3-alkyl-sulfonylamino, C1.3alkylsulfonylamino _2-C 3-alkyl-amino or C. _3-C 2-3 alkylsulfonylamino alkylN- (C1-3-a I kyl) -amino innovators group, a hydroxycarbonyl-C ₃ -alkylamino and / or N (Ci-3-alkyl) -hydroxy-carbonylalkyl CF A 3-alkyl-amino-, guanidine group in which the hydrogen atom may be replaced by a C 1-3 alkyl group, a group of the formula -N (R ⁸ ) -CO- (CH ₂ ) _n -R ⁹ (II) wherein R ⁸ represents a hydrogen atom or C 1-6 alkyl; _3- alkyl, n is 0, 1, 2, or 3, R ⁹ is an amino-, C 1-3 -alkylamino-, di-C 1-8 -alkyl-amino-, phenylamino-, benzylamino- or C 1-4 -alkoxy-, 5- to 7-membered cycloalkyleneimine group, with the methylene group in position 4 of the piperidine group may be replaced by an oxygen or sulfur atom; -195 ♦ • · · · · · • • · · · · · -NH-, -N / (C _n _ ₃ alkyl) -, N / (phenyl) -, -NÍCva-alkyl-carbonyl) - or - N (benzoyl) - or, when n is 1, 2 or 3, R ⁹ may also be a hydrogen atom, a group of formula (III) in which: R ¹⁰ is hydrogen, C 1-3 -alkyl, C 1-3 -alkylcarbonyl, C 1-6 -alkyl; _3- alkylsulfonyl, m is 1, 2 or 3, o is 1 or, when m is 2 or 3, o may also be 0 and R ¹¹ represents amino-, C 1-6 alkyl; _3- alkylamino-, di- (C _1-3 -alkyl) -amino-, or a C 1-6 -alkoxy-C 1-6 -alkoxy-, or a 5- to 7-membered cycloalkyleneimine group, wherein the methylene group at the 4-position of the piperidine group may be replaced by an oxygen atom or sulfur, -NH-, - N (C _1-3 -alkyl) -, - N - (phenyl) -, N - (C _1-3 -alkylcarbonyl) - or - N - (benzoyl) -, C _4-7 -cycloalkylamino- or C4. ₇ -cycloalkenylamino- in which position 1 of the ring does not participate in the double bond, A 4 to 7 membered cycloalkyleneimine group in which the cycloalkylene moiety may be fused to a phenyl group or, one or two hydrogen atoms may each be replaced by a C 3 alkyl group, and / or the methylene group at the 3-position of the pyrrolidine group may be substituted by hydroxy or C 1-3 -alkoxy-, the methylene group at the 4-position of a six- or seven-membered cycloalkyleneimine group may be substituted by hydroxy, hydroxy-C 1-3 -alkyl, C _1-3 -alkoxy-, carboxy-, C _1-3 -alkoxycarbonyl-, aminocarbonyl-, C 1-3 -alkylamino ·· · φ · · · · φ φ φ · · φ · · · φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φ φφ φφφ ······ -196carbonyl, di- (C 1-3 -alkyl) aminocarbonyl-, phenyl-C 1-3 -alkylamino- or / - / - (C 1-3 -alkyl) -phenyl- C 1-3 -alkylamino-, or said methylene group it can be replaced by an oxygen or sulfur atom, by a sulfinyl-, sulfonyl-, -NH-, - (X) (C 1-3 -alkyl) -, N - (phenyl) -, N - (phenyl-C 1-3 -alkyl) group -, - N (C 1-3 -alkylcarbonyl) -, - N (C 1-4 -alkoxycarbonyl) -, - N (benzoyl) - or - N (phenyl-C _1-3 -alkyl-) wherein the methylene group bonded to the imine nitrogen atom of the cycloalkylenimine group may be replaced by a carbonyl group or a sulfonyl group, or in a 5- to 6-membered monocyclic or phenyl-fused cycloalkyleneimine group, both methylene groups may each be bonded to the imethylene groups or R ⁶ represents a C 1-4 -alkyl group which is substituted at the terminal part by a carboxyl group, a C 1-3 -alkoxycarbonyl-, an aminocarbonyl-, a C 1-8 -alkyl group a minocarbonyl- or di-C 1-6 -alkyl-aminocarbonyl- or a 4- to 7-membered cycloalkyleneiminocarbonyl group of the formula -N (R ¹² ) -CO- (CH ₂ ) _p -R ¹³ (IV) wherein R ¹² represents a hydrogen atom; _3- alkyl or C 3-8 -cycloalkyl, phenyl-C 1-3 -alkyl or heteroaryl-C _1-3 -alkyl and p is 0, 1, 2 or 3; and R ¹³ has the same meaning as R ⁷ , or when p is 1,2 or 3, R ¹³ can be a hydrogen atom, a group of the formula -N (R ¹⁴ ) - (CH ₂ ) _q - (CO) r - R ¹⁵ (V) in which t ·· ·· ···················· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · -197R ¹⁴ is H, CM-alkyl, Ci-3-alkylcarbonyl, phenylcarbonyl, phenyl-C ^ s-alkylcarbonyl, heteroarylcarbonyl, heteroaryl-C. ₃ -alkylcarbonyl group, a C 4 alkylsulfonyl, phenylsulfonyl, phenyl-C ₃ alkylsulphonyl group, a heteroarylsulfonyl group or a heteroaryl-C. _{3 is an} alkylsulfonyl group, q is 1, 2, 3 or 4, r is 1, or, when q is 2, 3 or 4, r is also 0 and R ¹⁵ has the same meaning as R ⁷ , as defined above, -N (R ¹⁶ ) -SO ₂ -R ¹⁷ (VI) wherein R ¹⁶ represents a hydrogen atom or a terminal C 1-6 alkyl group optionally substituted by cyano-, trifluoromethylcarbonylamino- or N - (C 1-3 alkyl) -trifluoromethylcarbonylamino- and R ¹⁷ is C 1-6. _3- alkyl, amino substituted by di- (C _1-3 -alkyl) -amino-C 1-3 -alkylcarbonyla or di- (C _1-3 -alkyl) -amino-C 1-3 -alkylsulfonyl- and di- (C _1-3 -alkyl) -aminocarbonyl-C 1-3 -alkyl, wherein all the radicals mentioned for R ⁶ containing single-bonded or fused phenyl groups may be mono- or di- substituted by a fluorine, chlorine or bromine atom, by a C _1-3 group -alkyl-, trifluoromethyl-, hydroxy-, C 1-6 alkyl; _3- alkoxy-, carboxy-, β-3-alkoxycarbonyl-, aminocarbonyl-, C 1-3 alkylamino-carbonyl-, aminosulfonyl-, C 1-3 -alkyl-aminosulfonyl-, nitro- or cyano-, wherein the substituents may be the same or different , or two adjacent hydrogen atoms of the phenyl group may be replaced by a methylenedioxy- group, and R ⁵ represents a hydrogen atom or a C 1-3 -alkyl group, said heteroaryl group being optionally in a carbon skeleton A C 1-3 -alkyl substituted pyridinyl-, pyrazinyl-, pyrimidinyl- group; Pyridazinyl-, pyrrolyl-, furyl-, thienyl-, oxazolyl-, thiazolyl-, pyrazolyl-, imidazolyl- or triazolyl-, in which one hydrogen atom attached to the nitrogen atom can be replaced by C 1-3 -alkyl or phenyl-C 1-6. A 3-alkyl group and wherein the five-membered heteroaryl groups containing at least one imino group are bonded via a carbon or nitrogen atom, in the above groups the hydrogen atom which is bonded to the nitrogen atom may be replaced by an in vivo leaving group in the above groups, which contain carboxyl groups, the carboxyl groups may be substituted in vivo by a leaving group, the hydrogen atoms in the above alkyl and alkoxy groups, or in the alkyl moieties of the above groups of formula I may be replaced wholly or partially by fluorine atoms and tautomers, diastereomers, enantiomers , mixtures thereof and salts thereof. The indolinones of formula I according to claim 1, wherein: X is an oxygen atom, R ¹ represents a hydrogen atom, R ² represents a carboxyl group, a straight or branched C 1-4 alkoxycarbonyl group or a phenoxycarbonyl group, a straight or branched C 1-3 alkoxycarbonyl group which is substituted in the terminal alkyl part by phenyl, carboxyl, C 1-3 alkoxycarbonyl, C 1-4 aminocarbonyl, a 1-3-alkylaminocarbonyl or di- (C 1-3 -alkyl) aminocarbonyl group, a straight or branched C 2-3 alkoxycarbonyl group which is substituted in the terminal alkyl moiety by a hydroxy-, C 1-6 -alkyloxycarbonyl group; _3- alkoxy-, amino-, C _1-3 -alkylamino- or di- (C _1-3 -alkyl) -amino-, aminocarbonyl or methylaminocarbonyl, ethylaminocarbonyl, which may optionally be substituted at the 2-position in the ethyl group with hydroxy - or C 1-3 -alkoxy-, provided that when R ^{3 is} not aminosulfonylphenyl or / (C 1 -C 5 -alkyl) - C 1-3 -alkylaminocarbonyl- phenyl, then R ² may also be di- (C 1-2) -alkyl) -aminocarbonyl, -199 ································· ··············································· R ³ represents a C 1-6 -alkyl or a phenyl group, which may be substituted by a fluorine, chlorine or bromine atom, a trifluoromethyl-, C 1-3 -alkyl-, hydroxy- or C 1-3 -alkoxy- group, R ⁴ represents a C 5-6 -cycloalkyl group wherein the methylene group at the 4-position of the cyclohexyl group may be substituted by amino-, C 1-3 -alkylamino- or di- (C 1-3 -alkyl) -amino-, or replaced by -NH - or - N - (C 1-3 -alkyl) -, phenyl, phenyl disubstituted with C 1-3 -alkyl-, C 1-3 alkoxy- or nitro-, wherein the substituents may be the same or different, or a phenyl group substituted with R ⁶ , wherein said phenyl group may additionally be substituted by a fluorine, chlorine or bromine atom or an amino- or nitro- group, wherein R ⁶ represents a fluorine, chlorine or bromine atom, a C 1-3 -alkyl group, a C 1-3 -alkoxy group, a nitro group, an amino group or a C 6-6 A 6-cycloalkyl group, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a triazolyl group or a tetrazolyl group bonded via a carbon atom, said heteroaromatic groups may be in the carbon skeleton substituted by C 1-6 alkyl; _{The 3-} alkyl group or one hydrogen atom bonded to the nitrogen atom may be replaced by a C _1-3 -alkyl group or a phenyl-C 1 group. _A C 3-6 alkyl group, a carboxy-, C 1-4 -alkoxycarbonyl-, phenyl-C 1-3 -alkyl-amino-carbonyl- or C 5-7 cycloalkyl-carbonyl-, a 5- or 6-membered cycloalkyleneimine group, wherein the methylene group at the 4-position of the piperidine group may be replaced by oxygen or sulfur, -NH- or -N (C _1-3 alkyl) -, ··· -200 unbranched C ₃ alkyl group, in the end portion substituted with R ^7, wherein R ⁷ is C _{5-_7} cycloalkyl, wherein the five or six membered cycloalkyl group may be - (CH 2) 2 group is replaced by -CO-NH-, - (CH 2) 3 can be replaced by -NH-CO- NH- and - (CH 2) 4 -NH-CO-NH-CO-, wherein the hydrogen atom bonded to the nitrogen atom can always be replaced by a C 1-3 -alkyl, phenyl or pyridinyl group, or via a carbon atom or a nitrogen atom pyrrole, pyrazolyl, imidazolyl or triazolyl, wherein said heteroaryl groups may be substituted in the carbon skeleton by a C 1-3 -alkyl group, or the hydrogen bonded to the nitrogen atom may be replaced by a C 1-3 -alkyl group, a hydroxy- or C 1-6 -alkyl group . _3- alkoxy-, amino-, C 1-6 -alkyl; _6- alkylamino-, di- (C _1-6 -alkyl) -amino-, phenylamino-, N -phenylC 1-3 -alkyl-amino-, phenyl-C 1-4 -alkylamino- or N - (C _1-3 -alkyl) ) -phenyl-C. ₃ -alkylamino, a group RO ₂ C-hydroxy-3-amino- / \ Z (Ci_3-alkyl) -O-hydroxy-C ₂ .3-alkylamino, di- (io-hydroxy-C 2-3 -alkyl) -amino or di- (co- (Ci_3-alkoxy) -C ₂ .3-alkyl) amino, C _{first 3-} alkylcarbonylamino-C 2-3 -alkyl-amino- or C 1-6 -alkylcarbonylamino; ₃ -alkylkarbonyla no _I-2 C-3-a I kyl -Λ / - (C 1-3 alkyl-Al) I-a mono-, a C-3-alkylsulfonylamino, /V-(Ci.3-alkyl) -Ci- -alkylsulfonylamino- _3, CF 3alkylsulfonylamino-C 2-3 -alkyl-amino, or C ₂ -C 3alkylsulfonylamino 3-alkyl / N (Ci-3-alkyl) amino, hydroxycarbonyl group, -C 1-3 -alkyl-amino- or N - (C 1-3 -alkyl) -hydroxycarbonyl-C 1-3 -alkyl-amino-, a guanidine group in which hydrogen may be replaced by a C 1-3 -alkyl- group of the formula -N (R ⁸ ) -CO- (CH ₂ ) _n -R ⁹ (II) • · · · · · • · · · ·· ·· • · • · • · • • · · · • · • · • · • · · • · · • · ·· · • · · • • · · · • · • • · • • · · • · · · • · • · · • · ··· · -201 in which R ⁸ represents a hydrogen atom or C 1-6 alkyl; _3- alkyl, n is 0,1,2, or 3, R ⁹ is amino-, C 1-6 alkyl; _3- alkylamino-, di- (C _1-3 -alkyl) -aminoor C 1-6 -alkoxy-, 5- to 7-membered cycloalkyleneimine group, wherein the methylene group at the 4-position of the piperidine group may be replaced by -NH-, -A) (C _1-3 -alkyl) - or - (C 1-6 -alkylcarbonyl) -, or when n is 1, 2, or 3, R ⁹ may also be hydrogen, a group of the formula -N (R ° ¹⁾ - (CH ₂₎ m - (CO) ,, - R (III) wherein R ¹⁰ is hydrogen or C _1-3 -alkyl, m is 1, 2, or 3, o is 1, or, when m is 2 or 3, o can also be 0 and R ¹¹ represents amino-, C 1-6 alkyl; _{A 3-} alkylamino-, di- (C _1-3 -alkyl) -amino-, C 1-4 -alkoxy- or methoxy-C _1-3 -alkoxy- group, or a 5- or 6-membered cycloalkyleneimine group, with the methylene group in the 4-position The piperidine group can in each case be replaced by -NH-, - N - (C _1-3 -alkyl) -, or - N - (C _1-3 -alkylcarbonyl) -, azetidino-, pyrrolidino-, piperidino-, 2,6 -dimethyl-piperidino-, 3,5-dimethyl-piperidino- or azepino-, wherein the methylene group at the 3-position of the pyrrolidine group may be substituted by hydroxy, the methylene group at the 4-position of the piperidine group may be substituted by hydroxy, hydroxy-C 1. _3- alkyl- or C 1-6 alkyl; ₃ -alkoxy-, or ······························· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · The -202methylene group may be replaced by an oxygen or sulfur atom, a sulfinyl-, sulfonyl-, -NH-, - N (C 1-3 -alkyl) -, -N (C 1-4 alkyl-carbonyl) -, N - (benzoyl) or - (4- (phenyl-C 6 -alkyl-carbonyl)) - wherein the methylene group bonded to the imine nitrogen atom of the pyrrolidine, piperidine or piperazine group may be replaced by a carbonyl group, or R ⁶ represents a unbranched C 1-6 alkyl; _{A 3-} alkyl group whose terminal moiety is substituted by a carboxyl or a C _1-3 -alkoxycarbonyl group, a group of the formula -N (R ¹² ) -CO- (CH ₂ ) _p -R ¹³ (IV) wherein R ¹² represents a hydrogen atom; _3- alkyl or phenyl-C _1-3 -alkyl, p is 0, 1 or 2; and R ¹³ represents amino-, C 1-4 -alkylamino-, di- (C 1-4 -alkyl) -amino-, benzylamino-, N - (C _1-3 -alkyl) -benzylamino, C 1-6 -alkyl; _3- alkoxy-Ci. _3- alkylamino- N - (C _1-3 alkyl) -C _1-3 -alkoxy-C 1-6 alkyloxy-; _3- alkyl-amino-, di- (2-methoxy-ethyl) -amino-, di- (to-hydroxyC _2-3 alkyl) -amino- or aminocarbonyl-methyl- N - (methyl) -amino-, via an atom a nitrogen-linked, optionally C _1-3 -alkyl-substituted, pyrrolyl, pyrazolyl or imidazolyl group, a pyrrolidino-, piperidino-, morpholino-, thiomorpholino- or piperazine-group, which is optionally substituted at the 4-position with a C _1-3 -alkyl- , phenyl-C _1-3 -alkyl-, C-. _3- alkylcarbonyl- or C 1-4 -alkoxycarbonyl- or, when n is 1 or 2, R ¹² may also represent a hydrogen atom, a group of the formula ((6- 6 - (^ 6), - (00), - ^ ⁵ (V) in which · · · · · · · ··· ············ -203R ¹⁴ is H, Ci-4-alkyl, Ci. _3- alkylcarbonyl, phenylcarbonyl, phenyl-C 1-6 alkyl; _3- alkylcarbonyl, furylcarbonyl, pyridinylcarbonyl, furyl-C _1-3 -alkylcarbonyl, pyridinyl-C _1-3 -alkylcarbonyl, C 1-4 -alkylsulfonyl, phenylsulfonyl or phenyl-C 1-3 -alkylsulfonyl, q is 1, 2 or 3, r is 1 or, when q is 2 or 3, r is also 0 and R ¹⁵ is amino-, C 1-6 -alkylamino-, di- (C 1-6 alkyl) -amino-. phenylamino-, N - (C 1-6 -alkyl-phenylamino-, benzylamino- or N - (C 1-6 -alkyl) -benzylamino-, or a group of formula -N (R ¹⁶ ) -SO ₂ -R ¹⁷ (VI) wherein R ¹⁶ represents a hydrogen atom or a terminal C 1-3 -alkyl group optionally substituted by cyano-, trifluoromethyl-carbonyl-amino- or N- (C 1-3 -alkyl) -trifluoromethyl-carbonyl-amino- and R ¹⁷ represents a C 1-3 -alkyl group, all of the radicals mentioned under R ⁶ containing single bonded or fused phenyl groups may be substituted by a fluorine, chlorine or bromine atom, a methyl-, trifluoromethyl-, methoxy-, nitro- or kayno group - a R ⁵ represents a hydrogen atom, wherein in the abovementioned radicals the hydrogen atom bound to the nitrogen atom may be replaced by an acetyl or tert-butoxycarbonyl group, the carboxyl groups in the abovementioned residues may also be in the form of tert-butoxycarbonyl precursor groups and tautomers, diastereomers, enantiomers , mixtures thereof and salts thereof. ♦ · · t t t t t t t t t t t t t t t t t t t t t t t t t t t t · ·· ·· ·· ··· ·· ···· -204- The indolinones of general formula I according to claim 1, in which X is an oxygen atom, R ¹ and R ⁵ are each a hydrogen atom, R ² is methoxycarbonyl, ethoxycarbonyl or aminocarbonyl, R ³ represents a phenyl group, R ⁴ represents a phenyl group which is monosubstituted by R ⁶ , wherein R ⁶ represents a N-methyl-imidazol-2-yl group, straight or branched C 1-6 alkyl; _{A 3-} alkyl group whose terminal moiety is substituted with a C 1-4 -alkylamino-, di- (C 1-4 -alkyl) -amino-, piperidino- or 2,6-dimethyl-piperidino-, a group of formula IV -N (R ¹² ) -CO- (CH ₂ ) _p -R ¹³ (IV) wherein R ¹² represents a C 1-3 -alkyl group, p is the number 1 or 2 a R ¹³ represents a di- (C _1-3 -alkyl) amino group or a group of formula V -N (R ') - (O'), - (00), - R ' ⁵ (V) in which R ¹⁴ is C 3 alkylcarbonyl or C 3 alkylsulfonyl group, q is 1, 2 or 3, r is 1, and when q is 2 or 3, r can also be 0, and R ¹⁵ represents di- (C _1-3 -alkyl) amino, their tautomers, diastereomers, enantiomers, mixtures thereof and salts thereof. • · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· ··· ·· ···· -205- 5. A compound according to claim 1 selected from the group consisting of: (a) 3-Z- [1- (4- (piperidin-1-yl-methyl) -anilino) -1-phenylmethylene-6-ethoxycarbonyl-2-indolinone, (b) 3 -Z - [(1- (4- (piperidin-1-ylmethyl) -anilino) -1-phenyl-methylene] -6-carbamoyl-2-indolinone, (c) 3-Z- [1- (4) - (piperidin-1-ylmethyl) -anilino-1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (d) 3-Z- [1- (4- (dimethylaminomethyl)) (anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (e) 3-Z- [1- (4 - ((2,6-dimethyl-piperidin-1-yl)) (methyl) -anilino-1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (f) 3-Z- [1- (4 - (N - (2-dimethylamino-ethyl)) - N -acetyl-amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (g) 3-Z- [1- (4 - (N - (3-dimethylamino-propyl)) (N -acetyl-amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (h) 3-Z- [1- (4- (N - (2-dimethylaminoethyl)) - (N-Methylsulfonylamino) anilino) -1-phenylmethylene- 6-ethoxycarbonyl-2-indolinone, (i) 3-Z- [1- (4- (dimethylaminomethyl) anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, Q) 3-Z- [1- (4- (N-acetyl-N-dimethylaminocarbonylmethyl-amino) -anilino) -1-phenylmethylene] 6-methoxycarbonyl-2-indolinone, (k) 3-Z- [1- (4-ethylaminomethyl-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (1) 3-Z- [1- (4- (1-methyl-imidazol-2-yl) -anilino)) -1-Phenylmethylene] -6-methoxycarbonyl-2-indolinone, (m) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl- N -methylamino) anilino) -1-phenylmethylene] -6-methoxycarbonyl-2- (n) 3-Z- [1- (4- (N - (2-dimethylaminoethyl) - N -methylsulfonylamino) anilino) -1-phenylmethylene] 6-methoxycarbonyl-2-indolinone, (o) 3-Z- [1- (4 - (/ V- (3-dimethylaminopropyl) - / \ / - methylsulfonyl-amino) anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, -206 ·· ····································· (P) 3-Z- [1- (4- (N-dimethylaminocarbonylmethyl) - N -methylsulfonyl-] - (p) 3-Z- amino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (q) 3-Z- [1- (4 - (N - ((2-dimethylamino-ethyl) -carbonyl) - N) -] (methyl-amino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (R) 3-Z- [1- (4 - (N - (2-dimethylaminoethyl)) - N - acetyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone and (s) 3-Z- [1- (4-methylaminomethyl-anilino) -1-phenyl-methylene] -6-methoxycarbonyl- 2-indolinone, tautomers thereof, mixtures thereof and salts thereof. Physiologically acceptable salts of substituted indolinones according to claims 1 to 6 5th A pharmaceutical composition comprising an indolinone according to at least one of claims 1 to 5 or a salt according to claim 6 optionally with one or more carriers and / or diluents. Use of indolinones according to at least one of claims 1 to 5 or a salt according to claim 6 in the manufacture of a medicament for the treatment of excessive or anomalous cell proliferation. A process for the preparation of a pharmaceutical composition according to claim 7, characterized in that the indolinone according to at least one of claims 1 to 5 or the salt according to claim 6 is incorporated into one or more inert carriers and / or diluents in a non-chemical manner. Process for the preparation of indolinones according to claims 1 to 6, characterized in that (a) to the compound of the general formula VII -207- R ³ (VII) wherein X and R ³ are as defined in claims 1 to 5, R ² 'is defined as R ² in claim 1 to 5, R ¹⁸ represents a hydrogen atom or a nitrogen protecting group of the lactam group, wherein one of the radicals R ² 'and R ¹⁸ can optionally form a solid phase bond via a Spacer and the other of the radicals mentioned above, and Z ¹ represents an atom halogen, a hydroxy-, alkoxy- or arylalkoxy- group, is treated with an amine of formula VIII (VIII) R ⁴ in which R ⁴ and R ⁵ are as defined in claims 1 to 5 and, if desired, subsequently cleavage of the nitrogen protecting group of the lactam group or followed by cleavage from the solid phase, (b) for the preparation of a compound of formula I in which R ² is a carboxyl group other than specified in claims 1 to 5, resulting in a conversion of IX -208R ³ HOOC (IX) in which R ¹ and R ³ to R ⁵ are as defined in claims 1 to 5, or a reactive derivative thereof with a compound of formula X H - R ¹⁹ (X) in which R ¹⁹ is C 6 alkanol, C ₄ 7-cycloalkanol or an aromatic alcohol, C 1-6 -alkanol, which is substituted in the terminal alkyl moiety by phenyl, heteroaryl, carboxyl, C 1-3 -alkoxycarbonyl, aminocarbonyl, C 1-6 -alkanol; _3- alkylaminocarbonyl or di- (C 1-3 -alkyl) aminocarbonyl, C 1-6 -alkanol substituted in the terminal alkyl moiety with a chlorine atom or a hydroxy- group, C 1-6 -alkanol; _3- alkoxy-, amino-, C 1-6 -alkyl; _3- alkylamino- or di- (C _1-3 -alkyl) amino-, amino, or methylamino, ethylamino which optionally may be substituted in the 2-position of the ethyl group by hydroxy or C 1-6 alkyl; _3- alkoxy-, or di- (C 1-2 -alkyl) amino, or (c) for the preparation of a compound of formula I wherein R ⁴ is C 1-4 -alkyl substituted by R ⁷ , wherein: ·· ·· ··· · -209R ⁷ is an amino, C. _7- alkylamino-, di- (C _1-7 -alkyl) -amino-, phenylamino-, N -phenyl-C 1-8 -alkyl-amino-, phenyl-C 1-6 -alkyl- _3- alkyl-amino-, N- (C _1-3 -alkyl) -phenyl-C 1-3 -alkylamino- or di- (phenyl-C _1-3 -alkyl) -amino-, ω-hydroxyxy-C 2-3 -alkyl amino, A / - (Cl. ₃ alkyl) -O-hydroxy-C 2-3 alkylamino, di- (o-hydroxy-C 2-3 alkyl) amino, di (ro- (C .3 alkoxy) -C ₂ .3 alkyl) -aminoalebo A / - (dioxolan-2-yl) -C. _{3-alkyl-amino,} a C-3-alkylcarbonylamino-C2-3-alkyl-amino or Cf-3-alkylcarbonylamino-C2-alkyl ₃ - / \ / - (Ci.3 alkyl) amino, C1-3-alkylsulfonylamino-, N- (C1-3-alkyl) -C1. ₃ -alkylsulfonylamino-, C1.3alkylsulfonylamino-C2-alkyl _3-amino or C. _{3-alkylsulfonylamino} C 2-3 alkyl / N (Cl. ₃ alkyl) amino, a group of formula III -N (R ¹⁰⁾ - (CH _{2) m} - (CO) _a R ¹¹ (HI) wherein R ¹⁰ is H, C. _3- alkyl, C _1-3 -alkylcarbonyl, arylcarbonyl, phenyl-C _1-3 -alkylcarbonyl, C 1-6 -alkyl; _3- alkylsulfonyl, arylsulfonyl or phenyl-C _1-3 -alkylsulfonyl, m is 1, 2, 3 or 4, o is 1 and R ¹¹ represents amino-, C 1-6 alkyl; _4- alkylamino-, di- (C 1-4 -alkyl) -amino-, phenylamino-, N - (C 1-4 -alkyl) -phenylamino-, benzylamino-, N - (C _1-4 -alkyl) benzylamino-, C 1-6 -alkoxy- or C 1-6 -alkyl; _3- alkoxy-Ci. _{A 3-} alkoxy-, optionally C _1-3 -alkyl- substituted in the 1-position by a di (C 1-4 -alkyl) -amino-C 1-3 -alkylamino- or 4- to 7-membered cycloalkyleneimine group, wherein the cycloalkylene moiety may be condensed with a phenyl ring, or a methylene group at the 4-position of a 6-membered or 7-membered cycloalkylenimine group may be replaced by an oxygen or sulfur atom, · · · -210sulfinyl-, sulfonyl-, -NH-, - N - (C _1-3 -alkyl) -, - N - (phenyl) -, - N - (C _1-3 -alkylcarbonyl) - or - N - (benzoyl) - , C4-7-cycloalkylamino-, C4-7-cycloalkyl-C1-4alkyl; ₃ -alkylamino or C4.7cykloalkenylamino-, wherein the position of the ring 1 not involved in the double bond, and wherein said radicals may be additionally substituted at the amino nitrogen atom by _C-5 .7 cycloalkyl, _C2 -4 alkenyl or-CM -alkyl-, or a 4 to 7 membered cycloalkyleneimine group, the cycloalkylene moiety of which may be fused with a phenyl group, or with an oxazolo-, imidazolo-, thiazolo-, pyridino-, pyrazino- or pyrimidino- group optionally substituted by a fluorine, chlorine, bromine atom or iodine, nitro-, C _1-3 -alkyl-, C _1-3 -alkoxy or amino and in which one or two hydrogen atoms may be replaced by C 1-3 -alkyl, C 5-7 -cycloalkyl or phenyl, and / or whose methylene the group at the 3-position of the five membered cycloalkyleneimine group may be substituted by hydroxy-, hydroxy-C 1. C ₃ alkyl; _{A 3-} alkoxy- or C 1-3 -alkoxy-C 1-3 alkyl group in which the methylene group at the 3- or 4-position of the 6-membered or 7-membered cycloalkyleneimine group may be substituted with a hydroxy group, the hydroxy-C 1-6 alkyl group; _{A 3-} alkyl group, a C 1-3 alkoxy-, a C 1-3 -alkoxy-C 1-6 -alkyl group; _3- alkyl, C 1-4 -alkoxycarbonyl-, aminocarbonyl-, C 1-3 -alkylaminocarbonyl-, di- (C _1-3 -alkyl) -aminocarbonyl-, phenyl-C ₁ . _3- alkylamino- or N - (C _1-3 -alkyl) -phenyl-C 1-6 alkyl; _3- alkylamino-, or said methylene group may be replaced by oxygen or sulfur, sulfinyl-, sulfonyl-, -NH-, - (V (C 1-3 -alkyl) -, -A / (phenyl) -, -) N (phenyl-C _1-3 -alkyl) -, N - (C _1-3 -alkylcarbonyl) -, N - (C 1-4 -alkoxycarbonyl) -, N - (benzoyl) - or -A / (phenyl-C _1-3 -alkylcarbonyl) wherein the methylene group that is bonded to the imine nitrogen atom of the cycloalkylenimine group may be a 4-membered group. • 4 4 ·· · 4 · 44 ··· · 4 · 4 ··· 44 44 ·· ··· ······ -211 replaced by carbonyl or sulfonyl, or in a 5- to 7-membered monocyclic or phenyl-fused cycloalkylenimine group, both methylene groups bound by an imine nitrogen atom can be replaced by carbonyl groups, the compound of formula XI ³ R ⁵ is converted R ¹⁸ in which R ¹ , R ⁵ and X are as defined in claims 1 to 5, R ² 'has the same meaning as R ² in claims 1 to 5, R ¹⁸ represents a hydrogen atom or a nitrogen protecting group of the lactam group, wherein one of the radicals R ^2, and R ¹⁸ can optionally form a solid phase bond via the Spacer and the other of the radicals mentioned above, and A represents C 1-4; an alkyl group; and Z ² is a displaceable group, with an amine of formula XII H - R ⁷ '(XII) wherein R ⁷ 'has the same meaning as R ⁷ above 9 9 212 and, if desired, cleavage of the protecting group used from the nitrogen atom of the lactam group or from the solid phase; if the compound of formula I contains an alkoxycarbonyl group, it may be converted to the corresponding carboxyl compound by hydrolysis, or if the compound of formula I contains an amino- or alkylamino- group, the compound may be converted by reductive alkylation to the corresponding alkylamino- or dialkylamino- compound, or if the compound of formula I prepared contains an amino- or alkylamino- group, this compound can be converted to the corresponding acyl- or sulfonyl compound by acylation or sulfonation, or if the compound of formula I contains a carboxyl group by esterification or amidation, it can be converted to the corresponding ester or aminocarbonyl compound, or if the compound of formula I prepared contains a cycloalkyleneimine group in which one methylene group is replaced by a sulfur atom, the compound may be converted to the corresponding having a sulfinyl or sulfonyl compound, or if the compound of formula I contains a nitro group, this compound can be converted to the corresponding amino compound by reduction or a compound of formula I in which R ⁴ is an amino-, alkylamino-, aminoalkyl- or N-alkyl group an amino-substituted phenyl group may be subsequently converted into the corresponding urea compound of the formula I by conversion with an appropriate cyanate, isocyanate or carbamoyl halide, or a prepared compound of the formula I wherein R ⁴ is amino, alkylamino, aminoalkyl or an alkyl-amino-substituted phenyl group may be subsequently converted to the corresponding guanidine compound of formula I by treatment with the appropriate amidine transfer group or the corresponding nitrile, or, if desired, cleavage of the protecting group used during conversion n and the protection of reactive groups, or · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ···················································· If desired, the prepared compound of formula I is subsequently resolved into its stereoisomers, or the prepared compound of formula I is converted into its salts, in particular for pharmaceutical use, into physiologically acceptable salts with an inorganic or organic acid or base.