SK287312B6 - 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), 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 and a method for the production thereof.

Description

The invention relates to the 6-substituted indolinones of their tautomers and salts, in particular to physiologically acceptable salts having valuable properties, to a process for their preparation and to their use.

BACKGROUND OF THE INVENTION

Compounds of formula (I)

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 on 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 viral cyclins (see Mengtao L. in J. Virology 71 (3), 1984-1991 (1977)), further on proliferatively cultured human cells, in particular on endothelial cells, for example in angiogenesis, but also for the proliferation of other cells, especially tumor cells.

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

SUMMARY OF THE INVENTION

The present invention provides the indolinones of formula (I),

R ³ I / ^R!

(I) in which

X is an oxygen or sulfur atom,

R ¹ is H or a C ₄ -alkoxycarbonyl or C _{2nd A 4-} alkanoyl group,

R ² is carboxy, straight or branched Cj.e alkoxy-carbonyl group, a C ₄ _ ₇ cycloalkoxy-carbonyl or aryloxy carbonyl group, a linear or branched C ^ -alkoxy-carbonyl, which is the terminal alkyl substituted with phenyl, heteroaryl, carboxyl, C ₁ . _{A 3} -alkoxycarbonyl group, an aminocarbonyl group, a C 1-6 alkyl group; ₃ -alkylamino-carbonyl or di- (C ₃ alkyl) amino-carbonyl, linear or branched C _{2nd A 6} -alkoxycarbonyl group which is substituted in the terminal alkyl moiety by a chlorine atom or a hydroxy-, C _1-3 -alkoxy-, amino-, C 1-6 -alkyloxy group; _3- alkylamino- or di- (C _1-3 -alkyl) -amino, aminocarbonyl or methylaminocarbonyl, ethylaminocarbonyl optionally in the 2-position of the ethyl-substituted with hydroxy- or C 1-6 -alkyl. _3- alkoxy,

R ³ represents a hydrogen atom, C ₁ . _6- alkyl, C ₃ . _7- cycloalkyl, trifluoromethyl or heteroaryl, phenyl or naphthyl, phenyl or naphthyl mono- or di-substituted by fluorine, chlorine, bromine or iodine, trifluoromethyl, C _1-3 -alkyl- or C _1-3 -alkyl; ₃ alkoxy-, wherein in the case of disubstitution the substituents may be the same or different and wherein the abovementioned unsubstituted as well as mono- and di-substituted phenyl or naphthyl groups may additionally be substituted by hydroxy, hydroxy-C ₃ alkyl- or C _{I. 3} -alkoxy-C _{first 3} alkyl-, cyano group, carboxy, carboxy-Cl alkyl, C ₃ -alkoxycarbonyl-, amino-carbonyl, C _{first 3-} alkylaminocarbonyl- or di- (C _1-3 -alkyl) -aminocarbonyl, nitro-, amino-, C). _3- alkylamino-, di- (C _1-3 -alkyl) -amino or amino-C ₁ . _3- alkyl, C ₁ . _3- alkylcarbonylamino-, N - (C _1-3 -alkyl) -C ₁ . _3- alkylcarbonylamino-, C _1-3 -alkylcarbonylamino-C 1-6 alkylcarbonylamino-; ₃ alkyl-, 7V- (Ci. ₃ alkyl) ₃ -Ci_ alkylcarbonylamino-C ₃ alkyl-, C ^ -alkylsulfonylamino-, C ₃ -C alkylsulfonylamino. _3- alkyl, A- (C _1-3 -alkyl) -C ₁ . _3- alkylsulfonylamino-C _1-3 -alkyl- or aryl-C 1-6 -alkyl; ₃ -alkylsulfonylamino-, cycloalkylamino-, cycloalkylenimino-, cycloalkylenimino-carbonyl-, cycloalkylenimino-C 1 -C 3 -alkylsulfonylamino-; _3- alkyl-, cycloalkyleneiminocarbonyl-C 1. _3- alkyl or cycloalkyleneiminosulfonyl-C 1-6 alkyl; _{A 3-} alkyl group having from 4 to 7 ring members, the methylene group in the 4-position of the 6 or 7 membered cycloalkyleneimino group being replaced by an oxygen or sulfur atom, a sulfinyl-, sulfonyl-, -NH- or -N- (C 1-6 -alkyl) - or a heteroaryl group or a heteroaryl-C _{1 group} . _3- alkyl,

^R4 is _C3 _7 cycloalkyl group wherein a methylene group in the 4-position six or seven membered cycloalkyl group can be replaced by amino, C ^ -alkylamino group or a di (C ₃ alkyl) amino, or may be substituted with -NH- or -N (C _1-3 -alkyl) -, or represents a phenyl group substituted with R ⁶ , wherein the phenyl group may additionally be mono- or di- substituted with a fluorine, chlorine, bromine or iodine atom, with a C _1-5 group - alkyl-, trifluoromethyl-, hydroxy-, C1-6alkyl- ₃ -alkoxy, carboxy, C _{l. 3-} alkoxycarbonyl-, amino-, acetylamino-; _3- alkyl-sulfonyl-amino-, aminocarbonyl-, C _1-3 -alkyl-aminocarbonyl-, di- (C _1-3 -alkyl) -aminocarbonyl-, amino-sulfonyl-, C 1-6 -alkyl-; _3- alkylaminosulfonyl-, di- (C _1-3 -alkyl) -aminosulfonyl-, nitro- or cyano-, wherein the substituents may be the same or different and wherein

R ⁶ represents a hydrogen, fluorine, chlorine, bromine or iodine atom, a cyano-, nitro-, amino-, C _1-5 -alkyl-, C _{3 group} . _7- cycloalkyl-, trifluoromethyl-, phenyl-, tetrazolyl- or heteroaryl, a group of the formula

wherein the hydrogen atoms attached to the nitrogen atom may be replaced independently of one another by a C 33 -alkyl group,

A C 1 -alkoxy group, a C _1-3 -alkoxy-C 1-6 alkyl group; _3- alkoxy, phenyl-C _1-3 -alkoxy, amino-C ₂ . ₃ -alkoxy, C _{first 3} -alkylamino-C _{2nd 3-} alkoxy, di- (C _1-3 -alkyl) -amino-C ₂ . _3- alkoxy, phenyl-C 1. ₃ -alkylamino-C _{2nd 3-} alkoxy, N - (C 1-3 -alkyl) -phenyl-C 1-6 alkyl; ₃ -alkylamino-C _{2nd 3} -alkoxy, C 5-7 -cycloalkyl-C-alkylene imino _{second A 3-} alkoxy group or a C 1-6 group; _3- alkylmercapto-, carboxyl, C1-6alkyl; _{A 4-} alkoxycarbonyl group, an aminocarbonyl group, a C 1-6 alkyl group; ₃ -alkylamino-carbonyl, N- (C _l _ ₅ alkyl) -C |. _3- alkylaminocarbonyl, phenyl-C _1-3 -alkylamino-carbonyl, N- (C _1-3 -alkyl) -phenyl-C 1-6 -alkylaminocarbonyl; _3- alkyl-aminocarbonyl, piperazinocarbonyl or N - (C 1-3 -alkyl) piperazinocarbonyl,

C 1-6 -alkylaminocarbonyl or N - (C 1-5 -alkyl) - C 1. _{A 3-} alkylaminocarbonyl group in which the alkyl moiety is substituted with a carboxyl group or a C 1-6 alkyl group; ₃ alkoxycarbonyl group or in the 2 or the group di- (C ₃ -alkyl) -amino, piperazino group, a group <N (C _l _3-alkyl) -piperazino- or a four to seven membered cykloalkyléniminovou group,

C ₃ . _{7-cycloalkyl-carbonyl} group, wherein the methylene group in the 4-position six or seven membered cycloalkyl moiety may be substituted by amino, C ₃ -alkyl-amino group, or di- (C _{first 3} alkyl) amino, or substituted -NH- and -A ^I (c _{first 3} alkyl) -, up to 7 membered cykloalkylénimínovú group, the imino group is bound to the methylene group can be replaced by a carbonyl group or a sulfonyl group, wherein a cycloalkylene moiety may be fused with 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 a carboxyl group, C 1-6 -alkyl; _3- alkoxycarbonyl, aminocarbonyl, Ci. _3- alkyl-aminocarbonyl, di- (C 1-6 -alkyl) -aminocarbonyl, phenyl-C _1-3 -alkylamino or N - (C _1-3 -alkyl) -phenyl-C 1-6 -alkylamino; _3- alkyl-amino, or it may be replaced by an oxygen or sulfur atom, sulfonyl-, sulfonyl-, -NH-, -N (C _1-3 -alkyl) -, -7 N (phenyl) -, -V (C 1 -C ₃ -alkyl); _3- alkyl-carbonyl) - or -TV (benzoyl) -C 1-6 alkyl. _{A 4-} alkyl group substituted with R ⁷ wherein

R ⁷ is C ₃ . _{The 7-} cycloalkyl group, wherein the methylene group at the 4-position of the 6 or 7 membered cycloalkyl group may be substituted with an amino group, C 1-6 -cycloalkyl. _3- alkylamino, di- (C _1-3 -alkyl) -amino, or replaced by -NH- or -7V (C _1-3 -alkyl) -, in the 5-7 membered cycloalkyl group there may be one - (CH _{2) 12} - 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 attached to the nitrogen atom may be replaced by a C 1-3 -alkyl group, an aryl or heteroaryl group, a hydroxy- or C 1-6 -alkyl group. _3- alkoxy-, amino-, C _1-7 -alkylamino-, di- (C _1-7 -alkyl) -amino-, phenylamino-, 7 H -phenyl-C 1-6 -alkyloxy-; N-alkyl-amino-, phenyl-C 1-6 -alkyl-amino-, N - (C 1-6 -alkyl) -phenyl-C 1-6 -alkyl-amino- or di- (phenyl-C _1-3 -alkyl) -amino- , a> _{hydroxy-C2. 3} -alkylamino, ^R, - (Cl. ₃ alkyl) _{-R-hydroxy-C2. 3} -alkyl-amino, di- _{(co-hydroxy-C2. 3-alkyl)} amino, di (CO- (C ₃ alkoxy) C _{2. 3} alkyl) -amino or N- (dioxolan-2-yl) -C. ₃ -alkyl-amino, is C]. -C ₃ alkylcarbonylamino _{second 3} -alkyl-amino or C |. _{3 -alkylcarbonyl-amino-C2.} A _3-alkyl ^/ - (C | _ ₃ alkyl) amino group, no. ₃ -alkylsulfonylamino-, N- _{(C1. 3} alkyl) C |. _{3-alkyl-sulfonylamino,} C |. ₃ -C alkylsulfonylamino _{second 3} -alkyl-amino or C _{l. 3} - _{alkylsulfonylamino-C2. 3} alkyl- / N _{(C1. 3} alkyl) amino group, a hydroxycarbonyl-Ci.3-alkylamino or N- (Ci. ₃ alkyl) hydroxy-carbonyl-C _t . ₃ -alkyl-amino, guanidino, wherein one or two hydrogen atoms may each be replaced by _{C1. 3} -alkyl, a group of formula

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

R ⁸ is hydrogen or C _1-3 -alkyl, n is 0, 1, 2, or 3,

R ⁹ represents an amino, a C ₄ -alkylamino, di (C _l _ ₄ alkyl) amino, phenyl-amino, TV- (C ₄ alkyl) -fenylamino-, benzylamino, / N _{(C1. 4} alkyl) _or C -benzylamino-. _{A 4-} alkoxy-, 4- to 7-membered cycloalkyleneimine group, wherein the methylene group at the 4-position of the six- or seven-membered cycloalkyleneimine group may be replaced by an oxygen or sulfur atom, a sulfinyl-, sulfonyl-, -NH-, -TV (Ci) . ₃ alkyl) -, -N (phenyl) -, - / V _{(C1. 3} alkyl-carbonyl) - or -N (benzoyl) -, or when n is 1, 2, or 3 denotes also a hydrogen atom, a group of formula

-N (R ¹⁰ ) - (CH ₂ ) _m - (CO) _O -R ¹¹ (III) in which

R ¹⁰ represents a hydrogen atom, a C _1-3 -alkyl group, a C 1-6 alkyl group or a C _1-3 alkyl group; ₃ -alkylcarbonyl, arylcarbonyl, phenyl-C 1. _{A 3-} alkyl-carbonyl group, a C _1-3 -alkylsulfonyl group, an arylsulfonyl group or a phenylC 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 an amino, C] .4-alkylamino, di- (C1-4-alkyl) amino, phenyl-amino, A ^/ - (C | .4-alkyl) -fenylamino-, benzylamino _N - (C _1-4 -alkyl) -benzylamino-, C 1 -. _4- alkoxy- or C ₁ . ₃ -alkoxy-C _I _ ₃ -alkoxy, optionally a C ₃ in the 1-alkyl-substituted group di- (C. _4-alkyl) amino-C. _{A 3-} alkylamino- or 4- to 7-membered cycloalkylene-imine 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 oxygen or sulfur; -, -NH-, -TV (C _1-3 -alkyl) -, -N (phenyl) -, -TV (C _1-3 -alkylcarbonyl) - or -Mbenzoyl) -, C 4-7 -cycloalkylamino-, C 1-4- -cycloalkyl-C 1-6 -alkylamino- or C 1-6 -cycloalkenylamino- in which the 1-position of the ring does not participate in the double bond and wherein said groups may additionally be substituted on the amino nitrogen atom by a C ₅ group. ₇ -cycloalkyl- C _{2nd 4-} alkenyl- or C 1. _{A 4-} alkyl-, up 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 or iodine, nitro-, C _1-3 -alkyl-, C 1-4 -alkoxy or amino, and / or whose one or two hydrogen atoms may be replaced by C _1-3 -alkyl, C _5-6 . _{A 7-} cycloalkyl or phenyl group, and / or wherein the methylene group at the 3-position of the five-membered cycloalkylenimine group may be substituted by hydroxy, hydroxy-C _1-3 -alkyl, group C 1. _3- alkoxy- or C1-7. _3- alkoxy-Ci. _{A 3-} alkyl group whose methylene group at the 3- or 4-position of a six or seven membered cycloalkyleneimine group may be substituted by a hydroxy group, a hydroxy-C _1-3 -alkyl group, a C 1 group. _3- alkoxy- or C _1-3 -alkoxy-C 1-6 alkyl; _3- alkyl, carboxyl, C 1-6 alkyl; ₄ -alkoxycarbonyl-, aminocarbonyl-, C ₃ -alkyl-aminocarbonyl, di- (C _{first 3} -alkyl) aminocarbonyl-, phenyl-C ₁₃ alkylamino- or N - (C _l _ ₃ alkyl) phenyl -C. _3- alkylamino-, or said methylene group may be replaced by an oxygen or sulfur atom, sulfinyl-, sulfonyl-, -NH-, - N (C _1-3 -alkyl) -, -X (phenyl) -, -A / (phenyl-C |. ₃ alkyl) -, -In (C ₃ alkylcarbonyl) -, N / FCJ -hydroxykarbonyl ^) -, - / V (C | _ ₄ alkoxycarbonyl) -, -N (benzoyl ) - or -V (phenyl-C _1-3 -alkylcarbonyl) -, wherein the methylene group attached 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 condensed group the cycloalkylenimine group of the two methylene groups bonded to the imine nitrogen atom may be replaced by a carbonyl group, or R ⁶ represents C ₁ . _{A 4-} alkyl group which is substituted by a carboxyl group, a C _1-3 -alkoxycarbonyl group, an aminocarbonyl group, a C _1-3 -alkylaminocarbonyl group or a di- (C _1-3 -alkyl) aminocarbonyl group or a 4-7 membered cycloalkyleneiminocarbonyl group, V- group; (C _{first 3} -alkyl) -C _{second 4-} alkanoylamino-, which is in addition to the alkyl moiety 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 represents a hydrogen atom; _6- alkyl or C ₃ . _7- cycloalkyl, or terminal C _1-3 -alkyl, substituted with phenyl, heteroaryl, trifluoromethyl, hydroxy, C _1-3 -alkoxy, aminocarbonyl, C 1-6 -alkyl; _4- alkylamino-carbonyl, di- (C _1-4 -alkyl) aminocarbonyl, C _1-3 -alkyl-carbonyl, C _1-3 -alkylsulfonyl-amino, N - (C 1 -alkyl) -C 1-6 -alkyl -sulfonyl-amino, 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 can be hydrogen, a group of the formula

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

R ¹⁴ represents a hydrogen atom, C 1. _4- alkyl, C ₁₃ -alkylcarbonyl, arylcarbonyl, phenyl-C 1. _3- alkylcarbonyl, heteroarylcarbonyl, heteroaryl-C 1-6 alkyl; _{A 3-} alkylcarbonyl group, a C _1-4 alkylsulfonyl group, an arylsulfonyl group, a phenyl-C 1-6 alkyl group; ₃ -alkylsulfonyl, heteroarylsulfonyl or heteroaryl-C _1-3 -alkylsulfonyl, q is 1, 2, 3 or 4, r is 1, or when q is 2, 3 or 4, r is also number 0 a

R ¹⁵ has the same meaning as R ⁷ , the group of formula

-N (R ¹⁶⁾ - SO ₂ - R ¹⁷ (VI), wherein

R ¹⁶ represents a hydrogen atom or a terminal C 1. _{A 4-} alkyl group optionally substituted by cyano-, trifluoromethyl-carbonyl-amino- or N - (C _1-3 -alkyl) -trifluoromethyl-carbonyl-amino- and

R ¹⁷ is C _1-3 -alkyl, amino substituted with di- (C _1-3 -alkyl) -amino-C _1-3 -alkyl-carbonyl- or di- (C _1-3 -alkyl) -amino-C 1. _{3-alkyl-sulfonyl} group and a di- (Ci. ₃ alkyl) aminocarbonyl-C ₃ alkyl-, or a group A'XCu -alkyl is C ^ -alkylsulfonylamino- and 7V- (C]. 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 fluorine, chlorine, bromine or iodine, by C _{first 5-} alkyl-, trifluoromethyl-, hydroxy-, C _1-3 -alkoxy-, carboxy-, C _1-3 -alkyl-; _3- alkoxycarbonyl-, aminocarbonyl-, Ci. ₄ alkylaminocarbonyl, di (C _{first 4} -alkyl) -amino-carbonyl, aminosulfonyl, C _{first 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 the two adjacent hydrogen atoms of the phenyl group may be replaced by methylenedioxy-, a

R ⁵ represents a hydrogen atom or a C _1-3 -alkyl group, the term aryl being 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 1-6 -alkyl-; _3- alkoxy- and the term heteroaryl means a monocyclic five- or six-membered heteroaryl group, optionally substituted in the carbon residue by C 1-6. ₃ -alkyl, wherein said six-membered heteroaryl containing one, two or three nitrogen atoms and five-membered heteroaryl group contains an imino group optionally substituted by a C ₃ -alkyl or phenyl-C [. _{A 3-} alkyl group, an oxygen or sulfur atom, or an imino group optionally substituted by C 1-6 alkyl; ₃ -alkyl or phenyl-C ₃ -alkyl, or O or S, and also N, or NH optionally substituted by C _b3 -alkyl or phenyl-C ₃ -alkyl, and two nitrogen atoms, and the addition may be to said monocyclic heterocyclic groups via two adjacent carbon atoms a fused phenyl ring and the bond occurs through the nitrogen atom or through the carbon atom of the heterocyclic moiety or the fused phenyl ring, the hydrogen atoms in said alkyl and alkoxy groups or in the alkyl moieties of designated groups of formula (I) be partially or totally replaced by fluorine atoms, and any carboxyl group present in said groups may be replaced by a tert-butoxycarbonyl precursor group, and

each of the hydrogen atoms attached to the nitrogen atom may be replaced by hydroxy, benzoyl, pyridinoyl, formyl, acetyl, propionyl, butanoyl, pentanoyl, hexanoyl, allyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, isopropoxycarbonyl, isopropoxycarbonyl, , nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl, hexadecyloxycarbonyl, benzyloxycarbonyl, phenylethoxycarbonyl, phenylpropoxycarbonyl, C _1-3 -alkylsulfonyl-C ₂ . ₄ -alkoxycarbonyl, C ₃ -C -alkoxy _{second 4} -alkoxy-C _{2nd A 4-} alkoxycarbonyl group or a R ^e CO-O- (R ^f CR ^g ) -O-CO- group in which

R ^e is Cj.g-alkyl, C5-7-cycloalkyl, phenyl or phenyl-C [.3 alkyl group, R ^f is hydrogen, Ci_3-alkyl, _{C5. 7} -cycloalkyl or phenyl; and R ⁸ represents a hydrogen atom or a C 1-6 alkyl group. _{A 3-} alkyl group, tautomers and salts thereof.

A notable sub-group 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 a straight or branched C _1-6 -alkoxycarbonyl group, C ₄ . ₇ cyclo-alkoxycarbonyl or aryloxycarbonyl group, straight or branched C _{first A 6-} alkoxycarbonyl group which is substituted at the alkyl terminus with a phenyl-, heteroaryl-, carboxy-, C 1-6 -alkyl group; _3- alkoxycarbonyl-, aminocarbonyl-, C _1-3 -alkylaminocarbonyl- or di- (C _1-3 -alkyl) aminocarbonyl-, branched or branched C ₂ . _{A 6} -alkoxycarbonyl group which is substituted in the alkyl terminus by a chlorine atom or by a hydroxy- group, C 1-6. ₃ -alkoxy, amino, C ₃ -alkylamino or di- (C ₁ _ ₃ alkyl) amino, the tautomers and the salts thereof.

A second notable sub-group 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 an 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 amino-sulfonylphenyl- or a - (C 1-6-) group alkyl-C 1-6 -alkylaminocarbonyl-phenyl-, R ² may also be a di- (C _1-2 -alkyl) -aminocarbonyl group, their tautomers 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 a R ⁷ - (C _1-4 -alkyl) -phenyl group in which

R ⁷ is amino-, C 1-7 -alkylamino-, di- (C 1-7 -alkyl) -amino-, phenyl-amino-, N ^, -phenyl-C 1-3 -alkyl-amino-, phenyl-C 1-7 -alkyl- _{3-alkyl-amino,} and ^L - _{(C1. 3} alkyl) -phenyl-C. _3- alkylamino- or di- (phenyl-C _3-3 -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 carboxy, straight or branched C [. ₆ -alkoxycarbonyl, C ₅ . _7- cycloalkoxycarbonyl or phenoxycarbonyl, unbranched or branched C1. ₃ -alkoxycarbonyl which is substituted in the terminal alkyl moiety by phenyl, heteroaryl, carboxy, C _{( 3} -alkoxycarbonyl, aminocarbonyl, C 1-6 alkylaminocarbonyl or di- (C 1) ₃ ). alkyl) amino-carbonyl group, straight or branched _{C2. 3} -alkoxy-carbonyl group which is substituted with an alkyl end portion with chloro, hydroxy, C [. ₃ -alkoxy, amino, _{C1. 3-} alkylamino- or di- (C _1-3 -alkyl) -amino-, aminocarbonyl or methylaminocarbonyl, ethylaminocarbonyl optionally substituted at the 2-position of the ethyl group substituted with hydroxy- or C _1-3 -alkoxy- or, unless R ⁴ represents aminosulfonyl-phenyl- or V- (C 1-5 -alkyl) -C 1-3 -alkylaminocarbonyl-phenyl-, R ² may also be a di- (C _1-2 -alkyl) -aminocarbonyl group,

R ⁴ is C _{3. A 7-} cycloalkyl group, wherein the methylene group at the 4-position of a six- or seven-membered cycloalkyl group may be replaced by amino-, C _1-3 -alkyl-amino- or di- (C _1-3 -alkyl) -amino-, or may be replaced by -NH- or - _J V _{(Ci. 3} alkyl) -, or a group ^{R6-substituted} phenyl which may additionally be mono- or di - substituted by F, Cl, Br, C]. _3- alkyl-, trifluoromethyl-, hydroxy-, C 1-6 alkyl; ₃ -alkoxy, carboxy, alkoxycarbonyl Cu, amino, acetylamino, aminocarbonyl, C ₃ -alkyl-aminocarbonyl, di- (C ₁ _ ₃ alkyl) amino-carbonyl, nitro or cyano - wherein the substituents may be the same or different and wherein R ⁶ represents a hydrogen, fluorine, chlorine, bromine or iodine atom, a cyano-, nitro-, amino-, C 1 - group. _5- alkyl-, C ₃ . _7- cycloalkyl-, trifluoromethyl-, phenyl-, tetrazolyl- or heteroaryl, a group of the formula

wherein the hydrogen atom bonded to the nitrogen atom may be replaced by C 1-6. _3- alkyl, C 1-6. _3- alkoxy-, amino-C2. _3- alkoxy-, Ci. ₃ -alkylamino, C _{2nd 3-} alkoxy-, di- (C _1-3 -alkyl) -amino-C ₂ . _3- alkoxy-, phenyl-C 1-6 alkyl; ₃ -alkylamino-C _{2nd 3} -alkoxy, 7V- (C _{first 3-alkyl)} -phenyl-C _{first 3} -alkylamino-C _{2nd 3} alkoxy-, pyrrolidino-C ₂ _ ₃ -alkoxy, piperidino-C _{2nd 3-} alkoxy- or C _1-3 -alkylmercapto-, carboxy-, C _1-4 -alkoxycarbonyl-, aminocarbonyl-, C 1-4 -alkylamino-carbonyl-, phenyl-C _1-3 -alkylamino-carbonyl- or N- (C 1-6 -alkyloxycarbonyl-); _3- alkyl) -phenyl-C 1-6 alkyl; _3- alkylamino-carbonyl-, group C ₃ . _7- cycloalkyl-carbonyl-, wherein the methylene group at the 4-position of the 6-membered or 7-membered cycloalkyl moiety may be replaced by -NH- or -TV (C _1-3 -alkyl) -, up to a 7 membered cycloalkyleneimine group in which the methylene group may be attached to NH replaced by a carbonyl or sulfonyl, or one or two hydrogen atoms may each be replaced by a C [_ ₃ -alkyl and / or the methylene group in the 4-position six or seven membered cycloalkylene-imino group may be substituted by carboxy, C ₃ - 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 1-6 alkyl; ₃ an alkylamino group, or may be replaced by O or S, sulfmyl-, sulfonyl, -NH- or - / W _(b3 C alkyl) -, terminal C ^ -alkyl, substituted by R ^7, wherein

R ⁷ is C ₅ .7-cycloalkyl group wherein a methylene group in the 4-position six or seven membered cycloalkyl group can be replaced by -NH- or -N (C ₃ alkyl) -, or a five to seven membered cycloalkyl group may be substituted - (CH ₂ ) ₂ - -CO-NH-, - (CH ₂ ) ₃ - -NH-CO-NH-, or - (CH ₂ ) ₄ - -NH-CO-NH-CO - wherein the hydrogen atom bound to the nitrogen atom can in each case be replaced by a C [ _{beta] 3} -alkyl group, a phenyl or heteroaryl group, a hydroxy- or C1-group. _3- alkoxy-, amino-, C _1-6 -alkylamino-, di- (C _1-6 -alkyl) -amino-, phenylamino-, W-phenyl-C ₁ . _3- alkyl-amino-, phenyl-C 1. ₃ -alkylamino, N- (Cl. ₃ alkyl) phenyl-C ₃ -alkylamino or di- _{(phenyl-C1. 3} alkyl) amino, a group of) hydroxy-C ₂ _ ₃ - alkylamino-, N- (C _1-3 -alkyl) -ra-hydroxy-C ₂ . _{3-alkyl-amino,} di - _{((o-hydroxy-C2. 3} alkyl) amino, di (ro- (C]. ₃ -alkoxy) -C _{second 3-alkyl)} -amino- and 7V- (dioxolan-2-yl) C |. ₃ -alkyl-amino, a C. ₃ alkylcarbonylamino _{C-2. 3-alkyl-amino} or Cl. ₃ -alkylcarbonyl-amino-C _{2. 3} ^-alkyl-N - _{(C1. 3} alkyl) amino, a C. ₃ -alkylsulfonylamino-, 7V- (C ₃ -alkyl) -C. _{3-alkyl-sulfonylamino,} C ₃ -C alkylsulfonylamino _{second 3} -alkyl-amino or _{C1. 3} -C alkylsulfonylamino _{second 3-alkyl-7V- (Ci. 3} alkyl) amino group, a hydroxycarbonyl-C ₃ -alkylamino or N (C ( _3- alkyl) -hydroxy-carbonyl-C _1-3 -alkyl-amino-, a guanidine group in which one hydrogen atom can be replaced by a C _1-3 -alkyl group, a group of the formula

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

R ⁸ represents a hydrogen atom or C 1-6 alkyl; _3- alkyl, n is 0, 1, 2, or 3,

R ⁹ represents an amino, a C ₃ -alkylamino, di- (C _{first 3} -alkyl) amino, phenylamino, benzylamino or C] _ ₄ -alkoxy, a 5- to 7-membered cyclo-alkylene an amino group, wherein the methylene group at the 4-position of the 6-membered or 7-membered piperidine group may be replaced by an oxygen or sulfur atom, an -NH-, -7 '(C 1-3 -alkyl) -, -7 N (phenyl) -, - N - (C _1-3 -alkylcarbonyl) - or - N - (benzoyl) -, or when n is 1, 2, or 3, R ⁹ can also be hydrogen, a group of the formula

-N (R ¹⁰ ) - (CH ₂ ) _m - (CO) _o - R (III) in which

R ¹⁰ represents a hydrogen atom, C 1. _3- alkyl, C 1-6 alkyl; ₃ -alkylcarbonyl, C _1-3 -alkylasulfonyl, m is 1, 2 or 3, o is 1 or, when m is 2 or 3, also 0; and

R ¹¹ represents amino-, C 1-6 alkyl; _3- alkylamino-, di- (C _1-3 -alkyl) -amino-, or a C _1-3 -alkoxy-C 1-4 group. _{A 3-} alkoxy-, or 5- to 7-membered 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-, -MC _{( -3-} alkyl) -, -N (phenyl) -, - / V (C ₃ alkylcarbonyl) - or - / V (benzoyl) -, C ₄ .7-cycloalkylamino or C ₄ _7-cykloalkenylamino-, wherein the position of the ring 1 not involved in the a double bond, up to a 7 membered cycloalkyleneimine group in which the cycloalkylene moiety can be fused with a phenyl group or, one or two hydrogen atoms can each be replaced by a C 1-6 -alkyl group, and / or the methylene group at the 3-position of the pyrrolidine group can be substituted with hydroxy , the C 1-3 -alkoxy- group, the methylene group at the 4-position of a six- or seven-membered cycloalkyleneimine group may be substituted with a hydroxy group, hydroxy-C 1. _{A 3-} alkyl group; ₃ -alkoxy, carboxyl, C _3-al koxykarbonyl-, aminocarbonyl, C ₃ -alkylamino-carbonyl, di- (C ₁ _ ₃ alkyl) aminocarbonyl-, phenyl-Ci_3-alkylamino or YV-jCij- alkyl-phenyl-C 1-6 -alkylamino-, or said methylene group may be replaced by an oxygen or sulfur atom, a sulfinyl-, a sulfonyl-, -NH-, -N (C 1-4 -alkyl) -, -7 N (phenyl) -, -7 N (phenyl-C |. ₃ alkyl) -, -N (C _b3 -alkylcarbonyl) -, -N (C ₄ -hydroxykarbonyl) -, -TV _{(C1. 4} -alkoxy-carbonyl) -, -N (benzoyl - or - N - (phenyl-C _1-3 -alkylcarbonyl) wherein the methylene group attached 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 6-membered monocyclic or phenyl condensed group the cycloalkylenimine group of the two methylene groups bonded to the imine nitrogen atom may each be replaced by a carbonyl group, or R ⁶ is C ^1-6 . _{A 4-} alkyl group which is substituted at the terminal moiety by a carboxy-, C1-group; _3- alkoxycarbonyl-, aminocarbonyl-, Ci. _{A 3-} alkylamino-carbonyl- or di- (C _1-3 -alkyl) -aminocarbonylamino or 4 to 7 membered cycloalkylene-iminocarbonyl 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 ₅ -alkyl. _7- 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) in which

R ¹⁴ represents a hydrogen atom, C ₁ . ₄ -alkyl, C ₃ -alkylcarbonyl group, a phenylcarbonyl group, a phenyl-Ci.3-alkylcarbonyl, heteroarylcarbonyl, heteroaryl-C |. _3- alkylcarbonyl, C 1. _4- alkylsulfonyl, phenylsulfonyl, phenyl-C 1-6 -alkylsulfonyl, heteroarylsulfonyl or heteroaryl-C _1-3 -alkylsulfonyl, 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 , the group of formula

-N (R ¹⁶⁾ - SO ₂ - R ¹⁷ (VI), wherein

R ¹⁶ represents a hydrogen atom or a terminal C 1-6 alkyl; _{A 4-} alkyl group optionally substituted by cyano-, trifluoromethyl-carbonyl-amino- or N - (C _1-3 -alkyl) -trifluoromethyl-carbonyl-amino-;

R ¹⁷ is C 1-6. _3- alkyl, amino substituted by di- (C 1-3 -alkyl) -amino-C _1-3 -alkyl-carbonyl- or di- (C _1-3 -alkyl) -amino-C 1-3 -alkylsulfonyl-, and di- _{(C1. 3} alkyl) aminocarbonyl-C |. _3- alkyl, wherein all of the R ⁶ radicals mentioned 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 1-6 -alkyl group. ₃ -alkoxy, carboxy, C _{first 3-} alkoxycarbonyl-, aminocarbonyl-, Ci. _3- alkylaminocarbonyl-, 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 substituted in the carbon skeleton of a C 1-3 -alkyl group substituted by pyridinyl-, pyrazinyl-, pyrimidinyl-, pyridazinyl-, pyrrolyl-, furyl-, thienyl -, oxazolyl-, thiazolyl-, pyrazolyl-, imidazolyl- or triazolyl- in which one hydrogen atom attached to the nitrogen atom can be replaced by a C _1-3 -alkyl group or a phenyl-C 1-6 -alkyl group. ₃ -alkyl, and the five-membered, at least one NH-containing heteroaryl groups are linked via a carbon or nitrogen atom, the above groups can be hydrogen bonded to the nitrogen atom, is replaced with a leaving in vivo cling group, in particular acetyl or íerc- butoxycarbonyl, in said carboxyl-containing 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 portions of the designated 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 specified, their tautomers, diastereomers, enantiomers isomers, mixtures thereof 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 a C ₆ alkoxy-carbonyl, C ₅ _7-cycloalkoxycarbonyl or a phenoxycarbonyl group, a linear or branched C. _{A 3-} alkoxy-carbonyl group which is substituted in the terminal alkyl moiety by phenyl, carboxy, C _1-3 -alkoxy-carbonyl, aminocarbonyl, C _1-3 -alkylaminocarbonyl or di- (C _1-3 -alkyl) amino-carbonyl -, unbranched or branched C2. ₃ -alkoxy-carbonyl, which is the terminal alkyl substituted by hydroxy, C ₃ -alkoxy, amino, C ₃ -alkylamino or di- (C _{first 3} alkyl) amino, tautomers thereof, 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

R ² represents an aminocarbonyl or methylaminocarbonyl group, an ethylaminocarbonyl group which may be optionally substituted at the 2-position in the ethyl group by a hydroxy- or C 1-3 -alkoxy- group, provided that R ^{4 is} not an aminosulfonyl-phenyl- or alkyl) -C 1 group. 3-alkylaminocarbonyl-phenyl, then R ² may also be di- (C 1-2 -alkyl) -aminocarbonyl, their tautomers, diastereomers, enantiomers, mixtures and salts thereof.

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, R ⁷ - (n C _M alkyl) -phenyl, wherein

R ⁷ represents an amino, a C ₆ -alkylamino, di- (C _{first 6} alkyl) amino, phenyl-amino, / V-phenyl-C ₃ -alkyl-amino, phenyl-C ₃ - alkyl-amino- N - (C _1-3 -alkyl) -phenyl-C 1-6 alkyl; ₃ -alkylamino or di- (phenyl-C _{first 3} alkyl) amino, or phenyl which is substituted by 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 is carboxy, a linear or branched Ci.4-alkoxy-carbonyl or phenoxycarbonyl group, a linear or branched C]. _{A 3} -alkoxycarbonyl group which is substituted in the terminal alkyl moiety by phenyl, carboxyl, C _1-3 -alkoxycarbonyl, aminocarbonyl, C _1-3 -alkylaminocarbonyl or di- (C _1-3 -alkyl) -amino-carbonyl, straight or branched C ₂ . _{A 3} -alkoxycarbonyl group which is substituted in the terminal alkyl moiety by a hydroxy-, C 1 - 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 |. _3- alkoxy-, provided that when R ^{4 is} not an aminosulfonyl-phenyl or N- (C 1-5 -alkyl) -C 1-3 -alkylaminocarbonyl-phenyl group, then R ² may also be a di- (C 1-2 -alkyl) aminocarbonyl group

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-, a C _1-3 -alkyl-, a hydroxy- or a C _1-3 -alkoxy-,

^R4 is _C5, 6-cycloalkyl group wherein a methylene group in the 4-cyclohexyl may be substituted by amino, C-3-alkylamino or di-FCU-alkyljamino-, or replaced by a -NH- or -MCl- 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 by R ⁶ , wherein said phenyl group may additionally be substituted by a fluorine, chlorine or bromine atom or an amino- or nitro-,

Wherein R ⁶ represents a fluorine, chlorine or bromine atom,

Cl .3 alkyl, C _b3 alkoxy group, a nitro group, an amino group or a _C5-.6 cycloalkyl group, linked through a carbon atom of pyrrolyl, pyrazolyl, imidazolyl, triazolyl or tetrazolyl group, the said heteroaromatic groups may be C ₁ -substituted in the carbon skeleton. _{The 3-} alkyl group or one hydrogen atom bonded to the nitrogen atom may be replaced by a C 1-6 -alkyl group or a phenyl-C 1-6 -alkyl group. _3- alkyl, a group of formula

carboxyl group, C _{first 4-} alkoxycarbonyl-, phenyl-C 1-6 -alkyl; _{3-alkyl-amino-carbonyl} or a C ₅ _ ₇ cycloalkyl-carbonyl, a five-membered or six-membered cykloalkylénimínovú group, the methylene group at position 4 of the piperidine group can be replaced by oxygen, S, -NH- or - / A (C 1-3 -alkyl) -, unbranched, C _1-3 -alkyl group in the terminal portion substituted with R ⁷ , wherein:

R ⁷ is C ₅ . _7- cycloalkyl, wherein in a 5- or 6-membered cycloalkyl group the - (CH ₂ ) ₂ - group may be replaced by -CO-NH-, the - (CH ₂ ) ₃ - may be replaced by -NH-CO-NH- a - (CH ₂ ) ₄ - may be replaced by -NH-CO-NH-CO-, wherein the hydrogen atom bonded to the nitrogen atom may in each case be replaced by a C 1-3 -alkyl, phenyl or pyridinyl group, or by a carbon atom or a nitrogen-linked pyrrolyl, pyrazolyl, imidazolyl or triazolyl group, wherein said heteroaryl groups may be substituted in the carbon skeleton by a C 1-6 -alkyl group or the hydrogen bonded to the nitrogen atom may be replaced by a C _1-3 -alkyl group, a hydroxy- or _b C 3 alkoxy, an amino, a C ₆ -alkylamino, di (C ₆ alkyl) amino, phenylamino, ^A, _{phenyl-C-c3-alkyl} amino, phenyl-C ,, ₃ alkylamino- or N- (C _{first 3} -alk yl) -phenyl-C 1-3 -alkyl-amino-, a? -hydroxy-C _{2 group} . _3- alkyl-amino- N - (C _1-3 -alkyl) -ro-hydroxy-C ₂ . _{3-alkyl-amino,} di (s) a hydroxy-C _{2nd 3-alkyl)} amino or di- (i> - (C-j-alkoxyj CJJ-alkylj-amino, a C.-C ₃ alkylcarbonylamino _{second 3} -alkyl-amino or C. ₃ -alkylcarbonyl- amino-C ₂ .3-alkyl / N (C |. ₃ alkyl) amino, a C. -alkylsulfonylamino- _3, and ^f - (Ci_3-alkyl) -C _{first 3} -alkylsulfonylamino-, C . _{3-alkyl-sulfonyl-C 2} .3-alkylamino, alkylsulfonylamino or a C ₃ -C _{2. 3-alkyl-N-} (Ci. ₃ alkyl) amino group, a _{hydroxycarbonyl-C1. 3} alkyl amino group or _one N (C _b3 alkyl) hydroxy-carbonyl-C | .3-alkylamino, guanidino, wherein hydrogen may be replaced by _C-alkyl-B3, the group of formula

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

R ⁸ is hydrogen or C _1-3 -alkyl, n is 0, 1, 2, or 3,

R ⁹ represents an amino, a C ₃ -alkylamino, di- _{(C1. 3} alkyl) amino or C [. _{A 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-, -N (C _1-3 -alkyl) - or - N (C _1-3 -alkylcarbonyl) - or when n is 1, 2, or 3 may also be a hydrogen atom, a group of formula

-N (R ¹⁰ ) - (CH ₂ ) _m - (CO) _o - R (III) in which

R ¹⁰ represents a hydrogen atom or C 1. _3- alkyl, 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 _1-3 -alkylamino-, di- (C _1-3 -alkyl) -amino-, C _1-4 -alkoxy- or methoxyC _1-3 -alkoxy-, or a 5- or 6-membered cycloalkyleneimine group group, wherein the methylene group at position 4 of the piperidine group can always be replaced by -NH-, -N (Ci. ₃ alkyl) -, or -N (C ₃ -alkyl-carbonyl) - group 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 a hydroxy group, the methylene group at the 4-position of the piperidine group may be substituted hydroxy, hydroxyC ₃ alkyl- or C _kl - alkoxy, or said methylene group can be replaced by oxygen, S, sulfinyl, sulfonyl, -NH-, -TV (C ₃ alkyl) -, - TV (C]. ₃ -alkyl-carbonyl) -, -N (benzoyl) - or - / V (phenyl-C]. ₃ -alkyl-carbonyl) -, wherein the methylene group is bonded to the imine at m N pyrrolidine, piperidine or piperazine groups may be replaced by a carbonyl group, or R ⁶ is a straight C]. _{A 3-} alkyl group whose terminal moiety is substituted with a carboxyl group or a C 1 group. _{A 3-} alkoxy-carbonyl- group of formula

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

R ¹² represents a hydrogen atom, C ₁ . _3- alkyl or phenyl-C 1-6 alkyl, p is 0, 1 or 2;

R ¹³ represents amino-, C _1-4 -alkylamino-, di- (C _1-4 -alkyl) -amino-, benzyl-amino-, N - (C _1-3 -alkyl) -benzylamino, C 1-6 -alkyl; _3- alkoxy-Ci. _3- alkylamino-, N - (C _1-3 -alkyl) -C 1-6 alkyl. _3- alkoxy-Ci. _{3-alkyl-amino,} di (2-methoxyethyl) amino, di- (co-hydroxy-C _{2nd 3} alkyl) amino or aminocarbonyl-methyl-N- (methyl) amino, a nitrogen-bonded, optionally C 1-4 -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 _1-3 -alkylcarbonyl- or C _1-4 -alkoxycarbonyl-, when n is 1 or 2, R ¹² can also be a hydrogen atom, a group of the formula

-N (R ¹⁴ ) - (CH ₂ ) _q - (CO) _r - 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 1-6 alkyl group, or a C _1-4 alkyl group; _3- alkylcarbonyl, furylcarbonyl, pyridinylcarbonyl, furyl-C 1. _3- alkyl-carbonyl, 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 _1-4 -alkylamino-, di- (C _1-4 alkyl) -amino-, phenyl-amino-, N - (C _1-4 -alkyl) -phenylamino-, benzylamino- or N - (C _1-4) -alkyl) -benzyl-amino-, 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 j-alkyl optionally substituted by cyano, trifluoromethyl-carbonyl-amino or N- (C _{first 3} -alkyl) carbonyl-trifluoromethyl-amino and

R ¹⁷ is C 1-6. _3- alkyl, wherein all the R ⁶ moieties containing single bonded or fused phenyl groups mentioned above may be substituted by fluorine, chlorine or bromine, methyl, trifluoromethyl, methoxy, nitro or kayno-; and

R ⁵ represents a hydrogen atom, in which the hydrogen atom bonded to the nitrogen atom may be replaced by an acetyl group or a tert-butoxycarbonyl group,

The carboxyl groups in said radicals may also be in the form of tert-butoxycarbonyl precursor groups and in said radicals saturated alkyl or alkoxy moieties containing more than two carbon atoms may be unbranched or branched, unless otherwise indicated, their tautomers, diastereomers , enantiomers, mixtures thereof and salts thereof.

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,

^R2 is a linear or branched C. _{A 4-} alkoxycarbonyl group or a phenoxycarbonyl group, a straight or branched C _1-3 -alkoxycarbonyl group which in the terminal alkyl moiety may be substituted by a phenyl-, carboxy-, C 1-6 -alkyl group; ₃ -alkoxycarbonyl-, aminocarbonyl-; _3- alkylaminocarbonylamino or di- (C _1-3 -alkyl) -amino-carbonyl-, or unbranched or branched C _2-3 -alkoxy-carbonyl, which is substituted in the terminal alkyl moiety by hydroxy, C _1-3 -alkoxy-, amino- , C 1-4 -alkyl-amino- or di- (C _1-3 -alkyl) -amino-,

R ^4, R ⁷ - (n C _{I. 3-alkyl)} -phenyl, wherein

R ⁷ represents an amino, a C ₆ -alkylamino, di- (C _{first 4} alkyl) -amino-, o) hydroxy-C _{2nd 3-alkyl-amino,} N- (C \. ₃ alkyl) _{-R-hydroxy-C2. 3-alkyl-amino,} di (i> _{hydroxy-C2. 3} alkyl) amino group or a di (o) - (C |. ₃ -alkoxy) -C2_ ₃ -alkyl) amino, or means 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 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 ethylamino-carbonyl group optionally at the 2-position of the ethyl group substituted by a hydroxy- or a C 1-3 -alkoxy- group, or when R ^{4 is} not an aminosulfonyl-phenyl group or N- (C 1-5-) alkyl) -C |. _3- alkylaminocarbonyl R ² also denotes di- (C _1-2 -alkyl) aminocarbonyl,

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

R ⁷ is amino-, C 1 -. ₆ -alkylamino, di- (C _{first 4} alkyl) amino, and> hydroxy-C _{2nd 3-alkyl-amino,} N- (C ₃ alkyl) -R _{C-Hydroxy-second 3-alkyl-amino,} di - _{(<B-hydroxy-C2. 3} alkyl) amino group or a di - ((O (C. ₃ -alkoxy) -C2_ ₃ -alkyl) amino, or means 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 and salts thereof.

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 group,

R ³ represents a phenyl group,

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

R ⁶ represents an N-methyl-imidazol-2-yl group, a straight or branched C _1-3 -alkyl group, the terminal part of which is substituted by C 1-6. _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 is C 1-6. ₃ alkyl group, p is 1 or 2 and

R 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) in which

R ¹⁴ is C 1-3 -alkylcarbonyl or C 1-3 -alkylsulfonyl q is 1, 2 or 3, r is 1, or, if q is 2 or 3, r can be 0 and R ¹⁵ is di - (C 1-3 -alkyl) amino, wherein said saturated alkyl moieties having more than two carbon atoms may be unbranched or branched, unless otherwise indicated, their tautomers, diastereomers, enantiomers, mixtures thereof and salts thereof.

A particularly remarkable subset of the most preferred compounds of formula (I) are those wherein X, R ¹ , R ^3, and R ⁵ are as defined above,

^R2 is metoxykarbonyloá or ethoxycarbonyl, and

R ⁴ represents a di-C 1-6 -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 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-yl- (d) 3-Z- [1- (4- (dimethylaminomethyl) anilino) -1-phenylmethylene] -6- (methyl) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone ethoxycarbonyl-2-indolinone, (e) 3-Z- [1- (4 - ((2,6-dimethyl-piperidin-1-yl) -methyl) -anilino) -1-phenyl-methylene] -6-ethoxy -carbonyl-2-indolinone, (f) 3-Z- [1- (4 - (N- (2-dimethylamino-ethyl) -N-acetyl-amino) -anilino) -1-phenyl-methylene] -6 (g) 3-Z- [1- (4- (N - (3-dimethylamino-propyl) - N -acetyl-amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone; -ethoxycarbonyl-2-indolinone, (h) 3-Z- [1- (4- (N - (2-dimethylamino-ethyl) - N -methylsulfonyl-amino) -anilino) -1-phenyl-methylene] -6- ethoxycarbonyl-2-indolinone, (i) 3-Z- [1- (4- (dimethylaminomethyl) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (j) 3-Z- [1] - (4- (7V-acetyl-N-dimethylaminocarbonylmethyl (amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (k) 3-Z- [1- (4-ethylaminomethyl-anilino) -1-phenylmethylene] -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-methyl-amino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (n) 3-Z- [1 - ( 4- (N - (2-dimethylamino-ethyl) - N -methylsulfonyl-amino) -amino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (o) 3-Z- [1 - ( 4- (N ^- (3-dimethylaminopropyl) - / V-methylsulphonyl-amino) -anilino) -l-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-dimethylarmno-ethyl) -carbonyl) -N'-methyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (r) 3-Z - [l- (4- (N- (2-dimethylamino-ethyl) -N-acetyl-amino) anilino) -l-phenyl-methylene] -6-methoxycarbonyl-2-indolinone and (s) 3-Z- [1- (4-methylaminomethyl-anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, their tautomers, mixtures thereof, and salts thereof.

Another subgroup of compounds of formula (I) are those in which:

X is an oxygen or sulfur atom,

R ¹ represents a hydrogen atom or a prodrug group such as a C] _ ₄ -alkoxycarbonyl or C _{2nd 4-} alkanoyl group,

R ² is carboxy, a linear or branched C _1, 6-alkoxy-carbonyl, C5-7-cycloalkoxycarbonyl or phenyl-C. _3- alkoxycarbonyl, aminocarbonyl or

Ci. ₂ -alkylaniinokarbonylovú group, or when R ⁴ does not represent aminosulfonylfenyl- or N (Ci_6 alkyl) -C 1-3 alkylaminocarbonyl-phenyl group, and also di- (Ci_2-alkyl) -amiiio-carbonyl, R ³ is H , C 1-6 -alkyl, C ₃ . _7- cycloalkyl, trifluoromethyl or heteroaryl, phenyl or naphthyl, phenyl or naphthyl mono- or di- substituted by fluorine, chlorine, bromine or iodine, trifluoromethyl, C _1-3 -alkyl- or C 1 -substituted. ₃ -alkoxy, where in the case disubstitácie substituents may be the same or different and wherein the abovementioned unsubstituted as well as mono- and di-substituted phenyl or naphthyl groups may additionally be substituted by hydroxy, hydroxy-C ₃ -alkyl-, or a C _3- alkoxy-C _1-3 -alkyl-, cyano-, carboxy-, carboxy-C 1. _3- alkyl-, C _1-3 -alkoxycarbonyl-, aminocarbonyl-, C _1-3 . _3- alkylaminocarbonyl- or di- (C _1-3 -alkyl) amino-carbonyl, nitro-, amino-, C _1-3 -alkylamino-, di- (C _1-3 -alkyl) amino or amino-C _1-3 -alkyl group, group C]. _3- alkylcarbonylamino- N - (C _1-3 -alkyl) -C 1. _3- alkylcarbonylamino-, Ci. _3- alkylcarbonylamino-C 1-6 alkyl; _3- alkyl-, N- (C _1-3 -alkyl) -C ₁ . _3- alkylcarbonylamino- C 1-6 -alkyl-, C 1-6 -alkyl-; _3- alkylsulfonylamino-, C ₁ . ₃ alkylsulfonylamino _C-c3-alkyl, and ^s - (C _{first 3} alkyl) C _t _ -alkylsulfonylammo ₃ -C _l _ ₃ alkyl- or aryl-group _{1st 3} -alkylsulfonylamino-, cycloalkylamino-, cycloalkylenimino-, cycloalkyleneiminocarbonyl-, cycloalkylenimino-C1-6-cycloalkyleneimino-; ₃ alkyl-, cykloalkyléniminokarbonyl-C-alkyl, or-C cykloalkyléniminosulfonyl ₃ -alkyl each having 4 to 7 ring members, wherein the methylene group in the 4-position six-membered or seven-membered cycloalkyleneimino groups may be replaced by O or S, sulfmyl- , sulfonyl-, -NH- or -TV (C _1-3 -alkyl) -, or may be substituted with a heteroaryl group or a heteroaryl-C 1-6 -alkyl group,

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 substituted by amino-, C 1-6 -cycloalkyl. _3- alkylamino- or di- (C _1-3 -alkyl) -amino- or replaced by -NH- or - N (C _1-3 -alkyl) -, or represents a phenyl group substituted with R ⁶ , wherein the phenyl group may additionally be substituted by F, Cl, Br, I, a C _{1st 5-} alkyl-, trifluoromethyl-; _3- alkoxy-, carboxy-, C _1-3 -alkoxycarbonyl-, aminosulfonyl-, nitro- or cyano-, wherein

R ⁶ represents a hydrogen, fluorine, chlorine, bromine or iodine atom, a cyano-, nitro-, amino-, C 1-5 -alkyl-, C _{3 group} . _7- cycloalkyl-, trifluoromethyl-, phenyl-, tetrazolyl- or heteroaryl,

C _1-3 -alkoxy optionally substituted with 1 to 3 fluorine atoms, C _1-3 -alkoxy-C ₁ . _3- alkoxy, phenyl-C _1-3 -alkoxy, amino-C ₂ . _3- alkoxy, C 1. ₃ -alkylamino-C _{2nd 3} -alkoxy group, a di (C ₃ alkyl) amino-C _2-3 -alkoxy, phenyl-C. _3- alkylamino-C _2-3 -alkoxy, N - (C _1-3 -alkyl) -phenyl-C 1-6 -alkyloxy; ₃ -alkylamino-C _{2nd 3-} alkoxy, C5. _7-C -cykloalkylénimino _{second 3-} alkoxy or C _1-3 -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- Ci. _3- alkylamino-carbonyl, piperazinocarbonyl or N - (C _1-3 -alkyl ₎ piperazinocarbonyl,

A C ₃ -alkylaminokarbonylová or ^A, - (C |. ₅ alkyl) -C |. _{A 3-} alkylaminocarbonyl group in which the alkyl moiety is substituted with a carboxyl group or a C 1-6 alkyl group; ₃ alkoxycarbonyl group or in the 2 or the group di- _{(C1. 3} alkyl) -amino, piperazino group, a group of TV- (C]. ₃ alkyl) -piperazino- or a four to seven membered cykloalkyléniminovou group, to 7 membered cykloalkylénimínová group, the imino group is bound to the methylene group can be replaced by a carbonyl group or a sulfonyl group, wherein a cycloalkylene moiety may be fused to a phenyl ring, or one or two hydrogen atoms may be replaced by a C ₁ _ ₃ -alkyl and / or a methylene group in the 4 cykloalkylénimínovej six or seven membered group is optionally substituted by carboxy, C _{first 3-} alkoxycarbonyl, aminocarbonyl, C _1-3 -alkylaminocarbonyl, di- (C _1-3 -alkyl) aminocarbonyl, phenyl-C _1-4 alkyl; ₃ -alkylamino or ^N - (C _1-3 -alkyl) -phenyl-C ₁ . ₃ an alkylamino group, or may be replaced by O or S, sulfmyl-, sulfonyl, -NH-, -N _{(Ci. 3} alkyl) -, -N (phenyl) -, -MC |. _3- alkyl-carbonyl) - or -A '(benzoyl) -,

C]. _{A 4-} alkyl group, which may be substituted by a hydroxy- or a C 1 group. ₃ -alkoxy, amino group, C ₇ -alkylamino, di-FCI ^ -alkylj-amino, di-R / - _{(Ci. 3} alkyl) amino-C ₂ -3-amino- Ιή -Ν, Ν, Ν '- _{(Ci. 3} alkyl) _{amino-C2. 3-} alkylamino-, phenyl-amino-, N-phenyl-C _1-3 -alkyl-amino-, phenyl-C 1-6 -alkyl- ₃ -alkylamino,? N (Ci. ₃ alkyl) phenyl-C ₃ -alkylamino or di- _{(phenyl-C1. 3} alkyl) amino, a C ^ J-alkylcarbonylamino, 7V- (Cl. ₃ alkyl) -C. _3- alkylcarbobylamino-, C _1-3 -alkoxycarbonyl-C 1-6 -alkylcarbobylamino-; ₃ ^ -alkylamino, or - (C-alkyli-CI-CI-alkoxycarbonyl-alkylamino-, a C _4th -cykloalkylamino- _7, C _{4.-C 7} -cycloalkyl. ₃ -alkyl-amino, or C _4. -cykloalkenylamino- _7, wherein the position of the ring 1 does not participate in the double bond, and wherein the said groups may in addition to the amine nitrogen atom substituted by a C ₃ -alkyl-, and the hydrogen atoms may be partially or fully substituted by fluorine, and may be substituted by C _{5. 7} -cycloalkyl- C _{2nd 4} -alkyl-, and 7 membered cykloalkyléniminovou group, wherein the methylene group attached to imnoskupinu may be replaced by a carbonyl group or a sulfonyl group, a cycloalkylene moiety may be fused with a phenyl group or optionally with a fluorine, chlorine, bromine or iodine atom, a nitro-, C _1-3 -alkyl-, C 1-4 -alkoxy- or amino-substituted by an oxazolo-, imidazolo-, thiazolo-, pyridino-, pyrazino- or pyrimidino group -, one or two in Dikova atoms may be replaced with C |. ₃ -alkyl, C _{5. 7} -cycloalkyl or a phenyl group, a methylene group in the 4-position six or seven membered cykloalkylénimínovej group may be substituted with a hydroxy group, a carboxy group, a C _{1st 4-} alkoxycarbonyl-, amino-carbonyl-, C 1-4 -alkylamino-carbonyl, di- (C _1-3 -alkyl) -aminocarbonyl-, phenyl-C]. _3- alkylamino- or M (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) -, -N- (phenyl) -, - / V group. (C | _ ₃ -alkyl-carbonyl) - or -N (benzoyl) -, carboxy groups, Cu-alkoxycarbonyl, aminocarbonyl, C _{l. 3-} alkylamino-carbonyl- 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 1-6) group |. ₃ alkyl) -benzoylamino- group, TV- _{(C1. 3} alkyl) _{-C2. 4-} alkanoylamino-, which is additionally substituted in the alkyl moiety with a carboxyl group or C 1. _{A 3-} alkoxycarbonyl group, a group of formula (II)

- N (R ⁸ ) - CO - (CH ₂ ) _n - R ⁹ (II) 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 -. ₄ -alkylamino, phenylamino, N- (Ci. ₄ alkyl) -fenylamino-, benzylamino, N- (C ^ -alkylj-benzylamino-or di _{(C1. 4} alkyl) amino, 4 - a 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-, -7V (C _1-3 -alkyl) - group; - // (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 (III)

-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 1-6 alkyl group, or a C _1-3 alkyl group; ₃ -alkylcarbonyl, arylcarbonyl, phenyl-C 1-6 alkyl; ₃ -alkylcarbonyl, C _1-3 -alkylsulfonyl, arylsulfonyl or phenylCi. ₃ -alkylsulfonyl, m is 1, 2, 3 or 4, o is 0 or 1; and

R ¹¹ represents an amino, a C ₄ -alkylamino, phenylamino, N- (C ₄ alkyl) -fenylamino-, benzylamino, N- (Ci. ₄ alkyl) -benzylamino- or di- (C ₄ - alkyl) -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-, - N (C _1-3 -alkyl) -, -7 N (phenyl) -, -7 N (C _1-3 -alkyl-carbonyl) - or -Mbenzoyl) -, C _1-3 -alkoxy- or in position 1 optionally C 1. _A di-(C _1-4 -alkyl) amino-C 1-6 -substituted group substituted by an alkyl group. ₃ -alkylamino-,

Or a group V- (C 1-3 -alkyl) -C ₁ . -Alkylsulfonylatnino- ₅ or N (C _b 3-alkyl) sulfonylamino-phenyl, wherein the alkyl moiety is additionally substituted by a cyano or carboxyl, each of the R ⁶ radicals of the easily bonded or fused phenyl groups may be mono- or di- substituted by a fluorine, chlorine, bromine or iodine atom, a C 1-5 -alkyl-, trifluoromethyl-, C 1-6 -alkyl-, C 1-6 -alkyl-, C 1-6 -alkyl-, C 1-6 -alkyl-, C 1-4- _3- alkoxy-, carboxy-, C 1-6 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 a methylenedioxy- group, 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, trifluoromethyl-, C 1-6 alkyl; _3- alkyl- or C 3-6 -alkoxy- and the term heteroaryl refers to a monocyclic five- or six-membered heteroaryl group, optionally substituted with C 1-6 alkyl; _{A 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 alkyl; _3- alkyl, or optionally containing C ₁ . _{A 3-} alkyl-substituted amino group and an oxygen atom or a sulfur atom, or optionally contains C 1. _{A 3-} alkyl-substituted amino group and two nitrogen atoms, and in addition to said monocyclic heterocyclic groups a fused phenyl ring may be fused to two monocyclic heterocyclic groups, said saturated alkyl and alkoxy moieties of the predetermined groups containing more than 2 carbon atoms, unless otherwise indicated, their branched isomers, for example, isopropyl, tert-butyl and isobutyl groups, and wherein said carboxyl, amino and imino groups may be substituted with an in vivo cleavable residue, their isomers and salts thereof.

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 identified,

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 said radicals as defined above, and

Z ¹ represents a halogen atom, a hydroxy-, alkoxy- or arylalkoxy- group, for example a chlorine or bromine atom, a methoxy-, ethoxy- or benzyloxy- group, with an amine of the general formula (VIII) in which:

R ⁴ and R ⁵ are intended,

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

The conversion is conveniently carried out in a solvent 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, 20 and 175 ° C, wherein the protecting group used can be simultaneously cleaved off 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 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, 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, 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 the compound of formula (I), wherein R ² other than the carboxyl group is designated as the beginning, resulting in a conversion of a compound of formula (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 is C 1-6. ₆ -alkanol, C ₄ . ₇ -cycloalkanol or 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; _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 ₃ -alkylamino or di- (C _{first 3} alkyl) amino, amino, or methylamino, ethylamino or di- (Ci_2-alkyl) amino group which may optionally be substituted in the position 2 of the ethyl group with hydroxy- or C _1-3 -alkoxy-.

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 boiling point. the solvent used. The conversion is carried out with the appropriate acid, preferably in the presence of a water-withdrawing agent, for example in the presence of isobutyl chloroformate, tetraethyl ortho-carbonate, methyl ortho-acetic acid, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, phosphorochlorite N, N -dicyclohexylcarbodiimide, N, N-dicyclohexylcarbodiimide N-N-N-N-N-dicyclohexylcarbodiimide / 1-hydroxybenzotriazole, 2- (1H-benzotriazo-1-yl) -1,1,3, 3-tetramethyluronium tetrafluoroborate, 2- (1H-benzo-triazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate / 1-hydroxybenzotriazole, 1H-carbonyldiimidazole or triphenylphosphine / carbon tetrachloride and optionally with the 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 the acylation is carried out an appropriate reactive compound such as an anhydride, ester, imidazolide or halide optionally in the presence of a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine 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 1-4 -alkylamino-, di-C 1-4 -alkyl-amino-, phenylamino-, N-phenyl-C 1-4 -alkyl-amino-, phenyl-C 1-4 -alkyl-amino-, N - (C 1-3 -alkyl) -phenyl-C 1-3 -alkylamino- or di- (phenyl-C 1-3 -alkyl) -amino-, ci) -hydroxy-C 2-3 -alkylamino- group, alkyl-o-hydroxy-C 1-6 -alkyl-amino-, di- (ω-hydroxy-C 2-3 -alkyl) -amino-, di- (α- (C 1-3 -alkoxy) -C 2,3 -alkyl) - amino- or N ¹ - (dioxolan-2-yl) -C 1-3 -alkyl-amino-, a C 1-6 alkyl group; ₃ alkylcarbonylamino-C ₂ _ ₃ -alkyl-amino or C |. _3- alkylcarbonylamino-C2. ₃ alkyl- / T- _{(Art. 3} alkyl) amino group, Ci.3-alkylsulfonylamino, // - (C-alkyli-C-alkyl-sulfonylamino, C 1-3 alkylsulfonylamino-C2 .3-alkyl-amino or C | .3-alkylsulfonylamino-C _{2nd 3} -alkyl-N - (C | .3 alkyl) amino, a group of formula (III)

N ^ MCHA ^tCOjo-11-R (III) wherein

R ¹⁰ represents a hydrogen atom, a C _1-3 -alkyl group, a C 1-6 alkyl group or a C _1-3 alkyl group; ₃ -alkylcarbonyl, arylcarbonyl, phenyl-C 1-6 alkyl; _{3-alkyl-carbonyl,} C _{l. 3-} alkylsulfonyl, arylsulfonyl or phenylC ₁ . ₃ alkylsulphonyl group, m is 1, 2, 3 or 4, o is a value 1, and

R ¹¹ is amino-, C 1-6 -alkyl. ₄ alkylamino-, di _{(C1. 4} alkyl) amino, phenylamino, N- _{(Ci. 4} alkyl) -fenylamino-, benzylamino, N- (Ci. ₄ alkyl) benzylamino -, C]. _4- alkoxy- or a C 1-6 alkyl group; _3- alkoxy-C _1-3 -alkoxy-, optionally with C 1-6. _{A 3-} alkyl- substituted di- (C _1-4 -alkyl) amino-C 1-6 alkyl group; _{A 3-} alkylamino- or 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; , -NH-, -TV (Cl. ₃ alkyl) -, -N / phenyl) -, -TV _{(C1. 3} alkyl-carbonyl) - or -7V- (benzoyl) -, a group of _{C4. 7} -cycloalkylamino-, C ₄ . ₇ -cycloalkyl-C 1-3 -alkylamino- or C ₄ . ₇ -cycloalkenylamino- in which the ring 1 position does not participate in the double bond and wherein said groups may additionally be substituted on the amino nitrogen atom by a C ₅ group. ₇ -cycloalkyl- C _{2nd A 4-} alkenyl- or C 1-4 -alkyl-, or 4-7 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 or iodine atom, a nitro- group, a C 1-6 group. _3- alkyl-; ₃ -alkoxy or amino, and wherein one or two hydrogen atoms may be replaced by C ^ -alkyl, C _{5. A 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 a hydroxy group, hydroxy-C 1. _3- alkyl, C 1-6. ₃ -alkoxy or C _l .3-alkoxy-C ₃ -alkyl, where the methylene group in the 3- or 4 cykloalkylénimínovej six or seven membered group is optionally substituted by hydroxy, hydroxy-C ₃ -alkyl, C _{first 3-} alkoxy-, Ci. _3- alkoxy-C 1-3 -alkyl, carboxyl, C _1-4 -alkoxycarbonyl-, aminocarbonyl-, C 1-4 -alkyl; _3- alkylamino-carbonyl-, 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, sulfinyl-, sulfonyl-, -NH-, -TV ( _{C1. 3} alkyl) -, -N (phenyl) -, -N / _{(phenyl-C1. 3} alkyl) -, - / V "(C |. ₃ -alkyl-carbonyl) -, -TV ( ( _1-4 -alkoxycarbonyl) -, -7 N (benzoyl) - or - N - (phenyl-C _1-3 -alkylcarbonyl) -, wherein the methylene group which is bonded to the imine nitrogen atom of the cycloalkylenimine group may be substituted 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 may be replaced by carbonyl groups, by conversion of a compound of formula (XI)

(XI),

R ¹⁸ in which

R ¹ , R ⁵ and X are as previously defined,

R ² 'is as R ² above,

R ¹⁸ represents a hydrogen atom or a nitrogen protecting group of the lactam group, wherein one of R ² 'and R ¹⁸ may optionally form a solid phase bond through the Spacer and the other of said radicals is as defined above, and

A represents a C 1-6 alkyl group and

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

HR ⁷ '(XII), in which

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, Λ'-methylpyrrolidone or mixtures thereof, optionally with the addition of water as a co-solvent and / or with the addition of an inert auxiliary base such as 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, while the protective group used can simultaneously amidation cleave.

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 prepared compound of formula (I) of the present invention contains an alkoxycarbonyl group, the compound may be converted to the corresponding carboxyl compound by hydrolysis, or if the prepared compound of formula (I) of the present invention contains an amino- or alkylamino- group, by reductive alkylation to the corresponding alkylamino- or dialkylamino compound, or if the compound of formula (I) of the present invention contains an amino- or alkylamino- group, this compound can be converted by acylation or sulfonation to the corresponding acyl- or sulfonyl compound, or I) according to the invention contains a carboxyl group, this compound can be converted by esterification or amidation to the corresponding ester or aminocarbonyl compound, or if the compound of formula (I) contains a cycloalkyleneimine group in which there is one methylene group the sulfur-substituted pin may be converted to the corresponding sulfinyl or sulfonyl compound by oxidation, or if the compound of formula (I) of the present invention contains a nitro group, the compound may be converted to the corresponding amino compound or formula (I) of the present invention by reduction wherein R ⁴ represents an amino-, alkylamino-, aminoalkyl- or N'-alkyl-amino-substituted phenyl group, may subsequently be converted to the corresponding urea compound of formula (I) or compound of general formula by conversion with the appropriate cyanate, isocyanate or carbamoyl halide. of formula (I) according to the invention in which R ⁴ represents an amino-, alkylamino-, aminoalkyl- or N-alkyl-amino-substituted phenyl group can be subsequently converted to the corresponding amidine-transfer group or by conversion with the corresponding nitrile to the corresponding g a uanidine 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, 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.

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 of Raney nickel, platinum or palladium on carbon, or in the presence of a metal hydride such as sodium borohydride, lithium borohydride, sodium cyanoborohydride or lithium aluminum hydride at 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 dimethylsulfoxide. optionally 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, phosphoryl chloride phosphorus pentoxide, N, N-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N -hydroxysuccinimide, N, N-dicyclohexylcarbodiimide / 1-hydroxy-benzotriazole, 2- (1/7-benzotriazol-1-yl) -1, 1,3,3-tetramethyluronium tetrafluoroborate, 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate / 1-hydroxybenztriazole, N, IV-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. 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-methyl-morpholine 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 sulfmyl compound of 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, peroxyacid such as 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 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 ice 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 formula (I) is carried out by oxidation starting from the corresponding sulfmyl 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 glacial acetic acid / acetic anhydride, in trifluoroacetic acid or in 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 acid 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 0-20 ° C .

The 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 environment such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid optionally. 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 7 bar. 5 MPa (from 3 to 5 bars).

The subsequent preparation of the corresponding urea compound of 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, preferably at room temperature.

The subsequent preparation of the corresponding guanidine compound of formula (I) is conveniently carried out by conversion with a compound that 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 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.

Examples of carboxyl protecting groups include trimethylsilyl-, methyl-, ethyl-, tert-butyl-, benzyl- or tetrahydropyranyl-, and protecting groups for the protection of hydroxy-, amino-, alkylamino- or imino- groups, for example: acetyl-, trifluoroacetyl-, benzoyl-, ethoxycarbonyl-, tert-butoxycarbonyl-, benzyloxycarbonyl-, benzyl-, methoxybenzyl- or 2,4-dimethoxy-benzyl- and, in addition, a phthalyl group for the protection of the amino group.

Optional subsequent cleavage of the protecting group used can be carried out, for example, in an aqueous solvent environment, for example water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic, hydrochloric or sulfuric acid, or 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.

The 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. optionally with the addition of an acid such as hydrochloric acid or glacial acetic acid at temperatures between 0 and 50 ° C, preferably at room temperature, and under a hydrogen pressure of about 1 to 7 bar, preferably 0 3 to 0.5 MPa (3 to 5 bar).

Cleavage of the methoxybenzyl group may also be carried out in the presence of an oxidizing agent such as ammonium cerium nitrate in a solvent 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 such as methanol, ethanol, isopropanol, toluene / water or dioxane at temperatures between 20 and 50 ° C.

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

For example, the prepared compound of formula (I), which is in the form of a racemate, can be resolved into optical antipodes by methods generally known per se (see: Allinger NL and Eliel EL in Topics in Stereochemistry, Vol. 6. Wiley Interscience, 1871). ; the compounds of formula (I) having at least 2 asymmetric carbon atoms can be separated into their diastereomers by methods known per se, for example by chromatographic and / or fractional crystallization, owing to their different physicochemical properties; when obtained in racemic form, they can be further resolved into their enantiomers as indicated.

The enantiomeric separation may advantageously be effected 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, and diastereomeric salts or derivatives, for example because of their different solubility, whereby free antipodes can be released from the pure diastereomeric salts or derivatives by treatment with suitable agents. Particularly useful are 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, N-acetylase of parageic or cholineic 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 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), when they contain a carboxyl group, can then be converted into their salts with inorganic or organic bases, in particular for pharmaceutical use, into physiologically acceptable salts. Suitable bases are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

The starting materials of formulas (VII) to (XII) are either known from the literature or can be prepared in the literature by the methods described, or 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 1-6 alkyl. _{A 4-} alkyl-phenyl group, for example by conversion with alkyl- or aryl-sulfonyl 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 CDK.1, 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 viral cyclins, further proliferative cultured human cells, especially endothelial cells, e.g. angiogenesis, but also for 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 without 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 with 5 µg ^/ ml VEGF ₆₅ (vascular endothelial growth factor; Weich H., GBF Braunschweig) and 10 µg / ml 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-ylmethyl) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (b) 3-Z- [( 1- (4- (piperidin-1-ylmethyl) -anilino) -1-phenylmethylene] -6-carbamoyl-2-indolinone, (c) 3-Z- [1- (4- (piperidin-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-ethoxy-carbonyl-2-indolinone, (β 3 -Z- [1- 1-4 '- (N- (2-dimethylamino-ethyl) -A-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-methylsulfonyl-amino) -anilino) -1-phenyl-methylene] - (I) 3-Z- [1- (4- (dimethylaminomethyl) anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, 6-ethoxycarbonyl-2-indolinone,

Q) 3-Z- [1- (4- (N'-acetyl-N-dimethylaminocarbonylmethylamino) -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-indolinone, (n) 3-Z- [l- (4- ^(I - (2-dimethylaminoethyl) -N-methylsulfonylamino) anilino) -l-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (o) 3-Z- [1- (4- (17- (3-dimethylamino-propyl) -77-methylsulfonylamino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, ( p) 3-Z- [1- (4- (N-dimethylaminocarbonylmethyl-N-methylsulfonyl-amino) -amino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (q) 3-Z- [ 1 - (4- ^(I - ((2-dimethylamino-ethyl) carbonyl) -N-methyl-amino) anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (r) 3 Z- [l- (4 - (/ V- (2-dimethylamino-ethyl) -N-acetyl-amino) anilino) -lf enyl-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 (E) 0.05 (F) 0.01 (G) 0,003 (H) 0.01 (I) 0.03 (S) 0.02 (A) 0.03 (D 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, particularly on the proliferation of endothelial cells and tumor cells, said compounds of formula (I) are useful in the treatment of diseases associated with cell proliferation, 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)). The therapeutic need for endothelial cell proliferation inhibitors 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 Sci 93, 2002-2007 (1996)).

The compounds of formula (I), their tautomers, stereoisomers or their physiologically acceptable 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, throat and neck cancer, melanoma, ovarian cancer, prostate cancer, breast cancer, polycellular lung cancer, glioma, colorectal tumors, urogenital cancers such as polymyeloma), psoriasis, arthritis (e.g. rheumatoid arthritis), hemangioma, abgiofibrosis, diabetic retinopathy (eye diseases) kidney diseases (e.g. glomerulonephritis), diabetic nephropathy, malignant nephrosclerosis, microangiopathic thrombosis syndrome, transplant rejection and glomerulopathy, fibrotic diseases (e.g. liver cirrhosis), proliferative mesangiab cell diseases, arteriosclerosis erosion, nerve tissue damage, and for suppressing vascular reocclusion after balloon catheter treatment, vascular orthotics, or mechanical vascular 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 the invention generally taking in a warm, in particular humans, in doses of 0.01 to 100 mg.kg ^"1 of body weight, 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. / 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-1 H -benzotriazole

TBTU = O-benzotriazol-1-yl-WMM-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. 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 twice with 30 ml of methylene chloride. 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 Preparation 1 of the prepared resin was 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.

As in 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

A / - (4-Nitro-phenyl) - / V-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 4 N- (2-Dimethylamino-ethyl) - N -methylsulfonyl-4-nitroaniline

38.9 g of N-methylsulfonyl-4-nitroaniline was 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 of sodium 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] &lt; ^{+ &gt};.

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) -7-methylsulfonyl-amino] -nitrobenzene, (S) 4- [ N - (3-phthalimido-2-yl-propyl) - N -methylsulfonyl-amino] -nitrobenzene, (6) 4- [N - (3- (N -benzyl-N -methyl-amino) -propyl) - / V-methylsulphonyl-amino] -nitrobenzene.

Preparation 5 N- (Dimethylaminocarbonyl-methyl) - N -methylsulfonyl-4-nitro-aniline

^EXAMPLE A 7.0 g carboxymethyl-N '- methylsulfonyl-4-nitroamlínu, 2.5 g dimethylamino hydrochloride, 8.1 g of TBTU and

3.9 g of HOBT were dissolved in 125 ml of dimethylformamide and 17.6 ml of N-ethyldisopropylamine was added at 0 ° C. The reaction mixture was stirred at room temperature for 4 hours, diluted with 1 liter of water and the precipitate formed was collected by suction. 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).

CnH ^ OJS

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

As in 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-methyl-amino) methyl] nitrobenzene, prepared by the reaction of 4- [ (N-carboxymethyl-N'-methyl-amino) -methyl] -nitrobenzene and methylamine hydrochloride, (4) 4- [N - (dimethylcarbamoyl-methyl) - N -methyl-amino) methyl] nitrobenzene, prepared by 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.

Yield: 2.0 g (45%)

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

C12H17N3O3

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

Similar to 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-ethylamino) -nitrobenzene and propionyl chloride, (3) 4- _[1-acetyl-N - (dimethylaminocarbonylmethyl) amino] nitrobenzene a, prepared by reaction of 4- _[J N- (dimethylaminocarbonylmethyl) amino] nitrobenzene and acetyl chloride, (4) 4- [AA ( 2-dimethylamino-ethyl) -X-butyryl-amino] -nitrobenzene, prepared by the reaction of 4- (2-dimethylamino-ethylamino) -nitrobenzene and butyryl chloride, (S) 4- [N- (2-dimethylamino-ethyl) -7H-isobutyryl (amino) nitrobenzene, prepared by the reaction of 4- (2-dimethylamino-ethylamino) -nitrobenzene and isobutyryl chloride, (6) 4- [N- (2-dimethylamino-ethyl) -7-benzoylamino] -nitrobenzene, prepared by the reaction of 4- ( 2-dimethylamino-ethylamino-nitrobenzene and benzoyl chloride, (7) 4- [N- (2-dimethylamino-ethy) l) -N-acetyl-amino] -1,3-dinitrobenzene, prepared by the reaction of 4- (2-dimethylamino-ethylamino) -1,3-dinitrobenzene and acetyl chloride, (8) 4- [A ^L (2-dimethylamino) (ethyl) -N- (furan-2-carbonyl) amino] nitrobenzene, prepared by the reaction of 4- (2-dimethylamino-ethylamino) -nitrobenzene and furan-2-carbonyl chloride, (9) 4- N - (2-dimethylamino-) ethyl) - N- (2-methoxy-benzoyl) -amino] -nitrobenzene, prepared by reacting 4- (2-dimethylamino-ethylamino) -nitrobenzene and 2-methoxy-benzoyl chloride, (10) 4- [N - (2-dimethylamino- ethyl) -N- (pyridine-3-carbonyl) amino] nitrobenzene, prepared by reacting 4- (2-dimethylamino-ethylamino) -nitrobenzene and nicotinic acid chloride, (11) 4- [N- (2-dimethylamino-ethyl) - N - (phenyl-acetyl) amino] nitrobenzene, prepared by the reaction of 4- (2-dimethylamino-ethylamino) -nitrobenzene and phenylacetyl chloride, (12) 4- [N - (2-dimethylamino-ethyl) - N '-acetyl-amino] 3-bromo-nitrobenzene, prepared by reacting 4 - [, N- (2-dimethylaminoethyl) amino] -3-bromo-nitrobenzene and acetyl chloride (13), and ^{I-acryloyl-a /} -methyl-4-nitro (14) _N -acryloyl- N -isopropyl-4-nitro-aniline, prepared by reacting 4-isopropylamino-nitrobenzene and acrylic acid, (14) N-acryloyl- N -benzyl-4-nitroaniline, prepared by reaction of 4-benzylamino-nitro-benzene and acrylic acid chloride, (16) N -bromoacetyl-N -methyl-4-nitroaniline, prepared by reaction of 4- (17) N-bromoacetyl-N-isopropyl-4-nitroaniline, prepared by the reaction of 4-isopropylamino-nitrobenzene and bromoacetyl chloride, (18) N-bromoacetyl-N-benzyl-4-nitroaniline, prepared by the reaction of 4-benzylamino-nitrobenzene and bromoacetyl chloride,

Preparation 7 N - (Dimethylaminomethylcarbonyl) - N -methyl-4-nitroaniline

To 1.8 g of dimethylaminohydrochloride 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), mp 121-122 ° C.

Similar to 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) V - [(4-benzyl-piperazin-1-yl) -methylcarbonyl] -7V-methyl-4-nitroaniline, (4) <N (pyrrolidin-1-yl-methylcarbonyl) -N- ^/ methyl-4-nitroaniline, (5) N - [(N-aminocarbonylmethyl-N'-methyl-amino) -methylcarbonyl] -N-methyl-4-nitroaniline, (6) N '- [(N'-benzyl-N-methyl-amino) -metylkarbonylJ ^{A-f-methyl-4-nitroaniline,} (7) / N [di (2-methoxyethyl) -amino-methylcarbonyl] -N-methyl-4-nitroaniline, (8) 7V- (dimethylamino-methylcarbonyl) - N, N-isopropyl-4-nitroaniline, (9) N - (piperidin-1-ylmethylcarbonyl) - N, N-isopropyl-4-nitroaniline, (10) N - [(4-tert-butoxycarbonylpiperazin-1-yl) methylcarbonyl] - In-isopropyl-4-nitroaniline, (11) N - ^{[(7V-benzyl-N-} methyl-amino) -methylcarbonyl] -7V-benzyl-4-nitroamlín, (12) W (dimetylaminornetylkarbonyl) ^-N, benzyl -4-nitroaniline, (13) N- (piperidin-1-ylmethylcarbonyl) -N-benzyl-4-nitroaniline, (14) N- [di- (2-hydroxyethyl) amino-methylcarbonyl] -N-methyl -4-nitroaniline, (1 5) N - [N - (2-methoxyethyl) - N '-methyl-amino) -methylcarbonyl) - N' -methyl-4-nitroaniline, (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) V - [(imidazol-l-yl) -methylcarbonyl] - _J V-methyl-4-nitroaniline, (19) 7V - [(phthalimido-2-yl) methylcarbonyl] -7V-methyl-4-nitroaniline.

Preparation 8 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-aroyl-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) N - [(2- dimethylamino-ethyl) -carbonyl] -N-methyl-4-nitroaniline, prepared by the reaction of N-acryloyl-N-methyl-4-nitroaniline and dimethylamine hydrochloride, (3) N - [(2- (4-tert-butoxycarbonylpiperazine) - 1-yl) -ethyl) -carbonyl] -N-methyl-4-nitroaniline, prepared by reacting N-acryloyl-N-methyl-4-nitroaniline and N-tert-butoxycarbonylpiperazine, (4) N - [(2- (piperidin-1-yl) -ethyl) -carbonyl] -N-methyl-4-nitroaniline, prepared by the reaction of N ^, -acryloyl- N -methyl-4-nitroaniline and piperidine, (5) N - [(2- ( N-benzyl-N-methyl-amino) -ethyl) -carbonyl] -N-methyl-4-nitroaniline, prepared by reacting N'-acryloyl-N-methyl-4-nitroaniline and N-benzyl-N-methyl-amine .

Preparation 9

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

A mixture of 31.5 g of 4-chloro-1-nitrobenzene and 44.4 ml of 1-methylpiperazine was stirred together 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.

Similar to Preparation 9, the following compounds were prepared:

(1) N- (2-dimethylaminoethyl) -N-methyl-4-nitroaniline, prepared by the reaction of 1-fluoro-4-nitro-benzene and 1-dimethylamino-2-methylaminoethane, (2) N- (3-dimethylaminopropyl) - N-methyl-4-nitroanilm, prepared by reaction of 1-fluoro-4-nitrobenzene and 1-dimethylamino-3-methylamino-propane, (3) 4- (N-carboxymethyl-amino) -nitrobenzene, prepared by reaction of 1-fluoro-4 (4) N-cyclohexyl-p-phenylenediamine, prepared by the reaction of 1-fluoro-4-nitrobenzene and cyclohexylamine, (S) 6- [N- (2-dimethylamino-ethyl) -N-methylsulfonyl- amino] -3-phthalimido-2-yl-nitrobenzene, prepared by reacting 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-methylsulfonylamino] -1,3-dinitrobenzene, prepared by the reaction of 2,4-dinitrochlorobenzene, N- (2-dimethylamino-ethyl) -methanesulfonamide and sodium hydride as a base, (7) 4- [N - (2-dimethylamino-ethyl) - N -methylsulfonylamino] -3-chloro-mitobenzene, prepared by reaction of 2- Fluoro-5-nitro-chlorobenzene, N- (2-dimethylamino-ethyl) -methanesulfonamide and sodium hydride as base, (8) 4- (2-dimethylamino-ethyl-amino) -1,3-dinitrobenzene, prepared by reaction 1-chloro-2,4-dinitro-benzene and N, N -dimethylethylenediamine, (9) 4- [N - (2-dimethylamino-ethyl) - N - (ethylsulfonyl) amino] nitrobenzene, prepared by the reaction of 1-fluoro 4-nitro-benzene, N- (2-dimethylamino-ethyl) -ethanesulfonamide and sodium hydride as a 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) -7- (butylsulfonyl) (amino) -nitrobenzene, prepared by reacting 1-fluoro-4-nitro-benzene, N - (2-dimethylamino-ethyl) -butanesulfonamide and sodium hydride hydride as a base, (12) 4- [N - (2-dimethylamino) - ethyl) - N - (benzylsulfonyl) amino] -nitrobenzene, prepared by the reaction of 1-fluoro-4-nitro-benzene, N - (2-dimethylaminoethyl) -phenylmethanes (13) 4- [N - (2-dimethylamino-ethyl) - N - (phenylsulfonyl) amino] -trobenzene, prepared by the reaction of 1-fluoro-4-nitro-benzene, N - (2) (14) 4- [N - (2-dimethylamino-ethyl) - N - (isopropylsulfonyl) amino] nitrobenzene, prepared by the reaction of 1-fluoro-4-nitro-dimethylamino-ethyl) -benzenesulfonamide and sodium hydride as a base; (15) 4- [N - (2-dimethylamino-ethyl) -amino] -3-bromo-nitrobenzene, prepared by the reaction of 2- (2-dimethylamino-ethyl) -isopropylsulfonamide and sodium hydride as the base; (16) 4-isopropylamino-nitrobenzene, prepared by reaction of 1-fluoro-4-nitrobenzene and isopropylamine, (17) 4-benzylamino-nitrobenzene , prepared by reaction of 1-fluoro-4-nitrobenzene and benzylamines.

Preparation 10

4- (Imidazol-4-yl) -1-nitrobenzene

9.5 g of 2-phenyl-imidazole were carefully 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), Product value: 0.6 (silica gel, ethyl acetate / ethanol = 10: 1), C ₉ H ₇ N ₃ O ₂

Mass spectrum: m / z = 189 [M] &lt; ^{+ &gt};.

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-phenyl-imidazole (J. Heterocycl. 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 taken up in 25 ml diluted hydrochloric acid (c = 1 ci _H mol.dm ^'3) and 4 hours, heated to reflux. 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.

Yield: 1.0 g (47% of theory). Product value: 0.6 (silica gel, ethyl acetate / ethanol = 10: 1), m.p. 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), Product value: 0.6 (silica gel, methylene chloride / methanol = 9: 1), C ₁₂ H ₆ N ₂ O _{2 +}

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) -trobenzene, (3) 4- ( N, N -dimethyl-aminomethyl) -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-methylmethyl-aminomethyl) -nitrobenzene, (9) 4- [N- (n) (10) 4- (thiomorpholin-4-yl-methyl) -nitrobenzene, (11) 4 - [(4-methyl-piperazin-1-yl) -methyl] -hexyl) - N -methyl-aminomethyl) -nitrobenzene; -nitrobenzene, (12) 4- (imidazol-1-yl-methyl) -nitrobenzene, (13) 4- [2- (4-hydroxy-piperidin-1-yl) -ethyl-amino] -nitrobenzene, (14) 4 - [(3-hydroxy-pyrrolidin-1-yl) -methyl] -nitrobenzene, (15) 4- (1,2,4-triazol-1-ylmethyl) -nitrobenzene, (16) 4- (1) (2,3) triazol-2-ylmethyl) nitrobenzene, (17) 4- (1,2,3-triazol-1-ylmethyl) nitrobenzene, (18) 4 - [(N-ethoxycarbonyl- methyl- (N-methyl-amino) -methyl] nitrobenzene, (19) 4 - [(N-aminocarbonyl-methyl-N-methyl-amino) -methyl] -nitrobenzene, (20) 4- (azetidin-1 -) - yl (21) 4 - [(di- (2-methoxy-ethyl) -amino) -methyl] -nitrobenzene, (22) 4- [N- (N-tert-butoxycarbonyl-3-amino) -methyl] -nitrobenzene; (23) 4 - [(N'-propyl-N-methyl-amino) -methyl] -nitrobenzene, (24) 4 - [(N - (2-dimethylamino-) -propyl) -N-methylaminomethyl] -nitrobenzene; (25) 4 - [(N - (3-dimethylamino-propyl) - N -methyl-amino) -methyl] -nitrobenzene, (26) 4 - [(ethyl) -N- (methyl-amino) -methyl] -mtrobenzene; - [(N- (2-methoxy-ethyl) - N -methyl-amino) -methyl] -nitrobenzene, (2 S) 4 - [(N '- (2-hydroxy-ethyl) - N -methyl-amino) (methyl) -nitrobenzene, (2 S) 4 - [(N - (dioxolan-2-ylmethyl) - N -methyl-amino) methyl] nitrobenzene, (2 S) 4- (3-oxo-piperazine-1) yl-methyl) nitrobenzene.

Preparation 13 4 - [(N-Carboxymethyl- N -methyl-amino) -methyl] -nitrobenzene

7.33 g of 4 - [(N-ethoxycarbonyl-methyl- N -methyl-amino) -methyl] -trobenzene were dissolved in 140 ml of ethanol, and 34.0 ml of sodium hydroxide solution (c _NaOH = 1 mol. dm 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 the product: 0.4 (silica gel, methylene chloride / methanol = 2: 1), C10H12N2O4

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

Preparation 14

4- (W-ethyl-aminomethyl) -nitrobenzene

6.0 g of 4-nitrobenzyl bromide was dissolved in 25 ml of ethanol, the solution was mixed with 25 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) (11) 4- (morpholin-4-ylmethyl) -nitrobenzene, (12) 4- (hexamethyleniminomethyl) -nitrobenzene, (13) 4- (4-hydroxy-piperidin-1-yl-) -methyl- (14) 4- (4-methoxy-piperidin-1-ylmethyl) -nitrobenzene,

(15) 4- (4-methyl-piperidin-1-yl-methyl) -nitrobenzene, (16) 4- (4-ethyl-piperidin-1-yl-methyl) -nitrobenzene, (17) 4- (4-isopropyl-piperidin-1-yl-methyl) -nitrobenzene, (18) 4- (4-phenyl-piperidin-1-yl-methyl) -nitrobenzene, (19) 4- (4-benzyl-piperidin-1) (20) 4- (4-ethoxycarbonyl-piperidin-1-ylmethyl) -nitrobenzene, (21) 4- (N, N-dipropyl-aminomethyl) -nitrobenzene, (22) 4- (4-tert-butoxycarbonyl-piperazin-1-yl-methyl) -nitrobenzene, (23) 4- (2-morpholin-4-yl-ethyl) -nitrobenzene, (24) 4- (2-pyrrolidin-1) (25) 4- (2-piperidin-1-yl-ethyl) -nitrobenzene, (26) 4- ( ₁ -ethyl-N'-benzylaminomethyl) -nitrobenzene, (27) ) 4- (N-propyl-N-benzyl-aminomethyl) -nitrobenzene, (28) 4- [N-methyl-N- (4-chlorobenzyl) -aminomethyl] -nitrobenzene, (29) 4- [N-methyl] - ^N - (4-bromobenzyl) aminomethyl] -trobenzene, (30) 4- [N -methyl- N - (4-fluorobenzyl) -ammomethyl] nitrobenzene, (31) 4- [N ¹ -methyl- N- (4-methylbenzyl) aminomethyl] -nitrobenzene (32) 4- ^{[N-methyl-N-f} - (3-chloro-benzyl) -amino nomethyl] -nitrobenzene, (33) 4- [N-methyl-N - (3,4-dimethoxybenzyl) -aminomethyl] -nitrobenzene, (34) 4- [N-methyl-N- (4-methoxybenzyl) aminomethyl] (35) 4- (N-2,2,2-trifluoroethyl-N'-benzylaminomethyl) nitrobenzene, (36) 4- [N-2,2,2-trifluoroethyl-N - (4)] - nitrobenzene; (chlorobenzyl) aminomethyl] nitrobenzene _; (37) 4- (thiomorpholin-4-yl-methyl) -nitrobenzene, (38) 4- (azetidin-1-yl-methyl) -nitrobenzene, (39) 4- (3,4-dihydropyrrolidin-1-yl- methyl) -nitrobenzene, (40) 4- (3,4-dihydropiperidin-1-ylmethyl) -nitrobenzene, (41) 4- (2-methoxycarbonyl-pyrrolidin-1-ylmethyl) -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- [M (3) (47) 4- [N - ((2,6-dichlorobenzyl) -N'-methyl) aminomethyl] nitrobenzene, (48) 4- [4-dimethoxybenzyl] -N-ethyl-aminomethyl] -nitrobenzene, (48) 4- [N - (4-Trifluoromethylbenzyl) - N -methyl) aminomethyl] -nitrobenzene, (49) 4- (N -benzyl-N -isopropyl-aminomethyl) nitrobenzene, (50) 4- (N -benzyl- N-Zez-t-butyl-aminomethyl) -trobenzene, (51) 4- (N, N-diisopropyl-aminomethyl) -nitrobenzene, (5 2) 4- (ΛΛζ'-diisobutyl-aminomethyl) -nitrobenzene, ( 53) 4- (2,3,4,5-tetrahydro-benzo (d) azepin-3-ylmethyl) -nitrile robenzene, (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) -A ^'] (58) 4- [N - (1-ethyl-pentyl) - N - (pyridin-2-ylmethyl) -aminomethyl] -nitrobenzene, (59) 4- (piperidin-1-yl) -benzyl-aminomethyl] -nitrobenzene; -yl-methyl) -1,3-dinitrobenzene, (60) 4- (N-phenethyl- N -methyl-aminomethyl) nitrobenzene, (61) 4- [N- (3,4-dihydroxy-phenethyl) - N-methyl-aminomethyl] -nitrobenzene, (62) 4- [N - (3,4,5-trimethoxyphenethyl) -7 H -methyl-aminomethyl] nitrobenzene, (63) 4- [N- (3,4) (64) 4- [N- (3,4-dimethoxy-benzyl) - N -methyl-aminomethyl] -nitrobenzene, (65) 4- [N-methoxy-renethyl] - N -methyl-aminomethyl] -nitrobenzene, (65) 4- N - (4-chloro-benzyl) - N -methyl-aminomethyl] -nitrobenzene, (66) 4- [N - (4-bromo-benzyl) - N -methyl-aminomethyl] -trobenzene, (67) 4- [N- (4-fluoro-benzyl) - N -methyl-aminomethyl] -nitrobenzene, (68) 4- [N- (4-methyl-benzyl) -7-methyl-aminomethyl] -nitrobenzene, ( 69) 4- [N - (4-nitro-phenethyl) - N -methyl-aminomethyl] -nitrobenzene, (70) 4- (N ^, -phenethyl- N -benzylaminomethyl) -nitrobenzene, (71) 4- ( N-phenethyl-N-cyclohexyl-aminomethyl) -nitrobenzene, (72) 4- [N - (2- (pyridin-2-yl) -ethyl) - N -methyl-aminomethyl] -nitrobenzene, (73) 4- [N- (2- (pyridin-4-yl) ethyl) -N-methyl-aminomethyl] -nitrobenzene (74) 4- ^[I - (pyridin-4-yl-methyl) -zV-methyl-aminomethyl ] nitrobenzene, (75) 4- (A ^/, / V-dibenzyl-aminomethyl) nitrobenzene, (76) 4 - [/ V- (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-ylmethyl) -nitrobenzene, (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-yl-methyl) -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-ylmethyl) nitrobenzene, (91) 4- (7-methoxy-1,2,3,4-tetrahydro-isoquinolin-2-one); (92) 4 - [(2,3,4,5-tetrahydro-azepino (4,5-b) pyrazin-3-yl) methyl] nitrobenzene, (93) 4 - [(7-yl) methyl] nitrobenzene; -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-yl) -methyl] -nitrobenzene, (95) 4 - [(5,6,7,8-tetrahydro-azepino (4,5-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), C ₁₁ H ₁₄ N ₂ O ₄ S

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

As in Preparation 15, the following compound was prepared:

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

PREPARATION 16 4- ^[Λ, - (3-Amino-propyl) -7V ^{l ·} methylsulphonyl-amino] nitrobenzene

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 The mixture was stirred at 50 ° C for 1.5 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),

C ₁₀ H ₁₅ N ₃ O ₄ N

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

Similar to Preparation 16, a compound was prepared:

(1) 6- [A ^/ - (2-dimethylamino-ethyl) -7V-methylsulfonylamino] -3-amino-nitrobenzene is prepared from 6- [7V- (2-dimethylamino-ethyl) - / V-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), _{R f} value of the product: 0.6 (silica gel, methylene chloride / methanol = 10: 1). Mp 186-187 ° C.

As in 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 of 4- (imidazol-2-yl) -nitrobenzene and benzyl bromide.

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-methoxyethoxy) 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), _{R f} value of the product: 0.5 (aluminum oxide, toluene / ethyl acetate = 5: 1) C13H20N2O4

ESI-MS: m / z = 267 [M-H] -.

Preparation 19 4- (N'-Ethyl-N-tert-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-butoxycarbonyl anhydride) 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,

_{R f} value of the product: 0.3 (silica gel, methylene chloride / methanol = 50: 1), melting point: 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 - (/ V-cyclohexyl- <W-tert-butoxycarbonyl-aminomethyl) nitrobenzene, (4) 4- (N-isopropyl-7V- ^{I '/} t-butoxycarbonyl-aminomethyl) nitrobenzene, (5) -4- ( N-methyl- N - tert -butoxycarbonyl-aminomethyl) -nitrobenzene, (6) 4- (N -propyl- N - tert -butoxycarbonyl-aminomethyl) -nitrobenzene, (7) 4- (N -butyl-A) "tert-butoxycarbonyl-aminomethyl) nitrobenzene, (8) 4- ^{(N-methoxycarbonylmethyl-A} - / t-butoxycarbonyl-aminomethyl) nitrobenzene, (9) 4- (7V-benzyl-7V-tert butoxycarbonyl-aminomethyl) nitrobenzene, (10) 4- [N- (3-trifluoroacetylaminopropyl) - N -methylsulfonylamino] nitrobenzene, prepared by the reaction of 4- [N - (3-amino-propyl) - N -methylsulfonyl-amino] (11) 4 - [(4-tert-butoxycarbonyl-piperazin-1-yl) -methyl] -nitrobenzene] -nitrobenzene and trifluoroacetic anhydride.

Preparation 20

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

37.0 g of 4- (piperidin-1-ylmethyl) -nitrobenzene was dissolved in 300 ml of methanol, 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), Product value: 0.4 (silica gel; methylene chloride / methanol = 9: 1), C ₁₂ H ₁₈ N ₂

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-ethyl) -7V (7) 4- [N- (3-dimethylamino-propyl) -N-acetyl-amino] -aniline, (8) 4- [N- (2-dimethylamino-ethyl) -7H-acetyl-amino] -aniline; (9) 4- [N - (2-dimethylamino-ethyl) - N -propionyl-amino] -aniline, (10) 4- [N - (2-dimethylamino-ethyl) -A] -benzoyl-ainino] -aniline; ^f butyryl-amino] -aniline (11) 4- [TV- (2-dimethylamino-ethyl) -7V-isobutyryl-amino] -aniline (12) 4- (7V-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-butoxycarbonyl-aminomethyl) aniline, (16) 4 - (/ _{V-isopropyl-J-tert-butoxycarbonyl]} aminomethyl) aniline, (17) 4- ( N-propyl-N-tert-butoxycarbonyl-aminomethyl) -aniline, (18) 4- (N-methyl-N-tert-butoxy) (19) 4- (N-butyl-N-tert-butoxycarbonyl-aminomethyl) -aniline, (20) 4- (N-methoxycarbonylmethyl-N-tert-butoxycarbonylaminomethyl) -aniline, (21) 4 - (/ ^{V-benzyl-N-tert-butoxycarbonyl-f} 1-aminomethyl) -aniline (22) 4- (pyrrolidin-1-yl-methyl) -aniline (23) 4- (morpholin-4 (25) 4- (4-hydroxy-piperidin-1-ylmethyl) -aniline, (26) 4- (4-methoxy-4-methoxy-piperidin-1-ylmethyl) -aniline; piperidin-1-yl-methyl) -aniline, (27) 4- (4-methyl-piperidin-1-yl-methyl) -aniline, (28) 4- (4-ethyl-piperidin-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-ylmethyl) -aniline, (33) 4- (N, N-dipropyl- aminomethyl) -aniline, (34) 4- (4-tert-butoxycarbonyl-piperazin-1-ylmethyl) -aniline, (35) 4- (2-morpholin-4-yl-ethyl) -aniline, (36) 4- (2-pyrrolidin-1-yl-ethyl) -aniline, (37) 4- (2-piperidin-1-yl-ethyl) -aniline, (38) 4- (N-propyl-N'-benzyl) aminomethyl) aniline, (39) 4- (N- (n-hexyl) - / V-methyl-aminomethyl] -aniline (40) 4- [7V-methyl-A ^/ - (4-chlorobenzyl) aminomethyl ] -aniline (41) 4- (N-methyl- / V- (4-bromobenzyl) aminomethyl] -aniline (42) 4- [N-methyl ^d / N- (4-methylbenzyl) aminomethyl] aniline, (43) 4- [N-methyl-A ^/ - (4-fluorobenzyl) aminomethyl] -aniline (44) 4- [7V-methyl-N- (3-chlorobenzyl) aminomethyl] aniline, (45) 4 - [<V-methyl- / V- (3,4-dimethoxybenzyl) aminomethyl] -aniline (46) 4- | 7V-methyl-A ^/ - (4-methoxybenzyl) aminomethyl] -amlín (47) 4- (N-2,2,2-trifluoroethyl- N -benzyl-aminomethyl) -aniline, (48) 4- [N-2,2,2-trifluoroethyl-N - (4-chlorobenzyl) (aminomethyl) -aniline, (49) 4- (thiomorpholin-4-yl-methyl) -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-dihydropyrrolidin-1 -) - (54) 4- (3,4-dihydropiperidin-1-ylmethyl) -aniline, (55) 4- (2-methoxycarbonyl-pyrrolidin-1-yl] -methyl) -aniline, (56) 4- (3,5-dimethyl-piperidine-1) -yl-methyl) -aniline, (57) 4- (4-phenyl-piperazin-1-yl-methyl) -aniline, (58) 4- (4-phenyl-4-hydroxy-piperidin-1-yl- (59) 4- [N - (3,4,5-trimethoxy-benzyl) - N -methyl-aminomethyl] aniline, (60) 4- [N - (3,4-dimethoxy-benzyl) - N-Ethyl-aminomethyl] -aniline, (61) 4- (N-benzyl-7'-ethyl-aminomethyl) -amine, (62) 4- [N-(2,6-dichlorobenzyl) - N -methyl (63) 4- [N - (4-trifluoromethylbenzyl) - N -methyl-aminomethyl] -aniline, (64) 4- (N -benzyl- N -isopropyl-aminomethyl) -aniline, (65) 4- (N -benzyl-N ^' - tert -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] -anil n, (75) 4- [N- (1-ethyl-pentyl) -N- (pyridin-2-yl-methyl) -aminomethyl] -aniline, (76) 4- (piperidin-1-yl-methyl) - 3-nitro-aniline, (77) 4- (piperidin-1-yl-methyl) -3-amino-aniline, (78) 4- (N-benzyl- N -methyl-aminomethyl) -aniline, (79) ) -4- ^{(TV-ethyl-f-methyl-aminomethyl)} -aniline (80) 4- (N-phenethyl-7V-methyl-aminomethyl) -aniline (81) 4- [N- (3,4- dihydroxy-phenethyl) -N-methyl-aminomethyl] -amine, (82) 4- [N - (3,4,5-trimethoxy-phenethyl) - N -methyl-aminomethyl] -aniline, (83) 4- [N - (3,4-dimethoxy-phenethyl) - N ¹ -methyl-aminomethyl] -aniline, (84) 4- [N - (3,4-dimethoxy-benzyl) - N -methyl-aminomethyl] -aniline, (85) 4- [N - (4-chloro-benzyl) - N -methyl-aminomethyl] -aniline, (86) 4- [N - (4-bromo-benzyl) -7-methyl-aminomethyl] -aniline (87) 4- [N - (4-fluoro-benzyl) - N -methyl-aminomethyl] -aniline, (88) 4- [N - (4-methyl-benzyl) - N -methyl- (89) 4- [N-(4-nitro-phenethyl) -N-methyl-aminomethyl] -aniline, (90) 4- (N-phenethyl-N-benzylaminomethyl) -aniline, ( 91) 4- (N-phenethyl-N-cyclohexyl-aminomethyl) -aniline, (92) 4- N - (2- (pyridin-2-y) (1) -ethyl) - N -methyl-aminomethyl] -aniline, (93) 4- [N - (2- (pyridin-4-yl) -ethyl) - N -methyl-aminomethyl] -amino, ( 94) 4- [N - (pyridin-4-ylmethyl) - N -methyl-aminomethyl] -aniline, (95) 4- (N, N-dibenzylaminomethyl) -aniline, (96) 4- [A ^{1 '} - (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-yl-methyl) -methyl-aminomethyl] -aniline, (101) 4- (7-chloro-2,3,4,5-tetrahydro-benzo (d) azepin-3-yl) (102) 4- (7,8-dichloro-2,3,4,5-tetrahydro-benzo (d) azepin-3-ylmethyl) -aniline, (103) 4- (7-methyl) -aniline; -methoxy-2,3,4,5-tetrahydro-benzo (d) azepin-3-yl-methyl) -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-yl-methyl) -aniline, (106) 4- (6,7-dichloro-1,2,3,4-tetrahydro-isoquinolin-2-ylmethyl) -amine, (107) 4- (6,7-dimethyl-1,2,3) , 4-tetrahydro-isoquinolin In-2-yl-methyl) -aniline, (108) 4- (6-chloro-1,2,3,4-tetrahydro-isoquinolin-2-ylmethyl) -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) (111) 4- (7-methoxy-1,2,3,4-tetrahydro-isoquinolin-2-ylmethyl) -aniline, (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) pyrazine- 3-yl-methyl) -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-ylmethyl) -aniline, (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] -amine (121) N- (4-aminophenyl) -N-methyl-methanesulfonamide, (122) 4- (imidazol-4-yl) -aniline, (123) 4- (tetr azol-5-yl) -aniline, (124) 4- [N - (2-dimethylamino-ethyl) - N -propionyl-amino] -amino, (125) N - (dimethylaminomethylcarbonyl) - N -methyl- p-phenylenediamine, (126) N - [(2-dimethylamino-ethyl) -carbonyl] -N-methyl-p-phenylenediamine, (127) 4- (N-acetyl-N - (dimethylaminocarbonylmethyl) amino) - aniline, (128) N-methylaminocarbonyl-methyl-N-methylsulfonyl-p-phenylenediamine, (129) N-aminocarbonyl-methyl-N-methylsulfonyl-p-phenylenediamine, (130) 4- (imidazolidine-2,4-dione- 5-ylidene-methyl) -aniline, (131) 4- (imidazolidin-2,4-dione-5-ylmethyl) -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 -methylsulfonyl-amino] -aniline, (137) 4- [N- (3- (N-benzyl- N -methyl-amino) -propyl) - N -methylsulfonylamino] -aniline, (138) N -cyclohexyl-p-phenylenediamine, (139) 4- (pyridin-4-yl-methyl) -aniline, (140) 4- (imidazol-1-yl-methyl) -aniline n, (141) 4-benzyl-aniline, (142) N- (3-trifluoroacetylamino-propyl) -7H-methylsulfonyl-p-phenylenediamine, (143) 4-amino-phenylacetic acid tert-butyl ester, (144) 4- (145) 4- (1-methyl-imidazol-2-yl) -aniline, (146) 4- (1-ethyl-imidazol-2-yl) -aniline, (147) ) 4- (1-benzyl-imidazol-2-yl) -aniline, (148) 4- [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 A, (151) 4- [7V- (2-dimethylamino-ethyl) -N ^/ N-acetyl-amino] -3-bromo-aniline, (152) 4- [2- (4-hydroxy (153) N- (2-dimethylamino-ethyl) - N -ethylsulfonyl-p-phenylenediamine, (154) N - (2-dimethylamino-ethyl) - N -piperidin-1-yl) ethyl-amino] -aniline; -propylsulfonyl-p-phenylenediamine, (155) N - (2-dimethylamino-ethyl) - N -isopropyl-sulfonyl-p-phenylenediamine, (156) N- (2-dimethylamino-ethyl) - N -butylsulfonyl-p-phenylenediamine (157) N- (2-dimethylamino-ethyl) - N -benzylsulfonyl-p-phenylene diamine, (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 - (pyridine-3-carbonyl) -amino] -aniline, (163) 4- [1 '- (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] -7 H -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] -N-isopropyl-p-phenylenediamine, (170) N - [(2-dimethylamino-ethyl) -carbonyl] - N -benzyl-p-phenylenediamine, (171) N - (N-aminocarbonyl) ^-methyl-, -methyl-amino) methylcarbonyl) -N-methyl-p-phenylenediamine, (172) and ^f - [(N-benzyl - / V-methyl-amino) -methylcarbonyl] -N-methyl-p-phenylenediamine, (173) A ^/ - [di- (2-methoxyethyl) -amino-methylcarbonyl) -N-methyl-p-phenylenediamine, (174) N - [(2- (4-tert-butoxycarbonyl-piperazin-1-yl) ethyl) carbonyl] -N-methyl-p-phenylenediamine, (175) N - [2- (piperidin-1-yl) ) ethyl) carbonyl] -N-methyl-p-phenylenediamine, (176) N - [(2- _(benzyl-J V / V-methyl-amino) -ethyl]) - carbonyl] -N ^I - (177) N - (dimethylaminomethylcarbonyl) - N -isopropyl-p-phenylenediamine, (178) N- (piperidin-1-ylmethylcarbonyl) -N-isopropyl-p-phenylenediamine, (179) N - [(4-tert-butoxycarbonyl-piperazin-1-yl) methylcarbonyl] -Misopropyl-1H-phenylenediamine, (180) N - [(N-benzyl-N-methyl-amino) -methylcarbonyl] - N-benzyl-p-phenylenediamine, (181) N - (dimethylaminomethylcarbonyl) - N -benzyl-p-phenylenediamine, (182) N - (piperidin-1-ylmethylcarbonyl) - N -benzyl-p-phenylenediamine, (183) 4- (1,2,4-triazol-1-yl-methyl-aniline, (184) 4- (1,2,3-triazol-2-ylmethyl) -aniline, (185) 4- (1,2,3-triazol-1-ylmethyl) -aniline, (186) 4 - [(N-etox) (187) 4 - [(N-aminocarbonyl-methyl-; N -methyl-amino) -methyl] -aniline, (188) 4- (azetidine-) -carbonyl-methyl-N-methyl-amino) -methyl] aniline; 1-yl-methyl) -aniline, (189) 4 - [(di- (2-methoxy-ethyl) -amino) -methyl] -aniline, (190) 4 - [(N - (2- (2-methoxy) (191) 4- [N - (N-tert-butoxycarbonyl-3-amino-propyl) - N -methylaminomethyl] -aniline, (ethoxy) -ethyl) - N -methyl-amino) -methyl] -aniline; (192) 4 - [(N- (methylcarbamoyl-methyl) -N ^{& apos} methyl-amino) -methyl] -aniline (193) 4 - [(7V- (dimethylcarbamoyl-methyl) -N- ^/ methyl-amino) methyl] aniline,

EN 287 312 Β6 (194) 4 - [(7V-propyl-N-methyl-amino) -methyl] -aniline (195) 4 - ^[(A - (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] -amine, (199) 4 - [( N - (dioxolan-2-yl-methyl) - N '-methyl-amino) -methyl] -aniline, (200) 4- (3-oxo-piperazin-1-yl-methyl) -aniline, (201) N- [di- (2-hydroxyethyl) amino-methylcarbonyl] -N-methyl-p-phenylenediamine, (202) N - [(N '- (2-methoxyethyl) -N-methylamino) 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), mp 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 of 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),

Product value: 0.7 (silica gel, petroleum ether / ethyl acetate = 1: 1), mp 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), Product value: 0.4 (silica gel, methylene chloride / methanol = 10: 1), mp 208-211 ° C.

As in 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.

SK 287312-6

Preparation 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%), _{R f} value of the product: 0.5 (silica gel, petroleum ether / methylene chloride / ethyl acetate = 5: 4: 1), mp = 98-100 ° C ₂₂ H ₂₁ NO ₅ .

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-indolinone trifluoroacetate

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) -anilm, the reaction mixture was shaken at 70 ° C for 22 hours. 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 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,

Product value: 0.1 (silica gel, methylene chloride / methanol = 9: 1),

C ₂₈ H ₂₈ N ₄ O ₂ Mass spectrum: m / z = 452 [M] ⁺ .

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, C ₂₂ H ₇ N ₃ O ₂ , 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 and from 4-dimethylaminomethyl-aniline, C ₂₅ H ₂₄ N ₄ O ₂ , 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,

C ₂₈ H ₃₀ N ₄ O ₂ , mass spectrum: m / z = 454 [M] ⁺ , (4) 3-Z- [1- (4- (morpholin-4-ylmethyl) -anilino) -1- phenyl-methylene] -6-carbamoyl-2-indolinone trifluoroacetate, prepared from a resin prepared similar to Preparation 2 and from 4- (morpholin-4-ylmethyl) -anilm, Product Value: 0.50 (gel) silica, methylene chloride / methanol = 4: 1) C ₂₇ H 6 N ₄ O _{2 3,} MS: m / z = 454 [m] ^+, (5) 3-Z- [l - (4- (l-oxo (thiomorpholin-4-ylmethyl) -anilino) -1-phenylmethylene] -6-carbamoyl-2-indolinone trifluoroacetate, prepared from a resin prepared similar to Preparation 2 and from 4- (1-oxo- tiomorpholin-4-yl-methyl) -aniline,

Product value: 0.30 (silica gel, methylene chloride / methanol = 9: 1) C ₂₇ H ₂₆ N ₄ O ₃ S, mass spectrum: m / z = 486 [M] ⁺ , (6) 3-Z- [ 1- (4- (1,1-dioxo-thiomorpholin-4-ylmethyl) -aniline) -1-phenyl-methylene] -6-carbamoyl-2-indolinone trifluoroacetate,

Prepared by reaction from a resin prepared similar to Preparation 2 and 4- (1,1-dioxo-thiomorpholin-4-ylmethyl) -aniline,

Rf value of the product: 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 -butoxycarbonylamino-methyl] - aniline, R _r value of the product: 0.40 (silica gel, methylene chloride / methanol = 4: 1).

C30H26N4O2, + mass spectrum: m / z = 474 [M] ⁺ , (8) 3-Z- [1- (4- (aminomethyl) 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-aminomethyl) -aniline,

_{R f} value of the product: 0.10 (silica gel, methylene chloride / methanol = 4: 1).

C23H20N4O2, mass spectrum: m / z = 384 [M] ⁺ , (9) 3- Z- [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,

Product value: 0.45 (silica gel, methylene chloride / methanol = 4: 1), C30H32N4O2, mass spectrum: m / z = 480 [M] ⁺ , (10) 3-Z- [1- (4- (pyrrolidine) -1-ylmethyl) anilino) -1-phenylmethylene] -6-carbamoyl-2-indolinone trifluoroacetate, prepared from a resin prepared similar to Preparation 2 and from 4- (pyrrolidin-1-ylmethyl) - Aniline, Product Value: 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, prepared from a resin prepared similar to Preparation 2 and from 3-dimethylaminomethylamine, Product Value: 0.23 (acid gel) silica, methylene chloride / methanol = 4: 1), C 25 H 24 N 4 O 2, mass spectrum: m / z = 412 [M] ⁺ , (12) 3-Z- [1- (3- (N-methyl-) N -ethyl- (aminomethyl) -anilino) -1-phenylmethylene] -6-carbarnoyl-2-indolinone-trifluoroacetate, from a resin prepared similarly and ko in preparation 2 and N-N-ethyl-methyl-aminomethyl-aniline,

Product Value; 0.23 (silica gel, methylene chloride / methanol = 4: 1), C ₂₆ H ₂₆ N ₄ O 2, mass spectrum: m / z = 426 [M] ⁺ , (13) 3-Z- [1- (3- ( methylaminomethyl) anilino) -l-phenyl-methylene] -6-carbamoyl-2-indolinone-trifluoroacetate prepared from the resin prepared as in preparation 2 and 4- (S ^{I '-tert-butoxycarbonyl-methyl-X} aminomethyl) aniline,

Product value: 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, the compound was prepared from a resin prepared similar to that of Preparation 2 and from 3-aminobenzyl alcohol, Product Value: 0.7 (silica gel, methylene chloride) (methanol = 4: 1) C 23 H 19 N 3 O 3, mass spectrum: m / z = 385 [M] ⁺ , (15) 3-Z- [1- (4- (methoxycarbonylmethylaminomethyl) anilino) -1-phenylmethylene] -6- carbamoyl-2-indolinone trifluoroacetate, the compound was prepared from a resin prepared similar to Preparation 2 and from 4- (N-methoxycarbonyl-methyl-N-tert-butoxycarbonyl-aminomethyl) aniline,

Product value: 0.40 (silica gel, methylene chloride / methanol = 9: 1) C 26 H 24 N 4 O 4, mass spectrum: m / z = 457 [M + H] ⁺ , (16) 3-Z- [1- (4- ( N-methylsulfonyl-N- (dimethylaminocarbonyl-methyl) -amino) -anilino) -1-phenyl-methylene] -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 the product: 0.40 (silica gel, methylene chloride / methanol = 9: 1)

C27H27N5O5S, mass spectrum: m / z = 533 [M] ⁺ , (17) 3 -Z- [1- (4- (N-acetylaminomethyl) anilino) -1-phenylmethylene] -6-carbamoyl-2-indolinone, compound was prepared from a resin prepared similar to Preparation 2 and from 4- (N-acetyl-aminomethyl) -aniline, 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,

_{R f} value of the product: 0.40 (silica gel, methylene chloride / methanol = 9: 1).

C ₂₄ H ₂₁ N ₃ O ₄ , mass spectrum: m / z = 415 [M] ⁺ , (19) 3-Z- [1- (4- (morpholin-4-yl) 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-yl-aniline, Rf product value: 0.20 (silica gel, methylene chloride / methanol = 9: 1) C ₂₆ H ₂₄ N ₄ O ₃ , mass spectrum: m / z = 440 [M] ⁺ , (20) 3-Z1- (4-acetylamino-amino) -1-phenyl-methylene] -6- carbamoyl-2-indolinone prepared from the resin prepared as in preparation 2 and 4-acetylamino-aniline, R _r value of the product: 0.25 (silica gel, methylene chloride / methanol = 9: 1) C 2 H ₂₀ N _{4 4} O ₃ , mass spectrum: m / z = 412 [M] ⁺ , (21) 3 -Z- [1- (4-amino-anilino) -1-phenyl-methylene] -6-carbamoyl-2-indolinone, the compound was prepared from a resin prepared similar to Preparation 2 and from 4-amino-aniline, Rf value of the product: 0.40 (silica gel, methylene chloride / methanol = 9): 1) C ₂₂ H ₈ N ₄ O 2, mass spectrum: m / z = 370 [M] ⁺ , (22) 3-Z- [1- (4-N ^- methyl- N -acetylaminoanilino) -1-phenylmethylene ] -6-carbamoyl-2-indolinone, the compound was prepared from a resin prepared similar to Preparation 2 and 4- (N-methyl-N-acetyl-amino) -aniline,

₂ C 5 H ₂₂ N ₄ O ₃ MS: m / z = 426 [M] ^+, (23) 3-Z- [l- (4-ethoxycarbonyl-anilino) -l-phenyl-methylene] -6-carbamoyl -2-indolinone, the compound was prepared from a resin prepared similar to Preparation 2 and from ethyl 4-aminobenzoate,

₂ C 5 H ₂₁ N ₃ O _4, MS: m / z = 427 [M] ^+, (24) 3-Z- [l- (4-carboxy-anilino) -I-phenyl-methylene] -6-carbamoyl 2-indolinone prepared from the resin prepared as in preparation 2 and 4-amino-benzoic acid, _{R f} value of the product: 0.11 (silica gel, methylene chloride / methanol = 9: 1).

C2 ₃ H ₇ N ₃ O ₄ , mass spectrum: m / z = 398 (MH) -, (25) 3-Z- [1- (4-benzylcarbamoyl-anilino) -1-phenyl-methylene] -6-carbamoyl -2-indolinone, the compound was prepared from a resin prepared similar to Preparation 2 and from 4-aminobenzoic acid benzylamide,

_{R f} value of the product: 0.21 (silica gel, methylene chloride / methanol = 9: 1) C ₃ oH ₂₄ N ₄ 0 ₃ * MS: m / z = 488 [M], (26) 3-Z- [1- (cyclohexylamino) -1-phenyl-methylene] -6-carbamoyl-2-indolinone, prepared from a resin prepared similar to Preparation 2 and from cyclohexylamine,

Product value: 0.60 (silica gel, methylene chloride / methanol = 9: 1),

C ₂₂ H ₂₃ N ₃ O ₂ , 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, C ₂₂ H ₂₄ N ₄ O ₂ , mass spectrum: m / z = 376 [M] ⁺ , (28) 3-Z- [1- (N-methyl-piperidin-4-yl-amino) -1-phenyl-methylene] -6-carbamoyl-2-indolmonium trifluoroacetate, prepared from a resin prepared similarly to that described in preparation 2 and 4-amino-l-methyl-piperidine, R _r value of the product: 0.15 (silica gel, methylene chloride / methanol = 4: 1) C ₂₂ H ₂₄ N ₄ O ₂ MS: m / z = 376 [M] ⁺ , (29) 3-Z- [1- (4- (piperidin-1-ylmethyl) anilino) -1-methylmethylene] -6-carbamoyl-2-indolinone trifluoroacetate, compound prepared from a resin prepared similar to Preparation 2 (2) and from 4- (piperidin-1-ylmethyl) -aniline,

Product value: 0.30 (silica gel, methylene chloride / methanol = 4: 1),

C ₂₃ H ₂₆ N ₄ O ₂ , mass spectrum: m / z = 390 [M] ⁺ , (30) 3- Z- [1- (3-dimethylaminomethyl-anilino) -1-methyl-methylene] -6-carbamoyl -2-indolinone trifluoroacetate, prepared from a resin prepared similar to Preparation 2 (2) and from 3-dimethylaminomethyl-aniline, Product Value: 0.51 (silica gel, methylene chloride / methanol = 4: 1), C ₂₀ H ₂₂ N ₄ O ₂ , mass spectrum: m / z = 351 [M + H] ⁺ , (31) 3-Z- [1- (4- (N-methyl- N -benzylaminomethyl) -anilino) - 1-methyl-methylene] -6-carbamoyl-2-indolinone-trifluoroacetate prepared from the resin prepared as in preparation 2 (2) and 4- ^{(7V-methyl-N-} benzyl-aminomethyl) -aniline,

Rf value of the product: 0, 73 (silica gel, methylene chloride / methanol = 4: 1) ₂ C 6 H ₂₆ N ₄ O ₂ MS: m / z = 426 [M] ^+, (32) 3-Z- [l - (4- (N-methylsulfonyl-N- (2-dimethylaminoethyl) amino) amino) -1-methylmethylene] -6-carbamoyl-2-indolinone trifluoroacetate, the compound was prepared from a resin prepared similar to Preparation 2 (2) from 4- (N-methylsulfonyl- N - (2-dimethylamino-ethyl) -amino) -aniline,

C ₂₂ H ₂₇ N ₅ O ₄ S, mass spectrum: m / z = 458 [M + H] ⁺ , (33) 3-Z- [1- (4-chloro-anilmo) -1-methyl-methylene] - 6-carbamoyl-2-indolinone, the compound was prepared from a resin prepared similar to Preparation 2 (2) and from 4-chloroaniline,

_{R f} value of the product: 0, 10 (silica gel, methylene chloride / methanol = 9: 1), C ₁₇ H ₁₄ C1N ₂ O _3, MS: m / z = 327/329 [M] ^+, (34) 3 -Z- [1- (3-chloro-anilino) -1-methyl-methylene] -6-carbamoyl-2-indolinone, prepared from a resin prepared similar to Preparation 2 (2) and from 3-chloro-aniline,

Product value: 0.11 (silica gel, methylene chloride / methanol = 9: 1), C [ ₇ H ₁₄ ClN ₃ O ₂ , mass spectrum: m / z = 327/329 [M] ⁺ , (35) 3- Z- [1- (4-Methoxycarbonyl-anilino) -1-methyl-methylene] -6-carbamoyl-2-indolinone, prepared from a resin prepared similar to Preparation 2 (2) and from 4-amino-benzoic acid methyl ester .

Product value: 0.11 (silica gel, methylene chloride / methanol = 9: 1), C ₁₉ H ₁₇ N ₃ O ₄ , mass spectrum: 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-aminobenzoic 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-nitro-amine, Product Value: 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 similar to Preparation 2 (4) and 4- (piperidin-1-ylmethyl) aniline,

Rphodnota product: 0.37 (silica gel, methylene chloride / methanol = 4: 1), ₂ C 5 H ₃₀ N ₄ O 2 MS: m / z = 418 [M] +, (39) 3-Z- [l - (3-dimethylaminomethyl-anilino) -1-propylmethylene] -6-carbamoyl-2-indolinone trifluoroacetate, from a resin prepared similar to Preparation 2 (4) and 3-dimethylaminomethyl-aniline, Rf: 0.42 (gel) silicic acid, methylene chloride / methanol = 4: 1),

C ₂₂ H ₂₆ N ₄ O ₂ , 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 similarly to Preparation 2 (4) and 4- [N-methyl-N'-benzyl] aminomethyl] -aniline, Product Value: 0 , 81 (silica gel, methylene chloride / methanol = 4: 1), C ₂₈ H ₃₀ N ₄ O ₂ , 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- [, W-metylsu1fonyl N - (2-dimethylamino-ethyl) amino) -aniline,

Product value: 0.59 (silica gel, methylene chloride / methanol = 4: 1),

C ₂₄ H ₃₁ N ₅ O ₄ S, mass spectrum: m / z = 486 [M + H] ⁺ , (42) 3-Z- [1- (4-chloro-anilino) -1-propyl-methylene] - 6-carbamoyl-2-indolinone, from a resin prepared similar to Preparation 2 (4) and 4-chloroaniline,

Product value: 0.17 (silica gel, methylene chloride / methanol = 9: 1),

C ₁₉ H ₁₈ ClN ₃ O ₂ , mass spectrum: m / z = 355/357 [M] ⁺ , (43) 3-Z- [1- (3-chloro-anilino) -1-propylmethylene] -6 -carbamoyl-2-indolinone, from a resin prepared similar to Preparation 2 (4) and 3-chloroaniline,

Product value: 0.12 (silica gel, methylene chloride / methanol = 9: 1),

C ₁₉ H ₁₈ ClN ₃ O ₂ , mass spectrum: m / z = 355/357 [M] ⁺ , (44) 3-Z- [1- (4-methoxycarbonyl-anilino) -1-propyl-methylene] -6 -carbamoyl-2-indolinone, from a resin prepared similar to Preparation 2 (4) and 4-aminobenzoic acid methyl ester,

Rf value of the product: 0.8 (silica gel, methylene chloride / methanol = 4: 1),

C ₂₁ H ₂₁ N ₃ O ₄ , 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,

C ₂₀ H ₉ N ₃ 0 ₄ , mass spectrum: m / z = 364 [MH] ⁺ , (46) 3-Z- [1- (4-methyl-3-nitro-anilino) -1-propyl-methylene -6-carbamoyl-2-indolmone, from a resin prepared similar to Preparation 2 (4) and from 4-methyl-3-nitroaniline,

Rphodnota product: 0.86 (silica gel, methylene chloride / methanol = 4: 1), C ₂₀ H ₂₀ N ₄ O _4, MS: m / z = 380 [M] ^+.

Example 2 3-Z- [1- (3- (Piperidin-1-ylmethyl) -anilino) -1-phenyl-methylene] -6-carbamoyl-2-indolinone trifluoroacetate

2.0 g of 3-Aminobenzyl alcohol in 20 ml of diphenylformamide, similar to Example 1, was shaken at 70 ° C for 22 hours along with 2.0 g of a resin prepared similar to Preparation 2. 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, 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};.

As in Example 2, the following compounds were prepared:

(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] +, (2) 3-Z- [1- (3-) (benzylamino-methyl) anilino) -1-phenyl-methylene] -6-carbamoyl-2-indolinone-trifluoroacetate prepared from the resin prepared as in preparation 2 and benzylamine, the product, _{R f} value: 0.80 (gel silicic acid, methylene chloride / methanol = 4: 1),

C30H26N4O2, mass spectrum: m / z = 474 [M] &lt; ^{+ &gt};, (3) 3-Z- [1- (3- (N-methyl-N-benzylaminomethyl) anilino) -1-phenyl-methylene] - 6-carbamoyl-2-indolinone trifluoroacetate, the compound was prepared from a resin prepared similarly to Preparation 2 and N, N-methyl-benzylamine, Product Value: 0.80 (silica gel, methylene chloride / methanol = 4: 1),

C ₃₁ H ₂₈ N ₄ O ₂ , mass spectrum: m / z = 488 [M] ⁺ , (4) 3-Z- [1- (3- (butylaminomethyl) anilino) -1-phenylmethylene] -6 -carbamoyl-2-indolinone trifluoroacetate, the compound was prepared from a resin prepared similar to Preparation 2 and from butylamine, Product Value: 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, the compound was prepared from a resin prepared similar to Preparation 2 and ammonia, C ₂₃ H ₂₀ N ₄ O ₂ , mass spectrum: m / z = 385 [M + H] ⁺ , (6) 3 -Z- [ 1- (3- (N- (3-dimethylaminopropyl) -N-methylaminomethyl) anilino) -1-phenylmethylene] -6-carbamoyl-2-indolinone trifluoroacetate, prepared from a resin prepared similarly to preparation of 2 to 1-dimethylamino-3-methylaminopropane,

Product value: 0.67 (silica gel, methylene chloride / methanol = 4: 1), C ₂₉ H ₃₃ N ₅ O, mass spectrum: m / z = 484 [M + H] ⁺ , (7) 3-Z- [1- (3- (A ^L (2-Dimethylaminoethyl) - N -methyl-aminomethyl) -anilino) -1-phenylmethylene] -6-carbamoyl-2-indolinone trifluoroacetate, prepared from a resin prepared similarly as in preparation 2 and 1-dimethylamino-2-methylaminoethane,

Product value: 0.40 (silica gel, methylene chloride / methanol = 4: 1), C ₂₈ H ₃₁ N ₅ O ₂ , mass spectrum: m / z = 470 [M + H] ⁺ .

Example 3

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 (2 to 3 oxide activity) using methylene chloride and ethanol (100: 3) as eluent.

Yield: 1.1 g (58% of theory), Product value: 0.5 (aluminum oxide, methylene chloride / ethanol = 100: 3) C ₃ H ₃₁ N ₃ 0 ₃ , 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,

Product value: 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-phenylmethylene) -6-ethoxycarbonyl -2-indolinone and 3- (dimethylaminomethyl) aniline,

Product value: 0.5 (alumina, methylene chloride / ethanol = 30: 1),

C ₂₇ H ₂₇ N ₃ O ₃

ESI-MS: m / z = 442 [M + H] ⁺ , (3) 3-Z- [1- (4- (dimethylaminomethyl) anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2- indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-ethoxycarbonyl-2-indolinone and 4- (dimethylaminomethyl) aniline,

Product value: 0.7 (alumina, ethyl acetate / ethanol = 20: 1),

C ₂₇ H ₂₇ N ₃ O ₃

ESI-MS: m / z = 442 [M + H] ⁺ , (4) 3-Z- [1- (4 - [(2,6-dimethyl-piperidin-1-yl) -methyl] -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 - [( 2,6-dimethyl-piperidin-1-yl) methyl] -aniline,

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

C ₃₂ H ₃₅ N ₃ O ₃ , mass spectrum: m / z = 5O9 [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 .

Product value: 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) -7 H -acetyl- amino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-ethoxycarbonyl-2-indolinone and 4 - (/ V- (2-dimethylamino-ethyl) -N-acetyl-amino) -aniline,

Product value: 0.4 (alumina, methylene chloride / ethanol = 20: 1),

C ₃ H ₃₂ N ₄ O ₄ , mass spectrum: m / z = 512 [M] ⁺ , (7) 3-Z- [1- (4-tert-butyloxycarbonyl-anilino) -1-phenyl-methylene] -6 -ethoxycarbonyl-2-indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-ethoxycarbonyl-2-indolinone and 4-tert-butyloxycarbonyl-aniline,

Product value: 0.4 (alumina, methylene chloride / ethanol = 40: 1),

C ₂₉ H ₂₈ N ₂ O ₅ , mass spectrum: m / z = 484 [M] ⁺ , (8) 3-Z- [1- (4- (N - (3-dimethylaminopropyl) -N-acetyl) -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- (7V- (3-dimethylaminopropyl) -7V-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 - /) - 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) -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- (4-methyl-piperazin-1-yl) aniline,

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

C29H30N4O3.

ESI-MS: m / z = 483 [M + H] ⁺ , (11) 3-Z- [1- (4 - (N - (2-dimethylamino-ethyl) - N -methyl-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- (2-dimethylamino-ethyl) - / V-methyl-amino) -aniline,

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

C ₂₉ H ₃ N ₄ O ₃ ,

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 - (/ / - (3-dimethylaminopropyl) -7V-methyl-amino) -aniline,

R _r value of the 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,

Product Rf value: 0.3 (silica gel, methylene chloride / ethanol = 15: 1), C 7 H ₂₅ N ₂ O 3 ₃ MS: m / z = 455 [M] ^+, (14) 3-Z- [1 - (4- (N -methyl-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 - (4-aminophenyl) - N -methyl methanesulfonamide,

Product value: 0.8 (alumina, ethyl acetate),

C ₂₆ H ₂₅ N ₃ O ₅ S, mass spectrum: m / z = 491 [M] ⁺ , (15) 3-Z- [1- (4 - (N - (3-dimethylaminopropyl) -) (methylsulfonyl-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 N - (3-dimethylamino-propyl) - N -methylsulfonyl-p-phenylenediamine,

Product value: 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-dimethylaminocarbonyl-methyl-7-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 Rf value: 0.6 (silica gel, methylene chloride / ethanol = 10: 1), ₂ C 9 H ₃₀ N ₄ O6S, ESI-MS: m / z = 561 [MH] ', (17) 3-Z- [1- (4- (Imidazol-4-yl) -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- (imidazol-4-yl) aniline,

_{R f} value of the product: 0.5 (silica gel, methylene chloride / ethanol / ammonia 10: 1: 0.01), C ₂₇ H ₂₂ N ₄ O ₃ MS: m / z = 450 [M] ^+, (18) 3-Z- [1- (4- (tetrazol-5-yl) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, prepared by reaction of 1-acetyl-3- (1- ethoxy-1-phenyl-methylene) -6-ethoxycarbonyl-2-indolinone and 4- (tetrazol-5-yl) -aniline,

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

C ₂₅ H ₂₀ N ₆ O ₃

ESI-MS: m / z = 451 [MH], (19) 3- Z- [1- (4- (N-benzyl-N-methylaminomethyl) anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2- indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-ethoxycarbonyl-2-indolinone and 4- (N-benzyl-N-methyl-aminomethyl) aniline,

_{R f} value of the product: 0.4 (silica gel, methylene chloride / ethanol = 10: 1), C ₃₃ H ₃₁ N ₃ O _3; ESI-MS: m / z = 516 [MH], (20) 3- Z- [1 - (4- (A ^/ - (2-dimethylamino-ethyl) -7V-propionyl-amino) -aniline) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, prepared by reaction of l-acetyl -3- (1-ethoxy-1-phenyl-methylene) -6-ethoxycarbonyl-2-indolinone and 4- [N- (2-dimethylamino-ethyl) - N -propionylamino] -aniline,

Product value: 0.2 (silica gel, methylene chloride / ethanol = 5: 1),

C ₃ iH ₃₄ N ₄ O ₄ ,

ESI-MS: m / z = 525 [MH], (21) 3 -Z- [1- (4- (pyrrolidin-1-ylmethyl) -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 4- (pyrrolidin-1-ylmethyl) aniline,

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

C ₂₉ H 9 N ₃ O _{2 3,}

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-phenyl-methylene) -6-ethoxycarbonyl-2-indolinone and 4- (N-phenethyl-N-methyl-aminomethyl) -aniline .

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

C ₃₄ H ₃₃ N ₃ O ₃

ESI-MS: m / z = 530 [MH], (23) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl- N -methylamino) 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-dimethylaminomethylcarbonyl-N-methyl- N -phenylenediamine,

Product value: 0.1 (silica gel, methylene chloride / ethanol = 10: 1),

C ₂₉ H ₃ oN ₄ 0 ₄

ESI-MS: m / z = 497 [MH] -, (24) 3-Z- [1- (4- (N - (2-dimethylaminoethyl) -N-ethylsulfonylamino) 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- ethylsulfonyl-p-phenylenediamine,

R _r value of the product: 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-) V-ethylaminomethyl) -aniline,

R _r value of the product: 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 the reaction of 1-acetyl-3- (1-ethoxy-1-ethyl-methylene) -6-ethoxycarbonyl-2-indolinone and 4- (piperidin-1-ylmethyl) -aniline,

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

C ₂₆ H ₃ N ₃ O ₃ ,

ESI-MS: m / z = 432 [MH] +, (2 S) 3-Z- [1- (4- (N - (2-dimethylaminoethyl) - N -methylsulfonylamino) anilino) -1-ethylmethylene 6-ethoxycarbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-ethylmethylene) -6-ethoxycarbonyl-2-indolinone and N - (2-dimethylamino-ethyl) - N -. methylsulphonyl-p-phenylenediamine,

R _r value of the product: 0.3 (silica gel, methylene chloride / ethanol = 5: 1),

C ₂₅ H3 ₂ N ₄ O ₅ S

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 mass spectrum: m / z = 428 [M + H] ⁺ , (29) 3-Z- [1 - ( 4 - [(2,6-dimethyl-piperidin-1-yl) -methyl] -anilino) -1-phenyl-methylene] -6-methoxy-carbonyl-2-indolinone, prepared by 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] &lt; ^{+ &gt};, (30) 3-Z- [1- (4 - (N - (2-dimethylamino-ethyl) -7-methylsulfonylamino) anilino) -1 phenyl-methylene] -6-methoxycarbonyl-2-indolinone, prepared by reaction of l-acetyl-3- (l-ethoxy-l-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and a ^/ - (2-dimethylamino ethyl) - / V-methylsulfonyl-p-phenylenediamine,

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

C2 ₈ H ₃ oN ₄ 0 ₅ S

ESI-MS: m / z = 533 [MH] -, (31) 3-Z- [1- (4 - (N - (3-dimethylamino-propyl) - N -methylsulfonyl-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 - (3- dimethylaminopropyl) - / V-methylsulfonyl-p-phenylenediamine,

Product value: 0.5 (alumina, methyl chloride / methanol = 30: 1),

C29H ₃ 2N ₄ O ₅ S

ESI-MS: m / z = 547 [MH] -, (32) 3-Z- [1- (4- (7'-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),

C ₂ 8H ₂ 8N ₄ O ₆ S

ESI-mass spectrum: m / z = 547 [MH] -, (33) 3-Z- [1- (4- (N'-acetyl-N ^, -dimethylaminocarbonyl-methylamino) -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-acetyl-). ^N -dimethylaminocarbonylmethyl) amino-aniline,

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

C ₂ 9H ₂₈ N ₄ O ₅

ESI-MS: m / z = 511 [MH] -, (34) 3-Z- [1- (4- (N '- dimethylaminocarbonyl-methyl-amino) -amino) -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-dimethylaminocarbonylmethyl) amino) - aniline

R _r value of the product: 0.6 (alumina, methylene chloride / methanol = 30: 1),

C ₂₇ H ₂₆ N ₄ O ₄ ,

ESI-MS: m / z = 469 [MH] -, (35) 3- Z- [1- (4- (N - (3-dimethylamino-propyl) -7-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 N '- (3-dimethylamino) propyl) -7V-acetyl-p-phenylenediamine,

Product value: 0.5 (alumina, methylene chloride / methanol = 20: 1),

C ₃₀ H ₃₂ N ₄ O ₄

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 reacting 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and N-methylaminocarbonyl-methyl-N-methylsulfonyl-p- phenylenediamine,

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

C ₂₇ H ₂₆ N ₄ O ₆ S

ESI-MS: m / z = 533 [MH] -, (37) 3-Z- [1- (4 - ((imidazolidin-2,4-dione-5-ylidene) methyl) 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 - ((imidazolidine-2,4-) dione-5-ylidene) methyl) aniline,

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

C ₂₇ H ₂₀ N ₄ O ₅

ESI-MS: m / z = 479 [MH] -, (38) 3-Z- [1- (4- ( ₁ N - ((2-dimethylamino-ethyl) -carbonyl) - N -methyl-amino) (1-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, N- ((2-dimethylamino-ethyl) carbonyl) -7V-methyl-p-phenylenediamine,

Product value: 0.5 (alumina, methylene chloride / methanol = 20: 1),

C ₂₉ H ₃₀ N ₄ O ₄

ESI-MS: m / z = 497 [MH] -, (39) 3-Z- [1- (4- (N-tert-butoxycarbonylaminomethyl) anilino) -1-phenylmethylene] -6-methoxy -carbonyl-2-indolinone, prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4- (N-tert-butoxycarbonylaminomethyl) aniline,

Product value: 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 the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4- (2-oxo-pyrrolidin-1-ylmethyl) aniline,

Product value: 0.3 (silica gel, methylene chloride / methanol = 20: 1), C28H25N3O4, ESI mass spectrum: 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,

Product Rf value: 0.7 (silica gel, methylene chloride / methanol = 5: 1), C 6 H ₂₄ N ₂ O ₆ S _4, ESI-MS: m / z = 519 [MH] ', (42) 3- Z- [1- (4- (thiomorpholin-4-ylmethyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, prepared by reaction of 1-acetyl-3- (1-ethoxy-1) -phenyl-methylene) -6-methoxycarbonyl-2-indolinone and 4- (thiomorpholin-4-ylmethyl) -aniline,

Product value: 0.4 (silica gel, methylene chloride / methanol = 15: 1),

C ₂₈ H2 ₇ N ₃ O ₃ S

ESI-MS: m / z = 484 [MH] -, (43) 3-Z- [1- (4- (1,1-dioxo-thiomorpholin-4-ylmethyl) -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- (1,1-dioxo-thiomorpholine) 4-yl-methyl) -aniline,

Product value: 0.5 (silica gel, methylene chloride / methanol = 10: 1), C ₂₈ H ₂₇ N ₃ O ₅ S, ESI mass spectrum: m / z = 516 [MH] -, (45) 3- Z- [1- (4- (N-tert-butoxycarbonyl-ethylaminomethyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, prepared by reaction of 1-acetyl-3- (1-ethoxy- 1-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and 4- (N-ethyl-N-tert-butoxycarbonylaminomethyl) aniline,

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

C ₃₁ H ₃₃ N ₃ O ₅

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

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

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

C ₃₂ H ₂₉ N ₃ O ₃

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 ₂₈ H ₂₇ N ₃ O ₄ S,,

ESI-MS: m / z = 500 [MH] -, (48) 3- Z- [1- (4- (2- (imidazol-4-yl) ethyl) -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- (imidazol-4-yl) ) ethyl) aniline,

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

C ₂₈ H ₂₄ N ₄ O ₃

ESI-MS: m / z = 463 [MH] -, (49) 3-Z- [1- (4- (morpholin-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- (morpholin-4-ylmethyl) -aniline,

Product value: 0.5 (silica gel, methylene chloride / methanol = 10: 1), C28H27N3O4, ESI mass spectrum: m / z = 468 [MH] -, (50) 3-Z- [1- (4-) (4-methylpiperazin-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 - ((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-7 H -methylamino) ethyl)) - N -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] -, (52) 3-Z- [1- (4-cyclohexylaminoanilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared by reaction of 1-acetyl- 3- (1-ethoxy-1-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and N-cyclohexyl-p-phenylenediamine,

Product value: 0.8 (silica gel, methylene chloride / methanol = 10: 1),

C29H28N2O3.

ESI-MS: m / z = 451 [MH] -, (53) 3- Z- [1- (4- (pyridin-4-ylmethyl) amino) -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- (pyridin-4-ylmethyl) -aniline,

Product value: 0.6 (silica gel, methylene chloride / methanol / ammonia = 5: 1: 0.01), C29H23N3O3,

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,

Product value: 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,

Product value: 0.4 (silica gel, methylene chloride / methanol / ammonia = 10: 1: 0.01), C ₂₇ H ₂₂ N ₄ O ₃ ,

ESI-MS: m / z = 449 [MH] -, (S) 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,

Product value: 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,

Product value: 0.2 (silica gel, methylene chloride / methanol = 5: 1),

SK 287312-6

C ₂₇ H ₂₂ N ₄ O ₃

ESI-MS: m / z = 449 [MH] -, (58) 3-Z- [1- (4 - ((4-hydroxy-piperidin-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 - ((4-hydroxy -piperidin-1-yl) -methyl) -aniline,

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

C ₂₉ H ₂₉ N ₃ O ₃

ESI-MS: m / z = 482 [MH] -, (59) 3- Z- [1- (4 - ((4-methoxy-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-methoxy- piperidin-1-yl) -methyl) -aniline,

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

C ₃₀ H ₃₁ N ₃ O ₄

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,

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

C ₃ H ₂₄ N ₂ O ₃ , mp 224 ° C.

(61) 3-Z- [l- (4- _(I, N- (3-trifluóracetylaminopropyl) ^-N, -metylsulfonylamino) anilino) -l-phenyl-methylene] -6-Methoxycarbonyl-2-indolinone, prepared by reaction of l- acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and N - (3-trifluoroacetylamino-propyl) - N -methylsulfonyl-p-phenylenediamine,

Product value: 0.5 (alumina, methylene chloride / methanol = 20: 1),

C ₂₉ H ₂₇ F ₃ N ₄ O ₆ S

ESI-MS: m / z = 615 [MH] -, (62) 3-Z- [1- (4-tert-butoxycarbonyl-methyl-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2- indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4-aminophenylacetic acid tert-butyl ester,

Product value: 0.5 (alumina, ethyl acetate),

C ₃ oH ₃ oN ₂ 0 ₅

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

Product value: 0.4 (alumina, methylene chloride / ethanol = 20: 1),

C ₂₅ H ₂₉ N ₂ O ₅

ESI-MS: 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-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4- (4- tert -butoxycarbonyl-piperazine) -1-yl-methyl) -aniline,

Product value: 0.5 (silica gel, methylene chloride / methanol = 10: 1), C ₃₃ H ₃₆ N ₄ O ₅ , ESI mass spectrum: m / z = 567 [MH], (65) 3-Z- [1- (4- (1-Methyl-inidazol-2-yl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, prepared by reaction of 1-acetyl-3- (1-ethoxy-1) -phenyl-methylene) -6-methoxycarbonyl-2-indolinone and 4- (1-methyl-imidazol-2-yl) -aniline,

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

C ₂₇ H ₂₂ N ₄ O ₃

ESI-MS: m / z = 449 [MH], (66) 3- Z- [1- (4- (N - (2-dimethylaminoethyl) - N -methylsulfonylamino) -3-nitroanilino) -1-phenyl methylene] -6-methoxycarbonyl-2-indolinone, prepared by reaction of l-acetyl-3- (l-ethoxy-l-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and 6- ^(N - (2-dimethylamino ethyl) - A ^/ methylsulphonyl-amino) -3-amino-nitrobenzene,

Product value: 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- (A ^f - (2-dimethylamino-ethyl) - / V-methylsulfonyl-amino) -3-amino-aniline,

Product value: 0.5 (alumina, methylene chloride / methanol = 20: 1),

C ₂₈ H ₃₁ N ₅ O ₅ S

ESI-MS: m / z = 548 [MH] ', (68) 3-Z- [l- (4 - ((3- ^{(BENZYL-A /} -methyl-amino) propyl) -N-methyl (sulfonyl-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 - (3- (N-benzyl-N-methyl-amino) -propyl) - N -methylsulfonyl-amino) -aniline,

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

C ₃₅ H ₃₆ N ₄ O ₅ S

ESI-MS: m / z = 623 [MH] ', (69) 3-Z- [l- (4- (N ^- (2-dimethylamino-ethyl) ^-N, -metylsulfonylamino) -3-chloroanilino) -l -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 ^, -methylsulfonyl-amino) -3-chloro-aniline,

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

C ₂₈ H ₂₉ C1N ₄ O ₅ S

ESI-MS: m / z = 567/569 [MH] -, (70) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl-N-methylamino) 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 + dimethylaminomethylcarbonyl-N'-methyl-p-phenylenediamine,

Product value: 0.5 (silica gel, methylene chloride / methanol = 9: 1), C ₂₈ H ₂₈ N ₄ O ₄ , ESI mass spectrum: m / z = 483 [MH] -, (71) 3-Z- [ 1- (4- (N - (2-dimethylamino-ethyl) - N -acetyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, prepared by reaction of 1-acetyl-3 - (l-ethoxy-l-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and 4- (N ^- (2-dimethylamino-ethyl) -N-acetyl-amino) -aniline,

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

C ₂ 9H ₃ oN ₄ 0 ₄

ESI-MS: m / z = 497 [MH] ', (72) 3-Z- [l- (4- (A ^/ - (2-dimethylamino-ethyl) -Mpropionyl-amino) anilino) -l- 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 - (2- dimethylamino-ethyl) -N-propionyl-amino) -aniline,

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

C ₃ oH ₃₂ N ₄ 0 ₄

ESI-MS: m / z = 511 [MH] ^- , (73) 3-Z- [1- (4 - (N - (2-dimethylamino-ethyl) -7-butyryl-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-dimethylamino-ethyl) -N / butyryl-amino) -aniline,

Product value: 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, N- (2- dimethylamino-ethyl) -N-isobutyryl-amino-aniline,

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

C32H34N4O4.

ESI-MS: m / z = 525 [MH] ', (75) 3-Z- [l- (4- ^(N - (2-dimethylamino-ethyl) ^{-N-benzoyl-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 - ( 2-dimethylamino-ethyl) - / V-benzoyl-amino) -aniline,

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

C34H32N4O4.

ESI-MS: m / z = 559 [MH] -, (76) 3-Z- [1- (4- (N - (2-dimethylamino-ethyl) - N ¹ -acetyl-amino) -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) -7V-acetyl-amino) -3-amino-aniline,

Product value: 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 reacting 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and 4- (4-hydroxymethyl-piperidin-1-yl-methyl-amino) aniline,

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

C30H31N3O4.

ESI-MS: m / z = 496 [MH] &lt; - &gt;, (7 &lt; 8 &gt;) 3 - Z - [1- (4- (2- (4-hydroxy-piperidin-1-yl) -ethyl) -anilino) - 1-Phenyl 1-methylene] -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,

Rphodnota product: 0, 3 (silica gel, methylene chloride / methanol = 5: T), C3oH ₃₁ N 30 _4,

ESI-MS: m / z = 496 [MH] -, (79) 3- Z- [1- (4- (N - (2-dimethylamino-ethyl) - N -propylsulfonylamino) -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-propylsulfonyl-p-phenylenediamine,

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

C ₃ oH _{3 4} N ₂ 0 ₅ S,

ESI-MS: m / z = 561 [MH] -, (80) 3-Z- [1- (4- (N - (2-dimethylaminoethyl) -N-butylsulfonylamino) 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) - N butylsulfonyl-p-phenylenediamine,

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

C3iH ₃₆ N ₄ O ₅ S

ESI-MS: m / z = 575 [MH] -, (81) 3- Z- [1- (4- (N - (2-dimethylamino-ethyl) - N -phenylsulfonyl-amino) -amino) - 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- (2-dimethylamino- ethyl) -. / V-phenylsulfonyl-p-phenylenediamine,

Product value: 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) -7-benzylsulfonylamino) -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) - 7V-benzylsulfonyl-p-phenylenediamine,

Product value: 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-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) -7H ethyl-sulfonyl-p-phenylenediamine,

Product value: 0.5 (silica gel, methylene chloride / methanol = 9: 1), C29H32N4O5S,

ESI-MS: m / z - 547 [MH] -, (84) 3-Z- [1- (4 - ((imidazolidin-2,4-dione-5-yl) -methyl) -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 - ((imidazolidine- 2,4-dione-5-yl) methyl) aniline,

Product value: 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-phenyl -methylene] -6-methoxycarbonyl-2-indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4 - ((3-hydroxy- pyrrolidin-1-yl) -methyl) -aniline,

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)),

Product value: 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 reacting 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and 4- (cyclohexylcarbonyl) -aniline,

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 mass spectrum: m / z = 454 [MH] -, (89) 3-Z- [1- (4-) (/ V - ( «- hexyl) - _{I-N-methyl-aminomethyl)} -amlino) -l-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, prepared by reaction of l-acetyl-3- (l-ethoxy - 1-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and 4 - (N - (N-hexyl) - N -methyl-aminomethyl) -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) - / V- (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,

R _r value of the product: 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) amino) 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- (A ^L) (2-dimethylamino-ethyl) - / V- (2-methoxy-benzoyl) -amino) aniline,

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

C35H34N4O5.

ESI-MS: m / z = 589 [MH], (92) 3- [1- (4- (N - (2-dimethylarmnoethyl) - N - (pyridine-3-carbonyl) amino) anilino) - 1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4 - (; N - ( 2-dimethylamino-ethyl) - / V- (pyridin-3-carbonyl) amino) aniline,

Product value: 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) -A ^L (phenyl-acetyl) 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- (2-dimethylamino-ethyl) - / V- (phenyl-acetyl) amino) -aniline,

Product value: 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-methoxycarbonyl-2 -indolinone prepared by the reaction of 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and 4- (N-ethyl-N-methyl-aminomethyl) -aniline,

Product value: 0.3 (silica gel, methylene chloride / methanol = 10: 1),

C ₂₇ H ₂₇ N ₃ O ₃

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-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and 4- (imidazol-2-yl) -aniline,

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

C26H20N4O3.

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-phenylmethylene) -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 mass spectrum: m / z = 463 [MH], (97) 3-Z- [1- (4- ( 1-benzyl-imidazol-2-yl) -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- (1-benzyl-imidazol-2-yl) -aniline,

Product value: 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-dimethylaminoethyl) ) -N-isopropylsulfonyl-p-phenylenediamine,

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

C ₃₀ H ₃₄ N ₄ O ₅ S

ESI-MS: m / z = 561 [MH] -, (99) 3- Z- [1- (4- (N - (piperidin-1-ylmethylcarbonyl) - N -methylamino) -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 - (piperriin-1) yl-methylcarbonyl) -7V-methyl-p-phenylenediamine,

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

C ₃₁ H ₃₂ N ₄ O ₄ ,

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,

Product Rf value: 0.5 (silica gel, methylene chloride / methanol = 9: 1), C ₃ oH ₃ oN 0 _{4 5,} 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 reacting 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and N - ((4-benzyl-piperazin-1-yl) -methylcarbonyl) -N-methyl-p phenylenediamine,

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

C ₃₇ H ₃₇ N ₅ O ₄

ESI-MS: m / z = 614 [MH] -, (102) 3- Z- [1- (4- (N - (pyrrolidin-1-ylmethylcarbonyl) -N-methylamino-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 - (pyrrolidin-1-yl-) - methylcarbonyl) - / V-methyl-p-phenylenediamine,

Product value: 0.5 (silica gel, methylene chloride / methanol = 9: 1), c ₃₀ h ₃₀ n ₄ o ₄ ,

ESI-MS: m / z = 509 [MH] + (103) 3- Z- [1- (4- (N - (2-dimethylamino-ethyl) - N -acetyl-amino) -3-bromo- 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- (7H) - (2-ethyl-dimetylarnmo) -. "N-acetyl-amino) -3-bromo-aniline,

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

C ₂ 9H ₂₉ BrN ₄ O ₄

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,

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

C ₂₇ H ₂₂ N ₄ O ₃

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

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

C ₃ iH ₃₄ N ₄ O ₄ ,

SK 287312-6

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, N- ((2-dimethylamino-ethyl) carbonyl) -N-benzyl-p-phenylenediamine,

Product value: 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 .

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

C ₃₃ H ₃ 7N ₃ O ₅

ESI-MS: m / z = 554 [MH] -, (108) 3-Z- [1- (4- (M ((N-aminocarbonyl-methyl-X-methyl-amino) -methylcarbonyl) -7-) - 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 - (N-aminocarbonyl-methyl-N ^, -methylamino) methylcarbonyl) - N -methyl-p-phenylene diamine,

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

C ₂₉ H ₂₉ N ₅ O ₅

ESI-MS: m / z = 526 [MH] -, (109) 3-Z- [1- (4- (N - ((X-benzyl- N -methyl-amino) -methylcarbonyl) - 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 7H - ((/ V-benzyl-7V-methyl-amino) -methylcarbonyl) ^-N-methyl-L / t-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)) - N ¹ -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),

C ₃₂ H ₃₆ N ₄ O ₄

ESI-MS: m / z = 571 [MH] -, (111) 3-Z- [1- (4- (7H - ((2- (4-tert-butoxycarbonyl-piperazin-1-yl)) -ethyl) (carbonyl) - 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 - ((2- (4-tert-butoxycarbonylpiperazin-1-yl) ethyl) carbonyl) -N-methyl-p-phenylene diamine,

Product value: 0.8 (silica gel, methylene chloride / methanol = 5: 1),

C36H41N ₅ O ₆

ESI-MS: m / z = 638 [MH] +, (112) 3-Z- [1 - (4- ^(f - ((2- (piperidin-1-yl) 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- (piperidin-1-yl) ethyl) carbonyl) - N -methyl-p-phenylenediamine,

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

C ₃₂ H34N ₄ O4

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 7V - ((2- (7V-benzyl-7V-methyl-amino) ethyl) carbonyl) - / V-methyl-p-phenylenediamine,

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

C35H34N4O4.

ESI-MS: m / z = 573 [MH] -, (114) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl- N -isopropyl-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 - (dimethylaminomethylcarbonyl) - N -isopropyl-p-phenylenediamine .

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

C ₃₀ H ₃₂ N ₄ O ₄

ESI-MS: m / z = 511 [MH] -, (115) 3-Z- [1- (4- (N (piperidin-1-ylmethylcarbonyl) -N-isopropyl-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 - (piperidin-1- yl-methylcarbonyl) -N-isopropyl-p-phenylenediamine,

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

C ₃₃ H ₃₆ N ₄ O ₄ ,

ESI-MS: m / z = 551 [MH] -, (116) 3 -Z- [1- (4- (N - ((4-tert-butoxycarbonyl-piperazin-1-yl) -methylcarbonyl) -) N-iso-propyl-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 a ^f - ((4-tert-butoxycarbonyl-l-yl) methylcarbonyl) -N-isopropyl / 2-phenylenediamine,

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

C ₃₇ H ₄₃ N ₅ O ₆

ESI-MS: m / z = 652 [MH] +, (117) 3-Z- [1 - (4- ^(f - ((/ V-benzyl-N-methyl-amino) methylcarbonyl) -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, N- ((/ V-benzyl-N-methyl-amino) -methylcarbonyl) - / V-benzyl-p-phenylenediamine,

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

C ₄ oH ₃₆ N ₄ 0 ₄ ,

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,

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

C ₃₄ H ₃₂ N ₄ O ₄ ,

ESI-MS: m / z = 559 [MH] -, (119) 3-Z- [1- (4 - (N - (piperidin-1-ylmethylcarbonyl) - 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 4- (5 methyl-imidazol-4-yl) -aniline,

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

C ₃₇ H ₃₆ N ₄ O ₄

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 the reaction of 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4- (1,2,4-triazole) -1-yl-methyl) -aniline,

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

C ₂ 6H ₂ iN ₅ O ₃ ,

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

(121) 3-Z- [1- (4- (1,2,3-triazol-2-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- (1,2,3-triazol-2-ylmethyl) -aniline,

Product value: 0.5 (silica gel, methylene chloride / methanol = 20: 1),

C26H21N5O3.

ESI-MS: m / z = 450 [MH] -, (12 2) 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-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and 4- (1,2,3- triazol-1-yl-methyl) -aniline,

Product value: 0.4 (silica gel, methylene chloride / methanol = 9: 1),

C26H21N ₅ O ₃

ESI-MS: m / z = 450 [MH] -, (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-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4 - ((JV- aminocarbonyl-methyl- / V-methyl-amino) methyl) aniline,

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

C ₂₇ H ₂₆ N ₄ O ₄ ,

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

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

C ₃ o ₃₃ N ₃ 05,

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 the reaction of 1-acetyl-3- (1-ethoxy-1-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and 4- (pyrrolidin-1-ylmethyl) -aniline,

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

C ₂₈ H ₂₇ N ₃ O ₃

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-hydroxy) ethyl) amino) methyl) aniline,

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

C ^ H ^ N / Os.

ESI-MS: m / z = 486 [MH] -, (127) 3- Z- [1- (4 - ((N-ethoxycarbonyl-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 - ((N-ethoxycarbonyl- methyl-7V-methyl-amino) methyl) aniline,

Product value: 0.5 (alumina, methylene chloride / ethanol = 40: 1),

C ₂ 9H ₂ 9N ₃ O5

ESI-MS: m / z = 498 [MH] -, (12 8) 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-phenyl-methylene) -6-methoxycarbonyl-2-indolinone and 4- (azetidin-1-ylmethyl) -aniline,

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

C ₂₇ H ₂ 5N3O _3,

ESI-MS: m / z = 438 [MH] -, (129) 3-Z- [1- (4- (N-propyl-N-tert-butoxycarbonylaminomethyl) 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-propyl-N-tert-butoxycarbonylaminomethyl) 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) (1-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- (2- (2-methoxy-ethoxy) ethyl) - N -methyl-amino) -methyl) -aniline,

Product value: 0.4 (silica gel, methylene chloride / methanol = 9: 1),

C30H33N3O5.

ESI-MS: m / z = 514 [MH] -, (131) 3-Z- [1- (4 - ((N - (tert -butoxycarbonyl-3-aminopropyl)) - 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- (N-tert-biithoxycarbonyl-3-amino-propyl) - N -methyl-aminomethyl) -amine,

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

C ₃₃ H ₃₈ N ₄ O ₅

ESI-MS: m / z = 571 [MH] -, (132) 3-Z- [1- (4 - ((N - (methylcarbamoyl-methyl) - N -methyl-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 - ((R) - (methylcarbamoyl-methyl) -N-methyl-amino) methyl) aniline,

Product value: 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-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, prepared by reacting 1-acetyl-3- (1-ethoxy-1-phenylmethylene) -6-methoxycarbonyl-2-indolinone and 4 - ((? N - (dimethylcarbamoyl-methyl) - N -methyl-amino) -methyl) -aniline, Product value: 0.3 (silica gel, methylene chloride / methanol = 10: 1),

C29H ₃ oN ₄ 04

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,

Product value: 0.4 (silica gel, methylene chloride / methanol = 9: 1),

C ₂₄ H ₂₀ N ₂ O ₃

ESI-MS: m / z = 383 [MH], (135) 3- Z- [1- (4 - ((N-propyl- N -methyl-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 - ((N-propyl- N-methyl-amino) methyl) aniline,

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

C ₂₈ H ₂₉ N ₃ O ₃

ESI-MS: m / z = 454 [MH] -, (136) 3-Z- [1- (4 - ((N - (2-hydroxy-ethyl) -N-methylamino) 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- ( (77- (2-hydroxyethyl) -N-methyl-amino) methyl) aniline,

Product value: 0.5 (alumina, methylene chloride / ethanol = 40: 1),

C ₂₇ H ₂₇ N ₃ O ₄

ESI-MS: m / z = 456 [M-H]

(137) 3-Z- [1- (4 - ((N - (2-dimethylamino-ethyl) - N -methyl-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 - ((N - (2-dimethylaminoethyl)) -. N-methyl-amino) methyl) aniline,

R _r value of the 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 -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- ( (/ V- (3-dimethylaminopropyl) -7V-methyl-amino) methyl) aniline,

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

C ₃₀ H34N ₄ O ₃

ESI-MS: m / z = 497 [MH] -, (139) 3-Z- [1- (4- (3-oxo-piperazin-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- (3-oxo-piperazin-1-ylmethyl) ) aniline,

Product value: 0.46 (silica gel, methylene chloride / methanol = 9: 1),

C ₂₈ H ₂₆ N ₄ O ₄ , ESI mass spectrum: m / z = 481 [MH] -.

Example 4

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

485 mg of 3-Z- [1- (4-tert-butoxycarbonyl-anilino) -1-phenyl-methylene] -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),

Product value: 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,

Product value: 0.5 (silica gel, methylene chloride / methanol / ammonia = 5: 1: 0.01), C ₂₄ H ₂ iN ₃ O ₃ ,

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-phenyl-methylene] -6-methoxycarbonyl-2-indolinone,

Product value: 0.4 (silica gel, methylene chloride / methanol / ammonia = 10: 1: 0.01), C ₂₆ H ₂₅ N ₃ O ₃ ,

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)

C ₂₆ H ₂₂ N ₂ O ₅

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, Product value: 0.1 (aluminum oxide, methylene chloride / ethanol = 20: 1) .

C ₂₁ H ₂₀ N ₂ O ₅ ,

ESI-MS: m / z = 379 [M-H] -,

(5) 3-Z- [1- (4- (piperazin-1-ylmethyl) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared from 3-Z- [l- (4- (4-tert-butoxycarbonyl-piperazin-l-yl-methyl) anilino) -l-phenyl-methylene] -6-methoxycarbonyl-2-indolinone,

Product value: 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,

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

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- [l- (4- (N - / e / c-butoxycarbonyl-N-ethylaminomethyl) -anilino) -l-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone,

Product value: 0.3 (silica gel, methylene chloride / methanol / ammonia = 10: 1: 0, 01),

C ₂₇ H ₂₇ N ₃ O ₃

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

Product value: 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-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, prepared from 3-Z- [1- (4- (N - ((4-tert-butoxycarbonylpiperazin-1-yl) -methylcarbonyl) -7V) -isopropyl-amino) -anilino-1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone,

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-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, prepared from 3-Z- [1- (4- (7H - ((2- (4-tert- butoxycarbonyl-l-yl) ethyl) carbonyl) - / V-methyl-amino) anilino) -phenyl-methylene] -6-methoxycarbonyl-2-indolinone,

Product value: 0.4 (silica gel, methylene chloride / methanol / ammonia = 5: 1: 0.01),

C31H33N5O4.

ESI-MS: m / z = 540 [M + H] ⁺ , (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,

Product value: 0.35 (silica gel, methylene chloride / methanol = 9: 1),

C ₂₇ H ₂₇ N ₃ O ₃ ,

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

Product value: 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-amino-methyl) -amino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone was dissolved in 20 ml of ethanol, added 0.2 ml of HCl (c = 1 _HCl mol.dm ^'3), and the mixture is hydrogenated for 70 minutes at room temperature under a hydrogen pressure of 0.35 MPa (50 psi). 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),

Product value: 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-phenylmethylene] -6-methoxycarbonyl-2-indolinone,

Product value: 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-indolinone, prepared from 3-Z- [1- (4 - ((2- (N-benzyl-N-benzylamino) ethyl) -N-methylsulfonyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone,

Product value: 0.3 (silica gel, methylene chloride / methanol 1 / ammonia = 10: 1: 0, 01), C ₂₇ H ₂₈ N ₄ O ₅ S,

ESI-MS: m / z = 519 [MH] ^- , (3) 3-Z- [1- (4- (N- (2-amino-ethyl) -N-methylsulfonyl-amino) -anilino) -1 -phenylmethylene] -6-methoxycarbonyl-2-indolinone, prepared from 3-Z- [1- (4- (N -cyanomethyl-N-methylsulfonylamino) -anilino) -1-phenylmethylene] -6- methoxycarbonyl-2-indolinone,

Product value: 0.5 (silica gel, methylene chloride / methanol / ammonia = 5: 1: 0.01), C ₂₆ H ₂₆ N ₄ O ₅ S,

ESI-MS: m / z = 505 [MH] -, (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- methylsulfonyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone,

Product value: 0.3 (silica gel, methylene chloride / methanol / ammonia = 5: 1: 0.01), C ₂₈ H ₃₀ N ₄ O ₅ S,

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-Phenylmethylene] -6-methoxycarbonyl-2-indolinone

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

C ₃ oH ₃ iN ₅ 0 ₄ ,

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-N- [1- (4 - (N - ((N'-benzyl- N -methylamino) methylcarbonyl) - N -methylamino) -anilino) -l-phenyl-methylene] -6-methoxycarbonyl-2-indolinone,

Product value: 0.3 (silica gel, methylene chloride / methanol = 9: 1),

C ₂₇ H ₂₁ F, N ₄ O ₄ , ESI mass spectrum: m / z = 469 [MH] -, (7) 3-Z- [1- (4- (N - ((2-methylaminoethyl)) (carbonyl) - ( ^L- methyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone,

Prepared from 3-Z- [1- (4- (N ^, - ((2- (N ^, -benzyl) - N ^, -methylamino) ethyl) carbonyl) - N -methylamino) -anilino) -1- phenyl-methylene] -6-methoxycarbonyl-2-indolinone,

Product value: 0.3 (silica gel, methylene chloride / methanol / ammonia = 5: 1: 0.01), C28H28N4O4,

ESI-MS: m / z = 483 [MH] ^- .

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-phenyl-methylene] -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 [MH] ^- .

Example 7

-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),

Product value: 0.1 (reverse phase RP8, methanol / 5% sodium chloride solution = 6: 4), C25H23N5O3,

Mass spectrum: m / z = 441 [M] &lt; ^{+ &gt};.

Example 8

3-Z- [l- (4-acetylamino-anilino) -l-phenyl-methylene] -6-methoxycarbonyl-2-indolinone

100 mg of 3-Z- [1- (4-aminomethyl-anilino) -1-phenyl-methylene] -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 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),

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

G26H23N3O4, ESI-MS: m / z = 440 [M-H] &lt; + &gt;.

As in Example 8, the following compounds were prepared:

(1) 3-Z- [1- (4- (N-methylsulfonylammomethyl) 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),

C ₂₅ H ₂ 3N ₃ O ₅ S,

ESI-MS: m / z = 476 [MH] -, (2) 3-Z- [1- (4- (4-benzoyl-piperazin-1-ylmethyl) -anilino) -1-phenyl-methylene 6-Methoxy-carbonyl-2-indolinone prepared by the reaction of 3-Z- [1- (4- (piperazin-1-ylmethyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2- indolinone and benzoyl chloride,

Product value: 0.7 (silica gel, methylene chloride / methanol = 10: 1) C35H32N4O4, ESI mass spectrum: m / z = 571 [MH] ^- , (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-phenyl-methylene] -6-methoxycarbonyl-2-indolinone,

Product value: 0.3 (silica gel, methylene chloride / methanol = 9: 1),

C30H32N4O4, ESI mass spectrum: m / z = 511 [M-H] -.

Example 9

3-Z- [l- (4- (piperidin-l-yl-methyl) anilino) -l-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 sodium hydroxide solution (c _NaOH ⁼ 1 mol.dm &^lt; ^{3 &gt;} ) and the reaction mixture was stirred at 80 [deg.] C. for 1 hour. After cooling, the mixture was neutralized with dilute hydrochloric acid (8.3 mL, c _HCl = 1 mol.dm 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};.

As in Example 9, the following compounds were prepared:

(1) 3-Z- [1- (4-bromo-anilino) -1-phenyl-methylene] -6-carboxy-2-indolinone, prepared from 3-Z- [1- (4-bromo-anilino) - l-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, R _r value of the product: 0.4 (silica gel, toluene / ethyl acetate = 5: 1), C 22 H ₅ BrN ₂ O 3,

ESI-MS: 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, Product value: 0.7 (reverse phase RP8, methanol) / 5% sodium chloride solution = 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), C 10 H 11 N 3 O 3,

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 [MH] -, (6) 3-Z- [1- (4- (N-acetyl- N -dimethylaminocarbonylmethylamino) anilino) -1-phenylmethylene] -6 -carboxy-2-indolinone prepared from 3-Z- [1- (4- (N-acetyl- N -dimethylaminocarbonyl-methyl-amino) -anilino) -1-phenyl-methylene] -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-2-indolinone, Product value: 0.6 (reverse phase RP8, methanol / 5% aqueous sodium chloride solution = 4 : 1), C25H23N3O3

ESI-MS: m / z = 412 [MH] -, (8) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl- N -methylamino) anilino) -1-phenyl-methylene] -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 solution = 4: 1), C ₂₇ H ₂₆ N ₄ O ₄ ,

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),

C ₃₀ H ₃₁ N ₃ O ₅ ,

ESI-MS: m / z = 512 [MH], (10) 3- Z- [1- (4 - ((N-carboxymethyl-N -methyl-amino) -inetyl) -amino) -1-phenyl -methylene] -6-methoxycarbonyl-2-indolinone, prepared from 3-Z- [1- (4 - ((N-ethoxycarbonyl-methyl-N-methylamino) -methyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl of 2-indolinone,

Rf value of product: 0.4 (silica gel, methylene chloride / methanol = 6: 1),

C ₂₇ H ₂₅ N ₃ O ₅ , ESI mass spectrum: m / z = 470 [MH] -.

Example 10 3-N- [1- (4- (Piperidin-1-yl-methyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone

0.9 g of 3-Z- [1- (4- (piperidin-1-ylmethyl) -anilino) -1-phenyl-methylene] -6-carboxy-2-indolinone was stirred in 35 ml of dimethylformamide and added. 0.4 g of carbonyl-diimidazole. 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), Product value: 0.5 (alumina, methylene chloride / methanol = 30: 1), C C ^HjgNjOj,

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,

Product value: 0.6 (aluminum oxide, methylene chloride / methanol = 30: 1)

C ₃₅ H ₃₃ N ₃ O ₃ , mass spectrum: m / z = 543 [M] ⁺ , (2) 3-Z- [1- (4- (piperidin-1-ylmethyl) -anilino) -1- phenyl-methylene] -6-isopropyloxycarbonyl-2-indolinone, prepared by the reaction of 3-Z- [1- (4- (piperidin-1-ylmethyl) anilino) -1-phenylmethylene] -6-carboxy-2-indolinone and isopropanol,

Product value: 0.4 (alumina, methylene chloride / isopropanol = 30: 1),

C31H ₃₃ N ₃ O 3 MS: 95 [M] ^+, (3) 3-Z- [1 - (4- (piperidin-1-ylmethyl) anilino) -1-phenyl-methylene] -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 reacting 3-Z- [1- (4- (piperidin-1-ylmethyl) -anilino) -1-phenylmethylene] -6-carboxy-2-indolinone and n-butanol,

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

SK 287312-6

C32H35N3O3, + mass spectrum: m / z = 509 [M] ⁺ , (S) 3-Z- [1- (4-bromo-anilino) -1-phenyl-methylene] -6-carbamoyl-2-indolinone, prepared by reaction of 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), C ₂₂ H ₁₆ BrN ₂ O ₃ , mass spectrum: m / z = 432/434 [MH] -, (6) 3-Z- [1- (4- (piperidin-1-ylmethyl) anilino) -1- phenylmethylene] -6-ethylcarbamoyl-2-indolinone, prepared by the reaction of 3-Z- [1- (4- (piperidin-1-ylmethyl) -anilino) -1-phenylmethylene] -6-carboxy-2-indolinone and ethylamine gas,

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

C ₃₀ H ₃₂ N ₄ O ₂ , mass spectrum: m / z = 480 [M] ⁺ , (7) 3-Z- [1- (4- (dimethylaminomethyl) anilino) -1-phenyl-methylene] -6 - [(2-methyloxy-ethoxy) -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),

₂ C 5 H ₂₃ N3O3

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),

C ₂₉ H ₃₂ N ₄ O ₃

ESI-MS: m / z = 483 [MH] -, (9) 3-Z- [1- (4- (dimethylaminomethyl) amino) -1-phenylmethylene] -6 - [(2- N -t-tert-) butoxycarbonyl-amino-ethoxy) -carbonyl] -2-indolinone, prepared by reacting 3-Z- [1- (4- (dimethylaminomethyl) -anilino) -1-phenyl-methylene] -6-carboxy-2-indolinone and 2- 7V-tert-butoxycarbonyl-amino-ethanol,

Product value: 0.8 (silica gel, methylene chloride / methanol = 5: 2),

C ₃₂ H ₃₆ N ₄ O ₅

ESI-MS: m / z = 412 [MH] -, (10) 3-Z- [1- (4- (dimethylaminomethyl) anilino) -1-phenylmethylene] -6 - [(2,2, 2-trifluoroethoxy) carbonyl] -2-indolinone, prepared by reacting 3-Z- [1- (4- (dimethylaminomethyl) anilino) -1-phenylmethylene] -6-carboxy-2-indolinone, and 2,2 , 2-trifluoroethanol,

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

C ₂₇ H ₂₄ F ₃ N ₃ O ₃ ,

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-yl-methyl) -anilino) -1-phenyl-methylene] -6-carboxy-2-indolinone, 0.95 g, was stirred in 25 ml of dimethylformamide. 8 g 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), Product value: 0.4 (reverse phase RP8, methanol / 5% aqueous sodium chloride solution = 6: 4), C ₂₈ H ₂₈ N ₄ O ₂ ,

ESI-MS: m / z = 453 [M + H] &lt; ^{+ &gt};.

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,

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

C3 ₀ H ₃₂ N ₄ O ₂

ESI-MS: m / z = 481 [M + H] &lt; ^{+ &gt};, (2) 3-Z- [1- (4- (piperidin-1-ylmethyl) -anilino) -1-phenyl-methylene] - 6- (N-ethyl- N -methyl-carbamoyl) -2-indolmone prepared by the reaction of 3-Z- [1- (4- (piperidin-1-ylmethyl) anilino) -1-phenylmethylene] -6-carboxy -2-indolinone and N-ethyl-N-methylamine,

Product value: 0.5 (alumina, methylene chloride / ethanol = 20: 1),

C ₃ iH ₃₄ N ₄ O2,

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] diizopropyletylammu.

Product value: 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,

Product value: 0.3 (silica gel, methylene chloride / ethanol = 2: 1),

C26H26N4O2, mass spectrum: m / z = 426 [M] &lt; ^{+ &gt};, (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,

Product value: 0.5 (alumina, methylene chloride / methanol = 20: 1),

C ₃ o ₃₂ N40 ₃ ,

ESI-MS: m / z = 495 [MH] -, (6) 3-Z- [1- (4- (piperidin-1-ylmethyl) -anilino) -1-phenyl-methylene] -6- diethylcarbamoyl-2-indolinone, prepared by the reaction of 3-Z- [1- (4- (piperidin-1-ylmethyl) -anilino) -1-phenylmethylene] -6-carboxy-2-indolinone and diethylamine hydrochloride / diisopropylethylamine,

Product value: 0.8 (alumina, methylene chloride / methanol = 10: 1),

C ₃₂ H ₃₆ N ₄ O2

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,

Product value: 0.3 (silica gel, toluene / ethyl acetate / ethanol = 4: 2: 1), C ₃₀ H _{32 N 4} O ₄ ,

ESI-MS: m / z = 511 [MH] -, (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 -methyl-amino) -anilino) -1-phenyl-methylene] -6-carboxy-2- indolinone,

Product value: 0.5 (silica gel, methylene chloride / methanol / ammonia = 5: 1: 0.01),

C ₂₇ H ₂₇ N ₅ O ₃

ESI-MS: m / z = 468 [M-H] -.

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 at room temperature was added 5.0 g of 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl-N-methyl-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 product: 0.6 (silica gel, methylene chloride / methanol / ammonia = 5: 1: 0.01), mp 198 ° C,

C ₂₈ H ₂₈ N ₄ O ₅ xc ₆ h ₈ o ₇

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- (dimethylamino-methyl) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone and methanesulfonic acid,

Rf value of product: 0.6 (silica gel, methylene chloride / methanol / ammonia = 5: 1: 0.01), melting point: 275 ° C,

C ₂₆ H ₂₅ N ₃ O ₂ x CH ₄ O ₃ S,

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 examples, the following compounds can be prepared:

(1) 3-Z- (1-anilino-1-phenyl-methylene) -6-ethoxycarbonyl-2-indolinone, (2) 3-Z- [1- (4-nitro-anilino) -1-phenyl-methylene (3) 3-Z- [1- (4-fluoro-anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (4) 3-Z-] -6-ethoxycarbonyl-2-indolinone; [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, (6) 3-Z- [1- (4-cyano-anilino) -1-phenylmethylene] -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-trifluoromethyl-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (10) 3-Z- (1) - (4-methyl-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (11) 3-Z- [1- (4-methylmercapto-anilino) -1-phenyl-methylene] -6 -ethoxycarbonyl-2-indolinone, (12) 3-Z- [1- (4-aminomethyl-anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (13) 3-Z- [1- (4- (isopropylamino) -anil Ino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (14) 3-Z- [1- (4- (anilinomethyl) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2 (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] -6-ethoxycarbonyl -2-indolinone, (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-propylamino) (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, (2S) 3-Z- [1- (4 - ((N-ethyl-N-propylamino)) methyl) anilino) -lf enyl-methylene] -5-ethoxycarbonyl-2-indolinone, (2S) 3-Z- [1- (4 - ((N-ethyl-N-isopropyl-amino) -methyl) -anilino) -1- phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (2S) 3-Z- [1- (4- (dipropylaminomethyl) anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (26) 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-ethoxy-carbonyl-2-indolinone, (2 S) 3-Z- [1- (4- (dibenzylaminomethyl)) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (2 S) 3-Z- [1- (4- (3,6-dihydro-277-pyridin-1-ylmethyl) - (30) 3-Z- [1- (4- (3,5-dimethyl-piperidin-1-yl-methyl-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone -phenyl-methylene] -5-ethoxy-carbonyl-2-indolinone, (3 S) 3-Z- [1- (4- (azepan-1-ylmethyl) -anilino) -1-phenyl-methylene] -6 -ethoxycarbonyl-2-indolinone, (2 S) 3-Z- [1- (4- (piperazin-1-ylmethyl) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (33) 13-Z- [1- (4- (Morpholin-4-ylmethyl) -anilino) -1-phe (34) 3- Z- [1- (4- (thiomorpholin-4-ylmethyl) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl- 2-indolinone, (3 S) 3-N- [1- (4- (1-oxo-thiomorpholin-4-ylmethyl) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone (36) 3-Z- [1- (4- (1,1-dioxo-thiomorpholin-4-ylmethyl) -anilino) -1-phenyl-methylene] -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-phenyl-methylene] -6-ethoxycarbonyl- 2-indolinone, (4 S) 3-Z- [1- (4- (2-diethylamino-ethyl) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (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-ethoxycarbones 1-2-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 - (V) (47) 3-Z- [1- (4- (N-methylaminomethylcarbonyl-N-methyl) -aminomethylcarbonyl-N'-methyl-amino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone (amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (48) 3- Z- [1- (4- (N -ethylaminomethylcarbonyl-N-methyl-amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (49) 3-Z- [1- (4- (N-diethylaminomethylcarbonyl- ^{7 7} -methylamino) -anilino) -1-phenyl- methylene] -6-ethoxycarbonyl-2-

(50) 3-Z- [1- (4 - (N - (piperidin-1-ylmethylcarbonyl) - N '- methylamino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl -2-

(51) 3-Z- [1- (4- (N- (morpholin-4-ylmethylcarbonyl) -N ^- methyl-amino) -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-phenylmethylene] -6-ethoxycarbonyl -2-indolinone, (3 _S ) 3-N- [1- (4- (N - (2-diethylamino-ethylcarbonyl) - _N -methyl-amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl -

-2-indolinone, (2S) 3-Z- [1- (4 - (N-acetyl- N - (2-aminoethyl) amino) anilino) -1-phenylmethylene] -6-ethoxy- carbonyl-2-indolinone, (57) 3- Z - [1- (4- (N-acetyl-7 '- (2-methylamino-ethyl) -amino) -anilino) -1-phenyl-methylene] -6 -ethoxycarbonyl-2-indoline, (58) 3-Z- [1- (4- (77-acetyl-1H- (2-methylamino-propyl) -amino) -anilino) -1-phenyl-methylene] -6- ethoxycarbonyl-2-indolinone, (59) 3- Z - [1- (4 - (N -acetyl-N - (2-piperidin-1-yl-ethyl) -amino) -anilino) -1-phenyl- methylene] -6-ethoxycarbonyl-2-indolinone, (60) 3-Z- [1- (4- (N-acetyl- N - (aminocarbonylmethyl) amino) anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (2 S) 3-N- [1- (4- (N-acetyl-N - (dimethylaminocarbonylmethyl) amino) anilino) -1-phenylmethylene] -6- ethoxycarbonyl-2-indolinone, (62) 3-Z- [1- (4- (N-acetyl- N - (piperidin-1-ylcarbonylmethyl) amino) anilino) -1-phenyl- methylene] -6-ethoxycarbonyl-2-indolinone, (63) 3-Z- [1- (4- (N-methyl-N- (aminocarbonyl) amino) anilino) -1-phenylmethylene] -6- ethoxycarbonyl-2-indolinone (64) 3-Z- [l- (4- (N-methyl-A ^/ - (methylaminocarbonyl) amino (amino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (2S) 3-Z- [1- (4- (N-methyl-N - (dimethylaminocarbonyl) amino) -anilino) - 1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (66) 3-Z- [1- (4- (N-methyl- N - (piperidin-1-yl-carbonyl) amino) -anilino -1-Phenylmethylene] -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) -7 H -methylsulfonyl-amino) -anilino) -1- phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (69) 3- Z- [1- (4- (N - (2-ethylamino-ethyl) - N -methylsulfonyl-amino) -anilino) -1-phenyl methylene] -6-ethoxycarbonyl-2-indolinone (70) 3-Z- [l- (4- (R ^L (2-diethylamino-ethyl) -7V-methylsulphonyl-amino) -anilino) -l-phenyl- methylene] -6-ethoxycarbonyl-

-2-indolinone, (71) 3-Z- [1- (4- (N - (2-pyrrolidin-1-yl-ethyl) - N -methylsulfonylamino) -anilino) -1-phenyl-methylene] -6- ethoxycarbonyl-

-2-indolinone, (72) 3- Z- [1- (4- (N - (2-piperidin-1-yl-ethyl) - N -methylsulfonyl-amino) -anilino) -1-phenyl-methylene ] -6-ethoxycarbonyl-2-indolinone,

(73) 3-Z- [1- (4- (N '- (2-piperazin-1-yl-ethyl) - N -methylsulfonyl-amino) -amino) -1-phenyl-methylene] -6 -ethoxycarbonyl-2-indolinone, (74) 3- Z- [1- (4- (N - (2- (morpholin-4-yl) ethyl) - N -methylsulfonylamino) -anilino) -1-phenylmethylene ] -6-ethoxycarbonyl-2-indolinone, (75) 3- [1- (4- (N - (aminocarbonylmethyl) -N-methylsulfonylamino) -amino) -1-phenylmethylene] -6-ethoxycarbonyl -2-indolinone (76) 3-Z- [l- (4- ^(N - (methylaminocarbonyl-methyl) -N-methylsulphonyl-amino) -anilmo) -l-phenyl-methylene] -6-ethoxycarbonyl-2 (77) 3-Z- [1- (4- (N- (ethylaminocarbonyl-methyl) -X-methylsulfonyl-amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (78) 3-Z- [1- (4- (N - (N - (2-dimethylamino-ethyl) - N ¹ -methyl-amino) -carbonyl-methyl) -N-methylsulfonyl-amino) -anilino) -1-Phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (79) 3- Z- [1- (4- (N - (diethylaminocarbonylmethyl) - N -methylsulfonyl-amino) -anilino) -1- phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (80) 3-Z- [1- (4- ( _N - (pyrrolidin-1-yl-carbonyl-methyl) - N -methylsulfonyl-amino) (1-Anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (81) 3-Z- [1- (4 - (N - (piperidin-1-yl-carbonyl-methyl)) -] N-methylsulfonyl-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- (A '- ( (morpholin-4-yl) -carbonyl-methyl) -N-methylsulfonyl-amino) -amino) -1-phenyl-methylene] -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-phenylmethylene] -6-ethoxycarbonyl-2 (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-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (89) 3- Z- [1- (4- (pyridin-3-yl) ) anilino) -l-phenyl-methylene] -6-ethoxycarbonyl onyl-2-indolinone, (90) 3-Z- [1- (4- (pyridin-4-yl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (91) 3- N- [1- (4- (N-acetyl-N-methyl-amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (92) 3-Z- [1- (4) - (N-ethylcarbonyl-N - (dimethylaminocarbonylmethyl) -amino) -anilino) -1-phenyl-methylene] -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-yl-methyl) -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-ylmethyl) -anilino) -butylidene] -6-ethoxycarbonyl-2-indolinone, (98) 3- Z - [1- (4- (N - (3-dimethylamino-propyl) - N -acetyl-amino) -anilino) -methylene] - 6-ethoxy-carbonyl-2-indolinone, (99) 3- Z- [1- (4- (N - (3-dimethylamino-piperidin) -N'-acetyl-amino) -anilino) -ethylidene] -6- ethoxycarbonyl-2-indolinone, ( 100) 3-Z- [1- (4- (X- (3-dimethylamino-propyl) - N ^' -acetyl-amino) -anilino) -propylidene] -6-ethoxycarbonyl-2-indolinone, (101) 3- N- [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) -amino) -propylidene] -6-ethoxycarbonyl-2-indolinone, (104) 3-Z- [1- (4- (N 2 -) - dimethylamino-ethyl) - N -methylsulfonyl-amino) -aniol) -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 γ-anilino) -propylidene] -6-ethoxycarbonyl-2-indolinone, (111) 3-Z- [1- (4-carboxy-anilino) -butylidene] -6-ethoxycarbonyl-2-indolinone, (112) 3- N- [1- (4- (N- (3-dimethylamino-propionyl) - N -dimethylaminocarbonylmethyl-amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (113) 3- N- [1- (4- (N - (4-dimethylamino-butyryl) - N -dimethylaminocarbonyl-methyl-amino) -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-N- [1- (4- (N-dimethylaminocarbonyl-methyl-N - ('3-dimethylamino-propylsulfonyl) -amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2- (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- [l- (4 - ((2-dimethylamino-ethyl) -methyl-amino) anilino) -l-phenyl-methylene] -6-ethoxy carbonyl-2-indolinone, (119) 3-Z- [1- (4 - ((3-dimethylamino-propyl) amino-methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone (120) 3-Z- [1- (4 - ((N-tert-butoxycarbonyl-2-amino-ethyl) -aminomethyl) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (121) 3-Z- [1- (4 - ((N-tert-butoxycarbonyl-3-amino-propyl) -aminomethyl) -anilino) -1-phenyl-methylene] -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-ethoxy-carbonyl-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 (1) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (128) 3-Z- [1- (4- (N - (N-tert-butoxycarbonyl-2-amino-ethyl)) (N-methyl-amino-methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (129) 3- Z- [1- (4- (N-2-amino-ethyl) (N-Methyl-amino-methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (130) 3-Z- [1- (4- (N- (2-acetylami)) N-ethyl-N-methyl-1-amino-methyl) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (131) 3-Z- [1- (4 - (V) - (2-methylsulfonylamino-ethyl) - (N-methyl-amino-methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (132) 3-Z- [1- (4- (carboxymethyl-amino-methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (133) 3- Z- [1- (4- (ethoxycarbonyl-methyl-amino-methyl)) -anilino) -1-phenyl-methylene] -6-ethoxy-carbonyl-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-indolin (136) 3-Z- [1- (4- (methylcarbamoyl-methyl-amino-methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (137) 3-Z- [l- (4- (A ^/ -dimetylaminometylkarbonyl-N-methyl-amino) -3-amino-anilino) -l-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone (138) 3-Z- [ 1- (4- (N-dimethylaminomethylcarbonyl-; N -methylamino) -3-nitroanilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (139) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl-N-methyl-amino) -3-acetylamino-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (140) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl-N-methyl-amino) -3-methylsulfonyl-amino-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (141) 3-Z- [1 - ( 4- (N-dimethylaminomethylcarbonyl-N-methyl-amino) -3-cyano-amino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (142) 3-Z- [1- (4- ( (N-dimethylaminomethylcarbonyl- N -methyl-amino) -3-hydroxy-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (143) 3-Z- [1- (4- (N-dimethylamino-methylcarbonyl-7V-methyl-amino) -3-methoxy-anilino) -l-phenyl phenyl-methylene] -6-ethoxycarbonyl-2-indolinone (144) 3-Z- [1 - (4- (7V-dimethylamino-methylcarbonyl-R ^/ N-methyl-amino) -3-ethoxycarbonyl-anilino) -1-phenyl methylene] -6-ethoxycarbonyl-2-indolinone, (145) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl-N-methylamino) -3-carboxy-anilino) -1-phenyl-methylene] - 6-ethoxycarbonyl-2-indolinone, (146) 3- Z - [1- (4- (N-dimethylaminomethylcarbonyl-N-methyl-amino) -3-carbamoyl-anilino) -1-phenylmethylene] -6-ethoxycarbonyl -2-indolinone, (147) 3- [1- (4- (N + dimethylaminomethylcarbonyl- N -methylamino) -3-chloroanilino) -1-phenylmethylene] -6-ethoxycarbonyl-2 - indolinone,

(148) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl-N-methyl-amino) -3-fluoro-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (149) 3-Z- [1- (4- (N ^, -dimethylaminomethylcarbonyl-N'-methyl-amino) -3-bromoanilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (150) 3-N- [1- (4- (N-dimethylaminomethylcarbonyl- N -methyl-amino) -3-methyl-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (151) ) 3-N- [1- (4- (N-dimethylaminomethylcarbonyl- N -methyl-amino) -3-trifluoromethyl-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (152) 3 -Z- [1- (4- (N-dimethylaminomethylcarbonyl- N -methylamino) -3,5-dibromo-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (153) 3-Z - [1- (4- (N-dimethylaminomethylcarbonyl-N-methyl-amino) -3,5-dichloro-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (154) 3-Z- [1- (4- (dimethylaminomethyl) -3-amino-anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (155) 3-Z- [1- (4- (dimethylaminomethyl)) 3-nitrophenyl) -l-phenyl-methylene] -6-ethoxycarbonyl-2-in dolinone, (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, (160) 3-Z- [1- (4- (dimethylaminomethyl) -3-methoxy-anilino) -1-phenylmethylene] -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-chloro-anilino) -1-phenyl-methylene] -6-ethoxy-carbonyl-2-indolinone, (165) 3-Z- [1- (4- (dimethyl) aminomethyl) -3-fluoro-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (166) 3-Z- [1- (4- (dimethylaminomethyl) -3-bromo-anilino) -1-phenyl-methylene] -6-ethoxy-carbonyl-2-indolinone, (167) 3-Z- [1- (4- (dimethylaminomethyl) -3-methyl-anilino) -1-phenyl-methylene] -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 - (imidazol-1-yl-methylcarbonyl) -7V-methyl-amino) anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone (173) 3 -Z- [1 - (4- ^(f - (phthalimido-2-yl-methylcarbonyl) -7V-methyl-amino) anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indole (174) 3-Z- [1- (4- (N-aminomethylcarbonyl-N-methyl-amino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (175) 3- N- [1- (4- (N-acetylaminomethylcarbonyl- N -methylamino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (176) 3-Z- [1] - (4- (N-methylsulfonylaminomethylcarbonyl- N -methylamino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (177) 3-Z- [1- (4- (7 N - ( (/ V- (2-methoxyethyl) ^{-N-methyl-amino)} methylcarbonyl) -. V-methyl-amino) anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone (178) 3 Z- [l- (4 - (? / - ((X- (2-dimethylamino-ethyl) -7V-methyl-amino) -methylcarbonyl) - / V-methyl-amino) -anilino) -l-phenyl-methylene] 6-ethoxycarbonyl-2-indolinone, (179) 3-Z- [1- (4- (N - ((di- (2-hydroxyethyl) amino) methylcarbonyl) -7-methyl-amino) -anilino) -l-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone (180) 3-Z- [l- (4- ^(f -dimetylaminometylkarbonyl-N-methyl-amino) anilino) methylene] -6-ethoxycarbonyl 2-indolinone (181) 3-Z- [1 - (4- (7V-dimethylamino-methylcarbonyl and ^{f-methyl-amino)} anilino) ethyl dene] -6-ethoxycarbonyl-2-indolinone, (182) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl-1-methyl-1-amino) -anilino) -propylidene] -6-ethoxycarbonyl-2- (183) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl-N-methyl-amino) -amino) -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-methyl-amino) -anilino) -1-phenyl-methylene] -6- ethoxycarbonyl-2-indolinone, (189) 3- Z - [1- (4- (N - (3-dimethylamino-propyl) -7 H -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- (7H - ((2-dimethylanii)) (1-ethyl-carbonyl) - N -methyl-amino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (192) 3-Z- [1- (4 - (V) - (tert-butoxycarbonyl-aminomethyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (193) 3-Z- [1- (4- (2-oxo-pyrrolidin-1-yl) (methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (194) 3-Z- [1- (4- (N-aminocarbonyl-methyl) - N -methylsulfonyl- (amino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (195) 3-Z- [1- (4- (7-cyanomethyl-7 H -methylsulfonyl-amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (196) 3- Z- [1- (4- (2- (imidazol-4-yl) ethyl) -anilino) -1-phenyl- methylene] -6-ethoxycarbonyl-2-indolinone, (197) 3-Z- [1- (4 - ((2- (1H-benzyl-77-methyl-amino) -ethyl) -7 H -methylsulfonyl-amino) (-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (198) 3- Z- [1- (4-cyclohexylamino-amino) -1-phenylmethylene] -6-ethoxycarbonyl-2 (199) 3-Z- [1- (4- (imidazol-1-yl-methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (200) 3-Z - [l- (4- (imidazo (11-yl-methyl) -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-ylmethyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl -2-indolinone, (203) 3-Z- [1- (4 - ((4-hydroxy-piperidin-1-yl) -methyl) -anilino) -1-phenyl-methylene] -6-ethoxy-carbonyl- 2-indolinone, (204) 3-Z- [1- (4 - ((4-methoxy-piperidin-1-yl) -methyl) -anilino) -1-phenyl-methylene] -6-ethoxy-carbonyl-2 -indolinone, (205) 3- Z- [1- (4-benzyl-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (206) 3- Z- [1- (4- ( N - (3-Trifluoroacetylamino-propyl) - N -methylsulfonyl-amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (207) 3- Z- [1- (4- (4) (tert-butoxycarbonyl-piperazin-1-yl-methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (208) 3-Z- [1- (4- (1-methyl- imidazol-2-yl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indinone, (209) 3-Z- [1- (4- (1-methyl-imidazol-2-yl) (-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl- 2-indolinone (210) 3-Z- [l- (4- ^(f - (2-dimethylamino-ethyl) -7 / -metylsulfonylamino) -3-amino-anilino) -l-phenyl-methylene] -6 ethoxycarbonyl-2-indolinone (211) 3-Z- [l- (4 - ((3- _{^{(N-benzyl-I-N-methyl-amino)}} propyl) -N-methylsulphonyl-amino) 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-Phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (214) 3-Z- [1- (4- (N - (2-dimethylamino-ethyl) -7 H -isobutyryl-amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (215) 3-Z- [1- (4- (N - (2-dimethylamino-ethyl) - N -benzoylamino) amino] anilino -1-phenyl-methylene] -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-Phenylmethylene] -6-ethoxycarbonyl-2-indoline n, (218) 3- Z- [1- (4- (2- (4-hydroxy-piperidin-1-yl) -ethyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2 (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 '-butylsulfonyl-amino) -amino) -1-phenyl-methylene] -6-ethoxycarbonyl -2-indolinone, (221) 3-Z- [1- (4- (N - (2-dimethylamino-ethyl) - N -phenylsulfonyl-amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl -2-indolinone, (222) 3- Z- [1- (4- (N - (2-dimethylamino-ethyl) -7 H -benzylsulfonyl-amino) -anilino) -1-phenyl-methylene] -6- ethoxycarbonyl-2-indolinone, (223) 3-Z- [1- (4 - ((imidazolidin-2,4-dione-5-yl) methyl) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl -2-indolinone, (224) 3-Z- [1- (4 - ((3-hydroxy-pyrrolin-1-yl) -methyl) -amino) -1-phenyl-methylene] -6-ethoxycarbonyl-2- indolinone, (225) 3-Z- [1- (4- (cyclohexyl-methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (226) 3-Z- [1- ( 4- (cyclohexyl-carbonyl) -anilino) -l-phenyl-methylene] -6-e Toxicarbonyl-2-indolinone, (227) 3-Z- [1- (4-diethylaminomethyl-anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (228) 3-Z- [1- ( 4- (n ^- (n-hexyl) -? / - methyl-aminomethyl) anilino) -l-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone (229) 3-Z- [l- (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-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, ( 231) 3-N- [1- (4- (N - (2-dimethylamino-ethyl) - N - (pyridine-3-carbonyl) -amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl- 2-indolinone, (232) 3- [1- (4- (N - (2-dimethylamino-ethyl) -N- (phenyl-acetyl) -amino) -anilino) -1-phenyl-methylene] -6 -ethoxycarbonyl-2-indolinone, (233) 3-Z- [1- (4- (imidazol-2-yl) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (234) 3 -Z- [1- (4- (1-ethyl-imidazol-2-yl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (235) 3-Z- [1- ( 4- (l-benzyl-imidazol-2-yl) anilino) -l-phenyl-methylene 6-ethoxycarbonyl-2-indolinone, (236) 3- [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)--'-methyl-amino) (-anilino) -1-phenyl-1-methylene] -6-ethoxycarbonyl-2-indolinone, (239) 3-Z- [1- (4- (N - (2-dimethylamino-ethyl) -7H-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, (241) 3-Z- [1- (4- (N - ((2-dimethylamino-ethyl) -carbonyl) - N -isopropyl- amino) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (242) 3- Z- [1- (4- (7H - ((2-dimethylamino-ethyl)) -carbonyl) -7H (benzyl-amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (243) 3-Z- [1- (4- (N-butyl-N-tert-butoxycarbonyl-aminomethyl)) anilino) -l-phenyl-methylene] -6-e methoxycarbonyl-2-indolinone (244) 3-Z- [1 - (4- (N - ((aminocarbonyl and ^L-methyl-N- methyl-amino) -methylcarbonyl) - / V-methyl-amino) -aniline -1-Phenylmethylene] -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-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (247) 3-Z- [1- (4- (7H - ((2) - (4-tert-butoxycarbonyl-piperazin-1-yl) -ethyl) -carbonyl-N-methyl-amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (248) 3 Z- [l- (4- (N - ((2- (piperidin-l-yl) ethyl) carbonyl) -7V-methyl-amino) -anilino) -l-phenyl-methylene] -6-ethoxycarbonyl -2-indolinone, (249) 3-Z- [1- (4- (N - ((2 - (N-benzyl- _N -methyl-amino) ethyl)) carbonyl) -N (250-methyl-1-amino) -amino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone; (250) 3-Z- [1- (4- (N ^, -dimethylaminomethylcarbonyl- N -isopropyl- amino) anilino) -l-phenyl-methylene] -6-ethoxycarbonyl 1-2-indolinone, (251) 3- Z - [1- (4 - (N - (piperidin-1-ylmethylcarbonyl) - N '-isopropyl-amino) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (252) 3-Z- [1- (4- (N - (4-tert-butoxycarbonyl-piperazin-1-yl) -methylcarbonyl) -1-isopropyl-amino) - anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (253) 3-Z- [1- (4 - (N - ((N-benzyl- N -methylamino)) - methylcarbonyl-N-benzyl-amino) -anilino-1-phenyl-methylene] 6-ethoxycarbonyl-2-indolinone, (254) 3- Z- [1- (4- (N-dimethylaminomethylcarbonyl-N-benzylamino) (-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (255) 3- Z- [1- (4- (N - (piperidin-1-ylmethylcarbonyl) - N -benzylamino)] - (-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (256) 3- Z- [1- (4- (1,2,4-triazol-2-ylmethyl) -anilino) -1-Phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (257) 3- Z- [1- (4- (1,2,3-triazol-2-ylmethyl) -anilino) -1 -phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (258) 3- Z- [1- (4- (1,2,3-triazol-1-ylmethyl) -anilino) -1-phenyl- methylene] -6-ethoxycarbonyl-2-indolinone, (259) 3 -Z- [1- (4 - ((1H-aminocarbonyl-methyl-1H-methyl-amino) -methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (260) 3-Z- [1- (4 - ((di- (2-methoxy-ethyl) -amino) -methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (261 13-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'-methylamino) -methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-

-2-indolinone, (263) 3-Z- [1- (4- (azetidin-1-ylmethyl) -anilmo) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (264) 3 -Z- [1- (4- (N'-propyl-N-tert-butoxycarbonylaminomethyl) -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, (2 S) 3-Z- [1- (4 - ((N - (methylcarbamoyl-methyl) - N -methyl-amino) -methyl) -anilino) -1-phenyl-methylene ] -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- [l- (4 - _((me 7V- ALpropyl-ethyl-amino) methyl) anilino) -l-phenyl-methylene] -6 -ethoxy-carbonyl-2-indolinolium, (270) 3-Z- [1- (4 - ((N - (2-dimethylaminoimethyl) - N -methyl-amino) methyl) -anilio) -1-phenyl -methylene] -6-ethoxycarbonyl-2-indolinone, (271) 3-Z - [l- (4 - _((I, N- (3-dimethylaminopropyl) - / -N'-methyl-amino) methyl) anilino) -l-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (272) 3-Z- [1- (4 - ((N- (2-methoxy-ethyl) -N-methyl-amino) -methyl) -anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2 -indolinone, (273) 3-Z- [1- (4 - ((N - (2-hydroxy-ethyl) - N -methyl-amino) -methyl) -anilino) -1-phenyl-methylene] -6 ethoxycarbonyl-2-

-indolinone, (274) 3- Z - [1- (4 - ((N - (dioxolan-2-ylmethyl) - N -methyl-amino) methyl) -anilino) -1-phenyl-methylene] - 6-ethoxycarbonyl-2-indolinone, (275) 3-Z- [1- (4- (3-oxo-piperazin-1-ylmethyl) -anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2 -indolinón, (276) 3-Z- [l- (4- (A ^/ - (piperazin-l-yl-methylcarbonyl) -N-isopropyl-amino) -anilino) -l-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) -7 H -methylsulfonyl-amino) -anilino)) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (280) 3-Z- [1- (4-ureidomethyl-anilino) -1-phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, ( 2 81) 3-Z- [1- (4-guanidinomethyl-anilino) -1-phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (282) 3-Z- [1- (4- (N-methylsulfonyl)] (aminomethyl) -anilino) -1-phenyl-met ylene] -6-ethoxycarbonyl-2-indolmone, (283) 3-Z- [1- (4- (4-benzoyl-piperazin-1-ylmethyl) -anilino) -1-phenyl-methylene] - 6-ethoxy-carbonyl-2-indolinone, (284) 3-Z- [1- (4 - ((N - (3-acetylamino-propyl) - N -methyl-amino) -methyl) -anilino) -1- phenyl-methylene] -6-ethoxycarbonyl-2-indolinone, (285) 3-Z- [1- (4 - ((N - (3-methylsulfonylamino-propyl) -methyl-amino) -methyl) -anilino) - 1-Phenylmethylene] -6-ethoxycarbonyl-2-indolinone, (286) 3-Z- [1- (4 - ((N'-carboxymethyl- N -methylamino) methyl) -anilmo) -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-indolmone, (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, (292) 3- Z- [1- (4-iodo-anilino) -1-phenyl-methylene] -6- methoxycarbonyl-2-indolinone, (29 3) 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-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (296) 13-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-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (300) 3- Z- [1- (4- (anilinomethyl) anilino)] -1-Phenylmethylene] -6-methoxycarbonyl-2-indolinone, (301) 3-Z- [1- (4- (isobutylaminomethyl) anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone (302) 3-Z- [1- (4- (cyclohexylaminomethyl) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (303) 3-Z- [1- ( ⁴ - ( t ^'enz yl ^am i ^nornet yl) - ^{but an} ili) -l'f ^en yl' ^rnet ylene] -6-methoxycarbonyl-2-indolinone,

EN 287 312 Β6 (304) 3-Z- [1 - (4 - ^((N-methyl-A / propyl-amino) methyl) anilino) -1-phenyl-methylene] -6-methoxycarbonyl- 2-indolinone, (305) 3-N- [1- (4 - ((N-isopropyl-N-methyl-amino) -methyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2- indolinone, (306) 3-N- [1- (4 - ((N-ethyl-N-propylamino) -methyl) -amino) -1-phenyl-methylene] -6-methoxy-carbonyl-2- (307) 3-Z- [1- (4 - ((N-ethyl-N-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-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (310) 3-Z- [1- (4 - ((N-benzyl- N -ethyl-amino) -methyl) -anilino) -1-Phenylmethylene] -6-methoxycarbonyl-2-indolinone, (311) 3-Z- [1- (4- (dibenzylaminomethyl) anilino) -1-phenylmethylene] -6-methoxycarbonyl- 2-indolinone, (312) 3- [1- (4- (3,6-dihydro-2H-pyridin-1-ylmethyl) -anilino) -1-phenylmethylene] -6-methoxycarbonyl -2-indolinone, (313) 3-Z- [1- (4- (3,5-Dimethyl-piperidin-1-yl-methyl) -anilino) -1-phenyl-methylene] -6-methoxy-carbonyl-2-indolinone, (314) 3-Z- [1- (4- ( azepan-1-yl-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-phenylmethylene] -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- [1- (4- (2-diethylamino-ethyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolmone, (320) 3-Z- [1- (4- (2-piperidin-1-yl-ethyl) -anilino) -1-phenyl-methylene -6-methoxycarbonyl-2-indolinone, (321) 3- [1- (4- (2-acetylaminomethyl) anilino) -1-phenylmethylene] -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-dimethylaminopropyl) anilino) -l- phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (324) 3- Z- [1- (4- (N-aminomethylcarbonyl-N-methyl-amino) -anilino) -1-phenyl-methylene] -6- methoxycarbonyl-2-indolinone, (325) 3-Z- [1- (4- (N-ethylaminomethylcarbonyl-N-methyl-amino) -amino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, ( 326) 3-Z- [1- (4- (N-diethylaminomethylcarbonyl- N -methyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (327) 3-Z- [l- (4- ^{(7V-dipropylaminometylkarbonyl-N-methyl-amino)} -anilino) -l-phenyl-methylene] -6-methoxycarbonyl-2-indolinone (328) 3-Z- [l- (4- (N - ((N-ethyl-N-methyl-amino) -methylcarbonyl) -N-methyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (329) 3-Z - [l- (4- (N - ^((N-ethyl-N- propyl-amino) -methylcarbonyl) -N-methyl-amino) -anilmo) -l-phenyl-methylene] -6-methoxycarbonyl-2 -indolinone, (330) 3-N- [1- (4- (N - ((N ^, -methyl-N-propylamino) -methylcarbonyl) -7-methyl-amino) -anilino) -1-phenyl- methylene] -6-methoxycarbonyl-2-indolinone, (331) 3 -Z- [1- (4- (4-dimethylaminomethylcarbonyl-N-ethylamino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (332) 3-Z- [1- (4- (N ^' -dimethylaminomethylcarbonyl-N-propylamino) -anilino) -1-phenyl-methylene 6-Methoxycarbonyl-2-indolinone, (333) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl-N-butyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2 -indolinone, (334) 3-Z- [1- (4- (N - (2-amino-ethylcarbonyl) - N -methyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2 (335) 3- Z- [1- (4- (N - (2-diethylamino-ethylcarbonyl) -N-methyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2- indolinone (336) 3-Z- [1 - (4- (acetyl ^L-A / - (2-aminoethyl) amino) anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2- indolinone (337) 3-Z- [l- (4- ^(f-acetyl-N- (2-methylamino-ethyl) -amino) anilino) -l-phenyl-methylene] -6-methoxycarbonyl-2- (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-phenylmethylene] -6-methoxycarbonyl- 2-indoline (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-yl-carbonyl-methyl) -amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2 -indolinón, (342) 3-Z- [l- (4 - (/ _V-methyl-I, N (armnokarbonyl) amino) -anilmo) -l-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (343) 3-N- [1- (4- (N-methyl-N - (methylaminocarbonyl) amino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (344) 3 -Z- [1- (4- (77-methyl- N - (dimethylaminocarbonyl) amino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (345) 3-Z- [ 1- (4- (N-methyl-N - (piperidin-1-yl-carbonyl) -amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (346) 3-Z- [l- (4- ^(f - (2-methylaminoethyl) -N-methylsulfonylamino) anilino) -l-phenyl-methylene] -6-methoxycarbonyl-2-indolinone (347) 3-Z- [l- (4- (N - (2-diethylamino-ethyl) - N -methylsulfonyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (348) 3-Z- [1- (4- (7V- (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 - (diethylaminocarbonylmethyl) - N -methylsulfonylamino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (354) 3-Z- [1- (4- (N - (pyrrolidin-1-yl-carbonyl-methyl) - (N -methylsulfonyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (355 13-Z- [1- (4 - (N - (piperidin-1-yl-carbonyl-methyl) - N -methylsulfonyl-amino) -anilino) -1-phenyl-methylene] -6-methoxy Rbonyl-2-indolinone, (356) 3- Z - [1- (4- (N - (piperazin-1-yl-carbonyl-methyl) - N -methylsulfonyl-amino) -anilino) -1-phenyl-methylene] 6-Methoxycarbonyl-2-indolinone, (357) 3- [1- (4- (N - ((morpholin-4-yl) -carbonylmethyl) - N -methylsulfonyl-amino) -amino) - 1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (358) 3-Z- [1- (4- (2-dimethylamino-ethoxy) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl- 2-indolinone, (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-indolinone, (363) 3- [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- [l- (4- (7V-acetyl-N-me (366) 3-Z- [1- (4- (N-ethylcarbonyl) -N- (dimethylaminocarbonyl-methyl) - (1-phenyl-methylamino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone amino) -anilino) -1-phenyl-methylene] -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-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (369) 13-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-indolmone, (373) 3-Z- [ 1- (4- (piperidin-1-yl-methyl) -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-ylmethyl) -anilino) -butyl lidene] -6-methoxycarbonyl-2-indolinone, (376) 3- Z - (1- (4- (N - (3-dimethylamino-propyl) - N -acetyl-amino) -anilino) -methylene] -6- methoxycarbonyl-2-indolinone, (377) 3- Z- [1- (4- (N ^' - (3-dimethylamino-propyl) - N ^' -acetyl-amino) -anilino) -ethylidene] -6-methoxycarbonyl-2 (378) 3-Z- [1- (4- (N - (3-dimethylamino-piperidin) -N-acetyl-amino) -anilino) -propylidene] -6-methoxycarbonyl-2-indolinone, (379) 13-Z- [1- (4- (N '- (3-dimethylamino-propyl) - N -acetyl-amino) -amino) -butylidene] -6-methoxycarbonyl-2-indolinone, (380) 3-Z - [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- (AL (2-dimethylamino) (383) 3-Z- [1- (4- (N- (2-dimethylamino-ethyl) -R-methylsulfonylamino) -anilino) -propylidene] -6-methoxycarbonyl-2-indolinone; 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-amino) -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-methyl-methylene] -6-methoxycarbonyl-2-indolinone, (393) 3-Z - [1- (4- (2,3,4,5-tetrahydro-benzo (d) azepin-3-ylmethyl) -anilino) -1-methyl-methylene] -6-methoxycarbonyl-2-indolinone, ( 394) 3-N- [1- (4 - ((benzo (1,3) dioxol-5-ylmethyl) -methyl-aminomethyl) -anilino) -1-methyl-methylene] -6-methoxycarbonyl-2- indolinone, (395) 3-Z- [ 1- (4- (N-phenethyl-N-methyl-aminomethyl) -anilino) -1-methyl-methylene] -6-methoxycarbonyl-2-indolinone, (396) 3-Z- [1- (4) - (N - (3,4-dimethoxy-benzyl) - N -methyl-aininomethyl) -anilino) -1-methyl-methylene] -6-methoxycarbonyl-2-indolinone, (397) 3-Z- [1 - ( 4- (N - (4-chloro-benzyl) - N -methyl-amino-methyl) -anilino) -1-methyl-methylene] -6-methoxycarbonyl-2-indolinone, (398) 3-Z- [1- (4 - (/ V- (4-methylbenzyl) -N-methyl-amino-methyl) -amlino) -l-methyl-methylene] -6-methoxycarbonyl-2-

-indolinone, (399) 3-Z- [1- (4- (N (4-fluoro-benzyl) - N ¹ -methyl-amino-methyl) -anilino) -1-methyl-methylene] -6-methoxycarbonyl- 2

-indolinone, (400) 3-N- [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 -dimethylaminocarbonylmethyl-amino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl -2-indolinone, (402) 3-Z- [1- (4- (N - (4-dimethylamino-butyryl) - N ^, -dimethylaminocarbonylmethyl-amino) -anilino) -1-phenyl-methylene] -6- methoxycarbonyl-2-indolinone, (403) 3- [1- (4- (N-dimethylaminocarbonylmethyl- N - (2-dimethylamino-ethylsulfonyl) -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-methoxy-carbonyl-2 -indolinone, (406) 3-Z- [1- (4 - ((2-methoxy-ethyl) -amino-methyl) -anilino) phenyl-methylene] -6-methoxy-carbonyl-2-indolinone, (407) 3-Z- [l- (4 - ((2-dimethylamino-ethyl) -methyl-amino) anilino) -l-phenyl-methylene] -6-methoxy- ycarbonyl-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 - ((7Y-tert-butoxycarbonyl-2-amino-ethyl) -amino-methyl) -amino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (410) 3-Z- [1- (4 - ((N-tert-butoxycarbonyl-3-amino-propyl) -aminomethyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (411) 3-Z- [1- (4 - ((2-amino-ethyl) -amino-methyl) -anilino) -1-phenyl-methylene] -6-methoxy-carbonyl-2-indolinone, (412) 3-Z- [1- (4 - ((3-Amino-propyl) -amino-methyl) -anilino) -1-phenyl-methylene] -6-methoxy-carbonyl-2-indolinone, (413) 3-Z - [1- (4 - ((2-acetylaminoethyl) amino-methyl) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolmone, (414) 3-Z- [1- (4) - ((3-acetylamino-propyl) amino-methyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (415) 3-Z- [1- (4 - ((2- methylsulfonylamino-ethyl) -amino-methyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (416) 3-Z- [1- (4 - ((3-methylsulfonylamino-propyl) - amino-methyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (417) 3-Z- [1- (4- (N - (N '- tert -butoxycarbonyl-2-amino-ethyl)) - (N-methyl-aminomethyl) -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-phenyl-methylene] -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-methoxy-carbonyl-2-indolinone, (422) 3- Z- [1- (4- (ethoxycarbonyl-methyl-amino-methyl) -anilino) - 1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (423) 3-Z- [1- (4- (carbamoyl-methyl-amino-methyl) -anilino) -1-phenyl-methylene] -6- methoxy-carbonyl-2-indolinone, (424) 3-Z- [1- (4- (dimethylcarbamoyl-methyl-amino-methyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indoline (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-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (427) 3-Z- [1- ( 4- (N'-dimethylaminomethylcarbonyl- N -methyl-amino) -3-nitro-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (428) 3-Z- [1- (4) - (N-dimethylaminomethylcarbonyl- N -methyl-amino) -3-acetylamino-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (429) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl-N-methyl-amino) -3-methylsulfonyl-amino-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (430) 3-Z- [1- (4- ( N-dimethylaminomethylcarbonyl-N ^, -methyl-amino-3-cyano-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (431) 3-Z- [1- (4- (N, -) dimethylaminomethylcarbonyl-N-methyl-amino) -3-hydroxy-anilino-1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (432) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl) N-methyl-amino) -3-methoxy-anilino-1-phenyl-met ylene] -6-methoxycarbonyl-2-indolinone, (433) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl-N'-methylamino) -3-ethoxycarbonyl-anilino) -1-phenyl-methylene 6-Methoxycarbonyl-2-indolinone, (434) 3- [1- (4- (N-dimethylaminomethylcarbonyl-N-methyl-amino) -3-carboxy-anilino) -1-phenyl-methylene] - 6-methoxycarbonyl-2-indolinone, (435) 3-N- [1- (4- (N-dimethylaminomethylcarbonyl-N-methyl-amino) -3-carbamoyl-anilino) -1-phenyl-methylene] -6-methoxycarbonyl -2-indolinone, (436) 3-Z- [1- (4- (N-dimethylaininomethylcarbonyl-N-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-phenylmethylene] -6-methoxycarbonyl-2-indolinone (438) 3-N- [1- (4- (N-dimethylarninomethylcarbonyl-N-methylamino) -3-bromo-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (439) 3 Z- [l- (4 - (? ^{in-dimethylamino-methylcarbonyl-N-methylamino)} -3-methyl-anilino) -l-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (440) 3- Z- [1- (4- ( _N, N-dimethylaminomet (441) 3-Z- [1- (4- (N, N-dimethylaminomethylcarbonyl) -ylcarbonyl- N -methyl-amino) -3-trifluoromethyl-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone N-methylamino) -3,5-dibromo-anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (442) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl-N ⁾ - methyl-amino) -3,5-dichloro-amino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (443) 3-Z- [1- (4- (dimethylaminomethyl) -3-amino- anilino) -1-phenyl-methylene] -6-methoxy-carbonyl-2-indolinone, (444) 3-Z- [1- (4- (dimethylaminomethyl) -3-nitro-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (445) 3- [1- (4- (dimethylammomethyl) -3-acetylamino-anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (446) 3-Z- [1- (4- (dimethylammomethyl) -3-methylsulfonylamino-anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (447) 3-Z- [1- ( 4- (dimethylaminomethyl) -3-cyano-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (448) 3-Z- [1- (4- (dimethylaminomethyl) -3-hydroxy-anilino) ) -l-phenyl-methylene] -6-methoxycarbonyl-2-indole (449) 3-Z- [1- (4- (dimethylaminomethyl) -3-methoxy-anilino) -1-phenyl-methylene] -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-methoxy-carbonyl-2-indolinone, (452) 3-Z- [1- (4- (dimethylaminomethyl) -3-carbamoylanilino) -1-phenyl-methylene] - 6-methoxy-carbonyl-2-indolinone, (453) 3-Z- [1- (4- (dimethylaminomethyl) -3-chloro-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone (454) 3-Z- [1- (4- (dimethylaminomethyl) -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-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (457) 3-Z- [1- (4- (dimethylarninomethyl) -3-trifluoromethyl-anilino) -1- phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (458) 3-Z- [1- (4-dimethylaminomethyl-3,5-di) bromo-anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (459) 3-Z- [1- (4- (dimethylaminomethyl) -3,5-dichloro-anilino) -1- phenyl-methylene] -6-methoxy-carbonyl-2-indolinone, (460) 3-Z- [1- (4- (dimethylaminomethyl) anilino) -1-phenyl-methylene] -6 - [(2-hydroxy- ethoxy) carbonyl] -2-indolinone, (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-phenyl-methylene] -6 - [(2-hydroxy-ethoxy) -carbonyl] -2-indolinone, (465) 3-Z- [ 1- (4- (N ^' -dimethylaminomethylcarbonyl-N-methyl-amino) -anilino) -1-phenyl-methylene] -6 - [(ethoxycarbonylmethoxy) carbonyl] -2-indolinone, (466) 3-Z- [l- (4 - (/ V-dimetylaminometylkarbonyl- / V-methyl-amino) -anilino) -l-phenyl-methylene] -6 - [(carboxy-methoxy) -ka Rbonyl] -2-indolinone, (467) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl-N-methylamino) -anilino) -1-phenylmethylene] -6 - [(carbamoyl-methoxy) -carbonyl] -2-indolinone, (468) 3- [1- (4- (N-dimethylaminomethylcarbonyl-N-methyl-amino) -anilino) -1-phenyl-methylene] -6 - [(2-methoxy) (ethoxy) -carbonyl] -2-indolinone, (469) 3- [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-methyl-amino) -anilino) -1-phenyl-methylene] -6- [(2- (N-tert-butoxycarbonyl-amino) -ethoxy) -carbonyl] -2-indolinone, (471) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl-N-methyl-amino) -anilino] -1-phenyl-methylene] -6 - [(2-amino-ethoxy) -carbonyl] -2-indolinone, (472) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl-N ^, -methyl)] - (amino) -amino) -1-phenyl-methylene] -6 - [(2,2,2-trifluoroethoxy) carbonyl] -2-indolinone, (473) 3-Z- [1- (4- (V) - ((4-methyl-piperazin-1-yl) -methylcarbonyl) - N -methyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (474 13-Z- [1- (4- (N - (imidazo-1-yl-methylcarbonyl) -N-methyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, ( 475) 3-N- [1- (4- (N - (phthalimido-2-ylmethylcarbonyl) -N-methylamino) anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (476) 13-Z- [1- (4- (N-aminomethylcarbonyl-N-methyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (477) 3-Z- [1] - (4- (N-acetylaminomethylcarbonyl-N-methyl-amino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (478) 3-Z- [1- (4- (7-methyl-amino) carbonyl] -2-indolinone; metylsulfonylaminometylkarbonyl- / V-methyl-amino) -anilino) -l-phenyl-methylene] -6-methoxycarbonyl-2-indolinone (479) 3-Z- [l- (4- (N - ((A ^/ - ( 2-methoxyethyl) - N -methylamino) methylcarbonyl-N-methyl-amino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (480) 3-Z- [1- (4- (7V - ((/ V- (2-dimethylamino-ethyl) - / V-methyl-amino) -methylcarbonyl) -N-methyl-amino) -anilino) -l-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (481) 3-Z- [1- (4- (N - ((di- (2-hydroxyethyl) amino) methylcarbonyl) -, N -methyl-amino) -anilino) -1-phenylmethyl (482) 3- [1- (4-tert-butoxycarbonylmethyl-anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (483) 3-Z- [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-methoxycarbonyl-2-indolinone, (485) 3-Z- [1- (4- (N-dimethylaminomethylcarbonyl-A ^')) (methyl-amino) -anilino) -propylidene] -6-methoxycarbonyl-2-indolinone, (486) 3- Z- [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 -phenyls 1-methylene] -6-methoxycarbonyl-2-indolinone, (492) 3-Z- [1- (4- (N- (2-dimethylamino-ethyl) -N-methylamino) -anilino) -1-phenyl methylene] -6-methoxycarbonyl-2-

(493) 3-N- [1- (4- (N - (3-dimethylamino-propyl) - N -methyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2- (494) 3-Z- [1- (4- (N-methyl-acetylamino) -anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (495) 3-Z- [1] - (4- (imidazol-4-yl) anilino) -1 -phenyl-] -6-methoxycarbonyl-2-indolinone (496) 3-Z- [1 - (4 - _((I, N- (dioxolan-2 (49-methyl-N- (N-methyl-amino) -methyl) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, 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-yl-methyl) -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-Z- [1- (4-) (N-Phenethyl-N-methyl-amino-methyl) -anilino) -1-methyl-methylene] -6-carbamoyl-2-indolinone, (501) 3-Z- [1- (4- (M- (3) , 4-dimethoxy-benzyl) - <N-methyl-aminomethyl) anilino) -l-methyl-methylene] -6-carbamoyl-2-indole (502) 3-Z- [1- (4- (N- (4-chloro-benzyl) - N ^, -methyl-amino-methyl) -anilino) -1-methyl-methylene] -6-carbamoyl- 2-indolinone, (503) 3-N- [1- (4- (N - (4-methyl-benzyl) - N -methyl-amino-methyl) -amino) -1-methyl-methylene] -6 -carbamoyl-2-indolinone, (504) 3- [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) -7 H -methyl-amino-methyl) -anilino) -1-methyl- methylene] -6-carbamoyl-2-indolinone (506) 3-Z- [l- (4 - ((A ^/ - (2-methoxy-ethyl) -7V-methyl-amino) methyl) anilino) - 1-Phenylmethylene] -6-methoxycarbonyl-2-indolinone, (507) 3-Z- [1- (4- (dimethylaminomethyl) anilino) -1-phenylmethylene] -6 - [(2-amino- ethoxy) carbonyl] -2-indolinone, (508) 3-Z- [1- (4 - ((N - (3-methylsulfonylamino-propyl) - N ^, -methyl-amino) -methyl) -anilino) -l-phenyl-methylene] -6-methoxycarbonyl-2-indolinone.

Example 13

Dry ampoules with 75 mg of active substance per 10 ml

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

Composition: (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 mg 60 together 215.0 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). From this mixture, biplanar tablets with bilateral facets and one-sided score are compressed. Tablet diameter 9 mm.

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 mg total 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). From this mixture, biplanar tablets with bilateral facet and unilateral groove are compressed. Tablet diameter 12 mm.

Example 17

Capsules containing 50 mg of the active substance

Ingredients: (1) active ingredient 50.0 mg (2) dried corn starch 58.0 mg (3) powdered milk sugar 50.0 mg (4) magnesium stearate 2.0 mg total 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 ingredient 350.0mg (2) dried corn starch 46.0 mg (3) powdered milk sugar 30.0 mg (4) magnesium stearate ______ 4.0mg total 430.0mg

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

Caps containing 100 mg of active ingredient suppository contains: active ingredient 100.0 mg polyethylene glycol (mol. Wt. 1500) 600.0 mg polyethylene glycol (mol. Wt. 6000) 460.0 mg polyethylene sorbitan monostearate 840.0 mg 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)

An indolinone substituted in the 6-position of the general formula (I) R ³ I / ^R '(I) in which X is an oxygen or sulfur atom, R ¹ represents a hydrogen atom or C 1-6 alkyl; ₄ -alkoxycarbonyl or C ₂ .4-alkanoyl, R ² is carboxy, a linear or branched C] _ ₆ alkoxy-carbonyl, C _{4. 7-} cycloalkoxycarbonyl or aryloxycarbonyl, unbranched or branched C 1. ₆ alkoxy-carbonyl group which is in the terminal alkyl-substituted phenyl, heteroaryl, carboxyl, C _{first 3} -alkoxy-carbonyl, aminocarbonyl, Ci_3-alkylamino-carbonyl or di- (Ci. ₃ alkyl) amino-carbonyl, linear or branched C ₂ _6-alkoxy-carbonyl group which is in the terminal alkyl substituted with a chlorine atom or a hydroxy-, C 1 - group. _3- alkoxy-, amino-, C 1-6 -alkyl; ₃ -alkylamino or di- _{(C1. 3} alkyl) amino radical, an aminocarbonyl or methylaminocarbonyl group, an ethylaminocarbonyl group optionally in the 2-ethyl group substituted by hydroxy or C. _3- alkoxy, R ³ is H, C |. _6- alkyl, C ₃ . _7- cycloalkyl, trifluoromethyl or heteroaryl, phenyl or naphthyl, phenyl or naphthyl mono- or di-substituted by fluorine, chlorine, bromine or iodine, trifluoromethyl-, C1-6alkoxy; _3- alkyl- or C 1-6 -alkyl; ₃ alkoxy-, wherein in the case of disubstitution the substituents may be the same or different and wherein the abovementioned unsubstituted as well as mono- and di-substituted phenyl or naphthyl groups may additionally be substituted by hydroxy, hydroxy-C]. _3- alkyl- or C 1-3 -alkoxy-C 1-6 alkyl; _3- alkyl-, cyano-, carboxy-, carboxy-C1-6alkyl. _3- alkyl-, C 1-6 -alkoxycarbonyl-, amino-carbonyl-, C 1-6 -alkyl-; _3- alkylaminocarbonyl- or di- (C _1-3 -alkyl) -aminocarbonyl, nitro-, amino-, C 1-3 -alkylamino-, di- (C 1-3 -alkyl) -amino or amino-C 1-6 -alkyl; ₃ -alkyl, a C 3-alkylcarbonylamino, N- _{(Cl. 3} alkyl) _{-C1. 3-} alkylcarbonylamino-, C 1-3 -alkylcarbonylamino-C 1-3 -alkyl-, N- (C _1-3 -alkyl) -C ₁ . _3- alkylcarbonylamino-C 1-6 alkyl; _3- alkyl-; _3- alkylsulfonylamino-, C 1-6 -alkylsulfonylamino-C 1-6 alkylsulfonylamino-; _3- alkyl, N - (C 1-3 -alkyl) -C 1-6 alkyl; _3- alkylsulfonylamino-C1-6alkyl; _3- alkyl- or aryl-C ₁ . ₃ -alkylsulfonylamino-, cycloalkylamino-, cycloalkylenimino-, cycloalkyleneiminocarbonyl-, cycloalkylenimino-C1-6-cycloalkyleneimino-; _3- alkyl-, cycloalkyleneiminocarbonyl-C 1-3 -alkyl or cycloalkyleneiminosulfonyl-C 1-3. _{A 3-} alkyl group having from 4 to 7 ring members, the methylene group in the 4-position of the 6 or 7 membered cycloalkyleneimino group being replaced by an oxygen or sulfur atom, a sulfinyl-, sulfonyl-, -NH- or -N- (C 1-3 alkyl) group -, or may be substituted with a heteroaryl group or a heteroaryl-C 1-6 alkyl group; _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 -N (C _1-3 -alkyl) -, or is a phenyl group substituted with R ⁶ , wherein the phenyl group may additionally be mono- or di- substituted with a fluorine, chlorine, bromine or iodine atom, with a Cj group. _5- alkyl-, trifluoromethyl-, hydroxy-, C 1-6 alkyl; ₃ -alkoxy-, carboxy-, C1-6alkoxy-; _3- alkoxycarbonyl-, amino-, acetylamino-, C 1-3 -alkylsulfonyl-amino-, aminocarbonyl-, C 1-6 -alkyloxycarbonyl-; _3- alkyl-aminocarbonyl-, di- (C _1-3 -alkyl) -aminocarbonyl-, amino-sulfonyl-, C 1 -C ₃ -alkyl; _3- alkylaminosulfonyl-, di- (C _1-3 -alkyl) -aminosulfonyl-, nitro- or cyano-, wherein the substituents may be the same or different and wherein R ⁶ represents a hydrogen, fluorine, chlorine, bromine or iodine atom, a cyano-, nitro-, amino-, C _1-5 -alkyl-, C _{3 group} . _{A 7-} cycloalkyl-, trifluoromethyl-, phenyl-, tetrazolyl- or heteroaryl group, 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, Ci. ₃ -alkoxy, C _I _ ₃ alkoxy-C _{l. A 3-} alkoxy group; ₃ -alkoxy, amino-C _{2nd 3} -alkoxy, C _{first 3} -alkylamino-C _{2nd 3} -alkoxy, di- (C _{first 3} alkyl) amino-C _{2nd 3-} alkoxy, phenyl-C 1. ₃ -alkylamino-C _{2nd 3} -alkoxy, / V- (C |. _3-alkyl) -phenyl-C | _ ₃ alkylamino-C ₂ _ ₃ alkoxy group, C 5. ₇ cyclo-alkylene imino-C _{2nd A 3-} alkoxy group or a C _1-3 -alkylmercapto-, carboxyl group, a C 1-4 -alkoxycarbonyl group, an aminocarbonyl group, a C 1-6 group. _3- alkylaminocarbonyl, 77- (C _1-5 -alkyl) -C ₁ . _3- alkylaminocarbonyl, phenyl-C 1-4 -alkylamino-carbonyl, N - (C 1-3 -alkyl) -phenyl-C 1-6 -alkylaminocarbonyl; _3- alkyl-aminocarbonyl, piperazinocarbonyl or N - (C _1-3 -alkyl) -piperazinocarbonyl, Ci.3-alkylaminocarbonyl or 7V- (Ci. ₅ alkyl) -C. _{A 3-} alkylaminocarbonyl group in which the alkyl moiety is substituted with a carboxyl group or a C 1-6 -alkoxycarbonyl group, or in the 2-position; or 3 di- (C _1-3 -alkyl) -amino-, piperazino-, N- (C _1-3 -alkyl) -piperazino- or a 4- to 7-membered cycloalkyleneimine group, C ₃ . _{A 7-} cycloalkyl-carbonyl group, wherein the methylene group at the 4-position of the six- or seven-membered cycloalkyl moiety may be substituted by amino-, C _1-3 -alkyl-amino- or di- (C _1-3 -alkyl) -amino-, or replaced by -NH- or -7V (C _1-3 -alkyl) -, A 4 to 7 membered cycloalkyleneimine group in which the methylene-bonded methylene group may be replaced by a carbonyl group or a sulfonyl group in which the cycloalkylene moiety may be fused to a phenyl ring, or one or two hydrogen atoms may be replaced by C 1-6. _{The 3-} alkyl group and / or the methylene group at the 4-position of the 6-membered or 7-membered cycloalkyleneimine group may be substituted with a carboxyl group, C 1-6. _3- alkoxycarbonyl, aminocarbonyl, C 1. _3- alkyl-aminocarbonyl, di- (C _1-3 -alkyl) aminocarbonyl, phenyl-C 1-6 alkyl; _3- alkylamino or N - (C _1-3 -alkyl) -phenyl-C 1-6 alkyl; ₃ -alkyl-amino, or may be replaced by O or S, sulfmyl-, sulfonyl, -NH-, -MC | j-alkyl) -, -MTenyl) -, - / V (C _{first 3} - alkyl-carbonyl) - or -TV (benzoyl) -C _1-4 alkyl substituted by R ⁷ , wherein: R ⁷ is C ₃ _ ₇ cycloalkyl group wherein a methylene group in the 4-position six-membered or seven-membered cycloalkyl group may be substituted with amino, C ^ -alkylamino, di (C _{l. 3-alkyl)} -amino group, or replaced by -NH- or - V (C _1-3 -alkyl) -, in a 5-7 membered cycloalkyl group, one - (CH ₂ ) ₂ - group can be replaced by -CO-NH-, - (CH ₂ ) ₃ -NH-CO-NH- or -CO-NH-CO-, or - (CH ₂ ) ₄ - may be replaced by -NH-CO-NH-CO-, wherein the hydrogen atom bound to the nitrogen atom may be replaced by a C 1-4 -alkyl group, an aryl or a heteroaryl group, a hydroxy- or a C _1-3 -alkoxy- group, an amino-, C 1-4 -alkylamino-, di- (C _1-7 -alkyl) -amino-, phenylamino- N-phenyl-C _1-3 -alkyl-amino-, phenyl-C _1-3 -alkyl-amino-, N - (C 1-4 -alkyl) -phenyl-C 1-3 -alkyl-amino- or di- (phenyl- C |. ₃ alkyl) amino group, N-hydroxy-C ₂ _ ₃ -alkylamino- / N (C _{first 3} alkyl) -R _{C-Hydroxy-second 3-alkyl-amino,} di (o) hydroxy-C _2nd -Alkylj _3-amino, di- (co (C. ₃ -alkoxy) -C _{2. 3-alkyl)} amino and / or N- (dioxolan-2-yl) C |. _3- alkyl-amino-; _{3-alkylcarbonylamino} C ₂ .3-alkyl-amino, or a C ₃ alkylcarbonyl-amino-C _{2nd 3-} alkyl- N - (C 1-3 -alkyl) -amino-; ₃ -alkylsulfonylamino-, ^A, - (C |. ₃ alkyl) C | _ _{3-alkyl-sulfonylamino,} C | _ ₃ alkylsulfonylamino-C ₂ _ ₃ alkyl or _{amino-C1. 3-C} alkylsulfonylamino _{second 3-} alkyl- N - (C _1-3 -alkyl) -amino-, hydroxycarbonyl-C 1-8 -alkylamino- or N - (C _1-3 -alkyl) -hydroxy-carbonyl-C 1-8 -alkyl-; _{A 3-} alkyl-amino-, guanidino group in which one or two hydrogen atoms may each be replaced by C 1-6. _3- alkyl, a group of 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 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 1-6 -benzylamino-; _{A 4-} alkoxy-, 4- to 7-membered cycloalkyleneimine group, wherein the methylene group at the 4-position of the 6- or 7-membered cycloalkyleneimine group may be replaced by an oxygen or sulfur atom, a sulfinyl-, sulfonyl-, -NH-, -TV (C) ( _3- alkyl) -, -N (phenyl) -, - N (C _1-3 -alkylcarbonyl) - or -7 N (benzoyl) -, or when n is 1, 2, or 3 may also be hydrogen , a group of formula -N (R ¹⁰⁾ - (CH _{2) m} - (CO) _O - R @ ¹¹ (III), wherein R ¹⁰ is hydrogen, C _1-3 -alkyl, C 1-6. ₃ -alkylcarbonyl, arylcarbonyl, phenyl-C _1-3 -alkylcarbonyl, C 1-6 -alkylcarbonyl; _3- alkylsulfonyl, arylsulfonyl or phenylC1. 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 is amino-, C ₁ . ₄ -alkylamino, di- (C ₄ alkyl) amino, phenyl-amino, N- (C _{first 4} alkyl) -fenylamino-, benzylamino, 7V- (C ₄ alkyl) -benzylamino- , C ₁ . _4- alkoxy- or C ₁ . ₃ -alkoxy-C _{first 3-} alkoxy, optionally with C 1. ₃ at the 1-alkyl-substituted group di- (C _{l. 4} alkyl) amino-C] _ ₃ -alkylamino or a 4- to 7-membered cycloalkylene-imino 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-, - V (C _1-3 -alkyl) -, -N (phenyl) - , - / V _{(Art. 3} -alkyl-carbonyl) - or - / V (benzoyl) -, a group of _{C4. 7} -cycloalkylamino-, C ₄ . ₇ -cycloalkyl-Ci. _3- alkylamino- or C ₄ . ₇ -cycloalkenylamino- in which the ring 1 position does not participate in the double bond and wherein said groups may additionally be substituted on the amino nitrogen atom by a C ₅ group. ₇ -cycloalkyl- C _{2nd 4-} alkenyl- or C _1-4 -alkyl-, A 4 to 7 membered cycloalkyleneimine group, the cycloalkylene moiety of which may be fused to a phenyl group or oxazolo-, imidazolo-, thiazolo-, pyridino-, pyrazino- or pyrimidino- group, optionally substituted by a fluorine, chlorine, bromine or iodine atom, a nitro group -, a group of Cl alkyl, C ₃ -alkoxy or amino, and / or wherein one or two hydrogen atoms may be replaced by a C ₃ -alkyl, C _{5. A 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 a hydroxy group, hydroxy-C 1. _3- alkyl, C 1. _3- alkoxy- or C 1-6 -alkyl; _{A 3-} alkoxy-C _1-3 -alkyl group in which the methylene group at the 3- or 4-position of a six- or seven-membered cycloalkyleneimine group may be substituted by a hydroxy group, hydroxy-C 1-6 -alkyl; _3- alkyl, C _1-3 -alkoxy- or C 1-4 -alkoxy-C 1-8 -alkyl, carboxyl, C _1-4 -alkoxycarbonyl-, aminocarbonyl-, C 1-4 -alkyl. _3- alkyl-aminocarbonyl-, di- (C _1-3 -alkyl) aminocarbonyl-, phenyl-C ₁ . _3- alkylamino- or N - (C _1-3 -alkyl) phenyl-C 1-4 -alkylamino-, or said methylene group may be replaced by an oxygen or sulfur atom, sulfinyl-, sulfonyl-, -NH-, -7V (C]. ₃ alkyl) -, -7V (phenyl) -, N _{(phenyl-C1. 3} alkyl) -, -7V (C]. ₃ -alkylcarbonyl) -, - / V _{(C1. 4} -hydroxycarbonyl) -, _N - (C _1-4 -alkoxycarbonyl) -, N - (benzoyl) - or -7 N (phenyl-C _1-3 -alkylcarbonyl) -, wherein the methylene group which is bonded to the imine nitrogen atom of the cycloalkylenimine group may be replaced by a carbonyl or 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 _1-4 -alkyl group which is substituted carboxyl, C _1-3 -alkoxycarbonyl, aminocarbonyl, C _1-3 -alkylaminocarbonyl it or di (C _{first 3} alkyl) -aminokarbonylovou group or a 4-7 membered cykloalkyléniminokarbonylovou group, a group of 7V- (C 3 alkyl) -C2.4-alkanoylamino which is additionally substituted alkyl or carboxy A C _1-3 -alkoxycarbonyl group, a group of the formula -N (R ¹² ) -CO- (CH ₂ ) n -R ¹³ (IV) wherein R ¹² is H, C ^ g alkyl or C _{3. 7-} cycloalkyl, or terminal C _1-3 -alkyl substituted by phenyl, heteroaryl, trifluoromethyl, hydroxy, C _1-3 -alkoxy, aminocarbonyl, C ₁ . _{A 4-} alkylamino-carbonyl group, a di- (C _1-4 -alkyl) aminocarbonyl group, a C 1-6 alkyl group; _{3-alkyl-carbonyl,} C ₃ -alkyl-sulfonyl-amino, N- (C _{first 3} alkyl) -C _{first A 3} -alkylsulfonyl-amino group, 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 hydrogen, a group of the formula -N (R ¹⁴ ) - (CH ₂ ) _q - (CO) _r - R ¹⁵ (V) in which R ¹⁴ represents a hydrogen atom, C ₁ . _4- alkyl, C _1-3 -alkylcarbonyl, arylcarbonyl, phenyl-C _1-3 -alkylcarbonyl, heteroarylcarbonyl, heteroaryl-C 1. _3- alkylcarbonyl, C 1-6 alkyl; _An alkylsulfonyl group, an arylsulfonyl group, a phenyl-C _1-3 -alkylsulfonyl group, a heteroarylsulfonyl group or a heteroaryl-C _{1 group} . ₃ -alkylsulfonyl, 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 , the group of formula -N (R ¹⁶⁾ - SO ₂ - R ¹⁷ (VI), wherein R ¹⁶ represents a hydrogen atom or a terminal C 1. _{A 4-} alkyl group optionally substituted by cyano-, trifluoromethyl-carbonyl-amino- or N-C 1-6 -alkyl-trifluoromethyl-carbonyl-amino-; R ¹⁷ represents a C ₃ alkyl group, an amino group substituted by a di- (C _{first 3} alkyl) amino-C _{first 3-} alkyl-carbonyl- or di- (C _1-3 -alkyl) -amino-C 1. _{3-alkyl-sulfonyl} group and a di- (Ci. ₃ alkyl) aminocarbonyl-C ₃ alkyl-, or a group N-ICU-alkyli-alkylsulfonylamino or CM-N _{(C1. 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 fluorine, chlorine, bromine or iodine, C 1-6 -alkyl-, trifluoromethyl-, hydroxy-, C _1-3 -alkoxy-, carboxy-, C 1-6-. _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) 1-Aminosulfonyl-, C 1-6 -alkyl; ₃ -alkylsulfonylamino-, 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, the term aryl being 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 ₃ alkyl- or alkoxy-C _B3, and the term heteroaryl means a monocyclic five or six membered heteroaryl group, the carbonaceous residue, optionally substituted C _{first A 3-} alkyl group, wherein said six-membered heteroaryl group contains one, two or three nitrogen atoms and the five-membered heteroaryl group contains an imino group optionally substituted with C 1-6 alkyl; _{A 3-} alkyl or phenylC 1-3 -alkyl group, an oxygen or sulfur atom, or an imino group optionally substituted with C ₁ . _3- alkyl or phenyl-C 1. ₃ -alkyl, or O or S, and also N, or NH optionally substituted by C ^ -alkyl or phenyl-C ₃ -alkyl, and two nitrogen atoms, and in addition to that it may be said monocyclic heterocyclic groups via two adjacent carbon atoms of the fused phenyl ring and the bond occurs through the nitrogen atom or through the carbon atom of the heterocyclic moiety or the fused phenyl ring, the hydrogen atoms in said alkyl and alkoxy groups or in the alkyl moieties of the specified groups of formula I may be partially or fully replaced by fluorine atoms , and any carboxyl group present in said groups may be replaced by a tert-butoxycarbonyl precursor group, and each of the hydrogen atoms attached to the nitrogen atom can be replaced by hydroxy, benzoyl, pyridinoyl, formyl, acetyl, propionyl, butanoyl, pentanoyl, hexanoyl, allyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, isopropoxycarbonyl, isopropoxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl, hexadecyloxycarbonyl, benzyloxycarbonyl, phenylethoxycarbonyl, phenylpropoxycarbonyl, C ₁ . ₃ -alkylsulfonyl-C _{2nd 4-} alkoxycarbonyl, Ci. ₃ -alkoxy-C _{2nd 4} -alkoxy-C _{2nd A 4-} alkoxycarbonyl group or a R ^e CO-O- (R ^f CR ⁸ ) -O-CO- group in which R ^e is C, _8 alkyl, C 5-7 cycloalkyl, phenyl or phenyl-Ci_3-alkyl, R ^f is H, C] .3 alkyl, C _{5. 7} cycloalkyl group or a phenyl group and ^R is H or C]. _{A 3-} alkyl group, tautomers and salts thereof. The indolinones of general formula (I) according to claim 1, 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; ₆ -alkoxycarbonyl, C ₅ . _7- cycloalkoxycarbonyl or phenoxycarbonyl, unbranched or branched C _1-3 -alkoxycarbonyl, which in the terminal alkyl moiety is substituted by phenyl-, heteroaryl-, carboxy-, C 1-6 -alkyl; _3- alkoxy-carbonyl-, aminocarbonyl-, C 1-6 -alkylaminocarbonyl- or di- (C _1-3 -alkyl) -amino-carbonyl, straight or branched-chain C ₂ . _{A 3} -alkoxycarbonyl group, which is substituted in the alkyl terminal part by a chlorine atom, a hydroxy-, C _1-3 -alkoxy-, amino-, C _{1 - group} ; _{A 3-} alkylamino- or di (C 1-6 -alkyl) -amino-, aminocarbonyl or methylaminocarbonyl group, an ethylaminocarbonyl group optionally at the 2-position of the ethyl group substituted with a hydroxy- or C 1-6 -alkyl group; ₃ -alkoxy-, R ⁴ is C _{3. 7} cycloalkyl group wherein a methylene group in the 4-position six or seven membered cycloalkyl group can be replaced by amino, C _{first 3-alkyl-amino} group or a di _{(C1. 3} alkyl) amino, or can be replaced by -NH- or-MC |. _3- alkyl) -, or a phenyl-substituted phenyl group which may additionally be mono- or di-substituted by a fluorine, chlorine or bromine atom, a C _1-3 -alkyl-, trifluoromethyl-, hydroxy-, C ^1-6 -alkyl group. ₃ -alkoxy, carboxy, C _{l. 3-} alkoxycarbonyl-, amino-, acetyl-amino-, 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 wherein R ⁶ represents a hydrogen, fluorine, chlorine, bromine or iodine atom, a cyano-, nitro-, amino-, C _{1 - group} . _5- alkyl-, C ₃ . ₇ -cycloalkyl-, trifluoromethyl, phenyl, tetrazolyl or heteroaryl group of formula wherein the hydrogen atom bonded to the nitrogen atom may be replaced by C _{first A 3-} alkyl group; ₃ -alkoxy, amino-C _{2nd 3-} alkoxy-, C _1-3 -alkylamino-, C ₂ . _3- alkoxy-, di- (C _1-3 -alkyl) -amino-C ₂ . _3- alkoxy-, phenyl-C 1-6 alkyl; ₃ -alkylamino-C _{2nd 3} -alkoxy, N- (Cl. ₃ alkyl) _{-phenyl-C. 3} -alkylamino-C _{2nd 3} alkoxy-, C-pyrrolidino _{second 3} alkoxy-, piperidino-C _{2nd A 3-} alkoxy- or C _1-3 -alkylmercapto-, carboxyl group, a C 1 group. ₄ -alkoxycarbonyl-, aminocarbonyl-, C ₁ _ ₃ alkyl-amino-carbonyl, phenyl-C ₃ -alkylamino-carbonyl or N- (C ₃ -alkyl) phenyl-C]. _{3-alkyl-amino-carbonyl} group, C _{3. 7-} cycloalkyl-carbonyl-, wherein the methylene group at the 4-position of the 6-membered or 7-membered cycloalkyl moiety may be replaced by -NH- or -MC (alkyl) -, 4-7 membered cykloalkylénimínovú group in which the methylene group can be attached to the imino group substituted by a carbonyl or sulfonyl group, or one or two hydrogen atoms may each be replaced by C _{p i} -alkyl and / or the methylene group in the 4-position six or seven membered the cycloalkylenimine 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. _{A 3} -alkylamino group, or may be replaced by an oxygen or sulfur atom, a sulfinyl-, sulfonyl-, -NH- or -7V (C _1-3 -alkyl) -, terminal C _1-4 -alkyl group substituted with R ⁷ , while R ⁷ is C ₅ _7 cycloalkyl group wherein a methylene group in the 4-position six or seven membered cycloalkyl group can be replaced by -NH- or - / V (C ₃ alkyl) -, or a five to seven membered cycloalkyl group may be be replaced by - (CH ₂ ) ₂ - by -CO-NH-, - (CH ₂ ) ₃ - by -NH-CO-NH-, or - (CH ₂ ) 4 by -NH-CO-NH -CO-, wherein the hydrogen atom bonded to the nitrogen atom can always be replaced by C 1-6. _3- alkyl, phenyl or heteroaryl, hydroxy- or C 1-6 -alkyl; _3- alkoxy-, amino-, C1-6alkoxy-; ₆ -alkylamino, di- _{(C1. 6} alkyl) amino, phenylamino, / V-phenyl-C ₃ -alkyl-amino, phenyl-C |. ₃ -alkylamino, ^A, - (C |. ₃ alkyl) -phenyl] C | .3-alkylamino or di- _{(phenyl-C1. 3} alkyl) amino, CO-hydroxy-C ₂ . _3- alkyl-amino- N - (C _1-3 -alkyl) - N -hydroxy-C ₂ . _{3-alkyl-amino,} di (a-hydroxy-C _{second 3-alkyl)} amino, di (ro- (C _{first 3} -alkoxy) -C _{second 3-alkyl)} amino, or / N- (dioxolan-2-yl) -C. _{3-alkyl-amino,} C _{first 3-alkylcarbonylamino} C _{2nd 3-} alkyl-amino- or C 1-6 alkyl; ₃ -alkylcarbonyl-amino-C _{2nd 3} alkyl- / N (Cl. ₃ alkyl) amino group, Ci.3-alkylsulfonylamino, ^A, - _{(C1. 3} alkyl) -Ci_ ₃ -alkyl-sulfonylamino, _{C1. 3-C} alkylsulfonylamino _{second 3-} alkyl-amino- or C 1-6 alkyl; _3-C alkylsulfonylamino _{second 3-} alkyl-N - (C _1-3 -alkyl) -amino-, hydroxycarbonyl-C ₁ . _3- alkylamino- or M (C _1-3 -alkyl) -hydroxy-carbonyl-C ₁ . _{A 3-} alkyl-amino-, guanidino group in which the hydrogen atom can be replaced by C 1. _3- alkyl, a group of 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 amino-, C ₁ . ₃ -alkylamino, di- (C | .-- alkyl) amino, phenylamino, benzylamino or C | _ ₄ -alkoxy, a 5- to 7-membered cycloalkyl alkyleneimine group, the methylene group at position 4 the piperidine group may be replaced by an oxygen or sulfur atom, the group -NH-, -A '(C 1-6 -alkyl) -, -N (phenyl) -, -7 N (C _1-3 -alkylcarbonyl) - or -Menzoyl) -, or, when n is 1, 2, or 3, R ⁹ can also be a hydrogen atom, a group of the formula -N (R ¹⁰⁾ - (CH _{2) m} - (CO) _O - R @ ¹¹ (III), wherein R ¹⁰ represents a hydrogen atom, a C _1-3 -alkyl group, C ₁ . _3- alkylcarbonyl, C ₁ . _{A 3-} alkylsulfonyl group, 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 _1-3 -alkoxy-C _1-3 -alkoxy- group, or a 5- to 7-membered cycloalkyleneimine group, wherein the methylene group at the 4-position of the piperidine group may be replaced oxygen or sulfur atom, -NH-, - N (C _1-3 -alkyl) -, -N (phenyl) -, - N (C _1-3 -alkylcarbonyl) - or -Mbenzoyl) -, C ₄ - ₇ -cycloalkylamino- or C _{4 -} . 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 _1-3 -alkyl group, and / or The methylene group at the 3-position of the pyrrolidine group may be substituted with a hydroxy group or a C 1 group. _{The 3-} alkoxy-, methylene group at the 4-position of a 6-membered or 7-membered cycloalkyleneimine group may be substituted by a hydroxy group, a hydroxy-C _1-3 -alkyl group, a C 1-6 group. _3- alkoxy-, carboxy-, C1-8. ₃ -alkoxycarbonyl-, aminocarbonyl, C ^ alkylamino-carbonyl, di (C ₁ _3-alkyl) aminocarbonyl-, phenyl-C ₃ -alkylamino or N- (C _{first 3-alkyl)} -phenyl-C . _3- alkylamino-, or said methylene group may be replaced by an oxygen or sulfur atom, a sulfinyl-, sulfonyl-, -NH-, -A (C _1-3 -alkyl) -, - (V) phenyl, -, N ( phenyl-C _1-3 -alkyl) -, N - (C _1-3 -alkyl-carbonyl) -, -MC _1-4 -alkoxy-carbonyl) -, -7 _N (benzoyl) - or -TV (phenyl-C _1-3 - 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 imines may be bound to the methylene imine groups each be replaced by a carbonyl group, or R ⁶ is a C ₄ alkyl group, which is the end portion substituted by carboxy, C ^ alkoxycarbonyl- group, aminocarbonyl, C _{first A 3-} alkyl-aminocarbonyl- or di- (C _1-3 -alkyl) -aminocarbonyl- or a 4 to 7-membered cycloalkyleneiminocarbonyl group, a group of the formula -N (R ¹² ) -CO- (CH ₂ ) _p -R ¹³ (IV) wherein R ¹² represents a hydrogen atom, C 1-6. ₃ alkyl or C ₅ .7-cycloalkyl, phenyl-C ₃ -alkyl, or heteroaryl-C]. _{The 3-} alkyl group and p is the number 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 hydrogen, a group of the formula -N (R ¹⁴ ) - (CH ₂ ) _q - (CO) _r - R ¹⁵ (V) in which R ¹⁴ represents a hydrogen atom, a C 1-6 -alkyl group, a C _1-3 -alkylcarbonyl group, a phenylcarbonyl group, a phenyl-C 1-3 -alkylcarbonyl group, a heteroarylcarbonyl group, a heteroaryl-C 1-6 group. _3- alkylcarbonyl, C 1-4 -alkylsulfonyl, phenylsulfonyl, phenyl-C 1. ₃ -alkylsulfonyl, heteroarylsulfonyl or heteroaryl-C _1-3 -alkylsulfonyl, q is 1, 2, 3 or 4, r is 1, or when q is 2, 3 or 4, r is also number 0 and R ¹⁵ has the same meaning as R ⁷ , the group of formula -N (R ¹⁶⁾ - SO ₂ - R ¹⁷ (VI), wherein R ¹⁶ represents a hydrogen atom or a terminal C 1. _{A 4-} alkyl group optionally substituted by cyano-, trifluoromethylcarbonylamino- or N - (C 1-3 -alkyl) -trifluoromethylcarbonylamino- and R ¹⁷ is C _1-3 -alkyl, amino substituted with di- (C _1-3 -alkyl) -amino-C 1-6 -alkyl. _3- alkyl-carbonyl- or di- (C _1-3 -alkyl) -amino-C 1-6 alkyl; ₃ -alkylsulfonyl- and di-C 1-6 -alkyl-amino-carbonyl-C 1-6 -alkyl, all of the radicals mentioned for R ⁶ containing single bonded or fused phenyl groups may be mono- or di-substituted by fluorine, chlorine or bromine, group C 1. _3- alkyl-, trifluoromethyl-, hydroxy-, C _1-3 -alkoxy-, carboxy-, C _1-3 . _3- alkoxycarbonyl-, aminocarbonyl-, C _1-3 -alkylaminocarbonyl-, 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 group methylenedioxy-, a R ⁵ represents a hydrogen atom or a C _1-3 -alkyl group, said heteroaryl group being optionally substituted in the carbon skeleton by a C _1-3 -alkyl group substituted by pyridinyl-, pyrazinyl-, pyrimidinyl-, pyridazinyl-, pyrrolyl-, furyl-, thienyl-, oxazolyl-, thiazolyl-, pyrazolyl-, imidazolyl- or triazolyl- in which one hydrogen atom attached to the nitrogen atom can be replaced by a C _1-3 -alkyl or a phenyl-C _1-3 -alkyl group and wherein the five-membered heteroaryl groups containing at least one the imino group is bonded via a carbon or nitrogen atom, In said groups, the hydrogen atom which is bonded to the nitrogen atom may be replaced by hydroxy, benzoyl, pyridinoyl, formyl, acetyl, propionyl, butanoyl, pentanoyl, hexanoyl, allyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, propoxycarbonyl, propoxycarbonyl, propoxycarbonyl, propoxycarbonyl, propoxycarbonyl, t-butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyl-oxycarbonyl, hexadecyloxycarbonyl, benzyloxycarbonyl, phenylethoxycarbonyl, phenylpropoxycarbonyl, C _{first 3} -alkylsulfonyl-C ₂ .4-alkyloxycarbonyl, C1-3-alkoxy-C2-4-alkoxy-C2-4-alkoxycarbonyl, or R ^e CO-O- (R ^f CR ^g) -O-CO- group, in which R ^e represents C 1-8 -alkyl, C 5-7 -cycloalkyl, phenyl or phenyl-C 1-3 -alkyl, R ^f represents hydrogen, C 1-4 -alkyl, C 5. ₇ -cycloalkyl or phenyl; and R ⁸ represents a hydrogen atom or C 1-6 alkyl. _{The 3-} alkyl group or any amino nitrogen may form part of the phthalimido group, or any carboxyl group present in said groups may be replaced by a tert-butoxycarbonyl precursor group, and hydrogen atoms in said alkyl and alkoxy groups, or in alkyl portions of designated groups of formula (I) may be replaced, in whole or in part, by fluorine atoms and tautomers and salts thereof. The indolinones of general formula (I) according to claim 1, in which X is O, R ¹ is H, R ² is carboxyl, straight-chain or branched C]. _{4-alkoxy-carbonyl} or phenoxycarbonyl group, a linear or branched C _{i. 3} -alkoxy-carbonyl, which is the terminal alkyl-substituted phenyl, _carboxyl, C. _3- alkoxycarbonyl, aminocarbonyl, C ₁ . ₃ -alkylaminokarbonylovou or di- (Ci. ₃ alkyl) amino-carbonyl, linear or branched _{C2. A 3} -alkoxycarbonyl group which is substituted in the terminal alkyl moiety by a hydroxy-, C1-alkyl group; _3- alkoxy-, amino-, C 1-6 -alkyl; _{A 3-} alkyl-amino- or di- (C _1-3 -alkyl) -amino-, aminocarbonyl or methylaminocarbonyl group, an ethylaminocarbonyl group, which may optionally be substituted at the 2-position in the ethyl group with a hydroxy- or C 1-6 -alkyl group. ₃ -alkoxy-, R ³ is C 1-6. _4- alkyl or phenyl, which may be substituted by fluorine, chlorine or bromine, trifluoromethyl-, C _1-3 -alkyl-, hydroxy- or C 1-6 -alkyl; ₃ -alkoxy-, R ⁴ is C 5. _{A 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 -J- (C _1-3 -alkyl) -, phenyl, phenyl disubstituted with C 1 groups. _3- alkyl-; _3- alkoxy- or nitro-, wherein the substituents may be the same or different, or a phenyl group substituted by 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, C |. _{A 3-} alkyl group, e.g. _3- alkoxy, nitro, amino or C ₅ . _{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 being optionally substituted in the carbon skeleton 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 _1-3 -alkyl group, a group of the formula carboxy-, C ₁ -alkyl. ₄ -alkoxycarbonyl-, phenyl-C _{first 3-} alkyl-amino-carbonyl- or C ₅ . _{A 7-} cycloalkyl-carbonyl-, 5- or 6-membered cycloalkyleneimine group, wherein the methylene group at the 4-position of the piperidine group may be replaced by an oxygen or sulfur atom, an -NH- group or a --V (C _1-3 -alkyl) - group, unbranched Ci. _{A 3-} alkyl group, substituted at the terminal portion with R ⁷ , wherein R ⁷ represents a C _5-7 -cycloalkyl group, wherein in a 5- or 6-membered cycloalkyl group, the - (CH ₂ ) ₂ - group may be replaced by -CO-NH-, - (CH ₂ ) ₃ - may 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 C 1. _3- alkyl, phenyl or pyridinyl, or a pyrrolyl, pyrazolyl, imidazolyl or triazolyl group bonded via a carbon atom or a nitrogen atom, said heteroaryl groups may be C ₁ -substituted in the carbon skeleton. _{The 3-} alkyl group or the hydrogen bonded to the nitrogen atom can be replaced by a C _1-3 -alkyl group, a hydroxy- or a C 1-6 -alkyl group. ₃ -alkoxy, an amino, C _{first 6-} alkylamino-, di- (C _1-6 -alkyl) -amino-, phenylamino-, N -phenyl-C _1-3 -alkyl-amino-, phenyl-C _1-3 -alkylamino- or N - (C 1-3 -alkyl) phenyl-C | _ ₃ -alkyl-amino, a group of) hydroxy-C ₂ _ ₃ -alkylammo-, N- (Cl. ₃ alkyl) -R-hydroxy-C _{2. 3-alkyl-amino,} di- _{(co-hydroxy-C2. 3} alkyl) amino or di - (<o (C. ₃ -alkoxy) -C _{second 3-alkyl)} amino, alkylcarbonylamino group, a C ₃ -C ₂ _ ₃ -alkyl-amino, or a C ₃ alkylcarbonyl-amino-C _{2nd 3-alkyl-N-} (C ₃ alkyl) amino, C _{l. 3-} alkylsulfonylamino-, N-C 1-6 -alkyl- C 0-6 alkylsulfonylamino-, C ₎ . _3-C alkylsulfonylamino _{second 3-} alkyl-amino-, or C ₁ . _3-C alkylsulfonylamino _{second 3-alkyl-N-} (Cl. ₃ alkyl) amino group, a hydroxycarbonyl-C] _ ₃ -alkyl-amino or N- _{(C1. 3} alkyl) hydroxy-carbonyl-C ₃ alkyl- an amino-, guanidino group in which hydrogen can be replaced by C ₁ . _3- alkyl-, a group of 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 amino-, C _1-3 -alkylamino-, di- (C _1-3 -alkyl) amino or C ₁ . _{A 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-, -TV (C _1-3 -alkyl) - or -N (C _1-3 -alkyl-) carbonyl) - or, when n is 1, 2, or 3, R ⁹ can also be hydrogen, a group of the formula -N ^(I0), - (CH _{2) m} - (CO) _a R (III) wherein R ¹⁰ is H or C _b3 alkyl group, m is 1, 2, or 3, o is 1 or, when m is 2, or 3, o denotes 0, and also R ¹¹ represents an amino-, C _1-3 -alkylamino-, di- (C _1-3 -alkyl) -amino-, C _1-4 -alkoxy- or methoxyC _1-3 -alkoxy-, or a 5- or 6-membered cycloalkyleneimine group, wherein the methylene group is the 4-position of the piperidine group may in each case be replaced by -NH-, -TV (C _1-3 -alkyl) -, or -7V (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 a hydroxy group, the methylene group at the 4-position of the piperidine group may be substituted by a hydroxy group, the hydroxyC _1-3 -alkyl- or C 1-4 -alkoxy-, or the methylene group may be replaced by an oxygen or sulfur atom, a sulfmethyl-, a sulfonyl-, -NH-, - N (C _1-3 -alkyl) -, - / In (C _1-3 -alkyl-carbonyl) -, -M-benzoyl) - or -M-phenyl-C 1 -. _{3-alkyl-carbonyl)} -, wherein the methylene group is bonded to the imine nitrogen atom of the pyrrolidine, piperidine or piperazine groups may be replaced by a carbonyl group, or R ⁶ is a straight-chain C !. _{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, a C _1-3 -alkyl or a phenyl-C _1-3 -alkyl group, p is 0, 1 or 2 and R ¹³ represents an amino, a C ₄ -alkylamino, di- _{(C1. 4} alkyl) amino, benzyl amino, <N- (C |. ₃ alkyl) benzylamino, _{C1. 3-} alkoxy-Ci. ₃ alkylamino-, 7V- _{(C1. 3} alkyl) -C. ₃ -alkoxy-C ₃ -alkyl-amino, di- (2-methoxyethyl) amino, di- (hydroxy-ro-C _{2nd 3} alkyl) amino or aminocarbonyl-methyl-N- (methyl ) -amino-, nitrogen-bonded, optionally C _1-3 -alkyl substituted, pyrrolyl, pyrazolyl or imidazolyl, pyrrolidino-, piperidino-, morpholino-, thiomorpholino- or piperazine-group, which is optionally substituted at the 4-position group C |. _3- alkyl-, phenyl-C ₁ . ₃ -alkyl-, C _first Or C ₃ -alkyl.karbonyl- _{first 4-} alkoxy-carbonyl- or, when n is 1 or 2, R ¹² may also be a hydrogen atom, a group of the formula -N (R ¹⁴ ) - (CH ₂ ) _q - (CO) _r - R ¹⁵ (V) in which R ¹⁴ represents a hydrogen atom, C 1. _4- alkyl, C _1-3 -alkylcarbonyl, phenylcarbonyl, phenyl-C 1-6 alkyl; _3- alkylcarbonyl, furyl-carbonyl, pyridinylcarbonyl, t-butyl. _3- alkyl-carbonyl, pyridinyl-C _1-3 -alkylcarbonyl, C _1-4 -alkylsulfonyl, phenylsulfonyl or phenyl-C 1-6 alkyl. _{A 3} -alkylsulfonyl group, q is 1, 2 or 3, r is 1, or, when q is 2 or 3, r is also 0 and R ¹⁵ represents an amino, Ci.4-alkylamino, di- (C ₁ _ ₄ alkyl) amino. phenyl-amino-, N - (C _1-4 -alkyl) -phenylamino-, benzylamino- or N - (C _1-4 -alkyl) -benzyl-amino-, or a group of the formula -N (R ¹⁶⁾ - SO ₂ - R ¹⁷ (VI), wherein R ¹⁶ is H or a terminal a C ₃ alkyl group optionally substituted by a cyano, trifluoromethyl-carbonyl-amino or N- (C _{l. 3-alkyl)} carbonyl-trifluoromethyl-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- and R @ ⁵ represents a hydrogen atom, wherein in said radicals the hydrogen atom bound to the nitrogen atom may be replaced by an acetyl or tert-butoxycarbonyl group, the carboxyl groups in said radicals may also be in the form of tert-butoxycarbonyl precursor groups and tautomers and salts thereof. 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 is N-methyl-imidazol-2-yl, straight or branched C 1-6. _{A 3-} alkyl group whose terminal moiety is substituted by a C _1-4 -alkylamino-, di- (C _1-4 -alkyl) -amino-, piperidino- or 2,6-dimethyl-piperidino- group, 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 ¹⁴ ) - (CH ₂ ) _q - (CO) _r - R ¹⁵ (V) in which R ¹⁴ represents C _1-3 -alkylcarbonyl or C 1-6 -alkylcarbonyl; _3- alkylsulfonyl, q is 1, 2 or 3, r is 1, or, if q is 2 or 3, r can also be 0 and R ¹⁵ represents di- (C _1-3 -alkyl) amino, their tautomers and salts thereof. The substituted indolinones of formula (I) according to claim 1, selected from the group consisting of: (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-phenylmethylene] -6-carbamoyl-2-indolinone, (c) 3-Z- [1- (4- (piperidin-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-ethoxy-carbonyl-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) -amino) -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, (j) 3-Z- [1- (4- ( / V-acetyl-TV-dimethylaminocarbonylmethyl-amino) -I lino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, (k) 3-Z- [1- (4-ethylaminomethyl-anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone, ( l) 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- dimethylamino-ethyl) -7V-methylsulfonylamino) anilino) -1 -phenyl-] -6-methoxycarbonyl-2indolinón, (o) 3-Z- [l- (4- ^(N - (3-dimethylaminopropyl) -V-methylsulfonyl amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, (β) 3-Z- [1- (4- (N-dimethylaminocarbonylmethyl-N-methylsulfonyl-amino) -anilino) -1 -phenyl-methylene] -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, (s) 3-Z- [1- (4-methylaminomethyl-anilino)] -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone, and (1) 3-Z- [1- (4- (N - ((4-methyl-piperazin-1-yl) -methylcarbonyl) -v) (methyl-amino) -anilino) -1-phenyl-methylene] -6-methoxycarbonyl-2-indolinone tautomers and salts thereof. The substituted indolinone of formula (I) according to claim 1 which is 3-Z- [1- (4- (N - ((4-methyl-piperazin-1-yl) methylcarbonyl) -N-methyl-amino)) (anilino) -1-phenylmethylene] -6-methoxycarbonyl-2-indolinone or a pharmaceutically acceptable salt thereof. Physiologically acceptable salts of substituted indolinones according to claims 1 to 6. Pharmaceutical composition, characterized in that it comprises an indolinone according to at least one of claims 1 to 6 or a salt according to claim 7, optionally with one or more carriers and / or diluents. Process for the preparation of a pharmaceutical composition according to claim 8, characterized in that the indolinone according to at least one of claims 1 to 6 or the salt according to claim 7 is incorporated into one or more inert carriers and / or diluents in a non-chemical manner. A process for the preparation of indolinones according to claims 1 to 6 or a salt according to claim 7, characterized in that (a) to the compound of the general formula (VII) R ³ in which 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 R ² 'and R ¹⁸ may optionally form a solid phase bond via a Spacer and the other of said radicals as defined above, and Z ¹ is a halogen atom, a hydroxy-, alkoxy- or arylalkoxy- group, is treated with an amine of formula (VIII) (VIII) 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 a compound of formula (IX) R ³ R ^;: yC - j » V O = '' R HOOC 'N ] wherein 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) R ¹ (Ix) HR ¹⁹ (X) in which R ¹⁹ is C 1-6 -alkanol, C ₄ . ₇ -cycloalkanol or aromatic alcohol, C]. ₆ -alkanol substituted in the terminal alkyl moiety with phenyl, heteroaryl, carboxyl, C _1-3 -alkoxycarbonyl, aminocarbonyl, C _1-3 -alkylaminocarbonyl or di- (C _1-3 -alkyl) aminocarbonyl, C |. ₆ -alkanol substituted in the terminal alkyl moiety with a chlorine atom or a hydroxy-, C _1-3 -alkoxy-, amino-, C 1-6 -alkyl group; ₃ -alkylamino or di- (C _{first 3} alkyl) amino, amino, or methylamino, ethylamino which optionally can be substituted in the 2-hydroxy ethyl group or a group of a C ₃ -alkoxy or di- (C |. ₂ alkyl) amino, or (c) for the preparation of a compound of formula (I) wherein R ⁴ is C _{i. 4-} alkyl, substituted with R ⁷ , wherein R ⁷ is amino-, C _1-7 -alkylamino-, di- (C _1-7 -alkyl) -amino-, phenyl-amino-, N -phenyl-C 1. _{3-amino-alkyl,} phenyl-C ₃ -alkyl-amino, N - (C ₃ -alkyl) phenyl-C ₁ _ ₃ -alkylamino or di- (phenyl-C _{first 3} alkyl) - amino, a group of) hydroxy-C _{2nd 3-} alkyl-amino- N - (C _1-3 -alkyl) -ro-hydroxy-C ₂ . _{3-alkyl-amino,} di _{(ro-hydroxy-C2. 3} alkyl) amino, di (o) - (C |. ₃ -alkoxy) _{-C2. 3-alkyl)} -amino or N- (dioxolan-2-yl) -C _{first 3-amino-alkyl} group, a C ₃ -C alkylcarbonylamino _{second 3-} alkyl-amino- or C 1-6 alkyl; ₃ -alkylcarbonyl-amino-C _{2nd 3-TV-alkyl} (C ₁ _ ₃ alkyl) amino, a C. ₃ -alkylsulfonylamino-, / V- (C |. ₃ alkyl) C | .3-alkylsulfonylamino, C ₃ -C ₂ alkylsulfonylamino .3-alkyl-amino or _C), 3-alkylsulfonylamino-C _2. 3-alkyl-N- _(C1 .3 alkyl) amino, a group of formula (III) -N (R ¹⁰ ) - (CH ₂ ) _m - (CO) _o - R ¹¹ (III) wherein R ¹⁰ is H, C ₃ alkyl group, a C _k3 alkyl-carbonyl, arylcarbonyl, phenyl-C |. ₃ -alkylcarbonyl, C 1-6 alkyl; _3- alkylsulfonyl, arylsulfonyl or phenylC1. ₃ alkylsulphonyl group, m is 1, 2, 3 or 4, o is a value 1, and R ¹¹ is 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 _1-4 -alkoxy- or a C _1-3 -alkoxy-C 1 group. _3- alkoxy, optionally with C 1. ₃ at the 1-alkyl-substituted group di- (C _{1. 4} alkyl) amino-C. _{A 3-} alkylamino- or 4- to 7-membered cycloalkylene-imine 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; -NH-, - / V (C _k3 alkyl) -, -N (phenyl) -, - / in (C |. ₃ -alkyl-carbonyl) - or -? V (benzoyl) -, C ₄ _7- cycloalkylamino-, C ₄ . ₇ -cycloalkyl-C ₁ . _3- alkylamino- or C ₄ . ₇ -cycloalkenylamino- in which the ring 1 position does not participate in the double bond and wherein said groups may additionally be substituted on the amino nitrogen atom by a C ₅ group. ₇ -cycloalkyl- C _{2nd 4-} alkenyl- or C 1-6 -alkenyl; _{A 4-} alkyl- or 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 or iodine, nitro-, C 1-6. _3- alkyl-; _3- alkoxy or amino, and in which one or two hydrogen atoms may be replaced by C 1-6. _3- alkyl, C ₅ . ₇ -cycloalkyl or phenyl, and / or wherein a methylene group in position 3 of five cykloalkylénimínovej group may be substituted by hydroxy, hydroxy-C ₃ -alkyl, C _k3 -alkoxy or a C ₃ -alkoxy-C. _{A 3-} alkyl group in which the methylene group at the 3- or 4-position of a six- or seven-membered cycloalkyleneimine group may be substituted by a hydroxy group, hydroxy-C 1. _3- alkyl, C _1-3 -alkoxy-, C _1-3 -alkoxy-C 1. _3- alkyl, C _1-4 -alkoxycarbonyl-, aminocarbonyl-, C _1-3 -alkylaminocarbonyl-, di- (C _1-3 -alkyl) -amino-carbonyl-, phenyl-C _1-3 -alkylamino- or N - (C 1-6 -alkylaminocarbonyl ₎ ; _3- alkyl) -phenyl-C ₁ . ₃ -alkyl-amino, or said methylene group can be replaced by O or S, sulfmyl-, sulfonyl, -NH-, - _J V (C _{first 3} alkyl) -, -N (phenyl) -, -N (phenyl-C ₃ alkyl) -, -7V (C ₃ -alkyl-carbonyl) -, _K4 -MC-alkoxy-carbonyl) -, -v / benzoyl) - or -N (phenyl-C _{first 3} wherein the methylene group 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-fused cycloalkyleneimine group, both methylene groups may be substituted by an imine nitrogen atom carbonyl groups, is converted to a compound of formula (XI) wherein 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 R ² 'and R ¹⁸ may optionally form a solid phase bond via a Spacer and the other of said radicals is as defined above, and A represents a C _1-4 -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 and, if desired, cleavage of the protecting group used from the nitrogen atom of the lactam group or from the solid phase; if the prepared compound of formula (I) contains an alkoxycarbonyl group, it may be converted to the corresponding carboxyl compound by hydrolysis, or if the prepared compound of formula (I) contains an amino- or alkylamino- group, the compound may be converted by reductive alkylation to the corresponding alkylamino- or a dialkylamino compound, or if the compound of formula (I) contains an amino- or alkylamino- group, this compound can be converted by acylation or sulfonation to the corresponding acyl- or sulfonyl compound, or if the compound of formula (I) contains a carboxyl group, by esterification or amidation to convert to the corresponding ester or aminocarbonyl compound, or if the compound of formula (I) produced contains a cycloalkyleneimine group in which one methylene group is replaced by a sulfur atom, the compound may be converted by oxidation n and the corresponding 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 or a compound of formula (I) in which R ⁴ is amino-, alkylamino-, aminoalkyl- or a N-alkyl-amino-substituted phenyl group, may be subsequently transformed with the appropriate cyanate, isocyanate or carbamoyl halide to the corresponding urea compound of formula (I), or the prepared compound of formula (I) in which R ⁴ is amino the alkylamino-, aminoalkyl- or N-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 protective group group, pou during the conversion to protect the reactive groups or, if desired, the prepared compound of formula (I) is subsequently separated into its stereoisomers, or the prepared compound of formula is converted into its salts, in particular for pharmaceutical use into physiologically acceptable salts with inorganic or organic acid or base.