WO2010109008A1

WO2010109008A1 - Prodrugs of substituted 3-(4-hydroxyphenyl)-indolin-2-ones

Info

Publication number: WO2010109008A1
Application number: PCT/EP2010/054000
Authority: WO
Inventors: Fredrik Björkling; Mette Knark Christensen; Martins Ikaunieks; Andrei Zaichenko; Ilze Kaula; Einars Loza; Ivars Kalvinsh
Original assignee: Topotarget A/S; Gailite, Vija
Priority date: 2009-03-26
Filing date: 2010-03-26
Publication date: 2010-09-30

Abstract

The present application discloses novel prodrugs of substituted 3-(4-hydroxy-phenyl)-indolin-2-one compounds (oxindole compounds), and the use of such compounds for the preparation of a medicament for the treatment of cancer in a mammal. The prodrug compounds are of the formula (I).

Description

PRODRUGS OF SUBSTITUTED 3-(4-HYDROXYPHENYL)-INDOLIN-2-ONES

FIELD OF THE INVENTION

The present invention relates to novel prodrugs of substituted 3-(4- hydroxyphenyl)-indolin-2-one compounds (oxindole compounds), and the use of such compounds for the preparation of a medicament for the treatment of cancer in a mammal.

BACKGROUND OF THE INVENTION

US 1,624,675 describes O-0-diacyl derivatives of diphenolisatine and that these compounds possess laxative properties.

US 2004/0242563 Al discloses substituted diphenyl indanone, indane and indole compounds and analogues thereof useful for the treatment or prevention of diseases characterized by abnormal cell proliferation.

Magnus et al. (Magnus P and Turnbull R (2006) Organic Letters 8(16) : 3497- 3499) describe the synthesis of the following oxindole:

Felding et al. (WO 2005/097107) describe a number of oxindoles as anti-cancer agents, e.g. the following oxindoles:

Halperin et al. (WO 2005/080335) describe a number of oxindoles as potential anti-cancer agents, e.g. the following oxindoles;

Baskakova et al. (SU 90-4875262) describe the following oxindole for the manufacture of optical articles.

Kawada et al. (JP 94-114510) describe the following oxindole as a resist agent:

Hosta Pujol et al. (DE 2521966) describe the synthesis of the following oxindole as a potential laxative:

Esteve Subirana et al. (DE 2451592) describe the following oxindole as a laxative agent:

Kornowski (Kornowski H (1963) Bulletin de Ia Societe Chimique de France 10: 2035-2036) describes the synthesis of the following oxindoles:

Aktiebolaget "Ferrosan" ((1957) British patent application no. GB 1955-34509) describes the following oxindole as a laxative:

Geigy JR ((1955) British patent application no. GB 1952-23426) describes the synthesis of the following oxindoles:

Luk et al. (WO 2006/136606) describe oxindoles as potential anticancer agents:

Notably, these compounds comprise only one R¹ substituent. Also neither R² nor R⁴ are para-hydroxyphenyl.

Although, Felding et al. and Halperin et al. describe various ox-indole-2-one- type compounds as anti-cancer agents, there is still a need for novel ox-indol-2- one-type compounds as anti-cancer agents which provide useful alternatives upon selection of drug candidates.

BRIEF DESCRIPTION OF THE INVENTION

Following further developments within the field of ox-indol-2-one compounds, the present inventors have now found that that particular prodrug groups are particularly promising. The present inventors have now found that a new class of compounds represents an excellent alternative to existing ox-indol-2-one-type compounds as anti-cancer agents.

Hence, the present invention provides compounds of the general formulae (I) and (W), cf. claims 1 and 11.

The present invention further provides a pharmaceutical composition, cf. claim 13, the utilization of compounds of the general formulae (I) and (W) in medicine, cf. claims 15, 16 and 18.

DETAILED DESCRIPTION OF THE INVENTION

The Compounds of the general formula (I)

The present invention La. relates to particular prodrug compounds which are useful for the treatment of cancer in a mammal.

The useful prodrug compounds have the general formula (I), namely

(I) wherein r is 0 or 1;

D is selected from -CH₂-, -O-, -S-, -S(O)-, -S(O)₂- and -NR⁵-, wherein R⁵ is selected from hydrogen and optionally substituted Ci_-6-alkyl;

E is selected from optionally substituted Ci-i₂-alkyl, optionally substituted C_M2- cycloalkyl, optionally substituted C₂-i2-alkenyl, optionally substituted C_3-I₂- cycloalkenyl, optionally substituted C_2-i₂-alkynyl, optionally substituted heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; with the proviso that E is not optionally substituted phenyl when r is O;

X is selected from the groups (i)-(vi) :

(i) -S(=O)₂-Rⁿ,

(ii) -C(=O)-Z, wherein Z is selected from optionally substituted Ci-e-alkyl, optionally substituted C_2-6-alkenyl; aryl, heterocyclyl, heteroaryl, -OR⁷, -N(R⁷)R⁸, -(CH₂)₂-N(R⁷)R⁸, and -CH(R⁶)-N(R⁷)R⁸, and wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted,

(iii) -A-O-C(=O)-B-R⁵

(iv) -P(=O)(R⁹)(R¹⁰),

(v) -A-O-P(=O)(R⁹)(R¹⁰), and

(vi) -C(=O)-O-A-O-P(=O)(R⁹)(R¹⁰),

wherein A is selected from optionally substituted Ci_-6-alkylidene and optionally substituted benzylidene,

B is selected from a single bond, -O- and -NH-,

R⁵ is selected from hydrogen, optionally substituted Ci-e-alkyl, optionally substituted Ci-e-alkoxy, optionally substituted Ci_-6- alkoxycarbonyl, optionally substituted Ci_-6-alkylcarboπyl, mono- and ditCi-e-alkyOaminocarbonyl, amino, Ci-e-alkylcarbonylamino, mono- and di(Ci_-6-alkyl)amino, aryl, aryloxy, arylcarbonyl, arylamino, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, heterocyclylamino, heteroaryl, heteroaryloxy, heteroarylcarbonyl, and heteroarylamino; where any Ci-e-alkyl as an amino substituent is optionally substituted with hydroxy, Ci-e-alkoxy, amino, mono- and di(Ci_-6-alkyl)amino, carboxy, Ci-e-alkylcarbonylamino, C_1-6-alkylaminocarbonyl, or halogen(s), and wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted; or -C(=O)-B-R⁵ in prodrug groups (iii) and (vii) may represent an optionally N-substituted amino acid,

R⁶ is selected from hydrogen, optionally substituted Ci_-6-alkyl, optionally substituted C_2-6-alkenyl, aryl, heterocyclyl, and heteroaryl, wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted;

R⁷ and R⁸ are independently selected from hydrogen, optionally substituted Ci-e-alkyl, hydroxy, optionally substituted Ci-e-alkoxy, optionally substituted Ci_-6-alkoxycarbonyl, optionally substituted Ci_-6- alkylcarbonyl, formyl, mono- and di(Ci_-6-alkyl)aminocarbonyl, amino, Ci-₆-alkylcarbonylamino, mono- and di(Ci_-6-alkyl)amino, Ci_-6- alkylsulphonyl, Ci_-6-alkylsulphinyl, aryl, aryloxy, arylcarbonyl, arylamino, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, heterocyclylamino, heteroaryl, heteroaryloxy, heteroarylcarbonyl, and heteroarylamino; where any Ci-e-alkyl as an amino substituent is optionally substituted with hydroxy, Ci-e-alkoxy, amino, mono- and di(Ci-₆-alkyl)amino, carboxy, Ci-6-alkylcarbonylamino, Ci_-6-alkylamino- carbonyl, or halogen(s), and wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted, or R⁷ and R⁸ together with the nitrogen atoms to which they are attached form a heterocyclic ring, R⁹ is selected from hydrogen, hydroxy, optionally substituted Ci_-6- alkyl, optionally substituted Ci_-6-alkoxy, and optionally substituted C₂-₆-alkenyloxy; and

R¹⁰ is selected from hydroxy, optionally substituted Ci-e-alkyl, optionally substituted Ci-e-alkoxy, optionally substituted C_2-6- alkenyloxy; aryloxy, heterocyclyloxy, and heteroaryloxy, wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted; and

R¹¹ is selected from hydroxy, optionally substituted Ci-e-alkyl, optionally substituted C_2-6-alkenyl, aryl, heterocyclyl, heteroaryl, optionally substituted Ci-e-alkoxy, optionally substituted C_2-6- alkenyloxy; aryloxy, heterocyclyloxy, and heteroaryloxy, wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted;

fir X is selected from hydrogen, hydroxy, optionally substituted Ci_-6 alkoxy, optionally substituted Ci_-6 alkyl, optionally substituted C_2-6 alkenyl, carboxy, optionally substituted Ci_-6-alkoxycarbonyl, Ci_-6-alkylcarbonyloxy, optionally substituted Ci_-6 alkylcarbonyl, formyl, amino, mono- and di(Ci_-6-alkyl)amino, Ci-6-alkylcarbonylamino, Ci_-6-alkylsulphonylamino, mono- and di(d_-6-alkyl)- aminocarbonylamino, carbamoyl, mono-and di (Ci_-6-alkyl)aminocarbonyl, mercapto, optionally substituted Ci_-6-alkylthio, Ci_-6-alkylsulfonyl, mono- and di(Ci_-6-alkyl)aminosulfonyl, cyano, halogen, aryl, aryloxy, arylamino, arylcarbonyl, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocycylcarbonyl, heteroaryloxy, heteroarylamino, heteroarylcarbonyl, where any Ci_-6-alkyl as an amino substituent is optionally substituted with hydroxyl, Ci-e-alkoxy, amino, mono and di (Ci_-6-alkyl)amino, carboxy, Ci_-6-alkylcarbonyl- amino, Ci_-6 alkylaminocarbonyl or halogen(s) and wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted;

R^N represents a prodrug group of any of the types (vii)-(viii)

wherein A, B and R⁵ are as defined above for prodrug groups (i)-(vi);

or R^N is selected from hydrogen, optionally substituted Ci_-6-alkyl, hydroxy, optionally substituted Ci_-6-alkoxy, optionally substituted Ci_-6-alkoxycarbonyl, optionally substituted Ci-e-alkylcarbonyl, formyl, mono- and di(Ci_-6-alkyl)amino- carbonyl, amino, Ci-e-alkylcarbonylamino, mono- and di(Ci_-6-alkyl)amino, Ci_-6- alkylsulphonyl, and Ci_-6-alkylsulphinyl; where any Ci-e-alkyl as an amino substituent is optionally substituted with hydroxy, Ci-e-alkoxy, amino, mono- and di(Ci_-6-alkyl)amino, carboxy, Ci-e-alkylcarbonylamino, Ci_-6-alkylamino- carbonyl, or halogen(s);

V¹, V², V³, and V⁴ independently are selected from a carbon atom, a non- quaternary nitrogen atom, an oxygen atom, and a sulphur atom, and where V⁴ further may be selected from a bond, so that -V¹-V²-V³-V⁴- together with the atoms to which V¹ and V⁴ are attached form an aromatic or heteroaromatic ring;

R¹, R², R³, and R⁴, when attached to a carbon atom, independently are selected from hydrogen, optionally substituted Ci-i₂-alkyl, optionally substituted C_3-I2- cycloalkyl, optionally substituted C₂-i2-alkenyl, optionally substituted C_3-I₂- cycloalkenyl, hydroxy, optionally substituted d-₁₂-alkoxy, optionally substituted C₂-i2-alkenyloxy, carboxy, optionally substituted Ci-i₂-alkoxycarbonyl, optionally substituted Ci-i₂-alkylcarbonyl, optionally substituted Ci-12-alkylcarbonyloxy, formyl, amino, mono- and di(d-i2-alkyl)amino, carbamoyl, mono- and di(Ci-i₂- alkyl)aminocarbonyl, Ci-12-alkylcarbonylamino, Ci-12-alkylsulphonylamino, cyano, carbamido, mono- and di(Ci-i₂-alkyl)aminocarbonylamino, Ci-i₂-alkanoyloxy, Ci-12-alkylsulphonyl, Ci-i₂-alkylsulphinyl, aminosulphonyl, mono- and di(Ci-i₂- alkyl)aminosulphonyl, nitro, optionally substituted Ci_-12-alkylthio, aryl, aryloxy, arylcarbonyl, arylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylcarbonyl, heteroaryl, heteroaryloxy, heteroarylamino, heteroarylcarbonyl, and halogen, where any Ci-₁₂-alkyl as an amino substituent is optionally substituted with hydroxy, Ci-i₂-alkoxy, amino, mono- and di(Ci-i₂- alkyl)amino, carboxy, Ci-12-alkylcarbonylamino, Ci-12-alkylaminocarbonyl, or halogen(s), and wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted;

R¹, R², R³, and R⁴, when attached to a nitrogen atom, independently are selected from hydrogen, optionally substituted Ci-i₂-alkyl, hydroxy, oxide, optionally substituted Ci-i₂-alkoxy, optionally substituted Ci-12-alkoxycarbonyl, optionally substituted Ci-₁₂-alkylcarbonyl, formyl, mono- and di(Ci-i₂-alkyl)aminocarbonyl, amino, Ci-12-alkylcarbonylamino, mono- and di(Ci-i₂-alkyl)amino, Ci-I₂- alkylsulphonyl, Ci-i₂-alkylsulphinyl, aryl, aryloxy, arylcarbonyl, arylamino, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, heterocyclylamino, heteroaryl, heteroaryloxy, heteroarylcarbonyl, and heteroarylamino; where any Ci-₁₂-alkyl as an amino substituent is optionally substituted with hydroxy, Ci_-I2- alkoxy, amino, mono- and di(Ci-i₂-alkyl)amino, carboxy, Ci-i₂-alkylcarbonylami- no,

or halogen(s), and wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted;

or R¹ and R² together with the carbon atoms to which they are attached form a ring;

with the proviso that the compound comprises at least one of the prodrug groups (i)-(viii) and with the proviso that the compound is not l-acetyl-3- (acetyloxy)-3-[4-(acetyloxy)phenyl]-l,3-dihydro-2H-indol-2-one;

and pharmaceutically acceptable salts thereof. Definitions

In the present context, the terms "Ci-₁₂-alkyl" and "Ci_-6-alkyl" are intended to mean a linear, cyclic or branched hydrocarbon group having 1 to 12 carbon atoms and 1 to 6 carbon atoms, respectively, such as methyl, ethyl, propyl, iso- propyl, pentyl, cyclopentyl, hexyl, cyclohexyl. The term "Ci_-4-alkyl" is intended to cover linear, cyclic or branched hydrocarbon groups having 1 to 4 carbon atoms, e.g. methyl, ethyl, propyl, /so-propyl, cyclopropyl, butyl, /so- butyl, tert- butyl, cyclobutyl.

Although the term "C_3-i₂-cycloalkyl" is encompassed by the term

it refers specifically to the mono- and bicyclic counterparts, including alkyl groups having exo-cyclic atoms, e.g. cyclohexyl-methyl.

Similarly, the terms "C_2-i2-alkenyl" and "C_2-6-alkenyl" are intended to cover linear, cyclic or branched hydrocarbon groups having 2 to 12 carbon atoms and 2 to 6 carbon atoms, respectively, and comprising (at least) one unsaturated bond. Examples of alkenyl groups are vinyl, allyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, heptadecaenyl. Preferred examples of alkenyl are vinyl, allyl, butenyl, especially allyl.

Although the term "C_3-i₂-cycloalkenyl" is encompassed by the term "C_2-I2- alkenyl", it refers specifically to the mono- and bicyclic counterparts, including alkenyl groups having exo-cyclic atoms, e.g. cyclohexenyl-methyl.

In the present context, i.e. in connection with the terms "alkyl", "cycloalkyl", "alkylidene", "alkoxy", "alkenyl", "cycloalkenyl" and the like, the term "optionally substituted" is intended to mean that the group in question may be substituted one or several times, preferably 1-3 times, with group(s) selected from hydroxy (which when bound to an unsaturated carbon atom may be present in the tautomeric keto form), Ci-e-alkoxy {i.e. Ci_-6-alkyl-oxy), C_2-6-alkenyloxy, carboxy, oxo (forming a keto or aldehyde functionality), Ci_-6-alkoxycarbonyl, Ci_-6- alkylcarbonyl, formyl, aryl, aryloxy, arylamino, arylcarbonyl, aryloxycarbonyl, arylcarbonyloxy, arylaminocarbonyl, arylcarbonylamino, heteroaryl, heteroaryloxy, heteroarylamino, heteroarylcarbonyl, heteroaryloxycarbonyl, heteroarylcarbonyloxy, heteroarylaminocarbonyl, heteroarylcarbonylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylcarbonyloxy, heterocyclylaminocarbonyl, heterocyclylcarbonylamino, amino, mono- and di(Ci_-6-alkyl)amino, -N(Ci_-4- alkyl)₃ ⁺, carbamoyl, mono- and di(Ci_-6-alkyl)aminocarbonyl, Ci_-6-alkylcarbony- lamino, cyano, guanidino, carbamido, Ci_-6-alkyl-sulphonyl-amino, aryl- sulphonyl-amino, heteroaryl-sulphonyl-amino, Ci-e-alkanoyloxy, Ci-e-alkyl- sulphonyl, Ci_-6-alkyl-sulphinyl, Ci_-6-alkylsulphonyloxy, nitro, C_1-6-alkylthio, and halogen, where any aryl, heteroaryl and heterocyclyl may be substituted as specifically described below for aryl, heteroaryl and heterocyclyl, and any alkyl, alkoxy, and the like, representing substituents may be substituted with hydroxy, Ci-6-alkoxy, amino, mono- and di(Ci_-6-alkyl)amino, carboxy, Ci_-6-alkylcarbony- lamino, Ci-e-alkylaminocarbonyl, or halogen(s).

Typically, the substituents are selected from hydroxy (which when bound to an unsaturated carbon atom may be present in the tautomeric keto form), Ci_-6- alkoxy {i.e. Ci-e-alkyl-oxy), C_2-6-alkenyloxy, carboxy, oxo (forming a keto or aldehyde functionality), Ci-e-alkylcarbonyl, formyl, aryl, aryloxy, arylamino, arylcarbonyl, heteroaryl, heteroaryloxy, heteroarylamino, heteroarylcarbonyl, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylcarbonyl, amino, mono- and di(Ci_-6-alkyl)amino; carbamoyl, mono- and di(d_-6-alkyl)amino- carbonyl, amino-Ci-e-alkyl-aminocarbonyl, mono- and di(Ci_-6-alkyl)amino-Ci_-6- alkyl-aminocarbonyl, Ci-e-alkylcarbonylamino, guanidino, carbamido, Ci-e-alkyl- sulphonyl-amino, Ci_-6-alkyl-sulphonyl, Ci_-6-alkyl-sulphinyl, Ci_-6-alkylthio, halogen, where any aryl, heteroaryl and heterocyclyl may be substituted as specifically described below for aryl, heteroaryl and heterocyclyl.

In some embodiments, substituents are selected from hydroxy, Ci_-6-alkoxy, amino, mono- and di(Ci_-6-alkyl)amino, carboxy, Ci-e-alkylcarbonylamino, Ci_-6- alkylaminocarbonyl, or halogen.

The term "halogen" includes fluoro, chloro, bromo, and iodo. In the present context, the term "aryl" is intended to mean a fully or partially aromatic carbocyclic ring or ring system, such as phenyl, naphthyl, 1,2,3,4- tetrahydronaphthyl, anthracyl, phenanthracyl, pyrenyl, benzopyrenyl, fluorenyl and xanthenyl, among which phenyl is a preferred example.

The term "heteroaryl" is intended to mean a fully or partially aromatic carbocyclic ring or ring system where one or more of the carbon atoms have been replaced with heteroatoms, e.g. nitrogen ( = N- or -NH-), sulphur, and/or oxygen atoms. Examples of such heteroaryl groups are oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, coumaryl, furanyl, thienyl, quinolyl, benzo- thiazolyl, benzotriazolyl, benzodiazolyl, benzooxozolyl, phthalazinyl, phthalanyl, triazolyl, tetrazolyl, isoquinolyl, acridinyl, carbazolyl, dibenzazepinyl, indolyl, benzopyrazolyl, phenoxazonyl. Particularly interesting heteroaryl groups are benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, quinolyl, triazolyl, tetrazolyl, isoquinolyl, indolyl in particular benzimidazolyl, pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, furyl, thienyl, quinolyl, tetrazolyl, and isoquinolyl.

The term "heterocyclyl" is intended to mean a non-aromatic carbocyclic ring or ring system where one or more of the carbon atoms have been replaced with heteroatoms, e.g. nitrogen (=N- or -NH-), sulphur, and/or oxygen atoms. Examples of such heterocyclyl groups (named according to the rings) are imidazolidine, piperazine, hexahydropyridazine, hexahydropyrimidine, diazepane, diazocane, pyrrolidine, piperidine, azepane, azocane, aziridine, azirine, azetidine, pyroline, tropane, oxazinane (morpholine), azepine, dihydroazepine, tetrahydroazepine, and hexahydroazepine, oxazolane, oxazepane, oxazocane, thiazolane, thiazinane, thiazepane, thiazocane, oxazetane, diazetane, thiazetane, tetrahydrofuran, tetrahydropyran, oxepane, tetrahydrothiophene, tetrahydrothiopyrane, thiepane, dithiane, dithiepane, dioxane, dioxepane, oxathiane, oxathiepane. The most interesting examples are tetrahydrofuran, imidazolidine, piperazine, hexahydropyridazine, hexahydropyrimidine, diazepane, diazocane, pyrrolidine, piperidine, azepane, azocane, azetidine, tropane, oxazinane (morpholine), oxazolane, oxazepane, thiazolane, thiazinane, and thiazepane, in particular tetrahydrofuran, imidazolidine, piperazine, hexahydropyridazine, hexahydropyrimidine, diazepane, pyrrolidine, piperidine, azepane, oxazinane (morpholine), and thiazinane.

In the present context, i.e. in connection with the terms "aryl", "benzylidene", "heteroaryl", "heterocyclyl" and the like (e.g. "aryloxy", "heterarylcarbonyl", etc.), the term "optionally substituted" is intended to mean that the group in question may be substituted one or several times, preferably 1-5 times, in particular 1-3 times, with group(s) selected from hydroxy (which when present in an enol system may be represented in the tautomeric keto form), Ci_-6-alkyl, Ci-₆-alkoxy, C_2-6-alkenyloxy, oxo (which may be represented in the tautomeric enol form), oxide (only relevant as the N-oxide), carboxy, Ci_-6-alkoxycarbonyl, Ci-₆-alkylcarbonyl, formyl, aryl, aryloxy, arylamino, aryloxycarbonyl, arylcarbonyl, heteroaryl, heteroarylamino, amino, mono- and di(Ci_-6- alkyl)amino; carbamoyl, mono- and di(Ci_-6-alkyl)aminocarbonyl, amino-Ci_-6- alkyl-aminocarbonyl, mono- and di(Ci_-6-alkyl)amino-Ci_-6-alkyl-aminocarbonyl, Ci-₆-alkylcarbonylamino, cyano, guanidino, carbamido, Ci_-6-alkanoyloxy, Ci_-6- alkyl-sulphonyl-amino, aryl-sulphonyl-amino, heteroaryl-sulphonyl-amino, Ci_-6- alkyl-suphonyl, C_1-6-alkyl-sulphinyl, Ci_-6-alkylsulphonyloxy, nitro, sulphanyl, amino, amino-sulphonyl, mono- and di(Ci_-6-alkyl)amino-sulphonyl, dihalogen- Ci-₄-alkyl, trihalogen-Ci_-4-alkyl, halogen, where aryl and heteroaryl representing substituents may be substituted 1-3 times with Ci_-4-alkyl, Ci_-4-alkoxy, nitro, cyano, amino or halogen, and any alkyl, alkoxy, and the like, representing substituents may be substituted with hydroxy, Ci_-6-alkoxy, C_2-6-alkenyloxy, amino, mono- and di(Ci_-6-alkyl)amino, carboxy, Ci-e-alkylcarbonylamino, halogen, Ci_-6-alkylthio, Ci_-6-alkyl-sulphonyl-amino, or guanidino.

Typically, the substituents are selected from hydroxy, Ci_-6-alkyl, Ci_-6-alkoxy, oxo (which may be represented in the tautomeric enol form), carboxy, Ci_-6- alkylcarbonyl, formyl, amino, mono- and di(Ci_-6-alkyl)amino; carbamoyl, mono- and di(Ci-₆-alkyl)aminocarbonyl, amino-Ci-₆-alkyl-aminocarbonyl, Ci_-6- alkylcarbonylamino, guanidino, carbamido, Ci_-6-alkyl-sulphonyl-amino, aryl- sulphonyl-amino, heteroaryl-sulphonyl-amino, Ci_-6-alkyl-suphonyl, Ci_-6-alkyl- sulphinyl, Ci_-6-alkylsulphonyloxy, sulphanyl, amino, amino-sulphonyl, mono- and di(Ci_-6-alkyl)amino-sulphonyl or halogen, where any alkyl, alkoxy and the like, representing substituents may be substituted with hydroxy, Ci_-6-alkoxy, C₂-e- alkenyloxy, amino, mono- and di(Ci_-6-alkyl)amino, carboxy, Ci-e-alkylcarbony- lamino, halogen, Ci-e-alkylthio, Ci_-6-alkyl-sulphonyl-amino, or guanidino. In some embodiments, the substituents are selected from Ci-e-alkyl, Ci-e-alkoxy, amino, mono- and di(Ci_-6-alkyl)amino, sulphanyl, carboxy or halogen, where any alkyl, alkoxy and the like, representing substituents may be substituted with hydroxy, Ci_-6-alkoxy, C_2-6-alkenyloxy, amino, mono- and di(Ci_-6-alkyl)amino, carboxy, Ci-e-alkylcarbonylamino, halogen, Ci_-6-alkylthio, Ci_-6-alkyl-sulphonyl- amino, or guanidino.

The expression "optionally N-substituted amino acid" refers to an amino acid moiety wherein the α-nitrogen is represented by -N(R⁷)R⁸, wherein R⁷ and R⁸ are as defined herein. A non-substituted variant is the one where R⁷ and R⁸ are both hydrogen.

The term "pharmaceutically acceptable salts" is intended to include acid addition salts and basic salts. Illustrative examples of acid addition salts are pharmaceutically acceptable salts formed with non-toxic acids. Exemplary of such organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulphonic, ethanedisulphonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulphonic, and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline. Exemplary of such inorganic salts are those with hydrochloric, hydrobromic, sulphuric, sulphamic, phosphoric, and nitric acids. Examples of basic salts are salts where the (remaining) counter ion is selected from alkali metals, such as sodium and potassium, alkaline earth metals, such as calcium, and ammonium ions (⁺N(R)₃R', where R and R' independently designates optionally substituted Ci_-6- alkyl, optionally substituted C_2-6-alkenyl, optionally substituted aryl, or optionally substituted heteroaryl). Pharmaceutically acceptable salts are, e.g., those described in Remington's Pharmaceutical Sciences, 17. Ed. Alfonso R. Gennaro (Ed.), Mack Publishing Company, Easton, PA, U.S.A., 1985 and more recent editions and in Encyclopedia of Pharmaceutical Technology. Thus, the term "an acid addition salt or a basic salt thereof" used herein is intended to comprise such salts. Furthermore, the compounds as well as any intermediates or starting materials may also be present in hydrate form.

Moreover, it should be understood that the compounds may be present as racemic mixtures or the individual stereoisomers such as enantiomers or diastereomers. The present invention encompasses each and every of such possible stereoisomers (e.g. enantiomers and diastereomers) as well as racemates and mixtures enriched with respect to one of the possible stereoisomers.

Embodiments

It should be understood that the compound of the general formula (I) must include at least one prodrug group of any of the types (i), (ii), (iii), (iv), (v), (vi), (vii) and (viii). The compound may comprise only one prodrug group, i.e. X is a prodrug group of any of the types (i)-(vi), or R^N is a prodrug group of any of the types (vii)-(viii). Alternatively, the compound may comprise more than one prodrug group, e.g. R^N is a prodrug group of any of the types (vii)-(viii) while X is a prodrug group of any of the types (i)-(vi).

In one currently interesting embodiment, X represents a prodrug group (i) -SC=O)₂-R¹¹, in particular wherein R¹¹ represents -OH (including the salt -0^"Na⁺).

In another currently interesting embodiment, X represents a prodrug group (ii) -C(=O)-Z, in particular wherein Z is selected from optionally substituted Ci_-6- alkyl, optionally substituted C_2-6-alkenyl; aryl, heterocyclyl, heteroaryl, -OR⁷, -N(R⁷)R⁸, -(CH₂)₂-N(R⁷)R⁸, and -CH(R⁶)-N(R⁷)R⁸, and wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted. Particularly interesting meaning of Z are optionally substituted Ci_-6-alkyl, C₂-₆-alkenyl, and -N(R⁷)R⁸.

Typically, R⁷ and R⁸ are independently selected from hydrogen, optionally substituted Ci_-6-alkyl, hydroxy, optionally substituted Ci-e-alkoxy, optionally substituted Ci_-6-alkoxycarbonyl, optionally substituted Ci_-6-alkylcarbonyl, formyl, mono- and di(Ci-6-alkyl)aminocarbonyl, amino, Ci-e-alkylcarbonylamino, mono- and di(Ci_-6-alkyl)amino, Ci-e-alkylsulphonyl, Ci_-6-alkylsulphinyl, aryl, aryloxy, arylcarbonyl, arylamino, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, heterocyclylamino, heteroaryl, heteroaryloxy, heteroarylcarbonyl, and heteroarylamino; where any Ci_-6-alkyl as an amino substituent is optionally substituted with hydroxy, Ci_-6-alkoxy, amino, mono- and di(Ci_-6-alkyl)amino, carboxy, Ci-e-alkylcarbonylamino, Ci-e-alkylaminocarbonyl, or halogen(s), and wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted; fir R⁷ and R⁸ together with the nitrogen atoms to which they are attached form a heterocyclic ring.

Within this variant, however, R⁶ is preferably selected from side chains of essential amino acids, or R⁶ and R⁸ together with the intervening carbon and nitrogen atoms to which they are attached form a heterocyclic ring. In such instances, R⁶ is preferably selected from hydrogen (representing glycine), methyl (alanine), 2-propyl (valine), 2-methyl-l-propyl (leucine), 2-butyl (isoleucine), methylthioethyl (methionine), benzyl (phenylalanine), 3- indolylmethyl (tryptophan), hydroxymethyl (serine), 1-hydroxyethyl (threonine), mercaptomethyl (cysteine), 4-hydroxybenzyl (tyrosine), aminocarbonylmethyl (asparagine), 2-aminocarbonylethyl (glutamine), carboxymethyl (aspartic acid), 2-carboxyethyl (glutamic acid), 4-amino-l-butyl (lysine), 3-guanidino-l-propyl (arginine), and 4-imidazolylmethyl (histidine), or R⁶ and R⁸ together with the intervening carbon and nitrogen atoms to which they are attached form a pyrrolidine ring (proline).

In one currently interesting variant of the prodrug group (ii), Z is -N(R⁷)R⁸, wherein R⁷ and R⁸ together with the nitrogen atoms to which they are attached form a heterocyclic ring. In one currently interesting variant of the prodrug group (ii), Z is -(CH₂V N(R⁷)R⁸, wherein R⁷ and R⁸ together with the nitrogen atoms to which they are attached form a heterocyclic ring.

In another preferred embodiment, X represents a prodrug group (iii), -A-O- C(=O)-B-R⁵.

Typically, A is selected from optionally substituted Ci_-6-alkylidene and optionally substituted benzylidene; B is selected from a single bond, -O- and -NH-; and R⁵ is selected from hydrogen, optionally substituted Ci_-6-alkyl, optionally substituted Ci_-6-alkoxy, optionally substituted Ci-e-alkoxycarbonyl, optionally substituted Ci-e-alkylcarbonyl, mono- and di(Ci_-6-alkyl)aminocarbonyl, amino, Ci-₆-alkylcarbonylamino, mono- and di(Ci_-6-alkyl)amino, aryl, aryloxy, arylcarbonyl, arylamino, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, heterocyclylamino, heteroaryl, heteroaryloxy, heteroarylcarbonyl, and heteroarylamino; where any Ci_-6-alkyl as an amino substituent is optionally substituted with hydroxy, Ci-e-alkoxy, amino, mono- and di(Ci_-6-alkyl)amino, carboxy, Ci-e-alkylcarbonylamino, Ci-e-alkylaminocarbonyl, or halogen(s), and wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted; or -C(=O)-B-R⁵ in prodrug group (iii) may represent an optionally N-substituted amino acid.

In one variant, R⁵ is selected from hydrogen, optionally substituted Ci_-6-alkyl, optionally substituted Ci_-6-alkoxy, optionally substituted Ci_-6-alkoxycarbonyl, optionally substituted Ci_-6-alkylcarbonyl, mono- and di(Ci_-6-alkyl)aminocarbonyl, amino, Ci_-6-alkylcarbonylamino, mono- and di(Ci_-6-alkyl)amino, aryl, aryloxy, arylcarbonyl, arylamino, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, heterocyclylamino, heteroaryl, heteroaryloxy, heteroarylcarbonyl, and heteroarylamino; where any Ci_-6-alkyl as an amino substituent is optionally substituted with hydroxy, Ci_-6-alkoxy, amino, mono- and di(Ci_-6-alkyl)amino, carboxy, Ci-e-alkylcarbonylamino, Ci-e-alkylaminocarbonyl, or halogen(s), and wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted. In another currently preferred variant, -C(=O)-B-R⁵ in prodrug group (iii) may represent an optionally N-substituted amino acid, i.e. B is a single bond and R⁵ represents -CH(R⁶)-N(R⁷)R⁸, wherein R⁶, R⁷ and R⁸ are as defined above for prodrug groups (i) and (ii). In particular, R⁶ is preferably selected from side chains of essential amino acids, or R⁶ and R⁸ together with the intervening carbon and nitrogen atoms to which they are attached form a pyrrolidine ring (see the examples above for prodrug groups (i) and (ii)).

In still another embodiment, X represents a prodrug group of any of the types (iv)-(vi), in particular the type (iv) P(=O)(R⁹)(R¹⁰).

Typically, A is selected from optionally substituted Ci_-6-alkylidene and optionally substituted benzylidene; R⁹ is selected from hydrogen, hydroxy, optionally substituted Ci_-6-alkyl, optionally substituted Ci_-6-alkoxy, and optionally substituted C_2-6-alkenyloxy; and R¹⁰ is selected from hydroxy, optionally substituted Ci-e-alkyl, optionally substituted Ci_-6-alkoxy, optionally substituted C₂-6-alkenyloxy; aryloxy, heterocyclyloxy, and heteroaryloxy, wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted; provided that R⁹ and R¹⁰ are not both selected from hydroxy and C_1-6-alkoxy.

Within this embodiment, R⁹ is preferably selected from hydrogen and hydroxy, and R¹⁰ is preferably selected from optionally substituted Ci-e-alkoxy, optionally substituted C_2-6-alkenyloxy; aryloxy, heterocyclyloxy, and heteroaryloxy, wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted. More particular, R⁹ is hydroxy, and R¹⁰ is selected from optionally substituted Ci-e-alkoxy, aryloxy, heterocyclyloxy, and heteroaryloxy, wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted.

In yet another embodiment, R^N represents a prodrug group or any of the types (vii)-(viii).

In some preferred embodiments, R^N is not an acetyl group. Typically, A is selected from optionally substituted Ci_-6-alkylidene and optionally substituted benzylidene; B is selected from a single bond, -O-, and -NH-; and R⁵ is selected from hydrogen, optionally substituted Ci-6-alkyl, optionally substituted Ci-₆-alkoxy, optionally substituted Ci-6-alkoxycarbonyl, optionally substituted Ci_-6-alkylcarbonyl, mono- and di(Ci_-6-alkyl)aminocarbonyl, amino, Ci-₆-alkylcarbonylamino, mono- and di(Ci_-6-alkyl)amino, aryl, aryloxy, arylcarbonyl, arylamino, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, heterocyclylamino, heteroaryl, heteroaryloxy, heteroarylcarbonyl, and heteroarylamino; where any Ci_-6-alkyl as an amino substituent is optionally substituted with hydroxy, Ci-e-alkoxy, amino, mono- and di(Ci_-6-alkyl)amino, carboxy, Ci-₆-alkylcarbonylamino, Ci-₆-alkylaminocarbonyl, or halogen(s), and wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted; or -C(=O)-B-R⁵ in prodrug group (vii) may represent an optionally N-substituted amino acid.

In a currently preferred variant, -C(=O)-B-R⁵ in prodrug group (vii) represent an optionally N-substituted amino acid, i.e. B is a single bond and R⁵ represents -CH(R⁶)-N(R⁷)R⁸, wherein R⁶, R⁷ and R⁸ are as defined above for prodrug group (ii). In particular, R⁶ is preferably selected from side chains of essential amino acids, or R⁶ and R⁸ together with the intervening carbon and nitrogen atoms to which they are attached form a pyrrolidine ring (see the examples above for prodrug groups (i) and (ii)).

The function of V¹, V², V³, and V⁴ is mainly believed to be of sterical character, i.e. determinative for the orientation of the groups R^R⁴. It is, however, also believed that the selection of a heteroatom as one or more of V¹, V², V³, and V⁴ may create dipole interactions with other entities and thereby have influence on, e.g. , the solubility of the compounds of the general formula (I).

V¹, V², V³, and V⁴ are independently selected from a carbon atom, a non- quaternary nitrogen atom, an oxygen atom, and a sulfur atom, and where V⁴ further may be selected from a bond, so that -V¹-V²-V³-V⁴- together with the atoms to which V¹ and V⁴ are attached form an aromatic or heteroaromatic ring. Particularly useful examples of such aromatic rings and heteroaromatic rings are those selected from a benzene ring, a thiophene ring (N^=S, V²=V³=C(-) and V⁴=bond; V²=S, \/¹=\/³=C{-) and V⁴=bond; or V³=S, V¹^=C(O and V⁴=bond), a furan ring (V^O, V²=V³=C(-) and V⁴=bond; V²=0, V¹=V³=C(-) and V⁴=bond; or V³=0, V¹^=C(O and V⁴=bond), a pyrazole ring (V¹ = !^-), V²=N, V³=C(-) and V⁴=bond; V^N, V²=N(-), V³=C(-) and V⁴=bond), an imidazole ring

(V^NC-), V²=C(-), V³=N and V⁴=bond; V^N, V²=C(-), V³=N(-) and V⁴=bond), a pyridine ring (V^N, V²=V³=V⁴=C(-); V²=N, V¹=V³=V⁴=C(-); V³=N, V¹=V²=V⁴=C(-) and V⁴=N, V¹=V²=V³=C(-)), a pyrimidine ring (V¹=V³=N, V²=V⁴=C(-); V²=V⁴=N, V¹=V³=C(-)), pyrazines (V¹=V⁴=N, V²=V³=C(-)), a pyridazine ring (V¹=V²=N, V³=V⁴=C(-); V²=V³=N, V¹=V⁴=C(-); V³=V⁴=N,

V¹=v²=C(-)), a thiazole ring (V^N, V²=C(-), V³=S, V⁴=bond; V^S, V²=C(-), V³=N, V⁴=bond), and an isothiazole ring (V^N, V²=S, V³=C(-), V⁴=bond; V^S, V²=N, V³=C(-), V⁴=bond; V¹=^), V²=S, V³=N, V⁴=bond; V¹=^-), V²=N, V³=S, V⁴=bond).

The meaning of V¹, V², V³ and V⁴ for each heteroaromatic ring is merely specified for the purpose of illustrating that various orientations of the heteroatoms are possible. Furthermore, it should be understood that the respective rings carry the substituents R¹, R², R³ and R⁴ (where applicable) in accordance with the general formula (I). Thus, specification of "C(-)" and "N(-)" as possible meanings of V¹, V², V³ and V⁴ is made for the purpose of describing that the atoms in question carry a substituent (which may be hydrogen). Specification of "N" means that the respective atoms do not carry an "R" substituent, i.e. the corresponding "R" substituent is absent.

In one embodiment, -V¹-V²-V³-V⁴- together with the atoms to which V¹ and V⁴ are attached form a ring selected from a benzene ring, a thiophene ring, a furan ring, a pyrazole ring, an imidazole ring, a pyridine ring, a pyrimidine ring, pyrazines, and a pyridazine ring, in particular from a benzene ring and a pyridine ring where the nitrogen atom represents V³ (see also the Examples). In accordance with the general formula (I), the respective ring (aromatic or heteroaromatic) carries the substituents R*-R⁴ (where applicable). The substituents R*-R⁴ (where applicable) are believed to be at least partly responsible for the biological effect, e.g. the ability of the compounds to inhibit cell proliferation in cancer cells.

In one embodiment, R¹, R², R³, and R⁴ are, when attached to a carbon atom, independently selected from hydrogen, optionally substituted Ci_-6-alkyl, optionally substituted C₂-6-alkenyl, hydroxy, optionally substituted Ci_-6-alkoxy, optionally substituted C_2-6-alkenyloxy, carboxy, optionally substituted Ci_-6- alkoxycarbonyl, optionally substituted Ci_-6-alkylcarbonyl, optionally substituted Ci-₆-alkylcarbonyloxy, formyl, amino, mono- and di(Ci_-6-alkyl)amino, carbamoyl, mono- and di(Ci_-6-alkyl)aminocarbonyl, Ci-e-alkylcarbonylamino, Ci_-6- alkylsulphonylamino, cyano, carbamido, mono- and di(Ci_-6-alkyl)amino- carbonylamino, Ci_-6-alkanoyloxy, Ci_-6-alkylsulphonyl, Ci_-6-alkylsulphinyl, aminosulfonyl, mono- and di(Ci_-6-alkyl)aminosulfonyl, nitro, optionally substituted Ci_-6-alkylthio, and halogen, where any Ci_-6-alkyl as an amino substituent is optionally substituted with hydroxy, Ci_-6-alkoxy, amino, mono- and di(Ci_-6-alkyl)amino, carboxy, Ci-e-alkylcarbonylamino, Ci_-6-alkylamino- carbonyl, or halogen(s); and R¹, R², R³, and R⁴ are, when attached to a nitrogen atom, independently selected from hydrogen, optionally substituted C_1-6-alkyl, hydroxy, optionally substituted Ci_-6-alkoxy, optionally substituted Ci_-6- alkoxycarbonyl, optionally substituted Ci_-6-alkylcarbonyl, formyl, mono- and di(Ci_-6-alkyl)aminocarbonyl, amino, Ci-e-alkylcarbonylamino, mono- and di(Ci-₆- alkyl)amino, Ci_-6-alkylsulphonyl, and Ci_-6-alkylsulphinyl; where any Ci_-6-alkyl as an amino substituent is optionally substituted with hydroxy, Ci_-6-alkoxy, amino, mono- and di(Ci_-6-alkyl)amino, carboxy, Ci-e-alkylcarbonylamino, Ci_-6- alkylaminocarbonyl, or halogen(s), and wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted.

More particularly, R¹, R², R³, and R⁴ are independently selected from hydrogen, halogen, optionally substituted Ci_-6-alkyl, hydroxy, optionally substituted Ci_-6- alkoxy, optionally substituted Ci-e-alkoxycarbonyl, optionally substituted Ci_-6- alkylcarbonyl, amino, Ci_-6-alkylcarbonylamino, Ci_-6-alkylcarbonylamino, Ci_-6- alkylsulphonylamino, mono- and di(Ci_-6-alkyl)aminosulfonyl, and mono- and di(Ci_-6-alkyl)amino, where any Ci_-6-alkyl as an amino substituent is optionally substituted with hydroxy, Ci_-6-alkoxy, amino, mono- and di(Ci-₆-alkyl)amino, carboxy, Ci-₆-alkylcarbonylamino, Ci-₆-alkylaminocarbonyl, or halogen(s), such as from hydrogen, optionally substituted Ci-₆-alkyl, hydroxy, optionally substituted Ci-₆-alkoxy, optionally substituted Ci-6-alkoxycarbonyl, optionally substituted Ci_-6-alkylcarbonyl, amino, Ci-e-alkylcarbonylamino, Ci_-6-alkyl- carbonylamino, Ci_-6-alkylsulphonylamino, mono- and di(Ci_-6-alkyl)aminosulfonyl, and mono- and di(Ci-₆-alkyl)amino, where any Ci-6-alkyl as an amino substituent is optionally substituted with hydroxy, Ci-6-alkoxy, amino, mono- and di(Ci-6- alkyl)amino, carboxy, Ci-e-alkylcarbonylamino, Ci-e-alkylaminocarbonyl, or halogen(s).

As an alternative to the above, R¹ and R² may in one embodiment together with the carbon atoms to which they are attached form a heterocyclic ring or a heteroaromatic ring; and in another embodiment, R¹ and R² may together with the carbon atoms to which they are attached form an aromatic ring or a carbocyclic ring.

Preferably, R¹, R², R³ and R⁴ are not all hydrogen.

In a currently highly preferred embodiment, R¹ and R² are both halogen, in particular, R¹ and R² are both fluoro. In a variant within this embodiment, R^N, R³ and R⁴ are all hydrogen.

It is believed that R^N may be selected from a wide variety of substituents including the prodrug groups (vii) and (viii). If not being a prodrug group, R^N may advantageous be selected from hydrogen, Ci-6-alkyl, amino, and Ci-6- alkylcarbonylamino. Most preferred is the variants wherein R^N is selected from hydrogen and Ci_-6-alkyl, in particular from hydrogen and methyl, most typical hydrogen.

In one currently preferred variant,

each of V¹, V², V³, and V⁴ represents a carbon atom; R¹ and R² are selected from halogen, Ci_-6-alkyl, Ci_-6-alkoxy, in particular both are fluoro;

R³ and R⁴ are both hydrogen;

R^N is hydrogen;

X represents a prodrug group (i), (ii) or (iv),

and other substituents are as defined herein-above.

In one particular embodiment, R¹ is selected from hydrogen, halogen, Ci_-6-alkyl, trifluoromethyl and Ci-e-alkoxy, when V¹ is a carbon atom.

In a further embodiment, R² is selected from hydrogen, halogen, Ci-e-alkoxy, optionally substituted aryl, optionally substituted aryloxy, and optionally substituted heteroaryl, when V² is a carbon atom.

In a still further embodiment, R³ is selected from hydrogen, optionally substituted Ci-e-alkoxy, halogen, cyano, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl, amino, Ci-6-alkylcarbony- lamino, Ci-₆-alkylsulphonylamino, and mono- and di(Ci-6-alkyl)aminosulfonyl, when V³ is a carbon atom.

In an even still further embodiment, R⁴ is hydrogen, when V⁴ is a carbon atom.

It should be understood that relevant feature of the compounds of the formula (I) include that the group E is not optionally substituted phenyl when r is 0,. Preferably, at least one of the substituents R¹, R², R³, and R⁴ is not hydrogen; and preferably at least two of the substituents R¹, R², R³, and R⁴ are not hydrogen.

It appears that the group E (as defined hereinabove) plays an important role for the optimization of the biological activity of the compounds. This being said, E is in one interesting embodiment selected from optionally substituted d-₁₂-alkyl, optionally substituted C_3-i₂-cycloalkyl, optionally substituted C₂-i₂-alkenyl, optionally substituted C₃-i2-cycloalkenyl, optionally substituted C₂-i₂-alkynyl, and optionally substituted heterocyclyl.

In one variant hereof, E is selected from Ci-i₂-alkyl, C₃-i2-cycloalkyl, C_2-I₂- alkenyl, C_3-i₂-cycloalkenyl, and C_2-i₂-alkynyl.

In another variant hereof, E is selected from optionally substituted C_3-I₂- cycloalkyl and optionally substituted heterocyclyl (e.g. piperidine and morpholine), in particular from C_3-i₂-cycloalkyl, heterocyclyl, and mono- substituted heterocyclyl.

Currently most preferred are those variants where E is selected from optionally substituted C_3-i₂-cycloalkyl, such as from cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

In another interesting embodiment, E is optionally substituted heteroaryl, in particular heteroaryl.

In a still further interesting embodiment, E is aryl or, alternatively, E is di- or tri- substituted aryl.

The orientation of the group E is also in part defined by the presence (r = 1) and type of the group D.

In one interesting embodiment, r is 1 and D is -CH₂-.

In another interesting embodiment, r is 0.

The atoms V¹, V², V³, and V⁴ define whether the ring is an aromatic or heteroaromatic ring. Besides an aromatic ring (a benzene ring), a plethora of aromatic rings are possible. In one particularly interesting embodiment, however, each of V¹, V², V³, and V⁴ represents a carbon atom (a benzene ring), or V³ represents a nitrogen atom and each of V¹, V², and V⁴ represents a carbon atom (a pyridine ring). In the currently most interesting embodiments, each of V¹, V², V³, and V⁴ represents a carbon atom {i.e. the ring is a benzene ring).

The substituents R¹ and R² of the substituents R¹, R², R³, and R⁴ seem to play a particular role.

Preferably, R¹ is selected from halogen, Ci_-6-alkyl, trifluoromethyl and Ci_-6- alkoxy, when V¹ is a carbon atom.

Also preferably, R² is selected from halogen, optionally substituted Ci_-6-alkyl, and optionally substituted Ci-e-alkoxy, when V² is a carbon atom.

Further, it is preferred that R³ is selected from hydrogen, optionally substituted Ci-₆-alkoxy, halogen, cyano, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl, amino, Ci_-6-alkylcarbonylamino, Ci_-6- alkylsulphonylamino, and mono- and di(Ci_-6-alkyl)aminosulphonyl, when V³ is a carbon atom.

Even further, it is preferred that R⁴ is hydrogen, when V⁴ is a carbon atom.

This being said, it is preferred that at least two of the substituents R¹, R², R³, and R⁴ are not hydrogen.

In one variant hereof, R³ and R⁴ are both hydrogen.

In a further variant hereof, none of R¹ and R² are hydrogen. In a particular variant, R¹ and R² are both selected from halogen and methyl. In a specific variant hereof, R¹ and R² are both fluoro.

Alternatively, R¹ and R² together with the carbon atoms to which they are attached form a ring selected from aromatic rings, carbocyclic rings, heterocyclic rings and heteroaromatic rings, in particular aromatic rings, heterocyclic rings and heteroaromatic rings

The Compounds of general formula (W)

It has been found that certain compounds wherein R³ and R⁴ are both hydrogen and wherein none of R¹ and R² are hydrogen represent a particularly interesting aspect of the present invention. Hence, the present invention also provides a compound of the general formula (W)

wherein the substituents and groups are as defined hereinabove, with the proviso that none of R¹ and R² are hydrogen. In the currently most interesting embodiments, each of V¹, V², V³, and V⁴ represents a carbon atom {i.e. the ring is a benzene ring).

Currently most preferred compounds

Presently very interesting compounds of the formulae (I) and (W) are those listed in the following :

4-(3-cyclohexyl-6,7-difluoro-2-oxoindolin-3-yl)phenyl dihydrogen phosphate, 4-(3-cycloheptyl-6,7-difluoro-2-oxoindolin-3-yl)phenyl dihydrogen phosphate, 4-(l-acetyl-3-cyclohexyl-6,7-difluoro-2-oxoindolin-3-yl)phenylacetate, 4-(l-acetyl-3-cycloheptyl-6,7-difluoro-2-oxoindolin-3-yl)phenylacetate, 4-(3-cyclohexyl-6,7-difluoro-2-oxoindolin-3-yl)phenyl sulfate, 4-(3-cyclohexyl-6-fluoro-7-methyl-2-oxoindolin-3-yl)phenyl dimethylcarbamate, 4-(3-cyclohexyl-6,7-difluoro-2-oxoindolin-3-yl)phenyl 2,2-dichloroacetate, 4-(3-cycloheptyl-6-methoxy-7-methyl-2-oxoindolin-3-yl)phenyl 2,2-dichloro- acetate,

4-(3-cycloheptyl-6-fluoro-7-methyl-2-oxoindolin-3-yl)phenyl dimethylcarbamate,

4-(3-cycloheptyl-6-methoxy-7-methyl-2-oxoindolin-3-yl)phenyl dimethylcarbamate, 4-(3-cycloheptyl-6-methoxy-7-methyl-2-oxoindolin-3-yl)pheπyl morpholine-4- carboxylate,

4-(3-cycloheptyl-6-methoxy-7-methyl-2-oxoindolin-3-yl)pheπyl 4-methyl- piperazine-1-carboxylate, 4-(3-cycloheptyl-6-methoxy-7-methyl-2-oxoindolin-3-yl)pheπyl dihydrogen- phosphate,

4-(3-cycloheptyl-6-fluoro-7-methyl-2-oxoindolin-3-yl)phenyl acrylate, 4-(3-cycloheptyl-6-fluoro-7-methyl-2-oxoindolin-3-yl)phenyl 3-morpholino- propanoate, 4-(3-cyclohexyl-6-fluoro-7-methyl-2-oxoindolin-3-yl)phenyl acrylate, 4-(3-cyclohexyl-6-fluoro-7-methyl-2-oxoindolin-3-yl)phenyl 3-morpholino- propanoate,

4-(3-cyclohexyl-6,7-difluoro-2-oxoindolin-3-yl)phenyl acrylate, 4-(3-cyclohexyl-6,7-difluoro-2-oxoindolin-3-yl)phenyl 3-morpholinopropanoate, 4-(3-cyclopentyl-6,7-difluoro-2-oxoindolin-3-yl)phenyl dimethylcarbamate , 4-(3-cyclopentyl-6,7-difluoro-2-oxoindolin-3-yl)phenyl morpholine-4- carboxylate,

4-(3-cyclohexyl-7-methyl-2-oxoindolin-3-yl)phenyl morpholiπe-4-carboxylate, 4-(3-cyclohexyl-7-methyl-2-oxoindolin-3-yl)phenyl dimethylcarbamate, 4-(3-cycloheptyl-7-methyl-2-oxoindolin-3-yl)phenyl dimethylcarbamate, 4-(3-cycloheptyl-7-methyl-2-oxoindolin-3-yl)phenyl morpholine-4-carboxylate, 4-(6-chloro-3-cycloheptyl-7-methyl-2-oxoindolin-3-yl)phenyl dimethylcarbamate,

4-(6-chloro-3-cycloheptyl-7-methyl-2-oxoindolin-3-yl)phenyl morpholine-4- carboxylate, 4-(3-cyclopentyl-6,7-difluoro-2-oxoindolin-3-yl)phenyl 4-methylpiperazine-l- carboxylate,

4-(7-chloro-3-cycloheptyl-6-methyl-2-oxoindolin-3-yl)phenyl dimethylcarbamate, 4-(7-chloro-3-cycloheptyl-6-methyl-2-oxoindolin-3-yl)phenyl morpholine-4- carboxylate,

4-(3-cyclohexyl-2-oxo-7-(trifluoromethyl)indolin-3-yl)phenyl dimethylcarbamate,

4-(3-cyclohexyl-2-oxo-7-(trifluoromethyl)indolin-3-yl)phenyl morpholine-4- carboxylate,

(2S)-4-(6,7-difluoro-2-oxo-3-(thiophen-2-yl)indolin-3-yl)phenyl 2- aminopropanoate hydrochloride,

(2S)-4-(6,7-difluoro-2-oxo-3-(thiophen-2-yl)indolin-3-yl)phenyl 2-amino-3- methylbutanoate hydrochloride, 4-(3-cycloheptyl-6-methoxy-7-methyl-2-oxoindolin-3-yl)pheπyl 2-aminoacetate

2,2,2-trifluoroacetate ,

(2S)-4-(3-cyclohexyl-6,7-dimethyl-2-oxoindolin-3-yl)phenyl 2-amino-3- phenylpropanoate hydrochloride,

(2S)-4-(3-cycloheptyl-6-methoxy-7-methyl-2-oxoindolin-3-yl)phenyl 2-amino-3- methylbutanoate hydrochloride,,

(2S)-4-(3-cycloheptyl-6-methoxy-7-methyl-2-oxoindolin-3-yl)phenyl 3-methyl-

2-(methylamino)butanoate hydrochloride,

4-(3-cycloheptyl-7-methyl-2-oxoindolin-3-yl)phenyl 2-(dimethylamino)acetate, and 4-(3-cycloheptyl-6-methoxy-7-methyl-2-oxoindolin-3-yl)pheπyl 2-

(dimethylamino)acetate.

Preparation of compounds

The compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods outline below and in the Examples section, together with methods known in the art of synthetic organic chemistry, or variations thereof as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below.

The novel compounds of formula (I) may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and suitable for the transformations being effected. Also, in the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature duration of experiment and work-up procedures, are chosen to be conditions of standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the educt molecule must be compatible with the reagents and reactions proposed. Not all molecules of formula (I) falling into a given class may be compatible with some of the reaction conditions required in some of the methods described. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternative methods can be used.

Compounds (I) according to the present invention in which X is an amino acid ester (Ia) may be prepared from phenols of general formula (II) by coupling with a protected amino acid and subsequent removal of the protecting groups, if any, to yield compounds of general formula (Ia). The condensation is carried out using any of the many methods for the formation of ester bonds known to one skilled in the art of organic synthesis. These methods include, but are not limited to, use of Standard coupling procedures such as use of symmetric carbonic anhydrides, mixed carbonic anhydride method (e.g. isobutyl chloroformate) method, carbodiimides (e.g. N,N-dimethylaminopropyl-N'-ethyl carbodiimide, dicyclohexyl carbodiimide, diisopropyl carbodiimide), active ester (e.g. pentaflurophenyl ester, p-nitrophenyl ester, N-hydroxysuccinic imido ester), carbonyldiimidazole method, azide method, phosphorous reagents such as BOP- Cl, conversion of the protected amino acid derivative into an acid chloride. Some of these methods (especially carbodiimide) can be enhanced by addition of e.g. 1-hydroxybenzotriazole or N,N-dimethylaminopyridine.

Protection groups as referred to above are well known per se, for example from the techniques of peptide chemistry. Amino groups can often be protected by tert-butyloxycarbonyl, benzyloxycarbonyl or acetyl groups, or in the form of a phtalimido group. Hydroxy groups are often protected as readily cleavable ethers such as the t-butyl or benzyl ether, or as readily cleavable esters such as the acetate. Carboxylic acid groups are often protected as readily cleavable esters such as the t-butyl or benzyl ester. Thiols are often protected as readily cleavable ethers such as the trityl ether.

(Ia) (Ib)

IF R⁷ and R⁸ are both alkylgroups or hydrogen, compounds of general formula (Ia) can be converted into the corresponding trialkylammonium salts (Ib), e.g. by reaction with an alkyl halide and a base or alkyl methane sulfonate.

(Ic)

Compounds (I) according to the present invention in which X is a phosphonate group or a phosphinate group (Ic) may be prepared from phenols of general formula (II) e.g. by condensation with a phosphonochloridate or a phosphinic chloride in the presence of a base. Alternatively, phenols of general formula (II) may be treated with dibenzyl phosphate in the presence of a base, followed by removal of the benzyl groups by hydrogenation.

Compounds (I) according to the present invention in which X is -OA-O(C=O)-B- R⁵ (Id) can be prepared form compounds of general (II), in which R^N is an amide protecting group {e.g. a silyl-type or benzyl type protecting group,) by reaction with a base and chloromethyl or iodomethyl esters of general formula (III), and subsequent removal of the amide protecting group (e.g. by use of fluoride ion or hydrogenation). The chloromethyl or iodomethyl esters of general formula (III) may be prepared as described in Bioorg. Med. Chem. Lett. (2005) 13 2491-2494.

Alternatively, compounds of general formula (Id) may prepared by similar methods to those described in Bioorg. Med. Chem. Lett. (2003) 1695-1698 after suitable protection of the amide group and subsequent removal of the protecting group, as described above.

Compounds (I) according to the present invention in which both R^N and X is -A- 0(C=O)-B-R⁵ (Ie) can be prepared form compounds of general (II) by reaction with a base of the right choice and chloromethyl or iodomethyl esters of general formula (III).

Compounds (I) according to the present invention in which R^N is-O-A-O(C=O)-B- R⁵, and X is hydrogen (If) can be prepared form compounds of general (II) by reaction with a base of the right choice, e.g. NaH, and chloromethyl or iodomethyl esters of general formula (XII). The phenolic group may require protection prior to derivatization of the amide function, e.g. with a Boc-group, a silyl ether or an acyl group, followed by deprotection as the last step.

^R

Compounds (I) according to the present invention in which X is -C(=O)O-A-B-R⁵ (Ig) can be prepared form compounds of general (II) by reaction with chloromethyl carbonochloridate and a base, e.g. potassium carbonate or caesium carbonate, and subsequent reaction of the resulting chloromethyl phenylcarbonate with an alcohol or a thiol and a base. Compounds according to the present invention (I) in which R^N is -(C=O)-O-A-B-R⁵ and X is -(C=O)O-A-B- R⁵ (Ih) can be prepared from compounds of general (II) as described above with a different choice of base, e.g. NaH.

Compounds (I) according to the present invention in which R^N is -(C=O)-O-A-B- R⁵ (Ii) can be prepared form phenols of general formula (II) by protection of the phenolic function, e.g. with a Boc-group, a silyl ether or an acyl group, reaction with chloromethyl carbonochloridate and a base, e.g. NaH, and subsequent reaction of the resulting chloromethyl 3,3-bis(phenyl)-2-oxoindoline-l- carboxylate with an alcohol or a thiol and a base, followed by removal of the protecting group(s).

Compounds (I) according to the present invention which are carbamates (Ij) can be prepared from phenols of general formula (II) by reaction with a carbamoyl chloride in the presence of a base. Alternatively, phenols of general formula (II) can be derivatized with 4-nitrophenyl chloroformate followed by reaction with an amine.

Compounds (I) according to the present invention which are diacetates (Ik) can be prepared by refluxing phenols of general formula (II) in acetic acid anhydride.

(H) (Ik)

Compounds (I) according to the present invention which are sulfates (II) can be prepared by treating phenols of general formula (II) with sulfuric acid and acetic acid anhydride in pyridine.

(H) (Im)

Compounds (I) according to the present invention which are dichloroacetates (Im) can be prepared by reaction of phenols of general formula (II) with dichloroacetyl chloride in the presence of a base.

Compounds (I) according to the present invention which are acrylates (In) can be prepared by reaction of phenols of general formula (II) with acryloyl chloride in the presence of a base. Compounds (I) which are 3-aminopropanoates (Io) can subsequently be obtained from acrylates of general formula (In) by reaction with an amine in the presence of a catalyst such as e.g. bismuth(III) trifluoromethanesulfonate.

Medical uses

The compounds of the general formulae (I) and (W) are believed to be particularly useful in the treatment of cancer. The term cancer is typically describing cell growth not under strict control. In one embodiment of the invention, treatment of cancers in which inhibition of protein synthesis and/or inhibition of activation of the mTOR pathway is an effective method for reducing cell growth. Examples of such cancers include, but are not limited to, breast cancer, renal cancer, multiple myeloma, leukemia, glioblastoma, rhabdomyosarcoma, prostate, soft tissue sarcoma, colorectal sarcoma, gastric carcinoma, head and neck squamous cell carcinoma, uterine, cervical, melanoma, lymphoma, and pancreatic cancer.

Any type of cell may be treated, including but not limited to, lung, gastrointestinal (including e.g. bowel, colon), breast (mammary), ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain and skin.

Hence, the present invention generally provides a compound of the general formula (I) or (W) as defined herein for use as a medicament; more particular, the use of a compound of the general formula (I) or (W) as defined herein for the preparation of a medicament for the treatment of cancer in a mammal. Such medicaments may further comprise one or more other chemotherapeutic agents.

Moreover, the present invention provides a method of treating a mammal suffering from or being susceptible to cancer, the method comprising administering to the mammal a therapeutically effective amount of a compound of the general formula (I) or (W) as defined herein.

Formulation of pharmaceutical compositions

The compounds of the general formulae (I) and (W) are suitably formulated in a pharmaceutical composition so as to suit the desirable route of administration.

The administration route of the compounds may be any suitable route which leads to a concentration in the blood or tissue corresponding to a therapeutic effective concentration. Thus, e.g., the following administration routes may be applicable although the invention is not limited thereto: the oral route, the parenteral route, the cutaneous route, the nasal route, the rectal route, the vaginal route and the ocular route. It should be clear to a person skilled in the art that the administration route is dependent on the particular compound in question; particularly the choice of administration route depends on the physico- chemical properties of the compound together with the age and weight of the patient and on the particular disease or condition and the severity of the same.

The compounds may be contained in any appropriate amount in a pharmaceutical composition, and are generally contained in an amount of about 1-95%, e.g. 1-10%, by weight of the total weight of the composition. The composition may be presented in a dosage form which is suitable for the oral, parenteral, rectal, cutaneous, nasal, vaginal and/or ocular administration route. Thus, the composition may be in form of, e.g., tablets, capsules, pills, powders, granulates, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, drenches, delivery devices, suppositories, enemas, injectables, implants, sprays, aerosols and in other suitable form. The pharmaceutical compositions may be formulated according to conventional pharmaceutical practice, see, e.g., "Remington's Pharmaceutical Sciences" and "Encyclopedia of Pharmaceutical Technology", edited by Swarbrick, J. & J. C. Boylan, Marcel Dekker, Inc., New York, 1988. Typically, the compounds defined herein are formulated with (at least) a pharmaceutically acceptable carrier or excipient. Pharmaceutically acceptable carriers or excipients are those known by the person skilled in the art. Formation of suitable salts of the compounds of the Formulae (I) and (W) will also be evident in view of the before-mentioned.

Thus, the present invention provides in a further aspect a pharmaceutical composition comprising a compound of the general Formula (I) or (W) in combination with a pharmaceutically acceptable carrier.

Pharmaceutical compositions according to the present invention may be formulated to release the active compound substantially immediately upon administration or at any substantially predetermined time or time period after administration. The latter type of compositions is generally known as controlled release formulations.

In the present context, the term "controlled release formulation" embraces i) formulations which create a substantially constant concentration of the drug within the body over an extended period of time, ii) formulations which after a predetermined lag time create a substantially constant concentration of the drug within the body over an extended period of time, iii) formulations which sustain drug action during a predetermined time period by maintaining a relatively, constant, effective drug level in the body with concomitant minimization of undesirable side effects associated with fluctuations in the plasma level of the active drug substance (saw-tooth kinetic pattern), iv) formulations which attempt to localize drug action by, e.g., spatial placement of a controlled release composition adjacent to or in the diseased tissue or organ, v) formulations which attempt to target drug action by using carriers or chemical derivatives to deliver the drug to a particular target cell type. Controlled release formulations may also be denoted "sustained release", "prolonged release", "programmed release", "time release", "rate-controlled" and/or "targeted release" formulations.

Controlled release pharmaceutical compositions may be presented in any suitable dosage forms, especially in dosage forms intended for oral, parenteral, cutaneous nasal, rectal, vaginal and/or ocular administration. Examples include single or multiple unit tablet or capsule compositions, oil solutions, suspensions, emulsions, microcapsules, microspheres, nanoparticles, liposomes, delivery devices such as those intended for oral, parenteral, cutaneous, nasal, vaginal or ocular use.

Preparation of solid dosage forms for oral use, controlled release oral dosage forms, fluid liquid compositions, parenteral compositions, controlled release parenteral compositions, rectal compositions, nasal compositions, percutaneous and topical compositions, controlled release percutaneous and topical compositions, and compositions for administration to the eye will be well-known to those skilled in the art of pharmaceutical formulation. Specific formulations can be found in "Remington's Pharmaceutical Sciences".

Capsules, tablets and pills etc. may contain for example the following compounds: microcrystalline cellulose, gum or gelatin as binders; starch or lactose as excipients; stearates as lubricants; various sweetening or flavouring agents. For capsules the dosage unit may contain a liquid carrier like fatty oils. Likewise coatings of sugar or enteric agents may be part of the dosage unit. The pharmaceutical compositions may also be emulsions of the compound(s) and a lipid forming a micellular emulsion.

For parenteral, subcutaneous, intradermal or topical administration the pharmaceutical composition may include a sterile diluent, buffers, regulators of tonicity and antibacterials. The active compound may be prepared with carriers that protect against degradation or immediate elimination from the body, including implants or microcapsules with controlled release properties. For intravenous administration the preferred carriers are physiological saline or phosphate buffered saline.

Dosages

In one embodiment, the pharmaceutical composition is in unit dosage form. In such embodiments, each unit dosage form typically comprises 0.1-500 mg, such as 0.1-200 mg, e.g. 0.1-100 mg, of the compound.

More generally, the compound are preferably administered in an amount of about 0.1-250 mg per kg body weight per day, such as about 0.5-100 mg per kg body weight per day.

For compositions adapted for oral administration for systemic use, the dosage is normally 0.5 mg to 1 g per dose administered 1-4 times daily for 1 week to 12 months depending on the disease to be treated.

The dosage for oral administration of the composition in order to prevent diseases or conditions is normally 1 mg to 100 mg per kg body weight per day. The dosage may be administered once or twice daily for a period starting 1 week before the exposure to the disease until 4 weeks after the exposure.

For compositions adapted for rectal use for preventing diseases, a somewhat higher amount of the compound is usually preferred, i.e. from approximately 1 mg to 100 mg per kg body weight per day.

For parenteral administration, a dose of about 0.1 mg to about 100 mg per kg body weight per day is convenient. For intravenous administration, a dose of about 0.1 mg to about 20 mg per kg body weight per day administered for 1 day to 3 months is convenient. For intraarticular administration, a dose of about 0.1 mg to about 50 mg per kg body weight per day is usually preferable. For parenteral administration in general, a solution in an aqueous medium of 0.5- 2% or more of the active ingredients may be employed. For topical administration on the skin, a dose of about 1 mg to about 5 g administered 1-10 times daily for 1 week to 12 months is usually preferable.

Combination treatment

In an intriguing embodiment of the present invention, the compound of the general formula (I) or (W) is used therapeutically in combination with one or more other chemotherapeutic agents. Examples of such chemotherapeutic agents are those selected from daunorubicin, docetaxel, prednisone, dexamethasone, decadron, altretamine, amifostine, aminoglutethimide, dactinomycin, anastrozole, asparaginase, bicalutamide, bleomycin, busulfan, carboplatin, carmustine, chlorambucil, chlorodeoxyadenosine, cisplatin, cytosine arabinoside, dacarbazine, doxorubicin, epirubicin, estramustine, diethylstilbestrol, fludarabine, flutamide, 5-fluorouracil, gemcitabine, goserelin, idarubicin, irinotecan, levamisole, lomustine, mechlorathamine, alkeran, mercaptopurine, taxol (e.g. paclitaxel). In particular, the further chemotherapeutic agent is selected from taxanes such as Taxol, Paclitaxel and Docetaxel.

Thus, with respect to the use and the method of treatment defined herein, the medicament may further comprise one or more other chemotherapeutic agents.

EXPERIMENTALS

General Procedures, Preparations and Examples

For nuclear magnetic resonance ¹H NMR spectra (300 MHz, unless otherwise specified) and ¹³C NMR (75.6) chemical shift values (δ) (in ppm) are quoted, unless otherwise specified, for deuteriochloroform solutions relative to tetramethylsilane (δ= 0.0) or chloroform (δ = 7.25) or deuteriochloroform (δ = 76.81 for ¹³C NMR) standards. The value of a multiplet, either defined (dublet (d), triplet (t), double dublet (dd), double triplet (dt), quartet (q)) or not (m) at the approximate mid point is given unless a range is quoted , (bs) indicates a broad singlet.

MS was performed using an LC-MS using a Bruker Esquire 3000+ ESI Iontrap with an Agilent 1200 HPLC-system . Melting points are uncorrected .

The organic solvents used were anhydrous.

The following abbreviations have been used throughout:

CDI 1,1 ^' -carbonyldiimidazole

DCM dichloromethane

DCE 1,2-dichloroethane DIEA diisopropylehylamine

DMF /V_z/V-dimthylformamide

DMAP N, N dimethylaminopryridine

EDC Λ/-(dimethylaminopropyl)-N ^' -ethylcarbodiimide hydrochloride

EtOAc ethyl acetate FC flash chromatography

HATU 0-(7-Azabenzotriazol-l-yl)-Λ/,Λ/,Λ/',Λ/'-tetramethyluronium hexafluorophosphate

HOBt 1-hydroxybenzotriazole

M. p. melting point MS mass spectroscopy

NMM Λ/-methylmorpholine

NMR nuclear magnetic resonance rt room temperature

TFA trifluoroacetic acid THF tetrahydrofurane

TLC thin layer chromatography

General Procedure 1 : Formation of phosphate esters (Ic¹) from phenols of general formula (U). A multi-necked round-bottom flask containing a stir bar was oven-dried, fitted with septa, a thermometer, and an Argon inlet. The flask was charged with phenol of general formula (II) (1.0 eq.) and anhydrous CH₃CN. The mixture was stirred to dissolve the phenol, cooled to -17⁰C, and CCI₄ (5.0 eq.), (J-Pr)₂NEt (2.1 eq.), DMAP (0.1 eq.) were added. One minute later, a drop-wise addition of HPO(OBn)₂ (1.5 eq.) was begun. The reaction was exothermic and it was controlled by the addition rate; the internal temperature was kept below -1O⁰C. The reaction mixture was stirred for approx. Ih (control by TLC, CH₂CI₂-EtOH, 10: 0.5), 0.5M aq. KH₂PO₄ (8 ml) was added, and the mixture was allowed to warm to room temperature. The mixture was extracted three times with EtOAc. The combined organic phase was washed with H₂O and brine, dried over Na₂SO₄, and concentrated. The product was purified by column chromatography using system CH₂CI₂-EtOH (100:0.5) to afford the benzyl protected phosphate ester.

The benzyl protected phosphate ester (1 eq.) was dissolved in EtOH and 10% Pd-C (12 mg per mmol phenol) was added. The reaction mixture was stirred under H₂ atmosphere until consumption of starting material. The reaction mixture was filtered and the filtrate concentrated in vacuo. The desired product was purified by column chromatography with CHCI₃-MeOH-H₂O (60: 20 : 1) as eluent to afford phosphate ester of general formula (Ic).

General Procedure 2: Formation of carbamates of general formula (Ii) from phenols of general formula (II).

A mixture of phenol of general formula (II) (1.0 eq.), DMAP (0.2 eq.), NEt₃ (2.7 eq.), and the carbamoyl chloride (1.1 eq.) in THF was refluxed overnight. The precipitate was filtered off, the filtrate was concentrated, the residue was dissolved in DCM, washed with brine, dried (MgSO₄) and concentrated. The residue was purified by chromatography (1% methanol in DCM or mixtures of petroleum ether and EtOAc) to afford carbamates of general formula (Ij).

General Procedure 3: Formation of carbamates of general formula (Ii) from phenols of general formula (II). Phenol of general formula (II) (1.0 eq.) was dissolved in THF, cooled on an ice bath under N₂, 4-nitrophenyl chloroformate (1.2 eq.) and NEt₃ (1.2 eq.) were added with stirring, and the mixture gradually allowed to reach rt and stirred overnight. The precipitate was filtered off, the filtrate concentrated, the residue was dissolved in EtOAc, washed 4 times with H₂O, brine, dried (MgSO₄) and concentrated. The resulting 4-nitrophenylcarbonate was dissolved in DMF, the amine (2 eq.) and NEt₃ (20 eq.) were added with stirring and the mixture stirred at rt overnight and concentrated. The residue was purified by chromatography (1% methanol in DCM or mixtures of petroleum ether and EtOAc) to afford carbamates of general formula (Ij).

General Procedure 4: Formation of diacetates of general formula (Ik) from phenols of general formula (IY).

A mixture of phenol of general formula (II) (0.58 mmol) and Ac₂O (0.5 ml) was refluxed for 1 h and poured onto ice (10 g). The obtained mixture was extracted with EtOAc (2 x 35 ml), washed with brine, and dried (Na₂SO₄). The extract was concentrated and the residue was crystallized from MeOH (15 ml) to give the aceate of general formula (Ik).

General Procedure 5: Formation of sulfates of general formula (II) from phenols of general formula (II).

Sulfuric acid (0.21 ml_, 3.96 mmol) and acetic anhydride (0.37 ml_, 3.96 mmol) were added to dry pyridine (3.1 ml_). After 5 min stirring at 50-55⁰C, phenol of general formula (II) (0.66 mmol) was added and the mixture was stirred for 30 min upon the same conditions. The reaction mixture was concentrated and the residue was purified by chromatography (CH₃CN-Et₃N 98: 2) to yield the triethylammonium salt of sulfate of general formula (II). The triethylammonium salt was dissolved in a H₂O-EtOH (8: 2, 10 ml) mixture and percolated through a Dowex 50Wx2 (Na⁺ form) column with H₂O-EtOH (8: 2) as eluent to give sulfate of general formula (II) as a sodium salt. General Procedure 6: Formation of dichloroacetates of general formula (ImI from phenols of general formula (II).

To a solution of phenol of general formula (II) (1.0 eq.), triethylamine (3.0 eq.), and 4-dimethylaminopyridine (0.2 eq.) in THF at -18°C dichloroacetyl chloride (1.1 eq.) was added. The reaction mixture was stirred overnight allowing gradua warm up to room temperature, filtrated and the filtrate was concentrated. The residue was purified by reversed phase FC with CH₃CN-H₂O (gradient from 20 to 100%) as eluent to give to give dichloroacetate of general formula (Im).

General Procedure 7: Formation of acrylates of general formula (In) from phenols of general formula (II).

To a solution of phenol of general formula (II) (1.0 eq.) and triethylamine (3.2 eq.) in DCM at ice bath temperature acryloyl chloride (1.04 eq.l) was added and the resulting mixture was stirred at this temperature for 3 h. The reaction mixture was supplemented with dichloromethane, washed with brine, and dried (Na₂SO₄). The solvent was evaporated and the residue was purified by chromatography (mixtures of petroleum ether and EtOAc: DCM 1 : 1) to give acrylate of general formula (In).

General Procedure 8: Formation of 3-aminopropanoates of general formula (Io) from acrylates of general formula (In).

To a solution of acrylate of general formula (In) (1.0 eq.) in dry acetonitrile amine R⁷R⁸NH (1.08 eq.) followed by bismuth(III) trifluoromethanesulfonate (0.02 e.q) were added and the reaction mixture was stirred overnight at room temperature. The precipitated solid was filtered, crystallized from acetonitrile, and dried to give aminopropanoate of general formula (Io).

General Procedure 9: Formation of BOC-protected amino acid ester derivatives from phenols of general formula (II). The phenol of general formula (II) (1 eq.) and the BOC-protected amino acid (1.3 eq.) were dissolved in DCM, EDC (1.5 eq.) and DMAP (catalytic amount) were added with stirring and the mixture was left at room temperature overnight, and concentrated. The residue was purified by chromatography (1% methanol in DCM or mixtures of petroleum ether and EtOAc) to afford BOC- protected amino acid ester derivatives from phenols of general formula (II).

General Procedure 10: Removal of BOC-protectinq group from BOC-protected amino acid ester derivatives of phenols of general formula (H) using HCI to yield compounds of general formula (Ia).

The BOC-protected amino acid ester derivative of phenol of general formula (II) was dissolved in methanol and HCI in methanol (3 N) was added. When TLC showed no remaining starting material the mixture was concentrated and if necessary purified by crystallization to afford compounds of general formula (Ia).

General Procedure 11 : Removal of BOC-protecting group from BOC-protected amino acid ester derivatives of phenols of general formula (II) using TFA to yield compounds of general formula (Ia).

The BOC-protected amino acid ester derivative of phenol of general formula (II) was dissolved in TFA. After 30 minutes the mixture was concentrated twice with toluene and if necessary purified by crystallization to afford compounds of general formula (Ia).

General Procedure 12: Formation of Λ/,Λ/-dimethylamino acid esterdehvatives from phenols of general formula (II).

The phenol of general formula (II) (1.0 eq.) and the /V_z/V-dimethylamino acid (2.8 eq.) were dissolved in DMF, EDC (3.25 eq.) and DMAP (1.0 eq) were added with stirring. The mixture was stirred at room temperature overnight, concentrated, extracted with EtOAc/H₂O. The aqueous layer was back-extracted twice with EtOAc, and the combined organic layers were washed with brine, dried (MgSO₄) and concentrated. The residue was purified by crystallization to afford compound of general formula (Ia).

Preparation 1 : (2S>4-(6,7-difluoro-2-oxo-3-(thiophen-2-y0indolin-3-y0phenyl 2-(terf-butoxycarbonylamino')propanoate (compound 1).

General procedure 9. Starting materials: 6,7-difluoro-3-(4-hydroxyphenyl)-3- (thiophen-2-yl)indolin-2-one (see, e.g. WO/2008/129075) and N-{tert- butoxycarbonyl)-L-alanine.

¹H-NMR (CDCI₃): δ 7.93 (bs, IH), 7.29 (m, 2H), 7.06 (m, 5H), 6.99 (m, IH), 6.90 (m, IH), 5.05 (d, IH), 4.52 (m, IH), 1.52 (d, 3H), 1.45 (s, 9H).

Preparation 2: (2S>4-(6,7-difluoro-2-oxo-3-(thiophen-2-y0indolin-3-y0phenyl 2-(terf-butoxycarbonylaminoV3-methylbutanoate (compound 2).

General procedure 9. Starting materials: 6,7-difluoro-3-(4-hydroxyphenyl)-3- (thiophen-2-yl)indolin-2-one (see, e.g. WO/2008/129075) and N-{tert- butoxycarbonyl)-L-valine.

¹H-NMR (CDCI₃): δ 8.04 (bs, IH), 7.24 (m, 2H), 7.02 (m, 5H), 6.95 (m, IH), 6.85 (m, IH), 5.08 (d, IH), 4.43 (m, IH), 2.28 (m, IH), 1.44 (s, 9H), 1.03 (d, 3H), 0.97 (d, 3H).

Preparation 3: 4-(3-cvcloheptyl-6-methoxy-7-methyl-2-oxoindolin-3-yπphenyl 2-(terf-butoxycarbonylamino')acetate (compound 1003).

General procedure 9. Starting material : 3-cycloheptyl-3-(4-hydroxyphenyl)-6- methoxy-7-methylindolin-2-one (see, e.g. WO/2008/129075) and N-{tert- butoxycarbonyl)-glycine.

¹H-NMR (CDCI₃): δ 9.06 (bs, IH), 7.45 (m, 2H), 7.09 (d, IH), 7.01 (m, 2H), 6.57 (d, IH), 5.14 (t, IH), 4.14 (d, 2H), 3.85 (s, 3H), 2.62 (m, IH), 2.11 (s, 3H), 1.8-1.2 (m, 20H), 0.89 (m, IH).

Preparation 4: (2S>4-(3-cvclohexyl-6,7-dimetyl-2-oxoindolin-3-y0phenyl 2- (terf-butoxycarbonylamino>3-phenylpropanoate (compound 1004).

General procedure 9. Starting material : 3-cyclohexyl-3-(4-hydroxyphenyl)-6,7- dimethylindolin-2-one (see, e.g. WO/2008/129075) and N-(tert- butoxycarbonyl)-L-phenylalanine.

¹H-NMR (CDCI₃): δ 9.21 (bs, IH), 7.49 (m, 2H), 7.27 (m, 5H), 7.09 (m, IH), 6.92 (m, 3H), 5.10 (d, IH), 4.81 (m, 2H), 3.22 (d, 2H), 2.46 (m, IH), 2.32 (s, 3H), 2.17 (s, 3H), 1.58 (m, 5H), 1.44 (s, 9H), 1.4-0.85 (m, 4H), 0.74 (m, IH).

Preparation 5: (2SV4-(3-cvcloheptyl-6-methoxy-7-methyl-2-oxoindolin-3- vQphenyl 2-(terf-butoxycarbonylamino>3-methylbutanoate (compound 1005).

General procedure 9. Starting material : 3-cycloheptyl-3-(4-hydroxyphenyl)-6- methoxy-7-methylindolin-2-one (see, e.g. WO/2008/129075) and N-{tert- butoxycarbonyl)-L-valine.

¹H-NMR (CDCI₃): δ 8.96 (bs, IH), 7.46 (m, 2H), 7.09 (d, IH), 7.01 (m, 2H), 6.57 (d, IH), 5.10 (d, IH), 4.43 (m, IH), 3.86 (s, 3H), 2.63 (m, IH), 2.29 (m, IH), 2.12 (s, 3H), 1.8-1.2 (m, 20H), 1.05 (d, 3H), 1.00 (d, 3H), 0.89 (m, IH). Preparation 6: (2SV4-(3-cycloheptyl-6-methoxy-7-methyl-2-oxoindolin-3- yQphenyl 2-(terf-butoxycarbonyl(methv0amino^')-3-methylbutanoate (compound 10061.

General procedure 9. Starting material : 3-cycloheptyl-3-(4-hydroxyphenyl)-6- methoxy-7-methylindolin-2-one (see, e.g. WO/2008/129075) and N-(tert- butoxycarbonyl)-Λ/-methyl-L-valine.

¹H-NMR (CDCI₃): δ 8.63 (bs, IH), 7.45 (d, 2H), 7.09 (d, IH), 7.00 (d, 2H), 6.57 (d, IH), 4.44 (dd, IH), 3.86 (s, 3H), 2.91 (d, 3H), 2.63 (m, IH), 2.29 (m, IH), 2.11 (s, 3H), 1.75-1.2 (m, 20H), 1.08 (d, 3H), 0.96 (d, 3H), 0.87 (m, IH).

Examples

Example 1 : 4-(3-cyclohexyl-6,7-difluoro-2-oxoindolin-3-yQphenyl dihvdroqen phosphate (compound 1001).

General procedure 1. Starting material : 3-cyclohexyl-6,7-difluoro-3-(4- hydroxyphenyl)indolin-2-one (see, e.g. WO 2008/129075).

¹H-NMR (200 MHz, DMSOd₆) : δ 11.01 (bs, IH), 7.57-6.65 (m, 6H), 2.36 (m, IH), 1.85-0.57 (m, 10H). M. p. : 209-210⁰C (dec.) Example 2: 4-(3-cycloheptyl-6.7-difluoro-2-oxoindolin-3-y0phenyl dihydroαen phosphate (compound 1002V

General procedure 1. Starting material : 3-cycloheptyl-6,7-difluoro-3-(4- hydroxyphenyl)indolin-2-one (see, e.g. WO 2008/129075).

¹H-NMR (200 MHz, DMSOd₆): δ 11.09 (bs, IH), 7.28-6.81 (m, 6H), 2.3-2.7 (m, IH), 1.72-1-1.09 (m, HH), 0.98-0.71 (m, IH). M. p. : 245-247°C (dec.)

Example 3: 4-(l-acetyl-3-cvclohexyl-6,7-difluoro-2-oxoindolin-3- vQphenylacetate (compound 1003V

General procedure 4. Starting material : 3-cyclohexyl-6,7-difluoro-3-(4- hydroxyphenyl)indolin-2-one (see, e.g. WO 2008/129075).

¹H-NMR (200 MHz, DMSO-d₆) : δ 7.26 (d, 2H), 7.49-7.25 (m, 2H), 7.13 (d, 2H), 2.62 (s, 3H), 2.60 (m, IH), 2.25 (s, 3H), 1.80-0.87 (m, 9H), 0.87-0.61 (m, IH). M. p. : 162-164°C Example 4: 4-(l-acetyl-3-cvcloheptyl-6.7-difluoro-2-oxoindolin-3- vDphenylacetate (compound 1004).

General procedure 4. Starting material : 3-cycloheptyl-6,7-difluoro-3-(4- hydroxyphenyl)indolin-2-one (see, e.g. WO 2008/129075).

¹H-NMR (200 MHz, DMSOd₆): δ 7.34 (d, 2H), 7.49-7.26 (m, 2H), 7.13 (d, 2H), 2.88-2.66 (m, IH), 2.61 (s, 3H), 2.25 (s, 3H), 1.78-1.19 (m, HH), 1.03-0.76 (m, IH). M. p. : 158-159°C

Example 5: 4-(3-cvclohexyl-6,7-difluoro-2-oxoindolin-3-vhphenyl sulfate (compound 1005).

General procedure 5. Starting material : 3-cyclohexyl-6,7-difluoro-3-(4- hydroxyphenyl)indolin-2-one (see, e.g. WO 2008/129075).

¹H-NMR (200 MHz, DMSO-d₆): δ 11.7-10.5 (bs, IH), 7.22 (d, 2H), 7.10 (d, 2H), 7.29-6.91 (m, 2H), 2.60-2.40 (m, IH), 1.88-0.58 (m, 10 H).

LC ES^" MS (m/z): 422 [M-Na +⁺ 1]- Example 6: 4-(3-cvclohexyl-6-fluoro-7-methyl-2-oxoindolin-3-v0phenyl dimethylcarbamate (compound 1006).

General procedure 2. Starting materials: dimethylcarbamoyl chloride and 3- cyclohexyl-6-fluoro-3-(4-hydroxyphenyl)-7-methyl-indolin-2-one (see, e.g. WO 2008/129075).

¹H-NMR (200 MHz, DMSOd₆) : δ 10.77 (s, IH), 7.33 (d, 2H), 7.19 (dd, IH), 7.05 (d, 2H), 6.83 (dd, IH), 3.01 (s, 3H), 2.89 (s, 3H), 2.39 (m, IH), 2.15 (d, 3H), 1.85-0.60 (m, 1OH).

Example 7: 4-(3-cvclohexyl-6.7-difluoro-2-oxoindolin-3-vπphenyl 2,2- dichloroacetate (compound 1007).

General procedure 6. Starting materials: 3-cyclohexyl-6,7-difluoro-3-(4- hydroxyphenyl)indolin-2-one (see, e.g. WO 2008/129075).

¹H-NMR (200 MHz, CDCI3) : δ 7.90 (bs, IH), 7.46 (d, 2H), 7.13 (d, 2H), 7.13- 7.03 (m, IH), 6.93 (dt, IH), 6.13 (s, IH), 2.48 (m, IH), 1.81-1.43 (m, 5H), 1.43-0.85 (m, 4H), 0.85-0.57 (m, IH). M. p. : 228-230⁰C Example 8: 4-(3-cvcloheptyl-6-methoxy-7-methyl-2-oxoindolin-3-vQphenyl 2.2- dichloroacetate (compound 1008).

General procedure 6. Starting materials: 3-cycloheptyl-3-(4-hydroxyphenyl)-6- methoxy-7-methylindolin-2-one (see, e.g. WO 2008/129075).

¹H-NMR (200 MHz, DMSOd₆) : δ 10.53 (s, IH), 7.42 (d, 2H), 7.18 (d, 2H), 7.15 (s, IH), 7.12 (d, IH), 6.64 (d, IH), 3.80 (s, 3H), 2.64-2.37 (m, IH), 2.06 (s, 3H), 1.76-1.20 (m, HH), 1.01-0.76 (m, IH).

Example 9: 4-(3-cvdoheptyl-6-fluoro-7-methyl-2-oxoindolin-3-vQphenyl dimethylcarbamate (compound 1009).

General procedure 2. Starting materials: dimethylcarbamoyl chloride and 3- cycloheptyl-6-fluoro-3-(4-hydroxyphenyl)-7-methylindolin-2-one (see, e.g. WO 2008/129075).

¹H-NMR (200 MHz, DMSO-d₆) : δ 10.75 (s, IH), 7.30 (d, 2H), 7.16 (dd, IH), 7.05 (d, 2H), 6.83 (dd, IH), 3.02 (s, 3H), 2.89 (s, 3H), 2.57 (m, IH), 2.16 (d, 3H), 1.72-1.18 (m, HH), 1.00-0.75 (m, IH). Example 10: 4-(3-cycloheptyl-6-methoxy-7-methyl-2-oxoindolin-3-vπphenyl dimethylcarbamate (compound IQlCO.

General procedure 2. Starting materials: dimethylcarbamoyl chloride and 3- cycloheptyl-3-(4-hydroxyphenyl)-6-methoxy-7-methylindolin-2-one (see, e.g. WO 2008/129075).

¹H-NMR (200 MHz, DMSOd₆) : δ 10.48 (s, IH), 7.30 (d, 2H), 7.09 (dd, IH), 7.03 (d, 2H), 6.63 (d, IH), 3.79 (s, 3H), 3.01 (s, 3H), 2.89 (s, 3H), 2.61-2.41 (m, IH), 2.06 (s, 3H), 1.76-1.12 (m, HH), 1.00-0.72 (m, IH). M. p. : 264-264.5°C

Example 11 : 4-(3-cycloheptyl-6-methoxy-7-methyl-2-oxoindolin-3-v0phenyl morpholine-4-carboxylate (compound 1011).

General procedure 2. Starting materials: 4-morpholinecarbonylchloride and 3- cycloheptyl-3-(4-hydroxyphenyl)-6-methoxy-7-methylindolin-2-one (see, e.g. WO 2008/129075).

¹H-NMR (CDCI₃): δ 9.19 (bs, IH), 7.42 (d, 2H), 7.08 (d, IH), 7.02 (d, 2H), 6.56 (d, IH), 3.85 (s, 3H), 3.73 (m, 4H), 3.60 (m, 4H), 2.62 (m, IH), 2.11 (s, 3H), 1.75-1.15 (m, 12H).

MS [MH-H] ⁺ = 478.3. Example 12: 4-(3-cvcloheptyl-6-methoxy-7-methyl-2-oxoindolin-3-y0phenyl 4- methylpiperazine-1-carboxylate (compound 1012).

General procedure 3. Starting materials: 4-methylpiperazine and 3-cycloheptyl- 3-(4-hydroxyphenyl)-6-methoxy-7-methylindolin-2-one (see, e.g. WO 2008/129075).

¹H-NMR (CDCI₃): δ 8.68 (bs, IH), 7.40 (d, 2H), 7.08 (d, IH), 7.00 (d, 2H), 6.56 (d, IH), 3.85 (s, 3H), 3.67 (m, 4H), 2.62 (m, IH), 2.57 (m, 4H), 2.41 (s, 3H), 2.11 (s, 3H), 1.75-1.2 (m, HH), 0.87 (m, IH).

MS [MH-H] ⁺ = 492.3.

Example 13: 4-(3-cvcloheptyl-6-methoxy-7-methyl-2-oxoindolin-3-y0phenyl dihvdroqenphosphate (compound 1013^.

General procedure 1. Starting material : 3-cycloheptyl-3-(4-hydroxyphenyl)-6- methoxy-7-methylindolin-2-one (see, e.g. WO 2008/129075).

¹H-NMR (DMSO-de) : δ 10.40 (bs, IH), 7.15-6.95 (m, 5H), 6.60 (d, IH), 3.78 (s, 3H), 2.57 (m, IH), 2.05 (s, 3H), 1.7-1.15 (m, HH), 0.84 (m, IH). MS [MH-H] ⁺ = 446.1 [M-H]^"= 445.2

Example 14: 4-(3-cycloheptyl-6-fluoro-7-methyl-2-oxoindolin-3-yQphenyl acrylate (compound 1014).

General procedure 7. Starting material : 3-cycloheptyl-6-fluoro-3-(4- hydroxyphenyl)-7-methylindolin-2-one (see, e.g. WO 2008/129075).

¹H-NMR (200 MHz, DMSOd₆) : δ 10.77 (s, IH), 7.35 (d, 2H), 7.17 (dd, IH), 7.13 (d, 2H), 6.83 (dd, IH), 6.51 (dd, IH), 6.38 (dd, IH), 6.14 (dd, IH), 2.57 (m, IH), 2.15 (s, 3H), 1.74-1.12 (m, HH), 1.02-0.71 (m, IH).

Example 15: 4-(3-cycloheptyl-6-fluoro-7-methyl-2-oxoindolin-3-yQphenyl 3- morpholinopropanoate (compound 1015).

General procedure 8. Starting materials: compound 1014 and morpholine.

¹H-NMR (200 MHz, DMSOd₆) : δ 10.75 (s, IH), 7.34 (d, 2H), 7.17 (dd, IH), 7.06 (d, 2H), 6.83 (dd, IH), 3.64-3.50 (m, 4H), 2.79-2.46 (m, 5H), 2.46-2.34 (m, 4H), 2.16 (d, 3H), 1.73-1.19 (m, HH), 1.00-0.76 (m, IH). Example 16: 4-(^r3-cyclohexyl-6-fluoro-7-methyl-2-oxoindolin-3-vnphenyl acrylate (compound 1016).

General procedure 7. Starting material : 3-cyclohexyl-6-fluoro-3-(4- hydroxyphenyl)-7-methylindolin-2-one (see, e.g. WO 2008/129075).

¹H-NMR (200 MHz, DMSOd₆) : δ 10.80 (s, IH), 7.39 (d, 2H), 7.21 (dd, IH), 7.14 (d, 2H), 6.84 (dd, IH), 6.52 (dd, IH), 6.39 (dd, IH), 6.14 (dd, IH), 2.40 (m, IH), 2.16 (d, 3H), 1.79-0.61 (m, 1OH). M. p. 233-234°C.

Example 17: 4-(3-cyclohexyl-6-fluoro-7-methyl-2-oxoindolin-3-yQphenyl 3- morpholinopropanoate (compound 1017).

General procedure 8. Starting materials: compound 1016 and morpholine.

¹H-NMR (200 MHz, DMSOd₆) : δ 10.80 (s, IH), 7.38 (d, 2H), 7.20 (dd, IH), 7.07 (d, 2H), 6.84 (dd, IH), 3.64-3.50 (m, 4H), 2.79-2.58 (m, 4H), 2.47-2.30 (m, 5H), 2.16 (d, 3H), 1.80-0.61 (m, 1OH). Example 18: 4-(3-cvclohexyl-6.7-difluoro-2-oxoindolin-3-y0phenyl acrylate (compound 1018).

General procedure 7. Starting material : 3-cyclohexyl-6,7-difluoro-3-(4- hydroxyphenyl)-indolin-2-one (see, e.g. WO 2008/129075).

¹H-NMR (200 MHz, CDCI₃) : δ 7.53 (bs, IH), 7.42 (d, 2H), 7.08 (d, 2H), 7.13- 7.02 (m, IH), 6.92 (ddd, IH), 6.58 (dd, IH), 6.30 (dd, IH), 6.00 (dd, IH), 2.49 (m, IH), 1.79-0.59 (m, 1OH).

Example 19: 4-(3-cvclohexyl-6.7-difluoro-2-oxoindolin-3-y0phenyl 3- morpholinopropanoate (compound 1019).

General procedure 8. Starting materials: compound 18 and morpholine.

¹H-NMR (200 MHz, DMSOd₆) : δ 11.32 (bs, IH), 7.37 (d, 2H), 7.21 (dd, IH), 7.08 (d, 2H), 7.15-6.98 (m, IH), 3.56 (m, 4H), 2.68 (m, 4H), 2.41 (m, 5H), 1.77-0.62 (m, 1OH). Example 20: 4-(3-cvclopentyl-6,7-difluoro-2-oxoindolin-3-vπphenyl dimethylcarbamate (compound 102C0.

General procedure 2. Starting materials: dimethylcarbamoyl chloride and 3- cyclopentyl-6,7-difluoro-3-(4-hydroxyphenyl)indolin-2-one (see, e.g. WO/2008/129075).

¹H-NMR (CDCI₃): δ 8.79 (bs, IH), 7.36 (m, 2H), 7.04 (m, 2H), 7.00 (m, IH), 6.84 (m, IH), 3.06 (s, 3H), 2.98 (s, 3H), 2.93 (m, IH), 2.1-1.2 (m, 7H), 0.89 (m, IH).

Example 21 : 4-(3-cvclopentyl-6,7-difluoro-2-oxoindolin-3-vπphenyl morpholine- 4-carboxylate (compound 1021).

General procedure 2. Starting materials: 4-morpholinecarbonylchloride and and 3-cyclopentyl-6,7-difluoro-3-(4-hydroxyphenyl)indolin-2-one (see, e.g. WO/2008/129075).

¹H-NMR (CDCI₃): δ 8.90 (bs, IH), 7.38 (m, 2H), 7.04 (m, 2H), 7.00 (m, IH), 6.85 (m, IH), 3.70 (m, 4H), 3.63 (m, 4H), 3.03 (m, IH), 2.1-1.2 (m, 7H), 0.88 (m, IH). Example 22: 4-(3-cyclohexyl-7-methyl-2-oxoindolin-3-vπphenyl morpholine-4- carboxylate (compound 1022).

General procedure 2. Starting materials: 4-morpholinecarbonylchloride and 3- cyclohexyl-3-(4-hydroxyphenyl)-7-methylindolin-2-one (see, e.g. WO/2008/129075).

¹H-NMR (CDCI₃): δ 9.29 (bs, IH), 7.46 (m, 2H), 7.17 (d, IH), 7.08 (d, IH), 7.01 (m, 3H), 3.72 (m, 4H), 3.59 (m, 4H), 2.46 (m, IH), 2.26 (s, 3H), 1.89 (m, IH), 1.61 (m, 4H), 1.21 (m, 3H), 1.01 (m, IH), 0.71 (m, IH).

Example 23: 4-(3-cyclohexyl-7-methyl-2-oxoindolin-3-y0phenyl dimethylcarbamate (compound 1023).

General procedure 2. Starting materials: dimethylcarbamoyl chloride and 3- cyclohexyl-3-(4-hydroxyphenyl)-7-methylindolin-2-one (see, e.g. WO/2008/129075).

¹H-NMR (CDCI₃): δ 9.20 (bs, IH), 7.44 (m, 2H), 7.17 (d, IH), 7.07 (d, IH), 7.01 (m, 3H), 3.06 (s, 3H), 2.98 (s, 3H), 2.46 (m, IH), 2.26 (s, 3H), 1.89 (m, IH), 1.7-1.45 (m, 4H), 1.21 (m, 3H), 1.01 (m, IH), 0.72 (m, IH). Example 24: 4-(^r3-cvcloheptyl-7-methyl-2-oxoindolin-3-yπphenyl dimethylcarbamate (compound 1024).

General procedure 2. Starting materials: dimethylcarbamoyl chloride and 3- cycloheptyl-3-(4-hydroxyphenyl)-7-methylindolin-2-one (see, e.g. WO/2008/129075).

¹H-NMR (CDCI₃): δ 9.40 (bs, IH), 7.40 (m, 2H), 7.14 (d, IH), 7.07 (d, IH), 7.02 (m, 3H), 3.06 (s, 3H), 2.99 (s, 3H), 2.65 (m, IH), 2.25 (s, 3H), 1.8-1.2 (m, HH), 0.88 (m, IH).

Example 25: 4-(3-cycloheptyl-7-methyl-2-oxoindolin-3-yDphenyl morpholine-4- carboxylate (compound 1025¹).

¹H-NMR (CD₃OD): δ 7.40 (m, 2H), 7.17 (d, IH), 7.13 (d, IH), 7.04 (m, 3H), 3.71 (m, 4H), 3.59 (m, 4H), 2.68 (m, IH), 2.28 (s, 3H), 1.8-1.25 (m, HH), 0.93 (m, IH). Example 26: 4-(6-chloro-3-cycloheptyl-7-methyl-2-oxoindolin-3-vπphenyl dimethylcarbamate (compound 1026).

General procedure 2. Starting materials: dimethylcarbamoyl chloride and 6- chloro-3-cycloheptyl-3-(4-hydroxyphenyl)-7-methylindolin-2-one (see, e.g. WO/2008/129075).

¹H-NMR (CDCI₃): δ 9.33 (bs, IH), 7.36 (m, 2H), 7.08 (q, 2H), 7.03 (m, 2H), 3.06 (s, 3H), 2.99 (s, 3H), 2.64 (m, IH), 2.28 (s, 3H), 1.8-1.2 (m, HH), 0.86 (m, IH).

Example 27: 4-(6-chloro-3-cycloheptyl-7-methyl-2-oxoindolin-3-yQphenyl morpholine-4-carboxylate (compound 10271.

General procedure 2. Starting materials: 4-morpholinecarbonylchloride and 6- chloro-3-cycloheptyl-3-(4-hydroxyphenyl)-7-methylindolin-2-one (see, e.g. WO/2008/129075).

¹H-NMR (CDCI₃): δ 9.44 (bs, IH), 7.37 (m, 2H), 7.09 (q, 2H), 7.03 (m, 2H), 3.73 (m, 4H), 3.60 (m, 4H), 2.63 (m, IH), 2.28 (s, 3H), 1.8-1.2 (m, HH), 0.85 (m, IH). Example 28: 4-(3-cvclopentyl-6,7-difluoro-2-oxoindolin-3-vπphenyl 4- methylpiperazine-1-carboxylate (compound 1028).

General procedure 3. Starting materials: 4-methylpiperazine and 3-cyclopentyl- 6,7-difluoro-3-(4-hydroxyphenyl)indolin-2-one (see, e.g. WO/2008/129075).

¹H-NMR (DMSOd₆) : δ 11.34 (bs, IH), 7.34 (m, 2H), 7.18 (m, IH), 7.08 (m, 2H), 7.01 (m, IH), 3.55 (bs, 2H), 3.41 (bs, 2H), 3.03 (m, IH), 2.34 (t, 4H), 2.21 (s, 3H), 1.65-1.2 (m, 7H), 0.98 (m, IH).

Example 29: 4-(7-chloro-3-cvcloheptyl-6-methyl-2-oxoindolin-3-vπphenyl dimethylcarbamate (compound 1029).

General procedure 2. Starting materials: dimethylcarbamoyl chloride and 7- chloro-3-cycloheptyl-3-(4-hydroxyphenyl)-6-methylindolin-2-one (see, e.g. WO/2008/129075).

¹H-NMR (CDCI₃): δ 7.98 (bs, IH), 7.36 (m, 2H), 7.11 (d, IH), 7.03 (m, 2H),

6.97 (d, IH), 3.06 (s, 3H), 2.99 (s, 3H), 2.64 (m, IH), 2.40 (S, 3H), 1.8-1.2 (m, HH), 0.86 (m, IH). Example 30: 4-(7-chloro-3-cycloheptyl-6-methyl-2-oxoindolin-3-vπphenyl morpholine-4-carboxylate (compound 103C0.

General procedure 2. Starting materials: 4-morpholinecarbonylchloride and 7- chloro-3-cycloheptyl-3-(4-hydroxyphenyl)-6-methylindolin-2-one (see, e.g. WO/2008/129075).

¹H-NMR (CDCI₃): δ 8.19 (bs, IH), 7.37 (m, 2H), 7.11 (d, IH), 7.04 (m, 2H), 6.97 (d, IH), 3.73 (m, 4H), 3.60 (m, 4H), 2.64 (m, IH), 2.40 (s, 3H), 1.8-1.2 (m, HH), 0.87 (m, IH).

Example 31 : 4-(3-cyclohexyl-2-oxo-7-(trifluoromethy0indolin-3-yQphenyl dimethylcarbamate (compound 1031).

General procedure 2. Starting materials: dimethylcarbamoyl chloride and 3- cyclohexyl-3-(hydroxyphenyl)-7-trifluoroethyl)indolin-2-one (see, e.g. WO/2008/129075).

¹H-NMR (CDCI₃): δ 8.02 (bs, IH), 7.51 (t, 2H), 7.39 (m, 2H), 7.20 (t, IH), 7.07 (m, 2H), 3.07 (s, 3H), 2.99 (s, 3H), 2.50 (m, IH), 1.8-0.9 (m, 9H), 0.73 (m, IH). Example 32 : 4-(3-cyclohexyl-2-oxo-7-(trifluoromethy0indolin-3-y0phenyl morpholine-4-carboxylate (compound 1032).

General procedure 2. Starting materials: 4-morpholinecarbonylchloride and 3- cyclohexyl-3-(hydroxyphenyl)-7-trifluoroethyl)indolin-2-one (see, e.g. WO/2008/129075).

¹H-NMR (CDCI₃): δ 8.11 (bs, IH), 7.51 (t, 2H), 7.39 (m, 2H), 7.20 (t, IH), 7.06 (m, 2H), 3.73 (m, 4H), 3.64 (m, 4H), 2.50 (m, IH), 1.8-0.9 (m, 9H), 0.72 (m, IH).

Example 33: (25V4-(6.7-difluoro-2-oxo-3-(thiophen-2-y0indolin-3-yπphenyl 2- aminopropanoate hvdrochloride(compound 1033).

General procedure 10. Starting materials: compound 1.

MS [MH-H] ⁺ = 414.9, [M-H]^"= 413.2. Example 34: (2SV4-(6.7-difluoro-2-oxo-3-(thiophen-2-vnindolin-3-vπphenyl 2- amino-3-methylbutanoate hydrochloride (compound 10341.

General procedure 10. Starting materials: compound 2.

¹H-NMR(CD₃OD) : δ 7.43 (dd, IH), 7.35 (m, 2H), 7.17 (m, 3H), 7.03 (m, 3H), 4.23 (d, IH), 2.48 (m, IH), 1.21 (d, 3H), 1.19 (d, 3H).

Example 35: 4-(3-cvcloheptyl-6-methoxy-7-methyl-2-oxoindolin-3-yl)phenyl 2- aminoacetate 2.2,2-trifluoroacetate (compound 1035V

General procedure 11. Starting material : compound 3.

¹H-NMR (CD₃OD) : δ 7.47 (m, 2H), 7.14 (m, 3H), 6.70 (d, IH), 4.13 (s, 2H), 3.88 (s, 3H), 2.66 (m, IH), 2.14 (s, 3H), 1.8-1.25 (m, 11), 0.95 (m, IH). Example 36: (2SV4-(3-cyclohexyl-6,7-dimethyl-2-oxoindolin-3-vπphenyl 2- amino-3-phenylpropanoate hydrochloride (compound 1036).

General procedure 10. Starting material : compound 4.

MS [M + H] ⁺ = 483.2, [M-H]^"= 481.5.

Example 37 : (2S>4-(3-cvcloheptyl-6-methoxy-7-methyl-2-oxoindolin-3- vQphenyl 2-amino-3-methylbutanoate hydrochloride (compound 10371.

General procedure 10. Starting material : compound 5.

¹H-NMR (CD₃OD) : δ 7.49 (m, 2H), 7.15 (m, 3H), 6.70 (d, IH), 4.23 (d, IH), 3.88 (s, 3H), 2.66 (m, IH), 2.49 (m, IH), 2.15 (s, 3H), 1.8-1.3 (m, 11), 1.22 (d, 3H), 1.20 (d, 3H), 0.96 (m, IH). Example 38: (2SV4-(3-cvcloheptyl-6-methoxy-7-methyl-2-oxoindolin-3- vQphenyl 3-methyl-2-(methylamino)butanoate hydrochloride (compound 1038).

General procedure 10. Starting material : compound 6.

¹H-NMR (CD₃OD): δ 7.50 (m, 2H), 7.15 (m, 3H), 6.71 (d, IH), 4.25 (d, IH), 3.88 (s, 3H), 2.85 (s, 3H), 2.67 (m, IH), 2.52 (m, IH), 2.15 (s, 3H), 1.8-1.25 (m, 11), 1.28 (d, 3H), 1.18 (d, 3H), 0.95 (m, IH).

Example 39 : 4-(3-cycloheptyl-7-methyl-2-oxoindolin-3-yDphenyl 2- (dimethylamino^acetate (compound 1039V

General procedure 12. Starting materials: 3-cycloheptyl-3-(4-hydroxyphenyl)-7- methylindolin-2-one (see, e.g. WO/2008/129075) and /^/V-dimethylglycine.

MS [MH-H] ⁺ = 421.4, [M-H]^"= 419.4. Example 40 : 4-(3-cvcloheptyl-6-methoxy-7-methyl-2-oxoindolin-3-vQphenyl 2- (dimethylaminoiacetate (compound 10401.

General procedure 12. Starting materials: 3-cycloheptyl-3-(4-hydroxyphenyl)-6- methoxy-7-methylindolin-2-one (see, e.g. WO/2008/129075) and N,N- dimethylglycine.

MS [MH-H] ⁺ = 451.4, [M-H]^"= 449.4.

Claims

1. A compound of the general formula (I)

(I)

wherein

r is 0 or 1;

E is selected from optionally substituted Ci-i₂-alkyl, optionally substituted C_3-I2- cycloalkyl, optionally substituted C₂-i₂-alkenyl, optionally substituted C_3-I2- cycloalkenyl, optionally substituted C₂-i₂-alkynyl, optionally substituted heterocyclyl, optionally substituted aryl and optionally substituted heteroaryl; with the proviso that E is not optionally substituted phenyl when r is O;

X is selected from the groups (i)-(vi) :

(i) -S(=O)₂-Rⁿ,

(iii) -A-O-C(=O)-B-R⁵

(iv) -P(=O)(R⁹)(R¹⁰),

(v) -A-O-P(=O)(R⁹)(R¹⁰), and

(vi) -C(=O)-O-A-O-P(=O)(R⁹)(R¹⁰),

B is selected from a single bond, -O- and -NH-,

R⁵ is selected from hydrogen, optionally substituted Ci_-6-alkyl, optionally substituted Ci_-6-alkoxy, optionally substituted Ci_-6- alkoxycarbonyl, optionally substituted Ci_-6-alkylcarbonyl, mono- and di(Ci_-6-alkyl)aminocarbonyl, amino, Ci-e-alkylcarbonylamino, mono- and di(Ci-6-alkyl)amino, aryl, aryloxy, arylcarbonyl, arylamino, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, heterocyclylamino, heteroaryl, heteroaryloxy, heteroarylcarbonyl, and heteroarylamino; where any Ci-e-alkyl as an amino substituent is optionally substituted with hydroxy, Ci_-6-alkoxy, amino, mono- and di(Ci_-6-alkyl)amino, carboxy, Ci-e-alkylcarbonylamino, Ci-e-alkylaminocarbonyl, or halogen(s), and wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted; or -C(=O)-B-R⁵ in prodrug groups (iii) and (vii) may represent an optionally N-substituted amino acid,

R⁶ is selected from hydrogen, optionally substituted Ci-e-alkyl, optionally substituted C_2-6-alkenyl, aryl, heterocyclyl, and heteroaryl, wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted; R⁷ and R⁸ are independently selected from hydrogen, optionally substituted C_1-6-alkyl, hydroxy, optionally substituted Ci_-6-alkoxy, optionally substituted Ci_-6-alkoxycarbonyl, optionally substituted Ci_-6- alkylcarbonyl, formyl, mono- and di(Ci_-6-alkyl)aminocarbonyl, amino, Ci-₆-alkylcarbonylamino, mono- and di(Ci_-6-alkyl)amino, Ci_-6- alkylsulphonyl, Ci_-6-alkylsulphinyl, aryl, aryloxy, arylcarbonyl, arylamino, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, heterocyclylamino, heteroaryl, heteroaryloxy, heteroarylcarbonyl, and heteroarylamino; where any Ci_-6-alkyl as an amino substituent is optionally substituted with hydroxy, Ci_-6-alkoxy, amino, mono- and di(Ci_-6-alkyl)amino, carboxy, Ci-e-alkylcarbonylamino, Ci_-6-alkylamino- carbonyl, or halogen(s), and wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted, or R⁷ and R⁸ together with the nitrogen atoms to which they are attached form a heterocyclic ring,

R⁹ is selected from hydrogen, hydroxy, optionally substituted Ci_-6- alkyl, optionally substituted Ci_-6-alkoxy, and optionally substituted C_2-6-alkenyloxy; and

R¹⁰ is selected from hydroxy, optionally substituted Ci_-6-alkyl, optionally substituted Ci_-6-alkoxy, optionally substituted C_2-6- alkenyloxy; aryloxy, heterocyclyloxy, and heteroaryloxy, wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted; and

R¹¹ is selected from hydroxy, optionally substituted Ci_-6-alkyl, optionally substituted C_2-6-alkenyl, aryl, heterocyclyl, heteroaryl, optionally substituted Ci_-6-alkoxy, optionally substituted C_2-6- alkenyloxy; aryloxy, heterocyclyloxy, and heteroaryloxy, wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted;

fir X is selected from hydrogen, hydroxy, optionally substituted Ci_-6 alkoxy, optionally substituted Ci_-6 alkyl, optionally substituted C_2-6 alkenyl, carboxy, optionally substituted Ci_-6-alkoxycarbonyl, Ci_-6-alkylcarbonyloxy, optionally substituted Ci_-6 alkylcarbonyl, formyl, amino, mono- and di(Ci-6-alkyl)amino, Ci-₆-alkylcarbonylamino, Ci_-6-alkylsulphonylamino, mono- and di(d_-6-alkyl)- aminocarbonylamino, carbamoyl, mono-and di (Ci_-6-alkyl)aminocarbonyl, mercapto, optionally substituted Ci-e-alkylthio, Ci_-6-alkylsulfonyl, mono- and di(Ci_-6-alkyl)aminosulfonyl, cyano, halogen, aryl, aryloxy, arylamino, arylcarbonyl, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocycylcarbonyl, heteroaryloxy, heteroarylamino, heteroarylcarbonyl, where any Ci-e-alkyl as an amino substituent is optionally substituted with hydroxyl, Ci-₆-alkoxy, amino, mono and di (Ci_-6-alkyl)amino, carboxy, Ci_-6-alkylcarbonyl- amino, Ci-e alkylaminocarbonyl or halogen(s) and wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted;

R^N represents a prodrug group of any of the types (vii)-(viii)

wherein A, B and R⁵ are as defined above for prodrug groups (i)-(vi);

fir R^N is selected from hydrogen, optionally substituted Ci_-6-alkyl, hydroxy, optionally substituted Ci_-6-alkoxy, optionally substituted Ci_-6-alkoxycarbonyl, optionally substituted Ci_-6-alkylcarbonyl, formyl, mono- and di(d_-6-alkyl)amino- carbonyl, amino, Ci-e-alkylcarbonylamino, mono- and di(Ci_-6-alkyl)amino, Ci_-6- alkylsulphonyl, and Ci-e-alkylsulphinyl; where any Ci-e-alkyl as an amino substituent is optionally substituted with hydroxy, Ci-e-alkoxy, amino, mono- and di(Ci-6-alkyl)amino, carboxy, Ci-e-alkylcarbonylamino, Ci_-6-alkylamino- carbonyl, or halogen(s); V¹, V², V³, and V⁴ independently are selected from a carbon atom, a non- quaternary nitrogen atom, an oxygen atom, and a sulphur atom, and where V⁴ further may be selected from a bond, so that -V¹-V²-V³-V⁴- together with the atoms to which V¹ and V⁴ are attached form an aromatic or heteroaromatic ring;

R¹, R², R³, and R⁴, when attached to a carbon atom, independently are selected from hydrogen, optionally substituted Ci-i₂-alkyl, optionally substituted C_3-I₂- cycloalkyl, optionally substituted C₂-i2-alkenyl, optionally substituted C_3-I₂- cycloalkenyl, hydroxy, optionally substituted Ci-i₂-alkoxy, optionally substituted C_2-i₂-alkenyloxy, carboxy, optionally substituted Ci-i₂-alkoxycarbonyl, optionally substituted Ci-i₂-alkylcarbonyl, optionally substituted Ci-12-alkylcarbonyloxy, formyl, amino, mono- and di(Ci-i₂-alkyl)amino, carbamoyl, mono- and di(Ci-₁₂- alkyl)aminocarbonyl, Ci-12-alkylcarbonylamino, Ci-i₂-alkylsulphonylamino, cyano, carbamido, mono- and di(Ci-i₂-alkyl)aminocarbonylamino, Ci-12-alkanoyloxy, Ci-12-alkylsulphonyl, Ci-i₂-alkylsulphinyl, aminosulphonyl, mono- and di(Ci-i₂- alkyl)aminosulphonyl, nitro, optionally substituted Ci-i₂-alkylthio, aryl, aryloxy, arylcarbonyl, arylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylcarbonyl, heteroaryl, heteroaryloxy, heteroarylamino, heteroarylcarbonyl, and halogen, where any C_1-12-alkyl as an amino substituent is optionally substituted with hydroxy, Ci-i₂-alkoxy, amino, mono- and di(Ci-i₂- alkyl)amino, carboxy,

Ci-i₂-alkylaminocarbonyl, or halogen(s), and wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted;

R¹, R², R³, and R⁴, when attached to a nitrogen atom, independently are selected from hydrogen, optionally substituted Ci-i₂-alkyl, hydroxy, oxide, optionally substituted Ci-i₂-alkoxy, optionally substituted Ci-12-alkoxycarbonyl, optionally substituted Ci-i₂-alkylcarbonyl, formyl, mono- and di(Ci-i₂-alkyl)aminocarbonyl, amino,

mono- and di(Ci-i₂-alkyl)amino, Ci-I₂- alkylsulphonyl, Ci-i₂-alkylsulphinyl, aryl, aryloxy, arylcarbonyl, arylamino, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, heterocyclylamino, heteroaryl, heteroaryloxy, heteroarylcarbonyl, and heteroarylamino; where any Ci-12-alkyl as an amino substituent is optionally substituted with hydroxy, Ci-I₂- alkoxy, amino, mono- and di(Ci-i2-alkyl)amino, carboxy, Ci-12-alkylcarbonylami- no, Ci-₁₂-alkylaminocarbonyl, or halogen(s), and wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted;

and pharmaceutically acceptable salts thereof.

2. The compound according to claim 1, wherein X represents a prodrug group (i) -S(=O)₂-Rⁿ.

3. The compound according to claim 1, wherein X represents a prodrug group (ii) -C(=O)-Z.

4. The compound according to claim 3, wherein Z is selected from -N(R⁷)R⁸ and -(CH₂)₂-N(R⁷)R⁸, wherein R⁷ and R⁸ together with the nitrogen atoms to which they are attached form a heterocyclic ring.

5. The compound according to claim 1, wherein X represents a prodrug group of the type (iv) -P(=O)(R⁹)(R¹⁰).

6. The compound according to any one of the preceding claims, wherein r is 0.

7. The compound according to any one of the preceding claims, wherein each of V¹, V², V³, and V⁴ represents a carbon atom.

8. The compound according to any one of the preceding claims, wherein none of R¹ and R² are hydrogen.

9. The compound according to any one of the preceding claims, wherein R¹ and R² are both selected from halogen, Ci-6-methyl and Ci-6-alkoxy.

10. The compound according to claim 9, wherein R¹ and R² are both fluoro.

11. The compound according to any one of the preceding claims having the general formula (W)

wherein the substituents and groups are as defined in the preceding claims, with the proviso that none of R¹ and R² are hydrogen.

12. A compound selected from the group consisting of

4-(3-cyclohexyl-6,7-difluoro-2-oxoindolin-3-yl)phenyl dihydrogen phosphate, 4-(3-cycloheptyl-6,7-difluoro-2-oxoindolin-3-yl)phenyl dihydrogen phosphate, 4-(l-acetyl-3-cyclohexyl-6,7-difluoro-2-oxoindolin-3-yl)phenylacetate, 4-(l-acetyl-3-cycloheptyl-6,7-difluoro-2-oxoindolin-3-yl)phenylacetate, 4-(3-cyclohexyl-6,7-difluoro-2-oxoindolin-3-yl)phenyl sulfate, 4-(3-cyclohexyl-6-fluoro-7-methyl-2-oxoindolin-3-yl)phenyl dimethylcarbamate, 4-(3-cyclohexyl-6,7-difluoro-2-oxoindolin-3-yl)phenyl 2,2-dichloroacetate, 4-(3-cycloheptyl-6-methoxy-7-methyl-2-oxoindolin-3-yl)phenyl 2,2-dichloroacetate,

4-(3-cycloheptyl-6-fluoro-7-methyl-2-oxoindolin-3-yl)phenyl dimethylcarbamate, 4-(3-cycloheptyl-6-methoxy-7-methyl-2-oxoindolin-3-yl)phenyl dimethyl- carbamate,

4-(3-cycloheptyl-6-methoxy-7-methyl-2-oxoindolin-3-yl)phenyl morpholine-4- carboxylate,

4-(3-cycloheptyl-6-methoxy-7-methyl-2-oxoindolin-3-yl)phenyl 4-methyl- piperazine-1-carboxylate,

4-(3-cycloheptyl-6-methoxy-7-methyl-2-oxoindolin-3-yl)phenyl dihydrogen- phosphate,

4-(3-cycloheptyl-6-fluoro-7-methyl-2-oxoindolin-3-yl)phenyl acrylate,

4-(3-cycloheptyl-6-fluoro-7-methyl-2-oxoindolin-3-yl)phenyl 3-morpholino- propanoate,

4-(3-cyclohexyl-6-fluoro-7-methyl-2-oxoindolin-3-yl)phenyl acrylate, 4-(3-cyclohexyl-6-fluoro-7-methyl-2-oxoindolin-3-yl)phenyl 3-morpholino- propanoate,

4-(3-cyclohexyl-6,7-difluoro-2-oxoindolin-3-yl)phenyl acrylate,

4-(3-cyclohexyl-6,7-difluoro-2-oxoindolin-3-yl)phenyl 3-morpholinopropanoate,

4-(3-cyclopentyl-6,7-difluoro-2-oxoindolin-3-yl)phenyl dimethylcarbamate, 4-(3-cyclopentyl-6,7-difluoro-2-oxoindolin-3-yl)phenyl morpholine-4- carboxylate,

4-(3-cyclohexyl-7-methyl-2-oxoindolin-3-yl)phenyl morpholine-4-carboxylate,

4-(3-cyclohexyl-7-methyl-2-oxoindolin-3-yl)phenyl dimethylcarbamate,

4-(3-cycloheptyl-7-methyl-2-oxoindolin-3-yl)phenyl dimethylcarbamate, 4-(3-cycloheptyl-7-methyl-2-oxoindolin-3-yl)phenyl morpholine-4-carboxylate,

4-(6-chloro-3-cycloheptyl-7-methyl-2-oxoindolin-3-yl)phenyl dimethylcarbamate,

4-(7-chloro-3-cycloheptyl-6-methyl-2-oxoindolin-3-yl)phenyl dimethylcarbamate,

4-(7-chloro-3-cycloheptyl-6-methyl-2-oxoindolin-3-yl)phenyl morpholine-4- carboxylate,

4-(3-cyclohexyl-2-oxo-7-(trifluoromethyl)indolin-3-yl)phenyl dimethylcarbamate,

4-(3-cyclohexyl-2-oxo-7-(trifluoromethyl)indolin-3-yl)phenyl morpholine-4- carboxylate, (2S)-4-(6,7-difluoro-2-oxo-3-(thiophen-2-yl)indolin-3-yl)pheπyl 2- aminopropanoate hydrochloride,

(2S)-4-(6,7-difluoro-2-oxo-3-(thiophen-2-yl)indolin-3-yl)phenyl 2-amino-3- methylbutanoate hydrochloride, 4-(3-cycloheptyl-6-methoxy-7-methyl-2-oxoindolin-3-yl)phenyl 2-aminoacetate

2,2,2-trifluoroacetate,

(2S)-4-(3-cycloheptyl-6-methoxy-7-methyl-2-oxoindolin-3-yl)phenyl 2-amino-3- methylbutanoate hydrochloride,

(2S)-4-(3-cycloheptyl-6-methoxy-7-methyl-2-oxoindolin-3-yl)phenyl 3-methyl-

2-(methylamino)butanoate hydrochloride,

(dimethylamino)acetate

13. A pharmaceutical composition comprising a compound of the general formula (I) or (W) as defined in any one of the claims 1-12 and a pharmaceutically acceptable carrier.

14. The pharmaceutical composition according to claim 13, wherein further comprising one or more other chemotherapeutic agents.

15. A compound of the general formula (I) or (W) as defined in any one of the claims 1-12 for use as a medicament.

16. A compound of the general formula (I) or (W) as defined in any one of the claims 1-12 for use in treatment of cancer in a mammal.

17. Use of a compound of the general formula (I) or (W) as defined in any one of the claims 1-12 for the preparation of a medicament for the treatment of cancer in a mammal.

18. The use according to claim 17, wherein the medicament further comprises one or more other chemotherapeutic agents.

19. A method of treating a mammal suffering from or being susceptible to cancer, the method comprising administering to the mammal a therapeutically effective amount of a compound of the general formula (I) or (W) as defined in any one of the claims 1-12.