MXPA06010822A - Diphenyl ox-indol-2-on compounds and their use in the treatment of cancer - Google Patents

Abstract

The present invention relates to substituted 3, 3-diphenyl-1, 3-dihydro-indol -2-one compounds, and the use of such compounds for the preparation of a medicament for the treatment of cancer in a mammal. It is postulated that 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 are breast cancer, renal cancer, multiple myeloma, leucemia, glia blastoma, rhabdomyosarcoma, prostate, soft tissue sarcoma, colorectal sarcoma, gastric carcinoma, head and neck squamous cell carcinoma, uterine, cervical, melanoma, lymphoma, and pancreatic cancer. A particular subclass of compounds are represented by the formula (II) wherein at least one of X1 and X2 is a heteroatom substituent, e.g.6-chloro-3, 3-bis-(4-hydroxy -phenyl) -7-methyl-1, 3-dihydro-indol -2-one.

Description

COMPOUNDS OF DIFENIL-OX-INDOL-2-ONA AND ITS USE IN THE TREATMENT OF CANCER FIELD OF THE INVENTION The present invention relates to compounds of 3, 3-diphenyl-1,3-dihydro-indol-2-one substituted and the use of these compounds for the preparation of a medicament for the treatment of cancer in a mammal. BACKGROUND OF THE INVENTION U.S. Patent No. 1,624,675 discloses O-O-diacyl diphenolysatin derivatives and that these compounds possess laxative properties. While the inhibition of protein synthesis inhibits cell proliferation, highly proliferative cancer cells may be more sensitive than normal cells to the inhibition of protein synthesis because many oncogenes and growth-regulating proteins are required for protein synthesis. Effective cellular proliferation are encoded by the inefficiently translated mRNAs and are dependent on the initiation factors of eukaryotic translation (Aktas et al. (1998) Proc Nati Acad Sci 95, 8280 and references therein). Protein synthesis is regulated in response to cell stress, which can be induced by environmental or physiological challenges (such as hypoxia, amino acid or nutrient deprivation), intracellular calcium loading and inhibition of protein glycosylation. For example, cell stress factors such as clotrimazole, 3,3-diphenyloxindole, tapsigargin, tunicamycin and arsenite (Aktas et al. (1998) Proc Nati Acad Sci 95, 8280; Bre er et al. (1999) Proc Nati Acad Sci 96 , 8505-8510; Harding et al. (2000) Molecular Cell 5, 897-904; Natarajan et al. (2004) J Med Chem 47, 1882-1885) act as inhibitors of protein translation initiation, reducing both the synthesis of proteins such as cell proliferation. The possibility that inhibitors of protein translation initiation may have potential as anticancer drugs has been previously described (Aktas et al. (1998) Proc Nati Acad Sci 95; Natarajan et al. (2004) J. Med. Chem 47, 1882- 1885; Natarajan et al. (2004) J. Med. Chem 47, 4979-4982). The Natarajan documents further describe 3, 3-diaryl-l, 3-dihydroindol-2-ones which potentially inhibit protein translation. Protein synthesis is also regulated by the mTOR pathway, providing another binding to a state of nutrients and amino acids (Harris &Lawrence (2003) ScienceSTKE (212) rel5; Nave et al. (1999) Biochem J 344, 427; Beaunet and collaborators (2003) Biochem J 372, 555-566; Inoki et al. (2003) Cell 115, 577-590). This route is also linked to the regulation of the protein translation initiation complex (Cherkasova &Hinnebusch (2003) Genes &Dev 17, 859-872; Kubota et al. (2003) J Biol Chem 278, 20457). The inhibition of mTOR signaling inhibits the proliferation of cancer cell lines (Noh et al. (2004) Clinical Cancer Research 10, 1013-1023; Yu et al. (2001) Endocrine-Related Cancer 8, 249-258) and has been proposed as an objective for cancer therapy (Huang &Houghton (2003) Curr Opin Pharmacol 3, 371-377). The lead compound among the 3,3-diaryl-1,3-dihydroindol-2-one compounds of the first Natarajan et al. Document (Natarajan et al. (2004) J. Med. Chem 47, 1882-1885) is the third. - (2-hydroxy-5-t-butyl-phenyl) -3-phenyl-1,3-dihydroindol-2-one. US 2004/0242563 A1 discloses substituted diphenyl-indanone, indan and indole compounds and analogs thereof which are useful for the treatment or prevention of diseases characterized by abnormal cell proliferation. However, there is still a need for improved compounds that are capable of inhibiting the uncontrolled growth of cancer cells, in particular compounds that exhibit selective inhibition of cancer cell proliferation.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to the use of a subclass scarcely studied up to now of the 3, 3-diphenyl-1,3-dihydroindol-2-one compounds in which the phenyl portions are para-substituted by via particular heteroatoms, in particular via oxygen atoms, which in particular carry hydroxy groups. Thus, one aspect of the present invention relates to the use of a compound of the general formula (I) as defined herein for the preparation of a medicament for the treatment of cancer in a mammal, see claim 1. Another aspect of the present invention relates to a compound as defined herein for use as a medicament, with the proviso that the compound is not one selected from the 3, 3-bis- (4-hydroxy-phenyl) - 1,3-dihydro-indol-2-one and the 4- [3- (4-acetoxy-phenyl) -2-oxo-2,3-dihydro-l-indol-3-yl] -phenyl acetic acid ester , claim 30. A further aspect of the present invention relates to a novel compound of the general formula (I) or (II), see claims 31 and 32.

A still further aspect of the present invention relates to a pharmaceutical composition, see claim 33. A still further aspect of the present invention relates to a method of treating a mammal suffering from or being susceptible to cancer.

BRIEF DESCRIPTION OF THE FIGURES Figure 1: shows the results of the cell proliferation studies using the compounds described in the section of examples corresponding to the following formula (III) (Example 2): Figure 2: shows the results of the protein synthesis experiments using compound 3 in the human breast cancer cell lines MDA-468 and MDA-231 (Example 3). Figure 3: illustrates the Translation Control pathways (from the Cell Signaling Technology 2003-2004 catalog). Figure 4 shows the Western immunoblot analyzes performed on the proteins involved in the control of the translation using the MDA-468 cells (incubation with the compound for 24 hours). 1: DMSO (0.08%); 2: Compound 3 (200 nM); 2: Compound 3 (2 μM); 4: another (2 μM); 5: Rapamycin (100 nM); and 6: LY294002 (10 μM) (Example 4). Figure 5 shows the Western immunoblot analyzes performed on the proteins involved in the control of the translation by comparing the MDA-468 and MDA-231 cells (incubation for 48 hours). 1: DMSO (0.08%); 2: Compound 3 (200 nM); 4: another (2 μM); 5: Rapamycin (100 nM); and 6: LY294002 (10 μM) (Example 4). Figure 6: illustrates the results of xenograft experiments of human prostate cancer cells PC3M using compound 3 (Example 5). Figure 7: shows the effect of compound 3 on a cell proliferation assay using a panel of human breast cancer cell lines in a medium containing 1% FBS. PCTACT corresponds to the growth inhibition in relation to 50 μM terfenidine (100 PCTACT) (Example 6). Figure 8: shows the effect of compound 3 on the proliferation of the MCF10A untransformed human breast epithelial cell line. PCTACT corresponds to the growth inhibition in relation to 50 μM terfenidine (100 PCTÁCT) (Example 6). Figure 9: shows the effect of compound 3 in a cell proliferation assay using a panel of human breast cancer cell lines in a medium containing 10% FBS. PCTACT corresponds to the growth inhibition in relation to 50 μM terfenidine (100 PCTACT) (Example 6). Figure 10: shows the effect of compound 21 in a cell proliferation assay using a panel of breast cancer cell lines in a medium containing 10% FBS (except MCF10A which grows in a serum free MEGM medium). PCTACT corresponds to the inhibition of growth in relation to 50 pM terfenidine (100 PCTACT) (Example 6). Figure 11: shows the effect of oxyphenisitin in a cell proliferation assay using a panel of breast cancer cell lines in a medium containing 10% FBS (except MCF10A that grows in a serum free MEGM medium). PCTACT corresponds to the growth inhibition in relation to 50 μM terfenidine (100 PCTACT) (Example 6). Figure 12: shows the effect of compounds 3 and 21 and oxyphenatin in a cell proliferation assay using a panel of cancer prostate cell lines in a medium containing 10% FBS. PCTACT corresponds to the growth inhibition in relation to 50 μM terfenidine (100 PCTACT) (Example 6). Figure 13: shows the effect of compounds 3 and 41 on a cell proliferation assay using PC3 prostate cancer cell lines in a medium containing 10% FBS (Example 6). Figure 14: shows the results of the cell proliferation assay showing the effect of compound 3 on the colo205 colon cancer cell line in a medium containing 10% FBS. PCTACT corresponds to the growth inhibition in relation to 50 μM terfenidine (100 PCTACT) (Example 6). Figure 15: illustrates that compound 3 reduces the growth rate of MDA-MB-468 tumor cells in xenograft experiments in a dose-related manner when administered as a monotherapy by the route either PO or IV. further, a regression of the tumor is observed using the highest doses of compound 3 (Example 7). Figure 16: illustrates that compound 41 slows the growth rate of human breast cancer tumor cells MDA-MB-468 in xenograft experiments and induces tumor regression at all doses tested when administered as a monotherapy by the route either PO or IV. The effect is more pronounced than after the administration of paclitaxel (Example 7). Figure 17: illustrates that compound 41 reduces the growth rate of human breast cancer tumor cells MCF-7 in xenograft experiments and induces tumor regression at all doses tested when administered as a monotherapy by the route either PO or IV. The effect is more pronounced than after administration of paclitaxel (Example 8). Figure 18: illustrates that compound 3 stimulates caspase activity in most human breast cancer cell lines, indicating that the compound exhibits pro-apoptotic activity (Example 9).

DETAILED DESCRIPTION OF THE INVENTION Compounds for the treatment of cancer in a mammal An aspect of the present invention relates to particular compounds for the preparation of a medicament for the treatment of cancer in a mammal. The term cancer is to typically describe cell growth that is not under strict control. In one embodiment of the invention, the treatment of cancers in which the inhibition of protein synthesis and / or the inhibition of mTOR pathway activation is an effective method for reducing cell growth. Examples of these cancers are breast cancer, kidney cancer, multiple myeloma, leukemia, glioblastoma, rhabdomyosarcoma, prostate cancer, soft tissue sarcoma, colorectal sarcoma, gastric carcinoma, squamous cell carcinoma of the head and neck, uterine cancer , cervical, melanoma, lymphoma and pancreatic. The useful compounds have the general formula (I), specifically wherein 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 may be selected in addition to a bond, such 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, are independently selected from hydrogen, optionally substituted alkyl of 1 to 6 carbon atoms, optionally substituted 2 to 6 carbon alkenyl, hydroxy, alkoxy of 1 optionally substituted at 6 carbon atoms, optionally substituted C 2 -C 6 alkenyloxy, carboxy, optionally substituted C 1 -C 6 alkoxycarbonyl, optionally substituted C 1 -C 6 alkylcarbonyl, alkylcarbonyloxy of 1 to 6 carbon atoms optionally substituted carbon, formyl, amino, mono- and di (C 1 -C 6 alkyl) amino, carbamoyl, mono- and di (C 1 -C 6 alkyl) aminocarbonyl, alkylcarbonylamino of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms, cyano, carbamido, mono- and di (C 1 -C 6 alkyl) aminocarbonylamino, C 1 -C 6 alkanoyloxy, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, aminosul fonilo, mono- and di (C 1 -C 6 alkyl) aminosulfonyl, nitro, optionally substituted alkylthio of 1 to 6 carbon atoms, aryl, aryloxy, arylcarbonyl, arylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylcarbonyl, heteroaryl, heteroaryloxy, heteroarylamino, heteroarylcarbonyl and halogen, wherein any alkyl of 1 to 6 carbon atoms as an amino substituent is optionally substituted by hydroxy, alkoxy of 1 to 6 carbon atoms, amino, mono- and di (C 1 -C 6 alkyl) amino, carboxy , alkylcarbonylamino of 1 to 6 carbon atoms, alkylaminocarbonyl of 1 to 6 carbon atoms or halogen (s) and wherein any aryl, heterocyclyl and heteroaryl can be optionally substituted; R1, R2, R3 and R4, when attached to a nitrogen atom, are independently selected from hydrogen, optionally substituted alkyl of 1 to 6 carbon atoms, hydroxy, optionally substituted 1 to 6 carbon atoms, alkoxycarbonyl of 1 optionally substituted at 6 carbon atoms, optionally substituted alkylcarbonyl of 1 to 6 carbon atoms, formyl, mono- and di (C 1 -C 6 alkyl) aminocarbonyl, amino, alkylcarbonylamino of 1 to 6 carbon atoms, mono- and di ( C 1 -C 6 alkyl) amino, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, aryl, aryloxy, arylcarbonyl, arylamino, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, heterocyclylamino, heteroaryl, heteroaryloxy, heteroarylcarbonyl and heteroarylamino; wherein any alkyl of 1 to 6 carbon atoms as an amino substituent is optionally substituted by hydroxy, alkoxy of 1 to 6 carbon atoms, amino, mono- and di (alkyl Ci-Cg) amino, carboxy, alkoxycarbonylamino of 1 to 6 carbon atoms, alkylaminocarbonyl of 1 to 6 carbon atoms or halogen (s) and wherein any aryl, heterocyclyl and heteroaryl can be optionally substituted; or R1 and R2 together with the carbon atoms to which they are attached form a ring, for example an aromatic ring, a carbocyclic ring, a heterocyclic ring or a heteroaromatic ring, in particular an aromatic ring, a heterocyclic ring or a heteroaromatic ring; X1 and X2 are independently selected from halogen, hydroxy, optionally substituted C1-6 alkoxy, optionally substituted alkylcarbonyloxy of 1 to 6 carbon atoms, amino, mono- and di (alkyl Ci-) amino, alkylcarbonylamino of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms, mono- and di (Ci-Cß alkyl) aminocarbonylamino, C 1 -C 6 alkanoyloxy, mercapto, optionally substituted C 1 -C 6 alkylthio, alkylsulfonyl from 1 to 6 carbon atoms, mono- and di (C 1 -C 6 alkyl) aminosulfonyl, aryloxy, arylamino, heterocyclyloxy, heterocyclylamino, heteroaryloxy and heteroarylamino, wherein any alkyl of 1 to 6 carbon atoms as an amino or sulfur substituent is optionally substituted by hydroxy, alkoxy of 1 to 6 carbon atoms, amino, mono- and di (Ci-Cß alkyl) amino, carboxy, alkylcarbonylamino of 1 to 6 carbon atoms, alkylaminocarbonyl of 1 to 6 carbon atoms or halogen no (s) and wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted; > Y (= Q) n is selected from > C = 0, > C = S, > S = 0 and > S (= 0) 2; and RN is selected from the group consisting of hydrogen, optionally substituted alkyl of 1 to 6 carbon atoms, hydroxy, optionally substituted 1 to 6 carbon alkoxy, optionally substituted 1 to 6 carbon alkoxycarbonyl, - alkylcarbonyl of 1 optionally substituted carbon atoms, formyl, mono- and di (Ci- C6 alkyl) aminocarbonyl, amino, alkylcarbonylamino of 1 to 6 carbon atoms, mono- and di (Ci-Ce alkyl) amino, alkylsulfonyl of 1 to 6 carbon and alkylsulfinyl atoms of 1 to 6 carbon atoms; wherein any alkyl of 1 to 6 carbon atoms as an amino substituent is optionally substituted by hydroxy, alkoxy of 1 to 6 carbon atoms, amino, mono- and di (alkyl Ci-Cß) amino, carboxy, alkylcarbonylamino of 1 to 6 carbon atoms, alkylaminocarbonyl of 1 to 6 carbon atoms or halogen (s). Also included in the class of compounds of the formula (I) are pharmaceutically acceptable salts and prodrugs thereof. A variant of the compounds of the formula (I) are those in which each of the benzene rings to which X1 and X2 are attached can be further substituted by one, two, three or four fluorine atoms, in particular each ring of benzene to which X1 and X2 are attached is replaced by two fluorine atoms in the ortho positions relative to substituents X1 and X2, respectively.

Definitions In the present context, the term "alkyl of 1 to 6 carbon atoms" is intended to refer to a linear, cyclic or branched hydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl , pentyl, cyclopentyl, hexyl, cyclohexyl and the term "C 1 -C 4 alkyl" is intended to cover linear, cyclic or branched hydrocarbon groups having 1 to 4 carbon atoms, for example methyl, ethyl, propyl , iso-propyl, cyclopropyl, butyl, iso-butyl, tert-butyl, cyclobutyl. Similarly, the term "C2-C6 alkenyl" is intended to cover linear, cyclic or branched hydrocarbon groups having 2 to 6 carbon atoms and comprising an 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. In the present context, i.e. in connection with the terms "alkyl", "alkoxy" and "alkenyl", the term "optionally substituted" is intended to mean that the group in question can be substituted one or more times, preferably 1. -3 times, by a group (s) selected from hydroxy (which when attached to an unsaturated carbon atom may be present in the tautomeric keto form), alkoxy of from 1 to 6 carbon atoms (ie alkyl) -oxi of 1 to 6 carbon atoms), alkenyloxy of 2 to 6 carbon atoms, carboxy, oxo (forming a keto or aldehyde functionality), alkoxycarbonyl of 1 to 6 carbon atoms, alkylcarbonyl of 1 to 6 carbon atoms, formyl, aryl, aryloxy, arylamino, arylcarbonyl, aryloxycarbonyl, arylcarbonyloxy, arylaminocarbonyl, arylcarbonylamino, heteroaryl, heteroaryloxy, heteroarylamino, heteroarylcarbonyl, heteroaryloxycarbonyl, heteroarylcarbonyloxy, heteroarylaminocarbonyl, heteroarylcarbonylamino, heterocyclic ilo, heterocyclyloxy, heterocyclylamino, heterocyclylcarbonyl, heterocyclyloxycarbonyl, heterocyclylcarbonyloxy, heterocyclylaminocarbonyl, heterocyclylcarbonylamino, amino, mono- and di (alkyl Ci-Ce) amino, carbamoyl, mono- and di (C 1 -C 6 alkyl) aminocarbonyl, alkylcarbonylamino of 1 to 6 carbon atoms, cyano, guanidino, carbamido, alkyl-sulfonyl-amino of 1 to 6 carbon atoms, aryl-sulfonyl-amino, heteroaryl-sulfonyl-amino, alkanoyloxy of 1 to 6 carbon atoms, alkyl-sulfonyl of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, alkylsulfonyloxy of 1 to 6 carbon atoms, nitro, alkylthio of 1 to 6 carbon atoms and halogen, where any aryl, heteroaryl and heterocyclyl can be substituted as specifically described below for aryl, heteroaryl and heterocyclyl and where any substituent representative of alkyl, alkoxy and the like can be substituted by hydroxy, alkoxy of 1 to 6 carbon atoms, amino, mono- and di (C 1 -C 6 alkyl) amino, carboxy, alkylcarbonylamino of 1 to 6 carbon atoms, alkylaminocarbonyl of 1 to 6 carbon atoms or halogen (s). Typically, the substituents are selected from hydroxy (which when attached to an unsaturated carbon atom may be present in the tautomeric keto form), alkoxy having from 1 to 6 carbon atoms (i.e., alkyl-oxy from 1 to 6 carbon atoms). carbon), alkenyloxy of 2 to 6 carbon atoms, carboxy, oxo (forming a keto or aldehyde functionality), alkylcarbonyl of 1 to 6 carbon atoms, formyl, aryl, aryloxy, arylamino, arylcarbonyl, heteroaryl, heteroaryloxy, heteroarylamino, heteroarylcarbonyl , heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylcarbonyl, amino, mono- and di (Ci-Cß alkyl) amino; carbamoyl, mono- and di (alkyl C? -β) aminocarbonyl, amino-alkyl-aminocarbonyl of 1 to 6 carbon atoms, mono- and di (C 1 -C 6 alkyl) amino-alkyl-aminocarbonyl of 1 to 6 carbon atoms carbon, alkylcarbonylamino of 1 to 6 carbon atoms, guanidino, carbamido, alkyl-sulfonyl-amino of 1 to 6 carbon atoms, alkyl-sulfonyl of 1 to 6 carbon atoms, alkyl-sulfinyl of 1 to 6 carbon atoms, alkylthio of 1 to 6 carbon atoms, halogen , wherein any aryl, heteroaryl and heterocyclyl can be substituted as specifically described below for aryl, heteroaryl and heterocyclyl. In some embodiments, the substituents are selected from hydroxy, alkoxy of 1 to 6 carbon atoms, aM.no, mono- and di (C? -C6 alkyl) amino, carboxy, alkylcarbonylamino of 1 to 6 carbon atoms, alkylaminocarbonyl of 1 to 6 carbon atoms or halogen. The term "halogen" includes fluorine, chlorine, bromine and iodine. In the present context, the term "aryl" is intended to refer to a ring or systems of fully or partially aromatic carboxycic rings, such as phenyl, naphthyl, 1, 2, 3, 4-tetrahydronaphthyl, anthracyl, phenanthracil, pyrenyl, benzopyryl , fluorenyl and xanthenyl, among which phenyl is a preferred example. The term "heteroaryl" is intended to refer to a fully or partially aromatic ring or carbocyclic ring systems where one or more of the carbon atoms have been replaced by heteroatoms, for example nitrogen atoms (= N- or -NH-) , sulfur and / or oxygen. Examples of these heteroaryl groups are oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, coumaryl, furanyl, thienyl, quinolyl, benzothiazolyl, 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 refer to a ring or system of carbocyclic non-aromatic rings where one or more of the carbon atoms have been replaced by heteroatoms, for example nitrogen atoms (= N- or -NH-), sulfur and / or oxygen. Examples of these heterocyclyl groups (named according to the rings) are imidazolidine, piperazine, hexahydropyridazine, hexahydropyrimidine, diazepane, diazocane, pyrrolidine, piperidine, azepane, azocan, aziridine, azirine, azetidine, pyroline, tropane, oxazine (morpholine), azepine, dihydroazepine, tetrahydroazepine and hexahydroazepine, oxazolane, oxazepane, oxazocane, thiazolan, thiazine, thiazepane, thiazocane, oxazetane, diazetane, thiazetane, tetrahydrofuran, tetrahydropyran, oxepane, tetrahydrothiophene, tetrahydrothiopyran, tiepane, dithiane, dithiepane, dioxane, dioxepane, oxatian, oxatiepano. The most interesting examples are tetrahydrofuran, imidazolidine, piperazine, hexahydropyridazine, hexahydropyrimidine, diazepam, diazocane, pyrrolidine, piperidine, azepane, azocane, azetidine, tropane, oxazine (morpholine), oxazolane, oxazepane, thiazolan, thiazine and thiazepane, in particular tetrahydrofuran, imidazolidine, piperazine, hexahydropyridazine, hexahydropyrimidine, diazepam, pyrrolidine, piperidine, azepane, oxazine (morpholine) and thiazine. In the present context, ie in connection with the terms "aryl", "heteroaryl", "heterocyclyl" and the like (eg, "aryloxy", "heteroarylcarbonyl" and the like), the term "optionally substituted" is intended to refer to that the group in question can be substituted one or several times, preferably 1-5 times, in particular 1-3 times, by a selected group (s) of hydroxy (which when present in a system of enol can be represented in the tautomeric keto form), alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkenyloxy of 2 to 6 carbon atoms, oxo (which can be represented in the tautomeric enol form), carboxy, alkoxycarbonyl of 1 to 6 atoms carbon, alkylcarbonyl of 1 to 6 carbon atoms, formyl, aryl, aryloxy, arylamino, aryloxycarbonyl, arylcarbonyl, heteroaryl, heteroarylamino, amino, mono- and di (alkyl cyclamino); carbamoyl, mono- and di (C 1 -C 6 alkyl) aminocarbonyl, amino-alkyl-aminocarbonyl of 1 to 6 carbon atoms, mono- and di (C 1 -C 6 alkyl) amino-alkyl-aminocarbonyl of 1 to 6 carbon atoms carbon, alkrbonylamino of 1 to 6 carbon atoms, cyano, guanidino, carbamido, alkanoyloxy of 1 to 6 carbon atoms, alkyl-sulfonyl-amino of 1 to 6 carbon atoms, arylsulfonyl-amino, heteroaryl-sulfonyl-amino , alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, alkylsulfonyloxy of 1 to 6 carbon atoms, nitro, sulfañilo, amino, amino-sulfonilo, mono- and di (alkyl Ci-Ce) amino-sulfonyl, dihalogen-alkyl of 1 to 4 carbon atoms, trihalogen-alkyl of 1 to 4 carbon atoms, halogen, where the substituents representing aryl and heteroaryl can be substituted 1-3 times by alkyl of 1 to 4 atoms of carbon, alkoxy of 1 to 4 carbon atoms, nitro, cyano, amino or halogen and any substituent representing alkyl, alkoxy and the like can be substituted by hydroxy, alkoxy of 1 to 6 carbon atoms, alkenyloxy of 2 to 6 carbon atoms, amino, ono- and di (C 1 -C 6 alkyl) amino, carboxy, alkrbonylamino of 1 to 6 atoms of carbon, halogen, alkylthio of 1 to 6 carbon atoms, alkyl-sulfonyl-amino of 1 to 6 carbon atoms or guanidino. Typically, the substituents are selected from hydroxy, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, oxo (which can be represented in the tautomeric enol form), carboxy, alkrbonyl of 1 to 6 carbon atoms. carbon, formyl, amino, mono- and di (alkyl Ci-) amino); carbamoyl, mono- and di (C 1 -C 6 alkyl) aminocarbonyl, amino-alkyl-aminocarbonyl of 1 to 6 carbon atoms, alkrbonylamino of 1 to 6 carbon atoms, guanidino, carbamido, alkyl-sulfonyl-amino of 1 to 6 carbon atoms, aryl-sulphonyl-a, heteroaryl-sulfonyl-amino, alkylsulfonyl of 1 to 6 carbon atoms, alkyl-sulfinyl of 1 to 6 carbon atoms, alkylsulfonyloxy of 1 to 6 carbon atoms, sulfanyl, amino, amino-sulfonyl, mono- and di (Ci-Ce alkyl) amino-sulfonyl or halogen, where any substituent representing alkyl, alkoxy and the like can be substituted by hydroxy, alkoxy of 1 to 6 carbon atoms, alkenyloxy of 2 to 6 carbon atoms, amino, mono- and di (C?-C6 alkyl) amino, carboxy, alkrbonylamino of 1 to 6 carbon atoms, halogen, alkylthio of 1 to 6 carbon atoms, alkyl-sulfonyl-amino of 1 to 6 carbon or guanidino atoms. In some embodiments, the substituents are selected from alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, amino, mono- and di (C 1 -C 7 alkyl) amino, sulfanyl, carboxy or halogen, where substituent representative of alkyl, alkoxy and the like can be substituted by hydroxy, alkoxy of 1 to 6 carbon atoms, alkenyloxy of 2 to 6 carbon atoms, amino, mono- and di (C? -C6 alkyl) amino, carboxy, alkrbonylamino from 1 to 6 carbon atoms, halogen, alkylthio having from 1 to 6 carbon atoms, alkyl sulfonyl-amino having from 1 to 6 carbon atoms or guanidino. The term "prodrug" used herein is proposed to refer to a derivative of a compound of the formula (I) which - upon exposure to physiological conditions - will release a compound of the formula (I) which will then be capable of exhibit the desired biological action. Examples of prodrugs are esters (carboxylic acid ester, phosphate esters, sulfuric acid esters, etc.), acid-labile ethers, acetals, ketals, and the like. The term "pharmaceutically acceptable salts" is proposed to include the acid addition salts and basic salts. Illustrative examples of acid addition salts are pharmaceutically acceptable salts that are formed with non-toxic acids. Examples of these organic salts are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic acid, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic and theophylline-acetic, as well as the 8 - haloteophyllins, for example 8-bromoteophylline. Examples of these inorganic salts are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. Examples of basic salts are salts wherein the (remaining) counterion 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 Rr designate independently C 1-6 optionally substituted alkyl, optionally substituted C 2-6 alkenyl, optionally substituted aryl or optionally substituted heteroaryl). Pharmaceutically acceptable salts are, for example, those described in Remington's Pharmaceutical Sciences, 17. Ed. Alfonso R. Gennaro (Ed.), Mack Publishing Company, Easton, PA, USA, 1985 and the most recent editions and in Encyclopedia or Pharmaceutical Technology Thus, the term "an acid addition salt or a basic salt thereof" used in this document is proposed to comprise these salts. In addition, the compounds as well as any intermediate or starting materials may also be present in the hydrate form.

Modalities It is believed that the function of V1, V2, V3 and V is mainly of a broad nature, that is to say that it is determinant for the orientation of the groups R1-R4. However, it is also believed that the selection of a heteroatom as one or more of V1, V2, V3 and V4 can create dipolar interactions with other entities and thereby influence, for example, 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 can be selected in addition to a bond, such 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 these aromatic rings and heteroaromatic rings are those selected from a benzene ring, a thiophene ring (V1 = S, V2 = V3 = C (-) and V = bond; V2 = S, V2 = V3 = C (-) and V4 = bond; or V3 = S, Va = V2 = C (-) and V4 = bond), a furan ring (Vx = 0, V2 = V3 = C (-) and V4 = bond; V2 = 0, V1 = V3 = C (-) and V4 = bond; or V3 = 0, v ^ C -) and V4 = bond), a pyrazole ring (VX = N (-), V2 = N, V3 = C (-) and V4 = bond, V2 = N, V2 = N (-), V3 = C (-) and V4 = bond), an imidazole ring (VX = N (-), V2 = C (- ), V3 = N and V = bond, VX = N, V2 = C (-), V3 = N (-) and V4 = bond), a pyridine ring (V ^, V2 = V3 = V4 = C (- ); V2 = N, V ^ V ^ V ^ CÍ-); V3 = N, VZ = V2 = V4 = C (-) and V4 = N, VX = V2 = V3 = C (-)), a pyrimidine ring (Va = V3 = N, V2 = V4 = C (-); V2 = V4 = N, V ^ V ^ CÍ-)), pyrazines (VX = V = N, V2 = V3 = C (-)),, a pyridazine ring (VX = V2 = N, V3 = V4 = C (-); V2 = V3 = N, v ^ Cf-); V3 = V4 = N, vx = V2 = C (-)), a thiazole ring (V2 = N, V2 = C (-), V3 = S, V4 = bond, V = S, V2 = C (-) , V3 = N, V4 = bond) and an isothiazole ring (VX = N, V2 = S, V3 = C (-), V4 = bond, VX = S, V2 = N, V3 = C (-), V4 = link; VX = C (-), V2 = S, V3 = N, V4 = link, VX = C (-), V2 = N, V3 = S, V4 = link). The meaning of V1, V2, V3 and V4 for each heteroaromatic ring is specified simply for the purpose of illustrating that various orientations of the heteroatoms are possible. In addition, it should be understood that the respective rings bear the substituents R1, R2, R3 and R4 (where applicable) according to the general formula (I). In this way, the specification of "C (-)" and "N (-)" as the possible meanings of V1, V2, V3 and V4 is made with the purpose of describing that the atoms in question carry a substituent (which it can be hydrogen). The "N" specification means that the respective atoms do not carry an "R" substituent, ie 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 of a benzene ring and a pyridine ring where the nitrogen atom represents V3 (see also examples). According to the general formula (I), the respective ring (aromatic or heteroaromatic) carries the substituents R1-R4 (where applicable). It is believed that the substituents R1-R4 (where applicable) are at least partially responsible for the biological effect, for example the ability of the compounds to inhibit cell proliferation in cancer cells. In one embodiment, R1, R2, R3 and R4, when attached to a carbon atom, are independently selected from hydrogen, optionally substituted alkyl of 1 to 6 carbon atoms, optionally substituted 2 to 6 carbon alkenyl, hydroxy , optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyloxy, carboxy, optionally substituted C 1 -C 6 alkoxycarbonyl, optionally substituted C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkylcarbonyloxy to 6 carbon atoms optionally substituted, formyl, amino, mono- and di (C 1 -C 6 alkyl) amino, carbamoyl, mono- and di (C 1 -C 6 alkyl) aminocarbonyl, alkylcarbonylamino of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms, cyano, carbamido, mono- and di (alkyl Ci-Ce) aminocarbonylamino, alkanoyloxy of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, aminosulfonyl, mono- and di ( alkyl Ci- C6) aminosulfonyl, nitro, alkylthio having 1 to 6 carbon atoms optionally substituted and halogen, wherein any alkyl of 1 to 6 carbon atoms as an amino substituent is optionally substituted by hydroxy, alkoxy of 1 to 6 carbon atoms; carbon, amino, mono- and di (C 1 -C 6 alkyl) amino, carboxy, alkylcarbonylamino of 1 to 6 carbon atoms, alkylaminocarbonyl of 1 to 6 carbon atoms or halogen (s); and R1, R2, R3 and R4, when attached to a nitrogen atom, are independently selected from hydrogen, optionally substituted alkyl of 1 to 6 carbon atoms, hydroxy, optionally substituted C1-6 alkoxy, alkoxycarbonyl of 1 to 6 carbon atoms optionally substituted, optionally substituted alkylcarbonyl of 1 to 6 carbon atoms, formyl, mono- and di (C 1 -C 6 alkyl) aminocarbonyl, amino, alkylcarbonylamino of 1 to 6 carbon atoms, mono- and di- (C 1 -C 6 alkyl) amino, alkylsulfonyl of 1 to 6 carbon atoms and alkylsulfinyl of 1 to 6 carbon atoms, wherein any alkyl of 1 to 6 carbon atoms as an amino substituent is optionally substituted by hydroxy, alkoxy of 1 to 6 carbon atoms, amino, mono- and di (Ci-Cß alkyl) amino, carboxy, alkylcarbonylamino of 1 to 6 carbon atoms, alkylaminocarbonyl of 1 to 6 carbon atoms or halogen (s) and wherein any aryl, heterocyclyl and heteroaryl it can be optionally substituted. More particularly, R1, R2, R3 and R4 are independently selected from hydrogen, halogen, optionally substituted alkyl of 1 to 6 carbon atoms, hydroxy, optionally substituted C1-6 alkoxy, alkoxycarbonyl of 1 to 6 carbon atoms optionally substituted, optionally substituted alkylcarbonyl of 1 to 6 carbon atoms, amino, alkylcarbonylamino of 1 to 6 carbon atoms, alkylcarbonylamino of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms, mono- and di (alkyl C) Α-C 6) aminosulfonyl and mono- and di (C 1 -C 4 alkyl) amino, wherein any alkyl of 1 to 6 carbon atoms as an amino substituent is optionally substituted by hydroxy, alkoxy of 1 to 6 carbon atoms, amino , mono- and di (Ci-Cß alkyl) amino, carboxy, alkylcarbonylamino of 1 to 6 carbon atoms, alkylaminocarbonyl of 1 to 6 carbon atoms or halogen (s), such as hydrogen, alkyl of 1 to 6 carbon atoms replaced optional optionally substituted hydroxy, alkoxy of 1 to 6 carbon atoms, optionally substituted alkoxycarbonyl of 1 to 6 carbon atoms, optionally substituted alkylcarbonyl of 1 to 6 carbon atoms, amino, alkylcarbonylamino of 1 to 6 carbon atoms, alkylcarbonylamino of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms, mono- and di (alkyl Ci-Ce) aminosulfonyl and mono- and di (alkyl C? -C?) amino, wherein any alkyl of 1 to 6 carbon atoms as an amino substituent is optionally substituted by hydroxy, alkoxy of 1 to 6 carbon atoms, amino, mono- and di (C 1 -C 6 alkyl) amino, carboxy, alkylcarbonylamino of 1 to 6 carbon atoms, alkylaminocarbonyl of 1 to 6 carbon atoms or halogen (s). As an alternative to the above, R1 and R2, in one embodiment together with the carbon atoms to which they are attached, can form a heterocyclic ring or a heteroaromatic ring; and in another embodiment, R1 and R2, together with the carbon atoms to which they are attached, can form an aromatic ring or a carbocyclic ring. In a particular variant, R 1 is selected from hydrogen, halogen, alkyl of 1 to 6 carbon atoms, trifluoromethyl and alkoxy of 1 to 6 carbon atoms, when V 1 is a carbon atom. In a further variant, R2 is selected from hydrogen, halogen, optionally substituted aryl, optionally substituted aryloxy and optionally substituted heteroaryl, when V2 is a carbon atom. In a still further variant, R3 is selected from hydrogen, optionally substituted C1-6 alkoxy, halogen, cyano, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl, amino, alkylcarbonylamino of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms and mono- and di (Ci-Cß alkyl) aminosulfonyl, when V3 is a carbon atom. In a still further variant, R4 is hydrogen, when V4 is a carbon atom. In accordance with the main embodiment of the invention, it is believed that the substituents X1 and X2 should include a hetero atom directly linked to the phenyl ring, see the additional definition, above. (See also the alternative modality that is described further below). In one embodiment, X 1 and X 2 are independently selected from hydroxy, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 alkylcarbonyloxy, amino, mono- and di (C 1 -C 6 alkyl) amino, alkylcarbonylamino of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms, mono- and di (alkyl Ci-Ce) aminocarbonylamino, alkanoyloxy of 1 to 6 carbon atoms and mono- and di (Ci-C6 alkyl) aminosulfonyl , wherein any alkyl of 1 to 6 carbon atoms as an amino substituent is optionally substituted by hydroxy, alkoxy of 1 to 6 carbon atoms, amino, mono- and di (Ci-Cß alkyl) amino, carboxy, alkylcarbonylamino of 1 to 6 carbon atoms, alkylaminocarbonyl of 1 to 6 carbon atoms or halogen (s). In a more preferred embodiment, X1 and X2 are independently selected from halogen, OR6, OCOR5, N (R6) 2, NHCOR5, NHS02R5 and NHCON (R6) 2, wherein R5 is selected from alkyl of 1 to 6 carbon atoms, optionally substituted aryl and optionally substituted heteroaryl and each R6 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted aryl and optionally substituted heteroaryl, such as of OR6, OCOR5, N (R6) 2, NHCOR5, NHS02R5 and NHCON (R6) 2, wherein R5 is selected from alkyl of 1 to 6 carbon atoms, optionally substituted aryl and optionally substituted heteroaryl and each R6 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, aryl optionally substituted and optionally substituted heteroaryl, in particular X1 and X2 are independently selected from halogen, hydroxy, OAc, NH2, NMe2, NHAc, NHS02Me and NHCONMe2, such as from hydroxy, OAc, NH2, NMe2, NHAc, NHS02Me and NHCONMe2. Having said the above, it is currently believed that X1 and X2 can be the same for both phenyl rings, ie X1 = X2. This has the advantage that achiral compounds are obtained. In the pharmaceutical industry, the use of chiral drugs typically requires the isolation of individual, stereoisomeric forms. Another advantage is observed in the synthesis route. A one-step introduction of the two PhX groups saves at least one synthesis step and the associated time and increases the total throughput of the preparation process. Although not explicitly specified in general formula (I), it is believed that the introduction of fluorine atoms in benzene rings may provide certain advantages. Thus, as defined above, a variant of the compounds are those in which each of the benzene rings to which X1 and X2 are attached can be further substituted by one, two, three or four fluorine atoms, in in particular each benzene ring to which X1 and X2 are attached is replaced by two fluorine atoms in the ortho positions relative to substituents Xa and X2, respectively. The structural element >; Y (= Q) n is not considered particularly critical. However, for synthetic reasons, it is preferred that Y is a carbon atom and Q is an oxygen atom, ie that > Y (= Q) n be > C = 0 In an alternative, Y is a sulfur atom, n is 2 and each Q is an oxygen atom, meaning that > Y (= Q) nes > S (= 0) 2. It is believed that RN can be selected from a wide variety of substituents. However, it is currently believed that it may be advantageous if RN is selected from hydrogen, alkyl of 1 to 6 carbon atoms, amino and alkylcarbonylamino of 1 to 6 carbon atoms. Modes where RN is hydrogen are much more preferred (see Figure 1). In view of the above, and in view of the current set of biological data, it is postulated that certain subclasses of compounds may exhibit particular advantages, see the subclasses defined in the following: (a) A subclass of compounds are those in which V1, V2 , V3, V4 are all a carbon atom, > Y (= Q) n is > C = 0, and RN is hydrogen. In a first embodiment thereof, R4 is hydrogen; in particular, both R3 and R4 are hydrogen. In a second embodiment within the subclass, which can be combined with the first embodiment, R1 is alkyl of 1 to 4 carbon atoms and R2 is halogen, for example R1 is methyl and R2 is chlorine. In a third embodiment within this subclass, which can be combined with the first embodiment, R1 and R2 together with the carbon atoms to which they are attached form a ring, for example an aromatic ring, a carbocyclic ring, a ring heterocyclic or a heteroaromatic ring, in particular an aromatic ring or a carbocyclic ring. In a fourth embodiment within this subclass, which can be combined with the above embodiments, each of X1 and X2 is independently selected from halogen, hydroxy, alkoxy of 1 to 4 carbon atoms, amino and dimethylamino. In a fifth embodiment within this subclass, which can be combined with the first embodiment, R1, R2 and R4 are all hydrogen. In a sixth embodiment within this subclass, which may be combined with the fifth embodiment, R3 is selected from hydrogen, halogen (such as fluorine, chlorine, bromine, iodine), nitro, alkyl of 1 to 4 carbon atoms (such as methyl), alkoxy of 1 to 4 carbon atoms (such as methoxy), trifluoromethoxy, amino, carboxy and dimethylaminocarbonyl, in particular hydrogen, halogen (such as fluorine, chlorine, bromine, iodine), nitro, methyl, methoxy and amino . In a seventh embodiment within this subclass, which is combined with the fifth or sixth embodiment, each of X1 and X2 is independently selected from halogen, hydroxy, alkoxy of 1 to 4 carbon atoms, amino and dimethylamino. In an eighth embodiment within this subclass, R2, R3 and R4 are all hydrogen.

In a ninth embodiment within this subclass, which may be combined with the eighth embodiment, R 1 is selected from fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms (such as methyl or tert-butyl), trifluoromethyl, alkoxy from 1 to 4 carbon atoms (such as methoxy) and dimethylaminocarbonyl. In a tenth modality, which can be combined with any of the eighth and ninth modalities, each of X1 and X2 is independently selected from halogen (such as fluorine), hydroxy, alkoxy of 1 to 4 carbon atoms (such as methoxy), amino and dimethylamino. In a series of the eleventh embodiment, which may be combined with the first embodiment, R1 is selected from halogen (such as fluorine, chlorine, bromine), alkyl of 1 to 4 carbon atoms (such as methyl or tert-butyl) , trifluoromethyl, alkoxy of 1 to 4 carbon atoms (such as methoxy) and dimethylaminocarbonyl, R 2 is selected from hydrogen and halogen and R 3 is selected from hydrogen, halogen, alkyl of 1 to 4 carbon atoms (such as methyl) and amino; where R2 and R3 are not both hydrogen. Also preferred within this subclass and any of the embodiments are variants wherein X1 and X2 are the same. (b) Another subclass of compounds are those in which at least one of V1, V2, V3 and V4 is selected from a non-quaternary nitrogen atom, an oxygen atom and a sulfur atom and wherein V4 may be selected in addition to a bond, so that -V1-V2-V3-V4- together with the atoms to which they are bound V1 and V4 form a heteroaromatic ring. In this case, the heteroaromatic ring is preferably selected from a pyridine ring and an ote pyrazole ring. Within this subclass, it is further preferred that > Y (= Q) n be > C = 0 and that RH is hydrogen. Also preferred are the modalities, where X1 and X2 are the same. A further aspect of the invention relates to the use of a compound of type 3, 3-diphenyl-1,3-dihydro-indol-2-one of the formula (lia) wherein R1 is selected from hydrogen, halogen, alkyl of 1 to 6 carbon atoms, trifluoromethyl and alkoxy of 1 to 6 carbon atoms; R2 is selected from hydrogen, halogen, optionally substituted aryl, optionally substituted aryloxy and optionally substituted heteroaryl; R3 is selected from hydrogen, optionally substituted C1-6 alkoxy, halogen, optionally substituted cyano and aryl, optionally substituted aryloxy, optionally substituted heteroaryl, amino, alkylcarbonylamino of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 atoms carbon and mono- and di (C 1 -C 6 alkyl) aminosulfonyl; Z is CH or N; and X1 and X2 are independently selected from halogen, OR6, OCOR5, N (R5) 2 NHCOR5, NHS02R5 and NHCON (R6) 2, wherein R5 is selected from alkyl of 1 to 6 carbon atoms, optionally substituted aryl and substituted heteroaryl optionally and each R6 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted aryl and optionally substituted heteroaryl; and pharmaceutically acceptable salts and prodrugs thereof (as further defined above); for the preparation of a medicament for the treatment of cancer in a mammal. As before, each of the benzene rings to which X1 and X2 are attached can be further substituted by one, two, three or four fluorine atoms, in particular each benzene ring to which X1 and X are attached is substituted by two fluorine atoms in the ortho positions relative to the substituents X1 and X2, respectively. In one embodiment, X1 and X2 are independently selected from OR6, OCOR5, N (R6) 2, NHCOR5, NHS02R5 and NHCON (R6) 2, wherein R5 is selected from alkyl of 1 to 6 carbon atoms, aryl optionally substituted and optionally substituted heteroaryl and each R6 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted aryl and optionally substituted heteroaryl. In a variant which can be combined with the modalities mentioned above in this aspect, R1 is selected from alkyl of 1 to 6 carbon atoms and alkoxy of 1 to 6 carbon atoms, such as methyl, ethyl, isopropyl, methoxy, ethoxy and isopropoxy, in particular methoxy, ethoxy and isopropoxy, or methyl , ethyl and isopropyl. In another variant which can be combined with the aforementioned embodiments and variants within this aspect, R2 is selected from hydrogen, chloro, methoxy, dimethylamino, phenyl, phenoxy, optionally substituted thiophen-1-yl and thiophen-3-yl optionally substituted. In yet another variant which can be combined with the aforementioned embodiments and variants within this aspect, R3 is selected from hydrogen, methoxy, fluorine, chlorine, cyano, phenyl, phenoxy, optionally substituted thiophen-2-yl and thiophene- 3-yl optionally substituted, amino, acetylamino, methylsulfonylamino and dimethylaminosulfonyl. In a still further variant, X1 and X2 are independently selected from halogen, hydroxy, OAc, NH2, NMe2, NHAc, NHS02Me and NHCONMe2, such as from hydroxy, OAc, NH2, NMe2, NHAc, NHS02Me and NHCONMe2. Within this aspect, each X1 and X are preferably the same. A still further aspect of the invention relates to the use of a compound of type 3, 3-diphenyl-1,3-dihydro-indol-2-one of the formula (IIb) wherein R1, R2 and R3, when attached to a carbon atom, are independently selected from hydrogen, optionally substituted alkyl of 1 to 6 carbon atoms, optionally substituted 2 to 6 carbon alkenyl, hydroxy, alkoxy of 1 optionally substituted at 6 carbon atoms, optionally substituted C 2 -C 6 alkenyloxy, carboxy, optionally substituted C 1 -C 6 -alkoxycarbonyl, optionally substituted C 1 -C 6 -alkylcarbonyl, alkylcarbonyloxy of 1 to 6 carbon atoms optionally substituted carbon, formyl, amino, mono- and di (C 1 -C 6 alkyl) amino, carbamoyl, mono- and di (C 1 -C 6 alkyl) aminocarbonyl, alkylcarbonylamino of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms, cyano, carbamido, mono- and di (C 1 -C 4 alkyl) aminocarbonylamino, C 1 -C 6 alkanoyloxy, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, inosulfonyl, mono- and di (C 1 -C 6 alkyl) aminosulfonyl, nitro, optionally substituted C 1 -C 6 alkylthio and halogen, wherein any C 1 -C 6 alkyl or an amino substituent is optionally substituted by hydroxy alkoxy of 1 to 6 carbon atoms, amino, mono- and di (C 1 -C 6 alkyl) amino, carboxy, alkylcarbonylamino of 1 to 6 carbon atoms, alkylaminocarbonyl of 1 to 6 carbon atoms or halogen (s); and R1, R2 and R3, when attached to a nitrogen atom, are independently selected from hydrogen, optionally substituted alkyl of 1 to 6 carbon atoms, hydroxy, optionally substituted C1-6 alkoxy, alkoxycarbonyl of 1 to 6 carbon atoms optionally substituted, optionally substituted alkylcarbonyl of 1 to 6 carbon atoms, formyl, mono- and di (C 1 -C 5 alkyl aminocarbonyl, amino, alkylcarbonylamino of 1 to 6 carbon atoms, mono- and di (Ci alkyl) -Ce) amino, alkylsulfonyl of 1 to 6 carbon atoms and alkylsulfinyl of 1 to 6 carbon atoms; wherein any alkyl of 1 to 6 carbon atoms as an amino substituent is optionally substituted by hydroxy, alkoxy of 1 to 6 carbon atoms, amino, mono- and di (alkyl Ci-Ce) amino, carboxy, alkylcarbonylamino of 1 to 6 carbon atoms, alkylaminocarbonyl of 1 to 6 carbon atoms or halogen (s) and wherein any aryl, heterocyclyl and heteroaryl can be optionally substituted; or wherein R1 and R2 together with the carbon and / or nitrogen atoms to which they are attached form a heterocyclic ring, a heteroaromatic ring, an aromatic ring or a carbocyclic ring; Z is CH or N; and X1 and X2 are independently selected from halogen, OR6, OCOR5, N (R6) 2, NHCOR5, NHS02R5 and NHCON (R6) 2, wherein R5 is selected from alkyl of 1 to 6 carbon atoms, optionally substituted aryl and heteroaryl optionally substituted and each R6 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted aryl and optionally substituted heteroaryl; and pharmaceutically acceptable salts and prodrugs thereof; for the preparation of a medicament for the treatment of cancer in a mammal. In one embodiment, R1, R2 and R3 are independently selected from hydrogen, halogen, optionally substituted alkyl of 1 to 6 carbon atoms, hydroxy, optionally substituted C1-6 alkoxy, alkoxycarbonyl of 1 to 6 carbon atoms substituted optionally, alkylcarbonyl of 1 to 6 carbon atoms optionally substituted, amino, alkylcarbonylamino of 1 to 6 carbon atoms, alkylcarbonylamino of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms, mono- and di (alkyl) Cß) aminosulfonyl, nitro, cyano and ono-and di (alkyl Ci-Ce) amino, wherein any alkyl of 1 to 6 carbon atoms as an amino substituent is optionally substituted by hydroxy, alkoxy of 1 to 6 carbon atoms, amino, mono- and di (Ci-Cß alkyl) amino, carboxy, alkylcarbonylamino of 1 to 6 carbon atoms, alkylaminocarbonyl of 1 to 6 carbon atoms or halogen (s); preferably, R1, R2 and R3 are independently selected from hydrogen, optionally substituted alkyl of 1 to 6 carbon atoms, hydroxy, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 alkoxycarbonyl, alkylcarbonyl of 1 to 6 carbon atoms optionally substituted, amino, alkylcarbonylamino of 1 to 6 carbon atoms, alkylcarbonylamino of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms, mono- and di (alkyl Ci-Cß) aminosulfonyl, nitro, cyano and mono- and di (Ci-Cß alkyl) amino, wherein any alkyl of 1 to 6 carbon atoms as an amino substituent is optionally substituted by hydroxy, alkoxy of 1 to 6 carbon atoms, amino, mono- and di (C 1 -C 6 alkyl) amino, carboxy, alkylcarbonylamino of 1 to 6 carbon atoms, alkylaminocarbonyl of 1 to 6 carbon atoms or halogen (s). In another embodiment, R1 and R2 together with the carbon atoms to which they are attached form a heterocyclic ring or a heteroaromatic ring. In yet another embodiment, R1 and R2 together with the carbon atoms to which they are attached form an aromatic ring or a carbocyclic ring. In preferred variants of the above aspect and embodiments, Z is CH. In the preferred, additional variants of the above aspect, the embodiments and a variant, X1 and X2 are independently selected from halogen, OR6, OCOR5, N (R6) 2, NHCOR5, NHS02R5 and NHCON (R6) 2, wherein R5 is selected from alkyl of 1 to 6 carbon atoms, optionally substituted aryl and optionally substituted heteroaryl and each R6 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted aryl and optionally substituted heteroaryl; in particular X1 and X2 are independently selected from halogen, OR6 and OCOR5, wherein R5 is selected from alkyl of 1 to 6 carbon atoms, optionally substituted aryl and optionally substituted heteroaryl and each R6 is independently selected from hydrogen, alkyl from 1 to 6 carbon atoms, optionally substituted aryl and optionally substituted heteroaryl. In the preferred, additional variants of the above aspect, the embodiments and variants, R1 and R2 are independently selected from hydrogen, halogen, alkyl of 1 to 6 carbon atoms, cyano, trifluoromethyl and alkoxy of 1 to 6 carbon atoms; R3 is selected from hydrogen, alkoxy of 1 to 6 carbon atoms, halogen, nitro, cyano and amino.

Alternative Modalities An alternative subclass of a compound applicable for the use defined hereinbefore, is as essentially defined above for the compounds of formula I, but with the modification that X 1 and X 2 are not the same. In a main embodiment thereof, one of X1 and X2 is as defined for X1 and X2 above, while the other of X1 and X2 is a carbon substituent, for example a substituent selected from alkyl of 1 to 6 carbon atoms. optionally substituted carbon, optionally substituted C 2 -C 6 alkenyl, carboxy, optionally substituted C 1 -C 6 alkoxycarbonyl, optionally substituted C 1 -C 6 alkylcarbonyl, formyl, carbamoyl, mono- and di (Ci alkyl) -Cβ) aminocarbonyl, cyano, aryl, arylcarbonyl, heterocyclyl, heterocyclylcarbonyl, heteroaryl, heteroarylcarbonyl, wherein any alkyl of 1 to 6 carbon atoms as an amino substituent is optionally substituted by hydroxy, alkoxy of 1 to 6 carbon atoms, amino , mono- and di (Ci-Cß alkyl) amino, carboxy, alkylcarbonylamino of 1 to 6 carbon atoms, alkylaminocarbonyl of 1 to 6 carbon atoms or halogen (s) and wherein any aryl or, heterocyclyl and heteroaryl can be optionally substituted. The remaining substituents are as defined above. Thus, a further aspect of the invention relates to the use of a compound of the 3,3-diphenyl-1,3-dihydro-indol-2-one type of the formula (Ie) wherein R1 is selected from hydrogen, halogen, alkyl of 1 to 6 carbon atoms, trifluoromethyl and alkoxy of 1 to 6 carbon atoms; R2 is selected from hydrogen, halogen, optionally substituted aryl, optionally substituted aryloxy and optionally substituted heteroaryl; R3 is selected from hydrogen, optionally substituted C1-6 alkoxy, halogen, optionally substituted cyano and aryl, optionally substituted aryloxy, optionally substituted heteroaryl, amine, alkylcarbonylamino of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 atoms carbon and mono- and di (C 1 -C 6 alkyl) aminosulfonyl; Z is CH or N; and one of X1 and X2 is selected from halogen, OR6, OCOR5, N (R6) 2, NHCOR5, NHS02R5 and NHCON (R6) 2, wherein R5 is selected from alkyl of 1 to 6 carbon atoms, aryl optionally substituted and optionally substituted heteroaryl and each R6 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted aryl and optionally substituted heteroaryl; and the other of X1 and X2 is selected from optionally substituted alkyl of 1 to 6 carbon atoms, optionally substituted alkenyl of 2 to 6 carbon atoms, carboxy, optionally substituted 1 to 6 carbon atoms, alkylcarbonyl of from 1 to 6. carbon atoms optionally substituted, formyl, carbamoyl, mono- and di (Ci-Cβ alkyl) aminocarbonyl, cyano, aryl, arylcarbonyl, heterocyclyl, heterocyclylcarbonyl, heteroaryl, heteroarylcarbonyl, wherein any alkyl of 1 to 6 carbon atoms as an amino substituent is optionally substituted by hydroxy, alkoxy 1 to 6 carbon atoms, amino, mono- and di (C 1 -C 5 alkyl) amino, carboxy, alkylcarbonylamino of 1 to 6 carbon atoms, alkylaminocarbonyl of 1 to 6 carbon atoms or halogen (s) and wherein aryl, heterocyclyl and heteroaryl can be optionally substituted; and pharmaceutically acceptable salts and prodrugs thereof (as further defined above); for the preparation of a medicament for the treatment of cancer in a mammal. The modalities defined in the above compound (Ha) also apply to the compound of the formula (He), mutatis mutantis.

A still further aspect of the invention relates to the use of a compound of type 3, 3-diphenyl-1,3-dihydro-indol-2-one of the formula (lid) wherein R1, R2 and R3, when attached to a carbon atom, are independently selected from hydrogen, optionally substituted alkyl of 1 to 6 carbon atoms, optionally substituted 2 to 6 carbon alkenyl, hydroxy, alkoxy of 1 optionally substituted at 6 carbon atoms, optionally substituted C 2 -C 6 alkenyloxy, carboxy, optionally substituted C 1 -C 6 alkoxycarbonyl, optionally substituted C 1 -C 6 alkylcarbonyl, alkylcarbonyloxy of 1 to 6 carbon atoms optionally substituted carbon, formyl, amino, mono- and di (C 1 -C 6 alkyl) amino, carbamoyl, mono- and di (C 1 -C 6 alkyl) aminocarbonyl, alkylcarbonylamino of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms, cyano, carbamido, mono- and di (C 1 -C 7 alkyl) aminocarbonylamino, C 1 -C 6 -alkanyloxy, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, aminosulfonyl, mono- and di (C 1 -C 6 alkyl) aminosulfonyl, nitro, optionally substituted C 1 -C 6 alkylthio and halogen, wherein any alkyl of 1 to 6 carbon atoms as an amino substituent is optionally substituted by hydroxy alkoxy of 1 to 6 carbon atoms, amino, mono- and di (alkyl Ci-Ce) amino, carboxy, alkylcarbonylamino of 1 to 6 carbon atoms, alkylaminocarbonyl of 1 to 6 carbon atoms or halogen (s); and R1, R2 and R3, when attached to a nitrogen atom, are independently selected from hydrogen, optionally substituted alkyl of 1 to 6 carbon atoms, hydroxy, optionally substituted C1-6 alkoxy, alkoxycarbonyl of 1 to 6 carbon atoms optionally substituted, optionally substituted alkylcarbonyl of 1 to 6 carbon atoms, formyl, mono- and di (Ci-C6 alkyl) aminocarbonyl, amino, alkylcarbonylamino of 1 to 6 carbon atoms, mono- and di (Ci alkyl) -Ce) amino, alkylsulfonyl of 1 to 6 carbon atoms and alkylsulfinyl of 1 to 6 carbon atoms; wherein any alkyl of 1 to 6 carbon atoms as an amino substituent is optionally substituted by hydroxy, alkoxy of 1 to 6 carbon atoms, amino, mono- and di (C 1 -C 6 alkyl) amino, carboxy, alkylcarbonylamino of 1 to 6 carbon atoms, alkylaminocarbonyl of 1 to 6 carbon atoms or halogen (s) and wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted; or wherein R1 and R2 together with the carbon and / or nitrogen atoms to which they are attached form a heterocyclic ring, a heteroaromatic ring, an aromatic ring 0 a carbocyclic ring; Z is CH or N; and one of X1 and X2 is selected from halogen, OR6, OCOR5, N (R6) 2, NHCOR5, NHS02R5 and NHCON (R6) 2 wherein R5 is selected from alkyl of 1 to 6 carbon atoms, optionally substituted aryl and heteroaryl optionally substituted and each R6 is independently selected from hydrogen, alkyl 1 to 6 carbon atoms, optionally substituted aryl and optionally substituted heteroaryl; and the other of X1 and X2 is selected from optionally substituted alkyl of 1 to 6 carbon atoms, optionally substituted C2 to C6 alkenyl, carboxy, optionally substituted C1 to C6 alkoxycarbonyl, alkylcarbonyl of 1 to 6. optionally substituted carbon atoms, formyl, carbamoyl, mono- and di (alkyl Ci-Ce) aminocarbonyl, cyano, aryl, arylcarbonyl, heterocyclyl, heterocyclylcarbonyl, heteroaryl, heteroarylcarbonyl, wherein any alkyl of 1 to 6 carbon atoms as a substituent of amino is optionally substituted by hydroxy, alkoxy of 1 to 6 carbon atoms, amino, mono- and di (C 1 -C 5 alkyl) amino, carboxy, alkylcarbonylamino of 1 to 6 carbon atoms, alkylaminocarbonyl of 1 to 6 carbon atoms or halogen (s) and wherein any aryl, heterocyclyl and heteroaryl can be optionally substituted; and pharmaceutically acceptable salts and prodrugs thereof; for the preparation of a medicament for the treatment of cancer in a mammal. The modalities defined for the above compound (Hb) are also applied for the compound of the formula (lid), mutatis mutantis. The currently very interesting compounds of the formula I are those listed in the following as objects 1 to 225: 1 5-Amino-6-chloro-3, 3-bis- (4-hydroxy-phenyl) -7-methyl-l, 3-dihydro-indol-2-one 2 5-Chloro-3, 3-bis- ( 4-hydroxy-phenyl) -7-methyl-l, 3-dihydro-indol-2-one 3 5-Fluoro-3, 3-bis- (4-hydroxy-phenyl) -1, 3-dihydro-indole-2 -one 4 3, 3-Bis- (4-hydroxy-phenyl) -5-nitro-l, 3-dihydro-indol-2-one-5,3,3-Bis- (4-hydroxy-phenyl) -7-methyl -l, 3-dihydro-pyrrolo [3, 2-c] pyridin-2-one 6 6-Bromo-3, 3-bis- (4-hydroxy-phenyl) -1,3-dihydropyrrolo [3, 2 -c] pyridin-2-one 7 6-Bromo-3, 3-bis- (4-hydroxy-phenyl) -7-methyl-1,3-dihydropyrrolo [3,2-c] pyridin-2-one 8 6-Bromo-3, 3-bis- (4-hydroxy-phenyl) -5,7-dimethyl-l, 3-dihydro-indol-2-one 9 6-Bromo-3, 3-bis- (4- hydroxy-phenyl) -7-methyl-2-oxo-2, 3-dihydro-lH-indole-5-carbonitrile 10 6-Bromo-3, 3-bis- (4-hydroxy-phenyl) -5-methoxy-7 -methyl-l, 3-dihydro-indol-2-one 11 6-Bromo-3, 3-bis- (4-hydroxy-phenyl) -7-methoxy-l, 3-dihydro-pyrrolo [3, 2-c ] pyridin-2-one; 12 6-Bromo-7-ethyl-3, 3-bis- (4-hydroxy-f-nyl) -1, 3-dihydro-pyrrolo [3,2-c] pyridin-2-one 13 6-Bromo-7- ethyl-3, 3-bis- (4-hydroxy-phenyl) -5-methyl-l, 3-dihydro-indol-2-one 14 6-Bromo-5-ethyl-3, 3-bis- (4-hydroxy) phenyl) -7-methyl-l, 3-dihydro-indol-2-one, 6-Bromo-7-ethyl-3, 3-bis- (4-hydroxy-phenyl) -2-oxo-2, 3- dihydro-lH-indole-5-carbonitrile 16 6-Bromo-7-ethyl-3, 3-bis- (4-hydroxy-phenyl) -5-methoxy-l, 3-dihydro-indol-2-one 17 6- Chloro-3, 3-bis- (4-hydroxy-phenyl) -1,3-dihydro-pyrrolo [3,2-c] pyridin-2-one 18 6-Chloro-3, 3-bis- (4-hydroxy) phenyl) -7-methyl-l, 3-dihydropyrrolo [3,2-c] pyridin-2-one 19 6-chloro-3, 3-bis- (4-hydroxy-phenyl) -5, 7- di ethyl-l, 3-dihydro-indol-2-one, 6-chloro-3, 3-bis- (4-hydroxy-phenyl) -7-methyl-2-oxo-2, 3-dihydro-1H-indole -5-carbonitrile 21 6-Chloro-3, 3-bis- (4-hydroxy-phenyl) -5-methoxy-7-methyl-1, 3-dihydro-indol-2-one 22 6-Chloro-3, 3 -bis- (4-hydroxy-phenyl) -7-methoxy-l, 3-dihydropyrrolo [3,2-c] pyridin-2-one 23 6-chloro-7-ethyl-3, 3-bis- ( 4-hydroxy-phenyl) -1,3-dihydro-pyrrolo [3,2-c] pyridin-2-one 24 6-chloro-7-ethyl-3, 3-bis- (4-hydroxy-phenyl) -5-methyl-1, 3 -dihydro-indole-2-one 25 6-Chloro-5-ethyl-3, 3-bis- (4-hydroxy-phenyl) -7-methyl-l, 3-dihydro-indol-2-one 26 6-Chlorine -7-ethyl-3, 3-bis- (4-hydroxy-phenyl) -2-oxo-2,3-dihydro-lH-indole-5-carbonitrile 27 6-chloro-7-ethyl-3, 3-bis - (4-hydroxy-phenyl) -5-methoxy-l, 3-dihydro-indol-2-one 28 6-Chloro-3,3-bis- (4-hydroxy-phenyl) -5-methyl-7-methoxy -l, 3-dihydro-indol-2-one; 29 6-Chloro-3, 3-bis- (4-hydroxy-phenyl) -7-methoxy-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile; 6-Chloro-3, 3-bis- (4-hydroxy-phenyl) -7-methoxy-l, 3-dihydro-pyrrolo [3, 2-c] pyridin-2-one; 31 6-Chloro-3, 3-bis- (4-hydroxy-phenyl) -7-methoxy-5-methyl-l, 3-dihydro-indol-2-one; 32 6-Chloro-5-ethyl-3, 3-bis- (4-hydroxy-phenyl) -7-methoxy-l, 3-dihydro-indol-2-one; 33 6-Chloro-3, 3-bis- (4-hydroxy-phenyl) -5,7-dimethoxy-1,3-dihydro-indol-2-one; 34 N-. { 4- [3- (4-Acetylamino-phenyl) -5-chloro-7-methyl-2-oxo-2,3-dihydro-lH-indol-3-yl] -phenyl} -acetamide; 35 N-. { 4- [5-Chloro-3- (4-methanesulfonylamino-phenyl) -7-methyl-2-OXO-2, 3-dihydro-lH-indol-3-yl] -phenyl} -methanesulfonamide 36 N-. { 4- [3- (4-Acetylamino-phenyl) -6-chloro-7-methyl-2-oxo-2,3-dihydro-lH-indol-3-yl] -phenyl} -acetamide; 37 N-. { 4- [6-Chloro-3- (4-methanesulfonylamino-phenyl) -7-methyl-2-OXO-2, 3-dihydro-lH-indol-3-yl] -phenyl} -methanesulfonamide; 38 N-. { 4- [3- (4-Acetylamino-phenyl) -5-chloro-7-methoxy-2-oxo-2,3-dihydro-lH-indol-3-yl] -phenyl} -acetamide; 39 N-. { 4- [5-Chloro-3- (4-methanesulfonylamino-phenyl) -7-methoxy-2-oxo-2,3-dihydro-lH-indol-3-yl] -phenyl} -methanesulfonamide; 40 N-. { 4- [3- (4-Acetylamino-phenyl) -6-chloro-7-methoxy-2-oxo-2,3-dihydro-lH-indol-3-yl] -phenyl} -acetamide; and 41 N-. { 4- [6-Chloro-3- (4-methanesulfonylamino-phenyl) -7-methoxy-2-oxo-2,3-dihydro-lH-indol-3-yl] -phenyl} -methanesulfonamide 42 2-Chloro-6,6-bis- (4-hydroxy-phenyl) -3-methyl-4,6-dihydro-3H-pyrrolo [2,3-d] imidazol-5-one 43 Ester 4- [6 - (4-acetoxy-phenyl) -2-chloro-3-methyl-5-oxo-3,4,5,6-tetrahydro-pyrrolo [2,3-d] imidazol-6-yl] -phenyl acetic acid 44 6, 6-Bis- (4-amino-phenyl) -2-chloro-3-methyl-4, 6-dihydro-3H-pyrrolo [2,3-d] imidazol-5-one 45 2-Chloro-6,6-bis- (4-dimethylamino-phenyl) -3-methyl-4,6-dihydro-3H -pyrrolo [2,3-d] imidazol-5-one 46 N-. { 4- [6- (4-Acetylamino-phenyl) -2-chloro-3-methyl-5-oxo-3,4,5,6-tetrahydro-pyrrolo [2,3-d] imidazol-6-yl] - phenyl } - acetamide 47 N-. { 4- [2-Chloro-6- (4-methanesulfonylamino-phenyl) -3-methyl-5-OXO-3, 4,5,6-tetrahydro-pyrrolo [2,3-d] imidazol-6-yl] - phenyl } -methanesulfonamide 48 4, -Bis- (4-hydroxy-phenyl) -l-methyl-4,6-dihydro-lH-pyrrolo [2,3-c] pyrazol-5-one 49 Ester 4- [4- (4 -acetoxy-phenyl) -l-methyl-5-oxo-l, 4,5,6-tetrahydro-pyrrolo [2,3-c] pyrazol-4-yl] -phenyl acetic acid 50 4, 4-Bis- (4-Amino-phenyl) -l-methyl-4,6-dihydro-lH-pyrrolo [2, 3-c] pyrazol-5-one 51N-. { 4- [4- (4-Methanesulfonylamino-phenyl) -l-methyl-5-oxo-1,4,5,6-tetrahydro-pyrrolo [2, 3-c] pyrazol-4-yl] -phenyl} -methanesulfonamide 52,4,4-Bis- (4-dimethylamino-phenyl) -l-methyl-4,6-dihydro-lH-pyrrolo [2,3-c] pyrazol-5-one 53 N-. { 4- [4- (4-Acetylamino-phenyl) -l-methyl-5-oxo-l, 4,5,6-tetrahydro-pyrrolo [2, 3-c] pyrazol-4-yl] -phenyl} -acetamide 54 4, 4-Bis- (4-hydroxy-phenyl) -2-methyl-2,6-dihydro-4H-pyrrolo [2, 3-c] pyrazol-5-one 55 Ester 4- [4- ( 4-Acetoxy-phenyl) -2-methyl-5-oxo-2,4,5,6-tetrahydro-pyrrolo [2,3-c] pyrazol-4-yl] -phenyl acetic acid 56 4, 4-Bis - (4-Amino-phenyl) -2-methyl-2, β-dihydro-4H-pyrrolo [2, 3-c] pyrazol-5-one 57 4, 4-Bis- (4-dimethylamino-phenyl) -2 -methyl-2,6-dihydro-4H-pyrrolo [2, 3-c] pyrazol-5-one 58 N-. { 4- [4- (4-Acetylamino-phenyl) -2-methyl-5-oxo-2,4,6,6-tetrahydro-pyrrolo [2, 3-c] pyrazol-4-yl] -phenyl} -acetamide 59 N-. { 4- [4- (4-Methanesulfonylamino-phenyl) -2-methyl-5-oxo-2,4,5,6-tetrahydro-pyrrolo [2, 3-c] pyrazol-4-yl] -phenyl} -methanesulfonamide 60 4, 4-Bis- (4-hydroxy-phenyl) -4,6-dihydro-thieno [2, 3-b] -pyrrol-5-one 61 Ester 4- [4- (4-acetoxy-phenyl ) -5-oxo-5,6-dihydro-4H-thieno [2,3-b] pyrrol-4-yl] -phenyl acetic acid 62,4,4-Bis- (4-amino-phenyl) -4, 6-dihydro-thieno [2, 3-b] -pyrrol-5-one 63 4, 4-Bis- (4-dimethylamino-phenyl) -4,6-dihydro-thieno [2,3-b] pyrrole-5 -one 64 N-. { 4- [4- (4-Acetylamino-phenyl) -5-oxo-5,6-dihydro-4H-thieno [2, 3-b] pyrrol-4-yl] -phenyl} -acetamide 65 N-. { 4- [4- (4-Methanesulfonylamino-phenyl) -5-oxo-5,6-dihydro-4H-thieno [2, 3-b] pyrrol-4-yl] -phenyl} -methanesulfonamide 66 2-Chloro-4, 4-bis- (4-hydroxy-phenyl) -4,6-dihydro-thieno [2, 3-b] pyrrol-5-one 67 Ester 4- [4- (4-acetoxy- phenyl) -2-chloro-5-oxo-5,6-dihydro-4H-thieno [2,3-b] pyrrol-4-yl] -phenyl acetic acid 68,4,4-Bis- (4-amino- phenyl) -2-chloro-4,6-dihydro-thieno [2, 3-b] pyrrol-5-one 69 2-Chloro-4, 4-bis- (4-dimethylamino-phenyl) -4,6-dihydro -tiene [2, 3-b] pyrrol-5-one 70 N-. { 4- [4- (4-Acetylamino-phenyl) -2-chloro-5-oxo-5,6-dihydro-4H-thieno [2, 3-b] pyrrol-4-yl] -phenyl} -acetamide 71 N-. { 4- [2-Chloro-4- (4-methanesulfonylamino-phenyl) -5-oxo-5,6-dihydro-4H-thieno [2, 3-b] pyrrol-4-yl] -phenyl} - ethanesulfonamide 72,4,4-Bis- (4-hydroxy-phenyl) -4,6-dihydro-furo [2,3-b] pyrrol-5-one 73 Ester 4- [4- (4-acetoxy-phenyl) -5-oxo-5,6-dihydro-4H-furo [2,3-b] pyrrol-4-yl] -phenyl acetic acid 74,4,4-Bis- (4-amino-phenyl) -4,6 -dihydro-furo [2, 3-b] pyrrol-5-one 75 4, 4-Bis- (4-dimethylamino-phenyl) -4,6-dihydro-furo- [2, 3-b] pyrrole-5- ona 76 N-. { 4- [4- (4-Acetylamino-phenyl) -5-oxo-5,6-dihydro-4H-furo [2, 3-b] pyrrol-4-yl] -phenyl} -acetamide 77 N-. { 4- [4- (4-Methanesulfonylamino-phenyl) -5-oxo-5,6-dihydro-4H-furo [2, 3-b] pyrrol-4-yl] -phenyl} -methanesulfonamide 78 2-Chloro-4, 4-bis- (4-hydroxy-phenyl) -4,6-dihydro-furo [2,3- b] pyrrol-5-one 79 Ester 4- [4- (4-acetoxy- phenyl) -2-chloro-5-oxo-5,6-dihydro-4H-furo [2,3-b] pyrrol-4-yl] -phenyl acetic acid 80 4, 4-Bis- (4-amino- phenyl) -2-chloro-4,6-dihydro-furo- [2, 3-b] pyrrol-5-one 81 2-Chloro-4, 4-bis- (-dimethylamino-phenyl) -4,6-dihydro -furo [2,3-b] pyrrol-5-one 82 N-. { 4- [4- (4-Acetylamino-phenyl) -2-chloro-5-oxo-5,6-dihydro-4H-furo [2, 3-b] pyrrol-4-yl] -phenyl} -acetamide 83 N-. { 4- [2-Chloro-4- (4-methanesulfonylamino-phenyl) -5-oxo-5,6-dihydro-4H-furo [2, 3-b] pyrrol-4-yl] -phenyl} - ethanesulfonamide 84 3, 3-Bis- (4-hydroxy-phenyl) -6-methyl-3,8-dihydro-lH-l, 8-diaza-as-indacen-2-one 85 Ester 4- [3- ( 4-acetoxy-phenyl) -6-methyl-2-oxo-l, 2, 3, 8-tetrahydro-1,8-diaza-as-indacen-3-yl] -phenyl acetic acid 86 3, 3-Bis - (4-Amino-phenyl) -6-methyl-3,8-dihydro-lH-l, 8-diaza-as-indacen-2-one 87 3, 3-Bis- (4-dimethylamino-phenyl) -6 -methyl-3, 8-dihydro-lH-1, 8-diaza-as-indacen-2-one 88 N-. { 4- [3- (4-Acetylamino-phenyl) -6-methyl-2-oxo-l, 2,3,8-tetrahydro-1,8-diaza-as-indacen-3-yl] -phenyl} -acetamide 89 N-. { 4- [3- (4-Methanesulfonylamino-phenyl) -6-methyl-2-oxo-1,2,3,8-tetrahydro-l, 8-diaza-as-indacen-3-yl] -phenyl} - methanesulfonamide 90 3, 3-Bis- (4-hydroxy-phenyl) -1, 3-dihydro-benzo [g] indole-2-one 91 Ester 4- [3- (4-acetoxy-phenyl) -2-oxo -2, 3-dihydro-lH-benzo [g] indol-3-yl] -phenyl acetic acid 92 3, 3-Bis- (4-amino-phenyl) -1,3-dihydro-benzo [g] indole -2-one 93 3, 3-Bis- (4-dimethylamino-phenyl) -1,3-dihydro-benzo [g] indol-2-one 94 N-. { 4- [3- (4-Acetylamino-phenyl) -2-oxo-2,3-dihydro-lH-benzo [g] indol-3-yl] -phenyl} -acetamide 95 N-. { 4- [3- (4-Methanesulfonylamino-phenyl) -2-oxo-2,3-dihydro-lH-benzo [g] indol-3-yl] -phenyl} -methanesulfonamide 96 l-Amino-6-chloro-3, 3-bis- (4-hydroxy-phenyl) -7-methyl-l, 3-dihydro-indol-2-one 97 Ester 4- [3- (4- acetoxy-phenyl) -l-amino-6-chloro-7-methyl-2-oxo-2,3-dihydro-lH-indol-3-yl] -phenyl acetic acid 98 N-. { 4- [3- (4-Acetylamino-phenyl) -l-amino-6-chloro-7-methyl-2-OXO-2,3-dihydro-lH-indol-3-yl] -phenyl} -acetamide 99 N-. { 4- [l-Amino-6-chloro-3- (4-methanesulfonylamino-phenyl) -7-methyl-2-oxo-2,3-dihydro-lH-indol-3-yl] -phenyl} -methanesulfonamide 100 Ester 4- [3- (4-acetoxy-phenyl) -l-acetylamino-6-chloro-7-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl] -phenyl from acetic acid 101 N- [3, 3-Bis- (4-amino-phenyl) -6-chloro-7-methyl-2-oxo-2, 3-dihydro-indol-1-yl] -acetamide 102 N- [ β-Chloro-3, 3-bis- (4-dimethylamino-phenyl) -7-methyl-2-oxo-2,3-dihydro-indol-1-yl] -acetamide 103 N- [3, 3-Bis- (4-Acetylamino-phenyl) -6-chloro-7-methyl-2-oxo-2,3-dihydro-indol-1-yl] -acetamide 104 N- [β-Chloro-3, 3-bis- (4 -methanesulfonylamino-phenyl) -7-methyl-2-oxo-2,3-dihydro-indol-l-yl] -acetamide 105 6-Chloro-3, 3-bis- (4-hydroxy-phenyl) -7-methyl -l, 3-dihydro-indole-2-thione 106 Ester 4- [3- (4-acetoxy-phenyl) -6-chloro-7-methyl-2-thioxo-2, 3-dihydro-lH-indol-3-yl] -phenyl acetic acid 107 3, 3-Bis- (4-amino-phenyl) -6-chloro-7-methyl-l, 3-dihydro-indole-2 -thione 108 6-Chloro-3, 3-bis- (4-dimethylamino-phenyl) -7-methyl-1,3-dihydro-indol-2-thione 109 N-. { 4- [3- (4-Acetylamino-phenyl) -6-chloro-7-methyl-2-thioxo-2,3-dihydro-lH-indol-3-yl] -phenyl} -acetamide 110 Ester 4- [6-chloro-3- (4-methanesulfonyloxy-phenyl) -7-methyl-2-thioxo-2,3-dihydro-lH-indol-3-yl] -phenyl methanesulfonic acid 111 Ester 4- [4- (4-acetoxy-phenyl) -2-chloro-5-thioxo-5,6-dihydro-4H-thieno [2,3-b] pyrrol-4-yl] -phenyl acetic acid 112 Ester 4- [4- (4-acetoxy-phenyl) -2-chloro-5-thioxo-5,6-dihydro-4H-furo [2,3-b] pyrrol-4-yl] -phenyl acetic acid 113 6, 6-Bis- (4-amino-phenyl) -2-chloro-3-methyl-4,6-dihydro-thieno [3,2-b] pyrrole-5-thione 114 2-Chloro-6,6 -bis- (4-dimethylamino-phenyl) -3-methyl-4,6-dihydro-3H-pyrrolo [2,3-d] imidazole-5-thione 115 N-. { 4- [6- (4-Acetylamino-phenyl) -3-chloro-5-thioxo-1,4,6,6-tetrahydro-pyrrolo [3,2-c] pyrazol-6-yl] -phenyl} -acetamide 116 Ester 4- [2-chloro-4- (4-methanesulfonyloxy-phenyl) -5-thioxo-5,6-dihydro-4H-furo [2, 3-b] pyrrol-4-yl] -phenyl from methanesulfonic acid 117 6-chloro-7-cyclopropyl-3, 3-bis- (4-hydroxy-phenyl) -1,3-dihydro-indol-2-one 118 6-chloro-7-cyclopropyl-3, 3-bis - (4-hydroxy-phenyl) -1,3-dihydro-pyrrolo [3,2-c] pyridin-2-one 119 6-Chloro-3, 3-bis- (4-hydroxy-phenyl) -7-trifluoromethyl -1,3-dihydro-indol-2-one 120 6-Chloro-3, 3-bis- (4-hydroxy-phenyl) -7-trifluoromethyl-1,3-dihydro-pyrrolo [3,2-c] pyridine -2-one 121 6-Chloro-7-cyclopropoxy-3, 3-bis- (4-hydroxy-phenyl) -1,3-dihydro-indol-2-one 122 6-Chloro-7-cyclopropoxy-3, 3 -bis- (4-hydroxy-phenyl) -1,3-dihydro-pyrrolo [3,2-c] pyridin-2-one 123 6- (4-Fluoro-phenoxy) -3,3-bis- (4- hydroxy-phenyl) -7-trifluoromethyl-1,3-dihydro-indol-2-one 124 Ester 4- [3- (4-acetoxy-phenyl) -6-chloro-7-cyclopropyl-2-oxo-2,3 -dihydro-lH-indol-3-yl] -phenyl acetic acid 125 Ester 4- [3- (4-acetoxy-phenyl) -6-chloro-7-cyclopropyl-2-oxo-2,3-dihydro-lH-pyrrolo [3,2-c] pyridin-3-yl] - phenyl of acetic acid 126 Ester 4- [3- (4-acetoxy-phenyl) -6-chloro-2-oxo-7-trifluoro-methyl-2, 3-dihydro-lH-indol-3-yl] -phenyl of acetic acid 127 Ester 4- [3- (4-acetoxy-phenyl) -6-chloro-2-oxo-7-trifluoro-methyl-2,3-dihydro-lH-pyrrolo [3,2-c] pyridin-3-yl ] - acetic acid phenyl 128 Ester 4- [3- (4-acetoxy-phenyl) -6-chloro-7-cyclopropoxy-2-oxo-2,3-dihydro-lH-indol-3-yl] -phenyl ester acetic acid 129 Ester 4- [3- (4-acetoxy-phenyl) -6-chloro-7-cyclopropoxy-2-oxo-2,3-dihydro-lH-pyrrolo [3,2-c] pyridin-3-yl] - phenyl acetic acid 130 Ester 4- [3- (4-acetoxy-phenyl) -6- (4-fluoro-phenoxy) -2-oxo-7-trifluoromethyl-2,3-dihydro-lH-indol-3-yl ] - acetic acid phenyl 131 Ester 4-. { 6-Chloro-7-cyclopropyl-3- [4- (2-dimethylamino-acetoxy) -phenyl] -2-oxo-2,3-dihydro-lH-indol-3-yl} -phenylamino-acetic acid phenyl 132 Ester 4-. { 6-Chloro-7-cyclopropyl-3- [4- (2-dimethylamino-acetoxy) -phenyl] -2-oxo-2,3-dihydro-lH-pyrrolo [3,2-c] pyridin-3-yl} -phenylamino-acetic acid phenyl 133 Ester 4-. { 6-Chloro-3- [4- (2-dimethylamino-acetoxy) -phenyl] -7-methyl-2-oxo-2,3-dihydro-lH-indol-3-yl} phenyl-dimethylamino-acetic acid 134 6-chloro-3, 3-bis- (4-hydroxy-phenyl) -7-trifluoromethoxy-1,3-dihydro-indol-2-one 135 Ester 4- [3- (4 -acetoxy-phenyl) -6-chloro-2-oxo-7-trifluoromethoxy-2,3-dihydro-lH-indol-3-yl] -phenyl acetic acid 136 Ester 4-. { 6-Chloro-3- [4- (2-dimethylamino-acetoxy) -phenyl] -2-oxo-7-trifluoromethoxy-2,3-dihydro-lH-indol-3-yl} phenyl-dimethylaminoacetic acid 137 6-Chloro-4-fluoro-3, 3-bis- (4-hydroxy-phenyl) -7-methyl-l, 3-dihydro-indol-2-one 138 3-Chloro- 7, 7-bis- (4-hydroxy-phenyl) -4-methyl-5,7-dihydro-pyrrolo [3,2-c] pyridazin-6-one 139 Ester 4- [3- (4-acetoxy-phenyl ) -6-chloro-4-fluoro-7-methyl-2-oxo-2,3-dihydro-lH-indol-3-yl] -phenyl acetic acid 140 Ester 4- [3- (4-Acetoxy-phenyl) -6-chloro-4,7-dimethyl-2-oxo-2,3-dihydro-lH-indol-3-yl] -phenyl acetic acid 141 Ester 4- [7- (4-acetoxy-phenyl) -3-chloro-4-methyl-6-oxo-6,7-dihydro-5H-pyrrolo [3,2-c] pyridazin-7-yl] -phenyl from acetic acid 142 6-Chloro-4,5-difluoro-3, 3-bis- (4-hydroxy-phenyl) -7-methyl-1,3-dihydro-indol-2-one 143 Ester 4- [3- ( 4-Acetoxy-phenyl) -6-chloro-4,5-difluoro-7-methyl-2-oxo-2,3-dihydro-lH-indol-3-yl] -phenyl acetic acid 144 3, 3-Bis - (4-hydroxy-phenyl) -3,6,7,8-tetrahydro-lH-l-aza-as-indacen-2-one 145 3, 3-Bis- (-hydroxy-phenyl) -1,3, 6,7,8,9-hexahydrobenzo [g] indol-2-one 146 3, 3-Bis- (4-hydroxy-phenyl) -7-trifluoromethyl-1,3-dihydro-indol-2-one 147 7-Chloro-3, 3-bis- (4-hydroxy-phenyl) -1,3-dihydro-indol-2-one 148 3, 3-Bis- (4-hydroxy-phenyl) -2-oxo-2, 3-dihydro-lH-indol-7-carbonitrile 149 7-Ethyl-3, 3-bis- (4-hydroxy-phenyl) -1,3-dihydro-indol-2-one 150 3, 3-Bis- (4-hydroxy-phenyl) -7-morpholin-4-yl-1, 3 -dihydro-indole-2-one 151 3, 3-bis- (4-hydroxy-phenyl) -7-isopropyl-l, 3-dihydro-indol-2-one 152 7-tert-butyl-3, 3-bis - (4-hydroxy-phenyl) -1,3-dihydro-indol-2-one 153 3,3-bis- (4-hydroxy-phenyl) -2-oxo-2,3-dihydro-lH- acid dimethylamide indole-7-carboxylic acid 154 3, 3-Bis- (4-hydroxy-phenyl) -7- (4-methyl-piperazine-1-carbonyl) -1,3-dihydro-indol-2-one 155 Acid 3, 3 -bis- (4-hydroxy-phenyl) -2-oxo-2,3-dihydro-lH-indole-5-carboxylic acid 3, 3-bis- (4-hydroxy-phenyl) -2-oxo-3-dimethylamide 2,3-dihydro-lH-indole-5-carboxylic acid 3, 3-Bis- (4-hydroxy-phenyl) -5- (morpholine-4-carbonyl) -1, 3-dihydro-indol-2-one 3, 3-Bis- (4-hydroxy-phenyl) -4-methoxy-1,3-dihydro-indol-2-one 159 3, 3-Bis- (4-hydroxy-phenyl) -6-methoxy-1, 3-Dihydro-indol-2-one 160 3, 3-Bis- (4-hydroxy-phenyl) -5- (4-methyl-piperazine-1-carbonyl) -1,3-dihydro-indol-2-one 161 6-Chloro-3, 3-bis- (4-merca) pto-phenyl) -7-methyl-l, 3-dihydro-indol-2-one 162 N-. { 4- [3- (4-Acetylamino-phenyl) -7-methyl-2-oxo-2,3-dihydro-lH-indol-3-yl] -phenyl} -acetamide 163 3, 3-Bis- (4-hydroxy-phenyl) -7- (3-methoxy-prop-1-ynyl) -1,3-dihydro-indol-2-one 164 3, 3-Bis- ( 4-hydroxy-phenyl) -7-pyridin-3-yl-l, 3-dihydro-indol-2-one 165 7-Bromo-3, 3-bis- (4-hydroxy-phenyl) -1, 3-dihydro -indol-2-one 166 6-Chloro-3, 3-bis- (4-methanesulfonyl-f-enyl) -7-methyl-1,3-dihydro-indol-2-one 167 6, 6-Bis- ( 4-hydroxy-f-enyl) -4,6-dihydro-pyrrolo [3,2-d] thiazol-5-one 168 6,6-Bis- (4-hydroxy-phenyl) -2-methyl-4,6- dihydro-pyrrolo [3,2-d] thiazol-5-one 169 6,6-Bis- (4-hydroxy-phenyl) -2-isopropyl-4,6-dihydropyrrolo [3,2-d] thiazole- 5-one 170 2-Chloro-6, 6-bis- (4-hydroxy-phenyl) -4,6-dihydropyrrolo [3,2-d] thiazol-5-one 171 4, 4-Bis- (4 -hydroxy-phenyl) -4,6-dihydro-pyrrolo [3,2-d] -isothiazol-5-one 172 3, 3-Bis- (4-hydroxy-phenyl) -7-methyl-1,3-dihydro - pyrrolo [2, 3-c] pyridin-2-one 173 3, 3-Bis- (4-hydroxy-phenyl) -7-methyl-1,3-dihydro-pyrrolo [3, 2-b] pyridin-2 -one 174 3, 3-Bis- (4-fluoro-phenyl) -7-methyl-l, 3-dihydro-pyrrolo [3, 2-b] pyri din-2-one 175 3, 3-Bis- (4-fluoro-phenyl) -7-methyl-1,3-dihydro-pyrrolo [3,2-c] pyridin-2-one 176 3, 3-Bis- (4-fluoro-phenyl) -7-isopropyl-l, 3-dihydro-pyrrolo [3,2-c] pyridin-2-one 177 3, 3-Bis- (4-hydroxy-phenyl) -3,6, 7,8-tetrahydro-lH-l, 5-diaza-as-indacen-2-one 178 3, 3-Bis- (4-hydroxy-phenyl) -3,6,7,8-tetrahydro-lH-1, 4-diaza-as-indacen-2-one 179 3, 3-Bis- (4-hydroxy-phenyl) -1, 3, 6, 7, 8, 9-hexahydro-pyrrolo [3, 2-c] quinoline- 2-one 180 3, 3-Bis- (4-hydroxy-phenyl) -1, 3,6,7,8, 9-hexahydro-pyrrolo [3,2-c] isoquinolin-2-one 181 5-Fluoro- 3, 3-bis- (4-hydroxy-phenyl) -3,6,7,8-tetrahydro-l-aza-as-indacen-2-one 182 7-Ethyl-5-fluoro-3, 3- bis- (4-hydroxy-phenyl) -1,3-dihydro-indol-2-one 183 3, 3-Bis- (4-hydroxy-phenyl) -1,3,6,8-tetrahydro-7-oxa- l-aza-as-indacen-2-one 184 3, 3-Bis- (4-hydroxy-phenyl) -1,3,7,8-tetrahydro-6-oxa-1-aza-as-indacen-2 ona 185 3, 3-Bis- (4-hydroxy-phenyl) -1,6,7,9-tetrahydro-3H-8-oxa-1-aza-cyclopenta [a] naphthalen-2-one 186 3,3- Bis- (4- hydroxy-phenyl) -l, 7,8,9-tetrahydro-3H-pyran [2, 3-g] indol-2-one 187 3, 3-Bis- (4-hydroxy-phenyl) -7-methyl-3 , 6, 7, 8-tetrahydro-1H-1, 7-diaza-as-indacen-2-one 188 3, 3-Bis- (4-hydroxy-phenyl) -7-methyl-1,3,7,8 -tetrahydro-1, 7-diaza-as-indacen-2, 6-dione 189 3, 3-Bis- (4-hydroxy-phenyl) -7,8,8-trimethyl-1,3,7,8-tetrahydro -1,7-diaza-as-indacen-2,6-dione 190 3, 3-Bis- (4-hydroxy-phenyl) -5-iodo-l, 3-dihydro-indol-2-one 191 5-Amino -3, 3-bis- (4-hydroxy-phenyl) -1, 3-dihydro-indol-2-one 192 5-Amino-3, 3-bis- (4-hydroxy-phenyl) -7-methyl-1 , 3-dihydro-indol-2-one 193 6-Bromo-3, 3-bis- (4-hydroxy-phenyl) -7-methyl-l, 3-dihydro-indol-2-one 194 7-Fluoro-3 , 3-bis- (4-hydroxy-phenyl) -1, 3-dihydro-indol-2-one 195 3,3-Bis- (4-hydroxy-phenyl) -7-methoxy-l, 3-dihydro-indole -2- ona 196 4, 7-Dichloro-3, 3-bis- (4-hydroxy-phenyl) -1, 3-dihydro-indol-2-one 197 6-Chloro-3, 3-bis- (4- hydroxy-phenyl) -1, 7-dimethyl-l, 3-dihydro-indol-2-one 198 6-Chloro-3, 3-bis- (4-fluoro-phenyl) -7-methyl-1,3-dihydro-indol-2-one 199 3, 3-Bis- (4-hydroxy-phenyl) -7- (morpholine-4-carbonyl) -1, 3-dihydro-indol-2-one 200 3, 3-Bis- (4-hydroxy-phenyl) -1, 3-dihydro-pyrrolo [2,3-d] pyridin-2-one 201 N-. { 4- [6-Chloro-3- (4-methanesulfonylamino-phenyl) -7-methyl-2-OXO-2, 3-dihydro-lH-indol-3-yl] -phenyl} -methanesulfonamide 202 3, 3-Bis- (4-hydroxy-phenyl) -4,7-dimethyl-1,3-dihydro-indol-2-one 203 3, 3-Bis- (4-hydroxy-phenyl) -7-iodine -l, 3-dihydro-indol-2-one 204 3, 3-Bis- (4-hydroxy-phenyl) -7-pyridin-4-yl-l, 3-dihydro-indol-2-one 205 Ester 4- [3- (4-acetoxy-phenyl) -6-chloro-7-methyl-2-oxo-2,3-dihydro-lH-indol-3-yl] -phenyl acetic acid 206 3,3-Bis- ( 4-hydroxy-phenyl) -5-phenyl-1,3-dihydro-indol-2-one 207 3, 3-Bis- (4-hydroxy-phenyl) -7-thiophen-2-yl-l, 3-dihydro - indol-2-one 208 3, 3-Bis- (4-hydroxy-phenyl) -5-pyridin-4-yl-l, 3-dihydro-indol-2-one 209 3, 3-Bis- (4- hydroxy-phenyl) -5-thiophen-2-yl-l, 3-dihydro-indol-2-one 210 5,7-Difluoro-3, 3-bis- (4-hydroxy-phenyl) -1,3-dihydro - indol-2-one 211 6-Fluoro-3, 3-bis- (4-hydroxy-phenyl) -7-methyl-l, 3-dihydro-indol-2-one 212 3, 3-Bis- (4- hydroxy-phenyl) -6-methoxy-7-methyl-l, 3-dihydro-indol-2-one 213 6,7-Difluoro-3, 3-bis- (-hydroxy-phenyl) -1,3-dihydro- indole-2-one 214 6-chloro-7-fluoro-3, 3-bis- (4-hydroxy-phenyl) -1, 3-dihydro-indol-2-one 215 5-Flu Gold-3, 3-bis- (4-hydroxy-phenyl) -7-methyl-1,3-dihydro-indol-2-one 216,3-Bis- (4-hydroxy-phenyl) -5-methoxy- 7-methyl-l, 3-dihydro-indol-2-one 217 3, 3-Bis- (4-hydroxy-phenyl) -1,3-dihydro-pyrrolo [2,3-b] -pyridin-2-one 218 7-Chloro-3, 3-bis- (4-hydroxy-phenyl) -4-methoxy-l, 3-dihydro-indol-2-one 219 6-Fluoro-3, 3-bis- (4-hydroxy) phenyl) -1,3-dihydro-indol-2-one 220 N- [3, 3-Bis- (4-hydroxy-phenyl) -2-oxo-2,3-dihydro-indol-l-yl] -acetamide 221 5- [3, 3-bis- (4-hydroxy-phenyl) -7-methyl-2-oxo-2, 3-dihydro-lH-indol-6-yloxy] -pentanoic acid methyl ester 222 Acid 5- [3, 3-bis- (4-hydroxy-phenyl) -7-methyl-2-oxo-2, 3-dihydro-lH-indol-6-yloxy] -pentanoic acid 223 Methyl ester of 5- [3, 3] -bis- (4-hydroxy-phenyl) -7-methyl-2-oxo-2,3-dihydro-lH-indol-5-yloxy] -pentanoic acid 224 5- [3,3-bis- (4-hydroxy phenyl) -7-methyl-2-oxo-2,3-dihydro-lH-indol-5-yloxy] -pentanoic acid 225 7-chloro-6-fluoro-3, 3-bis- (4-hydroxy-phenyl) -1, 3-dihydro-indol-2-one.

Method of treatment A further aspect of the present invention relates to a method for treating a mammal suffering from or being susceptible to cancer, the method comprising administering to the mammal a therapeutically effective amount of a compound defined hereinbefore. The conditions with respect to the dosage, administration, etc. can be as defined further below.

Biological Effects The present inventors have discovered that it is shown that many compounds of the general formula (I) inhibit the proliferation of MDA-468 cells at lower concentrations than those required to inhibit the proliferation of MDA-231 cells. A possible mechanism to explain this discovery is the selective inhibition of protein synthesis by the compounds of the general formula (I) in the MDA-468 cells compared to the MDA-231 cells. The current hypothesis is that the compounds of the general formula (I) inhibit the synthesis of proteins by means of the selective inhibition of the activation of the mTOR pathway and / or other biochemical pathways involved in the regulation of protein synthesis. The selective inhibition of the activation of the mTOR pathway by the compounds of the general formula (I) in the Western blotting assays correlates with the data of cell proliferation and protein synthesis. This suggests that the detection of mTOR pathway activity by measuring the phosphorylation status of either p70S6K, 4E-BP1 or S6K using antibodies specific for phosphorus or total proteins by the Western blot or ELISA assay, or a measurement of p70S6K kinase activity, in samples of tumor material or blood from the patient, can provide a useful method for selecting patients who will respond to compounds of the general formula (I). Alternatively, the measurement of the phosphorylation status of p70S6K or S6K using antibodies specific for phosphorus or the activity of the p70S6K kinase, in samples of tumor material or blood can provide a useful biomarker for determining the drug dosage of the compounds of the general formula (I) in clinical trials in humans. Compounds for medical use In addition to the more specific medical use summarized above, it is also believed that most of the compounds defined in this document are generally applicable for medical use. Thus, in a further aspect, the present invention relates to a compound as defined hereinbefore for use as a medicament, with the proviso that the compound is not one selected from 3, 3-bis (4- hydroxy-phenyl) -1,3-dihydro-indol-2-one and the ester 4- [3- (4-acetoxy-phenyl) -2-oxo-2,3-dihydro-lH-indol-3-yl] phenyl of acetic acid. Particularly interesting compounds of the formula (i) are those of the formulas (Ha), (Hb), (He) and (lid) defined above.

Novel compounds As mentioned in the introductory section, some compounds according to the general formula (1) have been described in the literature and the biological effects (unrelated) have been previously described for some of these compounds. Thus, a still further aspect of the present invention relates to a compound of the formula (I) as defined further above, with the proviso that the compound is not one selected from 3, 3-bis- (4-hydroxy-phenyl) -1,3-dihydro-indol-2-one, 3, 3-bis- (4-hydroxy-phenyl) -7-methyl-1,3-dihydro-indol-2-one; 3, 3-bis- (4-hydroxy-phenyl) -4,5-dimethyl-1,3-dihydro-indol-2-one; 3, 3-bis- (4-hydroxy-phenyl) -5,7-dimethyl-1,3-dihydro-indol-2-one; 5-bromo-3, 3-bis- (4-hydroxy-phenyl) -1,3-dihydro-indol-2-one; 5-chloro-3, 3-bis- (4-hydroxy-phenyl) -1,3-dihydro-indol-2-one; 3, 3-bis- (4-hydroxy-phenyl) -5-methoxy-1,3-dihydro-indol-2-one; 3, 3-bis- (4-hydroxy-phenyl) -5-methyl-1,3-dihydro-indol-2-one; 6-chloro-3, 3-bis- (4-hydroxy-phenyl) -7-methyl-l, 3-dihydro-indol-2-one; 4- [3- (4-acetoxy-phenyl) -2-oxo-2,3-dihydro-1H-indol-3-yl] -phenyl acetic acid ester; and 4- [3- (4-acetoxy-phenyl) -5-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl] -phenyl ester of acetic acid. The specification of the compound of the formula (I) and the preferences are as described above in this document. In particular, the preferred compounds of the formula (I) are those of the formulas (Ha), (Hb), (He) and (Hd) defined above.

Preparation of compounds of the formula (I) and the formulas (Ha) - (lid) The compounds can be synthesized generally as described in the Examples section.

Formulation of pharmaceutical compositions The compound of the formula (I) (and the more specific compound of the formula (II)) is suitably formulated in a pharmaceutical composition to suit the desired route of administration. The route of administration of the compounds can be any suitable route which leads to a concentration in the blood or tissue corresponding to a therapeutically effective concentration. Thus, for example, the following administration routes may be applicable although the invention is not limited thereto: the oral route, parenteral route, cutaneous route, nasal route, rectal route, vaginal route and ocular route. It should be clear to a person skilled in the art that the route of administration is dependent on the particular compound in question; particularly, the selection of the route of administration depends on the physico-chemical properties of the compound together with the age and weight of the patient and the particular disease or condition and the severity thereof. The compounds may be contained in any suitable amount in a pharmaceutical composition and are generally contained in an amount of about 1-95%, for example 1-10%, by weight of the total weight of the composition. The composition can be presented in a dosage form that is suitable for the oral, parenteral, rectal, cutaneous, nasal, vaginal and / or ocular route of administration. In this way, the composition may be in the form of, for example, tablets, capsules, pills, powders, granules, suspensions, emulsions, solutions, gels including hydrogels, pastes, ointments, creams, plasters, liquid medicaments, delivery devices. , suppositories, enemas, injectable solutions, implants, sprays, aerosols and in another suitable form. The pharmaceutical compositions can be formulated in accordance with conventional pharmaceutical practice, see, for example, "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. The pharmaceutically acceptable carriers or excipients are those known to the person skilled in the art. The formation of suitable salts of the compounds of formula I will also be apparent in view of the above. In this way, the present invention provides in a further aspect a pharmaceutical composition comprising a compound of the general formula I in combination with a pharmaceutically acceptable carrier. The compound is preferably one of those defined according to the "Compounds for medical use". In a particular embodiment, the compound is as defined according to the "novel compounds", ie the novel compounds of the Formula (I) and Formula (II), respectively.

The pharmaceutical compositions according to the present invention can be formulated to release the active compound substantially immediately after administration or at any substantially predetermined time or a period of time after administration. The latter type of compositions is generally known as controlled release formulations. In the present context, the term "controlled release formulation" includes i) formulations that create a substantially constant concentration of the drug within the body for an extended period of time, ii) formulations that after a predetermined delay time create a substantially constant concentration of the drug within the body during an extended period of time, iii) formulations that sustain the action of the drug for a predetermined period of time by maintaining an effective, relatively constant drug level in the body with a concomitant minimization of undesirable side effects that are associated with fluctuations in the level in the plasma of the active substance of the drug (kinetic pattern of sawtooth), iv) formulations that attempt to localize the action of the drug by means of, for example, the spatial placement of a controlled release composition adjacent to or in the tissue or sick organ, v) formula which attempt to target the action of the drug by using carriers or chemical derivatives to deliver the drug to a particular type of target cell. Controlled release formulations may also be indicated as "sustained release", "prolonged release", "programmed release", "predetermined time release", "controlled rate" and / or "targeted release" formulations. Controlled release pharmaceutical compositions can be presented in any suitable dosage form, especially in dosage forms proposed 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 proposed for oral, parenteral, cutaneous, nasal, vaginal or ocular use . The preparation of solid dosage forms for oral use, controlled release oral dosage forms, fluid liquid compositions, parenteral compositions, parenteral controlled release compositions, rectal compositions, nasal compositions, percutaneous and topical compositions, percutaneous compositions and topical release Controlled and compositions for administration to the eyes will be well known to those skilled in the field 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 binding substances; starch or lactose as excipients; stearates as lubricants; various sweetening or flavoring agents. For capsules, the dosage unit may contain a liquid carrier such as fatty oils. Similarly, coatings of sugar or enteric agents may be part of the dosage unit. The pharmaceutical compositions can also be emulsions of the compound (s) and a lipid that forms a micellular emulsion. For parenteral, subcutaneous, intradermal or topical administration, the pharmaceutical composition may include a sterile diluent, buffers, tonicity regulators and antibacterial agents. The active compound can be prepared with carriers that protect against degradation or immediate elimination of 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 a unit dosage form. In these embodiments, each unit dosage form typically comprises 0.1-500 mg, such as 0.1-200 mg, for example 0.1-100 mg of the compound. More generally, the compounds are preferably administered in an amount of about 0.1-250 mg per kg of body weight per day, such as about 0.5-100 mg per kg of body weight per day. For compositions adapted for oral administration for systemic use, the dosage is usually 0.5 mg to 1 g per dose administered 1-4 times per day for 1 week to 12 months depending on the disease being treated. The dosage for oral administration of the composition in order to prevent diseases or conditions is usually from 1 mg to 100 mg per kg of body weight per day. The dosage can be administered once or twice a day for a period starting from 1 week before exposure to the disease until 4 weeks after exposure.

For compositions adapted for rectal use to prevent disease, a somewhat higher amount of the compound, i.e. from about 1 mg to 100 mg per kg of body weight per day, is usually preferred. For parenteral administration, a dose of about 0.1 mg to about 100 mg per kg of body weight per day is desirable. For intravenous administration, a dose of about 0.1 mg to about 20 mg per kg of body weight per day administered for 1 day to 3 months is convenient. For intra-articular administration, a dose of about 0.1 mg to about 50 mg per kg of 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 can be employed. For topical administration to the skin, a dose of about 1 mg to about 5 mg administered 1-10 times per day for 1 week to 12 months is usually preferable.

Treatment in combination In an interesting embodiment of the present invention, the compound of the general formula (I) or the general formula (II) is used therapeutically in combination with one or more other chemotherapeutic agents. Examples of these 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, decarbazine, doxorubicin, epirubicin, estramustine, diethylstilbestrol, fludarabine, flutamide, 5-fluorouracil, gemcitabine, goserelin, idarubicin, irinotecan, levamisole, lomustine, mechloratamine, alkene, mercaptopurine, taxol (for example, paclitaxel). In particular, the additional chemotherapeutic agent is selected from taxanes such as Taxol, Paclitaxel and Docetaxel. Thus, with respect to the use and method of treatment defined herein, the medicament may further comprise one or more different chemotherapeutic agents. With respect to the pharmaceutical composition defined herein, this composition may further comprise one or more different chemotherapeutic agents.

EXAMPLES Materials: The following cell lines were obtained from ATCC: MDA-MB-231, MDA-MB-435S, MDA-MB-453, MDA-MB-468, SKBr-3, BT-474, BT-549, MCF -7, MCF10A, T-47D, ZR75-1, HCC-1954, DU-145, PC-3, LnCaP, and Colo205. PC-3 / M was obtained from NCI. Terfenadine1411 was obtained from Sigma-Aldrich. Penicillin-Streptomycin and gentamicin were purchased from Invitrogen. The Alamar Blue reagent is from BioSource. The starting materials, reagents and solvents for chemical synthesis were obtained from commercial sources unless otherwise stated. Oxyfenisatin (Commercial A) and 7-methyl-oxypheisatin (Commercial B) were also obtained from commercial sources.

Example 1: Procedures for the preparation of isatin derivatives The isatin derivatives used as intermediates can be obtained by means of either the Protocol A or Protocol B. Protocol A, based on literature procedures, was used to generate aromatic isatins with either electron donor substituents (see Stolle: J. Prakt. Chem. (1922), 105, 137 and Sandmeyer: Helv. Chim.

Acta (1919), 2, 234) or a 5-member electron-rich heteroaromatic portion (see Shvedor et al.

(Chem. Heterocycl, Compd. Engl. Transí (1975), 11, 666). Examples of the preferred 5-membered heterocycles are thiophenes (VX = S, V2 = V3 = C (-) and V4 = bond; V2 = S, VX = V3 = C (-) and V = bond or V3 = S, VX = V2 = C (-) and V4 = link), furans (VX = 0, V2 = v3 = C (-) and V4 = link; V2 = 0, VX = V3 = C (-) and V4 = link or V3 = 0, V ^ V ^ CÍ-) and V = bond), pyrazoles (VX = N (-), V2 = N, V3 = C (-) and V4 = bond; V1 = N, V2 = N (- ), V3 = C (-) and V4 = bond) and imidazoles (VX = N (-), V2 = C (-), V3 = N and V4 = bond; VX = N, V2 = C (-), V3 = N (-) and V4 = link). Protocol B, based on literature procedures, was used to generate aromatic isatins with avid electron substituents (see Hewawasam and Maenwell: Tet Lett. (1994), 35, 7303) and 6-member electron-poor heteroaromatic isatins ( see Rivalle and Bisagni: J. Heterocycl, Chem. (1997), 34, 441). Examples of the preferred 6-membered heterocycles are pyridines (VX = N, V2 = V3 = V4 = C (-), V2 = N, VX = V3 = V = C (-); V3 = N, V ^ v ^ V ^ C (-) and V = N, v1 = V2 = V3 = C (-)), pyrimidines (VX = V3 = N, V2 = V4 = C (-), V2 = V4 = N, VX = V3 = C (-)), pyrazines (Va = V4 = N, V2 = V3 = C (-)) and pyridazines (VX = V2 = N, V3 = V4 = C (-), V2 = V3 = N, VX = V4 = C (-), V3 = V4 = N, V ^ V ^ CÍ-)). Other isatins of interest could be further prepared using one of the alternative methods published in the literature (see, ie, Tatsugi et al. ARKIVOC (2001), 67-73 or the review by Silva et al. In J. Braz. Chem. Soc. 2001), 12, 273-324).

Protocol A: Preparation of isatin derivatives To a well-stirred suspension of sodium sulphate (314 g, 2211 mmol) in water (700 L) at 60 ° C were added in sequence hydroxylamine hydrochloride (56 g, 806 mmol), chloral hydrate (47 g, 284 mmol), 2-methyl-3-chloro- aniline (40 g, 283 mmol) in water (500 L) and finally concentrated hydrochloric acid (12 M, 24.2 ml, 290 mmol). The temperature of the mixture was raised to 100 ° C. After 20 minutes, the brown solution was allowed to cool to room temperature and kept stirring overnight. The solid present was filtered, washed with water (3X), heptane (2X) and dried at 60 ° C under vacuum for 6 hours. 62 g of N- (3-chloro-2-methyl-phenyl) -2-hydroxyimino-acetimidoyl chloride (1) were obtained as a beige solid which were used without further purification. dH (400 MHz, DMSO-d6) 12.3 (1 H, s), 9.8 (1 H, s), 7.7 (1 H, s), 7.42 (1 H, d, J = 7.8), 7.36 (1 H, d, J = 7.6), 7.3 (1 H, m), 2.25 (3 H, s). To the well-stirred sulfuric acid (18.3 M, 300 ml) heated to 50 ° C was added N- (3-chloro-2-methyl-phenyl) -2-hydroxyimino-acetimidoyl chloride (1) in a small portion for 20 minutes. minutes (exothermic to 70 ° C) (60 g, 282 mmol). After the addition was complete, the temperature was raised to 80 ° C and maintained for 20 minutes after which the reaction was allowed to cool to room temperature. The brown mixture was poured slowly into ice (~ 500 g) and water (500 mL), diluted with more water (1 L) to produce a thick orange-brown suspension. The solid was collected by filtration, washed with water (2X) under suction to yield an orange solid. This solid was dissolved in 0.4 M sodium hydroxide (1 L). All the insoluble pitch was removed by filtration. Concentrated hydrochloric acid (12 M, 70 L) was added, the resulting orange-brown solid was collected by filtration, washed with water (3X), heptane (2X) and dried at 54 ° C under vacuum for 6 hours. 34.5 g (208 mmol, 62%) of 6-chloro-7-methyl-1H-indole-2,3-dione (2) were obtained. dH (400 MHz, DMSO-d6) 11.3 (1 H, s), 7.4 (1 H, d, J = 8.0), 7.2 (1 H, d, J = 8.1), 2.25 (3 H, s).

Protocol B: Preparation of isatin derivatives To a well-stirred solution of Boc anhydride (2.56 g, 11.7 mmol) in THF (10 mL) was added 4-aminopyridine (1.0 g, 10.6 mmol) in portions for 3 minutes while maintaining the temperature between 20 ° C and 25 ° C. After 5 minutes the exotherm was no longer observed. The reaction was then stirred at room temperature for 3.5 hours. After concentration in vacuo, the crude mixture was then triturated in hexane (20 mL), filtered and washed with more hexane. (~ 5 L). The resulting solid was dried under reduced pressure to yield 1.93 g (9.9 mmol, 94%) of the tert-butyl ester of pyridin-4-yl-carbamic acid as a white solid and was used without further purification. LC-MS (BDS-Hypersil C? 8, 50 mm X 2.1 mm, 5 μ, 2.5 minutes) m / z 195 [MH] + @ retention time 0.90 minutes, 100% by means of ultraviolet light at 215 nm. To a stirred solution of the tert-butyl ester of pyridin-4-yl-carbamic acid (0.62 g, 3.09 mmol) in THF (9 mL) cooled to -5 ° C was slowly added a solution of t-BuLi (1.7 M in THF, 5.5 L, 9.27 mmol) for 17 minutes while maintaining the temperature between -5 ° C and 1 ° C. A reddish-brown precipitated product resulted and the reaction mixture was stirred at 0 ° C for an additional 1.5 hours. The reaction mixture was then cooled again to -5 ° C and diethyl oxalate (1.3 mL, 9.27 mmol) was added. The reaction was allowed to reach room temperature and then after 2 hours it was quickly cooled with water (10 mL). After concentration in vacuo, the resulting mixture was diluted in ethyl acetate (20 mL) and washed with water (10 mL), dried over Na2SO4 and concentrated in vacuo. Purification by flash column chromatography (30% EtOAc / hexane) gave 0.16 g (0.54 mmol, 17%) of the ethyl ester of (4-tert-butoxycarbonylamino-pyridin-3-yl) -oxo- acetic as a brown oil. LC-MS (BDS-Hypersil C? 8, 50 mm X 2.1 mm, 5 μ, 2.5 minutes) m / z 295 [MH] + + H20 adduct @ retention time 1.07 minutes, 96% by ultraviolet light a 215 nm. The ethyl ester of (4-tert-butoxycarbonylamino-pyridin-3-yl) -oxo-acetic acid (0.14 g, 0.476 mmol) was heated at 186 ° C under 5 mmHg for 25 minutes in a Kugeirohr apparatus. The brown oil darkened and subsequently emitted gases to form a dark green solid. The solid was dissolved in MeOH and concentrated in vacuo to yield 0.04 g (0.3 mmol, 56%) of the 1H-pyrrolo [3,2-c] pyridin-2,3-dione as a dark solid. The isatin was then taken for the next step without further purification.

Protocol C: Introduction of functional groups in the isatin derivatives 6-Chloro-l-methyl-5-nitro-lH-indole-2,3-dione (4) To a well-stirred suspension of compound 2 (2.0 g, 10.2 mmol ) in glacial acetic acid (2 mL) and sulfuric acid (4 mL) cooled in ice / water was added a cold mixture of nitric acid (69%, 1 g, 10.9 mmol) and sulfuric acid (0.7 g, 7.3 mmol) to such speed that the internal temperature was kept below 5 ° C. After the addition was complete, the reaction mixture was stirred at room temperature for 1 hour, then poured slowly onto ice (~ 20 g) and allowed to stand for 10 minutes. The solid formed was collected by filtration, washed with cold water (3X), dried under vacuum overnight to yield 1.92 g (8.0 mmol, 78%) of 6-chloro-7-methyl-5 -nitro-lH-indole-2, 3-dione (4) as an orange solid. LC-MS m / z 118.79 [Fragment] * @ Rt 1.14 minutes, 95%.

Example 2: Procedures for the preparation of the final compounds of the invention The obtained isatin derivatives were used to generate the final compounds of the invention. Typically, an isatin derivative was heated with a benzene derivative at 100 ° C in a mixture of glacial acetic acid and sulfuric acid under nitrogen. Alternatively, the isatin derivative was reacted at room temperature with a benzene derivative in triflic acid under nitrogen (see Klumpp et al J. Org Chem. (1998), 63, 4481-84). The thioamide derivatives of the final compounds (Q = S and n = 1) were obtained by reacting the corresponding amides (Q = 0 and n = 1) with a Lawesson reagent as described in Organic Synthesis Coll. Vol. VII, p372.

Protocol D: Preparation of the final compounds (a) (7) To a suspension of phenol (0.28 g, 2.9 mmol) and 5-methoxy-lH-indole-2,3-dione (0.24 g, 1.3 mmol) in glacial acetic acid (1.5 ml) under nitrogen was added sulfuric acid (18.3 M, 0.145 mL). The mixture was heated at 100 ° C for 2 hours. The crude reaction mixture was diluted with water and extracted with ethyl acetate (2X). The organic layer was dried (Na2SO4) and concentrated under reduced pressure to yield a brown solid. This solid was mixed with DCM: AcOEt (9: 1) (3X) and yielded 0.08 g (0.35 mmol, 18%) of the 3,3-bis- (4-hydroxy-phenyl) -5-methoxy-3. -dihydro-indole-2-one (7). LC-MS m / z 348.19 [M + H] + @ Rt 1:09 minutes, 100%. dH (400 MHz, Methanol-d4) 6.92 (4 H, d, J = 8.80 Hz), 6.79-6.82 (1 H, m), 6.69-6.73 (1 H, m), 6.61 (5 H, m), 3.62 (3 H, s). (b) Phenol (15.3 g, 163.6 mmol) and 6-chloro-7-methyl-1H-indole-2,3-dione (16.0 g, 81.8 mmol) were suspended in glacial acetic acid (82 ml) and sulfuric acid (18.3 g). M, 8.8 mL) under a nitrogen atmosphere. The reaction mixture was heated to 85 ° C, after 2 hours it was allowed to cool to room temperature, diluted in ethyl acetate and washed with water (3X). The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by re-crystallization from toluene: ethyl acetate (20 volumes: 1 volume) to yield 13.3 g of a yellow solid containing toluene alone. It was dried overnight under high vacuum at 45 ° C to yield 10.65 g (29.2 mmol, 38%) of 6-chloro-3, 3-bis (4-hydroxy-phenyl) -7-methyl-1, 3 -dihydro-indole-2-one (3) as a white solid. LC-MS (? 215 nm, BDS-Hypersil Cis 50 mm X 2.1 mm, 5 μ, 2.5 minutes) m / z 366.3 [(Cl35) M + H] + @ Rt 1.3 minutes, 100%. dH (400 MHz, DMS0-d6) 10.9 (1 H, s), 9.5 (2 H, s), 7.1 (1 H, d, J = 9.8), 7.05 (1 H, d, J = 9.6), 6.95 (4 H, d, J = 10.2), 6.7 (4 H, d, J = 10.2), 2.35 (3 H, s).

Protocol E: Preparation of the final compounds To a well-stirred suspension of 6-chloro-7-methyl-1H-indole-2,3-dione (0.15 g, 0.76 mmol) in toluene (anhydrous) (1 mL) was added trifluoromethanesulfonic acid (1.25 mL). The tube was sealed and the mixture was stirred at room temperature for 12 hours. The dark brown reaction mixture was then poured slowly onto ice (~ 10 g) and allowed to stand for 10 minutes. The precipitated, formed product was collected by filtration, washed with cold water (3X 100 mL), dried under vacuum. Purification by flash column chromatography (gradient elution with EtOAc / Heptane (1: 9 to 1: 1)) followed by recrystallization (MeOH / EtOAc) gave 25.2 mg (0.07 mmol, 9%) of 6-chloro-7-methyl-3,3-di-p-tolyl-1,3-dihydro-indol-2-one (28) as a light brown solid. LC-MS (BDS-Hypersil C? 8, 50 mm X 2.1 mm, 5 μ, 2.5 minutes) m / z greater 362.12 [MH] + and minor 403.17 [MH + MeCN] + @ retention time 2.18 minutes, 100% by means of ultraviolet light at 215 nm. dH (400 MHz, DMSO-d6) 2.24 (6 H, s) 2.28 (3 H, s) 7.00 - 7.03 (5 H,), 7.05 - 7.12 (5 H, m) 10.96 (1 H, s).

The following compounds were prepared in accordance with Protocols D or E, unless otherwise specified. 6-Chloro-3 r 3-bis- (4-hydroxy-phenyl) -1-methyl-1 r 3 -dihydro-indol-2-one (3) See protocol D. 6-Chloro-3, 3-bis- (4-hydro? I-phenyl) -1-methyl-5-nitro-1,3-dihydro-indol-2-one (5) LC-MS m / z 411.1 [ (Cl35) M + H] + @ Rt 1.26 minutes, 93%. dH (400 MHz, DMSO-d6) 7.48 (1 H, s), 6.96-6.96 (4 H, m), 6.66 -6.59 (4 H,), 2.35 (3 H, s).

-Amino-6-chloro-3, 3-bis- (4-hydroxy-phenyl) -1-methyl-1,3-dihydro-indol-2-one (6) To a solution of compound 5 (0.1 g, 0.24 mmol) in methanol (2 mL) was added Pd / C (10% w / w, 0.03 g). The mixture was again stirred under hydrogen at room temperature for 16 hours. The catalyst was removed by filtration and the solvent was removed under reduced pressure to yield 0.084 g (0.22 mmol, 92%) of 5-amino-6-chloro-3, 3-bis- (4-hydroxy-phenyl) -7-methyl-l, 3-dihydro-indol-2-one (6). LC-MS m / z 381.16 [(Cl35) M + H] + @ Rt 0.94 minutes, 84%. dH (400 MHz, DMS0-d6) 11.7 (1 H, s), 8.1 (1 H, s), 2.3 (3 H, s). 3, 3-Bis- (4-hydroxy-phenyl) -5-methoxy-l, 3-dihydro-indol-2-one (1) See protocol D. 3 r3-Bis- (4-hydroxy-phenyl) -5-trifluoromethoxy-1,3-dihydro-indol-2-one (8) LC-MS m / z 402.12 [M + H] + @ Rt 1.27 minutes , 96%. dH (400 MHz, DMS0-d6) 10.78 (1 H, s), 9.43 (2 H, s), 7.23 (1 H, d, J = 8.56), 7.17 (1 H, s), 6.99 (1 H, d, J = 8.56), 6.93 (4 H, d, J = 8.80), 6.66 (4 H, d, J = 8.56). 3,3-Bis- (4-hydroxy-phenyl) -5,1-dimethyl-1,3-dihydro-indol-2-one (9) LC-MS m / z 346.19 [M + H] + @ Rt 1.24 minutes, 92%. dH (400 MHz, DMSO-d6) 10.39 (1 H, s), 9.25 (2 H, s), 6.8 (4 H, d, J = 8.6), 6.70 (1 H, s), 6.68 (1 H, s), 6.52 (4 H, d, J = 8.6), 2.09 (6 H, s). 3, 3-bis- (4-hydroxy-phenyl) -2-oxo-2,3-dihydro-lH-indole-l-carboxylic acid (10) LC-MS m / z 362.13 [M + H] + @ Rt 1.06 minutes, 90%. dH (400 MHz, DMSO-d6) 10.11 (1 H, s), 9.43 (2 H, s), 7.71 (1 H, dd, J = 8.1, 1.2), 7.38 (1 H, dd, J = 7.3, 0.7), 7.08 (1 H, t, J = 7.8), 6.92 (4 H, d, J = 8.8), 6.67 (4 H, d, J = 8.8).

-Chloro-3, 3-bis- (4-hydroxy-phenyl) -1 r3-dihydro-indol-2-one (11) LC-MS m / z 352.11 [(Cl35) M + H] + @ Rt 1.21 minutes, 100%. dH (400 MHz, DMSO-d6) 10.72 (1 H, s), 9.42 (2 H, s), 7.25 (1 H, dd, J = 8.2, 2.1), 7.18 (1 H, d, J = 2.2) , 6.89-6.95 (5 H, m), 6.68 (4 H, d, J = 8.6).

-Fluoro-3 r 3-bis- (4-hydroxy-phenyl) -1 r3-dihydro-indol-2-one (12) LC-MS m / z 336.16 [M + H] + @ Rt 1.14 minutes, 90 %. dH (400 MHz, DMSO-d6) 10.61 (1 H, s), 9.41 (2 H, s), 7.00-7.10 (2 H, m), 6.93 (4 H, d, J = 8.6), 6.89 (1 H, dd, J = 8.4, 4.5), 6.67 (4 H, d, J = 8.8). 3,3-Bis- (4-hydroxy-phenyl) -5-nitro-1,3-dihydro-indol-2-one (13) LC-MS m / z 362.86 [M + H] + @ Rt 1.25 minutes, 93% dH (400 MHz, DMSO-d6) 11.31 (1 H, s), 9.48 (2 H, S), 8.19 (1 H, dd, J = 8.7, 2.3), 7.90 (1 H, d, J = 2.2) , 7.12 (1 H, d, J = 8.8), 6.94 (4 H, d, J = 8.8), 6.70 (4 H, d, 7 = 8.8).

-Chloro-3, 3-bis- (4-hydroxy-phenyl) -1-methyl-l, 3-dihydro-indol-2-one (14) LC-MS m / z 365.92 [(Cl35) M + H ] + @ Rt 1.36 minutes, 91%. dH (400 MHz, DMSO-d6) 10.77 (1 H, s), 9.41 (2 H, S), 7.10 (1 H, d, J = 1.5), 6.98 (1 H, d, L.9), 6.91 (4 H, d, J = 8.6), 6.67 (4 H, d, J = 8.6), 2.22 (3 H, s). 3r3-Bis- (4-hydroxy-phenyl) -5-methyl-1,3-dihydro-indol-2-one (15) LC-MS m / z 331.97 [M + H] + @ Rt 1.37 minutes, 91 %. dH (400 MHz, DMSO-d6) 10.42 (1 H, s), 9.33 (2 H, s), 6.90-6.97 (2 H, m), 6.88 (4 H, d, J = 8.6), 6.75 (1 H, d, J = 7.8), 6.62 (4 H, d, J = 8.8), 2.17 (3 H, S).

-Bromo-3 r 3-bis- (4-hydroxy-phenyl) -1,3-dihydro-indol-2-one (16) LC-MS m / z 396.05 [(Br79) M + H] + @ Rt 1.14 minutes, 94%. dH (400 MHz, MeOD) 7.28 (1 H, dd, J = 8.3, 2.0), 7.14 (1 H, d, J = 2.0), 6.88-6.92 (4 H, m), 6.81 (1 H, d, J = 8.3), 6.60-6.64 (4 H, m). 3,3-Bis- (4-hydroxy-phenyl) -5-iodo-l, 3-dihydro-indol-2-one (11) LC-MS m / z 444.01 [M + H] + @ Rt 1.70 minutes, 100% dH (250 MHz, MeOD) 6.72 - 6.85 (5 H, m) 6.99 - 7.08 (5 H, m) 7.15 - 7.21 (1 H, m) 7.28 (1 H, t, J = 7.23 Hz) 7.41 - 7.52 (2 H, m) 7.60 (ÍH, dd, J = 8.23, 1.65 Hz).

-Amino-3, 3-bis- (4-hydroxy-phenyl) -1,3-dihydro-indol-2-one (18) LC-MS m / z 333.13 [M + H] + @ Rt 1.29 minutes, 90% dH (250 MHz, Methanol-D4) 6.71 (4 H, d, J = 8.60 Hz) 6.98 - 7.05 (4 H, m) 7.12 (1 H, d, J = 8.23 Hz) 7.20 (1 H, d, J = 1.83 Hz) 7.26 - 7.33 (1 H, m).

-Amino-3, 3-bis- (4-hydroxy-phenyl) -1-methyl-1,3-dihydz or -indol-2 -one (19) LC-MS m / z 347.14 [M + H] + @ Rt 1.28 minutes, 100%. dH (400 MHz, Methanol-D4) 7.02 (4 H, d, J = 8.8 Hz), 6.68 (4 H, d, J = 8.8 Hz), 6.42-6.52 (2 H, m), 2.21 (3 H, s). 6-Bromo-3, 3-bis- (4-hydroxy-phenyl) -1-methyl-l-3-dihydro-indol-2-one (20) LC-MS m / z 410.04 [M + H] + @ Rt 1.39 minutes, 94%. dH (400 MHz, Methanol-D4) 7.22 (1 H, d, J "= 7.8 Hz), 7.00 (4 H, d, < J = 8.8 Hz), 6.85 (1 H, d," = 7.8 Hz) , 6.69 (4 H, d, J = S .8 Hz), 2.35 (3H, s). 3,3-Bis- (4-hydroxy-phenyl) -1-fluoro or r3-dihydro-indol-2-one (21) LC-MS m / z 336.11 [M + H] + @ Rt 1.15 minutes, 97% . dH (400 MHz, Methanol-D4) 6.85-6.97 (7 H, m), 6.60 (4 H, d, J = 8.8 Hz). 3, 3-Bis- (4-hydroxy-phenyl) -1-methoxy-1,3-dihydro-indol-2-one (22) LC-MS m / z 348.13 [M + H] + @ Rt 1.14 minutes , 94%. dH (400 MHz, Methanol-D4) 6.95-7.06 (5 H, m), 6.89 (1 H, d, J = 8.3 Hz), 6.75 (1 H, d, J = 7.8 Hz), 6.68 (4 H, d, J = 8.8 Hz), 3.89 (3 H, s). 4,1-Dichloro-3, 3-bis- (4-hydroxy-phenyl) -1,3-dihydro-indol-2-one (23) LC-MS m / z 386.04 [M + H] + @ Rt 1.35 minutes, 97%. dH (400 MHz, Methanol-D4) 7.29 (1 H, d, J = 8.8 Hz), 7.06 (4 H, d, J = 8.8 Hz), 6.97 (1 H, d, J = 8.8 Hz), 6.71 ( 4 H, d, J = 8.8 Hz). 6-Chloro-3, 3-bis- (4-hydroxy-phenyl) -1,1-dimethyl-1,3-dihydro-indol-2-one (24) LC-MS m / z 380.11 [M + H ] + @ Rt 1.49 minutes, 100%. dH (400 MHz, Methanol-D4) 7.12 (1 H, d, J = 7.8 Hz), 6.85 - 7.02 (5 H, m), 6.60 - 6.72 (4 H, m), 3.57 (3 H, s), 2.69 (3 H, s). 6-Chloro-3 r 3 -bis ~ (4-f luoro-f-enyl) -1-methyl-1-f 3-dihydro-indol-2-one (25) dH (400 MHz, methanol-D 4) 7.15-7.30 ( 4 H, m), 6.97 - 7.13 (6 H, m), 2.34 (3 H, s). 3,3-Bis- (4-hydroxy-phenyl) -1- (morphine-4-carbonyl) -1, 3-dihydro-indol-2-one (26) To compound 10 (1 eq.) Dissolved in dimethylformamide S0C12 (3 eq.) was added at 0 ° C. The mixture was stirred for 1 hour and evaporated to remove excess S0C12. Morpholine (3 eq.) Was added and the reaction mixture was left for 3 hours at room temperature. The solvent was removed in vacuo and compound 26 was purified by filtration through a pad of silica using dichloromethane-MeOH as eluent. LC-MS m / z 431.04. [M + H] + @ Rt 1.13 minutes, 90%. dH (400 MHz, Methanol-D4) 7.19 - 7.29 (2 H, m), 7.11 (1 H, m), 6.97 - 7.05 (4 H, m), 6.64 - 6.75 (4 H, m), 3.69 (8 H, s broad). 3 r3-Bis- (4-hydroxy phenyl) -1 r 3-dihydro-pyrrolo [3,2-c] pyridin-2-one (21) LC-MS (BDS-Hypersil C? 8, 50 mm X 2.1 mm, 5 μ, 2.5 minutes) m / z 319.28 [MH] + @ Rt 0.76 minutes, 100% by ultraviolet light at 215 nm. dH (400 MHz, CD3OD) 6.63 (4H, d, J 8.6 Hz), 6.93 (4H, d, J 8.8 Hz), 6.95 (1H, d, J 5.4 Hz), 8.10 (H, s), 8.24 (H) , d, 5.4Hz). 6-Chloro-1'-methyl-3, 3-di-p-tolyl-1,3-dihydro-indol-2-one (28) See protocol E. 3,3-Bis- (4-hydroxy-phenyl) -3, 6r 1, 8-tetrahydro-lH-l-aza-as-indacen-2-one (29) Phenol (1.0 g, 10.84 mmol) was added to the crude 3,3-dibromo-1,3-dihydro-pyrrolo [2, 3-b] pyridin-2-one (0.15 g, 0.51 mmol, prepared according to Parrick et al. Tet. Lett. (1984), 25, 3099) and the mixture was heated at 100 ° C for 10 minutes, allowed to cool to room temperature and the excess phenol was removed by means of flash chromatography. The product adsorbed on silica was isolated by washing with methanol and concentration under reduced pressure. The pH was adjusted to approximately 6 using a sodium carbonate solution and the crude product was isolated by evaporation under reduced pressure. Purification by preparative HPLC provided the title compound (29) (3 mg, 2%). LC-MS m / z 358.35 [M + H] + @ Rt 1.26 minutes, 89%. dH (400 MHz, DMSO-D6) 10.62 (1 H, s), 9.35 (2 H, s), 6.90 - 6.95 (4 H, m), 6.82 - 6. 90 (2 H,), 6.62 -6.68 ( 4 H, m), 2.75 - 2.87 (4 H, m), 1.98 - 2.08 (2 H, m). l-Bromo-3, 3-bis- (4-hydroxy-phenyl) -1,3-dihydro-indol-2-one (30) LC-MS m / z 398.22 [M + H] + @ Rt 1.22 minutes, 100 %.

N-. { 4- [6-Chloro-3- (4-methanesulfonylamino-phenyl) -1-methyl-2-oxo-2,3-dihydro-lH-indol-3-yl] -phenyl} -methansulfonamide (31) LC-MS m / z 520.27 [M + H] + @ Rt 1.30 minutes, 96%. dH (400 MHz, DMSO-D6) 11.00 (1 H, s), 9.78 (2 H, s), 6.85 - 7.37 (10 H, m), 2.97 (6 H, s), 2.28 (3 H, s) . l-Ethyl-3 r 3-bis- (4-hydroxy-phenyl) -1,3-dihydro-indol-2-one (32) LC-MS m / z 345.97 [M + H] + @ Rt 1.30 minutes, 100% 3, 3-Bis- (4-hydroxy-phenyl) -7-iodo-1,3-dihydro-indol-2-one (33) LC-MS m / z 443.82 [M + H] + @ Rt 1.37 minutes, 100% 3,3-Bis- (4-hydroxy-phenyl) -7-chloro-1,3-dihydro-indol-2-one (34) LC-MS m / z 351.56 [M + H] + @ Rt 1.33 minutes, 100% dH (400 MHz, Methanol-D4) 7.23 (1 H, dd, J = 8.3, 1.0 Hz), 7.05 - 7.11 (1 H, m), 6.96 - 7.04 (5 H, m), 6.70 (4 H, d , J = 8.8 Hz). 3,3-Bis- (4-hydroxy-phenyl) -7-trif luoromethyl-1,3-dihydro-indol-2-one (35) LC-MS m / z 387.98 [M + H] + @ Rt 1.35 minutes, 94%. dH (400 MHz, Methanol-D4) 7.49 (1 H, d, J = 8.3 Hz), 7.38 (1 H, d, J = 1. 3 Hz), 7.17 (1 H, t, J = 7.6 Hz), 7.00 (4 H, d, J = 8.8 Hz), 6.71 (4 H, d, J = 8.8 Hz).

Ester 4- [3- (4-acetoxy-phenyl) -6-chloro-7-methyl-2-oxo-2,3-dihydro-lH-indol-3-yl] -phenyl acetic acid (36) CL- MS m / z 450.10 [M + H] + @ Rt 1.63 minutes, 94%. 3,3-Bis- (4-hydroxy-phenyl) -6-methoxy-l, 3-dihydro-indol-2-one (37) LC-MS m / z 348.22 [M + H] + @ Rt 1.14 minutes, 98%. dH (400 MHz, Methanol-D4) 6.95 - 7.05 (5 H, m), 6.63 - 6.74 (4 H, m), 6.53 - 6.61 (2 H, m), 3.77 (3 H, s). ,1-Dif luoro-3, 3-bis- (4-hydroxy-phenyl) -1,3-dihydro -indo 1-2 -one (38) LC-MS m / z 353.95 [M + H] + @ Rt 1.25 minutes, 100%. dH (400 MHz, Methanol-D4) 7.00 (4 H, d, J = 8.8 Hz), 6.93 (1 H, td, J = 9.8, 2.0 Hz), 6.81 (1 H, dd, J = 8.1, 2.2 Hz ), 6.72 (4 H, d, J = 8.8 Hz). 6-Fluoro-3, 3-bis- (4-hydroxy-phenyl) -7-methyl-1,3-dihydro-indol-2-one (39) LC-MS m / z 349.98 [M + H] + @ Rt 1.28 minutes, 100%. dH (400 MHz, Methanol-D4) 7.00 (4 H, d, J = Q .8 Hz), 6.93 (1 H, dd, J = 8.3, 5.4 Hz), 6.61 - 6.76 (5 H, m), 2.21 (3 H, d, J = 1 .0 Hz). 3,3-Bis- (4-hydroxy-phenyl) -6-methoxy-1'-methyl-1,3-dihydro-indol-2-one (40) LC-MS m / z 362.00 [M + H] + @ Rt 1.35 minutes, 100%. dH (400 MHz, Methanol-D4) 7.00 (4 H, d, J = 8.8 Hz), 6.89 (1 H, d, J = 8.3 Hz), 6.67 (4 H, d, J = 8.8 Hz), 6.59 ( 1 H, d, J = 8.3 Hz), 3.80 (3H, s), 2.14 (3 H, s). 6, 1-Difluoro-3, 3-bis- (4-hydroxy-phenyl) -1,3-dihydro-indol-2-one (41) LC-MS m / z 353.96 [M + H] + @ Rt 1.35 minutes, 96%. dH (400 MHz, Methanol-D4) 7.00 (4 H, d, J = 8.8 Hz), 6.82-6.96 (2 H, m), 6.70 (4 H, d, "= 8.8 Hz). 6-Chloro-7-f luoro-3, 3-bis- (4-hydroxy-phenyl) -1, 3-dihydro-indo-1-one-one (42) LC-MS m / z 369.95 [M + H] + @ Rt 1.30 minutes, 100%. dH (400 MHz, Methanol-D4) 7.10 (1 H, dd, J = 8.1, 6.6 Hz), 7.00 (4 H, d, J = 8.8 Hz), 6.95 (1 H, d, J = 8.8 Hz), 6.70 (4 H, d, J = 8.8 Hz). 3,3-Bis- (4-hydroxy-phenyl) -2-oxo-2,3-dihydro-1H-indole-7-carbonitrile (43) Compound 33 (0.35 g, 0.79 mmol) was treated with cyanide of zinc (0.14 g, 1.18 mmol) and tetracis (triphenylphosphine) palladium (0) (0.09 g, 10%) in anhydrous DMF (5 mL). The reaction mixture was degassed by bubbling nitrogen for 15 minutes. The reaction was then heated at 100 ° C overnight under nitrogen. After cooling to room temperature, the reaction was quenched with saturated aqueous NaHC03. The resulting turbid suspension was filtered and the filtrate was dissolved in a mixture of toluene and ethyl acetate (1: 1), washed with aqueous (saturated) NaHC03 (2X), water (2X) and dried over sodium sulfate. sodium. After filtration, the organic layer was concentrated under reduced pressure to provide the crude product. The treatment of the raw material again was carried out two additional times with the same amounts and conditions above. The compound was purified initially by flash column chromatography (DCM: MeOH with 95: 5 to 9: 1 gradient elution) followed by preparative HPLC to provide the desired compound (43) as a white solid (0.014 g, 5%). LC-MS m / z 343.07 [M + H] + @ Rt 1.15 minutes, 97%. dH (400 MHz, methanol-D4) 7. 51 (1 H, dd, J = 7.8, 1.0 Hz), 7.41 (1 H, dd, J = 7.8, 1.0 Hz), 7. 13 (1 H, t, J = 7.8 Hz), 6.99 (4 H, d, J = 8.8 Hz), 6.71 (4 H, d, J = 8.8 Hz).

-Fluoro-3, 3-bis- (4-hydroxy-phenyl) -7-methyl-1,3-dihydr-o-indole-2-one (44) LC-MS m / z 350.29 [M + H] + @ Rt 1.20 minutes, 95%. dH (400 MHz, Methanol-D4) 7.00 (4 H, d, J = 8.8 Hz), 6.82 (1 H, dd, J = 10.5, 2. 2 Hz), 6.62 - 6.75 (5 H, m), 2.30 (3 H, s). 3,3-Bis- (4-hydroxy-phenyl) -5-methoxy-1'-methyl-1,3-dihydro-indol-2-one (45) LC-MS m / z 362.25 [M + H] + @ Rt 1.16 minutes, 91%. dH (400 MHz, Methanol-D4) 7.01 (4 H, d, J = 8.8 Hz), 6.69 (4 H, d, J = 8.8 Hz), 6.64 (1 H, d, J = 2.5 Hz), 6.53 (1 H, d, J = 2.5 Hz), 3.68 (3 H, S), 2.28 (3 H, s). 3, 3-Bis- (4-hydroxy-phenyl) -1,3-dihydro-pyrrolo [2, 3-b] pyridin-2-one (46) LC-MS m / z 319.27 [M + H] + @ Rt 0.97 minutes, 100%. dH (400 MHz, Methanol-D4) 8.10 (1 H, dd, J = 4.9, 1.5 Hz), 7.55 (1 H, dd, J = 7.3, 1.5 Hz), 6.93 - 7.11 (5 H, m), 6.71 (4 H, d, J = S .8 Hz). 6-Fluoro-3, 3-bis- (4-hydroxy-phenyl) -1,3-dihydro-indol-2-one (47) LC-MS m / z 336.27 [M + H] + @ Rt 1.17 minutes, 100% dH (400 MHz, Methanol-D4) 7.04 - 7.18 (1 H, m), 7.00 (4 H, d, J = 8.80 Hz), 6.62 - 6.79 (6 H, m).

N- [3,3-Bis- (4-hydroxy-phenyl) -2-oxo-2,3-dihydro-indol-1-yl] -acetamide (48) LC-MS m / z 375.27 [M + H] + @ Rt 1.08 minutes, 100%. dH (400 MHz, Methanol-D4) 7.25 - 7.33 (1 H, m), 7.14 - 7.19 (1 H, m), 7.12 (1 H, dd, J = 7.3, 1.0 Hz), 7.08 (4 H, d , J = 8.8 Hz), 6.95 (ΔH, d, J = 7.8 Hz), 6.69 (4 H, d, J = 8.8 Hz), 2.17 (3 H, s). - [3, 3-bis- (4-Hydroxy-phenyl) -7-methyl-2-oxo-2,3-dihydro-lH-indol-6-yloxy] -pentanoic acid methyl ester (49) CL- MS m / z 462.28 [M + H] + @ Rt 1.41 minutes, 97%. - [3, 3-bis- (4-hydroxy-phenyl) -7-methyl-2-oxo-2,3-dihydro-1H-indo-1-6-yloxy] -pentanoic acid (50) LC-MS m / z 448.32 [M + H] + @ Rt 1.13 minutes, 95%. dH (400 MHz, Methanol-D4) 7.01 (4 H, d, J = 9.0 Hz), 6.86 (1 H, d, J = 8.2 Hz), 6.67 (4 H, d, J = 8.8 Hz), 6.56 ( 1 H, d, J = 8.4 Hz), 3.97 (2 H, t, J = 5.1 Hz), 2.36 (2 H, t, J = 6.4 Hz), 2.15 (3 H, s), 1.72 - 1.91 (4 H , m). 3,3-Bis- (4-hydroxy-phenyl) -6-methyl-1,3-dihydro-indol-2-one (51) LC-MS m / z 332.27 [M + H] + @ Rt 1.90 minutes, 100% dH (400 MHz, Methanol-D4) 6.92 - 7.08 (5 H, m), 6.85 (1 H, d, J = 8.3 Hz), 6.80 (1 H, s), 6.68 (4 H, d, J = 8.8 Hz), 2.33 (3 H, s). 7-Chloro-3, 3-bis- (4-hydroxy-phenyl) -6-methyl-1,3-dihydro-indol-2-one (52) LC-MS m / z 366.22 [M + H] + @ Rt 1.93 minutes, 100%. dH (400 MHz, Methanol-D4) 7.00 (4 H, d, J = 8.8 Hz), 6.96 (2 H, s), 6.69 (4 H, d, J = 8.8 Hz), 2.36 (3 H, s) .

-Hydroxy-3, 3-bis- (-hydroxy-phenyl) -7-methyl-1,3-dihydro-indol-2-one (53) LC-MS m / z 348.26 [M + H] + @ Rt 1.55 minutes, 100%. 3,3-Bis- (4-hydroxy-phenyl) -6,7-dimethyl-1,3-dihydro-indo 1-2 -one (54) LC-MS m / z 346.30 [M + H] + @ Rt 1.85 minutes, 100%. dH (400 MHz, Methanol-D4) 7.00 (4 H, d, J = 9.0 Hz), 6.84 (2 H, s), 6.67 (4 H, d, J = 9.0 Hz), 2.27 (3 H, s), 2.22 (3 H, s).

Protocol F: Preparation of final products General route for Friedel and Craft products alone and mixed via the addition of Grignard (a) Grignard addition: To a stirred solution of isatin in dry tetrahydrofuran under nitrogen at -78 ° C was added 3 eq. of Grignard reagent or 3 eq. of a freshly prepared solution of organo-lithium reagent. After 30 minutes, the dry ice bath was removed and the reaction was allowed to reach room temperature for 4 to 14 hours. Water was then added to the reaction mixture to rapidly quench excess Grignard reagent, acidified to pH 1-2 with 1 N HCl, extracted with EtOAc (2x), dried over Na 2 SO 4, filtered and concentrated to result in the raw products as yellow viscous oils, which are either purified on silica (eluted with a gradient of heptane / EtOAc of 95-5 to 1-1) to produce the desired racemic mixture of the compound of type 1 as solids or are taken for the next step without purification. (b) Reaction of Friedel and Craft: To a crude solution of tertiary alcohol in dichloroethane was added phenol (5 eq.) and p-TSA (7.5 eq.). The reaction mixture was heated at 90 ° C for 3 hours and the reaction was cooled to room temperature. The solid (mainly insoluble p-TSA) was filtered and washed (2x) with cold dichloroethane. The solution was concentrated and the remaining solid was purified on silica (eluted with a gradient of heptane / EtOAc of 95-5 to 1-1) to yield the desired racemic mixture of the type 2 product as a solid. The following compounds were prepared in accordance with Protocol F, unless otherwise specified. 6-Chloro-3- (4-hydroxy-phenyl) -7-methyl-3-p-tolyl-1,3-dihydro-indol-2-one (59) Intermediate: LC-MS (? 215 nm, BDS-Hypersil C? 8, 50 mm X 2.1 mm, 5 μ, 2.8 minutes, reference method reference: MET / CR / 0720) m / z 270 [M + H- H20] + @ retention time 1.99 minutes, 97%. Final product (59): LC-MS (? 215 nm, BDS-Hypersil C? 8, 50 mm X 2.1 mm, 5 μ, 2.5 minutes, method reference: MET / CR / 0720) m / z 364 [M + H] + @ retention time 1.64 minutes, 100%. Total yield 87% during 2 steps. dH (400 MHz, Methanol-D4) 2.28 (3 H, s), 2.33 (3 H, s), 6.69 (2 H, d, J = 8.8 Hz), 6.86 - 7.16 (8 H, m). 6-Chloro-3- (4-hydroxy-phenyl) -3- (4-methoxy-phenyl) -7-methyl-l, 3- dihydro-indo 1-2 -one (60) Intermediate: LC-MS ( ? 215 nm, BDS-Hypersil C? 8, 50 mm X 2.1 ipm, 5 μ, 2.8 minutes, method reference: MET / CR / 0720) m / z 286 [M + H-H20] + @ retention time 1.92 minutes, 100%. Final product (60): LC-MS (? 215 nm, BDS-Hypersil Cx8, 50 mm X 2.1 mm, 5 μ, 2.5 minutes, method reference: MET / CR / 0720) m / z 380 [M + H] + @ retention time 1.57 minutes, 100%. Total yield 60% during 2 steps. dH (400 MHz, methanol-d4) 2.34 (3 H, s), 3.75 (3 H, s), 6.69 (2 H, d, J = 8.8 Hz), 6.83 (2 H, d, J = 9.3 Hz) , 6.91 - 7.02 (3 H, m), 7.04 - 7.14 (3 H, m). 6,7-Difluoro-3- (4-hydroxy-phenyl) -3-p-tolyl-1,3-dihydro-indol-2-one (57) Intermediate: LC-MS (? 215 nm, BDS-Hypersil) C? 8, 50 mm X 2.1 mm, 5 μ, 2.8 minutes, method reference: MET / CR / 0720) m / z 258 [M + H-H20] + @ retention time 1.96 minutes, 96%. Final product: LC-MS (? 215 nm, BDS-Hypersil Ci8, 50 mm X 2. 1 mm, 5 μ, 2.8 minutes, method reference: MET / CR / 0720) m / z 352 [M + H] + @ retention time 2.06 minutes, 98%.

Total yield 57% during 2 steps. dH (250 MHz, CDC13) 2.31 (3 H, s), 4.76 (1 H, s), 6.60 - 6.97 (4 H, m), 7.03 - 7.15 (6 H, m), 7.55 (1 H, s) . 6,7-Difluoro-3- (4-hydroxy-phenyl) -3- (4-methoxy-phenyl) -1, 3-dihydro-indol-2-one (58) Intermediate: LC-MS (? 215 nm , BDS-Hypersil Ci8, 50 mm X 2.1 mm, 5 μ, 2.8 minutes, method reference: MET / CR / 0720) m / z 274 [M + H-H20] + @ retention time 1.81 minutes, 97%. Final product (58): LC-MS (? 215 nm, BDS-Hypersil CX8, 50 mm X 2.1 mm, 5 μ, 2.8 minutes, method reference: MET / CR / 0720) m / z 368 [M + H] + @ retention time 1.99 minutes, 94%. Total yield 14% during 2 steps. 3- (4-Benzyloxy-phenyl) -6-chloro-3- (4-hydroxy-phenyl) -7-methyl-1,3-dihydro-indol-2-one intermediate: LC-MS (? 215 nm, BDS-Hypersil C? 8, 50 mm X 2.1 mm, 5 μ, 2.8 minutes, method reference: MET / CR / 0720) m / z 362 [M + H-H20] + @ retention time 2.16 minutes, 88% . dH (400 MHz, Methanol-d4) 2.32 (3 H, s), 5.05 (2 H, s), 6.93 (2 H, d, J = S. 8 Hz), 6.96 - 7.02 (1 H, m), 7.03 - 7.13 (1 H, m), 7.20 - 7.46 (7 H, m). Final product: LC-MS (? 215 nm, BDS-Hypersil C? 8, 50 mm X 2.1 mm, 5 μ, 2.5 minutes, method reference: MET / CR / 0720) m / z 456 [MH] + @ time Retention 1.59 minutes, 100%. Total performance 11% during 2 steps. dH (400 MHz, Methanol-d4) 2.31 (3 H, s), 3.83 (2 H, d, J = 2.5 Hz), 6.60-6.72 (3 H, m), 6.77-6.89 (3 H, m), 6.91 - 7.21 (9 H, m). 3- (4-Benzyloxy-phenyl) -6,7-difluoro-3- (4-hydroxy-phenyl) -1,3-dihydro-indol-2-one Intermediate: LC-MS (? 215 nm, BDS -Hypersil C? 8, 50 mm X 2.1 mm, 5 μ, 2.8 minutes, method reference: MET / CR / 0720) m / z 350 [M + H-H20] + @ retention time 2.07 minutes, 94%. dH (400 MHz, Methanol-d4), 5.06 (2 H, s), 6.82 -7.01 (4 H, m), 7.24 - 7.31 (3 H, m), 7.34 (2 H, t, J = l .3 Hz), 7.38 - 7.45 (2 H, m). Final product: LC-MS (? 215 nm, BDS-Hypersil C18, 50 mm X 2.1 mm, 5 μ, 2.8 minutes, method reference: MET / CR / 0720) m / z 444 [M + H-H20] time Retention 2.03 minutes, Total yield 24% during 2 steps.

Protocol G - Debenzylation / dehalogenation 3-Hydroxy-3- (4-hydroxy-phenyl) -7-methyl-1,3-dihydro-indol-2-one A clean sample of tertiary alcohol (40.9 mg), Pd / C (10% by weight) in methanol was subjected to hydrogenation conditions. The reaction was monitored by means of the LCMS. After 14 hours at room temperature, the palladium on charcoal was filtered and washed with methanol. The combined organic layer was concentrated and the crude product was purified by silica (with a heptane / EtOAc gradient of 85-15 to 1-1) to yield the objective, racemic compound (4.5 mg, 16% yield) as a solid. LC-MS (? 215 nm, BDS-Hypersil C18, 50 mm X 2.1 mm, 5 μ, 2.5 minutes, method reference: MET / CR / 0720) m / z 238 [M + H-H20] + @ time of Retention 1.26 minutes, 100%. 6,7-Difluoro-3-hydroxy-3- (4-hydroxy-phenyl) -1,3-dihydro-indol-2-one A clean sample of tertiary alcohol (41.8 mg), Pd / C (10% by weight) in methanol was subjected to hydrogenation conditions. The reaction was monitored by means of the LCMS. After 14 hours at room temperature, the palladium on charcoal was filtered and washed with methanol. The combined organic layer was concentrated and the crude product was purified by silica (with a heptane / EtOAc gradient of 85-15 to 1-1) to yield the objective, racemic compound (5.5 mg, 17% yield) as a solid. LC-MS (? 215 nm, BDS-Hypersil Cx8, 50 mm X 2.1 mm, 5 μ, 2.5 minutes, method reference: MET / CR / 0720) m / z 238 [M + H-H20] + @ time of Retention 1.29 minutes, 100%.

Example 2: Cell Proliferation The inhibition of the proliferation of human cancer cells is widely used to predict the anti-cancer potential of novel chemicals. Typically, human cancer cell lines derived from tumor material are maintained in monolayer cultures and test chemicals are added in varying durations. It is expected that test compounds with anti-cancer potential reduce proliferation and thereby reduce the number of cells relative to control cell cultures treated with vehicle. The number of cells can be monitored by counting the cells, determining the metabolic rate (for example the metabolic reduction of tetrazolium salts, such as (3- (4,5-dimethylethiazol-2-yl) -2,5- diphenyltetrazolium or Blue Alamar), quantify the DNA content (using DNA-binding dyes such as BODIPY-FL-14-dUTP) or measure the incorporation of nucleotides into DNA (eg, incorporation of radiolabeled thymidine or bromo-deoxyuridine) An important consideration is whether any inhibitory effect of the test compounds is specific for the proliferation of cancer cells or is due to the general inhibition of cell proliferation.This problem can be addressed using pairs of cell lines, for example, the effects of the test compounds on the proliferation of transformed cancer cell lines can be compared with the effects of the test compounds on the proliferation n of untransformed cells of the same tissue source. Alternatively, phenotypic differences between cancer cell lines can be exploited to evaluate the selectivity of the test compounds. For example, the anti-proliferative effects of some compounds are only apparent in certain sub-types of human breast cancer cell lines (e.g. breast cancer cell lines with PTEN gene mutations or p70S6K protein kinase gene amplification). ), but not in breast cancer cell lines that do not exhibit this phenotype (Noh et al. (2004) Clinical Cancer Research 10, 1013-1023; Yu et al. (2001) Endocrine-Related Cancer 8, 249-258). The selectivity of the test compounds in the latter models is associated with the mechanism of action of the compound and is related to the presence, absence or relative abundance of the target protein of the test compound in the relevant cell lines.

Method The effects of the compounds were evaluated on the proliferation of human breast cancer cells MDA-468 and MDA-231. The cells were maintained in a growth medium: RPMl 1640 containing 10% fetal bovine serum and 1% pen / strep. The cells were divided 1: 4 or 1: 8 twice in a week when they were 90% confluent. For the cell proliferation assay, the cells were plated at 8,000 cells / well in 96-well Packard Viewplates ™ black plates in a growth medium. After 1 day, the growth medium was replaced by a growth medium containing test compounds or vehicle and the cells were kept in culture for an additional 2 days. The growth medium was then removed and replaced with 150 μl of Alamar Blue in RPMl medium containing 1% pen / strep. After 120 minutes of incubation at 37 ° C, the fluorescence intensity was measured using a plate reader.

Results The concentration (micromolar) of the compounds of the general formula (I) required to inhibit the proliferation of human breast cancer cells MDA-468 and MDA-231 in 50% (IC50) are shown in figure 1. The results shown in Figure 1 demonstrate the ability of the compounds of the general formula (I) to inhibit the proliferation of human breast cancer cells MDA-468 at concentrations lower than those required to inhibit the proliferation of human breast cancer cells MDA -231.

Example 3: Studies of protein synthesis The purpose of these studies to investigate the compounds of the general formula (I) have an effect on protein synthesis, measured as 1C-Leucine uptake or protein incorporation. As described in "Leucine Uptake [14C] Cytostar-T, Amersham Biosciences assay" (CFA773). MDA-MB-231 and MDA-MB-468 cells were seeded at 8000 cells / well in 96-well microplates CytoStar-T1. And they were incubated overnight in a growing medium. The next day, the medium was carefully aspirated (8-channel Vacuboy1®) and 50 μL of fresh medium previously heated (10% FCS, 10 mM HEPES pH 7.2 - 7.5) were added. The cells were allowed to equilibrate at 37 ° C for 60 minutes. Test compounds were added in 50 μL of medium and 14C-leucine was added in 100 μL of medium (0.5 μCi mL-1 final). The plates were sealed with a thin, adhesive, transparent sheet. The plates were then incubated at 37 ° C for 6 hours in a humidified incubator. The incorporation of radioactive leucine into proteins (a measure of protein synthesis) was then read by means of the scintillation in coincidence (counts per minute (CPM)) using a Wallac detector MicrobetaMR in the indicated time intervals. A reading at t = 0 (5 minutes after sealing the plates) for each well was subtracted as background. The results are shown in Figure 2 measured after 6 hours. The results indicate that compound 3 significantly inhibits the incorporation of 14C-Leucine in MDA-MB-468 in a manner dependent on the concentration observed after an incubation with the compound of 240 minutes up to 22 hours. The IC50 value is estimated for 100 nM (240 minutes at 22 hours). Interestingly, the effect seems to reach a plateau at high concentrations corresponding to approximately 1/6 of the total incorporated. This indicates that there is some proportion of the protein synthesis that compound 3 is not able to affect. No significant effect of compound 3 was observed in MDA-MB-231 up to 430 minutes. In 22 hours an effect lower than 30 μM is observed. IC50 »30 μM (22 hours).

Therefore, the inhibitory effect of compound 3 is very specific for MDA-MB-468. The control compounds Anisomycin and Cycloheximide (not shown) completely inhibits the incorporation of 14C-Leucine in both cell lines at all time points (as opposed to compound 3, see above).

Example 4: Western Transfer Studies To investigate the mechanism of action of the compounds of the general formula (I), Western blot studies were performed to investigate the activation state of the pathways linked to the regulation of protein synthesis (see Figures 4 and 5).

Method MDA-MB-468 cells (also called MDA-468) or MDA-MB-231 (also called MDA-231) were kept in culture and placed at 400,000 cells / well in a 6-well cell culture plate. 16-24 hours later, the growth medium was changed to a growth medium containing the compounds. After an incubation of 24 or 48 hours with the compounds, the cells were washed with ice cold PBS buffer and harvested in lysis buffer: Cytobuster1111 reagent (Novagen) containing a phosphatase inhibitor cocktail 1 and 2 and an inhibitor cocktail. protease (Sigma). Samples containing an equal amount of protein were loaded in 7% Tris-Acetate gels, 10% Bis-Tris in MES buffer or 12% Bis-Tris gels using a MOPS buffer (Invitrogen). After electrophoresis, the samples were transferred to a PVDF membrane (Invitrogen). For the blocking of the membrane and incubations of the p70 SdK ^, Phospho-p70 SdK1111 (Thr389), Pathscanl and S6 (Cell Signaling Technology) antibodies, a buffer containing 0.2% Tween-20, 5% milk was used in skimmed powder, 5% FBS, in saline buffered with Tris (TBS). For the transfer of 4EBP1MR, Phospho 4EBP1MR (Thr37 / 46), Phospho 4EBP1MR (Ser65) (Cell Signaling Technology) and Cyclin 03 ^ (Santa Cruz) a Cell Signaling Technology protocol was used. Cell Signaling Technology's blocking buffer contains 0.1% Tween-20, 5% skim milk powder in TBS and the primary antibody dilution buffer contains 0.1% Tween-20, 5% BSA in TBS. Before adding the primary antibody dilution buffer to the membranes, the blots were briefly rinsed in 0.1% Tween-20. All antibody incubations were performed overnight at 4 ° C. After equalizing the membranes with 0.1% Tween-20 in TBS, the blots were incubated with anti-rabbit IgG conjugated with horseradish peroxidase (1: 1000-1: 3000; Amersham Biosciences) at room temperature for 1 hour. Peroxidase activity was detected using the ECLMR detection system (Amersham Biosciences).

Results Western blot analysis shows that compounds of the general formula (I), such as compound 3 (lanes 2 and 3), inhibit phosphorylation of p70S6K and ribosomal protein S6 in MDA-468 cells after incubation 24 hours (figure 4). Similar effects are observed with the mTOR inhibitor, rapamycin (lane 5) and the PI3 kinase inhibitor LY294002 (lane 6). The phosphorylation of AKT in Ser473 is not inhibited by compound 3 or rapamycin, whereas LY294002 inhibits the phosphorylation of AKT in Ser473. In addition, compound 3 induces a change in gel mobility in 4E-BP1 as shown using total anti-4E-BPl phospho-specific antibodies and thr37 / 46, which is indicative of an alteration in the phosphorylation state of 4E- BP1. This is confirmed by the inhibitory effect of compound 3 on the phosphorylation of ser65 of 4E-BP1. Similar effects are observed with the mTOR inhibitor, rapamycin and the PI3 kinase inhibitor LY294002. In addition, the expression of the cell cycle regulatory protein cyclin D3 is reduced by compound 3, rapamycin and LY294002. These data suggest that the mammalian homologue of TOR kinase (mTOR) is active in MDA-468 cells under growth conditions, leading to phosphorylation of mTOR target proteins such as p70S6 (p70S6K) and 4EBP1 kinase and regulation downstream of protein synthesis and cell proliferation via ribosomal protein S6, the initiation factor of eukaryotic translation, eIF4 and cyclin D3. Compounds of the general formula (I), such as compound 3 as well as rapamycin and LY294002, inhibit this pathway in MDA-468 cells and could be expected to reduce protein synthesis and cell proliferation. Compound 3 (lane 2) did not inhibit phosphorylation of p70S6K or induced a change in gel mobility in the total p70S6K in MDA-231 cells after a 48 hour incubation (Figure 5). In contrast, rapamycin (lane 5) and LY294002 (lane 6) inhibit the phosphorylation of p70S6K and induce a change in gel mobility in the total p70S6K, after a 48-hour incubation in MDA-231 cells. Compound 3, rapamycin and LY294002 inhibit the phosphorylation of p70S6K and induce a change in gel mobility in the total p70S6K in MDA-468 cells after an incubation of 48 hours, demonstrating a selective effect on the cells of the compounds of the general formula (I), such as compound 3.

Example 5: Studies in Prostate Tumor Xenograft (Human PC3M Cell Line) The purpose of this study was to evaluate whether the compounds of the general formula (I), such as compound 3, inhibit the growth of cancer cells in a model xenograft animal.

Method Male nude NMRU nu / nu mice weighing 25-45 grams are implanted with PRXF PC3M tumors by means of the subcutaneous implant on both flanks. Compound 3 (50 and 100 mg) is administered daily via the peroral route (PO) in an appropriate vehicle (2% DMSO: 5% Tween 80: 93% saline) either alone or in combination with a suboptimal dose of paclitaxol (10 mg / kg, intravenous, administered once / week). The tumor volume is determined once or twice a week for a period of 17 days.

Results Compound 3 reduces the growth rate of tumor cells when administered as a monotherapy (see Figure 6). In addition, additive anti-growth effects are observed in combination with paclitaxol.

Example 6: Effect of Compound 3 on the Cell Proliferation of Breast, Prostate and Colon Cancer Cell Lines Methods: Cell culture: All cell lines except MCF10A are maintained in an RPMl medium containing 10% fetal bovine serum (FBS) 100 U / ml penicillin and 100 μg / ml streptomycin. The MCF10A line is maintained in a mammalian epithelial growth medium (MEGM) with the addition of Singlequot ™ (BPE, hydrocortisone, hEGF, insulin, gentamicin / amphotericin-B) (Clonetics / Cambrex Bio Science). All cell lines are incubated at 37 ° C, 5% C02 and 95% humidity.

Cell proliferation assay in Blue Alamar: Cells are placed in 96 Packard / Perkin Elmer viewplates111 black plates treated with cell culture medium in 100 μl / well of RPMl medium containing 10% FBS, 100 U / ml penicillin and 100 μg / ml of streptomycin. Cell proliferation has been estimated in triplicate in all cell lines in a medium containing either 1% FBS or 10% FBS. The cell densities are estimated based on the growth during the 80-90% confluency test and are shown in Table 1. The day after plating, the growth medium is loaded at either 100 μl / well of RPMl containing 1% FBS, 100 U / ml penicillin, 100 μg / ml streptomycin and 25 μg / ml gentamicin or 100 μl / well RPMl containing 10% FBS, 100 U / ml penicillin, 100 μg / ml streptomycin and 25 μg / ml gentamicin. The compounds are added in semilogarithmic dilution series of 9 points at the concentrations indicated in the graphs. All data based on multiple determinations have been aggregated according to the standard business rules for a person skilled in the field. In addition, two dilution formats have been used to determine IC50 values: (1) The standard condition is 9 semilogarithmic dilutions starting at 32 μM; and (2) if the compound IC50 < 100 nM, 9 semilogarithmic dilutions starting at 3.2 μM have been used. Briefly, the compounds are diluted in compound plates in a growth medium containing either 1% FBS or 10% FBS corresponding to the medium in the plates. The compounds are transferred to the cell plates by transferring 100 μl / well, resulting in a total volume of 200 μl / well containing a compound at the concentrations indicated in the graphs and 0.25% DMSO. Terfenedin is used as a control for maximum cell removal in wells containing 50 μM terfenedin and 0.5% DMSO (Smax). The negative control wells (So) contain a medium with 0.25% DMSO.

After the addition of the compounds, the cell plates are incubated undisturbed for 72 hours at 37 ° C, at 5% C02 and 95% humidity. The number of viable cells is estimated using an Alamar Blue assay that measures mitochondrial activity. The medium is decanted and replaced by 150 μl / well of RPMl medium without phenol red containing 100 U / ml of penicillin and 100 μg / ml of streptomycin and 10% of Alamar Blue. The plates are placed in the incubator at 37 ° C, in 5% C02 and 95% humidity for 2 hours. Then, the plates are brought to a table and allowed to cool to room temperature without stacking the plates. The Alamar Blue signal is read on a fluorescence plate reader using a 590 nm emission filter and a 530 nm excitation filter.

Manipulation / data calculations: The data is normalized to values of 0% activity (S0) to 100% activity (Smax). The average values for So and Sma? they are calculated and used to calculate the percentage of activity (PCTACT) in the tests by means of the formula: PCTACT = (Xraw-Smax) / (S0-Smax) * 100. The Z 'values for the test plates are calculated by means of: Z' = l-3 * (STDEV (S0) + STDEV (Smax)) / (S0-Smax). On average, Z '~ 0.8 and always higher than 0.6.

The sigmoid curve adjustment is made using a Prism that uses the equation: Y = Lower Part + (Upper Part-Lower Part) / (1 + 10? ((LogIC50-X) ^ Slope Hill)).

Table 1. Cell densities in 96-well plate placement Cell Line Cancer Cells / well in 1% FBS Cells / well in 10% FBS MDA-MB-231 Mama 6000 4000 MDA-MB-4355 Mama 10000 5000 MDA-MB-453 Mama 3000 2000 MDA-MB-468 Mama 6000 4000 SKBr-3 Mama 7000 6000 BT-474 Mama 10000 10000 BT-549 Mama 6000 5000 MCF-7 Mama 5000 5000 T-47D Mama 5000 5000 ZR75-1 Mama 7000 7000 HCC-1954 Mama 5000 2500 MCF-10A Epithelial cells 18000 (Medium MEGM) Normal breast PC-3 Prostate - 3000 PC-3 / Prostate - 3000 DU-145 Prostate - 1250 LnCaP Prostate - 8000 Colo205 Colon _ 5000 Results All cell lines are driven in a cell proliferation in a medium containing either 1% serum or 10% serum, both estimates are in triplicate. The percentage of activity (PCTACT) in the trials, equal to the percentage of inhibition of growth, is calculated as described in the methods.

Table 2 summarizes the IC50 values for the inhibition of cell proliferation of cell lines. The IC 50 values refer to the concentration of compound required to inhibit cell proliferation by 50%. The curve adjustments of cell proliferation are shown in Figures 7 to 14.

Breast cancer cell lines: A broad panel of breast cancer cell lines have been tested for their sensitivity to compound 3 as well as to compound 21 and oxyphe- sisatin. The cell lines under test fall into two very clear categories. 1) Cell lines that are sensitive to compound 3. IC50 values of cell proliferation vary from 0.6 nM to 30 nM when tested in 1% FBS and between 15 and 80 nM when tested in 10% of FBS. These include the breast cancer cell lines T47-D, MCF-7, MDA-MB-453, MDA-MB-468, BT-474, SKBr-3, BT-549 and HCC-1954 developed under both high Serum content (10% FBS) as low serum content (1% FBS). 2) Cell lines that are not sensitive to compound 3 with IC50 values greater than 3 μM. These include MDA-MB-231, MDA-MB435S and ZR75-1 developed under conditions of both high serum content (10% of FBS) as low serum content (1% FBS). The untransformed breast epithelial cell line, MCF10A, is also not sensitive to compound 3. The percentage of activity relative to growth inhibition with 50 μM terfenedin varied from 60% to 90% growth inhibition. In general, cell lines are more sensitive to the compound under conditions of low serum content (1% FBS) than under conditions of high serum content (10% FBS). The most sensitive breast cancer cell line is MDA-MB-453. Two other compounds in the series, compound 21 and oxyphe- sisatin, have also been tested. Both compounds have exactly the same antiproliferative profile of cell lines as compound 3, but have a slightly lower potency (compare Figures 9, 10 and 11).

The results are summarized in Table 2 and Figures 7-11.

Cancer prostate cell lines: Prostate cancer cell lines DU-145, PC-3, PC-3 / M and LnCaP have been tested in cell proliferation assays. PC-3 is highly sensitive to compound 3, while LnCaP is less sensitive and PC-3 / M and DU-145 are not sensitive. The compound 21 and oxypheisatin have the same sensitivity profile of the cell lines, however, these compounds have a lower potency than the compound 3. The results are summarized in Table 2 and Figure 12. The effect of the compounds 41 and 35 was also compared to compound 3; both compounds inhibit the proliferation of the human prostate cancer cell line PC3 (Figure 13).

Colon cancer cell lines: Colo205 colon cancer cell line has been tested in a cell proliferation assay with compound 3 resulting in an IC50 value = 66 nM. The results are summarized in Table 2 and Figure 14.

Table 2. Concise table of the IC 50 values for the inhibition of cell proliferation 21 Oxyphaisatin Cancer line 1% FBS 10% FBS 10% FBS 10% FBS EC50 (nM) EC50 (nM) EC50 (nM) EC50 (nM) T47-D Mama 11 37 83 324 MCF7 Mama 24 74 85 517 MDA-MB-435S Breast > 3000 > 3000 > 3000 > 3000 MDA-MB-453 Mama 4 18 38 228 MDA-MB-468 Mama 14 48 138 935 MDA-MB-231 Mama > 3000 > 3000 > 3000 > 3000 BT-474 Mama 13 37 85 324 SKBr-3 Mama 12 43 95 527 BT-549 Mama 18 68 131 859 ZR75-1 Mama > 3000 > 3000 > 3000 285 HCC-1954 Mama 27 84 119 912 MCF10A Epithelial cells > 3000 > 3000 > 3000 normal breast PC-3 Prostate - 87 138 899 LnCaP Prostate - 235 233 790 DU-145 Prostate - > 3000 > 3000 > 3000 PC-3 / M Prostate - > 3000 > 3000 > 3000 Colo205 Colon - 66 - - Notes: IC50 values are shown in a nanomolar concentration. Growth inhibition (PCTACT) less than 20% is considered negligible. The MCF10A cells are maintained in a serum-free MEGM medium. The values are calculated by means of a Prism.

Example 7: Xenograft studies using MDA-MB-468 tumors The purpose of this study was to evaluate whether compounds of the general formula (I), such as compounds 3 and 41, inhibit the growth of tumors derived from breast cancer cells MDA-MB-468 (hormone-insensitive human breast cancer cells) in an animal xenograft model.

Method Balb / c nude mice weighing 25-45 grams are implanted with MDA-MB-468 tumors by means of subcutaneous implantation on both flanks. Compounds 3 and 41 are administered either daily for 15 days via the peroral route (PO) (50 &100 mg) in an appropriate vehicle (2% DMSO: 5% Tween 80: 93% saline) ) or weekly for 4 weeks via the intravenous (IV) route (25 &50 mg / kg) in an appropriate vehicle (2% DMSO: 5% Tween 80: 93% saline). The volume of the tumor is determined once or twice / week.

Results Compound 3 reduces the growth rate of MDA-MB-468 tumor cells in a dose-related manner when administered as a monotherapy either by the PO or IV route (see Figure 15). In addition, tumor regression is observed using the highest doses of compound 3. Intravenous dosing with compound 3 appeared to be more effective than peroral dosing (Figure 15). Compound 41 is more effective than compound 3, inducing more pronounced tumor regression in all doses tested (Figure 16). In addition, compound 41 was equally effective by peroral and intravenous dosing (Figure 16). Compound 41 also appeared to be more effective than paclitaxel in these studies (Figure 16).

Example 8: Xenograft studies using MCF-7 tumors The purpose of this study was to evaluate whether the compounds of the general formula (I), such as compound 41, inhibit the growth of tumors derived from breast cancer cells MCF-7 (hormone-sensitive human breast cancer cells) in an animal xenograft model.

Method Balb / c nude mice weighing 25-45 grams are implanted with MCF-7 tumors by means of subcutaneous implantation on both flanks. Compounds 3 and 41 are administered either daily for 15 days via the peroral route (PO) (20 &100 mg) in an appropriate vehicle (2% DMSO: 5% Tween 80: 93% saline) ) or weekly for 4 weeks via the intravenous (IV) route (10 &50 mg / kg) in an appropriate vehicle (2% DMSO: 5% Tween 80: 93% saline). The volume of the tumor is determined once or twice / week.

Results Compound 41 reduces the size of MCF7 tumors when administered as a monotherapy either by the PO or IV route (see Figure 17). In addition, tumor regression is observed using all doses tested. The effect of compound 41 appears to be greater than paclitaxel in this model (Figure 17). Compound 41 was equally effective by peroral and intravenous dosing.

Example 9: Stimulation of caspase activity The purpose of this study was to evaluate whether the compounds of the general formula (I), such as compound 3, affect the activity of caspase as a marker of apoptosis, a form of cell death. The short-term, intermediate-term and long-term effects of compound 3 are evaluated by measuring the activity of caspase at 4, 6 and 22 hours after the addition of the compound.

Method The human breast cancer cell lines are seeded at 8,000 cells / well in 96-well black Packard Viewplates1 and maintained in an RPMI medium containing 10% fetal bovine serum (FBS), 100 U / ml penicillin. and 100 μg / ml streptomycin overnight at 37 ° C, in 5% C02 in a humidified incubator. Compounds such as compound 3 are then added to the well and the caspase activity is measured at various time points using equipment to measure the activity of caspase (fluorogenic equipment of the homogeneous caspase-3/7 assay Apo-ONE1111, # G7791) according to the manufacturer's instructions Fluorescence intensity (485/535 nm) is measured using an EnVision ™ plate reader Reagent background values (average of all 8 wells) are subtracted from experimental wells .

Results The addition of compound 3 for 6 hours stimulates the activity of caspase in human breast cancer cell lines that are sensitive to the anti-proliferative effects of compound 3 (Figure 18), although no activation is observed in MDA cells. -468 Stimulation of caspase activity is not observed in breast cancer cell lines that are not sensitive to the anti-proliferative effect of compound 3. These results suggest that compounds of the general formula (I), such as compound 3 , can induce apoptotic cell death in certain cancer cell lines of human breast.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.

Claims (33)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. The use of a compound of the general formula
2. (I) wherein 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 may be selected in addition to a bond, such 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, are independently selected from hydrogen, optionally substituted alkyl of 1 to 6 carbon atoms, optionally substituted 2 to 6 carbon alkenyl, hydroxy, alkoxy of 1 optionally substituted at 6 carbon atoms, optionally substituted C 2 -C 6 alkenyloxy, carboxy, optionally substituted C 1 -C 6 alkoxycarbonyl, optionally substituted C 1 -C 6 alkylcarbonyl, alkylcarbonyloxy of 1 to 6 carbon atoms optionally substituted carbon, formyl, amino, mono- and di (C?-C6 alkyl) amino, carbamoyl, mono- and di (Ci-Cß alkyl) aminocarbonyl, alkylcarbonylamino of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 atoms carbon, cyano, carbamido, mono- and di (C 1 -C 6 alkyl) aminocarbonylamino, C 1 -C 6 -alkoyloxy, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkylsulfinyl, aminos ulphonyl, mono- and di (C 1 -C 6 alkyl) aminosulfonyl, nitro, optionally substituted alkylthio of 1 to 6 carbon atoms, aryl, aryloxy, arylcarbonyl, arylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclylcarbonyl, heteroaryl, heteroaryloxy, heteroarylamino, heteroarylcarbonyl and halogen, wherein any alkyl of 1 to 6 carbon atoms as an amino substituent is optionally substituted by hydroxy, alkoxy of 1 to 6 carbon atoms, amino, mono- and di (Ci-Cß alkyl) amino, carboxy, alkylcarbonylamino of 1 to 6 carbon atoms, alkylaminocarbonyl of 1 to 6 carbon atoms or halogen (s) and in which any aryl, heterocyclyl and heteroaryl can be optionally substituted; R1, R2, R3 and R4, when attached to a nitrogen atom, are independently selected from hydrogen, optionally substituted alkyl of 1 to 6 carbon atoms, hydroxy, optionally substituted 1 to 6 carbon atoms, alkoxycarbonyl of 1 at 6 carbon atoms optionally substituted, optionally substituted alkylcarbonyl of 1 to 6 carbon atoms, formyl, mono- and di (C 1 -C 4 alkyl) aminocarbonyl, amino, alkylcarbonylamino of 1 to 6 carbon atoms, mono- and di (alkyl) Ci-Cβ) amino, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, aryl, aryloxy, arylcarbonyl, arylamino, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, heterocyclylamino, heteroaryl, heteroaryloxy, heteroarylcarbonyl and heteroarylamino; wherein any alkyl of 1 to 6 carbon atoms as an amino substituent is optionally substituted by hydroxy, alkoxy of 1 to 6 carbon atoms, amino, mono- and di (alkyl Ci-Ce) amino, carboxy, alkoxycarbonylamino of 1 to 6 carbon atoms, alkylaminocarbonyl of 1 to 6 carbon atoms or halogen (s) and wherein any aryl, heterocyclyl and heteroaryl can be optionally substituted; or R1 and R2 together with the carbon atoms to which they are attached form a ring, for example an aromatic ring, a carbocyclic ring, a heterocyclic ring or a heteroaromatic ring, in particular an aromatic ring, a heterocyclic ring or a heteroaromatic ring; X1 and X2 are independently selected from halogen, hydroxy, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 alkylcarbonyloxy, amino, mono- and di (C 1 -C 6 alkyl) amino, alkylcarbonylamino 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms, mono- and di (alkyl Ci-Ce) aminocarbonylamino, alkanoyloxy of 1 to 6 carbon atoms, mercapto, alkylthio of 1 to 6 carbon atoms optionally substituted, alkylsulfonyl of 1 to 6 atoms carbon, mono- and di (C 1 -C 6 alkyl) aminosulfonyl, aryloxy, arylamino, heterocyclyloxy, heterocyclylamino, heteroaryloxy and heteroarylamino, wherein any alkyl of 1 to 6 carbon atoms as an amino or sulfur substituent is optionally substituted by hydroxy alkoxy of 1 to 6 carbon atoms, amino, mono- and di (C 1 -C 6 alkyl) amino, carboxy, alkylcarbonylamino of 1 to 6 carbon atoms, alkylaminocarbonyl of 1 to 6 carbon atoms or halogen (s) and wherein any aryl, heterocyclyl and heteroaryl can be optionally substituted; > Y (= Q) n is selected from > C = 0, > C = S, > S = 0 and > S (= 0) 2; and RN is selected from the group consisting of hydrogen, optionally substituted alkyl of 1 to 6 carbon atoms, hydroxy, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 1 -C 6 alkoxycarbonyl, 1 to C 1 alkoxycarbonyl 6 carbon atoms optionally substituted, formyl, mono- and di (C 1 -C 6 alkyl) aminocarbonyl, amino, alkylcarbonylamino of 1 to 6 carbon atoms, mono- and di (C 1 -C 6 alkyl) amino, alkylsulfonyl of 1 to 6 carbon atoms and alkylsulfinyl having 1 to 6 carbon atoms; wherein any alkyl of 1 to 6 carbon atoms as an amino substituent is optionally substituted by hydroxy, alkoxy of 1 to 6 carbon atoms, amino, mono- and di (C 1 -C 6 alkyl) amino, carboxy, alkylcarbonylamino of 1 to 6 carbon atoms, alkylaminocarbonyl of 1 to 6 carbon atoms or halogen (s); and pharmaceutically acceptable salts and prodrugs thereof; for the preparation of a medicament for the treatment of cancer in a mammal. 2. The use according to claim 1, wherein R1, R2, R3 and R4 are not all hydrogen.
3. 3. The use according to any of the preceding claims, wherein the ring is selected from a benzene ring and a pyridine ring, wherein the nitrogen atom represents V3.
4. 4. The use according to any of the preceding claims, wherein R1 is selected from hydrogen, halogen, alkyl of 1 to 6 carbon atoms, trifluoromethyl and alkoxy of 1 to 6 carbon atoms, when V1 is a carbon atom .
5. 5. The use according to any of the preceding claims, wherein R2 is selected from hydrogen, halogen, optionally substituted aryl, optionally substituted aryloxy and optionally substituted heteroaryl, when V2 is a carbon atom.
6. 6. The use according to any of the preceding claims, wherein R3 is selected from hydrogen, optionally substituted C1-6 alkoxy, halogen, cyano, optionally substituted aryl, optionally substituted aryloxy, optionally substituted heteroaryl, amino, alkylcarbonylamino of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 carbon atoms and mono- and di (C 1 -C 6 alkyl) aminosulfonyl, when V 3 is a carbon atom.
7. 7. The use according to any of the preceding claims, wherein R4 is hydrogen, when V4 is a carbon atom.
8. 8. The use according to any of the preceding claims, wherein X1 and X2 are independently selected from hydroxy, OAc, NH2, NMe2, NHAc, NHS02Me and NHCONMe2.
9. 9. The use according to any of the preceding claims, wherein X1 and X2 are the same.
10. 10. The use according to any of the preceding claims, wherein Y is a carbon atom and Q is an oxygen atom, ie, > Y (= Q) n is > C = 0 and RN is selected from hydrogen, alkyl of 1 to 6 carbon atoms, amino and alkylcarbonylamino of 1 to 6 carbon atoms.
11. 11. The use according to any of the preceding claims, wherein V1, V2, V3, V4 are all a carbon atom, > Y (= Q) n is > C = 0 and RN is hydrogen.
12. 12. The use according to any of the preceding claims, wherein R4 is hydrogen.
13. 13. The use according to claim 12, wherein R3 and R4 are both hydrogen.
14. 14. The use according to any of claims 11-13, wherein R1 is alkyl of 1 to 4 carbon atoms and R2 is halogen.
15. 15. The use according to any of claims 11-13, wherein R1 and R2, together with the carbon atoms to which they are attached, form an aromatic ring or a carbocyclic ring.
16. 16. The use according to any of claims 11-15, wherein each of X1 and X2 are independently selected from halogen, hydroxy, alkoxy of 1 to 4 carbon atoms, amino and dimethylamino.
17. 17. The use according to claim 12, wherein R1, R2 and R4 are all hydrogen.
18. 18. The use according to any of claims 11 and 17, wherein R3 is selected from hydrogen, halogen, nitro, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, trifluoromethoxy, amino, carboxy and dimethylaminocarbonyl.
19. 19. The use according to any of claims 17-18, wherein each, one of X1 and X2 is independently selected from halogen, hydroxy, alkoxy of 1 to 4 carbon atoms, amino and dimethylamino.
20. 20. The use according to claim 12, wherein R2, R3 and R4 are all hydrogen.
21. 21. The use according to any of claims 11 and 20, wherein R1 is selected from fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms, trifluoromethyl, alkoxy of 1 to 4 carbon atoms and dimethylaminocarbonyl.
22. 22. The use according to any of claims 20-21, wherein each of X1 and X2 is independently selected from halogen, hydroxy, alkoxy of 1 to 4 carbon atoms, amino and dimethylamino.
23. 23. The use according to any of claims 11 and 12, wherein R1 is selected from halogen, alkyl of 1 to 4 carbon atoms, trifluoromethyl, alkoxy of 1 to 4 carbon atoms and dimethylaminocarbonyl, R2 is selected from hydrogen and halogen and R3 is selected from hydrogen, halogen, alkyl of 1 to 4 carbon atoms and amino; where R2 and R3 are not both hydrogen.
24. 24. The use of a compound of the type 3,3-diphenyl-3-dihydro-indol-2-one of the formula (Ha) wherein R1 is selected from hydrogen, halogen, alkyl of 1 to 6 carbon atoms, trifluoromethyl and alkoxy of 1 to 6 carbon atoms; R2 is selected from hydrogen, halogen, optionally substituted aryl, optionally substituted aryloxy and optionally substituted heteroaryl; R3 is selected from hydrogen, optionally substituted C1-6 alkoxy, halogen, optionally substituted cyano and aryl, optionally substituted aryloxy, optionally substituted heteroaryl, amino, alkylcarbonylamino of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 atoms carbon and mono- and di (C 1 -C 6 alkyl) aminosulfonyl; Z is CH or N; and X1 and X2 are independently selected from halogen, OR6, OCOR5, N (R6) 2, NHCOR5, NHS02R5 and NHCON (R6) 2, wherein R5 is selected from alkyl of 1 to 6 carbon atoms, optionally substituted aryl and heteroaryl optionally substituted and each R6 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted aryl and optionally substituted heteroaryl; and pharmaceutically acceptable salts and prodrugs thereof; for the preparation of a medicament for the treatment of cancer in a mammal.
25. 25. The use of a compound of the 3,3-diphenyl-1,3-dihydro-indol-2-one type of the formula (Hb) wherein R 1, R 2 and R 3, when attached to a carbon atom, are independently selected from hydrogen, optionally substituted alkyl of 1 to 6 carbon atoms, optionally substituted 2 to 6 carbon alkenyl, hydroxy, alkoxy of 1 optionally substituted at 6 carbon atoms, optionally substituted C 2 -C 6 alkenyloxy, carboxy, optionally substituted C 1 -C 6 -alkoxycarbonyl, optionally substituted C 1 -C 6 -alkylcarbonyl, alkylcarbonyloxy of 1 to 6 carbon atoms optionally substituted carbon, formyl, amino, mono- and di (alkyl Ci-Ce) amino, carbamoyl, mono- and di (C 1 -C 6 alkyl) aminocarbonyl, alkylcarbonylamino of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 atoms carbon, cyano, carbamido, mono- and di (Ci-C6 alkyl) aminocarbonylamino, alkanoyloxy of 1 to 6 carbon atoms, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, ami nosulfonyl, mono- and di (C 1 -C 6 alkyl) aminosulfonyl, nitro, optionally substituted C 1 -C 6 alkylthio and halogen, wherein any C 1 -C 6 alkyl as an amino substituent is optionally substituted by hydroxy, C 1 -C 6 alkoxy, amino, mono- and di (Ci-Cß alkyl) amino, carboxy, alkylcarbonylamino of 1 to 6 carbon atoms, alkylaminocarbonyl of 1 to 6 carbon atoms or halogen (s); and R1, R2 and R3, when attached to a nitrogen atom, are independently selected from hydrogen, optionally substituted alkyl of 1 to 6 carbon atoms, hydroxy, optionally substituted C1-6 alkoxy, alkoxycarbonyl of 1 to 6 carbon atoms optionally substituted, optionally substituted alkylcarbonyl of 1 to 6 carbon atoms, formyl, mono- and di (Cx-Ce alkyl aminocarbonyl, amino, alkylcarbonylamino of 1 to 6 carbon atoms, mono- and di (alkyl C) C6) amino, alkylsulfonyl of 1 to 6 carbon atoms and alkylsulfinyl of 1 to 6 carbon atoms; wherein any alkyl of 1 to 6 carbon atoms as an amino substituent is optionally substituted by hydroxy, alkoxy of 1 to 6 carbon atoms, amino, mono- and di (C 1 -C 6 alkyl) amino, carboxy, alkylcarbonylamino of 1 to 6 carbon atoms, alkylaminocarbonyl of 1 to 6 carbon atoms or halogen (s) and wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted; or wherein R1 and R2 together with the carbon and / or nitrogen atoms to which they are attached form a heterocyclic ring, a heteroaromatic ring, an aromatic ring or a carbocyclic ring; Z is CH or N; and X1 and X2 are independently selected from halogen, OR6, OCOR5, N (R6) 2, NHCOR5, NHS02R5 and NHCON (R6) 2, wherein R5 is selected from alkyl of 1 to 6 carbon atoms, optionally substituted aryl and heteroaryl optionally substituted and each R6 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted aryl and optionally substituted heteroaryl; and pharmaceutically acceptable salts and prodrugs thereof; for the preparation of a medicament for the treatment of cancer in a mammal.
26. 26. The use of a compound of the 3,3-diphenyl-1,3-dihydro-indol-2-one type of the formula (He) wherein R1 is selected from hydrogen, halogen, alkyl of 1 to 6 carbon atoms, trifluoromethyl and alkoxy of 1 to 6 carbon atoms; R2 is selected from hydrogen, halogen, optionally substituted aryl, optionally substituted aryloxy and optionally substituted heteroaryl; R3 is selected from hydrogen, optionally substituted 1 to 6 carbon atoms, halogen, optionally substituted cyano and aryl, optionally substituted aryloxy, optionally substituted heteroaryl, amino, alkylcarbonylamino of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 atoms carbon and mono- and di (Ci-Cß alkyl) aminosulfonyl; Z is CH or N; and one of X1 and X2 is selected from halogen, OR6, OCOR5, N (R6) 2, NHCOR5, NHS02R5 and NHCON (R6) 2, wherein R5 is selected from alkyl of 1 to 6 carbon atoms, aryl optionally substituted and optionally substituted heteroaryl and each R6 is independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, optionally substituted aryl and optionally substituted heteroaryl; and the other of X1 and X2 is selected from optionally substituted alkyl of 1 to 6 carbon atoms, optionally substituted C2 to C6 alkenyl, carboxy, optionally substituted C1 to C6 alkoxycarbonyl, alkylcarbonyl of 1 to 6. optionally substituted carbon atoms, formyl, carbamoyl, mono- and di (Ci-Cß alkyl) aminocarbonyl, cyano, aryl, arylcarbonyl, heterocyclyl, heterocyclylcarbonyl, heteroaryl, heteroarylcarbonyl, wherein any alkyl of 1 to 6 carbon atoms as a substituent of amino is optionally substituted by hydroxy, alkoxy of 1 to 6 carbon atoms, amino, mono- and di (Ci-Cß alkyl) amino, carboxy, alkylcarbonylamino of 1 to 6 carbon atoms, alkylaminocarbonyl of 1 to 6 carbon atoms or halogen (s) and wherein any aryl, heterocyclyl and heteroaryl can be optionally substituted; and paceutically acceptable salts and prodrugs thereof (as further defined above); for the preparation of a medicament for the treatment of cancer in a mammal.
27. 27. The use of a compound of the 3,3-diphenyl, 3-dihydro-indol-2-one type of the formula (Hd) wherein R1, R2 and R3, when attached to a carbon atom, are independently selected from hydrogen, optionally substituted alkyl of 1 to 6 carbon atoms, optionally substituted 2 to 6 carbon alkenyl, hydroxy, alkoxy of 1 optionally substituted at 6 carbon atoms, optionally substituted C 2 -C 6 alkenyloxy, carboxy, optionally substituted C 1 -C 6 alkoxycarbonyl, optionally substituted C 1 -C 6 alkylcarbonyl, alkylcarbonyloxy of 1 to 6 carbon atoms optionally substituted carbon, formyl, amino, mono- and di (alkyl Ci-Ce) amino, carbamoyl, mono- and di (C 1 -C 6 alkyl) aminocarbonyl, alkylcarbonylamino of 1 to 6 carbon atoms, alkylsulfonylamino of 1 to 6 atoms of carbon, cyano, carbamido, mono- and di (C 1 -C 7 alkyl) aminocarbonylamino, C 1 -C 6 -alkoyloxy, alkylsulfonyl of 1 to 6 carbon atoms, alkylsulfinyl of 1 to 6 carbon atoms, minosulfonyl, mono- and di (alkyl Ci-Ce) aminosulfonyl, nitro, alkylthio of optionally substituted 1 to 6 carbon atoms and halogen, wherein any alkyl of 1 to 6 carbon atoms as an amino substituent is optionally substituted by hydroxy, C 1 -C 6 alkoxy, amino, mono- and di (C 1 -C 6 alkyl) amino, carboxy, alkylcarbonylamino of 1 to 6 carbon atoms, alkylaminocarbonyl of 1 to 6 carbon atoms or halogen (s); and R1, R2 and R3, when attached to a nitrogen atom, are independently selected from hydrogen, optionally substituted alkyl of 1 to 6 carbon atoms, hydroxy, optionally substituted C1-6 alkoxy, alkoxycarbonyl of 1 to 6 carbon atoms optionally substituted, optionally substituted alkylcarbonyl of 1 to 6 carbon atoms, formyl, mono- and di (alkyl dC) aminocarbonyl, amino, alkylcarbonylamino of 1 to 6 carbon atoms, mono- and di (C 1 -C alkyl) C6) amino, alkylsulfonyl of 1 to 6 carbon atoms and alkylsulfinyl of 1 to 6 carbon atoms; wherein any alkyl of 1 to 6 carbon atoms as an amino substituent is optionally substituted by hydroxy, alkoxy of 1 to 6 carbon atoms, amino, mono- and di (alkyl Ci-Ce) amino, carboxy, alkylcarbonylamino of 1 to 6 carbon atoms, alkylaminocarbonyl of 1 to 6 carbon atoms or halogen (s) and wherein any aryl, heterocyclyl and heteroaryl can be optionally substituted; or wherein R1 and R2 together with the carbon and / or nitrogen atoms to which they are attached form a heterocyclic ring, a heteroaromatic ring, an aromatic ring 0 a carbocyclic ring; Z is CH or N; and one of X1 and X2 is selected from halogen, OR6, OCOR5, N (R6) 2, NHCOR5, NHS02R5 and NHCON (R6) 2 wherein R5 is selected from alkyl of 1 to 6 carbon atoms, optionally substituted aryl and heteroaryl optionally substituted and each R6 is independently selected from hydrogen, alkyl 1 to 6 carbon atoms, optionally substituted aryl and optionally substituted heteroaryl; and the other of X1 and X2 is selected from optionally substituted alkyl of 1 to 6 carbon atoms, optionally substituted alkenyl of 2 to 6 carbon atoms, carboxy, optionally substituted 1 to 6 carbon atoms, alkylcarbonyl of from 1 to 6. optionally substituted carbon atoms, formyl, carbamoyl, mono- and di (C 1 -C 6 alkyl) aminocarbonyl, cyano, aryl, arylcarbonyl, heterocyclyl, heterocyclylcarbonyl, heteroaryl, heteroarylcarbonyl, wherein any alkyl of 1 to 6 carbon atoms as a substituent of amino is optionally substituted by hydroxy, alkoxy of 1 to 6 carbon atoms, amino, mono- and di (C 1 -C 6 alkyl) amino, carboxy, alkylcarbonylamino of 1 to 6 carbon atoms, alkylaminocarbonyl of 1 to 6 carbon atoms carbon or halogen (s) and wherein any aryl, heterocyclyl and heteroaryl may be optionally substituted; and pharmaceutically acceptable salts and prodrugs thereof; for the preparation of a medicament for the treatment of cancer in a mammal.
28. 28. The use according to any of the preceding claims, wherein the compound is selected from the objects 1 to 225 listed in this document.
29. 29. The use according to any of the preceding claims, wherein the medicament further comprises one or more different chemotherapeutic agents.
30. 30. A compound according to any of claims 1-28 for use as a medicament, characterized in that the compound is not one selected from 3,3-bis- (4-hydroxy-phenyl) -1,3-dihydro- indole-2-one and 4- [3- (4-acetoxy-phenyl) -2-oxo-2,3-dihydro-1H-indol-3-yl] -phenyl ester of acetic acid.
31. 31. A compound of the general formula (I) according to any of claims 1-23, characterized in that the compound is not one selected from 3, 3-bis- (4-hydroxy-phenyl) -1,3-dihydro-indol-2-one, 3, 3-bis- (4-hydroxy-phenyl) -7-methyl-1,3-dihydro- indole-2-one; 3, 3-bis- (4-hydroxy-phenyl) -4,5-dimethyl-1,3-dihydro-indol-2-one; 3, 3-bis- (4-hydroxy-phenyl) -5,7-dimethyl-1,3-dihydro-indol-2-one; 5-bromo-3, 3-bis- (4-hydroxy-phenyl) -1,3-dihydro-indol-2-one; 5-chloro-3, 3-bis- (4-hydroxy-phenyl) -1,3-dihydro-indol-2-one; 3, 3-bis- (4-hydroxy-phenyl) -5-methoxy-1,3-dihydro-indol-2-one; 3, 3-bis- (4-hydroxy-phenyl) -5-methyl-1,3-dihydro-indol-2-one; 6-chloro-3, 3-bis- (4-hydroxy-phenyl) -7-methyl-1,3-dihydro-indol-2-one; 4- [3- (4-Acetoxy-phenyl) -2-oxo-2,3-dihydro-1H-indol-3-yl] -phenyl ester of acetic acid; and 4- [3- (4-acetoxy-phenyl) -5-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl] -phenyl ester of acetic acid.
32. 32. A compound of type 3, 3-diphenyl-1,3-dihydro-indol-2-one of the formula (II) according to any of claims 24-28, characterized in that the compound is not one selected from: 3, 3-bis- (4-hydroxy-phenyl) -1,3-dihydro-indol-2-one, 3, 3 -bis- (4-hydroxy-phenyl) -7-methyl-l, 3-dihydro-indol-2-one; 3, 3-bis- (4-hydroxy-phenyl) -4,5-dimethyl-1,3-dihydro-indol-2-one; 3, 3-bis- (4-hydroxy-phenyl) -5,7-dimethyl-1,3-dihydro-indol-2-one; 5-bromo-3, 3-bis- (4-hydroxy-phenyl) -1,3-dihydro-indol-2-one; 5-chloro-3, 3-bis- (4-hydroxy-phenyl) -1,3-dihydro-indol-2-one; 3, 3-bis- (4-hydroxy-phenyl) -5-methoxy-1,3-dihydro-indol-2-one; 3, 3-bis- (4-hydroxy-phenyl) -5-methyl-1,3-dihydro-indol-2-one; 6-chloro-3, 3-bis- (4-hydroxy-phenyl) -7-methyl-l, 3-dihydro-indol-2-one; 4- [3- (4-Acetoxy-phenyl) -2-oxo-2,3-dihydro-1H-indol-3-yl] -phenyl ester of acetic acid; and 4- [3- (4-acetoxy-phenyl) -5-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl] -phenyl ester of acetic acid.
33. 33. A pharmaceutical composition, characterized in that it comprises a compound according to any of claims 1-28 and a pharmaceutically acceptable carrier.